FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Goucher, DR Wincovitch, SM Garfield, SH Carbone, KM Malik, TH AF Goucher, DR Wincovitch, SM Garfield, SH Carbone, KM Malik, TH TI A quantitative determination of multi-protein interactions by the analysis of confocal images using a pixel-by-pixel assessment algorithm SO BIOINFORMATICS LA English DT Article ID DECONVOLUTION; MICROSCOPY; OBJECTS; MICE AB Motivation: Recent advances in confocal microscopy have allowed scientists to assess the expression, and to some extent, the interaction/colocalization of multiple molecules within cells and tissues. In some instances, accurately quantifying the colocalization of two or more proteins may be critical. This can require the acquisition of multiple Z plane images (Z stacks) throughout a specimen and, as such, we report here the successful development of a freeware, open-source image analysis tool, IMAJIN_COLOC, developed in PERL (v. 5.8, build 806), using the PERLMagick libraries (ImageMagick). Using a pixel-by-pixel analysis algorithm, IMAJIN_COLOC can analyze images for antigen expression (any number of colors) and can measure all possible combinations of colocalization for up to three colors by analyzing a Z stack gallery acquired for each sample. The simultaneous (i.e. in a single pass) analysis of three-color colocalization, and batch analysis capabilities are distinctive features of this program. Results: A control image, containing known individual and colocalized pixel counts, was used to validate the accuracy of IMAJIN_COLOC. As further validation, pixel counts and colocalization values from the control image were compared to those obtained with the software packaged with the Zeiss laser-scanning microscope (LSM AIM, version 3.2). The values from both programs were found to be identical. To demonstrate the applicability of this program in addressing novel biological questions, we examined the role of neurons in eliciting an immune reaction in response to viral infection. Specifically, we successfully examined expression of the chemokine RANTES in measles virus (MV) infected hippocampal neurons and quantified changes in RANTES production throughout the disease period. The resultant quantitative data were also evaluated visually, using a gif image created during the analysis. Availability: PERL (ActivePerl, version 5.8) is available at activestate.com; the PERLMagick libraries are available at imagemagick.org, and IMAJIN_COLOC, the source code and user documentation can be downloaded from http://www.fda.gov/cber/research/imaging/imageanalysis.htm Contact: Malik@cber.fda.gov C1 US FDA, DVP, OVRR, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Med, Baltimore, MD 21205 USA. RP Malik, TH (reprint author), US FDA, DVP, OVRR, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM Malik@cber.fda.gov NR 19 TC 10 Z9 10 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD AUG 1 PY 2005 VL 21 IS 15 BP 3248 EP 3254 DI 10.1093/bioinformatics/bti531 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 945OY UT WOS:000230513200007 PM 15947019 ER PT J AU Molinaro, AM Simon, R Pfeiffer, RM AF Molinaro, AM Simon, R Pfeiffer, RM TI Prediction error estimation: a comparison of resampling methods SO BIOINFORMATICS LA English DT Article ID DNA MICROARRAY DATA; B-CELL LYMPHOMA; CROSS-VALIDATION; CLASSIFICATION; REGRESSION AB Motivation: In genomic studies, thousands of features are collected on relatively few samples. One of the goals of these studies is to build classifiers to predict the outcome of future observations. There are three inherent steps to this process: feature selection, model selection and prediction assessment. With a focus on prediction assessment, we compare several methods for estimating the 'true' prediction error of a prediction model in the presence of feature selection. Results: For small studies where features are selected from thousands of candidates, the resubstitution and simple split-sample estimates are seriously biased. In these small samples, leave-one-out cross-validation (LOOCV), 10-fold cross-validation (CV) and the .632+ bootstrap have the smallest bias for diagonal discriminant analysis, nearest neighbor and classification trees. LOOCV and 10-fold CV have the smallest bias for linear discriminant analysis. Additionally, LOOCV, 5- and 10-fold CV, and the .632+ bootstrap have the lowest mean square error. The .632+ bootstrap is quite biased in small sample sizes with strong signal-to-noise ratios. Differences in performance among resampling methods are reduced as the number of specimens available increase. Contact: annette.molinaro@yale.edu Supplementary Information: A complete compilation of results and R code for simulations and analyses are available in Molinaro et al. (2005) (http://linus.nci.nih.gov/brb/TechReport.htm). C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diagnost, NIH, Rockville, MD 20852 USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. RP Molinaro, AM (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. EM annette.molinaro@yale.edu NR 30 TC 364 Z9 375 U1 8 U2 36 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD AUG 1 PY 2005 VL 21 IS 15 BP 3301 EP 3307 DI 10.1093/bioinformatics/bti499 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 945OY UT WOS:000230513200014 PM 15905277 ER PT J AU Evans, DL Charney, DS Lewis, L Golden, RN Gorman, JM Krishnan, KRR Nemeroff, CB Bremner, JD Carney, RM Coyne, JC Delong, MR Frasure-Smith, N Glassman, AH Gold, PW Grant, I Gwyther, L Ironson, G Johnson, RL Kanner, AM Katon, WJ Kaufmann, PG Keefe, FJ Ketter, T Laughren, TP Leserman, J Lyketsos, CG McDonald, WM McEwen, BS Miller, AH Musselman, D O'Connor, C Petitto, JM Pollock, BG Robinson, RG Roose, SP Rowland, J Sheline, Y Sheps, DS Simon, G Spiegel, D Stunkard, A Sunderland, T Tibbits, P Valvo, WJ AF Evans, DL Charney, DS Lewis, L Golden, RN Gorman, JM Krishnan, KRR Nemeroff, CB Bremner, JD Carney, RM Coyne, JC Delong, MR Frasure-Smith, N Glassman, AH Gold, PW Grant, I Gwyther, L Ironson, G Johnson, RL Kanner, AM Katon, WJ Kaufmann, PG Keefe, FJ Ketter, T Laughren, TP Leserman, J Lyketsos, CG McDonald, WM McEwen, BS Miller, AH Musselman, D O'Connor, C Petitto, JM Pollock, BG Robinson, RG Roose, SP Rowland, J Sheline, Y Sheps, DS Simon, G Spiegel, D Stunkard, A Sunderland, T Tibbits, P Valvo, WJ TI Mood disorders in the medically ill: Scientific review and recommendations SO BIOLOGICAL PSYCHIATRY LA English DT Review DE mood disorders; medical comorbidity; depression; antidepressant therapy ID CORONARY-ARTERY-DISEASE; PLACEBO-CONTROLLED TRIAL; HUMAN-IMMUNODEFICIENCY-VIRUS; ISCHEMIC-HEART-DISEASE; DOUBLE-BLIND PLACEBO; SEROTONIN REUPTAKE INHIBITORS; METASTATIC BREAST-CANCER; PITUITARY-ADRENAL AXIS; HIV-INFECTED MEN; ACUTE MYOCARDIAL-INFARCTION AB Objective. The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research. Data Sources. Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors. Study Selection/Data Extraction: Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed. Conclusions: A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted. C1 Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. Washington Univ, St Louis, MO USA. Emory Univ, Atlanta, GA 30322 USA. NCI, NIMH, NHLBI, Bethesda, MD 20892 USA. United States Food & Drug Adm, Rockville, MD USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Pittsburgh, Pittsburgh, PA USA. McGill Univ, Montreal, PQ, Canada. Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. Columbia Univ, New York, NY USA. Mt Sinai Sch Med, New York, NY USA. Rockefeller Univ, New York, NY 10021 USA. Univ N Carolina, Sch Med, Chapel Hill, NC USA. Duke Univ, Durham, NC USA. Stanford Univ, Stanford, CA 94305 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Univ Miami, Coral Gables, FL 33124 USA. Univ Florida, Gainesville, FL USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. St Lukes Hosp, Chicago, IL USA. Univ Washington, Ctr Hlth Studies, Grp Hlth Cooperat, Seattle, WA 98195 USA. Univ Iowa, Iowa City, IA USA. Amer Diabetes Assoc, Alexandria, VA USA. Mended Hearts, Dallas, TX USA. RP Evans, DL (reprint author), Univ Penn, Sch Med, Dept Psychiat, 305 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM psych@mail.med.upenn.edu RI Bremner, James/B-1632-2013 NR 274 TC 509 Z9 523 U1 19 U2 59 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 1 PY 2005 VL 58 IS 3 BP 175 EP 189 DI 10.1016/j.biopsych.2005.05.001 PG 15 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 953DR UT WOS:000231057100001 PM 16084838 ER PT J AU Dean, RM Fowler, DH Wilson, WH Odom, J Steinberg, SM Chow, C Kasten-Sportes, C Gress, RE Bishop, MR AF Dean, RM Fowler, DH Wilson, WH Odom, J Steinberg, SM Chow, C Kasten-Sportes, C Gress, RE Bishop, MR TI Efficacy of reduced-intensity allogeneic stem cell transplantation in chemotherapy-refractory non-Hodgkin lymphoma SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE reduced-intensity allogeneic stem cell transplantation; non-Hodgkin lymphoma; chemotherapy sensitivity; prognosis ID BONE-MARROW-TRANSPLANTATION; MYELOABLATIVE THERAPY; FOLLICULAR LYMPHOMA; TRIAL; ENGRAFTMENT; PREDICTS AB Chemotherapy sensitivity has been identified as an important prognostic factor in reduced-intensity allogeneic stem cell transplantation (RIST) for non-Hodgkin lymphoma (NHL). However, the effect of uniform salvage chemotherapy before KIST has not been studied prospectively. We examined whether the response to prospectively administered uniform salvage therapy (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and fludarabine) influenced the subsequent outcome of KIST in 28 patients with relapsed or refractory NHL. After RIST, overall survival (OS) at 36 months is 49%, whereas event-free survival (EFS) is 32%. In Cox model analyses, the response to chemotherapy was the best predictor of OS (P =.0006) and EFS (P =.0006) after KIST. Differentiating stable disease from progressive disease after salvage chemotherapy strengthened the association with survival. Among chemotherapy-sensitive patients, the median OS and EFS have not been reached. In patients with stable disease, OS and EFS at 24 months are 50% and 25%, respectively. In contrast, only 1 patient with progressive disease during salvage therapy survived longer than 12 months. These prospective data confirm the favorable prognosis for chemotherapy-sensitive NHL after KIST and suggest that chemotherapy resistance is not an absolute contraindication to KIST for NHL patients with stable disease during salvage therapy. (c) 2005 American Society for Blood and Marrow Transplantation. C1 NCI, Expt Transplantat & Immunol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Canc Res Ctr, Bethesda, MD USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Bishop, MR (reprint author), NCI, Expt Transplantat & Immunol Branch, Canc Res Ctr, NIH, 10 Ctr Dr,CRC 3-3330,MSC 1203, Bethesda, MD 20892 USA. EM mbishop@mail.nih.gov NR 30 TC 21 Z9 21 U1 1 U2 1 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD AUG PY 2005 VL 11 IS 8 BP 593 EP 599 DI 10.1016/j.bbmt.2005.04.005 PG 7 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 954ZE UT WOS:000231193400004 PM 16041309 ER PT J AU Solomon, SR Savani, BN Childs, R Montero, A Boss, C Read, EJ Leitman, SF Barrett, AJ AF Solomon, SR Savani, BN Childs, R Montero, A Boss, C Read, EJ Leitman, SF Barrett, AJ TI Improved outcome for peripheral blood stem cell transplantation for advanced primary myelodysplastic syndrome SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE peripheral blood stem cell transplantation; myelodysplastic syndrome; transplant-related mortality ID BONE-MARROW-TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; HLA-IDENTICAL SIBLINGS; LONG-TERM; MYELOGENOUS LEUKEMIA; DISEASE; CHIMERISM; DONORS AB Stem cell transplantation for myelodysplastic syndrome (MDS) is characterized by high transplant-related mortality (TRM), especially in older patients and those with more advanced disease. Outcome after peripheral blood stem cell transplantation (PBSCT) may be superior to earlier results with bone marrow transplantation. Forty-three patients (aged 12-73 years; median, 49 years) received an HLA-identical sibling donor PBSCT. Twenty three patients aged <= 55 years without prohibitive comorbidity received myeloablative total body irradiation-based conditioning, followed by a T cell-depleted PBSCT and delayed add-back of donor lymphocytes. Older patients or those with comorbidities (n = 20) received reduced-intensity conditioning and an unmanipulated PBSCT. Thirty-seven (86%) had advanced disease (refractory anemia with excess blasts [n = 9], refractory anemia with excess blasts in transformation [n = 6], acute myelogenous leukemia [n = 13], or treatment-related MDS [n = 9]); 6 had low-risk MDS (refractory anemia or refractory anemia with ringed sideroblasts). The median follow-up was 18 months (range, 5-89 months). Actuarial probabilities of 3-year overall survival (OS), disease-free survival, relapse, and TRM were 64%, 59%, 26%, and 23%, respectively, for 34 primary MDS patients. The best results were in 19 patients younger than 50 years of age undergoing myeloablative PBSCT (actuarial probabilities of OS, disease-free survival, relapse, and TRM were 81%, 72%, 22%, and 7%, respectively). Although outcomes for all stages of primary MDS were improved, that for therapy-related MDS remained dismal, with 11% OS, because of a high relapse rate (89%). (c) 2005 American Society for Blood and Marrow Transplantation. C1 NHLBI, Stem Cell Allogen Transplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. NIH, Clin Ctr Dept Transfus Med, Bethesda, MD USA. RP Barrett, AJ (reprint author), NHLBI, Stem Cell Allogen Transplantat Sect, Hematol Branch, NIH, Bldg 10,Hatfield CRC,Room 3-5320,10 Ctr Dr,MSC 12, Bethesda, MD 20892 USA. EM barrettj@nhlbi.nih.gov NR 23 TC 9 Z9 9 U1 0 U2 1 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD AUG PY 2005 VL 11 IS 8 BP 619 EP 626 DI 10.1016/j.bbmt.2005.05.004 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 954ZE UT WOS:000231193400007 PM 16041312 ER PT J AU Blackshear, PJ Phillips, RS Ghosh, S Ramos, SVB Richfield, EK Lai, WS AF Blackshear, PJ Phillips, RS Ghosh, S Ramos, SVB Richfield, EK Lai, WS TI Zfp36l3, a rodent X chromosome gene encoding a placenta-specific member of the tristetraprolin family of CCCH tandem zinc finger proteins SO BIOLOGY OF REPRODUCTION LA English DT Article DE AU-rich element; cytokines; deadenylation; gene regulation; mRNA turnover; placenta; rodent-specific genes; trophoblast ID AU-RICH ELEMENT; CONTAINING MESSENGER-RNAS; PRIMARY RESPONSE GENE; NUCLEOTIDE-SEQUENCE; TIS11 FAMILY; BINDING; IDENTIFICATION; ALPHA; CELLS; DESTABILIZATION AB Members of the tristetraprolin (TTP) family of CCCH tandem zinc finger (TZF) proteins can bind directly to AU-rich elements (ARE) in mRNA, causing deadenylation and destabilization of the transcripts to which they bind. We describe here a novel fourth mammalian member of the TTP protein family, designated ZFP36L3, which could also bind directly to ARE-containing RNAs and could promote the deadenylation and degradation of ARE-containing target RNAs. Zfp36l3 transcript expression was detected only in placenta and extraembryonic tissues in the mouse. It was expressed throughout development in the placenta and was particularly highly expressed in the cells of the labyrinthine layer of the trophoblastic placenta. Unlike the other family members, the expression of a ZFP36L3-green fluorescent protein fusion protein was entirely cytoplasmic when expressed in 293 cells, even in the presence of the CRM1-dependent nuclear export inhibitor leptomycin B. Zfp36l3 was located on the mouse X chromosome; a similar predicted gene was present on the rat X chromosome, but there was no evidence for a similar gene in humans. ZFP36L3 may thus be a rodent-specific or even murine-specific member of the TTP protein family. Its presumed role in placental physiology may be unique to rodents or murine rodents, but this role may be subsumed by other family members in nonrodents. C1 NIEHS, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Off Clin Res, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pathol & Lab Med, New Brunswick, NJ 08901 USA. Univ Med & Dent New Jersey, Environm & Occupat Hlth Sci Inst, Mol Histol Ctr, Piscataway, NJ 08854 USA. RP Blackshear, PJ (reprint author), NIEHS, Neurobiol Lab, A2-05,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov NR 37 TC 47 Z9 49 U1 0 U2 4 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD AUG PY 2005 VL 73 IS 2 BP 297 EP 307 DI 10.1095/biolreprod.105.040527 PG 11 WC Reproductive Biology SC Reproductive Biology GA 948UL UT WOS:000230741100011 PM 15814898 ER PT J AU Perkins, NJ Schisterman, EF AF Perkins, NJ Schisterman, EF TI The Youden index and the optimal cut-point corrected for measurement error SO BIOMETRICAL JOURNAL LA English DT Article DE Youden index; ROC curve; measurement error; sensitivity and specificity; optimal cut-point ID ROC CURVES; VARIABILITY; PREVENTION AB Random measurement error can attenuate a biomarker's ability to discriminate between diseased and non-diseased populations. A global measure of biomarker effectiveness is the Youden index, the maximum difference between sensitivity, the probability of correctly classifying diseased individuals, and I-specificity, the probability of incorrectly classifying health individuals. We present an approach for estimating the Youden index and associated optimal cut-point for a normally distributed biomarker that corrects for normally distributed random measurement error. We also provide confidence intervals for these corrected estimates using the delta method and coverage probability through simulation over a variety of situations. Applying these techniques to the biomarker thiobarbituric acid reaction substance (TBARS), a measure of sub-products of lipid peroxidation that has been proposed as a discriminating measurement for cardiovascular disease, yields a 50% increase in diagnostic effectiveness at the optimal cut-point. This result may lead to biomarkers that were once naively considered ineffective becoming useful diagnostic devices. C1 NICHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. American Univ, Dept Math & Stat, Washington, DC 20016 USA. RP Schisterman, EF (reprint author), NICHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. EM schistee@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Schisterman, Enrique/0000-0003-3757-641X NR 21 TC 70 Z9 71 U1 1 U2 5 PU AKADEMIE VERLAG GMBH PI BERLIN PA PALISADENSTR 40, D-10243 BERLIN, GERMANY SN 0323-3847 J9 BIOMETRICAL J JI Biom. J. PD AUG PY 2005 VL 47 IS 4 BP 428 EP 441 DI 10.1002/bimj.200410133 PG 14 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 959BQ UT WOS:000231492300003 PM 16161802 ER PT J AU Golub, M Costa, L Crofton, K Frank, D Fried, P Gladen, B Henderson, R Liebelt, E Lusskin, S Marty, S Rowland, A Scialli, J Vore, M AF Golub, M Costa, L Crofton, K Frank, D Fried, P Gladen, B Henderson, R Liebelt, E Lusskin, S Marty, S Rowland, A Scialli, J Vore, M TI NTP-CERHR expert panel report on the reproductive and developmental toxicity of methylphenidate SO BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY LA English DT Review ID DEFICIT-HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; PLACEBO-CONTROLLED EVALUATION; NERVOUS-SYSTEM STIMULANTS; DL-THREO-METHYLPHENIDATE; LA-TOURETTES SYNDROME; LATER SUBSTANCE-ABUSE; ORAL GAVAGE TOXICITY; GROWTH-HORMONE; FOLLOW-UP C1 Univ Washington, Seattle, WA 98195 USA. Calif Environm Protect Agcy, Sacramento, CA USA. US EPA, Res Triangle Pk, NC 27711 USA. Boston Med Ctr, Boston, MA USA. Carleton Univ, Ottawa, ON K1S 5B6, Canada. NIEHS, Res Triangle Pk, NC 27709 USA. Lovelace Resp Res Inst, Albuquerque, NM USA. Univ Alabama, Birmingham Sch Med, Birmingham, AL USA. NYU, Sch Med, New York, NY USA. Dow Chem Co USA, Midland, MI 48674 USA. Univ New Mexico, Albuquerque, NM 87131 USA. Univ Kentucky, Lexington, KY USA. RP Golub, M (reprint author), NIEHS EC32, POB 12233, Res Triangle Pk, NC 27709 USA. RI Vore, Mary/E-2177-2012; Crofton, Kevin/J-4798-2015 OI Crofton, Kevin/0000-0003-1749-9971 NR 161 TC 15 Z9 15 U1 4 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-9733 J9 BIRTH DEFECTS RES B JI Birth Defects Res. Part B-Dev. Reprod. Toxicol. PD AUG PY 2005 VL 74 IS 4 BP 300 EP 381 DI 10.1002/bdrb.20049 PG 82 WC Oncology; Genetics & Heredity; Toxicology SC Oncology; Genetics & Heredity; Toxicology GA 962SW UT WOS:000231753700002 PM 16127684 ER PT J AU O'Shea, JJ Gadina, M Chen, XM AF O'Shea, JJ Gadina, M Chen, XM TI Structure of a Janus kinase: molecular insights and prospects for optimizing a new class of immunosuppressants SO BLOOD LA English DT Editorial Material ID IMMUNODEFICIENCY; PATHWAYS AB Jaks,in general, are critical for cytokine signaling and Jak3 is crucial for key immunoregulatory cytokines. The study by Boggon and colleagues provides the first insights into the structure of these key tyrosine kinases. C1 NIAMSD, Bethesda, MD 20892 USA. Queens Univ Belfast, Belfast BT7 1NN, Antrim, North Ireland. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. RP O'Shea, JJ (reprint author), NIAMSD, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD AUG 1 PY 2005 VL 106 IS 3 BP 765 EP 766 DI 10.1182/blood-2005-05-1947 PG 2 WC Hematology SC Hematology GA 951RT UT WOS:000230949100001 ER PT J AU Dunleavy, K Hakim, F Kim, HK Janik, JE Grant, N Nakayama, T White, T Wright, G Kwak, L Gress, R Tosato, G Wilson, WH AF Dunleavy, K Hakim, F Kim, HK Janik, JE Grant, N Nakayama, T White, T Wright, G Kwak, L Gress, R Tosato, G Wilson, WH TI B-cell recovery following rituximab-based therapy is associated with perturbations in stromal derived factor-1 and granulocyte homeostasis SO BLOOD LA English DT Article ID NON-HODGKINS-LYMPHOMA; DOSE-ADJUSTED EPOCH; CHEMOKINE RECEPTOR CXCR4; BONE-MARROW; MONOCLONAL-ANTIBODY; ONSET NEUTROPENIA; MOBILIZATION; EFFICACY; TRIAL; CHEMOTHERAPY AB The occurrence of delayed neutropenia following rituximab is poorly defined and of unknown cause. We hypothesized it may be related to perturbations of stromal derived factor-1 (SDF-1) and granulocyte homeostasis. Late-onset neutropenia (LON) was investigated in 130 patients with untreated aggressive B-cell lymphoma receiving DA-EPOCH (dose-adjusted etoposide, prednisone, Oncovin [vincristine], cyclophosphamide, and hydroxydaunorubicin) chemotherapy with or without rituximab. All patients were in remission and had no known causes for neutropenia. LON occurred in 6 (8%) of 76 patients receiving rituximab and 0 of 54 patients not receiving rituximab (P = .04). The median onset was 175 days (range, 77-204 days) after treatment with a median duration of 14 days (range, 11-16 days). In a subset of 24 patients, a significant correlation was found between rapid B-cell recovery and granulocyte decline over the 6-month recovery period (R = -0.53; P = .04). Rapid B-cell recovery directly correlated with prerecovery SDF-1 levels (R = 0.65; P = .015) and SDF-1 decline (R = -0.67; P = .013) after recovery. Our results suggest that early B-cell lymphopoiesis is important for B-cell recovery following rituximab, and that perturbation of SDF-1 during B-cell recovery retards neutrophil egress from the bone marrow. These findings illustrate the dual role of SDF-1 in human B-cell and granulocyte homeostasis. C1 NCI, CCR, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Wilson, WH (reprint author), NCI, CCR, Expt Transplantat & Immunol Branch, NIH, Bldg 10,Rm 12-N-226, Bethesda, MD 20892 USA. EM wilsonw@mail.nih.gov NR 33 TC 57 Z9 61 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2005 VL 106 IS 3 BP 795 EP 802 DI 10.1182/blood-2004-08-3198 PG 8 WC Hematology SC Hematology GA 951RT UT WOS:000230949100016 PM 15718416 ER PT J AU Sloand, EM Mainwaring, L Fuhrer, M Ramkissoon, S Risitano, AM Keyvanafar, K Lu, J Basu, A Barrett, AJ Young, NS AF Sloand, EM Mainwaring, L Fuhrer, M Ramkissoon, S Risitano, AM Keyvanafar, K Lu, J Basu, A Barrett, AJ Young, NS TI Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome SO BLOOD LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; NECROSIS-FACTOR-ALPHA; BONE-MARROW FAILURE; APLASTIC-ANEMIA; ANTITHYMOCYTE GLOBULIN; T-CELLS; CYTOGENETIC ABNORMALITIES; EXCESSIVE APOPTOSIS; MULTIPLE-SCLEROSIS; MYELOID-LEUKEMIA AB Clinical observations and experimental evidence link bone marrow failure in myelodysplastic syndrome (MDS) with a T cell-dominated autoimmune process. Immunosuppressive therapy is effective in improving cytopenias in selected patients. Trisomy 8 is a frequent cytogenetic abnormality in bone marrow cells in patients with MDS, and its presence has been associated anecdotally with good response to immunotherapy. We studied 34 patients with trisomy 8 in bone marrow cells, some of whom were undergoing treatment with antithymocyte globulin (ATG). All had significant CD8(+) T-cell expansions of one or more T-cell receptor (TCR) V beta subfamilies, as measured by flow cytometry; expanded subfamilies showed CDR3 skewing by spectratyping. Sorted T cells of the expanded V beta subfamilies, but not of the remaining subfamilies, inhibited trisomy 8 cell growth in short-term hematopoletic culture. The negative effects of V beta-expanded T cells were inhibited by major histocompatibility complex (MHC) class 1 monoclonal antibody (mAb) and Fas antagonist and required direct cell-to-cell contact. Sixty-seven percent of patients who had de novo MDS with trisomy 8 as the sole karyotypic abnormality responded to ATG with durable reversal of cytopenias and restoration of transfusion independence, with stable increase in the proportion of trisomy 8 bone marrow cells and normalization of the T-cell repertoire. An increased number of T cells with apparent specificity for trisomy 8 cells is consistent with an autoimmune pathophysiology in trisomy 8 MDS. C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Sloand, EM (reprint author), NHLBI, NIH, Bldg 10,Rm 7C108, Bethesda, MD 20892 USA. EM sloande@nih.gov NR 58 TC 97 Z9 105 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 AUG 1 PY 2005 VL 106 IS 3 BP 841 EP 851 DI 10.1182/blood-2004-05-2017 PG 11 WC Hematology SC Hematology GA 951RT UT WOS:000230949100022 PM 15827127 ER PT J AU Doi, K Wu, XL Taniguchi, Y Yasunaga, J Satou, Y Okayama, A Nosaka, K Matsuoka, M AF Doi, K Wu, XL Taniguchi, Y Yasunaga, J Satou, Y Okayama, A Nosaka, K Matsuoka, M TI Preferential selection of human T-cell leukemia virus type I provirus integration sites in leukemic versus carrier states SO BLOOD LA English DT Article ID HUMAN GENOME; TAX PROTEIN; GENE; HTLV-1; DNA; TRANSCRIPTION; INFECTION; PROMOTER; SEQUENCE; TARGETS AB Human T-cell leukemia virus type I (HTLV-1) is a causative agent of neoplastic disease, adult T-cell leukemia (ATL). Although the encoding viral proteins play an important role in oncogenesis, the role of the HTLV-1 proviral integration site remains unsolved. We determined the integration sites of HTLV-1 proviruses in ATL cells and HTLV-1-infected cells in asymptomatic carriers. In carrier and ATL cells, HTLV-1 provirus was integrated into the transcriptional unit at frequencies of 26.8% (15/56) and 33.9% (20/59), respectively, which were equivalent to the frequency calculated based on random integration (33.2%). In addition, HTLV-1 provirus was prone to integration near the transcriptional start sites in leukemic cells (P =.006), and the transcriptional direction of the provirus was in accordance with that of integrated cellular genes in 70% of cases. More importantly, the integration sites in the carrier cells favored the alphoid repetitive sequences (11/56; 20%) whereas in leukemic cells they disfavored these sequences (2159; 3.4%). Taken together, during natural course from carrier to onset of ATL, HTLV-I-infected cells with integration sites favorable for viral gene transcription are susceptible to malignant transformation due to increased viral gene expression. C1 Kyoto Univ, Inst Virus Res, Lab Virus Immunol, Kyoto 6068507, Japan. Natl Canc Inst, Lab Mol Technol, Frederick, MD USA. Miyazaki Univ, Fac Med, Dept Lab Med, Miyazaki 88921, Japan. RP Matsuoka, M (reprint author), Kyoto Univ, Inst Virus Res, Lab Virus Immunol, Kyoto 6068507, Japan. EM mmatsuok@virus.kyoto-u.ac.jp RI Satou, Yorifumi/F-9091-2013; OI Matsuoka, Masao/0000-0002-0473-754X; Satou, Yorifumi/0000-0002-1495-7810; Yasunaga, Jun-ichirou/0000-0002-7939-2080 NR 35 TC 32 Z9 33 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2005 VL 106 IS 3 BP 1048 EP 1053 DI 10.1182/blood-2004-11-4350 PG 6 WC Hematology SC Hematology GA 951RT UT WOS:000230949100052 PM 15840694 ER PT J AU Cooperman, SS Meyron-Holtz, EG Olivierre-Wilson, H Ghosh, MC McConnell, JP Rouault, TA AF Cooperman, SS Meyron-Holtz, EG Olivierre-Wilson, H Ghosh, MC McConnell, JP Rouault, TA TI Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2 SO BLOOD LA English DT Article ID TRANSFERRIN RECEPTOR; RESPONSIVE ELEMENT; MESSENGER-RNA; 5-AMINOLEVULINATE SYNTHASE; MITOCHONDRIAL ACONITASE; HUMAN FERROCHELATASE; HEME-BIOSYNTHESIS; ERYTHROID-CELLS; LIVER-DISEASE; WILD-TYPE AB Iron-regulatory proteins (IRPs) 1 and 2 posittranscriptionally regulate expression of transferrin receptor (TfR), ferritin, and other iron metabolism proteins. Mice with targeted deletion of IRP2 overexpress ferritin and express abnormally low TfR levels in multiple tissues. Despite this misregulation, there are no apparent pathologic consequences in tissues such as the liver and kidney. However, in the central nervous system, evidence of abnormal iron metabolism in IRP2(-/-) mice precedes the development of adult-onset progressive neurodegeneration, characterized by widespread axonal degeneration and neuronal loss. Here, we report that ablation of IRP2 results in iron-limited erythropolesis. TfR expression in erythroid precursors of IRP2(-/-) mice is reduced, and bone marrow iron stores are absent, even though transferrin saturation levels are normal. Marked overexpression of 5-aminolevulinic acid synthase 2 (Alas2) results from loss of IRP-dependent translational repression, and markedly increased levels of free protoporphyrin IX and, zinc protoporphyrin are generated in IRP2(-/-) erythroid cells. IRP2(-/-) mice represent a new paradigm of genetic microcytic anemia. We postulate that IRP2 mutations or deletions may be a cause of refractory microcytic anemia and bone marrow iron depletion in patients with normal transferrin saturations, elevated serum ferritins, elevated red cell protoporphyrin IX levels, and adult-onset neurodegeneration. C1 NICHHD, Bethesda, MD 20892 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. RP Rouault, TA (reprint author), NICHHD, Bethesda, MD 20892 USA. EM trou@helix.nih.gov RI Meyron-Holtz, Esther/B-5991-2013 FU Intramural NIH HHS NR 53 TC 125 Z9 130 U1 0 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2005 VL 106 IS 3 BP 1084 EP 1091 DI 10.1182/blood-2004-12-4703 PG 8 WC Hematology SC Hematology GA 951RT UT WOS:000230949100057 PM 15831703 ER PT J AU Solomon, SR Mielke, S Savani, BN Montero, A Wisch, L Childs, R Hensel, N Schindler, J Ghetie, V Leitman, SF Mai, T Carter, CS Kurlander, R Read, EJ Vitetta, ES Barrett, AJ AF Solomon, SR Mielke, S Savani, BN Montero, A Wisch, L Childs, R Hensel, N Schindler, J Ghetie, V Leitman, SF Mai, T Carter, CS Kurlander, R Read, EJ Vitetta, ES Barrett, AJ TI Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; HLA-IDENTICAL SIBLINGS; IMMUNOREGULATORY T-CELLS; CHRONIC MYELOID-LEUKEMIA; GVHD PROPHYLAXIS; PREDICTIVE VALUE; IMMUNOTOXIN; ACTIVATION; RECEPTOR; ELIMINATION AB We have selectively depleted host-reactive donor T cells from peripheral blood stem cell (PBSC) transplant allografts ex vivo using an anti-CD25 immunotoxin. We report a clinical trial to decrease graft-versus-host disease (GVHD) in elderly patients receiving selectively depleted PBSC transplants from HLA-identical sibling donors. Sixteen patients (median age, 65 years [range, 51-73 years]), with advanced hematologic malignancies underwent transplantation following reduced-intensity conditioning with fludarabine and either cyclophosphamide (n = 5), melphalan (n = 5), or busulfan (n = 6). Cyclosporine was used as sole GVHD prophylaxis. The allograft contained a median of 4.5 x 10(6) CD34 cellstkg (range, 3.4-7.3 x 10(6) CD34 cells/kg) and 1.0 x 10(8)/kg (range, 0.2-1.5 x 10(8)/kg) selectively depleted T cells. Fifteen patients achieved sustained engraftment. The helper T-lymphocyte precursor (HTLp) frequency assay demonstrated successful (mean, 5-fold) depletion of host-reactive donor T cells, with conservation of third-party response in 9 of 11 cases tested. Actuarial rates of acute GVHD were 46% +/- 13% for grades II to IV and 12% +/- 8% for grades III to IV. These results suggest that allodepletion of donor cells ex vivo is clinically feasible in older patients and may reduce the rate of severe acute GVHD. Further studies with selectively depleted transplants to evaluate graft-versus-leukemia (GVL) and survival are warranted. C1 NHLBI, Stem Cell Allogene Transplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. NIH, Cell Proc Sect, Dept Transfus Med, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Microbiol, Dallas, TX 75230 USA. Univ Texas, SW Med Ctr, Ctr Canc Immunobiol, Dallas, TX 75230 USA. RP Barrett, AJ (reprint author), NHLBI, Stem Cell Allogene Transplantat Sect, Hematol Branch, NIH, Bldg 10,Hatfield CRC,RM 3-5320,10 Ctr Dr,MSC 1202, Bethesda, MD 20892 USA. EM barrettj@nhlbi.nih.gov NR 36 TC 100 Z9 103 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2005 VL 106 IS 3 BP 1123 EP 1129 DI 10.1182/blood-2005-01-0393 PG 7 WC Hematology SC Hematology GA 951RT UT WOS:000230949100062 PM 15817673 ER PT J AU Chen, XD Bian, XP Teslovich, TM Stephan, DA Young, MF AF Chen, XD Bian, XP Teslovich, TM Stephan, DA Young, MF TI Dissection of the sets of genes that control the behavior of biglycan-deficient pre-osteoblasts using oligonucleotide microarrays SO BONE LA English DT Article DE biglyean; osteoblast progenitors; gene expression patterns; BMP-4; differentiation ID TRANSCRIPTION FACTOR AP-2; COLLAGEN FIBRIL ABNORMALITIES; GROWTH-FACTOR-BETA; PROTEOGLYCANS BIGLYCAN; EPITHELIAL-CELLS; EXPRESSION; MICE; BONE; DIFFERENTIATION; IDENTIFICATION AB Biglycan (bgn) is a small leucine-rich proteoglycan (SLPR) that is enriched in the extracellular matrix of skeletal tissues. Bgn-deficient mice develop age-related osteopenia with a phenotype that resembles osteoporosis. In order to identify sets of genes that play a key role in the skeletal abnormality, we determined the global gene expression patterns in bgn-deficient (bgn-KO) pre-osteoblasts using oligonucleotide microarray technology. Calvarial cells were harvested from newborn mice and cultured in the presence or absence of BMP-4 for 7 days. The total RNA was purified, labeled and hybridized to Affymetrix (TM) chips (U74A), and analyzed with a software program called GeneSpring (TM). Our data suggested that biglycan regulates the activity of osteoblastic progenitors through sets of genes associated with cell cycle, cell growth, and differentiation. The biological outcome from the altered expression of these genes could cause a defect in the quantity and quality of osteoblastic progenitors, which could contribute to the development of age-related osteopenia in bgn-KO mice. Moreover, the data from this approach also revealed that biglycan deficiency affected the genes that control inflammation, immune response, and growth of tumor cells. These are new and unexpected findings that lead to the formation of new paradigms for biglycan function. Based on these findings, we propose that the reduction of this small proteoglycan with aging may increase the risk of infection and autoimmune diseases, impair wound healing, and cause higher incidences of malignancy. This study provides a broad and deep foundation for understanding SLRP function at a more complex level. (c) 2005 Elsevier Inc. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. NCI, CCR, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Res Ctr Genet Med, Washington, DC 20010 USA. RP Chen, XD (reprint author), Univ Arkansas Med Sci, Ctr Osteoporosis & Metabol Bone Dis, 4301 W Markham,Slot 587, Little Rock, AR 72205 USA. EM chenxiaodong@uams.edu NR 50 TC 10 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD AUG PY 2005 VL 37 IS 2 BP 192 EP 203 DI 10.1016/j.bone.2005.04.006 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 951RQ UT WOS:000230948800008 PM 15922682 ER PT J AU Neelapu, S Munshi, NC Jagannath, S Watson, TM Pennington, R Reynolds, C Barlogie, B Kwak, LW AF Neelapu, S Munshi, NC Jagannath, S Watson, TM Pennington, R Reynolds, C Barlogie, B Kwak, LW TI Tumor antigen immunization of sibling stem cell transplant donors in multiple myeloma SO BONE MARROW TRANSPLANTATION LA English DT Article DE idiotype; immunization; myeloma; donors; allogeneic ID BONE-MARROW TRANSPLANTATION; COLONY-STIMULATING FACTOR; HIGH-DOSE CHEMOTHERAPY; IDIOTYPE VACCINATION; ACTIVE IMMUNIZATION; IMMUNE-RESPONSES; DENDRITIC CELLS; LYMPHOMA; IMMUNOGLOBULIN; LYMPHOCYTES AB The unique antigenic determinants (idiotype ( Id)) of the immunoglobulin secreted by myeloma tumor can serve as a tumor-specific antigen for active immunotherapy. Our objective was to induce tumor-specific T-cell immunity in bone marrow transplant (BMT) donors to enhance antitumor effects of allografts. We vaccinated five HLA-matched sibling donors with myeloma Id proteins isolated from recipient plasma before bone marrow harvest. Recipients were administered booster Id immunizations following transplantation. Vaccination induced donor Id and carrier-specific cellular and/or humoral immune responses. Two recipients died within 30 days of BMT from transplant-related complications. Id and carrierspecific T-cell responses were detected in all three remaining patients post-, but not pre-BMT and persisted for 18 months. All three surviving patients converted from partial to complete responses following BMT. Two of the three patients remain disease-free 7 years and 8 years after BMT, and the third died of renal failure after 5.5 years while in complete remission from myeloma. Our results suggest that myeloma Id vaccination induces specific T-cell immunity in healthy donors which may be transferable by BMT, is associated with prolonged disease-free survival of recipients, and may represent a general strategy to enhance graft-versus-tumor effect in other malignancies for which defined tumor-specific antigens exist. C1 NCI, Expt & Transplantat Immunol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. NCI, Off Sci Operat, Frederick, MD 21701 USA. RP Kwak, LW (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Unit 429, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM lkwak@mdanderson.org FU NCI NIH HHS [N01-CO-12400] NR 33 TC 42 Z9 43 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 AUG PY 2005 VL 36 IS 4 BP 315 EP 323 DI 10.1038/sj.bmt.1705057 PG 9 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 950YO UT WOS:000230895400006 PM 15968284 ER PT J AU Raju, R Dalakas, MC AF Raju, R Dalakas, MC TI Gene expression profile in the muscles of patients with inflammatory myopathies: effect of therapy with IVIg and biological validation of clinically relevant genes SO BRAIN LA English DT Article DE neuroimmunology; autoimmunity; inflammation; adhesion molecules ID INTRAVENOUS IMMUNOGLOBULIN; ADHESION MOLECULES; CELL-ADHESION; DERMATOMYOSITIS; DISEASES; AUTOIMMUNE; CHEMOKINE; N-ACETYLGALACTOSAMINE-4-O-SULFOTRANSFERASE; LYMPHOCYTES; IMMUNOLOGY AB To explore the biological significance of gene expression in the pathogenesis of inflammatory myopathies, we performed microarray experiments followed by real-time PCR and immunohistochemistry on muscle biopsies obtained before and after therapy from patients with dermatomyositis (DM) who improved and patients with inclusion body myositis (sIBM) who did not improve after controlled trials with three monthly intravenous immunoglobulin (IVIg) infusions. The pretreatment biopsies showed high expression of immunoglobulin, adhesion molecules, chemokines and cytokine genes in both sIBM and DM (sIBM > DM). In the repeated biopsies of DM patients who clinically improved, 2206 genes were downregulated more than 1.5-fold; in contrast, 1700 of the same genes remained unchanged in sIBM patients who did not improve. Genes markedly downregulated in DM, but not sIBM, were interleukin 22, Kallmann syndrome 1 (KAL-1), an adhesion molecule shown for the first time in muscle, ICAM-1, complement C1q, and several structural protein genes. Because mRNA for KAL-1 was selectively upregulated in vitro by transforming growth factor (TGF) beta 1, a fibrogenic cytokine immunolocalized in the endomysial connective tissue of pretreatment DM muscles, the downregulation of both TGF-beta and KAL-1 after IVIg only in DM suggests that these molecules have a functional role in connective tissue proliferation and fibrosis. The improved muscles of DM, but not sIBM, showed upregulation of chemokines CXCL9 (Mig) and CXCL11, and several immunoglobulin-related genes, suggesting an effect on muscle remodelling and regeneration. The results suggest that IVIg modulates several immunoregulatory or structural muscle genes, but only a subset of them associated with inflammatory mediators, fibrosis and muscle remodelling are connected with the clinical response. Gene arrays, when combined with clinical assessments, may provide important information in the pathogenesis of inflammatory myopathies. C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10 Room 4N252,10 Ctr Dr, Bethesda, MD 20892 USA. EM dalakasm@ninds.nih.gov RI Raju, Raghavan/E-9219-2011 NR 30 TC 91 Z9 91 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 AUG PY 2005 VL 128 BP 1887 EP 1896 DI 10.1093/brain/awh518 PN 8 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 948OB UT WOS:000230724500017 PM 15857930 ER PT J AU Marti, GE Rawstron, AC Ghia, P Hillmen, P Houlston, RS Kay, N Schleinitz, TA Caporaso, N AF Marti, GE Rawstron, AC Ghia, P Hillmen, P Houlston, RS Kay, N Schleinitz, TA Caporaso, N CA Int Familial CLL Consortium TI Diagnostic criteria for monoclonal B-cell lymphocytosis SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Review DE monoclonal B-cell lymphocytosis; B cells; early detection; surrogate biomarker; familial chronic lymphocytic leukaemia ID UNDETERMINED SIGNIFICANCE MLUS; NATURAL-HISTORY; WORKING GROUP; LEUKEMIA CLL; EXPRESSION; PROGNOSIS; BLOOD; DIFFERENTIATION; GAMMOPATHIES; IL-1-BETA AB Very low levels of circulating monoclonal B-cell subpopulations can now be detected in apparently healthy individuals using flow cytometry. We propose the term 'monoclonal B-cell lymphocytosis' (MBL) to describe this finding. The aim of this document is to provide a working definition of MBL for future clinical, epidemiological and laboratory studies. We propose that the detection of a monoclonal B-cell population by light chain restriction is sufficient to define this condition in individuals not meeting the diagnostic criteria for other B-lymphoproliferative disorders. The majority of individuals with MBL will have cells that are indistinguishable from chronic lymphocytic leukaemia (CLL). However, this blood cell clonal expansion of CD5(+) or CD5(-) B-lymphocytes is age-dependent and immunophenotypic heterogeneity is common. Longitudinal studies are required to determine whether MBL is a precursor state to CLL or other B-lymphoproliferative disease in a situation analogous to a monoclonal gammopathy of undetermined significance and myeloma. Future studies of MBL should be directed towards determining its relationship to clinical disease, particularly in individuals from families with a genetic predisposition to developing CLL. C1 NIH, Flow & Image Cytometry Sect, LSCB DCGT OCTGT, CBER FDA, Bethesda, MD 20892 USA. Leeds Teaching Hosp NHS Trust, Leeds Gen Infirm, Haematol Malignancy Diagnost Serv, Leeds, W Yorkshire, England. Univ Turin, Dept Oncol Sci, Candiolo, TO, Italy. Ist Ric & Cura Cancro, Lab Canc Immunol, Candiolo, TO, Italy. Canc Res Inst, Sect Canc Genet, Sutton, Surrey, England. Mayo Clin, Div Hematol, Rochester, MN USA. Inst J Paoli I Calmettes, F-13009 Marseille, France. NCI, Dept Med, Div Canc Epidemiol & Genet, Genet Epidemiol Branch,NIH, Bethesda, MD 20892 USA. RP Marti, GE (reprint author), NIH, Flow & Image Cytometry Sect, LSCB DCGT OCTGT, CBER FDA, Bdg 29B,Rm 2NN08,8800 Rockville Pike, Bethesda, MD 20892 USA. RI Ghia, Paolo/K-7138-2016; OI Ghia, Paolo/0000-0003-3750-7342; Houlston, Richard/0000-0002-5268-0242 NR 47 TC 214 Z9 223 U1 0 U2 12 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 AUG PY 2005 VL 130 IS 3 BP 325 EP 332 DI 10.1111/j.1365-2141.2005.05550.x PG 8 WC Hematology SC Hematology GA 948OO UT WOS:000230725800001 PM 16042682 ER PT J AU Machado, RF Martyr, S Kato, GJ Barst, RJ Anthi, A Robinson, MR Hunter, L Coles, W Nichols, J Hunter, C Sachdev, V Castro, O Gladwin, MT AF Machado, RF Martyr, S Kato, GJ Barst, RJ Anthi, A Robinson, MR Hunter, L Coles, W Nichols, J Hunter, C Sachdev, V Castro, O Gladwin, MT TI Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE sickle cell disease; haemolysis; pulmonary hypertension; phosphodiesterase 5 inhibitors; nitric oxide; 6-min walk test ID BRAIN NATRIURETIC PEPTIDE; LONG-TERM TREATMENT; ARTERIAL-HYPERTENSION; ORAL SILDENAFIL; RISK-FACTOR; VASOCONSTRICTION; CAPACITY; BOSENTAN; DEATH AB Pulmonary hypertension is a frequent complication of sickle cell disease that is associated with haemolysis, impaired nitric oxide bioavailability and high mortality. We sought to evaluate the safety and efficacy of selective pulmonary vasodilators and antiproliferative agents in this at-risk population. After optimising sickle cell disease therapy to stabilise haemoglobin and fetal haemoglobin levels, we evaluated the safety and efficacy of sildenafil in 12 patients with sickle cell disease and pulmonary hypertension. Sildenafil therapy (mean duration 6 +/- 1 months) decreased the estimated pulmonary artery systolic pressure [50 +/- 4 to 41 +/- 3 mmHg; difference 9 mmHg, 95% confidence interval (CI): 0.3-17, P = 0.043] and increased the 6-min walk distance (384 +/- 30 to 462 +/- 28 m; difference 78 m, 95% CI: 40-117, P = 0.0012). Transient headaches occurred in two patients and transient eye-lid oedema in four patients. No episodes of priapism occurred in the three men in the study; two of them were on chronic exchange transfusions and one had erectile dysfunction. In conclusion: (1) sickle cell disease patients with anaemia and pulmonary hypertension have significant exercise limitation; (2) the 6-min walk distance may be a valid endpoint in this population; (3) therapy with sildenafil appears safe and improves pulmonary hypertension and exercise capacity. Additional phase I studies in males with sickle cell disease followed by phase II/III placebo controlled trials evaluating the safety and efficacy of sildenafil therapy in sickle cell disease patients with pulmonary hypertension are warranted. C1 NIH, Ctr Clin, Crit Care Med Dept, Bethesda, MD 20892 USA. NHLBI, Vasc Therapeut Sect, Cardiovasc Branch, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, New York, NY USA. NEI, NIH, Bethesda, MD 20892 USA. Howard Univ, Coll Med, Ctr Sickle Cell Dis, Washington, DC 20059 USA. RP Machado, RF (reprint author), NIH, Ctr Clin, Crit Care Med Dept, 9000 Rockville Pike,Bldg 10-CRC,Room 5-5140, Bethesda, MD 20892 USA. EM robertom@nhlbi.nih.gov RI Hunter, Christian/G-4344-2010; Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Intramural NIH HHS [Z01 CL001174-07, Z01 HL005802-02, Z99 HL999999, ZIA HL005803-05] NR 26 TC 123 Z9 128 U1 1 U2 2 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 AUG PY 2005 VL 130 IS 3 BP 445 EP 453 DI 10.1111/j.1365-2141.2005.05625.x PG 9 WC Hematology SC Hematology GA 948OO UT WOS:000230725800015 PM 16042696 ER PT J AU Barker, LA Dazin, PF Levine, JD Green, PG AF Barker, LA Dazin, PF Levine, JD Green, PG TI Sympathoadrenal-dependent sexually dimorphic effect of nonhabituating stress on in vivo neutrophil recruitment in the rat SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE adrenal medulla; sex differences; neutrophils; beta-adrenergic receptor ID INDUCED PLASMA EXTRAVASATION; METHIONYL-LEUCYL-PHENYLALANINE; IMMUNE-RESPONSES; SYMPATHETIC INNERVATION; INFLAMMATORY RESPONSE; RESPIRATORY BURST; ENDOTHELIAL-CELLS; INNATE IMMUNITY; JOINT INJURY; SEX-HORMONES AB 1 Since stress both activates the sympathoadrenal axis and profoundly affects inflammation and inflammatory diseases, many of which are sexually dimorphic, we tested whether the effect of stress on neutrophil recruitment, a primary component of the acute inflammatory response, is sexually dimorphic. 2 The effect of intermittent sound (over 4 days), a nonhabituating stress, on lipopolysaccharide (LPS)-induced recruitment of neutrophils was evaluated in vivo in the rat air pouch model. At 24 h following the last stress exposure, LPS-induced neutrophil recruitment was enhanced in male rats, but not in females. 3 When gonadectomized prepubertally and tested as adults, stress significantly inhibited the magnitude of LPS-induced neutrophil recruitment in males, while it still had no effect in gonadectomized females. In males, following adrenal denervation, the increase in LPS-induced neutrophil recruitment produced by stress was prevented. Since these data suggest that the effect of stress is dependent on the sympathoadrenal axis, we tested the hypothesis that catecholamines mediate the stress effects. 4 In male rats, the effect of stress on LPS-induced neutrophil recruitment was significantly attenuated by continuous administration of the beta-adrenergic receptor antagonist, propranolol (4 mg kg(-1) day(-1)), during sound stress exposure, and administration of isoproterenol (10 nmoles, i.v.) significantly increased neutrophil recruitment in males, an effect that was qualitatively and quantitatively similar to the effect of stress. Propranolol significantly increased neutrophil recruitment in nonstressed female rats, but did not significantly affect neutrophil recruitment in stressed females. 5 These findings indicate a marked male sex hormone-dependent sexual dimorphism in the sympathoadrenal-depen dent effect of stress on neutrophil migration, a primary component of the inflammatory response, and suggest that the sympathoadrenal axis contributes to this effect via release of epinephrine. C1 Univ Calif San Francisco, NIH, Pain Ctr, Dept Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. RP Green, PG (reprint author), Univ Calif San Francisco, NIH, Pain Ctr, Dept Oral & Maxillofacial Surg, C522 Box 0440,521 Parnassus Ave, San Francisco, CA 94143 USA. EM paul@itsa.ucsf.edu RI Green, Paul/C-5943-2011 NR 75 TC 13 Z9 13 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD AUG PY 2005 VL 145 IS 7 BP 872 EP 879 DI 10.1038/sj.bjp.0706257 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 955UC UT WOS:000231252100004 PM 15912135 ER PT J AU Trendelenburg, AU Meyer, A Wess, J Starke, K AF Trendelenburg, AU Meyer, A Wess, J Starke, K TI Distinct mixtures of muscarinic receptor subtypes mediate inhibition of noradrenaline release in different mouse peripheral tissues, as studied with receptor knockout mice SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE presynaptic muscarinic receptors; sympathetic axon terminals; H-3-noradrenaline; M-3-knockout; M-2/3-knockout; M-2/4-knockout; mouse atria; mouse urinary bladder; mouse vas deferens; heterogeneity ID POSTGANGLIONIC SYMPATHETIC-NERVES; ACETYLCHOLINE-RECEPTOR; PRESYNAPTIC ALPHA(2)-AUTORECEPTORS; CHOLINERGIC STIMULATION; TRANSMITTER RELEASE; HEART ATRIA; OUT MICE; AUTORECEPTORS; NEURONS; NEUROTRANSMISSION AB 1 The muscarinic heteroreceptors modulating noradrenaline release in atria, urinary bladder and vas deferens were previously studied in mice in which the M-2 or the M-4 muscarinic receptor genes had been disrupted. These experiments showed that these tissues possessed both M-2 and non-M-2 heteroreceptors. The analysis was now extended to mice in which either the M-3, both the M-2 and the M-3, or both the M-2 and the M-4 genes had been disrupted (M-3-knockout, M-2/3-knockout and M-2/4-knockout). Tissues were preincubated with H-3-noradrenaline and then stimulated electrically (20 pulses per 50 Hz). 2 In wild-type atria, carbachol (0.01 - 100 mu M) decreased the electrically evoked tritium overflow by maximally 60 - 78%. The maximum inhibition of carbachol was reduced to 57% in M-3-knockout and to 23% in M-2/4-knockout atria. Strikingly, the effect of carbachol was abolished in M-2/3-knockout atria. 3 In wild-type bladder, carbachol (0.01 - 100 mM) reduced the evoked tritium overflow by maximally 57 - 71%. This effect remained unchanged in the M-3-knockout, but was abolished in the M-2/4-knockout bladder. 4 In wild-type vas deferens, carbachol (0.01 - 100 mM) reduced the evoked tritium overflow by maximally 34 - 48%. The maximum inhibition of carbachol was reduced to 40% in the M-3-knockout and to 18% in the M-2/4-knockout vas deferens. 5 We conclude that the postganglionic sympathetic axons of mouse atria possess M-2 and M-3, those of the urinary bladder M-2 and M-4, and those of the vas deferens M-2, M-3 and M-4 release-inhibiting muscarinic receptors. C1 Inst Expt & Klin Pharmakol & Toxikol, D-79104 Freiburg, Germany. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Trendelenburg, AU (reprint author), Novartis Inst BioMed Res, DA Neurosci Ophthalmol, WSJ-386-7-46, CH-4002 Basel, Switzerland. EM anne-ulrike.trendelenburg@pharma.novartis.com NR 33 TC 17 Z9 18 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD AUG PY 2005 VL 145 IS 8 BP 1153 EP 1159 DI 10.1038/sj.bjp.0706297 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 962HO UT WOS:000231722000017 PM 15965496 ER PT J AU Tkacz, VL Tohnya, TM Figg, WD AF Tkacz, VL Tohnya, TM Figg, WD TI Cyclooxygenase-2 and angiogenesis in prostate cancer SO CANCER BIOLOGY & THERAPY LA English DT Article DE inflammation; angiogenesis; COX-2; prostate cancer; immunohistochemistry ID EXPRESSION; INFLAMMATION; CARCINOMA; GROWTH; COX-2 AB Chronic inflammation has been associated with resulting in malignancies in prostate cancer patients. In the May 2005 issue of Clinical Cancer Research, a study by Wang et al. demonstrates a relationship between COX-2 expression and the local chronic inflammation within prostate cancer and the increased angiogenesis. Confirming the existence and extent of this relationship is essential in the determination of therapeutic modalities for the prevention and treatment of prostate cancer. C1 NCI, Med Oncol Branch, Bethesda, MD 20892 USA. Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. Virginia Commonwealth Univ, Sch Pharm, Dept Pharmaceut, Richmond, VA USA. RP Figg, WD (reprint author), NCI, Med Oncol Branch, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU Intramural NIH HHS NR 17 TC 4 Z9 4 U1 0 U2 0 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG PY 2005 VL 4 IS 8 BP 813 EP 814 PG 2 WC Oncology SC Oncology GA 022GK UT WOS:000236043200010 PM 16123581 ER PT J AU Smith, NF Acharya, MR Desai, N Figg, WD Sparreboom, A AF Smith, NF Acharya, MR Desai, N Figg, WD Sparreboom, A TI Identification of OATP1B3 as a high-affinity hepatocellular transporter of paclitaxel SO CANCER BIOLOGY & THERAPY LA English DT Article DE OATP1B3; taxanes; paclitaxel; docetaxel; hepatic uptake ID C SLC21A6; MULTIDRUG-RESISTANCE; MAJOR DETERMINANT; P-GLYCOPROTEIN; CYCLOSPORINE-A; HUMAN LIVER; IN-VITRO; POLYPEPTIDE; PHARMACOKINETICS; TAXOL AB Interindividual variability in paclitaxel and docetaxel pharmacokinetics, toxicity and response is extensive, and largely unexplained. We hypothesized that this is due to affinity of taxanes for an uptake transporter that indirectly regulates elimination pathways. Here, we studied accumulation of [H-3] docetaxel and [H-3] paclitaxel in Xenopus laevis oocytes injected with cRNA of the liver-specific organic anion transporting polypeptide (OATP) family members OATP1B1 (OATP2) or OATP1B3 (OATP8). Taxane transport by OATP1B1 expressing oocytes was not significantly different from that by water-injected controls, whereas uptake by OATP1B3 was 2.2-fold higher for docetaxel (p = 0.0007) and 3.3-fold higher for paclitaxel (p < 0.0001). OATP1B3-mediated paclitaxel transport was saturable (Michaelis-Menten constant, 6.79 mu M), time-dependent, and highly sensitive to chemical inhibition. Paclitaxel uptake was not inhibited by ketoconazole or tariquidar. However, uptake was inhibited by the formulation excipient Cremophor (74.4% inhibition, p < 0.0001), cyclosporin A (25.2%, p = 0.005), glycyrrhizic acid (24.6%, p = 0.012), and hyperforin (28.4%, p = 0.003). Consistent with this finding, Cremophor was found to significantly affect the hepatic uptake of paclitaxel in mice. These data suggest that OATP1B3 is a key regulator of hepatic uptake, and may therefore play a role in the variable response to treatment with taxanes. C1 NCI, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, Canc therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Sparreboom, A (reprint author), NCI, Med Oncol Clin Res Unit, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM sparreba@mail.nih.gov RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 28 TC 138 Z9 144 U1 0 U2 17 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG PY 2005 VL 4 IS 8 BP 815 EP 818 PG 4 WC Oncology SC Oncology GA 022GK UT WOS:000236043200011 PM 16210916 ER PT J AU Qu, CF Song, YJ Rizvi, SMA Li, Y Smith, R Perkins, AC Morgenstern, A Brechbiel, M Allen, BJ AF Qu, CF Song, YJ Rizvi, SMA Li, Y Smith, R Perkins, AC Morgenstern, A Brechbiel, M Allen, BJ TI In vivo and in vitro inhibition of pancreatic cancer growth by targeted alpha therapy using Bi-213-CHX.A"-C595 SO CANCER BIOLOGY & THERAPY LA English DT Article DE radioimmunotherapy; alpha particles; pancreatic cancer; cell cluster; MUC-1 mucin; C595 monoclonal antibody ID HUMAN PROSTATE-CANCER; MULTICELL SPHEROIDS; MONOCLONAL-ANTIBODY; OVARIAN-CARCINOMA; MEMBRANE ANTIGEN; RADIOIMMUNOTHERAPY; CELLS; IMMUNOTHERAPY; APOPTOSIS; MODEL AB Purpose: The aim of this study was to investigate the effect of targeted alpha therapy for the control of in vitro pancreatic cancer cell clusters and micrometastatic cancer lesions in vivo. Methods: The expression of tumor-associated antigen MUC-1 on three pancreatic cancer cell clusters and animal xenografts was detected by indirect immmunostaining. Monoclonal antibodies C595 (test) and A2 (non-specific control) were labeled with Bi-213 using the chelator CHX.A '' to form the alpha-immunoconjugate (AIC). Cell clusters were incubated with AIC and examined at 48 h. Apoptosis was documented using the TUNEL assay. In vivo, an antiproliferative effect for tumors was tested at two days post-subcutaneous cell inoculation. Mice were injected with different concentrations of AIC by regional or systemic administration. Changes in tumor progression were assessed by tumor size. Results: MUC-1 is strongly expressed on CFPAC-1, PANC-1 and moderate expression was found CAPAN-1 cell clusters and tumor xenografts. The AICs can target and kill cancer cell clusters (100 mm) in vitro. Some 73-81 % of cells were TUNEL positive cells in the clusters after incubation with AIC. At two days post-cell inoculation in mice, a single local injection of 74 and 148 MBq/kg of AIC causes complete inhibition of tumor growth. Systemic injections of 111, 222 and 333 MBq/kg of AIC cause significant tumor growth delay after 16 weeks, compared with the nonspecific control providing 333 MBq/kg after 16 weeks. Conclusions: CFPAC-1, PANC-1 and CAPAN-1 pancreatic cancer cell clusters and pancreatic tumor xenografts show high expression of the MUC-1 target antigen. Bi-213-C595 can specifically target and regress pancreatic cancer cell clusters in vitro, and delay and inhibit tumor growth in vivo. Bi-213-C595 may be a useful agent for the treatment of micrometastatic pancreatic cancer with overexpression of MUC1 antigen in post-surgical patients with minimal residual disease. C1 St George Hosp, Ctr Expt Radiat Oncol, Canc Care Ctr, Kogarah, NSW 2217, Australia. Univ New S Wales, Kensington, NSW 2033, Australia. Royal N Shore Hosp, Dept Surg, St Leonards, NSW, Australia. Univ Sydney, Sydney, NSW 2006, Australia. Queens Med Ctr, Sch Med, Dept Med Phys, Nottingham NG7 2UH, England. Commiss European Communities, Joint Res Ctr, European Inst Transuranium Elements, D-7500 Karlsruhe, Germany. NIH, Bethesda, MD 20892 USA. RP Allen, BJ (reprint author), St George Hosp, Ctr Expt Radiat Oncol, Canc Care Ctr, Gray St Kogarah, Kogarah, NSW 2217, Australia. EM allenba@sesahs.nsw.gov.au NR 28 TC 16 Z9 16 U1 1 U2 5 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG PY 2005 VL 4 IS 8 BP 848 EP 853 PG 6 WC Oncology SC Oncology GA 022GK UT WOS:000236043200018 PM 16082185 ER PT J AU Shi, MQ Hao, SG Su, LP Zhang, XS Yuan, JY Guo, XL Zheng, CY Xiang, J AF Shi, MQ Hao, SG Su, LP Zhang, XS Yuan, JY Guo, XL Zheng, CY Xiang, J TI Vaccine of engineered tumor cells secreting stromal cell-derived factor-1 induces T-cell dependent antitumor responses SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Article DE engineered tumor cells; SDF-1; T-cell-dependent; antitumor responses ID GENE-TRANSFER; INFILTRATING LYMPHOCYTES; ESTABLISHED TUMORS; PROGNOSTIC-FACTOR; NECROSIS-FACTOR; CXC CHEMOKINES; BREAST-CANCER; MELANOMA; IMMUNITY; CHEMOATTRACTANT AB The CXC chemokine SDF-1 has been characterized as a T-cell chemoattractant both in vitro and in vivo. To determine whether SDF-1 expression within tumors can influence tumor growth, we transfected an expression vector pCl-SDF-1 for SDF-1 into J558 myeloma cells and tested their ability to form tumors in BALE/c. Production of biologically active SDF-1 (1.2 ng/mL) was detected in the culture supernatants of cells transfected with the expression vector pCl-SDF-1. J558 cells gave rise to a 100% tumor incidence, whereas SDF-1-expressing J558/SDF-1 tumors invariably regressed in BALB/c mice and became infiltrated with CD4(+) and CD8(+) T cells. Regression of the J558/SDF-1 tumors was dependent on both CD4+ and CD8+ T-cells. Our data also indicate that TIT cells containing both CD4+ and CD8+ T-cells within J558/SDF-1 tumors express the SDF-1 receptor CXCR4, and that SDF-1 specifically chemoattracts these cells in vitro. Furthermore, immunization of mice with engineered J558/SDF-1 cells elicited the most potent protective immunity against 0.5 x 10(6) cells J558 tumor challenge in vivo, compared to immunization with the J558 alone, and this antitumor immunity mediated by J558/SDF-1 tumor cell vaccination in vivo appeared to be dependent on CD8(+) CTL. Thus, SDF-1 has natural adjuvant activities that may augment antitumor responses through their effects on T-cells and thereby could be important in gene transfer immunotherapies for some cancers. C1 Univ Saskatchewan, Res Unit, Saskatchewan Canc Agcy, Dept Oncol, Saskatoon, SK S7N 4H4, Canada. Univ Saskatchewan, Dept Geog, Saskatoon, SK, Canada. NIDR, Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. RP Xiang, J (reprint author), Univ Saskatchewan, Res Unit, Saskatchewan Canc Agcy, Dept Oncol, 20 Campus Dr, Saskatoon, SK S7N 4H4, Canada. EM JXiang@SCF.SK.CA RI Shi, Meiqing/K-3665-2016 NR 38 TC 7 Z9 10 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD AUG PY 2005 VL 20 IS 4 BP 401 EP 409 DI 10.1089/cbr.2005.20.401 PG 9 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 958ZU UT WOS:000231487500004 PM 16114988 ER PT J AU Bonner, MR Nie, J Han, DW Vena, JE Rogerson, P Muti, P Trevisan, M Edge, SB Freudenheim, JL AF Bonner, MR Nie, J Han, DW Vena, JE Rogerson, P Muti, P Trevisan, M Edge, SB Freudenheim, JL TI Secondhand smoke exposure in early life and the risk of breast cancer among never smokers (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE breast cancer; secondhand smoke; passive smoking ID ENVIRONMENTAL TOBACCO-SMOKE; POLYCYCLIC AROMATIC-HYDROCARBONS; CIGARETTE-SMOKING; PASSIVE SMOKING; LUNG-CANCER; ACTIVE SMOKING; WOMEN; CARCINOGENESIS; ASSOCIATION; POPULATION AB Evidence is increasing that some early life exposures affect breast cancer risk. Exposure to secondhand smoke (SHS) during childhood may be one such exposure. As part of the WEB Study (Western New York Exposures and Breast Cancer Study), we conducted a population-based, case-control study with 1166 women aged 35 to 79 diagnosed with histologically confirmed, primary, incident breast cancer. Controls (n = 2105) were randomly selected from the Department of Motor Vehicles driver's license list (<= age 65) and the Center for Medicare & Medicaid Services rolls (> age 65). Participants were queried regarding household and workplace SHS exposure. Person-years of lifetime cumulative SHS exposure were computed as well as cumulative exposure up to 21 years of age. Unconditional logistic regression adjusting for potential confounders was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). Lifetime cumulative exposure to household SHS was not associated with an increase in breast cancer risk for premenopausal (OR = 1.17, 95% CI = 0.54-2.56) or postmenopausal (OR = 1.29; 95% CI = 0.82-2.01) women. Neither was risk increased among women exposed to SHS before the age of 21 or at the time of birth, menarche, or a women's first birth. In this study, exposure to SHS either in adult or early life does not appear to be associated with the risk of breast cancer. C1 SUNY Buffalo, Sch Publ Hlth & Hlth Profess, Dept Social & Prevent Med, Buffalo, NY 14214 USA. Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. SUNY Buffalo, Dept Geog, Buffalo, NY 14214 USA. Roswell Pk Canc Inst, Dept Surg, Buffalo, NY 14263 USA. RP Bonner, MR (reprint author), NCI, Occupat & Environm Epidemiol Branch, 6120 Execut Blvd,EPS 8121,MSC 7240, Bethesda, MD 20892 USA. EM bonnerm@mail.nih.gov RI Han, Daikwon/D-2950-2016 OI Han, Daikwon/0000-0001-7509-015X FU NCI NIH HHS [5R21 CA 87138-02, CA 09051] NR 47 TC 18 Z9 20 U1 1 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD AUG PY 2005 VL 16 IS 6 BP 683 EP 689 DI 10.1007/s10552-005-1906-x PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 950GC UT WOS:000230844600008 PM 16049807 ER PT J AU Das, B Feuer, EJ Mariotto, A AF Das, B Feuer, EJ Mariotto, A TI Geographic association between mammography use and mortality reduction in the US SO CANCER CAUSES & CONTROL LA English DT Article DE mammography; breast cancer; mortality; geographical association ID BREAST-CANCER AB Background: Breast cancer mortality rates in women have been declining at the same time as breast cancer incidence rates, mammography rates and use of effective adjuvant therapy have been increasing. The objective of this study was to examine population data on breast cancer screening and breast cancer mortality to see if there is any geographic association between mammographic screening and breast cancer mortality reduction in the US, after adjusting for therapy use. Methods: Regression analysis of the estimated annual percent reduction of breast cancer mortality was performed on mammography use from the Behavioral Risk Factors Surveillance System (BRFSS) at state level. A secondary regression analysis on the SEER-11 region, at an aggregated Health Services Area (HSA) level, was carried out to adjust for use of adjuvant therapy. The annual percent change in the incidence of early stage cancer, calculated from SEER cancer data was used as a surrogate for mammography use. Adjuvant therapy use was estimated from SEER data and adjusted using the Patterns of Care data. Results: All the analyses showed a small but significant negative correlation between mammography usage and mortality reduction (correlation of -0.285, p-value 0.045) in breast cancer (state level) and change in 'early' stage breast cancer and mortality reduction (at HSA level) unadjusted (correlation of -0.307, p-value 0.065) and adjusted (partial correlation of -0.337, p-value 0.044) for adjuvant therapy use. Discussion: The results of the two analyses appear to show a moderate effect of mammography usage on decreasing breast cancer mortality in the US, which seems to support the conclusions of randomized mammographic screening trials. While randomized controlled trials are certainly the gold standard in appraising the efficacy of new screening or treatment modalities, such trials are conducted under standardized conditions and do not always reflect the effect of these interventions at population level. This paper attempts to examine population level effects through ecologic analyses. Results, however, need to be interpreted cautiously owing to the limitations and biases inherent in such analyses. C1 NCI, Stat Res & Applicat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Das, B (reprint author), NCI, Stat Res & Applicat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM dasba@mail.nih.gov NR 20 TC 15 Z9 15 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD AUG PY 2005 VL 16 IS 6 BP 691 EP 699 DI 10.1007/s10552-005-1991-x PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 950GC UT WOS:000230844600009 PM 16049808 ER PT J AU Cronin, KA Yu, BB Krapcho, M Miglioretti, DL Fay, MP Izmirlian, G Ballard-Barbash, R Geller, BM Feuer, EJ AF Cronin, KA Yu, BB Krapcho, M Miglioretti, DL Fay, MP Izmirlian, G Ballard-Barbash, R Geller, BM Feuer, EJ TI Modeling the dissemination of mammography in the United States SO CANCER CAUSES & CONTROL LA English DT Article DE mammography; breast cancer screening; population-based sample; dissemination ID CANCER; DISEASE AB Objective: This paper presents a methodology for piecing together disparate data sources to obtain a comprehensive model for the use of mammography screening in the US population for the years 1975 - 2000. Methods: Two aspects of mammography usage, the age that a woman receives her first mammography and the interval between subsequent mammograms, are modeled separately. The initial dissemination of mammography is based on cross-sectional self report data from national surveys and the interval length between screening exams is fit using longitudinal mammography registry data. Results: The two aspects of mammography usage are combined to simulate screening histories for individual women that are representative of the US population. Simulated mammography patterns for the years 1994 - 2000 were found to be similar to observed screening patterns from the state level mammography registry for Vermont. Conclusions: The model presented gives insight into screening practices over time and provides an alternative public health measure for screening usage in the US population. The comprehensive description of mammography use from its introduction represents an important first step to understanding the impact of mammography on breast cancer incidence and mortality. C1 NCI, Stat Res & Applicat Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Informat Management Seerv Inc, Silver Spring, MD USA. Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ Vermont, Off Hlth Promot Res, Burlington, VT USA. RP Cronin, KA (reprint author), NCI, Appl Res Branch, 6116 Execut Blvd,Room 504,MSC 8317, Bethesda, MD 20892 USA. EM cronink@mail.nih.gov RI Fay, Michael/A-2974-2008; OI Fay, Michael P./0000-0002-8643-9625 NR 16 TC 30 Z9 30 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD AUG PY 2005 VL 16 IS 6 BP 701 EP 712 DI 10.1007/s10552-005-0693-8 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 950GC UT WOS:000230844600010 PM 16049809 ER PT J AU Mannisto, S Dixon, LB Balder, HF Virtanen, MJ Krogh, V Khani, BR Berrino, F van den Brandt, PA Hartman, AM Pietinen, P Tan, F Wolk, A Goldbohm, RA AF Mannisto, S Dixon, LB Balder, HF Virtanen, MJ Krogh, V Khani, BR Berrino, F van den Brandt, PA Hartman, AM Pietinen, P Tan, F Wolk, A Goldbohm, RA TI Dietary patterns and breast cancer risk: results from three cohort studies in the DIETSCAN project SO CANCER CAUSES & CONTROL LA English DT Article DE breast cancer; diet; dietary pattern; factor analysis; principal component analysis ID FOOD-FREQUENCY QUESTIONNAIRE; TYPE-2 DIABETES-MELLITUS; SCALE PROSPECTIVE COHORT; CORONARY-HEART-DISEASE; POOLED ANALYSIS; NUTRITIONAL EPIDEMIOLOGY; COLORECTAL-CANCER; SWEDISH WOMEN; OLIVE OIL; FAT AB Objective: Only a few consistent findings on individual foods or nutrients that influence breast cancer risk have emerged thus far. Since people do not consume individual foods but certain combinations of them, the analysis of dietary patterns may offer an additional aspect for assessing associations between diet and diseases such as breast cancer. It is also important to examine whether the relationships between dietary patterns and breast cancer risk are consistent across populations. Methods: We examined the risk of breast cancer with two dietary patterns, identified as "Vegetables" (VEG) and "Pork, Processed Meat, Potatoes" (PPP), common to all cohorts of the DIETSCAN project. During 7 to 13 years of follow-up, three of the cohorts - the Netherlands Cohort Study on diet and cancer (NLCS), the Swedish Mammography Cohort (SMC), and the Ormoni e Dieta nella Eziologia dei Tumori (Italy-ORDET) - provided data on 3271 breast cancer cases with complete information on their baseline diet measured by a validated food frequency questionnaire. Results: After adjustment for potential confounders, VEG was not associated with the risk of breast cancer across all cohorts. PPP was also not associated with the risk of breast cancer in SMC and ORDET, but a high PPP score tended to be inversely associated with breast cancer in the NLCS study (RR = 0.69; 95% CI, 0.52-0.92, highest versus lowest quartile). PPP differed in one aspect between the cohorts: butter loaded positively on the pattern in all cohorts except NLCS, in which butter loaded negatively and appeared to be substituted by low-fat margarine loading positively. Conclusion: In general, the dietary patterns showed consistent results across the three cohorts except for the possible protective effect of PPP in the NLCS cohort, which could be explained by a difference in that pattern for NLCS. The results supported the suggestion derived from traditional epidemiology that relatively recent diet may not have an important role in the etiology of breast cancer. C1 Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, FIN-00300 Helsinki, Finland. NYU, Dept Nutr Food Studies & Publ Hlth, New York, NY USA. TNO Nutr & Food Res, Dept Nutr Epidemiol, Zeist, Netherlands. Ist Nazl Studio & Cura Tumori, Epidemiol Unit, I-20133 Milan, Italy. Karolinska Inst, Inst Environm Epidemiol, Stockholm, Sweden. Maastricht Univ, Dept Epidemiol, Maastricht, Netherlands. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Maastricht Univ, Dept Methodol & Stat, Maastricht, Netherlands. RP Mannisto, S (reprint author), Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Mannerheimintie 166, FIN-00300 Helsinki, Finland. EM satu.mannisto@ktl.fi RI Krogh, Vittorio/K-2628-2016; OI Krogh, Vittorio/0000-0003-0122-8624; Mannisto, Satu/0000-0002-8668-3046 NR 52 TC 40 Z9 41 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD AUG PY 2005 VL 16 IS 6 BP 725 EP 733 DI 10.1007/s10552-005-1763-7 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 950GC UT WOS:000230844600012 PM 16049811 ER PT J AU Horak, CE Steeg, PS AF Horak, CE Steeg, PS TI Metastasis gets site specific SO CANCER CELL LA English DT Editorial Material ID BREAST-CANCER METASTASIS; TUMOR; CELLS; LUNG AB Organ-specific homing and colonization of cancer cells are important and interesting features of metastasis. Molecular programs that contribute to this tropism may be elucidated through gene expression profiling with DNA microarrays. Using experimentally derived breast cancer cells that home specifically to bone or to lung, several investigators have concluded that distinct alterations in gene expression underlie metastasis to these sites. Minn et al. (2005) report a set of genes involved in lung-specific metastasis of breast cancer; the authors have determined the functional contribution of several genes to the metastatic cascade, as well as the relevance of these genes to human disease. C1 NCI, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Horak, CE (reprint author), NCI, Ctr Canc Res, Mol Pharmacol Lab, Bldg 37,Room 112, Bethesda, MD 20892 USA. EM steegp@mail.nih.gov NR 10 TC 24 Z9 25 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG PY 2005 VL 8 IS 2 BP 93 EP 95 DI 10.1016/j.ccr.2005.07.013 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 956WG UT WOS:000231330100003 PM 16098461 ER PT J AU Isaacs, JS Jung, YJ Mole, DR Lee, S Torres-Cabala, C Chung, YL Merino, M Trepel, J Zbar, B Toro, J Ratcliffe, PJ Linehan, WM Neckers, L AF Isaacs, JS Jung, YJ Mole, DR Lee, S Torres-Cabala, C Chung, YL Merino, M Trepel, J Zbar, B Toro, J Ratcliffe, PJ Linehan, WM Neckers, L TI HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability SO CANCER CELL LA English DT Article ID HYPOXIA-INDUCIBLE FACTOR; HIPPEL-LINDAU PROTEIN; NUCLEAR TRANSLOCATOR ARNT; TUMOR-SUPPRESSOR PROTEIN; CELL-CANCER; HEREDITARY LEIOMYOMATOSIS; FACTOR 1-ALPHA; FAMILIAL PHEOCHROMOCYTOMA; SUCCINATE-DEHYDROGENASE; PROLYL HYDROXYLATION AB Individuals with hemizygous germline fumarate hydratase (FH) mutations are predisposed to renal cancer. These tumors predominantly exhibit functional inactivation of the remaining wild-type allele, implicating FH inactivation as a tumor-promoting event. Hypoxia-inducible factors are expressed in many cancers and are increased in clear cell renal carcinomas. Under normoxia, the HIFs are labile due to VHL-dependent proteasomal degradation, but stabilization occurs under hypoxia due to inactivation of HIF prolyl hydroxylase (HPH), which prevents HIF hydroxylation and VHL recognition. We demonstrate that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Further, we show that fumarate acts as a competitive inhibitor of HPH. These data delineate a novel fumarate-dependent pathway for regulating HPH activity and HIF protein levels. C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NCI, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NCI, Immunobiol Lab, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Bethesda, MD 20892 USA. Pusan Natl Univ, Coll Pharm, Lab Biomed Chem, Pusan 609735, South Korea. Univ Oxford, Oxford OX3 7BN, England. St George Hosp, Sch Med, Dept Basic Med Sci, Canc Res UK Biomed Magnet Resonance Res Grp, London SW17 0RE, England. RP Neckers, L (reprint author), Med Univ S Carolina, Dept Cell & Mol Pharmacol, Hollings Canc Ctr, 86 Jonathan Lucas St,POB 250955, Charleston, SC 29425 USA. EM len@helix.nih.gov OI Ratcliffe, Peter/0000-0002-2853-806X; Mole, David/0000-0002-0984-300X NR 62 TC 459 Z9 467 U1 3 U2 14 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG PY 2005 VL 8 IS 2 BP 143 EP 153 DI 10.1016/j.ccr.2005.06.017 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 956WG UT WOS:000231330100009 PM 16098467 ER PT J AU Hollingshead, M Alley, M Burger, AM Borgel, S Pacula-Cox, C Fiebig, HH Sausville, EA AF Hollingshead, M Alley, M Burger, AM Borgel, S Pacula-Cox, C Fiebig, HH Sausville, EA TI In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE heat shock protein 90; ansamycin; xenograft ID TUMOR-CELL-LINES; ROUS-SARCOMA VIRUS; RAT-KIDNEY CELLS; CRYSTAL-STRUCTURE; HSP90; INHIBITORS; COMPLEX; KINASE; GROWTH; AGENT AB Purpose: To describe the preclinical basis for further development of 17-dimethyl aminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG, NSC 707545). Methods: In vitro proliferation assays, and in vivo model studies in metastatic pancreatic carcinoma and subcutaneous xenograft melanoma and small-cell lung carcinoma models. Results: 17-DMAG emerged from screening studies as a potent geldanamycin analog, with the average concentration inhibiting the growth of the NCI anticancer cell line drug screen by 50% being 0.053 mu M. "Head to head" comparison with 17-allylamino-17-demethoxygeldanamycin (17-AAG, NSC 330507) revealed 17-DMAG to possess potent activity against certain cell types, e.g., MDA-MB-231 breast carcinoma and HL60-TB leukemia which were relatively insensitive to 17-AAG. Evidence of oral bioavailability of 17-DMAG in a saline-based formulation prompted more detailed examination of its antitumor efficacy in vivo. 17-DMAG inhibited the growth of the AsPC-1 pancreatic carcinoma xenografts growing as intrahepatic metastases at doses of 6.7-10 mg/kg twice daily for 5 days administered orally under conditions where 17-AAG was without activity. 17-DMAG in an aqueous vehicle at 7.5-15 mg/kg per day for 3 days on days 1-3, 8-10 and 13-17, or 1-5 and 8-12 showed evidence of antitumor activity by the parenteral and oral routes in the MEXF 276 and MEXF 989 melanomas and by the parenteral route in the LXFA 629 and LXFS 650 adenocarcinoma and small-cell carcinoma models. The latter activity was comparable to the historical activity of 17-AAG. Conclusions: Taken together, the in vivo activity of 17-DMAG supports the further development of this water-soluble and potentially orally administrable geldanamycin congener. C1 Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. NCI, Dev Therapeut Program, Div Canc Treatment & Diagnosis, Bethesda, MD 20892 USA. Inst Expt Oncol, D-79108 Freiburg, Germany. SAIC Frederick Inc, Frederick, MD 21702 USA. RP Sausville, EA (reprint author), Univ Maryland, Greenebaum Canc Ctr, 22 S Greene St, Baltimore, MD 21201 USA. EM esausville@umm.edu FU NCI NIH HHS [N01-CM-270, N01-CM-97017, N01-CO 12400] NR 33 TC 114 Z9 118 U1 2 U2 5 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 AUG PY 2005 VL 56 IS 2 BP 115 EP 125 DI 10.1007/s00280-004-0939-2 PG 11 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 933GA UT WOS:000229615700001 PM 15791458 ER PT J AU Smith, V Sausville, EA Camalier, RF Fiebig, HH Burger, AM AF Smith, V Sausville, EA Camalier, RF Fiebig, HH Burger, AM TI Comparison of 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17DMAG) and 17-allylamino-17-demethoxygeldanamycin (17AAG) in vitro: effects on Hsp90 and client proteins in melanoma models SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE 17DMAG; 17AAG; Hsp90 modulation; melanoma ID CANCER-CELLS; MOLECULAR CHAPERONE; SIGNAL-TRANSDUCTION; RAS MUTATIONS; GELDANAMYCIN; XENOGRAFTS; INHIBITION; EXPRESSION; APOPTOSIS; BRAF AB The heat shock protein Hsp90 is a potential target for drug discovery of novel anticancer agents. By affecting this protein, several cell signaling pathways may be simultaneously modulated. The geldanamycin analog 17AAG has been shown to inhibit Hsp90 and associated proteins. Its clinical use, however, is hampered by poor solubility and thus, difficulties in formulation. Therefore, a water-soluble derivative was desirable and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17DMAG) is such a derivative. Studies were carried out in order to evaluate the activity and molecular mechanism(s) of 17DMAG in comparison with those of 17-allylamino-demethoxygeldanamycin (17AAG). 17DMAG was found to be more potent than 17AAG in a panel of 64 different patient-derived tumor explants studied in vitro in the clonogenic assay. The tumor types that responded best included mammary cancers (six of eight), head and neck cancers (two of two), sarcomas (four of four), pancreas carcinoma (two of three), colon tumors (four of eight for 17AAG and six of eight for 17DMAG), and melanoma (two of seven). Bioinformatic comparisons suggested that, while 17AAG and 17DMAG are likely to share the same mode(s) of action, there was very little similarity with standard anticancer agents. Using three permanent human melanoma cell lines with differing sensitivities to 17AAG and 17DMAG (MEXF 276L, MEXF 462NL and MEXF 514L), we found that Hsp90 protein was reduced following treatment at a concentration associated with total growth inhibition. The latter occurred in MEXF 276L cells only, which are most sensitive to both compounds. The depletion of Hsp90 was more pronounced in cells exposed to 17DMAG than in those treated with 17AAG. The reduction in Hsp90 was associated with the expression of erbB2 and erbB3 in MEXF 276L, while erbB2 and erbB3 were absent in the more resistant MEXF 462NL and MEXF 514L cells. Levels of known Hsp90 client proteins such as phosphorylated AKT followed by AKT, cyclin D1 preceding cdk4, and craf-1 declined as a result of drug treatment in all three melanoma cell lines. However, the duration of drug exposure needed to achieve these effects was variable. All cell lines showed increased expression of Hsp70 and activated cleavage of PARP. No change in PI3K expression was observed and all melanoma cells were found to harbor the activating V599E BRAF kinase mutation. The results of our in vitro studies are consistent with both 17AAG and 17DMAG acting via the same molecular mechanism, i.e. by modulating Hsp90 function. Since 17DMAG can be formulated in physiological aqueous solutions, the data reported here strongly support the development of 17DMAG as a more pharmaceutically practicable congener of 17AAG. C1 Univ Freiburg, Tumor Biol Ctr, D-79106 Freiburg, Germany. NCI, Dev Therapeut Program, DCTD, Bethesda, MD 20892 USA. RP Sausville, EA (reprint author), Univ Maryland Med, Univ Maryland Greenebaum Canc Ctr, 22 S Greene St, Baltimore, MD 21201 USA. EM esausville@umm.edu FU NCI NIH HHS [N01-CM-27026] NR 34 TC 92 Z9 95 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD AUG PY 2005 VL 56 IS 2 BP 126 EP 137 DI 10.1007/s00280-004-0947-2 PG 12 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 933GA UT WOS:000229615700002 PM 15841378 ER PT J AU Morisaki, K Robey, R Ozvegy-Laczka, C Honjo, Y Polgar, O Steadman, K Sarkadi, B Bates, SE AF Morisaki, K Robey, R Ozvegy-Laczka, C Honjo, Y Polgar, O Steadman, K Sarkadi, B Bates, SE TI Single nucleotide polymorphisms modify the transporter activity of ABCG2 SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE nucleotides; polymorphism; ABCG2 ID CANCER RESISTANCE PROTEIN; P-GLYCOPROTEIN EXPRESSION; MULTIDRUG-RESISTANCE; SUBSTRATE-SPECIFICITY; DIETARY-CHOLESTEROL; ACQUIRED MUTATIONS; HALF-TRANSPORTER; DRUG-RESISTANCE; FUMITREMORGIN C; ATPASE ACTIVITY AB Single nucleotide polymorphism (SNP) analyses of the ABCG2 gene have revealed three nonsynonymous SNPs resulting in the amino acid changes at V12M, Q141K and D620N. To determine whether the SNPs have an effect on drug transport, human embryonic kidney cells (HEK-293) were stably transfected with full length ABCG2 coding wild-type or SNP variants of ABCG2. In 4-day cytotoxicity assays with mitoxantrone, topotecan, SN-38 or diflomotecan, cells transfected with wild-type R482 ABCG2 showed IC50 values up to 1.2-fold to 5-fold higher than cells expressing comparable levels of Q141K ABCG2, suggesting that the Q141K SNP affects drug transport. FTC-inhibitable mitoxantrone efflux normalized to ABCG2 surface expression as assayed by the anti-ABCG2 antibody 5D3 was significantly lower in cells transfected with Q141K ABCG2 than in those transfected with wild-type R482 ABCG2 (P=0.0048). Values for V12M and D620N ABCG2 were comparable to those for wild-type R482 ABCG2. The vanadate-sensitive ATPase activity of ABCG2 was assayed in Sf9 insect cells infected with wild-type or SNP variants of ABCG2. Basal ATPase activity in cells transfected with Q141K ABCG2 was 1.8-fold lower than in cells transfected with wild-type ABCG2, but was comparable among cells expressing wild-type, V12M or D620N ABCG2. Confocal studies of ABCG2 localization revealed higher intracellular staining in the Q141K transfectants than in cells transfected with wild-type or V12M ABCG2. Decreased transport of Hoechst 33342 was observed in Sf9 cells expressing V12M ABCG2; however, this was not true in HEK-293 cells expressing V12M ABCG2. These results suggest that the Q141K SNP affects the transport efficiency of ABCG2 and may result in altered pharmacokinetics or drug-resistance profiles in clinical oncology. C1 NCI, Canc Therapeut Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Hungarian Acad Sci, Inst Hematol & Immunol, Natl Med Ctr, Membrane Res Grp, H-1113 Budapest, Hungary. RP Bates, SE (reprint author), NCI, Canc Therapeut Branch, Canc Res Ctr, NIH, 9000 Rockville Pike,Bldg 10,Rm 12C103, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov RI Sarkadi, Balazs/I-5024-2013; Steadman, Kenneth/J-3883-2013 NR 51 TC 131 Z9 139 U1 0 U2 8 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 AUG PY 2005 VL 56 IS 2 BP 161 EP 172 DI 10.1007/s00280-004-0931-x PG 12 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 933GA UT WOS:000229615700006 PM 15838659 ER PT J AU Reed, GA Peterson, KS Smith, HJ Gray, JC Sullivan, DK Mayo, MS Crowell, JA Hurwitz, A AF Reed, GA Peterson, KS Smith, HJ Gray, JC Sullivan, DK Mayo, MS Crowell, JA Hurwitz, A TI A phase I study of indole-3-carbinol in women: Tolerability and effects SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID DRUG-METABOLIZING-ENZYMES; BREAST-CANCER; DIETARY INDOLES; CRUCIFEROUS VEGETABLES; MAMMARY CARCINOGENESIS; ESTROGEN METABOLISM; BETA-NAPHTHOFLAVONE; CERVICAL-CANCER; DT-DIAPHORASE; RAINBOW-TROUT AB We completed a phase I trial of indole-3-carbinol (13C) in 17 women (I postmenopausal and 16 premenopausal) from a high-risk breast cancer cohort. After a 4-week placebo run-in period, subjects ingested 400 mg 13C daily for 4 weeks followed by a 4-week period of 800 mg 13C daily. These chronic doses were tolerated well by all subjects. Hormonal variables were measured near the end of the placebo and dosing periods, including determination of the urinary 2-hydroxyestrone/16 alpha-hydroxyestrone ratio. Measurements were made during the follicular phase for premenopausal women. Serum estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, and sex hormone binding globulin showed no significant changes in response to 13C. Caffeine was used to probe for cytochrome P450 1A2 (CYP1A2), N-acetyltransferase-2 (NAT-2), and xanthine oxidase. Comparing the results from the placebo and the 800 mg daily dose period, CYP1A2 was elevated by 13C in 94% of the subjects, with a mean increase of 4.1-fold. In subjects with high NAT-2 activities, these were decreased to 11% by 13C administration but not altered if NAT-2 activity was initially low. Xanthine oxidase was not affected. Lymphocyte glutathione S-transferase activity was increased by 69% in response to 13C. The apparent induction of CYP1A2 was mirrored by a 66% increase in the urinary 2-hydroxyestrone/16 alpha-hydroxyestrone ratio in response to 13C. The maximal increase was observed with the 400 mg daily dose of 13C, with no further increase found at 800 mg daily. If the ratio of hydroxylated estrone metabolites is a biomarker for chemoprevention, as suggested, then 400 mg 13C daily will elicit a maximal protective effect. C1 Univ Kansas, Med Ctr, Dept Med, Kansas City, KS 66160 USA. Univ Kansas, Med Ctr, Dept Pharmacol, Kansas City, KS 66160 USA. Univ Kansas, Med Ctr, Dept Therapeut, Kansas City, KS 66160 USA. Univ Kansas, Med Ctr, Dept Nutr & Dietet, Kansas City, KS 66160 USA. Univ Kansas, Med Ctr, Ctr Biostat & Adv Informat, Kansas City, KS 66160 USA. Univ Kansas, Med Ctr, Kansas Mason Canc Res Ctr, Kansas City, KS 66160 USA. NCI, Div Chemoprevent, Bethesda, MD 20892 USA. RP Reed, GA (reprint author), Univ Kansas, Med Ctr, Dept Med, 3901 Rainbow Blvd,MS 1018, Kansas City, KS 66160 USA. EM greed@kumc.edu RI Mayo, Matthew/E-3774-2015 FU NCI NIH HHS [N01-CN55121] NR 46 TC 72 Z9 78 U1 0 U2 2 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 AUG PY 2005 VL 14 IS 8 BP 1953 EP 1960 DI 10.1158/1055-9965.EPI-05-0121 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 954ZZ UT WOS:000231195600021 PM 16103443 ER PT J AU Purdue, MP From, L Armstrong, BK Kricker, A Gallagher, RP McLaughlin, JR Klar, NS Marrett, LD AF Purdue, MP From, L Armstrong, BK Kricker, A Gallagher, RP McLaughlin, JR Klar, NS Marrett, LD CA Genes Env and Melanoma Study Grp TI Etiologic and other factors predicting nevus-associated cutaneous malignant melanoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SITE-SPECIFIC RISK; MELANOCYTIC NEVI; SUN EXPOSURE; WESTERN-AUSTRALIA; SOLAR KERATOSES; PRECURSORS; MARKERS; WOMEN AB Cutaneous malignant melanomas with histologic evidence of an associated nevus (N+) may have a different risk factor profile from that of melanomas without it (N-). To address this question, a case-only analysis of 932 people with cutaneous malignant melanoma was done to identify etiologic and other factors associated with N+ melanoma. Evidence of an associated nevus was found in 36% of melanomas. N+ melanomas were thinner (P-trend = 0.0009) and more likely to be of the superficial spreading type than other types of melanoma. Subjects with N+ melanomas were younger (P-trend < 0.0001) and reported a higher nevus density on their skin than subjects with N- melanomas [odds ratio (OR), 3.1; 95% confidence interval (CI), 1.6-6.0, for high nevus density versus no nevi]. Indicators of high accumulated sun exposure were less prevalent among subjects with N+ melanomas (OR, 0.3; 95% CI, 0.2-0.4, for melanoma location on the head and neck versus location on trunk; OR, 0.2; 95% Cl, 0.1-0.4, for severe solar elastosis adjacent to the melanoma versus no elastosis; OR, 0.2; 95% Cl, 0.1-0.4, for lentigo maligna melanoma subtype versus superficial spreading subtype). With the exception of solar elastosis and age, all of the aforementioned variables remained significantly associated with N+ melanomas in multivariate analyses. No associations with self-reported measures of sun exposure, sunburn, or pigmentation phenotype were apparent. Our findings provide some support for the hypothesis of etiologically separate pathways for melanoma, with N+ melanomas appearing less likely to develop in the presence of characteristics suggesting high accumulated sun exposure than N- melanomas. However, it is possible that high UV exposure causes involution of nevi, thus reducing the density of nevi in exposed skin and thereby the probability of N+ melanoma. C1 Canc Care Ontario, Div Prevent Oncol, Toronto, ON, Canada. Sunnybrook & Womens Coll, Hlth Sci Ctr, RK Schachter Dermatol Ctr, Toronto, ON, Canada. Univ Sydney, Sch Publ Hlth, Sydney, NSW 2006, Australia. British Columbia Canc Agcy, Canc Control Res Program, Vancouver, BC V5Z 4E6, Canada. Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. RP Purdue, MP (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, 6120 Execut Blvd,EPS 8111, Rockville, MD 20852 USA. EM purduem@mail.nih.gov RI McLaughlin, John/E-4577-2013; Armstrong, Bruce/K-9464-2015; Purdue, Mark/C-9228-2016 OI Armstrong, Bruce/0000-0001-8940-7525; Purdue, Mark/0000-0003-1177-3108 FU NCI NIH HHS [CA103394, U01 CA083180] NR 38 TC 31 Z9 31 U1 1 U2 2 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 AUG PY 2005 VL 14 IS 8 BP 2015 EP 2022 DI 10.1158/1055-9965.EPI-05-0097 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 954ZZ UT WOS:000231195600032 PM 16103454 ER PT J AU Sinha, R Kulldorff, M Gunter, MJ Strickland, P Rothman, N AF Sinha, R Kulldorff, M Gunter, MJ Strickland, P Rothman, N TI Dietary benzo[a]pyrene intake and risk of colorectal adenoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; HETEROCYCLIC AMINE CONTENT; MICE FED BENZO(A)PYRENE; MEAT CONSUMPTION; VARYING DEGREES; COOKING METHOD; FRIED FOODS; DNA ADDUCTS; WELL-DONE; RED MEAT AB We carried out a clinic-based case-control study specifically designed to address the hypothesis that dietary intake of polycyclic aromatic hydrocarbons (PAH) is associated with colorectal adenoma risk. We developed a food frequency questionnaire with detailed questions on meat-cooking methods and doneness levels and a benzo[a]pyrene (BaP) database (as a surrogate for total carcinogenic PAHs) based on the collection and analysis of a wide range of food samples. We estimated BaP intake derived from meat and from all foods to test its relationship with risk of colorectal adenomas. The median (10th and 90th percentiles) BaP intake in controls was 5 ng/d (0.2 and 66 ng/d) estimated from meat and 73 ng/d (35 and 140 ng/d) from all foods. In cases, median BaP intake was 17 ng/d (0.5 and 101 ng/d) from meat and 76 ng/d (44 and 163 ng/d) from all foods. Multivariate analysis was carried out on 146 cases and 228 controls. The odds ratios (95% confidence interval) for dietary BaP from meat with the first quintile as the reference group were 1.19 (0.51-2.80) for the second quintile, 1.71 (0.76-3.83) for the third quintile, 2.16 (0.964.86) for the fourth quintile, and 2.82 (1.24-6.43) for the fifth quintile (P-trend = 0.01). Increased risk of colorectal adenomas was more strongly associated with BaP intake estimated from all foods: 2.61 (1.08-6.29) for the second quintile, 4.21 (1.79-9.91) for the third quintile, 2.45 (0.986.12) for the fourth quintile, and 5.60 (2.20-14.20) for the fifth quintile (P-trend = 0.002). This study provides evidence that dietary BaP plays a role in colorectal adenoma etiology. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. Harvard Univ, Pilgrim Hlth Ctr, Boston, MA 02115 USA. Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Sinha, R (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,Room 430,6130 Execut Blvd, Bethesda, MD 20892 USA. EM sinhar@nih.gov RI Kulldorff, Martin/H-4282-2011; Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Kulldorff, Martin/0000-0002-5284-2993 FU PHS HHS [P01-E506052] NR 39 TC 66 Z9 70 U1 1 U2 5 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 AUG PY 2005 VL 14 IS 8 BP 2030 EP 2034 DI 10.1158/1055-9965.EPI-04-0854 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 954ZZ UT WOS:000231195600034 PM 16103456 ER PT J AU Cantwell, MM Forman, MR Albert, PS Snyder, K Schatzkin, A Lanza, E AF Cantwell, MM Forman, MR Albert, PS Snyder, K Schatzkin, A Lanza, E CA Polyp Prevention Trial Study Grp TI No association between fatty acid intake and adenomatous polyp recurrence in the polyp prevention trial SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID COLORECTAL-CANCER C1 NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Canc Prevent Fellowship Program, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Cantwell, MM (reprint author), NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, 6116 Execut Blvd,Suite 702,Room 7218, Bethesda, MD 20892 USA. EM cantwelm@mail.nih.gov NR 6 TC 6 Z9 6 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2005 VL 14 IS 8 BP 2059 EP 2060 DI 10.1158/1055-9965.EPI-05-0165 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 954ZZ UT WOS:000231195600041 PM 16103463 ER PT J AU Sarraf, S Tejada, R Abawi, M Oberst, M Dennis, T Simon, KC Blancato, J AF Sarraf, S Tejada, R Abawi, M Oberst, M Dennis, T Simon, KC Blancato, J TI The human ovarian teratocarcinoma cell line PA-1 demonstrates a single translocation: analysis with fluorescence in situ hybridization, spectral karyotyping, and bacterial artificial chromosome microarray SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID BREAST-CANCER; 20Q13; GENE; AMPLIFICATION; REGION; TUMORS AB Cell lines derived from tumors contain numerous chromosomal aberrations and are the focus of study in tumor evolution. The ovarian teratocarcinoma cell line PA-1 demonstrates a single chromosomal aberration: a reciprocal t(15;20)(p11.2;q11.2). A complete molecular genetic analysis was undertaken to characterize this cell line. The PA-1 cell line was studied with fluorescence in situ hybridization (FISH), spectral karyotyping (SKY), bacterial artificial chromosome (BAC) microarray, and Western blotting. Amplification of 20q is frequently implicated in both breast and ovarian cancer; this region contains a number of oncogenes including MDM2, ZNF217, and the ovarian tumor marker WFDC2 (alias HE4). FISH revealed gene amplification of AIB1 (nowknown as NCOA3) but not STK15 (now known as AURKA). Immunoblot analysis demonstrated 3.6-fold overexpression of the AIB1 protein product, but no elevation of the STK15. BAC cancer gene microarray analysis showed gene amplification of >= 1.20 for five oncogenes. The presence of a consistent single change in PA-1, the t(15;20)(p11.2;q11.2), suggests that the aberration is significant with respect to the transformation status of the cell line. This translocation appears to cause overexpression of AM I (and perhaps other proteins), which may provide an immortalizing effect on this cell line. (c) 2005 Elsevier Inc. All rights reserved. C1 Georgetown Univ, Dept Oncol, Washington, DC 20007 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Florida, Div Genet, Dept Pediat, Gainesville, FL 32610 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Blancato, J (reprint author), Georgetown Univ, Dept Oncol, 3800 Reservoir Rd NW, Washington, DC 20007 USA. EM blancatj@georgetown.edu NR 19 TC 2 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD AUG PY 2005 VL 161 IS 1 BP 63 EP 69 DI 10.1016/j.cancergencyto.2005.01.003 PG 7 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 952ZB UT WOS:000231043900007 PM 16080959 ER PT J AU Tahara, E Tahara, H Kanno, M Naka, K Takeda, Y Matsuzaki, T Yamazaki, R Ishihara, H Yasui, W Barrett, JC Ide, T Tahara, E AF Tahara, E Tahara, H Kanno, M Naka, K Takeda, Y Matsuzaki, T Yamazaki, R Ishihara, H Yasui, W Barrett, JC Ide, T Tahara, E TI G1P3, an interferon inducible gene 6-16, is expressed in gastric cancers and inhibits mitochondrial-mediated apoptosis in gastric cancer cell line TMK-1 cell SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE interferon inducible protein 6-16; G1P3; mitochondria; apoptosis; CIB; survival gene; Bcl-2 ID CALCIUM-BINDING PROTEIN; CYTOFLUOROMETRIC ANALYSIS; HUMAN FIBROBLASTS; CYTOCHROME-C; BCL-2; DEATH; DNA; INTERACTS; RECEPTOR; FAMILY AB Expression of an interferon inducible gene 6-16, G1P3, increases not only in type I interferon-treated cells but also in human senescent fibroblasts. However, the function of 6-16 protein is unknown. Here we report that 6-16 is 34 kDa glycosylated protein and localized at mitochondria. Interestingly, 6-16 is expressed at high levels in gastric cancer cell lines and tissues. One of exceptional gastric cancer cell line, TMK-1, which do not express detectable 6-16, is sensitive to apoptosis induced by cycloheximide (CHX), 5-fluorouracil (5-FU) and serum-deprivation. Ectopic expression of 6-16 gene restored the induction of apoptosis and inhibited caspase-3 activity in TMK-1 cells. Thus 6-16 protein has anti-apoptotic function through inhibiting caspas-3. This anti-apoptotic function is expressed through inhibition of the depolarization of mitochondrial membrane potential and release of cytochrome c. By two-hybrid screening, we found that 6-16 protein interacts with calcium and integrin binding protein, CIB/KIP/Calmyrin (CIB), which interacts with presenilin 2, a protein involved in Alzheimer's disease. These protein interactions possibly play a pivotal role in the regulation of apoptosis, for which further detailed analyses are need. These results overall indicate that 6-16 protein may have function as a cell survival protein by inhibiting mitochondrial-mediated apoptosis. C1 Hiroshima Univ, Grad Sch Biomed Sci, Dept Cellular & Mol Biol, Div Integerated Med Sci,Minamiku Ku, Hiroshima 7348551, Japan. Hiroshima Univ, Grad Sch Biomed Sci, Dept Immunol & Parasitol, Minamiku Ku, Hiroshima 7348551, Japan. Hiroshima Univ, Grad Sch Biomed Sci, Dept Mol Pathol, Minamiku Ku, Hiroshima 7348551, Japan. Yakult Cent Inst Microbiol Res, Kunitachi, Tokyo 1868650, Japan. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. Radiat Effects Res Fdn, Minamiku Ku, Hiroshima 7320815, Japan. RP Tahara, H (reprint author), Hiroshima Univ, Grad Sch Biomed Sci, Dept Cellular & Mol Biol, Div Integerated Med Sci,Minamiku Ku, 1-2-3 Kasumi, Hiroshima 7348551, Japan. EM toshi@hiroshima-u.ac.jp; toshi@hiroshima-u.ac.jp NR 34 TC 50 Z9 52 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD AUG PY 2005 VL 54 IS 8 BP 729 EP 740 DI 10.1007/s00262-004-0645-2 PG 12 WC Oncology; Immunology SC Oncology; Immunology GA 944WX UT WOS:000230462700002 PM 15685448 ER PT J AU Warburton, HE Brady, M Vlatkovic, N Linehan, WM Parsons, K Boyd, MT AF Warburton, HE Brady, M Vlatkovic, N Linehan, WM Parsons, K Boyd, MT TI p53 regulation and function in renal cell carcinoma SO CANCER RESEARCH LA English DT Article ID BINDING PROTEIN; EXPRESSION; RADIATION; PATHWAY; MDM2; ONCOPROTEIN; MUTATIONS; BCL-2; MTBP AB Loss of p53 function is a critical event in tumor evolution. This occurs through a range of molecular events, typically a missense p53 mutation followed by loss of heterozygosity. In many cancers, there is compelling evidence that cells that can compromise p53 function have a selective advantage. The situation in renal cell carcinoma is unclear. It has recently been suggested that p53 function is unusually compromised in renal carcinoma cells by a novel dominant, MDM2/p14(Arf)-independent mechanism. This is hard to reconcile with other recent studies that have identified p53 as an important prognostic indicator. Indeed, one of these latter studies found that the best predictor of poor outcome was the presence of high levels of both p53 (usually indicative of p53 mutation) and MDM2. Thus, it is important that we gain a clearer understanding of the regulation of p53 and the role of MDM2 in renal cell cancer. To address this, we have investigated the transcriptional activity of p53 in a panel of renal cell carcinoma cell lines and the contribution of MDM2 and p14(ARF) to p53 regulation. We have found that p53 is functional in p53 wild-type renal cell carcinoma cells and that this activity is significantly regulated by MDM2 and to a much lesser extent by p14(ARF). Moreover, following induction of DNA damage with UV, the p53 response in these cells is intact. Thus, future studies of renal cell carcinoma that focus on p53 and MDM2 and their role in determining disease outcome will be required to create a better understanding of this notoriously difficult to manage disease. C1 Univ Liverpool, Lab MDM2 P53, Div Surg & Oncol, Liverpool L69 3GA, Merseyside, England. Royal Liverpool Univ Hosp, Dept Urol, Liverpool, Merseyside, England. NCI, Urol Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. RP Boyd, MT (reprint author), Univ Liverpool, Lab MDM2 P53, Div Surg & Oncol, 5th Floor UCD Bldg,Daulby St, Liverpool L69 3GA, Merseyside, England. EM mboyd@liverpool.ac.uk RI Boyd, Mark/I-6792-2012; Vlatkovic, Nikolina/I-3481-2013 OI Boyd, Mark/0000-0002-2336-2106; Vlatkovic, Nikolina/0000-0003-3003-794X NR 24 TC 36 Z9 42 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2005 VL 65 IS 15 BP 6498 EP 6503 DI 10.1158/0008-5472.CAN-05-0017 PG 6 WC Oncology SC Oncology GA 950DN UT WOS:000230837900004 PM 16061625 ER PT J AU Ding, W Tang, Q Espina, V Liotta, LA Mauger, DT Mulder, KM AF Ding, W Tang, Q Espina, V Liotta, LA Mauger, DT Mulder, KM TI A transforming growth factor-beta receptor-interacting protein frequently mutated in human ovarian cancer SO CANCER RESEARCH LA English DT Article ID EPITHELIAL-CELLS; SIGNAL-TRANSDUCTION; LIGHT-CHAIN; ACTIVATION; DYNEIN; MOTOR; TRANSPORT; PATHWAYS; FAMILY; FAST-1 AB Ovarian carcinomas, particularly recurrent forms, are frequently resistant to transforming growth factor-beta (TGF-beta)mediated growth inhibition. However, mutations in the TGF-beta receptor I and receptor II (T beta R-I and T beta R-II) genes have only been reported in a minority of ovarian carcinomas, suggesting that alterations in TGF-beta-signaling components may play an important role in the loss of TGF-beta responsiveness. Using laser-capture microdissection and nested reverse-transcription-PCR, we found that km23, which interacts with the TGF-beta receptor complex, is altered at a high frequency in human ovarian cancer patients. A novel form of km23, missing exon 3 (Delta exon3-km23), was found in 2 of 19 tumor tissues from patients with ovarian cancer. In addition to this alteration, a stop codon mutation (TAA -> CAC) was detected in two patients. This alteration results in an elongated protein, encoding 107-amino-acid residues (Delta 107km23), instead of the wild-type 96-amino-acid form of km23. Furthermore, five missense mutations (T38I, S55G, T56S, I89V, and V90A) were detected in four patients, providing a total alteration rate of 42.1% (8 of 19 cases) in ovarian cancer. No km23 alterations were detected in 15 normal tissues. Such a high alteration rate in ovarian cancer suggests that km23 may play an important role in either TGF-beta resistance or tumor progression in this disease. In keeping with these findings, the functional studies described herein indicate that both the Delta exon3-km23 and S55G/I89V-km23 mutants displayed a disruption in binding to the dynein intermediate chain in vivo, suggesting a defect in cargo recruitment to the dynein motor complex. In addition, the Delta exon3-km23 resulted in an inhibition of TGF-beta-dependent transcriptional activation of both the p3TP-lux and activin responsive element reporters. Collectively, our results suggest that km23 alterations found in ovarian cancer patients result in altered dynein motor complex formation and/or aberrant transcriptional regulation by TGF-beta. C1 Penn State Univ, Coll Med, Dept Pharmacol MCH078, Hershey, PA 17033 USA. Penn State Univ, Coll Med, Dept Hlth Evaluat Sci, Hershey, PA 17033 USA. NCI, Natl Canc Inst Clin Proteom Program, Pathol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Mulder, KM (reprint author), Penn State Univ, Coll Med, Dept Pharmacol MCH078, 500 Univ Dr, Hershey, PA 17033 USA. EM kmm15@psu.edu FU NCI NIH HHS [CA-51452, CA-100239, CA-90765, CA-92889]; NCRR NIH HHS [M01RR10732] NR 39 TC 16 Z9 17 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 AUG 1 PY 2005 VL 65 IS 15 BP 6526 EP 6533 DI 10.1158/0008-5472.CAN-04-4385 PG 8 WC Oncology SC Oncology GA 950DN UT WOS:000230837900010 PM 16061631 ER PT J AU Birger, Y Catez, F Furusawa, T Lim, JH Prymakowska-Bosak, M West, KL Postnikov, YV Haines, DC Bustin, M AF Birger, Y Catez, F Furusawa, T Lim, JH Prymakowska-Bosak, M West, KL Postnikov, YV Haines, DC Bustin, M TI Increased tumorigenicity and sensitivity to ionizing radiation upon loss of chromosomal protein HMGN1 SO CANCER RESEARCH LA English DT Article ID DOUBLE-STRAND BREAKS; CELL-CYCLE CHECKPOINTS; HISTONE H2AX; DNA-DAMAGE; GENOMIC INSTABILITY; HIGH-MOBILITY; CHROMATIN; REPAIR; PHOSPHORYLATION; CANCER AB We report that loss of HMGN1, a nucleosome-binding protein that alters the compaction of the chromatin fiber, increases the cellular sensitivity to ionizing radiation and the tumor burden of mice. The mortality and tumor burden of ionizing radiation-treated Hmgn1(-/-) mice is higher than that of their Hmgn1(+/+) littermates. Hmgn1(-/-) fibroblasts have an altered G(2)-M checkpoint activation and are hypersensitive to ionizing radiation. The ionizing radiation hypersensitivity and the aberrant G(2)-M checkpoint activation of Hmgn1(-/-) fibroblasts can be reverted by transfections with plasmids expressing wild-type HMGN1, but not with plasmids expressing mutant HMGN proteins that do not bind to chromatin. Transformed Hmgn1(-/-) fibroblasts grow in soft agar and produce tumors in nude mice with a significantly higher efficiency than Hmgn1(+/+) fibroblasts, suggesting that loss of HMGN1 protein disrupts cellular events controlling proliferation and growth. Hingn1(-/-) mice have a higher incidence of multiple malignant tumors and metastases than their Hmgn1(+/+) littermates. We suggest that HMGN1 optimizes the cellular response to ionizing radiation and to other tumorigenic events; therefore, loss of this protein increases the tumor burden in mice. C1 NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NCI, Pathol Histotechnol Lab, Sci Applicat Int Corp, Frederick, MD 21701 USA. RP Bustin, M (reprint author), NCI, Prot Sect, Lab Metab, Ctr Canc Res,NIH, Bldg 37,Room 3122B,9000 Rockville Pike, Bethesda, MD 20892 USA. EM bustin@helix.nih.gov RI Bustin, Michael/G-6155-2015 FU Intramural NIH HHS [Z01 BC004496-30]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 34 TC 50 Z9 50 U1 4 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2005 VL 65 IS 15 BP 6711 EP 6718 DI 10.1158/0008-5472.CAN-05-0310 PG 8 WC Oncology SC Oncology GA 950DN UT WOS:000230837900031 PM 16061652 ER PT J AU Tsai, KKC Chuang, EYY Little, JB Yuan, ZM AF Tsai, KKC Chuang, EYY Little, JB Yuan, ZM TI Cellular mechanisms for low-dose ionizing radiation-induced perturbation of the breast tissue microenvironment SO CANCER RESEARCH LA English DT Article ID PHOSPHOINOSITIDE 3-OH KINASE; IN-VIVO; MATRIX METALLOPROTEINASES; HUMAN FIBROBLASTS; EPITHELIAL-CELLS; CANCER; INTEGRIN; SENESCENCE; EXPRESSION; INVASION AB Radiation exposure is an important form of environmental carcinogen and has been associated with increased risk of breast cancer. Epigenetic events, especially those involving alterations in the breast stromal microenvironment, may play an important role in radiation-induced carcinogenesis but remain not well understood. We here show that human mammary stromal fibroblasts respond to protracted low-dose ionizing radiation exposures by displaying a senescence-like phenotype. Using a three-dimensional coculture system to model the interactions of different mammary cell types with their neighbors and with their environment, we provide a direct experimental proof that ionizing radiation-induced senescence-like fibroblasts significantly perturb the mammary stromal microenvironment, which is highlighted by impaired formation of pseudopodia networks due to marked cytoskeletal alterations in senescence-like fibroblasts and increased extracellular matrix degradation because of the up-regulation of multiple secreted matrix metalloproteinases. Within such a perturbed environment, mammary ductal morphogenesis is completely disrupted and epithelial cells instead grow into enlarged cystic structures, which further develop and become disorganized cell masses on inactivation of cellular death pathways. Breast carcinoma cells growing in such an environment are enabled to fully express their malignant potential as evidenced by the alpha 6 beta 4 integrin/phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway-dependent invasive growth. Our results suggest that ionizing radiation, in addition to causing gene mutations in epithelial cells, can contribute to breast carcinogenesis by perturbing the tissue microenvironment that leads to dysregulated cell-cell and cell-matrix interactions. C1 Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. NCI, Radiat Biol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Yuan, ZM (reprint author), Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Room 508,Bldg 1,665 Huntington Ave, Boston, MA 02115 USA. EM zyuan@hsph.harvard.edu RI Tsai, Kun-Chih/C-1371-2010 NR 50 TC 56 Z9 59 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2005 VL 65 IS 15 BP 6734 EP 6744 DI 10.1158/0008-5472.CAN-05-0703 PG 11 WC Oncology SC Oncology GA 950DN UT WOS:000230837900034 PM 16061655 ER PT J AU Vearing, C Lee, FT Wimmer-Kleikamp, S Spirkoska, V To, C Stylianou, C Spanevello, M Brechbiel, M Boyd, AW Scott, AM Lackmann, M AF Vearing, C Lee, FT Wimmer-Kleikamp, S Spirkoska, V To, C Stylianou, C Spanevello, M Brechbiel, M Boyd, AW Scott, AM Lackmann, M TI Concurrent binding of anti-EphA3 antibody and ephrin-A5 amplifies EphA3 signaling and downstream responses: Potential as EphA3-specific tumor-targeting reagents SO CANCER RESEARCH LA English DT Article ID RECEPTOR TYROSINE KINASES; DIVERSE ROLES; LIGAND; CELLS; CARCINOGENESIS; EMBRYOGENESIS; INHIBITION; ATTACHMENT; EPHB2; HEK AB The Eph receptor tyrosine kinases and their membrane-bound ephrin ligands form a unique cell-cell contact-mediated system for controlling cell localization and organization. Their high expression in a wide variety of human tumors indicates a role in tumor progression, and relatively low Eph and ephrin levels in normal tissues make these proteins potential targets for anticancer therapies. The monoclonal antibody IIIA4, previously used to isolate EphA3, binds with subnanomolar affinity to a conformation-specific epitope within the ephrin-binding domain that is closely adjacent to the "low-affinity" ephrin-A5 heterotetramerization site. We show that similar to ephrin-A5, preclustered IIIA4 effectively triggers EphA3 activation, contraction of the cytoskeleton, and cell rounding. BIAcore analysis, immunoblot, and confocal microscopy of wild-type and mutant EphA3 with compromised ephrin-A5 or IIIA4-binding capacities indicate that IIIA4 binding triggers an EphA3 conformation which is permissive for the assembly of EphA3/ephrin-A5-type signaling clusters. Furthermore, unclustered IIIA4 and ephrin-A5 Fc applied in combination initiate greatly enhanced EphA3 signaling. Radiometal conjugates of ephrin-A5 and IIIA4 retain their affinity, and in mouse xenografts localize to, and are internalized rapidly into EphA3-positive, human tumors. These findings show the biological importance of EphA3/ ephrin-A5 interactions and that ephrin-A5 and IIIA4 have great potential as tumor targeting reagents. C1 Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia. Ludwig Inst Canc Res, Tumour Targeting Program, Heidelberg, Vic, Australia. PO Royal Brisbane Hosp, Queensland Inst Med Res, Leukemia Fdn Canc Res Unit, Brisbane, Qld, Australia. NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Lackmann, M (reprint author), Monash Univ, Dept Biochem & Mol Biol, POB 13D, Clayton, Vic 3800, Australia. EM Martin.Lackmann@med.monash.edu.au RI Boyd, Andrew/G-2083-2010 NR 32 TC 43 Z9 48 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2005 VL 65 IS 15 BP 6745 EP 6754 DI 10.1158/0008-5472.CAN-05-0758 PG 10 WC Oncology SC Oncology GA 950DN UT WOS:000230837900035 PM 16061656 ER PT J AU Zhao, H Cui, YZ Dupont, J Sun, H Hennighausen, L Yakar, S AF Zhao, H Cui, YZ Dupont, J Sun, H Hennighausen, L Yakar, S TI Overexpression of the tumor suppressor gene phosphatase and tensin homologue partially inhibits Wnt-1-induced mammary tumorigenesis SO CANCER RESEARCH LA English DT Article ID WNT SIGNALING PATHWAY; STEM-CELLS; PROSTATE-CANCER; BREAST-CANCER; CYCLIN D1; C-MYC; PTEN; EXPRESSION; GROWTH; APOPTOSIS AB The tumor suppressor phosphatase and tensin homologue (PTEN) is involved in cell proliferation, adhesion, and apoptosis. PTEN overexpression in mammary epithelium leads to reduced cell number and impaired differentiation and secretion. In contrast, overexpression of the proto-oncogene Wnt-1 in mammary epithelium leads to mammary hyperplasia and subsequently focal mammary tumors. To explore the possibility that PTEN intersects with Wnt-induced tumorigenesis, mice that ectopically express PTEN and Wnt-1 in mammary epithelium were generated. PTEN overexpression resulted in an 11% reduction of Wnt-1-induced tumors within a 12-month period and the onset of tumors was delayed from an average of 5.9 to 7.7 months. The rate of tumor growth, measured from 0.5 cm diameter until the tumors reached 1.0 cm diameter, was increased from 8.4 days in Wnt-1 mice to 17.7 days in Wnt-1 mice overexpressing PTEN. Here we show for the first time in vivo that overexpression of PTEN in the Wnt-1 transgenic mice resulted in a marked decrease in the insulin-like growth factor (IGF)-I receptor levels leading to a reduced IGF-I-mediated mitogenesis. Moreover, the percentage of BrdUrd-positive epithelial nuclei was decreased by 48%. beta-Catenin immunoreactivity was significantly decreased and the percentage of signal transducer and activator of transcription 5a (stat5a)-positive mammary epithelial cells was increased by 2-fold in Wnt-1 mice overexpressing PTEN. The present study shows that PTEN can partially inhibit the Wnt-1-induced mammary tumorigenesis in early neoplastic stages by blocking the AKT pathway and by reducing the IGF-I receptor levels in mammary gland. This study identifies the PTEN as a therapeutic target for the treatment of mammary cancer and presumably other types of cancer. C1 NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Yakar, S (reprint author), NIDDKD, Diabet Branch, NIH, Bldg 10,Room 8D12,9000 Rockville Pike, Bethesda, MD 20892 USA. EM ShoshanaY@intra.niddk.nih.gov NR 50 TC 26 Z9 27 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 AUG 1 PY 2005 VL 65 IS 15 BP 6864 EP 6873 DI 10.1158/0008-5472.CAN-05-0181 PG 10 WC Oncology SC Oncology GA 950DN UT WOS:000230837900049 PM 16061670 ER PT J AU Dote, H Cerna, D Burgan, CE Camphausen, K Tofilon, PJ AF Dote, H Cerna, D Burgan, CE Camphausen, K Tofilon, PJ TI ErbB3 expression predicts tumor cell radiosensitization induced by Hsp90 inhibition SO CANCER RESEARCH LA English DT Article ID RECEPTOR TYROSINE KINASES; BREAST-CANCER CELLS; KAPPA-B ACTIVATION; SIGNAL-TRANSDUCTION; CARCINOMA-CELLS; RADIORESISTANCE FACTOR; RADIATION-RESISTANCE; DNA-DAMAGE; IN-VITRO; SURVIVIN AB The ability to identify tumors that are susceptible to a given molecularly targeted radiosensitizer would be of clinical benefit. Towards this end, we have investigated the effects of a representative Hsp90 inhibitor, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG), on the radiosensitivity of a panel of human tumor cell lines. 17DMAG was previously shown to enhance the radiosensitivity of a number of human cell lines, which correlated with the loss of ErbB2. We now report on cell lines in which 17DMAG induced the degradation of ErbB2, yet had no effect on radiosensitivity. In a comparison of ErbB family members, ErbB3 protein was only detectable in cells resistant to 17DMAG-induced radio-sensitization. To determine whether ErbB3 plays a casual role in this resistance, short interfering RNA (siRNA) was used to knockdown ErbB3 in the resistant cell line AsPC1. Whereas individual treatments with siRNA to ErbB3 or 17DMAG had no effect on radiosensithity, the combination, which reduced both ErbB2 and ErbB3, resulted in a significant enhancement in AsPC1 radiosensitivity. In contrast to siRNA to ErbB3 or 17DMAG treatments only, AsPC1 cell exposure to the combination also resulted in a decrease in ErbB1 kinase activity. These results indicate that ErbB3 expression predicts for tumor cell susceptibility to and suggests that the loss of ErbB1 signaling activity is necessary for 17DMAG-induced radiosensitization. However, for cell lines sensitized by 17DMAG, treatment with siRNA to ErbB2, which reduced ErbB1 activity, had no effect on radiosensitivity. These results suggest that, whereas the loss of ErbB1 signaling may be necessary for 17DMAG-induced radiosensitization, it is not sufficient. C1 NCI, Mol Radiat Therapeut Branch, Radiat Res Program, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. NCI, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. RP Tofilon, PJ (reprint author), NCI, Mol Radiat Therapeut Branch, Radiat Res Program, EPN-6015A,6130 Execut Blvd,MSC 7440, Bethesda, MD 20892 USA. EM tofilonp@mail.nih.gov NR 42 TC 34 Z9 36 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2005 VL 65 IS 15 BP 6967 EP 6975 DI 10.1158/0008-5472.CAN-05-1304 PG 9 WC Oncology SC Oncology GA 950DN UT WOS:000230837900061 PM 16061682 ER PT J AU Liu, YM Borchert, GL Donald, SP Surazynski, A Hu, CA Weydert, CJ Oberley, LW Phang, JM AF Liu, YM Borchert, GL Donald, SP Surazynski, A Hu, CA Weydert, CJ Oberley, LW Phang, JM TI MnSOD inhibits proline oxidase-induced apoptosis in colorectal cancer cells SO CARCINOGENESIS LA English DT Article ID MANGANESE SUPEROXIDE-DISMUTASE; TUMOR-NECROSIS-FACTOR; OXYGEN SPECIES GENERATION; CYTOCHROME-C; NITRIC-OXIDE; OXIDATIVE STRESS; DEATH; ACTIVATION; EXPRESSION; OVEREXPRESSION AB Proline oxidase (POX), localized on inner mitochondrial membranes, is encoded by a p53-induced gene and metabolically participates in p53-induced apoptosis. Previously, we showed that POX catalyzed the generation of reactive oxygen species (ROS). We and others have demonstrated that overexpression of POX, independent of p53, causes apoptotic cell death in a variety of cancer cells. But a necessary role for ROS remains uncertain. Therefore, we asked whether superoxide dismutases (SOD) and catalase (CAT), important antioxidant enzymes, might interfere with the POX-dependent induction of apoptosis. In this study, we used DLD-1 colorectal cancer cells stably transfected with the POX gene under the control of a tetracycline-inducible promoter. When doxycycline was removed from the culture medium and the expression of POX was induced, apoptotic cell death was initiated. To examine the importance of the ROS-dependent component of the pathway, we infected DLD-1 POX cells with recombinant adenoviruses containing MnSOD, CuZnSOD, CAT or varying combinations of these adenoviruses followed by induced expression of POX. The expression of MnSOD inhibited POX-induced apoptosis, but others did not. Mechanistically, mitochondria-localized MnSOD dramatically reduced the release of cytochrome c to cytosol by POX. Compared with control cells, MnSOD-expressing DLD-1 POX cells generated a higher concentration of H2O2 owing to dismutation of superoxide radicals, which was elevated by POX. Thus, these data further suggest that the generation of superoxide radicals plays a crucial role in POX-induced apoptosis and the process is partially blocked by MnSOD. C1 NCI, Metab & Canc Susceptibil Sect, Comparat Carcinogenesis Lab, Ft Detrick, MD 21702 USA. SAIC Frederick Inc, Basic Res Program, Ft Detrick, MD 21702 USA. Univ New Mexico, Hlth Sci Ctr, Dept Biochem & Mol Biol, Albuquerque, NM 87131 USA. Univ Iowa, Dept Radiat Oncol, Free Rad & Radiat Biol Program, Iowa City, IA 52242 USA. RP Phang, JM (reprint author), NCI, Metab & Canc Susceptibil Sect, Comparat Carcinogenesis Lab, Bldg 538,Room 144, Ft Detrick, MD 21702 USA. EM phang@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 43 TC 63 Z9 64 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 2005 VL 26 IS 8 BP 1335 EP 1342 DI 10.1093/carcin/bgi083 PG 8 WC Oncology SC Oncology GA 948OD UT WOS:000230724700003 PM 15817612 ER PT J AU Huang, WY Chow, WH Rothman, N Lissowska, J Llaca, V Yeager, M Zatonski, W Hayes, RB AF Huang, WY Chow, WH Rothman, N Lissowska, J Llaca, V Yeager, M Zatonski, W Hayes, RB TI Selected DNA repair polymorphisms and gastric cancer in Poland SO CARCINOGENESIS LA English DT Article ID UPPER AERODIGESTIVE TRACT; N-NITROSO COMPOUNDS; LUNG-CANCER; GENE XRCC1; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE; CHINESE POPULATION; EXCISION-REPAIR; BLADDER-CANCER; CELL CARCINOMA; STOMACH-CANCER AB Impaired DNA repair capacity may adversely affect cancer risk, particularly in subjects exposed to DNA damaging carcinogens, as found in tobacco smoke, or among subjects deficient for protective factors, as found in fruits and vegetables. We studied tobacco use, fruit and vegetable intake, and common non-synonymous single nucleotide polymorphisms in four DNA repair genes in relation to gastric cancer risk, in a population-based, case-control study of 281 incident gastric cancer cases and 390 controls, in Warsaw, Poland. Multivariate logistic regression analysis was performed to calculate odds ratios (OR) and 95% confidence intervals (CI). Increased risks of gastric cancer were found for smokers (OR = 3.1, CI = 1.9-5.1 for pack-years >= 40 versus never smokers) and subjects with low fruit intake (OR = 2.2, CI = 1.3-3.6 for 1st versus 4th quartile); risk associated with vegetable intake was not statistically significant. Allele frequencies among the controls were consistent with those previously reported for the 5 polymorphisms studied: XRCC1-Arg399Gln, XPD-Lys751Gln, MGMT-Ile143Val, Leu84Phe, and XRCC3-Thr241Met. None of the studied polymorphisms were independently associated with gastric cancer risk. Smoking-associated risks, however, were greatest for carriers of the XRCC1-399 ArgArg genotype (P-interaction = 0.004). Risks associated with low intake of fruits or vegetables tended to be modified by selected polymorphisms in XRCC1, XPD and MGMT (P-interaction = 0.1-0.2). Risk modification was not found for the other repair polymorphisms. Selected DNA repair polymorphisms did not have independent effects on gastric cancer risk; however, they may modify smoking- and probably diet-related risks for this disease. These results need replication in larger epidemiological studies of gastric cancer. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Ctr Canc, Div Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. M Sklodowska Curie Inst Oncol, PL-02781 Warsaw, Poland. NCI Frederick, Core Genotyping Facil, Ctr Adv Technol, Gaithersburg, MD 20892 USA. RP Huang, WY (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, EPS 8113,MSC 7240, Bethesda, MD 20892 USA. EM huangw@mail.nih.gov OI Lissowska, Jolanta/0000-0003-2695-5799; Hayes, Richard/0000-0002-0918-661X NR 53 TC 54 Z9 57 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 2005 VL 26 IS 8 BP 1354 EP 1359 DI 10.1093/carcin/bgi084 PG 6 WC Oncology SC Oncology GA 948OD UT WOS:000230724700005 PM 15802298 ER PT J AU Ewart-Toland, A Dai, Q Gao, YT Nagase, H Dunlop, MG Farrington, SM Barnetson, RA Anton-Culver, H Peel, D Ziogas, A Lin, DX Miao, XP Sun, T Ostrander, EA Stanford, JL Langlois, M Chan, JM Yuan, JW Harris, CC Bowman, ED Clayman, GL Lippman, SM Lee, JJ Zheng, W Balmain, A AF Ewart-Toland, A Dai, Q Gao, YT Nagase, H Dunlop, MG Farrington, SM Barnetson, RA Anton-Culver, H Peel, D Ziogas, A Lin, DX Miao, XP Sun, T Ostrander, EA Stanford, JL Langlois, M Chan, JM Yuan, JW Harris, CC Bowman, ED Clayman, GL Lippman, SM Lee, JJ Zheng, W Balmain, A TI Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene: a meta-analysis of multiple cancer types SO CARCINOGENESIS LA English DT Article ID PROSTATE-CANCER; BREAST-CANCER; OVARIAN-CANCER; CHROMOSOMAL INSTABILITY; PHE31ILE POLYMORPHISM; COLORECTAL CANCERS; RISK; ASSOCIATION; KINASE; STK15 AB STK15 (Aurora-A) is a serine/threonine kinase involved in mitotic chromosomal segregation. A genetic variant in STK15 T+91A (resulting in the amino acid substitution F31I) is associated with increased aneuploidy in colon tumors and cell transformation in vitro. Since this polymorphism plays a role in mitotic control-a process critical for all cancer types-we conducted association analyses for risk of cancer development of the colon, breast, prostate, skin, lung and esophagus in 10 independent case-control populations. We carried out a meta-analysis of these 10 case-control studies together with 5 additional published studies for a total of 9549 cases of breast, colon, ovarian, prostate, lung, esophageal and non-melanoma skin cancer and 8326 population or hospital-based controls. Meta-analysis of three colorectal cancer studies showed an increased risk in T+91A homozygotes (OR = 1.50; 95% CI of 1.14-1.99). Meta-analysis of four breast cancer studies showed increased risk for T+91A homozygotes (OR = 1.35, 95% CI of 1.12-1.64). The results of the multiple cancer type meta-analysis for all 15 studies combined were significant for cancer risk in both homozygotes and heterozygotes. The T+91A heterozygotes show an OR of 1.10 (95% CI of 1.03-1.18, P-value = 0.006) and the T+91A homozygotes show an OR of 1.40 (95% CI of 1.22-1.59, P-value < 0.001) for cancer risk. These results confirm that the STK15 T+91A variant is a low penetrance cancer susceptibility allele affecting multiple cancer types, and provide genetic evidence from large-scale human population studies that genetic stability at the chromosome level is an important determinant of cancer susceptibility. The data also underline the advantages of comparative association studies involving study populations from different ethnic groups for determination of disease risk. C1 Univ Calif San Francisco, UCSF Comprehens Canc Ctr, San Francisco, CA 94143 USA. Vanderbilt Univ, Dept Med, Sch Med, Nashville, TN 37232 USA. Vanderbilt Univ, Vanderbilt Ingrim Canc Ctr, Sch Med, Nashville, TN 37232 USA. Inst Canc Res, Dept Epidemiol, Shanghai 200032, Peoples R China. Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. Univ Edinburgh, Western Gen Hosp, Div Oncol, Edinburgh EH4 2XU, Midlothian, Scotland. Univ Calif Irvine, Dept Med, Div Epidemiol, Irvine, CA 92717 USA. Chinese Acad Med Sci, Canc Inst & Hosp, Dept Etiol & Carcinogenesis, Beijing 100021, Peoples R China. Peking Union Med Coll, Beijing 100021, Peoples R China. Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98104 USA. Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Head & Neck Surg & Canc Biol, Houston, TX 77030 USA. Univ Calif San Francisco, Dept Biochem & Biophys AB, San Francisco, CA 94115 USA. RP Balmain, A (reprint author), Univ Calif San Francisco, UCSF Comprehens Canc Ctr, San Francisco, CA 94143 USA. EM abalmain@cc.ucsf.edu RI miao, xiaoping/C-4336-2011; Toland, Amanda/E-4202-2011; Dunlop, Malcolm/F-1973-2011; Farrington, Susan/C-7319-2013 OI miao, xiaoping/0000-0002-6818-9722; Dunlop, Malcolm/0000-0002-3033-5851; FU Medical Research Council [MC_U127527198]; NCI NIH HHS [CA56678, 1 P50 CA89520, 5P30 CA16672, CA 89520-01, CA82664, CA84244-03, N01-CN-05230, P01-5P01CA68233] NR 39 TC 109 Z9 113 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 2005 VL 26 IS 8 BP 1368 EP 1373 DI 10.1093/carcin/bgi085 PG 6 WC Oncology SC Oncology GA 948OD UT WOS:000230724700007 PM 15802297 ER PT J AU Moon, C Krawczyk, M Paik, D Lakatta, EG Talan, MI AF Moon, C Krawczyk, M Paik, D Lakatta, EG Talan, MI TI Cardioprotection by recombinant human erythropoietin following acute experimental myocardial infarction: Dose response and therapeutic window SO CARDIOVASCULAR DRUGS AND THERAPY LA English DT Article DE myocardial infarct; left ventricular remodeling; apoptosis; erythopoietin ID IN-VIVO; APOPTOSIS; INJURY; ACTIVATION; PROTECTION; OCCLUSION; ISCHEMIA; ARTERY; HEART; RATS AB Background: Recombinant human erythropoietin (rhEPO) protects tissue from ischemic damage, but translation of this finding into useful guidelines with respect to human trials for myocardial infarction (MI) requires a determination of the minimum effective rhEPO dose and the therapeutic window following MI. Method and Results: Serial echocardiography revealed that during four weeks following MI, induced by a permanent coronary ligation in rats, the LV end-diastolic and end-systolic volumes in untreated rats expanded from 0.35 +/- 0.01 and 0.14 +/- 0.01 ml to 0.84 +/- 0.04 and 0.61 +/- 0.06 ml, respectively, and ejection fraction (EF) reduced by 50%. A single i.v. injection of rhEPO immediately following MI in a dose of 150 IU/kg was as effective as 3000 IU/kg in causing a 2-fold reduction of the number of apoptotic nuclei in the AAR 24-h later, a 2-fold reduction of the MI size measured 4 weeks later, attenuation of progressive LV dilatation and fall in EF. A 3000 IU/kg dose had similar therapeutic effects when delayed by 4, 8, or 12 h following MI, but was not effective after a 24-h delay. A single dose of 150 IU/kg was effective within 4 It post-MI, but was without effect if administered after an 8-h delay. Conclusion: Cell death, final MI size, myocardial remodeling and functional decline are significantly reduced in rats by a single injection of rhEPO in a dose as low as 150 IU/kg if administered during the first 4 h after the ischemic event. Higher doses extend the therapeutic window up to 12 h. C1 NIA, Cardiovasc Gene Therapy Unit, Cardiovasc Sci Lab, Intramural Res Program,Gerontol Res Ctr, Baltimore, MD 21224 USA. Hanyang Univ, Dept Anat & Cell Biol, Seoul 133791, South Korea. RP Talan, MI (reprint author), NIA, Cardiovasc Gene Therapy Unit, Cardiovasc Sci Lab, Intramural Res Program,Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM talanm@grc.nia.nih.gov NR 25 TC 49 Z9 57 U1 3 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-3206 J9 CARDIOVASC DRUG THER JI Cardiovasc. Drugs Ther. PD AUG PY 2005 VL 19 IS 4 BP 243 EP 250 DI 10.1007/s10557-005-3189-6 PG 8 WC Cardiac & Cardiovascular Systems; Pharmacology & Pharmacy SC Cardiovascular System & Cardiology; Pharmacology & Pharmacy GA 988KM UT WOS:000233600000001 PM 16187008 ER PT J AU Resnick, MA Tomso, D Inga, A Menendez, D Bell, D AF Resnick, MA Tomso, D Inga, A Menendez, D Bell, D TI Functional diversity in the gene network controlled by the master regulator p53 in humans SO CELL CYCLE LA English DT Article DE transcription; mutation; SNP; master regulator; p53 ID TNF PROMOTER REGION; TRANSCRIPTION FACTOR; BINDING-SITE; TRANSACTIVATION; PROTEIN; CANCER; YEAST; POLYMORPHISM; MUTATIONS; SEQUENCE AB Individual differences in susceptibility to exposure induced diseases are likely due to variation in the DNA sequences of "environmental response" genes, many of which are arranged in complex regulatory networks. Among similar to 10 million inherited DNA variations, called single nucleotide polymorphisms ( SNPs), perhaps only a few thousand, will actually influence human disease risk. We have combined bioinformatics and laboratory approaches to investigate genetic variation within the p53 stress response network. p53, a prominent tumor suppressor protein, is a master regulator that targets over a hundred genes for transcriptional upregulation or repression through sequence-specific interactions with DNA response elements (REs). We identified many human genes in the network that contain SNPs in REs that can be transactivated by p53. The discovery of these individual differences has implications for variation in human responses to environmental stresses, risk of disease, and responsiveness to drug therapies. The findings also provide insight into the evolution of complex networks and the role of master regulatory genes, such as p53, in such networks. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. Natl Inst Canc Res, Lab Expt Oncol B, Genoa, Italy. RP Resnick, MA (reprint author), NIEHS, Mol Genet Lab, NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM resnick@niehs.nih.gov NR 31 TC 23 Z9 23 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 EI 1551-4005 J9 CELL CYCLE JI Cell Cycle PD AUG PY 2005 VL 4 IS 8 BP 1026 EP 1029 DI 10.4161/cc.4.8.1904 PG 4 WC Cell Biology SC Cell Biology GA 952EY UT WOS:000230986700011 PM 16082206 ER PT J AU Mattson, MP Haughey, NJ Nath, A AF Mattson, MP Haughey, NJ Nath, A TI Cell death in HIV dementia SO CELL DEATH AND DIFFERENTIATION LA English DT Review DE AIDS; apoptosis; cognitive impairment; inflammation; lipid rafts ID HUMAN-IMMUNODEFICIENCY-VIRUS; NECROSIS-FACTOR-ALPHA; AMYLOID BETA-PEPTIDE; BLOOD-BRAIN-BARRIER; TYPE-1 TAT PROTEIN; MICROVASCULAR ENDOTHELIAL-CELLS; INDUCED NEURONAL APOPTOSIS; CENTRAL-NERVOUS-SYSTEM; AIDS DEMENTIA; COAT PROTEIN AB Many patients infected with human immunodeficiency virus type-1 (HIV-1) suffer cognitive impairment ranging from mild to severe (HIV dementia), which may result from neuronal death in the basal ganglia, cerebral cortex and hippocampus. HIV-1 does not kill neurons by infecting them. Instead, viral proteins released from infected glial cells, macrophages and/or stem cells may directly kill neurons or may increase their vulnerability to other cell death stimuli. By binding to and/or indirectly activating cell surface receptors such as CXCR4 and the N-methyl-D-aspartate receptor, the HIV-1 proteins gp120 and Tat may trigger neuronal apoptosis and excitotoxicity as a result of oxidative stress, perturbed cellular calcium homeostasis and mitochondrial alterations. Membrane lipid metabolism and inflammation may also play important roles in determining whether neurons live or die in HIV-1-infected patients. Drugs and diets that target oxidative stress, excitotoxicity, inflammation and lipid metabolism are in development for the treatment of HIV-1 patients. C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, GRC 4F01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 171 TC 170 Z9 174 U1 1 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 AUG PY 2005 VL 12 SU 1 BP 893 EP 904 DI 10.1038/sj.cdd.4401577 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 945NI UT WOS:000230508800008 PM 15761472 ER PT J AU Chen, KQ Iribarren, P Gong, WH Wang, JM AF Chen, Keqiang Iribarren, Pablo Gong, Wanghua Wang, Ji-Ming TI The Essential Role of Phosphoinositide 3-Kinases (PI3Ks) in Regulating Pro-Inflammatory Responses and the Progression of Cancer SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Review DE PI3K; signal transduction; inflammation; malignant tumor AB Phosphoinositide 3-Kinases (PI3Ks) are proteins coupled to a variety of cell surface receptors and play a key role in signal transduction cascade regulating fundamental cellular functions such as transcription, proliferation, and survival. PI3Ks also are important in disease processes such as inflammation and cancer. The aim of this review is to outline current understandings of the PI3K family, mechanism of their activation, their role in inflammatory responses and the development of malignant tumors. C1 [Chen, Keqiang] Shanghai Jiao Tong Univ, Sch Agr & Biol, Shanghai 201101, Peoples R China. [Chen, Keqiang; Iribarren, Pablo; Wang, Ji-Ming] NCI, Lab Mol Immunoregulat, Ctr Canc Res, Frederick, MD 21702 USA. [Gong, Wanghua] NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA. RP Chen, KQ (reprint author), NCI, Lab Mol Immunoregulat, Ctr Canc Res, Bldg 560,Room 31-40, Frederick, MD 21702 USA. EM kchen@ncifcrf.gov FU National Cancer Institute; National Institutes of Health [NO1-CO-12400]; Intramural Research Program of the National Cancer Institution FX This project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. NO1-CO-12400, and by the Intramural Research Program of the National Cancer Institution.; The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. The publisher or recipient acknowledges right of the U. S. Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article. NR 104 TC 15 Z9 16 U1 0 U2 0 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 EI 2042-0226 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD AUG PY 2005 VL 2 IS 4 BP 241 EP 252 PG 12 WC Immunology SC Immunology GA V32AW UT WOS:000208925100001 PM 16274621 ER PT J AU Wood, JN Knutson, KM Grafman, J AF Wood, JN Knutson, KM Grafman, J TI Psychological structure and neural correlates of event knowledge SO CEREBRAL CORTEX LA English DT Article DE amygdala; functional MRI; multidimensional scaling; prefrontal cortex; scripts ID INFERIOR PREFRONTAL CORTEX; WORD-FREQUENCY; BRAIN ACTIVATION; SOCIAL EPISODES; LEXICAL ACCESS; FMRI; EMOTION; LESIONS; REPRESENTATIONS; INTELLIGIBILITY AB Humans are capable of storing and retrieving sequences of complex structured events. Here we report a study in which we establish the psychological structure of event knowledge and then use parametric event-related functional magnetic resonance imaging to identify its neural correlates. We demonstrate that event knowledge is organized along dissociable dimensions that are reflected in distinctive patterns of neural activation: social valence (amygdala and right orbitofrontal cortex), experience (medial prefrontal cortex) and engagement (left orbitofrontal cortex). Our study affirms the importance and uniqueness of the human prefrontal cortex in representing event knowledge. C1 NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 5C205,10 Ctr Dr, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov OI Grafman, Jordan H./0000-0001-8645-4457; Knutson, Kristine/0000-0003-4626-4514 NR 69 TC 24 Z9 24 U1 3 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD AUG PY 2005 VL 15 IS 8 BP 1155 EP 1161 DI 10.1093/cercor/bhh215 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 945PA UT WOS:000230513400007 PM 15563720 ER PT J AU Gottlieb, J Kusunoki, M Goldberg, ME AF Gottlieb, J Kusunoki, M Goldberg, ME TI Simultaneous representation of saccade targets and visual onsets in monkey lateral intraparietal area SO CEREBRAL CORTEX LA English DT Article DE attention; lateral intraparietal area; parallel representation; parietal cortex; saccades ID POSTERIOR PARIETAL CORTEX; NEURONS; ATTENTION; INTENTION; DECISION; 7A AB The monkey's lateral intraparietal area (LIP) has been associated with attention and saccades. LIP neurons have visual on-responses to objects abruptly appearing in their receptive fields (RFs) and sustained activity preceding saccades to the RF. We studied the relationship between the on-responses and delay activity in LIP using a 'stable-array' task. Monkeys viewed eight distinct, continuously illuminated objects, arranged in a circle with at least one object in the RF. A cue flashed instructing the monkey to make a saccade, after a delay, to the stable object physically matching the cue. The location of the cue was fixed in trial blocks, either in or out of the RF. If the cue was outside the RF, neurons developed delay-period activity tuned for the direction of the saccade target at similar to 190 ms after cue onset. If the cue appeared in the RF, neurons initially responded to cue onset and developed tuning for saccade direction only toward the end of the delay period, 390 ms after cue onset. The cue- and saccade-target responses coexisted throughout a significant portion of the delay period. The results show that visual-on responses and delay-period activity in LIP are functionally separable, and that, although highly selective, the salience representation in LIP can contain more than one object at a time. C1 Columbia Univ, Ctr Neurobiol & Behav, New York, NY 10032 USA. Columbia Univ, Sensorimotor Res Lab, Natl Inst Hlth, New York, NY 10032 USA. Univ Oxford, MRC, Cognit & Brain Sci Unit, Oxford OX1 2JD, England. Univ Oxford, Dept Expt Psychol, Oxford OX1 2JD, England. RP Gottlieb, J (reprint author), Columbia Univ, Ctr Neurobiol & Behav, New York, NY 10032 USA. EM jg2141@columbia.edu FU NEI NIH HHS [R01 EY014978, R01 EY014978-03, R24 EY015634-03, R24 EY015634-01, R01 EY014978-04, R24 EY015634, R24 EY015634-04, R01 EY014978-05, R24 EY015634-02, P30 EY019007] NR 21 TC 37 Z9 37 U1 1 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD AUG PY 2005 VL 15 IS 8 BP 1198 EP 1206 DI 10.1093/cercor/bhi002 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 945PA UT WOS:000230513400012 PM 15616137 ER PT J AU Beland, FA Churchwell, MI Von Tungeln, LS Chen, SJ Fu, PP Culp, SJ Schoket, B Gyorffy, E Minarovits, J Poirier, MC Bowman, ED Weston, A Doerge, DR AF Beland, FA Churchwell, MI Von Tungeln, LS Chen, SJ Fu, PP Culp, SJ Schoket, B Gyorffy, E Minarovits, J Poirier, MC Bowman, ED Weston, A Doerge, DR TI High-performance liquid chromatography electrospray ionization tandem mass spectrometry for the detection and quantitation of benzo[a]pyrene-DNA adducts SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID HYDROCARBON-DNA ADDUCTS; POLYCYCLIC AROMATIC-HYDROCARBONS; FED COAL-TAR; HUMAN-PLACENTA; HUMAN LUNG; BENZOPYRENE-DNA ADDUCTS; RISK ASSESSMENT; CANCER-RISK; QUANTIFICATION; EXPOSURE AB A method, using HPLC combined with electrospray tandem mass spectrometry (ES-MS/ MS), was developed and validated to detect and quantify the major DNA adduct resulting from exposure to the ultimate tumorigenic benzo[alpha]pyrene (BP) metabolite, trans-7,8-dihydroxyanti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[alpha]pyrene (BPDE). Calf thymus DNA was reacted with BPDE, digested enzymatically to nucleosides, and the major DNA adduct, 10-(deoxyguanosin-N-2-yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[alpha]pyrene (dG-BPDE), was purified by HPLC. Similar procedures were applied to prepare dG-BPDE-d(8) from [1,2,3,4,5,6,11,12(2)H(8)]BPDE for use as an internal standard. The HPLC-ES-MS/MS method was validated using a mixture of hydrolyzed salmon testis DNA (82 mu g) and 10 pg dG-BPDE (analogous to 6.9 adducts/10(8) nucleotides). The results indicated an inter- and intraday accuracy of 99-100% and precision of 1.6-1.7% (relative standard deviation). When applied to a calf thymus DNA sample modified in vitro with [1,3-H-3]BPDE, the method gave a value very similar to those obtained by radiolabeling, P-32-postlabeling, and immunoassay. HPLC-ES-MS/MS analysis of hepatic DNA from mice treated intraperitoneally with 0.5 and 1.0 mg of [7,8-H-3]BP gave values comparable to those determined by P-32-postlabeling and immunoassay. Lung DNA from mice fed a 0.3% coal tar diet (containing approximately 2 mg BP/g coal tar) for one month had 0.6 +/- 0.04 dG-BPDE adducts/10(8) nucleotides. This value is much lower than the 102 14 total DNA adducts/10(8) nucleotides determined by P-32-postlabeling, which suggests that dG-BPDE makes only a minor contribution to the DNA adducts formed in lung tissue of mice administered coal tar. The HPLC-ES-MS/MS method was used to assess human lung DNA samples for the presence of dG-BPDE. Based upon a limit of detection of 0.3 dG-BPDE adducts/10(8) nucleotides, when using 100,mu g of DNA, dG-BPDE was detected in only 1 out of 26 samples. These observations indicate that HPLC-ES-MS/MS is suitable to assess the contribution of BP to DNA damage caused by exposures to polycyclic aromatic hydrocarbon (PAH) mixtures. The results further suggest that dG-BPDE may contribute only a small fraction of the total DNA adducts detected by other DNA adduct methodologies in individuals exposed to PAHs. C1 Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. Jozsef Fodor Natl Ctr Publ Hlth, Natl Inst Environm Hlth, H-1097 Budapest, Hungary. Bela Johan Natl Ctr Epidemiol, H-1529 Budapest, Hungary. NCI, NIH, Bethesda, MD 20892 USA. Natl Inst Occupat Hlth Safety, Ctr Dis Control & Prevent, Morgantown, WV 26505 USA. RP Beland, FA (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. EM fbeland@nctr.fda.gov FU NCI NIH HHS [N02-CO-91012] NR 38 TC 63 Z9 66 U1 0 U2 15 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 AUG PY 2005 VL 18 IS 8 BP 1306 EP 1315 DI 10.1021/tx050068y PG 10 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 955OG UT WOS:000231235000014 PM 16097804 ER PT J AU Baccarelli, A Pfeiffer, R Consonni, D Pesatori, AC Bonzini, M Patterson, DG Bertazzi, PA Landi, MT AF Baccarelli, A Pfeiffer, R Consonni, D Pesatori, AC Bonzini, M Patterson, DG Bertazzi, PA Landi, MT TI Handling of dioxin measurement data in the presence of non-detectable values: Overview of available methods and their application in the Seveso chloracne study SO CHEMOSPHERE LA English DT Article DE 2,3,7,8-tetrachlorodibenzo-p-dioxin; exposure assessment; multiple imputation; non-detects; Seveso; detection limit ID MASS-SPECTROMETRIC ANALYSIS; ENVIRONMENTAL DATA SETS; DETECTION LIMIT; EXPOSURE; POPULATION; WATER; PHTHALATE; SAMPLES; SERUM; SOIL AB Exposure measurements of concentrations that are non-detectable or near the detection limit (DL) are common in environmental research. Proper statistical treatment of non-detects is critical to avoid bias and unnecessary loss of information. In the present work, we present an overview of possible statistical strategies for handling non-detectable values, including deletion, simple substitution, distributional methods, and distribution-based imputation. Simple substitution methods (e.g., substituting 0, DL/2, DL/root 2, or DL for the non-detects) are the most commonly applied, even though the EPA Guidance for Data Quality Assessment discouraged their use when the percentage of non-detects is > 15%. Distribution-based multiple imputation methods, also known as robust or "fill-in" procedures, may produce dependable results even when 50-70% of the observations are non-detects and can be performed using commonly available statistical software. Any statistical analysis can be conducted on the imputed datasets. Results properly reflect the presence of non-detectable values and produce valid statistical inference. We describe the use of distribution-based multiple imputation in a recent investigation conducted on subjects from the Seveso population exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in which 55.6% of plasma TCDD measurements were non-detects. We suggest that distribution-based multiple imputation be the preferred method to analyze environmental data when substantial proportions of observations are non-detects. (c) 2005 Elsevier Ltd. All rights reserved. C1 Univ Milan, EPOCA Res Ctr Occupat Clin & Environm Epidemiol, Dept Environm & Occupat Hlth, I-20122 Milan, Italy. Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20852 USA. Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Div Environm Hlth Lab Sci, Atlanta, GA 30341 USA. RP Baccarelli, A (reprint author), Univ Milan, EPOCA Res Ctr Occupat Clin & Environm Epidemiol, Dept Environm & Occupat Hlth, Via San Barnaba 8, I-20122 Milan, Italy. EM andrea.baccarelli@unimi.it RI Pfeiffer, Ruth /F-4748-2011; Bonzini, Matteo/K-7540-2016; bertazzi, pietro alberto/D-5039-2017; OI Bonzini, Matteo/0000-0002-6405-7554; bertazzi, pietro alberto/0000-0003-3475-2449; Baccarelli, Andrea/0000-0002-3436-0640; pesatori, angela/0000-0002-0261-3252 NR 32 TC 90 Z9 91 U1 2 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0045-6535 J9 CHEMOSPHERE JI Chemosphere PD AUG PY 2005 VL 60 IS 7 BP 898 EP 906 DI 10.1016/j.chemosphere.2005.01.055 PG 9 WC Environmental Sciences SC Environmental Sciences & Ecology GA 956LC UT WOS:000231300200008 PM 15992596 ER PT J AU Akpinar-Elci, M Stemple, KJ Enright, PL Fahy, JV Bledsoe, TA Kreiss, K Weissman, DN AF Akpinar-Elci, M Stemple, KJ Enright, PL Fahy, JV Bledsoe, TA Kreiss, K Weissman, DN TI Induced sputum evaluation in microwave popcorn production workers SO CHEST LA English DT Article DE airway inflammation; bronchiolitis obliterans; cytokines; diacetyl; flavoring; occupation ID BRONCHIOLITIS OBLITERANS SYNDROME; AIRWAY INFLAMMATION; OCCUPATIONAL ASTHMA; LUNG-TRANSPLANT; COUNTS; FLUID; PLANT AB Objective: Severe airways obstruction and bronchiolitis obliterans have been reported in microwave popcorn production workers and attributed to inhalation of flavoring agents. We investigated whether exposure to flavoring agents is associated with airways inflammation in popcorn production workers. Methods: Fifty-nine workers with high exposures and 22 patients with low exposures to flavoring vapors completed a questionnaire, spirometry, and sputum induction. Sputum cell counts were categorized as "high" if greater than (and "low" if less than or equal to) the median cell counts of a healthy external control group (n = 24). We compared high- and low-exposure groups as well as all workers with control subjects. Results: Neutrophil concentrations in nonsmoking workers were significantly higher than those of the healthy nonsmoking control group (p < 0.05). The smoking-adjusted odds ratio for high neutrophil count (> 1.63 X 10(5)/mL) was 3.8 (95% confidence interval, 1.3 to 11.5) in the high-exposure group compared with the low-exposure group. Sputum interleukin-8 and eosinophil cationic protein levels were higher in high-exposure workers than in low-exposure workers (p < 0.05). For the worker group, mean values of FEV1 percentage of predicted and FEV1/FVC percentage of predicted were > 95%. There were no relationships between sputum characteristics and the presence of airways obstruction. Conclusions: High exposure to popcorn flavoring agents is associated with neutrophilic airway inflammation in popcorn production workers. These data provide further evidence that popcorn production workers face a significant occupational hazard through exposure to flavoring agents. C1 NIOSH, Div Resp Dis Studies, Field Studies Branch, Ctr Dis Control & Prevent, Morgantown, WV 26505 USA. NIOSH, Ctr Dis Control & Prevent, Hlth Effects Lab Div, Morgantown, WV 26505 USA. NIH, NIAID, Bethesda, MD 20892 USA. Univ Calif San Francisco, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. RP Akpinar-Elci, M (reprint author), NIOSH, Div Resp Dis Studies, Field Studies Branch, Ctr Dis Control & Prevent, Mail Stop H-2800,1095 Willowdale Rd, Morgantown, WV 26505 USA. EM melci@cdc.gov NR 26 TC 18 Z9 19 U1 1 U2 1 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2005 VL 128 IS 2 BP 991 EP 997 DI 10.1378/chest.128.2.991 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 955BE UT WOS:000231198900074 PM 16100197 ER PT J AU Sternberg, KJ Lamb, ME Guterman, E Abbott, CB Dawud-Noursi, S AF Sternberg, KJ Lamb, ME Guterman, E Abbott, CB Dawud-Noursi, S TI Adolescents' perceptions of attachments to their mothers and fathers in families with histories of domestic violence: A longitudinal perspective SO CHILD ABUSE & NEGLECT LA English DT Article DE adolescents; attachment; domestic violence; child abuse ID PEER ATTACHMENT; INDIVIDUAL-DIFFERENCES; PARENTAL ATTACHMENT; BEHAVIOR PROBLEMS; COLLEGE-STUDENTS; UNITED-STATES; ADJUSTMENT; CHILDREN; PSYCHOPATHOLOGY; AGGRESSIVENESS AB Objective: The effects of both childhood and teenage experiences of domestic violence on adolescent-parent attachments were examined. Method: Israeli adolescents (M = 15.9 years) who were either victims of physical abuse, witnesses of physical spouse abuse, victims and witnesses of abuse, or neither victims nor witnesses of abuse were questioned about attachments to their parents using the Inventory of Parent and Peer Attachment [IPPA; Armsden, G. C., & Greenberg, M. T. (1987). The inventory of parent and peer attachment: Individual differences and their relationship to psychological well-being in adolescence. Journal of Youth and Adolescence, 16, 427-454]. Findings: Abuse status 5 years earlier was unrelated to the adolescents' current perceptions of their attachments whereas current abuse status predicted the adolescents' perceptions of attachment to their mothers. Adolescents who were victims of physical abuse reported weaker attachments to their parents than adolescents who were not abused or who had solely witnessed interparental physical abuse. Attachments to mothers were weaker whether or not mothers were the perpetrators of abuse. Conclusions: These findings suggest that victimization adversely affects children's perceptions of relationships with their parents, but that changes in the exposure to family violence are associated with changes in relationships with parents. These findings suggest that intervention can have positive effects on parent-child relationships despite violent histories. (c) 2005 Elsevier Ltd. All rights reserved. C1 NICHHD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Lamb, ME (reprint author), Univ Cambridge, Dept Social & Dev Psychol, Free Sch Lane, Cambridge CB2 3RQ, England. NR 63 TC 22 Z9 24 U1 5 U2 28 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2134 J9 CHILD ABUSE NEGLECT JI Child Abuse Negl. PD AUG PY 2005 VL 29 IS 8 BP 853 EP 869 DI 10.1016/j.chiabu.2004.07.009 PG 17 WC Family Studies; Psychology, Social; Social Work SC Family Studies; Psychology; Social Work GA 963BJ UT WOS:000231777500002 PM 16126269 ER PT J AU Eisenhofer, G AF Eisenhofer, G TI Sympathetic nerve function - Assessment by radioisotope dilution analysis SO CLINICAL AUTONOMIC RESEARCH LA English DT Review DE sympathetic nervous system; norepinephrine; spillover; clearance; turnover ID CONGESTIVE-HEART-FAILURE; CATECHOL-O-METHYLTRANSFERASE; FAILING HUMAN HEART; NOREPINEPHRINE SPILLOVER; ESSENTIAL-HYPERTENSION; PLASMA NOREPINEPHRINE; NEURONAL UPTAKE; WHOLE-BODY; MONOAMINE-OXIDASE; MENTAL STRESS AB Radioisotope dilution measurements of norepinephrine spillover (rate of entry of the transmitter into plasma) provide more accurate assessments of sympathoneural transmitter release than allowed by measurements of plasma catecholamine concentrations alone. Measurements of total body norepinephrine spillover, as an index of global sympathetic outflow, allow effects on plasma clearance to be distinguished from effects on release of catecholamines into plasma, while spillovers from specific tissues enable examination of regionalized sympathetic responses. However, spillovers of norepinephrine represent only a fraction of the transmitter that escapes neuronal and extraneuronal uptake after release by nerves. Numerous factors may influence this fraction and measures spillovers independently of transmitter release by nerves. Modified radioisotope dilution methods for assessment of rate processes operating within and between intracellular and extracellular compartments have further improved our understanding of the relationships of norepinephrine release, uptake, spillover, turnover, and metabolism. This article reviews the breadth of information about sympathetic nerve function attainable using catecholamine radioisotope dilution analyses against a backdrop of the relative advantages and methodological limitations associated with the methodology. C1 NIH, Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, Bethesda, MD 20892 USA. RP Eisenhofer, G (reprint author), NIH, Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, Bldg 10,Room 6N252,10 Ctr Dr, Bethesda, MD 20892 USA. EM ge@box-g.nih.gov NR 146 TC 21 Z9 23 U1 1 U2 2 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0959-9851 J9 CLIN AUTON RES JI Clin. Auton. Res. PD AUG PY 2005 VL 15 IS 4 BP 264 EP 283 DI 10.1007/s10286-005-0292-5 PG 20 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 954RX UT WOS:000231173600008 PM 16032382 ER PT J AU Mackay, H Hedley, D Major, P Townsley, C Mackenzie, M Vincent, M Degendorfer, P Tsao, MS Nicklee, T Birle, D Wright, J Siu, L Moore, M Oza, A AF Mackay, H Hedley, D Major, P Townsley, C Mackenzie, M Vincent, M Degendorfer, P Tsao, MS Nicklee, T Birle, D Wright, J Siu, L Moore, M Oza, A TI A phase II trial with pharmacodynamic endpoints of the proteasome inhibitor bortezomib in patients with metastatic colorectal cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID NF-KAPPA-B; PROSTATE-CANCER; CERVICAL-CANCER; HYPOXIC CELLS; PS-341; PATHWAY; ANGIOGENESIS; XENOGRAFTS; CARCINOMAS; ACTIVATION AB Purpose: To evaluate the effects of the proteasome inhibitor bortezomib on tumor growth in patients with advanced colorectal cancer, and to explore the relationship between correlative studies and clinical outcome. Design: Bortezomib (1.3 mg/m(2)) was administered i.v.. on days 1, 4, 8, and 11 of a 21-day cycle. Tumor response was assessed after every two cycles. Tumor biopsies were done prior to treatment and on day 9 of the first treatment cycle. Biopsies were examined for Ser(32/36)-I kappa B, Ser(276)-nuclear factor kappa B (NF kappa B), hypoxia-inducible factor-1 alpha (HIF-1 alpha), carbonic anhydrase IX (CAIX), p53, and microvessel density using immunohistochemistry. Results: Nineteen patients received 42 cycles (range 1-4) of bortezomib, No objective response was seen; three patients had stable disease at cycle 2, two patients had progressive disease after cycle1, and 11 patients had progressive disease at cycle 2. Of the three patients with stable disease, one had progressive disease after cycle 4, and two were withdrawn due to toxicity. The median time to progression was 5.1 weeks (95% confidence interval, 5.1-11.1 weeks). There was a significant increase in the expression of HIF-1 alpha relative to its transcriptional target CAIX following bortezomib, and a similar effect was also observed in a companion study using a human tumor xenograft model. Expression of p53, Ser(276)-NF kappa B, and Ser(32/36)-I kappa B was unchanged. Conclusion: Single agent bortezomib is inactive in metastatic colorectal cancer. Using this regimen, there was no detectable effect on NF kappa B, but a significant accumulation of HIF-1 alpha was seen relative to CAIX. This suggests that proteasome inhibition alters the response to tumor hypoxia, and further investigation of this effect is indicated. C1 Princess Margaret Phase II Consortium, Toronto, ON, Canada. NCI, Rockville, MD USA. RP Oza, A (reprint author), Princess Margaret Hosp, Univ Hlth Network, Dept Med Oncol & Hematol, 610 Univ Ave, Toronto, ON M5G 2M9, Canada. EM amit.oza@uhn.on.ca NR 25 TC 82 Z9 86 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 1 PY 2005 VL 11 IS 15 BP 5526 EP 5533 DI 10.1158/1078-0432.CCR-05-0081 PG 8 WC Oncology SC Oncology GA 950SX UT WOS:000230878900027 PM 16061869 ER PT J AU Yang, SX Tsang, KY Schlom, J AF Yang, SX Tsang, KY Schlom, J TI Induction of higher-avidity human CTLs by vector-mediated enhanced costimulation of antigen-presenting cells SO CLINICAL CANCER RESEARCH LA English DT Article ID CD8(+) T-CELLS; HUMAN CARCINOEMBRYONIC ANTIGEN; HUMAN DENDRITIC CELLS; FUNCTIONAL AVIDITY; IN-VITRO; ANTITUMOR-ACTIVITY; LYMPHOCYTE CLONES; IMMUNE-RESPONSES; FINE SPECIFICITY; CD40 LIGAND AB The efficacy of antigen-specific CID8(+) CTLs depends not only on the quantity of CTLs generated but also perhaps, more importantly, on the avidity of the CTLs. To date, however, no strategy has been shown to preferentially induce higher-avidity human CTLs. In the present study, antigen-presenting cells (APC) generated from human peripheral blood mononuclear cells were infected with a recombinant avipox vector (rF-) containing the transgenes for a triad of costimulatory molecules (human B7.1, intercellular adhesion molecule-1, and LFA-3, designated as rF-TRICOM) and then used to elicit peptide-specific CTLs from autologous T cells. Compared with peptide-pulsed noninfected APCs or peptide-pulsed APCs infected with wild-type vector, peptide-pulsed APCs infected with rF-TRICOM induced not only more CTLs but also higher-avidity CTLs; this was shown by tetramer staining, tetramer dissociation, IFN-gamma production, and cytolytic assays. Peptide-pulsed rF-TRICOM-infected dendritic cells were also shown to induce CTLs with a >10-fold higher avidity than CTLs induced using CD40L-matured dendritic cells; the use of peptide-pulsed CD40L-matured dendritic cells infected with rF-TRICOM as APCs induced CTLs of even greater avidity. To our knowledge, these studies are the first to show a methodology to induce higher-avidity human CTLs and have implications for the development of more efficient vaccines for a range of human cancers. C1 NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov FU NCI NIH HHS [Z01 BC010426-06, Z01 BC010428-06] NR 60 TC 22 Z9 24 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 1 PY 2005 VL 11 IS 15 BP 5603 EP 5615 DI 10.1158/1078-0432.CCR-05-0670 PG 13 WC Oncology SC Oncology GA 950SX UT WOS:000230878900037 PM 16061879 ER PT J AU Hortin, GL Meilinger, B AF Hortin, GL Meilinger, B TI Cross-reactivity of amino acids and other compounds in the biuret reaction: Interference with urinary peptide measurements SO CLINICAL CHEMISTRY LA English DT Article ID TRANSITIONAL-CELL CARCINOMA; MASS-SPECTROMETRY; LIQUID-CHROMATOGRAPHY; PROTEOMIC PATTERNS; PROTEIN-FRAGMENTS; HIPPURIC-ACID; SERUM; EXCRETION; PROFILES; BLADDER AB Background: Biuret assays for total protein measurement are considered to react with all peptides longer than 2 residues. Some studies using biuret assays of urine suggest that small peptides generally are more abundant than proteins in urine, but it is not clear whether this is a problem of assay specificity. Methods: We analyzed the specificity and kinetics of a biuret reaction for solutions of amino acids, organic compounds, peptides, proteins, and ultrafiltered urine specimens and compared the results with standard clinical assays for protein measurement. Results: The biuret assay cross-reacted with several amino acids, dipeptides, and other organic compounds able to form 5- or 6-member ring chelation complexes with copper. Reactions with amino acids and dipeptides had higher absorbance maxima (blue color) than with larger peptides and proteins (purple). Compounds forming potential 4-, 7-, 8-, or 9-member ring complexes with copper had low reactivity. Amino acid amides, dipeptides, and longer peptides had substantial reactivity, except those containing proline. Proteins and polypeptides had similar biuret reactivities per peptide bond, but reaction kinetics were slower for proteins than peptides. Urine specimens ultrafiltered through 3-kDa-cutoff membranes had substantial biuret reactivity, but absorbance maxima were consistent with cross-reactive amino acids rather than peptides. Conclusions: Many compounds, including amino acids, amino acid derivatives, and dipeptides, cross-react in biuret assays. Our studies improve understanding of the specificity of endpoint and kinetic biuret assays widely used in clinical laboratories. Amino acids, urea, and creatinine contribute to overestimation of urinary peptide content by biuret assays. (c) 2005 American Association for Clinical Chemistry. C1 NIH, Warren G Magnuson Clin Ctr, Dept Lab Med, Bethesda, MD 20892 USA. RP Hortin, GL (reprint author), NIH, Dept Lab Med, Bldg 10,Room 2C-407, Bethesda, MD 20892 USA. EM ghortin@mail.cc.nih.gov NR 40 TC 21 Z9 23 U1 1 U2 21 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 AUG PY 2005 VL 51 IS 8 BP 1411 EP 1419 DI 10.1373/clinchem.2005.052019 PG 9 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 949DV UT WOS:000230766000014 PM 15951313 ER PT J AU Jakupciak, JP Barker, PE Wang, W Srivastava, S Atha, DH AF Jakupciak, JP Barker, PE Wang, W Srivastava, S Atha, DH TI Preparation and characterization of candidate reference materials for telornerase assays SO CLINICAL CHEMISTRY LA English DT Article ID TELOMERASE ACTIVITY; CAPILLARY-ELECTROPHORESIS; REAL-TIME; CANCER; CELLS; VALIDATION; COMPONENTS; VARIANT AB Background: Telomerase has been measured in body fluids of cancer patients, and clinical tests for telomerase may have utility as noninvasive, cost-effective methods for the early detection of cancer. However, telomerase activity measured by common methods such as the telomerase repeat amplification protocol (TRAP) and telornerase reverse transcriptase catalytic subunit (hTERT) mRNA by reverse transcription-PCR (RT-PCR) varies among laboratories. Methods: We prepared a CHAPS buffer lysate from cultured A549 cells and stored it at -80 degrees C. Telomerase activity was measured by TRAP/PCR and real-time TRAP/RCR in conjunction with RT-PCR measurements of hTERT mRNA. Activity measured with use of the robot-assisted TRAP (RApidTRAP) multicapillary electrophoresis system was compared with single-capillary and slab-gel measurements in the range 10 to 10 000 cell equivalents. Results: Preparations made after flash freezing and sonication of cells were similar to 3-fold more active. Although the slab-gel and capillary instruments detected telomerase activity, the multicapillary instrument was better suited for high-throughput studies. Measurements of telomerase by TRAP/real-time PCR and hTERT mRNA/RT-PCR yielded reproducible titrations in the range 10 to 10 000 cell equivalents (CVs, 1%-8% and 1%-3%, respectively). Conclusions: We have prepared and characterized a candidate reference material that appears to be suitable for use in a wide range of assays of telomerase activity and expression. (c) 2005 American Association for Clinical Chemistry. C1 NIST, Div Biotechnol, Gaithersburg, MD 20899 USA. NCI, Canc Biomarkers Res Grp, Rockville, MD USA. RP Atha, DH (reprint author), NIST, Div Biotechnol, 100 Bur Sr,MS 8311, Gaithersburg, MD 20899 USA. EM donald.atha@nist.gov NR 22 TC 14 Z9 15 U1 1 U2 3 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 AUG PY 2005 VL 51 IS 8 BP 1443 EP 1450 DI 10.1373/clinchem.2004.044727 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 949DV UT WOS:000230766000017 PM 15951318 ER PT J AU Pinsky, PF Schoen, RE Weissfeld, JL Kramer, B Hayes, RB Yokochi, L AF Pinsky, PF Schoen, RE Weissfeld, JL Kramer, B Hayes, RB Yokochi, L CA PLCO Project Team TI Variability in flexible sigmoidoscopy performance among examiners in a screening trial SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article ID FECAL OCCULT-BLOOD; COLORECTAL-CANCER; RATES; MORTALITY; POLYP; SIZE AB Background & Aims: The efficacy of flexible sigmoidoscopy (FSG) in reducing colorectal cancer mortality is being evaluated in randomized trials. In 2 European trials, wide variability across examiners in FSG performance was noted. We report on the performance of examiners in the US randomized trial: the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Methods: Screening was performed at 10 geographically dispersed clinical centers. Patients with screens positive for a lesion or mass were referred to their private health care providers for endoscopic follow-up evaluation; lesions were not removed and a biopsy examination was not performed at screening. FSG performance among 64 examiners at these centers, each performing 100 or more baseline FSG examinations, with an aggregate of almost 50,000 examinations, was analyzed. Results: Screen-positivity results among examiners ranged from 9%-58%, with a coefficient of variation (CV) of 36%. CVs were 29% for distal polyp detection and 21% for distal adenoma detection. Inadequate rates ranged from 1%-27% (CV, 52%). Examiners with higher screen-positivity rates had higher false-positive rates, defined as a positive screen with no distal lesion found on endoscopic follow-up evaluation. Conclusions: Considerable variability exists in the rates of positive screens and in polyp and adenoma detection rates among FSG examiners performing the procedures using a common protocol. C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NIH, Off Prevent, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA USA. Pacific Hlth Res Inst, Honolulu, HI USA. RP Pinsky, PF (reprint author), 6130 Execut Blvd,EPN 3064, Bethesda, MD 20892 USA. EM pp4f@nih.gov NR 14 TC 28 Z9 29 U1 0 U2 0 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 AUG PY 2005 VL 3 IS 8 BP 792 EP 797 DI 10.1053/S1542-3565(05)00286-7 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 995MZ UT WOS:000234105700013 PM 16234008 ER PT J AU Gergely, P Pullmann, R Stancato, C Otvos, L Koncz, A Blazsek, A Poor, G Brown, KE Phillips, PE Perl, A AF Gergely, P Pullmann, R Stancato, C Otvos, L Koncz, A Blazsek, A Poor, G Brown, KE Phillips, PE Perl, A TI Increased prevalence of transfusion-transmitted virus and cross-reactivity with immunodominant epitopes of the HRES-1/p28 endogenous retroviral autoantigen in patients with systemic lupus erythematosus SO CLINICAL IMMUNOLOGY LA English DT Article DE SLE; HRES-1; endogenous retrovirus; TT virus ID TT-VIRUS; AUTOIMMUNE-DISEASE; BLOOD-DONORS; RHEUMATOID-ARTHRITIS; ANTIBODY REACTIVITY; REVISED CRITERIA; INFECTION; EXPRESSION; DNA; AUTOANTIBODIES AB Objective: Systemic lupus erythematosus (SLE) patients produce autoantibodies to HRES-1/p28, a human endogenous retrovirus-encoded nuclear protein. To identify cross-reactive viral antigens capable of triggering autoreactivity, HRES-1/p28 epitopes were mapped by SLE antibodies. Methods: Forty-four peptides overlapping HRES-1/p28 and 13 viral peptides were synthesized on cellulose membrane and tested for recognition by antibodies from 16 HRES-I Western blot seropositive SLE patients. Transfusion-transmitted virus (TTV) was detected by gene amplification in sera of 211 SLE patients, 78 healthy SLE family members, 199 unrelated healthy donors, and 91 rheumatoid arthritis (RA) patients. Results: HRES-1/p28 residues 41-55, 121-135, and 156-170 were recognized by 12/16 (75.0%), 11/16 (68.8%), and 9/16 lupus sera (56.25%) and considered immunodominant. HRES-1/p28 residues 121-135 harbor cross-reactive epitope with retroviral peptides and the 70 K U I snRNP lupus autoantigen. HRES-1/p28 residues 41-55 and 156-170 exhibited the highest prevalence of cross-reactivity with TTV peptide ORF2a (14/16, 87%). Prevalence of TTV DNA was increased in lupus patients (120/211) with respect to healthy (66/199, P < 0.0001) or RA controls (23/91; P < 0.0001). TTV prevalence in healthy lupus relatives (40/78) was decreased with respect to lupus patients (80/121; P = 0.0184) and increased with respect to unrelated healthy donors (66/199; P = 0.0026). HRES-1/p28 Western blot reactivity was observed in 12/23 TTV PCR-negative donors and 43/58 TTV PCR-positive donors (P < 0.0281). Conclusions: Increased prevalence of TTV and molecular mimicry with HRES-1/p28 may contribute to generation of antinuclear antibodies and pathogenesis of SLE. (c) 2005 Elsevier Inc. All rights reserved. C1 SUNY Upstate Med Univ, Rheumatol Sect, Dept Med, Coll Med, Syracuse, NY 13210 USA. SUNY Upstate Med Univ, Rheumatol Sect, Dept Microbiol, Coll Med, Syracuse, NY 13210 USA. SUNY Upstate Med Univ, Rheumatol Sect, Dept Immunol, Coll Med, Syracuse, NY 13210 USA. Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. Natl Inst Rheumatism & Physiotherapy, H-1023 Budapest, Hungary. NHLBI, NIH, Bethesda, MD 20892 USA. RP Perl, A (reprint author), SUNY Upstate Med Univ, Rheumatol Sect, Dept Med, Coll Med, 750 E Adams St, Syracuse, NY 13210 USA. EM perla@upstate.edu OI Perl, Andras/0000-0002-5017-1348 FU FIC NIH HHS [FO5 TW05421]; NIAID NIH HHS [R01 AI48079] NR 50 TC 32 Z9 33 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD AUG PY 2005 VL 116 IS 2 BP 124 EP 134 DI 10.1016/j.clim.2005.04.002 PG 11 WC Immunology SC Immunology GA 946ZI UT WOS:000230611400005 PM 15894513 ER PT J AU Macrae, J Friedman, AL Eggers, P Friedman, EA AF Macrae, J Friedman, AL Eggers, P Friedman, EA TI Improved survival in HIV-infected African-Americans with ESRD SO CLINICAL NEPHROLOGY LA English DT Article DE HIV nephropathy; highly active antiretroviral therapy; hemodialysis; therapy ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; AMBULATORY PERITONEAL-DIALYSIS; STAGE RENAL-DISEASE; HEMODIALYSIS; THERAPY AB Aims: To determine if there has been improvement in survival of HIV-infected patients with end-stage renal failure subsequent to widespread use of highly active antiretroviral therapy. Methods: The United States Renal Data System is a national data system funded by the National Institute of Diabetes and Digestive and Kidney Disease with the Centers for Medicare and Medicaid. Using the United States Renal Data System Standard Analysis Files, we analyzed all African-American end-stage renal failure patients in the United States from 1990 - 2001. We compared survival rates for patients with HIV disease, sickle cell anemia, diabetes, and all other diagnoses for the time periods 1990 - 1994 and 1995 - 2001. The main outcome measure was one- and five-year survival in each cohort. Results: One-year survival of African-American patients with end-stage renal disease and HIV increased from 46.6% during 1990 - 1994 to 65.1% during 1995 - 2001 (odds ratio 2.139). One-year survival decreased in the sickle cell group (odds ratio 0.595) and decreased slightly in the diabetic group (odds ratio 0.927) and all others (odds ratio 0.941). Five-year survival in the HIV group increased from 13.3% in 1990 - 1995 to 30.4% in 1995 - 2001 (odds ratio 2.847). There was no corresponding increase in survival for the sickle cell group (odds ratio 0.987), the diabetic group (odds ratio 1.06), or all others (odds ratio 1.137). Conclusions: We conclude that survival in African-American end-stage renal disease patients and HIV infection has substantially improved subsequent to introduction of highly active antiretroviral therapy. Our data support aggressive multi-drug treatment of end-stage renal failure patients with HIV infection. C1 Suny Downstate Med Ctr, Dept Med, Brooklyn, NY 11203 USA. Yale Univ, Sch Med, Dept Surg, New Haven, CT 06510 USA. NIDDKD, Bethesda, MD 20892 USA. RP Macrae, J (reprint author), Suny Downstate Med Ctr, Dept Med, Box 50,450 Clarkson Ave, Brooklyn, NY 11203 USA. EM Jeanne.Macrae@Downstate.edu NR 13 TC 10 Z9 10 U1 0 U2 0 PU DUSTRI-VERLAG DR KARL FEISTLE PI DEISENHOFEN-MUENCHEN PA BAHNHOFSTRASSE 9 POSTFACH 49, D-82032 DEISENHOFEN-MUENCHEN, GERMANY SN 0301-0430 J9 CLIN NEPHROL JI Clin. Nephrol. PD AUG PY 2005 VL 64 IS 2 BP 124 EP 128 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 952FL UT WOS:000230989300006 PM 16114788 ER PT J AU Garvey, MA Barker, CA Bartko, JJ Denckla, MB Wassermann, EM Castellanos, FX Dell, ML Ziemann, U AF Garvey, MA Barker, CA Bartko, JJ Denckla, MB Wassermann, EM Castellanos, FX Dell, ML Ziemann, U TI The ipsilateral silent period in boys with attention-deficit/hyperactivity disorder SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE transcallosal inhibition; interhemispheric interactions; transcranial magnetic stimulation; developmental disorders ID DEFICIT HYPERACTIVITY DISORDER; TRANSCRANIAL MAGNETIC STIMULATION; HUMAN CORPUS-CALLOSUM; TOURETTE-SYNDROME; MOTOR CORTEX; CHILDREN; INHIBITION; ADHD; MRI; MOVEMENTS AB Objective: Characterize maturation of transcallosal inhibition (ipsilateral silent period [iSP]) in attention deficit/hyperactivity disorder (ADHD) using transcranial magnetic stimulation (TMS). Background: Maturation of the iSP is related to acquisition of fine motor skills in typically developing children suggesting that dexterous fine motor skills depend upon mature interhemispheric interactions. Since neuromotor maturation is abnormal in boys with ADHD we hypothesized that iSP maturation in these children would be abnormal. We studied iSP maturation in 12 boys with ADHD and 12 age-matched, typically developing boys, 7-13 years of age. Methods: Surface electromyographic activity was recorded from right first dorsal interosseus (FDI). During background activation, focal TMS was delivered at maximal stimulator output over the ipsilateral motor cortex. Results: Maturation of finger speed in boys with ADHD was significantly slower than that in the control group. The iSP latency decreased with age in the control group but not in the ADHD group. Conclusions: These findings suggest the presence of a complex relationship between abnormalities of certain interhemispheric interactions (as represented by iSP latency) and delayed maturation of neuromotor skills in boys with ADHD. Significance: These data provide preliminary physiologic evidence supporting delayed or abnormal development of interhemispheric interactions in boys with ADHD. (c) 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 NINDS, MNB, Pediat Movement Disorders Unit, Human Motor Control Sect,NIH, Bethesda, MD 20892 USA. Kennedy Krieger Inst, Baltimore, MD USA. NINDS, Brain Stimulat Unit, Bethesda, MD 20892 USA. NYU, Ctr Child Study, New York, NY 10016 USA. Childrens Natl Med Ctr, Dept Psychiat, Washington, DC 20010 USA. Univ Frankfurt, Dept Neurol, D-60590 Frankfurt, Germany. RP Garvey, MA (reprint author), Natl Rehabil Hosp, Neurosci Res Ctr, 102 Irving St,NW, Washington, DC 20010 USA. EM marjorie.garvey@medstar.net RI Barker, Christopher/I-9477-2012; OI Castellanos, Francisco/0000-0001-9192-9437 NR 41 TC 34 Z9 36 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD AUG PY 2005 VL 116 IS 8 BP 1889 EP 1896 DI 10.1016/j.clinph.2005.03.018 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 956WM UT WOS:000231330700019 PM 15979402 ER PT J AU Glesby, MJ Aberg, JA Kendall, MA Fichtenbaum, CJ Hafner, R Hall, S Grosskopf, N Zolopa, AR Gerber, JG AF Glesby, MJ Aberg, JA Kendall, MA Fichtenbaum, CJ Hafner, R Hall, S Grosskopf, N Zolopa, AR Gerber, JG CA Adult AIDS Clin Trials Grp A51 TI Pharmacokinetic interactions between indinavir plus ritonavir and calcium channel blockers SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the Infectious-Diseases-Society-of-America CY SEP 30-OCT 03, 2004 CL Boston, MA SP Infect Dis Soc Amer ID ELEVATED BLOOD-PRESSURE; LIQUID-CHROMATOGRAPHY; HUMAN PLASMA; DILTIAZEM; AMLODIPINE; THERAPY; PHARMACODYNAMICS; LIPODYSTROPHY; INHIBITION; NIFEDIPINE AB Background: Hypertension is an important modifiable cardiac risk factor in human immunodeficiency virus (HIV)-infected patients. Calcium channel blockers are substrates of cytochrome P450 3A and are commonly prescribed for hypertension. We evaluated potential bidirectional pharmacokinetic interactions between calcium channel blockers and coadministered indinavir and ritonavir. Methods: Healthy HIV- seronegative subjects received 120 mg diltiazem daily or 5 mg amlodipine daily for days I to 7 and 20 to 26. All subjects received 100 mg ritonavir and 800 mg indinavir every 12 hours on days 8 to 26. Twenty-four-hour pharmacokinetic collection was performed on days 7 and 26, with 12-hour collection on day 19. Results: Indinavir plus ritonavir increased the median amlodipine area under the curve from 0 to 24 hours (AUC) by 89.8%, from 122 to 230 ng - h/mL (n = 18, P < .0001), and increased the median diltiazem AUC by 26.5%, from 800 to 1060 ng - h/mL (n = 13, P = .06). Of 13 subjects, 2 (15%) had greater than 4-fold increases in diltiazem AUC. Desacetyldiltiazem AUC increased by 102.2% (P = .001), and desmethyldiltiazem AUC decreased by 27.4% (P = .01). Neither amlodipine nor diltiazem affected steady-state AUCs of the protease inhibitors. No serious cardiovascular adverse effects were observed. Conclusions: Indinavir plus ritonavir increases the AUCs of both amlodipine and diltiazem, which may result in an increased response. If coadministration is indicated, amlodipine or diltiazem should be initiated at low doses with careful titration to response and side effects. C1 Cornell Univ, Weill Med Coll, Div Int Med & Infect Dis, Cornell Clin Trials Unit, New York, NY 10021 USA. Washington Univ, St Louis, MO 63130 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Cincinnati, Cincinnati, OH 45221 USA. NIAID, Div Aids, NIH, Bethesda, MD USA. Indiana Univ, Indianapolis, IN 46204 USA. Frontier Sci & Technol Res Fdn Inc, Buffalo, NY USA. Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. RP Glesby, MJ (reprint author), Cornell Univ, Weill Med Coll, Div Int Med & Infect Dis, Cornell Clin Trials Unit, 525 E 68th St,Box 566, New York, NY 10021 USA. EM mag2005@med.cornell.edu RI Kendall, Michelle/B-7665-2016 OI Kendall, Michelle/0000-0001-9160-4544 FU NCRR NIH HHS [M01-RR000070, M01-RR00036, M01-RR00047, M01-RR00052, M01-RR00083, M01-RR00044]; NIAID NIH HHS [AI-25897, AI-25903, AI-27668, AI-38855, AI-46386, AI-27658, AI-32775, AI-38858] NR 33 TC 42 Z9 45 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD AUG PY 2005 VL 78 IS 2 BP 143 EP 153 DI 10.1016/j.clpt.2005.04.005 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 953VY UT WOS:000231110700007 PM 16084849 ER PT J AU Beldarrain, MG Garcia-Monco, JC Astigarraga, E Gonzalez, A Grafman, J AF Beldarrain, MG Garcia-Monco, JC Astigarraga, E Gonzalez, A Grafman, J TI Only spontaneous counterfactual thinking is impaired in patients with prefrontal cortex lesions SO COGNITIVE BRAIN RESEARCH LA English DT Article DE prefrontal cortex; counterfactual thoughts; executive function; personality traits; emotional state AB Counterfactual thoughts (CFT) are mental simulations of what might have been if another behavior had been executed. They are pervasive in everyday life, help people learn from experience, modulate their emotional state, and contribute to decision-making and social functioning. To test the hypothesis that the prefrontal cortex (PFC) is involved in the generation, content, and use of CFT, we studied 18 patients with strictly prefrontal cortex lesions. Our results indicated that the PFC is crucial only for self-generated counterfactual reflections. We did not detect CFT generation differences based on lesion location within the PFC. CFT performance correlated positively with measures of attention, creativity, verbal skills, conscientiousness, and self-esteem and negatively with depression and dysexecutive symptoms. An impairment in counterfactual thinking may contribute to the lack of regret and insight often observed in patients with frontal lobe lesions. (c) 2005 Elsevier B.V. All rights reserved. C1 Hosp Galdakao, Dept Neurol, Galdakao 48960, Vizcaya, Spain. Magnet Resonance Imaging Unit, Osatek, Spain. NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Beldarrain, MG (reprint author), Hosp Galdakao, Dept Neurol, Galdakao 48960, Vizcaya, Spain. EM mgomezab@sarenet.es OI Grafman, Jordan H./0000-0001-8645-4457 NR 11 TC 16 Z9 16 U1 3 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0926-6410 J9 COGNITIVE BRAIN RES JI Cognit. Brain Res. PD AUG PY 2005 VL 24 IS 3 BP 723 EP 726 DI 10.1016/j.cogbrainres.2005.03.013 PG 4 WC Computer Science, Artificial Intelligence; Neurosciences; Neuroimaging SC Computer Science; Neurosciences & Neurology GA 962PH UT WOS:000231744200033 ER PT J AU Dobrovolskaia, MA Kozlov, SV AF Dobrovolskaia, MA Kozlov, SV TI Inflammation and cancer: When NF-kappa B amalgamates the perilous partnership SO CURRENT CANCER DRUG TARGETS LA English DT Review DE NF-kappa B; inflammation; cancer; drug discovery; drug development; cell-based assays ID TUMOR-NECROSIS-FACTOR; BASAL-CELL CARCINOMA; HELICOBACTER-PYLORI INFECTION; TOLL-LIKE RECEPTORS; IMIQUIMOD 5-PERCENT CREAM; HUMAN BREAST-CANCER; ASCORBIC-ACID CONCENTRATIONS; BENIGN PROSTATE HYPERPLASIA; GASTRIC EPITHELIAL-CELLS; CHRONIC ACTIVE HEPATITIS AB Chronic inflammation has long been suggested to constitute a risk factor for a variety of epithelial cancers such as malignancies of prostate, cervix, esophagus, stomach, liver, colon, pancreas, and bladder. An inflammatory response is typically accompanied by generation of free radicals, stimulation of cytokines, chemokines, growth and angiogenic factors. Free radicals, capable of both directly damaging DNA and affecting the DNA repair machinery, enhance genetic instability of affected cells, thus contributing to the first stage of neoplastic transformation also known as "initiation". Cytokines and growth factors can further promote tumor growth by stimulating cell proliferation, adhesion, vascularization, and metastatic potential of later stage tumors. Nuclear factor kappa B (NF-kappa B) is a family of ubiquitously expressed transcription factors that are widely believed to trigger both the onset and the resolution of inflammation. NF-kappa B also governs the expression of genes encoding proteins essential in control of stress response, maintenance of intercellular communications, and regulation of cellular proliferation and apoptosis. Recent data have expanded the concept of inflammation as a critical component in carcinogenesis suggesting new anti-inflammatory therapies for a complementary approach in treating a variety of tumor types. These observations highlighted the NF-kappa B pathway as an attractive avenue for drug discovery and development. The present review will outline recent advances in our understanding of NF-kappa B, function in the inflammatory processes and its input in tumor initiation/promotion, as well as summarize the development of animal and cell culture models for validating drug candidates with NF-kappa B-modulating activities, and applications of the latter in cancer therapy. C1 Natl Canc Inst Frederick, Ft Detrick, MD 21702 USA. PPD Dev, Richmond, VA 23230 USA. RP Kozlov, SV (reprint author), Natl Canc Inst Frederick, Boyles St,POB B, Ft Detrick, MD 21702 USA. EM skozlov@mail.ncifcrf.gov NR 239 TC 56 Z9 60 U1 0 U2 4 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0096 EI 1873-5576 J9 CURR CANCER DRUG TAR JI Curr. Cancer Drug Targets PD AUG PY 2005 VL 5 IS 5 BP 325 EP 344 DI 10.2174/1568009054629645 PG 20 WC Oncology SC Oncology GA 951CZ UT WOS:000230907800002 PM 16101381 ER PT J AU Higgins, RD AF Higgins, RD TI Ocular neovascularization: Genomic implications SO CURRENT GENOMICS LA English DT Article DE angiogenesis; eye; gene; neovascularization; pigment epithelium derived factor (PEDF); retinopathy; vascular endothelial growth factor (VEGF) ID ENDOTHELIAL GROWTH-FACTOR; EPITHELIUM-DERIVED FACTOR; VASCULAR-PERMEABILITY FACTOR; RETINAL NEOVASCULARIZATION; CHOROIDAL NEOVASCULARIZATION; FACTOR VEGF; PHOSPHOROTHIOATE OLIGONUCLEOTIDES; DIABETIC-RETINOPATHY; MACULAR DEGENERATION; CELL GROWTH AB Ocular neovascularization in the form of retinopathy, choroidal neovascularization, and age-related macular degeneration can be sight-threatening. Therapies have been directed at tissue ablation consisting of laser surgery and cryotherapy as well as medical therapies to reduce intraocular pressure. These therapies Occur later in the course of many kinds of ocular neovascularization. Advances in the field of angiogenesis biology have been critical to understanding the biology of various forms of ocular neovascularization. Vascular endothelial growth factor (VEGF) is the prime candidate for target of new therapies. Basic cellular experiments, animal studies and studies in genetically altered mice have been extremely helpful in elucidating ocular vascular pathology. Identification of factors involved in neovascularization, such as VFGF, and modification of their expression are vital to moving the field of ocular angiogenesis forward for ultimate clinical benefit. Applications of genomics to neovascularization are being developed both for detection of populations at high risk and for potential therapeutic intervention. Molecular biologic tools such as angiostatic gene transfer may prove to be sight-saving in the near future. C1 NICHD, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, Bethesda, MD 20892 USA. RP Higgins, RD (reprint author), NICHD, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, 6100 Execut Blvd,Room 4B03B,MSC 7510, Bethesda, MD 20892 USA. EM higginsr@mail.nih.gov NR 50 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 1389-2029 J9 CURR GENOMICS JI Curr. Genomics PD AUG PY 2005 VL 6 IS 5 BP 315 EP 318 DI 10.2174/1389202054750185 PG 4 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 959QU UT WOS:000231533900002 ER PT J AU Ferrari, M AF Ferrari, M TI Nanovector therapeutics SO CURRENT OPINION IN CHEMICAL BIOLOGY LA English DT Review ID IRON-OXIDE NANOPARTICLES; BLOOD-BRAIN-BARRIER; PHOTODYNAMIC THERAPY; CARRIER SYSTEM; DRUG-DELIVERY; CANCER; TUMORS; CHARGE; CELLS AB An ideal injected therapeutic drug would travel through the vasculature, reach the intended target at full concentration, and there act selectively on diseased cells and tissues only, without creating undesired side effects. Unfortunately, even the best current therapies fail to attain this ideal behavior, by a wide margin. A primary reason is the fact that the target recognition abilities of the current therapeutics molecules are quite limited. Furthermore, the natural defenses of the body present a sequence of formidable obstacles on the drug's pathway to the intended lesion. Requiring any molecule to have sufficient therapeutic efficacy, target recognition specificity, as well as all of the tools required to bypass multiple biological barriers is probably unrealistic. A different approach is to decouple the problem (i.e. employ the drug molecules for their therapeutic action only, and deliver them to the intended site by vectors that can be preferentially concentrated at desired body locations through the concurrent action of multiple targeting mechanisms). These vectors must also be large enough to comprise all the requirements for the evasion of the body defenses, while still sufficiently small so as not to create undesired blockages of even the smallest of blood vessels - and thus, by definition, nanotechnological. C1 Ohio State Univ, Columbus, OH 43210 USA. NCI, Bethesda, MD 20892 USA. RP Ferrari, M (reprint author), Ohio State Univ, 473 W 12th Ave, Columbus, OH 43210 USA. EM ferrari@lvd1.bme.ohio-state.edu NR 44 TC 81 Z9 84 U1 1 U2 15 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1367-5931 J9 CURR OPIN CHEM BIOL JI Curr. Opin. Chem. Biol. PD AUG PY 2005 VL 9 IS 4 BP 343 EP 346 DI 10.1016/j.cbpa.2005.06.001 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 957OA UT WOS:000231378000003 PM 15967706 ER PT J AU Oppenheim, JJ Yang, D AF Oppenheim, JJ Yang, D TI Alarmins: chemotactic activators of immune responses SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID EOSINOPHIL-DERIVED NEUROTOXIN; DENDRITIC CELL MATURATION; CHROMATIN PROTEIN HMGB1; GROUP BOX-1 PROTEIN; ANTIMICROBIAL-PEPTIDE; INNATE IMMUNITY; BETA-DEFENSIN; HOST-DEFENSE; EPITHELIAL-CELLS; NECROTIC CELLS AB The recruitment and activation of antigen-presenting cells are critical early steps in mounting an immune response. Many microbial components and endogenous mediators participate in this process. Recent studies have identified a group of structurally diverse multifunctional host proteins that are rapidly released following pathogen challenge and/or cell death and, most importantly, are able to both recruit and activate antigen-presenting cells. These potent immunostimulants, including defensins, cathelicidin, eosinophil-derived neurotoxin, and high-mobility group box protein 1, serve as early warning signals to activate innate and adaptive immune systems. We propose to highlight these proteins' unique activities by grouping them under the novel term 'alarmins', in recognition of their role in mobilizing the immune system. C1 NCI, Mol Immunoregulat Lab, Ctr Canc Res, Basic Res Program,Sci Applicat & Int Cooperat Inc, Frederick, MD 21702 USA. RP Oppenheim, JJ (reprint author), NCI, Mol Immunoregulat Lab, Ctr Canc Res, Basic Res Program,Sci Applicat & Int Cooperat Inc, Frederick, MD 21702 USA. EM Oppenhei@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 53 TC 394 Z9 426 U1 5 U2 24 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 AUG PY 2005 VL 17 IS 4 BP 359 EP 365 DI 10.1016/j.coi.2005.06.002 PG 7 WC Immunology SC Immunology GA 947UX UT WOS:000230673900005 PM 15955682 ER PT J AU Bray, M AF Bray, M TI Pathogenesis of viral hemorrhagic fever SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID EBOLA-VIRUS INFECTION; DENDRITIC CELLS; CYNOMOLGUS MACAQUES; MARBURG VIRUSES; PRIMATE MODELS; YELLOW-FEVER; COAGULATION; PATHOPHYSIOLOGY; ACTIVATION; APOPTOSIS AB Single-stranded RNA viruses from four different families cause a syndrome of fever and malaise, 'capillary leak' with loss of plasma volume, and coagulation defects which can lead to bleeding. Although direct cytopathic effects can contribute to disease severity, most features of illness are caused by innate immune responses, as the systemic spread of virus to macrophages and dendritic cells leads to the release of mediators that modify vascular function and have procoagulant activity. The synthesis of tissue factor by infected cells can also trigger coagulation. Failure of adaptive immunity through impaired dendritic cell function and lymphocyte apoptosis can have a crucial role in fatal infection. C1 NIAID, Biodef Clin Res Branch, Off Clin Res, NIH, Bethesda, MD 20892 USA. RP Bray, M (reprint author), NIAID, Biodef Clin Res Branch, Off Clin Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mbray@niaid.nih.gov NR 32 TC 92 Z9 96 U1 0 U2 29 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 AUG PY 2005 VL 17 IS 4 BP 399 EP 403 DI 10.1016/j.coi.2005.05.001 PG 5 WC Immunology SC Immunology GA 947UX UT WOS:000230673900010 PM 15955687 ER PT J AU Wang, E Panelli, MC Marincola, FM AF Wang, E Panelli, MC Marincola, FM TI Gene profiling of immune responses against tumors SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID METASTATIC MELANOMA; T-LYMPHOCYTES; IMMUNOTHERAPY; EXPRESSION; CELLS; IMMUNIZATION; ENHANCEMENT AB Clinical trials of tumor-antigen-specific immunization have clearly shown that immune-mediated tumor rejection requires more than simple T cell-target cell interactions. In vivo generation of tumor-specific T cells is one of a series of steps necessary for the induction of clinically relevant immune responses. In recent years, high-throughput functional genomics exposed the complexity of tumor immune biology, which underlies the kaleidoscopic array of variables associated with cancer instability and immunogenetic variability in humans. In the quest to understand immune rejection, hypothesis-driven approaches have failed to take into account the intricacy of human pathology by relying mostly on hypotheses derived from experimental models rather than direct clinical observation. Future investigations should reframe scientific thinking when applied to humans, utilizing descriptive tools to generate novel hypotheses relevant to human disease. C1 NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. 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 32 TC 25 Z9 25 U1 0 U2 0 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 AUG PY 2005 VL 17 IS 4 BP 423 EP 427 DI 10.1016/j.coi.2005.05.007 PG 5 WC Immunology SC Immunology GA 947UX UT WOS:000230673900014 PM 15950448 ER PT J AU Beekmann, SE Henderson, DK AF Beekmann, SE Henderson, DK TI Protection of healthcare workers from bloodborne pathogens SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Review DE bloodborne pathogens; healthcare workers; HIV transmission ID HIV POSTEXPOSURE PROPHYLAXIS; HEPATITIS-C VIRUS; OCCUPATIONAL-EXPOSURE; PERCUTANEOUS INJURIES; UNITED-STATES; NOSOCOMIAL TRANSMISSION; SURVEILLANCE-SYSTEM; NEEDLESTICK INJURY; SHARPS INJURIES; INFECTION AB Purpose of review For decades, healthcare workers have been known to be at risk from acquiring a variety of bloodborne pathogen infections as a result of occupational exposure. Primary prevention of exposures, as recommended by universal precautions guidelines, remains the cornerstone of protecting healthcare workers. Nonetheless, a substantial number of parenteral exposures continue to occur. Updated developments are summarized here, and recommendations for the protection of healthcare workers from bloodborne pathogens are provided. Recent findings The predominant evidence suggests that total percutaneous injuries have decreased over the last decade. Thoughtful adherence to universal precautions remains the primary means of preventing occupational exposures and thus of reducing occupational risk of infection with bloodborne pathogens. A number of studies' have provided additional evidence for the efficacy of safety devices in reducing specific subsets of injuries when combined with education and administrative interventions. Barriers to and positive predictors of universal precautions compliance have been identified. Postexposure prophylaxis remains the second line of defense; several authorities have now recommended three antiretroviral agents in this setting. Summary In summary; almost two decades of experience with universal/standard precautions has resulted in a decrease in parenteral injuries, but much work remains to be done. Vaccines, effective infection control procedures, safer procedures, and safer devices will all be necessary, along with a better understanding of factors that influence healthcare worker behaviors that result in injury. In addition, a number of issues relating to the postexposure management of occupational exposures with bloodborne pathogens need to be better understood. C1 Univ Iowa, Coll Med, Iowa City, IA USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Beekmann, SE (reprint author), Pathol 265 MRC, Iowa City, IA 52242 USA. EM susan-beekmann@uiowa.edu NR 50 TC 16 Z9 19 U1 1 U2 9 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 AUG PY 2005 VL 18 IS 4 BP 331 EP 336 DI 10.1097/01.qco.0000171921.52433.50 PG 6 WC Infectious Diseases SC Infectious Diseases GA 949UD UT WOS:000230812700007 PM 15985830 ER PT J AU Gillespie, PG Dumont, RA Kachar, B AF Gillespie, PG Dumont, RA Kachar, B TI Have we found the tip link, transduction channel, and gating spring of the hair cell? SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Review ID SHORT-INTERFERING RNAS; SYNDROME TYPE 1D; SENSORY TRANSDUCTION; KINOCILIAL LINKS; ION-CHANNEL; INNER-EAR; CADHERIN-23; HEARING; STEREOCILIA; DROSOPHILA AB Recent reports have offered candidates for key components of the apparatus used for mechanotransduction in hair cells. TRPA1 and cadherin 23 have been proposed to be the transduction channel and component of the tip link, respectively; moreover, ankyrin repeats in TRPA1 have been proposed to be the gating spring. Although these are excellent candidates for the three components, definitive experiments supporting each identification have yet to be per-formed. C1 Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, Portland, OR 97239 USA. Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97239 USA. Natl Inst Deafness & Other Commun Disorders, Sect Struct Cell Biol, NIH, Bethesda, MD 20892 USA. RP Gillespie, PG (reprint author), Oregon Hlth & Sci Univ, Oregon Hearing Res Ctr, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM gillespp@ohsu.edu OI Barr-Gillespie, Peter/0000-0002-9787-5860 FU Intramural NIH HHS; NIDCD NIH HHS [DC 003279, DC002368, DC004571, DC005983] NR 44 TC 37 Z9 41 U1 1 U2 8 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 AUG PY 2005 VL 15 IS 4 BP 389 EP 396 DI 10.1016/j.conb.2005.06.007 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 961KC UT WOS:000231660000003 PM 16009547 ER PT J AU Feller, SE Gawrisch, K AF Feller, SE Gawrisch, K TI Properties of docosahexaenoic-acid-containing lipids and their influence on the function of rhodopsin SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Review ID PROTEIN-COUPLED RECEPTOR; MOLECULAR-DYNAMICS SIMULATIONS; POLYUNSATURATED FATTY-ACIDS; ACYL-CHAIN UNSATURATION; ROD OUTER SEGMENTS; X-RAY-DIFFRACTION; PHOSPHOLIPID-MEMBRANES; H-2 NMR; PHYSICAL-PROPERTIES; WATER PERMEABILITY AB The importance of highly polyunsaturated fatty acids in health and development has been convincingly demonstrated by many studies over the past several decades. The mechanisms by which polyunsaturated lipid species might influence biological function at the molecular level are now attracting considerable attention. The G-protein-coupled receptor rhodopsin and docosahexaenoic acid, the dominant fatty acid in the retinal membrane, provide the best-studied example of protein function being influenced by lipid environment. C1 Wabash Coll, Dept Chem, Crawfordsville, IN 47933 USA. NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Feller, SE (reprint author), Wabash Coll, Dept Chem, Crawfordsville, IN 47933 USA. EM fellers@wabash.edu; gawrisch@helix.nih.gov NR 58 TC 66 Z9 69 U1 4 U2 11 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD AUG PY 2005 VL 15 IS 4 BP 416 EP 422 DI 10.1016/j.sbi.2005.07.002 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 959PX UT WOS:000231531300007 PM 16039844 ER PT J AU Thomas, D AF Thomas, D TI NIDA's virtual reality pain research program SO CYBERPSYCHOLOGY & BEHAVIOR LA English DT Meeting Abstract C1 NIDA, NIH, Bethesda, MD 20892 USA. EM Dthomas1@nida.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1094-9313 J9 CYBERPSYCHOL BEHAV JI CyberPsychol. Behav. PD AUG PY 2005 VL 8 IS 4 BP 362 EP 363 PG 2 WC Communication; Psychology, Applied SC Communication; Psychology GA 956KH UT WOS:000231298100099 ER PT J AU Yakar, S LeRoith, D Brodt, P AF Yakar, S LeRoith, D Brodt, P TI The role of the growth hormone/insulin-like growth factor axis in tumor growth and progression: Lessons from animal models SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE insulin-like growth factor; receptor; cancer; mouse models ID FACTOR-I RECEPTOR; FACTOR-BINDING PROTEIN-1; HUMAN-BREAST-CANCER; MOUSE EMBRYO FIBROBLASTS; TYROSINE KINASE-ACTIVITY; HORMONE-RELEASING-HORMONE; DOMINANT-NEGATIVE MUTANT; CELL LUNG-CARCINOMA; FACTOR IGF RECEPTOR; TRANSGENIC MICE AB Over the past two decades it has become widely appreciated that a relationship exists between the insulin-like growth factors (IGFs) and cancer. Many cancers have been shown to overexpress the IGF-I receptor and produce the ligands (IGF-I or IGF-II) and some combinations of the six IGF-binding proteins. With the recent demonstration by epidemiological studies that an elevated serum IGF-I level is associated with an increased relative risk of developing a number of epithelial cancers, interest has been sparked in this area of research with the possibility of targeting the IGF-I receptor in cancer treatment protocols. This review highlights many of the most relevant studies in this exciting area of research, focusing in particular on lessons learned from animal models of cancer. Published by Elsevier Ltd. C1 NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. McGill Univ, Royal Victoria Hosp, Ctr Hlth, Dept Med & Surg, Montreal, PQ H3A 1A1, Canada. RP Yakar, S (reprint author), NIDDKD, Diabet Branch, NIH, Bldg 10,Room 8D12,9000 Rockville Pike, Bethesda, MD 20892 USA. EM ShoshanaY@intra.niddk.nih.gov NR 154 TC 116 Z9 133 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD AUG-OCT PY 2005 VL 16 IS 4-5 BP 407 EP 420 DI 10.1016/j.cytogfr.2005.01.010 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 956WY UT WOS:000231332000004 PM 15886048 ER PT J AU Jiang, Q Li, WQ Aiello, FB Mazzucchelli, R Asefa, B Khaled, AR Durum, SK AF Jiang, Q Li, WQ Aiello, FB Mazzucchelli, R Asefa, B Khaled, AR Durum, SK TI Cell biology of IL-7, a key lymphotrophin SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE IL-7; Cdk; thymus; T cell; apoptosis; cell cycle ID THYMIC STROMAL LYMPHOPOIETIN; RECEPTOR-ALPHA-CHAIN; NAIVE T-CELLS; ACUTE LYMPHOBLASTIC-LEUKEMIA; PROTEIN-TYROSINE KINASE; COMMON GAMMA-CHAIN; SEVERE COMBINED IMMUNODEFICIENCY; FORKHEAD TRANSCRIPTION FACTOR; INTESTINAL EPITHELIAL-CELLS; STIMULATING FACTOR PPBSF AB IL-7 is essential for the development and survival of T lymphocytes. This review is primarily from the perspective of the cell biology of the responding T cell. Beginning with IL-7 receptor structure and regulation, the major signaling pathways appear to be via PI3K and Stat5, although the requirement for either has yet to be verified by published knockout experiments. The proliferation pathway induced by IL-7 differs from conventional growth factors and is primarily through posttranslational regulation of p27, a Cdk inhibitor, and Cdc25a, a Cdk-activating phosphatase. The survival function of IL-7 is largely through maintaining a favorable balance of bcl-2 family members including Bcl-2 itself and Mcl-1 on the positive side, and Bax, Bad and Bim on the negative side. There are also some remarkable metabolic effects of IL-7 withdrawal. Studies of IL-7 receptor signaling have yet to turn up unique pathways, despite the unique requirement for IL-7 in T cell biology. There remain significant questions regarding IL-7 production and the major producing cells have yet to be fully characterized. (C) 2005 Elsevier Ltd. All rights reserved. C1 NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Durum, SK (reprint author), NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Ctr Canc Res,NIH, Bldg 560,Rm 31-71, Frederick, MD 21702 USA. EM durums@ncifcrf.gov NR 280 TC 174 Z9 180 U1 1 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD AUG-OCT PY 2005 VL 16 IS 4-5 BP 513 EP 533 DI 10.1016/j.cytogfr.2005.05.004 PG 21 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 956WY UT WOS:000231332000009 PM 15996891 ER PT J AU Koo, BK Lim, HS Song, R Yoon, MJ Yoon, KJ Moon, JS Kim, YW Kwon, MC Yoo, KW Kong, MP Lee, J Chitnis, AB Kim, CH Kong, YY AF Koo, BK Lim, HS Song, R Yoon, MJ Yoon, KJ Moon, JS Kim, YW Kwon, MC Yoo, KW Kong, MP Lee, J Chitnis, AB Kim, CH Kong, YY TI Mind bomb 1 is essential for generating functional Notch ligands to activate Notch SO DEVELOPMENT LA English DT Article DE Notch signaling; mind bomb; endocytosis; Notch ligand; mouse ID DROSOPHILA-NEURALIZED GENE; UBIQUITIN LIGASE; SIGNALING PATHWAY; MICE LACKING; VASCULAR DEVELOPMENT; EMBRYONIC LETHALITY; ZEBRAFISH HINDBRAIN; PATTERNING DEFECTS; CELL FATE; DELTA AB The Delta-Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism essential for cell fate specification. Mind bomb 1 (Mib1) has been identified as a ubiquitin ligase that promotes the endocytosis of Delta. We now report that mice lacking Mib1 die prior to embryonic day 11.5, with pan-Notch defects in somitogenesis, neurogenesis, vasculogenesis and cardiogenesis. The Mib1(-/-) embryos exhibit reduced expression of Notch target genes Hes5, Hey1, Hey2 and Heyl, with the loss of N1icd generation. Interestingly, in the Mib1(-/-) mutants, DII1 accumulated in the plasma membrane, while it was localized in the cytoplasm near the nucleus in the wild types, indicating that Mib1 is essential for the endocytosis of Notch ligand. In accordance with the pan-Notch defects in Mib1(-/-) embryos, Mib1 interacts with and regulates all of the Notch ligands, jagged I and jagged 2, as well as DII1, DII3 and DII4. Our results show that Mib1 is an essential regulator, but not a potentiator, for generating functional Notch ligands to activate Notch signaling. C1 Pohang Univ Sci & Technol, Div Mol & Life Sci, Pohang 790784, South Korea. NICHD, Lab Mol Genet, NIH, Bethesda, MD 20892 USA. Chungnam Natl Univ, Dept Biol, Taejon 305764, South Korea. RP Kong, YY (reprint author), Pohang Univ Sci & Technol, Div Mol & Life Sci, Pohang 790784, South Korea. EM ykong@postech.ac.kr NR 50 TC 151 Z9 156 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD AUG PY 2005 VL 132 IS 15 BP 3459 EP 3470 DI 10.1242/dev.01922 PG 12 WC Developmental Biology SC Developmental Biology GA 960XZ UT WOS:000231627800012 PM 16000382 ER PT J AU Luo, T Zhang, YH Khadka, D Rangarajan, J Cho, KWY Sargent, TD AF Luo, T Zhang, YH Khadka, D Rangarajan, J Cho, KWY Sargent, TD TI Regulatory targets for transcription factor AP2 in Xenopus embryos SO DEVELOPMENT GROWTH & DIFFERENTIATION LA English DT Article DE dexamethasone; epidermis; neural crest; transcriptional control ID NEURAL CREST SPECIFICATION; FACTOR AP-2; PARAXIAL PROTOCADHERIN; DNA-BINDING; INDUCTION; GENE; CLONING; WNT; IDENTIFICATION; LAEVIS AB The transcription factor AP2 (TFAP2) has an important role in regulating gene expression in both epidermis and neural crest cells. In order to further characterize these functions we have used a hormone inducible TFAP2 alpha fusion protein in a Xenopus animal cap assay to identify downstream targets of this factor. The most common pattern comprised genes predominantly expressed in the epidermis. A second group was expressed at high levels in the neural crest, but all of these were also expressed in the epidermis as well as in other tissues in which TFAP2 alpha has not been detected, suggesting modular control involving both TFAP2-dependent and TFAP2-independent components. In addition, a few strongly induced genes did not overlap at all in expression pattern with that of TFAP2 alpha in the early embryo, and were also activated precociously in the experimentally manipulated ectoderm, and thus likely represent inappropriate regulatory interactions. A final group was identified that were repressed by TFAP2 alpha and were expressed in the neural plate. These results provide further support for the importance of TFAP2 alpha in ectoderm development, and also highlight the molecular linkage between the epidermis and neural crest in the Xenopus embryo. C1 NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Irvine, Irvine, CA 92697 USA. RP Sargent, TD (reprint author), NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM tsargent@nih.gov FU Intramural NIH HHS; NICHD NIH HHS [HD29507] NR 47 TC 16 Z9 16 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0012-1592 J9 DEV GROWTH DIFFER JI Dev. Growth Diff. PD AUG PY 2005 VL 47 IS 6 BP 403 EP 413 PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 955KN UT WOS:000231224900007 PM 16109038 ER PT J AU Liu, J Sempos, C Donahue, RP Dorn, J Trevisan, M Grundy, SM AF Liu, J Sempos, C Donahue, RP Dorn, J Trevisan, M Grundy, SM TI Joint distribution of non-HDL and LDL cholesterol and coronary heart disease risk prediction among individuals with and without diabetes SO DIABETES CARE LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; FACTOR INTERVENTION TRIAL; TREATMENT PANEL-III; CARDIOVASCULAR-DISEASE; APOLIPOPROTEIN-B; DYSLIPIDEMIA; MORTALITY; MANAGEMENT; EVENTS; PLASMA AB OBJECTIVE - To assess coronary heart disease (CHD) risk within levels of the joint distribution of non-HDL and LDL cholesterol among individuals with and Without diabetes. RESEARCH DESIGN AND METHODS - We used four publicly available data sets for this pooled post hoc analysis and confined the eligible subjects to white individuals aged >= 30 years and free of CHD at baseline (12,660 men and 6,721 women); Diabetes status Was defined as either "reported by physician-diagnosed and on medication" or having a fasting glucose level >= 126 mg/dl at the baseline examination. The primary end point was CHD death. Within diabetes categories, risk was assessed based on lipid levels (in mg/dl); non-HDL < 130 and LDL < 10.0 (group 1); nbn-HDL < 130 and LDL >= 100 (group 2); non-HDL >= 130 and LDL < 100 (group 3); and non-HDL : 130 and LDL >= 100 (group 4). Group I Within those without diabetes was I the overall reference group. RESULTS - Of the subjects studied, similar to 6% of then and 4% of women were defined as having diabetes. A total of 773 CHD deaths occurred during the average 13 years of follow-up time. A Cox proportional hazard model was used to estimate the relative risk (RR) of CHD death. Those with diabetes had a 200% higher RR than those without diabetes. In a multivariate model, CHD risk in those with diabetes did not increase with increasing LDL, whereas it did increase with increasing non-HDL: RR (95% confidence interval) for group 1: 5.7 (2.0-16.8); group 2: 5.7 (1.6-20.7); group 3: 7.2 (2.6-19.8); and group 4: 7.1 (3.7-13.6). CONCLUSIONS - Non-HDL is a stronger predictor of CHD death a among those with diabetes than LDL and should be given more consideration in the clinical approach to risk reduction among diabetic patients. C1 Brock Univ, Fac Appl Hlth Sci, St Catharines, ON L2S 3A1, Canada. NIH, Bethesda, MD 20892 USA. SUNY Buffalo, Buffalo, NY 14260 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. RP Liu, J (reprint author), Brock Univ, Fac Appl Hlth Sci, St Catharines, ON L2S 3A1, Canada. EM jliu@brocku.ca NR 30 TC 89 Z9 94 U1 0 U2 2 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 AUG PY 2005 VL 28 IS 8 BP 1916 EP 1921 DI 10.2337/diacare.28.8.1916 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 950PP UT WOS:000230869700011 PM 16043732 ER PT J AU Zaoutis, TE Foraker, E McGowan, KL Mortensen, J Campos, J Walsh, TJ Klein, JD AF Zaoutis, TE Foraker, E McGowan, KL Mortensen, J Campos, J Walsh, TJ Klein, JD TI Antifungal susceptibility of Candida spp. isolated from pediatric patients: A survey of 4 children's hospitals SO DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE LA English DT Article; Proceedings Paper CT 14th Focus on Fungal Infections Annual Meeting CY MAR 24-26, 2004 CL New Orleans, LA DE Candida; pediatric; susceptibility ID BLOOD-STREAM INFECTIONS; INTENSIVE-CARE-UNIT; ALBICANS; EPIDEMIOLOGY; STATES; SURVEILLANCE; FLUCONAZOLE; NEUTROPENIA; CASPOFUNGIN; OUTBREAK AB Candida species are the most common cause of fungal infections in hospitalized patients. Recent studies have reported a relative reduction in the rates of infection caused by Candida albicans and a shift toward non-albicans Candida spp. Data on the distribution and susceptibility of Candida spp. from children's hospitals are limited. Clinical isolates of Candida were collected from 4 US children's hospitals in 2003. Broth dilution MICs for amphotericin B, fluonazole, voriconazole, caspofungin, posaconazole, and ravuconazole were performed according to National Committee for Clinical Laboratory Standards-approved methodology. A total of 179 clinical isolates were identified and included. Of 179, 77 (43%) were C. albicans. Candida parapsilosis isolates were the second most frequently identified (57/175, 32%), followed by Candida glabrata, Candida tropicalis, and Candida lusitaniae (approximately 8% each). Caspofungin was the most active agent in vitro against all Candida spp. Fluconazole resistance was seen among C glabrata, C. tropicalis, and Candida krusei isolates. Newer azoles had improved activity against fluconazole-resistant isolates of Candida. Among isolates of C. parapsilosis, nearly 20% were resistant to amphotericin B. The current study highlights the emergence of C. parapsilosis as a distinct pediatric pathogen with clinical and therapeutic implications. Furthermore, our current susceptibility data include newer antifungal agents that appear to be quite active in vitro and may provide new therapeutic options for the treatment of serious yeast infections in children. (c) 2005 Elsevier Inc. All rights reserved. C1 Childrens Hosp Philadelphia, Div Infect Dis, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Educ & Res Therapeut, Philadelphia, PA 19104 USA. Infect Dis Lab Christiana Care Hlth Serv, Wilmington, DE USA. Cincinnati Childrens Hosp, Med Ctr, Dept Pathol & Lab Med, Cincinnati, OH 45299 USA. Childrens Natl Med Ctr, Dept Lab Med, Washington, DC 20010 USA. George Washington Univ, Med Ctr, Dept Pediat, Washington, DC 20037 USA. George Washington Univ, Med Ctr, Dept Pathol & Microbiol, Washington, DC 20037 USA. NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. AI DuPont Hosp Children, Div Infect Dis, Wilmington, DE 19803 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Pediat, Philadelphia, PA 19107 USA. RP Zaoutis, TE (reprint author), Childrens Hosp Philadelphia, Div Infect Dis, Philadelphia, PA 19104 USA. EM zaoutis@email.chop.edu NR 21 TC 33 Z9 37 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0732-8893 J9 DIAGN MICR INFEC DIS JI Diagn. Microbiol. Infect. Dis. PD AUG PY 2005 VL 52 IS 4 BP 295 EP 298 DI 10.1016/j.diagmicrobio.2005.03.002 PG 4 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA 972BY UT WOS:000232430100004 PM 15922535 ER PT J AU Saavedra, JM Pavel, J AF Saavedra, JM Pavel, J TI Angiotensin II AT(1) receptor antagonists inhibit the Angiotensin-CRF-AVP axis and are potentially useful for the treatment of stress-related and mood disorders SO DRUG DEVELOPMENT RESEARCH LA English DT Review DE renin-angiotensin system; natriuretic peptides; anxiety; depression; sympathetic system ID CORTICOTROPIN-RELEASING-FACTOR; ATRIAL-NATRIURETIC-PEPTIDE; CENTRAL-NERVOUS-SYSTEM; ANXIETY-RELATED BEHAVIOR; SPONTANEOUSLY HYPERTENSIVE-RATS; PITUITARY-ADRENAL AXIS; CEREBRAL-BLOOD-FLOW; MESSENGER-RNA EXPRESSION; V-1B RECEPTOR ANTAGONIST; CONVERTING ENZYME-INHIBITORS AB The corticotropin-releasing factor (CRF), arginine-vasopressin (AVP), atrial natriuretic peptide (ANP), and Angiotensin 11 (Ang 11) interact, regulating the central sympathetic system, the hypothalmic-pituitary-adrenal (HPA) axis, and the central behavioral mechanisms involved in the response to stress and the development of mood disorders. Non-peptidic, orally active AVP V-1, V-3, or CRF1 receptor antagonists reduce anxiety in animals. ANP is anxiolytic when administered to rodents and humans with anxiety disorders. These compounds are being developed for the therapy of anxiety and depression, but their clinical efficacy has not yet been established. Brain Ang 11, a physiological ANP antagonist, promotes CRF and AVP release and stimulates the peripheral and central sympathetic systems. The degree of Ang 11 AT(1) receptor stimulation determines the response to stress. An orally active, non-peptidic Ang 11 AT(1) receptor antagonist blocks CRF and AVP release during stress, prevents the sympathoadrenal and hormonal stress reaction, the cortical CRF1 and benzodiazepine receptor alterations, facilitates the effects of ANP, prevents stress-induced gastric ulcerations, and is anxiolytic in rodents. CRF, AVP, ANP, and the sympathetic system are intimately linked parts of a fundamental regulatory mechanism controlled by the brain Ang 11 system through AT(1) receptor stimulation, and should be studied together. Selective, safe antagonists of Ang 11 AT(1) receptors, with central effects after oral administration, have been actively used for the treatment of hypertension and should be considered also as potential anti-stress, anti-anxiety, and antidepressant compounds with properties similar or superior to the CRF and AVP antagonists or the ANP agonists under development. C1 NIMH, Pharmacol Sect, DIRP, NIH,DHHS, Bethesda, MD 20892 USA. RP Saavedra, JM (reprint author), NIMH, Pharmacol Sect, DIRP, NIH,DHHS, 10 Ctr Dr,MSC 1514,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM Saavedrj@mail.nih.gov NR 303 TC 9 Z9 9 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0272-4391 J9 DRUG DEVELOP RES JI Drug Dev. Res. PD AUG PY 2005 VL 65 IS 4 BP 237 EP 269 DI 10.1002/ddr.20027 PG 33 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 995VV UT WOS:000234133400006 ER PT J AU Hoffler, U Ghanayem, BI AF Hoffler, U Ghanayem, BI TI Increased bioaccumulation of urethane in CYP2E1-/- versus CYP2E1+/+ mice SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID ETHYL CARBAMATE URETHANE; VINYL CARBAMATE; OXIDATIVE CLEAVAGE; METABOLISM; ESTERS; CYTOCHROME-P450; INHIBITION; DNA AB Urethane is a fermentation by-product and a potent animal carcinogen. Human exposure to urethane occurs through consumption of alcoholic beverages and fermented foods. Recently, CYP2E1 was identified as the primary enzyme responsible for the metabolism of [C-14]carbonyl-labeled urethane. Subsequently, attenuation of urethane-induced cell proliferation and genotoxicity in CYP2E1-/- mice was reported. The present work compares the metabolism of single versus multiple exposures of CYP2E1-/- and CYP2E1-/- mice to C-14-ethyl-labeled urethane. Urethane was administered as a single 10 or 100 mg/kg gavage dose or at 100 mg/kg/day for 5 consecutive days. CYP2E1+/+ mice administered single or multiple doses exhaled 78 to 88% of dose as (CO2)-C-14/day. CYP2E1-/- mice eliminated 30 to 38% of a single dose as (CO2)-C-14 in 24 h and plateaued after day 3 at approximate to 52% of dose/day. The concentrations of urethane-derived radioactivity in plasma and tissues were dose-dependent, increased as a function of the number of doses administered, and were significantly higher in CYP2E1-/- versus CYP2E1-/- mice. Whereas urethane was the main chemical found in the plasma and tissues of CYP2E1-/- mice, it was not detectable in CYP2E1-/- mice. In conclusion, multiple dosing led to considerable bioaccumulation of urethane in mice of both genotypes; however, greater retention occurred in CYP2E1-/- versus CYP2E1-/- mice. Furthermore, greater bioaccumulation of C-14-ethyl-labeled than [C-14]carbonyl-labeled urethane was observed in mice. Comparison of the metabolism of ethyl-versus carbonyl-labeled urethane was necessary for tracing the source of CO2 and led us to propose for the first time that C-hydroxylation is a likely pathway of urethane metabolism. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Meharry Med Coll, Dept Pharmacol, Nashville, TN 37208 USA. RP Ghanayem, BI (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM ghanayem@niehs.nih.gov NR 27 TC 7 Z9 7 U1 0 U2 2 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 AUG PY 2005 VL 33 IS 8 BP 1144 EP 1150 DI 10.1124/dmd.105.003806 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 949VS UT WOS:000230816800009 PM 15879495 ER PT J AU Camara, JE Breier, AM Brendler, T Austin, S Cozzarelli, NR Crooke, E AF Camara, JE Breier, AM Brendler, T Austin, S Cozzarelli, NR Crooke, E TI Hda inactivation of DnaA is the predominant mechanism preventing hyperinitiation of Escherichia coli DNA replication SO EMBO REPORTS LA English DT Article DE replication; DnaA; oriC; Hda; initiation ID CHROMOSOME-REPLICATION; SEQA PROTEIN; INITIATION; CELLS; SEGREGATION; ORIGIN; SEQUESTRATION; COMPLEXES; BINDING; ROLES AB Initiation of DNA replication from the Escherichia coli chromosomal origin is highly regulated, assuring that replication occurs precisely once per cell cycle. Three mechanisms for regulation of replication initiation have been proposed: titration of free DnaA initiator protein by the datA locus, sequestration of newly replicated origins by SeqA protein and regulatory inactivation of DnaA (RIDA), in which active ATP-DnaA is converted to the inactive ADP-bound form. DNA microarray analyses showed that the level of initiation in rapidly growing cells that lack datA was indistinguishable from that in wild-type cells, and that the absence of SeqA protein caused only a modest increase in initiation, in agreement with flow-cytometry data. In contrast, cells lacking Hda overinitiated replication twofold, implicating RIDA as the predominant mechanism preventing extra initiation events in a cell cycle. C1 Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. NCI DBS, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Crooke, E (reprint author), Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, 3900 Reservoir Rd NW, Washington, DC 20007 USA. EM crooke@georgetown.edu FU NIGMS NIH HHS [R01 GM049700, R01 GM031655, R01GM49700] NR 35 TC 57 Z9 57 U1 0 U2 3 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 AUG PY 2005 VL 6 IS 8 BP 736 EP 741 DI 10.1038/sj.embor.7400467 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 955TC UT WOS:000231249500012 PM 16041320 ER PT J AU Stadler, K Roberts, A Becker, S Vogel, L Eickmann, M Kolesnikova, L Klenk, HD Murphy, B Rappuoli, R Abrignani, S Subbarao, K AF Stadler, K Roberts, A Becker, S Vogel, L Eickmann, M Kolesnikova, L Klenk, HD Murphy, B Rappuoli, R Abrignani, S Subbarao, K TI SARS vaccine protective in mice SO EMERGING INFECTIOUS DISEASES LA English DT Letter ID ACUTE RESPIRATORY SYNDROME; CORONAVIRUS SPIKE PROTEIN; NEUTRALIZATION; IMMUNIZATION; IMMUNITY C1 Chiron Vaccines, I-53100 Siena, Italy. NIH, Bethesda, MD 20892 USA. Inst Virol, Marburg, Germany. RP Abrignani, S (reprint author), Chiron Vaccines, Via Fiorentina 1, I-53100 Siena, Italy. EM sergio_abrignani@chiron.com RI Becker, Stephan/A-1065-2010 OI Becker, Stephan/0000-0002-2794-5659 NR 10 TC 19 Z9 22 U1 0 U2 1 PU CENTER DISEASE CONTROL PI ATLANTA PA ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD AUG PY 2005 VL 11 IS 8 BP 1312 EP 1314 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 950RL UT WOS:000230874900029 PM 16110580 ER PT J AU Marx, SJ Simonds, WF AF Marx, SJ Simonds, WF TI Hereditary hormone excess: Genes, molecular pathways, and syndromes SO ENDOCRINE REVIEWS LA English DT Review ID MULTIPLE ENDOCRINE NEOPLASIA; MEDULLARY-THYROID-CARCINOMA; TUMOR-SUPPRESSOR GENE; HIPPEL-LINDAU-DISEASE; PERSISTENT HYPERINSULINEMIC HYPOGLYCEMIA; FAMILIAL HYPOCALCIURIC HYPERCALCEMIA; POLYCYSTIC KIDNEY-DISEASE; CALCIUM-SENSING RECEPTOR; PROTEIN-KINASE-A; NEONATAL SEVERE HYPERPARATHYROIDISM AB Hereditary origin of a tumor helps toward early discovery of its mutated gene; for example, it supports the compilation of a DNA panel from index cases to identify that gene by finding mutations in it. The gene for a hereditary tumor may contribute also to common tumors. For some syndromes, such as hereditary paraganglioma, several genes can cause a similar syndrome. For other syndromes, such as multiple endocrine neoplasia 2, one gene supports variants of a syndrome. Onset usually begins earlier and in more locations with hereditary than sporadic tumors. Mono- or oligoclonal ("clonal") tumor usually implies a postnatal delay, albeit less delay than for sporadic tumor, to onset and potential for cancer. Hormone excess from a polyclonal tissue shows onset at birth and no benefit from subtotal ablation of the secreting organ. Genes can cause neoplasms through stepwise loss of function, gain of function, or combinations of these. Polyclonal hormonal excess reflects abnormal gene dosage or effect, such as activation or haploinsufficiency. Polyclonal hyperplasia can cause the main endpoint of clinical expression in some syndromes or can be a precursor to clonal progression in others. Gene discovery is usually the first step toward clarifying the molecule and pathway mutated in a syndrome. Most mutated pathways in hormone excess states are only partly understood. The bases for tissue specificity of hormone excess syndromes are usually uncertain. In a few syndromes, tissue selectivity arises from mutation in the open reading frame of a regulatory gene (CASR, TSHR) with selective expression driven by its promoter. Polyclonal excess of a hormone is usually from a defect in the sensor system for an extracellular ligand (e.g., calcium, glucose, TSH). The final connections of any of these polyclonal or clonal pathways to hormone secretion have not been identified. In many cases, monoclonal proliferation causes hormone excess, probably as a secondary consequence of accumulation of cells with coincidental hormone-secretory ability. C1 NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Marx, SJ (reprint author), NIDDKD, Metab Dis Branch, NIH, Bldg 10,Room 9C-101,10 Ctr Dr,MSC 1802, Bethesda, MD 20892 USA. EM StephenM@intra.niddk.nih.gov NR 461 TC 42 Z9 46 U1 1 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0163-769X EI 1945-7189 J9 ENDOCR REV JI Endocr. Rev. PD AUG PY 2005 VL 26 IS 5 BP 615 EP 661 DI 10.1210/er.2003-0037 PG 47 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 950HP UT WOS:000230848500002 PM 15632315 ER PT J AU Couse, JF Yates, MM Deroo, BJ Korach, KS AF Couse, JF Yates, MM Deroo, BJ Korach, KS TI Estrogen receptor-beta is critical to granulosa cell differentiation and the ovulatory response to gonadotropins SO ENDOCRINOLOGY LA English DT Article ID FOLLICLE-STIMULATING-HORMONE; MESSENGER-RIBONUCLEIC-ACID; PROSTAGLANDIN-ENDOPEROXIDE SYNTHASE-2; RAT OVARIAN FOLLICLES; LUTEINIZING-HORMONE; PROGESTERONE-RECEPTOR; GENE-EXPRESSION; NULL MICE; CYCLIC ADENOSINE-3',5'-MONOPHOSPHATE; MOUSE OVARY AB The process of granulosa cell differentiation that occurs in preovulatory follicles is dependent on FSH but requires augmentation by estradiol. To determine which estrogen receptor ( ER) form mediates the effects of estradiol during gonadotropin-induced follicle growth, differentiation, and rupture, we characterized the response of ER alpha- and ER beta-null mice to gonadotropin-induced ovulation. Immature mice were treated with an ovulatory regimen of exogenous gonadotropins and tissues were collected at distinct time points for morphological, biochemical, gene expression, and immunohistochemical analyses. Granulosa cells of ER beta knockout (ERKO) preovulatory follicles exhibited an attenuated response to FSH-induced differentiation, as evident by reduced aromatase activity and estradiol synthesis, and insufficient expression of LH receptor. As a result, beta ERKO ovaries were unable to fully respond to an ovulatory bolus of gonadotropin, leading to a reduced rate of follicle rupture; insufficient induction of prostaglandin-synthase 2 and progesterone receptor; an aberrant increase in aromatase activity and plasma estradiol; and incomplete expansion of the cumulus-oocyte complex. Parallel characterization of alpha ERKO females indicated a minimal role for ER alpha in granulosa cell differentiation, ovulation, and the concomitant changes in gene expression, although some abnormalities were revealed. These studies demonstrate that ER beta-mediated estradiol actions are vital to FSH-induced granulosa cell differentiation; and in the absence of ER beta, preovulatory follicles are deficient in the necessary cellular organization (i.e. antrum and cumulus oocyte complex), enzymatic activity (i.e. capacity to convert androgen precursor to estradiol), and receptor signaling pathways (i.e. LH receptor) to respond to a gonadotropin surge and expel a healthy oocyte. C1 NIEHS, Lab Reprod & Dev Toxicol, Receptor Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, Lab Reprod & Dev Toxicol, Receptor Biol Sect, NIH, POB 12233,MD B3-02, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X NR 97 TC 118 Z9 123 U1 0 U2 10 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 AUG PY 2005 VL 146 IS 8 BP 3247 EP 3262 DI 10.1210/en.2005-0213 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 944KR UT WOS:000230427400006 PM 15831568 ER PT J AU Martinez, JM Stephens, LC Jones, LA AF Martinez, JM Stephens, LC Jones, LA TI Long-term effects of neonatal exposure to hydroxylated polychlorinated biphenyls in the BALB/cCrgl mouse SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE BALB/cCrgl mouse; estrogenicity; female reproduction; hydroxylated polychlorinated biphenyls; OH-PCBs; tumorigenicity ID BALB-CCRGL MICE; BREAST-CANCER; MAMMARY-GLAND; HORMONAL CARCINOGENESIS; ESTROGEN-RECEPTOR; GESTATIONAL-AGE; PCB METABOLITES; NURSES HEALTH; ADENOCARCINOMA; DIOXINS AB The neonatal mouse model has been a valuable tool in determining the long-term effects of early exposure to estrogenic agents in mammals. Using this model, we compared the effects of 2,4',6'-trichloro-4-biphenylol (OH-PCB-30) and 2',3',4',5'-tetrachloro-4-biphenylol (OH-PCB-61) as prototype estrogenic hydroxylated PCBs (OH-PCBs) because they are reported to exhibit relatively high estrogenic activity both in vivo and in vitro. The purpose of this study was to examine the relationship between estrogenicity and carcinogenicity of OH-PCB congeners. The OH-PCBs were tested individually and in combination to determine whether effects of combined OH-PCBs differed from those of these OH-PCBs alone. We evaluated the long-term effects of neonatal exposure to OH-PCBs with treatment doses that were based on the reported binding affinity of specific OH-PCB congeners to estrogen receptor alpha. BALB/cCrgl female mice were treated within 16 hr after birth by subcutaneous injections every 24 hr, for 5 days. The mice treated with OH-PCB-30 (200 mu g/day) or 17 beta-estradiol (5 mu g/day) showed similar increased incidences of cervicovaginal (CV) tract carcinomas (43% and 47%, respectively). In addition, when mice were treated with OH-PCBs as a mixture, a change in the type of CV tract tumor was observed, shifting from predominantly squamous cell carcinomas to adenosquamous cell carcinoma. From our results, we conclude that the individual OH-PCBs tested were estrogenic and tumorigenic in mice when exposed during development of the reproductive tract. These data support the hypothesis that mixtures may act differently and unexpectedly than do individual compounds. Key words: BALB/cCrgl mouse, estrogenicity, female reproduction, hydroxylated polychlorinated biphenyls, OH-PCBs, tumorigenicity. C1 Univ Texas, MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Vet Med & Surg, Houston, TX 77030 USA. RP Martinez, JM (reprint author), NIEHS, POB 12233,MD C4-05, Res Triangle Pk, NC 27709 USA. EM martine2@niehs.nih.gov FU PHS HHS [16652] NR 60 TC 7 Z9 7 U1 1 U2 7 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 AUG PY 2005 VL 113 IS 8 BP 1022 EP 1026 DI 10.1289/ehp.7735 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 951OV UT WOS:000230941100040 PM 16079073 ER PT J AU Wilson, SH Schwartz, DA AF Wilson, SH Schwartz, DA TI Strategic planning: Establishing need and clarifying motivation SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov; schwartzd@niehs.nih.gov NR 0 TC 0 Z9 0 U1 1 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 AUG PY 2005 VL 113 IS 8 BP A506 EP A506 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 951OV UT WOS:000230941100002 PM 16079048 ER PT J AU Galperin, MY AF Galperin, MY TI To finish or not to finish? SO ENVIRONMENTAL MICROBIOLOGY LA English DT Editorial Material ID GENOME SEQUENCE; DICTYOSTELIUM-DISCOIDEUM; ABORTUS C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 NR 16 TC 2 Z9 2 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1462-2912 J9 ENVIRON MICROBIOL JI Environ. Microbiol. PD AUG PY 2005 VL 7 IS 8 BP 1061 EP 1064 DI 10.1111/j.1462-2920.2005.00879.x PG 4 WC Microbiology SC Microbiology GA 943EY UT WOS:000230336500001 PM 16011744 ER PT J AU Morris, SA Shibata, Y Noma, K Tsukamoto, Y Warren, E Temple, B Grewal, SIS Strahl, BD AF Morris, SA Shibata, Y Noma, K Tsukamoto, Y Warren, E Temple, B Grewal, SIS Strahl, BD TI Histone H3K36 methylation is associated with transcription elongation in Schizosaccharomyces pombe SO EUKARYOTIC CELL LA English DT Article ID RNA-POLYMERASE-II; H3 LYSINE-4 METHYLATION; SACCHAROMYCES-CEREVISIAE; FISSION YEAST; SET DOMAIN; METHYLTRANSFERASE; PROTEIN; CODE; PHOSPHORYLATION; HETEROCHROMATIN AB Set2 methylation of histone H3 at lysine 36 (K36) has recently been shown to be associated with RNA polymerase II (Pol II) elongation in Saccharomyces cerevisiae. However, whether this modification is conserved and associated with transcription elongation in other organisms is not known. Here we report the identification and characterization of the Set2 ortholog responsible for K36 methylation in the fission yeast Schizosaccharomyces pombe. We find that similar to the budding yeast enzyme, S. pombe Set2 is also a robust nucleosome-selective H3 methyltransferase that is specific for K36. Deletion of the S. pombe set2(+) gene results in complete abolishment of K36 methylation as well as a slow-growth phenotype on plates containing synthetic medium. These results indicate that Set2 is the sole enzyme responsible for this modification in fission yeast and is important for cell growth under stressed conditions. Using the chromatin immunoprecipitation assay, we demonstrate that K36 methylation in S. pombe is associated with the transcribed regions of Pol II-regulated genes and is devoid in regions that are not transcribed by Pol II. Consistent with a role for Set2 in transcription elongation, we find that S. pombe Set2 associates with the hyperphosphorylated form of Pol II and can fully rescue K36 methylation and Pol II interaction in budding yeast cells deleted for Set2. These results, along with our finding that K36 methylation is highly conserved among eukaryotes, imply a conserved role for this modification in the transcription elongation process. C1 Univ N Carolina, Sch Med, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Univ N Carolina, Sch Med, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. EM brian_strahl@med.unc.edu RI Strahl, Brian/C-7601-2012 OI Strahl, Brian/0000-0002-4947-6259 FU NCI NIH HHS [P30 CA016086]; NIGMS NIH HHS [R01 GM068088, GM68088] NR 54 TC 62 Z9 67 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 EI 1535-9786 J9 EUKARYOT CELL JI Eukaryot. Cell PD AUG PY 2005 VL 4 IS 8 BP 1446 EP 1454 DI 10.1128/EC.4.8.1446-1454.2005 PG 9 WC Microbiology; Mycology SC Microbiology; Mycology GA 956KP UT WOS:000231298900013 PM 16087749 ER PT J AU McShane, LM Altman, DG Sauerbrei, W Taube, SE Gion, M Clark, GM AF McShane, LM Altman, DG Sauerbrei, W Taube, SE Gion, M Clark, GM CA Stat Subcommittee NCI-EORTC TI REporting recommendations for tumour MARKer prognostic studies (REMARK) SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE tumour markers; guidelines; NCI; EORTC; REMARK; prognostic ID NEGATIVE BREAST-CANCER; DIAGNOSTIC-ACCURACY; RANDOMIZED TRIALS; COLORECTAL-CANCER; CONSORT STATEMENT; GUIDELINES; FUTURE; EPIDEMIOLOGY; METAANALYSIS; ELABORATION AB Despite years of research and hundreds of reports on tumour markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodologic problems have been cited to explain these discrepancies. Unfortunately, many tumour marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalisability of study results. The development of guidelines for the reporting of tumour marker studies was a major recommendation of the National Cancer Institute-European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. As for the successful CONSORT initiative for randomised trials and for the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, pre-planned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply. (C) 2005 Douglas G. Altman DSc, Gary M. Clark PhD, Dr. Massimo Gion, and Dr. Willi Sauerbrei. Published by Elsevier Ltd. All rights reserved. C1 NCI, Biometr Res Branch, DCTD, Bethesda, MD 20892 USA. RP McShane, LM (reprint author), NCI, Biometr Res Branch, DCTD, Room 8126,Execut Plaza N,MSC 7434,6130 Execut Blv, Bethesda, MD 20892 USA. EM Lm5h@nih.gov NR 42 TC 149 Z9 150 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD AUG PY 2005 VL 41 IS 12 BP 1690 EP 1696 DI 10.1016/j.ejca.2005.03.032 PG 7 WC Oncology SC Oncology GA 964PB UT WOS:000231891900015 PM 16043346 ER PT J AU Mahabir, S Baer, DJ Johnson, LL Frenkel, K Dorgan, JF Cambell, W Hartman, TJ Clevidence, B Albanes, D Judd, JT Taylor, PR AF Mahabir, S Baer, DJ Johnson, LL Frenkel, K Dorgan, JF Cambell, W Hartman, TJ Clevidence, B Albanes, D Judd, JT Taylor, PR TI No association between alcohol supplementation and autoantibodies to DNA damage in postmenopausal women in a controlled feeding study SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE alcohol; DNA damage; postmenopausal women ID 5-HYDROXYMETHYL-2'-DEOXYURIDINE; DIET AB Alcohol consumption is linked to increased breast cancer risk. Since oestrogens increase breast cancer risk, possibly through oxidative damage, and we have shown that alcohol consumption increases serum oestrogens, we tested whether moderate alcohol supplementation increased oxidative DNA damage among healthy postmenopausal women not on hormone replacement therapy in a randomized controlled crossover study. We used serum 5-hydroxymethyl-2-deoxyuridine (5-HMdU) autoantibodies (aAbs) as a marker of oxidative DNA damage. The results showed no evidence for increased or decreased levels of oxidative DNA damage among women who consumed 15 g or 30 g alcohol per day for 8 weeks compared with women in the 0g alcohol group. We conclude that among healthy women, it is possible that an 8-week trial of moderate alcohol supplementation might be too short to make enough 5-HMdU aAbs to compare differences by alcohol dose. In future studies, a panel of biomarkers for DNA damage should be used. European Journal of Cancer Prevention 14:427-429 (c) 2005 Lippincott Williams & Wilkins. C1 NCI, Canc Prevent Studies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. USDA ARS, Human Nutr Res Ctr, Beltsville, MD USA. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. Penn State Univ, Dept Nutr, University Pk, PA 16802 USA. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Mahabir, S (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Unit 1340, CPB4-3247,1515 Holcombe Blvd, Houston, TX 77030 USA. EM smahabir@mdanderson.org RI Mahabir, Somdat/A-9788-2008; Albanes, Demetrius/B-9749-2015 NR 8 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD AUG PY 2005 VL 14 IS 4 BP 427 EP 429 DI 10.1097/00008469-200508000-00017 PG 3 WC Oncology SC Oncology GA 955AF UT WOS:000231196300017 PM 16030435 ER PT J AU Kino, T Kozasa, T Chrousos, GP AF Kino, T Kozasa, T Chrousos, GP TI Statin-induced blockade of prenylation alters nucleocytoplasmic shuttling of GTP-binding proteins gamma 2 and beta 2 and enhances their suppressive effect on glucocorticoid receptor transcriptional activity SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE glucocorticoid receptor; GTP-binding protein beta; GTP-binding protein gamma; prenylation; statins; subcellular localization ID SUBUNITS; INTERACTS AB Background We previously reported that the guanine tri-phosphate-binding proteins (G) beta and gamma are both localized in the nucleus, in addition to their expected cytoplasmic/plasma membrane localization. These proteins, as a heterodimeric complex, suppress glucocorticoid response element-mediated transcriptional activity of the glucocorticoid receptor through direct physical interactions between G beta and the glucocorticoid receptor. Materials and methods As G gamma is prenylated at a cysteine residue in its C-terminal portion, and as this post-translational modification is required for many of the known G beta/G gamma activities, we examined the effect of its absence or diminution on G beta/G gamma-induced suppression of glucocorticoid receptor-induced transcriptional activity. Results In a functional reporter assay, G gamma 2C68S, which is defective at the prenylation site, was more potent than the wild-type G gamma 2 at increasing G beta 2-induced suppression of glucocorticoid receptor transactivation. Interestingly, the enhanced green fluorescent protein fusion of this mutant G gamma 2 was localized preferentially in the nucleus, while it was absent from the plasma membrane. Lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that abrogates the prenylation of G gamma, shifted the subcellular localization of enhanced green fluorescence protein-fused G gamma 2 and G beta 2 from the cytoplasm/plasma membrane to the nucleus and further suppressed glucocorticoid receptor-induced transcriptional activity. Conclusions These findings indicate that not only is the natural covalent addition of the prenyl residue to G gamma unnecessary for the transcriptional suppression induced by G beta/G gamma on the glucocorticoid receptor, but rather helps retain the G beta/G gamma complex away from the nucleus decreasing its antiglucocorticoid actions. C1 NICHHD, Pediat Endocrinol Sect, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA. Univ Athens, Sch Med, Dept Pediat 1, GR-11527 Athens, Greece. RP Kino, T (reprint author), NICHHD, Pediat Endocrinol Sect, Reprod Biol & Med Branch, NIH, Bldg 10,Room 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM kinot@mail.nih.gov NR 21 TC 15 Z9 15 U1 0 U2 0 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 AUG PY 2005 VL 35 IS 8 BP 508 EP 513 DI 10.1111/j.1365-2362.2005.01539.x PG 6 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 951KY UT WOS:000230930300007 PM 16101671 ER PT J AU Ishii, KJ Ito, S Tamura, T Hemmi, H Conover, J Ozato, K Akira, S Klinman, DM AF Ishii, KJ Ito, S Tamura, T Hemmi, H Conover, J Ozato, K Akira, S Klinman, DM TI CpG-activated Thy1.2(+) dendritic cells protect against lethal Listeria monocytogenes infection SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE CpG DNA; innate immunity; host protection; Listeria; TLR9 ID TOLL-LIKE RECEPTORS; ANTIGEN-PRESENTING CELLS; IFN-GAMMA-PRODUCTION; BACTERIAL-DNA; IMMUNE-RESPONSE; IN-VIVO; INNATE; OLIGODEOXYNUCLEOTIDES; MOTIFS; EXPRESSION AB Synthetic oligodeoxynucleotides containing CpG motifs (CpG ODN) activate the innate immune system by interacting with Toll-like receptor 9. The resultant immune response increases host resistance to infection by a variety of pathogenic microorganisms, including Listeria monocytogenes. There is a considerable interest in harnessing the immunoprotective properties of CpG ODN, yet little is known of the cell phenotype(s) responsible for mediating this protection. This work demonstrates that treatment of mice with CpG ODN increases the number of Thy1.2(+), CD11c(+) dendritic cells (Thy1.2(+) DC) in the spleen, which are both necessary and sufficient for transferring resistance to infection from CpG-treated donors to naive recipients. These CpG-activated Thy1.2(+) DC are distinct from conventional (CD11c(hi), Thy1.2(-)) or plasmacytoid DC (mPDCA(+)), and secrete IFN-gamma that contributes to protection. These findings suggest that a novel Thy1.2(+) DC subset plays a critical role in mediating the immunoprotective activity of CpG DNA. C1 US FDA, Sect Retroviral Immunol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Osaka Univ, ERATO, Japan Sci & Technol Agcy, Akira Innate Immun Project, Osaka, Japan. Osaka Univ, Microbial Dis Res Inst, Dept Host Def, Osaka, Japan. RP Klinman, DM (reprint author), US FDA, Sect Retroviral Immunol, Ctr Biol Evaluat & Res, Bldg 29A,Rm 3D 10, Bethesda, MD 20892 USA. EM klinman@cber.fda.gov RI Akira, Shizuo/C-3134-2009; Ishii, Ken/B-1685-2012 OI Ishii, Ken/0000-0002-6728-3872 NR 31 TC 16 Z9 18 U1 0 U2 0 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 AUG PY 2005 VL 35 IS 8 BP 2397 EP 2405 DI 10.1002/eji.200425795 PG 9 WC Immunology SC Immunology GA 957MK UT WOS:000231373700014 PM 16047338 ER PT J AU Monteiro, MC Nogueira, LG Souza, AAA Ribeiro, JMC Silva, JS Cunha, FQ AF Monteiro, MC Nogueira, LG Souza, AAA Ribeiro, JMC Silva, JS Cunha, FQ TI Effect of salivary gland extract of Leishmania vector, Lutzomyia longipalpis, on leukocyte migration in OVA-induced immune peritonitis SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE leukocyte migration; Lutzomyia longipalpis; salivary gland; neutrophils ID SAND FLY SALIVA; NITRIC-OXIDE PRODUCTION; HUMAN POLYMORPHONUCLEAR LEUKOCYTES; PROTEIN PHOSPHATASE-ACTIVITY; NECROSIS-FACTOR-ALPHA; TNF-ALPHA; PHLEBOTOMUS-PAPATASI; NEUTROPHIL MIGRATION; CUTANEOUS LEISHMANIASIS; RHEUMATOID-ARTHRITIS AB Salivary gland extracts (SGE) from Lutzomyia longipalpis potentate L. major infection by inducing a Th2 immune response. However, the effect of SGE on the effector phase of immune response is not known. Herein, we demonstrate that SGE inhibited neutrophil migration in ovalbumin (OVA)-induced peritonitis in immunized mice. SGE pretreatment of mice inhibited OVA-induced CD4(+) and CD8(+) T lymphocyte migration. The OVA-induced production of TNF-alpha, IL-1 beta and leukotriene B4 (LTB4), neutrophil chemotactic mediators in this model, were inhibited by SGE. On the other hand, SGE enhanced production of IL-10 and IL-4. In naive mice, SGE also blocked LTB4-induced neutrophil migration, but not that induced fMLP. Moreover, co-incubation of LTB4 (but not fMLP, TNF-alpha and MIP-1 alpha) with SGE inhibited the ability of LTB4 to induce neutrophil migration in vivo and in vitro. Altogether, the results suggest that SGE has anti-inflammatory properties that are associated with inhibition of TNF-alpha and LTB4 production and/or with the neutrophil chemotactic activity of LTB4. The effectiveness of SGE in inhibiting neutrophil migration and inflammatory mediators release in a Thl immune inflammatory response model reinforces the need for isolation of the compounds responsible for these activities, which could be used as prototypes for the development new anti-inflammatory drugs. C1 Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Pharmacol, BR-14049900 Ribeirao Preto, SP, Brazil. Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Biochem & Immunol, Sao Paulo, Brazil. Inst Evandro Chagas, Dept Parasitol, Belem, Para, Brazil. NIAID, Sect Med Entomol, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Cunha, FQ (reprint author), Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Pharmacol, Av Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP, Brazil. EM fdqcunha@fmrp.usp.br RI Silva, Joao/A-4484-2008; Monteiro, Marta Chagas/F-6575-2010; Cunha, Fernando/M-3090-2014; OI Monteiro, Marta Chagas/0000-0002-3328-5650; Ribeiro, Jose/0000-0002-9107-0818 NR 77 TC 10 Z9 10 U1 0 U2 2 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 AUG PY 2005 VL 35 IS 8 BP 2424 EP 2433 DI 10.1002/eji.200526160 PG 10 WC Immunology SC Immunology GA 957MK UT WOS:000231373700017 PM 15997469 ER PT J AU Julian, M Cacho, M Garcia, MA Martin-Santamaria, S de Pascual-Teresa, B Ramos, A Martinez, A Cuttitta, F AF Julian, M Cacho, M Garcia, MA Martin-Santamaria, S de Pascual-Teresa, B Ramos, A Martinez, A Cuttitta, F TI Adrenomedullin: a new target for the design of small molecule modulators with promising pharmacological activities SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Review DE adrenomedullin; cancer; diabetes; hypertension; positive and negative modulators ID GENE-RELATED-PEPTIDE; VASCULAR SMOOTH-MUSCLE; ADRENAL ZONA GLOMERULOSA; PROADRENOMEDULLIN-DERIVED PEPTIDES; AORTIC ENDOTHELIAL-CELLS; CENTRAL-NERVOUS-SYSTEM; RAT MESANGIAL CELLS; TERMINAL 20 PEPTIDE; ANGIOGENIC FACTOR ADRENOMEDULLIN; PROTEIN-COUPLED RECEPTOR AB Adrenomedullin (AM) is a 52-amino acid peptide with a pluripotential activity. AM is expressed in many tissues throughout the body, and plays a critical role in several diseases such as cancer, diabetes, cardiovascular and renal disorders, among others. While AM is a protective agent against cardiovascular disorders, it behaves as a stimulating factor in other pathologies such as cancer and diabetes. Therefore, AM is a new and promising target for the development of molecules which, through their ability to regulate AM levels, could be used in the treatment of these pathologies. (c) 2005 Elsevier SAS. All rights reserved. C1 Univ San Pablo, Fac Farm, Dept Quim, CEU, Madrid 28668, Spain. NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. RP Julian, M (reprint author), Univ San Pablo, Fac Farm, Dept Quim, CEU, Madrid 28668, Spain. EM m.julian@ceu.es RI Ramos, Ana/E-8740-2012; Martin-Santamaria, Sonsoles/A-8035-2012; Pascual-Teresa, Beatriz de/J-4318-2012; Martinez, Alfredo/A-3077-2013; Cuttitta, Frank/B-4758-2016 OI Ramos, Ana/0000-0003-2984-4672; Martin-Santamaria, Sonsoles/0000-0002-7679-0155; Pascual-Teresa, Beatriz de/0000-0002-1101-0373; Martinez, Alfredo/0000-0003-4882-4044; NR 278 TC 26 Z9 26 U1 1 U2 8 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 AUG PY 2005 VL 40 IS 8 BP 737 EP 750 DI 10.1016/j.ejmech.2004.10.016 PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 962OT UT WOS:000231742800001 PM 15927308 ER PT J AU Calon, F Lim, GP Morihara, T Yang, FS Ubeda, O Salem, N Frautschy, SA Cole, GM AF Calon, F Lim, GP Morihara, T Yang, FS Ubeda, O Salem, N Frautschy, SA Cole, GM TI Dietary n-3 polyunsaturated fatty acid depletion activates caspases and decreases NMDA receptors in the brain of a transgenic mouse model of Alzheimer's disease SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG-TERM POTENTIATION; DOCOSAHEXAENOIC ACID; LIPID-PEROXIDATION; NEURODEGENERATIVE DISORDERS; NEUROFIBRILLARY TANGLES; PRECURSOR PROTEIN; OXIDATIVE STRESS; BETA-PEPTIDE; APOPTOSIS; DEMENTIA AB Epidemiological data indicate that low n-3 polyunsaturated fatty acids (PFA) intake is a readily manipulated dietary risk factor for Alzheimer's disease (AD). Studies in animals confirm the deleterious effect of n-3 PFA depletion on cognition and on dendritic scaffold proteins. Here, we show that in transgenic mice overexpressing the human AD gene APPswe (Tg2576), safflower oil-induced n-3 PFA deficiency caused a decrease in N-methyl-D-aspartate (NMDA) receptor subunits, NR2A and NR2B, in the cortex and hippocampus with no loss of the presynaptic markers, synaptophysin and synaptosomal-associated protein 25 (SNAP-25). n-3 PFA depletion also decreased the NR1 subunit in the hippocampus and Ca(2+)/calmodulin-dependent protein kinase (CaMKII) in the cortex of Tg2576 mice. These effects of dietary n-3 PFA deficiency were greatly amplified in Tg2576 mice compared to nontransgenic mice. Loss of the NR2B receptor subunit was not explained by changes in mRNA expression, but correlated with p85 alpha phosphatidylinositol 3-kinase levels. Most interestingly, n-3 PFA deficiency dramatically increased levels of protein fragments, corresponding to caspase/calpain-cleaved fodrin and gelsolin in Tg2576 mice. This effect was minimal in nontransgenic mice suggesting that n-3 PFA depletion potentiated caspase activation in the Tg2576 mouse model of AD. Dietary supplementation with docosahexaenoic acid (DHA; 22 : 6n-3) partly protected from NMDA receptor subunit loss and accumulation of fodrin and gelsolin fragments but fully prevented CaMKII decrease. The marked effect of dietary n-3 PFA on NMDA receptors and caspase/calpain activation in the cortex of an animal model of AD provide new insights into how dietary essential fatty acids may influence cognition and AD risk. C1 Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. Greater Los Angeles Vet Affairs Healthcare Syst, Ctr Geriatr Res Educ & Clin, Sepulveda, CA USA. NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, Div Intramural Clin & Biol Res,NIH, Rockville, MD 20852 USA. RP Cole, GM (reprint author), Vet Adm Med Ctr, Greater Los Angeles Healthcare Syst, 16111 Plummer St,Bldg 7,Room A102, North Hills, CA 91343 USA. EM gmcole@ucla.edu FU NCCIH NIH HHS [R01 AT003008]; NIA NIH HHS [AG10685, AG13471, AG16793, P50 AG016570, R01 AG010685, R01 AG013741]; NINDS NIH HHS [NS43946] NR 84 TC 143 Z9 154 U1 1 U2 17 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 AUG PY 2005 VL 22 IS 3 BP 617 EP 626 DI 10.1111/j.1460-9568.2005.04253.x PG 10 WC Neurosciences SC Neurosciences & Neurology GA 954IE UT WOS:000231147700008 PM 16101743 ER PT J AU Kiyatkin, EA Brown, PL AF Kiyatkin, EA Brown, PL TI Dopamine-dependent and dopamine-independent actions of cocaine as revealed by brain thermorecording in freely moving rats SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE behavioural activation; dopamine uptake; metabolic brain activation; peripheral vasoconstriction; reinforcement; sodium channels ID CENTRAL-NERVOUS-SYSTEM; INTRAVENOUS COCAINE; RHESUS-MONKEYS; CONSCIOUS RATS; IN-VIVO; TEMPERATURE; RECEPTORS; FLUCTUATIONS; ACTIVATION; NEURONS AB Brain temperature fluctuates biphasically in response to repeated, intravenous (i.v.) cocaine injections, perhaps reflecting cocaine's inhibiting effect on both dopamine (DA) transporters and Na+ channels. By using a DA receptor blockade, one could separate these actions and determine the role of DA-dependent and DA-independent mechanisms in mediating this temperature fluctuation. Rats were chronically implanted with thermocouple probes in the brain, a non-locomotor head muscle and subcutaneously. Temperature fluctuations associated with ten repeated i.v. cocaine injections (1 mg/kg with 8-min inter-injection intervals) were examined after a combined, systemic administration of selective D1-like and D2-like receptor blockers (SCH-23390 and eticlopride) at doses that effectively inhibit DA transmission. In contrast to the initial temperature increases and subsequent biphasic fluctuations (decreases followed by increases) seen with repeated cocaine injections in saline-treated control, brain and muscle temperatures during DA receptor blockade decreased with each repeated cocaine injection. DA receptor blockade had no effects on skin temperature, which tonically decreased and biphasically fluctuated (decreases followed by increases) during repeated cocaine injections in both conditions. DA receptor blockade by itself slightly increased brain and muscle temperatures, with no evident effect on skin temperature. DA antagonists also strongly decreased spontaneous movement activity and completely blocked the locomotor activation normally induced by repeated cocaine injections. Although our data confirm that cocaine's inhibitory action on presynaptic DA uptake is essential for its ability to induce metabolic and behavioral activation, they also suggest that the physiological effects of this drug cannot be explained through this system alone. The continued hypothermic effect of cocaine points to its action on other central systems (particularly blockade of Na+ channels) that may be important for the development of cocaine abuse and adverse effects of this drug. C1 NIDA, Cellular Neurobiol Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), NIDA, Cellular Neurobiol Branch, Intramural Res Program, NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov NR 54 TC 20 Z9 20 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 AUG PY 2005 VL 22 IS 4 BP 930 EP 938 DI 10.1111/j.1460-9568.2005.04269.x PG 9 WC Neurosciences SC Neurosciences & Neurology GA 957UB UT WOS:000231397700015 PM 16115216 ER PT J AU Le Foll, B Melihan-Cheinin, P Rostoker, G Lagrue, G AF Le Foll, B Melihan-Cheinin, P Rostoker, G Lagrue, G CA Working Grp AFSSAPS TI Smoking cessation guidelines: evidence-based recommendations of the French Health Products Safety Agency SO EUROPEAN PSYCHIATRY LA English DT Review DE tobacco dependence; recommendations; treatment; nicotine replacement therapy; buproprion; review ID SUSTAINED-RELEASE BUPROPION; WEIGHT-GAIN; CIGARETTE-SMOKING; TRANSDERMAL NICOTINE; MAJOR DEPRESSION; HOSPITAL ANXIETY; TOBACCO SMOKING; COTININE LEVELS; DOUBLE-BLIND; DEPENDENCE AB Tobacco use is the leading preventable cause of death in developed countries. Millions of smokers are willing to stop, but few of them are able to do so. Clinicians should only use approaches that have demonstrated their efficacy in helping patients to stop smoking. This article summarizes the evidence-based major findings and clinical recommendations for the treatment of tobacco dependence of the French Health Products Safety Agency (AFSSAPS). Clinicians should enquire about the smoking status of each patient and provide information about health consequence of smoking and effective treatments available. These treatments include counseling (mainly individual or social support and behavioral and cognitive therapy) and pharmacological treatment with either nicotine replacement therapy (NRT) or bupropion LP. Pharmacological treatments should be used only for proven nicotine dependence, as assessed by the Fagerstrom test for Nicotine Dependence. The choice of pharmacologic treatment depends of the patient's preference and history and of the presence of contra-indications. The clinician should start with a single agent, but these treatments may be used in combination. Smoking behavior is a chronic problem that requires long-term management and follow-up. Access to intensive treatment combining pharmacological treatment and extensive behavioral and cognitive therapy should be available for highly dependent patients. Published by Elsevier SAS. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. Direct Gen Sante, Paris, France. French Hlth Prod Safety Agcy, AFSSAPS, F-92285 St Denis, France. Hop Albert Chenevier, Ctr Tabacol, Creteil, France. RP Le Foll, B (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, NIH,Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM blefoll@intra.nida.nih.gov RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 NR 98 TC 29 Z9 30 U1 2 U2 2 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0924-9338 J9 EUR PSYCHIAT JI Eur. Psychiat. PD AUG PY 2005 VL 20 IS 5-6 BP 431 EP 441 DI 10.1016/j.eurpsy.2004.12.008 PG 11 WC Psychiatry SC Psychiatry GA 969TL UT WOS:000232257600012 PM 16171657 ER PT J AU Kim, SM Kim, R Ryu, JH Jho, EH Song, KJ Jang, SI Kee, SH AF Kim, SM Kim, R Ryu, JH Jho, EH Song, KJ Jang, SI Kee, SH TI Multinuclear giant cell formation is enhanced by down-regulation of Wnt signaling in gastric cancer cell line, AGS SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE AGS cells; Wnt signaling; giant cell formation; beta-catenin; E-cadherin; ICAT ID ADENOMATOUS-POLYPOSIS-COLI; MITOTIC CHECKPOINT GENES; E-CADHERIN; BETA-CATENIN; TETRAPLOIDY CHECKPOINT; CHROMOSOME INSTABILITY; SUPPRESSOR GENE; EXPRESSION; P53; MUTATIONS AB AGS cells, which were derived from malignant gastric adenocarcinoma tissue, lack E-cadherin-mediated cell adhesion but have a high level of nuclear beta-catenin, which suggests altered Wnt signal. In addition, approximately 5% of AGS cells form multinuclear giant cells in the routine culture conditions, while taxol treatment causes most AGS cells to become giant cells. The observation of reduced nuclear beta-catenin levels in giant cells induced by taxol treatment prompted us to investigate the relationship between Wnt signaling and giant cell formation. After overnight serum starvation, the shape of AGS cells became flattened, and this morphological change was accompanied by decrease in Myc expression and an increase in the giant cell population. Lithium chloride treatment, which inhibits GSK3 beta activity, reversed these serum starvation effects, which suggests an inverse relationship between Wnt signaling and giant cell formation. Furthermore, the down-regulation of Wnt signaling caused by the over-expression of ICAT, E-cadherin, and Axin enhanced giant cell fort-nation. Therefore, down-regulation of Wnt signaling may be related to giant cell formation, which is considered to be a survival mechanism against induced cell death. (c) 2005 Elsevier Inc. All rights reserved. C1 Korea Univ, Coll Med, Dept Microbiol, Lab Epithelial Cell Biol, Seoul 136705, South Korea. Univ Seoul, Dept Life Sci, Seoul, South Korea. Natl Inst Dent & Craniofacial Res, Human Craniofacial Genet Sect, NIH, Bethesda, MD 20892 USA. RP Kee, SH (reprint author), Korea Univ, Coll Med, Dept Microbiol, Lab Epithelial Cell Biol, 126-1,Anam S Ga, Seoul 136705, South Korea. EM keesh@korea.ac.kr NR 52 TC 10 Z9 12 U1 0 U2 0 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495, UNITED STATES SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD AUG 1 PY 2005 VL 308 IS 1 BP 18 EP 28 DI 10.1016/j.yexcr.2005.04.002 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 948FV UT WOS:000230702300002 PM 15878526 ER PT J AU Chen, JC Brandt, JS Ellison, FM Calado, RT Young, NS AF Chen, JC Brandt, JS Ellison, FM Calado, RT Young, NS TI Defective stromal cell function in a mouse model of infusion-induced bone marrow failure SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID MEDIATED APLASTIC-ANEMIA; STEM-CELL; IN-VITRO; MYELODYSPLASTIC SYNDROME; GROWTH; EXPRESSION; CULTURE; MICE; TRANSPLANTATION; THROMBOPOIETIN AB Objective. To study bone marrow (BM) stromal damage in a mouse model of infusion-induced BM failure. Materials and Methods. Sublethally irradiated CByB6F1 mice were infused with 5 X 10(6) C57BL/ 6 (B6) lymph node (LN) cells. Recipient BM cells were taken at 3, 7, 10, and 14 days following LN infusion and were cultured in vitro in alpha-modified Eagle media for 2-3 weeks. Peripheral blood and was analyzed by complete blood counts while BM lymphocyte infiltration/expansion was analyzed by flow cytometry. Marrow cells from affected and control mice were mixed and cultured in vitro to test nonspecific stromal damage. Results. Donor lymphocytes infiltrated host BM within 3-7 days and expanded significantly between 7 and 10 days, concurrent with the development of leukopenia, thrombocytopenia, and marrow hypoplasia. BM cells from mice at 7, 10, and 14 days after B6-LN cell infusion were progressively defective in forming stromal feeder layers. A 1:1 mixture of BM cells from affected CByB6F1 mice and normal B6 mice failed to form an effective stromal feeder layer that could support cobblestone colony formation, indicating that lymphocytes in the BM of affected CByB6F1 mice were able to damage stromal cells in the normal B6 BM. Conclusion. Activated lymphocytes destroy both hematopoietic and stromal cells as innocent bystanders in the infusion-induced BM failure model. (c) 2005 International Society for Experimental Hematology. Published by Elsevier Inc. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Chen, JC (reprint author), NHLBI, Hematol Branch, NIH, NIH Bldg,10 CRC Room 3-5132 Ctr Dr, Bethesda, MD 20892 USA. EM chenji@nhlbi.nih.gov RI Calado, Rodrigo/G-2619-2011 NR 37 TC 12 Z9 15 U1 0 U2 2 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 AUG PY 2005 VL 33 IS 8 BP 901 EP 908 DI 10.1016/j.exphem.2005.04.008 PG 8 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 955PM UT WOS:000231238400007 PM 16038782 ER PT J AU Mi, RF Luo, YQ Cai, JL Limke, TL Rao, MS Hoke, A AF Mi, RF Luo, YQ Cai, JL Limke, TL Rao, MS Hoke, A TI Immortalized neural stem cells differ from nonimmortalized cortical neurospheres and cerebellar granule cell progenitors SO EXPERIMENTAL NEUROLOGY LA English DT Article DE neural stem cells; C17.2 cells; noninnnortalized stem cell population ID SPINAL-CORD; NEUROTROPHIC FACTORS; NEURONAL PRECURSORS; MOTOR-NEURONS; MOUSE-BRAIN; RHOMBIC LIP; IN-VITRO; DIFFERENTIATION; CULTURE; SYSTEM AB Pluripotent neural stem cells (NSCs) have been used as replacement cells in a variety of neurological disease models. Among the many different NSCs that have been used to date, most robust results have been obtained with the immortalized neural stem cell line (C17.2) isolated from postnatal cerebellum. However, it is unclear if other NSCs isolated from different brain regions are similar in their potency as replacement therapies. To assess the properties of NSC-like C17.2 cells, we compared the properties of these cells with those reported for other NSC populations identified by a variety of different investigators using biological assays, microarray analysis, RT-PCR, and immunocytochemistry. We show that C17.2 cells differ significantly from other NSCs and cerebellar granule cell precursors, from which they were derived. In particular, they secrete additional growth factors and cytokines, express markers that distinguish them from other progenitor populations, and do not maintain karyotypic stability. Our results provide a caution on extrapolating results from C17.2 to other nonimmortalized stem cell populations and provide an explanation for some of the dramatic effects that are seen with C17.2 transplants but not with other cells. We suggest that, while C17.2 cells can illustrate many fundamental aspects of neural biology and are useful in their own right, their unique properties cannot be generalized. (c) 2004 Elsevier Inc. All rights reserved. C1 Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. NIA, Neurosci Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21287 USA. RP Hoke, A (reprint author), Johns Hopkins Univ, Dept Neurol, 60 N Wolfe St,Path 509, Baltimore, MD 21287 USA. EM ahoke@jhmi.edu OI Hoke, Ahmet/0000-0003-1215-3373 NR 44 TC 37 Z9 42 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD AUG PY 2005 VL 194 IS 2 BP 301 EP 319 DI 10.1016/j.expneurol.2004.07.011 PG 19 WC Neurosciences SC Neurosciences & Neurology GA 950RW UT WOS:000230876100002 PM 16022860 ER PT J AU Seydel, KB Gaur, D Aravind, L Subramanian, G Miller, LH AF Seydel, KB Gaur, D Aravind, L Subramanian, G Miller, LH TI Plasmodium falciparum: Characterization of a late asexual stage Golgi protein containing both ankyrin and DHHC domains SO EXPERIMENTAL PARASITOLOGY LA English DT Article DE malaria; Plasmodium; palmitoylation; ankyrin ID PALMITOYLATION; LOCALIZATION; ENDOCYTOSIS; MECHANISMS; MEMBRANE; KINASE; AKR1P AB Proteins containing the DHHC motif have been shown to function as palmitoyl transferases. The palmitoylation of proteins has been shown to play an important role in the trafficking of proteins to the proper subcellular location. Herein, we describe a protein containing both ankyrin domains and a DHHC domain that is present in the Golgi of late schizonts of P.falciparum. The timing of expression as well as the location of this protein suggests that it may play an important role in the sorting of proteins to the apical organelles during the development of the asexual stage of the parasite. Published by Elsevier Inc. C1 NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Human Genome Sci, Rockville, MD USA. RP Miller, LH (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. EM lmiller@niaid.nih.gov NR 17 TC 11 Z9 11 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4894 J9 EXP PARASITOL JI Exp. Parasitol. PD AUG PY 2005 VL 110 IS 4 BP 389 EP 393 DI 10.1016/j.exppara.2005.03.030 PG 5 WC Parasitology SC Parasitology GA 950SV UT WOS:000230878600008 PM 15882865 ER PT J AU Cox, MC Scripture, CD Figg, WD AF Cox, MC Scripture, CD Figg, WD TI Leuprolide acetate given by a subcutaneous extended-release injection: less of a pain? SO EXPERT REVIEW OF ANTICANCER THERAPY LA English DT Review DE androgen; leuprolide acetate; luteinizing hormone; luteinizing hormone-releasing hormone; prostate cancer ID PROSTATE-CANCER; DELIVERY-SYSTEM AB Androgen deprivation therapy is a mainstay for the treatment of advanced prostate cancer. Hormonal therapy commonly consists of injection of gonadotropin hormone-releasing hormone agonists. Based on the need for improved convenience of administration, a novel formulation of leuprolide acetate (Ellgard (R); Atrix Laboratories Inc. & Sanofl Aventis) which incorporates a mixture of selected polymers and solvents to achieve sustained drug delivery after subcutaneous injection, was developed. The US Food and Drug Administration has approved 1-, 3-, 4- and 6-month formulations of leuprolide acetate. In clinical trials, leuprolide acetate achieves sustained suppression of serum testosterone to castration levels (<= 50 ng/dl). The adverse-event profile is consistent with the effects of testosterone suppression. This novel delivery system in addition to the availability of a 6-month formulation of leuprolide acetate, offers patients the option of a convenient twice-yearly injection schedule. C1 NCI, Med Oncol Clin Res Unit, Ctr Canc Res, Clin Pharmacol Res Core, Bethesda, MD 20892 USA. RP Cox, MC (reprint author), NCI, Med Oncol Clin Res Unit, Ctr Canc Res, Clin Pharmacol Res Core, 9000 Rockville Pike,Bldg 10,Rm 5A01,MSC 1910, Bethesda, MD 20892 USA. EM coxmi@mail.nih.gov; scrptuc@mail.nih.gov; wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 21 TC 15 Z9 16 U1 0 U2 5 PU FUTURE DRUGS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7140 J9 EXPERT REV ANTICANC JI Expert Rev. Anticancer Ther PD AUG PY 2005 VL 5 IS 4 BP 605 EP 611 DI 10.1586/14737140.5.4.605 PG 7 WC Oncology SC Oncology GA 995NF UT WOS:000234106300004 PM 16111462 ER PT J AU Martin, MJ AF Martin, MJ TI Current stage-specific chemotherapeutic options in colon cancer SO EXPERT REVIEW OF ANTICANCER THERAPY LA English DT Review DE chemotherapy; colon cancer; treatment ID METASTATIC COLORECTAL-CANCER; ADJUVANT CHEMOTHERAPY; RANDOMIZED-TRIAL; PHASE-III; DUKES-B; MICROSATELLITE-INSTABILITY; 1ST-LINE TREATMENT; PLUS FLUOROURACIL; ORAL CAPECITABINE; LEUCOVORIN AB Colorectal cancer is one of the most common cancers worldwide. Until recently, chemotherapeutic treatment options were limited to various 5-fluorouracil-leucovorin combinations. However, the lost 10 years have seen rapid developments in the treatment of colon cancer. These include the introduction of two additional chemotherapeutic agents, irinotecan and oxaliplatin. Additional agents have been developed, namely the targeted therapies in the form of the monoclonal antibodies bevacizumab and cetuximab. The oral forms of chemotherapy (i.e., capecitabine and uracil-tegafur) have been demonstrated to be as efficacious as traditional intravenously administered 5-fluorouracil. As a result, the number of possible treatment options available to patients has increased dramatically. The aim of this review is to report the currently accepted stage-specific chemotherapeutic treatment options for colon cancer, the evidence for these regimens and future developments. C1 NCI, Med Oncol Clin Res Unit, NIH, Rockville, MD 20852 USA. NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Martin, MJ (reprint author), NCI, Med Oncol Clin Res Unit, NIH, 6120 Execut Blvd EPS,Rm 7016, Rockville, MD 20852 USA. EM martmich@mail.nih.gov NR 46 TC 9 Z9 12 U1 0 U2 1 PU FUTURE DRUGS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7140 J9 EXPERT REV ANTICANC JI Expert Rev. Anticancer Ther PD AUG PY 2005 VL 5 IS 4 BP 695 EP 704 DI 10.1586/14737140.5.4.695 PG 10 WC Oncology SC Oncology GA 995NF UT WOS:000234106300011 PM 16111469 ER PT J AU Nahin, RL AF Nahin, RL TI Identifying and pursuing research priorities at the National Center for Complementary and Alternative Medicine SO FASEB JOURNAL LA English DT Article DE disease burden; NCCAM funding; public health ID OBSTRUCTIVE PULMONARY-DISEASE; COMMUNITY-ACQUIRED PNEUMONIA; CHRONIC KIDNEY-DISEASE; INSTITUTES-OF-HEALTH; UNITED-STATES; CARE EXPENDITURES; ECONOMIC BURDEN; COMORBIDITY-SURVEY; ALZHEIMERS-DISEASE; MAJOR DEPRESSION AB As part of its planning process, the National Center for Complementary and Alternative Medicine ( NCCAM), a component of the National Institutes of Health, periodically evaluates how well it applies its criteria for setting research priorities. For its most recent evaluation, NCCAM compared funding levels in fiscal years 2000 and 2003 for 18 diseases with a substantial public health burden including Alzheimer's disease, arthritis, back pain, cancer, diabetes, coronary heart disease, HIV/ AIDS, migraine, and stroke, with 7 measures of disease burden: 1) prevalence, 2) mortality, 3) years of life lost ( YLL), 4) years lost to disability ( YLD), 5) disability- adjusted life years ( DALY's), 6) direct costs of illness ( COI), and 7) total COI. There is an increasing relationship between NCCAM research funding and disease burden over the 4- year study period that reflects funding of specific research initiatives. The strength of the individual correlations varied among measures, with the strongest correlations seen with total COI and the weakest seen with mortality. When applied with its other criteria, measures of disease burden aid identification and matching of NCCAM priorities with levels of support. C1 NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Nahin, RL (reprint author), NIH, Natl Ctr Complementary & Alternat Med, 9000 Rockville Pike,Bldg 31,Room 2B-11, Bethesda, MD 20892 USA. EM nahinr@mail.nih.gov OI Nahin, Richard/0000-0002-3682-4816 NR 90 TC 8 Z9 8 U1 2 U2 7 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 AUG PY 2005 VL 19 IS 10 BP 1209 EP 1215 DI 10.1096/fj.05-3727LFE PG 7 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 963YW UT WOS:000231843700026 PM 16051686 ER PT J AU Cariou, B van Harmelen, K Duran-Sandoval, D van Dijk, T Grefhorst, A Bouchaert, E Fruchart, JC Gonzalez, FJ Kuipers, F Staels, B AF Cariou, B van Harmelen, K Duran-Sandoval, D van Dijk, T Grefhorst, A Bouchaert, E Fruchart, JC Gonzalez, FJ Kuipers, F Staels, B TI Transient impairment of the adaptive response to fasting in FXR-deficient mice SO FEBS LETTERS LA English DT Article DE farnesoid X receptor; fasting; PEPCK; gluconeogenesis ID FARNESOID-X-RECEPTOR; PHOSPHOENOLPYRUVATE CARBOXYKINASE; BILE-ACIDS; METABOLISM; LIVER; GLUCONEOGENESIS; HOMEOSTASIS; INHIBITION; EXPRESSION; CYCLE AB The farnesoid X receptor (FXR) has been suggested to play a role in gluconeogenesis. To determine whether FXR modulates the response to fasting in vivo, FXR-deficient (FXR-/-) and wild-type mice were submitted to fasting for 48 h. Our results demonstrate that FXR modulates the kinetics of alterations of glucose homeostasis during fasting, with FXR-/- mice displaying an early, accelerated hypoglycaemia response. Basal hepatic glucose production rate was lower in FXR-/- mice, together with a decrease in hepatic glycogen content. Moreover, hepatic PEPCK gene expression was transient lower in FXR(-/-)mice after 6 h of fasting and was decreased in FXR(-/-)hepatocytes. FXR therefore plays an unexpected role in the control of fuel availability upon fasting. (c) 2005 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 Univ Lille 2, Fac Pharm, Pasteur Inst Lille, Atherosclerosis Dept,INSERM,Res Unit 545, Lille, France. Univ Groningen Hosp, Pediat Lab, Ctr Liver Digest & Metab Dis, Groningen, Netherlands. NCI, Lab Metab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Staels, B (reprint author), Univ Lille 2, Fac Pharm, Pasteur Inst Lille, Atherosclerosis Dept,INSERM,Res Unit 545, Lille, France. EM bart.staels@pasteur-lille.fr NR 17 TC 57 Z9 57 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD AUG 1 PY 2005 VL 579 IS 19 BP 4076 EP 4080 DI 10.1016/j.febslet.2005.06.033 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 951ZP UT WOS:000230971200007 PM 16023103 ER PT J AU Mills, DA Rawsthorne, H Parker, C Tarnir, D Makarova, K AF Mills, DA Rawsthorne, H Parker, C Tarnir, D Makarova, K TI Genomic analysis of Oenococcus oeni PSU-1 and its relevance to winemaking SO FEMS MICROBIOLOGY REVIEWS LA English DT Review DE Oenococcus oeni; genome; physiology; genetic diversity ID LACTIC-ACID BACTERIA; FORMERLY LEUCONOSTOC-OENOS; MALOLACTIC FERMENTATION; LACTOCOCCUS-LACTIS; AMINO-ACID; SEQUENCE-ANALYSIS; GRAPE JUICE; HEAT-SHOCK; MOLECULAR CHARACTERIZATION; NITROGEN SUPPLEMENTATION AB Oenococcus oeni is an acidophilic member of the Leuconostoc branch of lactic acid bacteria indigenous to wine and similar environments. O. oeni is commonly responsible for the malolactic fermentation in wine and due to its positive contribution is frequently used as a starter culture to promote malolactic fermentation. In collaboration with the Lactic Acid Bacteria Genome Consortium the genome sequence of O. oeni PSU-1 has been determined. The complete genome is 1,780,517 nt with a GC content of 38%. 1701 ORFs could be predicted from the sequence of which 75% were functionally classified. Consistent with its classification as an obligately heterofermentative lactic acid bacterium the PSU-1 genome encodes all the enzymes for the phosphoketolase pathway. Moreover, genes related to flavor modification in wine, such as malolactic fermentation capacity and citrate utilization were readily identified. The completion of the O. oeni genome marks a significant new phase for wine-related research on lactic acid bacteria in which the physiology, genetic diversity and performance of O. oeni starter cultures can be more rigorously examined. (c) 2005 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved. C1 Univ Calif Davis, Dept Viticulture & Enol, Davis, CA 95616 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Mills, DA (reprint author), Univ Calif Davis, Dept Viticulture & Enol, Davis, CA 95616 USA. EM damills@ucdavis.edu RI Mills, David/G-2282-2011 OI Mills, David/0000-0003-1913-9865 NR 89 TC 92 Z9 101 U1 5 U2 23 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-6445 J9 FEMS MICROBIOL REV JI Fems Microbiol. Rev. PD AUG PY 2005 VL 29 IS 3 BP 465 EP 475 DI 10.1016/j.femsre.2005.04.011 PG 11 WC Microbiology SC Microbiology GA 950MP UT WOS:000230861700005 PM 16125008 ER PT J AU Dikalov, S Jiang, JJ Mason, RP AF Dikalov, S Jiang, JJ Mason, RP TI Characterization of the high-resolution ESR spectra of superoxide radical adducts of 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide (DEPMPO) and 5,5-dimethyl-1-pyrroline N-oxide (DMPO). Analysis of conformational exchange SO FREE RADICAL RESEARCH LA English DT Article DE spin trap; DEPMPO; DMPO; superoxide radical; radical adduct; oxygen-17 ID OXYGEN-CENTERED RADICALS; IN-VITRO; PHOSPHORYLATED NITRONE; SPIN-TRAP; VIVO; REASSIGNMENT; HYDROXYL AB It has been previously reported that the spin trap 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide (DEPMPO) can form stable radical adducts with superoxide radical. However, the presence of diastereomers of DEPMPO radical adducts and the appearance of superhyperfine structure complicates the interpretation of the ESR spectra. It has been suggested that the superhyperfine structure in the ESR spectrum of DEPMPO/(OOH)-O-center dot is a result of conformational exchange between conformers. The analysis of the temperature dependence of the ESR spectrum of DEPMPO/(OOH)-O-center dot and of its structural analog DMPO/(OOH)-O-center dot have demonstrated that both ESR spectra contain exchange effects resulting from conversion between two conformers. Computer simulation calculates a conformer lifetime on the order of 0.1 mu s for DMPO/(OOH)-O-center dot at room temperature. However, temperature dependence of the ESR spectrum of DEPMPO/(OOH)-O-center dot suggests that superhyperfine structure does not depend on the conformational exchange. We have now found that the six-line ESR spectrum with superhyperfine structure should be assigned to a DEPMPO-superoxide-derived decomposition product. Therefore, ESR spectra previously assigned to DEPMPO/(OOH)-O-center dot contain not only the two diastereomers of DEPMPO/(OOH)-O-center dot but also the decomposition product, and these spectra should be simulated as a combination of four species: two conformers of the first diastereomer, one conformer of the second diastereomer and the superoxide-derived decomposition product. The presence of four species has been supported by the temperature dependence of the ESR spectra, nucleophilic synthesis of radical adducts, and isotopic substitution experiments. It is clear that to correctly interpret DEPMPO spin trapping of superoxide radicals, one must carefully consider formation of secondary radical adducts. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Emory Univ, Sch Med, Div Cardiol, Atlanta, GA USA. RP Mason, RP (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM mason4@niehs.nih.gov NR 21 TC 32 Z9 32 U1 1 U2 13 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1071-5762 J9 FREE RADICAL RES JI Free Radic. Res. PD AUG PY 2005 VL 39 IS 8 BP 825 EP 836 DI 10.1080/10715760500155688 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 947AN UT WOS:000230614500003 PM 16036362 ER PT J AU Leland, JW Grafman, J AF Leland, JW Grafman, J TI Experimental tests of the Somatic Marker hypothesis SO GAMES AND ECONOMIC BEHAVIOR LA English DT Article DE prefrontal cortex; decision making; Somatic Marker hypothesis; frontal lobe lesion ID SIMILARITY JUDGMENTS; PREFRONTAL CORTEX; UTILITY; CHOICE; ANTICIPATION; PREFERENCES; UNCERTAINTY; ANOMALIES; DECISION; FUTURE AB Damasio's [Descarte's Error: Emotion, Rationality and the Human Brain. Putnam (Grosset Books), New York, 1994] Somatic Marker hypothesis posits that emotion-generated mental markers influence our decisions and, in particular, tend to curb inherent tendencies to seek risk, to be impatient and to be callous in social situations. Ventromedial (VM) prefrontal cortex damage interferes with this marking process, resulting in risk seeking behavior, impatience and socially inappropriate behavior. In the present study, we present 27 normal controls and 17 patients with prefrontal cortex lesions with batteries of questions designed to probe their attitudes toward risk, intertemporal preferences and behavior in social contexts. The results demonstrate that VM patients are no more risk seeking, impatient, or prone to behavior in socially inappropriate manners than normal subjects. Indeed, we find no significant differences of any sort between the two groups of subjects on any the dimensions investigated. We discuss why VM cortex damage in humans appears to influence decisions in certain circumstances but not in others. Published by Elsevier Inc. C1 NINDS, Bethesda, MD 20892 USA. Natl Sci Fdn, Arlington, VA 22230 USA. RP Grafman, J (reprint author), NINDS, 10 Ctr Dr,MSC 1440, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov OI Grafman, Jordan H./0000-0001-8645-4457 NR 32 TC 13 Z9 13 U1 6 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0899-8256 J9 GAME ECON BEHAV JI Games Econ. Behav. PD AUG PY 2005 VL 52 IS 2 BP 386 EP 409 DI 10.1016/j.geb.2004.09.001 PG 24 WC Economics SC Business & Economics GA 954VC UT WOS:000231182200009 ER PT J AU Schoen, RE Weissfeld, JL Kuller, LH Thaete, FL Evans, RW Hayes, RB Rosen, CJ AF Schoen, RE Weissfeld, JL Kuller, LH Thaete, FL Evans, RW Hayes, RB Rosen, CJ TI Insulin-like growth factor-I and insulin are associated with the presence and advancement of adenomatous polyps SO GASTROENTEROLOGY LA English DT Article ID VISCERAL ADIPOSE-TISSUE; COLORECTAL-CANCER RISK; IGF-BINDING PROTEIN-3; FACTOR (IGF)-I; COLON-CANCER; COMPUTED-TOMOGRAPHY; DIABETES-MELLITUS; PHYSICAL-ACTIVITY; GLYCEMIC LOAD; FACTOR BINDING-PROTEIN-3 AB Background & Aims: Insulin and insulin-like growth factor-I (IGF-I) affect proliferation, differentiation, and apoptosis and are potential risk factors for colorectal cancer (CRC). Visceral obesity, possibly via hyperinsulinemia, has also been linked to CRC risk. We evaluated the relationship of insulin, IGF-I, insulin-like growth factor binding protein (IGFBP) 3, and visceral adipose tissue (VAT) in subjects with adenomatous polyps, the precursor lesion of colorectal cancer. Methods: Participants were asymptomatic subjects who underwent screening flexible sigmoidoscopy (FSG) within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Subjects underwent single-slice, computerized tomography scanning to measure VAT and serum fasting insulin, IGF-I, and IGFBP-3 measurements. Results: Four hundred fifty-eight subjects were enrolled, of which 202 subjects had an adenoma, 70 of which were an advanced adenoma. IGF-I (P = .02), IGF-I/IGFBP-3 ratio (P = .003), and insulin (P = .02) were significantly increased in subjects with adenomas compared with controls. In an unadjusted logistic regression analysis using sex-specific quartile cut points, subjects in quartile 4 'in comparison with quartile 1 of IGF-I (odds ratio [OR] = 1.7; [95% CI: 1.0-2.9], Ptrend =.03), IGF-I/IGFBP-3 ratio (OR = 1.9 [95% CI: 1.1-3.3], Ptrend = .01), and insulin (OR = 2.1 [95% CI: 1.2-3.6], Ptrend =.04) were at increased risk of adenoma. When limiting the case group to advanced adenomas, the effect was more pronounced: IGF-I (OR = 2.8 [95% CI: 1.3-6.2], Ptrend =.006), IGF-I/IGFBP-3 ratio (OR 2.3, [95% CI: 1.0-5.2], Ptrend =.04), and insulin (OR 2.3 [95% CI: 1.1-4.9], Ptrend = .14). Visceral adipose tissue was not associated with adenoma risk. Conclusions: Levels of IGF-I, ratio of IGF-I/IGFBP-3, and insulin are associated with adenomas and even more so with advanced adenomas. These data support the hypothesis that insulin and IGF-I may contribute to the development and advancement of adenomatous polyps. C1 Univ Pittsburgh, Dept Med, Div Gastroenterol & Hepatol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15213 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Jackson Lab, Bar Harbor, ME 04609 USA. RP Schoen, RE (reprint author), Univ Pittsburgh, Dept Med, Div Gastroenterol & Hepatol, Mezzanine Level,C Wing,PUH 200 Lothrop St, Pittsburgh, PA 15213 USA. EM rschoen@pitt.edu FU NCI NIH HHS [K07-CA72561] NR 66 TC 90 Z9 99 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2005 VL 129 IS 2 BP 464 EP 475 DI 10.1053/j.gastro.2005.05.051 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 953IU UT WOS:000231070600010 PM 16083703 ER PT J AU Heller, F Florian, P Bojarski, C Richter, J Christ, M Hillenbrand, B Mankertz, J Gitter, AH Burgel, N Fromm, M Zeitz, M Fuss, I Strober, W Schulzke, JD AF Heller, F Florian, P Bojarski, C Richter, J Christ, M Hillenbrand, B Mankertz, J Gitter, AH Burgel, N Fromm, M Zeitz, M Fuss, I Strober, W Schulzke, JD TI Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution SO GASTROENTEROLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; NECROSIS-FACTOR-ALPHA; I-LIKE MOLECULE; NK-T-CELLS; BARRIER FUNCTION; HUMAN COLON; CROHNS-DISEASE; B-CELLS; EXPRESSION; IL-4 AB (Background& Aims:) under bar Ulcerative colitis (UC) is characterized by a Th2 immune response with inflammation and epithelial barrier dysfunction. So far, Th2 cytokines, have not been shown to directly influence epithelial barrier function. (Methods) under bar: Lamina propria mononuclear cells (LPMCs) were stimulated and interleukin (IL)-13 was measured by enzyme-linked immunosorbent assay. Functional IL-13 and IL-4 effects were studied on HT29/136 colonic epithelial cells in Ussing chambers and by conductance scanning. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assays. IL-13/IL-4 receptors were analyzed by reverse-transcription polymerase chain reaction and immunofluorescence. Western blotting combined with immunofluorescence was used to detect tight junction proteins. Furthermore, restitution velocity was measured. Finally, mucosal biopsy specimens from patients with UC were compared with cultured cells for these features. (Results) under bar: LPMCs from patients with UC produced large amounts of IL-13 (985 +/- 73 pg/mL), much more than from controls or patients with Crohn's disease. IL-13R alpha 1 and IL-4R alpha receptors were present in HT-29/B6 cells and colonic epithelial cells of control patients and patients with UC. IL-13 had a dose-dependent effect on transepithelial resistance of HT-29/B6 monolayers (reduction to 60% +/- 4%), whereas IL-4 had no effect. This was due to an increased number of apoptotic cells (5.6-fold +/- 0.9-fold) and an increased expression of the pore-forming tight junction protein claudin-2 to 295% +/- 37%, both of which contributed equally. Finally, epithelial restitution velocity decreased from 15.1 +/- 0.6 to 10.6 +/- 0.5 mu m/h after treatment with IL-13. Parallel changes were observed in human samples, with an increase in claudin-2 expression to 956% +/- 252%. (Conclusions) under bar: IL-13 was identified as an important effector cytokine in UC that impairs epithelial barrier function by affecting epithelial apoptosis, tight junctions, and restitution velocity. C1 Charite, Med Klin 1, Dept Gastroenterol, D-12200 Berlin, Germany. Charite, Med Klin 1, Dept Clin Physiol, D-12200 Berlin, Germany. Jena Univ Appl Sci, Dept Med Engn, Jena, Germany. NIAID, Mucosal Immun Sect, Clin Invest Lab, Bethesda, MD 20892 USA. RP Schulzke, JD (reprint author), Charite, Med Klin 1, Dept Gastroenterol, Campus Benjamin Franklin, D-12200 Berlin, Germany. EM joerg.schulzke@charite.de RI Fromm, Michael/K-6203-2013 OI Fromm, Michael/0000-0003-4497-7983 NR 43 TC 469 Z9 489 U1 4 U2 33 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2005 VL 129 IS 2 BP 550 EP 564 DI 10.1053/j.gastro.2005.05.002 PG 15 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 953IU UT WOS:000231070600019 PM 16083712 ER PT J AU Zhong, Z Connor, HD Froh, M Bunzendahl, H Lind, H Lehnert, M Mason, RP Thurman, RG Lemasters, JJ AF Zhong, Z Connor, HD Froh, M Bunzendahl, H Lind, H Lehnert, M Mason, RP Thurman, RG Lemasters, JJ TI Free radical-dependent dysfunction of small-for-size rat liver grafts: Prevention by plant polyphenols SO GASTROENTEROLOGY LA English DT Article ID CAROLINA RINSE SOLUTION; LIVING-DONOR; REPERFUSION INJURY; KUPFFER CELLS; ISCHEMIA-REPERFUSION; HYALINE GLOBULES; HEPATIC ISCHEMIA; OXYGEN RADICALS; FATTY LIVERS; GREEN TEA AB Background & Aims: The mechanisms by which small-for-size liver grafts decrease survival remain unclear. This study investigated the role of free radicals in injury to small-for-size grafts. Methods: Rat liver explants were reduced in size ex vivo and transplanted into recipients of the same or greater body weight, resulting in a graft weight and standard liver weight of approximately 50% and 25%, respectively. A polyphenol extract from Camellia sinenesis (20 mu g/mL) or an equivalent concentration of epicatechin was added to the storage solution and the lactated Ringer poststorage rinse solution. Results: Serum alanine aminotransferase release increased from approximately 60 U/L before implantation to 750, :14:10, and 2520 U/L after full-size, half-size, and quarter-size transplantation, respectively. Total bilirubin increased slightly after transplantation of full-size and half-size grafts but increased 104-fold in quarter-size grafts. In quarter-size grafts, histological changes included necrosis, leukocyte infiltration, and eosinophilic inclusion body formation. Polyphenol treatment ameliorated these effects by >= 67%. Survival was 30% after transplantation of small-for-size grafts. After polyphenol treatment, survival increased to 70%. Free radicals in bile assessed by spin trapping and 4-hydroxynonenal adducts measured by immunohistochemistry were also greater in reduced-size grafts, an effect ameliorated by polyphenols. Epicatechin, a major polyphenol from Camellia sinenesis, also improved graft function and decreased enzyme release, histopathologic changes, and free radical formation. Conclusions: Increased formation of free radicals occurs after transplantation of reduced-size livers, which contributes to graft dysfunction and failure. Plant polyphenols decrease liver graft injury and increase survival of small-for-size liver grafts, most likely by scavenging free radicals. C1 Univ N Carolina, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Surg, Chapel Hill, NC 27599 USA. RP Zhong, Z (reprint author), Univ N Carolina, Dept Cell & Dev Biol, CB 7090, Chapel Hill, NC 27599 USA. EM zzhong@med.unc.edu FU NIDDK NIH HHS [P30 DK34987, DK37034, K01 DK62089] NR 54 TC 29 Z9 32 U1 0 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2005 VL 129 IS 2 BP 652 EP 664 DI 10.1053/j.gastro.2005.05.060 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 953IU UT WOS:000231070600026 PM 16083719 ER PT J AU Brenner, DJ Hall, EJ Curtis, RE Ron, E AF Brenner, DJ Hall, EJ Curtis, RE Ron, E TI Prostate radiotherapy is associated with second cancers in many organs, not just the colorectum SO GASTROENTEROLOGY LA English DT Letter ID RADIATION; MALIGNANCIES; CARCINOMA C1 Columbia Univ, Med Ctr, Dept Radiat Oncol, Ctr Radiol Res, New York, NY 10027 USA. NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. RP Brenner, DJ (reprint author), Columbia Univ, Med Ctr, Dept Radiat Oncol, Ctr Radiol Res, New York, NY 10027 USA. NR 6 TC 10 Z9 10 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD AUG PY 2005 VL 129 IS 2 BP 773 EP 774 DI 10.1053/j.gastro.2005.06.045 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 953IU UT WOS:000231070600047 PM 16083746 ER PT J AU Veiga, ABG Ribeiro, JMC Guimaraes, JA Francischetti, IMB AF Veiga, ABG Ribeiro, JMC Guimaraes, JA Francischetti, IMB TI A catalog for the transcripts from the venomous structures of the caterpillar Lonomia obliqua: Identification of the proteins potentially involved in the coagulation disorder and hemorrhagic syndrome SO GENE LA English DT Article DE caterpillar venom; coagulation; fibrinolysis; hemorrhage; toxins ID AMINO-ACID-SEQUENCE; RHODNIUS-PROLIXUS; BLOOD-COAGULATION; FIBRIN FORMATION; SIALOME; ENVENOMATION; PROTHROMBIN; SATURNIIDAE; PROTEOLYSIS; RECEPTORS AB Accidents with the caterpillar Lonomia obliqua are often associated with a coagulation disorder and hemorrhagic syndrome in humans. In the present study, we have constructed cDNA libraries from two venomous structures of the caterpillar, namely the tegument and the bristle. High-throughput sequencing and bioinformatics analyses were performed in parallel. Over one thousand cDNAs were obtained and clustered to produce a database of 538 contigs and singletons (clusters) for the tegument library and 368 for the bristle library. We have thus identified dozens of full-length cDNAs coding for proteins with sequence homology to snake venom prothrombin activator, trypsin-like enzymes, blood coagulation factors and prophenoloxidase cascade activators. We also report cDNA coding for cysteine proteases, Group III phospholipase A2, C-type lectins, lipocalins, in addition to protease inhibitors including serpins, Kazal-type inhibitors, cystatins and trypsin inhibitor-like molecules. Antibacterial proteins and housekeeping genes are also described. A significant number of sequences were devoid of database matches, suggesting that their biologic function remains to be defined. We also report the N-terminus of the most abundant proteins present in the bristle, tegument, hemolymph, and "cryosecretion". Thus, we have created a catalog that contains the predicted molecular weight, isoetectric point, accession number, and putative function for each selected molecule from the venomous structures of L. obliqua. The role of these molecules in the coagulation disorder and hemorrhagic syndrome caused by envenomation with this caterpillar is discussed. All sequence information and the Supplemental Data, including figures and tables with hyperlinks to FASTA-formatted files for each contig and the best match to the databases, are available at http://www.ncbi.nih.gov/projects/omes. (c) 2005 Elsevier B.V. All rights reserved. C1 NIAID, Vector Biol Sect, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. UFRGS, Ctr Biotechnol, BR-43421 Porto Alegre, RS, Brazil. RP Francischetti, IMB (reprint author), NIAID, Vector Biol Sect, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkway,Twinbrook 3,Room 2E-28, Bethesda, MD 20892 USA. EM ifrancischetti@niaid.nih.gov RI Veiga, Ana/N-8581-2013; OI Veiga, Ana/0000-0003-1462-5506; Guimaraes, Jorge A./0000-0001-6354-6789; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS [Z01 AI000810-11, Z99 AI999999] NR 41 TC 51 Z9 65 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD AUG 1 PY 2005 VL 355 BP 11 EP 27 DI 10.1016/j.gene.2005.05.002 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 960WU UT WOS:000231624700002 PM 16023793 ER PT J AU Hwang, M Kalinin, A Morasso, MI AF Hwang, M Kalinin, A Morasso, MI TI The temporal and spatial expression of the novel Ca++-binding proteins, Scarf and Scarf2, during development and epidermal differentiation SO GENE EXPRESSION PATTERNS LA English DT Article DE calcium-binding protein; skin differentiation; Scarf; Scarf2; epidermal development ID CALMODULIN-LIKE PROTEIN; KERATINOCYTE DIFFERENTIATION; CA2+-BINDING PROTEIN; GENE-EXPRESSION; CULTURE; CELLS AB During the process of epidermal differentiation, intracellular and extracellular calcium (Ca++) concentrations induce an array of signaling pathways [Berridge, M.J., Lipp P., Bootman, M.D., 2000. The versatility and universality of calcium signaling. Nature Rev. Mol. Cell. Biol. 1, 11-21]. Keratinocytes follow a complex Ca++-dependent program of differentiation moving from the basal proliferative layer, through the spinous and granular differentiated layers to ultimately culminate in the formation of the cornified layer of the epidermis. Members of the Ca++-binding proteins play a central role in the transduction of Ca++ signals. Utilizing a Suppressive subtractive hybridization screen comparing basal and differentiated keratinocytes, we identified the novel Ca++-binding protein genes, Scarf (skin Calmodulin-related factor) and Scarf2, which have homology to calmodulin (CaM). In this study, we present a comprehensive analysis of the expression pattern for Scarf and Scarf2 transcripts and proteins in the developing mouse. To examine Scarf2 expression during embryogenesis, we performed in situ hybridization, and detected expression in the hair follicle, skin and nasal epithelium. These results showed substantial overlap with the previously reported Scarf gene expression [Hwang, M., Morasso, M.I., 2003. The novel murine Ca2 + -binding protein, Scarf, is differentially expressed during epidermal differentiation. J. Biol. Chem. 278, 47827-478331. Comparing the expression patterns of Scarf and Scarf2 proteins in neonatal and adult mouse skin with several structural epidermal proteins, i.e. keratin 14(K14),keratin 1 (K1), loricrin (LOR) and filaggrin (FIL) showed that their expression overlaps K1, an early marker of keratinocyte, differentiation. Interestingly, Scarf and Scarf2 were also detected in the tongue and oral epithelia, rib bone undergoing ossification and in the medullar region of thymus. (c) 2005 Elsevier B.V. All rights reserved. C1 NIAMSD, Dev Skin Biol Unit, NIAMS, NIH, Bethesda, MD 20892 USA. RP Morasso, MI (reprint author), NIAMSD, Dev Skin Biol Unit, NIAMS, NIH, Bldg 50,Room 1525, Bethesda, MD 20892 USA. EM morassom@mail.nih.gov FU NIAMS NIH HHS [Z01 AR041124-06] NR 23 TC 10 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-133X J9 GENE EXPR PATTERNS JI Gene Expr. Patterns PD AUG PY 2005 VL 5 IS 6 BP 801 EP 808 DI 10.1016/j.modgep.2005.03.010 PG 8 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 950NW UT WOS:000230865100011 PM 15922673 ER PT J AU Zudaire, E Cuesta, N Martinez, A Cuttitta, F AF Zudaire, E Cuesta, N Martinez, A Cuttitta, F TI Characterization of adrenomedullin in birds SO GENERAL AND COMPARATIVE ENDOCRINOLOGY LA English DT Article DE adrenomedullin; PAMP; Gallus; hypoxia; glucocorticoid; synteny ID SMOOTH-MUSCLE-CELLS; INDUCIBLE FACTOR-I; TRANSCRIPTION FACTOR; NERVOUS-SYSTEM; DNA-SEQUENCES; GENE; EXPRESSION; PEPTIDE; PROMOTER; BINDING AB Adrenomedullin (AM) is a multifunctional evolutionarily highly conserved peptide. Although its genomic and amino acid (aa) sequences are known in several mammalian species and in fish, the structure of the AM gene remains unknown in intermediate phyla, including birds. Here, we report the structure and aa sequence of the chicken (c) AM ortholog. The cAM gene is located at the short arm of chromosome 5, which shows high synteny with the short arm of human (h) chromosome 11, where hAM is located. Key sequences in the third intron have been conserved which allow for an alternative splicing mechanism, similar to the one found in mammals. The preprohormone contains two peptides with high homology to human proadrenomedullin N-terminal 20 peptide (PAMP) and hAM. We found through real-time PCR and immunocytochemistry cAM mRNA and peptide expression in a variety of chicken tissues, which parallel patterns observed for mammals, with the exception that cAM levels are almost non-detectable in brain. Similarly to mammals, cAM expression is upregulated under hypoxic conditions and following dexamethasone treatment. These data demonstrate a high degree of homology between the cAM gene and its mammalian ortholoa and evolutionary conservation of the regulatory mechanisms controlling its expression. (c) 2005 Elsevier Inc. All rights reserved. C1 NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. RP Zudaire, E (reprint author), NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. EM zudairee@mail.nih.gov RI Cuesta, Natalia/C-1358-2012; Martinez, Alfredo/A-3077-2013; Cuesta, Natalia/J-7761-2015; Cuttitta, Frank/B-4758-2016 OI Martinez, Alfredo/0000-0003-4882-4044; Cuesta, Natalia/0000-0003-0809-2934; NR 49 TC 13 Z9 13 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 0016-6480 J9 GEN COMP ENDOCR JI Gen. Comp. Endocrinol. PD AUG PY 2005 VL 143 IS 1 BP 10 EP 20 DI 10.1016/j.ygcen.2005.02.014 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 944IX UT WOS:000230421900002 PM 15993100 ER PT J AU Moldin, SO AF Moldin, SO TI Understanding Fragile X syndrome: molecular, cellular and genomic neuroscience at the crossroads SO GENES BRAIN AND BEHAVIOR LA English DT Editorial Material ID MENTAL-RETARDATION PROTEIN; SYNAPTIC PLASTICITY; MESSENGER-RNAS; MODEL; MICRORNAS C1 NIMH, Bethesda, MD 20892 USA. RP Moldin, SO (reprint author), NIMH, 6001 Execut Blvd Room 7191,MSC 9643, Bethesda, MD 20892 USA. EM smoldin@mail.nih.gov NR 16 TC 2 Z9 2 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD AUG PY 2005 VL 4 IS 6 BP 337 EP 340 DI 10.1111/j.1601-183X.2005.00150.x PG 4 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 959CI UT WOS:000231494100001 PM 16098132 ER PT J AU Klar, AJS AF Klar, AJS TI A 1927 study supports a current genetic model for inheritance of human scalp hair-whorl orientation and hand-use preference traits SO GENETICS LA English DT Article ID HANDEDNESS; SCHIZOPHRENIA; MECHANISM AB The basis of right-vs. left-hand-use preference in humans has been debated for a long time. Culturally learned, birth stress, and biologically specified causes are the prominent etiologies under consideration. A 2003 (KLAR 2003) study reported a correlation between a person's preferred hand and the scalp hair-whorl orientation developed on the head. By reinterpreting results of a 1927 (SCHWARZBURG 1927) study on the genetics of the hair-whorl trait, support for a recent single gene, two-allele "random-recessive model" for both hair-whorl orientation and handedness trait inheritance is demonstrated. C1 NCI, Gene Regulat & Chromosome Biol Lab, Canc Res Ctr, Developmental Genet Sect, Ft Detrick, MD 21702 USA. RP Klar, AJS (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, Canc Res Ctr, Developmental Genet Sect, 7th St,Bldg 539,POB B, Ft Detrick, MD 21702 USA. EM klar@ncifcrf.gov NR 12 TC 19 Z9 19 U1 0 U2 3 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD AUG PY 2005 VL 170 IS 4 BP 2027 EP 2030 DI 10.1534/genetics.104.039990 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 966PO UT WOS:000232033300049 PM 15944357 ER PT J AU King, DC Taylor, J Elnitski, L Chiaromonte, F Miller, W Hardison, RC AF King, DC Taylor, J Elnitski, L Chiaromonte, F Miller, W Hardison, RC TI Evaluation of regulatory potential and conservation scores for detecting cis-regulatory modules in aligned mammalian genome sequences SO GENOME RESEARCH LA English DT Review ID BETA-GLOBIN LOCUS; DOMINANT CONTROL REGION; MURINE ERYTHROLEUKEMIA-CELLS; DNASE HYPERSENSITIVE SITES; STAGE-SPECIFIC EXPRESSION; GENE STRUCTURE PREDICTION; HIDDEN MARKOV MODEL; ERYTHROID-CELLS; FUNCTIONAL-ANALYSIS; TRANSGENIC MICE AB Techniques of comparative genomes are being used to identify candidate functional DNA sequences, and objective evaluations are needed to assess their effectiveness. Different analytical methods score distinctive features of whole-genome alignments among human, Mouse, and rat to predict functional regions. We evaluated three of these methods for their ability to identify the positions of known regulatory regions in the well-studied HBB gene complex. Two methods, multispecies conserved sequences and phastCons, quantify levels of conservation to estimate a likelihood that aligned DNA sequences are under purifying selection. A third function, regulatory potential (RP), measures the similarity of patterns in the alignments to those in known regulatory regions. the methods call correctly identify 50%-60% of noncoding positions in the HBB gene complex as regulatory or nonregulatory, with RP performing better than do other methods. When evaluated by the ability to discriminate genomic intervals, RP reaches a sensitivity of 0.78 and a true discovery rate of similar to 0.6. the performance is better oil other reference sets; both phastCons and RP scores call capture almost all regulatory elements in those sets along with similar to 7% of the human genome. C1 Penn State Univ, Ctr Comparat Genom & Bioinformat, Huck Inst Life Sci, University Pk, PA 16802 USA. Penn State Univ, Dept Biochem, University Pk, PA 16802 USA. Penn State Univ, Dept Biol Mol, University Pk, PA 16802 USA. Penn State Univ, Dept Comp Sci & Engn, University Pk, PA 16802 USA. Penn State Univ, Dept Stat, University Pk, PA 16802 USA. Penn State Univ, Dept Biol, University Pk, PA 16802 USA. NHGRI, Rockville, MD 20852 USA. RP Hardison, RC (reprint author), Penn State Univ, Ctr Comparat Genom & Bioinformat, Huck Inst Life Sci, University Pk, PA 16802 USA. EM rch8@psu.edu RI Hardison, Ross/G-1142-2010; Taylor, James/F-1026-2011 OI Hardison, Ross/0000-0003-4084-7516; Taylor, James/0000-0001-5079-840X FU NHGRI NIH HHS [F32 HG002325, HG02238, HG02325, R01 HG002238]; NIDDK NIH HHS [DK65806, R01 DK065806, R56 DK065806] NR 103 TC 146 Z9 151 U1 0 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD AUG PY 2005 VL 15 IS 8 BP 1051 EP 1060 DI 10.1101/gr.3642605 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 952UW UT WOS:000231032000003 PM 16024817 ER PT J AU Sloand, E AF Sloand, E TI Genetic polymorphisms and the risk of acquired idiopathic aplastic anemia SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Editorial Material ID INDIVIDUALS; BENZENE C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Sloand, E (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM sloande@nih.gov NR 5 TC 3 Z9 3 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA STRADA NUOVA 134, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD AUG PY 2005 VL 90 IS 8 BP 1009 EP 1010 PG 2 WC Hematology SC Hematology GA 963HS UT WOS:000231795500002 ER PT J AU Biragyn, A AF Biragyn, A TI Rationale for dendritic cell-based vaccines for acute myelold leukemia SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Editorial Material ID IMMUNOTHERAPY; ANTIGENS C1 NIA, Immunol Lab, Baltimore, MD 21224 USA. RP Biragyn, A (reprint author), NIA, Immunol Lab, Baltimore, MD 21224 USA. EM biragyna@nih.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA STRADA NUOVA 134, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD AUG PY 2005 VL 90 IS 8 BP 1010 EP 1011 PG 2 WC Hematology SC Hematology GA 963HS UT WOS:000231795500005 ER PT J AU Levy-Clarke, GA Chan, CC Nussenblatt, RB AF Levy-Clarke, GA Chan, CC Nussenblatt, RB TI Diagnosis and management of primary intraocular lymphoma SO HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA LA English DT Article ID NERVOUS-SYSTEM LYMPHOMA; POLYMERASE-CHAIN-REACTION; PRIMARY OCULAR LYMPHOMA; RETICULUM-CELL SARCOMA; HIGH-DOSE METHOTREXATE; OF-THE-LITERATURE; CLINICAL-FEATURES; INTRATHECAL CHEMOTHERAPY; PRIMARY CNS; INVOLVEMENT AB Primary intraocular lymphoma (PIOL) is a subset of primary central nervous system lymphoma. The incidence of PIOL has increased in the past 20 years. PIOL often presents as chronic uveitis that is resistant to corticosteroid therapy. Diagnosing PIOL can be challenging and requires an expert pathologist. The treatment of PIOL is difficult because of its high recurrence rate and refractory nature. The objective for the future is to improve diagnostic techniques and therapeutic success while minimizing ocular toxicities. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Levy-Clarke, GA (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room 10N112, Bethesda, MD 20892 USA. EM clarkeg@nei.nih.gov NR 54 TC 44 Z9 45 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8588 J9 HEMATOL ONCOL CLIN N JI Hematol. Oncol. Clin. North Am. PD AUG PY 2005 VL 19 IS 4 BP 739 EP + DI 10.1016/j.hoc.2005.05.011 PG 12 WC Oncology; Hematology SC Oncology; Hematology GA 959BL UT WOS:000231491800011 PM 16083834 ER PT J AU Lok, ASF Ghany, MG Goodman, ZD Wright, EC Everson, GT Sterling, RK Everhart, JE Lindsay, KL Bonkovsky, HL Di Bisceglie, AM Lee, WM Morgan, TR Dienstag, JL Morishima, C AF Lok, ASF Ghany, MG Goodman, ZD Wright, EC Everson, GT Sterling, RK Everhart, JE Lindsay, KL Bonkovsky, HL Di Bisceglie, AM Lee, WM Morgan, TR Dienstag, JL Morishima, C CA HALT-C Trial Grp TI Predicting cirrhosis in patients with hepatitis C based on standard laboratory tests: Results of the HALT-C cohort SO HEPATOLOGY LA English DT Article ID LIVER FIBROSIS; VIRUS-INFECTION; ASPARTATE-AMINOTRANSFERASE; BIOCHEMICAL MARKERS; AST/ALT RATIO; VALIDATION; BIOPSY; COMPLICATIONS; RIBAVIRIN; MODEL AB Knowledge of the presence of cirrhosis is important for the management of patients with chronic hepatitis C (CHC). Most models for predicting cirrhosis were derived from small numbers of patients and included subjective variables or laboratory tests that are not readily available. The aim of this study was to develop a predictive model of cirrhosis in patients with CHC based on standard laboratory tests. Data from 1,141 CHC patients including 429 with cirrhosis were analyzed. All biopsies were read by a panel of pathologists (blinded to clinical features), and fibrosis stage was determined by consensus. The cohort was divided into a training set (n = 783) and a validation set (n = 358). Variables that were significantly different between patients with and without cirrhosis in univariate analysis were entered into logistic regression models, and the performance of each model was compared. The area under the receiver-operating characteristic curve of the final model comprising platelet count, AST/ALT ratio, and INR in the training and validation sets was 0.78 and 0.81, respectively. A cutoff of less than 0.2 to exclude cirrhosis would misclassify only 7.8 % of patients with cirrhosis, while a cutoff of greater than 0.5 to confirm cirrhosis would misclassify 14.8 % of patients without cirrhosis. The model performed equally well in fragmented and nonfragmented biopsies and in biopsies of varying lengths. Use of this model might obviate the requirement for a liver biopsy in 50 % of patients with CHC. In conclusion, a model based on standard laboratory test results can be used to predict histological cirrhosis with a high degree of accuracy in 50 % of patients with CHC. C1 Univ Michigan, Med Ctr, Div Gastroenterol, Taubman Ctr 3912, Ann Arbor, MI 48109 USA. NIDDKD, Div Digest Dis & Nutr, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Armed Forces Inst Pathol, Div Hepat Pathol, Washington, DC 20306 USA. Armed Forces Inst Pathol, Vet Adm Special Reference Lab Pathol, Washington, DC 20306 USA. New England Res Inst, Watertown, MA 02172 USA. Univ Colorado, Sch Med, Div Gastroenterol & Hepatol, Sect Hepatol, Denver, CO 80202 USA. Virginia Commonwealth Univ, Hlth Syst, Div Gastroenterol Hepatol & Nutr, Hepatol Sect, Richmond, VA USA. Univ So Calif, Div Gastrointestinal & Liver Dis, Los Angeles, CA USA. Univ Connecticut, Ctr Hlth, Liver Biliary Pancreat Ctr, Farmington, CT USA. Univ Connecticut, Ctr Hlth, Gen Clin Res Ctr, 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 75230 USA. Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA. Massachusetts Gen Hosp, Med Serv, Gastrointestinal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Univ Washington, Dept Pediat, Seattle, WA 98195 USA. Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. RP Lok, ASF (reprint author), Univ Michigan, Med Ctr, Div Gastroenterol, Taubman Ctr 3912, Ann Arbor, MI 48109 USA. EM aslok@umich.edu RI Lok, Anna /B-8292-2009 FU NCRR NIH HHS [M01 RR 00042, M01 RR 00043, M01 RR 00051, M01 RR 00065, M01 RR 00633, M01 RR 00827, M01 RR 01066, M01 RR 06192]; NIDDK NIH HHS [N01 DK 92320, N01 DK 92318, N01 DK 92319, N01 DK 92321, N01 DK 92322, N01 DK 92323, N01 DK 92324, N01 DK 92325, N01 DK 92326, N01 DK 92327, N01 DK 92328] NR 37 TC 167 Z9 178 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD AUG PY 2005 VL 42 IS 2 BP 282 EP 292 DI 10.1002/hep.20772 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 950NU UT WOS:000230864900007 PM 15986415 ER PT J AU Baffoe-Bonnie, AB Smith, JB Stephan, DA Schleutker, J Carpten, JD Kainu, T Gillanders, EM Matikainen, M Teslovich, TM Tammela, T Sood, R Balshem, AM Scarborough, SD Xu, JF Isaacs, WB Trent, JM Kallioniemi, OP Bailey-Wilson, JE AF Baffoe-Bonnie, AB Smith, JB Stephan, DA Schleutker, J Carpten, JD Kainu, T Gillanders, EM Matikainen, M Teslovich, TM Tammela, T Sood, R Balshem, AM Scarborough, SD Xu, JF Isaacs, WB Trent, JM Kallioniemi, OP Bailey-Wilson, JE TI A major locus for hereditary prostate cancer in Finland: localization by linkage disequilibrium of a haplotype in the HPCX region SO HUMAN GENETICS LA English DT Article ID MULTIPLE SUSCEPTIBILITY LOCI; ALLELIC ASSOCIATION; GERMLINE MUTATIONS; CELL LINES; FAMILIES; GENE; DISEASE; RISK; SCHIZOPHRENIA; POPULATION AB Background: Prostate cancer (PRCA) is the most common cancer in males in the western world. In Finland PRCA has an age-adjusted incidence of 81.5 per 100,000. We previously reported that in Finland, the late-onset cases in families with "no-male-to-male'' (NMM) transmission of PRCA accounted for most of the linkage to the HPCX region (Xq27-28). The aim of the present study was to test for linkage disequilibrium (LD) and haplotype-sharing around marker DXS1205 between cases from hereditary prostate cancer (HPC) families and population controls. The initial allelic association was performed between 108 PRCA cases and 257 population controls genotyped for 23 markers in the Xq26-28 region. This resulted in a highly significant nominal one-sided Fisher's exact P-value of 0.0003 for allele "180'' of marker DXS1205. Subsequently, a similar level of significance was observed for the same allele for marker DXS1205 (P = 0.0002) when comparing 60 NMM cases and 257 controls. These results were still significant after Bonferroni correction for multiple testing. Fine mapping efforts included the genotyping of four additional markers D3S2390, bG82i1.9, bG82i1.1, bG82i1.0 and four single nucleotide polymorphisms ( SNPs) to augment the original markers around DXS1205. Results: Our major finding is that markers extending from "D3S2390'' to "bG82i1.0'' flank the critical locus, about 150 kb. Levin and Bertell's LD measure (delta), a guide to localization of a possible variant, was 0.42 and 0.41 for alleles of markers bG82i1.9 and DXS1205, respectively. Conclusions: In this study, the most significant haplotype comprised the three tightly linked, contiguous markers: "cen-bG82i1.9-SNP-Hap B-bG82i1.1-tel'' ["197-2-234''] among several possible haplotypes ( nominal Fisher's one-sided P=0.003). The two transcription units mapping within this interval are the LDOC1 and SPANXC genes. Positional cloning of the HPCX gene(s) is being facilitated by this exploration of the Xq26-28 region. This study represents the first report identifying a haplotype in the Xq27-28 region for an association between HPCX and X-linked prostate cancer with no-male-to-male transmission in the Finnish population. C1 NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD 21224 USA. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. Vanderbilt Univ, Med Ctr, Med Res Serv, VA Tennessee Valley Healthcare Syst,Dept Med, Nashville, TN 37232 USA. TGEN, Phoenix, AZ 85004 USA. Univ Tampere, Inst Med Technol, Canc Genet Lab, Tampere 33014, Finland. Tampere Univ Hosp, Tampere 33014, Finland. NHGRI, NIH, Bethesda, MD 20892 USA. Univ Tampere, Dept Urol, Tampere Univ Hosp, FIN-33101 Tampere, Finland. Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. Wake Forest Univ, Sch Med, Ctr Human Genom, Winston Salem, NC 27157 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA. Univ Turku, VTT Tech Res Ctr Finland, Med Biotechnol Dept, Turku, Finland. RP Bailey-Wilson, JE (reprint author), NHGRI, Inherited Dis Res Branch, NIH, 333 Cassell Dr,Suite 2000, Baltimore, MD 21224 USA. EM jebw@nhgri.nih.gov RI Kallioniemi, Olli/H-5111-2011; Smith, Jeff/C-3484-2012; Kallioniemi, Olli/H-4738-2012; OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; Bailey-Wilson, Joan/0000-0002-9153-2920 FU NCI NIH HHS [CA-06927]; NHGRI NIH HHS [N01-HG-55389] NR 40 TC 22 Z9 22 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD AUG PY 2005 VL 117 IS 4 BP 307 EP 316 DI 10.1007/s00439-005-1306-z PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 952FY UT WOS:000230990600001 PM 15906096 ER PT J AU Kouprina, N Pavlicek, A Collins, NK Nakano, M Noskov, VN Ohzeki, JI Mochida, GH Risinger, JI Goldsmith, P Gunsior, M Solomon, G Gersch, W Kim, JH Barrett, JC Walsh, CA Jurka, J Masumoto, H Larionov, V AF Kouprina, N Pavlicek, A Collins, NK Nakano, M Noskov, VN Ohzeki, JI Mochida, GH Risinger, JI Goldsmith, P Gunsior, M Solomon, G Gersch, W Kim, JH Barrett, JC Walsh, CA Jurka, J Masumoto, H Larionov, V TI The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein SO HUMAN MOLECULAR GENETICS LA English DT Article ID CEREBRAL CORTICAL SIZE; MESSENGER-RNA DECAY; MAJOR DETERMINANT; BRAIN SIZE; UNCONVENTIONAL MYOSINS; CALMODULIN-BINDING; IQ-MOTIF; DROSOPHILA; EVOLUTION; SEQUENCE AB The most common cause of primary autosomal recessive microcephaly (MCPH) appears to be mutations in the ASPM gene which is involved in the regulation of neurogenesis. The predicted gene product contains two putative N-terminal calponin-homology (CH) domains and a block of putative calmodulin-binding IQ domains common in actin binding cytoskeletal and signaling proteins. Previous studies in mouse suggest that ASPM is preferentially expressed in the developing brain. Our analyses reveal that ASPM is widely expressed in fetal and adult tissues and upregulated in malignant cells. Several alternatively spliced variants encoding putative ASPM isoforms with different numbers of IQ motifs were identified. The major ASPM transcript contains 81 IQ domains, most of which are organized into a higher order repeat (HOR) structure. Another prominent spliced form contains an in-frame deletion of exon 18 and encodes 14 IQ domains not organized into a HOR. This variant is conserved in mouse. Other spliced variants lacking both CH domains and a part of the IQ motifs were also detected, suggesting the existence of isoforms with potentially different functions. To elucidate the biochemical function of human ASPM, we developed peptide specific antibodies to the N- and C-termini of ASPM. In a western analysis of proteins from cultured human and mouse cells, the antibodies detected bands with mobilities corresponding to the predicted ASPM isoforms. Immunostaining of cultured human cells with antibodies revealed that ASPM is localized in the spindle poles during mitosis. This finding suggests that MCPH is the consequence of an impairment in mitotic spindle regulation in cortical progenitors due to mutations in ASPM. C1 NCI, Lab Biosyst & Canc, Bethesda, MD 20892 USA. Genet Informat Res Inst, Mountain View, CA USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Howard Hughes Med Inst, Dept Neurol, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Larionov, V (reprint author), NCI, Lab Biosyst & Canc, Bethesda, MD 20892 USA. EM larionov@mail.nih.gov NR 37 TC 88 Z9 92 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 1 PY 2005 VL 14 IS 15 BP 2155 EP 2165 DI 10.1093/hmg/ddi220 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 948OG UT WOS:000230725000007 PM 15972725 ER PT J AU Mounkes, LC Kozlov, SV Rottman, JN Stewart, CL AF Mounkes, LC Kozlov, SV Rottman, JN Stewart, CL TI Expression of an LMNA-N195K variant of A-type lamins results in cardiac conduction defects and death in mice SO HUMAN MOLECULAR GENETICS LA English DT Article ID IDIOPATHIC DILATED CARDIOMYOPATHY; DREIFUSS MUSCULAR-DYSTROPHY; NUCLEAR-ENVELOPE; HEART-FAILURE; HYPERTROPHIC CARDIOMYOPATHY; PARTIAL LIPODYSTROPHY; NATRIURETIC PEPTIDES; DEFICIENT MICE; MUTATIONS; DISEASE AB The nuclear lamina is an similar to 10 nm thick proteinaceous layer underlying the inner nuclear membrane. The A-type lamins, nuclear intermediate filament proteins encoded by the LMNA gene, are basic components of the nuclear lamina. Mutations in LMNA are associated with the laminopathies, congenital diseases affecting tissue regeneration and homeostasis. One of these laminopathies associated with missense mutations in LMNA is dilated cardiomyopathy with conduction system disease (DCM-CD1). To understand how the laminopathies arise from different mutations in a single gene, we derived a mouse line by homologous recombination expressing the Lmna-N195K variant of the A-type lamins with an asparagine-to-lysine substitution at amino acid 195, which causes DCM in humans. This mouse line shows characteristics consistent with DCM-CD1. Continuous electrocardiographic monitoring of cardiac activity demonstrated that Lmna(N195K/N195K) mice die at an early age due to arrhythmia. By immunofluorescence and western analysis, the transcription factor Hf1b/Sp4 and the gap junction proteins connexin 40 and connexin 43 were misexpressed and/or mislocalized in Lmna(N195K/N195K) hearts. Desmin staining revealed a loss of organization at sarcomeres and intercalated disks. Mutations within the LMNA gene may therefore cause cardiomyopathy by disrupting the internal organization of the cardiomyocyte and/or altering the expression of transcription factors essential to normal cardiac development, aging or function. C1 NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. Vanderbilt Univ, Sch Med, Dept Internal Med, Nashville, TN 37232 USA. RP Stewart, CL (reprint author), NCI, Canc & Dev Biol Lab, POB B,Bldg 539,Room 121A, Frederick, MD 21702 USA. EM stewartc@ncifcrf.gov NR 54 TC 97 Z9 101 U1 0 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 AUG 1 PY 2005 VL 14 IS 15 BP 2167 EP 2180 DI 10.1093/hmg/ddi221 PG 14 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 948OG UT WOS:000230725000008 PM 15972724 ER PT J AU Roessler, E Ermilov, AN Grange, DK Wang, AQ Grachtchouk, M Dlugosz, AA Muenke, M AF Roessler, E Ermilov, AN Grange, DK Wang, AQ Grachtchouk, M Dlugosz, AA Muenke, M TI A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2 SO HUMAN MOLECULAR GENETICS LA English DT Article ID CUBITUS-INTERRUPTUS PROTEIN; BASAL-CELL CARCINOMA; FLOOR PLATE; DEPENDENT TRANSCRIPTION; SPINAL-CORD; HEDGEHOG; GENES; ACTIVATION; REPRESSOR; CANCER AB Zinc finger-containing Gli proteins mediate responsiveness to Hedgehog (Hh) signaling, with Gli2 acting as the major transcriptional activator in this pathway in mice. The discovery of disease-associated mutations points to a critical role for GLI2 in human Hh signaling as well. Here, we show that human GLI2 contains previously undescribed 5' sequence, extending the amino-terminus an additional 328 amino acids. In vitro, transcriptional activity of full-length GLI2 is up to 30 times lower than that of GLI2 Delta N (previously thought to represent the entire GLI2 protein), revealing the presence of an amino-terminal repressor domain in the full-length protein. GLI2 Delta N also exhibits potent transcriptional activity in vivo: overexpression in mouse skin leads to the formation of Hh-independent epithelial downgrowths resembling basal cell carcinomas, which in humans are associated with constitutive Hh signaling. The discovery of this additional, functionally relevant GLI2 sequence led us to re-examine several pathogenic human GLI2 mutants, now containing the entire amino-terminal domain. On the basis of the functional domains affected by the mutations, mutant GLI2 proteins exhibited either loss-of-function or dominant-negative activity. Moreover, deletion of the amino-terminus abrogated dominant-negative activity of mutant GLI2, revealing that this domain is required for transcriptional repressor activity of pathogenic GLI2. Our results establish the presence of an amino-terminal transcriptional repressor domain that plays a critical role in modulating the function of wild-type GLI2 and is essential for dominant-negative activity of a GLI2 mutant associated with human disease. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Michigan, Dept Dermatol, Ypsilanti, MI USA. Univ Michigan, Ctr Comprehens Canc, Ypsilanti, MI USA. Washington Univ, Dept Pediat Genet & Genom Med, St Louis, MO 63130 USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mmuenke@nhgri.nih.gov FU NCI NIH HHS [R01 CA087837, P30 CA046592, CA87837, R01 CA087837-07]; NIAMS NIH HHS [R01 AR045973, AR45973] NR 36 TC 83 Z9 84 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 AUG 1 PY 2005 VL 14 IS 15 BP 2181 EP 2188 DI 10.1093/hmg/ddi222 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 948OG UT WOS:000230725000009 PM 15994174 ER PT J AU Capponcelli, S Pedrini, E Cerone, MA Corti, V Fontanesi, S Alessio, M Bachi, A Soddu, S Ribatti, D Picci, P Helman, LJ Cantelli-Forti, G Sangiorgi, L AF Capponcelli, S Pedrini, E Cerone, MA Corti, V Fontanesi, S Alessio, M Bachi, A Soddu, S Ribatti, D Picci, P Helman, LJ Cantelli-Forti, G Sangiorgi, L TI Evaluation of the molecular mechanisms involvedin the gain of function of a Li-Fraumeni TP53 mutation SO HUMAN MUTATION LA English DT Article DE p53; TP53; Li-Fraumeni syndrome; LFS; germ line mutation; gain of function ID WILD-TYPE P53; HUMAN THIOREDOXIN HOMOLOG; LEUKEMIA-DERIVED FACTOR; CELL-CYCLE ARREST; BREAST-CANCER; SPONTANEOUS NECROSIS; FAMILIAL SYNDROME; CRYSTAL-STRUCTURE; IN-VIVO; GENE AB The TP53 tumor suppressor gene is the most frequent target for genetic alterations in human cancer. TP53 gene alterations may result in the gain of oncogenic functions such as neoangiogenesis and resistance to therapy. The TP53 germ line mutation c.659A > C (p.Y220S) was identified in stored DNA from related patients with Li-Fraumeni syndrome (LFS) who died after developing clinically aggressive tumors. All of the patients were treated with protocols that included doxorubicin hydrochloride (DX) as a pivotal drug. To define the in vitro mutational phenotype of this germ line mutation, we used murine fibroblasts explanted from wild-type (wt) and p53 knockout (KO) mice from the same littermate. p53Y220S and p53R175H fibroblasts, obtained from p53KO fibroblasts transfected with expression vectors encoding the human Y220S and R175H p53 mutants, respectively, exhibited resistance to DX treatment. Moreover, p53Y220S fibroblasts exhibited angiogenetic properties, and after DX treatment, p53Y220S failed to translocate into the nucleus and showed an increase in its cytosolic levels. DX treatment does not influence p53 distribution within the nuclear and cytosolic compartments in p53R175H fibroblasts. Peroxiredoxin 11 (Prx 11), a protein that is involved in eliminating reactive oxygen species (ROS), showed increased expression intensity in p53Y220S fibroblasts after DX treatment, as observed by two,dimensional electrophoresis analysis. Moreover, Thioredoxin (Trx), a protein that cooperates with Prx 11, is overexpressed in p53Y220S mutants under basal conditions. These data suggest a relationship between the presence of the p53Y220S mutation and enhanced levels of Prx 11 and Trx in mutant fibroblasts. Since one of the mechanisms of the DX antitumor effect has been ascribed to production of ROS, future studies will evaluate the involvement of PrxII and Trx in the chemoresistance of p53Y220S fibroblasts to DX. C1 Rizzoli Orthoped Inst, Lab Oncol Res, Genet Unit, I-40136 Bologna, Italy. Ist Sci San Raffaele, Milan, Italy. Ist Regina Elena, Mol Oncogenesis Lab, I-00161 Rome, Italy. Univ Bari, Dept Human Anat & Histol, Bari, Italy. NCI, Pediat Branch, NIH, Bethesda, MD 20892 USA. Univ Bologna, Dept Pharmacol, Bologna, Italy. RP Sangiorgi, L (reprint author), Rizzoli Orthoped Inst, Lab Oncol Res, Genet Unit, Via Barbiano 1-10, I-40136 Bologna, Italy. EM luca.sangiorgi@ior.it RI Picci, Piero/J-5979-2016; OI Picci, Piero/0000-0002-8519-4101; Alessio, Massimo/0000-0002-4133-3472 NR 56 TC 8 Z9 9 U1 1 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD AUG PY 2005 VL 26 IS 2 BP 94 EP 103 DI 10.1002/humu.20192 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 948TQ UT WOS:000230739000005 PM 15977174 ER PT J AU Kelsall, BL Leon, F AF Kelsall, BL Leon, F TI Involvement of intestinal dendritic cells in oral tolerance, immunity to pathogens, and inflammatory bowel disease SO IMMUNOLOGICAL REVIEWS LA English DT Review ID HUMAN PEYERS-PATCHES; MESENTERIC LYMPH-NODES; COLONIC LAMINA PROPRIA; TOLL-LIKE RECEPTORS; REGULATORY T-CELLS; GUT EPITHELIAL MONOLAYERS; ANTIGEN-PRESENTING CELLS; NEONATAL FC RECEPTOR; IN-VIVO; ULCERATIVE-COLITIS AB Dendritic cells (DCs) are composed of a family of cells, now recognized to be essential for innate and acquired immunity. DCs at mucosal surfaces have a particular capacity to induce the differentiation of regulatory T cells producing interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) in the steady state (non-infected, non-immunized), yet they retain the capacity to induce effector T cells in response to invasive pathogens. This decision between the induction of active immunity and tolerance will depend on the subpopulation of DC involved and the surface receptors engaged during DC activation and T-cell priming. The local microenvironment will likely play an important role both in defining the DC phenotype and in providing direct signals to responding T cells. Furthermore, DCs in organized mucosal lymphoid tissues preferentially induce the expression of CCR9 and alpha 4 beta 7 on T cells, which results in T-cell homing to the intestinal lamina propria. Finally, DCs may play an important role in the maintenance of abnormal intestinal inflammation either by driving pathogenic T-cell responses in mesenteric lymph nodes or by acting to expand or maintain pathogenic T cells locally at sites of inflammation. In this review, a brief discussion of general issues of DC biology that are pertinent to mucosal immunity is followed by a more in-depth discussion of the phenotype and function of DC populations in the intestine. C1 NIAID, Mucosal Immunobiol Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Kelsall, BL (reprint author), NIAID, Mucosal Immunobiol Sect, Lab Mol Immunol, NIH, 10-11N113,10 Ctr Dr, Bethesda, MD 20892 USA. EM kelsall@nih.gov NR 161 TC 105 Z9 112 U1 0 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD AUG PY 2005 VL 206 BP 132 EP 148 DI 10.1111/j.0105-2896.2005.00292.x PG 17 WC Immunology SC Immunology GA 949VW UT WOS:000230817200009 PM 16048546 ER PT J AU Sauer, JD Shannon, JG Howe, D Hayes, SF Swanson, MS Heinzen, RA AF Sauer, JD Shannon, JG Howe, D Hayes, SF Swanson, MS Heinzen, RA TI Specificity of Legionella pneumophila and Coxiella burnetii vacuoles and versatility of Legionella pneumophila revealed by coinfection SO INFECTION AND IMMUNITY LA English DT Article ID LEGIONNAIRES-DISEASE BACTERIUM; DOT/ICM SYSTEM; Q-FEVER; INTRACELLULAR MULTIPLICATION; MYCOBACTERIUM-TUBERCULOSIS; PARASITOPHOROUS VACUOLES; LEISHMANIA-AMAZONENSIS; TOXOPLASMA-GONDII; MOUSE MACROPHAGES; VIRULENCE SYSTEM AB Legionella pneumophila and Coxiella burnetii are phylogenetically related intracellular bacteria that cause aerosol-transmitted lung infections. In host cells both pathogens proliferate in vacuoles whose biogenesis displays some common features. To test the functional similarity of their respective intracellular niches, African green monkey kidney epithelial (Vero) cells, A/J mouse bone marrow-derived macrophages, human macrophages, and human dendritic cells (DC) containing mature C. burnetii replication vacuoles were super-infected with L. pneumophila, and then the acidity, lysosome-associated membrane protein (LAMP) content, and cohabitation of mature replication vacuoles was assessed. In all cell types, wild-type L. pneumophila occupied distinct vacuoles in close association with acidic, LAMP-positive C. burnetii replication vacuoles. In murine macrophages, but not primate macrophages, DC, or epithelial cells, L. pneumophila replication vacuoles were acidic and LAMP positive. Unlike wild-type L. pneumophila, type IV secretion-deficient dotA mutants trafficked to lysosome-like C. burnetii vacuoles in Vero cells where they survived but failed to replicate. In primate macrophages, DC, or epithelial cells, growth of L. pneumophila was as robust in superinfected cell cultures as in those singly infected. Thus, despite their noted similarities, L. pneumophila and C. burnetii are exquisitely adapted for replication in unique replication vacuoles, and factors that maintain the C burnetii replication vacuole do not alter biogenesis of an adjacent L. pneumophila replication vacuole. Moreover, L. pneumophila can replicate efficiently in either lysosomal vacuoles of A/J mouse cells or in nonlysosomal vacuoles of primate cells. C1 NIAID, Rocky Mt Lab, Lab Intracellular Parasites, Coxiella Pathogenesis Sect, Hamilton, MT 59840 USA. Univ Michigan, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. RP Heinzen, RA (reprint author), NIAID, Rocky Mt Lab, Lab Intracellular Parasites, Coxiella Pathogenesis Sect, 903 S 4th St, Hamilton, MT 59840 USA. EM rheinzen@niaid.nih.gov RI Shannon, Jeffrey/A-5735-2009; OI Shannon, Jeffrey/0000-0003-4211-4308; Sauer, John-Demian/0000-0001-9367-794X FU NIAID NIH HHS [R01 AI040694] NR 57 TC 41 Z9 41 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2005 VL 73 IS 8 BP 4494 EP 4504 DI 10.1128/IAI.73.8.4494-4504.2005 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 949BT UT WOS:000230760600005 PM 16040960 ER PT J AU Wolf, K Fischer, E Hackstadt, T AF Wolf, K Fischer, E Hackstadt, T TI Degradation of Chlamydia pneumoniae by peripheral blood monocytic cells SO INFECTION AND IMMUNITY LA English DT Article ID MONONUCLEAR-CELLS; GENE-EXPRESSION; INFECTED CELLS; IN-VITRO; CARDIOVASCULAR-DISEASE; MONOCLONAL-ANTIBODIES; DEVELOPMENTAL CYCLE; MESSENGER-RNA; HOST-CELLS; TRACHOMATIS AB Chlamydia pneumoniae is a common human respiratory pathogen that has been associated with a variety of chronic diseases, including atherosclerosis. The role of this organism in the pathogenesis of atherosclerosis remains unknown. A key question is how C pneumoniae is transferred from the site of primary infection to a developing atherosclerotic plaque. It has been suggested that circulating monocytes could be vehicles for dissemination of C pneumoniae since the organism has been detected in peripheral blood monocytic cells (PBMCs). In this study we focused on survival of C. pneumoniae within PBMCs isolated from the blood of healthy human donors. We found that C. pneumoniae does not grow and multiply in cultured primary monocytes. In C. pneumoniae-infected monocyte-derived macrophages, growth of the organism was very limited, and the majority of the bacteria were eradicated. We also found that the destruction of C. pneumoniae within infected macrophages resulted in a gradual diminution of chlamydial antigens, although some of these antigens could be detected for days after the initial infection. The detected antigens present in infected monocytes and monocyte-derived macrophages represented neither chlamydial inclusions nor intact organisms. The use of {N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]}-6-aminocaproyl-D-erythro-sphingosine as a vital stain for chlamydiae proved to be a sensitive method for identifying rare C. pneumoniae inclusions and was useful in the detection of even aberrant developmental forms. C1 NIAID, Rocky Mt Lab, Hosp Parasite Interact Sect, Lab Intracellular Parasites,NIH, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Rocky Mt Lab, Hosp Parasite Interact Sect, Lab Intracellular Parasites,NIH, Hamilton, MT 59840 USA. EM ted_hackstadt@nih.gov NR 54 TC 25 Z9 26 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2005 VL 73 IS 8 BP 4560 EP 4570 DI 10.1128/IAI.73.8.4560-4570.2005 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 949BT UT WOS:000230760600012 PM 16040967 ER PT J AU Tabbara, KS Peters, NC Afrin, F Mendez, S Bertholet, S Belkaid, Y Sacks, DL AF Tabbara, KS Peters, NC Afrin, F Mendez, S Bertholet, S Belkaid, Y Sacks, DL TI Conditions influencing the efficacy of vaccination with live organisms against Leishmania major infection SO INFECTION AND IMMUNITY LA English DT Article ID REGULATORY T-CELLS; CUTANEOUS LEISHMANIASIS; IMMUNE-RESPONSES; CONTROLLED-TRIAL; NATURAL MODEL; TH1 RESPONSE; DOUBLE-BLIND; PLUS BCG; MICE; SITE AB Numerous experimental vaccines have been developed with the goal of generating long-term cell-mediated immunity to the obligate intracellular parasite Leishmama major, yet inoculation with live, wild-type L. major remains the only successful vaccine in humans. We examined the expression of immunity at the site of secondary, low-dose challenge in the ear dermis to determine the kinetics of parasite clearance and the early events associated with the protection conferred by vaccination with live L. major organisms in C57BL/6 mice. Particular attention was given to the route of vaccination. We observed that the rapidity, strength, and durability of the memory response following subcutaneous vaccination with live parasites in the footpad are even greater than previously appreciated. Antigen-specific gamma interferon (IFN-gamma) -producing T cells infiltrate the secondary site by 1.5 weeks, and viable parasites are cleared as early as 2.5 weeks following rechallenge, followed by a rapid drop in IFN-gamma(+) CD4(+) cell numbers in the site. In comparison, intradermal vaccination with live parasites in the ear generates immunity that is delayed in effector cell recruitment to the rechallenge site and in the clearance of parasites from the site. This compromised immunity was associated with a rapid recruitment of interleukin-10 (IL-10) -producing CD4(+) T cells to the rechallenge site. Treatment with anti-IL-10-receptor or anti-CD25 antibody enhanced early parasite clearance in ear-vaccinated mice, indicating that chronic infection in the skin generates a population of regulatory cells capable of influencing the level of resistance to reinfection. A delicate balance of effector and regulatory T cells may be required to optimize the potency and durability of vaccines against Leishmaniasis and other intracellular pathogens. C1 NIAID, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. RP Sacks, DL (reprint author), NIAID, Lab Parasit Dis, NIH, Bldg 4,Rm 126,Ctr Dr,MSC 0425, Bethesda, MD 20892 USA. EM dsacks@nih.gov NR 34 TC 57 Z9 58 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2005 VL 73 IS 8 BP 4714 EP 4722 DI 10.1128/IAI.73.8.4714-4722.2005 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 949BT UT WOS:000230760600029 PM 16040984 ER PT J AU Flynn, B Wang, V Sacks, DL Seder, RA Verthelyi, D AF Flynn, B Wang, V Sacks, DL Seder, RA Verthelyi, D TI Prevention and treatment of cutaneous leishmaniasis in primates by using synthetic type D/A oligodeoxynucleotides expressing CpG motifs SO INFECTION AND IMMUNITY LA English DT Article ID INFECTED RHESUS MACAQUES; BACTERIAL-DNA; PROTECTIVE IMMUNITY; DENDRITIC CELLS; INNATE IMMUNITY; MACACA-MULATTA; IN-VIVO; B-CELL; RESISTANCE; VACCINE AB Oligodeoxynucleotides (ODN) containing CpG motifs mimic microbial DNA and are recognized by toll-like receptor 9 on immune cells. The resulting response limits the early spread of infectious organisms and promotes the development of adaptive immunity. In this regard, CpG ODN show promise as immunoprotective agents and as vaccine adjuvants. Previous studies of nonhuman primates showed that administration of CpG ODN type D (also known as type A) at the site of infection 3 days before and after a challenge with Leishmania major enhanced host resistance and reduced the lesion's severity. In this study, we show that systemic administration of D/A ODN limits the size of lesions following an intradermal infection with L. major. Importantly, the reduced morbidity was not associated with a reduction in long-term immunity, as such treated macaques were still protected following a secondary challenge. Finally, administration of D/A ODN to macaques that had established cutaneous lesions reduced the severity of the lesions, suggesting a potential role for CpG ODN in L. major treatment. Together, these findings support the development of clinical studies to assess the use of CpG ODN types D/A as immunoprotective and therapeutic agents. C1 US FDA, Ctr Drug Evaluat & Review, Div Therapeut Prot, Washington, DC 20204 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Verthelyi, D (reprint author), Bldg 29A Rm 3B19,8800 Rockville Pike, Bethesda, MD 20892 USA. EM Verthelyi@cber.fda.gov NR 30 TC 27 Z9 31 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD AUG PY 2005 VL 73 IS 8 BP 4948 EP 4954 DI 10.1128/IAI.73.8.4948-4954.2005 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 949BT UT WOS:000230760600054 PM 16041009 ER PT J AU Palmore, TN Sohn, S Malak, SF Eagan, J Sepkowitz, KA AF Palmore, TN Sohn, S Malak, SF Eagan, J Sepkowitz, KA TI Risk factors for acquisition of Clostridium difficile-associated diarrhea among outpatients at a cancer hospital SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the Infectious-Diseases-Society-of-America CY OCT 24-27, 2002 CL CHICAGO, IL SP Infect Dis Soc Amer ID PROPHYLAXIS; COLITIS; DISEASE AB BACKGROUND: Clostridium difficile-associated diarrhea (CDAD) is an important infection in hospital settings. Its impact on outpatient care has not been well defined. OBJECTIVE: To examine risk factors of ambulatory cancer patients with CDAD. DESIGN: Case-control study. SETTING: Memorial Sloan-Kettering Cancer Center, a tertiary-care hospital. METHODS: Cases of CDAD among oncology outpatients from January 1999 through December 2000 were identified via positive C. difficile toxin assay results on stool specimens sent from clinics or the emergency department. A 1:3 matched case-control study examined exposures associated with CDAD. RESULTS: Forty-eight episodes of CDAD were identified in cancer outpatients. The mean age was 51 years; 44% were female. Forty-one (85%) had received antibiotics within 60 days of diagnosis, completing courses a median of 16.5 days prior to diagnosis. Case-patients received longer courses of first-generation cephalosporins (4.8 vs 3.2 days; P =.03) and fluoroquinolones (23.6 vs 8 days; P <.01) than did control-patients. Those receiving clindamycin were 3.9-fold more likely to develop CDAD (P <.01). For each additional day of clindamycin or third-generation cephalosporin exposure, patients were 1.29- and 1.26-fold more likely to develop CDAD (P <.01 and .04, respectively). The 38 CDAD patients hospitalized during the risk period (79.2%) spent more time as inpatients than did control-patients (19.3 vs 9.7 days; P <.001). CONCLUSIONS: Antibiotic use, especially with cephalosporins and clindamycin, and prolonged hospitalization contributed to the development of CDAD. Outpatient CDAD appears to be most strongly related to inpatient exposures; reasons for the delayed development of symptoms are unknown. C1 Mem Sloan Kettering Canc Ctr, Infect Dis Serv, Dept Med, New York, NY 10021 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Arkansas Med Sci, Dept Radiol, Little Rock, AR 72205 USA. RP Sepkowitz, KA (reprint author), Mem Sloan Kettering Canc Ctr, Infect Dis Serv, Dept Med, 1275 York Ave, New York, NY 10021 USA. EM sepkowik@mskcc.org FU ODCDC CDC HHS [U50 CCU 215090] NR 15 TC 54 Z9 56 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD AUG PY 2005 VL 26 IS 8 BP 680 EP 684 DI 10.1086/502602 PG 5 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 970VD UT WOS:000232338800004 PM 16156323 ER PT J AU Marinotti, O Nguyen, QK Calvo, E James, AA Ribeiro, JMC AF Marinotti, O Nguyen, QK Calvo, E James, AA Ribeiro, JMC TI Microarray analysis of genes showing variable expression following a blood meal in Anopheles gambiae SO INSECT MOLECULAR BIOLOGY LA English DT Article DE gene expression; blood feeding; vector mosquito; Anopheles ID YELLOW-FEVER MOSQUITO; AEDES-AEGYPTI; MALARIA MOSQUITO; INSECTICIDE RESISTANCE; MOLECULAR-CLONING; TRYPSIN GENES; PROTEIN; VECTOR; GENOME; GUT AB A microarray analysis of 14 900 genes of the malaria vector mosquito, Anopheles gambiae, shows that as many as 33% (4924) of their corresponding transcription products vary in abundance within 24 h after a blood meal. Approximately half (2388) of these products increase in their accumulation and the remainder (2536) decrease. Expression dynamics of 80% of the genes analysed by expressed sequence tag (EST) projects reported previously are consistent with the observations from this microarray analysis. Furthermore, the microarray analysis is more sensitive in detecting variation in abundance of gene products expressed at low levels and is more sensitive overall in that a greater number of regulated genes are detected. Major changes in transcript abundance were seen in genes encoding proteins involved in digestion, oogenesis and locomotion. The microarray data and an electronic hyperlinked version of all tables are available to the research community at http://www.angagepuci.bio.uci.edu/1/. C1 Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. Univ Calif Irvine, Dept Biol Chem, Irvine, CA 92697 USA. NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. RP Marinotti, O (reprint author), Univ Calif Irvine, Dept Mol Biol & Biochem, 2305 McGaugh Hall, Irvine, CA 92697 USA. EM omarinot@uci.edu OI Marinotti, Osvaldo/0000-0002-7173-7160; Calvo, Eric/0000-0001-7880-2730; Ribeiro, Jose/0000-0002-9107-0818 FU NIAID NIH HHS [AI29746] NR 51 TC 93 Z9 95 U1 1 U2 16 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0962-1075 J9 INSECT MOL BIOL JI Insect Mol. Biol. PD AUG PY 2005 VL 14 IS 4 BP 365 EP 373 DI 10.1111/j.1365-2583.2005.00567.x PG 9 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 946MG UT WOS:000230575800004 PM 16033430 ER PT J AU Kovanen, PE Young, L Al-Shami, A Rovella, V Pise-Masison, CA Radonovich, MF Powell, J Fu, J Brady, JN Munson, PJ Leonard, WJ AF Kovanen, PE Young, L Al-Shami, A Rovella, V Pise-Masison, CA Radonovich, MF Powell, J Fu, J Brady, JN Munson, PJ Leonard, WJ TI Global analysis of IL-2 target genes: identification of chromosomal clusters of expressed genes SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE genomics; microarray; target gene; SAGE; interleukin-2 ID HUMAN TRANSCRIPTOME MAP; TISSUE-SPECIFIC GENES; FALSE DISCOVERY RATE; T-CELL-ACTIVATION; ALPHA-CHAIN; CAENORHABDITIS-ELEGANS; SELF-TOLERANCE; HUMAN GENOME; DROSOPHILA GENOME; PROTEIN AB T lymphocytes play a central role in controlling adaptive immune responses. IL-2 critically regulates both T cell growth and death and is involved in maintaining peripheral tolerance, but the molecules involved in these and other IL-2 actions are only partially known. We now provide a comprehensive compendium of the genes expressed in T cells and of those regulated by IL-2 based on a combination of DNA microarrays and serial analysis of gene expression (SAGE). The newly identified IL-2 target genes include many genes previously linked to apoptosis in other cellular systems that may contribute to IL-2-dependent survival functions. We also studied the mRNA expression of known regulators of signaling pathways for their induction in response to IL-2 in order to identify potential novel positive and/or negative feedback regulators of IL-2 signaling. We show that IL-2 regulates only a limited number of these genes. These include suppressors of cytokine signaling (SOCS) 1, SOCS2, dual-specificity phosphatase (DUSP) 5, DUSP6 and non-receptor type phosphatase-7 (PTPN7). Additionally, we provide evidence that many genes expressed in T cells locate in chromosomal clusters, and that select IL-2-regulated genes are located in at least two clusters, one at 5q31, a known cytokine gene cluster, and the other at 6p21.3, a region that contains genes encoding the tumor necrosis factor (TNF) superfamily members TNF, LT-alpha and LT-beta. C1 NHLBI, Lab Mol Immunol, Bethesda, MD 20892 USA. NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. NIH, Analyt Biostat Sect, Math & Stat Comp Lab, Div Computat Biosci,Ctr Informat Technol, Bethesda, MD 20892 USA. NIH, Analyt Biostat Sect, Computat Biosci & Engn Lab, Div Computat Biosci,Ctr Informat Technol, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, Bldg 10, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov RI Al-Shami, Amin/D-3889-2009 NR 82 TC 34 Z9 35 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD AUG PY 2005 VL 17 IS 8 BP 1009 EP 1021 DI 10.1093/intimm/dxh283 PG 13 WC Immunology SC Immunology GA 950GY UT WOS:000230846800004 PM 15980098 ER PT J AU Takase, H Yu, CR Mahdi, RM Douek, DC DiRusso, GB Midgley, FM Dogra, R Allende, G Rosenkranz, E Pugliese, A Egwuagu, CE Gery, I AF Takase, H Yu, CR Mahdi, RM Douek, DC DiRusso, GB Midgley, FM Dogra, R Allende, G Rosenkranz, E Pugliese, A Egwuagu, CE Gery, I TI Thymic expression of peripheral tissue antigens in humans: a remarkable variability among individuals SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE autoimmunity; retinal antigen; susceptibility to disease; tolerance; tumor immunity ID T-CELL TOLERANCE; EPITHELIAL-CELLS; SELF-ANTIGEN; MOLECULAR CHARACTERIZATION; INSULIN EXPRESSION; RETINAL ANTIGENS; BINDING PROTEIN; IDDM2 LOCUS; GENE; SELECTION AB The majority of maturing T lymphocytes that recognize self-antigens is eliminated in the thymus upon exposure to their target antigens. This physiological process of negative selection requires that tissue-specific antigens be expressed by thymic cells, a phenomenon that has been well studied in experimental animals. Here, we have examined the expression in human thymi of four retinal antigens, that are capable of inducing autoimmune ocular disease retinal S-antigen (S-Ag), recoverin, RPE65 and inter-photoreceptor retinoid-binding protein (IRBP)], as well as four melanocyte-specific antigens, two of which are used as targets for melanoma immunotherapy [gp100, melanoma antigen recognized by T cells 1, tyrosinase-related protein (TRP)-1 and TRP-2]. Using reverse transcription (RT)-PCR, we found that all thymic samples from the 18 donors expressed mRNA transcripts of most or all the eight tested tissue antigens. Yet, the expression of the transcripts varied remarkably among the individual thymic samples. In addition, S-Ag, RPE65 and IRBP were detected by immunostaining in rare cells in sections of human thymi by antibodies against these proteins. Quantitative real-time RT-PCR analysis revealed that the retinal antigen transcripts in the human thymus are present at trace levels, that are lower by approximately five orders of magnitude than those in the retina. Our observations thus support the notions that thymic expression is a common feature for all tissue-specific antigens and that the levels of expression play a role in determining the susceptibility to autoimmunity against these molecules. C1 NEI, NIH, Bethesda, MD 20892 USA. Tokyo Med & Dent Univ, Grad Sch, Dept Ophthalmol & Visual Sci, Tokyo, Japan. NIAID, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Univ Miami, Diabet Res Inst, Immunogenet Program, Miami, FL 33136 USA. Univ Miami, Div Cardiothorac Surg, Miami, FL 33136 USA. RP Gery, I (reprint author), NEI, NIH, Bldg 10,Room 10N112, Bethesda, MD 20892 USA. EM geryi@nei.nih.gov FU Intramural NIH HHS [Z99 EY999999] NR 38 TC 32 Z9 32 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD AUG PY 2005 VL 17 IS 8 BP 1131 EP 1140 DI 10.1093/intimm/dxh275 PG 10 WC Immunology SC Immunology GA 950GY UT WOS:000230846800014 PM 16030131 ER PT J AU Elmendorf, HG Rohrer, SC Khoury, RS Bouttenot, RE Nash, TE AF Elmendorf, HG Rohrer, SC Khoury, RS Bouttenot, RE Nash, TE TI Examination of a novel head-stalk protein family in Giardia lamblia characterised by the pairing of ankyrin repeats and coiled-coil domains SO INTERNATIONAL JOURNAL FOR PARASITOLOGY LA English DT Article DE Giardia; cytoskeleton; ankyrin repeats; coiled-coil; flagella ID SEQUENCE; EUKARYOTES; TUBULIN; CYTOSKELETON; PHYLOGENY; EVOLUTION; CDNA; GENE; RNA AB The intestinal pathogen Giardia lamblia possesses several unusual organelle features, including two equivalent nuclei, no mitochondria or peroxisomes, and a developmentally regulated rough endoplasmic reticulum and Golgi. Giardia also possesses a number of complex and unique cytoskeleton structures that dictate cell shape, motility and attachment. Our investigations of cytoskeletal proteins have revealed the presence of a new protein family. Proteins in this family contain both ankyrin repeats and coiled-coil domains; although these are common protein motifs, their pairing is unique, thus establishing a new class of head-stalk proteins. Examination of the G. lamblia genome shows evidence for at least 18 genes coding for proteins with a series of ankyrin repeats followed by a lengthy coiled-coil domain and at least an additional 14 genes coding for proteins with a prominent coiled-coil domain flanked by two series of ankyrin repeats. We have examined one of these proteins, Giardia Axoneme Associated Protein (GASP-180), in detail. GASP-180 is a 180 kDa protein containing five ankyrin repeats in a 200 amino acid N-terminal domain separated by a short spacer from an similar to 1375 amino acid coiled-coil domain. Using anti-peptide antibodies raised against a unique 20 amino acid sequence found at the C-terminus, we have determined that GASP-180 is present in cytoskeleton extractions of the parasite and localises to the proximal base of the anterior flagellar axonemes. The combination of the localisation and the structural and functional motifs of GASP-180 make it a strong candidate to participate in control of flagellar activity. (c) 2005 Published by Elsevier Ltd. on behalf of Australian Society for Parasitology Inc. C1 Georgetown Univ, Dept Biol, Washington, DC 20057 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Elmendorf, HG (reprint author), Georgetown Univ, Dept Biol, 348 Reiss Bldg,37th & O Sts NW, Washington, DC 20057 USA. EM hge@georgetown.edu NR 38 TC 15 Z9 15 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0020-7519 J9 INT J PARASITOL JI Int. J. Parasit. PD AUG PY 2005 VL 35 IS 9 BP 1001 EP 1011 DI 10.1016/j.ijpara.2005.03.009 PG 11 WC Parasitology SC Parasitology GA 956XL UT WOS:000231333300008 PM 15982656 ER PT J AU Bray, M Geisbert, TW AF Bray, M Geisbert, TW TI Ebola virus: The role of macrophages and dendritic cells in the pathogenesis of Ebola hemorrhagic fever SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE Ebola virus; ebolavirus; filovirus; disseminated intravascular coagulation; septic shock; therapy ID RHESUS-MONKEYS; CYNOMOLGUS MACAQUES; INFECTED PATIENTS; MARBURG VIRUSES; PRIMATE MODELS; TISSUE FACTOR; IN-VITRO; RESPONSES; APOPTOSIS; SEPSIS AB Ebola hemorrhagic fever is a severe viral infection characterized by fever, shock and coagulation defects. Recent studies in macaques show that major features of illness are caused by effects of viral replication on macrophages and dendritic cells. Infected macrophages produce proinflammatory cytokines, chemokines and tissue factor, attracting additional target cells and inducing vasodilatation, increased vascular permeability and disseminated intravascular coagulation. However, they cannot restrict viral replication, possibly because of suppression of interferon responses. Infected dendritic cells also secrete proinflammatory mediators, but cannot initiate antigen-specific responses. In consequence, virus disseminates to these and other cell types throughout the body, causing multifocal necrosis and a syndrome resembling septic shock. Massive "bystander" apoptosis of natural killer and T cells further impairs immunity. These findings suggest that modifying host responses would be an effective therapeutic strategy, and treatment of infected macaques with a tissue-factor inhibitor reduced both inflammation and viral replication and improved survival. Published by Elsevier Ltd. C1 NIAID, Biodef Clin Res Branch, Off Clin Res, NIH, Bethesda, MD 20892 USA. USA, Med Res Inst Infect Dis, Div Virol, Ft Detrick, MD 21702 USA. RP Bray, M (reprint author), NIAID, Biodef Clin Res Branch, Off Clin Res, NIH, Bethesda, MD 20892 USA. EM mbray@niaid.nih.gov; tom.geisbert@amedd.army.mil NR 29 TC 121 Z9 136 U1 1 U2 33 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 J9 INT J BIOCHEM CELL B JI Int. J. Biochem. Cell Biol. PD AUG PY 2005 VL 37 IS 8 BP 1560 EP 1566 DI 10.1016/j.biocel.2005.02.018 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 934LI UT WOS:000229709900003 PM 15896665 ER PT J AU Leroy, G Rindflesch, TC AF Leroy, G Rindflesch, TC TI Effects of information and machine learning algorithms on word sense disambiguation with small datasets SO INTERNATIONAL JOURNAL OF MEDICAL INFORMATICS LA English DT Article DE word sense disambiguation; machine learning; naive Bayes; decision tree; neural network; UMLS ID TERMS AB Current approaches to word sense disambiguation use (and often combine) various machine learning techniques. Most refer to characteristics of the ambiguity and its surrounding words and are based on thousands of examples. Unfortunately, developing large training sets is burdensome, and in response to this challenge, we investigate the use of symbolic knowledge for small datasets. A naive Bayes classifier was trained for 15 words with 100 examples for each. Unified Medical Language System (UMLS) semantic types assigned to concepts found in the sentence and relationships between these semantic types form the knowledge base. The most frequent sense of a word served as the baseline. The effect of increasingly accurate symbolic knowledge was evaluated in nine experimental conditions. Performance was measured by accuracy based on 10-fold cross-validation. The best condition used only the semantic types of the words in the sentence. Accuracy was then on average 10% higher than the baseline; however, it varied from 8% deterioration to 29% improvement. To investigate this large variance, we performed several follow-up evaluations, testing additional algorithms (decision tree and neural network), and gold standards (per expert), but the results did not significantly differ. However, we noted a trend that the best disambiguation was found for words that were the least troublesome to the human evaluators. We conclude that neither algorithm nor individual human behavior cause these large differences, but that the structure of the UMLS Metathesaurus (used to represent senses of ambiguous words) contributes to inaccuracies in the gold standard, leading to varied performance of word sense disambiguation techniques. (C) 2005 Elsevier Ireland Ltd. All rights reserved. C1 Claremont Grad Univ, Sch Informat Sci, Claremont, CA 91711 USA. Natl Lib Med, Bethesda, MD USA. RP Leroy, G (reprint author), Claremont Grad Univ, Sch Informat Sci, 130 E 9th St, Claremont, CA 91711 USA. EM gondy.leroy@cgu.edu NR 26 TC 22 Z9 22 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1386-5056 J9 INT J MED INFORM JI Int. J. Med. Inform. PD AUG PY 2005 VL 74 IS 7-8 BP 573 EP 585 DI 10.1016/j.ijmedinf.2005.03.013 PG 13 WC Computer Science, Information Systems; Health Care Sciences & Services; Medical Informatics SC Computer Science; Health Care Sciences & Services; Medical Informatics GA 954VY UT WOS:000231184500009 PM 15897005 ER PT J AU Kant, AK Graubard, BI AF Kant, AK Graubard, BI TI Energy density of diets reported by American adults: association with food group intake, nutrient intake, and body weight SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE NHANES III; energy-density; food group intake; body mass index; components of variance; nutrition survey ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; FREE-LIVING HUMANS; OBESE WOMEN; FAT-CONTENT; POPULATION AB OBJECTIVE: Recent reports suggest that dietary energy density may play a role in regulation of food intake. However, little is known about the energy density of diets consumed by free-living populations; therefore, the purpose of this study was to examine demographic, health, and nutritional correlates of energy density of self-reported diets. RESEARCH METHODS AND PROCEDURES: Using data from the NHANES III (n = 13 400), dietary energy density was defined three ways: (1) energy content (kJ/g) of all foods and beverages reported or ED1, (2) energy content (kJ/g) of all foods and energy yielding beverages or ED2, and (3) energy content (kJ/g) of all foods (no beverages) or ED3. Multiple linear or logistic regression methods were used to examine the association of energy density with intake of energy, nutrients, food groups, and body mass index (BMI). We computed the ratios of within- to between-person variance for the three energy density variables using the second recall obtained from the second exam subsample of NHANES III (n = 1037). RESULTS: The mean ED1, ED2, and ED3, respectively, were 3.84 +/- 0.02, 5.45 +/- 0.03, and 8.03 +/- 0.03. Dietary intakes of energy, fat, and low-nutrient-density foods were related positively, but amounts of micronutrients, fruit, and vegetables were related inversely with all types of energy density (P < 0.0001). ED2 and ED3 were modest positive predictors of BMI in both men and women (P <= 0.03). The ratios of within- to between-person components of variance for ED1, ED2, and ED3 were 1.34, 2.05, and 1.53, respectively. DISCUSSION: High-energy-density diets in the US were characterized by low fruit and vegetable intake, and high BMI. C1 CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. NCI, Div Canc Epidemiol & Genet, Biostat Branch, NIH, Bethesda, MD USA. RP Kant, AK (reprint author), CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Remson Hall,Room 306E, Flushing, NY 11367 USA. EM akant@qc.edu NR 25 TC 105 Z9 107 U1 1 U2 9 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 AUG PY 2005 VL 29 IS 8 BP 950 EP 956 DI 10.1038/sj.ijo.0802980 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 944KN UT WOS:000230427000009 PM 15917854 ER PT J AU Ruchkin, D AF Ruchkin, D TI EEG coherence SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Editorial Material C1 NINDS, Cognit Neurosci Sect, Bethesda, MD 20892 USA. RP Ruchkin, D (reprint author), NINDS, Cognit Neurosci Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM drucbkin@mindspring.com NR 6 TC 15 Z9 17 U1 0 U2 1 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 AUG PY 2005 VL 57 IS 2 BP 83 EP 85 DI 10.1016/j.ijpsycho.2005.04.001 PG 3 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 950KK UT WOS:000230855800003 PM 15925421 ER PT J AU Muanza, TM Albert, PS Smith, S Godette, D Crouse, NS Cooley-Zgela, T Sciuto, L Camphausen, K Coleman, CN Menard, C AF Muanza, TM Albert, PS Smith, S Godette, D Crouse, NS Cooley-Zgela, T Sciuto, L Camphausen, K Coleman, CN Menard, C TI Comparing measures of acute bowel toxicity in patients with prostate cancer treated with external beam radiation therapy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE bowel toxicity; radiation; endoscopy; prostate cancer ID QUALITY-OF-LIFE; CONFORMAL RADIOTHERAPY; RANDOMIZED-TRIAL; ONCOLOGY-GROUP; LOCAL-CONTROL; PROCTITIS; SUCRALFATE; CARCINOMA; SYMPTOMS; VALIDATION AB Purpose: This study strives to compare early measures of bowel toxicity in patients with prostate cancer receiving definitive or adjuvant 3D conformal external beam radiation therapy and concurrent daily endorectal application of amifostine. Methods: Eighteen patients were enrolled in the clinical study with a median follow-up of 12 months. Prescription doses ranged from 66 Gy to 76 Gy with a daily fractionation of 2 Gy. Acute bowel toxicity was measured at baseline, at Weeks 5 and 7 of radiotherapy, and at I and 3 months after the completion of therapy. Measures of acute bowel toxicity included the Radiation Therapy Oncology Group (RTOG) acute radiation morbidity scoring criteria, Expanded Prostate Cancer Index Composite (EPIC) self-assessment questionnaires, and proctoscopic examinations. Results: The mean EPIC bowel scores changed significantly through the course of therapy and follow-up (p < 0.0001), with a progressive decrease in scores at Weeks 5 and 7 of treatment, a partial recovery at 3 months, and a correlation to the gold standard RTOG grade (p = 0.004). Proctoscopic toxicity scores were low, did not vary over time, and did not correlate with either EPIC or RTOG scores. Conclusion: The EPIC questionnaire measurements are most sensitive to changes in acute bowel toxicity through a course of radiotherapy and correlate with RTOG acute toxicity scores. Endoscopic examination of the rectal mucosa at the end and immediate follow-up of a course of therapy does not seem to be informative or reproducible between observers in the acute setting. (c) 2005 Elsevier Inc. C1 NCI, Radiat Oncol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, DCTD, NIH,DHHS, Bethesda, MD 20892 USA. RP Menard, C (reprint author), NCI, Radiat Oncol Branch, Canc Res Ctr, NIH, Bldg 10,Rm B3B69,9000 Rockville Pike, Bethesda, MD 20892 USA. EM cynthia.menard@rmp.uhn.on.ca NR 25 TC 19 Z9 19 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2005 VL 62 IS 5 BP 1316 EP 1321 DI 10.1016/j.ijrobp.2004.12.083 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 949EI UT WOS:000230767300008 PM 16029787 ER PT J AU Li, J Shan, ZC Ou, GF Liu, XY Zhang, CM Baum, BJ Wang, SL AF Li, J Shan, ZC Ou, GF Liu, XY Zhang, CM Baum, BJ Wang, SL TI Structural and functional characteristics of irradiation damage to parotid glands in the miniature pig SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE radiation therapy; salivary glands; miniature pig; salivary hypofunction ID RADIATION-INDUCED XEROSTOMIA; MINIPIG SALIVARY-GLANDS; NECK-CANCER; SUBMANDIBULAR GLANDS; PORCINE MODEL; ORAL SEQUELAE; ANIMAL-MODEL; HEAD; RADIOTHERAPY; FLOW AB Purpose: To evaluate the effects of a solitary megadose protocol of ionizing radiation (IR) on the structure and function of the miniature pig (minipig) parotid gland. Methods and Materials: Fourteen minipigs were subjected to either 15 or 20 Gy to one parotid gland with a linear accelerator, whereas another four minipigs served as non-IR controls. Salivary flow rates and salivary chemistries were measured pre-IR and 4 and 16 weeks post-IR. A quantitative assessment of gland weight and acinar area and detailed serum chemistry and hematologic analyses were also performed. Results: Parotid flow rates decreased by approximately 50% either with 20 Gy at 4 weeks, or 15 Gy at 16 weeks post-IR. In the 20 Gy group, salivary flow rates were reduced by approximately 80% at 16 weeks post-IR. A significant decrease in salivary calcium and amylase and an increase of salivary potassium levels were found in both IR groups. There were also transient alterations in serum chemistry and hematology parameters post-IR. Parotid gland weights were significantly decreased (-50%) in the 15 and 20 Gy groups at 4 and 16 weeks post-IR. Additionally, the acinar cell area in glands of both IR groups was significantly reduced from that in control glands at both the 4 and 16 weeks time points. Conclusion: Structural changes in salivary gland parenchyma occurred relatively early after IR, whereas the alterations in salivary output were relatively delayed. Further, reductions in salivary flow were not proportional to acinar cell area loss. Together, these findings suggest that nonparenchymal IR damage likely contributes to IR-induced salivary hypofunction. (c) 2005 Elsevier Inc. C1 Capital Univ Med Sci, Fac Stomatol, Salivary Gland Dis Ctr & Mol Lab Gene Therapy, Beijing 100050, Peoples R China. Chinese Acad Med Sci, Dept Radiotherapy, Inst Canc, Beijing 100037, Peoples R China. Peking Union Med Coll, Beijing 100037, Peoples R China. NIDCR, Gene Therapy & Therapeut Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Wang, SL (reprint author), Capital Univ Med Sci, Fac Stomatol, Salivary Gland Dis Ctr & Mol Lab Gene Therapy, Tian Tan Xi Li 4, Beijing 100050, Peoples R China. EM bbaum@dir.nider.nih.gov; songlinwang@dentist.org.cn NR 43 TC 41 Z9 49 U1 3 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD AUG 1 PY 2005 VL 62 IS 5 BP 1510 EP 1516 DI 10.1016/j.ijrobp.2005.04.029 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 949EI UT WOS:000230767300036 PM 16029813 ER PT J AU Chang, SM Wen, P Cloughesy, T Greenberg, H Schiff, D Conrad, C Fink, K Robins, HI De Angelis, L Raizer, J Hess, K Aldape, K Lamborn, KR Kuhn, J Dancey, J Prados, MD AF Chang, SM Wen, P Cloughesy, T Greenberg, H Schiff, D Conrad, C Fink, K Robins, HI De Angelis, L Raizer, J Hess, K Aldape, K Lamborn, KR Kuhn, J Dancey, J Prados, MD CA N Amer Brain Tumor Consortium Natl Canc Inst TI Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE chemotherapy; CCI-779; rapamycin; glioblastoma multiforme; recurrent; efficacy ID GROWTH-FACTOR RECEPTOR; MAMMALIAN TARGET; CANCER-CELLS; MALIGNANT GLIOMA; RAPAMYCIN; PTEN; EXPRESSION; RESISTANCE; PATHWAY; AMPLIFICATION AB Purpose: Loss of PTEN, which is common in glioblastoma multiforme (GBM), results in activation of the mammalian target of rapapmycin (mTOR), thereby increasing mRNA translation of a number of key proteins required for cell-cycle progression. CCI-779 is an inhibitor of mTOR. The primary objectives of this study were to determine the efficacy of CCI-779 in patients with recurrent GBM and to further assess the toxicity of the drug. Experimental Design: CCI-779 was administered weekly at a dose of 250 mg intravenously for patients on enzyme-inducing anti-epileptic drugs (EIAEDs). Patients not on EIAEDs were initially treated at 250 mg; however, the dose was reduced to 170 mg because of intolerable side effects. Treatment was continued until unacceptable toxicity, tumor progression, or patient withdrawal. The primary endpoint was 6-month progression-free survival. Results: Forty-three patients were enrolled; 29 were not on EIAEDs. The expected toxicity profile of increased lipids, lymphopenia, and stomatitis was seen. There were no grade IV hematological toxicities and no toxic deaths. One patient was progression free at 6 months. Of the patients assessable for response, there were 2 partial responses and 20 with stabilization of disease. The median time to progression was 9 weeks. Conclusions: CCI-779 was well tolerated at this dose schedule; however, there was no evidence of efficacy in patients with recurrent GBM. Despite initial disease stabilization in approximately 50% of patients, the durability of response was short. Because of the low toxicity profile, CCI-779 may merit exploration in combination with other modalities. C1 Univ Calif San Francisco, Neurooncol Serv, San Francisco, CA 94143 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Virginia, Charlottesville, VA 22903 USA. Univ Texas San Antonio, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Texas San Antonio, Austin, TX 78712 USA. Univ Wisconsin, Madison, WI 53706 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Texas San Antonio, San Antonio, TX 78285 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Chang, SM (reprint author), Univ Calif San Francisco, Neurooncol Serv, 400 Parnassus Ave,A808, San Francisco, CA 94143 USA. EM changs@neurosurg.ucsf.edu FU NCI NIH HHS [CA62399, 5-U01CA62399-09, CA16672, CA62412, CA62422, CA62426, CA62455-08, U01 CA62399, U01 CA62407-08, U01CA62421-08]; NCRR NIH HHS [M01 RR03186, M01-RR00042, M01-RR00079, M01-RR00633, M01-RR0865] NR 21 TC 247 Z9 253 U1 1 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 EI 1573-0646 J9 INVEST NEW DRUG JI Invest. New Drugs PD AUG PY 2005 VL 23 IS 4 BP 357 EP 361 DI 10.1007/s10637-005-1444-0 PG 5 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 945GG UT WOS:000230490400009 PM 16012795 ER PT J AU Notari, L Miller, A Martinez, A Amaral, J Ju, MH Robinson, G Smith, LEH Becerra, SP AF Notari, L Miller, A Martinez, A Amaral, J Ju, MH Robinson, G Smith, LEH Becerra, SP TI Pigment epithelium-derived factor is a substrate for matrix metalloproteinase type 2 and type 9: Implications for downregulation in hypoxia SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; GANGLION-CELL DEATH; INTERPHOTORECEPTOR MATRIX; MACULAR DEGENERATION; CHOROIDAL NEOVASCULARIZATION; RETINAL NEOVASCULARIZATION; NEUROTROPHIC ACTIVITY; DIABETIC-RETINOPATHY; ANGIOGENIC SWITCH; FACTOR PEDF AB PURPOSE. Pigment epithelium - derived factor ( PEDF), a protein secreted by the retinal pigment epithelium (RPE), acts on retinal survival and angiogenesis. Because hypoxia and VEGF regulate matrix metalloproteinases ( MMPs), their effects on PEDF proteolysis were explored. METHODS. Mouse models for retinopathy of prematurity (ROP) were used. Cultured monkey RPE cells were exposed to low oxygen and chemical hypoxia mimetics. PEDF and VEGF mRNA levels in RPE were determined by RT-PCR. MMPs were assessed by zymography, DQ-gelatin degradation solution assays, and MMP immunostaining. PEDF proteolysis was assayed in solution and followed by SDS-PAGE and immunostaining. MMP induction by VEGF was performed in baby hamster kidney (BHK) cells. Retinal R28 cell survival, ex vivo chick embryonic aortic vessel sprouting, and directed in vivo angiogenesis assays were performed. RESULTS. Levels of PEDF in RPE/choroid significantly decreased in the ROP model. Hypoxia decreased PEDF levels in the media conditioned by RPE cells, with no significant change in PEDF mRNA. Conversely, PEDF proteolysis, gelatinolytic activities of similar to 57- kDa and similar to 86-kDa zymogens, and MMP-2 immunoreactivities increased with hypoxia. Addition of VEGF to BHK cells caused a time and dose-related upregulation of similar to 57- kDa zymogens and of DQ-gelatinolytic and PEDF-degrading activity. The PEDF- degrading activity and similar to 57- kDa zymogens in the BHK media shared MMP protease inhibition patterns and MMP-2 immunoreactivities with those in the vitreous. Limited proteolysis with MMP-2 and - 9 degraded PEDF in a Ca+2-dependent fashion. MMP-mediated proteolysis of PEDF abolished the retinal survival and antiangiogenic activities of the PEDF protein. CONCLUSIONS. Hypoxia and VEGF can downregulate PEDF through proteolytic degradation. PEDF is a novel substrate for MMP-2 and - 9. These results reveal a novel posttranslational mechanism for downregulating PEDF, and provide an explanation for hypoxia-provoked increases in VEGF/PEDF ratios, in angiogenesis and/or in neuronal death. C1 NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA. RP Becerra, SP (reprint author), NEI, Retinal Cell & Mol Biol Lab, NIH, Bldg 7,Room 305,7 Mem Dr MSC 0607, Bethesda, MD 20892 USA. EM becerrap@nei.nih.gov RI Martinez, Alfredo/A-3077-2013 OI Martinez, Alfredo/0000-0003-4882-4044 NR 78 TC 78 Z9 88 U1 0 U2 2 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 AUG PY 2005 VL 46 IS 8 BP 2736 EP 2747 DI 10.1167/iovs.04-1489 PG 12 WC Ophthalmology SC Ophthalmology GA 949AB UT WOS:000230756100015 PM 16043845 ER PT J AU Schopf, L Luccioli, S Bundoc, V Justice, P Chan, CC Wetzel, BJ Norris, HH Urban, JF Keane-Myers, A AF Schopf, L Luccioli, S Bundoc, V Justice, P Chan, CC Wetzel, BJ Norris, HH Urban, JF Keane-Myers, A TI Differential modulation of allergic eye disease by chronic and acute ascaris infection SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID REGULATORY T-CELLS; ENDOTOXIN-INDUCED UVEITIS; OCULAR TOXOCARIASIS; TROPICAL ENVIRONMENT; CYTOKINE PRODUCTION; TGF-BETA; REACTIVITY; MICE; SUUM; EOSINOPHIL AB PURPOSE. To assess alterations in allergic ocular responses to nonparasite antigens in an experimental system in which mice were skewed toward a Th2 cytokine profile by helminth infection. METHODS. Mice were inoculated with Ascaris suum ( A. suum) eggs concurrent with ragweed (RW) sensitization (RW/acute) or by repeated inoculation before RW sensitization (RW/ chronic). Control subjects were divided into RW, A. suum, and sham-sensitized groups. Animals were RW-challenged in the eye and examined for changes in ocular responses, inflammatory cell infiltrates, and in vitro assessment of cytokines after antigen restimulation. In subsequent experiments, CD4(+)/ CD25(+) T regulatory and CD4(+)/CD25(-) control T cells were adoptively transferred into mice before ocular challenge. RESULTS. RW sensitization and challenge increased ocular symptoms and eosinophil infiltration into the conjunctiva over PBS control eyes. Acute A. suum infection significantly increased RW-induced clinical symptoms and eosinophil infiltrates in the conjunctiva ( P = 0.0001) and resulted in the development of anterior uveitis. In contrast, RW/ chronic infection provided protection from allergic responses to RW with significantly fewer eosinophils in the eye and reduced eotaxin levels. Transfer of CD4(+)/CD25(+) T cells from RW/ chronic mice into RW/ acute animals also decreased disease intensity, suggesting that T regulatory cells may contribute to protection from allergic eye disease. CONCLUSIONS. The current studies suggest acute parasitic infections exacerbate allergic symptoms, whereas chronic infections offer protection and provide possible explanations for the role of parasitic infection in susceptibility and resistance to nonparasite allergens. C1 Agr Res Serv, Beltsville Human Nutr Res Ctr, Nutrient Requirements & Funct Lab, USDA, Beltsville, MD USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Keane-Myers, A (reprint author), NIAID, Lab Allerg Dis, NIH, Twinbrook 2 Room 125,12441 Parklawn Dr, Rockville, MD 20852 USA. EM akeane@niaid.nih.gov OI Urban, Joseph/0000-0002-1590-8869 NR 43 TC 27 Z9 28 U1 0 U2 0 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 AUG PY 2005 VL 46 IS 8 BP 2772 EP 2780 DI 10.1167/iovs.04-0899 PG 9 WC Ophthalmology SC Ophthalmology GA 949AB UT WOS:000230756100020 PM 16043850 ER PT J AU Kumar, R Perez-Casanova, AE Tirado, G Noel, RJ Torres, C Rodriguez, I Martinez, M Staprans, S Kraiselburd, E Yamamura, Y Higley, JD Kumar, A AF Kumar, R Perez-Casanova, AE Tirado, G Noel, RJ Torres, C Rodriguez, I Martinez, M Staprans, S Kraiselburd, E Yamamura, Y Higley, JD Kumar, A TI Increased viral replication in simian immunodeficiency virus/simian-HIV-infected macaques with self-administering model of chronic alcohol consumption SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE simian immunodeficiency virus; simian-HIV; real-time reverse transcriptase polymerase chain reaction; rhesus macaques; chronic alcohol consumption ID KAPPA-B ACTIVATION; VIRUS TYPE-1 REPLICATION; BLOOD MONONUCLEAR-CELLS; IN-VITRO ETHANOL; RHESUS MACAQUES; IMMUNE-RESPONSES; LIVER-DISEASE; TNF-ALPHA; CONFERRED PROTECTION; T-LYMPHOCYTES AB Alcohol abuse constitutes a major cohort among HIV-infected individuals. The precise effect of alcohol addiction on HIV pathogenesis remains inconclusive, however. This study was designed to determine the effect of alcohol dependence on virus replication and CD4 profiles in simian immunodeficiency virus/simian-HIV-infected rhesus macaques. A group of 3 male Indian rhesus macaques was adapted to a self-drinking model of alcohol consumption, whereas another group of 3 macaques was provided a Nutrasweet solution. After 7 weeks of alcohol consumption, the alcohol-dependent animals along with controls were intravenously inoculated with a mixture of SHIVKU, SHIV89.6P, and SIV/17E-Fr. These animals were followed for a period of 24 weeks for complete blood cell counts, CD4 cell profiles, and viral loads in the blood and cerebral compartments. The alcohol and control groups showed comparable peak viral loads in the blood. The plasma viral load in the alcohol group was 31- to 85-fold higher than that in the control group at weeks 18 through 24 after infection, however. The pattern of cerebrospinal fluid viral replication was also comparable during the acute phase; however, the virus continued to replicate in the brain of alcohol-dependent animals, whereas it became undetectable in the controls. The extent of CD4 cell loss in the alcohol group was significantly higher than that in the control animals at week I after infection. C1 Ponce Sch Med, Dept Microbiol, Lab Viral Immunol, Ponce, PR 00732 USA. Ponce Sch Med, Dept Microbiol, AIDS Res Program, San Juan, PR USA. Univ Puerto Rico, San Juan, PR 00936 USA. Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. NIAAA, Poolesville, MD USA. RP Kumar, A (reprint author), Ponce Sch Med, Dept Microbiol, Lab Viral Immunol, Ponce, PR 00732 USA. EM akumar@psm.edu FU NCRR NIH HHS [RR03050, G12 RR003050]; NIAAA NIH HHS [AA015045, R01 AA015045]; NIDA NIH HHS [DA015013, R01 DA015013] NR 54 TC 36 Z9 38 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 1 PY 2005 VL 39 IS 4 BP 386 EP 390 DI 10.1097/01.qai.0000164517.01293.84 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 946KZ UT WOS:000230572400002 PM 16010157 ER PT J AU Dabis, F Leroy, V Newell, ML Read, JS Coutsoudis, A Dabis, F Fawzi, W Gaillard, P Haverkamp, G Harris, RD Jackson, JB Meda, N Msellati, P Nduati, R Wiktor, S Keast, S Li, S Mitchell, R Muenz, L Owen, D Rukblya, A Coutsoudis, A Pillay, K Spooner, E Kuhn, L Coovadia, H Sinclair, G Mburu, A Mngqundaniso, N Uebel, K Coetzee, I Annamalai, K Doorasamy, T Govender, U Willumsen, J Rollins, N Moodley, J Moodley, D Gaillard, P Mwanyumba, F Verhofstede, C Temmerman, M Guay, L Musoke, P Fleming, T Bagenda, D Allen, M Nakabiito, C Sherman, J Bakaki, P Ducar, C Deseyve, M Emel, L Mirochnick, M Fowler, MG Mofenson, L Miotti, P Dransfield, K Bray, D Mmiro, F Jackson, JB Duefield, C Wiktor, S Ekpini, E Karon, J Nkengasong, J Maurice, C Severin, S Roels, T Kouassi, M Lackritz, E Coulibaly, IM Greenberg, A Fawzi, WW Msamanga, GI Hunter, DJ Spiegelman, D Urassa, W Mwakagile, D Antelman, G Coley, J Herrera, MG Willett, W McGrath, N Ballonzi, I Essex, M Renjifo, B Kapiga, S Fawzi, MCS Garland, M Mbise, R Hertzmark, E Kaaya, S Mbwambo, J Kagoma, C Swai, A Cartoux, M Dabis, F Meda, N Msellati, P Bazie, A Dao, B Likikouet, R Mandelbrot, L Welffens-Ekra, C Leroy, V Salamon, R Bonard, D Combe, P Dosso, M Gautier-Charpentier, L Ky, FD Ouangre, A Ouassa, T Sanou, O Sylla-Koko, E Traore, Y Van de Perre, P Cassel-Beraud, AM Kottan, JB Manigart, O Montcho, C Rouzioux, C Simonon, A Valea, D You, B Camara, R Elenga, N Nacro, B Tall, F Timite, M Gourvellec, G Ky-Zerbo, O Noba, V Ramon, R Sombie, I Tiendrebeogo, S Viho, I Yaro, S Dequae-Merchadou, L Lassalle, R Nduati, R Kreiss, JK Mbori-Ngacha, D Stewart, GJ Richardson, BA Saba, J Gray, G Ndugwa, C Coovadia, HM Kilewo, C Massawe, A Kituuka, P Okong, P Grulich, A McIntyre, J von Briesen, H Goudsmit, J Biberfeld, G Haverkamp, G Weverling, GJ Lange, JMA Mmiro, E Ndugwa, C Moodley, J Coovadia, HM Moodley, D Kilewo, C Massawe, A Okong, P Kituuka, P von Briesen, H Goudsmit, J Biberfeld, G Guliano, M Declich, S Clapp, S Haverkamp, G Weverling, GJ Cooper, D Grulich, A Bray, D Ngobeni, E Baguma, G Kyambadde, S Perriens, J Ngobeni, F Baguma, G Kyambadde, S Mmiro, F Ndugwa, C Okong, P Kituuka, P Kilewo, C Massawe, A Mhalu, F Gray, G Moodley, J Coovadia, HM Moodley, D Haus, GS Goudsmit, J AF Dabis, F Leroy, V Newell, ML Read, JS Coutsoudis, A Dabis, F Fawzi, W Gaillard, P Haverkamp, G Harris, RD Jackson, JB Meda, N Msellati, P Nduati, R Wiktor, S Keast, S Li, S Mitchell, R Muenz, L Owen, D Rukblya, A Coutsoudis, A Pillay, K Spooner, E Kuhn, L Coovadia, H Sinclair, G Mburu, A Mngqundaniso, N Uebel, K Coetzee, I Annamalai, K Doorasamy, T Govender, U Willumsen, J Rollins, N Moodley, J Moodley, D Gaillard, P Mwanyumba, F Verhofstede, C Temmerman, M Guay, L Musoke, P Fleming, T Bagenda, D Allen, M Nakabiito, C Sherman, J Bakaki, P Ducar, C Deseyve, M Emel, L Mirochnick, M Fowler, MG Mofenson, L Miotti, P Dransfield, K Bray, D Mmiro, F Jackson, JB Duefield, C Wiktor, S Ekpini, E Karon, J Nkengasong, J Maurice, C Severin, S Roels, T Kouassi, M Lackritz, E Coulibaly, IM Greenberg, A Fawzi, WW Msamanga, GI Hunter, DJ Spiegelman, D Urassa, W Mwakagile, D Antelman, G Coley, J Herrera, MG Willett, W McGrath, N Ballonzi, I Essex, M Renjifo, B Kapiga, S Fawzi, MCS Garland, M Mbise, R Hertzmark, E Kaaya, S Mbwambo, J Kagoma, C Swai, A Cartoux, M Dabis, F Meda, N Msellati, P Bazie, A Dao, B Likikouet, R Mandelbrot, L Welffens-Ekra, C Leroy, V Salamon, R Bonard, D Combe, P Dosso, M Gautier-Charpentier, L Ky, FD Ouangre, A Ouassa, T Sanou, O Sylla-Koko, E Traore, Y Van de Perre, P Cassel-Beraud, AM Kottan, JB Manigart, O Montcho, C Rouzioux, C Simonon, A Valea, D You, B Camara, R Elenga, N Nacro, B Tall, F Timite, M Gourvellec, G Ky-Zerbo, O Noba, V Ramon, R Sombie, I Tiendrebeogo, S Viho, I Yaro, S Dequae-Merchadou, L Lassalle, R Nduati, R Kreiss, JK Mbori-Ngacha, D Stewart, GJ Richardson, BA Saba, J Gray, G Ndugwa, C Coovadia, HM Kilewo, C Massawe, A Kituuka, P Okong, P Grulich, A McIntyre, J von Briesen, H Goudsmit, J Biberfeld, G Haverkamp, G Weverling, GJ Lange, JMA Mmiro, E Ndugwa, C Moodley, J Coovadia, HM Moodley, D Kilewo, C Massawe, A Okong, P Kituuka, P von Briesen, H Goudsmit, J Biberfeld, G Guliano, M Declich, S Clapp, S Haverkamp, G Weverling, GJ Cooper, D Grulich, A Bray, D Ngobeni, E Baguma, G Kyambadde, S Perriens, J Ngobeni, F Baguma, G Kyambadde, S Mmiro, F Ndugwa, C Okong, P Kituuka, P Kilewo, C Massawe, A Mhalu, F Gray, G Moodley, J Coovadia, HM Moodley, D Haus, GS Goudsmit, J CA Breastfeeding HIV Int Transmission TI Mortality among HIV-1-infected women according to children's feeding modality - An individual patient data meta-analysis SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT 2nd International-AIDS-Society Conference on HIV Pathogenesis and Treatment CY JUL 13-16, 2003 CL Paris, FRANCE SP Int AIDS Soc DE HIV-1; mortality; women; breast-feeding; meta-analysis ID MOTHER-TO-CHILD; BREAST-FED CHILDREN; HIV-INFECTED WOMEN; RANDOMIZED-TRIAL; FOLLOW-UP; VERTICAL TRANSMISSION; ORAL ZIDOVUDINE; CLINICAL-TRIAL; COTE-DIVOIRE; SOUTH-AFRICA AB Background: Two recent analyses of HIV-1-infected mothers' mortality according to their children's feeding modality have produced conflicting results. Methods: An individual patient data meta-analysis was conducted using data regarding HIV-1-infected women from eligible clinical trials. Analyses included Cox proportional hazards regression modeling, with children's feeding modality treated as a time-dependent covariate. Results: Of 4237 HIV-1-infected women, 162 (3.8%) died within 18 months after delivery. The risk of mortality during the 18-month period after delivery did not differ significantly by children's feeding modality (ever vs. never breast-fed), with or without adjustment for maternal CD4(+) count. Treating children's feeding modality as a time-dependent covariate, the risk of mortality was lower among women still breast-feeding (hazard ratio = 0.05, 95% confidence interval. 0.03, 0.09; P < 0.0001) than among those who had ceased, with similar results observed with adjustment for maternal CD4(+) count. Conclusions: HIV-1-infected women with lower CD4(+) counts were less likely to initiate breast-feeding. Mothers' mortality during the 18-month period after delivery did not differ significantly according to children's feeding modality (ever vs. never breast-fed). Of those women who initiated breast-feeding, the lower mortality risk among those still breast-feeding compared with those not breast-feeding likely represents better overall maternal health (with healthier women being able to breast-feed longer). C1 NICHHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. RP Read, JS (reprint author), NICHHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Execut Bldg,Room 4B11F,6100 Execut Blvd MSC 7510, Bethesda, MD 20892 USA. EM jennifer_read@nih.gov RI Van de Perre, Philippe/B-9692-2008; Leroy, Valeriane/F-8129-2013 OI Van de Perre, Philippe/0000-0002-3912-0427; Leroy, Valeriane/0000-0003-3542-8616 NR 21 TC 1 Z9 1 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 1 PY 2005 VL 39 IS 4 BP 430 EP 438 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 946KZ UT WOS:000230572400011 ER PT J AU Gradstein, L FitzGibbon, EJ Tsilou, ET Rubin, BI Huizing, M Gahl, WA AF Gradstein, L FitzGibbon, EJ Tsilou, ET Rubin, BI Huizing, M Gahl, WA TI Eye movement abnormalities in Hermansky-Pudlak syndrome SO JOURNAL OF AAPOS LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the American-Association-for-Pediatric-Ophthalmology-and-Strabismus CY MAR 27-31, 2004 CL Washington, DC SP Amer Assoc Pediat Ophthalmol & Strabismus ID PERIODIC ALTERNATING NYSTAGMUS; WAVE-FORM CHARACTERISTICS; CONGENITAL NYSTAGMUS; OCULOCUTANEOUS ALBINISM; HEMORRHAGIC DIATHESIS; DIAGNOSIS; BEHAVIOR; MOTOR; GENE AB Background. Hermansky-Pudlak Syndrome (HPS) is a type of oculocutaneous albinism associated with a bleeding diathesis and pulmonary fibrosis. Although it is known that patients with HPS exhibit nystagmus, the nature of these abnormal eye movements has not been studied. Methods: Twenty-seven patients with HPS, diagnosed by platelet morphology and genetic analysis, underwent a systemic evaluation and complete eye examination. Twenty-five had eye movement recordings using magnetic search coil, infrared, or video oculography. Results: All patients had iris transillumination, foveal hypoplasia, and variable hypopigmentation in skin and eyes. All had bleeding tendencies, and 2 reported excessive bleeding during strabismus surgery. Nine patients had pulmonary fibrosis. Visual acuities ranged from 20/20- to 20/320. Twenty patients had strabismus despite 6 having strabismus surgery previously. Ocular oscillations consistent with congenital nystagmus (CN) were clinically evident in 24 of 27 patients, and half showed periodic alternating nystagmus. In 3 patients without CN, eye movement recordings revealed minimal end-gaze nystagmus, square-wave jerks, drift during fixation and saccades, and low-gain pursuit. These patients had melanin in the posterior pole and better visual acuities than the others (P = 0.002). Conclusions: Most patients with HPS have CN, and many have periodic alternating nystagmus. Some have subtle eye movement abnormalities without clinically evident nystagmus, which can obscure the diagnosis, especially if hypopigmentation is mild. Absence of clinical nystagmus in a child with HPS suggests good vision. Patients with albinism, especially before surgery, should be evaluated for HPS to prevent life-threatening complications. C1 NEI, Lab Sensorimotor Res, NIH, Bethesda, MD 20892 USA. NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. NEI, Consult Serv Sect, NIH, Bethesda, MD 20892 USA. NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Gradstein, L (reprint author), NEI, Lab Sensorimotor Res, NIH, Bldg 10,Room 10s229,9000 Rockville Pike, Bethesda, MD 20892 USA. EM libe@nei.nih.gov NR 44 TC 9 Z9 10 U1 1 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 1091-8531 J9 J AAPOS JI J. AAPOS PD AUG PY 2005 VL 9 IS 4 BP 369 EP 378 DI 10.1016/j.jaapos.2005.02.017 PG 10 WC Ophthalmology; Pediatrics SC Ophthalmology; Pediatrics GA 958DZ UT WOS:000231426200013 PM 16102489 ER PT J AU Arbes, SJ Gergen, PJ Elliott, L Zeldin, DC AF Arbes, SJ Gergen, PJ Elliott, L Zeldin, DC TI Prevalences of positive skin test responses to 10 common allergens in the US population: Results from the Third National Health and Nutrition Examination Survey SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE allergens; allergic sensitization; allergy skin test; epidemiology; NHANES II; NHANES III; survey ID TEST REACTIVITY; AEROALLERGENS; SMOKING; ASTHMA; LEAD; IGE AB Background: Allergy skin tests were administered in the second and third National Health and Nutrition Examination Surveys (NHANES II and III) conducted in the United States from 1976 through 1980 and 1988 through 1994, respectively. Objectives: This study estimated positive skin test response rates in NHANES III and identified predictors of one or more positive test responses. Comparisons with NHANES II were also made. Methods: In NHANES III, 10 allergens and 2 controls were tested in all subjects aged 6 to 19 years and a random half-sample of subjects aged 20 to 59 years. A wheal-based definition of a positive test response was used. Results: In NHANES III, 54.3% of the population had positive test responses to 1 or more allergens. Prevalences were 27.5% for dust mite, 26.9% for perennial rye, 26.2% for short ragweed, 26.1% for German cockroach, 18.1% for Bermuda grass, 17.0% for cat, 15.2% for Russian thistle, 13.2% for white oak, 12.9% for Alternaria alternata, and 8.6% for peanut. Among those with positive test responses, the median number of positive responses was 3.0. Adjusted odds of a positive test response were higher for the following variables: age of 20 to 29 years, male sex, minority race, western region, old homes, and lower serum cotinine levels. For the 6 allergens common to NHANES II and III, prevalences were 2.1 to 5.5 times higher in NHANES III. Conclusions: The majority of the US population represented in NHANES III was sensitized to 1 or more allergens. Whether the higher prevalences observed in NHANES III reflect true changes in prevalence or methodological differences between the surveys cannot be determined with certainty. C1 NIEHS, NIH, Lab Resp Biol, Div Intramural Res, Res Triangle Pk, NC 27709 USA. NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. RP Zeldin, DC (reprint author), NIEHS, NIH, Lab Resp Biol, Div Intramural Res, POB 12233, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov NR 22 TC 340 Z9 344 U1 0 U2 13 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2005 VL 116 IS 2 BP 377 EP 383 DI 10.1016/j.jaci.2005.05.017 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 017ID UT WOS:000235686400021 PM 16083793 ER PT J AU Chinen, J Shearer, WT AF Chinen, J Shearer, WT TI Basic and clinical immunology SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE immunoregulation; HIV; immunodeficiency; innate immunity; complement ID PRIMARY IMMUNODEFICIENCY DISEASES; COMMON VARIABLE IMMUNODEFICIENCY; ESSENTIAL MODULATOR MUTATION; IMMUNE-RESPONSE; T-CELLS; HEREDITARY ANGIOEDEMA; ECTODERMAL DYSPLASIA; DIGEORGE-SYNDROME; GENE-THERAPY; MAST-CELLS AB The authors selected articles published in the literature from January 2004 through December 2004 that were relevant to the areas of basic and clinical immunology. Several articles explored the development of T(H)1 or T(H)2 response and the role of the monocyte-T cell interaction. Others were articles describing the action of drugs commonly used in asthma to inhibit cytokine responses and the anti-inflammatory role of nonimmune pulmonary cells present in the lung. Several reports show how dendritic cells are being developed as vehicles for DNA vaccines aimed at stimulating cellular responses, an advance of great importance for HIV researchers working on vaccines, who are concerned about the different ways HIV evades the immune response. Other publications described Toll-like receptors in diverse cells, including mast cells and CD4(+) T cells, for the recognition of viruses and bacteria. In the area of clinical immunology, an updated classification for primary immunodeficiencies with more than 100 identified genes responsible for these diseases and the report on the second clinical trial of gene therapy for X-linked severe combined immunodeficiency syndrome were published. Significant advances included the clinical prognosis in common variable immunodeficiency for patients presenting with lung pathology, the safety of live vaccines in partial DiGeorge syndrome, the report of patients with complete DiGeorge syndrome with the presence of peripheral blood T cells, the clinical spectrum of patients with NF-kappa B essential modifier (NEMO) gene deficiency, the publication of a consensus algorithm for the management of hereditary angioedema, and the report of immune restoration syndrome in pediatric HIV infection. C1 NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Texas Childrens Hosp, Dept Allergy & Immunol, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA. RP Chinen, J (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, 10 Ctr Dr,MSC 1611,Bldg 10-CRC Room 6-3340, Bethesda, MD 20892 USA. EM jchinen@mail.nih.gov NR 54 TC 20 Z9 21 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD AUG PY 2005 VL 116 IS 2 BP 411 EP 418 DI 10.1016/j.jaci.2005.05.010 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 017ID UT WOS:000235686400026 PM 16083798 ER PT J AU Teplyakov, A Obmolova, G Toedt, J Galperin, MY Gilliland, GL AF Teplyakov, A Obmolova, G Toedt, J Galperin, MY Gilliland, GL TI Crystal structure of the bacterial YhcH protein indicates a role in sialic acid catabolism SO JOURNAL OF BACTERIOLOGY LA English DT Article ID N-ACETYLNEURAMINIC ACID; MENINGITIDIS GROUP-B; ESCHERICHIA-COLI; PHOSPHOGLUCOSE ISOMERASE; HAEMOPHILUS-INFLUENZAE; QUERCETIN 2,3-DIOXYGENASE; PYROCOCCUS-FURIOSUS; ANGSTROM RESOLUTION; RHAMNOSE PATHWAY; SUPERFAMILY AB The yhcH gene is part of the nan operon in bacteria that encodes proteins involved in sialic acid catabolism. Determination of the crystal structure of YhcH from Haemophilus influenzae was undertaken as part of a structural genomics effort in order to assist with the functional assignment of the protein. The structure was determined at 2.2-angstrom resolution by multiple-wavelength anomalous diffraction. The protein fold is a variation of the double-stranded beta-helix. Two antiparallel beta-sheets form a funnel opened at one side, where a putative active site contains a copper ion coordinated to the side chains of two histidine and two carboxylic acid residues. A comparison to other proteins with a similar fold and analysis of the genomic context suggested that YhcH may lie a sugar isomerase involved in processing of exogenous sialic acid. C1 Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. Natl Inst Stand & Technol, Rockville, MD USA. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Teplyakov, A (reprint author), Centocor Inc, 145 King Prussia Rd, Radnor, PA 19087 USA. EM ATeplyak@cntus.jnj.com RI Galperin, Michael/B-5859-2013; OI Galperin, Michael/0000-0002-2265-5572; Teplyakov, Alexey/0000-0003-0296-0016 FU Intramural NIH HHS [Z99 LM999999]; NIGMS NIH HHS [P01 GM057890, P01-GM57890] NR 63 TC 13 Z9 15 U1 0 U2 3 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 AUG PY 2005 VL 187 IS 16 BP 5520 EP 5527 DI 10.1128/JB.187.16.5520-5527.2005 PG 8 WC Microbiology SC Microbiology GA 952SQ UT WOS:000231026200002 PM 16077096 ER PT J AU Chikova, AK Schaaper, RM AF Chikova, AK Schaaper, RM TI The bacteriophage P1 hot gene product can substitute for the Escherichia coli DNA polymerase III theta subunit SO JOURNAL OF BACTERIOLOGY LA English DT Article ID EPSILON-SUBUNIT; MISMATCH REPAIR; GENOME SEQUENCE; PROCESSIVE REPLICATION; SALMONELLA-TYPHIMURIUM; MUTATIONAL ANALYSIS; MUTATOR MUTD5; HOLOENZYME; PURIFICATION; EXONUCLEASE AB The 0 subunit (holE gene product) of Escherichia coli DNA polymerase (Pol) III holoenzyme is a tightly bound component of the polymerase core. Within the core (alpha-epsilon-theta), the alpha, and epsilon subunits carry the DNA polymerase and 3' proofreading functions, respectively, while the precise function of theta is unclear. holE homologs are present in genomes of other enterobacteriae, suggestive of a conserved function. Putative homologs have also been found in the genomes of bacteriophage P1 and of certain conjugative plasmids. The presence of these homologs is of interest, because these genomes are fully dependent on the host replication machinery and contribute few, if any, replication factors themselves. To study the role of these theta homologs, we have constructed an E. coli strain in which holE is replaced by the P1 homolog, hot. We show that hot is capable of substituting for holE when it is assayed for its antimutagenic action on the proofreading-impaired dnaQ49 mutator, which carries a temperature-sensitive F subunit. The ability of hot to substitute for holE was also observed with other, although not all, dnaQ mutator alleles tested. The data suggest that the P1 hot gene product can substitute for the theta subunit and is likely incorporated in the Pol III complex. We also show that overexpression of either theta or Hot further suppresses the dnaQ49 mutator phenotype. This suggests that the complexing of dnaQ49-epsilon with theta is rate limiting for its ability to proofread DNA replication errors. The possible role of hot for bacteriophage P1 is discussed. C1 Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. Russian Acad Med Sci, DI Ivanovskii Virol Inst, Moscow 123098, Russia. RP Schaaper, RM (reprint author), Natl Inst Environm Hlth Sci, Mol Genet Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM schaaper@niehs.nih.gov NR 52 TC 17 Z9 17 U1 1 U2 2 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 AUG PY 2005 VL 187 IS 16 BP 5528 EP 5536 DI 10.1128/JB.187.16.5528-5536.2005 PG 9 WC Microbiology SC Microbiology GA 952SQ UT WOS:000231026200003 PM 16077097 ER PT J AU Wright, JS Traber, KE Corrigan, R Benson, SA Musser, JM Novick, RP AF Wright, JS Traber, KE Corrigan, R Benson, SA Musser, JM Novick, RP TI The agr radiation: an early event in the evolution of staphylococci SO JOURNAL OF BACTERIOLOGY LA English DT Article ID VIRULENCE FACTOR EXPRESSION; GENETIC-VARIABILITY; AUREUS STRAINS; NATURAL-POPULATIONS; RECEPTOR; GENOME; TOXIN; EPIDERMIDIS; EPIDEMIC; LOCUS AB agr is a global regulatory system in the staphylococci, operating by a classical two-component signaling module and controlling the expression of most of the genes encoding extracellular virulence factors. As it is autoinduced by a peptide, encoded within the locus, that is the ligand for the signal receptor, it is a sensor of population density or a quorum sensor and is the only known quorum-sensing system in the genus. agr is conserved throughout the staphylococci but has diverged along lines that appear to parallel speciation and subspeciation within the genus. This divergence has given rise to a novel type of interstrain and interspecies cross-inhibition that represents a fundamental aspect of the organism's biology and may be a predominant feature of the evolutionary forces that have driven it. We present evidence, using a newly developed, luciferase-based agr typing scheme, that the evolutionary divergence of the agr system was an early event in the evolution of the staphylococci and long preceded the development of the nucleotide polymorphisms presently used for genotyping. These polymorphisms developed, for the most part, within different agr groups; mobile genetic elements appear also to have diffused recently and, with a few notable exceptions, have come to reside largely indiscriminately within the several agr groups. C1 NYU, Sch Med, Mol Pathogenesis Program, New York, NY 10016 USA. NYU, Sch Med, Skirball Inst Biomol Med, Dept Microbiol & Med, New York, NY 10016 USA. NIAID, Rocky Mt Labs, Lab Human Bact Pathogenesis, Hamilton, MT 59840 USA. NIAID, NIH, Hamilton, MT 59840 USA. Baylor Coll Med, Ctr Human Bact Pathogenesis Res, Dept Pathol, Houston, TX 77030 USA. RP NYU, Sch Med, Mol Pathogenesis Program, 540 1st Ave, New York, NY 10016 USA. EM novick@saturn.med.nyu.edu OI Corrigan, Rebecca/0000-0002-6031-1148; Traber, Katrina/0000-0002-8534-4480 FU NIAID NIH HHS [F32AI055242, F32 AI055242]; PHS HHS [R0142736] NR 56 TC 63 Z9 65 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 EI 1098-5530 J9 J BACTERIOL JI J. Bacteriol. PD AUG PY 2005 VL 187 IS 16 BP 5585 EP 5594 DI 10.1128/JB.187.16.5585-5594.2005 PG 10 WC Microbiology SC Microbiology GA 952SQ UT WOS:000231026200009 PM 16077103 ER PT J AU Bennett, KK Compas, BE Beckjord, E Glinder, JG AF Bennett, KK Compas, BE Beckjord, E Glinder, JG TI Self-blame and distress among women with newly diagnosed breast cancer SO JOURNAL OF BEHAVIORAL MEDICINE LA English DT Article DE self-blame; attributions; breast cancer; psychological distress ID PSYCHOLOGICAL ADJUSTMENT; ATTRIBUTIONS AB This study examined relations between behavioral and characterological self-blame attributions for breast cancer and psychological distress in the year following a diagnosis. One hundred fifteen women with newly diagnosed breast cancer participated. First, we predicted that both forms of self-blame would be associated with distress shortly after diagnosis (i.e., at 4 months). Second, we predicted that only characterological self-blame would be related to distress at 7 and 12 months post-diagnosis because behavioral self-blame would enhance perceptions of control, thereby protecting against distress. Results supported the first hypothesis; both forms of self-blame were related to symptoms of anxiety and depression at 4 months post-diagnosis. Findings did not support the second hypothesis because both forms of self-blame continued to be related to distress at 7 and 12 months post-diagnosis. Furthermore, perceptions of control did not mediate the self-blame/distress relation. Implications for social cognitive processes in adaptation to breast cancer are discussed. C1 Indiana State Univ, Dept Psychol, Terre Haute, IN 47809 USA. Vanderbilt Univ, Dept Psychol & Human Dev, Nashville, TN 37240 USA. Natl Canc Inst, Canc Prevent Fellowship Program, Div Canc Prevent, Bethesda, MD 20892 USA. Univ Vermont, Dept Psychol, Burlington, VT 05405 USA. RP Bennett, KK (reprint author), Indiana State Univ, Dept Psychol, Terre Haute, IN 47809 USA. EM kbennett9@isugw.indstate.edu FU NCI NIH HHS [R01CA67936]; NICHD NIH HHS [P30HD15052]; NIMH NIH HHS [T32-MH18921] NR 22 TC 34 Z9 34 U1 0 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0160-7715 J9 J BEHAV MED JI J. Behav. Med. PD AUG PY 2005 VL 28 IS 4 BP 313 EP 323 DI 10.1007/s10865-005-9000-0 PG 11 WC Psychology, Clinical SC Psychology GA 978FO UT WOS:000232859200002 PM 16049635 ER PT J AU Oyama, H Fujisawa, T Suzuki, T Dunn, BM Wlodawer, A Oda, K AF Oyama, H Fujisawa, T Suzuki, T Dunn, BM Wlodawer, A Oda, K TI Catalytic residues and substrate specificity of recombinant human tripeptidyl peptidase I (CLN2) SO JOURNAL OF BIOCHEMISTRY LA English DT Article DE classical late-infantile neuronal ceroid lipofuscinosis; CLN2; neurodegenerative disease; sedolisin; serine-carboxyl proteinase ID NEURONAL CEROID-LIPOFUSCINOSIS; INSENSITIVE CARBOXYL PROTEINASE; ANGSTROM CRYSTAL-STRUCTURE; HUMAN CATHEPSIN-D; SUBSITE PREFERENCES; ATP SYNTHASE; GENE-PRODUCT; SUBUNIT C; PURIFICATION; KUMAMOLYSIN AB Tripeptidyl peptidase I (TTP-I), also known as CLN2, a member of the family of serine-carboxyl proteinases (S53), plays a crucial role in lysosomal protein degradation and a deficiency in this enzyme leads to fatal neurodegenerative disease. Recombinant human TPP-I and its mutants were analyzed in order to clarify the biochemical role of TPP-I and its mechanism of activity. Ser280, Glu77, and Asp81 were identified as the catalytic residues based on mutational analyses, inhibition studies, and sequence similarities with other family members. TPP-I hydrolyzed most effectively the peptide Ala-Arg-Phe*Nph-Arg-Leu (*, cleavage site) (k(cat)/K-m = 2.94 mu M(-1.)s(-1)). The k(cat)/K-m value for this substrate was 40 times higher than that for Ala-Ala-PheMCA. Coupled with other data, these results strongly suggest that the substrate-binding cleft of TPP-I is composed of only six subsites (S-3-S-3'. TPP-I prefers bulky and hydrophobic amino acid residues at the P, position and Ala, Arg, or Asp at the P-2 position. Hydrophilic interactions at the S-2 subsite are necessary for TPP-I, and this feature is unique among serine-carboxyl proteinases. TPP-I might have evolved from an ancestral gene in order to cleave, in cooperation with cathepsins, useless proteins in the lysosomal compartment. C1 Kyoto Inst Technol, Fac Text Sci, Dept Appl Biol, Sakyo Ku, Kyoto 6068585, Japan. Katakura Ind Co Ltd, Chuo Sanken Lab, Sayama, Saitama 3501352, Japan. Univ Florida, Coll Med, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Kyoto Inst Technol, Fac Text Sci, Dept Appl Biol, Sakyo Ku, Kyoto 6068585, Japan. EM bika@ipc.kit.ac.jp NR 50 TC 17 Z9 17 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0021-924X EI 1756-2651 J9 J BIOCHEM JI J. Biochem. PD AUG PY 2005 VL 138 IS 2 BP 127 EP 134 DI 10.1093/jb/mvi110 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 958LI UT WOS:000231449400003 PM 16091586 ER PT J AU Chinopoulos, C Starkov, AA Grigoriev, S Dejean, LM Kinnally, KW Liu, XB Ambudkar, IS Fiskum, G AF Chinopoulos, C Starkov, AA Grigoriev, S Dejean, LM Kinnally, KW Liu, XB Ambudkar, IS Fiskum, G TI Diacylglycerols activate mitochondrial cationic channel(s) and release sequestered Ca2+ SO JOURNAL OF BIOENERGETICS AND BIOMEMBRANES LA English DT Article DE mitochondria; calcium; diacylglycerol; mitoplast; cation channel; permeability transition pore; protein kinase C; transient receptor potential; OAG ID PROTEIN-KINASE-C; PERMEABILITY TRANSITION PORE; RAT-LIVER MITOCHONDRIA; TRANSIENT RECEPTOR; PHOSPHOLIPASE-C; CARDIAC MITOCHONDRIA; BRAIN MITOCHONDRIA; OUTER MEMBRANE; RUTHENIUM RED; CYTOCHROME-C AB Mitochondria contribute to cytosolic Ca2+ homeostasis through several uptake and release pathways. Here we report that 1,2- sn- diacylglycerols ( DAGs) induce Ca2+ release fromCa(2+)- loaded mammalian mitochondria. Release is not mediated by the uniporter or the Na+/ Ca2+ exchanger, nor is it attributed to putative catabolites. DAGs- induced Ca2+ efflux is biphasic. Initial release is rapid and transient, insensitive to permeability transition inhibitors, and not accompanied by mitochondrial swelling. Following initial rapid release of Ca2+ and relatively slow reuptake, a secondary progressive release of Ca2+ occurs, associated with swelling, and mitigated by permeability transition inhibitors. The initial peak of DAGs- induced Ca2+ efflux is abolished by La3+ ( 1mM) and potentiated by protein kinase C inhibitors. Phorbol esters, 1,3- diacylglycerols and 1- monoacylglycerols do not induce mitochondrial Ca2+ efflux. Ca2+- loaded mitoplasts devoid of outer mitochondrial membrane also exhibit DAGsinduced Ca2+ release, indicating that this mechanism resides at the inner mitochondrial membrane. Patch clamping brain mitoplasts reveal DAGs- induced slightly cation- selective channel activity that is insensitive to bongkrekic acid and abolished by La3+. The presence of a second messenger- sensitive Ca2+ release mechanism in mitochondria could have an important impact on intracellular Ca2+ homeostasis. C1 Univ Maryland, Sch Med, Dept Anesthesiol, Baltimore, MD 21201 USA. Cornell Univ, Weill Med Coll, Dept Neurol, New York, NY 10021 USA. NYU, Coll Dent, Div Basic Sci, New York, NY USA. NIDCR, Secretory Physiol Sect, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD USA. RP Fiskum, G (reprint author), Univ Maryland, Sch Med, Dept Anesthesiol, 685 W Baltimore St, Baltimore, MD 21201 USA. EM gfisk001@umaryland.edu RI Chinopoulos, Christos/A-5175-2008; Starkov, Anatoly/B-2688-2012; OI Starkov, Anatoly/0000-0002-1334-4828; Chinopoulos, Christos/0000-0003-0183-4149 FU NIGMS NIH HHS [R01 GM057249, GM57249]; NINDS NIH HHS [NS34152, R01 NS034152, R01 NS034152-12] NR 65 TC 11 Z9 12 U1 0 U2 1 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 AUG PY 2005 VL 37 IS 4 BP 237 EP 247 DI 10.1007/s10863-005-6634-0 PG 11 WC Biophysics; Cell Biology SC Biophysics; Cell Biology GA 965HC UT WOS:000231940200003 PM 16167179 ER PT J AU Lindorff-Larsen, K Best, RB Vendruscolo, M AF Lindorff-Larsen, K Best, RB Vendruscolo, M TI Interpreting dynamically-averaged scalar couplings in proteins SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE protein dynamics; Karplus relationship; protein structure; scalar couplings ID SIDE-CHAIN DYNAMICS; MOLECULAR-DYNAMICS; NMR RELAXATION; CONSTANTS; MOTION; HOMONUCLEAR; CONSISTENT; UBIQUITIN; ANGLES AB The experimental determination of scalar three-bond coupling constants represents a powerful method to probe both the structure and dynamics of proteins. The detailed structural interpretation of such coupling constants is usually based on Karplus relationships, which allow the measured couplings to be related to the torsion angles of the molecules. As the measured couplings are sensitive to thermal fluctuations, the parameters in the Karplus relationships are better derived from ensembles representing the distributions of dihedral angles present in solution, rather than from single conformations. We present a method to derive such parameters that uses ensembles of conformations determined through dynamic-ensemble refinement - a method that provides structural ensembles that simultaneously represent both the structure and the associated dynamics of a protein. C1 Univ Copenhagen, Inst Mol Biol & Physiol, Dept Biochem, DK-2100 Copenhagen, Denmark. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. RP Lindorff-Larsen, K (reprint author), Univ Copenhagen, Inst Mol Biol & Physiol, Dept Biochem, Univ Pk 13, DK-2100 Copenhagen, Denmark. EM Klindorff-larsen@aki.ku.dk RI Vendruscolo, Michele/F-5901-2012; Lindorff-Larsen, Kresten/K-6469-2014; Best, Robert/H-7588-2016 OI Lindorff-Larsen, Kresten/0000-0002-4750-6039; Best, Robert/0000-0002-7893-3543 NR 26 TC 30 Z9 32 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD AUG PY 2005 VL 32 IS 4 BP 273 EP 280 DI 10.1007/s10858-005-8873-0 PG 8 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 971RU UT WOS:000232402800002 PM 16211481 ER PT J AU Lee, DY Rhee, SG Ferretti, J Gruschus, JM AF Lee, DY Rhee, SG Ferretti, J Gruschus, JM TI H-1, N-15, and C-13 chemical shift assignments of the human Sulfiredoxin (hSrx) SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. NIH, Lab Cell Signaling, Bethesda, MD 20892 USA. RP Gruschus, JM (reprint author), NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. EM gruschus@helix.nih.gov NR 2 TC 1 Z9 2 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD AUG PY 2005 VL 32 IS 4 BP 339 EP 339 DI 10.1007/s10858-005-0472-6 PG 1 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 971RU UT WOS:000232402800016 PM 16211494 ER PT J AU Nohria, A Shah, MR Hill, JA Abraham, WT Frantz, RP Hamilton, MA Warnica, JW Sopko, G Stebbins, A Stevenson, LW AF Nohria, A Shah, MR Hill, JA Abraham, WT Frantz, RP Hamilton, MA Warnica, JW Sopko, G Stebbins, A Stevenson, LW TI Effect of empiric versus PAC-guided therapy on renal function in patients hospitalized with decompensated HF SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 9th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 18-21, 2005 CL Boca Raton, FL SP Heart Failure Soc Amer C1 Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. Columbia Univ, Med Ctr, Dept Med, New York, NY 10027 USA. Univ Florida, Div Cardiol, Gainesville, FL 32611 USA. Ohio State Univ, Med Ctr, Div Cardiovasc Med, Columbus, OH 43210 USA. Mayo Clin, Rochester, MN USA. Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA 90024 USA. Univ Calgary, Dept Med, Calgary, AB T2N 1N4, Canada. NHLBI, NIH, Bethesda, MD 20892 USA. DCRI, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2005 VL 11 IS 6 SU S MA 339 BP S181 EP S181 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 962PV UT WOS:000231745600340 ER PT J AU Bellani, MA Romanienko, PJ Cairatti, DA Camerini-Otero, RD AF Bellani, MA Romanienko, PJ Cairatti, DA Camerini-Otero, RD TI SPO11 is required for sex-body formation, and Spo11 heterozygosity rescues the prophase arrest of Atm(-/-) spermatocytes SO JOURNAL OF CELL SCIENCE LA English DT Article DE H2AX; ATM; ATR; SPO11; sex body; meiosis ID DOUBLE-STRAND BREAKS; MEIOTIC CHROMOSOME SYNAPSIS; ATM-DEFICIENT MICE; HISTONE H2AX; XY BODY; SYNAPTONEMAL COMPLEXES; PSEUDOAUTOSOMAL REGION; ATAXIA-TELANGIECTASIA; MALE-MOUSE; PROTEIN AB SPO11 introduces double-strand breaks (DSBs) that trigger the phosphorylation of H2AX during meiotic prophase. In mice, SPO11 is strictly required for initiation of meiotic recombination and synapsis, yet SPO11 is still considered to be dispensable for sex-body formation in mouse spermatocytes. We provide conclusive evidence showing that functional SPO11, and consequently recombination and synapsis, are required for phosphorylation of H2AX in the X-Y chromatin and for sex-body formation in mouse spermatocytes. We investigated the role in meiosis of the three kinases [ATM (ataxia telangiectasia mutated), ATR (ataxiate-langiectasia- and Rad-3-related) and DNA-PKcs (DNA-dependent-protein-kinase catalytic subunit)] known to phosphorylate H2AX in mitotic cells. We found that DNA-PKcs can be ruled out as an essential kinase in this process, whereas ATM is strictly required for the chromatin-wide phosphorylation of H2AX occurring in leptotene spermatocytes in response to DSBs. Remarkably, we discovered that Spoil heterozygosity can rescue the prophase-I-arrest characteristic of ATM-deficient spermatocytes. Characterization of the rescued Atm(-/-) Spo11(+/-) mutant indicates that ATM is dispensable for sex-body formation and phosphorylation of H2AX in this subnuclear domain. The co-localization of ATR, phosphorylated H2AX and the sex chromatin observed in the Atm(-/-) Spo11(+/-) mutant, along with ATR transcription kinetics during the first wave of spermatogenesis, confirm and expand recent findings indicating that ATR is the kinase involved in H2AX phosphorylation in the sex body. C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Camerini-Otero, RD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM camerini@ncifcrf.gov NR 54 TC 103 Z9 109 U1 0 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD AUG 1 PY 2005 VL 118 IS 15 BP 3233 EP 3245 DI 10.1242/jcs.02466 PG 13 WC Cell Biology SC Cell Biology GA 960FM UT WOS:000231575600005 PM 15998665 ER PT J AU Nie, ZZ Fei, JJ Premont, RT Randazzo, PA AF Nie, ZZ Fei, JJ Premont, RT Randazzo, PA TI The Arf GAPs AGAP1 and AGAP2 distinguish between the adaptor protein complexes AP-1 and AP-3 SO JOURNAL OF CELL SCIENCE LA English DT Article DE ADP ribosylation factor; GTPase activating protein; clathrin adaptor protein; endocytosis; transferrin ID GTPASE-ACTIVATING PROTEIN; SORTING SIGNALS; COATED VESICLES; ACTIN CYTOSKELETON; PLASMA-MEMBRANE; GAMMA-ADAPTIN; CROSS-LINKING; CLATHRIN; TRANSPORT; ENDOSOMES AB ADP ribosylation factors (Arf) regulate membrane trafficking at multiple intracellular sites by recruiting coat proteins to membranes. The site-specific regulation of Arf is thought to be mediated by regulatory proteins including the guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Here, we test this hypothesis by comparing the site of action of the Arf GAP AGAP2 to the closely related AGAP1. AGAP1 has previously been found to associate with the adaptor protein complex AP-3 and regulate the function of AP-3 endosomes. We found that AGAP2 directly interacted with AP-1. AGAP2 colocalized with AP-1, transferrin receptor and Rab4 on endosomes. Overexpression of AGAP2 changed the intracellular distribution of AP-1 and promoted Rab4-dependent fast recycling of transferrin. Based on these results, we concluded that the closely related Arf GAPs, AGAP1 and AGAP2, distinguish between these related heterotetrameric adaptor protein complexes to specifically regulate AP-3 endosomes and AP-1 recycling endosomes. C1 NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP Randazzo, PA (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM randazzo@helix.nih.gov NR 60 TC 37 Z9 39 U1 0 U2 5 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD AUG 1 PY 2005 VL 118 IS 15 BP 3555 EP 3566 DI 10.1242/jcs.02486 PG 12 WC Cell Biology SC Cell Biology GA 960FM UT WOS:000231575600031 PM 16079295 ER PT J AU Du, CW Koretsky, AP Izrailtyan, I Benveniste, H AF Du, CW Koretsky, AP Izrailtyan, I Benveniste, H TI Simultaneous detection of blood volume, oxygenation, and intracellular calcium changes during cerebral ischemia and reperfusion in vivo using diffuse reflectance and fluorescence SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE blood volume; calcium; calcium indicator of Rhod2; cerebral hemoglobin oxygenation; cerebral ischemia; hemodynamics; intracellular calcium ID PERFUSED MOUSE HEART; CYTOSOLIC CALCIUM; SENSORY STIMULATION; BRAIN ACTIVITY; RABBIT HEART; CA2+; RAT; MITOCHONDRIA; CORTEX; HYPOXIA AB We describe an approach to measure changes in intracellular calcium along with changes in blood volume and oxygenation directly from the exposed rat cortex in vivo during cerebral ischemia and reperfusion. Measurements were made using a catheter-based optical system. The endface of a Y-shaped bifurcated fiber optic bundle was mounted on the cortical surface. It delivered the light at three wavelengths of 548, 555, and 572 nm to the brain through a fast monochromator coupled to a xenon lamp, and collected the calcium-dependent fluorescence emission from Rhod2 at 589 nm (excited at 548 nm) along with the diffuse reflections at the wavelengths of 555 and 572 nm to determine the changes in blood volume and hemoglobin oxygenation. The feasibility of this approach was experimentally examined by inducing transient cerebral ischemia and reperfusion in the rat. The ischemia induced an 8.5%+/- 1.7% fluorescence increase compared with the preischemic control values. Blood volume and tissue hemoglobin oxygenation decreased by 57.4%+/- 12.6% and 47.3%+/- 12.5%, respectively. All signals normalized on reperfusion. The ischemia-induced change in Rhod2-Ca2+ fluorescence was blocked using a calcium channel blocker, nimodipine, confirming that intracellular changes in calcium were responsible for the fluorescence changes. Thus, changes in cerebral hemodynamics and intracellular calcium concentration changes were measured simultaneously, facilitating future studies of the interrelationship between neuronal activation and metabolic and vascular processes in normal and diseased brain. C1 Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. SUNY Stony Brook, Dept Anesthesiol, Stony Brook, NY 11794 USA. RP Du, CW (reprint author), Brookhaven Natl Lab, Dept Med, Bldg 490,POB 5000, Upton, NY 11973 USA. EM congwu@bnl.gov RI Koretsky, Alan/C-7940-2015; Izrailtyan, Igor/G-8192-2016 OI Koretsky, Alan/0000-0002-8085-4756; Izrailtyan, Igor/0000-0003-1216-3467 FU Intramural NIH HHS [Z01 NS002989-08] NR 54 TC 22 Z9 23 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD AUG PY 2005 VL 25 IS 8 BP 1078 EP 1092 DI 10.1038/sj.jcbfm.9600102 PG 15 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 950SL UT WOS:000230877600015 PM 15744244 ER PT J AU Dickstein, DP Rich, BA Binstock, AB Pradella, AG Towbin, KE Pine, DS Leibenluft, E AF Dickstein, DP Rich, BA Binstock, AB Pradella, AG Towbin, KE Pine, DS Leibenluft, E TI Comorbid anxiety in phenotypes of pediatric bipolar disorder SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID OBSESSIVE-COMPULSIVE DISORDER; MANIC-DEPRESSIVE ILLNESS; DOUBLE-BLIND; I DISORDER; PANIC DISORDER; ANTIDEPRESSANT DISCONTINUATION; PSYCHIATRIC-DISORDERS; PSYCHOTIC FEATURES; LITHIUM-CARBONATE; CONDUCT DISORDER AB Objective: There has been limited research on anxiety in pediatric bipolar disorder (BPD). Adult BPD studies suggest comorbid anxiety disorders are common and impact treatment outcome. We explored the association of comorbid anxiety with two phenotypes of pediatric BPD. Methods: We studied two groups of children. The first group (BPD; N = 31) represents the "narrow phenotype" of pediatric BPD, meeting stringent DSM-IV criteria for mania, including duration and elevated/expansive mood. The second group (ED; N = 32) exhibited chronic, non-episodic irritability without elation or grandiosity ("broad phenotype"). Results: Both samples demonstrate high prevalence of anxiety (BPD 77.4%; ED 46.9%). In the BPD sample, anxiety predates BPD onset, and those with comorbid anxiety have earlier age of onset of BPD than those without. Children with BPD plus anxiety have more hospitalizations than those without anxiety. ED subjects with and without comorbid anxiety did not differ with respect to onset of ED symptoms or number of hospitalizations. Conclusions: Narrow and broad phenotype BPD children have high rates of comorbid anxiety, although only in the narrow phenotype group is comorbid anxiety associated with greater functional impairment BPD plus comorbid anxiety may represent a particularly severe phenotype of pediatric BPD. C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Cornell Univ, New York, NY USA. RP Dickstein, DP (reprint author), NIMH, Pediat & Dev Neuropsychiat Branch, 10 Ctr Dr,MSC 1255 Bldg 10,Room 4N208, Bethesda, MD 20892 USA. EM Dicksted@mail.nih.gov RI Dickstein, Daniel/L-3210-2016 OI Dickstein, Daniel/0000-0003-1647-5329 NR 75 TC 57 Z9 59 U1 2 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD AUG PY 2005 VL 15 IS 4 BP 534 EP 548 DI 10.1089/cap.2005.15.534 PG 15 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 973EZ UT WOS:000232507000003 PM 16190786 ER PT J AU Easter, J McClure, EB Monk, CS Dhanani, M Hodgdon, H Leibenluft, E Charney, DS Pine, DS Ernst, M AF Easter, J McClure, EB Monk, CS Dhanani, M Hodgdon, H Leibenluft, E Charney, DS Pine, DS Ernst, M TI Emotion recognition deficits in pediatric anxiety disorders: Implications for amygdala research SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID FACIAL EXPRESSION RECOGNITION; NEURAL SYSTEMS; SOCIAL ANXIETY; CHILDREN; ADOLESCENTS; FACES; DEPRESSION; CHILDHOOD; BRAIN; STIMULI AB Introduction: Anxiety disorders in adults involve aberrant processing of emotional information that is hypothesized to reflect perturbations in the amygdala. This study examines the relationship between face-emotion recognition and anxiety in a sample of children and adolescents participating in a brain-imaging study of amygdala structure and function. Methods: This study recruited 15 children and adolescents with ongoing anxiety disorders and 11 psychiatrically healthy comparisons group-matched on age, gender, and IQ. Face-emotion recognition was assessed using the Diagnostic Analysis of Nonverbal Accuracy Scale (DANVA). Results: Children and adolescents with anxiety disorders exhibited significantly poorer performance on the face-emotion recognition task compared to healthy controls (z = 2.2; p < 0.05). This difference was found only for expressions posed by adults but not children. Discussion: Reduced accuracy on a face-emotion recognition test is consistent with perturbed amygdala function in pediatric anxiety disorders. Conclusion: As this study was conducted in a sample undergoing a neuroimaging investigation of amygdala integrity, future analyses will examine associations among amygdala function, clinical anxiety, and face-recognition abilities. C1 NIMH, Sect Dev & Affect Neurosci, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Ernst, M (reprint author), NIMH, Sect Dev & Affect Neurosci, Mood & Anxiety Disorders Program, 15K N Dr,MSC-2670, Bethesda, MD 20892 USA. EM ernstm@intra.nimh.nih.gov RI Monk, Christopher/J-1805-2014 NR 57 TC 27 Z9 27 U1 5 U2 21 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD AUG PY 2005 VL 15 IS 4 BP 563 EP 570 DI 10.1089/cap.2005.15.563 PG 8 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 973EZ UT WOS:000232507000005 PM 16190788 ER PT J AU Deuster, PA Faraday, MM Chrousos, GP Poth, MA AF Deuster, PA Faraday, MM Chrousos, GP Poth, MA TI Effects of dehydroepiandrosterone and alprazolam on hypothalamic- pituitary responses to exercise SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; GAMMA-AMINOBUTYRIC-ACID; D-ASPARTATE NMDA; ADRENAL AXIS; GROWTH-HORMONE; STIMULATED ADRENOCORTICOTROPIN; VASOPRESSIN SECRETION; PROLACTIN SECRETION; TREADMILL EXERCISE; CORTISOL RESPONSE AB Context: The hypothalamic-pituitary-adrenal axis (HPA) is restrained by activation of gamma-amino-butyric acid receptors. Alprazolam (APZ) and dehydroepiandrosterone (DHEA) are purported to be gamma-amino-butyric acid agonists and antagonists, respectively. Objective: Our objective was to examine the effects of APZ and DHEA alone and in combination on HPA axis activity. Design: This was a double-blind, crossover, placebo-controlled study. Setting: The study setting was the general community. Participants: Subjects consisted of 15 men (age, 20-45 yr) with a body mass index of 20-25 kg/m(2). Interventions: DHEA (100 mg/d) or placebo was given for 4 wk, followed by a 2-wk washout; participants ingested 0.5 mg APZ or placebo 10 and 2 h before high-intensity exercise. Outcome Measures: We measured basal and exercise-induced ACTH, arginine vasopressin (AVP), cortisol, DHEA, and GH responses. It was hypothesized that DHEA would enhance and APZ would blunt exercise-induced ACTH and cortisol release. Results: DHEA significantly increased the AVP response to exercise (P < 0.01). APZ treatment significantly increased basal GH and blunted plasma cortisol, ACTH, AVP, and DHEA responses to exercise (P < 0.05). DHEA and APZ in combination significantly increased the GH response to exercise (P < 0.01). Conclusions: DHEA may alter a subset of receptors involved in AVP release. Together DHEA and APZ may up-regulate GH during exercise by blunting a suppressive (HPA axis) and potentiating an excitatory (glutamate receptor) system. C1 Uniformed Serv Univ Hlth Sci, Dept Mil & Emergency Med, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. NICHHD, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. RP Deuster, PA (reprint author), Uniformed Serv Univ Hlth Sci, Dept Mil & Emergency Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM pdeuster@usuhs.mil RI Deuster, Patricia/G-3838-2015 OI Deuster, Patricia/0000-0002-7895-0888 NR 38 TC 14 Z9 15 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 AUG PY 2005 VL 90 IS 8 BP 4777 EP 4783 DI 10.1210/jc.2004-2504 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 953HZ UT WOS:000231068500052 PM 15928250 ER PT J AU Ilias, I Torpy, DJ Pacak, K Mullen, N Wesley, RA Nieman, LK AF Ilias, I Torpy, DJ Pacak, K Mullen, N Wesley, RA Nieman, LK TI Cushing's syndrome due to ectopic corticotropin secretion: Twenty years' experience at the National Institutes of Health SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID DEXAMETHASONE-SUPPRESSION TEST; ADRENOCORTICOTROPIC HORMONE SYNDROME; BRONCHIAL CARCINOID-TUMORS; ACTH-PRODUCING TUMORS; DIFFERENTIAL-DIAGNOSIS; STIMULATION TEST; FOLLOW-UP; MANAGEMENT; LOCALIZATION; PITUITARY AB Context: Ectopic ACTH secretion (EAS) is difficult to diagnose and treat. We present our experience with EAS from 1983 to 2004. Setting: The study was performed at a tertiary care clinical research center. Patients: Ninety patients, aged 8-72 yr, including 48 females were included in the study. Interventions and Outcome Measures: Tests included 8 mg dexamethasone suppression, CRH stimulation, inferior petrosal sinus sampling (IPSS), computed tomography, octreotide scan, magnetic resonance imaging, and/or venous sampling. Therapies, pathological examinations, and survival were noted. Results: Eighty-six to 94% of patients did not respond to CRH or dexamethasone suppression, whereas 66 of 67 had negative IPSS. To control hypercortisolism, 62 patients received medical treatment, and 33 had bilateral adrenalectomy. Imaging localized tumors in 67 of 90 patients. Surgery confirmed an ACTH-secreting tumor in 59 of 66 patients and cured 65%. Nonthymic carcinoids took longest to localize. Deaths included three of 35 with pulmonary carcinoid, two of five with thymic carcinoid, four of six with gastrinoma, two of 13 with neuroendocrine tumor, two of two with medullary thyroid cancer, one of five with pheochromocytoma, three of three with small-cell lung cancer, and two of 17 with occult tumor. Patients with other carcinoids and ethesioneuroblastoma are alive. Conclusions: IPSS best identifies EAS. Initial failed localization is common and suggests pulmonary carcinoid. Although only 47% achieved cure, survival is good except in patients with small-cell lung cancer, medullary thyroid cancer, and gastrinoma. C1 NICHHD, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. Warren Grant Magnuson Clin Ctr, Dept Nursing, NIH, Bethesda, MD 20892 USA. Warren Grant Magnuson Clin Ctr, Biostat & Clin Epidemiol Serv, NIH, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), Clin Res Ctr, Bldg 10,1 E,Room 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM niemanl@exchange.nih.gov NR 51 TC 248 Z9 274 U1 0 U2 8 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 AUG PY 2005 VL 90 IS 8 BP 4955 EP 4962 DI 10.1210/jc.2004-2527 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 953HZ UT WOS:000231068500077 PM 15914534 ER PT J AU Seggewiss, R Dunbar, CE AF Seggewiss, R Dunbar, CE TI A new direction for gene therapy: intrathymic T cell-specific lentiviral gene transfer SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID SEVERE COMBINED IMMUNODEFICIENCY; HEMATOPOIETIC STEM; ZAP-70; TRANSPLANTATION; INTEGRATION; PRIMATES; DEFECTS AB Reports of neoplasia related to insertional activation of protooncogenes by retroviral vectors have raised serious safety concerns in the field of gene therapy. Modification of current approaches is urgently required to minimize the deleterious consequences of insertional mutagenesis. In this issue of the JCI, Adjali and colleagues report on their treatment of SCID mice lacking the 70-kDa protein tyrosine kinase, ZAP-70, with direct intrathymic injection of a ZAP-70-expressing T cell-specific lentiviral vector, which resulted in T cell reconstitution (see the related article beginning on page 2287). Using lentiviral. vectors and in situ gene transfer may represent a safer approach than using retroviral vectors for ex vivo gene transfer into HSCs. avoiding 3 factors potentially linked to leukemogenesis, namely HSC targets, ex vivo transduction and expansion, and standard Moloney leukemia virus-based retroviral vectors. C1 NHLBI, Mol Hematopoiesis Sect, Hematol Branch, NIH,US Dept HHS,Clin Res Ctr, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), NHLBI, Mol Hematopoiesis Sect, Hematol Branch, NIH,US Dept HHS,Clin Res Ctr, Bldg 10,Room 4E-5132,10 Ctr Dr,MSC 1202, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov NR 19 TC 8 Z9 10 U1 0 U2 0 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 AUG PY 2005 VL 115 IS 8 BP 2064 EP 2067 DI 10.1172/JCI26041 PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 951OJ UT WOS:000230939800016 PM 16075048 ER PT J AU Huang, Z Shiva, S Kim-Shapiro, DB Patel, RP Ringwood, LA Irby, CE Huang, KT Ho, C Hogg, N Schechter, AN Gladwin, MT AF Huang, Z Shiva, S Kim-Shapiro, DB Patel, RP Ringwood, LA Irby, CE Huang, KT Ho, C Hogg, N Schechter, AN Gladwin, MT TI Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID BLOOD-FLOW REGULATION; ISCHEMIA-REPERFUSION; S-NITROSOHEMOGLOBIN; VASOMOTOR RESPONSES; GUANYLATE-CYCLASE; HUMAN CIRCULATION; XANTHINE-OXIDASE; HEME PROTEINS; ACID-BASE; IN-VIVO AB Hypoxic vasodilation is a fundamental, highly conserved physiological response that requires oxygen and/or pH sensing coupled to vasodilation. While this process was first characterized more than 80 years ago, the precise identity and mechanism of the oxygen sensor and mediators of vasodilation remain uncertain. In support of a possible role for hemoglobin (Hb) as a sensor and effector of hypoxic vasodilation, here we show biochemical evidence that Hb exhibits enzymatic behavior as a nitrite reductase, with maximal NO generation rates occurring near the oxy-to-deoxy (R-to-T) allosteric structural transition of the protein. The observed rate of nitrite reduction by Hb deviates from second-order kinetics, and sigmoidal reaction progress is determined by a balance between 2 opposing chemistries of the heme in the R (oxygenated conformation) and T (deoxygenated conformation) allosteric quaternary structures of the Hb tetramer - the greater reductive potential of deoxyheme in the R state tetramer and the number of unligated deoxyheme sites necessary for nitrite binding, which are more plentiful in the T state tetramer. These opposing chemistries result in a maximal nitrite reduction rate when Hb is 40-60% saturated with oxygen (near the Hb P-50), an apparent ideal set point for hypoxia-responsive NO generation. These data suggest that the oxygen sensor for hypoxic vasodilation is determined by Hb oxygen saturation and quaternary structure and that the nitrite reductase activity of Hb generates NO gas under allosteric and pH control. C1 NHLBI, Viral Therapeut Sect, Cardiovasc Branch, Clin Res Ctr,NIH, Bethesda, MD 20892 USA. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. Wake Forest Univ, Dept Biomed Engn, Winston Salem, NC 27109 USA. Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. Univ Alabama, Ctr Free Radical Biol, Birmingham, AL 35294 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA. Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Free Radical Res Ctr, Milwaukee, WI 53226 USA. RP Gladwin, MT (reprint author), NHLBI, Viral Therapeut Sect, Cardiovasc Branch, Clin Res Ctr,NIH, Bldg 10,Room 5-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM mgladwin@mail.nih.gov RI Ho, Chien/O-6112-2016; OI Ho, Chien/0000-0002-4094-9232; Schechter, Alan N/0000-0002-5235-9408; Patel, Rakesh/0000-0002-1526-4303 FU NHLBI NIH HHS [HL58091, R01 HL058091, R29 HL058091, R37 HL058091]; NIGMS NIH HHS [GM55792, R01 GM055792, R29 GM055792] NR 57 TC 323 Z9 327 U1 2 U2 22 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 AUG PY 2005 VL 115 IS 8 BP 2099 EP 2107 DI 10.1172/JCI24650 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 951OJ UT WOS:000230939800024 PM 16041407 ER PT J AU Kovacs, JA Lempicki, RA Sidorov, IA Adelsberger, JW Sereti, I Sachau, W Kelly, G Metcalf, JA Davey, RT Falloon, J Polis, MA Tavel, J Stevens, R Lambert, L Hosack, DA Bosche, M Issaq, HJ Fox, SD Leitman, S Baseler, MW Masur, H Di Mascio, M Dimitrov, DS Lane, HC AF Kovacs, JA Lempicki, RA Sidorov, IA Adelsberger, JW Sereti, I Sachau, W Kelly, G Metcalf, JA Davey, RT Falloon, J Polis, MA Tavel, J Stevens, R Lambert, L Hosack, DA Bosche, M Issaq, HJ Fox, SD Leitman, S Baseler, MW Masur, H Di Mascio, M Dimitrov, DS Lane, HC TI Induction of prolonged survival of CD4(+) T lymphocytes by intermittent IL-2 therapy in HIV-infected patients SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article; Proceedings Paper CT 9th Conference on Retroviruses and Opportunistic Infection CY FEB 24-28, 2002 CL SEATTLE, WA ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; INTERLEUKIN-2 THERAPY; SUBCUTANEOUS INTERLEUKIN-2; POSITIVE PATIENTS; IN-VIVO; ENRICHMENT; EXPANSION; CELLS AB HIV infection leads to decreases in the number of CD4+ T lymphocytes and an increased risk for opportunistic infections and neoplasms. The administration of intermittent cycles of IL-2 to HIV-infected patients can lead to profound increases (often greater than 100%) in CD4 cell number and percentage. Using in vivo labeling with H-2-glucose and BrdU, we have been able to demonstrate that, although therapy with IL-2 leads to high levels of proliferation of CD4 as well as CD8 lymphocytes, it is a remarkable preferential increase in survival of CD4 cells (with half-fives that can exceed 3 years) that is critical to the sustained expansion of these cells. This increased survival was time-dependent: the median half-life, as determined by semiempirical modeling, of labeled CD4 cells in 6 patients increased from 1.7 weeks following an early IL-2 cycle to 28.7 weeks following a later cycle, while CD8 cells showed no change in the median half-life. Examination of lymphocyte subsets demonstrated that phenotypically naive (CD27(+)CD45RO(-)) as well as central memory (CD27(+)CD45RO(+)) CD4 cells were preferentially expanded, suggesting that IL-2 can help maintain cells important for host defense against new antigens as well as for long-term memory to opportunistic pathogens. C1 Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD USA. Sci Applicat Int Corp, Frederick, MD USA. NCI, Ctr Canc Res, Lab Expt & Computat Biol, Frederick, MD USA. NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. NIAID, NIH, Off Clin Res, Biostat Res Branch, Bethesda, MD 20892 USA. RP Kovacs, JA (reprint author), Bldg 10,Room 7D43,Mail Stop Code 1662, Bethesda, MD 20892 USA. EM jkovacs@niaid.nih.gov RI Lempicki, Richard/E-1844-2012; OI Lempicki, Richard/0000-0002-7059-409X; Polis, Michael/0000-0002-9151-2268; Sidorov, Igor/0000-0001-6519-4983 FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 25 TC 97 Z9 100 U1 0 U2 3 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 AUG PY 2005 VL 115 IS 8 BP 2139 EP 2148 DI 10.1172/JCI23196 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 951OJ UT WOS:000230939800028 PM 16025158 ER PT J AU Schaefer, L Babelova, A Kiss, E Hausser, HJ Baliova, M Krzyzankova, M Marsche, G Young, MF Mihalik, D Gotte, M Malle, E Schaefer, RM Grone, HJ AF Schaefer, L Babelova, A Kiss, E Hausser, HJ Baliova, M Krzyzankova, M Marsche, G Young, MF Mihalik, D Gotte, M Malle, E Schaefer, RM Grone, HJ TI The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID TUMOR-NECROSIS-FACTOR; INDUCED PULMONARY-FIBROSIS; FACTOR-ALPHA INTERACTS; INNATE IMMUNITY; SMALL PROTEOGLYCANS; EXTRACELLULAR-MATRIX; DERMATAN SULFATE; DENDRITIC CELLS; MESANGIAL CELLS; DECORIN AB Biglycan, a small leucine-rich proteoglycan, is a ubiquitous ECM component; however, its biological role has not been elucidated in detail. Here we show that biglycan acts in macrophages as an endogenous ligand of TLR4 and TLR2, which mediate innate immunity, leading to rapid activation of p38, ERK, and NF-kappa B and thereby stimulating the expression of TNF-alpha and macrophage inflammatory protein-2 (MIP-2). In agreement, the stimulatory effects of biglycan are significantly reduced in TLR4-mutant (TLR4-M), TLR2(-/-), and myeloid differentiation factor 88(-/-) (MyD88(-/-)) macrophages and completely abolished in TLR2(-/-)/TLR4-M macrophages. Biglycan-mill mice have a considerable survival benefit in LPS- or zymosan-induced sepsis due to lower levels of circulating TNF-alpha and reduced infiltration of mononuclear cells in the lung, which cause less end-organ damage. Importantly, when stimulated by LPS-induced proinflammatory factors, macrophages themselves are able to synthesize biglycan. Thus, biglycan, upon release from the ECM or from macrophages, can boost inflammation by signaling through TLR4 and TLR2, thereby enhancing the synthesis of TNF-alpha and MIP-2. Our results provide evidence for what is, to our knowledge, a novel role of the matrix component biglycan as a signaling molecule and a crucial proinflammatory factor. These findings are potentially relevant for the development of new strategies in the treatment of sepsis. C1 Interdisciplinary Ctr Clin Res, Dept Med D, Munster, Germany. German Canc Res Ctr, Dept Cellular & Mol Pathol, Heidelberg, Germany. Univ Ulm, Div Biochem Joint & Connect Tissue Dis, Ulm, Germany. Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria. NIDCR, NIH, Craniofacial & Skeletal Dis Branch, Bethesda, MD USA. Muenster Univ Hosp, Dept Gynecol, Munster, Germany. RP Schaefer, L (reprint author), Univ Klinikum Muenster, Med Klin & Poliklin D, Albert Schweitzer Str 33, D-48149 Munster, Germany. EM schaefl@uni-muenster.de RI Malle, Ernst/D-3071-2013; OI Marsche, Gunther/0000-0002-2422-5381; Gotte, Martin/0000-0003-2360-2496 NR 58 TC 384 Z9 393 U1 1 U2 15 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 AUG PY 2005 VL 115 IS 8 BP 2223 EP 2233 DI 10.1172/JC123755 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 951OJ UT WOS:000230939800038 PM 16025156 ER PT J AU Peter, J Armstrong, D Lyman, CA Walsh, TJ AF Peter, J Armstrong, D Lyman, CA Walsh, TJ TI Use of fluorescent probes to determine MICs of amphotericin B and caspofungin against Candida spp. and Aspergillus spp. SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID CONVOLUTED TUBULE CELLS; CALCIUM-TRANSPORT; FLOW-CYTOMETRY; SUSCEPTIBILITY; ALBICANS; YEASTS; PANEL AB We investigated the utility of mechanism-based fluorescent probes for determination of MICs (FMICs) of amphotericin B and caspofungin against Candida spp. and Aspergillus spp. Amphotericin B was selected as a membrane-active antifungal agent, and caspofungin was selected as a cell wall-active agent. FMICs were also compared to the MIC determined by CLSI (formerly NCCLS) methods. Five isolates per species of Candida albicans, Candida glabrata, Candida parapsilosis, Aspergillus fumigatus, and Aspergillus terreus were studied with either amphotericin B or caspofungin. The fluorescent probes, carboxyfluorescein diacetate (CFDA) for cytoplasmic esterase activity and dihexyloxacarbocyanine iodide (DiOC(6)) for cell membrane potential, were each added to their respective plates. MICs and FMICs were determined in at least three separate experiments (in duplicate). Fluorescence was measured using a 96-well plate fluorometer. For amphotericin B and caspofungin, the FMIC end point was the lowest concentration of drug at which the percent growth inhibition from treated organisms versus control organisms displayed 80% inhibition for amphotericin B and 50% inhibition for caspofungin as measured by a fluorescent signal. The MIC for amphotericin B was defined as the lowest concentration of antifungal displaying no visible growth for both Aspergillus and Candida spp. The MIC for caspofungin was the lowest concentration of drug that displayed a minimum effective concentration for Aspergillus spp. For Candida spp., the MIC for caspofungin was defined as the concentration at which the antifungal agent significantly inhibits the organism. The FMICs of both antifungals, as measured by the DiOC6 membrane probe, showed good agreement (83% to 100%), within one well dilution, with the MICs against amphotericin B and caspofungin for all species. Also, the FMICs measured by the CFDA cytoplasmic esterase probe reflecting damage due to cell wall or cell membrane showed strong agreement (79 to 100%) with the MICs of both amphotericin B and caspofungin for all species. There was no significant difference in comparisons of MIC and FMIC values (P >= 0.05). The use of fluorescent probes provides a mechanism-based method of determination of MICs of amphotericin B and caspofungin against Candida spp. and Aspergillus spp. that correlates well with standard methods. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bldg 10,Room 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov NR 23 TC 5 Z9 6 U1 1 U2 5 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 AUG PY 2005 VL 43 IS 8 BP 3788 EP 3792 DI 10.1128/JCM.43.8.3788-3792.2005 PG 5 WC Microbiology SC Microbiology GA 954EL UT WOS:000231136800028 PM 16081911 ER PT J AU Schwan, TG Raffel, SJ Schrumpf, ME Policastro, PF Rawlings, JA Lane, RS Breitschwerdt, EB Porcella, SF AF Schwan, TG Raffel, SJ Schrumpf, ME Policastro, PF Rawlings, JA Lane, RS Breitschwerdt, EB Porcella, SF TI Phylogenetic analysis of the spirochetes Borrelia parkeri and Borrelia turicatae and the potential for tick-borne relapsing fever in Florida SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID LYME-DISEASE SPIROCHETE; BDR PROTEIN FAMILY; LINEAR PLASMID; MOLECULAR CHARACTERIZATION; POPULATION-STRUCTURE; GEL-ELECTROPHORESIS; MONOCLONAL-ANTIBODY; ANTIGENIC VARIATION; CIRCULAR PLASMIDS; UNITED-STATES AB Isolates of Borrelia turicatae, Borrelia parkeri, and the Florida canine borrelia (FCB) were examined to further phylogenetically characterize the identities of these spirochetes in the United States. DNA sequences of four chromosomal loci (the 16S rRNA gene, flaB, gyrB, and glpQ) were determined for eight isolates of B. turicatae and six isolates of B. parkeri, which grouped the spirochetes into two distinct but closely related taxa (> 98% sequence identity) separate from Borrelia hermsii. The FCB was clearly separated with the group identified as B. turicatae, confirming this bacterium as a relapsing fever spirochete. Therefore, the potential for tick-borne relapsing fever in humans and other animals exists in Florida and future efforts are needed to determine the enzootic hosts and distribution of this spirochete in the southeastern United States. Analysis of plasmids demonstrated both linear and circular forms in B. turicatae but only linear plasmids in B. parkeri, which should be of interest to investigators concerned with plasmid diversity and evolution within this group of spirochetes. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Texas Dept State Hlth Serv, Community Preparedness Sect, Austin, TX USA. Univ Calif Berkeley, Dept Environm Sci Policy & Management, Berkeley, CA 94720 USA. N Carolina State Univ, Coll Vet Med, Dept Compan & Special Species Med, Raleigh, NC USA. RP Schwan, TG (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM tom_schwan@nih.gov FU NIAID NIH HHS [R01 AI022501, AI22501] NR 76 TC 44 Z9 45 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 AUG PY 2005 VL 43 IS 8 BP 3851 EP 3859 DI 10.1128/JCM.43.8.3851-3859.2005 PG 9 WC Microbiology SC Microbiology GA 954EL UT WOS:000231136800039 PM 16081922 ER PT J AU Corech, R Rao, A Laxova, A Moss, J Rock, MJ Li, Z Kosorok, MR Splaingard, ML Farrell, PM Barbieri, JT AF Corech, R Rao, A Laxova, A Moss, J Rock, MJ Li, Z Kosorok, MR Splaingard, ML Farrell, PM Barbieri, JT TI Early immune response to the components of the type III system of Pseudomonas aeruginosa in children with cystic fibrosis SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID EXOENZYME-S REGULON; OROPHARYNGEAL CULTURES; YERSINIA-PESTIS; YOUNG-CHILDREN; EXOTOXIN-A; V-ANTIGEN; ANTIBODY-RESPONSE; RISK-FACTORS; INFECTION; COLONIZATION AB The lungs of patients with cystic fibrosis (CF) are colonized initially by Pseudomonas aeruginosa, which is associated with progressive lung destruction and increased mortality. The pathogenicity of P. aeruginosa is caused by a number of virulence factors, including exotoxin A (ETA) and the type III cytotoxins (ExoS, ExoT, ExoU, and ExoY). P. aeruginosa contacts the plasma membrane to deliver type III cytotoxins through a channel formed by PopB, PopD, and PcrV; ETA enters mammalian cells via receptor-mediated endocytosis. The Wisconsin CF Neonatal Screening Project is a longitudinal investigation to assess the potential benefits and risks of newborn screening for CF; the project was the source of serum samples used in this study. Past studies evaluated the longitudinal appearance of antibodies to ETA and elastase and P. aeruginosa infections in patients with CF. The current study characterized the longitudinal appearance of antibodies to components of the type III system in children with CF. Western blot analyses showed that serum antibodies to PopB, PcrV, and ExoS were common. Longitudinal enzyme-linked immunosorbent assays determined that the first detection of antibodies to pooled ExoS/PopB occurred at a time similar to those of detection of antibodies to a P. aeruginosa cell lysate and the identification of oropharyngeal cultures positive for P. aeruginosa. This indicates that children with CF are colonized early with P. aeruginosa expressing the type III system, implicating it in early pathogenesis, and implies that surveillance of clinical symptoms, oropharyngeal cultures, and seroconversion to type III antigens may facilitate early detection of P. aeruginosa infections. C1 Med Coll Wisconsin, Dept Microbiol & Mol Genet, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. Univ Wisconsin, Sch Med, Dept Pediat, Madison, WI 53706 USA. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Sch Med, Dept Biostat & Med Informat, Madison, WI USA. RP Barbieri, JT (reprint author), Med Coll Wisconsin, Dept Microbiol & Mol Genet, 8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM jtb01@mcw.edu RI Splaingard, Mark/D-9206-2012 FU NCRR NIH HHS [M01 RR000058, M01 RR003186, M01-RR00058, RR03186]; NHLBI NIH HHS [HL68912, R01 HL068912]; NIDDK NIH HHS [DK34108, R01 DK034108, R56 DK034108] NR 44 TC 25 Z9 26 U1 0 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 AUG PY 2005 VL 43 IS 8 BP 3956 EP 3962 DI 10.1128/JCM.43.8.3956-3962.2005 PG 7 WC Microbiology SC Microbiology GA 954EL UT WOS:000231136800053 PM 16081936 ER PT J AU Santos, N Volotao, EM Soares, CC Campos, GS Sardi, SI Hoshino, Y AF Santos, N Volotao, EM Soares, CC Campos, GS Sardi, SI Hoshino, Y TI Predominance of rotavirus genotype G9 during the 1999, 2000, and 2002 seasons among hospitalized children in the city of Salvador, Bahia, Brazil: Implications for future vaccine strategies SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID POLYMERASE CHAIN-REACTION; RIO-DE-JANEIRO; P-TYPE; MOLECULAR CHARACTERIZATION; SEQUENCE-ANALYSIS; UNITED-STATES; NUCLEIC-ACID; SAO-PAULO; STRAINS; SEROTYPE AB Two hundred eight of 648 (32%) diarrheal stool samples collected from hospitalized children under 5 years of age during a 3-year period (1999, 2000, and 2002) in the city of Salvador, in the state of Bahia, Brazil, were rotavirus positive. One hundred sixty-four of 208 (78.8%) rotavirus-positive samples had genotype G9 specificity, predominantly in association with P[8]. Other specificities detected were G1 (12.0%) and G4 (1.4%). Viruses with G2, G3, or P[4] specificity were not detected. Rotavirus genotype G9 predominated during each of the three seasons studied; it represented 89.2% of rotavirus strains detected in 1999, 85.3% in 2000, and 74.5% in 2002. G1 viruses (the globally most common G type) have a unique epidemiological characteristic of maintaining predominance during multiple consecutive rotavirus seasons. We have shown in this study for the first time that the G9 viruses also have a similar epidemiological characteristic, albeit for a shorter period of surveillance. The next generation of rotavirus vaccines will need to provide adequate protection against disease caused by G9 viruses. C1 Univ Fed Rio de Janeiro, Inst Microbiol, Dept Virol, BR-21941590 Rio De Janeiro, RJ, Brazil. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Fed Bahia, Inst Ciencias Saude, BR-40110100 Salvador, BA, Brazil. RP Santos, N (reprint author), Univ Fed Rio de Janeiro, Inst Microbiol, Dept Virol, Cidade Univ,CCS-Bl 1,Ilha Fundao, BR-21941590 Rio De Janeiro, RJ, Brazil. EM nsantos@micro.ufrj.br RI Santos, Norma/H-6986-2015 OI Santos, Norma/0000-0002-5123-9172 NR 45 TC 54 Z9 56 U1 0 U2 4 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 AUG PY 2005 VL 43 IS 8 BP 4064 EP 4069 DI 10.1128/JCM.43.8.4064-4069.2005 PG 6 WC Microbiology SC Microbiology GA 954EL UT WOS:000231136800069 PM 16081952 ER PT J AU Green, NM Beres, SB Graviss, EA Allison, JE McGeer, AJ Vuopio-Varkila, J LeFebvre, RB Musser, JM AF Green, NM Beres, SB Graviss, EA Allison, JE McGeer, AJ Vuopio-Varkila, J LeFebvre, RB Musser, JM TI Genetic diversity among type emm28 group A Streptococcus strains causing invasive infections and pharyngitis SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID POPULATION-BASED SURVEILLANCE; RHEUMATIC-FEVER OUTBREAKS; COMPLETE GENOME SEQUENCE; ERYTHROMYCIN RESISTANCE; NONINVASIVE INFECTIONS; EPIDEMIOLOGIC FEATURES; MACROLIDE-RESISTANCE; ERM(A) GENE; M3 STRAIN; M PROTEIN AB Genome sequencing of group A Streptococcus (GAS) has revealed that prophages account for the vast majority of gene content differences between strains. Serotype M28 strains are a leading cause of pharyngitis and invasive infections, but little is known about genetic diversity present in natural populations of these organisms. To study this issue, population-based samples of 568 strains from Ontario, Canada; Finland; and Houston, Texas, were analyzed. Special attention was given to analysis of variation in prophage-encoded virulence gene content by a PCR-based method. Thirty and 29 distinct prophage-encoded virulence gene profiles were identified among pharyngitis and invasive infection isolates. Thirteen profiles, representing the majority of the strains, were shared between these two classes of isolates. Significant differences were observed in the frequency of occurrence of certain prophage toxin gene profiles and infection type. M28 strains are highly diverse in prophage-encoded virulence gene content and integration site, supporting the key concept that prophages are critical contributors to GAS genetic diversity and population biology. Nucleotide sequence variation in the emm gene (encodes M protein) was also examined. Only three allelic variants were identified in the hypervariable portion of the emm28 gene. All but one strain had the same inferred amino acid sequence in the first 100 amino acids of the mature M28 protein. In contrast, size differences in the emm28 gene and inferred protein due to variable numbers of C-terminal repeats were common. The presence of macrolide resistance genes (mefA, ermB, and ermTR) was analyzed by PCR, and less than 2% of the strains were positive. C1 Baylor Coll Med, Dept Pathol, Ctr Human Bacterial Pathogenesis Res, Houston, TX 77030 USA. NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Univ Calif Davis, Dept Pathol Microbiol & Immunol, Davis, CA 95616 USA. Pediat Med Grp, Houston, TX 77098 USA. Univ Toronto, Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. Univ Toronto, Dept Microbiol, Toronto, ON M5G 1X5, Canada. Natl Publ Hlth Inst, Helsinki, Finland. RP Musser, JM (reprint author), Baylor Coll Med, Dept Pathol, Ctr Human Bacterial Pathogenesis Res, 1 Baylor Plaza, Houston, TX 77030 USA. EM musser@bcm.tmc.edu RI mcgeer, allison /H-7747-2014 OI mcgeer, allison /0000-0001-5647-6137 FU NIAID NIH HHS [U01 AI060595, U01-AI-060595] NR 56 TC 34 Z9 37 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 2005 VL 43 IS 8 BP 4083 EP 4091 DI 10.1128/JCM.43.8.4083-4091.2005 PG 9 WC Microbiology SC Microbiology GA 954EL UT WOS:000231136800072 PM 16081955 ER PT J AU Quinto, C Danielsson, I Gellido, C Sander, H Chokroverty, S AF Quinto, C Danielsson, I Gellido, C Sander, H Chokroverty, S TI Brainstem hyperexcitability during cataplexy SO JOURNAL OF CLINICAL NEUROPHYSIOLOGY LA English DT Article DE narcolepsy; cataplexy; masseter reflex; F wave; Blink reflex excitability ID ORBICULARIS OCULI REFLEX; NARCOLEPSY; SLEEP; RECOVERY AB The exact cause of narcolepsy-cataplexy syndrome remains unclear; however, the recent discovery of hypocretin deficiency in the lateral hypothalamus of narcoleptic patients has increased our understanding of its etiology. The authors performed masseter reflex, tibial F response, and blink reflex excitability studies during and between attacks in a 66-year-old man with status cataplecticus. Masseter reflex and F responses were inhibited while the blink reflex R2 component was enhanced during attacks, suggesting either hyperexcitability or disinhibition of pontine and/or medullary interneurons but hypoexcitability of pontine and spinal motor neurons during cataplexy. C1 Hudson Neurosci PC, Bayonne, NJ 07002 USA. NIH, Epilepsy Res Sect, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Cornell Univ, Peripheral Neurol Ctr, New York, NY USA. JFK Med Ctr, New Jersey Neurosci Inst, Edison, NJ USA. RP Quinto, C (reprint author), Hudson Neurosci PC, 1222 Kennedy Blvd, Bayonne, NJ 07002 USA. NR 9 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0736-0258 J9 J CLIN NEUROPHYSIOL JI J. Clin. Neurophysiol. PD AUG PY 2005 VL 22 IS 4 BP 275 EP 278 DI 10.1097/01.WNP.0000167933.33532.71 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 956KS UT WOS:000231299200007 PM 16093900 ER PT J AU Freidlin, B Simon, R AF Freidlin, B Simon, R TI Evaluation of randomized discontinuation design SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CLINICAL-TRIAL DESIGNS; END-POINTS; ANTINEOPLASTIC AGENTS; CYTOSTATIC AGENTS; CANCER-TREATMENTS; THERAPY; ENRICHMENT; DRUGS AB Purpose Single-arm phase II trials may not be appropriate for testing cytostatic agents. We evaluate two kinds of randomized designs for the early development of target-based cytostatic agents. Methods We compared power of the randomized discontinuation and upfront randomization designs under two models for the treatment effect of targeted cytostatic agents. Results The randomized discontinuation design is not as efficient as upfront randomization if treatment has a fixed effect on tumor growth rate or if treatment benefit is restricted to slower-growing tumors. On the other hand, the randomized discontinuation design can be advantageous under a model where only a subset of patients, those expressing the molecular target, is sensitive to the agent. To achieve efficiency, the design parameters must be carefully structured to provide adequate enrichment of the randomly assigned patients. Conclusion With careful planning, the randomized discontinuation designs can be useful in some settings in the early development of targeted agents where a reliable assay to select patients expressing the target is not available. C1 NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, 6130 Execut Blvd,EPN 8122,MSC 7434, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov NR 22 TC 42 Z9 43 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 1 PY 2005 VL 23 IS 22 BP 5094 EP 5098 DI 10.1200/JCO.2005.02.520 PG 5 WC Oncology SC Oncology GA 952CL UT WOS:000230979300045 PM 15983399 ER PT J AU Carbone, DP Ciernik, IF Kelley, MJ Smith, MC Nadaf, S Kavanaugh, D Maher, VE Stipanov, M Contois, D Johnson, BE Pendleton, CD Seifert, B Carter, C Read, EJ Greenblatt, J Top, LE Kelsey, MI Minna, JD Berzofsky, JA AF Carbone, DP Ciernik, IF Kelley, MJ Smith, MC Nadaf, S Kavanaugh, D Maher, VE Stipanov, M Contois, D Johnson, BE Pendleton, CD Seifert, B Carter, C Read, EJ Greenblatt, J Top, LE Kelsey, MI Minna, JD Berzofsky, JA TI Immunization with mutant p53- and K-ras-derived peptides in cancer patients: Immune response and clinical outcome SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 12th European Cancer Conference (ECCO 12) CY SEP 21-25, 2003 CL COPENHAGEN, DENMARK ID CYTOTOXIC T-LYMPHOCYTES; ACTIVE SPECIFIC IMMUNOTHERAPY; PULSED DENDRITIC CELLS; HUMAN LUNG-CANCER; COLORECTAL-CANCER; WILD-TYPE; IMMUNOLOGICAL RESPONSES; COMPARING IMMUNIZATION; ANTIGEN PRESENTATION; MELANOMA PATIENTS AB Purpose To determine the ability to induce tumor-specific immunity with individual mutant K-ras- or p53-derived peptides and to monitor clinical outcome. Patients and Methods Patients in varying stages of disease underwent genetic analysis for mutations in K-ras and p53. Thirty-nine patients were enrolled. Seventeen-mer peptides were custom synthesized to the corresponding mutation. Baseline immunity was assessed for cytotoxic T-lymphocyte (CTL) response and interferon gamma (IFN-gamma) release from mutant peptide-primed lymphocytes. Patients' peripheral-blood mononuclear cells were pulsed with the corresponding peptide, irradiated, and applied intravenously. Patients were observed for CTL, IFN-gamma, interleukin (IL)-2, IL-5, and granulocyte-macrophage colony-stimulating factor responses, for treatment-related toxicity, and for tumor response. Results No toxicity was observed. Ten (26%) of 38 patients had detectable CTL against mutant p53 or K-ras, and two patients were positive for CTL at baseline. Positive IFN-gamma responses occurred in 16 patients (42%) after vaccination, whereas four patients had positive IFN-gamma reaction before vaccination. Of 29 patients with evident disease, five experienced a period of stable disease. Favorable prognostic markers were detectable CTL activity and a positive IFN-gamma reaction but not IL-5 release. Median survival times of 393 v 98 days for a positive versus negative CTL response (P = .04), respectively, and of 470 v 88 days for a positive versus negative IFN-gamma response (P = .02), respectively, were detected. Conclusion Custom-made peptide vaccination is feasible without any toxicity. CTL and cytokine responses specific to a given mutation can be induced or enhanced with peptide vaccines. Cellular immunity to mutant p53 and K-ras oncopeptides is associated with longer survival. C1 Univ Zurich Hosp, Dept Radiat Oncol, CH-8091 Zurich, Switzerland. Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol Res, Dept Internal Med,Div Hematol Oncol, Dallas, TX USA. Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75235 USA. Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. NCI, Vaccine Branch, Navy Med Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NCI, Monoclonal Antibody Recombinant Prot Prod Facil, Bethesda, MD 20892 USA. NIH, Div Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Univ Zurich, Inst Social & Prevent Med, CH-8006 Zurich, Switzerland. RP Ciernik, IF (reprint author), Univ Zurich Hosp, Dept Radiat Oncol, Ramistr 100, CH-8091 Zurich, Switzerland. EM d.carbone@vanderbilt.edu; ciernik@usz.ch OI Kelley, Michael/0000-0001-9523-6080; Seifert, Burkhardt/0000-0002-5829-2478 FU NCI NIH HHS [P50 CA70907, R01 CA57856, R01 CA61242] NR 51 TC 73 Z9 75 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 1 PY 2005 VL 23 IS 22 BP 5099 EP 5107 DI 10.1200/JCO.2005.03.158 PG 9 WC Oncology SC Oncology GA 952CL UT WOS:000230979300046 PM 15983396 ER PT J AU McCaskill-Stevens, W McKinney, MM Whitman, CG Minasian, LM AF McCaskill-Stevens, W McKinney, MM Whitman, CG Minasian, LM TI Increasing minority participation in cancer clinical trials: The minority-based community clinical oncology program experience SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BREAST-CANCER; PREVENTION; TAMOXIFEN AB Purpose The National Cancer Institute's (NCI) Minority-Based Community Clinical Oncology Program (MBCCOP) seeks to enhance minority participation in cancer clinical trials by building clinical trials outreach and management capacity in healthcare institutions serving large numbers of minority cancer patients. This article examines temporal trends in MBCCOP accruals to cancer prevention and control (CP/C) and cancer treatment trials and the racial distribution of study participants, along with the major factors affecting minority enrollment. Methods We used NCI databases to analyze temporal trends in overall accruals and accruals by race. We analyzed transcripts from an NCI-sponsored meeting with MBCCOP principal investigators and data from a follow-up survey to identify factors affecting minority enrollment. Results Between 1992 and 2003, annual patient accruals to treatment trials increased 39% despite little change in the number of MBCCOP grantees. During this same period, annual participant accruals to CP/C trials more than doubled. Between 1995 and 2003, minorities comprised 51% to 67% of the MBCCOP patients accrued to cooperative group treatment trials compared with <= 23% of the patients accrued by other cooperative group members and affiliates. Major factors affecting minority enrollment include the availability of "clinically relevant" protocols, regulatory requirements, characteristics of the patient population, and the level of support from sponsoring institutions and community physicians. Conclusion MBCCOPs have demonstrated their ability to facilitate the participation of racial/ethnic minorities in clinical trials. However, the contributions that they could make to the design and conduct of minority-focused research studies merit further exploration. C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Community Hlth Solut Inc, Richmond, KY USA. RP McCaskill-Stevens, W (reprint author), NCI, Div Canc Prevent, 6130 Execut Blvd,EPN 2014, Bethesda, MD 20892 USA. EM wm57h@nih.gov NR 20 TC 39 Z9 39 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 1 PY 2005 VL 23 IS 22 BP 5247 EP 5254 DI 10.1200/JCO.2005.22.236 PG 8 WC Oncology SC Oncology GA 952CL UT WOS:000230979300064 PM 16051967 ER PT J AU Husain, FT Lozito, TP Ulloa, A Horwitz, B AF Husain, FT Lozito, TP Ulloa, A Horwitz, B TI Investigating the neural basis of the auditory continuity illusion SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID PRIMARY VISUAL-CORTEX; ILLUSORY CONTOURS; NEURONS; FMRI; REPRESENTATION; PRIMATE; MACAQUE; OBJECT; BRAIN; NOISE AB in this study, we investigated one type of auditory perceptual grouping phenomena-the auditory continuity illusion (also called temporal induction). We employed a previously developed, neurobiologically realistic, large-scale neural network model of the auditory processing pathway in the cortex, ranging from the primary auditory cortex to the prefrontal cortex, and simulated temporal induction without changing any model parameters. The model processes tonal contour stimuli, composed of combinations of upward and downward FM sweeps and tones, in a delayed match-to-sample task. The local electrical activities of the neuronal units of the model simulated accurately the experimentally observed electrophysiological data, where available, and the model's simulated BOLD-fMRI data were quantitatively matched with experimental fMRI data. in the present simulations, intact stimuli were matched with fragmented versions (i.e., with inserted silent gaps). The ability of the model to match fragmented stimuli declined as the duration of the gaps increased. However, when simulated broadband noise was inserted into these gaps, the matching response was restored, indicating that a continuous stimulus was perceived. The electrical activities of the neuronal units of the model agreed with electrophysiological data, and the behavioral activity of the model matched human behavioral data. in the model, the predominant mechanism implementing temporal induction is the divergence of the feedforward connections along the auditory processing pathway in the temporal cortex. These simulation results not only attest to the robustness of the model, but further predict the primary role of the anatomical connectivity of the auditory processing areas in mediating the continuity illusion. C1 NIDCD, Brain Imaging & Modeling Sect, NIH, Bethesda, MD 20892 USA. RP Husain, FT (reprint author), NIDCD, Brain Imaging & Modeling Sect, NIH, Bldg 10,Rm 8S235E,MSC 1407,9000 Rockville Pike, Bethesda, MD 20892 USA. EM husainf@nidcd.nih.gov OI Ulloa, Antonio/0000-0002-7554-4542 FU Intramural NIH HHS NR 49 TC 23 Z9 24 U1 5 U2 6 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 AUG PY 2005 VL 17 IS 8 BP 1275 EP 1292 DI 10.1162/0898929055002472 PG 18 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 958SM UT WOS:000231468500007 PM 16197683 ER PT J AU Gresh, N Piquemal, JP Krauss, M AF Gresh, N Piquemal, JP Krauss, M TI Representation of Zn(II) complexes in polarizable molecular mechanics. Further refinements of the electrostatic and short-range contributions. Comparisons with parallel ab initio computations SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE Zn(II) cation; intermolecular interactions; polarizable molecular mechanics; ab initio computations; energy decomposition; metalloprotein binding sites ID METALLO-BETA-LACTAMASE; INTERMOLECULAR INTERACTION ENERGY; BIOLOGICALLY RELEVANT LIGANDS; CHARGE-TRANSFER CONTRIBUTION; LOCAL CORRELATION TREATMENT; DYNAMICS SIMULATIONS; PEPTIDE HYDROLYSIS; SELF-ORGANIZATION; CRYSTAL-STRUCTURE; ZN2+ BINDING AB We present refinements of the SIBFA molecular mechanics procedure to represent the intermolecular interaction energies of Zn(II). The two first-order contributions, electrostatic (E(MTP)) and short-range repulsion (E,.,P), are refined following the recent developments due to Piquemal et al. (Piquemal et al. J Phys Chem A 2003, 107, 9800; and Piquemal et al.. submitted). Thus, E(MTP) is augmented with a penetration component, E(pen), which accounts for the effects of reduction in electronic density of a given molecular fragment sensed by another interacting fragment upon mutual overlap. E(pen) is fit in a limited number of selected Zn(II)-mono-ligated complexes so that the sum of E(MTP) and E(pen) reproduces the Coulomb contribution E, from an ab initio Hartree-Fock energy decomposition procedure. Denoting by S, the overlap matrix between localized orbitals on the interacting monomers, and by R, the distance between their centroids, E(rep) is expressed by a S(2)/R term now augmented with an S(2)/R(2) one. It is calibrated in selected monoligated Zn(II) complexes to fit the corresponding exchange repulsion E(exch) from ab initio energy decomposition, and no longer as previously the difference between (E(c) + E(exch)) and E(MTP), Along with the reformulation of the first-order contributions, a limited recalibration of the second-order contributions was carried out. As in our original formulation (Gresh, J Comput Chem 1995, 16, 856), the Zn(II) parameters for each energy contribution were calibrated to reproduce the radial behavior of its ab initio HF counterpart in monoligated complexes with N, O, and S ligands. The SIBFA procedure was subsequently validated by comparisons with parallel ab initio computations on several Zn(II) polyligated complexes, including binuclear Zn(U) complexes as in models for the Gal4 and P-lactamase metalloproteins. The largest relative error with respect to the RVS computations is 3%, and the ordering in relative energies of competing structures reproduced even though the absolute numerical values of the ab initio interaction energies can be as large as 1220 kcal/mol. A term-to-term identification of the SIBFA contributions to their ab initio counterparts remained possible even for the largest sized complexes. (c) 2005 Wiley Periodicals, Inc. C1 CNRS, Lab Pharmacochim Mol & Cellulaire, IFR Biomed, FRE 2718, F-75006 Paris, France. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. RP Gresh, N (reprint author), CNRS, Lab Pharmacochim Mol & Cellulaire, IFR Biomed, FRE 2718, 45 Rue St Peres, F-75006 Paris, France. EM Nohad.gresh@univ-paris5.fr RI Piquemal, Jean-Philip/B-9901-2009 OI Piquemal, Jean-Philip/0000-0001-6615-9426 NR 72 TC 64 Z9 65 U1 3 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD AUG PY 2005 VL 26 IS 11 BP 1113 EP 1130 DI 10.1002/jcc.20244 PG 18 WC Chemistry, Multidisciplinary SC Chemistry GA 941PD UT WOS:000230225800004 PM 15934064 ER PT J AU Antony, J Piquemal, JP Gresh, N AF Antony, J Piquemal, JP Gresh, N TI Complexes of thiomandelate and captopril mercaptocarboxylate inhibitors to metallo-beta-lactamase by polarizable molecular mechanics. Validation on model binding sites by quantum chemistry SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE metallo-beta-lactamase; mercaptocarboxylate inhibitors; polarizable molecular mechanics; quantum chemistry; validation ID PARALLEL AB-INITIO; INTRAMOLECULAR INTERACTION ENERGIES; INTERMOLECULAR INTERACTION ENERGY; CHARGE-TRANSFER CONTRIBUTION; LOCAL CORRELATION TREATMENT; BROAD-SPECTRUM INHIBITOR; BACTEROIDES-FRAGILIS; ACTIVE-SITE; BACILLUS-CEREUS; DYNAMICS SIMULATIONS AB Using the polarizable molecular mechanics method SIBFA, we have performed a search for the most stable binding modes of D- and L-thioniandelate to a 104-residue model of the metallo-beta-lactamase from B. fragilis, an enzyme involved in the acquired resistance of bacteria to antibiotics. Energy balances taking into account solvation effects computed with a continuum reaction field procedure indicated the D-isomer to be more stably bound than the L-one, conform to the experimental result. The most stably bound complex has the S(-) ligand bridging monodentately the two Zn(II) cations and one carboxylate O(-) H-bonded to the Asn193 side chain. We have validated the SIBFA energy results by performing additional SIBFA as well as quantum chemical (QC) calculations on small (88 atoms) model complexes extracted from the 104-residue complexes, which include the residues involved in inhibitor binding, Computations were done in parallel using uncorrelated (HF) as well as correlated (DFT, LMP2. MP2) computations, and the comparisons extended to corresponding captopril complexes (Antony et al., J Comput Chem 2002, 23, 1281). The magnitudes of the SIBFA intermolecular interaction energies were found to correctly reproduce their QC counterparts and their trends for a total of twenty complexes. (c) 2005 Wiley Periodicals, Inc. C1 CNRS, Lab Pharmacochim Mol & Cellulaire, IFR Biomed, FRE 2718, F-75006 Paris, France. Free Univ Berlin, FB Math & Informat, Inst Math 2, AG Biocomp, D-14195 Berlin, Germany. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Gresh, N (reprint author), CNRS, Lab Pharmacochim Mol & Cellulaire, IFR Biomed, FRE 2718, 45 Rue St Peres, F-75006 Paris, France. EM Nohad.gresh@univ-paris5.fr RI Piquemal, Jean-Philip/B-9901-2009 OI Piquemal, Jean-Philip/0000-0001-6615-9426 NR 77 TC 44 Z9 44 U1 1 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD AUG PY 2005 VL 26 IS 11 BP 1131 EP 1147 DI 10.1002/jcc.20245 PG 17 WC Chemistry, Multidisciplinary SC Chemistry GA 941PD UT WOS:000230225800005 PM 15937993 ER PT J AU Berghorn, KA Clark, PA Encarnacion, B DeRegis, CJ Folger, JK Morasso, MI Soares, MJ Wolfe, MW Roberson, MS AF Berghorn, KA Clark, PA Encarnacion, B DeRegis, CJ Folger, JK Morasso, MI Soares, MJ Wolfe, MW Roberson, MS TI Developmental expression of the homeobox protein Distal-less 3 and its relationship to progesterone production in mouse placenta SO JOURNAL OF ENDOCRINOLOGY LA English DT Article ID EARLY-PREGNANCY; GENE; CELLS; DLX3; DIFFERENTIATION; ACTIVATION; GONADOTROPIN; PROMOTER; HORMONE; KINASE AB Distal-less 3 (Dlx3) is a homeobox factor that functions as a placental-specific transcriptional regulator. Dlx3 null mice (-/-) have compromised placental development and do not survive in utero past embryonic day (E) 9-5. The current studies were undertaken to examine the expression of Dlx3 in mouse placenta during gestation, and to determine whether Dlx3 was involved in placental progesterone production. Dlx3 was not detectable at E8.5 but was detected in E9.5 placenta with continuing but diminished expression through E15.5. Dlx3 immunolocalization was restricted to the labyrinth, was nuclear and was found in cytokeratin-positive cells. Previous studies in choriocarcinoma cell lines support the conclusion that Dlx3 is required for expression of 3 beta-hydroxysteroid dehydrogenase VI (3 beta HSD VI), an obligate enzyme in the production of progesterone by trophoblast giant cells. In a rat trophoblast stem cell line (Rcho-l), Dlx3 expression was non-detectable in Rcho-l cells induced to differentiate using mitrogen withdrawal. In vitro progesterone production in placental cultures and 3 beta HSD VI rriRNA from Dlx3 (+/+), (+/ -) and (- / -) mice were equivalent. In situ hybridization for 3 beta HSD VI revealed mRNA expression restricted to trophoblast giants cells with no detectable expression in the labyrinth suggesting that Dlx3 and 3 beta HSD VI were not colocalized within the placenta. These studies support the conclusion that Dlx3 protein expression is restricted to the labyrinth region of the murine placenta into late gestation and that Dlx3 does not appear to be expressed in trophoblast giant cells. Further, loss of Dlx3 was not correlated with synthesis of progesterone from E9.5 mouse placentas. C1 Cornell Univ, Dept Biomed Sci, Ithaca, NY 14853 USA. NIAMS, Dev Skin Biol Unit, Bethesda, MD USA. Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA. Univ Kansas, Med Ctr, Dept Mol & Integrat Physiol, Kansas City, KS 66103 USA. RP Berghorn, KA (reprint author), Cornell Univ, Dept Biomed Sci, T3 004C VRT, Ithaca, NY 14853 USA. EM kab35@cornell.edu FU NCRR NIH HHS [T32 RR0759]; NICHD NIH HHS [R01 HD039354, R01 HD 39354] NR 20 TC 14 Z9 14 U1 0 U2 1 PU SOC ENDOCRINOLOGY PI BRISTOL PA 22 APEX COURT, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 J9 J ENDOCRINOL JI J. Endocrinol. PD AUG PY 2005 VL 186 IS 2 BP 315 EP 323 DI 10.1677/joe.1.06217 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 962BV UT WOS:000231706900005 PM 16079257 ER PT J AU Dabrowski, K Terjesen, BF Zhang, YF Phang, JM Lee, KJ AF Dabrowski, K Terjesen, BF Zhang, YF Phang, JM Lee, KJ TI A concept of dietary dipeptides: A step to resolve the problem of amino acid availability in the early life of vertebrates SO JOURNAL OF EXPERIMENTAL BIOLOGY LA English DT Article DE dipeptide; protein; amino acid; proline; teleost; rainbow trout; Oncorhynchus mykiss ID TROUT ONCORHYNCHUS-MYKISS; SALMON SALMO-SALAR; CLARIAS-GARIEPINUS BURCHELL; BASS DICENTRARCHUS-LABRAX; RAINBOW-TROUT; PROLINE METABOLISM; CLINICAL NUTRITION; GROWTH-RATE; PROTEIN; FISH AB The premise that a dietary dipeptide approach will improve the understanding of amino acid utilization in the fastest-growing vertebrate, the teleost fish, was tested by examining the muscle free amino acid (FAA) pool and enzyme activities, in concert with growth response, when dietary amino acids were provided in free, dipeptide or protein molecular forms. We present the first evidence in fish that, in response to a synthetic dipeptide diet, muscle FAA varies as a result of both growth rate and amino acid availability of specific peptides. We demonstrate significantly diminished muscle indispensable FAA (3-10-fold) in rainbow trout alevins fed a dipeptide-based diet compared with a protein-based diet. The dipeptide-based diet did not contain proline, resulting in 10-27-fold less muscle free proline and hydroxyproline in alevins. The response of alevins fed FAA-based or peptide-based diets can be indicative of collagen turnover (Hyp/Pro ratio) and showed significant differences between dietary treatments. Pyrroline-5-carboxylate (P5C) reductase activity was detected, suggesting that P5C may ameliorate proline deficiency, but synthesis from glutamate could not maintain free proline levels in muscle. This finding will provide an impetus to test whether proline is conditionally indispensable in young fish, as in mammals and birds. This study shows that amino acids given entirely as dipeptides can sustain fish growth, result in muscle FAA and enzyme responses in line with dietary levels and identify growth-limiting amino acids. The understanding of these factors necessitates a diet formulation that will improve the accuracy of determining amino acid requirements in the early life stages of vertebrates. C1 Ohio State Univ, Sch Nat Resources, Columbus, OH 43210 USA. Inst Aquaculture Res, N-6600 Sunndalsora, Norway. Aquaculture Prot Ctr CoE, Prot & Amino Acid Sect, N-6600 Sunndalsora, Norway. Ohio State Univ, Interdisciplinary Program Nutr, Columbus, OH 43210 USA. NCI, Metab & Canc Susceptibil Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. Cheju Natl Univ, Fac Appl Marine Sci, Cheju 690756, South Korea. RP Dabrowski, K (reprint author), Ohio State Univ, Sch Nat Resources, Columbus, OH 43210 USA. EM dabrowski.1@osu.edu NR 49 TC 28 Z9 31 U1 1 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0022-0949 J9 J EXP BIOL JI J. Exp. Biol. PD AUG PY 2005 VL 208 IS 15 BP 2885 EP 2894 DI 10.1242/jeb.01689 PG 10 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 960FO UT WOS:000231575800017 PM 16043593 ER PT J AU Akaki, M Dvorak, JA AF Akaki, M Dvorak, JA TI A chemotactic response facilitates mosquito salivary gland infection by malaria sporozoites SO JOURNAL OF EXPERIMENTAL BIOLOGY LA English DT Article DE malaria; sporozoite; salivary gland; chemotaxis; mosquito ID PLASMODIUM-BERGHEI SPOROZOITES; THERMAL-DENATURATION; FALCIPARUM; PARASITES; LECTIN; HOST AB Sporozoite invasion of mosquito salivary glands is critical for malaria transmission to vertebrate hosts. After release into the mosquito hemocoel, the means by which malaria sporozoites locate the salivary glands is unknown. We developed a Matrigel-based in vitro system to observe and analyze the motility of GFP-expressing Plasmodium berghei sporozoites in the presence of salivary gland products of Anopheles stephensi mosquitoes using temperature-controlled, low-light-level video microscopy. Sporozoites moved toward unheated salivary gland homogenate (SGH) but not to SGH that had been heated at 56 degrees C for 30 min. We also investigated the origin of the attracted population. Attraction to SGH was restricted to hemolymph- and oocyst-derived sporozoites; salivary gland-derived sporozoites were not attracted to SGH. These data imply that sporozoites employ a chemotactic response to high molecular mass proteins or carbohydrate-binding proteins to locate salivary glands. This raises the possibility of utilizing anti-chemotactic factors for the development of mosquito transmission blocking agents. C1 NIAID, Biochem & Biophys Parasitol Sect, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Dvorak, JA (reprint author), NIAID, Biochem & Biophys Parasitol Sect, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Bethesda, MD 20892 USA. EM jdvorak@niaid.nih.gov NR 24 TC 23 Z9 24 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0022-0949 J9 J EXP BIOL JI J. Exp. Biol. PD AUG PY 2005 VL 208 IS 16 BP 3211 EP 3218 DI 10.1242/jeb.01756 PG 8 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 967LN UT WOS:000232092800021 PM 16081617 ER PT J AU Goold, SD Biddle, AK Klipp, G Hall, CN Danis, M AF Goold, SD Biddle, AK Klipp, G Hall, CN Danis, M TI Choosing healthplans all together: A deliberative exercise for allocating limited health care resources SO JOURNAL OF HEALTH POLITICS POLICY AND LAW LA English DT Article ID DEMOCRATIC DECISION-MAKING; PUBLIC-PARTICIPATION; MANAGED CARE; PROCEDURAL JUSTICE; CITIZENS; TRUST; ANTECEDENTS; PREFERENCES; AUTHORITY; JUDGMENTS AB CHAT (Choosing Healthplans All Together) is an exercise in participatory decision making designed to engage the public in health care priority setting. Participants work individually and then in groups to distribute a limited number of pegs on a board as they select from a wide range of insurance options. Randomly distributed health events illustrate the consequences of insurance choices. In 19992000, the authors conducted fifty sessions of CHAT involving 592 residents of North Carolina. The exercise was rated highly regarding ease of use, informativeness, and enjoyment. Participants found the information believable and complete, thought the group decision-making process was fair, and were willing to abide by group decisions. CHAT holds promise as a tool to foster group deliberation, generate collective choices, and incorporate the preferences and values of consumers into allocation decisions. It can serve to inform and stimulate public dialogue about limited health care resources. C1 Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. Univ N Carolina, Chapel Hill, NC 27515 USA. Univ Michigan, Hlth Serv, Ann Arbor, MI 48109 USA. NIH, Bethesda, MD 20892 USA. RP Goold, SD (reprint author), Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. OI Biddle, Andrea/0000-0003-0273-7439; Goold, Susan Dorr/0000-0002-0258-9774 NR 73 TC 30 Z9 30 U1 1 U2 8 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 0361-6878 J9 J HEALTH POLIT POLIC JI J. Health Polit. Policy Law PD AUG PY 2005 VL 30 IS 4 BP 563 EP 601 DI 10.1215/03616878-30-4-563 PG 39 WC Health Care Sciences & Services; Health Policy & Services; Medicine, Legal; Social Issues; Social Sciences, Biomedical SC Health Care Sciences & Services; Legal Medicine; Social Issues; Biomedical Social Sciences GA 037PL UT WOS:000237159100002 PM 16318163 ER PT J AU Li, W Yu, ZX Kotin, RM AF Li, W Yu, ZX Kotin, RM TI Profiles of PrKX expression in developmental mouse embryo and human tissues SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE PrKX; type I cAMP-dependent protein kinase; immunohistological staining; Western blot ID DEPENDENT PROTEIN-KINASE; ADENOASSOCIATED VIRUS TYPE-2; REGULATORY SUBUNIT; CATALYTIC SUBUNIT; CYCLIC-AMP; PKA; DIFFERENTIATION; INHIBITION; ACTIVATION AB Protein kinase X (PrKX), karyotypically located on the human X chromosome, is a type I cAMP-dependent protein kinase. Although a specific role for PrKX has not yet been defined, PrKX gene expression in mouse and human tissues has been profiled only by in situ hybridization and Northern blot analyses and not by protein expression. To determine more precisely the PrKX protein levels, we developed specific anti-PrKX antibodies and examined gestationally staged mouse embryo sections by immunohistochemistry. These results showed that PrKX is ubiquitously distributed and highly expressed in murine central nervous system and heart tissues in early developmental stages and in most organs at later stages but was not detected in either connective tissues or bone. Using Western blots to detect PrKX, total protein extracts from eight different adult or fetal human tissues including brain, heart, kidney, liver, lung, pancreas, spleen, and thymus were analyzed. Although PrKX protein was present in each of the tissues tested, the protein levels varied depending on tissue type and developmental stage. Very low protein levels were found in heart tissues from a 5-month-old fetus and from an adult, whereas PrKX proteins were more abundant in fetal brain, kidney, and liver tissues compared with adult samples of the same tissue type. C1 NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Kotin, RM (reprint author), NHLBI, Lab Biochem Genet, NIH, Bldg 10,Rm 7D05,10 Canc Ctr Dr, Bethesda, MD 20892 USA. EM kotinr@nhlbi.nih.gov RI kotin, robert/B-8954-2008 NR 18 TC 13 Z9 16 U1 0 U2 2 PU HISTOCHEMICAL SOC INC PI SEATTLE PA UNIV WASHINGTON, DEPT BIOSTRUCTURE, BOX 357420, SEATTLE, WA 98195 USA SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD AUG PY 2005 VL 53 IS 8 BP 1003 EP 1009 DI 10.1369/jhc.4A6568.2005 PG 7 WC Cell Biology SC Cell Biology GA 949TM UT WOS:000230811000010 PM 15879576 ER PT J AU Fedorova, OV Agalakova, NI Talan, MI Lakatta, EG Bagrov, AY AF Fedorova, OV Agalakova, NI Talan, MI Lakatta, EG Bagrov, AY TI Brain ouabain stimulates peripheral marinobufagenin via angiotensin II signalling in NaCl-loaded Dahl-S rats SO JOURNAL OF HYPERTENSION LA English DT Article; Proceedings Paper CT 14th Congress of the European-Society-of-Hypertension CY JUN, 2004 CL Paris, FRANCE SP European Soc Hypertens DE adrenal cortex; angiotensin; bufanolides; dietary sodium; inbred Dahl rats; marinobufagenin; ouabain; Na(+)-K(+)-exchanging ATPase; transmembrane electrolyte transport ID SALT-SENSITIVE HYPERTENSION; PLASMALEMMAL NA/K-ATPASE; BLOOD-PRESSURE; PUMP LIGANDS; SODIUM-PUMP; SYSTEM; CELLS; NA,K-ATPASE; INHIBITOR; COMPOUND AB Objective In NaCl-loaded Dahl salt-sensitive (DS) rats the transient stimulation of brain endogenous ouabain (EO) precedes the increase in renal excretion of marinobufagenin (MBG), a vasoconstrictor and natriuretic. In hypertensive DS rats, EO raises blood pressure (BP) via an ATII-sensitive pathway. We hypothesized that an NaCl-induced increase in MBG is linked to the EO-stimulated ATII pathway. Methods We studied the effects of 3 h of NaCl loading (117 mmol/kg, intraperitoneally) in male DS rats treated with antibodies to MBG or ouabain, or with losartan (25 mg/kg). adrenocortical ATII, and adrenocortical MBG. Losartan mimicked the effects of the anti-ouabain antibody, but did not affect the excretion of EO. In adrenocortical cells of DS rats, ATII stimulated MBG secretion, and losartan blocked this effect. Results NaCl loading alone induced a transient stimulation of pituitary EO (22.4 +/- 1.8 versus 12.2 +/- 1.3 pmol/g) and ATII (39.4 +/- 2.8 versus 18.4 +/- 3.2 ng/g), a sustained increase in MBG excretion (5.2 +/- 0.6 versus 1.1 +/- 0.2 pmol/h), a 40% inhibition of the renal sodium pump, a natriuretic response, a 35 mmHg increase in systolic BID, and an increase in adrenocortical ATII and MBG levels and in plasma norepinephrine. The anti-MBG antibody reduced the natriuresis (36%) and BP (40 mmHg), and restored renal sodium pump activity. The anti-ouabain antibody prevented the increase in pituitary ATII, reduced MBG excretion, natriuresis and BP, increased sodium pump activity, and prevented increases in plasma norepinephrine, pituitary and adrenocortical ATII, and adrenocortical MBG. Losartan mimicked the effects of the anti-ouabain antibody, but did not affect the excretion of EO. In adrenocortical cells of DS rats, ATII stimulated MBG secretion, and losartan blocked this effect. Conclusions In response to NaCl loading, brain EO, via an AT, receptor pathway and probably via sympathetic activation, stimulates adrenocortical MBG, which inhibits the renal sodium pump and elevates BP. C1 NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Bagrov, AY (reprint author), NIA, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM bagrova@grc.nia.nih.gov NR 30 TC 42 Z9 44 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD AUG PY 2005 VL 23 IS 8 BP 1515 EP 1523 DI 10.1097/01.hjh.0000174969.79836.8b PG 9 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 953RS UT WOS:000231098800014 PM 16003178 ER PT J AU Ji, QY Gondek, D Hurwitz, AA AF Ji, QY Gondek, D Hurwitz, AA TI Provision of granulocyte-macrophage colony-stimulating factor converts an autoimmune response to a self-antigen into an antitumor response SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELLS; CTLA-4 BLOCKADE; COMBINATION IMMUNOTHERAPY; PROSTATE-CANCER; TUMOR-ANTIGENS; MELANOMA; IMMUNITY; TOLERANCE; MICE; ACTIVATION AB Many tumor Ags recognized by T cells are self-Ags. Because high avidity, self-reactive T cells are deleted in the thymus, any residual self-reactive T cells existing in the periphery are likely to be low avidity and nonresponsive due to peripheral tolerance mechanisms. Activation of these residual T cells is critical for targeting tumors for immunotherapy. In this study, we studied immune responses against the murine B16 melanoma using a tyrosinase-related protein 2 (TRP-2) peptide as a model tumor/ self-Ag. Our results showed that TRP-2 peptide vaccination alone elicited a weak T cell response and modestly decreased B16 lung tumor nodules. The combination of peptide vaccination and treatment with an Ab directed against the inhibitory receptor CTLA-4 enhanced the immune response against TRP-2 peptide, inducing autoimmune depigmentation and further decreasing lung tumor nodules. However, both vaccination methods failed to protect against orthotopic (s.c.) B16 tumor challenge. The addition of an irradiated GM-CSF-expressing, amelanotic tumor cell vaccine significantly delayed s.c. B16 tumor growth. Subsequent studies revealed that provision of GM-CSF increased dendritic cell numbers in lymph nodes and spleen. Furthermore, addition of CTLA-4 blockade increased the frequency of TRP-2-specific, IFN-secreting T cells in spleen and lymph nodes. Overall, our results indicate that combining enhancement of Ag presentation with removal of CTLA-4-mediated inhibition can convert a "weaker" autoimmune response into a more potent antitumor immune response. C1 NCI, Frederick Canc Res & Dev Ctr, Tumor Immun & Tolerance Sect, Mol Immunoregulat Lab, Frederick, MD 21702 USA. SUNY Upstate Med Univ, Dept Microbiol & Immunol, Syracuse, NY 13210 USA. RP Hurwitz, AA (reprint author), NCI, Frederick Canc Res & Dev Ctr, Tumor Immun & Tolerance Sect, Mol Immunoregulat Lab, POB B, Frederick, MD 21702 USA. EM hurwitza@ncifcrf.gov NR 35 TC 15 Z9 16 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2005 VL 175 IS 3 BP 1456 EP 1463 PG 8 WC Immunology SC Immunology GA 989BN UT WOS:000233648000013 PM 16034082 ER PT J AU Carlos, CA Dong, HF Howard, OMZ Oppenheim, JJ Hanisch, FG Finn, OJ AF Carlos, CA Dong, HF Howard, OMZ Oppenheim, JJ Hanisch, FG Finn, OJ TI Human tumor antigen MUC1 is chemotactic for immature dendritic cells and elicits maturation but does not promote Th1 type immunity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID O-GLYCOSYLATION; SIALOSYL-TN; CANCER; CHEMOKINE; BREAST; RECEPTORS; MONOCYTES; INDUCE; CARCINOMAS; EXPRESSION AB The immunostimulatory outcome of the interactions of many pathogens with dendritic cells (DCs) has been well characterized. There are many fewer examples of similar interactions between DCs and self-molecules, especially the abnormal self-proteins such as many tumor Ags, and their effects on DC function and the immune response. We show that human epithelial cell Ag MUC1 mucin is recognized in its aberrantly glycosylated form on tumor cells by immature human myeloid DCs as both a chemoattractant (through its polypeptide core) and a maturation and activation signal (through its carbohydrate moieties). On encounter with MUC1, similar to the encounter with LPS, immature DCs increase cell surface expression of CD80, CD86, CD40, and CD83 molecules and the production of IL-6 and TNF-alpha cytokines but fail to make IL-12. When these DCs are cocultured with allogeneic CD4(+) T cells, they induce production of IL-13 and IL-5 and lower levels of IL-2, thus failing to induce a type I response. Our data suggest that, in vivo in cancer patients, MUC1 attracts immature DCs to the tumor through chemotaxis and subverts their function by negatively affecting their ability to stimulate type 1 helper T cell responses important for tumor rejection. C1 Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA 15261 USA. Sci Applicat Int Corp, Frederick, MD 21702 USA. NCI, Ctr Canc Res, Lab Mol Immunoregulat, Frederick, MD 21702 USA. Univ Cologne, Fac Med, Inst Biochem 2, Cologne, Germany. RP Finn, OJ (reprint author), Univ Pittsburgh, Sch Med, Dept Immunol, E1040 Biomed Sci Tower, Pittsburgh, PA 15261 USA. EM ojfinn@pitt.edu RI Howard, O M Zack/B-6117-2012 OI Howard, O M Zack/0000-0002-0505-7052 FU NCI NIH HHS [2PO1-CA73743, R01-CA56103, R01-CA84106, T32-CA82084]; PHS HHS [N01-C0-12400] NR 48 TC 58 Z9 65 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2005 VL 175 IS 3 BP 1628 EP 1635 PG 8 WC Immunology SC Immunology GA 989BN UT WOS:000233648000033 PM 16034102 ER PT J AU Starost, MF Karjala, Z Brinster, LR Miller, G Eckhaus, M Bryant, M Hoffman, V AF Starost, MF Karjala, Z Brinster, LR Miller, G Eckhaus, M Bryant, M Hoffman, V TI Demodex spp. in the hair follicles of rhesus macaques (Macaca mulatta) SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article DE Demodex; ectoparasite; hair follicle; Macaca mulatta; parasite; rhesus macaque; skin ID FOLLICULORUM; MONKEY AB The perineal or perineal and facial skin were evaluated on 53 rhesus macaques as part of a necropsy protocol. Microscopic evaluation of H & E stained skin sections revealed 19 animals positive for Demodex spp. Mites were seen within all portions of the hair follicles. Infestation varied from minimal to severe. Mites were found in macaques of all ages and in both sexes. Reaction to the mites ranged from no reaction, to minimal follicular epidermal hyperplasia to furunculosis. Immune status of the animal did not determine infestation but immune compromised macaques had more severe lesions. This is the first known report of Demodex spp. in rhesus macaques. C1 NIH, Div Vet Resources, Bethesda, MD 20892 USA. RP Starost, MF (reprint author), NIH, Div Vet Resources, Bldg 28A,Room 115,9000 Rockville Pike, Bethesda, MD 20892 USA. EM starostm@mail.nih.gov NR 11 TC 11 Z9 11 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD AUG PY 2005 VL 34 IS 4 BP 215 EP 218 DI 10.1111/j.1600-0684.2005.00112.x PG 4 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 937GV UT WOS:000229913500008 PM 16053500 ER PT J AU Bae, MA Jun, DY Kim, KM Kim, SK Chun, JS Taub, D Park, W Moons, BJ Kim, YH AF Bae, MA Jun, DY Kim, KM Kim, SK Chun, JS Taub, D Park, W Moons, BJ Kim, YH TI Protein tyrosine kinases, p56(lck) and p59(fyn) and MAP kinase JNK1 provide an early signal required for upregulation of Fas ligand expression in aburatubolactam C-induced apoptosis of human Jurkat T cells SO JOURNAL OF MICROBIOLOGY AND BIOTECHNOLOGY LA English DT Article DE aburatubolactam C; PTK activator; apoptosis; FasL-upregulation; PKC/ERK signaling pathway; PTK/JNK signaling pathway ID DRUG-INDUCED APOPTOSIS; APO-1/FAS RECEPTOR/LIGAND SYSTEM; MEDIATED APOPTOSIS; TUMOR-CELLS; BCL-XL; ACTIVATION; CD95; DEATH; LEUKEMIA; CHEMOTHERAPY AB The signaling mechanism underlying aburatubolactam C-induced FasL upregulation was investigated in human Jurkat T cells. After treatment with aburatubolactam C, the src-family PTKs p56(lck) and p59(fyn), and MAP kinases ERK2 and JNK1, were activated prior to FasL upregulation: Both p56(lck) and p59(fyn) were directly activated 2.4- and 2.2-fold, respectively, in vitro by aburatubolactam C. The aburatubolactam C-induced cellular changes, including the activation of ERK2 and JNK1, and FasL upregulation, were completely prevented by the PTK inhibitor genistein. The activation of protein kinase C (PKC delta, epsilon, and mu) was also induced following aburatubolactam C treatment. Although the activation of p56(lck) and tyrosine phosphorylation of the cellular proteins were not blocked by the PKC inhibitor GF109203X, the activation of ERK2 was completely abrogated, along with a detectably enhanced JNK1 activation; FasL upregulation, and apoptosis. However, the FasL upregulation and apoptosis were significantly inhibited by the PKC activator PMA, With a remarkable increase in the ERK2 activation. The cytotoxic effect of aburatubolactam C was reduced in the presence of the anti-Fas neutralizing antibody ZB-4. Although ectopic expression of Bc1-2 failed to completely block the cytotoxicity of aburatubolactam C, it was clearly suppressed. The c-Fos mRNA expression was upregulated in a biphasic manner, where the second phasic expression overlapped with the Fast upregulation. Accordingly, these results demonstrate that aburatubolactam C-induced apoptosis is exerted, at least in part, by FasL upregulation dictated by activation of the PTK (p56(lck) and p59(fyn))/JNK1 pathway, which is negatively affected by the concurrent activation of the PKC/ERK2 pathway proximal to PTK activation. C1 Kyungpook Natl Univ, Coll Nat Sci, Dept Microbiol, Immunobiol Lab, Taegu 702701, South Korea. Kyungpook Natl Univ, Inst Genet Engn, Taegu 702701, South Korea. Kwangju Inst Sci & Technol, Dept Life Sci, Kwangju 500712, South Korea. NIA, Immunol Lab, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. Kyungpook Natl Univ, Coll Nat Sci, Dept Biochem, Taegu 702701, South Korea. RP Kim, YH (reprint author), Kyungpook Natl Univ, Coll Nat Sci, Dept Microbiol, Immunobiol Lab, Taegu 702701, South Korea. EM ykim@knu.ac.kr NR 42 TC 3 Z9 3 U1 0 U2 1 PU KOREAN SOC MICROBIOLOGY & BIOTECHNOLOGY PI SEOUL PA KOREA SCI TECHNOL CENTER #507, 635-4 YEOGSAM-DONG, KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1017-7825 J9 J MICROBIOL BIOTECHN JI J. Microbiol. Biotechnol. PD AUG PY 2005 VL 15 IS 4 BP 756 EP 766 PG 11 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 959JS UT WOS:000231514600013 ER PT J AU Balogh, J Wihlborg, AK Isackson, H Joshi, BV Jacobson, KA Arner, A Erlinge, D AF Balogh, J Wihlborg, AK Isackson, H Joshi, BV Jacobson, KA Arner, A Erlinge, D TI Phospholipase C and cAMP-dependent positive inotropic effects of ATP in mouse cardiomyocytes via P2Y(11)-like receptors SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE P2 receptors; heart; cardiomyocytes; ATP; cAMP; IP3; desmin; contractility ID MICE LACKING DESMIN; ACTIVE FORCE GENERATION; ADENOSINE-TRIPHOSPHATE; EXTRACELLULAR ATP; CARDIAC MYOCYTES; ADENYLYL-CYCLASE; SKELETAL-MUSCLE; P2Y(1) RECEPTOR; RAT-HEART; AGONIST AB ATP is released as a cotransmitter together with catecholamines from sympathetic nerves. In the heart ATP has been shown to cause a pronounced positive inotropic effect and may also act in synergy with beta-adrenergic agonists to augment cardiomyocyte contractility. The aim of the present study was to investigate the inotropic effects mediated by purinergic P2 receptors using isolated mouse cardiomyocytes. Stable adenine nucleotide analogs were used and the agonist rank order for adenine nucleotide stimulation of the mouse cardiomyocytes was AR-C67085 > ATP gamma S > 2-MeSATP >>> 2-MeSADP = 0, that fits the agonist profile of the P2Y(11) receptor. ATP gamma S induced a positive inotropic response in single mouse cardiomyocytes. The response was similar to that for the 0, receptor agonist isoproterenol. The most potent response was obtained using AR-C67085, a P2Y(11) receptor agonist. This agonist also potentiated contractions in isolated trabecular preparations. The adenylyl cyclase blocker (SQ22563) and phospholipase C (PLC) blocker (U73122) demonstrated that both pathways were required for the inotropic response of AR-C67085. A cAMP enzyme immunoassay confirmed that AR-C67085 increased cAMP in the cardiomyocytes. These findings are in agreement with the P2Y(11) receptor, coupled both to activation of IP3 and cAMP, being a major receptor for ATP induced inotropy. Analyzing cardiomyocytes from desmin deficient mice, Des-/-, with a congenital cardiomyopathy, we found a lower sensitivity to AR-C67085, suggesting a down-regulation of P2Y(11) receptor function in heart failure. The prominent action of the P2Y(11) receptor in controling cardiomyocyte contractility and possible alterations in its function during cardiomyopathy may suggest this receptor as a potential therapeutic target. It is possible that agonists for the P2Y(11) receptor could be used to improve cardiac output in patients with circulatory shock and that P2Y(11) receptor antagonist could be beneficial in patients with congestive heart failure (CHF). (c) 2005 Elsevier Ltd. All rights reserved. C1 Lund Univ, Dept Cardiol, Lund, Sweden. NIH, Mol Recognit Sect, Bethesda, MD 20892 USA. Lund Univ, Dept Physiol Sci, Lund, Sweden. RP Erlinge, D (reprint author), Lund Univ, Dept Cardiol, Lund, Sweden. EM david.erlinge@kard.lu.se RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031116-20] NR 42 TC 37 Z9 39 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD AUG PY 2005 VL 39 IS 2 BP 223 EP 230 DI 10.1016/j.yjmcc.2005.03.007 PG 8 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 954LE UT WOS:000231155800003 PM 15893764 ER PT J AU Pettit, GR Anderson, CR Gapud, EJ Jung, MK Knight, JC Hamel, E Pettit, RK AF Pettit, GR Anderson, CR Gapud, EJ Jung, MK Knight, JC Hamel, E Pettit, RK TI Antineoplastic agents. 515. Synthesis of human cancer cell growth inhibitors derived from 3,4-methylenedioxy-5,4 '-dimethoxy-3 '-amino-Z-stilbene SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID COMBRETASTATIN A-4 PRODRUG; DOLASTATIN 10; PHASE-II; ANTIMITOTIC AGENTS; LUNG-CANCER; TUBULIN; PHOSPHATE; ANALOGS; BINDING; ADENOCARCINOMA AB Further structure-activity relationship (SAR) exploration of 3,4-methylenedioxy-5,4'-dimethoxy-3'-amino-Z-stilbene (la) derivatives resulted in the efficient synthesis of tyrosine amide hydrochloride 9, two tyrosine amide phosphate prodrugs (3a and 6), and sodium aspartate amide 11. Two additional cancer cell growth inhibitors (14 and 16) were synthesized by employing peptide coupling between amine la and the Dap unit of dolastatin 10 (4a) to yield amide 14 followed by Dov-Val-Dil (15) to yield peptide 16. The latter represents a combination of stilbene la with the des-Doe tetrapeptide unit of the powerful tubulin assembly inhibitor dolastatin 10. Peptide 16 was examined for potential binding to tubulin in the vinca and/or colchicine regions and found to perform primarily as a relative of dolastatin 10. Amide 14 had anticryptococcal and antibacterial activities. C1 Arizona State Univ, Inst Canc Res, Tempe, AZ 85287 USA. Arizona State Univ, Dept Chem & Biochem, Tempe, AZ 85287 USA. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. SAIC Frederick Inc, Frederick, MD 21702 USA. RP Pettit, RK (reprint author), Arizona State Univ, Inst Canc Res, POB 872404, Tempe, AZ 85287 USA. EM bpettit@asu.edu FU NCI NIH HHS [R01 CA090441-03, R01 CA090441-01, N01CO12400, R01 CA090441-02, R35 CA044344-11, CA44344-05-12, R01 CA090441, R35 CA044344-12, R35 CA044344, R01 CA90441-01-03] NR 44 TC 10 Z9 10 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD AUG PY 2005 VL 68 IS 8 BP 1191 EP 1197 DI 10.1021/np058033l PG 7 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 960GJ UT WOS:000231578000010 PM 16124759 ER PT J AU Klausmeyer, P McCloud, TG Tucker, KD Cardellina, JH Shoemaker, RH AF Klausmeyer, P McCloud, TG Tucker, KD Cardellina, JH Shoemaker, RH TI Aspirochlorine class compounds from Aspergillus flavus inhibit azole-resistant Candida albicans SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID ANTIBIOTIC A30641 AB Dereplication of the antifungal extracts of Aspergillus flavus indicated that the primary antifungal compound present was the known aspirochlorine (1). Preparative isolation work resulted in the identification of the new compounds tetrathioaspirochlorine (2) and cyclo(D-N-methyl-Leu-L-Trp) (3). C1 SAIC Frederick Inc, Nat Prod Support Grp, Ft Detrick, MD 21702 USA. NCI, Screening Technol Branch, Depv Therapeut Program, Div Canc Treatment & Diag, Ft Detrick, MD 21702 USA. RP McCloud, TG (reprint author), SAIC Frederick Inc, Nat Prod Support Grp, Bldg 431,FCRDC, Ft Detrick, MD 21702 USA. EM mccloud@dtpax2.ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 10 TC 17 Z9 18 U1 2 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD AUG PY 2005 VL 68 IS 8 BP 1300 EP 1302 DI 10.1021/np050141k PG 3 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 960GJ UT WOS:000231578000036 PM 16124785 ER PT J AU North, CS Pollio, DE Pfefferbaum, B Megivern, D Vythilingam, M Westerhaus, ET Martin, GJ Hong, BA AF North, CS Pollio, DE Pfefferbaum, B Megivern, D Vythilingam, M Westerhaus, ET Martin, GJ Hong, BA TI Concerns of capitol hill staff workers after bioterrorism - Focus group discussions of authorities' response SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article DE anthrax; bioterrorism; Capitol Hill; mental health; psychological; posttraumatic stress ID WASHINGTON; ANTHRAX AB Systematic studies of mental health effects of bioterrorism on exposed populations have not been carried out. Exploratory focus groups were conducted with an exposed population to provide qualitative data and inform empirical research. Five focus groups of 28 political worker volunteers were conducted 3 months after the October 15, 2001, anthrax attack on Capitol Hill. More than 2000 transcribed focus group passages were categorized using qualitative software. The category with the most items was authorities ' response (23% passages), and much of this discussion pertained to communication by authorities. The category with the fewest items was symptoms (4%). Identified issues were less within individuals and more between them and authorities. Risk communication by authorities regarding safety and medical issues was a prominent concern among Capitol Hill office staff workers regarding the anthrax incident on Capitol Hill. This suggests focus on risk communication in developing interventions, but more systematic investigation is needed. C1 Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Washington Univ, George Warren Brown Sch Social Work, St Louis, MO 63130 USA. Univ Oklahoma, Hlth Sci Ctr, Dept Psychiat & Behav Sci, Oklahoma City, OK 73190 USA. NIMH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. RP North, CS (reprint author), Washington Univ, Sch Med, Dept Psychiat, 660 S Euclid Ave,Campus Box 8134, St Louis, MO 63110 USA. FU NIMH NIH HHS [MH40025] NR 9 TC 20 Z9 20 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD AUG PY 2005 VL 193 IS 8 BP 523 EP 527 DI 10.1097/01.mid.0000172598.82779.12 PG 5 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 954TK UT WOS:000231177600004 PM 16082296 ER PT J AU Szabo, ST Einat, H Wu, J Chen, W Falke, CA Huang, FL Huang, KP Du, J Manji, HK AF Szabo, ST Einat, H Wu, J Chen, W Falke, CA Huang, FL Huang, KP Du, J Manji, HK TI Neurogranin: A critical molecule at the nexus of 3 major signaling pathways and mood modulation SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 20th Biennial Meeting of the International-Society-for-Neurochemistry/European-Society-for-Neurochemi stry CY AUG 21-26, 2005 CL Innsbruck, AUSTRIA SP Int Soc Neurochem, European Soc Neurochem C1 NIH, Bethesda, MD USA. NIMH, Bethesda, MD 20892 USA. Mol Pathophysiol Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2005 VL 94 SU 2 BP 32 EP 32 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 961PD UT WOS:000231673400075 ER PT J AU Dambinova, S Izykenova, A Granstrem, O Chang, C Hoffer, B Wang, Y AF Dambinova, S Izykenova, A Granstrem, O Chang, C Hoffer, B Wang, Y TI Extracellular trafficking of NR2 peptide in cerebral ischemia SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 20th Biennial Meeting of the International-Society-for-Neurochemistry/European-Society-for-Neurochemi stry CY AUG 21-26, 2005 CL Innsbruck, AUSTRIA SP Int Soc Neurochem, European Soc Neurochem C1 Pavlovs State Med Univ, St Petersburg, Russia. Natl Inst Drug Abuse, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2005 VL 94 SU 2 BP 55 EP 55 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 961PD UT WOS:000231673400156 ER PT J AU Wenthold, RJ Sans, N Wang, PY Wang, YX Nakka, S Chang, K Petralia, RS AF Wenthold, RJ Sans, N Wang, PY Wang, YX Nakka, S Chang, K Petralia, RS TI Trafficking of NMDA receptors requires an interaction with PDZ proteins and the exocyst complex SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 20th Biennial Meeting of the International-Society-for-Neurochemistry/European-Society-for-Neurochemi stry CY AUG 21-26, 2005 CL Innsbruck, AUSTRIA SP Int Soc Neurochem, European Soc Neurochem C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2005 VL 94 SU 2 BP 68 EP 69 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 961PD UT WOS:000231673400196 ER PT J AU Pelled, G Dodd, S Koretsky, AP AF Pelled, G Dodd, S Koretsky, AP TI Functional magnetic resonance imaging detection of cortical plasticity in the rodent brain following peripheral nerve injury SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 20th Biennial Meeting of the International-Society-for-Neurochemistry/European-Society-for-Neurochemi stry CY AUG 21-26, 2005 CL Innsbruck, AUSTRIA SP Int Soc Neurochem, European Soc Neurochem C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2005 VL 94 SU 2 BP 154 EP 155 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 961PD UT WOS:000231673401028 ER PT J AU Ciruela, F Ferre, S Casado V Mallol, J Cortes, A Canela, EI Lluis, C Franco, R AF Ciruela, F Ferre, S Casado, V Mallol, J Cortes, A Canela, EI Lluis, C Franco, R TI Heteromerization of heptaspanning membrane receptors: Focus on adenosine, dopamine and metabotropic glutamate receptor function SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 20th Biennial Meeting of the International-Society-for-Neurochemistry/European-Society-for-Neurochemi stry CY AUG 21-26, 2005 CL Innsbruck, AUSTRIA SP Int Soc Neurochem, European Soc Neurochem C1 Univ Barcelona, Dept Biochem & Mol Biol, E-08007 Barcelona, Spain. NIDA, Behav Neurosci Branch, US Dept HHS, NIH, Baltimore, MD 21224 USA. RI Ciruela, Francisco/A-5096-2013; Franco, Rafael/C-3694-2015 OI Ciruela, Francisco/0000-0003-0832-3739; Franco, Rafael/0000-0003-2549-4919 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2005 VL 94 SU 2 BP 160 EP 160 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 961PD UT WOS:000231673401038 ER PT J AU Kamal, MA Al-Jafari, AA Greig, NH AF Kamal, MA Al-Jafari, AA Greig, NH TI Interaction of new anti-Alzheimer's disease agents with cholinesterase SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 20th Biennial Meeting of the International-Society-for-Neurochemistry/European-Society-for-Neurochemi stry CY AUG 21-26, 2005 CL Innsbruck, AUSTRIA SP Int Soc Neurochem, European Soc Neurochem C1 KSU, Dept Biochem, Riyadh, Saudi Arabia. NIA, DDDS, LN, NIH, Baltimore, MD 21224 USA. RI Kamal, Mohammad/H-9643-2012; Kamal, Mohammad/J-4622-2013; OI Kamal, Mohammad/0000-0003-1862-173X; Kamal, Mohammad Amjad/0000-0003-0088-0565 NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2005 VL 94 SU 2 BP 168 EP 168 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 961PD UT WOS:000231673401056 ER PT J AU Lindell, SG Barr, CS Chappelle, A Keawphalouk, M Suomi, SJ Goldman, D Higley, JD AF Lindell, SG Barr, CS Chappelle, A Keawphalouk, M Suomi, SJ Goldman, D Higley, JD TI Sequence variation of the Macaca mulatta neuropeptide Y gene and its relation to CSF levels and alcohol consumption patterns SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 20th Biennial Meeting of the International-Society-for-Neurochemistry/European-Society-for-Neurochemi stry CY AUG 21-26, 2005 CL Innsbruck, AUSTRIA SP Int Soc Neurochem, European Soc Neurochem C1 NIAAA, LCTS, Poolesville, MD USA. NIAAA, LNG, Poolesville, MD USA. NICHHD, LCE, Poolesville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2005 VL 94 SU 2 BP 185 EP 185 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 961PD UT WOS:000231673401111 ER PT J AU Golovko, MY Faergeman, NJ Cole, NB Castagnet, PI Nussbaum, RL Murphy, EJ AF Golovko, MY Faergeman, NJ Cole, NB Castagnet, PI Nussbaum, RL Murphy, EJ TI Alpha-synuclein gene-deletion alters brain palmitate and arachidonate uptake and metabolism SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 20th Biennial Meeting of the International-Society-for-Neurochemistry/European-Society-for-Neurochemi stry CY AUG 21-26, 2005 CL Innsbruck, AUSTRIA SP Int Soc Neurochem, European Soc Neurochem C1 Univ N Dakota, Grand Forks, ND 58201 USA. NIH, Bethesda, MD USA. Univ So Denmark, Odense, Denmark. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2005 VL 94 SU 2 BP 242 EP 243 PG 2 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 961PD UT WOS:000231673401275 ER PT J AU Jiang, XY Tian, F Mearow, K Okagaki, P Lipsky, RH Marini, AM AF Jiang, XY Tian, F Mearow, K Okagaki, P Lipsky, RH Marini, AM TI The excitoprotective effect of N-methyl-D-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampal neurons SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE autocrine loop; brain-derived neurotrophic factor; excitotoxicity; hippocampal neurons; neuroprotection; N-methyl-D-aspartate ID NERVE GROWTH-FACTOR; CEREBELLAR GRANULE CELLS; TRK PROTOONCOGENE PRODUCT; DEVELOPING RAT-BRAIN; NMDA RECEPTORS; FACTOR FAMILY; SURVIVAL PATHWAYS; PROTEIN-KINASE; BDNF-GENE; KAPPA-B AB The neuroprotective effect and molecular mechanisms underlying preconditioning with N-methyl-D-aspartate (NMDA) in cultured hippocampal neurons have not been described. Pre-incubation with subtoxic concentrations of the endogenous neurotransmitter glutamate protects vulnerable neurons against NMDA receptor-mediated excitotoxicity. As a result of physiological preconditioning, NMDA significantly antagonizes the neurotoxicity resulting from subsequent exposure to an excitotoxic concentration of glutamate. The protective effect of glutamate or NMDA is time- and concentration-dependent, suggesting that sufficient agonist and time are required to establish an intracellular neuroprotective state. In these cells, the TrkB ligand, brain-derived neurotrophic factor (BDNF) attenuates glutamate toxicity. Therefore, we tested the hypothesis that NMDA protects neurons via a BDMF-dependent mechanism. Exposure of hippocampal cultures to a neuroprotective concentration of NMDA (50 mu M) evoked the release of BDNF within 2 min without attendant changes in BDNF protein or gene expression. The accumulated increase of BDNF in the medium is followed by an increase in the phosphorylation (activation) of TrkB receptors and a later increase in exon 4-specific BDNF mRNA. The neuroprotective effect of NMDA was attenuated by pre-incubation with a BDNF-blocking antibody and TrkB-IgG, a fusion protein known to inhibit the activity of extracellular BDNF, suggesting that BDNF plays a major role in NMDA-mediated survival. These results demonstrate that low level stimulation of NMDA receptors protect neurons against glutamate excitotoxicity via a BDNF autocrine loop in hippocampal neurons and suggest that activation of neurotrophin signaling pathways plays a key role in the neuroprotection of NMDA. C1 Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Div Neurosci, Bethesda, MD 20814 USA. NIAAA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD USA. Mem Univ Newfoundland, St John, NF, Canada. RP Marini, AM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Neurol & Neurosci, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM amarini@usuhs.mil OI Lipsky, Robert/0000-0001-7753-1473 NR 70 TC 113 Z9 116 U1 0 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2005 VL 94 IS 3 BP 713 EP 722 DI 10.1111/j.1471-4159.2005.03200.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 951WM UT WOS:000230963100015 PM 16000165 ER PT J AU Castagnet, PI Golovko, MY Barcelo-Coblijn, GC Nussbaum, RL Murphy, EJ AF Castagnet, PI Golovko, MY Barcelo-Coblijn, GC Nussbaum, RL Murphy, EJ TI Fatty acid incorporation is decreased in astrocytes cultured from alpha-synuclein gene-ablated mice SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE arachiclonid acid; astrocytes; docosahexaenoic acid; fatty acid uptake; palmitic acid; alpha-synuclein ID STEROL CARRIER PROTEIN-2; L-CELL FIBROBLASTS; PERFORMANCE LIQUID-CHROMATOGRAPHY; NBD-STEARATE UPTAKE; BINDING PROTEIN; PARKINSONS-DISEASE; CYTOPLASMIC DIFFUSION; PHOSPHOLIPID CONTENT; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E AB Because alpha-synuclein may function as a fatty acid binding protein, we measured fatty acid incorporation into astrocytes isolated from wild-type and alpha-synuclein gene-ablated mice. alpha-Synuclein deficiency decreased palmitic acid (16:0) incorporation 31% and arachidonic acid [20:4 (n-6)] incorporation 39%, whereas 22:6 (n-3) incorporation was unaffected. In neutral lipids, fatty acid targeting of 20:4 (n-6) and 22:6 (n-3) (docosahexaenoic acid) to the neutral lipid fraction was increased 1.7-fold and 1.6-fold, respectively, with an increase in each of the major neutral lipids. This was consistent with a 3.4- to 3.8-fold increase in cholesteryl ester and triacylglycerol mass. In the phospholipid fraction, alpha-synuclein deficiency decreased 16:0 esterification 39% and 20:4 (n-6) esterification 43% and decreased the distribution of these fatty acids, including 22:6 (n-3), into this lipid pool. alpha-Synuclein geneablation significantly decreased the trafficking of these fatty acids to phosphaticlylinositol. This observation is consistent with changes in phospholipid fatty acid composition in the a-synuclein-deficient astrocytes, including decreased 22:6 (n-3) content in the four major phospholipid classes. In summary, these studies demonstrate that alpha-synuclein deficiency significantly disrupted astrocyte fatty acid uptake and trafficking, with a marked increase in fatty acid trafficking to cholesteryl esters and triacylglycerols and decreased trafficking to phospholipids, including phosphaticlylinositol. C1 Univ N Dakota, Sch Med & Hlth Sci, Dept Pharmacol Physiol & Therapeut, Grand Forks, ND 58202 USA. Univ N Dakota, Sch Med & Hlth Sci, Dept Chem, Grand Forks, ND 58202 USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Murphy, EJ (reprint author), Univ N Dakota, Sch Med & Hlth Sci, Dept Pharmacol Physiol & Therapeut, 501 N Columbia Rd,Room 3700, Grand Forks, ND 58202 USA. EM emurphy@medicine.nodak.edu FU NINDS NIH HHS [1R21-NS043697-01A]; PHS HHS [5P20-R017699-02] NR 67 TC 49 Z9 49 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2005 VL 94 IS 3 BP 839 EP 849 DI 10.1111/j.1471-4159.2005.032747.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 951WM UT WOS:000230963100027 PM 16033426 ER PT J AU DeMar, JC Ma, KZ Chang, L Bell, JM Rapoport, SI AF DeMar, JC Ma, KZ Chang, L Bell, JM Rapoport, SI TI alpha-Linolenic acid does not contribute appreciably to docosahexaenoic acid within brain phospholipids of adult rats fed a diet enriched in docosahexaenoic acid SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE brain; docosahexaenoic; incorporation; alpha-linolenic; phospholipid; rat ID POLYUNSATURATED FATTY-ACIDS; DELTA-6 DESATURASE GENE; CHAIN ACYL-COENZYME; IN-VIVO; ARACHIDONIC-ACID; NUTRITIONAL DEPRIVATION; SIGNAL-TRANSDUCTION; RHESUS-MONKEYS; MAJOR PATHWAY; COA ESTERS AB Adult male unanesthetized rats, reared on a diet enriched in both alpha-linolenic acid (alpha-LNA) and docosahexaenoic acid ( DHA), were infused intravenously for 5 min with [1-C-14]alpha-LNA. Timed arterial samples were collected until the animals were killed at 5 min and the brain was removed after microwaving. Plasma and brain lipid concentrations and radio-activities were measured. Within plasma lipids, > 99% of radioactivity was in the form of unchanged [1-C-14]alpha- LNA. Eighty-six per cent of brain radioactivity at 5 min was present as beta-oxidation products, whereas the remainder was mainly in 'stable' phospholipid or triglyceride as a- LNA or DHA. Equations derived from kinetic modeling demonstrated that unesterified unlabeled alpha-LNA rapidly enters brain from plasma, but that its incorporation into brain phospholipid and triglyceride, as in the form of synthesized DHA, is <= 0.2% of the amount that enters the brain. Thus, in rats fed a diet containing large amounts of both alpha-LNA and DHA, the alpha-LNA that enters brain from plasma largely undergoes beta-oxidation, and is not an appreciable source of DHA within brain phospholipids. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Rapoport, SI (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Room 1S128, Bethesda, MD 20892 USA. EM sir@helix.nih.gov NR 78 TC 109 Z9 111 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2005 VL 94 IS 4 BP 1063 EP 1076 DI 10.1111/j.1471-4159.2005.03258.x PG 14 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 950WA UT WOS:000230888200019 PM 16092947 ER PT J AU Strong, MJ Kesavapany, S Pant, HC AF Strong, MJ Kesavapany, S Pant, HC TI The pathobiology of amyotrophic lateral sclerosis: A proteinopathy? SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Review DE Cdk5; neurofilament; protein aggregation; regulation/deregulation; SOD1; topographic phosphorylation ID MOLECULAR-WEIGHT NEUROFILAMENT; MOTOR-NEURON DISEASE; CU/ZN-SUPEROXIDE-DISMUTASE; TUMOR-NECROSIS-FACTOR; CENTRAL-NERVOUS-SYSTEM; G93A-SOD1 MOUSE MODEL; CERVICAL-SPINAL-CORD; UP-REGULATION; FRONTOTEMPORAL DEMENTIA; CEREBROSPINAL-FLUID AB Amyotrophic lateral sclerosis (ALS) is increasingly considered to be a disorder of multiple etiologies that have in common progressive degeneration of both upper and lower motor neurons, ultimately giving rise to a relentless loss of muscle function. This progressive degeneration is associated with heightened levels of oxidative injury, excitotoxicity, and mitochondrial dysfunction-all occurring concurrently. In this article, we review the evidence that suggests, in common with other age-dependent neurodegenerative disorders, that ALS can be considered a disorder of protein aggregation. Morphologically, this is evident as Bunina bodies, ubiquitin-immunoreactive fibrils or aggregates, neurofilamentous aggregates, mutant copper/zinc superoxide dismutase (SOD1) aggregates in familial ALS variants harboring mutations in SOD1, peripherin-immunoreactive aggregates within spinal motor neurons and as neuroaxonal spheroids, and in an increasingly greater population of patients with ALS with cognitive impairment, both intra- and extraneuronal tau aggregates. We review the evidence that somatotopically specific patterns of altered kinase and phosphatase activity are associated with alterations in the phosphorylation state of these proteins, altering either solubility or assembly characteristics. The role of nonneuronal cells in mediating motor neuronal injury is discussed in the context of alterations in tyrosine kinase activity and enhanced protein phosphorylation. C1 Univ Western Ontario, Robarts Res Inst, London, ON, Canada. Univ Western Ontario, Dept Clin Neurol Sci, London, ON, Canada. Natl Inst Neurol Disorders & Stroke, Cytoskeletal Prot Regulat Sect, Neurochem Lab, NIH, Bethesda, MD USA. RP Strong, MJ (reprint author), London Hlth Sci Ctr, Room 7OF10,Univ Campus,339 Windermere Rd, London, ON N6A 5A5, Canada. EM mstrong@uwo.ca RI Strong, Michael/H-9689-2012 NR 101 TC 113 Z9 118 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD AUG PY 2005 VL 64 IS 8 BP 649 EP 664 DI 10.1097/01.jnen.0000173889.71434.ea PG 16 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 956VF UT WOS:000231327300001 PM 16106213 ER PT J AU Floeter, MK Zhai, P Saigal, R Kim, Y Statland, J AF Floeter, MK Zhai, P Saigal, R Kim, Y Statland, J TI Motor neuron firing dysfunction in spastic patients with primary lateral sclerosis SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID SPINAL-CORD-INJURY; MOTONEURONS IN-VIVO; PRESYNAPTIC INHIBITION; H-REFLEX; RECIPROCAL INHIBITION; PLATEAU POTENTIALS; PERSISTENT SODIUM; CALCIUM CURRENTS; TENDON VIBRATION; FOREARM MUSCLES C1 NINDS, Electromyog Sect, NIH, Bethesda, MD 20892 USA. RP Floeter, MK (reprint author), 10,CRC Rm 7-5680,10 Ctr Dr,MSC 1404, Bethesda, MD 20892 USA. EM floeterm@ninds.nih.gov FU NINDS NIH HHS [Z01 NS002976-07] NR 55 TC 9 Z9 9 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG PY 2005 VL 94 IS 2 BP 919 EP 927 DI 10.1152/jn.00185.2005 PG 9 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 950UA UT WOS:000230882300004 PM 15829597 ER PT J AU Voller, B Gibson, AS Lomarev, M Kanchana, S Dambrosia, J Dang, N Hallett, M AF Voller, B Gibson, AS Lomarev, M Kanchana, S Dambrosia, J Dang, N Hallett, M TI Long-latency afferent inhibition during selective finger movement SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID MOTOR CORTEX; HUMAN HAND; CUTANEOMOTOR INTEGRATION; SURROUND INHIBITION; DIGIT STIMULATION; MODULATION; DYSTONIA; CIRCUITS; HUMANS; INPUT AB Stimulation of a peripheral nerve of a hand at rest modulates excitability in the motor cortex and, in particular, leads to inhibition when applied at an interval of similar to 200 ms ( long- latency afferent inhibition; LAI). Surround inhibition ( SI) is the process that inhibits neighboring muscles not involved in a particular task. The neuronal mechanisms of SI are not known, and it is possible that LAI might contribute to it. Using transcranial magnetic stimulation ( TMS) with and without movement of the index finger, the motor- evoked potentials ( MEPs) were measured of two functionally distinct target muscles of the hand ( abductor digiti minimi muscle = ADM, 1st dorsal interosseus muscle = FDI). Electrical stimulation was applied 180 ms before TMS to either the fifth finger or the index finger. Both homotopic and heterotopic finger stimulation resulted in LAI without movement. With index finger movement, motor output further decreased with homo- and heterotopic stimulation in the ADM. In the moving FDI, however, there was no change with either homo- or heterotopic stimulation. Additionally, in the unstimulated movement trials, LAI increased with the amount of unintentional co- activation that occurred despite attempts to maintain the ADM at rest. However, with finger stimulation added, there were almost no increased MEPs despite co- activation. These findings suggest that LAI increases during movement and can enhance SI. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Med Univ Vienna, Dept Neurol, Vienna, Austria. Univ Cape Town, Dept Human Biol, Res Unit Exercise Sci & Sports Med, ZA-7700 Rondebosch, South Africa. NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10-5N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov OI Voller, Bernhard/0000-0001-5809-874X NR 21 TC 12 Z9 12 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG PY 2005 VL 94 IS 2 BP 1115 EP 1119 DI 10.1152/jn.00333.2005 PG 5 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 950UA UT WOS:000230882300024 PM 15843479 ER PT J AU Oz, M Yang, KH O'Donovan, MJ Renaud, LP AF Oz, M Yang, KH O'Donovan, MJ Renaud, LP TI Presynaptic angiotensin II AT(1) receptors enhance inhibitory and excitatory synaptic neurotransmission to motoneurons and other ventral horn neurons in neonatal rat spinal cord SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; SIGNALING PATHWAYS; 2 CONDUCTANCES; BINDING-SITES; BRAIN; VASOPRESSIN; EMBRYO; IMMUNOREACTIVITY; ASTROCYTES; PEPTIDES AB In neonatal spinal cord, we previously reported that exogenous angiotensin II (ANG II) acts at postsynaptic AT(1) receptors to depolarize neonatal rat spinal ventral horn neurons in vitro. This study evaluated an associated increase in synaptic activity. Patch clamp recordings revealed that 38/81 thoracolumbar (T-7 -L-5) motoneurons responded to bath applied ANG II (0.3 - 1 mu M; 30 s) with a prolonged ( 5 - 10 min) and reversible increase in spontaneous postsynaptic activity, selectively blockable with Losartan (n = 5) but not PD123319 (n = 5). ANG-II-induced events included both spontaneous inhibitory (IPSCs; n = 6) and excitatory postsynaptic currents (EPSCs; n = 5). While most ANG induced events were tetrodotoxin-sensitive, ANG induced a significant tetrodotoxin-resistant increase in frequency but not amplitude of miniature IPSCs ( n = 7/13 cells) and EPSCs ( n = 2/7 cells). In 35/77 unidentified neurons, ANG II also induced a tetrodotoxin-sensitive and prolonged increase in their spontaneous synaptic activity that featured both IPSCs ( n = 5) and EPSCs ( n = 4) when tested in the presence of selective amino acid receptor antagonists. When tested in the presence of tetrodotoxin, ANG II was noted to induce a significant increase in the frequency but not the amplitude of mIPSCs ( n = 9) and mEPSCs ( n = 8). ANG also increased spontaneous motor activity from isolated mouse lumbar ventral rootlets. Collectively, these observations support the existence of a wide pre- and postsynaptic distribution of ANG II AT(1) receptors in neonatal ventral spinal cord that are capable of influencing both inhibitory and excitatory neurotransmission. C1 NIDA, IRP, Cellular Neurobiol Branch, Baltimore, MD 21224 USA. NIH, Neural Control Lab, Sect Dev Neurobiol, Bethesda, MD 20892 USA. Ottawa Hlth Res Inst, Ottawa, ON, Canada. Univ Ottawa, Ottawa, ON, Canada. RP Oz, M (reprint author), NIDA, IRP, Cellular Neurobiol Branch, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM moz@intra.nida.nih.gov RI Oz, Murat/E-2148-2012; o'donovan, michael/A-2357-2015 OI o'donovan, michael/0000-0003-2487-7547 NR 47 TC 13 Z9 14 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG PY 2005 VL 94 IS 2 BP 1405 EP 1412 DI 10.1152/jn.00165.2005 PG 8 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 950UA UT WOS:000230882300048 PM 16061493 ER PT J AU Read, JCA Cumming, BG AF Read, JCA Cumming, BG TI Effect of interocular delay on disparity-selective V1 neurons: Relationship to stereoacuity and the Pulfrich effect SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID CAT STRIATE CORTEX; MACAQUE VISUAL-CORTEX; SHORT-TERM-MEMORY; RECEPTIVE-FIELDS; SIMPLE CELLS; DIRECTION SELECTIVITY; CORTICAL-NEURONS; SPATIOTEMPORAL ORGANIZATION; CONTRAST SENSITIVITY; BINOCULAR DISPARITY AB The temporal properties of disparity-sensitive neurons place important temporal constraints on stereo matching. We examined these constraints by measuring the responses of disparity-selective neurons in striate cortex of awake behaving monkeys to random-dot stereograms that contained interocular delays. Disparity selectivity was gradually abolished by increasing interocular delay (when the delay exceeds the integration time, the inputs from the 2 eyes become uncorrelated). The amplitude of the disparity-selective response was a Gaussian function of interocular delay, with a mean of 16 ms (+/- 5 ms, SD). Psychophysical measures of stereoacuity, in both monkey and human observers, showed a closely similar dependency on time, suggesting that temporal integration in V1 neurons is what determines psychophysical matching constraints over time. There was a slight but consistent asymmetry in the neuronal responses, as if the optimum stimulus is one in which the right stimulus leads by about 4 ms. Because all recordings were made in the left hemisphere, this probably reflects nasotemporal differences in conduction times; psychophysical data are compatible with this interpretation. In only a few neurons (5/72), interocular delay caused a change in the preferred disparity. Such tilted disparity/delay profiles have been invoked previously to explain depth perception in the stroboscopic version of the Pulfrich effect (and other variants). However, the great majority of the neurons did not show tilted disparity/delay profiles. This suggests that either the activity of these neurons is ignored when viewing Pulfrich stimuli, or that current theories relating neuronal properties to perception in the Pulfrich effect need to be reevaluated. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Read, JCA (reprint author), 49-2A50 Convent Dr, Bethesda, MD 20892 USA. EM jcr@lsr.nei.nih.gov RI Read, Jenny/A-7493-2013 OI Read, Jenny/0000-0002-9029-5185 FU NEI NIH HHS [Z01 EY000404-04] NR 59 TC 21 Z9 22 U1 1 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD AUG PY 2005 VL 94 IS 2 BP 1541 EP 1553 DI 10.1152/jn.01177.2004 PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 950UA UT WOS:000230882300059 PM 15788521 ER PT J AU Vogel, TWA Vortmeyer, AO Lubensky, IA Lee, YS Furuta, M Ikejiri, B Kim, HJ Lonser, RR Oldfield, EH Zhuang, ZP AF Vogel, TWA Vortmeyer, AO Lubensky, IA Lee, YS Furuta, M Ikejiri, B Kim, HJ Lonser, RR Oldfield, EH Zhuang, ZP TI Coexpression of erythropoietin and its receptor in endolymphatic sac tumors SO JOURNAL OF NEUROSURGERY LA English DT Article DE erythropoietin; erythropoietin receptor; endolymphatic sac tumor; von Hippel-Lindau disease; renal cell carcinoma; hemangioblastoma; tumorigenesis ID HIPPEL-LINDAU-DISEASE; BLOOD-VESSELS; CANCER; GENE; ADENOCARCINOMA; GLOMERULUS; PROTEIN; EAR AB Object. VOD Hippel-Lindau (VHL) disease is characterized by multiple tumors in specific organs. The cell of origin and the reason for the particular organ distribution of the tumors remains unknown. Endolymphatic sac tumor (ELST) is one of the lesions associated with VHL disease. Data from previous studies of VHL disease-associated hemangioblastomas (HBs) and renal cell carcinomas (RCCs) have indicated that VHL gene deficiency causes coexpression of erythropoietin (Epo) and its receptor (Epo-R), which facilitates tumor growth. Methods. The authors studied ELSTs from five patients with VHL germline mutations. Analysis of the five ELST samples revealed loss of the wild-type allele, consistent with Knudson's two-hit hypothesis for tumorigenesis. All five ELST specimens were characterized microscopically and by immunohistochemical analysis. Coexpression of Epo and Epo-R was found in all five tumors on immunohistochemical studies and confirmed through reverse transcription-polymerase chain reaction and Western blot analysis. Conclusions. Expression of Epo appears to be a result of VHL gene deficiency, whereas the simultaneous coexpression of Epo-R may reflect a developmental mechanism of tumorigenesis. Coexpression of Epo and Epo-R in ELSTs together with the morphological and genetic similarities of these lesions with other VHL disease-associated tumors indicates that VHL disease-associated tumors in different organs share common pathogenetic pathways. C1 Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Neurootol Branch, NIH, Bethesda, MD USA. Georgetown Univ, Med Ctr, Dept Otolaryngol Head & Neck Surg, Washington, DC 20057 USA. RP Zhuang, ZP (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bldg 10,Room 5D-37, Bethesda, MD 20892 USA. EM zhuangp@ninds.nih.gov NR 27 TC 6 Z9 6 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD AUG PY 2005 VL 103 IS 2 BP 284 EP 288 DI 10.3171/jns.2005.103.2.0284 PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 957KI UT WOS:000231368300014 PM 16175858 ER PT J AU Chen, MY Hoffer, A Morrison, PE Hamilton, JF Hughes, J Schlageter, KS Lee , J Kelly, BR Oldfield, EH AF Chen, MY Hoffer, A Morrison, PE Hamilton, JF Hughes, J Schlageter, KS Lee , J Kelly, BR Oldfield, EH TI Surface properties, more than size, limiting convective distribution of virus-sized particles and viruses in the central nervous system SO JOURNAL OF NEUROSURGERY LA English DT Article DE gene therapy; brain; convection; drug delivery; virus; rat ID BLOOD-BRAIN-BARRIER; ENHANCED DELIVERY; GENE-TRANSFER; PRIMATE BRAIN; INTERSTITIAL INFUSION; PROTEIN ADSORPTION; SPINAL-CORD; RAT-BRAIN; MACROMOLECULES; PENETRATION AB Object. Achieving distribution of gene-carrying vectors is a major barrier to the clinical application of gene therapy. Because of the blood-brain barrier, the distribution of genetic vectors to the central nervous system (CNS) is even more challenging than delivery to other tissues. Direct intraparenchymal microinfusion, a minimally invasive technique, uses bulk flow (convection) to distribute suspensions of macromolecules widely through the extracellular space (convection-enhanced delivery [CED]). Although acute injection into solid tissue is often used for delivery of oligonucleotides, viruses, and liposomes, and there is preliminary evidence that certain of these large particles can spread through the interstitial space of the brain by the use of convection, the use of CED for distribution of viruses in the brain has not been systematically examined. That is the goal of this study. Methods. Investigators used a rodent model to examine the influence of size, osmolarity of buffering solutions, and surface coating on the volumetric distribution of virus-sized nanoparticles and viruses (adeno-associated viruses and adenoviruses) in the gray matter of the brain. The results demonstrate that channels in the extracellular space of gray matter in the brain are large enough to accommodate virus-sized particles and that the surface characteristics are critical determinants for distribution of viruses in the brain by convection. Conclusions. These results indicate that convective distribution can be used to distribute therapeutic viral vectors in the CNS. C1 Natl Inst Neurol Disorders & Stroke, NIH, Surg Neurol Branch, ORS, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, NIH, Div Bioengn & Phys Sci, ORS, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Sch Med, Dept Neurosurg, Richmond, VA 23284 USA. RP Oldfield, EH (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Surg Neurol Branch, ORS, Bldg 10,Room 5D37-1414, Bethesda, MD 20892 USA. EM eo10d@nih.gov NR 31 TC 60 Z9 60 U1 1 U2 7 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD AUG PY 2005 VL 103 IS 2 BP 311 EP 319 DI 10.3171/jns.2005.103.2.0311 PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 957KI UT WOS:000231368300018 PM 16175862 ER PT J AU Ahlqvist, J Fotheringham, J Akhyani, N Yao, K Fogdell-Hahn, A Jacobson, S AF Ahlqvist, J Fotheringham, J Akhyani, N Yao, K Fogdell-Hahn, A Jacobson, S TI Differential tropism of human herpesvirus 6 (HHV-6) variants and induction of latency by HHV-6A in oligodendrocytes SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE human herpesvirus 6; latency; MO3.13; multiple sclerosis; oligodendrocytes ID HUMAN-HERPESVIRUS 6; CENTRAL-NERVOUS-SYSTEM; MULTIPLE-SCLEROSIS PATIENTS; CELL-LINES; EXANTHEM-SUBITUM; PERSISTENT INFECTION; FATAL ENCEPHALITIS; BRAIN-TISSUE; REACTIVATION; DNA AB Human herpesvirus 6 (HHV-6) is a ubiquitous beta-herpesvirus associated with a number of clinical disorders. Two closely but biologically distinct variants have been described. HHV-6 variant B causes the common childhood disease exhanthem subitum, and although the pathologic characteristics for HHV-6 variant A are less well defined, HHV-6A has been suggested to be more neurotropic. We studied the effect of both HHV-6 variants in an oligodendrocyte cell line (MO3.13). Infection of M03.13 was monitored by cytopathic effect (CPE), quantitative TaqMan PCR for viral DNA in cells and supernatant, reverse transcriptase-polymerase chain reaction (RT-PCR) to detect viral RNA, and indirect immunofluorescence (IFA) to detect viral protein expression. HHV-6A infection induced significantly more CPE than infection with HHV-6B. HHV-6B induced an abortive infection associated with a decrease of the initial viral DNA load over time, early RNA expression, and no expression of viral antigen. In contrast, infection with HHV-6A DNA persisted in cells for at least 62 days. During the acute phase of infection with HHV-6A, intracellular and extracellular viral load increased and cells expressed the viral protein IE-2 and gp116/54/64. No HHV-6A RNA or protein was expressed after 30 days post infection, suggesting that HHV-6A formed a latent infection. These studies provide in vitro support to the hypothesis that HHV-6 can actively infect oligodendrocytes. Our results suggest that HHV-6A and HHV-6B have different tropism in MO3.13 cells and that an initially active HHV-6A infection can develop latency. Differences between HHV-6A and -6B infection in different neural cell types may be associated with different neurological diseases. C1 NINDS, Viral Immunol Sect, NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. Huddinge Univ Hosp, Karolinska Inst, Neurotec Dept, Div Neurol, S-14186 Huddinge, Sweden. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, NIH, Neuroimmunol Branch, 10 Ctr Dr,Bldg 10,Room 5B16, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov NR 61 TC 55 Z9 56 U1 0 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD AUG PY 2005 VL 11 IS 4 BP 384 EP 394 DI 10.1080/13550280591002379 PG 11 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 964JL UT WOS:000231877000008 PM 16162481 ER PT J AU Percival, SS Milner, JA AF Percival, SS Milner, JA TI Challenges and opportunities for support of nutritional science conferences and scientific meetings at National Institutes of health SO JOURNAL OF NUTRITION LA English DT Article AB Opportunities exist throughout the institutes, centers, and offices of the NIH for obtaining support for conferences and scientific meetings. The number of conferences funded by NIH that thematically involve nutrition, health, and biomedical research is very small relative to the total number of conference grants awarded by NIH. Only 4% of conference grant (R13 and U13) applications awarded by all institutes and centers of the NIH over the last 15 y were determined to be focused on nutrition in some way. The National Cancer Institute has the largest proportion of these awards, and the numbers of such applications submitted each year appear to be increasing. Only similar to 18 nutrition research-related conference grant applications appear to have been funded, on average, per year over the last 5 y. Success rates are high; an average of 85% of nutrition-related applications submitted over the last 5 y were funded. The purpose of this article is to encourage applications from the nutrition community and to provide information for consideration when developing an application for a conference or workshop. C1 NCI, Nutr Sci Res Grp, Div Canc Prevent, NIH,DHHS, Bethesda, MD 20892 USA. RP Percival, SS (reprint author), NCI, Nutr Sci Res Grp, Div Canc Prevent, NIH,DHHS, Bethesda, MD 20892 USA. EM percival@ufl.edu NR 3 TC 0 Z9 0 U1 1 U2 1 PU AMER SOCIETY NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD AUG PY 2005 VL 135 IS 8 BP 2006 EP 2008 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 972TQ UT WOS:000232476500027 PM 16046730 ER PT J AU Davis, CD Swanson, CA Ziegler, RG Clevidence, B Dwyer, JT Milner, JA AF Davis, CD Swanson, CA Ziegler, RG Clevidence, B Dwyer, JT Milner, JA TI Promises and perils of lycopene/tomato supplementation and cancer prevention - Executive summary report SO JOURNAL OF NUTRITION LA English DT Editorial Material ID INDUCED PROSTATE CARCINOGENESIS; TOMATO; RATS; PROLIFERATION C1 NCI, Div Canc Prevent, Rockville, MD 20852 USA. NIH, Off Dietary Supplements, Rockville, MD 20852 USA. NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. ARS, Beltsville Human Nutr Res Ctr, Beltsville, MD 20705 USA. RP Davis, CD (reprint author), NCI, Div Canc Prevent, Rockville, MD 20852 USA. EM davisci@mail.nih.gov NR 25 TC 6 Z9 6 U1 0 U2 1 PU AMER SOCIETY NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD AUG PY 2005 VL 135 IS 8 BP 2014S EP 2029S PG 16 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 972TQ UT WOS:000232476500031 PM 16046731 ER PT J AU Davis, CD Clevidence, B Swanson, CA Ziegler, RG Dvyer, JT Milner, JA AF Davis, CD Clevidence, B Swanson, CA Ziegler, RG Dvyer, JT Milner, JA TI A research agenda for lycopene/tomato supplementation and cancer prevention SO JOURNAL OF NUTRITION LA English DT Article; Proceedings Paper CT Conference on Promises and Perils of Lycopena/Tomato Supplementation and Cancer Prevention CY FEB 17-18, 2005 CL British Inst Int Comparat Law, Bethesda, MD SP Div Canc Prevent, Div Canc Epidemiol & Genet, Ctr Canc Res, Natl Canc Inst, Natl Inst Hlth, Dept DHHS, Agr Res Serv HO British Inst Int Comparat Law C1 NCI, Div Canc Prevent, Rockville, MD 20852 USA. ARS, Beltsville Human Nutr Res Ctr, Beltsville, MD 20705 USA. NIH, Off Dietary Supplements, Rockville, MD 20852 USA. NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Davis, CD (reprint author), NCI, Div Canc Prevent, Rockville, MD 20852 USA. EM davisci@mail.nih.gov NR 0 TC 3 Z9 3 U1 0 U2 0 PU AMER SOCIETY NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD AUG PY 2005 VL 135 IS 8 BP 2074S EP 2074S PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 972TQ UT WOS:000232476500047 PM 16046747 ER PT J AU Lee, HJ Guo, HY Lee, SK Jeon, BH Jun, CD Lee, SK Park, MH Kim, EC AF Lee, HJ Guo, HY Lee, SK Jeon, BH Jun, CD Lee, SK Park, MH Kim, EC TI Effects of nicotine on proliferation, cell cycle, and differentiation in immortalized and malignant oral keratinocytes SO JOURNAL OF ORAL PATHOLOGY & MEDICINE LA English DT Article DE cell cycle; differentiation; growth; immortalized oral keratinocytes; nicotine; oral cancer; organotypic culture ID HUMAN-PAPILLOMAVIRUS; DNA-SYNTHESIS; IN-VITRO; EPITHELIAL DIFFERENTIATION; GINGIVAL FIBROBLASTS; CIGARETTE-SMOKING; SNUFF DIPPERS; GROWTH; EXPOSURE; COLLAGEN AB BACKGROUND: Numerous epidemiological studies have reported that tobacco smoking is a major risk factor for oral cancer, but relatively little is known about the effect of nicotine, a major product of cigarette smoking, on immortalized oral keratinocytes and cancer cells. METHODS: We investigated the effects of nicotine on the growth and differentiation of immortalized human oral keratinocytes (IHOK), primary oral cancer cells (HN4), metastatic oral cancer cells (HN12), and human skin keratinocytes (HaCaT), in the monolayer and in the three-dimensional (3D) raft cultures using the MTT assay, Western blotting, and cell cycle analysis. RESULTS: Nicotine inhibited the proliferation of immortalized and malignant keratinocytes in dose- and time-dependent manners as determined by MTT assay. The 3D organotypic culture showed that nicotine at high concentration (300 mu M) inhibits epithelial maturation, surface keratinization, and decreased epithelial thickness. Flow cytometry showed that nicotine inhibited cell cycle progression by inducing G(0)/G(1) arrest of HaCaT, IHOK, HN4, and HN12 cells without causing apoptosis. Nicotine treatment increased p21 expression in immortalized cells (HaCaT, IHOK) and oral cancer cells (HN4, HN12), but decreased pRb and p53 expression in oral cancer cells. Moreover, after high-dose nicotine treatment, the involucrin expression increased markedly in immortalized cells, but not in oral cancer cells. CONCLUSIONS: We demonstrated that nicotine inhibits growth through cell cycle arrest at G(0)/G(1) phase probably by increasing the expression of p21(WAF1/CIP1). Nicotine also affects epithelial differentiation in immortalized and malignant oral keratinocytes. Malignant oral keratinocytes appear to be more resistant to the effects of nicotine on epithelial growth and differentiation as compared to the immortalized cells. C1 Wonkwang Univ, Coll Dent, Dept Oral & Maxillofacial Pathol, Iksan 570749, Jeonbuk, South Korea. Wonkwang Univ, Coll Oriental Med, Dept Pathol, Iksan, South Korea. Kyungpook Natl Univ, Coll Med, Dept Physiol, Taegu, South Korea. Kangnung Natl Univ, Coll Dent, Dept Oral Pathol, Kangnung, South Korea. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Kim, EC (reprint author), Wonkwang Univ, Coll Dent, Dept Oral & Maxillofacial Pathol, Shinyoungdong 344-2, Iksan 570749, Jeonbuk, South Korea. EM eckwkop@wonkwang.ac.kr NR 35 TC 42 Z9 44 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0904-2512 J9 J ORAL PATHOL MED JI J. Oral Pathol. Med. PD AUG PY 2005 VL 34 IS 7 BP 436 EP 443 DI 10.1111/j.1600-0714.2005.00342.x PG 8 WC Dentistry, Oral Surgery & Medicine; Pathology SC Dentistry, Oral Surgery & Medicine; Pathology GA 942NC UT WOS:000230288100010 PM 16011614 ER PT J AU Minton, AP AF Minton, AP TI Influence of macromolecular crowding upon the stability and state of association of proteins: Predictions and observations SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Review DE protein denaturation; protein aggregation; macromolecular excipients ID SELF-ASSOCIATION; EXCLUDED-VOLUME; BIOCHEMICAL REACTIONS; INERT MACROMOLECULES; ALPHA-SYNUCLEIN; RATES; ACTIN; POLYMERIZATION; CONSEQUENCES; CONFINEMENT AB The concept of excluded volume and possible effects of excluded volume on the reactivity of macromolecules in highly volume-occupied or 'crowded' media are introduced and briefly summarized. Theoretical and experimental studies of the effect of crowding on protein folding and unfolding, and on the effect of crowding on protein association and aggregation, are reviewed. Possible effects of the effect of crowding on an initially native protein that can undergo unfolding, self-association of native protein, and/or aggregation of non-native protein are considered. (c) 2005 Wiley-Liss, Inc. C1 NIDDKD, Lab Biochem & Genet, NIH, US PHS, Bethesda, MD 20892 USA. RP Minton, AP (reprint author), NIDDKD, Lab Biochem & Genet, NIH, US PHS, Bethesda, MD 20892 USA. EM minton@helix.nih.gov OI Minton, Allen/0000-0001-8459-1247 NR 41 TC 160 Z9 164 U1 5 U2 40 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0022-3549 J9 J PHARM SCI-US JI J. Pharm. Sci. PD AUG PY 2005 VL 94 IS 8 BP 1668 EP 1675 DI 10.1002/jps.20417 PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 952BS UT WOS:000230977300004 PM 15986476 ER PT J AU Maudsley, S Martin, B Luttrell, LM AF Maudsley, S Martin, B Luttrell, LM TI The origins of diversity and specificity in G protein-coupled receptor signaling SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID BETA(2) ADRENERGIC-RECEPTOR; A-MEDIATED PHOSPHORYLATION; TERNARY COMPLEX MODEL; MU-OPIOID RECEPTOR; BETA(2)-ADRENERGIC RECEPTOR; EFFECTOR PATHWAY; KINASE-A; CONSTITUTIVE ACTIVATION; ANTAGONISTS PROMOTE; PERTUSSIS-TOXIN AB The modulation of transmembrane signaling by G protein-coupled receptors ( GPCRs) constitutes the single most important therapeutic target in medicine. Drugs 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 which are 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 confer signal preorganization, efficiency, and specificity. 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. 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, Neurosci Lab, Intramural Res Program, Gerontol Res Ctr,Johns Hopkins Med Ctr, Baltimore, MD 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 USA. RP Maudsley, S (reprint author), NIA, Neurosci Lab, Intramural Res Program, Gerontol Res Ctr,Johns Hopkins Med Ctr, 5600 Nathan Shock Dr, Baltimore, MD USA. EM maudsleyst@grc.nia.nih.gov FU Intramural NIH HHS [Z01 AG000318-01]; NIDDK NIH HHS [DK 55524, DK 58283, DK 64353, R01 DK055524, R01 DK058283, R01 DK064353, R56 DK055524] NR 95 TC 128 Z9 130 U1 0 U2 15 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 2005 VL 314 IS 2 BP 485 EP 494 DI 10.1124/jpet.105.083121 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 946CS UT WOS:000230550300001 PM 15805429 ER PT J AU Wang, Y Wei, X Xiao, X Hui, RT Card, JW Carey, MA Wang, DW Zeldin, DC AF Wang, Y Wei, X Xiao, X Hui, RT Card, JW Carey, MA Wang, DW Zeldin, DC TI Arachidonic acid epoxygenase metabolites stimulate endothelial cell growth and angiogenesis via mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signaling pathways SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID HYPERPOLARIZING FACTOR; HYDROGEN-PEROXIDE; NITRIC-OXIDE; EPOXYEICOSATRIENOIC ACIDS; CORONARY MICROVESSELS; TUBE FORMATION; GENE-TRANSFER; ARTERIES; EDHF; EICOSANOIDS AB Cytochrome P450 arachidonic acid (AA) epoxygenase metabolites, the epoxyeicosatrienoic acids (EETs), dilate arteries via hyperpolarization of smooth muscle cells and also have nonvasodilatory effects within the vasculature. The present study investigated the angiogenic effects of endogenous and exogenous EETs and the relevant signaling mechanisms involved. Bovine aortic endothelial cells (BAECs) were incubated with synthetic EETs or infected with recombinant adeno-associated viruses (rAAVs) containing CYP2C11-NADPH-cytochrome P450 oxidoreductase (CYPOR), CYP2J2, or CYP102 F87V mutant to increase endogenous levels of EETs. The following endpoints were measured: BAEC proliferation, migration, capillary formation, and in vivo angiogenesis. The potential involvement of various signaling pathways was explored using selective inhibitors. The results showed that transfection with either rAAV- CYP2C11- CYPOR, rAAV- CYP2J2, or rAAV- CYP102 F87V, or incubation with EETs promoted BAEC proliferation, increased migration of BAECs as assessed by Transwell analysis and wound healing assays, and enhanced capillary tubule formation as determined by chicken embryo chorioallantoic membrane assays and tube formation tests on matrigel. The effects of EETs on proliferation, migration, and capillary tubule formation were attenuated by inhibitors of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 (PI3)-kinase/ Akt pathways and partially attenuated by an endothelial nitricoxide synthase (eNOS) inhibitor but not by a protein kinase C inhibitor. In a rat ischemic hind limb model, rAAV- mediated AA epoxygenase transfection induced angiogenesis. We conclude that AA epoxygenase metabolites can promote angiogenesis, which may provide protection to ischemic tissues. The results also suggest that the angiogenic effects of EETs involve the MAPK and PI3-kinase/Akt signaling pathways, and to some extent, the eNOS pathway. C1 Huazhong Univ Sci & Technol, Inst Hypertens, Wuhan 430030, Peoples R China. Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, Wuhan 430030, Peoples R China. Univ Pittsburgh, Dept Mol Genet & Biochem, Pittsburgh, PA USA. Univ Pittsburgh, Gene Therapy Ctr, Pittsburgh, PA USA. Fuwai Hosp, Peking Union Med Coll, Sino German Lab Mol Med, Beijing, Peoples R China. Fuwai Hosp, Peking Union Med Coll, Ctr Mol Cardiol, Beijing, Peoples R China. Chinese Acad Med Sci, Beijing 100037, Peoples R China. NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC USA. RP Wang, DW (reprint author), Huazhong Univ Sci & Technol, Inst Hypertens, 1095 Jiefang Ave, Wuhan 430030, Peoples R China. EM dwwang@tjh.tjmu.edu.cn NR 41 TC 125 Z9 137 U1 0 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 2005 VL 314 IS 2 BP 522 EP 532 DI 10.1124/jpet.105.083477 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 946CS UT WOS:000230550300005 PM 15840765 ER PT J AU Ukairo, OT Bondi, CD Newman, AH Kulkarni, SS Kozikowski, AP Pan, S Surratt, CK AF Ukairo, OT Bondi, CD Newman, AH Kulkarni, SS Kozikowski, AP Pan, S Surratt, CK TI Recognition of benztropine by the dopamine transporter (DAT) differs from that of the classical dopamine uptake inhibitors cocaine, methylphenidate, and mazindol as a function of a DAT transmembrane 1 aspartic acid residue SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NON-NITROGEN INHIBITORS; MONOAMINE TRANSPORTERS; SEROTONIN TRANSPORTER; SYNTAXIN 1A; DIFFERENTIALLY ALTER; GABA TRANSPORTER; PLASMA-MEMBRANE; AMINO-ACIDS; ANALOGS; BINDING AB Binding of cocaine to the dopamine transporter (DAT) protein blocks synaptic dopamine clearance, triggering the psychoactive effects associated with the drug; the discrete drug-protein interactions, however, remain poorly understood. A longstanding postulate holds that cocaine inhibits DAT-mediated dopamine transport via competition with dopamine for formation of an ionic bond with the DAT transmembrane aspartic acid residue D79. In the present study, DAT mutations of this residue were generated and assayed for translocation of radiolabeled dopamine and binding of radiolabeled DAT inhibitors under identical conditions. When feasible, dopamine uptake inhibition potency and apparent binding affinity K-i values were determined for structurally diverse DAT inhibitors. The glutamic acid substitution mutant (D79E) displayed values indistinguishable from wild-type DAT in both assays for the charge-neutral cocaine analog 8-oxa-norcocaine, a finding not supportive of the D79 "salt bridge" ligand-docking model. In addressing whether the D79 side chain contributes to the DAT binding sites of other portions of the cocaine pharmacophore, only inhibitors with modifications of the tropane ring C-3 substituent, i.e., benztropine and its analogs, displayed a substantially altered dopamine uptake inhibition potency as a function of the D79E mutation. A single conservative amino acid substitution thus differentiated structural requirements for benztropine function relative to those for all other classical DAT inhibitors. Distinguishing the precise mechanism of action of this DAT inhibitor with relatively low abuse liability from that of cocaine may be attainable using DAT mutagenesis and other structure-function studies, opening the door to rational design of therapeutic agents for cocaine abuse. C1 Duquesne Univ, Div Pharmaceut Sci, Dept Pharmacol & Toxicol, Pittsburgh, PA 15282 USA. NIDA, Med Chem Sect, Intramural Res Program, Baltimore, MD USA. Univ Illinois, Dept Med Chem & Pharmacognosy, Chicago, IL USA. RP Surratt, CK (reprint author), Duquesne Univ, Div Pharmaceut Sci, Dept Pharmacol & Toxicol, Mellon Hall,Room 453,600 Forbes Ave, Pittsburgh, PA 15282 USA. EM surratt@duq.edu FU NIDA NIH HHS [DA 16604, DA 10458] NR 40 TC 31 Z9 31 U1 1 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 2005 VL 314 IS 2 BP 575 EP 583 DI 10.1124/jpet.105.085829 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 946CS UT WOS:000230550300011 PM 15879005 ER PT J AU Hamelink, C Hampson, A Wink, DA Eiden, LE Eskay, RL AF Hamelink, C Hampson, A Wink, DA Eiden, LE Eskay, RL TI Comparison of cannabidiol, antioxidants, and diuretics in reversing binge ethanol-induced neurotoxicity SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NEURONAL DEGENERATION; BRAIN-DAMAGE; COGNITIVE DEFICITS; GLUTAMATE UPTAKE; SLICE CULTURES; GLIAL-CELLS; ALCOHOL; RATS; EXPOSURE; MK-801 AB Binge alcohol consumption in the rat induces substantial neurodegeneration in the hippocampus and entorhinal cortex. Oxidative stress and cytotoxic edema have both been shown to be involved in such neurotoxicity, whereas N-methyl-D-aspartate (NMDA) receptor activity has been implicated in alcohol withdrawal and excitoxic injury. Because the nonpsychoactive cannabinoid cannabidiol (CBD) was previously shown in vitro to prevent glutamate toxicity through its ability to reduce oxidative stress, we evaluated CBD as a neuroprotectant in a rat binge ethanol model. When administered concurrently with binge ethanol exposure, CBD protected against hippocampal and entorhinal cortical neurodegeneration in a dose- dependent manner. Similarly, the common antioxidants butylated hydroxytoluene and alpha-tocopherol also afforded significant protection. In contrast, the NMDA receptor antagonists dizocilpine (MK-801) and memantine did not prevent cell death. Of the diuretics tested, furosemide was protective, whereas the other two anion exchanger inhibitors, L-644,711 [(R)-(+)-(5,6-dichloro2,3,9,9a-tetrahydro 3-oxo- 9a- propyl- 1H- fluoren-7-yl) oxy acetic acid] and bumetanide, were ineffective. In vitro comparison of these diuretics indicated that furosemide is also a potent antioxidant, whereas the nonprotective diuretics are not. The lack of efficacy of L-644,711 and bumetanide suggests that the antioxidant rather than the diuretic properties of furosemide contribute most critically to its efficacy in reversing ethanol- induced neurotoxicity in vitro, in our model. This study provides the first demonstration of CBD as an in vivo neuroprotectant and shows the efficacy of lipophilic antioxidants in preventing binge ethanol-induced brain injury. C1 NIMH, Mol Neurosci Sect, Cellular & Mol Regulat Lab, NIH, Bethesda, MD 20892 USA. NIAAA, Sect Neurochem & Neuroendocrinol, Clin Studies Lab, NIH, Bethesda, MD USA. NCI, Radiol & Biol Branch, NIH, Bethesda, MD 20892 USA. RP Eskay, RL (reprint author), Bldg 49,Room 5A-35,9000 Rockville Pike, Bethesda, MD 20892 USA. EM bobsk@mail.nih.gov OI Eiden, Lee/0000-0001-7524-944X FU Intramural NIH HHS [Z01 MH002386-21, Z01 MH002386-22] NR 40 TC 60 Z9 63 U1 1 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 2005 VL 314 IS 2 BP 780 EP 788 DI 10.1124/jpet.105.085779 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 946CS UT WOS:000230550300036 PM 15878999 ER PT J AU Nightingale, B Dersch, CM Boos, TL Greiner, E Calhoun, WJ Jacobson, AE Rice, KC Rothman, RB AF Nightingale, B Dersch, CM Boos, TL Greiner, E Calhoun, WJ Jacobson, AE Rice, KC Rothman, RB TI Studies of the biogenic amine transporters. XI. Identification of a 1-[2-[bis(4-fluorophenyl) methoxy]ethyl]-4-(3phenylpropyl) piperazine (GBR12909) analog that allosterically modulates the serotonin transporter SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID GUINEA-PIG BRAIN; BINDING-SITE; NEUROTRANSMITTER TRANSPORTERS; DOPAMINE TRANSPORTER; NOREPINEPHRINE; ANTAGONISTS; PAROXETINE; MEMBRANES; AGENTS AB Previous studies identified partial inhibitors of serotonin (5-HT) transporter and dopamine transporter binding. We report here on a partial inhibitor of 5-HT transporter (SERT) binding identified among a group of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]4-( 3-phenylpropyl)piperazine analogs ( 4-[ 2-[ bis( 4- fluorophenyl)methoxy] ethyl]-1-(2-trifluoromethyl-benzyl)-piperidine; TB-1- 1099). Membranes were prepared from rat brains or human embryonic kidney cells expressing the cloned human dopamine (hDAT), serotonin (hSERT), and norepinephrine (hNET) transporters. beta-(4'-(125)lodophenyl)tropan-2 beta-carboxylic acid methyl ester ([I-125] RTI-55) binding and other assays followed published procedures. Using rat brain membranes, TB-1-099 weakly inhibited DAT binding (K-i = 439 nM), was inactive at NET binding ([ H-3] nisoxetine), and partially inhibited SERT binding with an extrapolated plateau ("A" value) of 20%. Similarly, TB-1-099 partially inhibited [I-125] RTI-55 binding to hSERT with an extrapolated olated plateau (A value) of 14%. Upon examining the effect of increasing concentrations of TB-1-099 on the apparent K-d and B max of [I-125] RTI-55 binding to hSERT, we found that TB-1-099 decreased the B max in a dose-dependent manner and affected the apparent K-d in a manner well described by a sigmoid dose-response curve. TB-1-099 increased the K-d but not to the magnitude expected for a competitive inhibitor. In rat brain synaptosomes, TB-1-099 noncompetitively inhibited [H-3] 5-HT, but not [ 3H] dopamine, uptake. Dissociation experiments indicated that TB-1-099 promoted the rapid dissociation of a small component of [I-125]RTI-55 binding to hSERT. Association experiments demonstrated that TB-1-099 slowed [125I] RT-1-55 binding to hSERT in a manner unlike that of the competitive inhibitor indatraline. Viewed collectively, these results support the hypothesis that TB-1-099 allosterically modulates hSERT binding and function. C1 NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. NIDDKD, Med Chem Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Rothman, RB (reprint author), NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH,Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rrothman@intra.nida.nih.gov NR 26 TC 14 Z9 14 U1 1 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 2005 VL 314 IS 2 BP 906 EP 915 DI 10.1124/jpet.105.084376 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 946CS UT WOS:000230550300051 PM 15860577 ER PT J AU Bleasby, K Hall, LA Perry, JL Mohrenweiser, HW Pritchard, JB AF Bleasby, K Hall, LA Perry, JL Mohrenweiser, HW Pritchard, JB TI Functional consequences of single nucleotide polymorphisms in the human organic anion transporter hOAT1 (SLC22A6) SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID EPITHELIAL-CELL LINE; CATION TRANSPORTER; RENAL SECRETION; HUMAN KIDNEY; EXPRESSION; PROTEIN; CLONING; GENES; IDENTIFICATION; CIDOFOVIR AB The human organic anion transporter hOAT1 (SLC22A6) contributes to the uptake of a range of small organic anions across the basolateral membrane of the renal proximal tubule and drives their urinary elimination. The aim of this study was to identify genetic variants of hOAT1 and to investigate potential effects on the functional properties of this transporter. Twenty single nucleotide polymorphisms ( SNPs) in hOAT1 were identified in genomic DNA from 92 individuals of African, Asian, and Caucasian origin. Two SNPs encoded changes in amino acid sequence; arginine to histidine ( residue 50) and lysine to isoleucine ( residue 525). Significantly, these SNPs were only present in the samples of African origin. When expressed in Xenopus oocytes, wild-type R50-hOAT1 and the variants R50H-hOAT1 and K525I-hOAT1 all mediated the probenecidsensitive uptake of the classic organic anion para-aminohippurate (PAH). Kinetic analysis indicated that the transport affinity (K-m) for PAH was unchanged in the variants, compared with wild type. Interestingly, the K m for the nucleoside phosphonate analogs adefovir, cidofovir, and tenofovir seemed to be decreased in the R50H-hOAT1 variant compared with the wild type, whereas the kinetics of K525I-hOAT1 remained unchanged. In conclusion, this is the first study to identify variation of hOAT1 in a racially diverse sample and to investigate the functional properties of the resulting variants. Since hOAT1 has been suggested as the basis of nephrotoxicity induced by nucleoside phosphonate analogs, this study raises the intriguing possibility that individuals with genetic variation in hOAT1, such as R50H, may display different handling of these drugs. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Lawrence Livermore Natl Lab, Livermore, CA USA. RP Pritchard, JB (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM pritcha3@niehs.nih.gov FU NIEHS NIH HHS [Y1-ES-8054-05]; Wellcome Trust NR 38 TC 69 Z9 76 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD AUG PY 2005 VL 314 IS 2 BP 923 EP 931 DI 10.1124/jpet.105.084301 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 946CS UT WOS:000230550300053 PM 15914676 ER PT J AU O'Donovan, MJ AF O'Donovan, MJ TI Serotonergic neurones drive spontaneous activity in the developing mouse hindbrain SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material C1 NINDS, Bethesda, MD 20892 USA. RP O'Donovan, MJ (reprint author), NINDS, 35 Convent Ave, Bethesda, MD 20892 USA. EM odonovm@ninds.nih.gov RI o'donovan, michael/A-2357-2015 OI o'donovan, michael/0000-0003-2487-7547 NR 5 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD AUG 1 PY 2005 VL 566 IS 3 BP 643 EP 643 DI 10.1113/jphysiol.2005.093278 PG 1 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 954EA UT WOS:000231135700001 PM 15994178 ER PT J AU Fayuk, D Yakel, JL AF Fayuk, D Yakel, JL TI Ca2+ permeability in rat hippocampal of nicotinic acetylcholine receptors CA1 interneurones SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID LONG-TERM POTENTIATION; PHARMACOLOGICAL-PROPERTIES; SYNAPTIC TRANSMISSION; CALCIUM PERMEABILITY; ALPHA-7 SUBUNITS; ACH RECEPTORS; NEURONS; CHANNEL; MODULATION; CELLS AB Neuronal nicotinic acetylcholine receptors (nAChRs) are widely expressed in the brain where they are involved in a variety of physiological processes, including cognition and development. The nAChRs are ligand-gated cationic channels, and different subtypes are known to be differentially permeable to Ca2+; the alpha 7-containing nAChRs are generally considered to be the most permeable. Ca2+ can activate and regulate a variety of signal transduction cascades, and the influx of Ca2+ through these receptors may have implications for synaptic plasticity. To determine the Ca2+ permeability of the nAChRs in rat hippocampal interneurones in the slice, which contain diverse subtypes of alpha 7- and non-alpha 7-containing nAChRs, we combined patch-clamp electrophysiology recordings with conventional fura-2 fluorescence imaging techniques. We estimated the relative Ca2+ permeability of the channels by determining the ratio of the increase in [Ca2+](i) level (Delta [Ca2+](i)) in the soma to the integrated transmembrane current (charge, Q) induced by the activation of the nAChRs, and compared this ratio to the highly Ca2+ permeable NMDA subtype of glutamate receptor channel. In all cells tested, the Delta[Ca2+](i)/Q ratio was significantly larger (i.e. more than twice as big) for responses activated by NMDA than for alpha 7-containing nAChRs in interneurones; the activation of the non-alpha 7 nAChRs did not produce any significant increase in [Ca2+](i). Interestingly, the Ca2+ permeability of native alpha 7 nAChRs in PC12 cells was significantly larger than in hippocampal interneurones, and not significantly different from NMDA receptors. Therefore, the a7-containing nAChRs in rat hippocampal interneurones are significantly less permeable to Ca2+ than not only NMDA receptors but also alpha 7 nAChRs in PC12 cells. C1 NIEHS, Neurobiol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Neurobiol Lab, NIH, DHHS, F2-08,POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM yakel@niehs.nih.gov NR 46 TC 37 Z9 37 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD AUG 1 PY 2005 VL 566 IS 3 BP 759 EP 768 DI 10.1113/jphysiol.2005.089789 PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 954EA UT WOS:000231135700010 PM 15932886 ER PT J AU Kuczewski, N Aztiria, E Gautam, D Wess, J Domenici, L AF Kuczewski, N Aztiria, E Gautam, D Wess, J Domenici, L TI Acetylcholine modulates cortical synaptic transmission via different muscarinic receptors, as studied with receptor knockout mice SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID CAT VISUAL-CORTEX; LONG-TERM POTENTIATION; RAT PREFRONTAL CORTEX; CEREBRAL-CORTEX; CHOLINERGIC SUPPRESSION; OLFACTORY CORTEX; ATTENTIONAL TASK; FUNCTIONAL-ROLE; RELEASE; SYNAPSES AB The central cholinergic system plays a crucial role in synaptic plasticity and spatial attention; however, the roles of the individual cholinergic receptors involved in these activities are not well understood at present. In the present study, we show that acetylcholine (ACh) can facilitate or depress synaptic transmission in occipital slices of mouse visual cortex. The precise nature of the ACh effects depends on the ACh concentration, and is input specific, as shown by stimulating different synaptic pathways. Pharmacological blockade of muscarinic receptor (mAChR) subtypes and the Use of M-1-M-5 mAChR-deficient mice showed that specific mAChR subtypes, together with the activity of the cholinesterases (ChEs), mediate facilitation or depression of synaptic transmission. The present data suggest that local ACh, acting through mAChRs, regulates the cortical dynamics making cortical circuits respond to specific stimuli. C1 SISSA, Cognit Neurosci Sector, I-34014 Trieste, Italy. NIDDK, Mol Signalling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. CNR, Inst Neurosci, I-56100 Pisa, Italy. RP Domenici, L (reprint author), SISSA, Cognit Neurosci Sector, Via Beirut 2-4, I-34014 Trieste, Italy. EM domenici@in.cnr.it OI Domenici, Luciano/0000-0003-2923-9421 NR 69 TC 28 Z9 28 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD AUG 1 PY 2005 VL 566 IS 3 BP 907 EP 919 DI 10.1113/jphysiol.2005.089987 PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 954EA UT WOS:000231135700021 PM 15919709 ER PT J AU Nishikawa, T Suematsu, S Saito, J Soyama, A Ito, H Kino, T Chrousos, G AF Nishikawa, T Suematsu, S Saito, J Soyama, A Ito, H Kino, T Chrousos, G TI Human renal mesangial cells produce aldosterone in response to low-density lipoprotein (LDL) SO JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE mesangial cells; aldosterone; pregnenolone; LDL receptor; P450scc; 3 beta-HSD; 21-hydroxylase; CYP11B2; low-density lipoprotein (LDL); mineralocorticoid receptor ID RECEPTOR-MEDIATED UPTAKE; GENE-EXPRESSION; RAT; BIOSYNTHESIS; HYPERTROPHY; DISEASE AB Systemic aldosterone plays an important role in the development of the microvascular disease and glomerular damage of the kidney in patients with diabetes mellitus and hyperlipidemia. Here, we investigated the possibility of local production of aldosterone in the kidney, using human primary glomerular mesangial cells. These cells produced both pregnenolone and aldosterone measured by specific radioimmunoassay and/or gas chromatography/mass spectrometry (GUMS) methods. The production of both steroids was significantly stimulated by treatment with LDL, while angiotensin II had a synergistic effect. Adrenocorticotropic hormone (ACTH) and (Bu)2cAMP, on the other hand, failed to stimulate aldosterone production by these,cells, suggesting that the local production of this steroid by mesangial cells is regulated differently from that of adrenal zona glomerulosa cells. Mesangial cells expressed the mRNA of the LDL receptor and steroidogenic enzymes, such as P450scc, 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 21-hydroxylase and CYP11B2. Mesangial cells also expressed mRNA of the mineralocorticoid receptor (MR), and LDL stimulated its abundance by three-fold, while spironolactone, a completive antagonist of aldosterone, completely abolished this LDL effect. Since MR is a known mineralocorticoid-responsive gene as well as an intracellular receptor molecule for this steroid, these results suggest that locally produced a1dosterone is biologically active, stimulating the transcription rates of the mineralocorticoid-responsive genes by activating the MR in mesangial cells. These pieces of evidence indicate that human mesangial cells are an aldosterone-producing tissue in which LDL plays a major regulatory role. Therefore, human renal mesangial endocrine system may contribute to local aldosterone concentrations and effects in the renal glomerulus independently of the systemic renin-angiotensin-aldosterone system and may participate in the development and progression of glomerular damage in several pathologic conditions. (c) 2005 Elsevier Ltd. All rights reserved. C1 Yokohama Rosai Hosp, Dept Med, Kohoku Ku, Yokohama, Kanagawa 2220036, Japan. NICHHD, Reprod Biol & Marine Branch, NIH, Bethesda, MD 20892 USA. RP Nishikawa, T (reprint author), Yokohama Rosai Hosp, Dept Med, Kohoku Ku, 3211 Kozukue Cho, Yokohama, Kanagawa 2220036, Japan. EM tetsuon@yokohamah.rofuku.go.jp NR 24 TC 38 Z9 41 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-0760 J9 J STEROID BIOCHEM JI J. Steroid Biochem. Mol. Biol. PD AUG PY 2005 VL 96 IS 3-4 BP 309 EP 316 DI 10.1016/j.jsbmb.2005.03.005 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 959MM UT WOS:000231521900010 PM 15993578 ER PT J AU Cardone, G Grunewald, K Steven, AC AF Cardone, G Grunewald, K Steven, AC TI A resolution criterion for electron tomography based on cross-validation SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE Fourier shell correlation coefficient; anisotropic resolution; signal-to-noise ratio ID HERPES-SIMPLEX-VIRUS; TO-NOISE RATIO; CRYOELECTRON MICROSCOPY; 3-DIMENSIONAL STRUCTURE; SINGLE PARTICLES; PROTEIN; RECONSTRUCTION; VISUALIZATION; SECTIONS; CRYOMICROSCOPY AB Despite much progress in electron tomography, quantitative assessment of resolution has remained a problematic issue. The criteria that are used in single particle analysis, based on gauging the consistency between density maps calculated from half data sets, are not directly applicable because of the uniqueness of a tomographic volume. Here, we propose two criteria based on a cross-validation approach. One, called FSCe/o, is based on a Fourier shell correlation comparison between tomograms calculated from the even and odd members of a tilt series. The other, called noise-compensated leave-one-out (NLOO), is based on Fourier ring correlation comparisons between an original projection and the corresponding reprojection of the tomogram calculated from all the other projections, taking into account the differing noise statistics. Plotted as a function of tilt angle, they allow assessment of the angular dependence of resolution and quality control over the series of projections. Integrated over all projections, the results give a global figure for resolution. Tests on simulated tomograms established consistency between these criteria and the FSCref, a correlation coefficient calculated between a known reference structure and the corresponding portion of a tomogram containing that structure. The two criteria-FSCe/o and NLOO-are mutually consistent when residual noise is the major resolution-limiting factor. When the size of the tilt increment becomes a significant factor, NLOO provides a more reliable criterion, as expected, although it is computationally intensive. Applicable to entire tomograms or selected structures, NLOO has also been tested on experimental tomographic data. Published by Elsevier Inc. C1 NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. Max Planck Inst Biochem, Dept Mol Struct Biol, D-82152 Martinsried, Germany. RP Steven, AC (reprint author), NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. EM Alasdair_Steven@nih.gov OI Grunewald, Kay/0000-0002-4788-2691 NR 42 TC 75 Z9 75 U1 3 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD AUG PY 2005 VL 151 IS 2 BP 117 EP 129 DI 10.1016/j.jsb.2005.04.006 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 954XA UT WOS:000231187400001 PM 15964766 ER PT J AU Heymann, JB Chagoyen, M Belnap, DM AF Heymann, JB Chagoyen, M Belnap, DM TI Common conventions for interchange and archiving of three-dimensional electron microscopy information in structural biology SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE cryo-electron microscopy; electron cryo-microscopy; file formats; geometrical convention; geometry; image processing; image standards; imaging; single-particle analysis; standard geometry; standards; symmetry notation; tomography; two-dimensional crystallography ID IMAGE; RECONSTRUCTION; DEPOSITION; RESOLUTION; DATABASE; SYSTEM AB Three-dimensional electron microscopy (3DEM) has made significant contributions to structural biology. To accomplish this feat, many image-processing software packages were developed by various laboratories. The independent development of methods naturally implied the adoption of dissimilar conventions-penalizing users who want to take advantage of the wealth of algorithms from different packages. In addition, a public repository of 3DEM research results, the EM Data Bank, is now established. In an era where information exchange is important, standardizing conventions is a necessity. The 3DEM field requires a consistent set of conventions. We propose a set of common conventions named the "3DEM Image Conventions." They are designed as a standardized approach to image interpretation and presentation. In this regard., the conventions serve as a first step on which to build data-exchange solutions among existing software packages and as a vehicle for homogenous data representation in data archives, such as the EM Data Bank. Published by Elsevier Inc. C1 NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. CALTECH, Div Biol, Pasadena, CA 91125 USA. CSIC, Ctr Nacl Biotecnol, E-28049 Madrid, Spain. RP Belnap, DM (reprint author), Brigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USA. EM David_Belnap@byu.edu RI Heymann, Bernard/F-6825-2011; Chagoyen, Monica/J-4391-2013; OI Chagoyen, Monica/0000-0001-6911-1591; Heymann, Bernard/0000-0002-8872-5326 NR 14 TC 33 Z9 34 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD AUG PY 2005 VL 151 IS 2 BP 196 EP 207 DI 10.1016/j.jsb.2005.06.001 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 954XA UT WOS:000231187400007 PM 16043364 ER PT J AU Donenberg, GR AF Donenberg, GR TI Youths and HIV/AIDS: Psychiatry's role in a changing epidemic SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Review DE human immunodeficiency virus/acquired immunodeficiency syndrome; psychosocial; psychiatric; prevention; treatment ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED CHILDREN; AFRICAN-AMERICAN FAMILIES; SEXUAL RISK BEHAVIOR; COMBINATION ANTIRETROVIRAL THERAPY; SCHOOL-AGE-CHILDREN; OF-THE-LITERATURE; ADOLESCENT GIRLS; MATERNAL HIV; CONDOM USE AB Objective: To review the past 10 years of published research on human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) in the United States, including psychosocial and psychiatric risk factors, epidemiology, biology, neurocognitive and psychiatric sequelae, disclosure issues, prevention strategies, and biological and behavioral treatments. Method: Researchers reviewed the English-language literature with a focus on child and adolescent risk factors associated with HIV/AIDS, prevention, and treatment. Results: Substantial scientific advances have occurred over the past two decades leading to decreased morbidity and mortality in the United States from AIDS-related opportunistic infections. At the same time, rates of HIV infection are increasing in teenagers, young women, and minorities, and growing numbers of youths are living with an infected family member. Understanding HIV risk behavior requires a broad theoretical framework. Comprehensive HIV prevention programs have led to reduced risk behavior among HIV-affected youths and teens at risk of infection. Biological and behavioral treatments of HIV infection continue to evolve and have led to longer life span, improved quality of life, and fewer psychiatric problems. Conclusions: HIV/AIDS has significant mental health implications, and psychiatry can play a critical role in curbing the epidemic. With minimal effort, mental health professionals can adapt and apply the strategies that they use to treat psychiatric symptoms to prevent HIV transmission behaviors. C1 Univ Illinois, Chicago, IL 60608 USA. NIMH, Bethesda, MD 20892 USA. RP Donenberg, GR (reprint author), Univ Illinois, 1747 W Roosevelt Rd,Room 155, Chicago, IL 60608 USA. EM gdonenberg@psych.uic.edu FU NIMH NIH HHS [R01 MH058545, R01 MH063008, R01 MH065155, R01 MH068225, R01MH068225, R01MH58545, R01MH63008, R01MH65155] NR 206 TC 125 Z9 127 U1 6 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD AUG PY 2005 VL 44 IS 8 BP 728 EP 747 DI 10.1097/01.chi.0000166381.68392.02 PG 20 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 948EV UT WOS:000230699700004 PM 16034275 ER PT J AU Kant, AK Graubard, BI AF Kant, AK Graubard, BI TI A comparison of three dietary pattern indexes for predicting biomarkers of diet and disease SO JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION LA English DT Article DE diet quality; dietary indexes; biomarkers; BMI; blood pressure; NHANES III; components of variance ID NUTRITION EXAMINATION SURVEY; HEALTHY EATING INDEX; 3RD NATIONAL-HEALTH; CARDIOVASCULAR-DISEASE; PLASMA BIOMARKERS; QUALITY; RISK; MORTALITY; SAMPLE; ADULTS AB Objective: Examination of dietary indexes in association with objective biomarkers of dietary intake and chronic disease risk is an important step in their validation. We compared three dietary pattern indexes-Healthy Eating Index (HEI), Recommended Foods Score (RFS-24 hour recall), and Dietary Diversity Score for recommended foods (DDS-R)-for their ability to predict biomarkers of dietary intake, obesity, cardiovascular disease, and diabetes. Methods: We used dietary and laboratory data from the third National Health and Nutrition Examination Survey to study these associations in 8719 disease-free adults aged >= 20 y. The HEI, developed by the USDA, was a sum of scores on consideration of ten individual components; the RFS was a sum of all recommended foods (lean meat, poultry and fish, whole grains, fruits and juices, low-fat dairy, and vegetables) mentioned in the recall; the DDS-R examined whether or not a recommended food was mentioned from each of the five major food groups. The independent association of the dietary pattern indexes with body mass index (BMI), blood pressure, and serum concentrations of several biomarkers were examined using regression methods to adjust for multiple covariates. Results: All indexes were strong independent positive predictors of serum concentrations of vitamin C, E, folate, and all carotenoids (p <= 0.00001), except lycopene, and were negative predictors of BMI, serum homocysteine, C-reactive protein, plasma glucose, and hemoglobin A I C (p < 0.05). The RFS and DDS-R were inversely associated with blood pressure and serum cholesterol (p <= 0.03). Conclusions: The RFS and DDS-R performed as well or better than the HEI for predicting serum concentration of nutrients and biomarkers of disease risk. C1 CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Flushing, NY 11367 USA. NCI, Div Canc Epidemiol & Genet, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Kant, AK (reprint author), CUNY Queens Coll, Dept Family Nutr & Exercise Sci, Remsen Hall,Room 306E, Flushing, NY 11367 USA. EM akant@qc.edu FU NHLBI NIH HHS [HL 72050] NR 31 TC 98 Z9 101 U1 1 U2 27 PU AMER COLLEGE NUTRITION PI CLEARWATER PA 300 SOUTH DUNCAN AVENUE, STE 225, CLEARWATER, FL 33755 USA SN 0731-5724 J9 J AM COLL NUTR JI J. Am. Coll. Nutr. PD AUG PY 2005 VL 24 IS 4 BP 294 EP 303 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 955FX UT WOS:000231212000009 PM 16093407 ER PT J AU Ershler, WB Sheng, S McKelvey, J Artz, AS Denduluri, N Tecson, J Taub, DD Brant, LJ Ferrucci, L Longo, DL AF Ershler, WB Sheng, S McKelvey, J Artz, AS Denduluri, N Tecson, J Taub, DD Brant, LJ Ferrucci, L Longo, DL TI Serum erythropoietin and aging: A longitudinal analysis SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE erythropoietin; anemia; BLSA; aging ID UNEXPLAINED ANEMIA; NURSING-HOME; AGE; PREVALENCE; DEFICIENCY; CANCER; OLDER AB OBJECTIVES: To determine the changes in serum erythropoietin with age in patients with and without anemia and to assess the importance of certain comorbidities on changes in erythropoietin level and the development of anemia. DESIGN: Clinical history, hematological parameters, and serum erythropoietin levels were examined at 1- to 2-year intervals for 8 to 30 years. SETTING: Baltimore Longitudinal Study on Aging (BLSA), National Institute on Aging. PARTICIPANTS: One hundred forty-three BLSA participants. MEASUREMENTS: Complete blood count and serum chemistries were performed at the time of each visit, and archived serum samples were used for erythropoietin level. RESULTS: Although all subjects were healthy and without anemia at the time of initial evaluation, some developed chronic illness-most notably hypertension and diabetes mellitus. Erythropoietin levels rose significantly for the group as a whole, and the slope of the rise was found to be greater for those who did not have associated diabetes mellitus or hypertension. During the subsequent years, subjects who developed anemia but did not have hypertension or diabetes mellitus had the greatest slope in erythropoietin rise over time, whereas those with hypertension or diabetes mellitus and anemia had the lowest erythropoietin slope. CONCLUSIONS: The increase in serum erythropoietin with aging may be compensation for subclinical blood loss, increased red blood cell turnover, or increased erythropoietin resistance of red cell precursors. It is suspected that, with very advanced age, or in those with compromised renal function (e.g., diabetes mellitus or hypertension), the compensatory mechanism becomes inadequate and anemia results. C1 Harbor Hosp, Clin Res Branch, NIA, Intramural Res Program, Baltimore, MD 21225 USA. Inst Adv Studies Aging, Washington, DC USA. RP Ershler, WB (reprint author), Harbor Hosp, Clin Res Branch, NIA, Intramural Res Program, NM 526,3100 S Hanover St, Baltimore, MD 21225 USA. EM ershlerwi@grc.nia.nih.gov NR 26 TC 73 Z9 74 U1 1 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2005 VL 53 IS 8 BP 1360 EP 1365 DI 10.1111/j.1532-5415.2005.53416.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 948OY UT WOS:000230726800012 PM 16078962 ER PT J AU Hood, BL Lucas, DA Kim, G Chan, KC Blonder, J Issaq, HJ Veenstra, TD Conrads, TP Pollet, I Karsan, A AF Hood, BL Lucas, DA Kim, G Chan, KC Blonder, J Issaq, HJ Veenstra, TD Conrads, TP Pollet, I Karsan, A TI Quantitative analysis of the low molecular weight serum proteome using O-18 stable isotope labeling in a lung tumor xenograft mouse model SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY LA English DT Article ID HUMAN PLASMA PROTEOME; MASS-SPECTROMETRY; OVARIAN-CANCER; FLUID; BIOMARKERS; PATTERNS; DISEASE; BLOOD AB With advancements in the analytical technologies and methodologies in proteomics, there is great interest in biomarker discovery in biofluids such as serum and plasma. Current hypotheses suggest that the low molecular weight (LMW) serum proteome possesses an archive of clipped and cleaved protein fragments that may provide insight into disease development. Though these biofluids represent attractive samples from which new and more accurate disease biomarkers may be found, the intrinsic person-to-person variability in these samples complicates their discovery. Mice are one of the most extensively used animal models for studying human disease because they represent a highly controllable experimental model system. In this study, the LMW serum proteome was compared between xenografted tumor-bearing mice and control mice by differential labeling utilizing trypsin-mediated incorporation of the stable isotope of oxygen, O-18. The digestates were combined, fractionated by strong cation exchange chromatography, and analyzed by nanoflow reversed-phase liquid chromatography coupled online with tandem mass spectrometry, resulting in the identification of 6003 proteins identified by at least a single, fully tryptic peptide. Almost 1650 proteins were identified and quantitated by two or more fully tryptic peptides. The methodology adopted in this work provides the means for future quantitative measurements in comparative animal models of disease and in human disease cohorts. C1 SAIC Frederick Inc, Natl Canc Inst, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. RP Veenstra, TD (reprint author), SAIC Frederick Inc, Natl Canc Inst, Lab Proteom & Analyt Technol, POB B, Frederick, MD 21702 USA. EM veenstra@ncifcrf.gov; conrads@ncifcrf.gov RI Tang, Macy/B-9798-2014; Karsan, Aly/K-2067-2015 FU NCI NIH HHS [N01-CO-12400] NR 25 TC 51 Z9 52 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1044-0305 J9 J AM SOC MASS SPECTR JI J. Am. Soc. Mass Spectrom. PD AUG PY 2005 VL 16 IS 8 BP 1221 EP 1230 DI 10.1016/j.jasms.2005.02.005 PG 10 WC Chemistry, Analytical; Chemistry, Physical; Spectroscopy SC Chemistry; Spectroscopy GA 952BF UT WOS:000230975700003 PM 15979327 ER PT J AU Bauer, F Jones, M Qin, JX Castro, P Asada, J Sitges, M Cardon, LA Tsujino, H Zetts, AD Panza, JA Thomas, JD Shiota, T AF Bauer, F Jones, M Qin, JX Castro, P Asada, J Sitges, M Cardon, LA Tsujino, H Zetts, AD Panza, JA Thomas, JD Shiota, T TI Quantitative analysis of left atrial function during left ventricular ischemia with and without left atrial ischemia: A real-time 3-dimensional echocardiographic study SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article ID DIASTOLIC STIFFNESS; CORONARY-ARTERY; VOLUME; OCCLUSION; DISEASE; MODEL AB Left atrial (LA) systolic and diastolic function were analyzed in an animal model of acute left ventricular ischemia with LA ischemia by proximal left circumflex coronary artery occlusion or without LA ischemia by midleft anterior descending coronary artery occlusion (7 sheep in each group). LA pressures and LA volumes were simultaneously recorded using a catheter and real-time 3-dimensional echocardiography, respectively. LA stroke volume represented 63% of left ventricular stroke volume during left anterior descending coronary artery occlusion, but only 32% during left circumflex coronary artery occlusion. This animal study with 3-dimensional echocardiographic determination of absolute LA volumes demonstrated dramatic depression of LA function during proximal left circumflex coronary artery occlusion as compared with left anterior descending coronary artery occlusion. C1 Cleveland Clin Fdn, Dept Cardiovasc Med, Cleveland, OH 44195 USA. Natl Heart Lung & Blood Inst Hlth, Bethesda, MD USA. RP Shiota, T (reprint author), Cleveland Clin Fdn, Dept Cardiovasc Med, Desk F15,9500 Euclid Ave, Cleveland, OH 44195 USA. EM Shiotat@cef.org NR 20 TC 10 Z9 11 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD AUG PY 2005 VL 18 IS 8 BP 795 EP 801 DI 10.1016/j.echo.2005.01.018 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 953RQ UT WOS:000231098600004 PM 16084330 ER PT J AU Asano, T Niimura, F Pastan, I Fogo, AB Ichikawa, I Matsusaka, T AF Asano, T Niimura, F Pastan, I Fogo, AB Ichikawa, I Matsusaka, T TI Permanent genetic tagging of podocytes: Fate of injured podocytes in a mouse model of glomerular sclerosis SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article; Proceedings Paper CT 37th Annual Meeting of the American-Society-of-Nephrology CY OCT 27-NOV 01, 2004 CL St Louis, MO SP Amer Soc Nephrol ID FOCAL SEGMENTAL GLOMERULOSCLEROSIS; DEPENDENT KINASE INHIBITORS; EPITHELIAL-CELL; NEPHROPATHY; EXPRESSION; MICE; PROLIFERATION; PATHOGENESIS; SEVERITY; DISEASE AB Injured podocytes lose differentiation markers. Therefore, the true identity of severely injured podocytes remains unverified. A transgenic mouse model equipped with a podocyte-selective injury induction system was established. After induction of podocyte injury, mice rapidly developed glomerulosclerosis, with downregulation of podocyte marker proteins. Proliferating epithelial cells accumulated within Bowman's space, as seen in collapsing glomerulosclerosis. In this study, the fate of injured podocytes was pursued. Utilizing Cre-loxP recombination, the podocyte lineage was genetically labeled with lacZ in an irreversible manner. After podocyte injury, the number of lacZ-labeled cells, which were often negative for synaptopodin, progressively declined, correlating with glomerular damage. Parietal epithelial cells, but not lacZ-labeled podocytes, avidly proliferated. The cells proliferating within Bowman's capsule and, occasionally, on the outer surface of the glomerular basement membrane were lacZ-negative. Thus, when podocytes are severely injured, proliferating parietal epithelial cells migrate onto the visceral site, thereby mimicking proliferating podocytes. C1 Tokai Univ, Sch Med, Inst Med Sci, Isehara, Kanagawa 2591193, Japan. Tokai Univ, Sch Med, Dept Pediat, Isehara, Kanagawa 2591193, Japan. Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA. Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA. Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA. Tokyo Med & Dent Univ, Grad Sch, Dept Pediat & Dev Biol, Bunkyo Ku, Tokyo, Japan. NCI, Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Matsusaka, T (reprint author), Tokai Univ, Sch Med, Inst Med Sci, Isehara, Kanagawa 2591193, Japan. EM taijim@is.icc.u-tokai.ac.jp FU NIDDK NIH HHS [DK37868, DK447577] NR 29 TC 56 Z9 58 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD AUG PY 2005 VL 16 IS 8 BP 2257 EP 2262 DI 10.1681/ASN.2004121134 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 949HC UT WOS:000230774700003 PM 15987751 ER PT J AU Shavers, VL Fagan, P Lawrence, D McCaskill-Stevens, W McDonald, P Browne, D McLinden, D Christian, M Trimble, E AF Shavers, Vickie L. Fagan, Pebbles Lawrence, Deirdre McCaskill-Stevens, Worta McDonald, Paige Browne, Doris McLinden, Dan Christian, Michaele Trimble, Edward TI Barriers to racial/ethnic minority application and competition for NIH research funding SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE race; ethnicity; research funding; minority underrepresentotion AB Background: Despite recognition of the need to increase the pool of racial/ethnic minority investigators, racial/ethnic minority representation among National Institutes of Health (NIH)-funded investigators remains low. Racial/ethnic minority investigators bring unique perspectives and experiences that enhance the potential for understanding factors that underlie racial/ethnic variation in health and health status. Identification of barriers to successful minority competition for NIH funding and suggestions for strategies to overcome them were obtained from a concept mapping project and a meeting of minority investigators and investigators at minority-serving institutions. Methods: Concept mapping, a mixed-methods planning approach that integrates common data collection processes with multivariate statistical analyses, was used in this exploratory project. The concept mapping approach generated a series of related "concept maps" that were used for data interpretation and meeting discussions. Results: Barriers to minority investigator competition for NIH funding identified by concept mapping participants include: 1) inadequate research infrastructure, training and development; 2) barriers to development as independent researchers; 3) inadequate mentoring; 4) insensitivity, misperceptions and miscommunication about the specific needs of investigators involved in research with minority communities; 5) institutional bids in NIH policies; 6) unfair competitive environment; 7) lack of institutional support; 8) lack of support for research topics/methods relevant to research with minority communities; and 9) social, cultural and environmental barriers. Discussion: Data from both the concept mapping and the meeting discussions suggest the need to use a multilevel approach to increase minority representation among funded NIH investigators. Specifically, the NIH should use strategies that overcome barriers at the home institution, within NIH and at the investigator level. C1 [Shavers, Vickie L.] NCI, Div Canc Control & Populat Sci, Appl Res Program, HSEB, Bethesda, MD 20892 USA. [McCaskill-Stevens, Worta; Browne, Doris] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Christian, Michaele; Trimble, Edward] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [McLinden, Dan] McLinden Consulting, Montgomery, IL USA. RP Shavers, VL (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res Program, HSEB, 6130 Execut Blvd,EPN 4005 MSC 7344, Bethesda, MD 20892 USA. EM shaversv@mail.nih.gov RI McLinden, Daniel/E-1966-2015 OI McLinden, Daniel/0000-0002-2333-5765 NR 18 TC 30 Z9 30 U1 0 U2 2 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD AUG PY 2005 VL 97 IS 8 BP 1063 EP 1077 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA V50IZ UT WOS:000203403300001 PM 16173321 ER PT J AU Arlen, PM Gulley, JL Todd, N Lieberman, R Steinberg, SM Morin, S Bastian, A Marte, J Tsang, KY Beetham, P Grosenbach, DW Schlom, J Dahut, W AF Arlen, PM Gulley, JL Todd, N Lieberman, R Steinberg, SM Morin, S Bastian, A Marte, J Tsang, KY Beetham, P Grosenbach, DW Schlom, J Dahut, W TI Antiandrogen, vaccine and combination therapy in patients with nonmetastatic hormone refractory prostate cancer SO JOURNAL OF UROLOGY LA English DT Article DE prostatic neoplasms; immunotherapy; clinical trials; vaccines ID FLUTAMIDE WITHDRAWAL; IMMUNE-RESPONSES; PHASE-I; ANTIGEN; CELLS; TRIAL; NILUTAMIDE; CARCINOMA; GENE; PSA AB Purpose: There is no current standard treatment for patients with prostate cancer who have received hormonal therapy but have an increasing prostate specific antigen (PSA) without radiographic evidence of metastasis. This trial was designed to analyze toxicity, immunogenicity and time to treatment failure using vaccine, antiandrogen therapy or their sequential use. Materials and Methods: A total of 42 patients were randomized to receive vaccine vs antiandrogen therapy with nilutamide. The vaccine consisted of recombinant vaccinia viruses containing the PSA and B7.1 costimulatory genes as prime vaccinations, and avipox-PSA as boosters. After 6 months patients with an increasing PSA and no metastasis may receive a combination of both treatments. Results: Three patients on nilutamide were removed from study secondary to grade 3 toxicities but no grade 3 toxicities were attributed to vaccine. In the vaccine arm median time to treatment failure was 9.9 months with 13 of 21 decreases in PSA velocity vs 7.6 months with 16 of 21 decreases in PSA velocity in the nilutamide arm (p = 0.28). Of the patients in the nilutamide arm 8 had vaccine added at the time of PSA progression. Median time to treatment failure with combined therapy was 5.2 months, with a median duration from study entry of 15.9 months. Of the patients in the vaccine arm 12 had nilutamide added at the time of PSA progression. Median time to treatment failure with combined therapy was 13.9 months and a median of 25.9 months from initiation of therapy. Conclusions: Further studies are merited to investigate the role of combining vaccine with antiandrogen therapy or vaccine followed by vaccine plus antiandrogen therapy in this patient population. C1 NCI, Ctr Canc Res, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Med Oncol Clin Res Unit, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Ctr Canc Res, Lab Tumor Immunol & Biol, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 20 TC 82 Z9 84 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2005 VL 174 IS 2 BP 539 EP 546 DI 10.1097/01.ju.0000165159.33772.5b PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 946WP UT WOS:000230604300038 PM 16006888 ER PT J AU Stephenson, RA Mori, M Hsieh, YC Beer, TM Stanford, JL Gilliland, FD Hoffman, RM Potosky, AL AF Stephenson, RA Mori, M Hsieh, YC Beer, TM Stanford, JL Gilliland, FD Hoffman, RM Potosky, AL TI Treatment of erectile dysfunction following therapy for clinically localized prostate cancer: Patient reported use and outcomes from the surveillance, epidemiology, and end results prostate cancer outcomes study SO JOURNAL OF UROLOGY LA English DT Article DE penis; prostate; impotence; prostatic neoplasms; treatment outcome ID QUALITY-OF-LIFE; BEAM RADIATION-THERAPY; RADICAL PROSTATECTOMY; HEALTH OUTCOMES; SEXUAL FUNCTION; SILDENAFIL; RADIOTHERAPY; RECALL AB Purpose: Erectile dysfunction (ED) persists for years following curative therapies for clinically localized prostate cancer. We report use and treatment outcomes in a 5-year interval in a population based cohort from the Surveillance, Epidemiology, and End Results Prostate Cancer Outcomes Study. Materials and Methods: A sample of 1,977 men with localized prostate cancer who received external beam radiation therapy or radical prostatectomy in 1994 to 1995 were surveyed for 5 outcome measures of ED treatment, namely treatment, perceived helpfulness, erectile sufficiency, sexual activity frequency and erection maintenance. Subjects were surveyed 6, 12, 24 and 60 months after prostate cancer diagnosis. Results: Overall 50.5% of men ever used ED treatment. The use of ED treatments increased during the study course. Subject age, regular sexual partner and baseline sexual activity were factors positively associated with ED treatments. While it was used uncommonly (1.9%), a penile prosthesis was perceived as the most helpful ED treatment (helped a lot in 52% of respondents). Sildenafil helped a lot in 12% of respondents. Erectile fullness, erection maintenance and sexual activity frequency were modestly improved in men using ED treatment compared with those in men not using ED treatment. Conclusions: Approximately half of the patients in this population based cohort of men used ED treatment during the 5 years following prostate cancer diagnosis. Men using ED treatments had modest improvement in sexual function compared with men that in who did not receive ED treatment at 60 months. More effective treatments for ED following local therapy for prostate cancer are needed. C1 Univ Utah, Sch Med, Div Urol, Salt Lake City, UT 84132 USA. Oregon Hlth Sci Univ, Biostat Shared Resource Canc Inst, Portland, OR 97201 USA. Oregon Hlth & Sci Univ, Div Hematol & Med Oncol, Portland, OR USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Dept Epidemiol, Seattle, WA 98195 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. New Mexico Vet Affairs Hlth Care Syst, Med Serv, Albuquerque, NM USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Stephenson, RA (reprint author), Univ Utah, Sch Med, Div Urol, 50 N Med Dr,Room 3B420, Salt Lake City, UT 84132 USA. EM robert.stephenson@hse.utah.edu FU NCI NIH HHS [N01-PC-67009, N01-PC-67000, N01-PC-67006, N01-PC-67007, N01-PC-67010, N01-PC-67005] NR 20 TC 66 Z9 69 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2005 VL 174 IS 2 BP 646 EP 650 DI 10.1097/01.ju.0000165342.85300.14 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 946WP UT WOS:000230604300065 PM 16006930 ER PT J AU Donati, D Martinelli, E Cassiani-Ingoni, R Ahlqvist, J Hou, J Major, EO Jacobson, S AF Donati, D Martinelli, E Cassiani-Ingoni, R Ahlqvist, J Hou, J Major, EO Jacobson, S TI Variant-specific tropism of human herpesvirus 6 in human astrocytes SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-HERPESVIRUS 6; MYELIN BASIC-PROTEIN; MULTIPLE-SCLEROSIS LESIONS; CELLULAR RECEPTOR; CROSS-REACTIVITY; GENE-EXPRESSION; CODING CONTENT; INFECTION; VIRUS; CD46 AB Though first described as a lymphotropic virus, human herpesvirus 6 (HRV-6) is highly neuropathogenic. Two viral variants are known: HHV-6A and HHV-6B. Both variants can infect glial cells and have been differentially associated with central nervous system diseases, suggesting an HHV-6 variant-specific tropism for glial cell subtypes. We have performed infections with both viral variants in human progenitor-derived astrocytes (HPDA) and monitored infected cell cultures for cytopathic effect (CPE), intra- and extracellular viral DNA load, the presence of viral particles by electronic microscopy, mRNA transcription, and viral protein expression. HHV-6A established a productive infection with CPE, visible intracellular virions, and high virus DNA loads. HHV-6B-infected HPDA showed no morphological changes, intracellular viral particles, and decreasing intra- and extracellular viral DNA over time. After long-term passage, HHV-6B-infected HPDA had stable but low levels of intracellular viral DNA load with no detectable viral mRNA. Our results demonstrate that HHV-6A and HHV-6B have differential tropisms and patterns of infection for HPDA in vitro, where HIIV-6A results in a productive lytic infection. In contrast, HHV-6B was associated with a nonproductive infection. These findings suggest that HHV-6 variants might be responsible for specific infection patterns in glial cells in vivo. Astrocytes may be an important reservoir for this virus in which differential tropism of HHV-6A and HHV-6B may be associated with different disease outcomes. C1 NINDS, Neuroimmunol Branch, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. RP Jacobson, S (reprint author), NINDS, Neuroimmunol Branch, Viral Immunol Sect, NIH, Bldg 10,Room 5N214, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov NR 43 TC 51 Z9 56 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2005 VL 79 IS 15 BP 9439 EP 9448 DI 10.1128/JVI.79.15.9439-9448.2005 PG 10 WC Virology SC Virology GA 946MC UT WOS:000230575300008 PM 16014907 ER PT J AU Townsley, AC Senkevich, TG Moss, B AF Townsley, AC Senkevich, TG Moss, B TI Vaccinia virus A21 virion membrane protein is required for cell entry and fusion SO JOURNAL OF VIROLOGY LA English DT Article ID INTRACELLULAR MATURE VIRIONS; ACTIN-CONTAINING MICROVILLI; NEUTRALIZING MONOCLONAL-ANTIBODIES; DISULFIDE BOND FORMATION; SURFACE HEPARAN-SULFATE; OPEN READING FRAME; ENVELOPE PROTEIN; RNA-POLYMERASE; ESSENTIAL COMPONENT; CORE PROTEINS AB We provide the initial characterization of the product of the vaccinia virus A21L (VACWR140) gene and demonstrate that it is required for cell entry and low pH-triggered membrane fusion. The A21L open reading frame, which is conserved in all sequenced members of the poxvirus family, encodes a protein of 117 amino acids with an N-terminal hydrophobic domain and four invariant cysteines. Expression of the A21 protein occurred at late times of infection and was dependent on viral DNA replication. The A21 protein contained two intramolecular disulfide bonds, the formation of which required the vaccinia virus-encoded cytoplasmic redox pathway, and was localized on the surface of the lipoprotein membrane of intracellular mature virions. A conditional lethal mutant, in which A21L gene expression wag regulated by isopropyl-beta-D-thiogalactopyranoside, was constructed. In the absence of inducer, cell-to-cell spread of virus did not occur, despite the formation of morphologically normal intracellular virions and extracellular virions with actin tails. Purified virions lacking A21 were able to bind to cells, but cores did not penetrate into the cytoplasm and synthesize viral RNA. In addition, virions lacking A21 were unable to mediate low pH-triggered cell-cell fusion. The A21 protein, like the A28 and H2 proteins, is an essential component of the poxvirus entry/fusion apparatus for both intracellular and extracellular virus particles. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 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 55 TC 63 Z9 66 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2005 VL 79 IS 15 BP 9458 EP 9469 DI 10.1128/JVI.79.15.9458-9469.2005 PG 12 WC Virology SC Virology GA 946MC UT WOS:000230575300010 PM 16014909 ER PT J AU Bukreyev, A Belyakov, IM Prince, GA Yim, KC Harris, KK Berzofsky, JA Collins, PL AF Bukreyev, A Belyakov, IM Prince, GA Yim, KC Harris, KK Berzofsky, JA Collins, PL TI Expression of interleukin-4 by recombinant respiratory syncytial virus is associated with accelerated inflammation and a nonfunctional cytotoxic T-lymphocyte response following primary infection but not following challenge with wild-type virus SO JOURNAL OF VIROLOGY LA English DT Article ID ENHANCED PULMONARY HISTOPATHOLOGY; VACCINIA VIRUS; CYTOKINE EXPRESSION; DENDRITIC CELL; RSV CHALLENGE; BALB/C MICE; M2 PROTEIN; IN-VIVO; IMMUNIZATION; DISEASE AB The outcome of a viral infection or of immunization with a vaccine can be influenced by the local cytokine environment. In studies of experimental vaccines against respiratory syncytial virus (RSV), an increased stimulation of Th2 (T helper 2) lymphocytes was associated with increased immunopathology upon subsequent RSV infection. For this study, we investigated the effect of increased local expression of the Th2 cytokine interleukin-4 (IL-4) from the genome of a recombinant RSV following primary infection and after a challenge with wild-type (wt) RSV. Mice infected with RSV/IL-4 exhibited an accelerated pulmonary inflammatory response compared to those infected with wt RSV, although the wt RSV group caught up by day 8. In the first few days postinfection, RSV/IL-4 was associated with a small but significant acceleration in the expansion of pulmonary T lymphocytes specific for an RSV CD8(+) cytotoxic T-lymphocyte (CTL) epitope presented as a major histocompatibility complex class I tetramer. However, by day 7 the response of tetramer-positive T lymphocytes in the wt RSV group caught up and exceeded that of the RSV/IL-4 group. At all times, the CTL response of the RSV/IL-4 group was deficient in the production of gamma interferon and was nonfunctional for in vitro cell killing. The accelerated inflammatory response coincided with an accelerated accumulation and activation of pulmonary dendritic cells early in infection, but thereafter the dendritic cells were deficient in the expression of B7-1, which governs the acquisition of cytolytic activity by CTL. Following a challenge with wt RSV, there was an increase in Th2 cytokines in the animals that had previously been infected with RSV/IL-4 compared to those previously infected with wt RSV, but the CD8(+) CTL response and the amount of pulmonary inflammation were not significantly different. Thus, a strong Th2 environment during primary pulmonary immunization with live RSV resulted in early inflammation and a largely nonfunctional primary CTL response but had a minimal effect on the secondary response. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Immunogenet & Vaccine Res Sect, Vaccine Branch, NIH, Bethesda, MD 20892 USA. Virion Syst Inc, Rockville, MD USA. RP Bukreyev, A (reprint author), NIAID, Infect Dis Lab, NIH, 50 S Dr,MSC 8007, Bethesda, MD 20892 USA. EM AB176v@nih.gov NR 42 TC 20 Z9 21 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2005 VL 79 IS 15 BP 9515 EP 9526 DI 10.1128/JVI.79.15.9515-9526.2005 PG 12 WC Virology SC Virology GA 946MC UT WOS:000230575300015 PM 16014914 ER PT J AU Kim, MK Claiborn, KC Levin, HL AF Kim, MK Claiborn, KC Levin, HL TI The long terminal repeat-containing retrotransposon Tf1 possesses amino acids in Gag that regulate nuclear localization and particle formation SO JOURNAL OF VIROLOGY LA English DT Article ID VIRUS-LIKE PARTICLES; PORE COMPLEX; REVERSE TRANSCRIPTION; SCHIZOSACCHAROMYCES-POMBE; NUCLEOLAR LOCALIZATION; FISSION YEAST; TRANSPORT; PROTEIN; IMPORT; MECHANISM AB Tf1 is a long terminal repeat-containing retrotransposon of Schizosaccharomyces pombe that is studied to further our understanding of retrovirus propagation. One important application is to examine Tf1 as a model for how human immunodeficiency virus type 1 proteins enter the nucleus. The accumulation of Tf1 Gag in the nucleus requires an N-terminal nuclear localization signal (NLS) and the nuclear pore factor Nup124p. Here, we report that NLS activity is regulated by adjacent residues. Five mutant transposons were made, each with sequential tracts of four amino acids in Gag replaced by alanines. All five versions of Tf1 transposed with frequencies that were significantly lower than that of the wild type. Although all five made normal amounts of Gag, two of the mutations did not make cDNA, indicating that Gag contributed to reverse transcription. The localization of the Gag in the nucleus was significantly reduced by mutations A1, A2, and A3. These results identified residues in Gag that contribute to the function of the NLS. The Gags of A4 and A5 localized within the nucleus but exhibited severe defects in the formation of virus-like particles. Of particular interest was that the mutations in Gag-A4 and Gag-A5 caused their nuclear localization to become independent of Nup124p. These results suggested that Nup124p was only required for import of Tf1 Gag because of its extensive multimerization. C1 NICHHD, Sect Eukaryot Transposable Elements, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP NICHHD, Sect Eukaryot Transposable Elements, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM Henry_Levin@nih.gov NR 39 TC 14 Z9 15 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD AUG PY 2005 VL 79 IS 15 BP 9540 EP 9555 DI 10.1128/JVI.79.15.9540--9555.2005 PG 16 WC Virology SC Virology GA 946MC UT WOS:000230575300017 PM 16014916 ER PT J AU Wu, TY Yan, YH Kozak, CA AF Wu, TY Yan, YH Kozak, CA TI Rmcf2, a xenotropic provirus in the Asian mouse species Mus castaneus, blocks infection by polytropic mouse gammaretroviruses SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA VIRUSES; CELL-SURFACE RECEPTOR; WILD MICE; RESISTANCE; SEQUENCE; RETROVIRUSES; GENE; SUSCEPTIBILITY; SUPERINFECTION; INTERFERENCE AB Cells from the Asian wild mouse species Mus castaneus are resistant to infection by the polytropic host range group of mouse gammaretroviruses. Two factors are responsible for this resistance: a defective XPR1 cell surface receptor for polytropic murine leukemia viruses (P-MLVs), and a resistance factor detectable only in interspecies hybrids between M. castaneus and mice with an XPR1 variant that permits infection by xenotropic MLVs (X-MLVs) as well as P-MLVs. This second novel virus resistance phenotype has been associated with expression of viral Env glycoprotein; Northern blotting with specific hybridization probes identified a spliced X-MLV env message unique to virus-resistant mice. These observations suggest that resistance is due to expression of one or more endogenous X-MLV envelope genes that interfere with infection by exogenous P-MLVs. M. castaneus contains multiple X-MLV proviruses, but serial backcrosses reduced this proviral content and permitted identification of a single proviral env sequence inherited with resistance. The resistance phenotype and the provirus were mapped to the same site on distal chromosome 18. The provirus was shown to be a full-length provirus highly homologous to previously described X-MLVs. Use of viral pseudotypes confirmed that this resistance gene, termed Rmcf2, prevents entry of P-MLVs. Rmcf2 resembles the virus resistance genes Fv4 and Rmcf in that it produces Env glycoprotein but fails to produce infectious virus; the proviruses associated with all three resistance genes have fatal defects. This type of provirus Env-mediated resistance represents an important defense mechanism in wild mouse populations exposed to endemic infections. C1 NIAID, LMM, NIH, Bethesda, MD 20892 USA. RP Kozak, CA (reprint author), NIAID, LMM, NIH, Bldg 4,Room 329,4 Ctr Dr,MSC 0460, Bethesda, MD 20892 USA. EM ckozak@niaid.nih.gov NR 46 TC 25 Z9 25 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2005 VL 79 IS 15 BP 9677 EP 9684 DI 10.1128/JVI.79.15.9677-9684.2005 PG 8 WC Virology SC Virology GA 946MC UT WOS:000230575300030 PM 16014929 ER PT J AU Pancera, M Lebowitz, J Schon, A Zhu, P Freire, E Kwong, PD Roux, KH Sodroski, J Wyatt, R AF Pancera, M Lebowitz, J Schon, A Zhu, P Freire, E Kwong, PD Roux, KH Sodroski, J Wyatt, R TI Soluble mimetics of human immunodeficiency virus type 1 viral spikes produced by replacement of the native trimerization domain with a heterologous trimerization motif: Characterization and ligand binding analysis SO JOURNAL OF VIROLOGY LA English DT Article ID GP120 ENVELOPE GLYCOPROTEIN; HUMAN MONOCLONAL-ANTIBODY; HIV-1 GP120; NEUTRALIZATION SENSITIVITY; TRANSMEMBRANE GLYCOPROTEIN; OLIGOMERIC STRUCTURE; IMMUNE-RESPONSES; MEMBRANE-FUSION; INFLUENZA-VIRUS; LEUCINE-ZIPPER AB The human immunodeficiency virus type 1 (HIV-1) exterior envelope glycoprotein, gp120, mediates binding to the viral receptors and, along with the transmembrane glycoprotein gp41, is a major target for neutralizing antibodies. We asked whether replacing the gp41 fusion/trimerization domain with a stable trimerization motif might lead to a more stable gp120 trimer that would be amenable to structural and immunologic analysis. To obtain stable gp120 trimers, a heterologous trimerization motif, GCN4, was appended to the C terminus of YU2gp120. Biochemical analysis indicated that the gp120-GCN4 trimers were superior to gp140 molecules in their initial homogeneity, and trilobed structures were observable by electron microscopy. Biophysical analysis of gp120-GCN4 trimers by isothermal titration calorimetry (ITC) and ultracentrifugation analyses indicated that most likely two molecules of soluble CD4 could bind to one gp120-GCN4 trimer. To further examine restricted CD4 stoichiometric binding to the gp120-GCN4 trimers, we generated a low-affinity CD4 binding trimer by introducing a D457V change in the CD4 binding site of each gp120 monomeric subunit. The mutant trimers could definitively bind only one soluble CD4 molecule, as determined by ITC and sedimentation equilibrium centrifugation. These data indicate that there are weak interactions between the gp120 monomeric subunits of the GCN4-stabilized trimers that can be detected by low-affinity ligand sensing. By similar analysis, we also determined that removal of the variable loops V1, V2, and V3 in the context of the gp120-GCN4 proteins allowed the binding of three CD4 molecules per trimer. Interestingly, both the gp120-GCN4 variants displayed a restricted stoichiometry for the CD4-induced antibody 17b of one antibody molecule binding per trimer. This restriction was not evident upon removal of the variable loops V1 and V2 loops, consistent with conformational constraints in the wild-type gp120 trimers and similar to those inherent in the functional Env spike. Thus, the gp120-GCN4 trimers demonstrate several properties that are consistent with some of those anticipated for gp120 in the context of the viral spike. C1 NIH, Vaccine Res Ctr, Struct Virol Sect, Bethesda, MD 20892 USA. NIH, Div Bioengn & Phys Sci, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. Florida State Univ, Inst Mol Biophys, Tallahassee, FL 32306 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Wyatt, R (reprint author), NIH, Vaccine Res Ctr, Struct Virol Sect, 40 Convent Dr, Bethesda, MD 20892 USA. EM richardwyatt@nih.gov NR 75 TC 58 Z9 60 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2005 VL 79 IS 15 BP 9954 EP 9969 DI 10.1128/JVI.79.15.9954-9969.2005 PG 16 WC Virology SC Virology GA 946MC UT WOS:000230575300057 PM 16014956 ER PT J AU Severson, W Xu, XL Kuhn, M Senutovitch, N Thokala, M Ferron, F Longhi, S Canard, B Jonsson, CB AF Severson, W Xu, XL Kuhn, M Senutovitch, N Thokala, M Ferron, F Longhi, S Canard, B Jonsson, CB TI Essential amino acids of the Hantaan virus N protein in its interaction with RNA SO JOURNAL OF VIROLOGY LA English DT Article ID HANTAVIRUS NUCLEOCAPSID PROTEIN; DISORDERED PROTEIN; S-SEGMENT; SEQUENCE; BINDING; IDENTIFICATION; ENCAPSIDATION; PREDICTION; PANHANDLE; REGION AB The nucleocapsid (N) protein of hantavirus encapsidates viral genomic and antigenomic RNAs. Previously, deletion mapping identified a central, conserved region (amino acids 175 to 217) within the Hantaan virus (HTNV) N protein that interacts with a high affinity with these viral RNAs (vRNAs). To further define the boundaries of the RNA binding domain (RBD), several peptides were synthesized and examined for the ability to bind full-length S-segment vRNA. Peptide 195-217 retained 94% of the vRNA bound by the HTNV N protein, while peptides 175-186 and 205-217 bound only 1% of the vRNA. To further explore which residues were essential for binding vRNA, we performed a comprehensive mutational analysis of the amino acids in the RBD). Single and double Ala substitutions were constructed for 18 amino acids from amino acids 175 to 217 in the full-length N protein. In addition, Ala substitutions were made for the three R residues in peptide 185-217. An analysis of protein-RNA interactions by electrophoretic mobility shift assays implicated E192, Y206, and S217 as important for binding. Chemical modification experiments showed that lysine residues, but not arginine or cysteine residues, contribute to RNA binding, which agreed with bioinformatic predictions. Overall, these data implicate lysine residues dispersed from amino acids 175 to 429 of the protein and three amino acids located in the RBD as essential for RNA binding. C1 New Mexico State Univ, Dept Entomol Plant Pathol & Weed Sci, Las Cruces, NM 88003 USA. Univ Alberta, Dept Med Microbiol & Immunol, Edmonton, AB, Canada. Univ Witten Herdecke, Inst Microbiol & Virol, D-58448 Witten, Germany. New Mexico State Univ, NIH, RISE, Undergrad Program,Dept Biol, Las Cruces, NM 88003 USA. New Mexico State Univ, Dept Entomol Plant Pathol & Weed Sci, Grad Program Biochem, Las Cruces, NM 88003 USA. CNRS, UMR 6098, F-13288 Marseille, France. Univ Aix Marseille 1, ESIL, F-13288 Marseille, France. Univ Aix Marseille 2, ESIL, F-13288 Marseille, France. So Res Inst, Dept Biochem & Mol Biol, Birmingham, AL 35205 USA. RP Jonsson, CB (reprint author), So Res Inst, Dept Biochem & Mol Biol, 2000 9th Ave S, Birmingham, AL 35205 USA. EM jonsson@sri.org RI Longhi, Sonia/M-5305-2014 OI Longhi, Sonia/0000-0002-6829-6771 FU NIAID NIH HHS [R03 AI041114, R03 AI041114-03]; NIGMS NIH HHS [S06 GM008136-230035, GM61222-01, S06 GM008136, R25 GM061222] NR 39 TC 33 Z9 33 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2005 VL 79 IS 15 BP 10032 EP 10039 DI 10.1128/JVI.79.15.10032-10039.2005 PG 8 WC Virology SC Virology GA 946MC UT WOS:000230575300064 PM 16014963 ER PT J AU Lowther, W Wiley, K Smith, GH Callahan, R AF Lowther, W Wiley, K Smith, GH Callahan, R TI A new common integration site, Int7, for the mouse mammary tumor virus in mouse mammary tumors identifies a gene whose product has furin-like and thrombospondin-like sequences SO JOURNAL OF VIROLOGY LA English DT Article ID LARGE-SCALE IDENTIFICATION; TRANSGENIC MICE; TUMORIGENESIS; PROGRESSION; LEUKEMIA; WNT-1 AB A novel common integration site for the mouse mammary tumor virus (MMTV) was identified (designated Int7) in five independently arising mouse mammary tumors. The insertion sites all cluster within a 1-kb region that is 2 to 3 kb 5' of the transcription initiation site of a gene, 2610028F08RIK, whose gene product contains furin-like and thrombospondin-like sequences. Expression of Int7 is normally very low or silent during various stages of mammary gland development, but MMTV integration at this site results in the activation of high steady-state levels of expression of the gene. These five tumors were also found to have two or three additional viral insertions, which in each case occurred flanking a member of either the Wnt and/or FGF gene family. Reverse transcriptase PCR results demonstrated that each of the viral insertions led to elevated expression of the presumed target flanking genes. C1 NCI, Mammary Biol & Tumorigenesis Lab, Bethesda, MD 20892 USA. RP Callahan, R (reprint author), NCI, Mammary Biol & Tumorigenesis Lab, Bldg 37,Room 1118A, Bethesda, MD 20892 USA. EM rc54d@nih.gov NR 14 TC 34 Z9 38 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2005 VL 79 IS 15 BP 10093 EP 10096 DI 10.1128/JVI.79.15.10093-10096.2005 PG 4 WC Virology SC Virology GA 946MC UT WOS:000230575300074 PM 16014973 ER PT J AU Mascola, JR D'Souza, P Gilbert, P Hahn, BH Haigwood, NL Morris, L Petropoulos, CJ Polonis, VR Sarzotti, M Montefiori, DC AF Mascola, JR D'Souza, P Gilbert, P Hahn, BH Haigwood, NL Morris, L Petropoulos, CJ Polonis, VR Sarzotti, M Montefiori, DC TI Recommendations for the design and use of standard virus panels to assess neutralizing antibody responses elicited by candidate human immunodeficiency virus type 1 vaccines SO JOURNAL OF VIROLOGY LA English DT Editorial Material ID HUMAN MONOCLONAL-ANTIBODIES; CROSS-CLADE NEUTRALIZATION; HIV-1/SIV CHIMERIC VIRUS; CELL-LINE; ENVELOPE GLYCOPROTEIN; PRIMARY INFECTION; PROTECTION; ASSAYS; TRANSMISSION; MACAQUES C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. Univ Washington, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98109 USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. Seattle Biomed Res Inst, Seattle, WA 98109 USA. Natl Inst Communicable Dis, Johannesburg, South Africa. ViroLog Inc, San Francisco, CA 94080 USA. Henry M Jackson Fdn, Rockville, MD 20850 USA. Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,MSC3015, Bethesda, MD 20892 USA. EM jmascola@nih.gov OI , Lynn/0000-0003-3961-7828 NR 46 TC 174 Z9 182 U1 0 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2005 VL 79 IS 16 BP 10103 EP 10107 DI 10.1128/JVI.79.16.10103-10107.2005 PG 5 WC Virology SC Virology GA 950UX UT WOS:000230884700001 PM 16051803 ER PT J AU Li, M Gao, F Mascola, JR Stamatatos, L Polonis, VR Koutsoukos, M Voss, G Goepfert, P Gilbert, P Greene, KM Bilska, M Kothe, DL Salazar-Gonzalez, JF Wei, XP Decker, JM Hahn, BH Montefiori, DC AF Li, M Gao, F Mascola, JR Stamatatos, L Polonis, VR Koutsoukos, M Voss, G Goepfert, P Gilbert, P Greene, KM Bilska, M Kothe, DL Salazar-Gonzalez, JF Wei, XP Decker, JM Hahn, BH Montefiori, DC TI Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies SO JOURNAL OF VIROLOGY LA English DT Review ID HUMAN MONOCLONAL-ANTIBODY; ENVELOPE GLYCOPROTEIN COMPLEX; INTERMOLECULAR DISULFIDE BOND; HIV-1/SIV CHIMERIC VIRUS; 2ND HYPERVARIABLE REGION; PRIMARY HIV-INFECTION; SYNERGISTIC NEUTRALIZATION; IMMUNE-RESPONSES; PARTIAL DELETION; RHESUS MACAQUES AB Induction of broadly cross-reactive neutralizing antibodies is a high priority for AIDS vaccine development but one that has proven difficult to be achieved. While most immunogens generate antibodies that neutralize a subset of T-cell-line-adapted strains of human immunodeficiency virus type 1 (HIV-1), none so far have generated a potent, broadly cross-reactive response against primary isolates of the virus. Even small increments in immunogen improvement leading to increases in neutralizing antibody titers and cross-neutralizing activity would accelerate vaccine development; however, a lack of uniformity in target strains used by different investigators to assess cross-neutralization has made the comparison of vaccine-induced antibody responses difficult. Thus, there is an urgent need to establish standard panels of HIV-1 reference strains for wide distribution. To facilitate this, full-length gp160 genes were cloned from acute and early subtype B infections and characterized for use as reference reagents to assess neutralizing antibodies against clade B HIV-1. Individual gp160 clones were screened for infectivity as Env-pseudotyped viruses in a luciferase reporter gene assay in JC53-BL (TZM-bl) cells. Functional env clones were sequenced and their neutralization phenotypes characterized by using soluble CD4, monoclonal antibodies, and serum samples from infected individuals and noninfected recipients of a recombinant gp120 vaccine. Env clones from 12 R5 primary HIV-1 isolates were selected that were not unusually sensitive or resistant to neutralization and comprised a wide spectrum of genetic, antigenic, and geographic diversity. These reference reagents will facilitate proficiency testing and other validation efforts aimed at improving assay performance across laboratories and can be used for standardized assessments of vaccine-elicited neutralizing antibodies. C1 Duke Univ, Med Ctr, Dept Surg, Lab AIDS Vaccine Res & Dev, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Seattle Biomed Res Inst, Seattle, WA 98109 USA. Henry M Jackson Fdn, Rockville, MD 20850 USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. GlaxoSmithKline Biol, B-1330 Rixensart, Belgium. Univ Washington, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98109 USA. RP Montefiori, DC (reprint author), Duke Univ, Med Ctr, Dept Surg, Lab AIDS Vaccine Res & Dev, POB 2926, Durham, NC 27710 USA. EM monte@acpub.duke.edu FU NIAID NIH HHS [AI27742, AI055386, AI27767, AI41530, AI46705, AI47708, AI54497, AI85338, N01AI30034, N01AI85338, P30 AI027742, P30 AI027767, R01 AI047708, R21 AI055386, R56 AI047708, U01 AI041530] NR 125 TC 685 Z9 699 U1 3 U2 36 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2005 VL 79 IS 16 BP 10108 EP 10125 DI 10.1128/JVI.79.16.10108-10125.2005 PG 18 WC Virology SC Virology GA 950UX UT WOS:000230884700002 PM 16051804 ER PT J AU Peng, B Wang, LR Gomez-Roman, VR Davis-Warren, A Montefiori, DC Kalyanaraman, VS Venzon, D Zhao, J Kan, E Rowell, TJ Murthy, KK Srivastava, I Barnett, SW Robert-Guroff, M AF Peng, B Wang, LR Gomez-Roman, VR Davis-Warren, A Montefiori, DC Kalyanaraman, VS Venzon, D Zhao, J Kan, E Rowell, TJ Murthy, KK Srivastava, I Barnett, SW Robert-Guroff, M TI Replicating rather than nonreplicating adenovirus-human immunodeficiency virus recombinant vaccines are better at eliciting potent cellular immunity and priming high-titer antibodies SO JOURNAL OF VIROLOGY LA English DT Article ID NEUTRALIZING ANTIBODIES; RHESUS MACAQUES; DENDRITIC CELLS; GENE-TRANSFER; SIVMAC251 CHALLENGE; NASAL EPITHELIUM; PARTIAL DELETION; CYSTIC-FIBROSIS; T-LYMPHOCYTES; VECTOR AB A major challenge in combating the human immunodeficiency virus (HIV) epidemic is the development of vaccines capable of inducing potent, persistent cellular immunity and broadly reactive neutralizing antibody responses to HIV type 1 (HIV-1). We report here the results of a preclinical trial using the chimpanzee model to investigate a combination vaccine strategy involving sequential priming immunizations with different serotypes of adenovirus (Ad)/H1V-1(MN)env/rev recombinants and boosting with an HIV envelope subunit protein, oligomeric HIVSF162 gp140 Delta V2. The immunogenicities of replicating and nonreplicating Ad/HIV1(MN)env/rev recombinants were compared. Replicating Ad/HIV recombinants were better at eliciting HIV-specific cellular immune responses and better at priming Immoral immunity against HIV than nonreplicating Ad-HIV recombinants carrying the same gene insert. Enhanced cellular immunity was manifested by a greater frequency of HIV envelope-specific gamma interferon-secreting peripheral blood lymphocytes and better priming of T-cell proliferative responses. Enhanced humoral immunity was seen in higher anti-envelope binding and neutralizing antibody titers and better induction of antibody-dependent cellular cytotoxicity. More animals primed with replicating Ad recombinants mounted neutralizing antibodies against heterologous R5 viruses after one or two booster immunizations with the mismatched oligomeric HIV-1(SF162) gp140 Delta V2 protein. These results support continued development of the replicating Ad-HIV recombinant vaccine approach and suggest that the use of replicating vectors for other vaccines may prove fruitful. C1 NCI, NIH, Vaccine Branch, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Surg, Lab AIDS Vaccine Res & Dev, Durham, NC 27710 USA. Adv BioSci Labs Inc, Kensington, MD 20895 USA. Chiron Corp, Emeryville, CA 94608 USA. Univ Louisiana Lafayette, New Iberia Res Ctr, New Iberia, LA 70560 USA. SW Fdn Biomed Res, Dept Virol & Immunol, San Antonio, TX 78227 USA. RP Robert-Guroff, M (reprint author), NCI, NIH, Vaccine Branch, 41 Medlars Dr,Bldg 41,Rm D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov RI Venzon, David/B-3078-2008 NR 51 TC 57 Z9 59 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2005 VL 79 IS 16 BP 10200 EP 10209 DI 10.1128/JVI.79.16.10200-10209.2005 PG 10 WC Virology SC Virology GA 950UX UT WOS:000230884700011 PM 16051813 ER PT J AU Frahm, N Adams, S Kiepiela, P Linde, CH Hewitt, HS Lichterfeld, M Sango, K Brown, NV Pae, E Wurcel, AG Altfeld, M Feeney, ME Allen, TM Roach, T St John, MA Daar, ES Rosenberg, E Korber, B Marincola, F Walker, BD Goulder, PJR Brander, C AF Frahm, N Adams, S Kiepiela, P Linde, CH Hewitt, HS Lichterfeld, M Sango, K Brown, NV Pae, E Wurcel, AG Altfeld, M Feeney, ME Allen, TM Roach, T St John, MA Daar, ES Rosenberg, E Korber, B Marincola, F Walker, BD Goulder, PJR Brander, C TI HLA-B63 presents HLA-B57/B58-restricted cytotoxic T-lymphocyte epitopes and is associated with low human immunodeficiency virus load SO JOURNAL OF VIROLOGY LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; HIV-1 INFECTION; HLA-B; TYPE-1 INFECTION; ESCAPE MUTATION; POLYMORPHISM; SPECIFICITY; REVERSION; VIREMIA; AIDS AB Several HLA class I alleles have been associated with slow human immunodeficiency virus (HIV) disease progression, supporting the important role HLA class I-restricted cytotoxic T lymphocytes (CTL) play in controlling HIV infection. HLA-B63, the serological marker for the closely related HLA-B*1516 and HLA-B*1517 alleles, shares the epitope binding motif of HLA-B57 and HLA-B58, two alleles that have been associated with slow HIV disease progression. We investigated whether HIV-infected individuals who express HLA-B63 generate CTL responses that are comparable in breadth and specificity to those of HLA-B57/58-positive subjects and whether HLA-B63-positive individuals would also present with lower viral set points than the general population. The data show that HLA-B63-positive individuals indeed mounted responses to previously identified HLA-B57-restricted epitopes as well as towards novel, HLA-B63-restricted CTL targets that, in turn, can be presented by HLA-B57 and HLA-B58. HLA-B63-positive subjects generated these responses early in acute HIV infection and were able to control HIV replication in the absence of antiretroviral treatment with a median viral load of 3,280 RNA copies/ml. The data support an important role of the presented epitope in mediating relative control of HIV replication and help to better define immune correlates of controlled HIV infection. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. NIH, Ctr Clin, HLA Typing Lab, Bethesda, MD 20892 USA. Univ Natal, UHIV Pathogenesis Program, ZA-4001 Durban, South Africa. Fenway Community Hlth Ctr, Boston, MA 02115 USA. Lemuel Shattuck Hosp, Jamaica Plain, MA 02130 USA. Queen Elizabeth Hosp, Bridgetown, Barbados. Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90502 USA. Los Alamos Natl Lab, Los Alamos, NM 87545 USA. Santa Fe Inst, Santa Fe, NM 87501 USA. RP Brander, C (reprint author), AIDS Res Ctr, 5th Floor,MGH E,5214,149 13th St, Charlestown, MA 02129 USA. EM cbrander@partners.org RI Allen, Todd/F-5473-2011; OI Brander, Christian/0000-0002-0548-5778; Korber, Bette/0000-0002-2026-5757 FU NIAID NIH HHS [AI-067077, AI-043638, N01-AI-15422, R01 AI067077, U01 AI043638] NR 34 TC 57 Z9 57 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2005 VL 79 IS 16 BP 10218 EP 10225 DI 10.1128/JVI.79.16.10218-10225.2005 PG 8 WC Virology SC Virology GA 950UX UT WOS:000230884700013 PM 16051815 ER PT J AU Chang, KW Barsov, EV Ferris, AL Hughes, SH AF Chang, KW Barsov, EV Ferris, AL Hughes, SH TI Mutations of a residue within the polyproline-rich region of Env alter the replication rate and level of cytopathic effects in chimeric avian retroviral vectors SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; LEUKOSIS-SARCOMA-VIRUSES; ENVELOPE PROTEIN; HOST-RANGE; MAMMALIAN-CELLS; INFECTION; DNA; APOPTOSIS; RECEPTOR; ACCUMULATION AB Previous attempts to extend the host range of the avian sarcoma/leukosis virus (ASLV)-based RCASBP vectors produced two viral vectors, RCASBP M2C (4070A) and RCASBP M2C (797-8), which replicate using the amphotropic murine leukemia virus 4070A Env protein (2). Both viruses were adapted to replicate efficiently in the avian cell line DF-1, but RCASBP M2C (4070A) caused extensive cytopathic effects (CPE) in DF-1 cells whereas RCASBP M2C (797-8) induced low levels of CPE. The two viruses differed only at amino acid 242 of the polyproline-rich region in the surface (SU) subunit of the Env protein. In RCASBP M2C (4070A), an isoleucine replaced the wild-type proline residue, whereas a threonine residue was found in RCASBP M2C (797-8). In the present study, we show that other amino acid substitutions at position 242 strongly influence the CPE and replication rate of the chimeric viruses. There was a correlation between the amount of unintegrated linear retroviral DNA present in infected DF-1 cells and the level of CPE. This suggests that there may be a role for superinfection in the CPE. The treatment of RCASBP M2C (4070A) -infected cells with dantrolene, which inhibits the release of calcium from the endoplasmic reticulum (ER), reduced the amount of CPE seen during infection with the highly cytotoxic virus. Dantrolene treatment did not appear to affect virus production, suggesting that Ca2+ release from the ER had a role in the CPE caused by these viruses. C1 NCI Frederick, HIV Drug Resistance Program, Frederick, MD 21702 USA. NCI Frederick, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21702 USA. RP Hughes, SH (reprint author), NCI Frederick, HIV Drug Resistance Program, POB B,Bldg 539,Rm 130A, Frederick, MD 21702 USA. EM hughes@ncifcrf.gov NR 34 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2005 VL 79 IS 16 BP 10258 EP 10267 DI 10.1128/JVI.79.16.10258-10267.2005 PG 10 WC Virology SC Virology GA 950UX UT WOS:000230884700017 PM 16051819 ER PT J AU Zelinskyy, G Robertson, SJ Schimmer, S Messer, RJ Hasenkrug, KJ Dittmer, U AF Zelinskyy, G Robertson, SJ Schimmer, S Messer, RJ Hasenkrug, KJ Dittmer, U TI CD8(+) T-cell dysfunction due to cytolytic granule deficiency in persistent friend retrovirus infection SO JOURNAL OF VIROLOGY LA English DT Article ID HEPATITIS-C VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; GAMMA-INTERFERON; CD8+T CELLS; INDUCED ERYTHROLEUKEMIA; FUNCTIONAL IMPAIRMENT; SPONTANEOUS-RECOVERY; PERFORIN EXPRESSION; VIRAL PERSISTENCE; PERIPHERAL-BLOOD AB Virus-specific CD8(+) T cells are critical for the control of acute Friend virus (FV) infections, but are rendered impotent by CD4(+) regulatory T cells during the chronic phase of infection. The current study examines this CD8(+) T-cell dysfunction by analyzing the production and release of cytolytic molecules by CD8(+) T cells. CD8(+) T cells with an activated phenotype (CD43(+)) from acutely infected mice produced all three key components of lytic granules: perforin, granzyme A, and granzyme B. Furthermore, they displayed evidence of recent degranulation and in vivo cytotoxicity. In contrast, activated CD8(+) T cells from chronically infected mice were deficient in cytolytic molecules and showed little evidence of recent degranulation and poor in vivo cytotoxicity. Evidence from tetramer-positive CD8(+) T cells with known virus specificity confirmed the findings from the activated subset of CD8(+) T cells. Interestingly, perforin and granzyme A mRNA levels were not significantly reduced during chronic infection, indicating control at a posttranscriptional level. Granzyme B deficiency was associated with a significant decrease in mRNA levels, but posttranscriptional control also appeared to contribute to deficiency. These results demonstrate a broad impairment of cytotoxic CD8(+) T-cell effector function during chronic retroviral infection and explain the inability of virus-specific CD8(+) T cells to eliminate persistent virus. C1 Univ Klinikum Essen, Inst Virol, D-45122 Essen, Germany. NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Dittmer, U (reprint author), Univ Klinikum Essen, Inst Virol, D-45122 Essen, Germany. EM ulf.dittmer@uni-essen.de FU Intramural NIH HHS NR 55 TC 46 Z9 48 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2005 VL 79 IS 16 BP 10619 EP 10626 DI 10.1128/JVI.79.16.10619-10626.2005 PG 8 WC Virology SC Virology GA 950UX UT WOS:000230884700052 PM 16051854 ER PT J AU Lee, JS Kritchevsky, SB Tylavsky, F Harris, T Simonsick, EM Rubin, SM Newman, AB AF Lee, JS Kritchevsky, SB Tylavsky, F Harris, T Simonsick, EM Rubin, SM Newman, AB CA Hlth ABC Study TI Weight change, weight change intention, and the incidence of mobility limitation in well-functioning community-dwelling older adults SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article; Proceedings Paper CT 56th Annual Meeting of the Gerontological-Society-of-America CY NOV 21-25, 2003 CL San Diego, CA SP Gerontol Soc Amer ID IOWA WOMENS HEALTH; AGED 40-64 YEARS; BODY-MASS INDEX; PHYSICAL FUNCTION; UNITED-STATES; RISK-FACTORS; MUSCLE MASS; MORTALITY; MEN; OVERWEIGHT AB Background. Obesity increases the risk for functional decline in later years, but the functional consequences of weight change in older adults are currently Unclear. The aim Of this Study was to determine whether weight, weight change, and weight change intention are associated with risk for mobility limitation in elderly persons. Methods. This study included 2932 well-functioning black and white men and women aged 70 to 79 years, participating in the Health, Aging and Body Composition (Health ABC) Study, who were followed for 30 months. At baseline, reported weight change of 5 or more pounds during the previous year and weight change intention were assessed. Mobility limitation was defined as reported difficulty or inability to walk one-quarter mile or to climb 10 steps during two consecutive semiannual assessments during a period of 30 months. Results. Approximately 30% of participants developed mobility limitation. Higher body mass index (BMI) was associated with increased risk for mobility limitation. Unintentional weight loss in the previous year was associated with increased risk for mobility limitation in the extremely obese, which wits defined as BMI >= 35 (hazard ratios [HR], = 3.79; 95% confidence interval [CI], 1.84-7.79), and the normal BMI, which was defined as BMI < 25 (HR, 2.55; 95% CI, 1.80-3.60). In persons with BMI 25 to 29.9, intentional weight loss (HR, 1.59; 95% CI, 1.12-2.25) and weight fluctuation with any intention (HR, 1.59; 95% CI, 1.10-2.28) increased the risk for mobility limitation. Unintentional weight gain Or fluctuation did not confer additional risk for mobility limitation compared with weight stability, regardless of the level of body weight. Conclusion. In this cohort of well-functioning elderly persons, functional consequences of past weight change depended on the type of weight change, intentionality, and current measured body weight. C1 Univ Pittsburgh, Healthy Aging Res Program, Dept Epidemiol, Pittsburgh, PA 15213 USA. Wake Forest Univ, J Paul Sticht Ctr Aging, Winston Salem, NC 27109 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. NIA, Clin Res Branch, Baltimore, MD 21224 USA. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94143 USA. RP Lee, JS (reprint author), Univ Pittsburgh, Healthy Aging Res Program, Dept Epidemiol, 130 N Bellefield Ave, Pittsburgh, PA 15213 USA. EM jung-sun.lee@mail.cscc.unc.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 39 TC 42 Z9 43 U1 2 U2 3 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD AUG PY 2005 VL 60 IS 8 BP 1007 EP 1012 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 960JH UT WOS:000231586000010 PM 16127104 ER PT J AU Koster, A Penninx, BWJH Bosma, H Kempen, GIJM Harris, TB Newman, AB Rooks, RN Rubin, SM Simonsick, EM van Eijk, JTM Kritchevsky, SB AF Koster, A Penninx, BWJH Bosma, H Kempen, GIJM Harris, TB Newman, AB Rooks, RN Rubin, SM Simonsick, EM van Eijk, JTM Kritchevsky, SB TI Is there a biomedical explanation for socioeconomic differences in incident mobility limitation? SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID OLDER PERSONS; WHITEHALL-II; RISK-FACTORS; CARDIOVASCULAR-DISEASE; HEALTH INEQUALITIES; FUNCTIONAL DECLINE; METABOLIC SYNDROME; DISABILITY; MORTALITY; OBESITY AB Background. The association between low socioeconomic status and poor physical functioning has been well described; biomedical factors may play an important role in explaining these differences. This study examines the association between socioeconomic status and incident mobility limitation in well-functioning older adults, and seeks to determine whether this link could be explained by biomedical factors. Methods. Data were obtained from 3066 men and women, aged 70-79 years from Pittsburgh, Pennsylvania and Memphis, Tennessee participating in the Health, Aging and Body Composition (Health ABC) study. Three indicators of socioeconomic status were used: education, income, and ownership of financial assets. Mobility limitation was defined as reporting difficulty walking 1/4 mile or climbing 10 steps during two consecutive semiannual assessments over 4.5 years. Biomedical factors included a wide range of diseases (e.g., heart and cerebrovascular disease) and biological risk factors (e.g. hypertension, poor pulmonary function, and high serum levels of inflammatory markers). Results. Adjusted hazard ratios of incident mobility limitation were significantly higher in those persons with low education, low income, and few assets. Hazard ratios ranged from 1.66 to 2.80 in the lowest socioeconomic groups. Additional adjustment for biomedical factors reduced the hazard ratios by an average of 41% for education, 17% for income, and 29% for assets. Conclusion. Biomedical factors can account for some of the association between socioeconomic status and incident mobility limitation. However, to reduce physical disabilities and, in particular, the socioeconomic differences therein, it may not be sufficient to solely intervene upon biological risk factors and risks of diseases. C1 Univ Maastricht, Dept Hlth Care Studies, Sect Med Sociol, NL-6200 MD Maastricht, Netherlands. Wake Forest Univ, Sch Med, Sticht Ctr Aging, Sect Geronotol & Geriatr Med, Winston Salem, NC 27109 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Med, Div Geriatr Med, Pittsburgh, PA USA. Kent State Univ, Dept Sociol, Kent, OH 44242 USA. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94143 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Koster, A (reprint author), Univ Maastricht, Dept Hlth Care Studies, Sect Med Sociol, POB 616, NL-6200 MD Maastricht, Netherlands. EM a.koster@zw.unimaas.nl RI Koster, Annemarie/E-7438-2010; Bosma, Hans/A-6184-2013; Newman, Anne/C-6408-2013; Kempen, Gertrudis/H-5978-2016 OI Newman, Anne/0000-0002-0106-1150; Kempen, Gertrudis/0000-0002-7053-2198 FU NIA NIH HHS [N01-AG-6-2103, N01-AG-6-2106, N01-AG-6-2101] NR 39 TC 42 Z9 44 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD AUG PY 2005 VL 60 IS 8 BP 1022 EP 1027 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 960JH UT WOS:000231586000013 PM 16127107 ER PT J AU Menon, V Greene, T Wang, XL Pereira, AA Marcovina, SM Beck, GJ Kusek, JW Collins, AJ Levey, AS Sarnak, MJ AF Menon, V Greene, T Wang, XL Pereira, AA Marcovina, SM Beck, GJ Kusek, JW Collins, AJ Levey, AS Sarnak, MJ TI C-reactive protein and albumin as predictors of all-cause and cardiovascular mortality in chronic kidney disease SO KIDNEY INTERNATIONAL LA English DT Article DE C-reactive protein; albumin; inflammation; chronic kidney disease; outcomes ID STAGE RENAL-DISEASE; MAINTENANCE HEMODIALYSIS-PATIENTS; PERITONEAL-DIALYSIS PATIENTS; CORONARY-HEART-DISEASE; CIRCULATING MARKERS; SERUM-ALBUMIN; RISK-FACTORS; INFLAMMATION; ATHEROSCLEROSIS; MALNUTRITION AB C-reactive protein and albumin as predictors of all-cause and cardiovascular mortality in chronic kidney disease. Background. High C-reactive protein (CRP) and hypoalbuminemia are associated with increased risk of mortality in patients with kidney failure. There are limited data evaluating the relationships between CRP, albumin, and outcomes in chronic kidney disease (CKD) stages 3 and 4. Methods. The Modification of Diet in Renal Disease (MDRD) Study was a randomized controlled trial conducted between 1989 and 1993. CRP was measured in frozen samples taken at baseline. Survival status and cause of death, up to December 31, 2000, were obtained from the National Death Index. Multivariable Cox models were used to examine the relationship of CRP [stratified into high CRP >= 3.0 mg/L (N = 414) versus low CRP < 3.0 mg/L (N = 283)], and serum albumin, with all-cause and cardiovascular mortality. Results. Median follow-up time was 125 months, all-cause mortality was 20% (N = 138) and cardiovascular mortality was 10% (N = 71). In multivariable analyses adjusting for demographic, cardiovascular and kidney disease factors, both high CRP (HR, 95% CI = 1.56, 1.07-2.29) and serum albumin (HR = 0.94 per 0.1 g/dL increase, 95% CI = 0.89-0.99) were independent predictors of all-cause mortality. High CRP (HR 1.94, 95% CI 1.13-3.31), but not serum albumin (HR 0.94, 95% CI 0.87-1.02), was an independent predictor of cardiovascular mortality. Conclusion. Both high CRP and low albumin, measured in CKD stages 3 and 4, are independent risk factors for all-cause mortality. High CRP, but not serum albumin, is a risk factor for cardiovascular mortality. These results suggest that high CRP and hypoalbuminemia provide prognostic information independent of each other in CKD. C1 Tufts Univ New England Med Ctr, Dept Med, Div Nephrol, Boston, MA 02111 USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. NIH, Bethesda, MD 20892 USA. Hennepin Cty Med Ctr, Div Nephrol, Minneapolis, MN 55415 USA. RP Sarnak, MJ (reprint author), Tufts Univ New England Med Ctr, Dept Med, Div Nephrol, 750 Washington St,NEMC 391, Boston, MA 02111 USA. EM msarnak@tufts-nemc.org FU NIDDK NIH HHS [1 K23 DK02904, 1 K23 DK67303, UO1 DK 35073] NR 44 TC 177 Z9 189 U1 2 U2 9 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD AUG PY 2005 VL 68 IS 2 BP 766 EP 772 DI 10.1111/j.1523-1755.2005.00455.x PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 943GW UT WOS:000230342500035 PM 16014054 ER PT J AU Meyer, TW Walther, JL Pagtalunan, ME Martinez, AW Torkamani, A Fong, PD Recht, NS Robertson, CR Hostetter, TH AF Meyer, TW Walther, JL Pagtalunan, ME Martinez, AW Torkamani, A Fong, PD Recht, NS Robertson, CR Hostetter, TH TI The clearance of protein-bound solutes by hemofiltration and hemodiafiltration SO KIDNEY INTERNATIONAL LA English DT Article DE hemofiltration; hemodiafiltration; CVVH; protein binding ID ACUTE-RENAL-FAILURE; CONTINUOUS VENOVENOUS HEMOFILTRATION; ULTRAFILTRATION FLOW-RATES; RANDOMIZED CLINICAL-TRIAL; INTENSIVE-CARE-UNIT; REPLACEMENT THERAPY; UREMIC TOXINS; HEMODIALYSIS; MEMBRANE; DIALYSIS AB The clearance of protein-bound solutes by hemofiltration and hemodiafiltration. Background. Hemofiltration in the form of continuous venovenous hemofiltration (CVVH) is increasingly used to treat acute renal failure. Compared to hemodialysis, hemofiltration provides high clearances for large solutes but its effect on protein-bound solutes has been largely ignored. Methods. Standard clinical systems were used to remove test solutes from a reservoir containing artificial plasma. Clearances of the protein-bound solutes phenol red (C-PR) and indican (C-IN) were compared to clearances of urea (C-UREA) during hemofiltration and hemodiafiltration. A mathematical model was developed to predict clearances from values for plasma flow Q(p), dialysate flow Q(d), ultrafiltration rate Q(f), filter size and the extent of solute binding to albumin. Results. When hemofiltration was performed with Q(p) 150 mL/min and Q(f) 17 mL/min, clearance values were C-PR 1.0 +/- 0.1 mL/min; C-IN 3.7 +/- 0.5 mL/min; and C-UREA 14 +/- 1 mL/min. The clearance of the protein-bound solutes was approximately equal to the solute-free fraction multiplied by the ultrafiltration rate corrected for the effect of predilution. Addition of Q(d) 42 mL/min to provide HDF while Q(p) remained 150 mL/min resulted in proportional increases in the clearance of protein-bound solutes and urea. In contrast, the clearance of protein-bound solutes relative to urea increased when hemodiafiltration was performed using a larger filter and increasing Q(d) to 300 mL/min while Q(p) was lowered to 50 mL/min. The pattern of observed results was accurately predicted by mathematical modeling. Conclusion. In vitro measurements and mathematical modeling indicate that CVVH provides very limited clearance of protein-bound solutes. Continuous venous hemodiafiltration (CVVHDF) increases the clearance of protein-bound solutes relative to urea only when dialysate flow rate and filter size are increased above values now commonly employed. C1 VAHCS, Dept Med, Palo Alto, CA 94303 USA. Stanford Univ, Dept Med, Palo Alto, CA 94304 USA. Stanford Univ, Dept Chem Engn, Stanford, CA 94305 USA. Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. NIDDK, Bethesda, MD USA. RP Meyer, TW (reprint author), VAHCS, Dept Med, 3801 Miranda Ave, Palo Alto, CA 94303 USA. EM twmeyer@stanford.edu FU NIDDK NIH HHS [R01 DK52841] NR 37 TC 34 Z9 37 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD AUG PY 2005 VL 68 IS 2 BP 867 EP 877 DI 10.1111/j.1523-1755.2005.00469.x PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 943GW UT WOS:000230342500049 PM 16014068 ER PT J AU Agodoa, L Norris, K Pugsley, D AF Agodoa, L Norris, K Pugsley, D TI The disproportionate burden of kidney disease in those who can least afford it - Foreword SO KIDNEY INTERNATIONAL LA English DT Editorial Material ID HIV-ASSOCIATED NEPHROPATHY; STAGE RENAL-DISEASE; TYPE-2 DIABETES/; COCAINE USE; HYPERTENSION; IRBESARTAN; OUTCOMES; FAILURE; RISK C1 NIDDK, Off Minor Hlth Res Coordinat, NIH, Bethesda, MD 20892 USA. Univ Adelaide, Adelaide, SA, Australia. Charles R Drew Univ Med & Sci, Los Angeles, CA 90059 USA. RP Agodoa, L (reprint author), NIDDK, Off Minor Hlth Res Coordinat, NIH, Bethesda, MD 20892 USA. NR 19 TC 2 Z9 2 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD AUG PY 2005 VL 68 SU 97 BP S1 EP S3 DI 10.1111/j.1523-1755.2005.09700.x PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 950YU UT WOS:000230896100001 ER PT J AU Valencia, ME Weil, EJ Nelson, RG Esparza, J Schulz, LO Ravussin, E Bennett, PH AF Valencia, ME Weil, EJ Nelson, RG Esparza, J Schulz, LO Ravussin, E Bennett, PH TI Impact of lifestyle on prevalence of kidney disease in Pima Indians in Mexico and the United States SO KIDNEY INTERNATIONAL LA English DT Article DE Arizona Pima Indians; diabetic nephropathy; lifestyle; Mexican Pima Indians; type 2 diabetes mellitus ID DEPENDENT DIABETES-MELLITUS; URINARY ALBUMIN EXCRETION; STAGE RENAL-DISEASE; PROTEINURIA; MORTALITY; NIDDM; NEPHROPATHY; DETERMINANTS; OBESITY AB Pima Indians in the United States and Mexico share a common genetic background but have very different lifestyles. Comparisons were made of the frequency of obesity, diabetes, hypertension, and kidney disease in these geographically separated but susceptible populations. Mexican Pimas had higher levels of physical activity, less obesity, and a lower prevalence of diabetes than their US Pima counterparts. Mean blood pressure rose with worsening glucose tolerance, and the prevalence of elevated urinary albumin excretion was higher in patients with diabetes than in those without, regardless of whether they lived in I he United States or Mexico. These findings illustrate the importance of lifestyle in the development of diabetes and in the subsequent occurrence of diabetic kidney disease. C1 Ctr Invest Alimentac & Desarrollo, Hermosillo, Sonora, Mexico. NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. RP Valencia, ME (reprint author), Ctr Invest Alimentac & Desarrollo, Hermosillo, Sonora, Mexico. EM mauro@cascabel.ciad.mx RI Nelson, Robert/B-1470-2012 NR 29 TC 4 Z9 4 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD AUG PY 2005 VL 68 SU 97 BP S141 EP S144 DI 10.1111/j.1523-1755.2005.09724.x PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 950YU UT WOS:000230896100025 ER PT J AU Jin, B Alter, HJ Zhang, ZC Shih, JWK Esteban, JM Sun, T Yang, YS Qiu, Q Liu, XL Yao, L Wang, HD Cheng, LF AF Jin, B Alter, HJ Zhang, ZC Shih, JWK Esteban, JM Sun, T Yang, YS Qiu, Q Liu, XL Yao, L Wang, HD Cheng, LF TI Reversibility of experimental rabbit liver cirrhosis by portal collagenase administration SO LABORATORY INVESTIGATION LA English DT Article DE liver cirrhosis; experimental; therapeutics; collagenase; portal vein; rabbit; carbon tetrachloride ID CLOSTRIDIUM-HISTOLYTICUM; RAT-LIVER; MATRIX METALLOPROTEINASES; INDIVIDUAL COLLAGENASES; PEYRONIES DISEASE; CLASS-I; FIBROSIS; HYDROXYPROLINE; MECHANISMS; INHIBITORS AB The regression of cirrhosis is associated with increased intrahepatic collagenolytic enzyme activity. Weinvestigated whether collagenase supplementation via portal vein infusion can retard cirrhosis development and/or reverse cirrhosis. In all, 35 rabbits were initially assigned to study. However, because of high surgical mortality and infection, only 15 animals completed study. Four normal controls (group I) received olive oil subcutaneously (SC) for 12 weeks followed by normal saline portal perfusion for 12 weeks. Four (group II) received CCl4 SC for 6 weeks followed by portal vein collagenase, 6 mg twice weekly, plus SC CCl4 for 6 additional weeks and then killed. Four rabbits (group III) received CCl4 SC for 12 weeks and then 6 mg of collagenase portally for 12 weeks, while three control rabbits (group IV) received CCl4 for 12 weeks followed by saline for 12 weeks. After 12 weeks of CCl4, liver hydroxyproline content of collagenase-treated group II (361.1 +/- 106.6 mu g/g) was significantly reduced compared with group III+IV that had not yet received collagenase (589.0 +/- 162.9 mu g/g; P < 0.05). In the main comparison, hydroxyproline content of collagenase-treated group III (177.5 +/- 35.6 mu g/g) was significantly decreased compared with saline-treated controls (446.3 +/- 150.1 mu g/g; P < 0.01). Further, liver histology showed complete regression of cirrhosis in the collagenase-treated animals. No toxicity of liver, kidney, lung, brain or heart was observed histologically. Anaphylaxis occurred in 2/35 original animals (one fatal). In conclusion, this study provides 'proof of principle' that collagenase portal administration can retard cirrhosis development and speed regression of established cirrhosis in the rabbit CCl4 model. Potential application to humans is premature, but feasible, if these findings are confirmed in additional animal studies. C1 NIH, Infect Dis Sect, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Mil Med Grad Sch, Dept Digest Dis, Beijing, Peoples R China. Naval Gen Hosp, Beijing, Peoples R China. RP Jin, B (reprint author), NIH, Infect Dis Sect, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bldg 10,Rm 1C711, Bethesda, MD 20892 USA. EM bjin@cc.nih.gov; halter@cc.nih.gov NR 35 TC 11 Z9 16 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD AUG PY 2005 VL 85 IS 8 BP 992 EP 1002 DI 10.1038/labinvest.3700304 PG 11 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 947LI UT WOS:000230645800007 PM 15965490 ER PT J AU Hortin, GL AF Hortin, GL TI Does point-of-care testing save money or cost more? SO LABORATORY MEDICINE LA English DT Article ID GLUCOSE C1 NIH, Bethesda, MD 20892 USA. RP Hortin, GL (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 18 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0007-5027 J9 LAB MED JI Lab. Med. PD AUG PY 2005 VL 36 IS 8 BP 465 EP 467 DI 10.1309/AJ9DOGHYYWEDYHPD PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 949GA UT WOS:000230771900007 ER PT J AU Fibich, G Hammer, A Gannot, G Gandjbakhche, A Gannot, I AF Fibich, G Hammer, A Gannot, G Gandjbakhche, A Gannot, I TI Modeling and simulations of the pharmacokinetics of fluorophore conjugated antibodies in tumor vicinity for the optimization of fluorescence-based optical imaging SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE modeling; optical imaging; pharmacokinetics; diagnosis ID IN-VIVO; MARKERS AB Background and Objectives: One of the methods to detect and localize tumors in tissue is to use fluorophore conjugated specific antibodies as tumor surface markers. The goals of this study are to understand and quantify the pharmacokineties of fluorophore conjugated antibodies in the vicinity of a tumor. This study concludes another stage of the development of a non-invasive fluorescenated antibody-based technique for imaging and localization of tumors in vivo. Study Design/Materials and Methods: A mathematical model of the pharmacokineties of fluorophore conjugated antibodies in the vicinity of a tumor was developed based on histological staining experiments. We present the model equations of concentrations of antibodies and free binding sites. We also present a powerful simulation tool that we developed to simulate the imaging process. We analyzed the model and studied the effects of various independent parameters on the imaging result. These parameters included initial volume of markers (injected volume), total number of binding sites, tumor size, binding and dissociation rate constants, and the diffusion coefficient. We present the relations needed between these parameters in order to optimize the imaging results. Results and Conclusions: A powerful and accurate tool was developed which may assist in optimizing the imaging system results by setting the injection volume and concentration of fluorophore conjugated antibodies in tissue and approximating the time interval where maximum specific binding occurs and the tumor can be imaged. C1 NIH, Lab Integrat & Med Biophys, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Gaithersburg, MD 20877 USA. NCI, Urol Oncol Branch, NIH, Gaithersburg, MD 20877 USA. Tel Aviv Univ, Fac Engn, Dept Biomed Engn, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Fac Exact Sci, Dept Appl Math, IL-69978 Tel Aviv, Israel. RP Gannot, I (reprint author), NIH, Lab Integrat & Med Biophys, Bldg 10, Bethesda, MD 20892 USA. EM gannoti@mail.nih.gov RI Fibich, Gadi/A-4116-2008 NR 11 TC 6 Z9 7 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD AUG PY 2005 VL 37 IS 2 BP 155 EP 160 DI 10.1002/lsm.20200 PG 6 WC Dermatology; Surgery SC Dermatology; Surgery GA 961DT UT WOS:000231642800009 PM 16037970 ER PT J AU Thompson, RB Aviles, RJ Faranesh, AZ Raman, VK Wright, V Balaban, RS McVeigh, ER Lederman, RJ AF Thompson, RB Aviles, RJ Faranesh, AZ Raman, VK Wright, V Balaban, RS McVeigh, ER Lederman, RJ TI Measurement of skeletal muscle perfusion during postischemic reactive hyperemia using contrast-enhanced MRI with a step-input function SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE blood flow; peripheral artery disease; claudication; angiogenesis; MRI ID VENOUS OCCLUSION PLETHYSMOGRAPHY; WATER-EXCHANGE; BLOOD-FLOW; IN-VIVO; VOLUME FRACTION; EXERCISE; TISSUE; QUANTIFICATION; ISCHEMIA; PERMEABILITY AB The regional distribution of skeletal muscle blood flow was measured during postischemic reactive hyperemia using GdDTPA contrast-enhanced (CE) MRI. The release of an occlusive thigh cuff was used to deliver a step-input of contrast concentration that was coincident with the onset of reactive hyperemia. A first-order tracer kinetic equation was used to estimate the unidirectional influx constant, K-i, (ml/100 g/min), and the distribution volume of Gd-DTPA in the tissue, v(e), from T-1-weighted images acquired with saturation recovery (SR) steady-state free precession (SSFP) and spoiled gradient-echo (SPGR) protocols. The capillary permeability surface [PS) area increased significantly during reactive hyperemia, which facilitated rapid extraction of Gd-DTPA during the first pass. Regional muscle group studies from 11 normal volunteers yielded blood flow (K-i) values of 108.3 +/- 34.1 ml/100 g/min in the gastrocnemius, 184.3 +/- 41.3 ml/100 g/min in the soleus, and 122.4 +/- 34.4 ml/100 g/min in the tibialis anterior. The distribution volumes (Ve) in the corresponding muscle groups were respectively 8.3% +/- 2.1%,9.3% +/- 1.9%, and 7.9% +/- 1.8% from the kinetic model, and 8.8% +/- 2.4%, 9.1 % +/- 1.9%, and 7.2% +/- 1.4% from tissue relaxometry studies. Bulk blood flow studies in the same volunteers using phase-contrast velocimetry (popliteal artery) yielded significantly lower flow values, but with a correlation coefficient R-2 = 0.62 and P = 0.004. C1 Univ Alberta, Dept Biomed Engn, Edmonton, AB T6G 2V2, Canada. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD USA. RP Thompson, RB (reprint author), Univ Alberta, Dept Biomed Engn, Room 1098 RFF, Edmonton, AB T6G 2V2, Canada. EM richard.thompson@ualberta.ca RI Thompson, Richard/E-9821-2011; Balaban, Robert/A-7459-2009; OI Balaban, Robert/0000-0003-4086-0948; lederman, robert/0000-0003-1202-6673 FU Intramural NIH HHS [Z01 HL004608-08] NR 40 TC 33 Z9 33 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD AUG PY 2005 VL 54 IS 2 BP 289 EP 298 DI 10.1002/mrm.20535 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 949DS UT WOS:000230765700006 PM 16032661 ER PT J AU Ikonomidou, VN van Gelderen, P de Zwart, JA Fukunaga, M Duyn, JH AF Ikonomidou, VN van Gelderen, P de Zwart, JA Fukunaga, M Duyn, JH TI Optimizing brain tissue contrast with EPI: A simulated annealing approach SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE brain tissue labeling; T-1; weighting; optimization (simulated annealing); functional mapping; double inversion recovery ID RELAXATION-TIMES; MR-IMAGES; 3.0 TESLA; OPTIMIZATION; SEGMENTATION; SPECTROSCOPY; SEQUENCES; MATTER; PULSES; CORTEX AB A new magnetization preparation and image acquisition scheme was developed to obtain high-resolution brain images with optimal tissue contrast. The pulse sequence was derived from an optimization process using simulated annealing, without prior assumptions with regard to the number of radiofrequency (RF) pulses and flip angles. The resulting scheme combined two inversion pulses with the acquisition of three images with varying contrast. The combination of the three images allowed separation of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) based on T-1 contrast. It also enabled the correction of small errors in the initial T, estimates in post-processing. The use of three-dimensional (313) sensitivity-encoded (SENSE) echo-planar imaging (EPI) for image acquisition made it possible to achieve a 1.15(3) mm(3) isotropic resolution within a scan time of 10 min 21 s. The cortical GM signal-to-noise ratio (SNR) in the calculated GIVI-only image varied between 30 and 100. The novel technique was evaluated in combination with blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRl) on human subjects, and provided for excellent coregistration of anatomical and functional data. C1 NINDS, Adv MRI Sect, LFMI, NIH, Bethesda, MD 20892 USA. RP Ikonomidou, VN (reprint author), NINDS, Adv MRI Sect, LFMI, NIH, Bldg 10,Rm B1D-722,MSC 1065,9000 Rockville Pike, Bethesda, MD 20892 USA. EM viko@nih.gov RI Duyn, Jozef/F-2483-2010; Fukunaga, Masaki/F-6441-2013 OI Fukunaga, Masaki/0000-0003-1010-2644 NR 33 TC 10 Z9 10 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD AUG PY 2005 VL 54 IS 2 BP 373 EP 385 DI 10.1002/mrm.20561 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 949DS UT WOS:000230765700015 PM 16032676 ER PT J AU Brinkmeyer-Langford, C Raudsepp, T Lee, EJ Goh, G Schaffer, AA Agarwala, R Wagner, ML Tozaki, T Skow, LC Womack, JE Mickelson, JR Chowdhary, BP AF Brinkmeyer-Langford, C Raudsepp, T Lee, EJ Goh, G Schaffer, AA Agarwala, R Wagner, ML Tozaki, T Skow, LC Womack, JE Mickelson, JR Chowdhary, BP TI A high-resolution physical map of equine homologs of HSA19 shows divergent evolution compared with other mammals SO MAMMALIAN GENOME LA English DT Article ID RADIATION HYBRID MAP; ZOO-FISH ANALYSIS; HORSE EQUUS-CABALLUS; CONSERVED CHROMOSOMAL SEGMENTS; GENE-MAPPING WORKSHOP; GENOME ORGANIZATION; MICROSATELLITE LOCI; LINKAGE MAP; PHYLOGENETIC-RELATIONSHIPS; CYTOGENETIC LOCALIZATION AB A high-resolution (1 marker/700 kb) physically ordered radiation hybrid (RH) and comparative map of 122 loci on equine homologs of human Chromosome 19 (HSA19) shows a variant evolution of these segments in equids/Perissodactyls compared with other mammals. The segments include parts of both the long and the short arm of horse Chromosome 7 (ECA7), the proximal part of ECA21, and the entire short arm of ECA10. The map includes 93 new markers, of which 89 (64 gene-specific and 25 microsatellite) were genotyped on a 5000-rad horse x hamster RH panel, and 4 were mapped exclusively by FISH. The orientation and alignment of the map was strengthened by 21 new FISH localizations, of which 15 represent genes. The approximately sevenfold-improved map resolution attained in this study will prove extremely useful for candidate gene discovery in the targeted equine chromosomal regions. The highlight of the comparative map is the fine definition of homology between the four equine chromosomal segments and corresponding HSA19 regions specified by physical coordinates (bp) in the human genome sequence. Of particular interest are the regions on ECA7 and ECA21 that correspond to the short arm of HSA19-a genomic rearrangement discovered to date only in equids/Perissodactyls as evidenced through comparative Zoo-FISH analysis of the evolution ofancestral HSA19 segments in eight mammalian orders involving about 50 species. C1 Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, US Dept HHS, NIH, Bethesda, MD 20894 USA. Univ Minnesota, Dept Vet Biosci, St Paul, MN 55108 USA. Lab Racing Chem, Mol Genet Sect, Utsunomiya, Tochigi 3200851, Japan. Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Pathobiol, College Stn, TX 77843 USA. Texas A&M Univ, Coll Agr & Life Sci, Dept Anim Sci, College Stn, TX 77843 USA. RP Chowdhary, BP (reprint author), Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. EM bchowdhary@cvm.tamu.edu RI Schaffer, Alejandro/F-2902-2012 NR 92 TC 20 Z9 21 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD AUG PY 2005 VL 16 IS 8 BP 631 EP 649 DI 10.1007/s00335-005-0023-1 PG 19 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 963WR UT WOS:000231837400009 PM 16180145 ER PT J AU Aumailley, M Bruckner-Tuderman, L Carter, WG Deutzmann, R Edgar, D Ekblom, P Engel, J Engvall, E Hohenester, E Jones, JCR Kleinman, HK Marinkovich, MP Martin, GR Mayer, U Meneguzzi, G Miner, JH Miyazaki, K Patarroyo, M Paulsson, M Quaranta, V Sanes, JR Sasaki, T Sekiguchi, K Sorokin, LM Talts, JF Tryggvason, K Uitto, J Virtanen, I von der Mark, K Wewer, UM Yamada, Y Yurchenco, PD AF Aumailley, M Bruckner-Tuderman, L Carter, WG Deutzmann, R Edgar, D Ekblom, P Engel, J Engvall, E Hohenester, E Jones, JCR Kleinman, HK Marinkovich, MP Martin, GR Mayer, U Meneguzzi, G Miner, JH Miyazaki, K Patarroyo, M Paulsson, M Quaranta, V Sanes, JR Sasaki, T Sekiguchi, K Sorokin, LM Talts, JF Tryggvason, K Uitto, J Virtanen, I von der Mark, K Wewer, UM Yamada, Y Yurchenco, PD TI A simplified laminin nomenclature SO MATRIX BIOLOGY LA English DT Review DE basement membrane; laminin; laminin-type domains; nomenclature ID GLYCOPROTEIN AB A simplification of the laminin nomenclature is presented. Laminins are multidomain heterotrimers composed of alpha, beta and gamma chains. Previously, laminin trimers were numbered with Arabic numerals in the order discovered, that is laminins-1 to -5. We introduce a new identification system for a trimer using three Arabic numerals, based on the alpha, beta and gamma chain numbers. For example, the laminin with the chain composition alpha 5 beta 1 gamma 1 is termed laminin-511, and not laminin-10. The current practice is also to mix two overlapping domain and module nomenclatures. Instead of the older Roman numeral nomenclature and mixed nomenclature, all modules are now called domains. Some domains are renamed or renumbered. Laminin epidermal growth factor-like (LE) domains are renumbered starting at the N-termini, to be consistent with general protein nomenclature. Domain IVb of alpha chains is named laminin 4a (L4a), domain IVa of alpha chains is named L4b, domain IV of gamma chains is named L4, and domain IV of beta chains is named laminin four (LF). The two coiled-coil domains I and II are now considered one laminin coiled-coil domain (LCC). The interruption in the coiled-coil of 13 chains is named laminin beta-knob (L beta) domain. The chain origin of a domain is specified by the chain nomenclature, such as alpha IL4a. The abbreviation LM is suggested for laminin. Otherwise, the nomenclature remains unaltered. (C) 2005 Elsevier B.V./Intemational Society of Matrix Biology. All rights reserved. C1 Lund Univ, Dept Expt Med Sci, Lund, Sweden. Univ Cologne, Fac Med, Ctr Biochem, Cologne, Germany. Univ Freiburg, Dept Dermatol, D-7800 Freiburg, Germany. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Regensburg, Dept Biochem Microbiol & Genet, D-8400 Regensburg, Germany. Univ Liverpool, Dept Anat, Liverpool L69 3BX, Merseyside, England. Univ Basel, Biozentrum, Basel, Switzerland. Burnham Inst, La Jolla, CA 92037 USA. Univ London Imperial Coll Sci & Technol, Dept Biol Sci, London, England. Northwestern Univ, Dept Cell & Mol Biol, Chicago, IL 60611 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. Stanford Univ, Sch Med, VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA. Stanford Univ, Sch Med, Program Epithelial Biol, Palo Alto, CA 94304 USA. Univ Manchester, Wellcome Trust Ctr Cell Matrix Res, Manchester, Lancs, England. Univ Nice, Sch Med, INSERM, U634, Nice, France. Washington Univ, Sch Med, Div Renal, St Louis, MO 63110 USA. Yokohama City Univ, Kihara Inst Biol Res, Yokohama, Kanagawa 232, Japan. Karolinska Inst, Dept Odontol, Stockholm, Sweden. Vanderbilt Univ, Dept Canc Biol, Nashville, TN USA. Harvard Univ, Ctr Brain Sci, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. Max Planck Inst Biochem, D-82152 Martinsried, Germany. Osaka Univ, Inst Prot Res, Osaka, Japan. Lund Univ, Dept Expt Pathol, Lund, Sweden. Royal Vet & Agr Univ, Dept Anim & Vet Basic Sci, Frederiksberg, Denmark. Karolinska Inst, Dept Biochem & Biophys, Stockholm, Sweden. Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. Univ Helsinki, Dept Anat, FIN-00014 Helsinki, Finland. Univ Erlangen Nurnberg, Dept Expt Med 1, Erlangen, Germany. Univ Copenhagen, Inst Mol Pathol, Copenhagen, Denmark. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pathol, Piscataway, NJ 08854 USA. RP Ekblom, P (reprint author), Lund Univ, Dept Expt Med Sci, Lund, Sweden. EM Peter.Ekblom@med.lu.se RI Quaranta, Vito/G-6512-2016; OI Quaranta, Vito/0000-0001-7491-8672; Meneguzzi, Guerrino/0000-0002-1609-6540 FU NIDDK NIH HHS [R37 DK036425]; Wellcome Trust [054334] NR 10 TC 447 Z9 457 U1 1 U2 29 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0945-053X J9 MATRIX BIOL JI Matrix Biol. PD AUG PY 2005 VL 24 IS 5 BP 326 EP 332 DI 10.1016/j.matbio.2005.05.006 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 955DL UT WOS:000231205300002 PM 15979864 ER PT J AU Zerhouni, EA AF Zerhouni, EA TI Fasten your seat belts SO MAYO CLINIC PROCEEDINGS LA English DT Editorial Material C1 NIH, Off Director, Bethesda, MD 20817 USA. RP Zerhouni, EA (reprint author), NIH, Off Director, Bldg 1 Shannon Bldg,Room 126,1 Ctr Dr, Bethesda, MD 20817 USA. EM execsec1@od.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU MAYO CLINIC PROCEEDINGS PI ROCHESTER PA 660 SIEBENS BLDG MAYO CLINIC, ROCHESTER, MN 55905 USA SN 0025-6196 J9 MAYO CLIN PROC JI Mayo Clin. Proc. PD AUG PY 2005 VL 80 IS 8 BP 1058 EP 1060 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 952BZ UT WOS:000230978100012 PM 16092585 ER PT J AU Berger, VW AF Berger, VW TI Allocation concealment and blinding: when ignorance is bliss SO MEDICAL JOURNAL OF AUSTRALIA LA English DT Letter C1 Univ Maryland Baltimore Cty, NCI, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), Univ Maryland Baltimore Cty, NCI, 6130 Execut Blvd,MSC 7354, Bethesda, MD 20892 USA. EM Vb78c@nih.gov NR 5 TC 10 Z9 10 U1 1 U2 3 PU AUSTRALASIAN MED PUBL CO LTD PI PYRMONT PA LEVEL 2, 26-32 PYRMONT BRIDGE RD, PYRMONT, NSW 2009, AUSTRALIA SN 0025-729X J9 MED J AUSTRALIA JI Med. J. Aust. PD AUG 1 PY 2005 VL 183 IS 3 BP 165 EP 165 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 961GB UT WOS:000231648800025 PM 16053426 ER PT J AU Banovac, F Tang, J Xu, S Lindisch, D Chung, HY Levy, EB Chang, T McCullough, MF Yaniv, Z Wood, BJ Cleary, K AF Banovac, F Tang, J Xu, S Lindisch, D Chung, HY Levy, EB Chang, T McCullough, MF Yaniv, Z Wood, BJ Cleary, K TI Precision targeting of liver lesions using a novel electromagnetic navigation device in physiologic phantom and swine SO MEDICAL PHYSICS LA English DT Article DE electromagnetic navigation; instrument tracking; radiofrequency ablation; liver tumor ID RADIOFREQUENCY THERMAL ABLATION; HEPATIC METASTASES; NEEDLE-ASPIRATION; CT; TUMORS; LOCALIZATION; PLACEMENT AB Radiofrequency ablation of primary and metastatic liver tumors is becoming a potential alternative to surgical resection. We propose a novel system that uses real-time electromagnetic position sensing of the needle tip to help with precision guidance into a liver tumor. The purpose of this study was to evaluate this technology in phantom and animal models. Using an electromagnetic navigation device, instrumented 18 g needles were advanced into radioopaque tumor targets in a respiratory liver phantom. The phantom featured a moving liver target that-simulated cranio-caudal liver motion due to respiration. Skin-to-target path planning and real-time needle guidance were provided by a custom-designed software interface based on pre-operative 1 mm CT data slices. Needle probes were advanced using only the electromagnetic navigation device and software display. No conventional real-time imaging was used to assist in advancing the needle to the target. Two experienced operators (interventional radiologists) and two inexperienced ones (residents) used the system. The same protocol was then also used in two anesthetized 45 kg Yorkshire swine where radioopaque agar nodules were injected into the liver to serve as targets. A total of 76 tumor targeting attempts were performed in the liver phantom, and 32 attempts were done in the swine. The average time for path planning was 30 s in the phantom, and 63 s in the swine. The median time for the actual needle puncture to reach the desired target was 33 s in the phantom, and 42 s in the swine. The average registration error between the CT coordinate system and electromagnetic coordinate system was 1.4 mm (SD 0.3 mm) in the phantom, and 1.9 mm (SD 0.4 mm) in the swine. The median distance from the final needle tip position to the center of the tumor was 6.4 mm (SD 3.3 mm, n=76) in the phantom, and 8.3 mm (SD 3.7 mm, n=32) in the swine. There was no statistical difference in the planning time, procedure time, or accuracy of needle placement between experienced and inexperienced operators. The novel electromagnetic navigation system allows probe de delivery into hepatic tumors of a physiologic phantom and live anesthetized swine. The system allows less experienced operators to perform equally well as experienced radiologists in terms of procedure time and accuracy of needle probe delivery. (c) 2005 American Association of Physicists s in Medicine. C1 Georgetown Univ, Dept Radiol, Imaging Sci & Informat Syst Ctr, Washington, DC 20007 USA. Johns Hopkins Univ, Ctr Comp Integrat Surg Syst & Technol, Baltimore, MD 21211 USA. Georgetown Univ Hosp, Washington, DC 20007 USA. NIH, Special Procedures DRD, Bethesda, MD 20892 USA. RP Georgetown Univ, Dept Radiol, Imaging Sci & Informat Syst Ctr, Washington, DC 20007 USA. EM banovac@isis.imac.georgetown.edu RI Yaniv, Ziv/Q-1177-2015 OI Yaniv, Ziv/0000-0003-0315-7727 NR 22 TC 60 Z9 62 U1 0 U2 6 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 EI 2473-4209 J9 MED PHYS JI Med. Phys. PD AUG PY 2005 VL 32 IS 8 BP 2698 EP 2705 DI 10.1118/1.1992267 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 958VM UT WOS:000231476300031 PM 16193801 ER PT J AU Huang, JB Espinoza, J Romero, R Petty, HR AF Huang, JB Espinoza, J Romero, R Petty, HR TI Transaldolase is part of a supramolecular complex containing glucose-6-phosphate dehydrogenase in human neutrophils that undergoes retrograde trafficking during pregnancy SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID RAT PERITONEAL-MACROPHAGES; PENTOSE-PHOSPHATE PATHWAY; HEXOKINASE TRANSLOCATION; SUPEROXIDE PRODUCTION; GLYCOLYTIC-ENZYMES; LIVING CELLS; METABOLISM; PHAGOCYTOSIS; PROXIMITY; INFECTION AB Previous studies have shown that glucose-6-phosphate dehydrogenase (G6PDase) and 6-phosphogluconate dehydrogenase form a supramolecular complex in human neutrophils that undergoes retrograde trafficking in cells from pregnant women, but anterograde trafficking in cells from nonpregnant individuals. Using fluorescence resonance energy transfer techniques, we now demonstrate that transaldolase (TALase), a key regulatory enzyme in the nonoxidative branch of the hexose monophosphate shunt, is in close physical proximity with G6PDase, but not with lactate dehydrogenase, thus suggesting the formation of a TALase-G6PDase complex. Moreover, immunofluorescence microscopy demonstrated that TALase undergoes anterograde trafficking in neutrophils from nonpregnant individuals, whereas retrograde trafficking is found during pregnancy. However, pregnancy did not affect lactate dehydrogenase distribution. Colchicine treatment blocked the retrograde distribution of TALase, suggesting that microtubules are involved in TALase trafficking. We suggest that TALase is part of a supramolecular hexose monophosphate shunt complex, which likely increases the efficiency of the shunt via substrate channeling. We further suggest that TALase's retrograde motion contributes to uncoupling the shunt from its source of glucose-6-phosphate at the plasma membrane, thereby blunting nicotinamide adenine dinucleotide phosphate (reduced form) production and downstream oxidant production by neutrophils. C1 Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. NICHHD, Perinatol Res Branch, Bethesda, MD 20892 USA. Hutzel Hosp, Detroit, MI 48201 USA. RP Petty, HR (reprint author), Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. EM hpetty@umich.edu FU Intramural NIH HHS NR 35 TC 10 Z9 10 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD AUG PY 2005 VL 54 IS 8 BP 1027 EP 1033 DI 10.1016/j.metabol.2005.03.005 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 955TU UT WOS:000231251300008 PM 16092052 ER PT J AU Sacci, JB Ribeiro, JMC Huang, FY Alam, U Russell, JA Blair, PL Witney, A Carucci, DJ Azad, AF Aguiar, JC AF Sacci, JB Ribeiro, JMC Huang, FY Alam, U Russell, JA Blair, PL Witney, A Carucci, DJ Azad, AF Aguiar, JC TI Transcriptional analysis of in vivo Plasmodium yoelii liver stage gene expression SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE liver stage; Plasmodium yoelii; in vivo; cDNA library ID LIFE-CYCLE; MALARIA ANTIGENS; GENOME SEQUENCE; SURFACE-ANTIGEN; FALCIPARUM; SPOROZOITE; PROTEIN; DATABASE; IDENTIFICATION; HEPATOCYTES AB The transcriptional repertoire of the in vivo liver stage of Plasmodium has remained largely unidentified and seemingly not amenable to traditional molecular analysis because of the small number of parasites and large number of uninfected hepatocytes. We have overcome this obstruction by utilizing laser capture microdissection to provide a high quality source of parasite mRNA for the construction of a liver stage cDNA library. Sequencing and annotation of this library demonstrated expression of 623 different Plasmodium yoelii genes during development in the hepatocyte. Of these genes, 25% appear to be unique to the liver stage. This is the first comprehensive analysis of in vivo gene expression undertaken for the liver stage of P. yoelii, and provides insights into the differential expression of P. yoelii genes during this critical stage of development. (c) 2005 Elsevier B.V. All rights reserved. C1 Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. NIH, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. USN, Med Res Ctr, Malaria Program, Silver Spring, MD 20910 USA. Univ London St Georges Hosp, Sch Med, Dept Cellular & Mol Med, London SW17 0RE, England. RP Sacci, JB (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, 655 W Baltimore St, Baltimore, MD 21201 USA. EM jsacc001@umaryland.edu OI Witney, Adam/0000-0003-4561-7170; Ribeiro, Jose/0000-0002-9107-0818 FU PHS HHS [R01 A1 47445] NR 31 TC 33 Z9 33 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD AUG PY 2005 VL 142 IS 2 BP 177 EP 183 DI 10.1016/j.molbiopara.2005.03.018 PG 7 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 947ZY UT WOS:000230687000005 PM 15876462 ER PT J AU Lynch, M Chen, L Ravitz, MJ Mehtani, S Korenblat, K Pazin, MJ Schmidt, EV AF Lynch, M Chen, L Ravitz, MJ Mehtani, S Korenblat, K Pazin, MJ Schmidt, EV TI hnRNP K binds a core polypyrimidine element in the eukaryotic translation initiation factor 4E (eIF4E) promoter, and its regulation of eIF4E contributes to neoplastic transformation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Review ID HUMAN C-MYC; NUCLEAR RIBONUCLEOPROTEIN-K; SINGLE-STRANDED-DNA; TATA-LESS PROMOTERS; MESSENGER-RNA; TRANSCRIPTION INITIATION; PROTEIN-SYNTHESIS; GENE-EXPRESSION; FACTOR EIF-4E; HELA-CELLS AB Translation initiation factor eukaryotic translation initiation factor 4E (eIF4E) plays a key role in regulation of cellular proliferation. Its effects on the m(7) GpppN mRNA cap are critical because overexpression of eIF4E transforms cells, and eIF4E function is rate-limiting for G, passage. Although we identified eIF4E as a c-Myc target, little else is known about its transcriptional regulation. Previously, we described an element at position -25 (TTACCCCCCCTT) that was critical for eIF4E promoter function. Here we report that this sequence (named 4EBE, for eIF4E basal element) functions as a basal promoter element that binds hnRNP K. The 4EBE is sufficient to replace TATA sequences in a heterologous reporter construct. Interactions between 4EBE and upstream activator sites are position, distance, and sequence dependent. Using DNA affinity chromatography, we identified hnRNP K as a 4EBE-binding protein. Chromatin immunoprecipitation, siRNA interference, and hnRNP K overexpression demonstrate that hnRNP K can regulate eIF4E mRNA. Moreover, hnRNP K increased translation initiation, increased cell division, and promoted neoplastic transformation in an eIF4E-dependent manner. hnRNP K binds the TATA-binding protein, explaining how the 4EBE might replace TATA in the eIF4E promoter. hnRNP K is an unusually diverse regulator of multiple steps in growth regulation because it also directly regulates c-myc transcription, mRNA export, splicing, and translation initiation. C1 Massachusetts Gen Hosp, Canc Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Washington Univ, Sch Med, Div Gastroenterol, St Louis, MO 63110 USA. NIA, NIH, LCMB, Baltimore, MD 21224 USA. Harvard Univ, Sch Med, Dept Pediat, MassGen Hosp Children, Boston, MA 02114 USA. RP Schmidt, EV (reprint author), Massachusetts Gen Hosp, Canc Res Ctr, 55 Fruit St, Boston, MA 02114 USA. EM Schmidt@helix.mgh.harvard.edu OI Pazin, Michael/0000-0002-7561-3640 FU NCI NIH HHS [5T32 CA009216-24, R01 CA063117, R01-CA63117, T32 CA009216]; NIDDK NIH HHS [T32 DK007191] NR 108 TC 72 Z9 79 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2005 VL 25 IS 15 BP 6436 EP 6453 DI 10.1128/MCB.25.15.6436-6453.2005 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 947YY UT WOS:000230684400013 PM 16024782 ER PT J AU Pedeux, R Sengupta, S Shen, JC Demidov, ON Saito, S Onogi, H Kumamoto, K Wincovitch, S Garfield, SH McMenamin, M Nagashima, M Grossman, SR Appella, E Harris, CC AF Pedeux, R Sengupta, S Shen, JC Demidov, ON Saito, S Onogi, H Kumamoto, K Wincovitch, S Garfield, SH McMenamin, M Nagashima, M Grossman, SR Appella, E Harris, CC TI ING2 regulates the onset of replicative senescence by induction of p300-dependent p53 acetylation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CANDIDATE TUMOR-SUPPRESSOR; HUMAN-DIPLOID FIBROBLASTS; DNA-DAMAGE; HUMAN-CELLS; HISTONE ACETYLATION; CELLULAR SENESCENCE; ONCOGENIC RAS; PHD-FINGER; LIFE-SPAN; POSTTRANSLATIONAL MODIFICATIONS AB ING2 is a candidate tumor suppressor gene that can activate p53 by enhancing its acetylation. Here, we demonstrate that ING2 is also involved in p53-mediated replicative senescence. ING2 protein expression increased in late-passage human primary cells, and it colocalizes with serine 15-phosphorylated p53. ING2 and p53 also complexed with the histone acetyltransferase p300. ING2 enhanced the interaction between p53 and p300 and acted as a cofactor for p300-mediated p53 acetylation. The level of ING2 expression directly modulated the onset of replicative senescence. While overexpression of ING2 induced senescence in young fibroblasts in a p53-dependent manner, expression of ING2 small interfering RNA delayed the onset of senescence. Hence, ING2 can act as a cofactor of p300 for p53 acetylation and thereby plays a positive regulatory role during p53-mediated replicative senescence. C1 NCI, Human Carcinogenesis Lab, CCR, NIH, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Toho Univ, Sakura Hosp, Dept Surg, Sakura, Japan. Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01605 USA. Natl Inst Immunol, New Delhi 110067, India. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, CCR, NIH, 37 Convent Dr,Bldg 37,Room 3068, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov OI Sengupta, Sagar/0000-0002-6365-1770; Demidov, Oleg/0000-0003-4323-7174 FU NCI NIH HHS [R01 CA107532, R01 CA107532-02] NR 54 TC 82 Z9 83 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2005 VL 25 IS 15 BP 6639 EP 6648 DI 10.1128/MCB.25.15.6639-6648.2005 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 947YY UT WOS:000230684400030 PM 16024799 ER PT J AU Campaner, S Kaldis, P Izraeli, S Kirsch, IR AF Campaner, S Kaldis, P Izraeli, S Kirsch, IR TI Sil phosphorylation in a Pin1 binding domain affects the duration of the spindle checkpoint SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; CELL-CYCLE; ANAPHASE INITIATION; MAMMALIAN-CELLS; KINASE-ACTIVITY; P34CDC2 KINASE; BUDDING YEAST; PROTEIN MAD2; MITOSIS; GENE AB SIL is an immediate-early gene that is essential for embryonic development and is implicated in T-cell leukemia-associated translocations. We now show that the Sil protein is hyperphosphorylated during mitosis or in cells blocked at prometaphase by microtubule inhibitors. Cell cycle-dependent phosphorylation of Sil is required for its interaction with Pin1, a regulator of mitosis. Point mutation of the seven (S/T)P sites between amino acids 567 and 760 reduces mitotic phosphorylation of Sil, Pin1 binding, and spindle checkpoint duration. When a phosphorylation site mutant Sil is stably expressed, the duration of the spindle checkpoint is shortened in cells challenged with taxol or nocodazole, and the cells revert to a G(2)-like state. This event is associated with the downregulation of the kinase activity of the Cdc2/cyclin B1 complex and the dephosphorylation of the threonine 161 on the Cdc2 subunit. Sil downregulation by plasmid-mediated RNA interference limited the ability of cells to activate the spindle checkpoint and correlated with a reduction of Cdc2/cyclin B1 activity and phosphorylation on T161 on the Cdc2 subunit. These data suggest that a critical region of Sil is required to mediate the presentation of Cdc2 activity during spindle checkpoint arrest. C1 NCI, Ctr Canc Res, Genet Branch, Bethesda, MD 20892 USA. NCI, CCR, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Kirsch, IR (reprint author), Amgen Inc, Res Oncol, 1201 Amgen Court W,AW1-J4144, Seattle, WA 98119 USA. EM lkirsch@amgen.com RI Kaldis, Philipp/G-2714-2010 OI Kaldis, Philipp/0000-0002-7247-7591 NR 42 TC 26 Z9 30 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2005 VL 25 IS 15 BP 6660 EP 6672 DI 10.1128/MCB.25.15.6660-6672.2005 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 947YY UT WOS:000230684400032 PM 16024801 ER PT J AU Basile, JR Afkhami, T Gutkind, JS AF Basile, JR Afkhami, T Gutkind, JS TI Semaphorin 4D/Plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; NUCLEOTIDE EXCHANGE FACTORS; FOCAL ADHESION KINASE; TYROSINE KINASE; AXON GUIDANCE; PDZ-RHOGEF; PLEXIN-B; RECEPTOR PLEXIN-B1; INVASIVE GROWTH; ACTIVE RAC AB Semaphorins are cell surface and secreted proteins that provide axonal guidance in neuronal tissues and regulate cell motility in many cell types. They act by binding a family of transmembrane receptors known as plexins, which belong to the c-Met family of scatter factor receptors but lack an intrinsic tyrosine kinase domain. Interestingly, we have recently shown that Plexin-B1 is highly expressed in endothelial cells and that its activation by Semaphorin 4D elicits a potent proangiogenic response (J. R. Basile, A. Barac, T. Zhu, K. L. Guan, and J. S. Gutkind, Cancer Res. 64:5212-5224, 2004). In searches for the underlying molecular mechanism, we observed that Semaphorin 4D-stimulated endothelial cell migration requires the activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Surprisingly, we found that Plexin-B1 stimulates PI3K-Akt through the activation of an intracellular tyrosine kinase cascade that involves the sequential activation of PYK2 and Src. This results in the tyrosine phosphorylation of Plexin-B1, the rapid recruitment of a multimeric signaling complex that includes PYK2, Src, and PI3K to Plexin-B1 and the activation of Akt. These findings suggest that Plexin-B1 may achieve its numerous physiological functions through the direct activation of intracellular tyrosine kinase cascades. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Dent, Baltimore, MD 21201 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Rm 211, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009 NR 64 TC 93 Z9 103 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2005 VL 25 IS 16 BP 6889 EP 6898 DI 10.1128/MCB.25.16.6889-6898.2005 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 952JW UT WOS:000231000800004 PM 16055703 ER PT J AU Dietrich, A Schnitzler, MMY Gollasch, M Gross, V Storch, U Dubrovska, G Obst, M Yildirim, E Salanova, B Kalwa, H Essin, K Pinkenburg, O Luft, FC Gudermann, T Birnbaumer, L AF Dietrich, A Schnitzler, MMY Gollasch, M Gross, V Storch, U Dubrovska, G Obst, M Yildirim, E Salanova, B Kalwa, H Essin, K Pinkenburg, O Luft, FC Gudermann, T Birnbaumer, L TI Increased vascular smooth muscle contractility in TRPC6(-/-) mice SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RECEPTOR POTENTIAL CHANNELS; CA2+-PERMEABLE CATION CHANNEL; CAPACITATIVE CA2+ ENTRY; TRANSIENT RECEPTOR; TRP CHANNELS; G-PROTEIN; CELLS; EXPRESSION; HOMOLOG; FAMILY AB Among the TRPC subfamily of TRP (classical transient receptor potential) channels, TRPC3, -6, and -7 are gated by signal transduction pathways that activate C-type phospholipases as well as by direct exposure to diacylglycerols. Since TRPC6 is highly expressed in pulmonary and vascular smooth muscle cells, it represents a likely molecular candidate for receptor-operated cation entry. To define the physiological role of TR-PC6, we have developed a TRPC6-deficient mouse model. These mice showed an elevated blood pressure and enhanced agonist-induced contractility of isolated aortic rings as well as cerebral arteries. Smooth muscle cells of TRPC6-deficient mice have higher basal cation entry, increased TRPC-carried cation currents, and more depolarized membrane potentials. This higher basal cation entry, however, was completely abolished by the expression of a TRPC3-specific small interference RNA in primary TPPC6(-/-) smooth muscle cells. Along these lines, the expression of TRPC3 in wild-type cells resulted in increased basal activity, while TRPC6 expression in TRPC6(-/-) smooth muscle cells reduced basal cation influx. These findings imply that constitutively active TRPC3-type channels, which are up-regulated in TRPC6-deficient smooth muscle cells, are not able to functionally replace TRPC6. Thus, TRPC6 has distinct nonredundant roles in the control of vascular smooth muscle tone. C1 Univ Marburg, Inst Pharmakol & Toxikol, D-35043 Marburg, Germany. HELIOS Klinikum Berlin, Max Delbruck Ctr Mol Med, Charite, Med Fak,Franz Volhard Klin, Berlin, Germany. NIEHS, Res Triangle Pk, NC 27709 USA. RP Gudermann, T (reprint author), Univ Marburg, Inst Pharmakol & Toxikol, Karl von Frisch Str 1, D-35043 Marburg, Germany. EM guderman@staff.uni-marburg.de RI Dietrich, Alexander/G-8619-2013; OI Yildirim, Eda/0000-0002-4796-3854; Luft, Friedrich/0000-0002-8635-1199; Dietrich, Alexander/0000-0002-1168-8707 FU NHLBI NIH HHS [HL-45198] NR 33 TC 287 Z9 306 U1 2 U2 15 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2005 VL 25 IS 16 BP 6980 EP 6989 DI 10.1128/MCB.25.16.6980-6989.2005 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 952JW UT WOS:000231000800012 PM 16055711 ER PT J AU Wang, BD Eyre, D Basrai, M Lichten, M Strunnikov, A AF Wang, BD Eyre, D Basrai, M Lichten, M Strunnikov, A TI Condensin binding at distinct and specific chromosomal sites in the Saccharomyces cerevisiae genome SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID XENOPUS EGG EXTRACTS; CHROMATID SEGREGATION; REPLICATION ORIGINS; PROTEIN COMPLEXES; BUDDING YEAST; 13S CONDENSIN; DNA; COHESIN; BARREN; RDNA AB Mitotic chromosome condensation is chiefly driven by the condensin complex. The specific recognition (targeting) of chromosomal sites by condensin is an important component of its in vivo activity. We previously identified the rRNA gene cluster in Saccharomyces cerevisiae as an important condensin-binding site, but both genetic and cell biology data suggested that condensin also acts elsewhere. In order to characterize the genomic distribution of condensin-binding sites and to assess the specificity of condensin targeting, we analyzed condensin-bound sites using chromatin immunoprecipitation and hybridization to whole-genome microarrays. The genomic condensin-binding map shows preferential binding sites over the length of every chromosome. This analysis and quantitative PCR validation confirmed condensin-occupied sites across the genome and in the specialized chromatin regions: near centromeres and telomeres and in heterochromatic regions. Condensin sites were also enriched in the zones of converging DNA replication. Comparison of condensin binding in cells arrested in G, and mitosis revealed a cell cycle dependence of condensin binding at some sites. In mitotic cells, condensin was depleted at some sites while enriched at rRNA gene cluster, subtelomeric, and pericentromeric regions. C1 NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. NCI, Biochem Lab, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Strunnikov, A (reprint author), NICHD, NIH, LGRD, 18T Lib Dr,Room 106, Bethesda, MD 20892 USA. EM strunnik@mail.nih.gov RI Lichten, Michael/C-5795-2013; OI Lichten, Michael/0000-0001-9707-2956; Strunnikov, Alexander/0000-0002-9058-2256 NR 59 TC 60 Z9 60 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD AUG PY 2005 VL 25 IS 16 BP 7216 EP 7225 DI 10.1128/MCB.25.16.7216-7225.2005 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 952JW UT WOS:000231000800031 PM 16055730 ER PT J AU Mu, JB Joy, DA Duan, JH Huang, YM Carlton, J Walker, J Barnwell, J Beerli, P Charleston, MA Pybus, OG Su, XZ AF Mu, JB Joy, DA Duan, JH Huang, YM Carlton, J Walker, J Barnwell, J Beerli, P Charleston, MA Pybus, OG Su, XZ TI Host switch leads to emergence of Plasmodium vivax malaria in humans SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE malaria; mitochondrial DNA; host switch; Plasmodium vivax; cophylogeny mapping ID BLOOD-GROUP LOCUS; AMINO-ACID SITES; NATURAL-SELECTION; GENE-SEQUENCES; CYTOCHROME-B; ORIGIN; EVOLUTIONARY; MONKEYS; PHYLOGENY; PARASITES AB The geographical origin of Plasmodium vivax, the most widespread human malaria parasite, is controversial. Although genetic closeness to Asian primate malarias has been confirmed by phylogenetic analyses, genetic similarities between P. vivax and Plasmodium simium, a New World primate malaria, suggest that humans may have acquired P. vivax from New World monkeys or vice versa. Additionally, the near fixation of the Duffy-negative blood type (FY X B-null/FY X B-null) in West and Central Africa, consistent with directional selection, and the association of Duffy negativity with complete resistance to vivax malaria suggest a prolonged period of host-parasite coevolution in Africa. Here we use Bayesian and likelihood methods in conjunction with cophylogeny mapping to reconstruct the genetic and coevolutionary history of P. vivax from the complete mitochondrial genome of 176 isolates as well as several closely related Plasmodium species. Taken together, a haplotype network, parasite migration patterns, demographic history, and cophylogeny mapping support an Asian origin via a host switch from macaque monkeys. C1 NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. NIAID, Malaria Vaccine Dev Unit, NIH, Rockville, MD USA. Guangxi Zhuang Autonomous Reg Ctr Dis Prevent & C, Guangxi, Guangxi, Peoples R China. Inst Genom Res, Parasite Genom Grp, Rockville, MD USA. Westmead Hosp, Parasitol Sect, Ctr Infect Dis, Westmead, NSW 2145, Australia. Westmead Hosp, Microbiol Lab Serv, ICPMR, Westmead, NSW 2145, Australia. Florida State Univ, Sch Comp Sci, Tallahassee, FL 32306 USA. Florida State Univ, Dept Sci Biol, Tallahassee, FL 32306 USA. Ctr Dis Control & Prevent, Div Parasit Dis, Atlanta, GA USA. Univ Sydney, Sch Informat Technol, Sydney, NSW 2006, Australia. Univ Sydney, SUBIT, Sydney, NSW 2006, Australia. Univ Oxford, Dept Zool, Oxford OX1 3PS, England. RP Joy, DA (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD USA. EM djoy@niaid.nih.gov; x.su@niaid.nih.gov RI pybus, oliver/B-2640-2012; Beerli, Peter/A-3638-2009; OI Beerli, Peter/0000-0003-0947-5451; Pybus, Oliver/0000-0002-8797-2667; Su, Xinzhuan/0000-0003-3246-3248 NR 48 TC 123 Z9 128 U1 0 U2 21 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD AUG PY 2005 VL 22 IS 8 BP 1686 EP 1693 DI 10.1093/molbev/msi160 PG 8 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 945XW UT WOS:000230537300005 PM 15858201 ER PT J AU Novozhilov, AS Karev, GP Koonin, EV AF Novozhilov, AS Karev, GP Koonin, EV TI Mathematical modeling of evolution of horizontally transferred genes SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE horizontal gene transfer; mathematical modeling; evolution of prokaryotes ID THERMOTOGA-MARITIMA; MICROBIAL GENOMES; BACTERIAL GENOMES; DNA UPTAKE; SEQUENCE; ARCHAEA; LIFE; TREE; TRANSFORMATION; TRANSPOSONS AB describe a stochastic birth-and-death model of evolution of horizontally transferred genes in microbial populations. The model is a generalization of the stochastic model described by Berg and Kurland and includes five parameters: the rate of mutational inactivation, selection coefficient, invasion rate (i.e., rate of arrival of a novel sequence from outside of the recipient population), within-population horizontal transmission ("infection") rate, and population size. The model of Berg and Kurland included four parameters, namely, mutational inactivation, selection coefficient, population size, and "infection." However, the effect of "infection" was disregarded in the interpretation of the results, and the overall conclusion was that horizontally acquired sequences can be fixed in a population only when they confer a substantial selective advantage onto the recipient and therefore are subject to strong positive selection. Analysis of the present model in different domains of parameter values shows that, as long as the rate of within-population horizontal transmission is comparable to the mutational inactivation rate and there is even a low rate of invasion, horizontally acquired sequences can be fixed in the population or at least persist for a long time in a substantial fraction of individuals in the population even when they are neutral or slightly deleterious. The available biological data strongly suggest that intense within-population and even between-poputations gene flows are realistic for at least some prokaryotic species and environments. Therefore, our modeling results are compatible with the notion of a pivotal role of horizontal gene transfer in the evolution of prokaryotes. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM kooiiin@ncbi.nlm.nih.gov RI Novozhilov, Artem/D-7544-2012; Novozhilov, Artem/C-9248-2013 OI Novozhilov, Artem/0000-0001-5469-2557 NR 58 TC 47 Z9 47 U1 0 U2 11 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 EI 1537-1719 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD AUG PY 2005 VL 22 IS 8 BP 1721 EP 1732 DI 10.1093/molbev/msi167 PG 12 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 945XW UT WOS:000230537300009 PM 15901840 ER PT J AU Choudhury, R Diao, AP Zhang, F Eisenberg, E Saint-Pol, A Williams, C Konstantakopoulos, A Lucocq, J Johannes, L Rabouille, C Greene, LE Lowe, M AF Choudhury, R Diao, AP Zhang, F Eisenberg, E Saint-Pol, A Williams, C Konstantakopoulos, A Lucocq, J Johannes, L Rabouille, C Greene, LE Lowe, M TI Lowe syndrome protein OCRL1 interacts with clathrin and regulates protein trafficking between endosomes and the trans-Golgi network SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID INOSITOL POLYPHOSPHATE 5-PHOSPHATASE; PLECKSTRIN-HOMOLOGY-DOMAIN; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; VESICLE TRAFFICKING; PLASMA-MEMBRANE; COATED VESICLES; BINDING; COMPLEX; ADAPTER; ENDOCYTOSIS AB Oculocerebrorenal syndrome of Lowe is caused by mutation of OCRL1, a phosphatidylinositol 4,5-bisphosphate 5-phosphatase localized at the Golgi apparatus. The cellular role of OCRL1 is unknown, and consequently the mechanism by which loss of OCRL1 function leads to disease is ill defined. Here, we show that OCRL1 is associated with clathrin-coated transport intermediates operating between the trans-Golgi network (TGN) and endosomes. OCRL1 interacts directly with clathrin heavy chain and promotes clathrin assembly in vitro. Interaction with clathrin is not, however, required for membrane association of OCRL1. Overexpression of OCRL1 results in redistribution of clathrin and the cation-independent mannose 6-phosphate receptor (CI-MPR) to enlarged endosomal structures that are defective in retrograde trafficking to the TGN. Depletion of cellular OCRL1 also causes partial redistribution of a CI-MPR reporter to early endosomes. These findings suggest a role for OCRL1 in clathrin-mediated trafficking of proteins from endosomes to the TGN and that defects in this pathway might contribute to the Lowe syndrome phenotype. C1 Univ Manchester, Fac Life Sci, Manchester M13 9PT, Lancs, England. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Inst Curie, Dept Cellular Compartmentalizat & Dynam, Traffic & Signaling Lab, CNRS,Unite Mixte Rech 144, F-75248 Paris, France. Univ Utrecht, Ctr Med, Dept Cell Biol, AZU, NL-3584 CX Utrecht, Netherlands. Univ Dundee, Sch Life Sci, Dundee DD1 5EH, Scotland. RP Lowe, M (reprint author), Univ Manchester, Fac Life Sci, Manchester M13 9PT, Lancs, England. EM martin.lowe@manchester.ac.uk NR 56 TC 113 Z9 113 U1 1 U2 9 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG PY 2005 VL 16 IS 8 BP 3467 EP 3479 DI 10.1091/mbc.E05-02-0120 PG 13 WC Cell Biology SC Cell Biology GA 952WT UT WOS:000231037300002 PM 15917292 ER PT J AU Gardner, MK Pearson, CG Sprague, BL Zarzar, TR Bloom, K Salmon, ED Odde, DJ AF Gardner, MK Pearson, CG Sprague, BL Zarzar, TR Bloom, K Salmon, ED Odde, DJ TI Tension-dependent regulation of microtubule dynamics at kinetochores can explain metaphase congression in yeast SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID BUDDING YEAST; SACCHAROMYCES-CEREVISIAE; MITOTIC SPINDLE; SISTER CENTROMERES; PLUS-END; DIRECTIONAL INSTABILITY; PRECOCIOUS SEPARATION; NUCLEAR MIGRATION; EXTRACT SPINDLES; CHECKPOINT AB During metaphase in budding yeast mitosis, sister kinetochores are tethered to opposite poles and separated, stretching their intervening chromatin, by singly attached kinetochore microtubules (kMTs). Kinetochore movements are coupled to single microtubule plus-end polymerization/depolymerization at kinetochore attachment sites. Here, we use computer modeling to test possible mechanisms controlling chromosome alignment during yeast metaphase by simulating experiments that determine the 1) mean positions of kinetochore Cse4-GFP, 2) extent of oscillation of kinetochores during metaphase as measured by fluorescence recovery after photobleaching (FRAP) of kinetochore Cse4-GFP, 3) dynamics of kMTs as measured by FRAP of GFP-tubulin, and 4) mean positions of unreplicated chromosome kinetochores that lack pulling forces from a sister kinetochore. We rule out a number of possible models and find the best fit between theory and experiment when it is assumed that kinetochores sense both a spatial gradient that suppresses kMT catastrophe near the poles and attachment site tension that promotes kMT rescue at higher amounts of chromatin stretch. C1 Univ Minnesota, Dept Biomed Engn, Minneapolis, MN 55455 USA. Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. NCI, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. RP Odde, DJ (reprint author), Univ Minnesota, Dept Biomed Engn, Minneapolis, MN 55455 USA. EM oddex002@umn.edu RI Sprague, Brian/A-8923-2009; Odde, David/H-4925-2011 FU NIGMS NIH HHS [R01 GM024364, GM-24364, GM-32238, R01 GM032238, R37 GM024364, R37 GM032238] NR 53 TC 93 Z9 94 U1 1 U2 6 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG PY 2005 VL 16 IS 8 BP 3764 EP 3775 DI 10.1091/mbc.E05-04-0275 PG 12 WC Cell Biology SC Cell Biology GA 952WT UT WOS:000231037300027 PM 15930123 ER PT J AU Park, SK Hartnell, LM Jackson, CL AF Park, SK Hartnell, LM Jackson, CL TI Mutations in a highly conserved region of the Arf1p activator GEA2 block anterograde Golgi transport but not COPI recruitment to membranes SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID NUCLEOTIDE-EXCHANGE FACTORS; ADP-RIBOSYLATION FACTORS; ENDOPLASMIC-RETICULUM; SACCHAROMYCES-CEREVISIAE; PROTEIN-TRANSPORT; RETROGRADE TRANSPORT; SECRETORY PATHWAY; COAT PROTEINS; YEAST; COMPLEX AB We have identified an important functional region of the yeast Arf1 activator Gea2p upstream of the catalytic Sec7 domain and characterized a set of temperature-sensitive (ts) mutants with amino acid substitutions in this region. These gea2-ts mutants block or slow transport of proteins traversing the secretory pathway at exit from the endoplasmic reticulum (ER) and the early Golgi, and accumulate both ER and early Golgi membranes. No defects in two types of retrograde trafficking/sorting assays were observed. We find that a substantial amount of COPI is associated with Golgi membranes in the gea2-ts mutants, even after prolonged incubation at the nonpermissive temperature. COPI in these mutants is released from Golgi membranes by brefeldin A, a drug that binds directly to Gea2p and blocks Arf1 activation. Our results demonstrate that COPI function in sorting of at least three retrograde cargo proteins within the Golgi is not perturbed in these mutants, but that forward transport is severely inhibited. Hence this region of Gea2p upstream of the Sec7 domain plays a role in anterograde transport that is independent of its role in recruiting COPI for retrograde transport, at least of a subset of Golgi-ER cargo. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Jackson, CL (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM cathyj@helix.nih.gov OI Jackson, Catherine/0000-0002-0843-145X NR 49 TC 14 Z9 14 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG PY 2005 VL 16 IS 8 BP 3786 EP 3799 DI 10.1091/mbc.E05-04-0289 PG 14 WC Cell Biology SC Cell Biology GA 952WT UT WOS:000231037300029 PM 15930122 ER PT J AU Becker, M Becker, A Miyara, F Han, ZM Kihara, M Brown, DT Hager, GL Latham, K Adashi, EY Misteli, T AF Becker, M Becker, A Miyara, F Han, ZM Kihara, M Brown, DT Hager, GL Latham, K Adashi, EY Misteli, T TI Differential in vivo binding dynamics of somatic and oocyte-specific linker histones in oocytes and during ES cell nuclear transfer SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID GLOBULAR DOMAIN; COOPERATIVE BINDING; LIVING CELLS; H1; CHROMATIN; H5; TRANSCRIPTION; MOUSE; FERTILIZATION; REPLACEMENT AB The embryonic genome is formed by fusion of a maternal and a paternal genome. To accommodate the resulting diploid genome in the fertilized oocyte dramatic global genome reorganizations must occur. The higher order structure of chromatin in vivo is critically dependent on architectural chromatin proteins, with the family of linker histone proteins among the most critical structural determinants. Although somatic cells contain numerous linker histone variants, only one, H1FOO, is present in mouse oocytes. Upon fertilization H1FOO rapidly populates the introduced paternal genome and replaces sperm-specific histone-like proteins. The same dynamic replacement occurs upon introduction of a nucleus during somatic cell nuclear transfer. To understand the molecular basis of this dynamic histone replacement process, we compared the localization and binding dynamics of somatic H1 and oocyte-specific H1FOO and identified the molecular determinants of binding to either oocyte or somatic chromatin in living cells. We find that although both histones associate readily with chromatin in nuclei of somatic cells, only H1FOO is capable of correct chromatin association in the germinal vesicle stage oocyte nuclei. This specificity is generated by the N-terminal and globular domains of H1FOO. Measurement of in vivo binding properties of the H1 variants suggest that H1FOO binds chromatin more tightly than somatic linker histones. We provide evidence that both the binding properties of linker histones as well as additional, active processes contribute to the replacement of somatic histones with H1FOO during nuclear transfer. These results provide the first mechanistic insights into the crucial step of linker histone replacement as it occurs during fertilization and somatic cell nuclear transfer. C1 NCI, NIH, Bethesda, MD 20892 USA. Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19140 USA. Chiba Univ, Sch Med, Dept Obstet & Gynaecol, Chuo Ku, Chiba 2608670, Japan. Univ Mississippi, Sch Med, Jackson, MS 39216 USA. Temple Univ, Sch Med, Dept Biochem, Philadelphia, PA 19140 USA. Univ Utah, Hlth Sci Ctr, Huntsman Canc Inst, Div Reprod Sci, Salt Lake City, UT 84132 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov FU NCI NIH HHS [Z01 BC010309-07]; NICHD NIH HHS [HD43092, R01 HD043092] NR 29 TC 29 Z9 31 U1 0 U2 6 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG PY 2005 VL 16 IS 8 BP 3887 EP 3895 DI 10.1091/mbc.E05-04-0350 PG 9 WC Cell Biology SC Cell Biology GA 952WT UT WOS:000231037300037 PM 15944219 ER PT J AU He, GB Muga, S Thuillier, P Lubet, RA Fischer, SM AF He, GB Muga, S Thuillier, P Lubet, RA Fischer, SM TI The effect of PPAR ligands on UV-gamma or chemically-induced carcinogenesis in mouse skin SO MOLECULAR CARCINOGENESIS LA English DT Article DE troglitazone; rosiglitazone; chemoprevention; skin carcinogenesis ID ACTIVATED-RECEPTOR-GAMMA; GENE-EXPRESSION; IN-VITRO; DIFFERENTIATION; MAMMARY; MICE; CANCER; ALPHA; KERATINOCYTES; TROGLITAZONE AB Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a ligand activated transcription factor. There have been suggestions that PPAR gamma ligands may have utility in preventing tumor development in rodent mammary glands and colon. The recent finding that mice lacking one allele of the PPAR gamma gene were significantly more susceptible to 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis compared to wild-type mice highlights mouse skin as another potential organ in which PPAR-gamma ligands may be effective as chemopreventive agents. In this study, we assessed the effect of two PPAR gamma ligands (rosiglitazone and troglitazone) on UV and DMBA/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin carcinogenesis, two of the most commonly used mouse skin carcinogenesis models. Unexpectedly, neither rosiglitazone (dietary 200 ppm) nor troglitazone (topical 100 mu g) significantly inhibited UV-induced skin tumor development in SKH-1 hairless mice. Likewise, dietary rosiglitazone did not statistically significantly inhibit DMBA/TPA-induced skin tumor development. Interestingly, dietary troglitazone significantly inhibited basal level keratinocyte proliferation as shown by 5-bromo-2'-deoxyuridine (BrdU) labeling, but it had no effect on TPA-induced epidermal cell proliferation. Northern blot analysis showed that PPAR gamma expression was extremely low in normal mouse epidermis and was virtually undetectable in skin tumors. Collectively, our data suggest that PPAR gamma ligands may not be useful in the prevention of chemically or UV-induced skin tumors. (c) 2005 Wiley-Liss, Inc. C1 Univ Texas, MD Anderson Canc Ctr, Div Sci Pk Res, Smithville, TX 78957 USA. Univ S Carolina, Sch Med, S Carolina Canc Ctr, Columbia, SC 29208 USA. Oregon Hlth Sci Univ, Oregon Canc Inst, Portland, OR 97201 USA. NIH, Div Canc Prevent & Control, Bethesda, MD 20892 USA. RP Fischer, SM (reprint author), Univ Texas, MD Anderson Canc Ctr, Div Sci Pk Res, Smithville, TX 78957 USA. FU NCI NIH HHS [CN65110-72, CA16672]; NIEHS NIH HHS [ES07784] NR 28 TC 20 Z9 21 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD AUG PY 2005 VL 43 IS 4 BP 198 EP 206 DI 10.1002/mc.20111 PG 9 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 953MG UT WOS:000231079900003 PM 15864802 ER PT J AU Barile, M Pisitkun, T Yu, MJ Chou, CL Verbalis, MJ Shen, RF Knepper, MA AF Barile, M Pisitkun, T Yu, MJ Chou, CL Verbalis, MJ Shen, RF Knepper, MA TI Large scale protein identification in intracellular aquaporin-2 vesicles from renal inner medullary collecting duct SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID NONMUSCLE MYOSIN-II; RAT-KIDNEY; PLASMA-MEMBRANE; WATER CHANNEL; GOLGI MEMBRANES; EPITHELIAL-CELLS; SYNTAXIN 13; VASOPRESSIN; TRAFFICKING; TRANSPORT AB Vasopressin acts on renal collecting duct cells to stimulate translocation of aquaporin-2 (AQP2)-containing membrane vesicles from throughout the cytoplasm to the apical region. The vesicles fuse with the plasma membrane to increase water permeability. To identify the intracellular membrane compartments that contain AQP2, we carried out LC-MS/MS-based proteomic analysis of immunoisolated AQP2-containing intracellular vesicles from rat inner medullary collecting duct. Immunogold electron microscopy and immunoblotting confirmed heavy AQP2 labeling of immunoisolated vesicles. Vesicle proteins were separated by SDS-PAGE followed by in-gel trypsin digestion in consecutive gel slices and identification by LC-MS/MS. Identification of Rab GTPases 4, 5, 18, and 21 ( associated with early endosomes); Rab7 ( late endosomes); and Rab11 and Rab25 ( recycling endosomes) indicate that a substantial fraction of intracellular AQP2 is present in endosomal compartments. In addition, several endosome-associated SNARE proteins were identified including syntaxin-7, syntaxin-12, syntaxin-13, Vti1a, vesicle-associated membrane protein 2, and vesicle-associated membrane protein 3. Rab3 was not found, however, either by mass spectrometry or immunoblotting, suggesting a relative lack of AQP2 in secretory vesicles. Additionally, we identified markers of the trans-Golgi network, components of the exocyst complex, and several motor proteins including myosin 1C, non-muscle myosins IIA and IIB, myosin VI, and myosin IXB. Beyond this, identification of multiple endoplasmic reticulum-resident proteins and ribosomal proteins indicated that a substantial fraction of intracellular AQP2 is present in rough endoplasmic reticulum. These results show that AQP2-containing vesicles are heterogeneous and that intracellular AQP2 resides chiefly in endosomes, trans-Golgi network, and rough endoplasmic reticulum. C1 NHLBI, NIH, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. NHLBI, NIH, Proteom Core Facil, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, NIH, Kidney & Electrolyte Metab Lab, Bldg 10,10 Ctr Dr,Rm 6N260, Bethesda, MD 20892 USA. EM knep@helix.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271 FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 43 TC 104 Z9 106 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD AUG PY 2005 VL 4 IS 8 BP 1095 EP 1106 DI 10.1074/mcp.M500049-MCP200 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 954SY UT WOS:000231176300007 PM 15905145 ER PT J AU Albermann, K Fritz, A Wenger, K Komatsoulis, G Covitz, P Wright, L Hartel, F AF Albermann, K. Fritz, A. Wenger, K. Komatsoulis, G. Covitz, P. Wright, L. Hartel, F. TI Towards a comprehensive catalog of gene-disease and gene-drug relationships in cancer SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Albermann, K.; Fritz, A.; Wenger, K.] Biomax Informat AG, Martinsried, Germany. [Komatsoulis, G.; Covitz, P.; Hartel, F.] NCI, Ctr Bioinformat, Rockville, MD USA. [Wright, L.] NCI, Off Commun, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD AUG PY 2005 VL 4 IS 8 SU 1 BP S17 EP S17 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V44IB UT WOS:000202995300051 ER PT J AU Ali, I Luke, B Zhen, X Malone, W McLarty, J Greenwald, P AF Ali, I. Luke, B. Zhen, X. Malone, W. McLarty, J. Greenwald, P. TI Biomarkers for early detection of lung cancer SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Ali, I.] Natl Canc Inst, Canc Prevent Div, Bethesda, MD USA. [Ali, I.; Malone, W.; Greenwald, P.] Natl Canc Inst, Lab Canc Prevent, Frederick, MD USA. [Luke, B.; Zhen, X.] Natl Canc Inst, SAIC, Frederick, MD USA. [McLarty, J.] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD AUG PY 2005 VL 4 IS 8 SU 1 BP S98 EP S98 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V44IB UT WOS:000202995300266 ER PT J AU Kuzdzal, S Lopez, M Mikulskis, A Bennett, D Whitele, G Wolfe, G Della Cioppa, G AF Kuzdzal, S. Lopez, M. Mikulskis, A. Bennett, D. Whitele, G. Wolfe, G. Della Cioppa, G. TI Alzheimer's Disease-specific mass signatures identified by carrier protein-bound proteomic profiling SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Kuzdzal, S.; Lopez, M.] PerkinElmer Life & Analyt Sci, Shelton, CT USA. [Mikulskis, A.; Bennett, D.] PerkinElmer Life & Analyt Sci, Boston, MA USA. [Whitele, G.] Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Wolfe, G.] NCI Frederick, SAIC Frederick Inc, Clin Prote Reference Lab, Gaithersburg, MD USA. [Della Cioppa, G.] Predict Diagnost Inc, Vacaville, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD AUG PY 2005 VL 4 IS 8 SU 1 BP S155 EP S155 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V44IB UT WOS:000202995300406 ER PT J AU Tani, C Forlino, A Bianchi, L Armini, A Marini, J Cetta, G Bini, L AF Tani, C. Forlino, A. Bianchi, L. Armini, A. Marini, J. Cetta, G. Bini, L. TI Proteomic study of phenotypic variability in a murine model of osteogenesis imperfecta SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Tani, C.; Bianchi, L.; Armini, A.; Bini, L.] Univ Siena, I-53100 Siena, Italy. [Forlino, A.; Cetta, G.] Univ Pavia, I-27100 Pavia, Italy. [Marini, J.] Natl Inst Hlth, Bethesda, MD USA. RI Forlino, Antonella/H-5385-2015 OI Forlino, Antonella/0000-0002-6385-1182 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD AUG PY 2005 VL 4 IS 8 SU 1 BP S207 EP S207 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V44IB UT WOS:000202995300536 ER PT J AU Van Eyk, J Elliott, S Sheng, S Gundry, R Crider, D Boheler, K Cotter, R AF Van Eyk, J. Elliott, S. Sheng, S. Gundry, R. Crider, D. Boheler, K. Cotter, R. TI Combining 2-dimensional liquid chromatography with whole mass MALDI for a powerful 3-dimensional proteomic analysis SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Van Eyk, J.; Elliott, S.; Sheng, S.; Gundry, R.; Cotter, R.] Johns Hopkins Univ, Baltimore, MD USA. [Crider, D.; Boheler, K.] NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD AUG PY 2005 VL 4 IS 8 SU 1 BP S352 EP S352 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V44IB UT WOS:000202995300912 ER PT J AU Wu, S Kim, J Bandle, R Petricoin, E Liotta, L Hancock, W Karger, B AF Wu, S. Kim, J. Bandle, R. Petricoin, E. Liotta, L. Hancock, W. Karger, B. TI New approaches to full characterization of cancer biomarkers at the trace level; Epidermal growth factor receptor SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Wu, S.; Kim, J.; Hancock, W.; Karger, B.] Northeastern Univ, Boston, MA 02115 USA. [Bandle, R.] Natl Inst Hlth, Bethesda, MD USA. [Petricoin, E.; Liotta, L.] George Mason Univ, Fairfax, VA 22030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD AUG PY 2005 VL 4 IS 8 SU 1 BP S312 EP S312 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V44IB UT WOS:000202995300804 ER PT J AU Pithukpakorn, M AF Pithukpakorn, M TI Disorders of pyruvate metabolism and the tricarboxylic acid cycle SO MOLECULAR GENETICS AND METABOLISM LA English DT Editorial Material ID CARBOXYLASE DEFICIENCY; LACTIC-ACIDOSIS; SUCCINATE-DEHYDROGENASE; FUMARATE-HYDRATASE; COMPLEX; ABNORMALITIES; MITOCHONDRIAL; MUTATIONS; THIAMINE C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Pithukpakorn, M (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM mpithukp@mail.nih.gov RI Pithukpakorn, Manop/K-9825-2013 OI Pithukpakorn, Manop/0000-0003-3611-5718 NR 14 TC 15 Z9 18 U1 2 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD AUG PY 2005 VL 85 IS 4 BP 243 EP 246 DI 10.1016/j.ymgme.2005.06.006 PG 4 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 955YE UT WOS:000231265300001 PM 16156009 ER PT J AU Liu, PC Chen, YW Centeno, JA Quezado, M Lem, K Kaler, SG AF Liu, PC Chen, YW Centeno, JA Quezado, M Lem, K Kaler, SG TI Downregulation of myelination, energy, and translational genes in Menkes disease brain SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE brain; copper; gene expression; Menkes disease; myelination; neurodegeneration ID KINKY-HAIR DISEASE; CULTURED SKIN FIBROBLASTS; OCCIPITAL-HORN-SYNDROME; CANDIDATE GENE; COPPER TRANSPORT; BINDING-PROTEIN; EXPRESSION; PLASMA; LOCALIZATION; METABOLISM AB Menkes disease (MD) is an X-linked recessive neurodegenerative disorder caused by mutations in a copper-transporting p-type ATPase (ATP7A) that normally delivers copper to the central nervous system. The precise reasons for neurodegeneration in MID are poorly understood. We hypothesized that gene expression changes in a MID patient with a lethal ATP7A mutation would indicate pathophysiological cascades relevant to the effects of copper deficiency in the developing brain. To test this hypothesis, oligonucleotide probes for 12,000 genes arrayed on Affymetrix Human Genome U95 GeneChips were used for expression profiling of fluorescently labeled primary cRNAs from post-mortem cerebral cortex and cerebellum of a MD patient who died at 6 months of age and a normal control brain matched for age, gender, and race. Histopathologic analysis of the proband's brain showed preservation of neuronal integrity and no hypoxic effects. However, cerebrospinal fluid and brain copper levels were subnormal, and expression profiling identified over 350 known dysregulated genes. For a subset of genes (approximate to 12%) analyzed by quantitative RT-PCR, the correct cross-validation rate was 88%. Thirty known genes were altered in both cortex and cerebellum. Downregulation of genes involved in myelination, energy metabolism, and translation was the major finding. The cerebellum was more sensitive to copper deficiency. Published by Elsevier Inc. C1 NICHHD, Unit Pediat Genet, Lab Clin Genom, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. Armed Forces Inst Pathol, Washington, DC 20306 USA. NCI, Surg Pathol Sect, NIH, Bethesda, MD 20892 USA. RP Kaler, SG (reprint author), NICHHD, Unit Pediat Genet, Lab Clin Genom, NIH, Bethesda, MD 20892 USA. EM kalers@mail.nih.gov NR 42 TC 38 Z9 38 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD AUG PY 2005 VL 85 IS 4 BP 291 EP 300 DI 10.1016/j.ymgme.2005.04.007 PG 10 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 955YE UT WOS:000231265300008 PM 15923132 ER PT J AU Mohlke, KL Skol, AD Scott, LJ Valle, TT Bergman, RN Tuomilehto, J Boehnke, M Collins, FS AF Mohlke, KL Skol, AD Scott, LJ Valle, TT Bergman, RN Tuomilehto, J Boehnke, M Collins, FS CA FUSION Study Grp TI Evaluation of SLC2A10 (GLUT10) as a candidate gene for type 2 diabetes and related traits in Finns SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE SLC2A10; GLUT10; type 2 diabetes; single nucleotide polymorphism; association analysis; Finnish; 20q ID NUCLEAR FACTOR-4-ALPHA GENE; GLUCOSE-TRANSPORTER; LINKAGE DISEQUILIBRIUM; COMPLEX TRAITS; SUSCEPTIBILITY; ASSOCIATION; POPULATION; PROMOTER; MELLITUS; DESIGN AB The SLC2A10 gene encodes a glucose transporter and is located on chromosome 20q13, where evidence has been found for linkage to type 2 diabetes (T2D) in multiple studies. We investigated SLC2A10 as a T2D candidate gene in Finns. We did not confirm the previously reported association between Ala206Thr and fasting insulin and we observed no statistically significant evidence for T2D association with any single marker. We tested haplotypes for association with diabetes-related traits and observed no excess of significant results. Published by Elsevier Inc. C1 NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. Natl Publ Hlth Inst, Diabet & Genet Epidemiol Unit, Dept Epidmiol & Hlth Promot, Helsinki, Finland. Natl Publ Hlth Inst, Dept Biochem, Helsinki, Finland. Univ So Calif, Dept Physiol & Biophys, Keck Sch Med, Los Angeles, CA 90089 USA. Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. RP Mohlke, KL (reprint author), Univ N Carolina, Dept Genet, Chapel Hill, NC USA. EM mohlke@med.unc.edu FU NHGRI NIH HHS [HG00376]; NIDDK NIH HHS [DK27619, R01 DK029867, DK62370, DK29867] NR 19 TC 12 Z9 13 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD AUG PY 2005 VL 85 IS 4 BP 323 EP 327 DI 10.1016/j.ymgme.2005.04.011 PG 5 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 955YE UT WOS:000231265300012 PM 15936967 ER PT J AU Maasho, K Masilamani, M Valas, R Basu, S Coligan, JE Borrego, F AF Maasho, K Masilamani, M Valas, R Basu, S Coligan, JE Borrego, F TI The inhibitory leukocyte-associated Ig-like receptor-1 (LAIR-1) is expressed at high levels by human naive T cells and inhibits TCR mediated activation SO MOLECULAR IMMUNOLOGY LA English DT Article DE LAIR-1; naive T cell; inhibitory receptor; CD8 ID COLONY-STIMULATING FACTOR; HUMAN NATURAL-KILLER; IFN-GAMMA; IN-VITRO; LYMPHOCYTES; RESPONSES; MECHANISM; SURVIVAL; LIGANDS; CTLA-4 AB Human leukocyte-associated Ig-like receptor-1 (LAIR-1) is a transmembrane glycoprotein with a single extracellular Ig-like domain and a cytoplasmic tail containing two immunoreceptor tyrosine-based inhibition motifs (ITIMs). It is constitutively expressed on the majority of human mononuclear leukocytes and functions as an inhibitory receptor. In this study, we show that freshly isolated peripheral blood T cells are heterogeneous in their expression levels of LAIR. We have found that naive T cells express the highest levels of LAIR-1, even more than memory cells. The cross-linking of LAIR-1 inhibits T cell receptor (TCR) mediated signals in freshly isolated human naive T cells and whole populations of CD4(+) or CD8(+) T cells. TCR cross-linking increased cell surface expression of LAIR-1 in a process that requires p38 MAP kinase and ERK signaling. Altogether, these results indicate that LAIR-1 is capable of negatively regulating T cell functions, and its high level of expression by naive T cells suggests that it may function at an early stage in the development of an immune response. (c) 2005 Elsevier Ltd. All rights reserved. C1 NIAID, Receptor Cell Biol Sect, Lab Allerg Dis, NIH, Rockville, MD 20852 USA. RP Borrego, F (reprint author), NIAID, Receptor Cell Biol Sect, Lab Allerg Dis, NIH, Twinbrook 2,12441 Parklawn Dr, Rockville, MD 20852 USA. EM Fborrego@niaid.nih.gov OI Masilamani, Madhan/0000-0001-8181-8848 NR 45 TC 26 Z9 36 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD AUG PY 2005 VL 42 IS 12 BP 1521 EP 1530 DI 10.1016/j.molimm.2005.01.004 PG 10 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 956BD UT WOS:000231273000010 PM 15950745 ER PT J AU Pesu, M O'Shea, J Hennighausen, L Silvennoinen, O AF Pesu, M O'Shea, J Hennighausen, L Silvennoinen, O TI Identification of an acquired mutation in Jak2 provides molecular insights into the pathogenesis of myeloproliferative disorders SO MOLECULAR INTERVENTIONS LA English DT Editorial Material ID TYROSINE KINASE JAK2; POLYCYTHEMIA-VERA; PSEUDOKINASE DOMAIN; SURFACE EXPRESSION; JANUS KINASES; STAT PATHWAYS; RECEPTORS; ERYTHROPOIESIS; JANUS-KINASE-2; PROLIFERATION C1 NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. Tampere Univ Hosp, Dept Clin Microbiol, FIN-33014 Tampere, Finland. Univ Tampere, Inst Med Technol, FIN-33014 Tampere, Finland. RP Pesu, M (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM pesum@mail.nih.gov; osheaj@arb.niams.nih.gov; lotharh@amb.niddk.nih.gov; olli.silvennoinen@uta.fi RI Pesu, marko/L-6344-2013 NR 39 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 1534-0384 J9 MOL INTERV JI Mol. Interv. PD AUG PY 2005 VL 5 IS 4 BP 211 EP 215 DI 10.1124/mi.5.4.4 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 961EZ UT WOS:000231646000005 PM 16123535 ER PT J AU Romling, U Gomelsky, M Galperin, MY AF Romling, U Gomelsky, M Galperin, MY TI C-di-GMP: the dawning of a novel bacterial signalling system SO MOLECULAR MICROBIOLOGY LA English DT Review ID 3',5'-CYCLIC DIGUANYLIC ACID; STORAGE HMS(+) PHENOTYPE; DIRECT OXYGEN SENSOR; ESCHERICHIA-COLI; BIOFILM FORMATION; ACETOBACTER-XYLINUM; CELLULOSE SYNTHESIS; VIBRIO-CHOLERAE; SALMONELLA-TYPHIMURIUM; BORDETELLA-PERTUSSIS AB Bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) has come to the limelight as a result of the recent advances in microbial genomics and increased interest in multicellular microbial behaviour. Known for more than 15 years as an activator of cellulose synthase in Gluconacetobacter xylinus, c-di-GMP is emerging as a novel global second messenger in bacteria. The GGDEF and EAL domain proteins involved in c-di-GMP synthesis and degradation, respectively, are (almost) ubiquitous in bacterial genomes. These proteins affect cell differentiation and multicellular behaviour as well as interactions between the microorganisms and their eukaryotic hosts and other phenotypes. While the role of GGDEF and EAL domain proteins in bacterial physiology and behaviour has gained appreciation, and significant progress has been achieved in understanding the enzymology of c-di-GMP turnover, many questions regarding c-di-GMP-dependent signalling remain unanswered. Among these, the key questions are the identity of targets of c-di-GMP action and mechanisms of c-di-GMP-dependent regulation. This review discusses phylogenetic distribution of the c-di-GMP signalling pathway in bacteria, recent developments in biochemical and structural characterization of proteins involved in its metabolism, and biological processes affected by c-di-GMP. The accumulated data clearly indicate that a novel ubiquitous signalling system in bacteria has been discovered. C1 Karolinska Inst, Ctr Microbiol & Tumor Biol, SE-17177 Stockholm, Sweden. Univ Wyoming, Dept Mol Biol, Laramie, WY 82071 USA. Natl Lib Med, NCBI, NIH, Bethesda, MD 20894 USA. RP Romling, U (reprint author), Karolinska Inst, Ctr Microbiol & Tumor Biol, Box 280, SE-17177 Stockholm, Sweden. EM ute.romling@mtc.ki.se RI gomelsky, mark/F-6209-2010; Galperin, Michael/B-5859-2013; OI Galperin, Michael/0000-0002-2265-5572; Romling, Ute/0000-0003-3812-6621 NR 69 TC 401 Z9 425 U1 9 U2 61 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD AUG PY 2005 VL 57 IS 3 BP 629 EP 639 DI 10.1111/j.1365-2958.2005.04697.x PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 942SU UT WOS:000230303500004 PM 16045609 ER PT J AU Ferracci, F Schubot, FD Waugh, DS Plano, GV AF Ferracci, F Schubot, FD Waugh, DS Plano, GV TI Selection and characterization of Yersinia pestis YopN mutants that constitutively block Yop secretion SO MOLECULAR MICROBIOLOGY LA English DT Article ID OUTER-MEMBRANE PROTEINS; HIGH-LEVEL EXPRESSION; LOW-CALCIUM RESPONSE; TARGET-CELL CONTACT; III SECRETION; EUKARYOTIC CELLS; V-ANTIGEN; SUBSTRATE-SPECIFICITY; VIRULENCE PLASMID; GENETIC-ANALYSIS AB Secretion of Yop effector proteins by the Yersinia pestis plasmid pCD1-encoded type III secretion system (T3SS) is regulated in response to specific environmental signals. Yop secretion is activated by contact with a eukaryotic cell or by growth at 37 degrees C in the absence of calcium. The secreted YopN protein, the SycN/YscB chaperone and TyeA form a cytosolic YopN/SycN/YscB/TyeA complex that is required to prevent Yop secretion in the presence of calcium and prior to contact with a eukaryotic cell. The mechanism by which these proteins prevent secretion and the subcellular location where the block in secretion occurs are not known. To further investigate both the mechanism and location of the YopN-dependent block, we isolated and characterized several YopN mutants that constitutively block Yop secretion. All the identified amino-acid substitutions that resulted in a constitutive block in Yop secretion mapped to a central domain of YopN that is not directly involved in the interaction with the SycN/YscB chaperone or TyeA. The YopN mutants required an intact TyeA-binding domain and TyeA to block secretion, but did not require an N-terminal secretion signal, an intact chaperone-binding domain or the SycN/YscB chaperone. These results suggest that a C-terminal domain of YopN complexed with TyeA blocks Yop secretion from a cytosolic, not an extracellular, location. A hypothetical model for how the YopN/SycN/YscB/TyeA complex regulates Yop secretion is presented. C1 Univ Miami, Sch Med, Dept Microbiol & Immunol, Miami, FL 33136 USA. Natl Canc Inst, Ctr Canc Res, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Plano, GV (reprint author), Univ Miami, Sch Med, Dept Microbiol & Immunol, Miami, FL 33136 USA. EM gplano@med.miami.edu FU NIAID NIH HHS [AI39575, AI50552] NR 57 TC 67 Z9 69 U1 3 U2 7 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD AUG PY 2005 VL 57 IS 4 BP 970 EP 987 DI 10.1111/j.1365-2958.2005.04738.x PG 18 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 950WB UT WOS:000230888300010 PM 16091038 ER PT J AU Olivares-Reyes, JA Shah, BH Hernandez-Aranda, J Garcia-Caballero, A Farshori, MP Garcia-Sainz, JA Catt, KJ AF Olivares-Reyes, JA Shah, BH Hernandez-Aranda, J Garcia-Caballero, A Farshori, MP Garcia-Sainz, JA Catt, KJ TI Agonist-induced interactions between angiotensin AT(1) and epidermal growth factor receptors SO MOLECULAR PHARMACOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; SMOOTH-MUSCLE-CELLS; G-BETA-GAMMA; KINASE ACTIVATION; TYROSINE KINASE; EGF RECEPTOR; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOINOSITIDE 3-KINASE; TYPE-1 RECEPTOR; II RECEPTORS AB In rat hepatic C9 cells, angiotensin II (Ang II)-induced activation of angiotensin type 1 (AT(1)) receptors (AT(1)-Rs) stimulates extracellular signal-regulated kinase (ERK) 1/2 phosphorylation via transactivation of the endogenous epidermal growth factor (EGF) receptor (EGF-R) by a protein kinase C (PKC) delta/Src/ Pyk2-dependent pathway. This leads to phosphorylation of the EGF-R as well as its subsequent internalization. On the other hand, EGF-induced activation of the EGF-R in C9 cells was found to cause phosphorylation of the AT(1)-R. This was prevented by selective inhibition of the intrinsic tyrosine kinase activity of the EGF-R by AG1478 [4-(3'-chloroanilino)-6,7-dimethoxyquinazoline] and was reduced by inhibition of PKC and phosphoinositide 3-kinase. EGF-induced AT(1)-R phosphorylation was associated with a decrease in membrane- associated AT(1)-Rs and a reduced inositol phosphate response to Ang II. Agonist activation of endogenous AT(1)-Rs and EGF-Rs induced the formation of a multireceptor complex containing both the AT(1)-R and the transactivated EGF-R. The dependence of these responses on caveolin was indicated by the finding that cholesterol depletion of C9 cells abolished Ang II-induced inositol phosphate production, activation of Akt/PKB and ERK1/2, and AT(1)-R internalization. Confocal microscopy demonstrated that caveolin-1 was endogenously phosphorylated and was distributed on the plasma membrane in patches that undergo redistribution during Ang II stimulation. Agonist-induced phosphorylation and association of caveolin 1 with the AT(1)-R was observed, consistent with a scaffolding role of caveolin during transactivation of the EGF-R by Ang II. The EGF-induced AT(1)-R/caveolin association was abolished by AG1478, suggesting that activation of the EGF-R promotes the association of caveolin and the AT(1)-R. C1 Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Bioquim, Mexico City 07000, DF, Mexico. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Univ Nacl Autonoma Mexico, Inst Fisiol Celular, Dept Biol Celular, Mexico City 04510, DF, Mexico. RP Olivares-Reyes, JA (reprint author), Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Bioquim, AP 14-740, Mexico City 07000, DF, Mexico. EM jolivare@cinvestav.mx RI GARCIA-SAINZ, JESUS ADOLFO/A-5389-2008 OI GARCIA-SAINZ, JESUS ADOLFO/0000-0002-5235-0657 NR 41 TC 53 Z9 56 U1 1 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD AUG PY 2005 VL 68 IS 2 BP 356 EP 364 DI 10.1124/mol.104.010637 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 946CO UT WOS:000230549900012 PM 15905421 ER PT J AU Kohn, MJ Kaneko, KJ DePamphilis, ML AF Kohn, MJ Kaneko, KJ DePamphilis, ML TI DkkL1 (Soggy), a Dickkopf family member, localizes to the acrosome during mammalian spermatogenesis SO MOLECULAR REPRODUCTION AND DEVELOPMENT LA English DT Article DE sperm; acrosome; glycoprotein; Wnt-signaling ID SPERM PROTEIN SP56; MOUSE DEVELOPMENT; GENE-EXPRESSION; TRANSCRIPTION FACTORS; ZONA-PELLUCIDA; FERTILIZATION; CELLS; GLYCOPROTEINS; ACTIVATION; MATURATION AB Dickkopf-like 1 (DkkL1) is related to the Dickkopf gene family, a group of proteins that are characterized as secreted antagonists of Wingless (Wnt) signal transduction proteins. DkkL1 mRNA is found in preimplantation mouse embryos and in developing neural tissue, but in adults it is found primarily in the testes. In an effort to elucidate its function, the distribution of DkkL1 protein in mouse testis and mature sperm was analyzed by immunohistochemistry and immuno-blotting techniques. DkkL1 first appeared in the developing spermatocytes in seminiferous tubules as early as StageXII, coincident with the appearance of DkkL1 mRNA. Surprisingly, however, DkkL1 localized to the developing acrosome in spermatocytes and spermatids and to the acrosome in mature sperm. Furthermore, DkkL1 was N-glycosylated in the testis, but it did not appear to be excreted, and the DkkL1 in mature sperm was no longer N-glycosylated, suggesting that additional post-translational modifications occurred during the final stages of spermatogenesis. These results identify a member of the Dickkopf family as a novel acrosomal protein that may be involved in acrosome assembly or function, a unique role for a secreted signaling molecule. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP DePamphilis, ML (reprint author), NICHHD, NIH, Bldg 6-3A-15,9000 Rockville Pike, Bethesda, MD 20892 USA. EM depamphm@mail.nih.gov FU Intramural NIH HHS [Z01 HD000507-12] NR 29 TC 28 Z9 33 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1040-452X J9 MOL REPROD DEV JI Mol. Reprod. Dev. PD AUG PY 2005 VL 71 IS 4 BP 516 EP 522 DI 10.1002/mrd.20314 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology SC Biochemistry & Molecular Biology; Cell Biology; Developmental Biology; Reproductive Biology GA 940WU UT WOS:000230177400015 PM 15892050 ER PT J AU Alesci, S Gerschenson, M Ilias, L AF Alesci, S Gerschenson, M Ilias, L TI L-carnitine, immunomodulation, and human immunodeficiency virus (HIV)-related disorders SO MONATSHEFTE FUR CHEMIE LA English DT Article DE carnitine; immunity; glucocorticoid receptor; HIV ID ACTIVE ANTIRETROVIRAL THERAPY; ACETYL-L-CARNITINE; SUBCUTANEOUS ADIPOSE-TISSUE; AIDS PATIENTS; HIV-1-INFECTED SUBJECTS; MITOCHONDRIAL MYOPATHY; LYMPHOCYTE APOPTOSIS; PROPIONIC ACIDEMIA; PLASMA CARNITINE; FAT DISTRIBUTION AB The use of pharmacologic doses of the conditionally-essential nutrient L-carnitine (LC) has been associated with positive effects on the immune system. We have recently suggested that this property of LC could be mediated through activation of the glucocorticoid receptor alpha. Human immunodeficiency virus (HIV)-infected individuals, especially those on antiretroviral therapy, may become W-deficient. This evidence, together with the immunomodulatory properties of LC, its known major role in lipid and energy metabolisms, and its proposed antiapoptotic and neuroprotective actions, have encouraged the use of LC supplementation as a potential treatment for HIV-related disorders, such as lipodystrophy and peripheral neuropathy. Preliminary results, mostly from small-scale uncontrolled studies are conflicting, whilst larger controlled trials are warranted. C1 NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Hawaii, John A Burns Sch Med, Dept Med, Hawaii AIDS Clin Res Program, Honolulu, HI 96816 USA. Univ Patras, Sch Med, Dept Pharmacol, GR-26504 Rion Patras, Greece. RP Alesci, S (reprint author), NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. EM alescisa@mail.nih.gov NR 59 TC 3 Z9 3 U1 0 U2 3 PU SPRINGER WIEN PI VIENNA PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 VIENNA, AUSTRIA SN 0026-9247 J9 MONATSH CHEM JI Mon. Chem. PD AUG PY 2005 VL 136 IS 8 BP 1493 EP 1500 DI 10.1007/s00706-005-0333-8 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 959SB UT WOS:000231538500019 ER PT J AU Bara-Jimenez, W Bibbiani, F Morris, MJ Dimitrova, T Sherzai, A Mouradian, MM Chase, TN AF Bara-Jimenez, W Bibbiani, F Morris, MJ Dimitrova, T Sherzai, A Mouradian, MM Chase, TN TI Effects of serotonin 5-HT1A agonist in advanced Parkinson's disease SO MOVEMENT DISORDERS LA English DT Article DE 5-HT1A receptor; serotonin; dopamine; Parkinson's disease; dyskinesias; levodopa; striatum ID LEVODOPA-INDUCED DYSKINESIAS; DOPA-INDUCED DYSKINESIA; EXTRACELLULAR DOPAMINE; MOTOR COMPLICATIONS; NUCLEUS-ACCUMBENS; RAT STRIATUM; RECEPTOR; ANTAGONIST; RELEASE; NEURONS AB Intermittent stimulation of striatal dopaminergic receptors seems to contribute to motor dysfunction in advanced Parkinson's disease (PD). With severe dopaminergic denervation, exogenous levodopa is largely decarboxylated to dopamine in serotonergic terminals. If 5-HT1A autoreceptors regulate dopamine as well as serotonin release, in parkinsonian patients inhibition of striatal serotonergic neuron firing might help maintain more physiological intrasynaptic dopamine concentrations and thus ameliorate motor fluctuations and dyskinesias. To evaluate this hypothesis, effects of a selective 5-HT1A agonist, sarizotan, given orally at 2 and 5 mg twice daily to 18 relatively advanced parkinsonian patients, were compared with baseline placebo function during a 3-week, double-blind, placebo-controlled, proof-of-concept study. Sarizotan alone or with intravenous levodopa had no effect on parkinsonian severity. But at safe and tolerable doses, sarizotan coadministration reduced levodopa-induced dyskmesias and prolonged its antiparkinsonian response (P <= 0.05). Under the conditions of this study, our findings suggest that 5-HT1A receptor stimulation in levodopa-treated parkinsonian patients can modulate striatal dopaminergic function and that 5-HT1A agonists may be useful as levodopa adjuvants in the treatment of PD. (c) 2005 Movement Disorder Society. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Bara-Jimenez, W (reprint author), NINDS, Expt Therapeut Branch, NIH, Bldg 10,Rm 5C103, Bethesda, MD 20892 USA. EM baraw@ninds.nih.gov OI Mouradian, M. Maral/0000-0002-9937-412X NR 32 TC 105 Z9 108 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG PY 2005 VL 20 IS 8 BP 932 EP 936 DI 10.1002/mds.20370 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 958JM UT WOS:000231440600003 PM 15791634 ER PT J AU Ikeda, A Kurihara, S Shibasaki, H AF Ikeda, A Kurihara, S Shibasaki, H TI Possible anticipation in BAFME: Three generations examined in a Japanese family SO MOVEMENT DISORDERS LA English DT Letter ID CORTICAL REFLEX MYOCLONUS; EPILEPSY; TREMOR; LOCALIZATION; GENE C1 Kyoto Univ, Sch Med, Kyoto 606, Japan. NINDS, NIH, Bethesda, MD 20892 USA. RP Ikeda, A (reprint author), Kyoto Univ, Sch Med, Kyoto 606, Japan. EM akio@kuhp.kyoto-u.ac.jp OI Ikeda, Akio/0000-0002-0790-2598 NR 10 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 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG PY 2005 VL 20 IS 8 BP 1076 EP 1077 DI 10.1002/mds.20558 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 958JM UT WOS:000231440600031 PM 16001402 ER PT J AU Hardy, J Lees, AJ AF Hardy, J Lees, AJ TI Parkinson's disease: A broken nosology SO MOVEMENT DISORDERS LA English DT Article; Proceedings Paper CT International Meeting on Atypical Parkinsonian Disorders CY FEB 19-21, 2003 CL Innsbruck, AUSTRIA SP Movement Disorder Soc DE nosology; Parkinson's disease; Lewy body dementia ID ALPHA-SYNUCLEIN; ALZHEIMERS-DISEASE; LEWY BODIES; DIAGNOSIS; DEMENTIA; GENETICS; MUTATION; BODY; FAMILIES AB Parkinson's disease (PD) is a clinical diagnosis. We argue here that if we are to make progress in understanding its underlying pathogenesis, there is a need to have a pathological definition of disease that includes the presence of Lewy bodies and nigral loss in the ventrolateral tier of the pars compacta of the substantia nigra. Using such a definition, there is only one certain and known cause: mutations in the et-synuclein gene. However, the phenotype of this one known cause is broader than PD and encompasses Lewy body dementia. (c) 2005 Movement Disorder Society. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. UCL, Reta Lila Weston Inst Neurol Studies, London, England. RP Hardy, J (reprint author), NIA, Neurogenet Lab, NIH, Bldg 10,Room 6C103,MSC1589, Bethesda, MD 20892 USA. EM hardyj@mail.nih.gov RI Hardy, John/C-2451-2009; Lees, Andrew/A-6605-2009 NR 34 TC 11 Z9 11 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG PY 2005 VL 20 SU 12 BP S2 EP S4 DI 10.1002/mds.20532 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 959UX UT WOS:000231545900002 PM 16092073 ER PT J AU Litvan, I Chase, T AF Litvan, I Chase, T TI Current and novel therapeutic approaches for the atypical parkinsonian disorders SO MOVEMENT DISORDERS LA English DT Meeting Abstract CT International Meeting on Atypical Parkinsonian Disorders CY FEB 19-21, 2003 CL Innsbruck, AUSTRIA SP Movement Disorder Soc C1 Univ Louisville, Dept Neurol, Louisville, KY 40292 USA. NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG PY 2005 VL 20 SU 12 BP S128 EP S129 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 959UX UT WOS:000231545900027 ER PT J AU Wang, W Budhu, A Forgues, M Wang, XW AF Wang, W Budhu, A Forgues, M Wang, XW TI Temporal and spatial control of nucleophosmin by the Ran-Crm1 complex in centrosome duplication SO NATURE CELL BIOLOGY LA English DT Letter ID VIRUS-X PROTEIN; RIBOSOME BIOGENESIS; DEPENDENT KINASE; CELL-DIVISION; RAN GTPASE; RIGHT TIME; CYCLE; P53; PHOSPHORYLATION; LOCALIZATION AB Centrosome duplication is tightly controlled during faithful cell division, and unnecessary reduplication can lead to supernumerary centrosomes and multipolar spindles that are associated with most human cancer cells(1-5). In addition to nucleocytoplasmic transport, the Ran-Crm1 network is involved in regulating centrosome duplication to ensure the formation of a bipolar spindle(6-8). Here, we discover that nucleophosmin (NPM) may be a Ran-Crm1 substrate that controls centrosome duplication. NPM contains a functional nuclear export signal (NES) that is responsible for both its nucleocytoplasmic shuttling and its association with centrosomes, which are Ran-Crm1-dependent as they are sensitive to Crm1-specific nuclear export inhibition, either by leptomycin B (LMB) or by the expression of a Ran-binding protein, RanBP1. Notably, LMB treatment induces premature centrosome duplication in quiescent cells, which coincides with NPM dissociation from centrosomes. Moreover, deficiency of NPM by RNA interference results in supernumerary centrosomes, which can be reversed by reintroducing wild-type but not NES-mutated NPM. Mutation of a potential proline-dependent kinase phosphorylation site at residue 95, from threonine to aspartic acid (T95D) within the NES motif, abolishes NPM association and inhibition of centrosome duplication. Our results are consistent with the hypothesis that the Ran-Crm1 complex may promote a local enrichment of NPM on centrosomes, thereby preventing centrosome reduplication. C1 NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Wang, XW (reprint author), NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM xw3u@nih.gov RI Wang, Xin/B-6162-2009 NR 28 TC 164 Z9 169 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD AUG PY 2005 VL 7 IS 8 BP 823 EP 830 DI 10.1038/ncb1282 PG 8 WC Cell Biology SC Cell Biology GA 950TU UT WOS:000230881500017 PM 16041368 ER PT J AU Aleem, E Kiyokawa, H Kaldis, P AF Aleem, E Kiyokawa, H Kaldis, P TI Cdc2-cyclin E complexes regulate the G1/S phase transition SO NATURE CELL BIOLOGY LA English DT Letter ID DEPENDENT-KINASE INHIBITOR; CYCLIN-E; MAMMALIAN-CELLS; MICE LACKING; P27(KIP1); ENTRY; CDK2; HYPERPLASIA; GROWTH; MOUSE AB The cyclin-dependent kinase inhibitor p27(Kip1) is known as a negative regulator of cell-cycle progression and as a tumour suppressor(1). Cdk2 is the main target of p27 (refs 2, 3) and therefore we hypothesized that loss of Cdk2 activity should modify the p27(-/-) mouse phenotype(4-6). Here, we show that although p27(-/-) Cdk2(-/-) mice developed ovary tumours and tumours in the anterior lobe of the pituitary, we failed to detect any functional complementation in p27(-/-) Cdk2(-/-) double-knockout mice, indicating a parallel pathway regulated by p27. We observed elevated levels of S phase and mitosis in tissues of p27(-/-) Cdk2(-/-) mice concomitantly with elevated Cdc2 activity in p27(-/-) Cdk2(-/-) extracts. p27 binds to Cdc2, cyclin B1, cyclin A2, or suc1 complexes in wild-type and Cdk2(-/-) extracts. In addition, cyclin E binds to and activates Cdc2. Our in vivo results provide strong evidence that Cdc2 may compensate the loss of Cdk2 function. C1 NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. Univ Illinois, Coll Med, Dept Biochem & Mol Genet, Chicago, IL 60607 USA. RP Kaldis, P (reprint author), NCI, Mouse Canc Genet Program, Bldg 560-22-56,1050 Boyles St, Frederick, MD 21702 USA. EM kaldis@ncifcrf.gov RI Kaldis, Philipp/G-2714-2010; OI Kaldis, Philipp/0000-0002-7247-7591; Aleem, Eiman/0000-0002-9215-8213 NR 24 TC 236 Z9 242 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD AUG PY 2005 VL 7 IS 8 BP 831 EP U93 DI 10.1038/ncb1284 PG 10 WC Cell Biology SC Cell Biology GA 950TU UT WOS:000230881500018 PM 16007079 ER PT J AU McShane, LM Altman, DG Sauerbrei, W Taube, SE Gion, M Clark, GM AF McShane, LM Altman, DG Sauerbrei, W Taube, SE Gion, M Clark, GM CA Stat Subcomm NCI-EORTC Grp TI REporting recommendations for tumor MARKer prognostic studies (REMARK) SO NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY LA English DT Article DE EORTC; guidelines; NCI; REMARK; tumor markers ID NEGATIVE BREAST-CANCER; DIAGNOSTIC-ACCURACY; RANDOMIZED TRIALS; COLORECTAL-CANCER; CONSORT STATEMENT; GUIDELINES; FUTURE; EPIDEMIOLOGY; METAANALYSIS; ELABORATION AB Despite years of research and hundreds of reports on tumor markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons why multiple studies of the same marker lead to differing conclusions. A variety of methodological problems have been cited to explain these discrepancies. Unfortunately, many tumor marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalizability of study results. The development of guidelines for the reporting of tumor marker studies was a major recommendation of the National Cancer Institute-European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. As for the successful CONSORT initiative for randomized trials and for the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines provide helpful suggestions on how to present data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. Ctr Stat Med, Oxford, England. Univ Hosp Freiburg, Inst Med Biometry & Med Informat, Freiburg, Germany. Natl Canc Inst, Div Canc Treatment & Diag, Canc Diag Program, Bethesda, MD USA. Reg Gen Hosp, Unit Lab Med, Ctr Study Biol Markers Malignancy & Head, Venice, Italy. OSI Pharmaceut Inc, Boulder, CO USA. RP McShane, LM (reprint author), NCI, Biometr Res Branch, DCTD,Room 8126,Execut Plaza N,MSC 7434,6130 Execu, Bethesda, MD 20892 USA. EM Lm5h@nih.gov NR 42 TC 5 Z9 5 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1743-4378 J9 NAT CLIN PRACT GASTR JI Nat. Clin. Pract. Gastroenterol. Hepatol. PD AUG PY 2005 VL 2 IS 8 BP A416 EP A422 DI 10.1038/ncponc0252 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 962SE UT WOS:000231751800010 ER PT J AU Yarchoan, R Tosato, G Little, RF AF Yarchoan, R Tosato, G Little, RF TI Therapy Insight: AIDS-related malignancies - the influence of antiviral therapy on pathogenesis and management SO NATURE CLINICAL PRACTICE ONCOLOGY LA English DT Review DE AIDS; antiviral; HIV; Kaposi's sarcoma; lymphoma ID ACTIVE ANTIRETROVIRAL THERAPY; SARCOMA-ASSOCIATED HERPESVIRUS; PEGYLATED-LIPOSOMAL DOXORUBICIN; NERVOUS-SYSTEM LYMPHOMA; NON-HODGKINS-LYMPHOMA; HIV-PROTEASE INHIBITORS; VIRUS-INFECTED PATIENTS; PHASE-III TRIAL; KAPOSIS-SARCOMA; GROWTH-FACTOR AB Patients with HIV infection are at an increased risk of a number of malignancies, including Kaposi's sarcoma (KS) and certain B-cell lymphomas. Most of these tumors are caused by oncogenic DNA viruses, including KS-associated herpesvirus and Epstein-Barr virus. HIV contributes to the development of these tumors through several mechanisms, including immunodeficiency, immunodysregulation, and the effects of HIV proteins such as Tat. The development of highly active antiretroviral therapy (HAART) has reduced the incidence of many HIV-associated tumors and has generally improved their responsiveness to therapy. However, the number of people living with AIDS is increasing, and it is possible that the number of AIDS-associated malignancies will rise and the pattern of tumors will change as more people live longer with HIV infection. The goal of KS therapy is long-term tumor control with minimal toxicity. HAART is an important component of this therapy, and some patients do not require other KS-specific therapies. By contrast, the goal of AIDS-related lymphoma therapy in most cases is the attainment of a complete response with curative intent, and the benefits of administering HAART during therapy must be weighed against possible disadvantages. The past decade has seen substantial improvements in the treatment of AIDS-related lymphoma, which is attributed partially to a shift in tumor type and more effective regimens. There is currently an interest in developing new therapies for HIV-associated malignancies, based on viral, vascular or other pathogenesis-based targets. C1 NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol & Cell Biol Sect, Expt Transplantat & Immunol Branch, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. RP Yarchoan, R (reprint author), NCI, HIV & AIDS Malignancy Branch, NIH, Bldg 10,Rm 10S255,MSC 1868,10 Ctr Dr, Bethesda, MD 20892 USA. EM yarchoan@helix.nih.gov NR 73 TC 32 Z9 34 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1743-4254 J9 NAT CLIN PRACT ONCOL JI Nat. Clin. Pract. Oncol. PD AUG PY 2005 VL 2 IS 8 BP 406 EP 415 DI 10.1038/ncponc0253 PG 10 WC Oncology SC Oncology GA 962QL UT WOS:000231747200010 PM 16130937 ER PT J AU McShane, LM Altman, DG Sauerbrei, W Taube, SE Gion, M Clark, GM AF McShane, LM Altman, DG Sauerbrei, W Taube, SE Gion, M Clark, GM CA Stat Subcomm NCI-EORTC Working Grp TI REporting recommendations for tumor MARKer prognostic studies (REMARK) SO NATURE CLINICAL PRACTICE ONCOLOGY LA English DT Article DE EORTC; guidelines; NCI; REMARK; tumor markers ID NEGATIVE BREAST-CANCER; DIAGNOSTIC-ACCURACY; RANDOMIZED TRIALS; COLORECTAL-CANCER; CONSORT STATEMENT; GUIDELINES; FUTURE; EPIDEMIOLOGY; METAANALYSIS; ELABORATION AB Despite years of research and hundreds of reports on tumor markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons why multiple studies of the same marker lead to differing conclusions. A variety of methodological problems have been cited to explain these discrepancies. Unfortunately, many tumor marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalizability of study results. The development of guidelines for the reporting of tumor marker studies was a major recommendation of the National Cancer Institute-European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. As for the successful CONSORT initiative for randomized trials and for the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines provide helpful suggestions on how to present data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply. C1 NCI, Biometr Res Branch, DCTD, Bethesda, MD 20892 USA. Ctr Stat Med, Oxford, England. Univ Hosp Freiburg, Inst Med Biometry & Med Informat, Freiburg, Germany. NCI, Canc Diag Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. Reg Gen Hosp, Ctr Study Biol Markers Malignancy, Venice, Italy. Reg Gen Hosp, Unit Lab Med, Venice, Italy. OSI Pharmaceut Inc, Biostat & Data Management, Boulder, CO USA. RP McShane, LM (reprint author), NCI, Biometr Res Branch, DCTD, Room 8126,Execut Plaza N,MSC 7434,6130 Execut Blv, Bethesda, MD 20892 USA. EM Lm5h@nih.gov NR 42 TC 269 Z9 272 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1743-4254 J9 NAT CLIN PRACT ONCOL JI Nat. Clin. Pract. Oncol. PD AUG PY 2005 VL 2 IS 8 BP 416 EP 422 DI 10.1038/ncponc0252 PG 7 WC Oncology SC Oncology GA 962QL UT WOS:000231747200011 PM 16130938 ER PT J AU McShane, LM Altman, DG Sauerbrei, W Taube, SE Gion, M Clark, GM AF McShane, LM Altman, DG Sauerbrei, W Taube, SE Gion, M Clark, GM CA Statistics Subcomm NCI EORTC Grp TI REporting recommendations for tumor MARKer prognostic studies (REMARK) SO NATURE CLINICAL PRACTICE UROLOGY LA English DT Article DE EORTC; guidelines; NCI; REMARK; tumor markers ID NEGATIVE BREAST-CANCER; DIAGNOSTIC-ACCURACY; RANDOMIZED TRIALS; COLORECTAL-CANCER; CONSORT STATEMENT; GUIDELINES; FUTURE; EPIDEMIOLOGY; METAANALYSIS; ELABORATION AB Despite years of research and hundreds of reports on tumor markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons why multiple studies of the same marker lead to differing conclusions. A variety of methodological problems have been cited to explain these discrepancies. Unfortunately, many tumor marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalizability of study results. The development of guidelines for the reporting of tumor marker studies was a major recommendation of the National Cancer Institute-European Organisation for Research and Treatment of Cancer (NCl-EORTC) First International Meeting on Cancer Diagnostics in 2000. As for the successful CONSORT initiative for randomized trials and for the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines provide helpful suggestions on how to present data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply. C1 NCI, DCTD, Biometr Res Branch, Bethesda, MD 20892 USA. Ctr Stat Med, Oxford, England. Univ Hosp Freiburg, Inst Med Biometry & Med Informat, Freiburg, Germany. NCI, Canc Diagnosis Program, Div Canc Treatment & Diagnosis, Bethesda, MD 20892 USA. Ctr Study Biol Markers Malignancy, Venice, Italy. Reg Gen Hosp, Unit Lab Med, Venice, Italy. OSI Pharmaceut Inc, Boulder, CO USA. RP McShane, LM (reprint author), NCI, DCTD, Biometr Res Branch, Room 8126,Execut Plaza N,MSC 7434,6130 Executive, Bethesda, MD 20892 USA. EM Lm5h@nih.gov NR 42 TC 5 Z9 5 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1743-4270 J9 NAT CLIN PRACT UROL JI Nat. Clin. Pract. Urol. PD AUG PY 2005 VL 2 IS 8 BP A416 EP A422 DI 10.1038/ncponc0252 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 962NO UT WOS:000231739700013 ER PT J AU Cam, HP Sugiyama, T Chen, ES Chen, X FitzGerald, PC Grewal, SIS AF Cam, HP Sugiyama, T Chen, ES Chen, X FitzGerald, PC Grewal, SIS TI Comprehensive analysis of heterochromatin- and RNAi-mediated epigenetic control of the fission yeast genome SO NATURE GENETICS LA English DT Article ID HISTONE LYSINE METHYLATION; SCHIZOSACCHAROMYCES-POMBE; TRANSPOSABLE ELEMENTS; CHROMODOMAIN PROTEIN; DNA METHYLATION; H3 METHYLATION; INTERFERENCE; DISTINCT; DOMAIN; POLYMERASE AB The organization of eukaryotic genomes into distinct structural and functional domains is important for the regulation and transduction of genetic information. Here, we investigated heterochromatin and euchromatin profiles of the entire fission yeast genome and explored the role of RNA interference (RNAi) in genome organization. Histone H3 methylated at Lys4, which defines euchromatin, was not only distributed across most of the chromosomal landscape but was also present at the centromere core, the site of kinetochore assembly. In contrast, histone H3 methylated at Lys9 and its interacting protein Swi6/HP1, which define heterochromatin, coated extended domains associated with a variety of repeat elements and small islands corresponding to meiotic genes. Notably, RNAi components were distributed throughout all these heterochromatin domains, and their localization depended on Clr4/Suv39h histone methyltransferase. Sequencing of small interfering RNAs (siRNAs) associated with the RITS RNAi effector complex identified hot spots of siRNAs, which mapped to a diverse array of elements in these RNAi-heterochromatin domains. We found that Clr4/Suv39h predominantly silenced repeat elements whose derived transcripts, transcribed mainly by RNA polymerase II, serve as a source for siRNAs. Our analyses also uncover an important role for the RNAi machinery in maintaining genomic integrity. C1 NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Genome Anal Unit, NIH, Bethesda, MD 20892 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 NR 49 TC 297 Z9 308 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD AUG PY 2005 VL 37 IS 8 BP 809 EP 819 DI 10.1038/ng1602 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 950TK UT WOS:000230880400010 PM 15976807 ER PT J AU Salzer, U Chapel, HM Webster, ADB Pan-Hammarstrom, Q Schmitt-Graeff, A Schlesier, M Peter, HH Rockstroh, JK Schneider, P Schaffer, AA Hammarstrom, L Grimbacher, B AF Salzer, U Chapel, HM Webster, ADB Pan-Hammarstrom, Q Schmitt-Graeff, A Schlesier, M Peter, HH Rockstroh, JK Schneider, P Schaffer, AA Hammarstrom, L Grimbacher, B TI Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans SO NATURE GENETICS LA English DT Article ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; APRIL-DEFICIENT MICE; B-CELL SURVIVAL; IGA DEFICIENCY; TNF RECEPTOR; LINKAGE ANALYSIS; T-CELL; BAFF-R; FAMILY; APOPTOSIS AB The functional interaction of BAFF and APRIL with TNF receptor superfamily members BAFFR, TACI and BCMA is crucial for development and maintenance of humoral immunity in mice and humans. Using a candidate gene approach, we identified homozygous and heterozygous mutations in TNFRSF13B, encoding TACI, in 13 individuals with common variable immunodeficiency. Homozygosity with respect to mutations causing the amino acid substitutions S144X and C104R abrogated APRIL binding and resulted in loss of TACI function, as evidenced by impaired proliferative response to IgM-APRIL costimulation and defective class switch recombination induced by IL-10 and APRIL or BAFF. Family members heterozygous with respect to the C104R mutation and individuals with sporadic common variable immunodeficiency who were heterozygous with respect to the amino acid substitutions A181E, S194X and R202H had humoral immunodeficiency. Although signs of autoimmunity and lymphoproliferation are evident, the human phenotype differs from that of the Tnfrsf13b(-/-) mouse model. C1 Univ Hosp, Med Ctr, Div Clin Immunol & Rheumatol, D-79106 Freiburg, Germany. Oxford Radcliffe Hosp, Dept Immunol, Oxford, England. Royal Free Hosp, Dept Clin Immunol, London NW3 2QG, England. Karolinska Inst Huddinge, Div Clin Immunol, Stockholm, Sweden. Univ Freiburg, Inst Pathol, D-7800 Freiburg, Germany. Med Univ Klin 1, Bonn, Germany. Univ Lausanne, Dept Biochem, CH-1015 Lausanne, Switzerland. NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Grimbacher, B (reprint author), Univ Hosp, Med Ctr, Div Clin Immunol & Rheumatol, Hugstetterstr 55, D-79106 Freiburg, Germany. EM grimbacher@medizin.ukl.uni-freiburg.de RI Schaffer, Alejandro/F-2902-2012; OI Schneider, Pascal/0000-0003-0677-9409 NR 41 TC 372 Z9 383 U1 4 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD AUG PY 2005 VL 37 IS 8 BP 820 EP 828 DI 10.1038/ng1600 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 950TK UT WOS:000230880400011 PM 16007087 ER PT J AU Ule, J Ule, A Spencer, J Williams, A Hu, JS Cline, M Wang, H Clark, T Fraser, C Ruggiu, M Zeeberg, BR Kane, D Weinstein, JN Blume, J Darnell, RB AF Ule, J Ule, A Spencer, J Williams, A Hu, JS Cline, M Wang, H Clark, T Fraser, C Ruggiu, M Zeeberg, BR Kane, D Weinstein, JN Blume, J Darnell, RB TI Nova regulates brain-specific splicing to shape the synapse SO NATURE GENETICS LA English DT Article ID RNA-BINDING PROTEIN; FRAGILE-X-SYNDROME; MESSENGER-RNAS; GENE-EXPRESSION; GENOME; SEQUENCE; ISOFORMS; RECEPTOR; CAMKII; DOMAIN AB Alternative RNA splicing greatly increases proteome diversity and may thereby contribute to tissue-specific functions. We carried out genome-wide quantitative analysis of alternative splicing using a custom Affymetrix microarray to assess the role of the neuronal splicing factor Nova in the brain. We used a stringent algorithm to identify 591 exons that were differentially spliced in the brain relative to immune tissues, and 6.6% of these showed major splicing defects in the neocortex of Nova2(-/-) mice. We tested 49 exons with the largest predicted Nova-dependent splicing changes and validated all 49 by RT-PCR. We analyzed the encoded proteins and found that all those with defined brain functions acted in the synapse (34 of 40, including neurotransmitter receptors, cation channels, adhesion and scaffold proteins) or in axon guidance ( 8 of 40). Moreover, of the 35 proteins with known interaction partners, 74% (26) interact with each other. Validating a large set of Nova RNA targets has led us to identify a multi-tiered network in which Nova regulates the exon content of RNAs encoding proteins that interact in the synapse. C1 Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. Rockefeller Univ, Mol Neurooncol Lab, New York, NY 10021 USA. Univ Amsterdam, Fac Econ & Econometr, NL-1012 WX Amsterdam, Netherlands. Affymetrix Inc, Emeryville, CA USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. SRA Int Inc, Fairfax, VA 22033 USA. RP Darnell, RB (reprint author), Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. EM darnelr@rockefeller.edu RI Darnell, Robert/B-9022-2008; Ule, Jernej/C-6315-2013; OI Darnell, Robert/0000-0002-5134-8088; Ule, Jernej/0000-0002-2452-4277; Spencer-Segal, Joanna/0000-0003-0467-2173 NR 50 TC 295 Z9 305 U1 2 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD AUG PY 2005 VL 37 IS 8 BP 844 EP 852 DI 10.1038/ng1610 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 950TK UT WOS:000230880400014 PM 16041372 ER PT J AU Fauci, AS AF Fauci, AS TI The global challenge of infectious diseases: the evolving role of the National Institutes of Health in basic and clinical research SO NATURE IMMUNOLOGY LA English DT Editorial Material ID AIDS AB The US has entered a new period of fiscal restraint. What does this mean for basic research? Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, discusses the way forward for research scientists in the US. C1 NIAID, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov NR 14 TC 12 Z9 12 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2005 VL 6 IS 8 BP 743 EP 747 DI 10.1038/ni0805-743 PG 5 WC Immunology SC Immunology GA 947LM UT WOS:000230646200003 PM 16034426 ER PT J AU Rosa, P AF Rosa, P TI Lyme disease agent borrows a practical coat SO NATURE MEDICINE LA English DT Editorial Material ID OUTER-SURFACE PROTEIN; BORRELIA-BURGDORFERI; SALIVA; HOST AB The bacterium that causes Lyme disease is a manipulative creature. This pathogen exploits a component in the saliva of its vector, a tick, to facilitate invasion of vertebrate hosts. C1 NIAID, Rocky Mt Lab, Lab Zoonot Pathogens, NIH, Hamilton, MT 59840 USA. RP Rosa, P (reprint author), NIAID, Rocky Mt Lab, Lab Zoonot Pathogens, NIH, Hamilton, MT 59840 USA. EM prosa@niaid.nih.gov NR 12 TC 16 Z9 18 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2005 VL 11 IS 8 BP 831 EP 832 DI 10.1038/nm0805-831 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 951XC UT WOS:000230964700020 PM 16079876 ER PT J AU Kim, CH Takamiya, K Petralia, RS Sattler, R Yu, S Zhou, WG Kalb, R Wenthold, R Huganir, R AF Kim, CH Takamiya, K Petralia, RS Sattler, R Yu, S Zhou, WG Kalb, R Wenthold, R Huganir, R TI Persistent hippocampal CA1 LTP in mice lacking the C-terminal PDZ ligand of GluR1 SO NATURE NEUROSCIENCE LA English DT Article ID AMPA RECEPTOR TRAFFICKING; SYNAPTIC PLASTICITY; SYNAPSES; SUBUNIT AB The C-terminal PDZ ligand of the AMPA receptor GluR1 subunit may be important for expression of CA1 hippocampal long-term potentiation. To test this directly in vivo, we generated a knock-in mouse lacking the last seven residues of GluR1, comprising the PDZ ligand. This deletion did not affect basal GluR1 synaptic localization, basal synaptic transmission, long-term potentiation or long-term depression, indicating that the ligand is not required for CA1 hippocampal synaptic plasticity. C1 Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Howard Hughes Med Inst, Baltimore, MD 21205 USA. Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Joseph Stokes Jr Res Inst, Philadelphia, PA 19104 USA. RP Huganir, R (reprint author), Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21205 USA. EM rhuganir@jhmi.edu RI yu, yan/C-2322-2012 FU NINDS NIH HHS [NS36715] NR 12 TC 54 Z9 57 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD AUG PY 2005 VL 8 IS 8 BP 985 EP 987 DI 10.1038/nn1432 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 949BP UT WOS:000230760200007 PM 16007085 ER PT J AU Meyer-Lindenberg, A Hariri, AR Munoz, KE Mervis, CB Mattay, VS Morris, CA Berman, KF AF Meyer-Lindenberg, A Hariri, AR Munoz, KE Mervis, CB Mattay, VS Morris, CA Berman, KF TI Neural correlates of genetically abnormal social cognition in Williams syndrome SO NATURE NEUROSCIENCE LA English DT Article ID PREFRONTAL CORTEX; AMYGDALA RESPONSE; BEHAVIOR; STIMULI; ANXIETY AB Williams-Beuren syndrome (WBS), caused by a microdeletion of approximately 21 genes on chromosome 7q11.23, is characterized by unique hypersociability combined with increased non-social anxiety. Using functional neuroimaging, we found reduced amygdala activation in individuals with WBS for threatening faces but increased activation for threatening scenes, relative to matched normal controls. Activation and interactions of prefrontal regions linked to amygdala, especially orbitofrontal cortex, were abnormal, suggesting a genetically controlled neural circuitry for regulating human social behavior. C1 NIMH, Sect Integrat Neuroimaging, NIH, US Dept HHS, Bethesda, MD 20892 USA. NIMH, Neuroimaging Core Facil, NIH, US Dept HHS, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. Univ Louisville, Dept Psychol & Brain Sci, Neurodev Sci Lab, Louisville, KY 40292 USA. Univ Nevada, Sch Med, Dept Pediat, Las Vegas, NV 89102 USA. RP Meyer-Lindenberg, A (reprint author), NIMH, Sect Integrat Neuroimaging, NIH, US Dept HHS, Bethesda, MD 20892 USA. EM andreasml@nih.gov RI Hariri, Ahmad/D-5761-2011; OI Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU NINDS NIH HHS [R01 NS035102, NS35102] NR 15 TC 224 Z9 229 U1 2 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD AUG PY 2005 VL 8 IS 8 BP 991 EP 993 DI 10.1038/nn1494 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 949BP UT WOS:000230760200009 PM 16007084 ER PT J AU Woo, NH Teng, HK Siao, CJ Chiaruttini, C Pang, PT Milner, TA Hempstead, BL Lu, B AF Woo, NH Teng, HK Siao, CJ Chiaruttini, C Pang, PT Milner, TA Hempstead, BL Lu, B TI Activation of p75(NTR) by proBDNF facilitates hippocampal long-term depression SO NATURE NEUROSCIENCE LA English DT Article ID NEUROTROPHIN RECEPTOR P75(NTR); ACTIVITY-DEPENDENT SECRETION; NERVE GROWTH-FACTOR; RAT DENTATE GYRUS; SIGNAL-TRANSDUCTION; SYNAPTIC PLASTICITY; AREA CA1; BDNF; MICE; NEURONS AB Pro- and mature brain-derived neurotrophic factor (BDNF) activate two distinct receptors: p75 neurotrophin receptor (p75(NTR)) and TrkB. Mature BDNF facilitates hippocampal synaptic potentiation through TrkB. Here we report that proBDNF, by activating p75(NTR), facilitates hippocampal long-term depression (LTD). Electron microscopy showed that p75(NTR) localized in dendritic spines, in addition to afferent terminals, of CA1 neurons. Deletion of p75(NTR) in mice selectively impaired the NMDA receptor - dependent LTD, without affecting other forms of synaptic plasticity. p75(NTR-/-) mice also showed a decrease in the expression of NR2B, an NMDA receptor subunit uniquely involved in LTD. Activation of p75(NTR) by proBDNF enhanced NR2B-dependent LTD and NR2B-mediated synaptic currents. These results show a crucial role for proBDNF-p75(NTR) signaling in LTD and its potential mechanism, and together with the finding that mature BDNF promotes synaptic potentiation, suggest a bidirectional regulation of synaptic plasticity by proBDNF and mature BDNF. C1 NICHD, Sect Neural Dev & Plast, LCSN, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. Cornell Univ, Weill Med coll, Dept Med, Div Hematol, New York, NY 10021 USA. Cornell Univ, Weill Med coll, Dept Neurol & Neurosci, New York, NY 10021 USA. RP Lu, B (reprint author), NICHD, Sect Neural Dev & Plast, LCSN, Porter Neurosci Res Ctr, 35 Lincoln Dr, Bethesda, MD 20892 USA. EM bailu@mail.nih.gov RI Lu, Bai/A-4018-2012 FU NHLBI NIH HHS [HL18974]; NINDS NIH HHS [NS30658] NR 50 TC 372 Z9 390 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD AUG PY 2005 VL 8 IS 8 BP 1069 EP 1077 DI 10.1038/nn1510 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 949BP UT WOS:000230760200019 PM 16025106 ER PT J AU Smith, MW O'Brien, SJ AF Smith, MW O'Brien, SJ TI Mapping by admixture linkage disequilibrium: Advances, limitations and guidelines SO NATURE REVIEWS GENETICS LA English DT Review ID MULTILOCUS GENOTYPE DATA; GENOME-WIDE ASSOCIATION; 3 ETHNIC-GROUPS; POPULATION-STRUCTURE; AFRICAN-AMERICAN; ADMIXED POPULATIONS; RACIAL-DIFFERENCES; HEART-FAILURE; RISK-FACTORS; DISEASE AB Mapping by admixture linkage disequilibrium (MALD) is a theoretically powerful, although unproven, approach to mapping genetic variants that are involved in human disease. MALD takes advantage of long-range haplotypes that are generated by gene flow among recently admixed ethnic groups, such as African-Americans and Latinos. Under ideal circumstances, MALD will have more power to detect some genetic variants than other types of genome-wide association study that are carried out among more ethnically homogeneous populations. It will also require 200-500 times fewer markers, providing a significant economic advantage. The MALD approach is now being applied, with results expected in the near future. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. NCI, Basic Re Program, SAIC Frederick, Frederick, MD 21702 USA. RP Smith, MW (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM smithm@ncifcrf.gov RI Smith, Michael/B-5341-2012 NR 68 TC 133 Z9 138 U1 2 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD AUG PY 2005 VL 6 IS 8 BP 623 EP U6 DI 10.1038/nrg1657 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 950TM UT WOS:000230880700013 PM 16012528 ER PT J AU Hitte, C Madeoy, J Kirkness, EF Priat, C Lorentzen, TD Senger, F Thomas, D Derrien, T Ramirez, C Scott, C Evanno, G Pullar, B Cadieu, E Oza, V Lourgant, K Jaffe, DB Tacher, S Dreano, S Berkova, N Andre, C Deloukas, P Fraser, C Lindblad-Toh, K Ostrander, EA Galibert, F AF Hitte, C Madeoy, J Kirkness, EF Priat, C Lorentzen, TD Senger, F Thomas, D Derrien, T Ramirez, C Scott, C Evanno, G Pullar, B Cadieu, E Oza, V Lourgant, K Jaffe, DB Tacher, S Dreano, S Berkova, N Andre, C Deloukas, P Fraser, C Lindblad-Toh, K Ostrander, EA Galibert, F TI Facilitating genome navigation: survey sequencing and dense radiation-hybrid gene mapping SO NATURE REVIEWS GENETICS LA English DT Review ID CANINE GENOME; DOG GENOME; MOUSE GENOME; LINKAGE MAP; CONSTRUCTION; STRATEGY; MULTIMAP; SYSTEM; MODEL AB Accurate and comprehensive sequence coverage for large genomes has been restricted to only a few species of specific interest. Lower sequence coverage (survey sequencing) of related species can yield a wealth of information about gene content and putative regulatory elements. But survey sequences lack long-range continuity and provide only a fragmented view of a genome. Here we show the usefulness of combining survey sequencing with dense radiation-hybrid (RH) maps for extracting maximum comparative genome information from model organisms. Based on results from the canine system, we propose that from now on all low-pass sequencing projects should be accompanied by a dense, gene-based RH map-construction effort to extract maximum information from the genome with a marginal extra cost. C1 NHGRI, NIH, Bethesda, MD 20892 USA. Fac Med, CNRS, UMR 6061, F-35043 Rennes, France. Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. Inst Genome Res, Rockville, MD 20850 USA. Wellcome Trust Sanger, Inst Hixton, Hixton, Cambs, England. MIT, Broad Inst, Cambridge, MA 02141 USA. Harvard Univ, Cambridge, MA 02141 USA. RP Ostrander, EA (reprint author), NHGRI, NIH, 50 South Dr,MSC 8000,Bldg 50,Room 5351, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov; galibert@univ-rennes1.fr RI Deloukas, Panos/B-2922-2013; OI Deloukas, Panos/0000-0001-9251-070X; Fraser, Claire/0000-0003-1462-2428; Ostrander, Elaine/0000-0001-6075-9738 NR 34 TC 51 Z9 53 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD AUG PY 2005 VL 6 IS 8 BP 643 EP 649 DI 10.1038/nrg1658 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 950TM UT WOS:000230880700015 PM 16012527 ER PT J AU Youle, RJ Karbowski, M AF Youle, RJ Karbowski, M TI Mitochondrial fission in apoptosis SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID DYNAMIN-RELATED PROTEIN; DOMINANT OPTIC ATROPHY; OUTER-MEMBRANE PROTEIN; CYTOCHROME-C RELEASE; ENDOPLASMIC-RETICULUM; CELL-DEATH; LIPID-BILAYERS; FUSION; GTPASE; BAX AB Mitochondria fuse and divide continuously within cells to form a dynamic network. One of the steps in apoptosis is the fragmentation of mitochondria, and recent evidence indicates that the mitochondrial fission machinery actively participates in the process of programmed cell death. C1 Natl Inst Neurol Disorders & Stroke, Biochem Sect, Surg Neurol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), Natl Inst Neurol Disorders & Stroke, Biochem Sect, Surg Neurol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov NR 73 TC 398 Z9 411 U1 1 U2 32 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0072 J9 NAT REV MOL CELL BIO JI Nat. Rev. Mol. Cell Biol. PD AUG PY 2005 VL 6 IS 8 BP 657 EP 663 DI 10.1038/nrm1697 PG 7 WC Cell Biology SC Cell Biology GA 950TH UT WOS:000230880100014 PM 16025099 ER PT J AU Lu, B Pang, PT Woo, NH AF Lu, B Pang, PT Woo, NH TI The yin and yang of neurotrophin action SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID NERVE GROWTH-FACTOR; LONG-TERM POTENTIATION; TISSUE-PLASMINOGEN ACTIVATOR; ACTIVITY-DEPENDENT SECRETION; RAT VISUAL-CORTEX; AFFINITY NGF RECEPTOR; BDNF KNOCKOUT MICE; CELL-DEATH; SYNAPTIC PLASTICITY; HIPPOCAMPAL-NEURONS AB Neurotrophins have diverse functions in the CNS. Initially synthesized as precursors (proneurotrophins), they are cleaved to produce mature proteins, which promote neuronal survival and enhance synaptic plasticity by activating Trk receptor tyrosine kinases. Recent studies indicate that proneurotrophins serve as signalling molecules by interacting with the p75 neurotrophin receptor (p75(NTR)). Interestingly, proneurotrophins often have biological effects that oppose those of mature neurotrophins. Therefore, the proteolytic cleavage of proneurotrophins represents a mechanism that controls the direction of action of neurotrophins. New insights into the 'yin and yang' of neurotrophin activity have profound implications for our understanding of the role of neurotrophins in a wide range of cellular processes. C1 NICHHD, Sect Neural Dev & Plast, NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Lu, B (reprint author), NICHHD, Sect Neural Dev & Plast, NIH, Porter Neurosci Res Ctr, Bldg 35,35 Lincoln Dr, Bethesda, MD 20892 USA. EM bailu@mail.nih.gov RI Lu, Bai/A-4018-2012 NR 121 TC 596 Z9 621 U1 2 U2 43 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0048 J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD AUG PY 2005 VL 6 IS 8 BP 603 EP 614 DI 10.1038/nrn1726 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 950TC UT WOS:000230879500013 PM 16062169 ER PT J AU Wlodawer, A AF Wlodawer, A TI Giving credit where credit is due SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Letter ID PROTEIN DATA-BANK; STRUCTURAL GENOMICS C1 NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM wlodawer@ncifcrf.gov NR 8 TC 4 Z9 4 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD AUG PY 2005 VL 12 IS 8 BP 634 EP 634 DI 10.1038/nsmb0805-634a PG 1 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 951UH UT WOS:000230956400002 PM 16077721 ER PT J AU Hickman, AB Perez, ZN Zhou, LQ Musingarimi, P Ghirlando, R Hinshaw, JE Craig, NL Dyda, F AF Hickman, AB Perez, ZN Zhou, LQ Musingarimi, P Ghirlando, R Hinshaw, JE Craig, NL Dyda, F TI Molecular architecture of a eukaryotic DNA transposase SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID V(D)J RECOMBINATION; MUTATIONAL ANALYSIS; HERMES TRANSPOSASE; DIFFRACTION DATA; BINDING DOMAIN; TRANSFER STEPS; AMINO-ACIDS; ACTIVE-SITE; PROTEIN; RAG1 AB Mobile elements and their inactive remnants account for large proportions of most eukaryotic genomes, where they have had central roles in genome evolution. Over 50 years ago, McClintock reported a form of stress-induced genome instability in maize in which discrete DNA segments move between chromosomal locations. Our current mechanistic understanding of enzymes catalyzing transposition is largely limited to prokaryotic transposases. The Hermes transposon from the housefly is part of the eukaryotic hAT superfamily that includes hobo from Drosophila, McClintock's maize Activator and Tam3 from snapdragon. We report here the three-dimensional structure of a functionally active form of the transposase from Hermes at 2.1-angstrom resolution. The Hermes protein has some structural features of prokaryotic transposases, including a domain with a retroviral integrase fold. However, this domain is disrupted by the insertion of an additional domain. Finally, transposition is observed only when Hermes assembles into a hexamer. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Sch Med, Dept Mol Biol & Genet, Howard Hughes Med Inst, Baltimore, MD 21205 USA. NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Dyda, F (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM Fred.Dyda@nih.gov RI Ghirlando, Rodolfo/A-8880-2009; OI Zhou, Li Qin/0000-0001-8900-2835 NR 42 TC 67 Z9 71 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1545-9993 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD AUG PY 2005 VL 12 IS 8 BP 715 EP 721 DI 10.1038/nsmb970 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 951UH UT WOS:000230956400022 PM 16041385 ER PT J AU Sharma, VM Shareef, MM Bhaskar, K Kalidas, S Shetty, PA Christopher, R Ramamohan, Y Pant, HC Shetty, TK AF Sharma, VM Shareef, MM Bhaskar, K Kalidas, S Shetty, PA Christopher, R Ramamohan, Y Pant, HC Shetty, TK TI Nuclear localization of Muncl8-1 (p67) in the adult rat brain and PC12 cells SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE MuncI8-1; Cdk5; DNA binding; nuclear localization signal (NLS); nuclear export signal (NES) ID UNC-18 GENE ENCODES; SYNAPTIC VESICLE; PROTEIN; KINASE; MUNC18-1; PHOSPHORYLATION; SECRETION; SYNTAXIN; ELEGANS; NEURONS AB Munc18-1, also referred to as p67, co-purifies with Cdk5 and has an important role in neurotransmitter release. The role of Munc18-1 for functional connectivity of the nervous system was demonstrated by gene knockout experiments in mice, wherein accumulation of neurotransmitter and silencing of synaptic activity was observed. Our earlier studies have shown that both Munc18-1 and Cdk5 co-purify and co-localize with cytoskeletal components, implying that apart from having a regulatory role in vesicle docking and fusion, Munc18-1 could also affect the dynamics of neuronal cytoskeleton. In the present study we have shown the presence of Munc 18-1 in nuclear rich fraction from rat brain and confirmed the nuclear localization of this protein in PC12 cells and adult rat brain neurons by immunofluorescence and immunoelectron microscopy. We also demonstrate the binding of Munc18-1 to double stranded (ds) DNA. The ability of Munc18-1 to bind dsDNA, albeit the lack of DNA binding domains, suggests that the binding may be mediated through protein-protein interaction through some other DNA-binding proteins. The presence of both nuclear import and export signals in Munc 18-1 primary structure corroborates its nuclear localization and makes it a putative shuttle protein between nuclear and cytoplasmic compartments, the precise physiological relevance of which needs to be elucidated. (c) 2005 Elsevier Ltd. All rights reserved. C1 Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Bangalore 560029, Karnataka, India. Natl Inst Mental Hlth & Neurosci, Dept Neuropathol, Bangalore 560029, Karnataka, India. NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Shetty, TK (reprint author), Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Bangalore 560029, Karnataka, India. EM tara@nimhans.kar.nic.in RI SHETTY, PAVAN/B-9804-2012 NR 29 TC 4 Z9 4 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 J9 NEUROCHEM INT JI Neurochem. Int. PD AUG PY 2005 VL 47 IS 3 BP 225 EP 234 DI 10.1016/j.neuint.2005.01.005 PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 947OC UT WOS:000230654600008 PM 15869823 ER PT J AU Assaf, Y Basser, PJ AF Assaf, Y Basser, PJ TI Composite hindered and restricted model of diffusion (CHARMED) MR imaging of the human brain SO NEUROIMAGE LA English DT Article DE diffusion; restricted; hindered; DTI; q space; white matter; MRI ID APPARENT DIFFUSION; WEIGHTED MRI; WHITE-MATTER; TENSOR MRI; INTRACELLULAR WATER; FIELD-GRADIENT; B-VALUES; TISSUE; ANISOTROPY; COMPARTMENTATION AB High b value diffusion-weighted images sampled at high angular resolution were analyzed using a composite hindered and restricted model of diffusion (CHARMED). Measurements and simulations of diffusion in white matter using CHARMED provide an unbiased estimate of fiber orientation with consistently smaller angular uncertainty than when calculated using a DTI model or with a dual tensor model for any given signal-to-noise level. Images based on the population fraction of the restricted compartment provide a new contrast mechanism that enhances white matter like DTI. Nevertheless, it is assumed that these images might be more sensitive than DTI to white matter disorders. We also provide here an experimental design and analysis framework to implement CHARMED MRI that is feasible on human clinical scanners. (c) 2005 Elsevier Inc. All rights reserved. C1 Tel Aviv Univ, Fac Life Sci, Dept Neurobiochem, IL-69978 Tel Aviv, Israel. Tel Aviv Sourasky Med Ctr, Wohl Inst Adv Imaging, Funct Brain Imaging Unit, Tel Aviv, Israel. NICHHD, Sect Tissue Biophys & Biomimet, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Assaf, Y (reprint author), Tel Aviv Univ, Fac Life Sci, Dept Neurobiochem, IL-69978 Tel Aviv, Israel. EM asafyan@zahav.net.il RI Basser, Peter/H-5477-2011 NR 45 TC 280 Z9 282 U1 0 U2 20 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2005 VL 27 IS 1 BP 48 EP 58 DI 10.1016/j.neuroimage.2005.03.042 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 948FK UT WOS:000230701200005 PM 15979342 ER PT J AU Birn, RM Bandettini, PA AF Birn, RM Bandettini, PA TI The effect of stimulus duty cycle and "off" duration on BOLD response linearity SO NEUROIMAGE LA English DT Article ID CEREBRAL BLOOD-FLOW; HUMAN VISUAL-CORTEX; HEMODYNAMIC-RESPONSE; BALLOON MODEL; REFRACTORY PERIOD; TEMPORAL DYNAMICS; BRAIN ACTIVATION; FMRI; ADAPTATION; MRI AB An ongoing question in functional MRI is precisely how measured signal changes relate to neuronal activity. While this question has been probed using animal models and electrophysiologic measures of neuronal activity, it has also been probed by examining, in humans, the spatial location, magnitude, and temporal dynamics of signal changes to well understood stimuli. With regard to dynamics, several earlier studies have revealed a larger than expected response to brief stimuli, hypothesized to result from nonlinearities in either the hemodynamics or the neuronal activity. In this study, we investigate the linearity of the increase in blood oxygenation level dependent (BOLD) contrast as a function of stimulus duty cycle, as well as the linearity of the decrease in BOLD as a function stimulus "off" duration. These findings not only shed further light on the mechanisms behind BOLD contrast but also give practical information as to what to keep in mind when performing and interpreting event related fMRI experiments. These experiments demonstrated: a) the BOLD signal decrease, on stimulus cessation, was smaller than predicted by a linear system-opposite to what has been reported in the literature associated with a signal increase, and b) the deconvolved event-related BOLD signal is highly dependent on duty cycle (the fraction of time activated vs. non-activated), Several potential mechanisms explaining these dynamics are discussed and modeled. We find that the experimental results are most consistent with a nonlinear neuronal response, but do not rule out significant effects of nonlinear hemodynamic factors, in particular the nonlinear relationship between oxygen extraction fraction and blood flow. Published by Elsevier Inc. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Birn, RM (reprint author), NIMH, Lab Brain & Cognit, 10 Ctr Dr,Bldg 10,Room 1D80, Bethesda, MD 20892 USA. EM rbirn@nih.gov FU Intramural NIH HHS NR 29 TC 37 Z9 39 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2005 VL 27 IS 1 BP 70 EP 82 DI 10.1016/j.neuroimage.2005.03.040 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 948FK UT WOS:000230701200007 PM 15914032 ER PT J AU Schaefer, M Heirize, HJ Rotte, M AF Schaefer, M Heirize, HJ Rotte, M TI Task-relevant modulation of primary somatosensory cortex suggests a prefrontal-cortical sensory gating system SO NEUROIMAGE LA English DT Article DE short-term plasticity; somatosensory cortex; magnetoencephalography; prefrontal cortex; Tower of Hanoi; gating ID FUNCTIONAL-ORGANIZATION; LONDON TASK; HUMANS; REPRESENTATION; ACTIVATION; SHIFTS; MOVEMENTS; ATTENTION; MEMORY; INPUT AB Increasing evidence suggests that somatosensory information is modulated cortically for task-specific sensory inflow: Several studies report short-term adaptation of representational maps in primary somatosensory cortex (SI) due to attention or induced by task-related motor activity such as handwriting. Recently, it has been hypothesized that the frontal or prefrontal cortex may modulate SI. In order to test this hypothesis, we studied the functional organization of SI while subjects performed the Tower of Hanoi task. This task is known to be related to activation of frontal or prefrontal areas. The functional organization of SI while performing the Tower of Hanoi task was compared to the organization of SI during performing the same movements but without the Tower of Hanoi task and with rest. Topography of SI was assessed using neuromagnetic source imaging based on tactile stimulation of the first (D1) and fifth digits (D5). Performing the Tower of Hanoi task was accompanied by plastic changes in SI as indicated by significant shifts in the cortical representations of D1 and D5: They moved further apart during the Tower of Hanoi task compared to the control task containing the same movements but without the cognitive characteristic. Thus, we conclude that SI maps undergo dynamic modulation depending on motor tasks with different cognitive demands. The results suggest that this short-term plasticity may be regulated by a prefrontal-cortical sensory gating system. (c) 2005 Elsevier Inc. All rights reserved. C1 NINDS, Human Cortical Physiol Sect, NIH, Bethesda, MD 20892 USA. Otto Von Guericke Univ, Dept Neurol 2, D-39120 Magdeburg, Germany. RP Schaefer, M (reprint author), NINDS, Human Cortical Physiol Sect, NIH, Bldg 10,Room 5N234, Bethesda, MD 20892 USA. EM schaefem@ninds.nih.gov NR 35 TC 20 Z9 21 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2005 VL 27 IS 1 BP 130 EP 135 DI 10.1016/j.neuroimage.2005.04.005 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 948FK UT WOS:000230701200012 PM 15886021 ER PT J AU Yang, SL Ross, TJ Zhang, YQ Stein, EA Yang, YH AF Yang, SL Ross, TJ Zhang, YQ Stein, EA Yang, YH TI Head motion suppression using real-time feedback of motion information and its effects on task performance in fMRI SO NEUROIMAGE LA English DT Article DE head motion; real-time fMRI; feedback ID FUNCTIONAL MRI; WORKING-MEMORY; SERIES; BRAIN; REGISTRATION; PHYSIOLOGY; ARTIFACTS; ALGORITHM; ROTATION; TRACKING AB A voluntary head motion suppression method using feedback to subjects of their own head motion information is demonstrated. A real-time fMRI system was developed on standard MR imaging hardware for this purpose. The head motion information was simplified as a four-way arrow display that changed color from green to red when a composite head motion index went beyond a specified threshold. The arrow indicators were integrated into a version of the commonly used visual N-BACK task. Results suggest a significant suppression of head motion consistently in all subjects while the influence on task performance and brain activation was minimal. It is proposed that under certain experimental conditions, voluntary head motion suppression may feasibly be employed without significant compromise of fMRI data. Published by Elsevier Inc. C1 NIDA, Neurosimaging Res Branch, NIH, Baltimore, MD 21224 USA. RP Yang, YH (reprint author), NIDA, Neurosimaging Res Branch, NIH, 5500 Nathan Shock Dr,Room 383, Baltimore, MD 21224 USA. EM yihongyang@intra.nida.nih.gov RI Ross, Thomas/B-7469-2008; Stein, Elliot/C-7349-2008 OI Ross, Thomas/0000-0002-7745-3572; NR 35 TC 16 Z9 17 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2005 VL 27 IS 1 BP 153 EP 162 DI 10.1016/j.neuroimage.2005.02.050 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 948FK UT WOS:000230701200015 PM 16023040 ER PT J AU Slawecki, CJ Thorsell, AK El Khoury, A Mathe, AA Ehlers, CL AF Slawecki, CJ Thorsell, AK El Khoury, A Mathe, AA Ehlers, CL TI Increased CRF-like and NPY-like immunoreactivity in adult rats exposed to nicotine during adolescence: Relation to anxiety-like and depressive-like behavior SO NEUROPEPTIDES LA English DT Article DE adolescent; nicotine; anxiety; depression; NPY; CRF ID CORTICOTROPIN-RELEASING-FACTOR; ELEVATED PLUS-MAZE; NEUROPEPTIDE-Y NPY; ANIMAL-MODEL; MOTOR-ACTIVITY; BRAIN-REGIONS; SWIM TEST; STRESS; EXPRESSION; RECEPTORS AB Objective: Recently, animal models have been developed that demonstrate that adolescent nicotine exposure produces neurobehavioral changes which persist into adulthood. This study further examined the impact of adolescent nicotine exposure on anxiety-like and depressive-like behavior, as well as on levels of corticotropin-releasing factor (CRF) and neuropeptide Y (NPY) in this model. Methods: Male adolescent rats (35-40 days old) were administered nicotine using Nicoderm CQ (TM) patches (Smith-Kline Beecham). Behavior in the elevated plus maze (EPM) and forced swim test (FST) was assessed 2-3 weeks after exposure ended. Brain levels of CRF and NPY were then assessed 5-6 weeks after behavioral tests were completed. In addition, blood and brain levels of nicotine resulting from nicotine treatment were examined. Results: After 5 days of exposure to 5 mg/kg/day nicotine, blood levels of nicotine averaged 66 +/- 5 ng/ml and brain nicotine levels averaged 52 +/- 4 ng/g. Rats exposed to nicotine displayed an anxiety-like profile in the EPM (i.e., decreased time spent in the open arms) and an antidepressant-like profile in the FST (i.e., less time spent immobile). Rats exposed to nicotine also had increased hypothalamic and frontal cortical CRF, increased hypothalamic and hippocampal NPY, and a decreased ratio of NPY to CRF in the amygdala. Conclusions: This study demonstrates that adolescent nicotine exposure produces lasting increases in anxiety-like behavior and may reduce depressive-like behavior. These behavioral changes also occurred in concert with alterations in CRF and NPY systems. Thus, lasting neurobehavioral changes associated with adolescent nicotine exposure may be related to allostatic changes in stress peptide systems. (c) 2005 Elsevier Ltd. All rights reserved. C1 Scripps Res Inst, Dept Neuropharmacol, CVN 14, La Jolla, CA 92037 USA. NIAAA, Div Intramural Clin & Biol Res, Bethesda, MD USA. Karolinska Inst, Neurotec Dept, Div Psychiat, Stockholm, Sweden. RP Slawecki, CJ (reprint author), Scripps Res Inst, Dept Neuropharmacol, CVN 14, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM cslawecki@scripps.edu OI Thorsell, Annika/0000-0003-3535-3845 FU NIAAA NIH HHS [AA06059] NR 64 TC 41 Z9 41 U1 1 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4179 J9 NEUROPEPTIDES JI Neuropeptides PD AUG PY 2005 VL 39 IS 4 BP 369 EP 377 DI 10.1016/j.npep.2005.06.002 PG 9 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 956ZK UT WOS:000231338700002 PM 16038974 ER PT J AU Marrazzo, A Caraci, F Salinaro, ET Su, TP Copani, A Ronsisvalle, G AF Marrazzo, A Caraci, F Salinaro, ET Su, TP Copani, A Ronsisvalle, G TI Neuroprotective effects of sigma-I receptor agonists against beta-amyloid-induced toxicity SO NEUROREPORT LA English DT Article DE beta-amyloid; neuronal apoptosis; sigma(1) receptor agonists ID ALZHEIMERS-DISEASE; NEURONAL DEATH; BINDING-SITES; PEPTIDE; BRAIN; APOPTOSIS; LIGAND; ISCHEMIA; DEFICITS; PRE-084 AB Prolonged exposure of cultured cortical neurons to the residue 25-35 fragment of P-amyloid protein, in the presence of dizocilpine, an antagonist of the N-methyl-D-aspartate receptor, and of 6,7-dinitroquinoxaline-2,3-dione, an antagonist of (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors, resulted in the expression of the proapoptotic protein Bax and neuronal death. Beta-amyloid protein(25-35)-induced neuronal death was substantially attenuated by the sigma(1), receptor agonist 2-(4-morpholinethyl) I phenylcyclohexanecarboxylate. The neuroprotective action of 2-(4-morpholinethyl)l-phenylcyclohexanecarboxylate was mimicked by the (71 ligand methyl (IS,2R)-2-[I-adamantyl(methyl)amino]methyl-I-phenylcyclopropanecarboxylate and was antagonized by the sigma(1), receptor antagonist N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine monohydrochloride. These results suggest that a, receptor agonists might function as neuroprotectant agents in Alzheimer's disease. C1 Univ Catania, Dept Pharmaceut Sci, I-95124 Catania, Italy. CNR, IBB, Catania, Italy. NIDA, Cellular Neurobiol Res Branch, NIH, Baltimore, MD 21224 USA. RP Copani, A (reprint author), Univ Catania, Dept Pharmaceut Sci, I-95124 Catania, Italy. EM acopani@katamail.com NR 21 TC 63 Z9 66 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 1 PY 2005 VL 16 IS 11 BP 1223 EP 1226 DI 10.1097/00001756-200508010-00018 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 953CV UT WOS:000231054700018 PM 16012353 ER PT J AU Butler, T Pan, H Epstein, J Protopopescu, X Tueschen, O Goldstein, M Cloitre, M Yang, YH Phelps, E Gorman, J Ledoux, J Stern, E Silbersweig, D AF Butler, T Pan, H Epstein, J Protopopescu, X Tueschen, O Goldstein, M Cloitre, M Yang, YH Phelps, E Gorman, J Ledoux, J Stern, E Silbersweig, D TI Fear-related activity in subgenual anterior cingulate differs between men and women SO NEUROREPORT LA English DT Article DE anticipatory anxiety; emotion; functional magnetic resonance imaging; instructed fear; sex; sex differences; ventromedial prefrontal cortex ID POSTTRAUMATIC-STRESS-DISORDER; MEDIAL PREFRONTAL CORTEX; GENDER-DIFFERENCES; SEX-DIFFERENCES; NEURAL BASIS; AMYGDALA; DEPRESSION; EMOTION; BRAIN; ACTIVATION AB Functional magnetic resonance imaging in association with an instructed fear/anticipatory anxiety paradigm was used to explore sex differences in the human fear response. During anticipation of mild electrodermal stimulation, women, as compared with men, demonstrated increased activity in the subgenual anterior cingulate cortex and functionally related regions of the insula and brainstem. The subgenual anterior cingulate cortex is a region critical for emotional control implicated in the pathogenesis of psychiatric disease. Present findings suggest a contributory neural substrate for the greater susceptibility of women to anxiety and affective disorders, and emphasize the importance of considering participant sex when designing and interpreting functional neuroimaging studies. C1 Cornell Univ, Weill Med Coll, Funct Neuroimaging Lab, Ithaca, NY 14853 USA. NYU, Dept Psychiat, Ctr Child Study, New York, NY 10016 USA. NYU, Dept Psychol, New York, NY 10016 USA. NYU, Ctr Neural Sci, New York, NY 10003 USA. NIDA, MRI Phys Unit, Neuroimaging Res Branch, NIH, Washington, DC USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. RP Butler, T (reprint author), Cornell Univ, Weill Med Coll, Funct Neuroimaging Lab, Ithaca, NY 14853 USA. EM tab2006@med.cornell.edu RI Stern, Emily/E-6035-2011 FU NIMH NIH HHS [5-P50MH58911] NR 25 TC 38 Z9 39 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 1 PY 2005 VL 16 IS 11 BP 1233 EP 1236 DI 10.1097/00001756-200508010-00020 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 953CV UT WOS:000231054700020 PM 16012355 ER PT J AU Corrigall, W AF Corrigall, W TI Translating neuroscience to practice: Efforts related to tobacco addiction at the National Institutes of Health SO NICOTINE & TOBACCO RESEARCH LA English DT Meeting Abstract C1 Corrigall Consulting, NIDA, Thornhill, ON, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD AUG PY 2005 VL 7 IS 4 BP 659 EP 659 PG 1 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 972SY UT WOS:000232474700045 ER PT J AU Heishman, SJ Myers, CS Taylor, RC Moolchan, ET AF Heishman, SJ Myers, CS Taylor, RC Moolchan, ET TI Dose-related effects of nicotine nasal spray on cognitive processing SO NICOTINE & TOBACCO RESEARCH LA English DT Meeting Abstract C1 NIDA, Intramural Res Program, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD AUG PY 2005 VL 7 IS 4 BP 695 EP 695 PG 1 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 972SY UT WOS:000232474700099 ER PT J AU Engelke, UFH Tangerman, A Willemsen, MAAP Moskau, D Loss, S Mudd, SH Wevers, RA AF Engelke, UFH Tangerman, A Willemsen, MAAP Moskau, D Loss, S Mudd, SH Wevers, RA TI Dimethyl sulfone in human cerebrospinal fluid and blood plasma confirmed by one-dimensional H-1 and two-dimensional H-1-C-13 NMR SO NMR IN BIOMEDICINE LA English DT Article DE H-1-NMR spectroscopy; dimethyl sulfone; methionine adenosyltransferase I/III deficiency; methanethiol metabolism; H2S metabolism ID MAGNETIC-RESONANCE SPECTROSCOPY; HIGH-RESOLUTION H-1-NMR; HYDROGEN-SULFIDE; HUMAN BRAIN; METABOLISM; METHIONINE; SULFOXIDE; METHYLSULFONYLMETHANE; IDENTIFICATION; METHANETHIOL AB H-1-NMR spectroscopy at 500 MHz was used to confirm that a previously unidentified singlet resonance at 3.14ppm in the spectra of cerebrospinal fluid and plasma samples corresponds to dimethyl sulfone (DMSO2). A triple resonance inverse cryogenic NMR probe, with pre-amplifier and the RF-coils cooled to low temperature, was used to obtain an H-1-C-13 HSQC spectrum of CSF containing 8 mu m (753 ng/ml) DMSO2. The H-1-C-13 correlation signal for DMSO2 was assigned by comparison with the spectrum from an authentic reference sample. In plasma and CSF from healthy controls, the concentration of DMSO2 ranged between 0 and 25 mu mol/l. The concentration of DMSO2 in plasma from three of four patients with severe methionine adenosyltransferase I/III (MAT I/III) deficiency was about twice the maximum observed for controls. Thus, DMSO2 occurs as a regular metabolite at low micromolar concentrations in cerebrospinal fluid and plasma. It derives from dietary sources, from intestinal bacterial metabolism and from human endogenous methanethiol metabolism. Copyright (c) 2005 John Wiley & Sons, Ltd. C1 Radboud Univ, Nijmegen Med Ctr, Div Gastroenterol & Hepatol, NL-6525 HB Nijmegen, Netherlands. Radboud Univ, Nijmegen Med Ctr, Dept Pediat Neurol, NL-6525 HB Nijmegen, Netherlands. Bruker BioSpin AG, CH-8117 Fallanden, Switzerland. NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Wevers, RA (reprint author), Radboud Univ, Nijmegen Med Ctr, Neurol Inst, Lab Pediat & Neurol, Reinier Postlaan 4, NL-6525 GC Nijmegen, Netherlands. EM r.wevers@cukz.umcn.nl RI Willemsen, Michel/H-8119-2014; Wevers, Ron/H-8116-2014; Engelke, U.F.H./L-4293-2015 OI Wevers, Ron/0000-0003-2278-9746; NR 25 TC 39 Z9 40 U1 1 U2 8 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD AUG PY 2005 VL 18 IS 5 BP 331 EP 336 DI 10.1002/nbm.966 PG 6 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 957LY UT WOS:000231372500007 PM 15996001 ER PT J AU Seneca, N Andree, B Sjoholm, N Schou, M Pauli, S Mozley, PD Stubbs, JB Liow, JS Sovago, J Gulyas, B Innis, R Halldin, C AF Seneca, N Andree, B Sjoholm, N Schou, M Pauli, S Mozley, PD Stubbs, JB Liow, JS Sovago, J Gulyas, B Innis, R Halldin, C TI Whole-body biodistribution, radiation dosimetry estimates for the PET norepinephrine transporter probe (S,S)-[F-18]FMeNER-D-2 in non-human primates SO NUCLEAR MEDICINE COMMUNICATIONS LA English DT Article DE (S,S)-[F-18]FMeNER-D-2; norepinephrine transporter; dosimetry; whole-body biodistribution; PET; positron emission tomography ID POSITRON EMISSION TOMOGRAPHY; HEART; RADIOTRACER; DEPRESSION; DOPAMINE; BRAIN AB Background (S,S)[F-18]FMeNER-D-2 is a recently developed norepinephrine transporter ligand which is a potentially useful radiotracer for mapping the brain and heart norepinephrine transporter in vivo using positron emission tomography. In this work, we quantified the biodistribution over time and radiation exposure to multiple organs with (S,S)[F-18]FMeNER-D-2. Methods Whole-body images were acquired for 21 time points in two cynomolgus monkeys for approximately 270 min after injection of radioligand. Compressed 3-D to 2-D planar images were used to identify organs with the highest radiation exposure at each time point. Estimates of the absorbed dose of radiation were calculated using the MIRDOSE 3.1 software program performed with the dynamic bladder and ICRP 30 gastrointestinal tract models. Results In planar images, peak values of the percent injected dose (%ID) at a time after radioligand injection were calculated for the lungs (26.76% ID at 1.42 min), kidneys (13.55% 1 D at 2.18 min), whole brain (5.65% 1 D at 4.48 min), liver (7.20% I D at 2 min), red bone marrow (5.02% ID at 2.06 min), heart (2.36% 1 D at 1.42 min) and urinary bladder (23% ID at 250 min). Assuming a urine voiding interval of 2.4 h, the four organs with highest exposures in mu Gy center dot MBq(-1) (mrad center dot mCi(-1)) were kidneys 126 (468), heart wall 108 (399), lungs 88.4 (327) and urinary bladder 114 (422). The effective doses were estimated with and without urine voiding at a range of 123 (33) and to 131 (35.5) mu Gy center dot MBq(-1) (mrad center dot mCi(-1)). Conclusion The estimated radiation burden of (S,S)[F-18]FMeNER-D-2 is comparable to that of other F-18 radioligands. C1 Karolinska Inst, Dept Clin Neurosci, Karolinska Hosp, Stockholm, Sweden. NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. Radiat Dosimetry Syst Inc, Alpharetta, GA USA. RP Seneca, N (reprint author), Karolinska Hosp & Inst, Psychiat Sect, Dept Clin Neurosci, Karolinska Inst, S-17176 Stockholm, Sweden. EM Nick.Seneca@cns.ki.se RI Sovago, Judit/G-7961-2011; Gulyas, Balazs/F-9508-2015 NR 25 TC 12 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0143-3636 J9 NUCL MED COMMUN JI Nucl. Med. Commun. PD AUG PY 2005 VL 26 IS 8 BP 695 EP 700 DI 10.1097/01.mnm.0000171780.72908.e7 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 953CT UT WOS:000231054500004 PM 16000987 ER PT J AU Franks, PW Brage, S Luan, J Ekelund, U Rahman, M Farooqi, IS Halsall, I O'Rahilly, S Wareham, NJ AF Franks, PW Brage, S Luan, J Ekelund, U Rahman, M Farooqi, IS Halsall, I O'Rahilly, S Wareham, NJ TI Leptin predicts a worsening of the features of the metabolic syndrome independently of obesity SO OBESITY RESEARCH LA English DT Article DE metabolic syndrome; insulin resistance; glucose intolerance; prospective cohort study; hyperleptinemia ID HABITUAL ENERGY-EXPENDITURE; ACTIVATED PROTEIN-KINASE; WEIGHT-GAIN; PLASMA LEPTIN; SERUM LEPTIN; INSULIN-RESISTANCE; ADIPOSE-TISSUE; VENTROMEDIAL HYPOTHALAMUS; CARDIORESPIRATORY FITNESS; PHYSICAL-ACTIVITY AB Objective: The term metabolic syndrome (MS) describes a cluster of cardiovascular risk factors including dyslipidemia, glucose intolerance, insulin resistance, and hypertension. Obesity increases the risk of MS, but as obesity is neither necessary nor sufficient to cause the syndrome, there is considerable interest in identifying obesity-independent pathways. One such pathway may involve the actions of the adipokine leptin, which is associated cross-sectionally with MS and prospectively with coronary heart disease and stroke, independently of obesity. Our goal was to test the hypothesis that leptin predicts the development of the features of MS independently of obesity. Research Methods and Procedures: This study used a prospective population-based cohort of 748 middle-aged whites in whom baseline measures of leptin and repeated measurement of the subcomponents of the MS at 5 and 10 years were available. The features of the MS were characterized as five factors (obesity, dyslipidemia, elevated blood pressure, glucose intolerance, and insulin resistance), which were combined to create an MS summary score. Results: Baseline leptin significantly predicted the development of obesity (p = 0.001) and, after adjustment for BMI, development of glucose intolerance (p = 0.016) and insulin resistance (p < 0.0001). Leptin levels did not independently predict a change in lipids or blood pressure. Leptin levels significantly predicted the development of the MS (p = 0.036), independently of baseline BMI. Discussion: Leptin predicts the development of the MS independently of baseline obesity. This association is specifically related to the development of glucose intolerance and insulin resistance. The extent to which these relationships are explained through residual confounding by obesity remains to be determined. C1 NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85014 USA. MRC, Epidemiol Unit, Cambridge, England. Univ Cambridge, Inst Publ Hlth, Cambridge CB2 1TN, England. Addenbrookes Hosp, Dept Clin Biochem, Cambridge, England. Addenbrookes Hosp, Dept Med, Cambridge, England. RP Franks, PW (reprint author), NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM pfranks@niddk.nih.gov RI Ekelund, Ulf/A-1046-2008; Brage, Soren/C-6415-2013 OI Brage, Soren/0000-0002-1265-7355 FU Wellcome Trust [, 068086] NR 60 TC 95 Z9 106 U1 0 U2 3 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD AUG PY 2005 VL 13 IS 8 BP 1476 EP 1484 DI 10.1038/oby.2005.178 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 963XD UT WOS:000231838700024 PM 16129731 ER PT J AU Myslobodsky, MS AF Myslobodsky, MS TI Laparophobia: a cognitive perspective on appetite control in anorexia nervosa SO OBESITY REVIEWS LA English DT Review DE environmental autonomy syndrome; hyperactivity; interventional neuropsychiatry; phobia ID POSITRON-EMISSION-TOMOGRAPHY; NUCLEUS-ACCUMBENS SHELL; ACOUSTIC STARTLE REFLEX; BODY-IMAGE DISTORTION; IN-VIVO MICRODIALYSIS; FOOD-INTAKE; EATING-DISORDERS; WEIGHT-GAIN; SODIUM VALPROATE; STRIA TERMINALIS AB Decades of research have demonstrated that anorexia nervosa (AN) may be associated with aberrant cognition, yet, its role in maintaining stringent dieting has received relatively little attention from mainstream researchers of eating disorders. The purpose of the present article is to highlight cognitive ('top-down') factors that are considered responsible for anticipatory anxiety of stoutness and frank fat-phobia (laparophobia). A cognitive model proposed departs from the formulation suggesting that phobia of over caring is superimposed on avoidant tendencies ('environmental autonomy syndrome'), whereas excessive exercising becomes a natural coping strategy with laparophobia, an instrument of reward. AN ideation involves complex neuronal circuitries and multiple neurochemical components that may conceivably represent a mirror image of those underlying obesity. The emphasis on phobia and aberrant membrane excitability akin to channelopathies behoves the clinicians to be aware of potential uses of drugs acting at the gamma-aminobutyric acid and the N-methyl-D-aspartate/AMPA [2-amino3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid] receptors sites as the adjuncts to conventional agents in managing AN. C1 NIMH, Cerebral Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Howard Univ, Washington, DC 20059 USA. RP Myslobodsky, MS (reprint author), NIMH, Cerebral Brain Disorders Branch, NIH, 10 Ctr Dr,4S-235 MSC 1379, Bethesda, MD 20892 USA. EM myslobom@intra.nimh.nih.gov NR 134 TC 0 Z9 0 U1 2 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1467-7881 J9 OBES REV JI Obes. Rev. PD AUG PY 2005 VL 6 IS 3 BP 217 EP 228 DI 10.1111/j.1467-789X.2005.00188.x PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 974VF UT WOS:000232618800009 PM 16045637 ER PT J AU Basso, O Nohr, EA Olsen, J Christensen, K AF Basso, O Nohr, EA Olsen, J Christensen, K TI Relationship of maternal body mass index and height to twinning SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ Aarhus, Inst Publ Hlth, Danish Epidemiol Sci Ctr, Aarhus, Denmark. Univ So Denmark, Odense, Denmark. RP Basso, O (reprint author), NIEHS, Epidemiol Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM bassoo2@niehs.nih.gov RI Christensen, Kaare/C-2360-2009 OI Christensen, Kaare/0000-0002-5429-5292 NR 2 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2005 VL 106 IS 2 BP 411 EP 411 DI 10.1097/01.AOG.0000173416.41358.79 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 948LR UT WOS:000230717800033 PM 16055604 ER PT J AU Reddy, U Branum, A Klebanoff, M AF Reddy, U Branum, A Klebanoff, M TI Relationship of maternal body mass index and height to twinning - Reply SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 NICHHD, Pregnancy & Perinatol Branch, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Infant Child & Womens Hlth Stat Branch, Natl Ctr Hlth Stat, Atlanta, GA USA. NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Reddy, U (reprint author), NICHHD, Pregnancy & Perinatol Branch, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2005 VL 106 IS 2 BP 411 EP 411 DI 10.1097/01.AOG.0000169607.78155.7f PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 948LR UT WOS:000230717800034 ER PT J AU Ivy, SP AF Ivy, SP TI Cancer management in patients with end-stage renal disease - The Eneman/Philips article reviewed SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID DYSFUNCTION-WORKING-GROUP; OXALIPLATIN C1 Natl Canc Inst, Invest Drug Branch Canc Therapy Evaluat Program, Rockville, MD USA. RP Ivy, SP (reprint author), Natl Canc Inst, Invest Drug Branch Canc Therapy Evaluat Program, Rockville, MD USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD AUG PY 2005 VL 19 IS 9 BP 1212 EP 1213 PG 2 WC Oncology SC Oncology GA 052EO UT WOS:000238214500019 ER PT J AU Yeudall, WA Miyazaki, H Ensley, JF Cardinali, M Gutkind, JS Patel, V AF Yeudall, WA Miyazaki, H Ensley, JF Cardinali, M Gutkind, JS Patel, V TI Uncoupling of epidermal growth factor-dependent proliferation and invasion in a model of squamous carcinoma progression SO ORAL ONCOLOGY LA English DT Article DE squamous cell carcinoma; metastasis; invasion; growth factor ID ACTIVATED PROTEIN-KINASE; BREAST EPITHELIAL-CELLS; MATRIX METALLOPROTEINASE-7; PLASMINOGEN-ACTIVATOR; GENE-EXPRESSION; COLON-CANCER; IN-VITRO; MATRIX-METALLOPROTEINASE-9 EXPRESSION; EXPERIMENTAL METASTASIS; MATRILYSIN EXPRESSION AB Cell lines pairs were established from a primary squamous carcinoma of tongue and a lymph node metastasis and their biological behavior characterized. HN12 cells, derived from metastatic SCC, formed tumors upon subcutaneous transplantation to athymic mice, whereas HN4, derived from a primary lesion in the same individual, were non-tumorigenic in this assay. EGF stimulated proliferation of HN4 cells; in comparison, not only were metastatic HN12 cells refractory to the stimulatory effects of this growth factor but showed inhibition at higher growth factor concentrations. However, in contrast to the effects on proliferation, EGF (10 ng/ml) readily induced HN12 cells to invade in Boyden chamber assays whereas HN4 were non-invasive under these conditions. The invasive properties of HN12 cells were apparently independent of MMP-2 activity, as levels of active MMP-2 were higher in the non-invasive cells. However, EGF stimulated MMP-9 activity in invasive cells. Additionally, HN12 cells expressed constitutively high levels of active MMP-7 and MMP-3/10. The pharmacological agents LY294002, PD098059, SP600125, or SB202190 inhibited invasion of HN12 cells, suggesting requirement for phosphoinositide 3-OH kinase- and mitogen activated protein kinase-dependent pathways in the process. The data indicate that distinct biochemical differences distinguish metastatic squamous carcinoma cells from those derived from corresponding primary tumors, resulting in their contrasting biological properties. (c) 2005 Elsevier Ltd. All rights reserved. C1 Virginia Commonwealth Univ, Philips Inst Oral & Craniofacial Mol Biol, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Dept Biochem, Richmond, VA 23298 USA. Wayne State Univ, Karmanos Canc Inst, Div Hematol Oncol, Detroit, MI 48201 USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. RP Yeudall, WA (reprint author), Virginia Commonwealth Univ, Philips Inst Oral & Craniofacial Mol Biol, POB 980566,521 N 11th St, Richmond, VA 23298 USA. EM wayeudall@vcu.edu RI Gutkind, J. Silvio/A-1053-2009 NR 81 TC 19 Z9 20 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD AUG PY 2005 VL 41 IS 7 BP 698 EP 708 DI 10.1016/j.oraloncology.2005.03.004 PG 11 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 954BI UT WOS:000231128700007 PM 15935723 ER PT J AU Nathan, PC Long, L Bernstein, D Mackall, CL Helman, LJ Tsokos, M Wexler, LH AF Nathan, PC Long, L Bernstein, D Mackall, CL Helman, LJ Tsokos, M Wexler, LH TI Effectiveness of chemotherapy in non-rhabdomyosarcoma soft tissue sarcomas - Response SO PEDIATRIC BLOOD & CANCER LA English DT Letter C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Helman, LJ (reprint author), NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. EM helmanl@nih.gov NR 1 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 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2005 VL 45 IS 2 BP 228 EP 228 DI 10.1002/pbc.20393 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 942KC UT WOS:000230280300022 ER PT J AU Chelimo, K Ofulla, AV Narum, DL Kazura, JW Lanar, DE John, CC AF Chelimo, K Ofulla, AV Narum, DL Kazura, JW Lanar, DE John, CC TI Antibodies to Plasmodium falciparum antigens vary by age and antigen in children in a malaria-holoendemic area of Kenya SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE malaria; IgG; liver stage antigen-1; thrombospondin-related adhesive protein; circurnsporozoite protein; apical membrane antigen-1; erythrocyte-binding antigen-175; merozoite surface protein-1; child ID APICAL MEMBRANE ANTIGEN-1; LIVER-STAGE ANTIGEN-1; CIRCUMSPOROZOITE PROTEIN; CLINICAL MALARIA; SURFACE-ANTIGEN; RESPONSES; INFANTS; TRANSMISSION; INFECTION; INVASION AB Background: Antibodies are important in protection against infection and disease caused by Plasmodium falciparum, but the frequencies of antibodies to multiple P. falciparum antigens in children are not well-characterized. Methods: IgG and IgM antibodies to the vaccine candidate antigens circurnsporozoite protein, thrombospondin-related adhesive protein, liver stage antigen-1, apical membrane antigen-1, erythrocyte-binding antigen-175 and merozoite surface protein-1 were measured by enzyme-linked immunosorbent assay in 110 children 0-50 months of age in a malaria holoendemic area of Kenya. Results: A similar pattern was seen for IgG antibodies to circumsporozoite protein, thrombospondin-related adhesive protein, apical membrane antigen-1 and erythrocyte-binding antigen-175: high frequencies (70-90%) in children 0-4 months of age; a decrease in children 5-20 months of age (35-71%); and progressive increases in children 21-36 and 37-50 months of age (53-80% and 60-100%, respectively). In contrast, IgG antibodies to liver stage antigen-1 were infrequent in children 0-4 months of age (5%) and increased with age to 64%, and IgG antibody frequencies to merozoite surface protein-1 were similar across age groups (26-52%). IgG antibodies to all antigens were predominantly of the IgG1 and IgG3 subclasses. Frequencies of IgM antibodies to all antigens were low in children 0-4 months of age (0-15%) and increased with age (24-56% in the oldest children). Conclusion: In children in a malaria-holoendemic area, IgM antibody to all P. falciparum antigens is infrequent in the first 4 months of life but increases with age and increased exposure. The pattern of age-related IgG response frequencies to P. falciparum antigens varies significantly by antigen. C1 Rainbow Babies & Childrens Hosp, Rainbow Ctr Int Child Hlth, Cleveland, OH 44106 USA. Rainbow Babies & Childrens Hosp, Div Pediat Infect Dis, Cleveland, OH 44106 USA. Maseno Univ, Dept Biomed Sci & Technol, Maseno, Kenya. Kenya Govt Med Res Ctr, Kisian, Kenya. NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Ctr Global Hlth & Dis, Cleveland, OH 44106 USA. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Washington, DC 20307 USA. RP John, CC (reprint author), Rainbow Babies & Childrens Hosp, Rainbow Ctr Int Child Hlth, RBC 487,11100 Euclid Ave,MS 6008, Cleveland, OH 44106 USA. EM chandy.john@case.edu RI John, Chandy/B-4164-2008; Lanar, David/B-3560-2011 FU NIAID NIH HHS [AI 43906] NR 22 TC 17 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD AUG PY 2005 VL 24 IS 8 BP 680 EP 684 DI 10.1097/01.inf.0000172151.28851.fd PG 5 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 958EQ UT WOS:000231427900004 PM 16094220 ER PT J AU Zaoutis, TE Coffin, SE Chu, JH Heydon, K Zhao, HQ Greves, HM Walsh, TJ AF Zaoutis, TE Coffin, SE Chu, JH Heydon, K Zhao, HQ Greves, HM Walsh, TJ TI Risk factors for mortality in children with candidemia SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE pediatric; candidemia; fungal infections; invasive candidiasis; mortality ID PEDIATRIC-PATIENTS; UNITED-STATES; INFECTIONS; EPIDEMIOLOGY; CANDIDIASIS AB We performed a retrospective cohort study of hospitalized children with positive blood cultures for Candida species. Independent risk factors for mortality by multivariable analysis were location in the pediatric intensive care unit at the time of infection (hazard ratio, 6.3; 95% confidence interval, 1.6-24.3) and the presence of an arterial catheter (hazard ratio, 2.4; 95% confidence interval, 1.1-5.8). Our findings help identify a group of pediatric patients that should be targeted for future interventions to prevent and treat candidemia. C1 Childrens Hosp Philadelphia, Div Infect Dis, Philadelphia, PA 19104 USA. Childrens Hosp Philadelphia, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Educ & Res Therapeut, Philadelphia, PA 19104 USA. Univ Washington, Sch Med, Childrens Hosp & Reg Med Ctr, Dept Pediat, Seattle, WA 98195 USA. NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Zaoutis, TE (reprint author), Childrens Hosp Philadelphia, Div Infect Dis, 34th & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM zaoutis@email.chop.edu FU AHRQ HHS [U-18-HS10399] NR 12 TC 32 Z9 34 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD AUG PY 2005 VL 24 IS 8 BP 736 EP 739 DI 10.1097/01.inf.0000172938.76561.8e PG 4 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 958EQ UT WOS:000231427900018 PM 16094234 ER PT J AU Chamberlain, CE FitzGibbon, E Wassermann, EM Butman, JA Kettl, D Hale, D Kirk, AD Mannon, RB AF Chamberlain, CE FitzGibbon, E Wassermann, EM Butman, JA Kettl, D Hale, D Kirk, AD Mannon, RB TI Idiopathic intracranial hypertension following kidney transplantation: A case report and review of the literature SO PEDIATRIC TRANSPLANTATION LA English DT Review DE idiopathic intracranial hypertension; tacrolimus; papilledema; kidney transplant; headache ID PSEUDOTUMOR CEREBRI; RENAL-TRANSPLANTATION; IRON-DEFICIENCY; DISK EDEMA; ACETAZOLAMIDE; CYCLOSPORINE; CHILDREN; ANEMIA AB A pediatric kidney transplant recipient receiving tacrolimus for immunosuppression experienced symptoms consistent with idiopathic intracranial hypertension. The diagnosis of idiopathic intracranial hypertension and possible secondary causes of intracranial hypertension are reviewed in association with the patient's clinical course. Treatment options for the reversal of intracranial hypertension are summarized. Because of the complexity of associated conditions in kidney transplant recipients, symptoms of persistent headaches, visual changes and nausea and vomiting should be promptly investigated by fundoscopic examination in the setting of immunosuppression therapy to prevent vision loss. C1 NEI, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. NINDS, Brain Stimulat Unit, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. Georgetown Univ Fac, Rockville, MD USA. NIDDKD, Transplantat Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Chamberlain, CE (reprint author), Room 1N257,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM cchamberla@nih.gov RI Butman, John/A-2694-2008; Kirk, Allan/B-6905-2012; OI Butman, John/0000-0002-1547-9195 NR 21 TC 6 Z9 6 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1397-3142 J9 PEDIATR TRANSPLANT JI Pediatr. Transplant. PD AUG PY 2005 VL 9 IS 4 BP 545 EP 550 DI 10.1111/j.1399-3046.2005.00329.x PG 6 WC Pediatrics; Transplantation SC Pediatrics; Transplantation GA 949VP UT WOS:000230816500022 PM 16048612 ER PT J AU Lynch, JK Han, CJ Nee, LE Nelson, KB AF Lynch, JK Han, CJ Nee, LE Nelson, KB TI Prothrombotic factors in children with stroke or porencephaly SO PEDIATRICS LA English DT Article DE cerebrovascular diseases; children; coagulation; genetic polymorphisms ID FACTOR-V-LEIDEN; ARTERIAL ISCHEMIC-STROKE; RISK-FACTORS; METHYLENETETRAHYDROFOLATE REDUCTASE; PROTEIN-C; CEREBRAL THROMBOEMBOLISM; VENOUS THROMBOSIS; VASCULAR-DISEASE; CHILDHOOD STROKE; PEDIATRIC STROKE AB Objective. This study compared the frequencies of genetic and functional coagulation abnormalities in children with arterial ischemic stroke or porencephaly with frequencies in previously published studies. Methods. A series of 59 children ( age 0-18 years) with arterial ischemic stroke or porencephaly were referred to the National Institutes of Health. A blood sample, buccal smear sample, questionnaire, and pedigree were requested for each child. Blood samples were analyzed for protein C (PC); protein S; antithrombin (AT); activated PC resistance (APCR); lipoprotein ( a) [Lp(a)]; lupus anticoagulant; anticardiolipin antibodies; and the methylenetetrahydrofolate reductase C677T (MTHFR), factor V G1619A, factor II G20210A (PT), plasminogen activator inhibitor-1 4G6755G, and tissue factor pathway inhibitor C536T mutations. The frequency of each coagulation abnormality was compared with published international pediatric stroke case and control rates. Results. At least 1 prothrombotic abnormality was identified in 63% (36 of 57) of children studied, including plasminogen activator inhibitor-1 4G6755G (15 of 56), MTHFR (12 of 56), elevated Lp(a) (12 of 59), APCR (11 of 58), factor V G1619A (5 of 57), PT (3 of 57), PC deficiency (1 of 59), and AT deficiency (1 of 59). The MTHFR mutation, elevated Lp(a), the PT mutation, and AT deficiency rates were similar to rates in cases and more common than control subjects in previously published studies. The rate of children with APCR or multiple abnormalities was higher than in previous pediatric stroke studies. A family history of early thrombosis was identified in one third of the children with a prothrombotic abnormality. Conclusions. Two thirds of children in this study had at least 1 of the prothrombotic risk factors tested, and several children had multiple risk factors. These results provide additional evidence that prothrombotic abnormalities are common among children with AIS or porencephaly. C1 NINDS, Neuroepidemiol Branch, Bethesda, MD 20892 USA. NINDS, Family Studies Unit, Bethesda, MD 20892 USA. RP Lynch, JK (reprint author), NINDS, Neuroepidemiol Branch, Bldg 10,Room 5S220,10 Ctr Dr,MSC 1447, Bethesda, MD 20892 USA. EM lynchj@ninds.nih.gov NR 50 TC 46 Z9 46 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 2005 VL 116 IS 2 BP 447 EP 453 DI 10.1542/peds.2004-1905 PG 7 WC Pediatrics SC Pediatrics GA 951FU UT WOS:000230915600038 PM 16061602 ER PT J AU Winter, JC Kieres, AK Zimmerman, MD Reissig, CJ Eckler, JR Ullrich, T Rice, KC Rabin, RA Richards, JB AF Winter, JC Kieres, AK Zimmerman, MD Reissig, CJ Eckler, JR Ullrich, T Rice, KC Rabin, RA Richards, JB TI The stimulus properties of LSD in C57BL/6 mice SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article; Proceedings Paper CT 34th Annual Meeting of the Society-for-Neuroscience CY OCT 23-27, 2004 CL San Diego, CA SP Soc Neurosci DE drug discrimination; DOM; LSD; M100907; mouse ID LYSERGIC-ACID DIETHYLAMIDE; INDUCED LOCOMOTOR-ACTIVITY; RECEPTOR MUTANT MICE; DISCRIMINATIVE-STIMULUS; COCAINE DISCRIMINATION; DRUG DISCRIMINATION; KNOCKOUT MICE; SEROTONIN; ANTAGONISTS; ETHANOL AB Rationale: Drug-induced stimulus control has proven to be a powerful tool for the assessment of a wide range of psychoactive drugs. Although a variety of species has been employed, the majority of studies have been in the rat. However, with the development of techniques which permit the genetic modification of mice, the latter species has taken on new importance. Lysergic acid diethylamide [LSD], the prototypic indoleamine hallucinogen, has not previously been trained as a discriminative stimulus in mice. Objective: To demonstrate the feasibility of LSD-induced stimulus control in the mouse and to provide a preliminary characterization of the stimulus properties of LSD in that species. Methods: Male C57BL/6 mice were trained using a left or right nose-poke operant on a fixed ratio 10, water reinforced task following the injection of lysergic acid diethylamide [LSD, 0.17 or 0.30 mg/kg, SC; 15 min pretreatment] or vehicle. Results: Stimulus control was established in 6 of 16 mice at a dose of LSD of 0.17 mg/kg after 39 sessions. An increase in dose to 0.30 mg/ kg for the remaining mice resulted in stimulus control in an additional 5 subjects. In the low dose group, subsequent experiments demonstrated an orderly dose-effect relationship for LSD and a rapid offset of drug action with an absence of LSD effects 60 min after injection. When LSD [0.17 mg/kg] was administered in combination with the selective 5-HT2A antagonist, M100907, LSD-appropriate responding was significantly but incompletely reduced to approximately 50%; concurrently, response rates declined significantly. In mice trained with a dose of LSD of 0.30 mg/kg, full generalization to the phenethylamine hallucinogen, [-]-2,5-dimethoxy-4-methylamphetamine [DOM] was observed. Conclusions: The present data demonstrate the feasibility of LSD-induced stimulus control in the mouse. The general features of stimulus control by LSD in the mouse closely resemble those observed in the rat but the present data suggest that there may be significant differences as well. (c) 2005 Elsevier Inc. All rights reserved. C1 Univ Buffalo, Dept Pharmacol & Toxicol, Sch Med & Biomed Sci, Buffalo, NY 14214 USA. Univ Buffalo, Res Inst Addict, Sch Med & Biomed Sci, Buffalo, NY 14214 USA. Univ Buffalo, Dept Pediat, Sch Med & Biomed Sci, Buffalo, NY 14214 USA. NIDDK, Med Chem Lab, Bethesda, MD 20892 USA. RP Winter, JC (reprint author), Univ Buffalo, Dept Pharmacol & Toxicol, Sch Med & Biomed Sci, 102 Farber Hall, Buffalo, NY 14214 USA. EM jcwinter@buffalo.edu FU NIDA NIH HHS [F31 DA013920, R21 DA014183, DA 16457, R01 DA003385, DA 13920, R01 DA003385-17, F31 DA016457, DA 14183, R56 DA003385, DA 03385] NR 60 TC 14 Z9 14 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD AUG PY 2005 VL 81 IS 4 BP 830 EP 837 DI 10.1016/j.pbb.2005.05.014 PG 8 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 965AQ UT WOS:000231922500016 PM 16005500 ER PT J AU Desai, RI Terry, P Katz, JL AF Desai, RI Terry, P Katz, JL TI A comparison of the locomotor stimulant effects of D-1-like receptor agonists in mice SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE dopamine D-1-like receptors; locomotor activity; cocaine; adenylyl cyclase; inositol phosphate; D-1-like agonists ID D-1 DOPAMINE AGONISTS; ETHOLOGICALLY BASED RESOLUTION; ADENYLATE-CYCLASE ACTIVITY; BEHAVIORAL TOPOGRAPHY; VARYING EFFICACIES; D1-RECEPTOR AGONISTS; OROFACIAL MOVEMENTS; RHESUS-MONKEYS; RATS; COCAINE AB Efficacy in stimulating adenylyl cyclase (AC) has traditionally been used to distinguish dopamine D-1-like receptor agonists from dopamine D-2-like receptor agonists. However, there is a limited association between the effects of D-1-like agonists in behavioral assays and their effectiveness at stimulating AC. Other second messenger actions might contribute to the behavioral effects of D-1-like agonists, as there is evidence for a link to the hydrolysis of phosphomositide (PI). The present study compared the locomotor stimulant effects of five D-1-like receptor agonists having different efficacies in assays of AC and PI activity. All D-1-like agonists produced long-lasting biphasic effects on locomotor activity. SKF 38393, the prototypical partial agonist (based on AC activity), produced limited changes in locomotor activity, whereas the partial agonists SKF 75670 and SKF 77434 produced locomotor stimulant effects that were similar to or greater than those of the full efficacy agonists SKF 82958 and SKF 81297. However, there did not appear to be a relationship between maximal behavioral effects and AC stimulation or PI hydrolysis. The results suggest a complex relationship between the behavioral effects of D-1-like agonists and their intrinsic efficacies as measured by AC and /or PI stimulation. Although a limited number of compounds were examined, neither second messenaer system alone appears to account fully for these behavioral effects. The current classification of D-1-like agonists according to their intrinsic efficacies as defined by AC stimulation needs further scrutiny. Published by Elsevier Inc. C1 NIDA, Med Discovery Res Branch, Psychobiol Sect, NIH,Intramural Res Program, Baltimore, MD 21224 USA. RP Katz, JL (reprint author), NIDA, Med Discovery Res Branch, Psychobiol Sect, NIH,Intramural Res Program, Bldg C,Room 327,5500 Nathan Shock Dr,POB 5180, Baltimore, MD 21224 USA. EM jkatz@intra.nida.nih.gov OI Katz, Jonathan/0000-0002-1068-1159 NR 45 TC 22 Z9 22 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD AUG PY 2005 VL 81 IS 4 BP 843 EP 848 DI 10.1016/j.pbb.2005.06.006 PG 6 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 965AQ UT WOS:000231922500018 PM 16000217 ER PT J AU Robertson, SM Scarsi, KK Postelnick, MJ Lynch, P AF Robertson, SM Scarsi, KK Postelnick, MJ Lynch, P TI Elevated plasma concentrations of protease inhibitors and nonnucleoside reverse transcriptase inhibitors in patients coinfected with human immunodeficiency virus and hepatitis B or C: Case series and literature review SO PHARMACOTHERAPY LA English DT Article DE hepatitis B; hepatitis C; coinfection; HIV; antiretroviral therapy; protease inhibitors; reverse transcriptase inhibitors ID HIV-POSITIVE PATIENTS; INFECTED PATIENTS; NELFINAVIR; NEPHROLITHIASIS; DISEASE AB Study Objective. To evaluate antiretroviral pharmacokinetics in patients who are coinfected with human immunodeficiency virus (HIV) and hepatitis B and/or C virus. Specifically, we sought to determine whether coinfection results in higher than expected concentrations of protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Design. Case series. Setting. Human immunodeficiency virus clinic. Patients. Twenty-six patients infected with HIV and hepatitis B and/or C virus. Measurements and Main Results. Patients' plasma trough concentrations (C-measured) of protease inhibitors and NNRTIs were compared with population average trough concentrations reported in the literature (C-predicted). Trough concentrations were obtained irrespective of the patients' liver function. A concentration ratio Of Cmeasured:Cpredicted was determined for each patient. The mean concentration ratio of the 26 patients was 1.43 (95% confidence interval 1.08-1.78). For the six patients taking nelfinavir, the ratio of nelfinavir's active metabolite (M8):parent drug was calculated. The median M8:nelfinavir ratio for these six patients was 69% lower than what has been reported in a general HIV population. Conclusion. These preliminary findings suggest that trough concentrations of protease inhibitors and NNRTIs may be elevated in patients with HIV infection who are coinfected with hepatitis B and/or C, compared with a general population of patients with HIV infection. Until further investigation defines the relationship between coinfection, metabolic dysfunction, and increased antiretroviral exposure, therapeutic drug monitoring may be helpful to identify coinfected patients at risk for antiretroviral toxicity secondary to elevated plasma drug concentrations. C1 NIH, Ctr Clin, Dept Pharm, Clin Pharmacokinet Res Lab, Bethesda, MD 20892 USA. NW Mem Hosp, Dept Pharm, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Robertson, SM (reprint author), NIH, Ctr Clin, Dept Pharm, Clin Pharmacokinet Res Lab, Bldg 10,Room 1 N 257, Bethesda, MD 20892 USA. EM robertsonsa@cc.nih.gov NR 21 TC 9 Z9 10 U1 0 U2 1 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD AUG PY 2005 VL 25 IS 8 BP 1068 EP 1072 DI 10.1592/phco.2005.25.8.1068 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 951NV UT WOS:000230938300005 PM 16207097 ER PT J AU Murakami, H Arnheiter, H AF Murakami, H Arnheiter, H TI Sumoylation modulates transcriptional activity of MITF in a promoter-specific manner SO PIGMENT CELL RESEARCH LA English DT Article DE melanocyte; transcription regulation; post-translational regulation; cooperation; Sox10 ID MELANOCYTE-SPECIFIC EXPRESSION; UBIQUITIN-CONJUGATING ENZYME; WAARDENBURG SYNDROME TYPE-2; DOPACHROME-TAUTOMERASE; SUMO-1 MODIFICATION; ANDROGEN RECEPTOR; MODIFIER-1 SUMO-1; FACTOR FAMILY; IN-VIVO; MICROPHTHALMIA AB The microphthalmia transcription factor MITF plays important roles in several cell lineages including retinal and neural crest-derived pigment cells. Previous reports have shown that besides its regulation at the transcriptional level, MITF is also regulated post-translationally by phosphorylation and ubiquitination which affect the protein's activity and stability. Here we demonstrate that in addition, MITF is modified in melanoma cells by small ubiquitin-like modifier (SUMO). In vitro assays further show that sumoylation occurs at two lysine residues, K182 and K316, and depends on SUMO E1 activating enzyme (SAE I/SAE II) and E2 conjugating enzyme (Ubc9). Interestingly, MITF with double lysine 182/316 to arginine mutations, although displaying normal DNA binding, stability and nuclear localization, shows a substantial increase in the transcriptional stimulation of promoters containing multiple but not single MITF binding sites. MITF containing the double lysine-to-arginine substitution also shows enhanced cooperation with Sox10 on the Dct promoter. We conclude that SUMO modification of MITF regulates the protein's transcriptional activity especially with respect to synergistic activation. The results suggest that sumoylation plays a significant role among the multiple mechanisms that regulate MITF during development and in adulthood. C1 NINDS, Mammalian Dev Sect, NIH, Bethesda, MD 20892 USA. RP Arnheiter, H (reprint author), NINDS, Mammalian Dev Sect, NIH, Bethesda, MD 20892 USA. EM ha3p@nih.gov FU NINDS NIH HHS [Z01 NS002790-17] NR 54 TC 52 Z9 52 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PD AUG PY 2005 VL 18 IS 4 BP 265 EP 277 DI 10.1111/j.1600-0749.2005.00234.x PG 13 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 946LO UT WOS:000230573900006 PM 16029420 ER PT J AU Smith, DL Dushoff, J Morris, JG AF Smith, DL Dushoff, J Morris, JG TI Agricultural antibiotics and human health - Does antibiotic use in agriculture have a greater impact than hospital use? SO PLOS MEDICINE LA English DT Editorial Material ID VANCOMYCIN-RESISTANT ENTEROCOCCI; ANTIMICROBIAL GROWTH PROMOTERS; FOOD ANIMALS POSE; FAECIUM; NETHERLANDS; EMERGENCE; PATHOGENS; RISK; POULTRY; SPREAD C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Princeton Univ, Dept Ecol & Evolutionary Biol, Res Staff, Princeton, NJ 08544 USA. Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Smith, DL (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM smitdave@helix.nih.gov RI Smith, David/L-8850-2013 OI Smith, David/0000-0003-4367-3849 NR 52 TC 52 Z9 54 U1 1 U2 25 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD AUG PY 2005 VL 2 IS 8 BP 731 EP 735 AR e232 DI 10.1371/journal.pmed.0020232 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 961QM UT WOS:000231676900019 PM 15984910 ER PT J AU Longo, DL AF Longo, Dan L. TI Radical prostatectomy for early stage prostate cancer SO POSTGRADUATE MEDICINE LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Longo, DL (reprint author), NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU VENDOME GROUP LLC PI NEW YORK PA 149 FIFTH AVE, 10TH FLOOR, NEW YORK, NY 10010 USA SN 0032-5481 J9 POSTGRAD MED JI Postgrad. Med. PD AUG PY 2005 VL 118 IS 2 BP 16 EP 17 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA V44DN UT WOS:000202983500005 ER PT J AU Longo, DL AF Longo, Dan L. TI Use of statin drugs may lower the risk of colorectal cancer SO POSTGRADUATE MEDICINE LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Longo, DL (reprint author), NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU VENDOME GROUP LLC PI NEW YORK PA 149 FIFTH AVE, 10TH FLOOR, NEW YORK, NY 10010 USA SN 0032-5481 J9 POSTGRAD MED JI Postgrad. Med. PD AUG PY 2005 VL 118 IS 2 BP 16 EP 16 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA V44DN UT WOS:000202983500004 ER PT J AU Longo, DL AF Longo, Dan L. TI Colonoscopy versus sigmoidoscopy in screening women for colorectal cancer SO POSTGRADUATE MEDICINE LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Longo, DL (reprint author), NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU VENDOME GROUP LLC PI NEW YORK PA 149 FIFTH AVE, 10TH FLOOR, NEW YORK, NY 10010 USA SN 0032-5481 J9 POSTGRAD MED JI Postgrad. Med. PD AUG PY 2005 VL 118 IS 2 BP 18 EP 18 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA V44DN UT WOS:000202983500008 ER PT J AU Sly, DF Arheart, K Dietz, N Trapido, EJ Nelson, D Rodriguez, R McKenna, J AF Sly, DF Arheart, K Dietz, N Trapido, EJ Nelson, D Rodriguez, R McKenna, J TI The outcome consequences of defunding the Minnesota youth tobacco-use prevention program SO PREVENTIVE MEDICINE LA English DT Article DE tobacco-use prevention; state tobacco budget cuts; state tobacco program elimination; youth tobacco use ID SMOKING; SETTLEMENT; INITIATION; CAMPAIGN AB Objective. To assess the immediate and intermediate outcome consequences of defunding a successful tobacco use prevention program. Methods. A four-survey repeated cross-sectional design is employed. Two surveys were completed while the program was fully operational, one after program dismantling was initiated and another about 6 months after the campaign was completely dismantled. Survey to survey trends for five immediate and six intermediate outcomes are analyzed. Changes in measures are tested employing chi-square estimated using SAS 8. Results. Each immediate outcome measure declined significantly from the third to the fourth survey except one, and this measure declined from the second to the third survey when it was eliminated. All intermediate outcomes showed significant change from the third or second to the fourth survey. These include two measures of openness to smoking, three attitude/belief scales and one measure of intention to smoke. Conclusions Defunding a successful tobacco-use prevention campaign results in rapid erosion of program messages, parallel increases in susceptibility, a rapid and sharp re-emergence of pro-tobacco attitudes/beliefs and a marked rise in intentions to smoke. (c) 2005 Elsevier Inc. All rights reserved. C1 Univ Miami, Sch Med, Dept Epidemiol & Publ Hlth, Tobacco Res & Evaluat Ctr, Miami, FL 33136 USA. Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Off Smoking & Hlth, Atlanta, GA 30341 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Sly, DF (reprint author), Univ Miami, Sch Med, Dept Epidemiol & Publ Hlth, Tobacco Res & Evaluat Ctr, Miami, FL 33136 USA. EM dsly@med.miami.edu NR 31 TC 21 Z9 21 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD AUG PY 2005 VL 41 IS 2 BP 503 EP 510 DI 10.1016/j.ypmed.2004.11.027 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 938MR UT WOS:000230008000018 PM 15917046 ER PT J AU Shavers, VL Lawrence, D Fagan, P Gibson, JT AF Shavers, VL Lawrence, D Fagan, P Gibson, JT TI Racial/ethnic variation in cigarette smoking among the civilian US population by occupation and industry, TUS-CPS 1998-1999 SO PREVENTIVE MEDICINE LA English DT Article DE race; ethnicity; smoking; occupation; workplace; industry ID AFRICAN-AMERICAN WOMEN; HEALTH; RISK; EXPERIENCES; PREVALENCE; STRESS AB Background. Although observational research studies have shown variance in the prevalence of smoking among occupations and industries, few have examined the role of race/ethnicity. This study examined racial/ethnic variation in the prevalence of current smoking and cigarette consumption patterns by occupation, industry and workplace smoking policy. Methods. Data were examined for 9095 African American (AA), 1025 American Indian/Alaska Native, 3463 Asian/Pacific Islander (AAPI), 8428 Hispanic, and 86,676 white participants in the 1998-1999 Tobacco Use Supplement to the Current Population Survey. Race-stratified multivariate logistic regression analyses, Chi-square tests, and ANOVA were used to examine the association between the covariates and smoking prevalence and cigarette consumption patterns. Results. Current smoking prevalence ranged from a high of 35.1% for AI/AN to 15.2% for AAPI. Occupation was not significantly associated with current smoking for Hispanics, AI/ANs, and AAPIs while neither occupation nor industry was associated with current smoking among African Americans after adjustment for gender, age group, education, income, or workplace smoking policies. Discussion. These data confirm results of previous studies that show occupation and industry variation in smoking prevalence and also highlight the importance of examining racial/ethnicity as a covariate in studies of smoking prevalence. Published by Elsevier Inc. C1 NCI, Div Canc Control & Populat Sci, Appl Res Program, Hlth Serv & Econ Branch, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Behav Res Program, Tobacco Control Res Branch, Bethesda, MD 20892 USA. IMS, Silver Spring, MD 20904 USA. RP Shavers, VL (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res Program, Hlth Serv & Econ Branch, 6130 Execut Blvd,MSC-7344,EPN Room 4005, Bethesda, MD 20892 USA. EM shaversv@mail.nih.gov NR 43 TC 21 Z9 21 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 0091-7435 J9 PREV MED JI Prev. Med. PD AUG PY 2005 VL 41 IS 2 BP 597 EP 606 DI 10.1016/j.ypmed.2004.12.004 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 938MR UT WOS:000230008000030 PM 15917058 ER PT J AU Kidd, LCR Paltoo, DN Wang, SP Chen, WD Akereyeni, F Isaacs, W Ahaghotu, C Kittles, R AF Kidd, LCR Paltoo, DN Wang, SP Chen, WD Akereyeni, F Isaacs, W Ahaghotu, C Kittles, R TI Sequence variation within the 5 ' regulatory regions of the vitamin D binding protein and receptor genes and prostate cancer risk SO PROSTATE LA English DT Article DE vitamin D receptor; vitamin D binding protein; prostate cancer; African-Americans; single nucleotide polymorphisms (SNPs) ID BONE-MINERAL DENSITY; BREAST-CANCER; TRANSCRIPTION FACTORS; CELL-LINES; POLYMORPHISM; ASSOCIATION; EXPRESSION; PROMOTER; PROLIFERATION; DELTA-EF1 AB BACKGROUND. The vitamin D receptor (VDR) and binding protein (DBP) mediate the cellular transport, activity, and anti-tumor action of 1,25-dihydroxyvitamin D3 [1,25-(OH)(2)D3]. The purpose of this investigation is to determine whether novel single nucleotide polymorphisms (SNPs) within the transcriptional regulatory regions of the VDR and DBP are associated with prostate cancer risk. METHODS. Novel SNPs were identified in the VDR and DBP transcription regulatory gene regions and genotyped in a case-control study using male subjects with (n = 258) or without (n=434) prostate cancer. RESULTS. African-American men who possessed at least one variant VDR-5132 C allele had a increased risk of prostate cancer (OR=1.83; 95%. CI: 1.02, 3.31). Further study revealed that the VDR-5132 T/C SNP eliminates a GATA-1 transcription factor-binding site. CONCLUSION. The VDR-5132 T/C SNP, resulting in potential elimination of the GATA-I transcription factor-binding site, may increase prostate cancer susceptibility in African-Americans. Confirmation of these findings is needed in larger observational studies. (c) 2005 Wiley-Liss, Inc. C1 Ohio State Univ, Ctr Comprehens Canc, Tzagournis Med Res Facil 690C, Columbus, OH 43210 USA. Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Canc Prevent & Control Program,James Graham Brown, Louisville, KY 40292 USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA. Johns Hopkins Univ Hosp, Dept Urol, Baltimore, MD 21205 USA. RP Kittles, R (reprint author), Ohio State Univ, Ctr Comprehens Canc, Tzagournis Med Res Facil 690C, 420 W 12th Ave, Columbus, OH 43210 USA. EM kittles-1@medctr.osu.edu FU NCI NIH HHS [IU54CA91431-01]; NCRR NIH HHS [RR03048-13S1]; NIDA NIH HHS [DAMD 17-02-1-0067, DAMD17-00-1-0025] NR 68 TC 22 Z9 23 U1 0 U2 1 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 AUG 1 PY 2005 VL 64 IS 3 BP 272 EP 282 DI 10.1002/pros.20204 PG 11 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 943RE UT WOS:000230371000007 PM 15717311 ER PT J AU Tsai, CJ Nussinov, R AF Tsai, CJ Nussinov, R TI The implications of higher (or lower) success in secondary structure prediction of chain fragments SO PROTEIN SCIENCE LA English DT Editorial Material ID EVOLUTIONARY INFORMATION; PROTEINS C1 SAIC Frederick Inc, Basic Res Program, Lab Expt & Computat Biol, NCI Frederick, Frederick, MD 21701 USA. Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Tsai, CJ (reprint author), SAIC Frederick Inc, Basic Res Program, Lab Expt & Computat Biol, NCI Frederick, Bldg 469,Room 151, Frederick, MD 21701 USA. EM ruthn@ncifcrf.gov FU NCI NIH HHS [N01CO12400, N01-CO-12400] NR 8 TC 5 Z9 6 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2005 VL 14 IS 8 BP 1943 EP 1944 DI 10.1110/ps.051581805 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 950QT UT WOS:000230872900001 PM 16046621 ER PT J AU Inbar, Y Schneidman-Duhovny, D Halperin, I Oron, A Nussinov, R Wolfson, HJ AF Inbar, Y Schneidman-Duhovny, D Halperin, I Oron, A Nussinov, R Wolfson, HJ TI Approaching the CAPRI challenge with an efficient geometry-based docking SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE CAPRI; unbound docking; flexible docking; symmetry docking; PatchDock; FlexDock; SymmDock ID PROTEIN-PROTEIN INTERACTIONS; LICT TRANSCRIPTIONAL ANTITERMINATOR; CRYSTAL-STRUCTURE; ASPERGILLUS-NIGER; ENVELOPE GLYCOPROTEIN; ANGSTROM RESOLUTION; STRUCTURAL BASIS; DOMAIN; PHOSPHATASE; XYLANASE AB The last 3 rounds (3-5) of CAPRI included a wide range of docking targets. Several targets were especially challenging, since they involved large-scale movements and symmetric rearrangement, while others were based on homology models. We have approached the targets with a variety of geometry-based docking algorithms that include rigid docking, symmetric docking, and flexible docking with symmetry constraints. For all but 1 docking target, we were able to submit at least 1 acceptable quality prediction. Here, we detail for each target the prediction methods used and the specific biological data employed, and supply a retrospective analysis of the results. We highlight the advantages of our techniques, which efficiently exploit the geometric shape complementarity properties of the interaction. These enable them to run only few minutes on a standard PC even for flexible docking, thus proving their scalability toward computational genomic scale experiments. We also outline the major required enhancements, such as the introduction of side-chain position refinement and the introduction of flexibility for both docking partners. (c) 2005 Wiley-Liss, Inc. C1 Tel Aviv Univ, Sch Comp Sci, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Frederick, MD 21701 USA. RP Wolfson, HJ (reprint author), Tel Aviv Univ, Sch Comp Sci, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. EM wolfson@post.tau.ac.il RI Wolfson, Haim/A-1837-2011 FU NCI NIH HHS [N01-CO-12400] NR 30 TC 16 Z9 16 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD AUG 1 PY 2005 VL 60 IS 2 BP 217 EP 223 DI 10.1002/prot.20561 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 941YB UT WOS:000230249000011 PM 15981251 ER PT J AU Schneidman-Duhovny, D Inbar, Y Nussinov, R Wolfson, HJ AF Schneidman-Duhovny, D Inbar, Y Nussinov, R Wolfson, HJ TI Geometry-based flexible and symmetric protein docking SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE CAPRI; unbound docking; flexible docking; symmetric docking; PatchDock; FlexDock; SymmDock ID MOLECULAR-SURFACE RECOGNITION; HOUGH TRANSFORM; POINTS; SPARSE; SUITE AB We present a set of geometric docking algorithms for rigid, flexible, and cyclic symmetry docking. The algorithms are highly efficient and have demonstrated very good performance in CAPRI Rounds 3-5. The flexible docking algorithm, FlexDock, is unique in its ability to handle any number of hinges in the flexible molecule, without degradation in run-time performance, as compared to rigid docking. The algorithm for reconstruction of cyclically symmetric complexes successfully assembles multimolecular complexes satisfying C. symmetry for any n in a matter of minutes on a desktop PC. Most of the algorithms presented here are available at the Tel Aviv University Structural Bioinformatics Web server (http://bioinfo3d.cs. tau.ac.il/). (c) 2005 Wiley-Liss, Inc. C1 Tel Aviv Univ, Sch Comp Sci, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Frederick, MD 21701 USA. Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Wolfson, HJ (reprint author), Tel Aviv Univ, Sch Comp Sci, Raymond & Beverly Sackler Fac Exact Sci, IL-69978 Tel Aviv, Israel. EM wolfson@post.tau.ac.il RI Wolfson, Haim/A-1837-2011 FU NCI NIH HHS [N01-CO-12400] NR 24 TC 111 Z9 113 U1 1 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD AUG 1 PY 2005 VL 60 IS 2 BP 224 EP 231 DI 10.1002/prot.20562 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 941YB UT WOS:000230249000012 PM 15981269 ER PT J AU Nishigaki, R Osaki, M Hiratsuka, M Toda, T Murakami, K Jeang, KT Ito, H Inoue, T Oshimura, M AF Nishigaki, R Osaki, M Hiratsuka, M Toda, T Murakami, K Jeang, KT Ito, H Inoue, T Oshimura, M TI Proteomic identification of differentially-expressed genes in human gastric carcinomas SO PROTEOMICS LA English DT Article DE gastric carcinoma; immunohistochemistry; mitochondria; mitotic checkpoint ID MASS-SPECTROMETRY; CHROMOSOMAL INSTABILITY; CLINICAL-IMPLICATIONS; GEL-ELECTROPHORESIS; EPITHELIAL-CELLS; HUMAN CANCERS; PROTEIN EB1; GROWTH; ADENOCARCINOMA; RUNX3 AB Although genetic alterations in proto-oncogenes, tumor-suppressor genes, cell cycle regulators, and cell growth factors have been implicated in the process of human gastric carcinogenesis, the principle carcinogenic mechanisms are not fully understood. In this study, we used a proteomic approach to search for genes that may be involved in gastric carcinogenesis and that might serve as diagnostic markers. We identified nine proteins with increased expression and 13 proteins with decreased expression in gastric carcinomas. The two most notable groups included proteins involved in mitotic checkpoint (MAD1L1 and EB1) and mitochondrial functions (CLPP, COX5A, and ECH1). This suggested that there are links between dysfunctions in these processes and gastric carcinogenesis. We also observed the differential expression of HSP27 and CYR61 proteins in gastric carcinoma, whose expression is known to be altered in other types of tumors. Furthermore, the study identified proteins whose function in gastric carcinomas was previously unsuspected and that may serve as new molecular markers for gastric carcinomas. Importantly, immunohistochemical analyses confirmed that the levels of expression of MAD1L1, HSP27, and CYR61 were altered in gastric carcinoma tissues. Therefore, our study suggested not only that the proteins identified in this study can be useful diagnostic markers but also that a proteomics-based approach is useful for developing a more complete picture of the pathogenesis and function of gastric carcinomas. C1 Tottori Univ, Grad Sch Med Sci, Inst Regenerat Med & Biofunct, Dept Biomed Sci, Yonago, Tottori 6838503, Japan. Tottori Univ, Grad Sch Med Sci, Dept Human Genome Sci Kirin Brewery, Yonago, Tottori 6838503, Japan. Tottori Univ, Grad Sch Med Sci, Dept Mol & Cell Genet, Yonago, Tottori 6838503, Japan. Tottori Univ, Fac Med, Dept Microbiol & Pathol, Div Organ Pathol, Yonago, Tottori 683, Japan. Tokyo Metropolitan Inst Gerontol, Proteom Collaborat Res Grp, Tokyo, Japan. NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Oshimura, M (reprint author), Tottori Univ, Grad Sch Med Sci, Inst Regenerat Med & Biofunct, Dept Biomed Sci, Nishi Cho 86, Yonago, Tottori 6838503, Japan. EM oshimura@grape.med.tottori-u.ac.jp RI Jeang, Kuan-Teh/A-2424-2008 NR 53 TC 80 Z9 90 U1 1 U2 6 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD AUG PY 2005 VL 5 IS 12 BP 3205 EP 3213 DI 10.1002/pmic.200401307 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 956QW UT WOS:000231315900025 PM 16003825 ER PT J AU Knox, S Weidner, G AF Knox, S Weidner, G TI Hostility & cardiovascular risk in the NHLBI family heart study SO PSYCHOLOGY & HEALTH LA English DT Meeting Abstract C1 NICHHD, Dept Epidemiol Stat & Prevent, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0887-0446 J9 PSYCHOL HEALTH JI Psychol. Health PD AUG PY 2005 VL 20 SU 1 BP 134 EP 135 PG 2 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary SC Public, Environmental & Occupational Health; Psychology GA 977XF UT WOS:000232836100238 ER PT J AU Knox, S AF Knox, S TI The national children's study - social determinants of health SO PSYCHOLOGY & HEALTH LA English DT Meeting Abstract C1 NICHHD, Dept Epidemiol Stat & Prevent, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0887-0446 J9 PSYCHOL HEALTH JI Psychol. Health PD AUG PY 2005 VL 20 SU 1 BP 135 EP 135 PG 1 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary SC Public, Environmental & Occupational Health; Psychology GA 977XF UT WOS:000232836100239 ER PT J AU Lu, L Chen, H Su, WJ Ge, X Yue, W Su, F Ma, L AF Lu, L Chen, H Su, WJ Ge, X Yue, W Su, F Ma, L TI Role of withdrawal in reinstatement of morphine-conditioned place preference SO PSYCHOPHARMACOLOGY LA English DT Article DE conditioned place preference; drug-seeking; withdrawal; cue conditioning; morphine; relapse ID CORTICOTROPIN-RELEASING-FACTOR; STRESS-INDUCED RELAPSE; OPPONENT-PROCESS THEORY; OPIATE WITHDRAWAL; INDUCED REACTIVATION; DRUG-DEPENDENCE; COCAINE SEEKING; HEROIN-SEEKING; RATS; ADDICTION AB Rationale: Relapse is a major characteristic of drug addiction and the primary problem in treating drug abuse. Based on the negative reinforcement view of addiction, in which the motivation to take drugs is thought to result from the desire to avoid the aversive effect of drug withdrawal, it has been theorized that withdrawal symptoms play a major role in the maintenance of and relapse to drug taking. However, the role of withdrawal in relapse has not yet been systemically investigated in the reinstatement model. Objectives: Using a conditioned place preference (CPP) paradigm, we examined the role of different morphine withdrawal states (spontaneous withdrawal, naloxone-precipitated withdrawal, and conditioned withdrawal) in relapse to drug seeking. Methods: Rats alternately received morphine (10 mg/kg, s.c.) and saline for 8 days to acquire the CPP. The morphine CPP disappeared after a 2-week extinction phase of saline-paired training. Rats were then chronically administered morphine to induce physical dependence. The different withdrawal states were induced and their roles in the reinstatement of extinguished CPP were assessed. During conditioned withdrawal, trunk blood samples were taken and the corticosterone level was measured by radioimmunoassay. To examine the role of cortiotropin-releasing factor (CRF) receptor antagonist on conditioned-withdrawal-induced reinstatement of CPP, different doses of alpha-helical CRF (0.1 and 1 mu g, i.c.v.) were administered 30 min prior to the CPP testing. Results: The results show that morphine spontaneous withdrawal and naloxone-precipitated morphine withdrawal were ineffective in reinstating morphine CPR However, the withdrawal cues significantly elicited the reinstatement of CPP and increased corticosterone level. Moreover, pretreatment with the CRF receptor antagonist alpha-helical CRF (1 mu g, i.c.v.) significantly attenuated the effects of withdrawal cues on reinstatement of CPP and corticosterone levels. Conclusion: These findings demonstrate that the cues associated with previous drug withdrawal play a major role in drug relapse and that activation of the CRF receptor is involved in conditioned-withdrawal-induced reinstatement. The present study suggests that CRF receptor antagonists might be of value in the treatment and prevention of relapse to drug seeking after long-term abstinence. C1 NIDA, Behav Neurosci Branch, IRP, NIH, Baltimore, MD 21224 USA. Fudan Univ, Natl Lab Med Neurobiol, Shanghai 200032, Peoples R China. Fudan Univ, Pharmacol Res Ctr, Shanghai 200032, Peoples R China. RP Lu, L (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM llu@intra.nida.nih.gov; Lanma@shmu.edu.cn RI Ma, Lan/C-9653-2010; Ma, Lan/B-9295-2009 OI Ma, Lan/0000-0001-9034-5472 NR 68 TC 43 Z9 46 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD AUG PY 2005 VL 181 IS 1 BP 90 EP 100 DI 10.1007/s00213-005-2207-5 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 963LC UT WOS:000231804800011 PM 15739075 ER PT J AU Bhattacharjee, AK Chang, L Lee, HJ Bazinet, RP Seemann, R Rapoport, SI AF Bhattacharjee, AK Chang, L Lee, HJ Bazinet, RP Seemann, R Rapoport, SI TI D-2 but not D-1 dopamine receptor stimulation augments brain signaling involving arachidonic acid in unanesthetized rats SO PSYCHOPHARMACOLOGY LA English DT Article DE dopamine; phospholipase A(2); SKF-38393; quinpirole; arachidonic acid; brain ID PHOSPHOLIPASE A(2) ACTIVATION; POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL GLUCOSE-UTILIZATION; DISCRIMINATIVE STIMULUS; PARKINSONS-DISEASE; RODENT MODEL; FATTY-ACIDS; AGONIST; D1; STRIATUM AB Rationale and objectives: Signal transduction involving the activation of phospholipase A(2) (PLA(2)) to release arachidonic acid (AA) from membrane phospholipids, when coupled to dopamine D-1- and D-2-type receptors, can be imaged in rats having a chronic unilateral lesion of the substantia nigra. It is not known, however, if the signaling responses occur in the absence of a lesion. To determine this, we used our in vivo fatty acid method to measure signaling in response to D-1 and D-2 receptor a nists given acutely to unanesthetized rats. Methods: [1-C-14] AA was injected intravenously in unanesthetized rats, and incorporation coefficients k* for AA (brain radioactivity/integrated plasma radioactivity) were measured using quantitative autoradiography in 61 brain regions. The animals were administered i.v. the D-2 receptor agonist, quinpirole (1 mg kg(-1), i.v.), the D-1 receptor agonist SKF-38393 (5 mg kg(-1), i.v.), or vehicle/saline. Results: Quinpirole increased k* significantly in multiple brain regions rich in D-2-type receptors, whereas SKF-38393 did not change k* significantly in any of the 61 regions examined. Conclusions: In the intact rat brain, D-2 but not D-1 receptors are coupled to the activation of PLA(2) and the release of AA. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Bhattacharjee, AK (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Room 1S128, Bethesda, MD 20892 USA. EM abeshb@mail.nih.gov NR 53 TC 34 Z9 34 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD AUG PY 2005 VL 180 IS 4 BP 735 EP 742 DI 10.1007/s00213-005-2208-4 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 962KN UT WOS:000231731800017 PM 16163535 ER PT J AU Partain, CL Chan, HP Gelovani, JG Giger, ML Izatt, JA Jolesz, FA Kandarpa, K Li, KCP McNitt-Gray, M Napel, S Summers, RM Gazelle, GS AF Partain, CL Chan, HP Gelovani, JG Giger, ML Izatt, JA Jolesz, FA Kandarpa, K Li, KCP McNitt-Gray, M Napel, S Summers, RM Gazelle, GS TI Biomedical imaging research opportunities workshop II: Report and recommendations SO RADIOLOGY LA English DT Editorial Material ID COMPUTER-AIDED DETECTION; AUTOMATED NODULE DETECTION; SMALL PULMONARY NODULES; BREAST-CANCER DETECTION; HELICAL CT IMAGES; LUNG-CANCER; OBSERVER-PERFORMANCE; TOMOGRAPHY IMAGES; COLONIC POLYPS; COLORECTAL NEOPLASIA C1 Vanderbilt Univ, Dept Radiol, Med Ctr, Nashville, TN 37232 USA. Univ Michigan Hlth Syst, Dept Radiol, Ann Arbor, MI USA. Univ Texas, MD Anderson Canc Ctr, Dept Radiol, Houston, TX 77030 USA. Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. Harvard Univ, Sch Med, Dept Radiol, Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Massachusetts, Sch Med, Dept Radiol, Worcester, MA 01605 USA. NIH, Imaging Sci Program, Bethesda, MD 20892 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Radiol, Los Angeles, CA USA. Stanford Univ, Sch Med, Dept Radiol, Stanford, CA 94305 USA. NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Inst Technol Assessment, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Partain, CL (reprint author), Vanderbilt Univ, Dept Radiol, Med Ctr, RR 1223,MCN,1161 21st Ave S, Nashville, TN 37232 USA. EM leon.partain@vanderbilt.edu OI Giger, Maryellen/0000-0001-5482-9728; McNItt-Gray, Michael/0000-0003-3004-4613 FU NIBIB NIH HHS [1 R13 EB003553-01] NR 54 TC 19 Z9 19 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2005 VL 236 IS 2 BP 389 EP 403 DI 10.1148/radiol.2362041876 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 947TM UT WOS:000230670200005 PM 16040898 ER PT J AU Detrano, RC Anderson, M Nelson, J Wong, ND McNitt-Gray, M Bild, DE AF Detrano, RC Anderson, M Nelson, J Wong, ND McNitt-Gray, M Bild, DE TI Coronary calcium measurements: Effect of CT scanner type and calcium measure on rescan reproducibility - MESA study SO RADIOLOGY LA English DT Article ID ELECTRON-BEAM CT; ULTRAFAST COMPUTED-TOMOGRAPHY; ARTERY CALCIUM; QUANTIFICATION; CALCIFICATION; ATHEROSCLEROSIS; INDIVIDUALS; MOTION AB PURPOSE: To evaluate the effect of scanner type and calcium measure on the reproducibility of calcium measurements. MATERIALS AND METHODS: This investigation was approved by the institutional review boards of each study site and by the Institutional Review Board of the Los Angeles Biomedical Research Institute. Informed consent for scanning and participation was obtained from all participants. The study was Health Insurance Portability and Accountability Act compliant. The Multi-Ethnic Study of Atherosclerosis (MESA) is a multicenter observational study of 6814 participants undergoing demographic, risk factor, and subdinical disease evaluations. Coronary artery calcium was measured by using duplicate CT scans. Three study centers used electron-beam computed tomography (CT), and three used multi-detector row CT. Coronary artery calcium was detected in 3355 participants. Three calcium measurement methods-Agatston score, calcium volume, and interpolated volume score-were evaluated. Mean absolute differences between calcium measures on scans 1 and 2, excluding cases for which both scans had a measure of zero, was modeled by using linear regression to compare reproducibility between scanner types. A repeated measures analysis of variance test was used to compare reproducibility across calcium measures, with mean percentage absolute difference as the outcome measure. Rescan reproducibility in relation to misregistrations, noise, and motion artifacts was also examined. Variables were log transformed to create a more normal distribution. RESULTS: Concordance for presence of calcium between duplicate scans was high and similar for both electron-beam and multi-detector row CT (96%, kappa = 0.92). Mean absolute difference between calcium scores for the two scans was 15.8 for electron-beam and 16.9 for multi-detector row CT scanners (P = .06). Mean relative differences were 20.1 for Agatston score, 18.3 for calcium volume, and 18.3 for interpolated volume score (P < .01). Reproducibility was lower for scans with versus those without image misregistrations or motion artifacts (P < .01 for both). CONCLUSION: Electron-beam and multi-detector row CT scanners have equivalent reproducibility for measuring coronary artery calcium. Calcium volumes and interpolated volume scores are slightly more reproducible than Agatston scores. Reproducibility is lower for scans with misregistrations or motion artifacts. (c) RSNA, 2005. C1 Los Angeles Biomed Res Inst, Div Cardiol, Torrance, CA 90502 USA. Univ Washington, Ctr Hlth Studies, Grp Hlth Cooperat, Seattle, WA 98195 USA. Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA. Wake Forest Univ, Sch Med, Dept Radiol, Winston Salem, NC 27109 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Detrano, RC (reprint author), Los Angeles Biomed Res Inst, Div Cardiol, 1124 W Carson St,Bldg E-5, Torrance, CA 90502 USA. EM rdetrano@labiomed.org OI McNItt-Gray, Michael/0000-0003-3004-4613 FU NHLBI NIH HHS [N01-HC-95159-95165] NR 26 TC 158 Z9 158 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD AUG PY 2005 VL 236 IS 2 BP 477 EP 484 DI 10.1148/radiol.23620405013 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 947TM UT WOS:000230670200015 PM 15972340 ER PT J AU Song, X Tao, YG Zeng, L Yang, J Tang, FQ Lee, LM Gong, JP Wu, Q Cao, Y AF Song, X Tao, YG Zeng, L Yang, J Tang, FQ Lee, LM Gong, JP Wu, Q Cao, Y TI Epstein-Barr virus-encoded latent membrane protein 1 modulates cyclin D1 by c-Jun/Jun B heterodimers SO SCIENCE IN CHINA SERIES C-LIFE SCIENCES LA English DT Article DE latent membrane protein1; c-Jun; Jun B; heterodimer; cyclin D1; cell cycle ID NASOPHARYNGEAL CARCINOMA-CELL; NF-KAPPA-B; TRANSCRIPTION FACTOR; EXPRESSION; INHIBITORS; CANCER; CARCINOGENESIS; CHECKPOINTS; PERSPECTIVE; PROGRESSION AB In our recent studies, we found that LMP1 encoded by Epstein-Barr virus could accelerate the formation of active c-Jun/Jun B heterodimer. We studied the regulation of cyclinD1 by c-Jun/Jun B heterodimers by laser scanning confocal influorescence microscopy, Western blot, luciferase activity assay, super-EMSA and flow cytometry in the Tet-on-LMP1 HNE2 cell line, in which LMP1 expression was regulated by Tet-on system. c-Jun/Jun B heterodimers induced by LMP1 could up regulate cyclin D1 promoter activity and expression. Overexpression of cyclin-D1 accelerated the progression of cell cycle. C1 Cent S Univ, Canc Res Inst, Xiangya Sch Med, Changsha 410078, Peoples R China. NCI, Lab Mol Technol, SAIC Frederick, Frederick, MD 21702 USA. Tongji Med Univ, Mol Med Ctr, Tongji Hosp, Wuhan 430030, Peoples R China. Xiamen Univ, Key Lab Cell Biol & Tumor Cell Engn, Minist Educ, Sch Life Sci, Xiamen 361005, Peoples R China. RP Cao, Y (reprint author), Cent S Univ, Canc Res Inst, Xiangya Sch Med, Changsha 410078, Peoples R China. EM Ycao98@public.cs.hn.cn RI Cao, Ya/C-6801-2008; Wu, Q/G-4646-2010 NR 41 TC 5 Z9 7 U1 0 U2 5 PU SCIENCE PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1006-9305 J9 SCI CHINA SER C JI Sci. China Ser. C-Life Sci. PD AUG PY 2005 VL 48 IS 4 BP 385 EP 393 DI 10.1360/03yc0251 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 968PP UT WOS:000232174800009 PM 16248432 ER PT J AU Johansson, C Kelsall, BL AF Johansson, C Kelsall, BL TI Phenotype and function of intestinal dendritic cells SO SEMINARS IN IMMUNOLOGY LA English DT Review DE intestine; Peyer's patches; mesenteric lymph nodes; lamina propria ID INFLAMMATORY-BOWEL-DISEASE; MESENTERIC LYMPH-NODES; MURINE SMALL-INTESTINE; REGULATORY T-CELLS; IN-VIVO; PEYERS PATCH; SUBEPITHELIAL DOME; EPITHELIAL-CELLS; IMMUNE-RESPONSE; LAMINA PROPRIA AB It is now appreciated that dendritic cells (DCs) play a primary role in oral tolerance and defense against mucosal pathogens. Specific DC subpopulations are localized to discrete regions within primary inductive tissues, like the Peyer's patch and mesenteric lymph node, and effector sites, like the lamina propria, and may have unique roles in driving regulatory, effector and memory T cell responses. Certain DC subpopulations may also help maintain T cell responses at sites of abnormal intestinal inflammation. While early in our understanding, knowledge about the involvement of DC subpopulations in the regulation of mucosal immunity may well provide a basis for the development of novel vaccines and therapeutics. (c) 2005 Elsevier Ltd. All rights reserved. C1 NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Kelsall, BL (reprint author), NIAID, Lab Mol Immunol, NIH, 10 Ctr Dr,10-11N214, Bethesda, MD 20892 USA. EM Cjohansson@niaid.nih.gov; Bkelsall@niaid.nih.gov OI Johansson, Cecilia/0000-0002-6607-5000 NR 83 TC 69 Z9 76 U1 0 U2 5 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD AUG PY 2005 VL 17 IS 4 BP 284 EP 294 DI 10.1016/j.smim.2005.05.010 PG 11 WC Immunology SC Immunology GA 952SK UT WOS:000231025600005 PM 15978836 ER PT J AU Arnaud, F Hammett, M Asher, L Philbin, N Rice, J Dong, F Pearce, B Flournoy, WS Nicholson, C McCarron, R Freilich, I AF Arnaud, F Hammett, M Asher, L Philbin, N Rice, J Dong, F Pearce, B Flournoy, WS Nicholson, C McCarron, R Freilich, I TI Effects of bovine polymerized hemoglobin on coagulation in controlled hemorrhagic shock in swine SO SHOCK LA English DT Article DE blood substitutes; hemoglobin-based oxygen carriers; trauma; coagulopathy; resuscitation ID CARDIAC-SURGERY; TRAUMA PATIENTS; OXYGEN CARRIER; COMBAT INJURY; LIVER-INJURY; IN-VITRO; COAGULOPATHY; MODEL; RESUSCITATION; SEQUESTRATION AB HBOC-201, a bovine polymerized hemoglobin, has been proposed as a novel oxygen-carrying resuscitative fluid for patients with hemorrhagic shock (HS). Herein, we evaluated the hemostatic effects of HBOC-201 in an animal model of HS. A 40% blood loss-controlled hemorrhage and soft tissue injury were performed in 24 invasively monitored Yucatan mini-pigs. Pigs were resuscitated with HBOC-201 (HBOC) or hydroxyethyl starch (HEX), or were not resuscitated (NON) based on cardiac parameters during a 4-h prehospital phase. Afterward, animals received simulated hospital care for 3 days with blood or saline transfusions. Hemostasis measurements included in vivo bleeding time (BT), thromboelastography (TEG), in vitro bleeding time (platelet function; PFA-CT), prothrombin time (PT), and partial thromboplastin time (PTT). Serum lactate was measured and lung sections were evaluated for microthrombi by electron microscopy. During the prehospital phase, BT remained unchanged in the HBOC group. TEG reaction time increased in HBOC pigs during the late prehospital phase and was greater than in NON or HEX pigs at 24 h (P= 0.03). TEG maximum amplitude was similar for the two fluid-resuscitated groups. PFA-CT increased in both resuscitated groups but less with HBOC (P = 0.02) in the prehospital phase; this effect was reversed by 24 h (P= 0.02). In the hospital phase, PT decreased (P< 0.02), whereas PTT increased above baseline (P < 0.01). Lactic acidosis in HBOC and HEX groups was similar. Aspartate aminotransferase was relatively elevated in the HBOC group at 24 h. Electron microscopy showed no evidence of platelet/fibrin clots or microthrombi in any of the animals. Twenty-four-hour group differences mainly reflected the fact that all HEX animals (8/8) received blood transfusions compared with only one HBOC animal (1/8). In swine with HS, HBOC resuscitation induced less thrombopathy than HEX during the prehospital phase. Mild delayed effects on platelet and clot formation during the hospital phase are transient and likely related to fewer blood transfusions. In swine with HS, HBOC resuscitation induced less thrombopathy than HEX during the prehospital phase but more thrombopathy in the hospital phase. The delayed effects on platelet and clot formation during the hospital phase are transient and may be related to the need for fewer blood transfusions. C1 USN, Med Res Ctr, RMD Hematomimet Program, Silver Spring, MD 20910 USA. Walter Reed Army Inst Res, Silver Spring, MD USA. Biopure Corp, Cambridge, MD USA. Walter Reed Army Inst Res, Dept Vet Med, Silver Spring, MD USA. NICHHD, NIH, Natl Ctr Med Rehabil Res, Bethesda, MD 20892 USA. RP Arnaud, F (reprint author), USN, Med Res Ctr, RMD Hematomimet Program, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM arnaudf@nmrc.navy.mil NR 38 TC 16 Z9 17 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 J9 SHOCK JI Shock PD AUG PY 2005 VL 24 IS 2 BP 145 EP 152 DI 10.1097/01.shk.0000170354.18437.2f PG 8 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 952SV UT WOS:000231026700008 PM 16044085 ER PT J AU Anderson, DK Beattie, M Blesch, A Bresnahan, J Bunge, M Dietrich, D Dietz, V Dobkin, B Fawcett, J Fehlings, M Fischer, I Grossman, R Guest, J Hagg, T Hall, ED Houle, J Kleitman, N McDonald, J Murray, M Privat, A Reier, P Steeves, J Steward, O Tetzlaff, W Tuszynski, MH Waxman, SG Whittemore, S Wolpaw, J Young, W Zheng, B AF Anderson, DK Beattie, M Blesch, A Bresnahan, J Bunge, M Dietrich, D Dietz, V Dobkin, B Fawcett, J Fehlings, M Fischer, I Grossman, R Guest, J Hagg, T Hall, ED Houle, J Kleitman, N McDonald, J Murray, M Privat, A Reier, P Steeves, J Steward, O Tetzlaff, W Tuszynski, MH Waxman, SG Whittemore, S Wolpaw, J Young, W Zheng, B TI Recommended guidelines for studies of human subjects with spinal cord injury SO SPINAL CORD LA English DT Editorial Material ID RELIABILITY; MULTICENTER; WALKING; TRIAL C1 Univ Calif San Diego, La Jolla, CA 92093 USA. Univ Florida, Gainesville, FL USA. Ohio State Univ, Columbus, OH 43210 USA. Miami Project, Miami, FL USA. Univ Hosp Balgrist, Zurich, Switzerland. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Cambridge, Cambridge CB2 1TN, England. Univ Toronto, Toronto, ON, Canada. Drexel Univ, Philadelphia, PA 19104 USA. Baylor Univ, Houston, TX 77030 USA. Univ Louisville, Louisville, KY 40292 USA. Univ Kentucky, Lexington, KY USA. Univ Arkansas, Little Rock, AR 72204 USA. NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. Univ Calif Irvine, Irvine, CA USA. Yale Univ, New Haven, CT USA. New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. Rutgers State Univ, Newark, NJ 07102 USA. Stanford Univ, Stanford, CA 94305 USA. RP Tuszynski, MH (reprint author), Univ Calif San Diego, La Jolla, CA 92093 USA. RI Fischer, Itzhak/D-1080-2012; OI Fischer, Itzhak/0000-0003-3187-8740; Kleitman, Naomi/0000-0003-1089-0257; Blesch, Armin/0000-0003-1133-1174; Fawcett, James/0000-0002-7990-4568 NR 16 TC 47 Z9 49 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1362-4393 J9 SPINAL CORD JI Spinal Cord PD AUG PY 2005 VL 43 IS 8 BP 453 EP 458 DI 10.1038/sj.sc.3101746 PG 6 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 952IG UT WOS:000230996600001 PM 15824756 ER PT J AU Baker, SG Kramer, BS AF Baker, SG Kramer, BS TI Simplemaximum likelihood estimates of efficacy in randomized trials and before-and-after studies, with implications formeta-analysis SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article ID OR-NONE COMPLIANCE; TO-TREAT ANALYSIS; CLINICAL-TRIALS; BAYESIAN-INFERENCE; INSTRUMENTAL VARIABLES; CAUSAL INFERENCE; NONCOMPLIANCE; CANCER; DESIGNS; METAANALYSIS AB Efficacy, which we define as the effect of receiving intervention on health outcomes among a group of subjects, is the quantity of interest for many investigators. In contrast, intent-to-treat analyses in randomized trials and their analogue for observational before-and-after studies compare outcomes between randomization groups or before-and-after time periods. When there is switching of interventions, estimates based on intent-to-treat are biased for estimating efficacy. By constructing a model based on potential outcomes, one can make reasonable assumptions to estimate efficacy under `all-or-none' switching of interventions in which switching occurs immediately after randomization or at the start of the time period. This paper reviews the basic methodology, with emphasis on simple maximum likelihood estimates that arise with completely observed outcomes, partially missing binary outcomes, and discrete-time survival outcomes. Particular attention is paid to estimating efficacy in meta-analysis, where the interpretation is much more straightforward than with intent-to-treat analyses. C1 NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. NIH, Off Dis Prevent, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, Biometry Res Grp, Div Canc Prevent, EPN 3131 6130 Execut Blvd MSC 7354, Bethesda, MD 20892 USA. EM sb16i@nih.gov NR 47 TC 15 Z9 15 U1 0 U2 3 PU ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 0962-2802 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD AUG PY 2005 VL 14 IS 4 BP 349 EP 367 DI 10.1191/0962280205sm404oa PG 19 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA 959MC UT WOS:000231520800003 PM 16178137 ER PT J AU Sanchez-Pernaute, R Studer, L Ferrari, D Perrier, A Lee, H Vinuela, A Isacson, O AF Sanchez-Pernaute, R Studer, L Ferrari, D Perrier, A Lee, H Vinuela, A Isacson, O TI Long-term survival of dopamine neurons derived from parthenogenetic primate embryonic stem cells (Cyno-1) after transplantation SO STEM CELLS LA English DT Article DE Parkinson's disease; embryonic stem (ES) cell; transplantation; primate; differentiation ID NEURAL PROGENITOR CELLS; CENTRAL-NERVOUS-SYSTEM; IN-VITRO; RAT MODEL; PARKINSONS-DISEASE; SEROTONERGIC NEURONS; FATE SPECIFICATION; HUMAN BLASTOCYSTS; DEVELOPING BRAIN; ES CELLS AB Dopamine (DA) neurons can be derived from human and primate embryonic stem (ES) cells in vitro. An ES cell-based replacement therapy for patients with Parkinson's disease requires that in vitro-generated neurons maintain their phenotype in vivo. Other critical issues relate to their proliferative capacity and risk of tumor formation, and the capability of migration and integration in the adult mammalian brain. Neural induction was achieved by coculture of primate parthenogenetic ES cells (Cyno-1) with stromal cells, followed by sequential exposure to midbrain patterning and differentiation factors to favor DA phenotypic specification. Differentiated ES cells were treated with mitomycin C and transplanted into adult immunosuppressed rodents and into a primate (allograft) without immunosuppression. A small percentage of DA neurons survived in both rodent and primate hosts for the entire term of the study (4 and 7 months, respectively). Other neuronal and glial populations derived from Cyno-1 ES cells showed, in vivo, phenotypic characteristics and growth and migration patterns similar to fetal primate transplants, and a majority of cells (> 80 %) expressed the forebrain transcription factor brain factor 1. No teratoma formation was observed. In this study, we demonstrate long-term survival of DA neurons obtained in vitro from primate ES cells. Optimization of differentiation, cell selection, and cell transfer is required for functional studies of ES-derived DA neurons for future therapeutic applications. C1 Harvard Univ, Udall Parkinsons Dis Res Ctr Excellence, McLean Hosp, Belmont, MA 02478 USA. McLean Hosp, Neuroregenerat Labs, Belmont, MA 02178 USA. Mem Sloan Kettering Canc Ctr, Lab Stem Cell & Tumor Biol, Div Neurosurg, New York, NY 10021 USA. RP Sanchez-Pernaute, R (reprint author), Harvard Univ, Udall Parkinsons Dis Res Ctr Excellence, McLean Hosp, 115 Mill St, Belmont, MA 02478 USA. EM rosario_pernaute@hms.harvard.edu RI Perrier, Anselme/E-3764-2010; OI Perrier, Anselme/0000-0001-7915-1968 FU NCRR NIH HHS [P51 RR000168, P51RR00168]; NINDS NIH HHS [P50 NS039793, NS-39793, P50 NS039793-06A1] NR 49 TC 87 Z9 92 U1 0 U2 6 PU ALPHAMED PRESS PI MIAMISBURG PA ONE PRESTIGE PLACE, STE 290, MIAMISBURG, OH 45342-3758 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD AUG PY 2005 VL 23 IS 7 BP 914 EP 922 DI 10.1634/stemcells.2004-0172 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 957MN UT WOS:000231374000007 PM 15941857 ER PT J AU Batra, VK Beard, WA Shock, DD Pedersen, LC Wilson, SH AF Batra, VK Beard, WA Shock, DD Pedersen, LC Wilson, SH TI Nucleotide-induced DNA polymerase active site motions accommodating a mutagenic DNA intermediate SO STRUCTURE LA English DT Article ID BASE EXCISION-REPAIR; INDUCED-FIT MECHANISM; CENTER-DOT-T; STRUCTURAL INSIGHTS; HIGH-FIDELITY; CRYSTAL-STRUCTURES; LARGE FRAGMENT; ERROR-PRONE; BETA; REPLICATION AB DNA polymerases occasionally insert the wrong nucleotide. For this error to become a mutation, the mispair must be extended. We report a structure of DNA polymerase beta (pol beta) with a DNA mismatch at the boundary of the polymerase active site. The structure of this complex indicates that the templating adenine of the mispair stacks with the primer terminus adenine while the templating (coding) cytosine is flipped out of the DNA helix. Soaking the crystals of the binary complex with dGTP resulted in crystals of a ternary substrate complex. In this case, the templating cytosine is observed within the DNA helix and forms Watson-Crick hydrogen bonds with the incoming dGTP. The adenine at the primer terminus has rotated into a syn-conformation to interact with the opposite adenine in a planar configuration. Yet, the X-hydroxyl on the primer terminus is out of position for efficient nucleotide insertion. C1 Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov NR 44 TC 29 Z9 29 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD AUG PY 2005 VL 13 IS 8 BP 1225 EP 1233 DI 10.1016/j.str.2005.05.010 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 959MW UT WOS:000231523000017 PM 16084394 ER PT J AU Sugawara, Y Akechi, T Okuyama, T Matsuoka, Y Nakano, T Inagaki, M Imoto, S Fujimori, M Hosaka, T Uchitomi, Y AF Sugawara, Y Akechi, T Okuyama, T Matsuoka, Y Nakano, T Inagaki, M Imoto, S Fujimori, M Hosaka, T Uchitomi, Y TI Occurrence of fatigue and associated factors in disease-free breast cancer patients without depression SO SUPPORTIVE CARE IN CANCER LA English DT Article DE fatigue; breast cancer; survivors; depression; neuroticism ID QUALITY-OF-LIFE; SURVIVORS; SCALE; CHEMOTHERAPY; RADIOTHERAPY; PREVALENCE; VERSION; IMPACT AB Goals of work: Studies on fatigue in disease-free breast cancer patients have consistently found a significant association between fatigue and depression; and some characteristics of this fatigue may be confused with and/or concealed by those of depression. To clarify the characteristics of fatigue in disease-free breast cancer patients, we examined the frequency of fatigue and associated factors in disease-free breast cancer patients without major depression. Patients and methods: Seventy-nine ambulatory breast cancer patients without major depression who had been disease-free for more than 3 years since their surgery completed the Cancer Fatigue Scale (CFS), a multidimensional scale assessing cancer-related fatigue. Participants also completed the Short-form Eysenck Personality Questionnaire-Revised (EPQR) for assessing their personalities. Sociodemographic, physical, and treatment-related factors were also obtained by interview. Main results: We found that 36.7% of the patients exhibited fatigue and that fatigue was significantly associated with neuroticism. Conclusions: These results suggest that a considerable number of disease-free breast cancer patients without major depression experience fatigue and that careful attention to those exhibiting high neuroticism may be of benefit in ameliorating their fatigue. C1 Natl Canc Ctr, Res Inst E, Psychooncol Div, Chiba 2778577, Japan. Tokai Univ, Sch Med, Dept Psychiat & Behav Sci, Kanagawa 2591193, Japan. Nagoya City Univ, Sch Med, Dept Psychiat, Mizuho Ku, Aichi 4678601, Japan. Natl Ctr Neurol & Psychiat, Natl Inst Mental Hlth, Adult Mental Hlth Div, Chiba 2720827, Japan. Natl Canc Ctr, Div Psychiat, Chuo Ku, Tokyo 1040015, Japan. NIMH, Mood & Anxiety Disorder Program, Bethesda, MD 20892 USA. Natl Canc Ctr Hosp E, Div Breast Surg, Chiba 2778577, Japan. RP Uchitomi, Y (reprint author), Natl Canc Ctr, Res Inst E, Psychooncol Div, 6-5-1 Kashiwanoha, Chiba 2778577, Japan. EM yuchitom@east.ncc.go.jp RI Matsuoka, Yutaka/D-1171-2011 NR 38 TC 31 Z9 34 U1 3 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0941-4355 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD AUG PY 2005 VL 13 IS 8 BP 628 EP 636 DI 10.1007/s00520-004-0763-6 PG 9 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 948LS UT WOS:000230717900007 PM 15668753 ER PT J AU Schanen, JG Iribarren, C Shahar, E Punjabi, NM Rich, SS Sorlie, PD Folsom, AR AF Schanen, JG Iribarren, C Shahar, E Punjabi, NM Rich, SS Sorlie, PD Folsom, AR TI Asthma and incident cardiovascular disease: The Atherosclerosis Risk in Communities Study SO THORAX LA English DT Article ID CORONARY-HEART-DISEASE; LUNG-FUNCTION; FOLLOW-UP; PULMONARY-FUNCTION; GENERAL-POPULATION; MORTALITY; STROKE; ADULTS; LIFE; DECLINE AB Background: A possible association between asthma and cardiovascular disease has been described in several exploratory studies. Methods: The association of self-reported, doctor diagnosed asthma and incident cardiovascular disease was examined in a biracial cohort of 45 - 64 year old adults (N = 13501) followed over 14 years. Results: Compared with never having asthma, the multivariate adjusted hazard ratio (HR) of stroke (n = 438) was 1.50 (95% CI 1.04 to 2.15) for a baseline report of ever having asthma ( prevalence 5.2%) and 1.55 ( 95% CI 0.95 to 2.52) for current asthma ( prevalence 2.7%). The relative risk of stroke was 1.43 ( 95% CI 1.03 to 1.98) using a time dependent analysis incorporating follow up reports of asthma. Participants reporting wheeze attacks with shortness of breath also had greater risk for stroke ( HR = 1.56, 95% CI 1.18 to 2.06) than participants without these symptoms. The multivariate adjusted relative risk of coronary heart disease ( n = 1349) was 0.87 ( 95% CI 0.66 to 1.14) for ever having asthma, 0.69 ( 95% CI 0.46 to 1.05) for current asthma at baseline, and 0.88 ( 95% CI 0.69 to 1.11) using the time dependent analysis. Conclusions: Asthma may be an independent risk factor for incident stroke but not coronary heart disease in middle aged adults. This finding warrants replication and may motivate a search for possible mechanisms that link asthma and stroke. C1 Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. Kaiser Permanente, Div Res, Oakland, CA USA. Johns Hopkins Univ, Div Pulm & Crit Care Med, Baltimore, MD USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. RP Folsom, AR (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300 S 2nd St,Suite 300, Minneapolis, MN 55454 USA. EM folsom@epi.umn.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 36 TC 68 Z9 70 U1 0 U2 2 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD AUG PY 2005 VL 60 IS 8 BP 633 EP 638 DI 10.1136/thx.2004.026484 PG 6 WC Respiratory System SC Respiratory System GA 950YX UT WOS:000230896400006 PM 16061703 ER PT J AU Matheson, MC Benke, G Raven, J Sim, MR Kromhout, H Vermeulen, R Johns, DP Walters, EH Abramson, MJ AF Matheson, MC Benke, G Raven, J Sim, MR Kromhout, H Vermeulen, R Johns, DP Walters, EH Abramson, MJ TI Biological dust exposure in the workplace is a risk factor for chronic obstructive pulmonary disease SO THORAX LA English DT Article ID CHRONIC RESPIRATORY SYMPTOMS; CHRONIC-BRONCHITIS; OCCUPATIONAL EXPOSURES; GENERAL-POPULATION; RESPONSE RELATIONSHIPS; HEALTH; WOMEN; EPIDEMIOLOGY; ASSOCIATION; WORKERS AB Background: Chronic obstructive pulmonary disease ( COPD) is a major cause of morbidity and mortality. Although the main risk factor is smoking, 15 - 19% of COPD even in smokers has been attributed to occupational exposures. The aim of this study was to investigate the association between occupational exposure and risk of COPD. Methods: Participants were part of a cross sectional study of risk factors for COPD. A total of 1232 completed a detailed respiratory questionnaire, spirometric testsing and measurement of gas transfer. Job histories were coded according to the International Standard Classification of Occupations. These codes were then used to establish occupational exposures using the ALOHA job exposure matrix. Results: The prevalence of emphysema was 2.4%, chronic obstructive bronchitis 1.8%, and COPD 3.4%. Subjects ever exposed to biological dusts had an increased risk of chronic obstructive bronchitis ( OR 3.19; 95% CI 1.27 to 7.97), emphysema ( OR 3.18; 95% CI 1.41 to 7.13), and COPD ( OR 2.70, 95% CI 1.39 to 5.23). These risks were higher in women than in men. For biological dust, the risk of emphysema and COPD was also significantly increased in both the duration of exposure categories, again in women but not in men. No significant increased risks for COPD were found for mineral dust ( OR 1.13; 95% CI 0.57 to 2.27) or gases/fumes ( OR 1.63; 95% CI 0.83 to 3.22). Conclusion: In this general population sample of adults, occupational exposures to biological dusts were associated with an increased risk of COPD which was higher in women. Preventive strategies should be aimed at reducing exposure to these agents in the workplace. C1 Monash Univ, Dept Epidemiol & Prevent Med, Cent & Eastern Clin Sch, Melbourne, Vic 3004, Australia. Alfred Hosp, Dept Allergy Immunol & Resp Med, Melbourne, Vic, Australia. Univ Utrecht, Div Occupat & Environm Hlth, Inst Risk Assessment Sci, NL-3508 TC Utrecht, Netherlands. NCI, Occupat & Environm Epidemiol Branch, Rockville, MD 20852 USA. Univ Tasmania, Sch Med, Cardioresp Res Grp, Hobart, Tas, Australia. RP Matheson, MC (reprint author), Monash Univ, Dept Epidemiol & Prevent Med, Cent & Eastern Clin Sch, Commercial Rd, Melbourne, Vic 3004, Australia. EM Melanie.Matheson@med.monash.edu.au RI Kromhout, Hans/A-9159-2008; Johns, David/D-1933-2014; Vermeulen, Roel/F-8037-2011; Matheson, Melanie/O-4721-2015; OI Johns, David/0000-0002-1575-6850; Vermeulen, Roel/0000-0003-4082-8163; Matheson, Melanie/0000-0002-5822-3499; Abramson, Michael/0000-0002-9954-0538 NR 39 TC 113 Z9 116 U1 1 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD AUG PY 2005 VL 60 IS 8 BP 645 EP 651 DI 10.1136/thx.2004.035170 PG 7 WC Respiratory System SC Respiratory System GA 950YX UT WOS:000230896400008 PM 16061705 ER PT J AU Chavakis, T Wiechmann, K Preissner, KT Herrmann, M AF Chavakis, T Wiechmann, K Preissner, KT Herrmann, M TI Staphylococcus aureus interactions with the endothelium - The role of bacterial "Secretable Expanded Repertoire Adhesive Molecules" (SERAM) in disturbing host defense systems SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE Staphylococcus aureus; endothelium; extracellular adhesive protein; endovascular infection ID FIBRINOGEN-BINDING-PROTEIN; VON-WILLEBRAND-FACTOR; EXTRACELLULAR ADHERENCE PROTEIN; PLATELET MICROBICIDAL PROTEIN; CHEMOTAXIS INHIBITORY PROTEIN; CLUMPING FACTOR; SURFACE PROTEIN; MAP PROTEIN; IN-VITRO; EAP AB The intravascular manifestation of Staphylococcus aureus infection is often associated with a severe, and sometimes catastrophic disease. Many host factors contribute to endothelial tropism of S. aureus including subendothelial matrix proteins, endothelial cell receptors, and platelets that are engaged together with S. aureus cell wall adhesins such as the fibronectin binding proteins. Recently, the role of secreted staphylococcal factors that were initially identified by virtue of their binding function with host proteins and ligands, has been reappraised in this regard. Among these, bacterial proteins without significant homology among each other, coagulase (Coa), the extracellular fibrinogen binding protein (Efb), the extracellular matrix binding protein (Emp), or the extracellular adhesive protein (Eap), are the most prominent ones to be associated with endovascular disease. Newly discovered interactions with host components may account for profound effects on immunmodulation and wound healing which are summarized in this short review and which ascribe an important role of these molecules in acute and chronic endo- and extravascular staphylococcal disease. Further research in the complex functional role of these "secretable expanded repertoire adhesive molecules" (SERAM) may not only help to increase our understanding in the pathogenesis of S. aureus infection but can specify novel targets for preventive or therapeutic strategies. C1 Univ Saarland Hosp, Inst Med Microbiol & Hyg, D-66421 Homburg, Germany. Univ Giessen, Inst Biochem, Giessen, Germany. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Herrmann, M (reprint author), Univ Saarland Hosp, Inst Med Microbiol & Hyg, D-66421 Homburg, Germany. EM mathias.herrmann@uniklinik-saarland.de RI Herrmann, Mathias/B-6475-2013 NR 94 TC 88 Z9 89 U1 1 U2 10 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 2005 VL 94 IS 2 BP 278 EP 285 DI 10.1160/TH05-05-0306 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 952RS UT WOS:000231023800008 PM 16113816 ER PT J AU Chidakel, A Mentuccia, D Celi, FS AF Chidakel, A Mentuccia, D Celi, FS TI Peripheral metabolism of thyroid hormone and glucose homeostasis SO THYROID LA English DT Article ID TYPE-2 IODOTHYRONINE DEIODINASE; BETA-3-ADRENERGIC RECEPTOR; DIABETES-MELLITUS; ADAPTIVE THERMOGENESIS; 5'-DEIODINASE ACTIVITY; TARGETED DISRUPTION; INSULIN-RESISTANCE; SKELETAL-MUSCLE; GENE PROMOTER; EXPRESSION AB Thyroid hormone action has long been recognized as an important determinant of glucose homeostasis. Recent advances in the knowledge of the physiology of the deiodinases indicate that through tissue-specific regulation of thyroid hormone metabolism, leading to local specificity of thyroid hormone action and target gene transcription patterns, they may have an important function in the modulation of carbohydrate metabolism. This review briefly addresses the role of thyroid hormone action on glucose homeostasis with a specific focus on the significance of the peripheral metabolism of thyroid hormone in the regulation of glucose homeostasis and insulin sensitivity. C1 NIDDKD, Clin Endocrinol Brnach, NIH, Bethesda, MD 20892 USA. Univ Roma Tor Vergata, Div Endocrinol, Dept Med, Rome, Italy. RP Celi, FS (reprint author), NIDDK, Clin Endocrinol Branch, NIH, 10 Ctr Dr,MSC 1758,Bldg 10,Room 8D-12C, Bethesda, MD 20892 USA. EM fc93a@NIH.GOV NR 50 TC 51 Z9 53 U1 1 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD AUG PY 2005 VL 15 IS 8 BP 899 EP 903 DI 10.1089/thy.2005.15.899 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 966TL UT WOS:000232044700016 PM 16131332 ER PT J AU Malkki, M Single, R Carrington, M Thomson, G Petersdorf, E AF Malkki, M Single, R Carrington, M Thomson, G Petersdorf, E TI MHC microsatellite diversity and linkage disequilibrium among common HLA-A, HLA-13, DR131 haplotypes: implications for unrelated donor hematopoietic transplantation and disease association studies SO TISSUE ANTIGENS LA English DT Article DE haplotype; hematopoietic cell transplantation; HLA; MHC; microsatellite ID MAJOR HISTOCOMPATIBILITY COMPLEX; BONE-MARROW TRANSPLANTATION; RECOMBINATION HOTSPOT; RHEUMATOID-ARTHRITIS; FREQUENCY ESTIMATION; REGION; LOCUS; SUSCEPTIBILITY; GENE; ALGORITHM AB Twenty-two human major histocompatibility complex (MHC) region microsatellite (Msat) markers were studied for diversity and linkage disequilibrium (LD) with HLA loci in hematopoietic cell transplant recipients and their HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele-matched unrelated donors. These Msats showed highly significant LD over much of the MHC region. The Msat diversity of five common Caucasian haplotypes (HLA-A1-B8- DR3 A3-B7-DR15 A2-B44-DR4 A29-B44-DR7 and A2-B7-DR15) was examined using a new measure called 'haplotype specific heterozygosity' (HSH) Each of. the five haplotypes had at least one Msat marker with an HSH value of zero indicating that only one Msat allele was observed for the particular HLA haplotype. In addition, the ability of Msats to predict HLA-A-B-DRB1 haplotypes was studied. Over 90% prediction probability of two common haplotypes (HLA-A1-B8-DR3 and HLA-A3-B7-DR15) was achieved with information from three Msats (D6S265/D6S2787/D6S2894 and D6S510/D6S2810/D6S2876, respective We demonstrate how the HSH index can be used in the selection of informative Msats for transplantation and disease association studies. Markers with low HSH values can be used to predict specific HLA haplotypes or mulfilocus genotypes to supplement the screening of HLA-matched donors for transplantation. Markers with high HSH values will be most informative in studies investigating MHC region disease-susceptibility genes where HLA haplotypic effects are known to exist. C1 Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. Univ Vermont, Dept Math & Stat, Burlington, VT 05405 USA. SAIC Frederick Inc, Basic Res Program, Lab Genom Divers, NCI, Frederick, MD USA. Univ Calif Berkeley, Dept Integrat Biol, Berkeley, CA 94720 USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. RP Malkki, M (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, D4-100,1100 Fairview Ave N, Seattle, WA 98109 USA. EM mmalkki@fhcrc.org FU NCI NIH HHS [N01-CO-12400, CA18029, P30CA22435]; NIAID NIH HHS [AI33484, AI49213]; NIGMS NIH HHS [GM 35326]; PHS HHS [AL49213] NR 49 TC 37 Z9 41 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD AUG PY 2005 VL 66 IS 2 BP 114 EP 124 DI 10.1111/j.1399-0039.2005.00453.x PG 11 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 950XB UT WOS:000230890900006 PM 16029431 ER PT J AU Guo, TL Germolec, DR Musgrove, DL Delclos, KB Weis, C White, KL AF Guo, TL Germolec, DR Musgrove, DL Delclos, KB Weis, C White, KL TI Myelotoxicity in genistein-, nonylphenol-, methoxychlor-, vinclozolin- or ethinyl estradiol-exposed F-1 generations of Sprague-Dawley rats following developmental and adult exposures SO TOXICOLOGY LA English DT Article DE endocrine active chemicals; genistem; nonylphenol; ethinyl estradiol; vinclozolin; methoxychlor and developmental myelotoxicity ID ESTROGEN-RECEPTORS ALPHA; PHENOTYPIC MARKER EXPRESSION; DOSE ORAL-CONTRACEPTIVES; FORMING CELL RESPONSE; IN-VITRO; SOY ISOFLAVONES; BETA; PHYTOESTROGENS; MICE; CHEMICALS AB The myelotoxicity of five endocrine active chemicals was evaluated in F, generation of Sprague-Dawley rats following developmental and adult exposures at three concentration levels. Rats were exposed to genistein (GEN: 25, 250 and 1250 ppm), nonylphenol (NPH: 25, 500 and 2000 ppm), methoxychlor (MXC: 10, 100 and 1000 ppm), vinclozolin (VCZ: 10, 150 and 750 ppm) and ethinyl estradiol (EE2: 5, 25 and 200 ppb) gestationally and lactationally through dams from day 7 of gestation and through feed after weaning on postnatal day (PND) 22 to PND 64. The parameters examined included the number of recovered bone marrow cells, DNA synthesis, and colony forming units (CFU) in the presence of granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF) and erythropoietin. Except for the EE2, the concentrations of other individual chemicals in the diet were in an approximate range that allowed for a comparison to be made in terms of myelotoxic potency. Decreases in the DNA synthesis, CFU-GM and CFU-M seemed to be the common findings among the alterations induced by these compounds. Using the numbers of alterations induced by each chemical in the parameters examined as criteria for comparison, the order of myelotoxic potency in F, males was: GEN > MXC > NPH > VCZ; the order in females: GEN > NPH > VCZ. Additionally, some of the functional changes induced by these compounds were gender-specific or dimorphic. Overall, the results demonstrated that developmental and adult exposures of F, rats to these endocrine active chemicals at the concentrations tested had varied degrees of myelotoxicity with GEN being the most potent. Furthermore, the sex-specific effects of these chemicals in F, male and female rats suggest that there may be interactions between these compounds and sex hormone in modulating these responses. (C) 2005 Elsevier Ireland Ltd. All rights reserved. C1 Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. US FDA, Div Biochem Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Guo, TL (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, POB 980613, Richmond, VA 23298 USA. EM tlguo@hsc.vcu.edu FU NIEHS NIH HHS [ES55094]; PHS HHS [224-93-0001] NR 57 TC 19 Z9 24 U1 1 U2 5 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 AUG 1 PY 2005 VL 211 IS 3 BP 207 EP 219 DI 10.1016/j.tox.2005.03.008 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 934OY UT WOS:000229719300004 PM 15925024 ER PT J AU Sakurai, T Ochiai, M Kojima, C Ohta, T Sakurai, MH Takada, NO Qu, W Waalkes, MP Himeno, S Fujiwara, K AF Sakurai, T Ochiai, M Kojima, C Ohta, T Sakurai, MH Takada, NO Qu, W Waalkes, MP Himeno, S Fujiwara, K TI Preventive mechanism of cellular glutathione in monomethylarsonic acid-induced cytolethality SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE monomethylarsonic acid; arsenic; glutathione; apoptosis; ICP MS ID INDUCED MALIGNANT-TRANSFORMATION; ORGANIC ARSENIC COMPOUND; MALE F344 RATS; DIMETHYLARSINIC ACID; INDUCED APOPTOSIS; SODIUM ARSENITE; IN-VITRO; GENE-EXPRESSION; DRINKING-WATER; TRIOXIDE AS2O3 AB Human pentavalent arsenic metabolic intermediate, monomethylarsonic acid (MMAsV), is a major arsenic type found in the blood in chronic arsenic poisoning patients, but little information is available on its toxicity potential or mechanisms of action. In this study, we investigated the molecular mechanisms of in vitro cytolethality of MMAsV using rat liver TRL 1215 cells. Cellular arsenic concentrations reached the nanomolar range in TRL 1215 cells when cells were exposed to millimolar levels of MMAsV and most of the MMAsV was not metabolized during the 48-h incubation. Under these conditions, MMAsV showed significant cytolethality when cellular reserves of reduced glutathione (GSH) were depleted. Morphological and biochemical evidence confirmed that MMAsV induced both necrosis and apoptosis in the cellular GSH-depleted cells. MMAsV significantly enhanced cellular caspase 3 activity in the cellular GSH-depleted cells, and a caspase 3 inhibitor blocked MMAsV-induced apoptosis. MMAsV also enhanced the production of cellular reactive oxygen species (ROS) in the cellular GSH-depleted cells, and addition of a membrane-permeable radical trapping reagent completely prevented both MMAsV-induced cellular caspase 3 activation and cytolethality in these cells. These observations suggest that MMAsV typically generates harmful ROS in cells, and cellular GSH prevents cytolethality by scavenging these toxic ROS. However, when cellular GSH levels are decreased, MMAsV induces oxidative stress in the cells, and this leads to apoptosis and/or necrosis depending on the cellular ROS/GSH ratio. (c) 2004 Elsevier Inc. All rights reserved. C1 Tokyo Univ Pharm & Life Sci, Sch Life Sci, Environm Chem Lab, Hachioji, Tokyo 1920392, Japan. Azabu Univ, Dept Environm Hlth, Lab Environm Hyg, Sagamihara, Kanagawa 2298501, Japan. NIEHS, NCI, Inorgan Carcinogenesis Sect, Lab Comparat Carcinogenesis,NIH, Res Triangle Pk, NC 27709 USA. Tokushima Bunri Univ, Fac Pharmaceut Sci, Lab Mol Nutr & Toxicol, Yamashiro, Tokushima 7708514, Japan. RP Sakurai, T (reprint author), Tokyo Univ Pharm & Life Sci, Sch Life Sci, Environm Chem Lab, 1432-1 Horinouchi, Hachioji, Tokyo 1920392, Japan. EM sakurai@ls.toyaku.ac.jp NR 54 TC 19 Z9 21 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD AUG 1 PY 2005 VL 206 IS 1 BP 54 EP 65 DI 10.1016/j.taap.2004.11.008 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 940CB UT WOS:000230120200006 PM 15963344 ER PT J AU Mintz, PD Anderson, G Avery, N Clark, P Bonner, RF AF Mintz, PD Anderson, G Avery, N Clark, P Bonner, RF TI Assessment of the correlation of platelet morphology with in vivo recovery and survival SO TRANSFUSION LA English DT Article ID STORED PLATELETS; QUALITY ASSESSMENT; P-SELECTIN; STORAGE; TRANSFUSION; MAINTENANCE; CLEARANCE; SHAPE AB BACKGROUND: There is continuing interest in the development of in vitro tests evaluating the in vivo function, recovery, and survival of platelets stored for transfusion. A recent forum concluded that no completely reliable test exists, although discoid morphology indicates a platelet's good health. We evaluated a novel device, the NAPSAC (Noninvasive Assessment of Platelet Shape and Concentration), designed to determine noninvasively the proportion of discoid platelets in a stored concentrate, as well as platelet concentration. STUDY DESIGN AND METHODS: Twenty-eight plateletapheresis concentrates stored 24 hours in PL-146 were evaluated. Percent discoid platelet results were correlated with radiolabeled autologous recovery and survival performed using 111 Indium oxyquinoline and calculated using linear (L) and multiple-hit (M) models. pH of 8 concentrates was raised at the end of storage with 6N NaOH. Platelet concentration measured by NAPSAC and Coulter Thrombocounter C was compared in 256 plateletapheresis products. RESULTS: Percent discoid platelets at 24 hours did not correlate significantly with platelet recovery or survival (recovery L= 0.29, M = 0.28(+); survival L= 0.16, M = 0.03). Raising the pH (mean 6.38 to 6.94) resulted in a significant increase in percent discoid platelets (21% to 41%). Platelet concentration values for both methods studied were linearly correlated with a slope of 1.01 +/- 0.03, r = 0.81. CONCLUSION: Percent discoid platelets was not predictive of posttransfusion platelet recovery or survival. The results suggest that non-discoid platelets may survive posttransfusion and even revert to discoid shape, since raising the pH approximately doubled the percent of discoid platelets. The NAPSAC was shown to be a reliable instrument for noninvasively determining platelet concentration in PL-146 concentrates. C1 Univ Virginia Hlth Syst, Charlottesville, VA 22908 USA. NIH, Bethesda, MD 20892 USA. RP Mintz, PD (reprint author), Univ Virginia Hlth Syst, POB 800286, Charlottesville, VA 22908 USA. EM Mintz@virginia.edu RI Bonner, Robert/C-6783-2015 NR 29 TC 10 Z9 10 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD AUG PY 2005 VL 45 IS 2 SU S BP 72S EP 80S DI 10.1111/j.1537-2995.2005.00537.x PG 9 WC Hematology SC Hematology GA 954KS UT WOS:000231154600012 PM 16086792 ER PT J AU Marinissen, MJ Gutkind, JS AF Marinissen, MJ Gutkind, JS TI Scaffold proteins dictate Rho GTPase-signaling specificity SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Article ID COMPLEX-FORMATION; KINASE CASCADE; C-JUN; RAC; CDC42; PATHWAY; DOWNSTREAM; ACTIVATION; INTERACTS; TIAM1 AB Given the numerous mechanisms that regulate the activity of Rho GTPases and the multiple effectors for Rho proteins, how is specificity achieved when transducing signals via Rho GTPase-regulated molecular networks? The finding that the scaffold protein hCNK1 links Rho guanine-nucleotide-exchange factors and Rho to JNK (c-Jun N-terminal kinase), while limiting stress-fiber formation and serum-response-factor activation, suggests that scaffold proteins govern the selection of signal outputs, thus helping to solve the Rho GTPase-signaling puzzle. C1 Univ Autonoma Madrid, Fac Med, CSIC, Dept Bioquim,Inst Invest Biomed A Sols, E-28029 Madrid, Spain. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Marinissen, MJ (reprint author), Univ Autonoma Madrid, Fac Med, CSIC, Dept Bioquim,Inst Invest Biomed A Sols, Arzobispo Morcillo 4, E-28029 Madrid, Spain. EM mjmarinissen@iib.uam.es; sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009 NR 22 TC 30 Z9 32 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD AUG PY 2005 VL 30 IS 8 BP 423 EP 426 DI 10.1016/j.tibs.2005.06.006 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 957MU UT WOS:000231374700001 PM 15996870 ER PT J AU Zaas, AK Schwartz, DA AF Zaas, AK Schwartz, DA TI Innate immunity and the lung: Defense at the interface between host and environment SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Review ID TOLL-LIKE RECEPTOR-4; SURFACTANT PROTEIN-A; MANNOSE-BINDING LECTIN; MYCOBACTERIUM-TUBERCULOSIS INFECTION; RESPIRATORY SYNCYTIAL VIRUS; ALVEOLAR EPITHELIAL-CELLS; GRAM-NEGATIVE BACTERIA; DEFICIENT MICE; CUTTING EDGE; CYSTIC-FIBROSIS AB The lung serves as a major interface between the host and the external environment. As such, numerous lines of defense protect the host from inhaled potential pathogens. A breach in pulmonary innate immunity can lead to deleterious outcomes, such as pneumonia and disseminated infection. Pulmonary innate immunity, the first line of defense, is mediated by airway and alveolar epithelial cells as well as resident and recruited leukocytes. This article will discuss the key cellular and secreted components of the pulmonary innate immune system. C1 Duke Univ, Med Ctr, Dept Med, Div Infect Dis & Int Hlth, Burnham, NC USA. Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC USA. RP Zaas, AK (reprint author), USA, MD Box 3355,Duke S Blue Zone, Durham, NC 27710 USA. EM aimee.zaas@duke.edu NR 96 TC 35 Z9 37 U1 0 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1050-1738 J9 TRENDS CARDIOVAS MED JI Trends Cardiovasc. Med. PD AUG PY 2005 VL 15 IS 6 BP 195 EP 202 AR PII S1050-1738(05)00117-9 DI 10.1016/j.tcm.2005.07.001 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 974TS UT WOS:000232614900001 PM 16182128 ER PT J AU Rajagopalan, S Long, EO AF Rajagopalan, S Long, EO TI Viral evasion of NK-cell activation SO TRENDS IN IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; HUMAN CYTOMEGALOVIRUS; DOWN-REGULATION; RECEPTOR; RECOGNITION; INHIBITION; PROTEIN; CYTOTOXICITY; MODULATION; PROTECTION AB Viruses, such as human cytomegalovirus (HCMV), have developed mechanisms to evade recognition by, and activation of, natural killer (NK) cells, which are cells that provide crucial innate immune defense. Such mechanisms help viruses persist in the human host and attain a state of chronic infection. A recent report documents an antagonistic effect of the main HCMV tegument protein, pp65, on NKp30, a natural cytotoxicity-inducing receptor expressed uniquely on NK cells. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM eLong@nih.gov RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 NR 22 TC 18 Z9 20 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD AUG PY 2005 VL 26 IS 8 BP 403 EP 405 DI 10.1016/j.it.2005.06.008 PG 3 WC Immunology SC Immunology GA 955DY UT WOS:000231206700001 PM 15979408 ER PT J AU Singleton, AB AF Singleton, AB TI Altered alpha-synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin SO TRENDS IN NEUROSCIENCES LA English DT Editorial Material ID AUTOSOMAL-DOMINANT PARKINSONISM; COMMON LRRK2 MUTATION; LOCUS TRIPLICATION; LEWY BODIES; GENE; SUSCEPTIBILITY; POLYMORPHISM; PROMOTER; RISK; DUPLICATION AB The past decade has been a fruitful one for geneticists involved in Parkinson's disease (PD) research. The initial hurdle of identifying the first gene underlying parkinsonism was cleared with apparent ease in 1997 and four additional genes have since been found to contain mutations causing this disorder. Driving this research is the belief that these data will highlight disease mechanisms and directly implicate a pathway amenable to therapeutic intervention. This article will focus on recent genetic advances in the field, focusing on data that suggest alpha-synuclein expression is key in the etiology of PD. In addition, it will discuss the recent identification of LRRK2 mutation as a cause of PD and the potential of this finding to provide further insight into disease. C1 NIA, Mol Genet Unit, NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Singleton, AB (reprint author), NIA, Mol Genet Unit, NIH, Porter Neurosci Res Ctr, Room 1A1000,MSC3707,35 Lincoln Dr, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009 NR 31 TC 35 Z9 36 U1 1 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD AUG PY 2005 VL 28 IS 8 BP 416 EP 421 DI 10.1016/j.tins.2005.05.009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 957AU UT WOS:000231342400005 PM 15955578 ER PT J AU Ambudkar, SV Sauna, ZE Gottesman, MM Szakacs, G AF Ambudkar, SV Sauna, ZE Gottesman, MM Szakacs, G TI A novel way to spread drug resistance in tumor cells: functional intercellular transfer of P-glycoprotein (ABCB1) SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Article ID MULTIDRUG-RESISTANCE AB Intercellular transfer of proteins is a mode of communication between cells that is crucial for certain physiological processes. Chemotherapy is the treatment of choice for similar to 50% of all cancers. However, multidrug resistance mediated by drug-efflux pumps such as P-glycoprotein (Pgp) minimizes the effectiveness of such therapy in a large number of patients. A new study demonstrates the functional intercellular transfer of Pgp. Non-genetic transfer of the multidrug resistance phenotype raises fascinating questions about the mechanism and regulation of cell-surface membrane-protein-mediated spread of traits. C1 NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ambudkar@helix.nih.gov RI Ambudkar, Suresh/B-5964-2008; Szakacs, Gergely/A-2580-2009 OI Szakacs, Gergely/0000-0002-9311-7827 FU NCI NIH HHS [Z01 BC010030-10] NR 12 TC 41 Z9 44 U1 1 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD AUG PY 2005 VL 26 IS 8 BP 385 EP 387 DI 10.1016/j.tips.2005.06.001 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 957AZ UT WOS:000231342900001 PM 15978680 ER PT J AU Couty, JP Gershengorn, MC AF Couty, JP Gershengorn, MC TI G-protein-coupled receptors encoded by human herpesviruses SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID SARCOMA-ASSOCIATED HERPESVIRUS; BETA-CHEMOKINE RECEPTOR; MUSCLE-CELL MIGRATION; NF-KAPPA-B; HUMAN ENDOTHELIAL-CELLS; FRAME U12 ENCODES; KAPOSIS-SARCOMA; CONSTITUTIVE ACTIVITY; PARACRINE NEOPLASIA; INVERSE AGONISTS AB G-protein-coupled receptors (GPCRs) encoded by herpesviruses and poxviruses are homologous to mammalian chemokine receptors. GPCRs encoded by herpesvirus-6, herpesvirus-7, herpesvirus-8 and cytomegalovirus are among the best studied. Virally encoded GPCRs engage many different signal-transduction cascades, and have important roles in the life-cycles of the viruses and pathogenesis of human disease. Although signaling by these GPCRs might be modified by ligand binding, they often exhibit constitutive (basal) signaling activities that appear to provide selective advantages to the virus. C1 NIDDK, NIH, Bethesda, MD 20892 USA. CNRS, INSERM, Dept Immunol, Inst Cochin,U567,UMR 8104, F-75014 Paris, France. RP Gershengorn, MC (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM MarvinG@intra.niddk.nih.gov NR 53 TC 18 Z9 19 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD AUG PY 2005 VL 26 IS 8 BP 405 EP 411 DI 10.1016/j.tips.2005.06.004 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 957AZ UT WOS:000231342900005 PM 15990176 ER PT J AU Scalco, FB Correa-Cerro, LS Wassif, CA Porter, FD Moretti-Ferreira, D AF Scalco, FB Correa-Cerro, LS Wassif, CA Porter, FD Moretti-Ferreira, D TI DHCR7 mutations in Brazilian Smith-Lemli-Opitz syndrome patients SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Letter ID DEFECTIVE CHOLESTEROL-BIOSYNTHESIS; DELTA-7-STEROL REDUCTASE; OPTIZ-SYNDROME; GENE; DELTA(7)-REDUCTASE; FREQUENCY; SPECTRUM C1 NICHHD, Heritable Disorders Branch, DHHS, Unit Mol Dysmorphol,NIH, Bethesda, MD 20892 USA. Sao Paulo State Univ, Inst Biosci, Genet Counseling Serv, Sao Paulo, Brazil. RP Porter, FD (reprint author), NICHHD, Heritable Disorders Branch, DHHS, Unit Mol Dysmorphol,NIH, Bld 10,RM 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM fdporter@mail.nih.gov RI Moretti-Ferreira, Danilo/F-9565-2012 NR 22 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 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL 30 PY 2005 VL 136A IS 3 BP 278 EP 281 DI 10.1002/ajmg.a.30810 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 942NF UT WOS:000230288400010 PM 15952211 ER PT J AU Busija, DW Katakam, P Rajapakse, NC Kis, B Grover, G Domoki, F Bari, F AF Busija, DW Katakam, P Rajapakse, NC Kis, B Grover, G Domoki, F Bari, F TI Effects of ATP-sensitive potassium channel activators diazoxide and BMS-191095 on membrane potential and reactive oxygen species production in isolated piglet mitochondria SO BRAIN RESEARCH BULLETIN LA English DT Article DE diazoxide; BMS-191095; potassium channels; mitochondria; succinate dehydrogenase; ischemia; inwardly rectifying potassium channel; sulfonylurea receptors ID FOCAL CEREBRAL-ISCHEMIA; NEURONAL CELL-DEATH; K-ATP; OXIDATIVE STRESS; ARTERY OCCLUSION; NEWBORN PIGS; BRAIN; RAT; PROTECTS; OPENER AB Mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel openers protect the piglet brain against ischemic stress. Effects of mitoKNI-p channel agonists on isolated mitochondria, however, have not been directly examined. We investigated the effects of K-ATP channel openers and blockers on membrane potential and on the production of reactive oxygen species (ROS) in isolated piglet mitochondria. Diazoxide and BMS-191095. putative selective openers of initoK(ATP), decreased the mitochondrial membrane potential (Delta Psi(m)). On a inolar basis, diazoxide was less effective than BMS-191095. In contrast, diazoxide but not BMS- 191095 increased ROS production by mitochondria. Since diazoxide also inhibits succinate dehydrogenase (SDH), we examined the effects of 3-nitropropionic acid (3-NPA), an inhibitor of SDH. 3-NPA failed to change the Delta Psi(m) but increased ROS production. Inhibitors of K-ATP channels did not affect resting Delta Psi(M) or ROS production, but glibenclamide and 5-hydroxydecanoate (5-HD) blocked effects of diazoxide and BMS-191095 on Delta Psi(m) and diazoxide effects on ROS production. We Conclude that BN4S-191095 has selective effects on mitolK(ATP) channels while diazoxide also increases ROS production probably via inhibition of SDH. (c) 2005 Elsevier Inc. All rights reserved. C1 Wake Forest Univ, Dept Physiol & Pharmacol, Winston Salem, NC 27157 USA. Wake Forest Univ, Mol Med Grad Program, Winston Salem, NC 27157 USA. Bristol Myers Squibb Co, Pharmaceut Res Inst, Pennington, NJ USA. Univ Szeged, Sch Med, Dept Physiol, Szeged, Hungary. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Busija, DW (reprint author), Wake Forest Univ, Dept Physiol & Pharmacol, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM dbusija@wfubmc.edu RI Domoki, Ferenc/K-5336-2012; OI Katakam, Prasad/0000-0002-4708-9140 FU NHLBI NIH HHS [HL-30260, HL-50587, HL-66074, HL-77731, HL-65380]; NIDDK NIH HHS [DK-62372] NR 24 TC 39 Z9 40 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD JUL 30 PY 2005 VL 66 IS 2 BP 85 EP 90 DI 10.1016/j.brainresbull.2005.03.022 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 945XZ UT WOS:000230537600001 PM 15982523 ER PT J AU Piquemal, JP Marquez, A Parisel, O Giessner-Prettre, C AF Piquemal, JP Marquez, A Parisel, O Giessner-Prettre, C TI A CSOV study of the difference between HF and DFT intermolecular interaction energy values: The importance of the charge transfer contribution SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE intermolecular interaction energy decomposition; DFT vs. HF results; CSOV ID DENSITY-FUNCTIONAL THEORY; MOLECULAR-ORBITAL METHODS; VAN-DER-WAALS; PERTURBATION-THEORY; BASIS-SETS; HARTREE-FOCK; ELECTRONIC DISTRIBUTION; LOCALIZED ORBITALS; PAULI REPULSION; HYDROGEN BONDS AB Intermolecular interaction energy decompositions using the Constrained Space Orbital Variation (CSOV) method are carried out at the Hartree-Fock level on the one hand and using DFT with usual GGA functionals on the other for a number of model complexes to analyze the role of electron correlation in the intermolecular stabilization energy. In addition to the overall stabilization, the results provide information on the variation, with respect to the computational level, of the different contributions to the interaction energy. The complexes studied are the water linear dimer, the N-methylformamide dimer, the nucleic acid base pairs, the benzene-methane and benzene-N-2 van der Waals complexes, [Cu+-(ImH)(3)](2), where "ImH" stands for the Imidazole ligand, and ImH-Zn++. The variation of the frozen core energy (the sum of the intermolecular electrostatic energy and the Pauli repulsion energy) calculated from the unperturbed orbitals of the interacting entities indicates that the intramolecular correlation contributions can be stabilizing as well as destabilizing, and that general trends can be derived from the results obtained using usual density functionals. The most important difference between the values obtained from HF and DFT computations concerns the charge transfer contribution, which, in most cases, undergoes the largest increase. The physical meaning of these results is discussed. The present work gives reference calculations that might be used to parametrize new correlated molecular mechanics potentials. (c) 2005 Wiley Periodicals, Inc. C1 Univ Paris 06, CNRS, UMR 7616, Chim Theor Lab, F-75252 Paris, France. Univ Seville, Fac Quim, Dept Quim Fis, E-41012 Seville, Spain. Univ Nice, Fac Sci, Lab Etude Theor Milieux Extremes, F-06108 Nice, France. RP NIEHS, Struct Biol Lab, Mail Drop F0-08,POB 12233, Res Triangle Pk, NC 27709 USA. EM parisel@lct.jussieu.fr RI Piquemal, Jean-Philip/B-9901-2009; Marquez, Antonio/M-2878-2014 OI Piquemal, Jean-Philip/0000-0001-6615-9426; Marquez, Antonio/0000-0001-6699-064X NR 62 TC 80 Z9 80 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0192-8651 EI 1096-987X J9 J COMPUT CHEM JI J. Comput. Chem. PD JUL 30 PY 2005 VL 26 IS 10 BP 1052 EP 1062 DI 10.1002/jcc.20242 PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 934IQ UT WOS:000229702900009 PM 15898112 ER PT J AU Vythilingam, M Luckenbaugh, DA Lam, T Morgan, CA Lipschitz, D Charney, DS Bremner, JD Southwick, SM AF Vythilingam, M Luckenbaugh, DA Lam, T Morgan, CA Lipschitz, D Charney, DS Bremner, JD Southwick, SM TI Smaller head of the hippocampus in Gulf War-related posttraumatic stress disorder SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE PTSD; combat; stress; magnetic resonance imaging; memory ID RECURRENT MAJOR DEPRESSION; CHILDHOOD SEXUAL-ABUSE; PREFRONTAL CORTEX; TEMPORAL-LOBE; VOLUME; MRI; DYSFUNCTION; TRAUMA; WOMEN; PTSD AB Reductions in hippocampal volume and impairment in short-term verbal memory have been reported in Vietnam combat veterans with posttraumatic stress disorder (PTSD) and in women with abuse-related PTSD. The present investigation evaluated hippocampal volume and memory in Gulf War veterans. This research is timely given the ongoing war in Iraq and the anticipated high rates of PTSD among returning combat soldiers. Fourteen veterans with PTSD related to traumatic experiences during the Gulf War (1990-1991), 23 deployed veterans without PTSD, 22 non-deployed reservists and 29 healthy civilians were studied. Volumes of the hippocampus, temporal lobe, and whole brain were measured on coronal MRI scans, and hippocampal mediated memory function was evaluated. The head of the hippocampus was the only subregion that was significantly smaller in Gulf War veterans with PTSD than in healthy civilians. Deployed veterans with PTSD, deployed veterans without PTSD, and non-deployed reservists had significantly smaller whole hippocampal volume and lower scores on immediate and delayed verbal and visual retrieval compared with healthy civilians. (c) 2005. Published by Elsevier Ireland Ltd. C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Kaiser Permanente Med Grp, Internal Med, Fresno, CA USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. Mt Sinai Sch Med, New York, NY USA. Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Radiol, Atlanta, GA 30322 USA. PTSD, Natl Ctr, West Haven, CT USA. RP Vythilingam, M (reprint author), NIMH, Mood & Anxiety Disorders Program, MAP,15K N Dr,Room 111,MSC 2670, Bethesda, MD 20892 USA. EM meena.vythi@nih.gov RI Bremner, James/B-1632-2013 NR 57 TC 66 Z9 70 U1 2 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD JUL 30 PY 2005 VL 139 IS 2 BP 89 EP 99 DI 10.1016/j.pscyresns.2005.04.003 PG 11 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 949SB UT WOS:000230807300002 PM 15967648 ER PT J AU Hunsberger, S Rubinstein, LV Dancey, J Korn, EL AF Hunsberger, S Rubinstein, LV Dancey, J Korn, EL TI Dose escalation trial designs based on a molecularly targeted endpoint SO STATISTICS IN MEDICINE LA English DT Article DE phase I; toxicity; clinical trial ID PHASE-I TRIAL; CLINICAL-TRIALS; NONCYTOTOXIC AGENTS; OUTCOMES; CANCER AB Traditional phase I dose-finding studies for chemotoxic agents base dose escalation on toxicity, with escalation continuing until unacceptable toxicity is observed. Recent development of molecularly targeted agents that have little or no toxicity in the therapeutic dose range has raised questions over the best study designs for phase I studies. Two types of designs are proposed and evaluated in this paper. In these designs, escalation is based on a binary response that indicates whether or not the agent has had the desired effect on the molecular target. One design is developed to ensure that if the true target response rate is low there will be a high probability of escalating and if the true target response rate is high there will be a low probability of escalating. The other design is developed to continue to escalate as long as the true response rate is increasing and to stop escalating when the response rate plateaus or decreases. A limited simulation study is performed and the designs are compared with respect to the dose level at the end of escalation and the number of patients treated on study. Published in 2005 by John Wiley & Sons, Ltd. C1 NCI, Biomet Res Branch, NIH, Bethesda, MD 20892 USA. NCI, Invest Drug Branch, NIH, Bethesda, MD 20892 USA. RP Hunsberger, S (reprint author), NCI, Biostat Res Branch, 6130 Execut Blvd,Rm 8120, Bethesda, MD 20892 USA. EM sallyh@ctep.nci.nih.gov NR 17 TC 46 Z9 46 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JUL 30 PY 2005 VL 24 IS 14 BP 2171 EP 2181 DI 10.1002/sim.2102 PG 11 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 943CL UT WOS:000230329500004 PM 15909289 ER PT J AU Wooldridge, L van den Berg, HA Glick, M Gostick, E Laugel, B Hutchinson, SL Milicic, A Brenchley, JM Douek, DC Price, DA Sewell, AK AF Wooldridge, L van den Berg, HA Glick, M Gostick, E Laugel, B Hutchinson, SL Milicic, A Brenchley, JM Douek, DC Price, DA Sewell, AK TI Interaction between the CD8 coreceptor and major histocompatibility complex class I stabilizes T cell receptor-antigen complexes at the cell surface SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MHC CLASS-I; ALPHA-3 DOMAIN MUTANTS; SIGNAL-TRANSDUCTION; LIGAND-BINDING; TCR AFFINITY; PEPTIDE; ACTIVATION; MOLECULES; ASSOCIATION; LYMPHOCYTES AB The off-rate (k(off)) of the T cell receptor (TCR)/peptide-major histocompatibility complex class I (pMHCI) interaction, and hence its half-life, is the principal kinetic feature that determines the biological outcome of TCR ligation. However, it is unclear whether the CD8 coreceptor, which binds pMHCI at a distinct site, influences this parameter. Although biophysical studies with soluble proteins show that TCR and CD8 do not bind cooperatively to pMHCI, accumulating evidence suggests that TCR associates with CD8 on the T cell surface. Here, we titrated and quantified the contribution of CD8 to TCR/pMHCI dissociation in membrane-constrained interactions using a panel of engineered pMHCI mutants that retain faithful TCR interactions but exhibit a spectrum of affinities for CD8 of > 1,000-fold. Data modeling generates a "stabilization factor" that preferentially increases the predicted TCR triggering rate for low affinity pMHCI ligands, thereby suggesting an important role for CD8 in the phenomenon of T cell cross-reactivity. C1 Univ Oxford, Nuffield Dept Med, T Cell Modulat Grp, Oxford OX1 3SY, England. Univ Kent, Inst Math Stat & Actuarial Sci, Canterbury CT2 7NF, Kent, England. Novartis Inst Biomed Res, Cambridge, MA 02139 USA. NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Sewell, AK (reprint author), Univ Oxford, Nuffield Dept Med, T Cell Modulat Grp, Peter Medawar Bldg Pathogen Res,S Parks Rd, Oxford OX1 3SY, England. EM andy.sewell@ndm.ox.ac.uk RI Milicic, Anita/B-7693-2011; Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU Intramural NIH HHS [Z01 AI001029-01, Z99 AI999999, ZIA AI001029-02]; Medical Research Council [G108/441]; Wellcome Trust NR 80 TC 95 Z9 97 U1 1 U2 9 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 JUL 29 PY 2005 VL 280 IS 30 BP 27491 EP 27501 DI 10.1074/jbc.M500555200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 947WS UT WOS:000230678600004 PM 15837791 ER PT J AU Thiefes, A Wolter, S Mushinski, JF Hoffmann, E Dittrich-Breiholz, O Graue, N Dorrie, A Schneider, H Wirth, D Luckow, B Resch, K Kracht, M AF Thiefes, A Wolter, S Mushinski, JF Hoffmann, E Dittrich-Breiholz, O Graue, N Dorrie, A Schneider, H Wirth, D Luckow, B Resch, K Kracht, M TI Simultaneous blockade of NF kappa B, JNK, and p38 MAPK by a kinase-inactive mutant of the protein kinase TAK1 sensitizes cells to apoptosis and affects a distinct spectrum of tumor necrosis target genes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MONOCYTE-CHEMOATTRACTANT PROTEIN-1; BETA SIGNAL-TRANSDUCTION; INTERLEUKIN-1 RECEPTOR; ENDOTHELIAL-CELLS; TNF-ALPHA; MICROARRAY ANALYSIS; ACTIVATION; EXPRESSION; PATHWAY; BINDING AB The inflammatory response is characterized by the induction ( or repression) of hundreds of genes. The activity of many of these genes is controlled by MAPKs and the I kappa B kinase-NF kappa B pathway. To reveal the effects of blocking these pathways simultaneously, fibroblasts were infected with retroviruses encoding TAK1K63W, an inactive mutant of the protein kinase TAK1. Expression of this protein inhibited tumor necrosis factor (TNF)-induced activation of NF kappa B, JNK, and p38 MAPK and sensitized the cells to TNF-induced apoptosis. 23 different microarray experiments were used to analyze the expression of > 7000 genes in these cells. We identified 518 genes that were regulated by TNF in both TAK1K63W-expressing cells and control cells, 37 genes induced by TNF only when TAK1K63W was present, and 48 TNF-induced genes that were suppressed by TAK1K63W. The TNF-inducible genes that were most strongly suppressed by TAK1K63W, ccl2, ccl7, ccl5, cxcl1, cxcl5, cxcl10, saa3, and slpi also had much lower basal levels of expression, indicating that TAK1 also played a role in their normal expression. Chromatin immunoprecipitation studies on four of these genes suggested that inactivation of TAK1 activity led to direct suppression of expression at the transcriptional level because of impaired recruitment of RNA polymerase II to their promoters. ccl2 induction by TNF or interleukin-1 was also suppressed in cells that expressed TAK1 antisense RNA or that were genetically deficient in JNK1/2 or p65 NF kappa B. These data suggest that regulation of the expression of a selected group of inflammation-related genes is funneled through TAK1, making it a potentially useful target for more specific anti-inflammatory drug development. C1 Hannover Med Sch, Inst Pharmacol, D-30625 Hannover, Germany. NCI, Mol Genet Sect, Genet Lab, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. GBF, Natl Res Inst Biotechnol, Dept Gene Regulat & Differentiat, D-38124 Braunschweig, Germany. Univ Munich, D-80336 Munich, Germany. RP Kracht, M (reprint author), Hannover Med Sch, Inst Pharmacol, Carl Neuberg Str 1, D-30625 Hannover, Germany. EM Kracht.Michael@MH-Hannover.de NR 61 TC 42 Z9 44 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 JUL 29 PY 2005 VL 280 IS 30 BP 27728 EP 27741 DI 10.1074/jbc.M411657200 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 947WS UT WOS:000230678600032 PM 15837794 ER PT J AU Fu, LZ Ishizuya-Oka, A Buchholz, DR Amano, T Matsuda, H Shi, YB AF Fu, LZ Ishizuya-Oka, A Buchholz, DR Amano, T Matsuda, H Shi, YB TI A causative role of stromelysin-3 in extracellular matrix remodeling and epithelial apoptosis during intestinal metamorphosis in Xenopus laevis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HORMONE RESPONSE GENES; CONNECTIVE-TISSUE; METALLOPROTEINASE STROMELYSIN-3; BRANCHING MORPHOGENESIS; AMPHIBIAN METAMORPHOSIS; MOUSE STROMELYSIN-3; EXPRESSION PATTERN; FROG METAMORPHOSIS; BREAST-CANCER; TADPOLE TAIL AB The matrix metalloproteinases are a family of proteases capable of degrading various components of the extracellular matrix. Expression studies have implicated the involvement of the matrix metalloproteinase stromelysin-3 (ST3) in tissue remodeling and pathogenesis. However, the in vivo role of ST3 has been difficult to study because of a lack of good animal models. Here we used intestinal remodeling during thyroid hormone-dependent metamorphosis of Xenopus laevis as a model to investigate in vivo the role of ST3 during postembryonic organ development in vertebrates. We generated transgenic tadpoles expressing ST3 under control of a heat shock-inducible promoter. We showed for the first time in vivo that wild type ST3 but not a catalytically inactive mutant was sufficient to induce larval epithelial cell death and fibroblast activation, events that normally occur only in the presence of thyroid hormone. We further demonstrated that these changes in cell fate are associated with altered gene expression in the intestine and remodeling of the intestinal basal lamina. These results thus suggest that ST3 regulates cell fate and tissue morphogenesis through direct or indirect ECM remodeling. C1 NICHD, NIH, LGRD, Bethesda, MD 20892 USA. Nippon Med Coll, Dept Biol, Kawasaki, Kanagawa 2110063, Japan. RP Shi, YB (reprint author), NICHD, NIH, LGRD, Bldg 18 T,Rm 106, Bethesda, MD 20892 USA. EM Shi@helix.nih.gov NR 67 TC 44 Z9 45 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 JUL 29 PY 2005 VL 280 IS 30 BP 27856 EP 27865 DI 10.1074/jbc.M413275200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 947WS UT WOS:000230678600047 PM 15929979 ER PT J AU Ghosh, M Meiss, G Pingoud, A London, RE Pedersen, LC AF Ghosh, M Meiss, G Pingoud, A London, RE Pedersen, LC TI Structural insights into the mechanism of Nuclease A, a beta beta alpha metal nuclease from Anabaena SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SERRATIA-MARCESCENS ENDONUCLEASE; SUGAR-NONSPECIFIC NUCLEASE; DNA-BINDING; EXTRACELLULAR NUCLEASE; ACTIVE-SITE; I-PPOI; PERIPLASMIC NUCLEASE; ESCHERICHIA-COLI; AMINO-ACIDS; CLEAVAGE AB Nuclease A (NucA) is a nonspecific endonuclease from Anabaena sp. capable of degrading single- and double-stranded DNA and RNA in the presence of divalent metal ions. We have determined the structure of the Delta(2-24), D121A mutant of NucA in the presence of Zn2+ and Mn2+ (PDB code 1ZM8). The mutations were introduced to remove the N-terminal signal peptide and to reduce the activity of the nonspecific nuclease, thereby reducing its toxicity to the Escherichia coli expression system. NucA contains a beta beta alpha metal finger motif and a hydrated Mn2+ ion at the active site. Unexpectedly, NucA was found to contain additional metal binding sites similar to 26 angstrom apart from the catalytic metal binding site. A structural comparison between NucA and the closest analog for which structural data exist, the Serratia nuclease, indicates several interesting differences. First, NucA is a monomer rather than a dimer. Second, there is an unexpected structural homology between the N-terminal segments despite a poorly conserved sequence, which in Serratia includes a cysteine bridge thought to play a regulatory role. In addition, although a sequence alignment had suggested that NucA lacks a proposed catalytic residue corresponding to Arg(57) in Serratia, the structure determined here indicates that Arg(93) in NucA is positioned to fulfill this role. Based on comparison with DNA-bound nuclease structures of the beta beta alpha metal finger nuclease family and available mutational data on NucA, we propose that His(124) acts as a catalytic base, and Arg(93) participates in the catalysis possibly through stabilization of the transition state. C1 NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Univ Giessen, Inst Biochem, FB08, D-35392 Giessen, Germany. RP London, RE (reprint author), NIEHS, Struct Biol Lab, MR 01,111 Alexnder Dr,Box 12233, Res Triangle Pk, NC 27709 USA. EM london@niehs.nih.gov NR 54 TC 32 Z9 35 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 JUL 29 PY 2005 VL 280 IS 30 BP 27990 EP 27997 DI 10.1074/jbc.M51798200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 947WS UT WOS:000230678600061 PM 15897201 ER PT J AU Sharma, S Sommers, JA Choudhary, S Faulkner, JK Cui, S Andreoli, L Muzzolini, L Vindigni, A Brosh, RM AF Sharma, S Sommers, JA Choudhary, S Faulkner, JK Cui, S Andreoli, L Muzzolini, L Vindigni, A Brosh, RM TI Biochemical analysis of the DNA unwinding and strand annealing activities catalyzed by human RECQ1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STALLED REPLICATION FORKS; WERNER-SYNDROME HELICASE; HOLLIDAY JUNCTIONS; SYNDROME PROTEIN; D-LOOPS; HOMOLOGOUS RECOMBINATION; SACCHAROMYCES-CEREVISIAE; SUBSTRATE-SPECIFICITY; ROTHMUND-THOMSON; BLOOMS AB RecQ helicases play an important role in preserving genomic integrity, and their cellular roles in DNA repair, recombination, and replication have been of considerable interest. Of the five human RecQ helicases identified, three are associated with genetic disorders characterized by an elevated incidence of cancer or premature aging: Werner syndrome, Bloom syndrome, and Rothmund-Thomson syndrome. Although the biochemical properties and protein interactions of the WRN and BLM helicases defective in Werner syndrome and Bloom syndrome, respectively, have been extensively investigated, less information is available concerning the functions of the other human RecQ helicases. We have focused our attention on human RECQ1, a DNA helicase whose cellular functions remain largely uncharacterized. In this work, we have characterized the DNA substrate specificity and optimal cofactor requirements for efficient RECQ1-catalyzed DNA unwinding and determined that RECQ1 has certain properties that are distinct from those of other RecQ helicases. RECQ1 stably bound to a variety of DNA structures, enabling it to unwind a diverse set of DNA substrates. In addition to its DNA binding and helicase activities, RECQ1 catalyzed efficient strand annealing between complementary single-stranded DNA molecules. The ability of RECQ1 to promote strand annealing was modulated by ATP binding, which induced a conformational change in the protein. The enzymatic properties of the RECQ1 helicase and strand annealing activities are discussed in the context of proposed cellular DNA metabolic pathways that are important in the maintenance of genomic stability. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Int Ctr Genet Engn & Biotechnol, I-34012 Trieste, Italy. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM BroshR@grc.nia.nih.gov RI CUI, Sheng/M-6405-2013; OI CUI, Sheng/0000-0001-6329-3582; Sharma, Sudha/0000-0003-2765-2482 NR 46 TC 114 Z9 116 U1 2 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 29 PY 2005 VL 280 IS 30 BP 28072 EP 28084 DI 10.1074/jbc.M500264200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 947WS UT WOS:000230678600070 PM 15899892 ER PT J AU Doherty, KM Sharma, S Uzdilla, LA Wilson, TM Cui, S Vindigni, A Brosh, RM AF Doherty, KM Sharma, S Uzdilla, LA Wilson, TM Cui, S Vindigni, A Brosh, RM TI RECQ1 helicase interacts with human mismatch repair factors that regulate genetic recombination SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BLOOMS-SYNDROME HELICASE; WERNER-SYNDROME PROTEIN; SACCHAROMYCES-CEREVISIAE; DNA HELICASE; ESCHERICHIA-COLI; HOMOLOGOUS RECOMBINATION; HETERODUPLEX REJECTION; MITOTIC RECOMBINATION; MUTATION AVOIDANCE; UNWINDING ACTIVITY AB Understanding the molecular and cellular functions of RecQ helicases has attracted considerable interest since several human diseases characterized by premature aging and/or cancer have been genetically linked to mutations in genes of the RecQ family. Although a human disease has not yet been genetically linked to a mutation in RECQ1, the prominent roles of RecQ helicases in the maintenance of genome stability suggest that RECQ1 helicase is likely to be important in vivo. To acquire a better understanding of RECQ1 cellular and molecular functions, we have investigated its protein interactions. Using a co-immunoprecipitation approach, we have identified several DNA repair factors that are associated with RECQ1 in vivo. Direct physical interaction of these repair factors with RECQ1 was confirmed with purified recombinant proteins. Importantly, RECQ1 stimulates the incision activity of human exonuclease 1 and the mismatch repair recognition complex MSH2/6 stimulates RECQ1 helicase activity. These protein interactions suggest a role of RECQ1 in a pathway involving mismatch repair factors. Regulation of genetic recombination, a proposed role for RecQ helicases, is supported by the identified RECQ1 protein interactions and is discussed. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Univ Maryland, Dept Radiat Oncol, Radiat Oncol Res Lab, Baltimore, MD 21201 USA. Int Ctr Genet Engn & Biotechnol, I-34012 Trieste, Italy. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM BroshR@grc.nia.nih.gov RI CUI, Sheng/M-6405-2013; OI CUI, Sheng/0000-0001-6329-3582; Sharma, Sudha/0000-0003-2765-2482 FU NCI NIH HHS [CA095690] NR 55 TC 58 Z9 61 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 29 PY 2005 VL 280 IS 30 BP 28085 EP 28094 DI 10.1074/jbc.M500265200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 947WS UT WOS:000230678600071 PM 15886194 ER PT J AU Matsumoto, M Beltaifa, R Weickert, CS Herman, MM Hyde, TM Saunders, RC Lipska, BK Weinberger, DR Kleinman, JE AF Matsumoto, M Beltaifa, R Weickert, CS Herman, MM Hyde, TM Saunders, RC Lipska, BK Weinberger, DR Kleinman, JE TI A conserved mRNA expression profile of SREB2 (GPR85) in adult human, monkey, and rat forebrain SO MOLECULAR BRAIN RESEARCH LA English DT Article DE G-protein-coupled receptor; orphan; evolution; conservation; neuron; hippocampus; neurogenesis; glutamate; plasticity ID PROTEIN-COUPLED RECEPTOR; CENTRAL-NERVOUS-SYSTEM; CELL-ADHESION MOLECULE; PUFFER FISH; PLASTICITY; BRAIN; NEUROGENESIS; GENES; CLONING; OLIGOMERIZATION AB SREB is a subfamily of G-protein-coupled receptors, which consists of SREB1 (GPR27), SREB2 (GPR85), and SREB3 (GPR 173). Its high evolutionary conservation and predominant expression in the CNS suggest that SREB family members and their undiscovered ligand(s) may have significant functions in the nervous system. SREB2 is the most conserved receptor throughout vertebrate evolution. As a first step in understanding the function of the SREB family, we have determined the anatomical gene expression profile of SREB2 in adult human, monkey, and rat forebrain using in situ hybridization histochemistry. The expression pattern of SREB2 mRNA was well conserved across three mammalian species. SREB2 mRNA was expressed in neurons throughout the brain and the most abundant expression was detected in the hippocampal dentate gyrus, in all species examined. The areas expressing high levels of SREB2 mRNA overlap with brain structures known to possess high levels of plasticity, namely, the hippocampal formation, olfactory system, and supraoptic and paraventricular nuclei. Further, the anatomical expression of SREB1 and SREB3 overlapped with that of SREB2 in the adult monkey brain, Together, these data suggest a possible link between, SREB family and neural plasticity, which may explain its extremely high conservation throughout vertebrate evolution. (c) 2005 Elsevier B.V. All rights reserved. C1 Astellas Pharma Inc, Mol Med Res Labs, Drug Discovery Res, Tsukuba, Ibaraki 3058585, Japan. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Matsumoto, M (reprint author), Astellas Pharma Inc, Mol Med Res Labs, Drug Discovery Res, 21 Miyukigaoka, Tsukuba, Ibaraki 3058585, Japan. EM mitsuyuki.matsumoto@jp.astellas.com RI Shannon Weickert, Cynthia/G-3171-2011; Matsumoto, Mitsuyuki/G-3207-2012 OI Matsumoto, Mitsuyuki/0000-0002-1172-2354 NR 39 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD JUL 29 PY 2005 VL 138 IS 1 BP 58 EP 69 DI 10.1016/j.molbrainres.2005.04.002 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 955DN UT WOS:000231205600007 ER PT J AU Harding, WW Tidgewell, K Byrd, N Cobb, H Dersch, CM Butelman, ER Rothman, RB Prisinzano, TE AF Harding, WW Tidgewell, K Byrd, N Cobb, H Dersch, CM Butelman, ER Rothman, RB Prisinzano, TE TI Neoclerodane diterpenes as a novel scaffold for mu opioid receptor ligands SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MINT SALVIA-DIVINORUM; SALVINORIN-A; AGONIST; POTENT; HALLUCINOGEN; ANTAGONISTS; STEREOCHEMISTRY; PEPTIDE; BRAIN; ACIDS AB Structural modification of salvinorin A, the active component of Salvia divinorum, has resulted in the synthesis of novel neoclerodane diterpenes with opioid receptor affinity and activity. We report in this study a nonnitrogenous neoclerodane diterpene with mu opioid receptor affinity (13) that is an agonist at mu opioid receptors. This represents the identification of a novel structural class of mu opioid receptor agonists. C1 Univ Iowa, Coll Pharm, Div Med & Nat Prod Chem, Iowa City, IA 52242 USA. NIDA, Clin Psychopharmacol Sect, IRP, NIH,DHHS, Baltimore, MD 21224 USA. Rockefeller Univ, Lab Biol Adict Dis, New York, NY 10021 USA. RP Prisinzano, TE (reprint author), Univ Iowa, Coll Pharm, Div Med & Nat Prod Chem, Iowa City, IA 52242 USA. EM thomas-prisinzano@uiowa.edu RI Prisinzano, Thomas/B-7877-2010; OI Tidgewell , Kevin/0000-0002-0501-2604 FU NIDA NIH HHS [DA 1-7725] NR 45 TC 83 Z9 85 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUL 28 PY 2005 VL 48 IS 15 BP 4765 EP 4771 DI 10.1021/jm048963m PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 949PJ UT WOS:000230800300005 PM 16033256 ER PT J AU Ioanoviciu, A Antony, S Pommier, Y Staker, BL Stewart, L Cushman, M AF Ioanoviciu, A Antony, S Pommier, Y Staker, BL Stewart, L Cushman, M TI Synthesis and mechanism of action studies of a series of norindenoisoquinoline topoisomerase I poisons reveal an inhibitor with a flipped orientation in the ternary DNA-enzyme-inhibitor complex as determined by X-ray crystallographic analysis SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ANTICANCER ACTIVITY; ISOQUINOLINES; CAMPTOTHECIN; 1,2-DIHYDROISOQUINOLINES; DERIVATIVES; 1,2,3,4-TETRAHYDROISOQUINOLINES; CYCLIZATION; SYSTEM; AGENTS; DRUGS AB Several norindenoisoquinolines substituted with methoxy or methylenedioxy groups have been prepared and their anticancer properties evaluated in cancer cell cultures and in topoisomerase I inhibition assays. 2,3-Dimethoxy-8,9-methylenedioxy-11H-indeno[1,2-c]isoquinoline hydrochloride (14) is a strong topoisomerase I inhibitor and also displays very high cytotoxicity in the NCI cancer cell culture screen (mean graph midpoint of 50 nM). The X-ray crystal structure of norindenoisoquirroline 14 in complex with topoisomerase I and DNA has been solved, providing insight into the structure-activity relationships within this class of new anticancer agents. The number and position of the norindenoisoquinoline substituents have a significant influence on biological activity and demonstrate that substitution on the nitrogen atom is not an absolute requirement for the antitumor effect of the indenoisoquinolines. Removal of the 11-keto group from the lead compound 1 and replacement of the N-alkyllactam with an unsubstituted pyridine ring causes the indenoisoquinoline ring system to flip over in the DNA-enzyme-inhibitor ternary complex. This allows the nitrogen atom to assume the hydrogen bond acceptor role of the 11-keto group, resulting in hydrogen bonding to Arg364. C1 Purdue Univ, Sch Pharm & Pharmaceut Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. Purdue Univ, Sch Pharm & Pharmaceut Sci, Purdue Canc Ctr, W Lafayette, IN 47907 USA. NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. deCODE Biostruct Inc, Bainbridge Isl, WA 98110 USA. RP Cushman, M (reprint author), Purdue Univ, Sch Pharm & Pharmaceut Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. EM cushman@pharmacy.purdue.edu FU NCI NIH HHS [UO1 CA89566, N01-CO-56000]; PHS HHS [C06-14499] NR 37 TC 81 Z9 83 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUL 28 PY 2005 VL 48 IS 15 BP 4803 EP 4814 DI 10.1021/jm050076b PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 949PJ UT WOS:000230800300009 PM 16033260 ER PT J AU Perreira, M Jiang, JK Klutz, AM Gao, ZG Shainberg, A Lu, CR Thomas, CJ Jacobson, KA AF Perreira, M Jiang, JK Klutz, AM Gao, ZG Shainberg, A Lu, CR Thomas, CJ Jacobson, KA TI "Reversine" and its 2-substituted adenine derivatives as potent and selective A(3) adenosine receptor antagonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HIGHLY POTENT; LIGANDS; NUCLEOSIDES; EFFICACY; AFFINITY; AGONISTS; CELLS; PHARMACOLOGY; INHIBITOR; SUBTYPES AB The dedifferentiation agent "reversine" [2-(4-morpholinoanilino)-N-6-cyclohexyladenine 2] was found to be a moderately potent antagonist for the human A(3) adenosine receptor (AR) with a K-i value of 0.66 mu M. This result prompted an exploration of the structure-activity relationship of related derivatives, synthesized via sequential substitution of 6-chloro-2-fluoropurine with selected nucleophiles. Optimization of substituents at these two positions identified 2-(phenylamino)-N6-cyclohexyladenine (12), 2-(phenylamino)-N-6-cycloheptyladenine (19), and 2-phenylamino-N-6-endo-norbornyladenine (21) as potent A(3) AR ligands with K-i values of 51, 42, and 37 nM, respectively, with 30-200-fold selectivity in comparison to A(1) and A(2A) ARs. The most selective A(3) AR antagonist (> 200-fold) was 2-(phenyloxy)-N-6-cyclohexyladenine (22). 9-Methylation of 12, but not 19, was well-tolerated in A(3) AR binding. Extension of the 2-phenylamino group to 2-benzyl- and 2-(2-phenylethylamino) reduced affinity. In the series of 2-(phenylamino), 2-(phenyloxy), and 2-(phenylthio) substitutions, the order of affinity at the A(3) AR was oxy >= amino > thio. Selected derivatives, including reversine (K-B value of 466 nM via Schild analysis), competitively antagonized the functional effects of a selective A(3) AR agonist, i.e., inhibition of forskolin-stimulated cAMP production in stably transfected Chinese hamster ovary (CHO) cells. These results are in agreement with other studies suggesting the presence of a lipophilic pocket in the AR binding site that is filled by moderately sized cycloalkyl rings at the N-6 position of both adenine and adenosine derivatives. Thus, the compound series reported herein comprise an important new series of selective A(3) AR antagonists. We were unable to reproduce the dedifferentiation effect of reversine, previously reported, or to demonstrate any connection between A(3) AR antagonist effects and dedifferentiation. C1 NIDDKD, Chem Biol Core Facil, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol Recognit Sect, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. Bar Ilan Univ, Fac Life Sci, IL-52900 Ramat Gan, Israel. RP Jacobson, KA (reprint author), NIDDKD, Chem Biol Core Facil, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; Lu, Changrui/0000-0002-2171-9888 FU Intramural NIH HHS [Z01 DK031117-20, Z01 DK070005-04] NR 34 TC 40 Z9 44 U1 0 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUL 28 PY 2005 VL 48 IS 15 BP 4910 EP 4918 DI 10.1021/jm050221l PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 949PJ UT WOS:000230800300019 PM 16033270 ER PT J AU Smego, RA AF Smego, RA TI Effectiveness of antimalarial drugs SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID RESISTANT MALARIA; AFRICA C1 NIAID, Rockville, MD 20852 USA. RP Smego, RA (reprint author), NIAID, Rockville, MD 20852 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 28 PY 2005 VL 353 IS 4 BP 420 EP 421 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 949JW UT WOS:000230782800021 PM 16050053 ER PT J AU Simonsen, L Viboud, C AF Simonsen, L Viboud, C TI Respiratory syncytial virus infection in elderly adults SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID INFLUENZA; MORTALITY C1 NIAID, Bethesda, MD 20892 USA. Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Simonsen, L (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. OI Simonsen, Lone/0000-0003-1535-8526 NR 4 TC 8 Z9 9 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 JUL 28 PY 2005 VL 353 IS 4 BP 422 EP 423 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 949JW UT WOS:000230782800025 PM 16050055 ER PT J AU Kyng, KJ May, A Stevnsner, T Becker, KG Kolvra, S Bohr, VA AF Kyng, KJ May, A Stevnsner, T Becker, KG Kolvra, S Bohr, VA TI Gene expression responses to DNA damage are altered in human aging and in Werner Syndrome SO ONCOGENE LA English DT Article DE microarray; Werner syndrome; DNA damage; aging ID REPLICATIVE SENESCENCE; CALORIC RESTRICTION; 4-NITROQUINOLINE 1-OXIDE; SACCHAROMYCES-CEREVISIAE; SYNDROME FIBROBLASTS; ADAPTIVE RESPONSE; OXIDATIVE STRESS; CELL-LINES; LIFE-SPAN; REPAIR AB The accumulation of DNA damage and mutations is considered a major cause of cancer and aging. While it is known that DNA damage can affect changes in gene expression, transcriptional regulation after DNA damage is poorly understood. We characterized the expression of 6912 genes in human primary. broblasts after exposure to three different kinds of cellular stress that introduces DNA damage: 4- nitroquinoline-1-oxide (4NQO), gamma-irradiation, or UV-irradiation. Each type of stress elicited damage specific gene expression changes of up to 10-fold. A total of 85 genes had similar changes in expression of 3-40- fold after all three kinds of stress. We examined transcription in cells from young and old individuals and from patients with Werner syndrome (WS), a segmental progeroid condition with a high incidence of cancer, and found various age-associated transcriptional changes depending upon the type of cellular stress. Compared to young individuals, both WS and old individuals had similarly aberrant transcriptional responses to gamma- and UV-irradiation, suggesting a role for Werner protein in stress- induced gene expression. Our results suggest that aberrant DNA damage-induced gene regulation may contribute to the aging process and the premature aging in WS. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Aarhus Univ, Dept Mol Biol, Danish Ctr Mol Gerontol, DK-8000 Aarhus, Denmark. NIA, Gene Express & Genom Unit, Baltimore, MD 21224 USA. Univ Aarhus, Inst Human Genet, DK-8000 Aarhus, Denmark. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vbohr@nih.gov OI Kyng, Kasper Jacobsen/0000-0001-7940-1656; Becker, Kevin/0000-0002-6794-6656 NR 58 TC 31 Z9 32 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 JUL 28 PY 2005 VL 24 IS 32 BP 5026 EP 5042 DI 10.1038/sj.onc.1208692 PG 17 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 949VT UT WOS:000230816900003 PM 15897889 ER PT J AU Ludlow, CL AF Ludlow, CL TI Central nervous system control of the laryngeal muscles in humans SO RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY LA English DT Review DE speech; voice; swallowing; respiration; cough; laryngospasm ID NORMAL ADULT HUMANS; CEREBRAL CORTICAL REPRESENTATION; PHARYNGOGLOTTAL CLOSURE REFLEX; ADDUCTOR SPASMODIC DYSPHONIA; FUNDAMENTAL VOICE FREQUENCY; SHIFTED AUDITORY-FEEDBACK; AIR-PRESSURE STIMULATION; EVENT-RELATED FMRI; LOWER BRAIN-STEM; THYROARYTENOID MUSCLE AB Laryngeal muscle control may vary for different functions such as: voice for speech communication, emotional expression during laughter and cry, breathing, swallowing, and cough. This review discusses the control of the human laryngeal muscles for some of these different functions. Sensori-motor aspects of laryngeal control have been studied by eliciting various laryngeal reflexes. The role of audition in learning and monitoring ongoing voice production for speech is well known; while the role of somatosensory feedback is less well understood. Reflexive control systems involving central pattern generators may contribute to swallowing, breathing and cough with greater cortical control during volitional tasks such as voice production for speech. Volitional control is much less well understood for each of these functions and likely involves the integration of cortical and subcortical circuits. The new frontier is the study of the central control of the laryngeal musculature for voice, swallowing and breathing and how volitional and reflexive control systems may interact in humans. (C) 2005 Elsevier B.V. All rights reserved. C1 NINDS, Laryngeal & Speech Sect, Med Neurol Branch, Bethesda, MD 20892 USA. RP Ludlow, CL (reprint author), NINDS, Laryngeal & Speech Sect, Med Neurol Branch, Bldg 10,Room 5D 38,10 Ctr Dr MSC 1416, Bethesda, MD 20892 USA. EM ludlowc@ninds.nih.gov OI Ludlow, Christy/0000-0002-2015-6171 NR 119 TC 60 Z9 61 U1 1 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-9048 J9 RESP PHYSIOL NEUROBI JI Respir. Physiol. Neuro. PD JUL 28 PY 2005 VL 147 IS 2-3 BP 205 EP 222 DI 10.1016/j.resp.2005.04.015 PG 18 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 959OF UT WOS:000231526800007 PM 15927543 ER PT J AU Kim, T Zhang, CF Sun, ZQ Wu, HL Loh, YP AF Kim, T Zhang, CF Sun, ZQ Wu, HL Loh, YP TI Chromogranin A deficiency in transgenic mice leads to aberrant chromaffin granule biogenesis SO JOURNAL OF NEUROSCIENCE LA English DT Article DE chromogranin A; dense-core; secretory granule; biogenesis; transgenic; chromaffin; catecholamine; adrenal medulla ID REGULATED SECRETORY PROTEINS; QUANTAL SIZE; AGGREGATION; CELLS; EXPRESSION; CALCIUM; BINDING; PH AB The biogenesis of dense- core secretory granules ( DCGs), organelles responsible for the storage and secretion of neurotransmitters and neuropeptides in chromaffin cells, is poorly understood. Chromogranin A( CgA), which binds catecholamines for storage in the lumen of chromaffin granules, has been shown to be involved in DCG biogenesis in neuroendocrine PC12 cells. Here, we report that downregulation of CgA expression in vivo by expressing antisense RNA against CgA in transgenic mice led to a significant reduction in DCG formation in adrenal chromaffin cells. The number of DCGs formed in CgA antisense transgenic mice was directly correlated with the amount of CgA present in adrenal medulla. In addition, DCGs showed an increase in size, with enlargement in the volume around the dense core, a phenomenon that occurs to maintain constant " free" catecholamine concentration in the lumen of these granules. The extent of DCG swelling was inversely correlated with the number of DCGs formed, as well as the amount of CgA present in the adrenal glands of CgA antisense transgenic mice. These data indicate an essential role of CgA in regulating chromaffin DCG biogenesis and catecholamine storage in vivo. C1 NICHHD, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. Peking Univ, Coll Biol, Beijing 100871, Peoples R China. RP Loh, YP (reprint author), 49 Convent Dr,MSC-4480, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov NR 20 TC 52 Z9 52 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 JUL 27 PY 2005 VL 25 IS 30 BP 6958 EP 6961 DI 10.1523/JNEUROSCI.1058-05.2005 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 949WB UT WOS:000230817700003 PM 16049171 ER PT J AU Zhao, ML Adams, JP Dudek, SM AF Zhao, ML Adams, JP Dudek, SM TI Pattern-dependent role of NMDA receptors in action potential generation: Consequences on extracellular signal-regulated kinase activation SO JOURNAL OF NEUROSCIENCE LA English DT Article DE long-term potentiation; transcription; translation; cAMP response element-binding protein; Elk-1; synapse-to-nucleus signal ID LONG-TERM POTENTIATION; D-ASPARTATE RECEPTORS; PROTEIN-KINASE; LATE-PHASE; SYNAPTIC PLASTICITY; HIPPOCAMPAL-NEURONS; THETA-FREQUENCY; CALCIUM INFLUX; DENTATE GYRUS; IN-VIVO AB Synaptic long- term potentiation is maintained through gene transcription, but how the nucleus is recruited remains controversial. Activation of extracellular signal- regulated kinases ( ERKs) 1 and 2 with synaptic stimulation has been shown to require NMDA receptors ( NMDARs), yet stimulation intensities sufficient to recruit action potentials ( APs) also appear to be required. This has led us to ask the question of whether NMDARs are necessary for AP generation as they relate to ERK activation. To test this, we examined the effects of NMDAR blockade on APs induced with synaptic stimulation using whole- cell current- clamp recordings from CA1 pyramidal cells in hippocampal slices. NMDAR antagonists were found to potently inhibit APs generated with 5 and 100 Hz synaptic stimulation. Blockade of APs and ERK activation could be overcome with the addition of the GABA(A) antagonist bicuculline, indicating that APs are sufficient to activate signals such as ERK in the nucleus and throughout the neuron in the continued presence of NMDAR antagonists. Interestingly, no effects of the NMDAR antagonists were observed when theta- burst stimulation ( TBS) was used. This resistance to the antagonists is conferred by temporal summation during the bursts. These results clarify findings from a previous study showing that ERK activation induced with TBS is resistant to 2- amino- 5- phosphonovalerate, in contrast to that induced with 5 or 100 Hz stimulation, which is sensitive. By showing that NMDAR blockade inhibits AP generation, we demonstrate that a major role that NMDARs play in cell- wide and nuclear ERK activation is through their contribution to action potential generation. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Dudek, SM (reprint author), NIEHS, NIH, POB 12233,Maryland F2-04, Res Triangle Pk, NC 27709 USA. EM dudek@niehs.nih.gov OI Dudek, Serena M./0000-0003-4094-8368 FU NIEHS NIH HHS [Z01 ES100221-04] NR 43 TC 30 Z9 30 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 27 PY 2005 VL 25 IS 30 BP 7032 EP 7039 DI 10.1523/JNEUROSCI.1579-05.2005 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 949WB UT WOS:000230817700011 PM 16049179 ER PT J AU Ding, K Lu, Y Nikolovska-Coleska, Z Qiu, S Ding, YS Gao, W Stuckey, J Krajewski, K Roller, PP Tomita, Y Parrish, DA Deschamps, JR Wang, SM AF Ding, K Lu, Y Nikolovska-Coleska, Z Qiu, S Ding, YS Gao, W Stuckey, J Krajewski, K Roller, PP Tomita, Y Parrish, DA Deschamps, JR Wang, SM TI Structure-based design of potent non-peptide MDM2 inhibitors SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID P53; ANTAGONISTS C1 Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA. Univ Michigan, Comprehens Canc Ctr, Ann Arbor, MI 48109 USA. Univ Michigan, Life Sci Inst, Ann Arbor, MI 48109 USA. NCI, Lab Med Chem, NIH, Ft Detrick, MD 21702 USA. Georgetown Univ, Ctr Med, Lombardi Canc Ctr, Washington, DC 20007 USA. USN, Res Lab, Lab Struct Matter, Washington, DC 20375 USA. RP Wang, SM (reprint author), Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. EM shaomeng@umich.edu RI Wang, Shaomeng/E-9686-2010; Ding, Yousong/F-2629-2010; Ding, Ke/B-3257-2010; OI Deschamps, Jeffrey/0000-0001-5845-0010; ding, ke/0000-0001-8167-0476; Ding, Ke/0000-0001-9016-812X NR 9 TC 354 Z9 362 U1 10 U2 58 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 JUL 27 PY 2005 VL 127 IS 29 BP 10130 EP 10131 DI 10.1021/ja051147z PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 948FF UT WOS:000230700700004 PM 16028899 ER PT J AU Ammosova, T Washington, K Debebe, Z Brady, J Nekhai, S AF Ammosova, T Washington, K Debebe, Z Brady, J Nekhai, S TI Dephosphorylation of CDK9 by protein phosphatase 2A and protein phosphatase-1 in Tat-activated HIV-1 transcription SO RETROVIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; LONG-TERMINAL REPEAT; RNA-POLYMERASE-II; P-TEFB; CYCLIN T1; TRANSACTIVATION; ACETYLATION; TYPE-1; PHOSPHORYLATION; REPLICATION AB Background: HIV-1 Tat protein recruits human positive transcription elongation factor P-TEFb, consisting of CDK9 and cyclin T1, to HIV-1 transactivation response (TAR) RNA. CDK9 is maintained in dephosphorylated state by TFIIH and undergo phosphorylation upon the dissociation of TFIIH. Thus, dephosphorylation of CDK9 prior to its association with HIV-1 preinitiation complex might be important for HIV-1 transcription. Others and we previously showed that protein phosphatase-2A and protein phosphatase-1 regulates HIV-1 transcription. In the present study we analyze relative contribution of PP2A and PP1 to dephosphorylation of CDK9 and to HIV-1 transcription in vitro and in vivo. Results: In vitro, PP2A but not PP1 dephosphorylated autophosphorylated CDK9 and reduced complex formation between P-TEFb, Tat and TAR RNA. Inhibition of PP2A by okadaic acid inhibited basal as well as Tat-induced HIV-1 transcription whereas inhibition of PP1 by recombinant nuclear inhibitor of PP1 (NIPP1) inhibited only Tat-induced transcription in vitro. In cultured cells, low concentration of okadaic acid, inhibitory for PP2A, only mildly inhibited Tat-induced HIV-1 transcription. In contrast Tat-mediated HIV-1 transcription was strongly inhibited by expression of NIPP1. Okadaic acid induced phosphorylation of endogenous as well transiently expressed CDK9, but this induction was not seen in the cells expressing NIPP1. Also the okadaic acid did not induce phosphorylation of CDK9 with mutation of Thr 186 or with mutations in Ser-329, Thr-330, Thr-333, Ser-334, Ser-347, Thr-350, Ser-353, and Thr-354 residues involved in autophosphorylation of CDK9. Conclusion: Our results indicate that although PP2A dephosphorylates autophosphorylated CDK9 in vitro, in cultured cells PP1 is likely to dephosphorylate CDK9 and contribute to the regulation of activated HIV-1 transcription. C1 Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. Howard Univ, Coll Med, Dept Biochem & Mol Biol, Washington, DC 20059 USA. NCI, Virus Tumor Biol Sect, LRBGE, Bethesda, MD 20892 USA. RP Nekhai, S (reprint author), Howard Univ, Ctr Sickle Cell Dis, 2121 Georgia Ave NW, Washington, DC 20059 USA. EM tammosova@mail.ru; ER223LK@aol.com; zdebebe@howard.edu; bradyj@dce41.nci.nih.gov; snekhai@howard.edu FU NHLBI NIH HHS [UH1 HL003679, UH1 HL03679]; NIAID NIH HHS [AI 056973-01S1, R21 AI056973, AI 156973-01] NR 36 TC 30 Z9 32 U1 0 U2 5 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 JUL 27 PY 2005 VL 2 AR 47 DI 10.1186/1742-4690-2-47 PG 15 WC Virology SC Virology GA 033DT UT WOS:000236827500001 PM 16048649 ER PT J AU Lyubarsky, AL Savchenko, AB Morocco, SB Daniele, LL Redmond, TM Pugh, EN AF Lyubarsky, AL Savchenko, AB Morocco, SB Daniele, LL Redmond, TM Pugh, EN TI Mole quantity of RPE65 and its productivity in the generation of 11-cis-retinal from retinyl esters in the living mouse eye SO BIOCHEMISTRY LA English DT Article ID VERTEBRATE VISUAL CYCLE; PIGMENT EPITHELIUM; RHODOPSIN REGENERATION; RPE65-DEFICIENT MICE; DARK-ADAPTATION; BINDING-PROTEIN; DEGENERATION; MUTATIONS; ISOMEROHYDROLASE; RETINALDEHYDE AB RPE65, a protein expressed in cells of the retinal pigment epithelium of the eye, is essential for the synthesis by isomerohydrolase of 11-cis-retinal, the chromophore of rod and cone opsins. Recent work has established that RPE65 is a retinyl ester binding protein, and as all-trans-retinyl esters are the substrate for isomerohydrolase activity, the hypothesis has emerged that RPE65 serves to deliver substrate to this enzyme or complex. We bred mice with five distinct combinations of the RPE65 Leu450/Met450 variants (Leu/Leu, Met/Met, Leu/Met, Leu/-, and Met/-), measured in mice of each genotype the mole quantity of RPE65 per eye, and measured the initial rate of rhodopsin regeneration after a nearly complete bleach of rhodopsin to estimate the maximum rate of 11-cis-retinal synthesis in vivo. The quantity of RPE65 per eye ranged from 5.7 pmol (Balb/c) to 0.32 pmol (C57BL/6N x Rpe65(-/-)); the initial rate of rhodopsin regeneration was a Michaelis function of RPE65, where V-max = 18 pmol/min per eye and K-m = 1.7 pmol, and not dependent on the Leu450/Met450 variant. At RPE65 levels well below the K-m the rate of production of 11-cis-retinal per RPE65 molecule was similar to 10 min(-1). Thus, the results imply that as a chaperone each RPE65 molecule can deliver retinyl ester to the isomerohydrolase at a rate of 10 molecules/min; should RPE65 itself be identified as the isomerase, each copy must be able to produce at least 10 molecules of 11-cis-retinal per minute. C1 Univ Penn, FM Kirby Ctr Mol Ophthalmol, Dept Ophthalmol, Sch Med, Philadelphia, PA 19104 USA. NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Pugh, EN (reprint author), Univ Penn, FM Kirby Ctr Mol Ophthalmol, Dept Ophthalmol, Sch Med, 422 Curie Blvd, Philadelphia, PA 19104 USA. EM pugh@mail.med.upenn.edu OI Redmond, T. Michael/0000-0002-1813-5291 FU NEI NIH HHS [EY02660, R01 EY002660] NR 31 TC 36 Z9 36 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 26 PY 2005 VL 44 IS 29 BP 9880 EP 9888 DI 10.1021/bi0505363 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 947FF UT WOS:000230628100007 PM 16026160 ER PT J AU Arai, H Berlett, BS Chock, PB Stadtman, ER AF Arai, H Berlett, BS Chock, PB Stadtman, ER TI Effect of bicarbonate on iron-mediated oxidation of low-density lipoprotein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ZINC SUPEROXIDE-DISMUTASE; AMINO-ACID OXIDATION; LIPID-PEROXIDATION; HYDROGEN-PEROXIDE; CROSS-LINKING; CU,ZN-SUPEROXIDE DISMUTASE; MODIFICATION HYPOTHESIS; METHIONINE OXIDATION; LDL-OXIDATION; PROTEINS AB Oxidation of low-density lipoprotein (LDL) may play an important role in atherosclerosis. We studied the effects of bicarbonate/CO2 and phosphate buffer systems on metal ion-catalyzed oxidation of LDL to malonclialdehyde (MDA) and to protein carbonyl and MetO derivatives. Our results revealed that LDL oxidation in mixtures containing free iron or heme derivatives was much greater in bicarbonate/CO2 compared with phosphate buffer. However, when copper was substituted for iron in these mixtures, the rate of LDL oxidation in both buffers was similar. Iron-catalyzed oxidation of LDL was highly sensitive to inhibition by phosphate. Presence of 0.3-0.5 mM phosphate, characteristic of human serum, led to 30-40% inhibition of LDL oxidation in bicarbonate/CO2 buffer. Iron-catalyzed oxidation of LDL to MDA in phosphate buffer was inhibited by increasing concentrations of albumin (10-200 mu M), whereas MDA formation in bicarbonate/CO2 buffer was stimulated by 10-50 mu M albumin but inhibited by higher concentrations. However, albumin stimulated the oxidation of LDL proteins to carbonyl derivatives at all concentrations examined in both buffers. Conversion of LDL to MDA in bicarbonate/CO2 buffer was greatly stimulated by ADP, ATP, and EDTA but only when EDTA was added at a concentration equal to that of iron. At higher than stoichiometric concentrations, EDTA prevented oxidation of LDL. Results of these studies suggest that interactions between bicarbonate and iron or heme derivatives leads to complexes with redox potentials that favor the generation of reactive oxygen species and/or to the generation of highly reactive CO2 anion or bicarbonate radical that facilitates LDL oxidation. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, ER (reprint author), NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. EM erstadtman@nih.gov NR 42 TC 25 Z9 25 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 JUL 26 PY 2005 VL 102 IS 30 BP 10472 EP 10477 DI 10.1073/pnas.0504685102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 950JL UT WOS:000230853300014 PM 16027354 ER PT J AU Schueler, MG Dunn, JM Bird, CP Ross, MT Viggiano, L Rocchi, M Willard, HF Green, ED AF Schueler, MG Dunn, JM Bird, CP Ross, MT Viggiano, L Rocchi, M Willard, HF Green, ED CA NISC Comparative Sequencing Progra TI Progressive proximal expansion of the primate X chromosome centromere SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE evolution; alpha satellite; comparative genomics; genome sequencing ID ALPHA-SATELLITE DNA; CENP-B BOX; TOPOISOMERASE-II; SEQUENCE ANALYSIS; HUMAN GENOME; EVOLUTION; ARRAY; CONSTRUCTION; ORGANIZATION; CHROMATIN AB Previous studies of the pericentromeric region of the human X chromosome short arm (Xp) revealed an age gradient from ancient DNA that contains expressed genes to recent human-specific DNA at the functional centromere. We analyzed the finished sequence of this human genomic region to investigate its evolutionary history. Phylogenetic analysis of > 1,500 alpha-satellite monomers from the region revealed the presence of five physical domains, each containing monomers from a distinct phylogenetic clade. The most distal domain contains long interspersed nucleotide element repeats that were active > 35 million years ago, whereas the four proximal domains contain more recently active long interspersed nucleotide element repeats. An out-of-register, unequal recombination (i.e., crossover) detected at the edge of the X chromosome-specific alpha-satellite array (DXZ1) may reflect the most recent of a series of punctuating events during evolution that resulted in a proximal physical expansion of the X centromere. The first 18 kb of this array has 97-99% pairwise identity among all 2-kb repeat units. To perform more detailed evolutionary comparisons, we sequenced the junction between the ancient DNA of Xp and the primate-specific alpha satellite in chimpanzee, gorilla, orangutan, vervet, macaque, and baboon. The striking conservation found in all cases supports the ancestral nature of the alpha satellite at this location. These studies demonstrate that the primate X centromere appears to have evolved through repeated expansion events occurring within the central, active region of centromeric DNA, with the newly added sequences then conferring centromere function. C1 Duke Univ, Inst Genome Sci & Policy, Ctr Interdisciplinary Engn Med & Appl Sci, Durham, NC 27708 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Natl Inst Hlth Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. Univ Bari, Sez Genet, Dipartimento Anat Patol & Genet, I-70126 Bari, Italy. RP Willard, HF (reprint author), Duke Univ, Inst Genome Sci & Policy, Ctr Interdisciplinary Engn Med & Appl Sci, 101 Sci Dr,Room 2379, Durham, NC 27708 USA. EM willa009@mc.duke.edu; egreen@nhgri.nih.gov OI Viggiano, Luigi/0000-0002-2067-5166; Rocchi, Mariano/0000-0002-9451-5616 NR 58 TC 50 Z9 51 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 26 PY 2005 VL 102 IS 30 BP 10563 EP 10568 DI 10.1073/pnas.0503346102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 950JL UT WOS:000230853300030 PM 16030148 ER PT J AU Datta, K Neumann, RD Winters, TA AF Datta, K Neumann, RD Winters, TA TI Characterization of complex apurinic/apyrimidinic-site clustering associated with an authentic site-specific radiation-induced DNA double-strand break SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DNA damage clustering; multiply damaged site; enzymatic probing; high linear energy transfer; triplex-forming oligonucliotide ID TRIPLEX-FORMING OLIGONUCLEOTIDE; BASE-EXCISION-REPAIR; IONIZING-RADIATION; MAMMALIAN-CELLS; GAMMA-RADIATION; AUGER PROCESSES; DAMAGE; I-125; DECAY; INDUCTION AB Radiation lethality is largely attributed to radiation-induced DNA double-strand breaks (DSBs). A range of structural complexity is predicted for radiation-induced DSBs. However, this lesion has never been analyzed in isolation at the molecular level. To address this problem, we have created authentic site-specific radiation-induced DSBs in plasmid DNA by triplex-forming oligonucleotide-targeted 1251 decay. No significant difference in DSB yield was observed after irradiation in the presence or absence of the radical scavenger DMSO, suggesting that DSB formation is a result of the direct effect of the radiation. A restriction fragment terminated by the DSB was isolated and probed with the Escherichia coli DNA repair enzyme endonuclease IV (endo IV), which recognizes apurinic/apyrimidinic (AP) sites. Enzymatic probing demonstrated clustering of AP sites within 10 bases of the I-125-targeted base in the DNA duplex. Our results suggest scavengeable radicals may not play a large role in the generation of AP sites associated with DSB formation, because at least 30% of all fragments have endo IV-sensitive sites, regardless of irradiation conditions. An internal control fragment recovered from the 1251 linearized plasmid did not exhibit endo IV sensitivity in excess of that observed for a similar fragment recovered from an undamaged plasmid. Thus, AP site clustering proximal to the DSB resulted from the 1251 decays responsible for DSB formation and was not due to untargeted background irradiation. C1 NIH, Dept Nucl Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Winters, TA (reprint author), NIH, Dept Nucl Med, Warren Grant Magnuson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. EM twinters@mail.cc.nih.gov NR 49 TC 33 Z9 33 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 26 PY 2005 VL 102 IS 30 BP 10569 EP 10574 DI 10.1073/pnas.0503975102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 950JL UT WOS:000230853300031 PM 16024726 ER PT J AU Nakayashiki, T Kurtzman, CP Edskes, HK Wickner, RB AF Nakayashiki, T Kurtzman, CP Edskes, HK Wickner, RB TI Yeast prions [URE3] and [PSI+] are diseases SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DOUBLE-STRANDED-RNA; SACCHAROMYCES-CEREVISIAE; NUCLEOTIDE-SEQUENCE; KILLER GENE; SELFISH DNA; 20-S RNA; PROTEIN; CONSERVATION; REVEALS; CLONING AB Viruses, plasmids, and prions can spread in nature despite being a burden to their hosts. Because a prion arises de novo in more than one in 106 yeast cells and spreads to all offspring in meiosis, its absence in wild strains would imply that it has a net deleterious effect on its host. Among 70 wild Saccharomyces strains, we found the [PIN+] prion in 11 strains, but the [URE3] and [PSI+] prions were uniformly absent. In contrast, the "selfish" 2 mu DNA was in 38 wild strains and the self ish RNA replicons L-BC, 20S, and 23S were found in 8, 14, and 1 strains, respectively. The absence of [URE3] and [PSI+] in wild strains indicates that each prion has a net deleterious effect on its host. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. USDA ARS, Natl Ctr Agr Utilizat Res, Microbial Genom & Bioproc Res Unit, Peoria, IL 61604 USA. RP Wickner, RB (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Room 225, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov NR 54 TC 146 Z9 146 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 26 PY 2005 VL 102 IS 30 BP 10575 EP 10580 DI 10.1073/pnas.0504882102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 950JL UT WOS:000230853300032 PM 16024723 ER PT J AU Bonaparte, MI Dimitrov, AS Bossart, KN Crameri, G Mungal, BA Bishop, KA Choudhry, V Dimitrov, DS Wang, LF Eaton, BT Broder, CC AF Bonaparte, MI Dimitrov, AS Bossart, KN Crameri, G Mungal, BA Bishop, KA Choudhry, V Dimitrov, DS Wang, LF Eaton, BT Broder, CC TI Ephrin-B2 ligand is a functional receptor for Hendra virus and Nipah virus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MEMBRANE-FUSION TROPISM; MEASLES-VIRUS; HEMAGGLUTININ-NEURAMINIDASE; EQUINE MORBILLIVIRUS; VACCINIA VIRUS; ENVELOPE GLYCOPROTEINS; PARAMYXOVIRUS FUSION; CELLULAR RECEPTOR; CRYSTAL-STRUCTURE; STRUCTURAL BASIS AB Hendra virus (HeV) and Nipah virus (NiV) belong to the genus Henipavirus of the family Paramyxoviridae and are unique in that they exhibit a broad species tropism and cause fatal disease in both animals and humans. They infect cells through a pH-independent membrane fusion process mediated by their fusion and attachment glycoproteins. Previously, we demonstrated identical cell fusion tropisms for HeV and NiV and the protease-sensitive nature of their unknown cell receptor and identified a human cell line (HeLa-USU) that was nonpermissive for fusion and virus infection. Here, a microarray analysis was performed on the HeLa-USU cells, permissive HeLa-CCL2 cells, and two other permissive human cell lines. From this analysis, we identified a list of genes encoding known and predicted plasma membrane surf ace-expressed proteins that were highly expressed in all permissive cells and absent from the HeLa-USU cells and rank-ordered them based on their relative levels. Available expression vectors containing the first 10 genes were obtained and individually transfected into HeLa-USU cells. One clone, encoding human ephrin-B2 (EFNB2), was found capable of rendering HeLa-USU cells permissive for HeV- and NiV-mediated cell fusion as well as infection by live virus. A soluble recombinant EFNB2 could potently block fusion and infection and bind soluble recombinant HeV and NiV attachment glycoproteins with high affinity. Together, these data indicate that EFNB2 serves as a functional receptor for both HeV and NiV. The highly conserved nature of EFNB2 in humans and animals is consistent with the broad tropism exhibited by these emerging zoonotic viruses. C1 Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. CSIRO, Livestock Ind, Australian Anim Hlth Lab, Geelong, Vic 3220, Australia. NCI, Prot Interact Grp, Lab Expt & Computat Biol, NIH, Frederick, MD 21702 USA. RP Broder, CC (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. EM cbroder@usuhs.mil RI Crameri, Gary/H-8441-2013; OI Bossart, Katharine/0000-0001-6886-6896 FU NIAID NIH HHS [U54 AI057168, AI057168] NR 59 TC 202 Z9 214 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 26 PY 2005 VL 102 IS 30 BP 10652 EP 10657 DI 10.1073/pnas.0504887102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 950JL UT WOS:000230853300045 PM 15998730 ER PT J AU Nelson, DE Virok, DP Wood, H Roshick, C Johnson, RM Whitmire, WM Crane, DD Steele-Mortimer, O Kari, L McClarty, G Caldwell, HD AF Nelson, DE Virok, DP Wood, H Roshick, C Johnson, RM Whitmire, WM Crane, DD Steele-Mortimer, O Kari, L McClarty, G Caldwell, HD TI Chlamydial IFN-gamma immune evasion is linked to host infection tropism SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immunity; virulence factors; pathogenesis; defense; coevolution ID TRYPTOPHAN SYNTHASE; BINDING PROTEINS; P47 GTPASES; TRACHOMATIS; FAMILY; CELLS; INCLUSION; MEMBER; GENES; HOOK3 AB Chlamydiae are obligate intracellular pathogens that can exhibit a broad host range in infection tropism despite maintaining near genomic identity. Here, we have investigated the molecular basis for this unique host-pathogen relationship. We show that human and murine chlamydial infection tropism is linked to unique host and pathogen genes that have coevolved in response to host immunity. This intimate host-pathogen niche revolves around a restricted repertoire of host species-specific IFN-gamma-mediated effector responses and chlamydial virulence factors capable of inhibiting these effector mechanisms. In human epithelial cells, IFN-gamma induces indoleamine 2,3-dioxygenase expression that inhibits chlamydial growth by depleting host tryptophan pools. Human chlamydial strains, but not the mouse strain, avoid this response by the production of tryptophan synthase that rescues them from tryptophan starvation. Conversely, in murine epithelial cells IFN-gamma induces expression of p47 GTPases, but not indoleamine 2,3-dioxygenase. One of these p47 GTPases (ligp1) was shown by small interfering RNA silencing experiments to specifically inhibit human strains, but not the mouse strain. Like human strains and their host cells, the murine strain has coevolved with its murine host by producing a large toxin possessing YopT homology, possibly to circumvent host GTPases. Collectively, our findings show chlamydial host infection tropism is determined by IFN-gamma-mediated immunity. C1 NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 0W3, Canada. Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46202 USA. RP Caldwell, HD (reprint author), NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. EM hcaldwell@niaid.nih.gov NR 29 TC 143 Z9 146 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 26 PY 2005 VL 102 IS 30 BP 10658 EP 10663 DI 10.1073/pnas.0504198102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 950JL UT WOS:000230853300046 PM 16020528 ER PT J AU Dmitrieva, NI Celeste, A Nussenzweig, A Burg, MB AF Dmitrieva, NI Celeste, A Nussenzweig, A Burg, MB TI Ku86 preserves chromatin integrity in cells adapted to high NaCl SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Caenorhabditis elegans; DNA breaks; DNA repair; mammalian cell culture; osmotic stress ID DEPENDENT PROTEIN-KINASE; DOUBLE-STRAND BREAKS; V(D)J RECOMBINATION; DNA-REPAIR; CAENORHABDITIS-ELEGANS; END; LINE; SENSITIVITY; RADIATION; SUBUNIT AB Cells adapted to high NaCl have many DNA breaks both in cell culture and in the renal inner medulla in vivo; yet they survive, function, and even proliferate. Here, we show that Ku86 is important for maintaining chromosomal integrity despite the continued presence of DNA breaks. The Ku heterodimer is part of DNA-dependent PK (DNA-PK), a complex that contributes by nonhomologous end joining to repair of double-strand breaks. We demonstrate that cells deficient in Ku86, but not cells deficient in DNA-PKcs (the catalytic subunit of DNA-PK), are hypersensitive to high NaCl as manifested by profound inhibition of proliferation, aberrant mitosis, and increased chromosomal fragmentation. Lower eukaryotes, including the soil nematode Caenorhabditis elegans, lack a DNA-PKcs homologue but are able to adapt to high NaCl. We show that cells of C. elegans adapted to high NaCl have many DNA breaks, similar to the mammalian cells adapted to high NaCl. Ku86 mutant C. elegans as well as C. elegans fed with cku86 dsRNA also display hypersensitivity to high NaCl, characterized by a reduced number of progeny and prolonged generation time in high NaCl. We propose that Ku86 ameliorates the effects of high NaCl-induced DNA breaks in adapted cells by supporting alignment of the broken ends of the DNA and thus maintaining integrity of the fragmented chromatin. C1 NHLBI, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Dmitrieva, NI (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, Bldg 10,9000 Rockville Pike, Room 6N260, Bethesda, MD 20892 USA. EM dmitrien@nhlbi.nih.gov RI Dmitrieva, Natalia/A-2924-2013 OI Dmitrieva, Natalia/0000-0001-8074-6950 NR 35 TC 24 Z9 25 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 26 PY 2005 VL 102 IS 30 BP 10730 EP 10735 DI 10.1073/pnas.0504870102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 950JL UT WOS:000230853300058 PM 16027367 ER PT J AU Strotmeyer, ES Cauley, JA Schwartz, AV Nevitt, MC Resnick, HE Bauer, DC Tylavsky, FA de Rekeneire, N Harris, TB Newman, AB AF Strotmeyer, ES Cauley, JA Schwartz, AV Nevitt, MC Resnick, HE Bauer, DC Tylavsky, FA de Rekeneire, N Harris, TB Newman, AB TI Nontraumatic fracture risk with diabetes mellitus and impaired fasting glucose in older white and black adults - The health, aging, and body composition study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID HIP FRACTURE; CARDIOVASCULAR-DISEASE; MEXICAN-AMERICAN; ADIPOSE-TISSUE; BONE-DENSITY; WOMEN; FALLS; MEN; INDIVIDUALS; ASSOCIATION AB Background: Diabetes mellitus (DM) and related complications may increase clinical fracture risk in older adults. Methods: Our objectives were to determine if type 2 diabetes mellitus or impaired fasting glucose was associated with higher fracture rates in older adults and to evaluate how diabetic individuals with fractures differed from those without fractures. The Health, Aging, and Body Composition Study participants were well-functioning, community-dwelling men and women aged 70 to 79 years (N=2979; 42% black), of whom 19% had DM and 6% had impaired fasting glucose at baseline. Incident non-traumatic clinical fractures were verified by radiology reports for a mean SD of 4.5 +/- 1.1 years. Cox proportional hazards regression models determined how DM and impaired fasting glucose affected subsequent risk of fracture. Results: Diabetes mellitus was associated with elevated fracture risk (relative risk, 1.64; 95% confidence interval, 1.07-2.51) after adjustment for a hip bone mineral density (BMD) and fracture risk factors. Impaired fasting glucose was not significantly associated with fractures (relative risk, 1.34; 95% confidence interval, 0.67-2.67). Diabetic participants with fractures had lower hip BMD (0.818 g/cm(2) vs 0.967 g/cm(2); P <.001) and lean mass (44.3 kg vs 51.7 kg) and were more likely to have reduced peripheral sensation (35% vs 14%), transient ischemic attack/stroke (20% vs 8%), a lower physical performance battery score (5.0 vs 7.0), and falls (37% vs 21%) compared with diabetic participants without fractures (P <.05). Conclusions: These results indicate that older white and black adults with DM are at higher fracture risk compared with nondiabetic adults with a similar BMD since a higher risk of nontraumatic fractures was found after adjustment for hip BMD. Fracture prevention needs to target specific risk factors found in older adults with DM. C1 Univ Pittsburgh, Healthy Aging Res Program, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. MedStar Res Inst, Dept Epidemiol & Stat, Hyattsville, MD USA. Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. NIA, Lab Epidemiol Demographys & Biometry, Bethesda, MD USA. Univ Pittsburgh, Sch Med, Dept Epidemiol, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Div Geriatr Med, Pittsburgh, PA USA. Sch Publ Hlth, Pittsburgh, PA USA. RP Newman, AB (reprint author), Univ Pittsburgh, Healthy Aging Res Program, 130 N Bellefield Ave,5th Floor, Pittsburgh, PA 15213 USA. EM newmana@edc.pitt.edu RI Newman, Anne/C-6408-2013; Strotmeyer, Elsa/F-3015-2014; Cauley, Jane/N-4836-2015; OI Newman, Anne/0000-0002-0106-1150; Cauley, Jane/0000-0003-0752-4408; Strotmeyer, Elsa/0000-0002-4093-6036 FU NIA NIH HHS [5-T32-AG00181, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 36 TC 161 Z9 164 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 25 PY 2005 VL 165 IS 14 BP 1612 EP 1617 DI 10.1001/archinte.165.14.1612 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 948BT UT WOS:000230691700007 PM 16043679 ER PT J AU Engels, FK Sparreboom, A Mathot, RAA Verweij, J AF Engels, FK Sparreboom, A Mathot, RAA Verweij, J TI Potential for improvement of docetaxel-based chemotherapy: a pharmacological review SO BRITISH JOURNAL OF CANCER LA English DT Review DE docetaxel; taxotere; taxanes; pharmacology ID ERYTHROMYCIN BREATH TEST; P-GLYCOPROTEIN; IN-VITRO; PHASE-I; ORAL BIOAVAILABILITY; UNBOUND DOCETAXEL; SYSTEMIC EXPOSURE; PHARMACOKINETICS; TAXANE; VIVO AB Since the introduction of docetaxel, research has focused on various approaches to overcome treatment limitations and improve outcome. This review discusses the pharmacological attempts at treatment optimisation, which include reducing interindividual pharmacokinetic and pharmacodynamic variability, optimising schedule, route of administration, reversing drug resistance and the development of structurally related second-generation taxanes. (c) 2005 Cancer Research UK. C1 Erasmus MC Daniel Den Hoed Canc Ctr Rotterdam, Dept Med Oncol, NL-3075 EA Rotterdam, Netherlands. NCI, Clin Pharmacol Res Core, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. Erasmus MC, Dept Hosp Pharm & Clin Pharmacol, Rotterdam, Netherlands. RP Engels, FK (reprint author), Erasmus MC Daniel Den Hoed Canc Ctr Rotterdam, Dept Med Oncol, Groene Hilledijk 301, NL-3075 EA Rotterdam, Netherlands. EM f.engels@erasmusmc.nl RI Sparreboom, Alex/B-3247-2008 NR 30 TC 51 Z9 51 U1 0 U2 4 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 JUL 25 PY 2005 VL 93 IS 2 BP 173 EP 177 DI 10.1038/sj.bkc.6602698 PG 5 WC Oncology SC Oncology GA 946ZN UT WOS:000230611900001 PM 16012521 ER PT J AU Olsen, JH Hahnemann, JMD Borresen-Dale, AL Tretli, S Kleinerman, R Sankila, R Hammarstrom, L Robsahm, T Kaariainen, H Bregard, A Brondum-Nielsen, K Yuen, J Tucker, M AF Olsen, JH Hahnemann, JMD Borresen-Dale, AL Tretli, S Kleinerman, R Sankila, R Hammarstrom, L Robsahm, T Kaariainen, H Bregard, A Brondum-Nielsen, K Yuen, J Tucker, M TI Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia SO BRITISH JOURNAL OF CANCER LA English DT Article DE ATM heterozygosity; early-onset breast cancer; cancer predisposition; familial cancer ID HEPATOCELLULAR-CARCINOMA; HETEROZYGOTES; RISK; FAMILIES; COUNTRIES; MUTATIONS AB Epidemiological studies have consistently shown elevated rates of breast cancer among female blood relatives of patients with ataxia telangiectasia ( AT), a rare autosomal recessive disease. A large proportion of the members of AT families are carriers of AT-causing gene mutations in ATM ( Ataxia Telangiectasia Mutated), and it has been hypothesised that these otherwise healthy carriers are predisposed to breast cancer. This is an extended and enlarged follow-up study of cancer incidence in blood relatives of 75 patients with verified AT in 66 Nordic families. Blood relatives were identified through population registry linkages, and the occurrence of cancer was determined from cancer registry files in each country and compared with national incidence rates. The ATM mutation carrier probabilities of relatives were assigned from the combined information on location in family, consanguinity, if any, and supplementary carrier screening in some families. Among the 1445 blood relatives of AT patients, 225 cancers were observed, with 170.4 expected, yielding a standardised incidence ratio ( SIR) of 1.3 (95% confidence interval (CI), 1.1-1.4). Invasive breast cancer occurred in 34 female relatives (SIR, 1.7; 95% CI, 1.2-2.4) and was diagnosed in 21 women before the age of 55 years ( SIR, 2.9; 95% CI, 1.8-4.5), including seven mothers of probands (SIR, 8.1; 95% CI, 3.3-17). When the group of mothers was excluded, no clear relationship was observed between the allocated mutation carrier probability of each family member and the extent of breast cancer risk. We concluded that the increased risk for female breast cancer seen in 66 Nordic AT families appeared to be restricted to women under the age of 55 years and was due mainly to a very high risk in the group of mothers. The findings of breast cancer risk in mothers, but not other likely mutation carriers, in this and other studies raises questions about the hypothesis of a simple causal relationship with ATM heterozygosity. (c) 2005 Cancer Research UK. C1 Danish Canc Soc, Inst Canc Epidemiol, DK-2100 Copenhagen, Denmark. John F Kennedy Inst, Natl Eye Clin, DK-2600 Glostrup, Denmark. Norwegian Radium Hosp, Dept Genet, Inst Canc Res, Fac Div, N-0310 Oslo, Norway. Univ Oslo, Norwegian Radium Hosp, Dept Genet, Fac Div, N-0310 Oslo, Norway. Canc Registry Norway, Inst Epidemiol Canc Res, N-0310 Oslo, Norway. NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Finnish Canc Registry, FIN-00170 Helsinki, Finland. Karolinska Inst, Huddinge Hosp, Div Clin Immunol, S-14157 Huddinge, Sweden. Turku Univ, Dept Med Genet, FIN-20520 Turku, Finland. Turku Univ Hosp, Dept Clin Genet, FIN-20520 Turku, Finland. Swedish Univ Agr Sci, S-75007 Uppsala, Sweden. RP Olsen, JH (reprint author), Danish Canc Soc, Inst Canc Epidemiol, Strandblvd 49, DK-2100 Copenhagen, Denmark. EM jorgen@cancer.dk RI Tucker, Margaret/B-4297-2015; OI Olsen, Jorgen Helge/0000-0001-9633-5662; Kleinerman, Ruth/0000-0001-7415-2478 FU NCI NIH HHS [N01-CP-91046] NR 18 TC 25 Z9 26 U1 0 U2 0 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 JUL 25 PY 2005 VL 93 IS 2 BP 260 EP 265 DI 10.1038/sj.bjc.6602658 PG 6 WC Oncology SC Oncology GA 946ZN UT WOS:000230611900013 PM 15942625 ER PT J AU Coxon, B AF Coxon, B TI Deuterium isotope effects in carbohydrates revisited. Cryoprobe studies of the anomerization and NH to ND deuterium isotope induced C-13 NMR chemical shifts of acetamidodeoxy and aminodeoxy sugars SO CARBOHYDRATE RESEARCH LA English DT Article DE acetamidodeoxy sugars; anomerization; C-13 NMR chemical shifts; COSY; cryoprobe; deuterium isotope effects; H-1 NMR chemical shifts; HMBC; HSQC; TOCSY ID MAGNETIC-RESONANCE SPECTROSCOPY; PARTIALLY LABELED ENTITIES; COUPLING-CONSTANTS; SIGNAL ASSIGNMENT; SPECTRA; DERIVATIVES; SUCROSE; POLYSACCHARIDES; CONFORMATIONS; DISACCHARIDES AB Complete H-1 and C-13 NMR chemical shift assignments have been generated from a series of acetamidodeoxy and aminodeoxy sugar derivatives. For free sugars, the enhanced sensitivity of an NMR cryoprobe allowed simple ID and 21) NMR spectra to be obtained from essentially single anomers, before significant mutarotation had occurred. The NMR assignments have been used to characterize deuterium isotope effects on C-13 chemical shifts measured under conditions of slow NH to ND exchange in single solutions. Within a range of 0 to -0.138 ppm, beta, gamma, delta, and zeta deuterium isotope effects have been observed, thus providing additional reference data for assignment of the C-13 NMR spectra of nitrogenous saccharides. (c) 2005 Elsevier Ltd. All rights reserved. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Coxon, B (reprint author), NICHHD, NIH, 31 Ctr Dr,MSC 2423, Bethesda, MD 20892 USA. EM coxonb@mail.nih.gov NR 29 TC 9 Z9 10 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD JUL 25 PY 2005 VL 340 IS 10 BP 1714 EP 1721 DI 10.1016/j.carres.2005.04.022 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 943CN UT WOS:000230329700006 PM 15936003 ER PT J AU Wang, E AF Wang, E TI RNA amplification for successful gene profiling analysis SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID MESSENGER-RNA; EXPRESSION ANALYSIS; CDNA MICROARRAY; AMPLIFIED RNA; OLIGONUCLEOTIDE MICROARRAYS; REVERSE TRANSCRIPTION; IMMUNE RESPONSIVENESS; MOLECULAR ANALYSIS; OVARIAN-CANCER; PCR AB The study of clinical samples is often limited by the amount of material available to study. While proteins cannot be multiplied in their natural form, DNA and RNA can be amplified from small specimens and used for high-throughput analyses. Therefore, genetic studies offer the best opportunity to screen for novel insights of human pathology when little material is available. Precise estimates of DNA copy numbers in a given specimen are necessary. However, most studies investigate static variables such as the genetic background of patients or mutations within pathological specimens without a need to assess proportionality of expression among different genes throughout the genome. Comparative genomic hybridization of DNA samples represents a crude exception to this rule since genomic amplification or deletion is compared among different specimens directly. For gene expression analysis, however, it is critical to accurately estimate the proportional expression of distinct RNA transcripts since such proportions directly govern cell function by modulating protein expression. Furthermore, comparative estimates of relative RNA expression at different time points portray the response of cells to environmental stimuli, indirectly informing about broader biological events affecting a particular tissue in physiological or pathological conditions. This cognitive reaction of cells is similar to the detection of electroencephalographic patterns which inform about the status of the brain in response to external stimuli. As our need to understand human pathophysiology at the global level increases, the development and refinement of technologies for high fidelity messenger RNA amplification have become the focus of increasing interest during the past decade. The need to increase the abundance of RNA has been met not only for gene specific amplification, but, most importantly for global transcriptome wide, unbiased amplification. Now gene-specific, unbiased transcriptome wide amplification accurately maintains proportionality among all RNA species within a given specimen. This allows the utilization of clinical material obtained with minimally invasive methods such as fine needle aspirates (FNA) or cytological washings for high throughput functional genomics studies. This review provides a comprehensive and updated discussion of the literature in the subject and critically discusses the main approaches, the pitfalls and provides practical suggestions for successful unbiased amplification of the whole transcriptome in clinical samples. C1 NIH, Ctr Clin, Immunogenet Sect, Dept Transfus Med, Bethesda, MD 20892 USA. RP Wang, E (reprint author), NIH, Ctr Clin, Immunogenet Sect, Dept Transfus Med, Bldg 10, Bethesda, MD 20892 USA. EM ewang@mail.cc.nih.gov NR 74 TC 0 Z9 0 U1 0 U2 3 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 JUL 25 PY 2005 VL 3 DI 10.1186/1479-5876-3-28 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 968KQ UT WOS:000232161800001 ER PT J AU Belluco, C Mammano, E Petricoin, E Prevedello, L Calvert, V Liotta, L Nitti, D Lise, M AF Belluco, C Mammano, E Petricoin, E Prevedello, L Calvert, V Liotta, L Nitti, D Lise, M TI Kinase substrate protein microarray analysis of human colon cancer and hepatic metastasis SO CLINICA CHIMICA ACTA LA English DT Article; Proceedings Paper CT International Conference on Laboratory Medicine CY OCT 29, 2002 CL Padua, ITALY SP Int Soc Enzymol DE proteomics; colorectal cancer; metastasis; protein kinases ID ACTIVATION AB Background: Liver metastases represent the major determinant of survival in patients with colorectal cancer (CRC). In cases with unresectable liver disease, more effective agents are needed, since chemotherapy achieves median survival of only 15 months. Protein kinases coordinate complex functions that are often disregulated in cancer and are therefore considered important targets for molecular therapeutics. In this study, we investigated the phosphoproteomic status of different protein kinases in primary CRC and in liver metastases. Methods: The status of 29 key endpoints was evaluated using reverse phase protein array on laser capture microdissected neoplastic cells from five primary CRCs without metastases, three patient-matched primary CRCs and synchronous liver metastases and five CRC metachronous liver metastases. Results: Unsupervised hierarchical two-way clustering analysis showed an entirely different phosphoproteomic profile in primary CRCs compared to liver metastases. This difference was observed also in primary and metastatic patient-matched lesions. Conclusions: Our findings of different signaling pathways between primary and metastatic CRC suggest a possible microenvironment effect, and emphasize the need to perform molecular network analysis of metastatic tissue when molecular targeting is considered. (c) 2005 Elsevier B.V. All rights reserved. C1 Univ Padua, Surg Branch, Dept Oncol & Surg Sci, Padua, Italy. US FDA, Ctr Biol Evaluat & Res, NCI Clin Prote Program, Bethesda, MD 20014 USA. US FDA, Clin Prote Program, Pathol Lab, NCI, Bethesda, MD 20014 USA. RP Belluco, C (reprint author), Univ Padua, Surg Branch, Dept Oncol & Surg Sci, Padua, Italy. EM claudio.belluco@unipd.it OI belluco, claudio/0000-0001-5972-9574 NR 9 TC 30 Z9 32 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD JUL 24 PY 2005 VL 357 IS 2 SI SI BP 180 EP 183 DI 10.1016/j.cccn.2005.03.024 PG 4 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 950IN UT WOS:000230850900010 PM 15921671 ER PT J AU Childs, R Srinivasan, R AF Childs, R Srinivasan, R TI High-dose chemotherapy and allogeneic immunotherapy SO LANCET LA English DT Editorial Material ID METASTATIC BREAST-CANCER; STEM-CELL TRANSPLANTATION C1 NIH, Hematol Branch, Bethesda, MD 20892 USA. NIH, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Childs, R (reprint author), NIH, Hematol Branch, Bethesda, MD 20892 USA. EM childsr@nih.gov NR 14 TC 0 Z9 0 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 23 PY 2005 VL 366 IS 9482 BP 273 EP 275 DI 10.1016/S0140-6736(05)66963-2 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 948RJ UT WOS:000230733100008 PM 16039317 ER PT J AU Kimm, SYS Glynn, NW Obarzanek, E Kriska, AM Daniels, SR Barton, BA Liu, K AF Kimm, SYS Glynn, NW Obarzanek, E Kriska, AM Daniels, SR Barton, BA Liu, K TI Relation between the changes in physical activity and body-mass index during adolescence: a multicentre longitudinal study SO LANCET LA English DT Article ID WEIGHT CHANGE; NHLBI GROWTH; YOUNG-ADULTS; FRAMINGHAM CHILDRENS; BIRACIAL COHORT; DIETARY-INTAKE; RISK-FACTORS; WHITE GIRLS; LIFE-STYLE; OBESITY AB Background The role of physical activity in preventing obesity during adolescence remains unknown. We examined changes in activity in relation to changes in body-mass index (BMI) and adiposity in a cohort of 1152 black and 1135 white girls from the USA, who were followed up prospectively from ages 9 or 110 to 18 or 19 years. Methods BMI and sum of skinfold thickness were assessed annually, whereas habitual activity was assessed at years 1 (baseline), 3, 5, and 7-10. Each girls' overall activity status was categorised as active, moderately active, or inactive. Longitudinal regression models examined associations between changes in activity and in overall activity status with changes in BMI and in sum of skinfold thickness. Findings Each decline in activity of 10 metabolic equivalent [MET]-times per week was associated with an increase in BMI of 0.14 kg/m(2)(SE 0.03) and in sum of skinfold thickness of 0.62 mm (0.17) for black girls, and of 0.09 kg/m(2) (0.02) and 0.63 mm (0.13) for white girls. At ages 18 or 19 years, BMI differences between active and inactive girls were 2.98 kg/m(2) (p<0.0001) for black girls and 2.10 kg/ml (p<0.0001) for white girls. Similar results were apparent for sum of skinfold thickness. For moderately active girls, changes in BMI and sum of skinfold thickness were about midway between those for active and inactive girls. Interpretation Changes in activity levels of US girls during adolescence significantly affected changes in BMI and adiposity. Thus, preventing the steep decline in activity during adolescence is an important method to reduce obesity. C1 Univ New Mexico, Sch Med, Dept Internal Med, Albuquerque, NM 87131 USA. Univ Pittsburgh, Sch Med, Dept Family Med, Pittsburgh, PA USA. NHLBI, Prevent Sci Res Grp, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. Childrens Hosp, Med Ctr, Div Cardiol, Cincinnati, OH 45229 USA. Maryland Med Res Inst, Baltimore, MD USA. Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL USA. RP Kimm, SYS (reprint author), Univ New Mexico, Hlth Sci Ctr, Dept Internal Med Epidemiol, 1 Univ New Mexico,MSC 105550, Albuquerque, NM 87131 USA. EM skimm@salud.unm.edu OI Kriska, Andrea/0000-0002-3522-0869; Barton, Bruce/0000-0001-7878-8895; Glynn, Nancy/0000-0003-2265-0162 FU NHLBI NIH HHS [U01-HL48941-44, N01-HC-55023-26] NR 42 TC 191 Z9 195 U1 0 U2 16 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 23 PY 2005 VL 366 IS 9482 BP 301 EP 307 DI 10.1016/S0140-6736(05)66837 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 948RJ UT WOS:000230733100028 PM 16039332 ER PT J AU Emanuel, EJ Currie, XE Herman, A AF Emanuel, EJ Currie, XE Herman, A CA Project Phidisa TI Undue inducement in clinical research in developing countries: is it a worry? SO LANCET LA English DT Editorial Material ID ETHICS; CONSENT C1 NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. S African Natl Def Force, Project Phidisa, Pretoria, Gauteng, South Africa. Med Univ S Africa, Natl Sch Publ Hlth, Pretoria, Gauteng, South Africa. RP Emanuel, EJ (reprint author), NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM eemanuel@nih.gov NR 25 TC 49 Z9 52 U1 0 U2 2 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 23 PY 2005 VL 366 IS 9482 BP 336 EP 340 DI 10.1016/S0140-6736(05)66992-9 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 948RJ UT WOS:000230733100035 PM 16039339 ER PT J AU Pau, AK Moodley, NK Holland, DT Fomundam, H Matchaba, GU Capparelli, EV AF Pau, AK Moodley, NK Holland, DT Fomundam, H Matchaba, GU Capparelli, EV TI Instability of lopinavir/ritonavir capsules at ambient temperatures in sub-Saharan Africa: relevance to WHO antiretroviral guidelines SO AIDS LA English DT Article AB WHO recommends lopinavir/ritonavir as an antiretroviral option in resource-limited countries. Lopinavir/ritonavir is recommended to be stored at 2-8 degrees C until dispensing, and afterwards, may be kept at <= 25 degrees C for <= 2 months. Anticipating lopinavir/ritonavir use in countries lacking adequate cold-chains, we assessed its physical and chemical stability at 35 and 45 degrees C. Although maintaining chemical stability for 4 weeks at 35 degrees C, at 45 degrees C the capsules clumped after 7 days, supporting a need for more temperature-stable formulations for hotter climates. C1 NIAID, NIH, Bethesda, MD 20892 USA. S African Mil Hlth Syst, Pretoria, South Africa. Univ Calif San Diego, Sch Pharm & Pharmaceut Sci, San Diego, CA 92103 USA. MEDUNSA Natl Sch Publ Hlth, Pretoria, South Africa. Project PHIDISA Pretoria, Pretoria, South Africa. RP Pau, AK (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 2 TC 5 Z9 5 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 22 PY 2005 VL 19 IS 11 BP 1233 EP 1234 DI 10.1097/01.aids.0000176227.01850.9e PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 948BX UT WOS:000230692100017 PM 15990580 ER PT J AU Chen, XL Matsumoto, H Hinck, CS Al-Hasani, H St-Denis, JF Whiteheart, SW Cushman, SW AF Chen, XL Matsumoto, H Hinck, CS Al-Hasani, H St-Denis, JF Whiteheart, SW Cushman, SW TI Demonstration of differential quantitative requirements for NSF among multiple vesicle fusion pathways of GLUT4 using a dominant-negative ATPase-deficient NSF SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE N-ethylmaleimide-sensitive factor; GLUT4; trafficking; endocytic recycling; adipose cell ID INSULIN-STIMULATED TRANSLOCATION; GLUCOSE-TRANSPORTER GLUT4; RAT ADIPOSE-CELLS; REGULATED TRANSPORT; SNAP RECEPTORS; PROTEIN; TRAFFICKING; ADIPOCYTES; MEMBRANE; DYNAMIN AB In this study, we investigated the relative participation of N-ethylmaleimide-sensitive factor (NSF) in vivo in a complex multistep vesicle trafficking system, the translocation response of GLUT4 to insulin in rat adipose cells. Transfections of rat adipose cells demonstrate that over-expression of wild-type NSF has no effect on total, or basal and insulin-stimulated cell-surface expression of HA-tagged GLUT4. In contrast, a dominant-negative NSF (NSF-D1EQ) can be expressed at a low enough level that it has little effect on total HA-GLUT4, but does reduce both basal and insulin-stimulated cell-surface HA-GLUT4 by similar to 50% without affecting the GLUT4 fold-translocation response to insulin. However, high expression levels of NSF-D1EQ decrease total HA-GLUT4. The inhibitory effect of NSF-D1EQ on cell-surface HA-GLUT4 is reversed when endocytosis is inhibited by co-expression of a dominant-negative dynamin (dynamin-K44A). Moreover, NSF-DIEQ does not affect cell-surface levels of constitutively recycling GLUT1 and TfR, suggesting a predominant effect of low-level NSF-D1EQ on the trafficking of GLUT4 from the endocytic recycling compared to the intracellular GLUT4-specific compartment. Thus, our data demonstrate that the multiple fusion steps in GLUT4 trafficking have differential quantitative requirements for NSF activity. This indicates that the rates of plasma and intracellular membrane fusion reactions vary, leading to differential needs for the turnover of the SNARE proteins. Published by Elsevier Inc. C1 NIDDK, Expt Diabet Metab & Nutr Sect, Diabet Branch, NIH, Bethesda, MD 20892 USA. Univ Cologne, Inst Biochem, Cologne, Germany. Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY USA. RP Cushman, SW (reprint author), NIDDK, Expt Diabet Metab & Nutr Sect, Diabet Branch, NIH, Bethesda, MD 20892 USA. EM sam_cushman@nih.gov OI Whiteheart, Sidney/0000-0001-5577-0473 NR 31 TC 5 Z9 5 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 22 PY 2005 VL 333 IS 1 BP 28 EP 34 DI 10.1016/j.bbrc.2005.05.075 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 939XE UT WOS:000230105200005 PM 15935991 ER PT J AU Ahmet, I Lakatta, EG Talan, M AF Ahmet, I Lakatta, EG Talan, M TI Pharmacological stimulation of beta 2-adrenergic receptors (beta 2AR) enhances therapeutic effectiveness of beta 1AR blockade in rodent dilated ischemic cardiomyopathy SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT 2nd Annual Symposium of the American-Heart-Association-Council-on-Basic-Cardiovascular-Sciences CY JUL 24-27, 2005 CL Keystone, CO SP Amer Heart Assoc Council Basic Cardiovasc Sci, Amer Heart Assoc Interdisciplinary Working Grp Functional Geonom & Translat Biol, Natl Heart, Lung & Blood Inst C1 NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUL 22 PY 2005 VL 97 IS 2 MA 082 BP E23 EP E23 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 947TH UT WOS:000230668900091 ER PT J AU Gabel, SA London, RE Steenbergen, C Murphy, E AF Gabel, SA London, RE Steenbergen, C Murphy, E TI Glucose-dependent insulinotropic polypeptide treatment eliminates gender differences in ischemia-reperfusion injury by affecting substrate selection SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT 2nd Annual Symposium of the American-Heart-Association-Council-on-Basic-Cardiovascular-Sciences CY JUL 24-27, 2005 CL Keystone, CO SP Amer Heart Assoc Council Basic Cardiovasc Sci, Amer Heart Assoc Interdisciplinary Working Grp Functional Geonom & Translat Biol, Natl Heart, Lung & Blood Inst C1 NIEHS, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Durham, NC 27706 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUL 22 PY 2005 VL 97 IS 2 MA 158 BP E39 EP E39 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 947TH UT WOS:000230668900163 ER PT J AU Groban, L Callahan, MF Liu, TF Duesbery, NS Leppla, SH Eichacker, P Frankel, AF AF Groban, L Callahan, MF Liu, TF Duesbery, NS Leppla, SH Eichacker, P Frankel, AF TI Anthrax-induced biventricular failure SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT 2nd Annual Symposium of the American-Heart-Association-Council-on-Basic-Cardiovascular-Sciences CY JUL 24-27, 2005 CL Keystone, CO SP Amer Heart Assoc Council Basic Cardiovasc Sci, Amer Heart Assoc Interdisciplinary Working Grp Functional Geonom & Translat Biol, Natl Heart, Lung & Blood Inst C1 Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Wake Forest Univ, Baptist Med Ctr, Winston Salem, NC 27109 USA. Van Andel Res Inst Labs, Grand Rapids, MI USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUL 22 PY 2005 VL 97 IS 2 MA 142 BP E35 EP E35 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 947TH UT WOS:000230668900148 ER PT J AU Imahashi, K Steenbergen, C Philipson, KD Murphy, E AF Imahashi, K Steenbergen, C Philipson, KD Murphy, E TI Cardiac-specific ablation of Na+/Ca2+ exchanger confers protection against ischemia/reperfusion injury SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT 2nd Annual Symposium of the American-Heart-Association-Council-on-Basic-Cardiovascular-Sciences CY JUL 24-27, 2005 CL Keystone, CO SP Amer Heart Assoc Council Basic Cardiovasc Sci, Amer Heart Assoc Interdisciplinary Working Grp Functional Geonom & Translat Biol, Natl Heart, Lung & Blood Inst C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Durham, NC 27706 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. NR 0 TC 2 Z9 2 U1 0 U2 2 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 JUL 22 PY 2005 VL 97 IS 2 MA 145 BP E36 EP E36 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 947TH UT WOS:000230668900151 ER PT J AU Nikolic, I Steenbergen, C Murphy, E AF Nikolic, I Steenbergen, C Murphy, E TI Cardioprotective effects of a selective beta estrogen receptor agonist in a mouse ischemia-reperfusion injury model SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT 2nd Annual Symposium of the American-Heart-Association-Council-on-Basic-Cardiovascular-Sciences CY JUL 24-27, 2005 CL Keystone, CO SP Amer Heart Assoc Council Basic Cardiovasc Sci, Amer Heart Assoc Interdisciplinary Working Grp Functional Geonom & Translat Biol, Natl Heart, Lung & Blood Inst C1 Duke Univ, Sch Med, Durham, NC 27706 USA. Duke Univ, Med Ctr, Durham, NC 27706 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUL 22 PY 2005 VL 97 IS 2 MA 157 BP E39 EP E39 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 947TH UT WOS:000230668900162 ER PT J AU Tocchetti, CG Wang, W Valdivia, HH Aon, M Di Benedetto, G O'Rourke, B Froehlich, JP Zaccolo, M Cheng, H Kass, DA Paolocci, N AF Tocchetti, CG Wang, W Valdivia, HH Aon, M Di Benedetto, G O'Rourke, B Froehlich, JP Zaccolo, M Cheng, H Kass, DA Paolocci, N TI Nitroxyl anion: A novel thiol-sensitive positive inotrope that enhances SR Ca2+ release SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT 2nd Annual Symposium of the American-Heart-Association-Council-on-Basic-Cardiovascular-Sciences CY JUL 24-27, 2005 CL Keystone, CO SP Amer Heart Assoc Council Basic Cardiovasc Sci, Amer Heart Assoc Interdisciplinary Working Grp Functional Geonom & Translat Biol, Natl Heart, Lung & Blood Inst C1 Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. Univ Wisconsin, Sch Med, Madison, WI 53706 USA. Venetian Inst Mol Med, Padua, Italy. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RI Zaccolo, Manuela/B-3802-2011 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUL 22 PY 2005 VL 97 IS 2 MA 137 BP E34 EP E35 PG 2 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 947TH UT WOS:000230668900143 ER PT J AU Andric, SA Zivadinovic, D Gonzalez-Iglesias, AE Lachowicz, A Tomic, M Stojilkovic, SS AF Andric, SA Zivadinovic, D Gonzalez-Iglesias, AE Lachowicz, A Tomic, M Stojilkovic, SS TI Endothelin-induced, long lasting, and Ca2+ influx-independent blockade of intrinsic secretion in pituitary cells by G(z) subunits SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; GROWTH-HORMONE-SECRETION; MOTOR-NERVE ENDINGS; BETA-GAMMA-SUBUNITS; PRESYNAPTIC INHIBITION; RECEPTOR ACTIVATION; CHROMAFFIN CELLS; IN-VIVO; CALCIUM; EXOCYTOSIS AB The G protein-coupled receptors in excitable cells have prominent roles in controlling Ca2+-triggered secretion by modulating voltage-gated Ca2+ influx. In pituitary lactotrophs, spontaneous voltage-gated Ca2+ influx is sufficient to maintain prolactin release high. Here we show that endothelin in picomolar concentrations can interrupt such release for several hours downstream of spontaneous and high K+-stimulated voltage-gated Ca2+ influx. This action occurred through the G(z) signaling pathway; the adenylyl cyclase-signaling cascade could mediate sustained inhibition of secretion, whereas rapid inhibition also occurred at elevated cAMP levels regardless of the status of phospholipase C, tyrosine kinases, and protein kinase C. In a nanomolar concentration range, endothelin also inhibited voltage-gated Ca2+ influx through the G(i/o) signaling pathway. Thus, the coupling of seven-transmembrane domain endothelin receptors to Gz proteins provided a pathway that effectively blocked hormone secretion distal to Ca2+ entry, whereas the cross-coupling to G(i/o) proteins reinforced such inhibition by simultaneously reducing the pacemaking activity. C1 NICHD, Sect Cellular Signaling, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Stojilkovic, SS (reprint author), NICHD, Sect Cellular Signaling, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Rm 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. EM stankos@helix.nih.gov RI Tomic, Melanija/C-3371-2016 NR 49 TC 13 Z9 13 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 JUL 22 PY 2005 VL 280 IS 29 BP 26896 EP 26903 DI 10.1074/jbc.M502226200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 946RI UT WOS:000230589500032 PM 15919662 ER PT J AU Liu, X Shu, S Kovacs, M Korn, ED AF Liu, X Shu, S Kovacs, M Korn, ED TI Biological, biochemical, and kinetic effects of mutations of the cardiomyopathy loop of Dictyostelium myosin II - Importance of ALA(400) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FAMILIAL HYPERTROPHIC CARDIOMYOPATHY; HEAVY-CHAIN GENE; REGULATORY LIGHT-CHAIN; BETA-CARDIAC MYOSIN; MOTOR DOMAIN; IN-VIVO; DISCOIDEUM MYOSIN; PHOSPHORYLATION SITE; FUNCTIONAL-ANALYSIS; ACANTHAMOEBA MYOSIN AB The cardiomyopathy (CM)-loop of the heavy chain of class-II myosins begins with a highly conserved Arg residue ( whose mutation in human beta-cardiac myosin II results in familial hypertrophic cardiomyopathy). The CM-loop of Dictyostelium myosin II (Arg(397) - Gln(407)) is essential for its biological functions and biochemical activities. We found that the CM-loop of smooth muscle myosin II substituted partially, and the CM-loop of beta-cardiac myosin II less well, for growth, capping of surface receptors and development, and the actin-activated MgATPase and in vitro motility activities of purified myosins. There was little correlation between the biochemical and biological activities of the two chimeras and 19 point mutants, but only the five mutants with k(cat)/K-actin values equivalent to wild-type myosin supported essentially full biological function. The three point mutations of Arg397 equivalent to those that result in hypertrophic cardiomyopathy in humans had minimal biological effects and different biochemical effects. The A400V mutation rendered full-length wild-type myosin almost completely inactive, both in vitro and in vivo, and the reverse V400A mutation in the cardiac CM-loop chimera restored almost full activity, even though the sequence still differed from wild-type in 7 of 11 positions. Transient kinetic studies of acto-subfragment-1 (S1) showed that the chimeras and the Ala/Val, Val/Ala mutations do not affect the equilibrium or the association and dissociation rate constants for either ATP or ADP binding to acto-S1 or the rate of ATP-induced dissociation of acto-S1. We conclude that the Ala/Val, Val/Ala mutations affect the release of Pi from acto-S1 center dot ADP center dot P-i. In addition, Val at position 400 substantially reduces the affinity of actin for S1 in the absence of nucleotide. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Korn, ED (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 50,Rm 2517-8017, Bethesda, MD 20892 USA. EM edk@nih.gov RI Korn, Edward/F-9929-2012; Kovacs, Mihaly/A-6841-2011 FU NHLBI NIH HHS [Z01 HL000506-30] NR 66 TC 10 Z9 10 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 JUL 22 PY 2005 VL 280 IS 29 BP 26974 EP 26983 DI 10.1074/jbc.M504453200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 946RI UT WOS:000230589500041 PM 15897189 ER PT J AU Paul, BD Buchholz, DR Fu, LZ Shi, YB AF Paul, BD Buchholz, DR Fu, LZ Shi, YB TI Tissue- and gene-specific recruitment of steroid receptor coactivator-3 by thyroid hormone receptor during development SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID XENOPUS-LAEVIS METAMORPHOSIS; IN-VIVO ANALYSIS; NUCLEAR-RECEPTOR; TRANSCRIPTIONAL COACTIVATOR; EMBRYONIC-DEVELOPMENT; PROTEIN METHYLTRANSFERASE; HISTONE ACETYLTRANSFERASE; POSTEMBRYONIC DEVELOPMENT; AMPHIBIAN DEVELOPMENT; COREPRESSOR COMPLEX AB Numerous coactivators that bind nuclear hormone receptors have been isolated and characterized in vitro. Relatively few studies have addressed the developmental roles of these cofactors in vivo. By using the total dependence of amphibian metamorphosis on thyroid hormone (T-3) as a model, we have investigated the role of steroid receptor coactivator 3 (SRC3) in gene activation by thyroid hormone receptor (TR) in vivo. First, expression analysis showed that SRC3 was expressed in all tadpole organs analyzed. In addition, during natural as well as T-3-induced metamorphosis, SRC3 was up-regulated in both the tail and intestine, two organs that undergo extensive transformations during metamorphosis and the focus of the current study. We then performed chromatin immunoprecipitation assays to investigate whether SRC3 is recruited to endogenous T-3 target genes in vivo in developing tadpoles. Surprisingly, we found that SRC3 was recruited in a gene- and tissue-dependent manner to target genes by TR, both upon T-3 treatment of premetamorphic tadpoles and during natural metamorphosis. In particular, in the tail, SRC3 was not recruited in a T-3-dependent manner to the target TR beta A promoter, suggesting either no recruitment or constitutive association. Finally, by using transgenic tadpoles expressing a dominant negative SRC3 (F-dnSRC3), we demonstrated that F-dnSRC3 was recruited in a T-3-dependent manner in both the intestine and tail, blocking the recruitment of endogenous coactivators and histone acetylation. These results suggest that SRC3 is utilized in a gene- and tissue-specific manner by TR during development. C1 NICHD, LGRD, NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NICHD, LGRD, NIH, Bldg 18T,Rm 106, Bethesda, MD 20892 USA. EM shi@heliz.nih.gov NR 79 TC 36 Z9 36 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 JUL 22 PY 2005 VL 280 IS 29 BP 27165 EP 27172 DI 10.1074/jbc.M503999200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 946RI UT WOS:000230589500064 PM 15901728 ER PT J AU Sandhoff, R Geyer, R Jennemann, R Paret, C Kiss, E Yamashita, T Gorgas, K Sijmonsma, TP Iwamori, M Finaz, C Proia, RL Wiegandt, H Grone, HJ AF Sandhoff, R Geyer, R Jennemann, R Paret, C Kiss, E Yamashita, T Gorgas, K Sijmonsma, TP Iwamori, M Finaz, C Proia, RL Wiegandt, H Grone, HJ TI Novel class of glycosphingolipids involved in male fertility SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHAIN FATTY-ACIDS; MICE; GANGLIOSIDE; EXPRESSION; METHYLATION; CELLS; LONG; SPHINGOMYELIN; INFERTILITY; SENSITIVITY AB Mice require testicular glycosphingolipids (GSLs) for proper spermatogenesis. Mutant mice strains deficient in specific genes encoding biosynthetic enzymes of the GSL pathway including Galgt1 ( encoding GM2 synthase) and Siat9 ( encoding GM3 synthase) have been established lacking various overlapping subsets of GSLs. Although male Galgt1 -/- mice are infertile, male Siat9 -/- mice are fertile. Interestingly, GSLs thought to be essential for male spermatogenesis are not synthesized in either of these mice strains. Hence, these GSLs cannot account for the different phenotypes. A novel class of GSLs was observed composed of eight fucosylated molecules present in fertile but not in infertile mutant mice. These GSLs contain polyunsaturated very long chain fatty acid residues in their ceramide moieties. GSLs of this class are expressed differentially in testicular germ cells. More importantly, the neutral subset of this new GSL class strictly correlates with male fertility. These data implicate polyunsaturated, fucosylated GSLs as essential for spermatogenesis and male mouse fertility. C1 German Canc Res Ctr, Dept Cellular & Mol Pathol, D-69120 Heidelberg, Germany. German Canc Res Ctr, Dept Tumor Progress & Tumor Def, D-69120 Heidelberg, Germany. Univ Giessen, Fac Med, Inst Biochem, D-35392 Giessen, Germany. NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Heidelberg, Dept Anat & Cell Biol 2, D-69120 Heidelberg, Germany. Kinki Univ, Fac Sci & Technol, Dept Biochem, Osaka 5778502, Japan. Univ Paris 7 11, INSERM,U566, CEA,Atom Energy Dept,Radiobiol & Radiopathol Dept, Lab Gametogenesis Apoptosis & Genotox, F-92265 Fontenay Aux Roses, France. RP Sandhoff, R (reprint author), German Canc Res Ctr, Dept Cellular & Mol Pathol, INF 280, D-69120 Heidelberg, Germany. EM r.sandhoff@dkfz-heidelberg.de; h.-j.groene@dkfz.de RI Proia, Richard/A-7908-2012 NR 40 TC 55 Z9 58 U1 2 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 JUL 22 PY 2005 VL 280 IS 29 BP 27310 EP 27318 DI 10.1074/jbc.M502775200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 946RI UT WOS:000230589500081 PM 15917254 ER PT J AU Pu, YM Perry, NA Yang, DZ Lewin, NE Kedei, N Braun, DC Choi, SH Blumberg, PM Garfield, SH Stone, JC Duan, DH Marquez, VE AF Pu, YM Perry, NA Yang, DZ Lewin, NE Kedei, N Braun, DC Choi, SH Blumberg, PM Garfield, SH Stone, JC Duan, DH Marquez, VE TI A novel diacylglycerol-lactone shows marked selectivity in vitro among C1 domains of protein kinase C (PKC) isoforms alpha and delta as well as selectivity for RasGRP compared with PKC alpha SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CONFORMATIONALLY CONSTRAINED ANALOGS; PHORBOL 12-MYRISTATE 13-ACETATE; ESTER RECEPTORS; DOWN-REGULATION; BINDING ASSAY; BRYOSTATIN 1; PHOSPHORYLATION; ACTIVATION; ISOZYMES; DAG AB Although multiple natural products are potent ligands for the diacylglycerol binding C1 domain of protein kinase C (PKC), RasGRP, and related targets, the high conservation of C1 domains has impeded the development of selective ligands. We characterized here a diacylglycerol-lactone, 130C037, emerging from a combinatorial chemical synthetic strategy, which showed substantial selectivity. 130C037 gave shallow binding curves for PKC isoforms alpha, beta, gamma, delta, and epsilon, with apparent K-i values ranging from 340 nM for PKC alpha to 29 nM for PKC epsilon. When binding to isolated C1 domains of PKC alpha and -delta, 130C037 showed good affinity (K-i = 1.78 nM) only for delta C1b, whereas phorbol 12,13-dibutyrate showed affinities within 10-fold for all. In LNCaP cells, 130C037 likewise selectively induced membrane translocation of delta C1b. 130C037 bound intact RasGRP1 and RasGRP3 with K-i values of 3.5 and 3.8 nM, respectively, reflecting 8- and 90-fold selectivity relative to PKC epsilon and PKC alpha. By Western blot of Chinese hamster ovary cells, 130C037 selectively induced loss from the cytosol of RasGRP3 (ED50 = 286 nM), partial reduction of PKC epsilon (ED50 > 10 mu M), and no effect on PKC alpha. As determined by confocal microscopy in LNCaP cells, 130C037 caused rapid translocation of RasGRP3, limited slow translocation of PKC epsilon, and no translocation of PKC alpha. Finally, 130C037 induced Erk phosphorylation in HEK-293 cells ectopically expressing RasGRP3 but not in control cells, whereas phorbol ester induced phosphorylation in both. The properties of 130C037 provide strong proof of principle for the feasibility of developing ligands with selectivity among C1 domain-containing therapeutic targets. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Univ Alberta, Dept Biochem, Edmonton, AB T6G 2H7, Canada. NCI Frederick, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Blumberg, PM (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, NIH, Bldg 37,Rm 4048,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov NR 36 TC 42 Z9 42 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 JUL 22 PY 2005 VL 280 IS 29 BP 27329 EP 27338 DI 10.1074/jbc.M414132200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 946RI UT WOS:000230589500083 PM 15923197 ER PT J AU Ramirez, DC Mejiba, SEG Mason, RP AF Ramirez, DC Mejiba, SEG Mason, RP TI Copper-catalyzed protein oxidation and its modulation by carbon dioxide - Enhancement of protein radicals in cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMINO-ACID-RESIDUES; HYDROGEN-PEROXIDE; CU,ZN-SUPEROXIDE DISMUTASE; SUPEROXIDE-DISMUTASE; DEPENDENT HYDROXYL; TRANSITION-METALS; ALBUMIN; BICARBONATE; GENERATION; DAMAGE AB It is well known that hydrogen peroxide (H2O2)-induced copper-catalyzed fragmentation of proteins follows a site-specific oxidative mechanism mediated by hydroxyl radical-like species (i.e. Cu(I) O, Cu( II)/(OH)-O-center dot or Cu(III)) that ends in increased carbonyl formation and protein fragmentation. We have found that the nitrone spin trap DMPO ( 5,5-dimethyl-1-pyrroline N-oxide) prevented such processes by trapping human serum albumin (HSA)-centered radicals, in situ and in real time, before they reacted with oxygen. When (bi) carbonate (CO2, H2CO3, HCO3-, and CO3-2) was added to the reaction mixture, it blocked fragmentation mediated by hydroxyl radical-like species but enhanced DMPO-trappable radical sites in HSA. In the past, this effect would have been explained by oxidation of ( bi) carbonate to a carbonate radical anion (CO3radical anion) by a bound hydroxyl radical-like species. We now propose that the CO3radial anion radical is formed by the reduction of HOOCO2- ( a complex of H2O2 with CO2) by the protein- Cu( I) complex. CO3radical anion diffuses and produces more DMPO-trappable radical sites but does not fragment HSA. We were also able, for the first time, to detect discrete but highly specific H2O2-induced copper-catalyzed CO3radical anion-mediated induction of DMPO-trappable protein radicals in functioning RAW 264.7 macrophages. We conclude that carbon dioxide modulates H2O2-induced copper-catalyzed oxidative damage to proteins by preventing site-specific fragmentation and enhancing DMPO-trappable protein radicals in functioning cells. The pathophysiological significance of our findings is discussed. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Ramirez, DC (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, 111 TW Alexander Dr,Bldg 101,MD F0-02, Res Triangle Pk, NC 27709 USA. EM ramirez1@niehs.nih.gov RI RAMIREZ, DARIO/K-3312-2013 OI RAMIREZ, DARIO/0000-0001-6725-3326 NR 59 TC 52 Z9 57 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 22 PY 2005 VL 280 IS 29 BP 27402 EP 27411 DI 10.1074/jbc.M504241200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 946RI UT WOS:000230589500091 PM 15905164 ER PT J AU Cisneros, GA Piquemal, JP Darden, TA AF Cisneros, GA Piquemal, JP Darden, TA TI Intermolecular electrostatic energies using density fitting SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID AUXILIARY BASIS-SETS; DECOMPOSITION ANALYSIS; PERTURBATION-THEORY; MOLECULAR-INTERACTIONS; POLARIZATION ENERGIES; FUNCTIONAL METHODS; CHARGE-TRANSFER; WATER DIMER; MODEL; IMPLEMENTATION AB A method is presented to calculate the electron-electron and nuclear-electron intermolecular Coulomb interaction energy between two molecules by separately fitting the unperturbed molecular electron density of each monomer. This method is based on the variational Coulomb fitting method which relies on the expansion of the ab initio molecular electron density in site-centered auxiliary basis sets. By expanding the electron density of each monomer in this way the integral expressions for the intermolecular electrostatic calculations are simplified, lowering the operation count as well as the memory usage. Furthermore, this method allows the calculation of intermolecular Coulomb interactions with any level of theory from which a one-electron density matrix can be obtained. Our implementation is initially tested by calculating molecular properties with the density fitting method using three different auxiliary basis sets and comparing them to results obtained from ab initio calculations. These properties include dipoles for a series of molecules, as well as the molecular electrostatic potential and electric field for water. Subsequently, the intermolecular electrostatic energy is tested by calculating ten stationary points on the water dimer potential-energy surface. Results are presented for electron densities obtained at four different levels of theory using two different basis sets, fitted with three auxiliary basis sets. Additionally, a one-dimensional electrostatic energy surface scan is performed for four different systems (H2O dimer, Mg2+-H2O, Cu+-H2O, and n-methyl-formamide dimer). Our results show a very good agreement with ab initio calculations for all properties as well as interaction energies. (C) 2005 American Institute of Physics. C1 Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27707 USA. RP Cisneros, GA (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27707 USA. EM cisnero1@niehs.nih.gov RI Piquemal, Jean-Philip/B-9901-2009; Cisneros, Gerardo/B-3128-2010 OI Piquemal, Jean-Philip/0000-0001-6615-9426; FU Intramural NIH HHS [NIH0011757912]; PHS HHS [NIH0011757912] NR 66 TC 38 Z9 38 U1 1 U2 5 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD JUL 22 PY 2005 VL 123 IS 4 AR 044109 DI 10.1063/1.1947192 PG 10 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 952GK UT WOS:000230991800011 PM 16095348 ER PT J AU Stan, G Brooks, BR Thirumalai, D AF Stan, G Brooks, BR Thirumalai, D TI Probing the "annealing" mechanism of GroEL mini-chaperone using molecular dynamics simulations SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE GroEL minichaperone; transient binding release mechanism; protein-protein interactions; MD simulations ID PROTEIN; CAVITY; PREDICTION; SUBSTRATE; SEQUENCES; WATER AB Although the intact chaperonin machinery is needed to rescue natural substrate proteins (SPs) under non-permissive conditions the "mini-chaperone" alone, containing only the isolated apical domain of GroEL, can assist folding of a certain class of proteins. To understand the annealing function of the minichaperone, we have carried out molecular dynamics simulations in the NPT ensemble totaling 300 ns for four systems; namely, the isolated strongly binding peptide (SBP), the minichaperone, and the SBP and a weakly binding peptide (WBP) in complex with the minichaperone. The SBP, which is structureless in isolation, adopts a beta-hairpin conformation in complex with the minichaperone suggesting that favorable non-specific interactions of the SPs confined to helices H and I of the apical domains can induce local secondary structures. Comparison of the dynamical fluctuations of the apo and the liganded forms of the minichaperone shows that the stability (needed for SP capture) involves favorable hydrophobic interactions and hydrogen bond network formation between the SBP and WBP, and helices H and I. The release of the SP, which is required for the annealing action, involves water-mediated interactions of the charged residues at the ends of H and I helices. The simulation results are consistent with a transient binding release (TBR) model for the annealing action of the minichaperone. According to the TBR model, SP annealing occurs in two stages. In the first stage the SP is captured by the apical domain. This is followed by SP release (by thermal fluctuations) that places it in a different region of the energy landscape from which it can partition rapidly to the native state with probability (D or be trapped in another misfolded state. The process of binding and release can result in enhancement of the native state yield. The TBR model suggests "that any cofactor that can repeatedly bind and release SPs can be effective in assisting protein folding." By comparing the structures of the non-chaperone a-casein (which has no sequence similarity with the apical domain) and the minichaperone and the hydrophobicity profiles we show that alpha-casein has a pair of helices that have similar sequence and structural profiles as H and I. Based on this comparison we identify residues that stabilize (destabilize) a-casein-protein complexes. This suggests that a-casein assists folding by the TBR mechanism. (c) 2005 Elsevier Ltd. All rights reserved. C1 Univ Maryland, Inst Phys Sci & Technol, Biophys Program, College Pk, MD 20742 USA. NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. RP Thirumalai, D (reprint author), Univ Maryland, Inst Phys Sci & Technol, Biophys Program, College Pk, MD 20742 USA. EM thirum@glue.umd.edu FU NIGMS NIH HHS [1R01GM067851-01] NR 30 TC 17 Z9 17 U1 1 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUL 22 PY 2005 VL 350 IS 4 BP 817 EP 829 DI 10.1016/j.jmb.2005.05.012 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 944RG UT WOS:000230446000017 PM 15967467 ER PT J AU Zhang, QJ Guo, XM Xiao, XS Jia, XY Li, SQ Hejtmancik, JF AF Zhang, QJ Guo, XM Xiao, XS Jia, XY Li, SQ Hejtmancik, JF TI A new locus for autosomal dominant high myopia maps to 4q22-q27 between D4S1578 and D4S1612 SO MOLECULAR VISION LA English DT Article ID REFRACTIVE ERROR; LINKAGE ANALYSIS; PREVALENCE; CHILDREN; CHINA; SCAN; FAMILIES; GENE; 12Q; 18P AB Purpose: Myopia is the most common visual problem in the world. High myopia, the extreme form of myopia that can be complicated by retinal detachment and macular degeneration, affects 1%-2% of the general population. The genes responsible for nonsyndromic high myopia have not been identified although several chromosome loci have been suggested. Additional loci for the majority of high myopia, especially in Asian populations, await discovery. A large Chinese family with autosomal dominant high myopia was collected in order to map the genetic locus as an initial step towards identifying the genetic cause of high myopia in this family. Methods: A Chinese family with 12 individuals affected with high myopia was ascertained from a small village in central China. Phenotypic information and DNA samples were collected from 18 individuals, including 11 affected and 7 unaffected individuals. A genome-wide scan was performed using markers spaced at about 10 cM intervals for genotyping and two-point linkage analysis was carried out. Candidate genes were sequenced. Results: High myopia, ranging from -5.00 D to -20.00 D with typical fundus changes, is transmitted as an autosomal dominant trait in this family. High myopia in this family shows linkage to markers in a 20.4 cM region between D4S1578 and D4S1612, with maximum lod scores of 3.11 and 3.61 at theta=0 by D4S1564 and by the D4S2986-D4S1572-D4S1564-D4S406-D4S1580-D4S402 haplotype, respectively. Sequence analysis of the retinal pigment epithelium-derived rhodopsin homolog (RRH; OMIM 605224) gene inside the linked region did not identify any causative mutations. Conclusions: A novel locus (MYP11) for autosomal dominant high myopia in a Chinese family maps to 4q22-q27 but is not associated with mutations in RRH. C1 Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou 510060, Peoples R China. NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. RP Zhang, QJ (reprint author), Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, 54 Xianlie Rd, Guangzhou 510060, Peoples R China. EM qingjiongzhang@yahoo.com NR 21 TC 76 Z9 87 U1 0 U2 6 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 JUL 22 PY 2005 VL 11 IS 64-65 BP 554 EP 560 PG 7 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 950GS UT WOS:000230846200002 PM 16052171 ER PT J AU Murphy, WJ Larkin, DM Everts-van der Wind, A Bourque, G Tesler, G Auvil, L Beever, JE Chowdhary, BP Galibert, F Gatzke, L Hitte, C Meyers, SN Milan, D Ostrander, EA Pape, G Parker, HG Raudsepp, T Rogatcheva, MB Schook, LB Skow, LC Welge, M Womack, JE O'Brien, SJ Pevzner, PA Lewin, HA AF Murphy, WJ Larkin, DM Everts-van der Wind, A Bourque, G Tesler, G Auvil, L Beever, JE Chowdhary, BP Galibert, F Gatzke, L Hitte, C Meyers, SN Milan, D Ostrander, EA Pape, G Parker, HG Raudsepp, T Rogatcheva, MB Schook, LB Skow, LC Welge, M Womack, JE O'Brien, SJ Pevzner, PA Lewin, HA TI Dynamics of mammalian chromosome evolution inferred from multispecies comparative maps SO SCIENCE LA English DT Article ID HUMAN GENOME SEQUENCE; RADIATION HYBRID MAP; SEGMENTAL DUPLICATIONS; MOUSE GENOMES; CENTROMERE; REARRANGEMENTS; BREAKPOINT; RESOLUTION; INVERSION; REGION AB The genome organizations of eight phylogenetically distinct species from five mammalian orders were compared in order to address fundamental questions relating to mammalian chromosomal evolution. Rates of chromosome evolution within mammalian orders were found to increase since the Cretaceous-Tertiary boundary. Nearly 20% of chromosome breakpoint regions were reused during mammalian evolution; these reuse sites are also enriched for centromeres. Analysis of gene content in and around evolutionary breakpoint regions revealed increased gene density relative to the genome-wide average. We found that segmental duplications populate the majority of primate-specific breakpoints and often flank inverted chromosome segments, implicating their role in chromosomal rearrangement. C1 Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. Texas A&M Univ, Dept Vet Pathobiol, College Stn, TX 77843 USA. SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Lab Genom Divers, Frederick, MD 21702 USA. Univ Illinois, Dept Anim Sci, Urbana, IL 61801 USA. Univ Illinois, Natl Ctr Supercomp Applicat, Urbana, IL 61801 USA. Univ Illinois, Inst Genom Biol, Urbana, IL 61801 USA. Genome Inst Singapore, Singapore 138672, Singapore. Univ Calif San Diego, Dept Math, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Comp Sci & Engn, La Jolla, CA 92093 USA. Univ Rennes 1, CNRS, UMR6061, F-35043 Rennes, France. INRA, Lab Genet Cellulaire, F-31326 Castanet Tolosan, France. NHGRI, Bethesda, MD 20892 USA. RP Murphy, WJ (reprint author), Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. EM wmurphy@cvm.tamu.edu; h-lewin@uiuc.edu RI Parker, Heidi/C-6954-2008 FU NCI NIH HHS [N01-CO-12400, R01CA-92167] NR 31 TC 346 Z9 359 U1 3 U2 31 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 JUL 22 PY 2005 VL 309 IS 5734 BP 613 EP 617 DI 10.1126/science.1111387 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 948SE UT WOS:000230735200049 PM 16040707 ER PT J AU McGowan, E Pickford, F Kim, J Onstead, L Eriksen, J Yu, C Skipper, L Murphy, MP Beard, J Das, P Jansen, K DeLucia, M Lin, WL Dolios, G Wang, R Eckman, CB Dickson, DW Hutton, M Hardy, J Golde, T AF McGowan, E Pickford, F Kim, J Onstead, L Eriksen, J Yu, C Skipper, L Murphy, MP Beard, J Das, P Jansen, K DeLucia, M Lin, WL Dolios, G Wang, R Eckman, CB Dickson, DW Hutton, M Hardy, J Golde, T TI A beta 42 is essential for parenchymal and vascular amyloid deposition in mice SO NEURON LA English DT Article ID FAMILIAL BRITISH DEMENTIA; TRANSGENIC MOUSE MODEL; ALZHEIMERS-DISEASE; A-BETA; PRECURSOR-PROTEIN; APOLIPOPROTEIN-E; MEMORY DEFICITS; PEPTIDE; MUTANT; BRAIN AB Considerable circumstantial evidence suggests that A beta 42 is the initiating molecule in Alzheimer's disease (AD) pathogenesis. However, the absolute requirement for A beta 42 for amyloid deposition has never been demonstrated in vivo. We have addressed this by developing transgenic models that express A beta 1-40 or A beta 1-42 in the absence of human amylold 0 protein precursor (APP) overexpression. Mice expressing high levels of A beta 1-40 do not develop overt amyloid pathology. In contrast, mice expressing lower levels of A beta 1-42 accumulate insoluble A beta 1-42 and develop compact amyloid plaques, congophilic amyloid angiopathy (CAA), and diffuse A beta deposits. When mice expressing A beta 1-42 are crossed with mutant APP (Tg2576) mice, there is also a massive increase in amyloid deposition. These data establish that A beta 1-42 is essential for amyloid deposition in the parenchyma and also in vessels. C1 Mayo Clin, Coll Med, Dept Neurosci, Jacksonville, FL 32224 USA. Mt Sinai Sch Med, Dept Human Genet, New York, NY 10029 USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP McGowan, E (reprint author), Mayo Clin, Coll Med, Dept Neurosci, Jacksonville, FL 32224 USA. EM mcgowan.eileen@mayo.edu; golde.todd@mayo.edu RI Kim, Jungsu/A-1372-2009; Hardy, John/C-2451-2009; Kim, Jungsu/F-2457-2012; Wang, Rong/A-8721-2009; Eriksen, Jason/A-8054-2008; OI Kim, Jungsu/0000-0002-6931-8581; Eriksen, Jason/0000-0003-1549-4165; Skipper, Lisa/0000-0002-1524-9787; Dickson, Dennis W/0000-0001-7189-7917 FU NCI NIH HHS [CA88325, R24 CA088325]; NIA NIH HHS [R01 AG022595, R01 AG022595-01, R01 AG022595-02] NR 39 TC 322 Z9 329 U1 2 U2 12 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 21 PY 2005 VL 47 IS 2 BP 191 EP 199 DI 10.1016/j.neuron.2005.06.030 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 948CP UT WOS:000230693900007 PM 16039562 ER PT J AU Genovesio, A Brasted, PJ Mitz, AR Wise, SP AF Genovesio, A Brasted, PJ Mitz, AR Wise, SP TI Prefrontal cortex activity related to abstract response strategies SO NEURON LA English DT Article ID NEURONAL-ACTIVITY; WORKING-MEMORY; FRONTAL-CORTEX; VISUOSPATIAL ATTENTION; VISUAL CATEGORIZATION; PARKINSONS-DISEASE; TEMPORAL-ORDER; SINGLE NEURONS; BASAL GANGLIA; TASK AB Many monkeys adopt abstract response strategies as they learn to map visual symbols to responses by trial and error. According to the repeat-stay strategy, if a symbol repeats from a previous, successful trial, the monkeys should stay with their most recent response choice. According to the change-shift strategy, if the symbol changes, the monkeys should shift to a different choice. We recorded the activity of prefrontal cortex neurons while monkeys chose responses according to these two strategies. Many neurons had activity selective for the strategy used. In a subsequent block of trials, the monkeys learned fixed stimulus-response mappings with the same stimuli. Some neurons had activity selective for choosing responses based on fixed mappings, others for choosing based on abstract strategies. These findings indicate that the prefrontal cortex contributes to the implementation of the abstract response strategies that monkeys use during trial-and-error learning. C1 NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Wise, SP (reprint author), NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. EM stevenwise@mail.nih.gov FU NIMH NIH HHS [Z01 MH001092-27] NR 69 TC 118 Z9 118 U1 2 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 21 PY 2005 VL 47 IS 2 BP 307 EP 320 DI 10.1016/j.neuron.2005.06.006 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 948CP UT WOS:000230693900016 PM 16039571 ER PT J AU Sugarman, J Emanuel, EJ AF Sugarman, J Emanuel, EJ CA Consortium Examine Clin Res Ethics TI The costs of institutional review boards - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Johns Hopkins Univ, Baltimore, MD 21202 USA. NIH, Bethesda, MD 20892 USA. RP Sugarman, J (reprint author), Johns Hopkins Univ, Baltimore, MD 21202 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 21 PY 2005 VL 353 IS 3 BP 316 EP 317 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 946YH UT WOS:000230608700025 ER PT J AU Korkmaz, CG Korkmaz, KS Kurys, P Elbi, C Wang, L Klokk, TI Hammarstrom, C Troen, G Svindland, A Hager, GL Saatcioglu, F AF Korkmaz, CG Korkmaz, KS Kurys, P Elbi, C Wang, L Klokk, TI Hammarstrom, C Troen, G Svindland, A Hager, GL Saatcioglu, F TI Molecular cloning and characterization of STAMP2, an androgen-regulated six transmembrane protein that is overexpressed in prostate cancer SO ONCOGENE LA English DT Article DE androgens; prostate cancer; six transmembrane; Golgi; transcription ID GREEN FLUORESCENT PROTEIN; KALLIKREIN GENE FAMILY; NEOPLASTIC PROSTATE; RESPONSIVE GENES; SERINE-PROTEASE; GOLGI-COMPLEX; HOMEOBOX GENE; IN-VIVO; ANTIGEN; LOCALIZATION AB We have identified a novel gene, six transmembrane protein of prostate 2 (STAMP2), named for its high sequence similarity to the recently identified STAMP1 gene. STAMP2 displays a tissue-restricted expression with highest expression levels in placenta, lung, heart, and prostate and is predicted to code for a 459-amino acid six transmembrane protein. Using a form of STAMP2 labeled with green flourescent protein (GFP) in quantitative time-lapse and immuno fluorescence confocal microscopy, we show that STAMP2 is primarily localized to the Golgi complex, trans-Golgi network, and the plasma membrane. STAMP 2 also localizes to vesicular-tubular structures in the cytosol and colocalizes with the Early Endosome Antigen1 (EEA1) suggesting that it may be involved in the secretory/endocytic pathways. STAMP2 expression is exquisitely androgen regulated in the androgen-sensitive, androgen receptor-positive prostate cancer cell line LNCaP, but not in androgen receptor-negative prostate cancer cell lines PC-3 and DU145. Analysis of STAMP2 expression in matched normal and tumor samples microdissected from prostate cancer specimens indicates that STAMP2 is overexpressed in prostate cancer cells compared with normal prostate epithelial cells. Further more, ectopic expression of STAMP2 in prostate cancer cells significantly increases cell growth and colony formation suggesting that STAMP2 may have a role in cell proliferation. Taken together, these data suggest that STAMP2 may contribute to the normal biology of the prostate cell, as well as prostate cancer progression. C1 Univ Oslo, Dept Mol Biosci, N-0316 Oslo, Norway. NCI, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. Aker Univ Hosp, Dept Pathol, Oslo, Norway. Norwegian Radium Hosp, Dept Pathol, Oslo, Norway. RP Saatcioglu, F (reprint author), Univ Oslo, Dept Mol Biosci, Postboks 1050, N-0316 Oslo, Norway. EM fahris@imbv.uio.no NR 45 TC 63 Z9 67 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 21 PY 2005 VL 24 IS 31 BP 4934 EP 4945 DI 10.1038/sj.onc.1208677 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 947LO UT WOS:000230646500006 PM 15897894 ER PT J AU Thakurta, AG Gopal, G Yoon, JH Kozak, L Dhar, R AF Thakurta, AG Gopal, G Yoon, JH Kozak, L Dhar, R TI Homolog of BRCA2-interacting Dss1p and Uap56p link Mlo3p and Rae1p for mRNA export in fission yeast SO EMBO JOURNAL LA English DT Article DE Dss1p; Mlo3p; mRNA export; Uap56p ID NUCLEAR-PORE COMPLEX; SCHIZOSACCHAROMYCES-POMBE; BINDING-PROTEIN; POLY(A)(+) RNA; GENE; INTERACTS; MRNP; MEX67P; YRA1P; SUB2P AB The breast cancer tumor suppressor BRCA2-interacting protein, DSS1, and its homologs are critical for DNA recombination in eukaryotic cells. We found that Dss1p, along with Mlo3p and Uap56p, Schizosaccharomyces pombe homologs of two messenger RNA (mRNA) export factors of the NXF-NXT pathway, is required for mRNA export in S. pombe. Previously, we showed that the nuclear pore-associated Rae1p is an essential mRNA export factor in S. pombe. Here, we show that Dss1p and Uap56p function by linking mRNA adapter Mlo3p to Rae1p for targeting mRNA-protein complex (mRNP) to the proteins of the nuclear pore complex (NPC). Dss1p preferentially recruits to genes in vivo and interacts with -FG (phenylalanine glycine) nucleoporins in vivo and in vitro. Thus, Dss1p may function at multiple steps of mRNA export, from mRNP biogenesis to their targeting and translocation through the NPC. C1 NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Sungshin Womens Univ, Coll Nat Sci, Dept Biol, Seoul, South Korea. Univ Hosp Brno, Ctr Mol Biol & Gene Therapy, Brno, Czech Republic. RP NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM dharr@mail.nih.gov NR 46 TC 41 Z9 46 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD JUL 20 PY 2005 VL 24 IS 14 BP 2512 EP 2523 DI 10.1038/sj.emboj.7600713 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 951UJ UT WOS:000230956600003 PM 15990877 ER PT J AU Brambillasca, S Yabal, M Soffientini, P Stefanovic, S Makarow, M Hegde, RS Borgese, N AF Brambillasca, S Yabal, M Soffientini, P Stefanovic, S Makarow, M Hegde, RS Borgese, N TI Transmembrane topogenesis of a tail-anchored protein is modulated by membrane lipid composition SO EMBO JOURNAL LA English DT Article DE endoplasmic reticulum; membrane proteins; protein targeting; protein translocation; Sec61 translocon ID ENDOPLASMIC-RETICULUM MEMBRANE; CYTOCHROME B(5); C-TERMINUS; RAT-LIVER; TRANSLOCATION; INSERTION; BINDING; TRANSPORT; VESICLES; COMPLEX AB A large class of proteins with cytosolic functional domains is anchored to selected intracellular membranes by a single hydrophobic segment close to the C-terminus. Although such tail-anchored (TA) proteins are numerous, diverse, and functionally important, the mechanism of their transmembrane insertion and the basis of their membrane selectivity remain unclear. To address this problem, we have developed a highly specific, sensitive, and quantitative in vitro assay for the proper membrane-spanning topology of a model TA protein, cytochrome b5 (b5). Selective depletion from membranes of components involved in cotranslational protein translocation had no effect on either the efficiency or topology of b5 insertion. Indeed, the kinetics of transmembrane insertion into protein-free phospholipid vesicles was the same as for native ER microsomes. Remarkably, loading of either liposomes or microsomes with cholesterol to levels found in other membranes of the secretory pathway sharply and reversibly inhibited b5 transmembrane insertion. These results identify the minimal requirements for transmembrane topogenesis of a TA protein and suggest that selectivity among various intracellular compartments can be imparted by differences in their lipid composition. C1 CNR, Inst Neurosci Cell Mol Pharmacol, I-20129 Milan, Italy. Univ Milan, Dept Med Pharmacol, Milan, Italy. Univ Helsinki, Inst Biotechnol, Program Cellular Biotechnol, Helsinki, Finland. Univ Helsinki, Dept Appl Chem & Microbiol, Helsinki, Finland. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Univ Catanzaro Magna Graecia, Fac Pharm, Roccelletta Di Borgia, CZ, Italy. RP Hegde, RS (reprint author), NICHD, Cell Biol & Metab Branch, NIH, 18 Lib Dr,Bldg 18,Room 101, Bethesda, MD 20892 USA. EM hegder@mail.nih.gov; n.borgese@in.cnr.it OI Borgese, Nica/0000-0002-7537-3974; Hegde, Ramanujan/0000-0001-8338-852X FU Intramural NIH HHS; Telethon [GGP04129] NR 37 TC 74 Z9 74 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JUL 20 PY 2005 VL 24 IS 14 BP 2533 EP 2542 DI 10.1038/sj.emboj.7600730 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 951UJ UT WOS:000230956600005 PM 15973434 ER PT J AU Wu, L Chan, KL Ralf, C Bernstein, DA Garcia, PL Bohr, VA Vindigni, A Janscak, P Keck, JL Hickson, ID AF Wu, L Chan, KL Ralf, C Bernstein, DA Garcia, PL Bohr, VA Vindigni, A Janscak, P Keck, JL Hickson, ID TI The HRDC domain of BLM is required for the dissolution of double Holliday junctions SO EMBO JOURNAL LA English DT Article DE Bloom's syndrome; Holliday junction resolution; HRDC domain; RecQ DNA helicases; topoisomerase III ID TOPOISOMERASE-III-ALPHA; BLOOMS-SYNDROME HELICASE; REPLICATION PROTEIN-A; SYNDROME GENE-PRODUCT; WERNER-SYNDROME PROTEIN; STRAND BREAK REPAIR; SGS1 DNA HELICASE; RECQ HELICASES; HOMOLOGOUS RECOMBINATION; SACCHAROMYCES-CEREVISIAE AB Bloom's syndrome is a hereditary cancer-predisposition disorder resulting from mutations in the BLM gene. In humans, BLM encodes one of five members of the RecQ helicase family. One function of BLM is to act in concert with topoisomerase III alpha (TOPO III alpha) to resolve recombination intermediates containing double Holliday junctions by a process called double Holliday junction dissolution, herein termed dissolution. Here, we show that dissolution is highly specific for BLM among human RecQ helicases and critically depends upon a functional HRDC domain in BLM. We show that the HRDC domain confers DNA structure specificity, and is required for the efficient binding to and unwinding of double Holliday junctions, but not for the unwinding of a simple partial duplex substrate. Furthermore, we show that lysine-1270 of BLM, which resides in the HRDC domain and is predicted to play a role in mediating interactions with DNA, is required for efficient dissolution. C1 Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Canc Res UK Labs,Oxford Canc Ctr, Oxford OX3 9DS, England. Univ Wisconsin, Dept Biomol Chem, Madison, WI USA. Univ Zurich, Inst Mol Canc Res, Zurich, Switzerland. NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Int Ctr Genet Engn & Biotechnol, I-34012 Trieste, Italy. RP Hickson, ID (reprint author), Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Canc Res UK Labs,Oxford Canc Ctr, Oxford OX3 9DS, England. EM ian.hickson@cancer.org.uk RI Janscak, Pavel/G-6189-2014 NR 56 TC 103 Z9 104 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JUL 20 PY 2005 VL 24 IS 14 BP 2679 EP 2687 DI 10.1038/sj.emboj.7600740 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 951UJ UT WOS:000230956600018 PM 15990871 ER PT J AU Wedam, SB Swain, SM AF Wedam, SB Swain, SM TI Contralateral breast cancer: Where does it all begin? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID ESTROGEN-RECEPTOR STATUS; ENDOCRINE THERAPY; TAMOXIFEN; CELLS C1 NCI, Canc Therapeut Branch, Ctr Canc Res, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Wedam, SB (reprint author), NCI, Canc Therapeut Branch, Ctr Canc Res, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. OI Swain, Sandra/0000-0002-1320-3830 NR 23 TC 4 Z9 4 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2005 VL 23 IS 21 BP 4585 EP 4587 DI 10.1200/JCO.2005.01.910 PG 3 WC Oncology SC Oncology GA 950QK UT WOS:000230872000006 PM 15837973 ER PT J AU Strouse, JJ Fears, TR Tucker, MA Wayne, AS AF Strouse, JJ Fears, TR Tucker, MA Wayne, AS TI Pediatric melanoma: Risk factor and survival analysis of the surveillance, epidemiology and end results database SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 40th Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 05-08, 2004 CL New Orleans, LA SP Amer Soc Clin Oncol ID MALIGNANT-MELANOMA; CHILDHOOD MELANOMA; CUTANEOUS MELANOMA; HISTOPATHOLOGIC DIAGNOSIS; ULTRAVIOLET-RADIATION; CANCER; ADOLESCENTS AB Purpose To evaluate risk factors for the development of and factors influencing survival in pediatric melanoma. Patients and Methods We evaluated 1,255 children (age < 20 years) and 2,673 young adults (age 20 to 24 years) with melanoma in the 2001 National Cancer Institute (NCI) Surveillance, Epidemiology and End Results (SEER) database. We estimated exposure to UV radiation based on Environmental Protection Agency (EPA) measurements. Results The incidence of pediatric melanoma increased 46% (95% Cl, 40 to 52) per year of age and 2.9% (95% Cl, 2.1 to 3.6) per year from 1973 to 2001. Incidence rates were lower in black patients (-95%; 95% Cl, -98 to -90) compared with white patients and in male patients (-39%; 95% Cl -46 to -31) compared with females. Increased ambient UV radiation was associated with elevated risk (19% per kJ; 95% Cl, 9 to 30). Children with melanoma had a 5-year melanoma-specific survival of 93.6% (95% Cl, 91.9 to 94.9), which improved from 1973 to 2001. The hazard ratio of death from melanoma increased with male sex; older age; advanced disease; location of the primary other than extremities or torso; earlier year of diagnosis; and previous cancer. Conclusion The incidence of melanoma in the United States is increasing rapidly in children. Risk factors for pediatric melanoma include being white, being female, increasing age, and environmental UV radiation. Survival is decreased for children and adolescents with unfavorable prognostic factors (male sex, unfavorable site, and/or second primary or regional or distant metastasis). More effective therapeutic strategies are needed for these groups. C1 Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. NCI, Biostat Branch, NIH, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Strouse, JJ (reprint author), Div Pediat Hematol, 720 Rutland Ave,Ross 1125, Baltimore, MD 21205 USA. EM jstrous1@jhmi.edu RI Strouse, John/A-2690-2008; Tucker, Margaret/B-4297-2015 OI Strouse, John/0000-0003-0341-1457; FU NCI NIH HHS [2K12CA001709-11] NR 29 TC 175 Z9 178 U1 0 U2 5 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 JUL 20 PY 2005 VL 23 IS 21 BP 4735 EP 4741 DI 10.1200/JCO.2005.02.899 PG 7 WC Oncology SC Oncology GA 950QK UT WOS:000230872000025 PM 16034049 ER PT J AU Park, J Bungay, PM Lutz, RJ Augsburger, JJ Millard, RW Roy, AS Banerjee, RK AF Park, J Bungay, PM Lutz, RJ Augsburger, JJ Millard, RW Roy, AS Banerjee, RK TI Evaluation of coupled convective-diffusive transport of drugs administered by intravitreal injection and controlled release implant SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE convective-diffusive transport; drug delivery; drug distribution; eye; intravitreal injection; controlled release implant ID VITREOUS-HUMOR; RETINAL TOXICITY; EYE; PHARMACOKINETICS; PERMEABILITY; ANTIBIOTICS; GANCICLOVIR; RETINITIS; DELIVERY; APHAKIA AB A 3-dimensional finite element model was developed to simulate pharmacokinetics in the eye following drug administration by intravitreal injection and implant for the treatment of retinal disease. The contributions of (1) convection to the transport of drug through the vitreous and aqueous humor and (2) diffusion of drug in the vitreous were varied to study the drug elimination from a normal and diseased eye. Drug distribution achieved by intravitreal injection was compared to that for the same dose released at a constant rate over 15 h from an implant. The model was constructed for a rabbit eye and validated with experimental data for intravitreal injection of fluorescein. The implant reduced peak concentration by 43% and increased residence time by 71% for the baseline (6 x 10(-6) cm(2)/s drug diffusivity in vitreous and 0.1 mu L/min vitreous outflow), when compared with that of intravitral injection. Therefore, the implant could be beneficial in reducing the peak concentration and sustaining release of the drug for a longer duration. Convection has a relatively small influence in the normal eye for high diffusivity drugs (1 x 10(-5) cm(2)/s), but could have a significant effect for low diffusivity drugs (1 x 10(-7) cm(2)/s) in pathophysiologically elevated fluid outflow across the retina. By interpolating the results of this benchmark study, one could estimate the distributions for drugs of different molecular weight, and assess the effect of variable vitreous outflows associated with different pathophysiological conditions. (c) 2005 Elsevier B.V. All rights reserved. C1 Univ Cincinnati, Dept Mech Engn, Cincinnati, OH 45221 USA. Univ Cincinnati, Dept Biomed Engn, Cincinnati, OH 45221 USA. Univ Cincinnati, Dept Ophthalmol, Cincinnati, OH 45267 USA. Univ Cincinnati, Dept Pharmacol & Cell Biophys, Cincinnati, OH 45267 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. RP Banerjee, RK (reprint author), Univ Cincinnati, Dept Mech Ind & Nucl Engn, 598 Rhodes Hall,POB 210072, Cincinnati, OH 45221 USA. EM Rupak.Banejee@UC.Edu NR 28 TC 44 Z9 47 U1 4 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD JUL 20 PY 2005 VL 105 IS 3 BP 279 EP 295 DI 10.1016/j.jconrel.2005.03.010 PG 17 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 949SE UT WOS:000230807600009 PM 15896868 ER PT J AU McShane, LM Altman, DG Sauerbrei, W AF McShane, LM Altman, DG Sauerbrei, W TI Identification of clinically useful cancer prognostic factors: What are we missing? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID BREAST-CANCER; TUMOR-MARKERS; GUIDELINES; FUTURE; VARIABLES; ONCOLOGY; SYSTEM C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. Canc Res UK, NHS, Ctr Stat Med, Oxford, England. Univ Hosp Freiburg, Inst Med Biometry & Informat, Freiburg, Germany. RP McShane, LM (reprint author), NCI, Biometr Res Branch, MSC 7434,6130 Execut Blvd, Bethesda, MD 20892 USA. EM lm5h@nih.gov NR 20 TC 55 Z9 57 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 20 PY 2005 VL 97 IS 14 BP 1023 EP 1025 DI 10.1093/jnci.dji193 PG 3 WC Oncology SC Oncology GA 945SV UT WOS:000230523400002 PM 16030294 ER PT J AU Fossa, SD Chen, JB Schonfeld, SJ McGlynn, KA McMaster, ML Gail, MH Travis, LB AF Fossa, SD Chen, JB Schonfeld, SJ McGlynn, KA McMaster, ML Gail, MH Travis, LB TI Risk of contralateral testicular cancer: A population-based study of 29515 US men SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GERM-CELL TUMORS; CARCINOMA-IN-SITU; TESTIS CANCER; EXPERIENCE; CHEMOTHERAPY; PATTERNS; INSITU; CARE AB Background. Although risk estimates for synchronous and metachronous contralateral testicular cancers vary widely, many clinicians recommend routine biopsy of the contralateral testis for patients diagnosed with unilateral testicular cancer. We evaluated the risk of contralateral testicular cancer and survival in a large population-based cohort of men diagnosed with testicular cancer before age 55 years. Methods: For 29515 testicular cancer cases reported to the National Cancer Institute's Surveillance, Epidemiology and End Results Program from 1973 through 2001, we estimated the prevalence of synchronous contralateral testicular cancer, the observed-to-expected ratio (O/E) and 15-year cumulative risk of metachronous contralateral testicular cancer, and the 10-year overall survival rate of both synchronous and metachronous contralateral testicular cancer, using the Kaplan-Meier method for the two latter assessments. Age-adjusted multivariable analyses were used to examine risk according to histologic type of the original cancer. Results: A total of 175 men presented with synchronous contralateral testicular cancer; 287 men developed metachronous contralateral testicular cancer (O/E = 12.4 [95% confidence interval {CI} = 11.0 to 13.9]; 15-year cumulative risk = 1.9% [95% CI = 1.7% to 2.1%]). In the multivariable analysis, only nonseminornatous histology of the first testicular cancer was associated with a statistically significantly decreased risk of metachronous contralateral testicular cancer (hazard ratio [HR] = 0.60,95% confidence interval [CI] = 0.46 to 0.79; P <.001). Increasing age at first testicular cancer diagnosis was associated with decreasing risk of nonseminomatous metachronous contralateral testicular cancer (odds ratio = 0.90, 95% CI = 0.86 to 0.94). The 10-year overall survival rate after metachronous contralateral testicular cancer diagnosis was 93% (95% CI = 88% to 96%), and that after synchronous contralateral testicular cancer was 85% (95% CI = 78% to 90%). Conclusions: The low cumulative risk of metachronous contralateral testicular cancer and favorable overall survival of patients diagnosed with metachronous contralateral testicular cancer is in accordance with the current U.S. approach of not performing a biopsy on the contralateral testis. C1 Norwegian Radium Hosp, Dept Clin Canc Res, N-0310 Oslo, Norway. Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Fossa, SD (reprint author), Norwegian Radium Hosp, Dept Clin Canc Res, N-0310 Oslo, Norway. EM s.d.fossa@radiumhospitalet.no NR 58 TC 114 Z9 117 U1 0 U2 3 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 JUL 20 PY 2005 VL 97 IS 14 BP 1056 EP 1066 DI 10.1093/jnci/dji185 PG 11 WC Oncology SC Oncology GA 945SV UT WOS:000230523400010 PM 16030303 ER PT J AU Castle, PE Solomon, D Schiffman, M Wheeler, CM AF Castle, PE Solomon, D Schiffman, M Wheeler, CM CA ALTS Grp TI Human papillomavirus type 16 infections and 2-year absolute risk of cervical precancer in women with equivocal or mild cytologic abnormalities SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ATYPICAL SQUAMOUS-CELLS; RANDOMIZED-TRIAL; UNDETERMINED SIGNIFICANCE; INTRAEPITHELIAL LESIONS; MANAGEMENT STRATEGIES; COSTA-RICA; NEOPLASIA; CANCER; PARTICIPANTS; POPULATION AB Background. The 2-year absolute risk for cervical precancer attributable to infection by human papillomavirus type 16 (HPV16), the most common and oncogenic HPV type, in the millions of women diagnosed annually with equivocal or mildly abnormal cytology has not been definitively evaluated. Methods: Baseline cervical specimens of 5060 women with equivocal (atypical squamous cells of undetermined significance [ASCUS]) or mildly abnormal (low-grade squamous intraepithelial lesion [LSIL]) cytology were tested for HPV DNA using Hybrid Capture 2 (HC2) and typespecific L1 consensus primer polymerase chain reaction. We calculated absolute risks with 95% confidence intervals (CIs) for cumulative diagnosis, during the 2-year study period, of cervical intraepithelial neoplasia grade 3 (CIN3) (n = 535) or cancer (n = 7) (collectively referred to as CIN3) and compared risk by HPV16 status and by other oncogenic HPV types using logistic regression. All statistical tests were two-sided. Results: The baseline prevalences of HPV16 in women with ASCUS or LSIL cytology were 14.9% and 21.1%, respectively. Women with ASCUS or LSIL cytology who were HPV16 DNA positive at baseline had 2-year cumulative absolute risks for >= CIN3 of 32.5% (95% CI = 28.4% to 36.8%) and 39.1% (95% CI = 33.8% to 44.7%), respectively. By comparison, women with ASCUS who were positive by HC2 for other oncogenic HPV types combined had an 8.4% (95% CI = 6.9% to 10.4%) risk for >= CIN3, which was similar to the risk posed by having ASCUS (risk = 8.8%, 95% CI = 7.9% to 9.8%) without knowledge of the oncogenic HPV DNA status. Women with LSILs who were positive by HC2 for other oncogenic HPV types combined had a 9.9% (95% CI = 8.0% to 12.0%) 2-year risk for >= CIN3, which was less than the risk posed by having LSILs (risk = 15.0%,95% CI = 13.3% to 16.9%) without knowledge of the oncogenic HPV DNA status. Together, women with ASCUS or LSILs who were HPV16-positive had the highest 2-year risk for >= CIN3 compared with women who were HPV-negative (odds ratio [OR] = 38, 95% CI = 22 to 68; P <.001), fivefold greater than the increased risk in women who were positive for other oncogenic HPV types (OR = 7.2, 95%CI = 4.2 to 13, P <.001). Conclusions: Distinguishing the high absolute risk for cervical precancer in HPV16-positive women from the lower risk posed by other oncogenic HPV types might have clinical implications. C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, NIH, DHHS, Bethesda, MD 20892 USA. Univ New Mexico, Sch Med, Hlth Sci Ctr, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. Univ New Mexico, Sch Med, Hlth Sci Ctr, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU NCI NIH HHS [CN-55105, CN-55154, CN-55156, CN-55158, CN-55159, CN-55157, CN-55155, CN-55153] NR 25 TC 203 Z9 220 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 20 PY 2005 VL 97 IS 14 BP 1066 EP 1071 DI 10.1093/jnci/dji186 PG 6 WC Oncology SC Oncology GA 945SV UT WOS:000230523400011 PM 16030304 ER PT J AU Khan, MJ Castle, PE Lorincz, AT Wacholder, S Sherman, M Scott, DR Rush, BB Glass, AG Shiffman, M AF Khan, MJ Castle, PE Lorincz, AT Wacholder, S Sherman, M Scott, DR Rush, BB Glass, AG Shiffman, M TI The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ATYPICAL SQUAMOUS-CELLS; INTRAEPITHELIAL NEOPLASIA; COSTA-RICA; UNDETERMINED SIGNIFICANCE; RANDOMIZED-TRIAL; NATURAL-HISTORY; YOUNG-WOMEN; INFECTION; DNA; MANAGEMENT AB Background. Human papillomavirus (HPV) types 16 and 18 cause 60%-70% of cervical cancer worldwide, and other HPV types cause virtually all remaining cases. Pooled HPV testing for 13 oncogenic types, including HPV16 and 18, is currently used in clinical practice for triage of equivocal cytology and, in conjunction with Pap tests, is an option for general screening among women 30 years of age and older. It is not clear to what extent individual identification of HPV16 or HPV18 as an adjunct to pooled oncogenic HPV testing might effectively identify women at particularly high risk of cervical cancer or its immediate precursor, cervical intraepithelial neoplasia 3 (CIN3). Methods: From April 1989, to November 2, 1990, a total of 20810 women in the Kaiser Permanente health plan in Portland, OR, enrolled in a cohort study of HPV and cervical neoplasia. Women were tested for 13 oncogenic HPV types by Hybrid Capture 2 (HC2), and those women with a positive HC2 test were tested for HPV16 and 18. Enrollment Pap smear interpretation and HPV test results were linked to histologically confirmed CIN3 and cervical cancer (?:CIN3) occurring during 10 years of cytologic follow-up. We calculated cumulative incidence rates with 95% confidence intervals for each interval up to 122 months using Kaplan-Meier methods. Results: The 10-year cumulative incidence rates of >= CIN3 were 17.2% (95% confidence interval [CI] = 11.5% to 22.9%) among HPV16+ women and 13.6% (95% CI = 3.6% to 23.7%) among HPV18+ (HPV16-) women, but only 3.0% (95% CI = 1.9% to 4.2%) among HC2+ women negative for HPV16 or HPV18. The 10-year cumulative incidence among HC2(-) women was 0.8% (95% CI = 0.6% to 1.1 %). A subanalysis among women 30 years of age and older with normal cytology at enrollment strengthened the observed risk differences. Conclusions: HPV screening that distinguishes HPV16 and HPV18 from other oncogenic HPV types may identify women at the greatest risk of >= CIN3 and may permit less aggressive management of other women with oncogenic HPV infections. C1 NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Rockville, MD 20852 USA. Howard Hughes Med Inst, Chevy Chase, MD USA. Digene Corp, Gaithersburg, MD USA. Kaiser Permanente, Portland, OR USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, 6120 Execut Blvd,Rm 7074, Rockville, MD 20852 USA. EM castlep@mail.nih.gov NR 37 TC 536 Z9 577 U1 4 U2 25 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 JUL 20 PY 2005 VL 97 IS 14 BP 1072 EP 1079 DI 10.1093/jnci/dji187 PG 8 WC Oncology SC Oncology GA 945SV UT WOS:000230523400012 PM 16030305 ER PT J AU Yokoyama, F Suzuki, N Kadoya, Y Utani, A Nakatsuka, H Nishi, N Haruki, M Kleinman, HK Nomizu, M AF Yokoyama, F Suzuki, N Kadoya, Y Utani, A Nakatsuka, H Nishi, N Haruki, M Kleinman, HK Nomizu, M TI Bifunctional peptides derived from homologous loop regions in the laminin alpha chain LG4 modules interact with both alpha 2 beta 1 integrin and syndecan-2 SO BIOCHEMISTRY LA English DT Article ID CELL-BINDING SEQUENCES; G-DOMAIN; BIOLOGICAL-ACTIVITY; SYNTHETIC PEPTIDES; IDENTIFICATION; EXPRESSION; HEPARIN; SITES; FIBRONECTIN; ADHESION AB Laminin alpha chains show diverse biological functions in a chain-specific fashion. The laminin G-like modules (LG modules) of the laminin alpha chains consist of a 14-stranded beta-sheet sandwich structure with biologically active sequences found in the connecting loops. Previously, we reported that connecting loop regions between beta-strands E and F in the mouse laminin alpha chain LG4 modules exhibited chain-specific activities. In this study, we focus on the homologous loop regions in human laminin alpha chain LG4 modules using five synthetic peptides (hEF-1-hEF-5). These homologous peptides induced chain-specific cellular responses in various cell types. Next, to examine the dual-receptor recognition model, we synthesized chimeras (cEF13A-cEF13E) derived from peptides hEF-1 and hEF-3. All of the chimeric peptides promoted fibroblast attachment as well as the parental peptides. Attachment of fibroblasts to cEF13A and cEF13B was inhibited by anti-integrin alpha 2 and beta 1 antibodies and by heparin, while cell adhesion to cEF13C, cEF13D, and cEF13E was blocked only by heparin. Actin organization of fibroblasts on cEF13C was not different from that on hEF-3, but cEF13B induced membrane ruffling at the tips of the actin stress fibers. These results suggest that cEF13B had bifunctional effects on cellular behaviors through alpha 2 beta 1 integrin and heparin/heparan sulfate proteoglycan. We conclude that the approach utilizing chimeric peptides is useful for examining cellular mechanisms in dual-receptor systems. C1 Tokyo Univ Pharm & Life Sci, Sch Pharm, Lab Clin Biochem, Tokyo 1920392, Japan. Hokkaido Univ, Grad Sch Environm Earth Sci, Sapporo, Hokkaido 0600810, Japan. Kitasato Univ, Sch Med, Dept Anat, Sagamihara, Kanagawa 2288555, Japan. Kyoto Univ, Grad Sch Med, Dept Dermatol, Kyoto 6068507, Japan. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Nomizu, M (reprint author), Tokyo Univ Pharm & Life Sci, Sch Pharm, Lab Clin Biochem, 1432-1 Horinouchi, Tokyo 1920392, Japan. EM nomizu@ps.toyaku.ac.jp RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X NR 43 TC 10 Z9 10 U1 1 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 JUL 19 PY 2005 VL 44 IS 28 BP 9581 EP 9589 DI 10.1021/bi050598t PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 944YB UT WOS:000230466000003 PM 16008343 ER PT J AU Hanson, L May, L Tuma, P Keeven, J Mehl, P Ferenz, M Ambudkar, SV Golin, J AF Hanson, L May, L Tuma, P Keeven, J Mehl, P Ferenz, M Ambudkar, SV Golin, J TI The role of hydrogen bond acceptor groups in the interaction of substrates with Pdr5p, a major yeast drug transporter SO BIOCHEMISTRY LA English DT Article ID HUMAN P-GLYCOPROTEIN; SACCHAROMYCES-CEREVISIAE; SIMULTANEOUS BINDING; GENE-PRODUCT; RESISTANCE; EFFLUX; CLONING AB The yeast ABC (ATP-binding cassette protein) multidrug transporter Pdr5p transports a broad spectrum of xenobiotic compounds, including antifungal and antitumor agents. Previously, we demonstrated that substrate size is an important factor in substrate-transporter interaction and that Pdr5p has at least three substrate-binding sites. In this study, we use a combination of whole cell transport assays and photoaffinity labeling of Pdr5p with [I-125]iodoarylazidoprazosin in purified plasma membrane vesicles to study the behavior of two series of novel substrates: trityl (triphenylmethyl) and carbazole derivatives. The results indicate that site 2, defined initially by tritylimidazole efflux, requires at least a single hydrogen bond acceptor group (electron pair donor). In contrast, complete inhibition of rhodamine 6G efflux and [I-125]iodoarylazidoprazosin binding at site 1 requires substrates with three electronegative groups. Carbazole and trityl substrates with two groups show saturating, incomplete inhibition at this site. This type of inhibition is frequently observed in bacterial multidrug-binding proteins that use a pocket with multiple binding sites. The presence of multiple sites with different requirements for substrate-Pdr5p interaction may explain the broad specificity of xenobiotic compounds transported by this protein. C1 Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. Catholic Univ Amer, Dept Chem, Washington, DC 20064 USA. Catholic Univ Amer, Vitreous State Lab, Washington, DC 20064 USA. Dickinson Coll, Dept Biol, Carlisle, PA 17013 USA. NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Golin, J (reprint author), Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. EM golin@cua.edu RI Ambudkar, Suresh/B-5964-2008 NR 17 TC 20 Z9 21 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 JUL 19 PY 2005 VL 44 IS 28 BP 9703 EP 9713 DI 10.1021/bi0502994 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 944YB UT WOS:000230466000015 PM 16008355 ER PT J AU Longley, MJ Graziewicz, MA Bienstock, RJ Copeland, WC AF Longley, MJ Graziewicz, MA Bienstock, RJ Copeland, WC TI Consequences of mutations in human DNA polymerase gamma SO GENE LA English DT Article; Proceedings Paper CT Meeting on Cross Talk between Nucleus and Organelles CY SEP 15-18, 2004 CL Stazione Zool Anton Dohrn, Naples, ITALY HO Stazione Zool Anton Dohrn DE mitochondrial DNA replication; PEO; Alpers syndrome; POLG ID PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; P55 ACCESSORY SUBUNIT; MITOCHONDRIAL-DNA; POLG MUTATIONS; AUTOSOMAL-DOMINANT; MULTIPLE DELETIONS; MALE-INFERTILITY; ALPERS-SYNDROME; MTDNA; GENE AB DNA polymerase gamma is responsible for replication and repair of the mitochondrial genome. Human DNA polymerase gamma is composed of a 140-kDa catalytic subunit and a 55-kDa accessory subunit. Mutations in the gene for the catalytic subunit (POLG) have been shown to be a frequent cause of mitochondrial disorders. To date over 40 disease mutations and 9 nonsynonymous polymorphisms in POLG have been found to be associated with autosomal recessive and dominant progressive external ophthalmoplegia (PEO), Alpers syndrome, sensory ataxia, neuropathy, dysarthria and ophthalmoparesis (SANDO), Parkinsonism, and male infertility. In this paper we review the literature of POLG mutations and discuss their impact on mitochondrial diseases. We also describe a public access web database to annotate POLG mutations for the research community. (c) 2005 Elsevier B.V. All rights reserved. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Comp Sci Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov OI Bienstock, Rachelle/0000-0001-5228-3610 NR 45 TC 97 Z9 98 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JUL 18 PY 2005 VL 354 SI SI BP 125 EP 131 DI 10.1016/j.gene.2005.03.029 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 959DN UT WOS:000231497200019 PM 15913923 ER PT J AU Goodwin, JS Drake, KR Rogers, C Wright, L Lippincott-Schwartz, J Philips, MR Kenworthy, AK AF Goodwin, JS Drake, KR Rogers, C Wright, L Lippincott-Schwartz, J Philips, MR Kenworthy, AK TI Depalmitoylated Ras traffics to and from the Golgi complex via a nonvesicular pathway SO JOURNAL OF CELL BIOLOGY LA English DT Article ID PLASMA-MEMBRANE LOCALIZATION; H-RAS; ENDOPLASMIC-RETICULUM; PALMITOYL ACYLTRANSFERASE; PROTEIN PALMITOYLATION; CAAX MOTIF; K-RAS; BIOCHEMICAL-CHARACTERIZATION; SACCHAROMYCES-CEREVISIAE; INTERACTING PROTEIN AB Palmitoylation is postulated to regulate Ras signaling by modulating its intracellular trafficking and membrane microenvironment. The mechanisms by which palmitoylation contributes to these events are poorly understood. Here, we show that dynamic turnover of palmitate regulates the intracellular trafficking of HRas and NRas to and from the Golgi complex by shifting the protein between vesicular and nonvesicular modes of transport. A combination of time-lapse microscopy and photobleaching techniques reveal that in the absence of palmitoylation, GFP-tagged HRas and NRas undergo rapid exchange between the cytosol and ER/Golgi membranes, and that wild-type GFP-HRas and GFP-NRas are recycled to the Golgi complex by a non-vesicular mechanism. Our findings support a model where palmitoylation kinetically traps Ras on membranes, enabling the protein to undergo vesicular transport. We propose that a cycle of depalmitoylation and repalmitoylation regulates the time course and sites of Ras signaling by allowing the protein to be released from the cell surface and rapidly redistributed to intracellular membranes. C1 Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Dept Cell & Dev Biol, Nashville, TN 37232 USA. NICHHD, Cell Biol & Metab Branch, NIH, Baltimore, MD 21218 USA. NYU, Sch Med, Dept Cell Biol, New York, NY 10016 USA. RP Kenworthy, AK (reprint author), Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. EM anne.kenworthy@vanderbilt.edu NR 74 TC 168 Z9 170 U1 2 U2 6 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 JUL 18 PY 2005 VL 170 IS 2 BP 261 EP 272 DI 10.1083/jcb.200502063 PG 12 WC Cell Biology SC Cell Biology GA 946UF UT WOS:000230597900013 PM 16027222 ER PT J AU Yabroff, KR Kerner, JF AF Yabroff, KR Kerner, JF TI Variations in surgery for early-stage breast cancer: what are we measuring? SO LANCET LA English DT Editorial Material ID OLDER WOMEN; GEOGRAPHIC-VARIATION; MASTECTOMY; RADIATION; THERAPY; CARE C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Yabroff, KR (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 NR 16 TC 4 Z9 4 U1 0 U2 1 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 16 PY 2005 VL 366 IS 9481 BP 188 EP 190 DI 10.1016/S0140-6736(05)66888-2 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 945RG UT WOS:000230519200009 PM 16023495 ER PT J AU Perez-Poveda, JC Palacio, LG Arcos-Burgos, M AF Perez-Poveda, JC Palacio, LG Arcos-Burgos, M TI Description of an endogamous, multigenerational and extensive family with benign hereditary chorea from the Paisa community SO REVISTA DE NEUROLOGIA LA Spanish DT Article DE benign hereditary chorea; Colombia; genetics; inheritance; movement disorders; Paisa ID EARLY-ONSET; ENTITY AB Introduction. The benign chorea hereditary (BCH, OMIM 118700) represents a childhood movement disorder characterized by its early onset, a slow progressive course (mostly stable) and the absence of mental compromise, which contrast with the clinical features exhibited by the Huntington Disease. Case reports. Here we describe a multigenerational, extended and inbreed family belonging to a genetic isolate, the Paisa community from Antioquia Colombia, with seven children exhibiting clinical features of BCH. Even though some patients with BCH are heterozygous for a dominant mutation in the thyroid transcription factor-1 gene (TITFl), the pattern in this family resembles a recessive mode of inheritance, which suggests that genetic heterogeneity may be playing a role. Conclusion. Currently, linkage analysis is underway to determine if TITF1 is the gene responsible for this movement disorder in this family. C1 Univ Antioquia, Inst Neurol, Medellin, Colombia. Univ Antioquia, Inst Biol, Grp Genet Poblac Mutacarcinogenesis & Epidemiol G, Medellin, Colombia. Pontificia Univ Javeriana, Bogota, Colombia. NHGRI, NIH, Bethesda, MD 20892 USA. RP Palacio, LG (reprint author), Univ Antioquia, Inst Neurol, Calle 55,46-36, Medellin, Colombia. EM lpalacio@mail.nih.gov.co NR 14 TC 1 Z9 1 U1 0 U2 1 PU REVISTA DE NEUROLOGIA PI BARCELONA PA C/O CESAR VIGUERA, EDITOR, APDO 94121, 08080 BARCELONA, SPAIN SN 0210-0010 J9 REV NEUROLOGIA JI Rev. Neurologia PD JUL 16 PY 2005 VL 41 IS 2 BP 95 EP 98 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 950KS UT WOS:000230856600007 PM 16028188 ER PT J AU Alexander, D AF Alexander, D TI Reducing the risk of SIDS through community partnerships SO AMERICAN FAMILY PHYSICIAN LA English DT Editorial Material C1 Natl Inst Hlth, Natl Inst Child Hlth & Human Dev, Bethesda, MD 20892 USA. RP Alexander, D (reprint author), Natl Inst Hlth, Natl Inst Child Hlth & Human Dev, 31 Ctr Dr,Bldg 31,Room 2A32,MSC 2425, Bethesda, MD 20892 USA. EM alexandd@exchange.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 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 JUL 15 PY 2005 VL 72 IS 2 BP 228 EP + PG 2 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 947ZX UT WOS:000230686900004 PM 16050449 ER PT J AU Wattendorf, DJ Muenke, M AF Wattendorf, DJ Muenke, M TI Fetal alcohol spectrum disorders SO AMERICAN FAMILY PHYSICIAN LA English DT Article AB To complement the 2005 Annual Clinical Focus on medical genomics, AFP will be publishing a series of short reviews on genetic syndromes. This series was designed to increase awareness of these diseases so that family physicians can recognize and diagnose children with these disorders and understand the kind of care they might require in the future. The second review in this series discusses fetal alcohol syndrome and fetal alcohol spectrum disorders. C1 Natl Human Genome Res Inst, Med Genet Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Family Med, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. RP Muenke, M (reprint author), Natl Human Genome Res Inst, Med Genet Branch, Natl Inst Hlth, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mmuenke@nhgri.nih.gov NR 12 TC 41 Z9 44 U1 0 U2 6 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 JUL 15 PY 2005 VL 72 IS 2 BP 279 EP + PG 5 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 947ZX UT WOS:000230686900007 PM 16050451 ER PT J AU Depietropaolo, DL Powers, JH Gill, JM Foy, AJ AF Depietropaolo, DL Powers, JH Gill, JM Foy, AJ TI Diagnosis of Lyme disease SO AMERICAN FAMILY PHYSICIAN LA English DT Article ID LABORATORY EVALUATION; ERYTHEMA MIGRANS; CHILDREN; GUIDELINES; OUTCOMES AB The use of serologic testing and its value in the diagnosis of Lyme disease remain confusing and controversial for physicians, especially concerning persons who are at low risk for the disease. The approach to diagnosing Lyme disease varies depending on the probability of disease (based on endemicity and clinical findings) and the stage at which the disease may be. In patients from endemic areas, Lyme disease may be diagnosed on clinical grounds alone in the presence of erythema migrans. These patients do not require serologic testing, although it may be considered according to patient preference. When the pretest probability is moderate (e.g., in a patient from a highly or moderately endemic area who has advanced manifestations of Lyme disease), serologic testing should be performed with the complete two-step approach in which a positive or equivocal serology is followed by a more specific Western blot test. Samples drawn from patients within four weeks of disease onset are tested by Western blot technique for both immunoglobulin M and immunoglobulin G antibodies; samples drawn more than four weeks after disease onset are tested for immunoglobulin G only. Patients who show no objective signs of Lyme disease have a low probability of the disease, and serologic testing in this group should be kept to a minimum because of the high risk of false-positive results. When unexplained nonspecific systemic symptoms such as myalgia, fatigue, and paresthesias have persisted for a long time in a person from an endemic area, serologic testing should be performed with the complete two-step approach described above. C1 Christiana Care Hlth Serv, Wilmington, DE USA. NIH, Bethesda, MD 20892 USA. RP Depietropaolo, DL (reprint author), 11 Lindsey Pl, Wilmington, DE 19809 USA. EM drdan1954@aol.com NR 24 TC 25 Z9 25 U1 0 U2 1 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 JUL 15 PY 2005 VL 72 IS 2 BP 297 EP 304 PG 8 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 947ZX UT WOS:000230686900009 PM 16050454 ER PT J AU Cao, JJ Hudson, M Jankowski, M Whitehouse, F Weaver, WD AF Cao, JJ Hudson, M Jankowski, M Whitehouse, F Weaver, WD TI Relation of chronic and acute glycemic control on mortality in acute myocardial infarction with diabetes mellitus SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID GLUCOSE; HYPERGLYCEMIA; ATHEROSCLEROSIS; VASODILATION; DYSFUNCTION; ADMISSION; RISK AB Acute hyperglycemia during myocardial infarction predicts adverse short-term outcomes and mortality in diabetic patients. Conversely, chronic hyperglycemia is associated with an increased incidence of long-term cardiovascular complications, although its effect on acute hyperglycemic response and mortality after acute myocardial infarction is unknown. We investigated the prognostic relation of the glucose concentration at admission and the baseline average glycohemoglobin on acute myocardial infarction mortality. Of 808 consecutive diabetic patients with acute myocardial infarction, the most significant independent predictor of in-hospital mortality was the glucose concentration at admission. Baseline glycohemoglobin strongly correlated with admission hyperglycemia but did not predict mortality independently. (c) 2005 Elsevier Inc. All rights reserved. C1 NHLBI, NIH, Bethesda, MD 20892 USA. Henry Ford Heart & Vasc Inst, Detroit, MI USA. Henry Ford Hosp, Detroit, MI 48202 USA. RP Cao, JJ (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM caoj@nhlbi.nih.gov NR 16 TC 61 Z9 71 U1 0 U2 2 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 15 PY 2005 VL 96 IS 2 BP 183 EP 186 DI 10.1016/j.amjcard.2005.03.040 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 945WF UT WOS:000230532500004 PM 16018838 ER PT J AU Djousse, L Levy, D Herbert, AG Wilson, PWF D'Agostino, RB Cupples, LA Karamohamed, S Ellison, RC AF Djousse, L Levy, D Herbert, AG Wilson, PWF D'Agostino, RB Cupples, LA Karamohamed, S Ellison, RC TI Influence of alcohol dehydrogenase 1C polymorphism on the alcohol-cardiovascular disease association (from the Framingham Offspring Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; CORONARY-HEART-DISEASE; US MALE PHYSICIANS; MYOCARDIAL-INFARCTION; INTERMITTENT CLAUDICATION; CONSUMPTION; RISK; METAANALYSIS; CHOLESTEROL; MORTALITY AB Although moderate alcohol consumption is associated with a lower risk of cardiovascular disease (CVD), little is known of the effects of alcohol dehydrogenase 1C (ADH1C) polymorphism on the association between alcohol and CVD. We used data on 1,805 unrelated subjects in the Framingham Offspring Study to assess whether rs1693482 and rs698, 2 single nucleotide polymorphisms of the ADH1C gene, modify the relation between alcohol consumption and prevalent CVD. The 2 single nucleotide polymorphisms were in linkage disequilibrium (D' = 0.99, R-2 = 0.96). There was evidence for a U-shaped association between alcohol consumption and CVD in this population. Multivariable adjusted odds ratios for prevalent CVD were 0.63 (95% confidence interval 0.41 to 0.97) and 0.80 (95% confidence interval 0.46 to 1.41) for CT and TT genotypes of rs1693482 relative to CC genotype (model p < 0.0001). Corresponding values for AG and GG genotypes of rs698 were 0.68 (95% confidence interval 0.45 to 1.04) and 0.84 (95% confidence interval 0.49 to 1.46), respectively, compared with the AA genotype (model p < 0.0001). There were nonstatistically significant associations between rs693482 C -> T and rs698 A -> G mutations and prevalent CVD among current drinkers (lower CVD prevalence with minor allele) but not among nondrinkers in whom the minor allele was associated with a trend toward higher CVD prevalence (p values for interaction are 0.16 for rs1693482 and 0.52 for rs698). Alcohol consumption was associated with high-density lipoprotein cholesterol across all genotypes of the 2 single nucleotide polymorphisms in a dose-response fashion without evidence for interaction. In conclusion, these data suggest borderline interactions between genes and environment of ADH1C variation and alcohol intake on prevalent CVD. The interaction does not appear to be mediated through effects on high-density lipoprotein cholesterol. (c) 2005 Elsevier Inc. All rights reserved. C1 Boston Univ, Prevent Med & Epidemiol Sect, Evans Dept Med, Boston, MA 02215 USA. Boston Univ, Dept Neurol, Boston, MA 02215 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Univ, Sch Publ Hlth, Dept Math, Boston, MA 02215 USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. RP Djousse, L (reprint author), Boston Univ, Prevent Med & Epidemiol Sect, Evans Dept Med, Boston, MA 02215 USA. EM ldjousse@bu.edu RI Djousse, Luc/F-5033-2017; OI Djousse, Luc/0000-0002-9902-3047; Ellison, Robert Curtis/0000-0002-0582-7467; Cupples, L. Adrienne/0000-0003-0273-7965 FU NHLBI NIH HHS [5K01 HL 070444, N01 HC 25195] NR 28 TC 24 Z9 25 U1 0 U2 2 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 15 PY 2005 VL 96 IS 2 BP 227 EP 232 DI 10.1016/j.amjcard.2005.03.050 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 945WF UT WOS:000230532500014 PM 16018848 ER PT J AU Harrington, PD Vieira, NE Espinoza, J Nien, JK Romero, R Yergey, AL AF Harrington, PD Vieira, NE Espinoza, J Nien, JK Romero, R Yergey, AL TI Analysis of variance-principal component analysis: A soft tool for proteomic discovery SO ANALYTICA CHIMICA ACTA LA English DT Article; Proceedings Paper CT 9th International Conference on Chemometrics in Analytical Chemistry CY SEP 20-23, 2004 CL Lisbon, PORTUGAL DE ANOVA-PCA; analysis of variance-principal component analysis; amniotic fluid; premature delivery; MALDI-MS; proteomic biomarker; hotelling T-2; mass spectrometry; matrix-assisted laser desorption/ionization ID MASS-SPECTRA; MIXTURES AB A soft tool for detection of biomarkers in high dimensional data sets has been developed. The tool combines analysis of variance (ANOVA) and principal component analysis (PCA). Covariations are separated using ANOVA into main effects and interaction. The covariances for each effect are combined with the pure error and subjected to PCA. If the main effect is significant compared to the residual error, the first principal component will span this source of variation. This technique avoids rotation of the principal components and when significant the variable loadings are amenable to interpretation. ANOVA-PCA is demonstrated as a tool for optimization of a proteomic assay for biomarkers. Two independent sets of matrix assisted laser desorption/ionization-mass spectra (MALDI-MS) were collected from ammotic fluids. These studies gave consistent biomarkers for premature delivery. (c) 2005 Elsevier B.V. All rights reserved. C1 Ohio Univ, Ctr Intelligent Chem Instrumentat, Dept Chem & Biochem, Clippinger Labs, Athens, OH 45701 USA. Natl Inst Child Hlth & Human Dev, Sect Mass Spectrometry & Metab, Bethesda, MD 20892 USA. Natl Inst Child Hlth & Human Dev, Perinatol Res Branch, Bethesda, MD 20892 USA. RP Harrington, PD (reprint author), Ohio Univ, Ctr Intelligent Chem Instrumentat, Dept Chem & Biochem, Clippinger Labs, Athens, OH 45701 USA. EM peter.harrington@ohio.edu OI Harrington, Peter/0000-0003-0268-8630 NR 22 TC 68 Z9 71 U1 3 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0003-2670 J9 ANAL CHIM ACTA JI Anal. Chim. Acta PD JUL 15 PY 2005 VL 544 IS 1-2 BP 118 EP 127 DI 10.1016/j.aca.2005.02.042 PG 10 WC Chemistry, Analytical SC Chemistry GA 941KT UT WOS:000230214400013 ER PT J AU Fitch, RW Daly, JW AF Fitch, RW Daly, JW TI Phosphorimaging detection and quantitation for isotopic ion flux assays SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE nicotine; acetylcholine receptor; epibatidine; radioisotope tracing; sodium channel; sodium influx; rubidium efflux; batrachotoxin; autoradiography ID NICOTINIC ACETYLCHOLINE-RECEPTORS; NEUROBLASTOMA CLONAL LINE; BINDING-SITES; LIGAND-BINDING; RAT; ALKALOIDS; CHANNEL; CELLS; PHARMACOLOGY; EPIBATIDINE AB A 96-well-microplate-based ion flux method utilizing readily available autoradiographic phosphorimaging detection is described. Nicotinic acetylcholine receptor-mediated Na-22 influx in four cultured cell lines provided satisfactory concentration-response data for epibatidine and several other nicotinic agonists. The data were consistent with data obtained using standard 6-well assays. Assays for nicotinic-receptor-mediated Rb-86 efflux produced data similar to data obtained with the Na-22 influx assay. However, assays for Ca-45 influx were not successful, although Ca-45 was readily detected and quantified. Voltage-gated sodium channel-mediated Na-22 influx in a neuroblastoma cell line allowed assay of the effects of such sodium channel activators as batrachotoxin and a pumiliotoxin B/scorpion venom combination. Phosphorimaging detection allows for reliable beta Counting of up to 1200 simultaneous samples with excellent sensitivity and is amenable for application to high-throughput screening. Published by Elsevier Inc. C1 NIDDKD, Sect Drug Receptor Interact, Bioorgan Chem Lab, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. RP Fitch, RW (reprint author), Indiana State Univ, Dept Chem, Sci S35E, Terre Haute, IN 47809 USA. EM rfitch@indstate.edu NR 30 TC 6 Z9 6 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JUL 15 PY 2005 VL 342 IS 2 BP 260 EP 270 DI 10.1016/j.ab.2005.04.041 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 945SK UT WOS:000230522300012 PM 15950910 ER PT J AU Jackson, SN Wang, HYJ Woods, AS AF Jackson, SN Wang, HYJ Woods, AS TI Direct profiling of lipid distribution in brain tissue using MALDI-TOFMS SO ANALYTICAL CHEMISTRY LA English DT Article ID ASSISTED LASER-DESORPTION; FLIGHT MASS-SPECTROMETRY; ALZHEIMERS-DISEASE; RAT-BRAIN; DESORPTION/IONIZATION; PHOSPHOLIPIDS; GANGLIOSIDES; SULFATIDE; SECTIONS; PROTEINS AB Recent developments in mass spectrometry have permitted direct analysis of biomolecules in tissue. However, most studies have focused on proteins with emphasis on biomarker discovery. In the present work, matrix-assisted laser desorption/ionization mass spectrometry was used for the direct analysis of lipids in rat cerebellum. The lipid bilayer role as a storage depot for small organic molecules such as therapeutic drugs and pollutants such as DDT, as well as the ability to compare lipid profiles in healthy and diseased animal models, are a few of the many reasons why the direct probing of tissue to determine the qualitative and possibly quantitative lipid content could be a very useful tool. Molecular ions corresponding to cholesterol, phosphatidylcholines, sphingomyelins, and phosphatidylethanolamines were recorded in positive ion mode, while ones corresponding to phosphatidylinositols, sulfatides, and gangliosides were recorded in negative ion mode. Overall, representatives from all major categories of brain lipids including cholesterol, 15 phospholipid species (9 phosphatidylcholines, 1 sphingomyelin, 3 phosphatidylethanolamines, 2 phosphatidylinositols), 10 sulfatides (5 hydroxylated species and 5 nonhydroxylated species), and 7 species of gangliosides were detected. C1 NIDA, IRP, NIH, Baltimore, MD 21224 USA. RP Woods, AS (reprint author), NIDA, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov NR 32 TC 130 Z9 137 U1 4 U2 29 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 JUL 15 PY 2005 VL 77 IS 14 BP 4523 EP 4527 DI 10.1021/ac050276v PG 5 WC Chemistry, Analytical SC Chemistry GA 945VL UT WOS:000230530300032 PM 16013869 ER PT J AU Bailey, A Zhukovsky, M Gliozzi, A Chernomordik, LV AF Bailey, A Zhukovsky, M Gliozzi, A Chernomordik, LV TI Liposome composition effects on lipid mixing between cells expressing influenza virus hemagglutinin and bound liposomes SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE membrane fusion; influenza hemagglutinin; liposome; lysophosphatidylcholine; non-bilayer lipid; stalk-pore hypothesis ID MEDIATED MEMBRANE-FUSION; LOW-PH; PLASMA-MEMBRANE; CYTOPLASMIC TAIL; RECEPTOR-BINDING; PORE FORMATION; EARLY-STAGE; HEMIFUSION; VESICLES; INACTIVATION AB The involvement of contacting and distal lipid monolayers in different stages of protein-mediated fusion was studied for fusion mediated by influenza virus hemagglutinin. Inclusion of non-bilayer lipids in the composition of the liposomes bound to hemagglutinin-expressing cells affects fusion triggered by low pH. Lysophosphatidylcholine added to the outer membrane monolayers inhibits fusion. The same lipid added to the inner monolayer of the liposomes promotes both lipid and content mixing. In contrast to the inverted cone-shaped lysophosphatidylcholine, lipids of the opposite effective shape, oleic acid or cardiolipin with calcium, present in the inner monolayers inhibit fusion. These results along with fusion inhibition by a bipolar lipid that does not support peeling of one monolayer of the liposomal membrane from the other substantiate the hypothesis that fusion proceeds through a local hemifusion intermediate. The transition from hemifusion to the opening of an expanding fusion pore allows content mixing and greatly facilitates lipid mixing between liposomes and cells. Published by Elsevier Inc. C1 NICHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD USA. Univ Genoa, Dept Phys, Genoa, Italy. RP Chernomordik, LV (reprint author), NICHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD USA. EM chernoml@mail.nih.gov NR 59 TC 11 Z9 13 U1 0 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 JUL 15 PY 2005 VL 439 IS 2 BP 211 EP 221 DI 10.1016/j.abb.2005.05.010 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 948BV UT WOS:000230691900008 PM 15963452 ER PT J AU Heo, J Lee, JS Chu, IS Takahama, Y Thorgeirsson, SS AF Heo, J Lee, JS Chu, IS Takahama, Y Thorgeirsson, SS TI Spontaneous differentiation of mouse embryonic stem cells in vitro: Characterization by global gene expression profiles SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE embryonic stem cell; oligonucleotide microarray; spontaneous differentiation; monolayer culture; germ layer lineages ID MICROARRAY ANALYSIS; CARCINOMA-CELLS; CULTURE; SPECIFICATION; APOPTOSIS; PATTERNS; PATHWAY; BODIES; LINE AB We characterized the temporal gene expression changes during four weeks of spontaneous differentiation of mouse ES cells in a monolayer culture in order to obtain better insight into the differentiation process. The overall gene expression pattern was changed dramatically during the first two weeks of spontaneous differentiation, but stabilized after the second week. Most of the genes regulated within the first two weeks of spontaneous differentiation were genes related to development including morphogenesis, cell differentiation, embryonic development, pattern specification, mesoderm development, post-embryonic development, and blastocyst development. While most of the ectoderm lineage related genes were down-regulated, genes related to the mesoderm or endoderm lineage were up-regulated through the first week and second week, respectively. This study revealed that the development of ectoderm lineage is a recessive process during the spontaneous differentiation of mouse ES cells in monolayer culture. Our time-course characterization might provide a useful time line for directed differentiation of mouse ES cells. Published by Elsevier Inc. C1 NCI, Expt Carcinogenesis Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. EM snorri_s_thorgeirsson@nih.gov NR 24 TC 16 Z9 17 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUL 15 PY 2005 VL 332 IS 4 BP 1061 EP 1069 DI 10.1016/j.bbrc.2005.04.173 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 937AC UT WOS:000229895900020 PM 15922302 ER PT J AU Qian, X Mitchell, J Wei, SJ Williams, J Petrovich, RM Shears, SB AF Qian, X Mitchell, J Wei, SJ Williams, J Petrovich, RM Shears, SB TI The Ins(1,3,4)P-3 5/6-kinase/Ins(3,4,5,6)P-4 1-kinase is not a protein kinase SO BIOCHEMICAL JOURNAL LA English DT Article DE ATP-grasp; inositol phosphate; inositol 3,4,5,6-tetra-kisphosphate 1-kinase; protein kinase ID INOSITOL 1,3,4-TRISPHOSPHATE 5/6-KINASE; CARBAMOYL-PHOSPHATE SYNTHETASE; COP9 SIGNALOSOME; 1,4,5-TRISPHOSPHATE 3-KINASE; BIOTIN CARBOXYLASE; ATP BINDING; B-DOMAIN; RESIDUES; LIGASE; CLASSIFICATION AB Among inositol phosphate kinases, Ins(3,4,5,6)P-4 1-kinase has been considered to be an outsider with disparate sequence, a proclaimed capacity to also phosphorylate proteins and apparent I-phosphatase activity. Such multifunctionality, coupled with ignorance of its operational domains, complicates any mechanistic rationale behind literature reports that Ins(3,4,5,6)P, 1-kinase regulates apoptosis, salt and fluid secretion, and transcription. We have expressed poly(His)-tagged human Ins(3,4,5,6)P4 I-kinase in Sf9 insect cells and purified the enzyme using Ni-agarose chromatography. Protein kinase activity was eluted from the Ni-agarose column, but this did not co-elute with the Ins(3,4,5,6)P, 1-kinase, indicating that the protein kinase and inositol kinase activities belong to separate proteins. To pursue this conclusion, we prepared catalytically inactive mutants of the Ins(3,4,5,6)P4 I-kinase by identifying and targeting the ATP-binding site. Our strategy was based on sequence alignments suggesting homology of the Ins(3,4,5,6)P4 1-kinase with ATP-grasp metabolic enzymes. Individual mutation of four candidate MgATP-binding participants, Lys(157), Asp(281), Asp(295) and Asn(297), severely compromised Ins(3,4,5,6)P, I-kinase activity. Yet, these mutations did not affect the protein kinase activity. We conclude that the Ins(3,4,5,6)P4 I-kinase is not a protein kinase, contrary to earlier reports [e.g. Wilson, Sun, Cao and Majerus (2001) J. Biol. Chem. 276, 40998-41004]. Elimination of protein kinase activity from the enzyme's repertoire and recognition of its ATP-grasp homology together indicate that structural, functional and catalytic relationships between Ins(3,4,5,6)P4 I-kinase and other inositol phosphate kinases are closer than previously thought [Gonzalez, Schell, Letcher, Veprintsev, Irvine and Williams (2004) Mol. Cell 15, 689-701]. C1 NIEHS, Inositide Signaling Grp, Lab Signal Transduct, NIH,DHSS, Res Triangle Pk, NC 27709 USA. NIEHS, Natl Ctr Toxicogenom, NIH, DHSS, Res Triangle Pk, NC 27709 USA. NIEHS, Prot Microcharacterizat Core Facil, Struct Biol Lab, NIH,DHSS, Res Triangle Pk, NC 27709 USA. NIEHS, Prot Express Core Facil, Struct Biol Lab, NIH,DHSS, Res Triangle Pk, NC 27709 USA. RP Shears, SB (reprint author), NIEHS, Inositide Signaling Grp, Lab Signal Transduct, NIH,DHSS, POB 12233, Res Triangle Pk, NC 27709 USA. EM shears@niehs.nih.gov NR 31 TC 11 Z9 12 U1 0 U2 0 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 JUL 15 PY 2005 VL 389 BP 389 EP 395 DI 10.1042/BJ20050297 PN 2 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 949IQ UT WOS:000230779000016 PM 15762844 ER PT J AU Britto, PJ Knipling, L McPhie, P Wolff, J AF Britto, PJ Knipling, L McPhie, P Wolff, J TI Thiol-disulphide interchange in tubulin: kinetics and the effect on polymerization SO BIOCHEMICAL JOURNAL LA English DT Article DE leaving group; mixed disulphide; polymerization; stop-flow kinetics; thiol-disulphide interchange; tubulin ID BOVINE BRAIN TUBULIN; SECONDARY STRUCTURE; SULFHYDRYL-GROUPS; OXIDATIVE STRESS; REDUCTASE SYSTEM; BETA-TUBULIN; PROTEIN; INVITRO; IDENTIFICATION; MICROTUBULES AB All 20 cysteine residues are accessible to disulphide reagents in the tubulin dimer, whereas only four are accessible in taxot-stabilized microtubules. Reaction rates with disulphide reagents are a function of the reagent, are decreased by G nucleotides, and increased with increase in pH and urea. With transient (stop-flow) kinetics, DTNB [5,5'-dithiobis-(2-nitrobenzoic acid)] and 2,2'-di-thiodipyridine progress curves cannot be fitted by the sum of exponential terms based only on classes of cysteines. The mixed disulphicle products react further to form both intra- and intermonomer disulphide bonds that can be reversed by reducing agents. With MMTS (methyl methanethiosulphonate) or ODNB (n-octyl-dithio-2-nitrobenzoate), virtually no protein-protein disulphide bonds are formed and the ODNB reaction can be given as the sum of three exponential terms with pseudo-first-order rate constants of 0.206, 0.069 and 0.010 s(-1) at pH 6.5, suggesting three classes of thiol reactivities. Limited cysteine substitution leads to only small changes in tryptophan or CD spectra, whereas complete substitution leads to loss of the helix content. MMTS-induced loss of SH groups leads to progressive increases in the critical concentration and loss of polymerization competence that can be reversed by assembly promoters such as higher protein concentration, taxol or high ionic strength. Under such conditions, the substituted tubulin forms protofilament-based structures such as microtubules, open tubules, sheets and/or bundles. C1 NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wolff, J (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM wolffj@mail.nih.gov NR 42 TC 33 Z9 33 U1 1 U2 10 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 JUL 15 PY 2005 VL 389 BP 549 EP 558 PN 2 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 949IQ UT WOS:000230779000033 PM 15743274 ER PT J AU Kim, YC Lee, JS Sak, K Marteau, F Mamedova, L Boeynaems, JM Jacobson, KA AF Kim, YC Lee, JS Sak, K Marteau, F Mamedova, L Boeynaems, JM Jacobson, KA TI Synthesis of pyridoxal phosphate derivatives with antagonist activity at the P2Y(13) receptor SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE PPADS (pyridoxal-5 '-phosphate-6-azo-phenyl-2,4-disulfonate); pyridoxal phosphate derivatives; adenine nucleolidcs; P2Y1; recepton; inositol trisphosphate; purines ID ADP RECEPTOR; PHARMACOLOGICAL CHARACTERIZATION; NUCLEOTIDE RECEPTORS; ADENYLYL-CYCLASE; INHIBITION; CLONING; IDENTIFICATION; P2X(1); CELLS AB We have synthesized a series of derivatives of the known P2 receptor antagonist PPADS (pyridoxit-5'-phosphate-6-azo-phenyl-2.4-disulfonate) and examined their ability to inhibit functional activity of the recombinant human P2Ytt nucleotide receptor expressed in 1321N1 human astrocytoma cells co-expressing G alpha(16) protein (AG32). Analogues of PPADS modified through substitution of the phenylazo ring, including halo and nitro substitution, and 5'-alkyl phosphonate analogues were synthesized and tested. A 6-benzyl-5'-methyl phosphonate analogue was prepared to examine the effect of stable replacement of the azo linkage, The highest antagonistic poteney was observed for 6-(3-nitrophenylazo) derivatives of pyridoxal-5'-phosphate, The 2-chloro-5-nitro analogue (MRS 2211) and 4-chloro-3-nitro analogue (MRS 2603) inhibited ADP (100 nM)-induced inositol trisphosphate (IP3) formation with pIC(50) values of 5.97 and 6.18, respectively, being 45- and 74-fold more potent than PPADS. The antagonism of MRS 2211 was competitive with a pA(2) value of 6.3. MRS2211 and MRS2603 inhibited phospholipase C (PLC) responses to 30 nM 2-methylthio-ADP in human P2Y(1) receptor-mediated 1321N1 astrocytoma cells with IC50 values of > 10and 0.245 mu M, respectively. Both analogues were inactive(> 10 mu M) as antagonists of human P2Y(12) receptor-mediated PLC responses in 1321N1 astrocytoma cells, Thus. MRS2211 displayed > 20-fold selectivity as antagonist of the P2Y(13) receptor in comparison to P2Y(1) and P2Y12 receptors, while MRS2603 antagonized both P2Y(1) and P2Y(13), receptors. (c) 2005 Elsevier Inc. All rights reserved. C1 NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Gwangju Inst Sci & Technol, Dept Life Sci, Lab Drug Discovery, Kwangju 500712, South Korea. Univ Libre Brussels, Inst Interdisciplinary Res, B-1070 Brussels, Belgium. Univ Libre Brussels, Hop Erasme, Dept Clin Pathol, Med Chem Lab, B-1070 Brussels, Belgium. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; Sak, Katrin/0000-0003-0736-2525 FU Intramural NIH HHS [Z01 DK031116-20] NR 23 TC 43 Z9 47 U1 0 U2 4 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 JUL 15 PY 2005 VL 70 IS 2 BP 266 EP 274 DI 10.1016/j.bcp.2005.04.021 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 942QA UT WOS:000230295700010 PM 15913566 ER PT J AU Jeffries, N AF Jeffries, N TI Algorithms for alignment of mass spectrometry proteomic data SO BIOINFORMATICS LA English DT Article ID LASER DESORPTION/IONIZATION-TIME; PROSTATE-CANCER; SERUM; REPRODUCIBILITY; PATTERNS AB Motivation: The analysis of biological samples with high-throughput mass spectrometers has increased greatly in recent years. As larger datasets are processed, it is important that the spectra are aligned to ensure that the same protein intensities are correctly identified in each sample. Without such an alignment procedure it is possible to make errors in identifying the signals from peptides with similar molecular weight. Two algorithms are provided that can improve the alignment among samples. One algorithm is designed to work with SELDI data produced from a Ciphergen instrument, and the other can be used with data in a more general format. Results: The two algorithms were applied to samples drawn from a common pool of reference serum. The results indicate substantial improvement in consistently identifying peptide signals in different samples. C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Jeffries, N (reprint author), NINDS, NIH, Bethesda, MD 20892 USA. EM neal.jeffries@nih.gov NR 14 TC 52 Z9 54 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JUL 15 PY 2005 VL 21 IS 14 BP 3066 EP 3073 DI 10.1093/bioinformatics/bti482 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 941GX UT WOS:000230204400002 PM 15879456 ER PT J AU Xu, JS Mendrek, A Cohen, MS Monterosso, J Rodriguez, P Simon, SL Brody, A Jarvik, M Domier, CP Olmstead, R Ernst, M London, ED AF Xu, JS Mendrek, A Cohen, MS Monterosso, J Rodriguez, P Simon, SL Brody, A Jarvik, M Domier, CP Olmstead, R Ernst, M London, ED TI Brain activity in cigarette smokers performing a working memory task: Effect of smoking abstinence SO BIOLOGICAL PSYCHIATRY LA English DT Article DE functional magnetic resonance imaging; tobacco; nicotine; withdrawal; brain imaging; prefrontal cortex ID PREFRONTAL CORTEX DYSFUNCTION; N-BACK TASKS; WITHDRAWAL SYNDROME; FUNCTIONAL MRI; CANNABIS USE; MARIJUANA USE; NICOTINE; SCHIZOPHRENIA; FMRI; DOPAMINE AB Background: When nicotine-dependent human subjects abstain from cigarette smoking, they exhibit deficits in working memory. An understanding of the neural substrates of such impairments may help to understand how nicotine affects cognition. Our aim, therefore, was to identify abnormalities in the circuitry that mediates working memory in nicotine-dependent subjects after they initiate abstinence from smoking. Methods: We used blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to study eight smokers while they performed a letter version of the N-Back working memory task under satiety (<= 1.5 hours abstinence) and abstinence (>= 14 hours abstinence) conditions. Results: Task-related activity in the left dorsal lateral prefrontal cortex (DLPFC) showed a significant interaction between test session (Satiety, abstinence) and task load (1-back, 2-back, and 3-back). This interaction reflected the fact that task-related activity in the satiety condition was relatively low during performance of the 1-back task but greater at the more difficult task levels, whereas task-related activity in the abstinence condition was relatively high at the 1-back level and did not increase at the more difficult task levels. Conclusions: We conclude that neural processing related to working memory in the left DLPFC is less efficient during acute abstinence from smoking than at smoking satiety. C1 Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, David Geffen Sch Med, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Neurol Radiol Sci & Biomed Phys, David Geffen Sch Med, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Brain Res Inst, David Geffen Sch Med, Los Angeles, CA 90024 USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP London, ED (reprint author), 760 Westwood Plaza,C8-532, Los Angeles, CA 90024 USA. EM elondon@mednet.ucla.edu RI Cohen, Mark/C-6610-2011 OI Cohen, Mark/0000-0001-6731-4053 FU NCRR NIH HHS [M01 RR 00865, M01 RR000865, RR08655]; NIDA NIH HHS [R01 DA014093.03, DA13637, R01 DA014093, R01 DA015059, R01 DA015059-04, R01 DA020872, R01 DA020872-01, R21 DA 13627, R21 DA013627]; PHS HHS [R12169] NR 65 TC 69 Z9 72 U1 5 U2 14 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 JUL 15 PY 2005 VL 58 IS 2 BP 143 EP 150 DI 10.1016/j.biopsych.2005.03.028 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 946WZ UT WOS:000230605300008 PM 16038685 ER PT J AU Nabel, EG AF Nabel, EG TI A vision for the future: notes from the NHLBI director SO BLOOD LA English DT Editorial Material C1 NHLBI, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2005 VL 106 IS 2 BP 399 EP 400 DI 10.1182/blood-2005-05-2122 PG 2 WC Hematology SC Hematology GA 945AG UT WOS:000230472100012 PM 15994293 ER PT J AU Dejam, A Hunter, CJ Pelletier, MM Hsu, LL Machado, RF Shiva, S Power, GG Kelm, M Gladwin, MT Schechter, AN AF Dejam, A Hunter, CJ Pelletier, MM Hsu, LL Machado, RF Shiva, S Power, GG Kelm, M Gladwin, MT Schechter, AN TI Erythrocytes are the major intravascular storage sites of nitrite in human blood SO BLOOD LA English DT Article ID OXIDE SYNTHASE ACTIVITY; SICKLE-CELL-DISEASE; S-NITROSOHEMOGLOBIN; PLASMA NITRITE; HUMAN CIRCULATION; RED-CELL; NO; DEOXYHEMOGLOBIN; OXIDATION; NITRATE AB Plasma levels of nitrite ions have been used as an index of nitric oxide synthase (NOS) activity in vivo. Recent data suggest that nitrite is a potential intravascular repository for nitric oxide (NO), bioactivated by a nitrite reductase activity of deoxyhemoglobin. The precise levels and compartmentalization of nitrite within blood and erythrocytes have not been determined. Nitrite levels in whole blood and erythrocytes were determined using reductive chemiluminescence in conjunction with a ferricyanide-based hemoglbin oxidation assay to prevent nitrite destruction. This method yields sensitive and linear measurements of whole blood nitrite over 24 hours at room temperature. Nitrite levels measured in plasma, erythrocytes, and whole blood from 15 healthy volunteers were 121 plus or minus 9, 288 plus or minus 47, and 176 plus or minus 17 nM, indicating a surprisingly high concentration of nitrite within erythrocytes. The majority of nitrite in erythrocytes is located in the cytosol unbound to proteins. In humans, we found a significant artery-to-vein gradient of nitrite in whole blood and erythrocytes. Shear stress and acetylcholine-mediated stimulation of endothelial NOS significantly increased venous nitrite levels. These studies suggest a dynamic intravascular NO metabolism in which endothelial NOS-derived NO is stabilized as nitrite, transported by erythrocytes, and consumed during arterial-to-venous transit. C1 NIDDK, Biol Chem Lab, NIH, Mol Med Branch, Bethesda, MD 20892 USA. NHLBI, Vasc Therapeut Sect, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. Drexel Univ, St Christophers Hosp Children, Philadelphia, PA 19104 USA. Loma Linda Univ, Sch Med, Ctr Perinatal Biol, Loma Linda, CA USA. Univ Dusseldorf, Dept Med, Div Cardiol, D-4000 Dusseldorf, Germany. NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Schechter, AN (reprint author), NIDDK, Biol Chem Lab, NIH, Mol Med Branch, Bethesda, MD 20892 USA. EM aschecht@helix.nih.gov RI Hsu, Lewis/A-3360-2008; Hunter, Christian/G-4344-2010; OI Schechter, Alan N/0000-0002-5235-9408 NR 47 TC 199 Z9 204 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 15 PY 2005 VL 106 IS 2 BP 734 EP 739 DI 10.1182/blood-2005-02-0567 PG 6 WC Hematology SC Hematology GA 945AG UT WOS:000230472100059 PM 15774613 ER PT J AU Fang, H Tong, W Perkins, R Shi, L Hong, H Cao, X Xie, Q Yim, SH Ward, JM Pitot, HC Dragan, YP AF Fang, H Tong, W Perkins, R Shi, L Hong, H Cao, X Xie, Q Yim, SH Ward, JM Pitot, HC Dragan, YP TI Bioinformatics approaches for cross-species liver cancer analysis based on microarray gene expression profiling SO BMC BIOINFORMATICS LA English DT Article; Proceedings Paper CT 2nd Annual Conference of the MidSouth-Computational-Biology-and-Bioinformatics-Society CY OCT 07-09, 2004 CL Little Rock, AR SP MidSouth Computat Biol & Bioinformat Soc ID COMPARATIVE GENOMIC HYBRIDIZATION; HEPATOCELLULAR CARCINOMAS; TRANSGENIC MICE; DNA MICROARRAY; BREAST-CANCER; CELL-LINES; HEPATOCARCINOGENESIS; TUMORIGENESIS; MODELS; GROWTH AB Background: The completion of the sequencing of human, mouse and rat genomes and knowledge of cross-species gene homologies enables studies of differential gene expression in animal models. These types of studies have the potential to greatly enhance our understanding of diseases such as liver cancer in humans. Genes co-expressed across multiple species are most likely to have conserved functions. We have used various bioinformatics approaches to examine microarray expression profiles from liver neoplasms that arise in albumin-SV40 transgenic rats to elucidate genes, chromosome aberrations and pathways that might be associated with human liver cancer. Results: In this study, we first identified 2223 differentially expressed genes by comparing gene expression profiles for two control, two adenoma and two carcinoma samples using an F-test. These genes were subsequently mapped to the rat chromosomes using a novel visualization tool, the Chromosome Plot. Using the same plot, we further mapped the significant genes to orthologous chromosomal locations in human and mouse. Many genes expressed in rat 1q that are amplified in rat liver cancer map to the human chromosomes 10, 11 and 19 and to the mouse chromosomes 7, 17 and 19, which have been implicated in studies of human and mouse liver cancer. Using Comparative Genomics Microarray Analysis (CGMA), we identified regions of potential aberrations in human. Lastly, a pathway analysis was conducted to predict altered human pathways based on statistical analysis and extrapolation from the rat data. All of the identified pathways have been known to be important in the etiology of human liver cancer, including cell cycle control, cell growth and differentiation, apoptosis, transcriptional regulation, and protein metabolism. Conclusion: The study demonstrates that the hepatic gene expression profiles from the albumin-SV40 transgenic rat model revealed genes, pathways and chromosome alterations consistent with experimental and clinical research in human liver cancer. The bioinformatics tools presented in this paper are essential for cross species extrapolation and mapping of microarray data, its analysis and interpretation. C1 US FDA, Div Syst Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. Z Tech Corp, Div Bioinformat, Jefferson, AR 72079 USA. NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Vet & Tumor Pathol Sect, Ctr Canc Res, Ft Detrick, MD 21702 USA. Univ Wisconsin, McArdle Lab Canc Res, Madison, WI 53706 USA. RP Tong, W (reprint author), US FDA, Div Syst Toxicol, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA. EM hfang@nctr.fda.gov; wtong@nctr.fda.gov; rperkins@nctr.fda.gov; lshi@nctr.fda.gov; hhong@nctr.fda.gov; xcao@nctr.fda.gov; qxie@nctr.fda.gov; yims@mail.nih.gov; jeward@niaid.nih.gov; pitot@oncology.wisc.edu; ydragan@nctr.fda.gov NR 42 TC 19 Z9 22 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JUL 15 PY 2005 VL 6 SU 2 AR S6 DI 10.1186/1471-2105-6-S2-S6 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 022NC UT WOS:000236061500006 PM 16026603 ER PT J AU Xie, Q Ratnasinghe, LD Hong, HX Perkins, R Tang, ZZ Hu, N Taylor, PR Tong, WD AF Xie, Q Ratnasinghe, LD Hong, HX Perkins, R Tang, ZZ Hu, N Taylor, PR Tong, WD TI Decision forest analysis of 61 single nucleotide polymorphisms in a case-control study of esophageal cancer; a novel method SO BMC BIOINFORMATICS LA English DT Article; Proceedings Paper CT 2nd Annual Conference of the MidSouth-Computational-Biology-and-Bioinformatics-Society CY OCT 07-09, 2004 CL Little Rock, AK SP MidSouth Computational Biol Bioinformat Soc ID ESTROGEN-RECEPTOR BINDING; HAPLOTYPE FREQUENCIES; PREDICTION; MODELS; RISK; CASE/CONTROL; SELECTION; ALCOHOL; SMOKING; DISEASE AB Background: Systematic evaluation and study of single nucleotide polymorphisms ( SNPs) made possible by high throughput genotyping technologies and bioinformatics promises to provide breakthroughs in the understanding of complex diseases. Understanding how the millions of SNPs in the human genome are involved in conferring susceptibility or resistance to disease, or in rendering a drug efficacious or toxic in the individual is a major goal of the relatively new fields of pharmacogenomics. Esophageal squamous cell carcinoma is a high-mortality cancer with complex etiology and progression involving both genetic and environmental factors. We examined the association between esophageal cancer risk and patterns of 61 SNPs in a case-control study for a population from Shanxi Province in North Central China that has among the highest rates of esophageal squamous cell carcinoma in the world. Methods: High-throughput Masscode mass spectrometry genotyping was done on genomic DNA from 574 individuals ( 394 cases and 180 age-frequency matched controls). SNPs were chosen from among genes involving DNA repair enzymes, and Phase I and Phase II enzymes. We developed a novel adaptation of the Decision Forest pattern recognition method named Decision Forest for SNPs (DF-SNPs). The method was designated to analyze the SNP data. Results: The classifier in separating the cases from the controls developed with DF-SNPs gave concordance, sensitivity and specificity, of 94.7%, 99.0% and 85.1%, respectively; suggesting its usefulness for hypothesizing what SNPs or combinations of SNPs could be involved in susceptibility to esophageal cancer. Importantly, the DF-SNPs algorithm incorporated a randomization test for assessing the relevance ( or importance) of individual SNPs, SNP types ( Homozygous common, heterozygous and homozygous variant) and patterns of SNP types ( SNP patterns) that differentiate cases from controls. For example, we found that the different genotypes of SNP GADD45B E1122 are all associated with cancer risk. Conclusion: The DF-SNPs method can be used to differentiate esophageal squamous cell carcinoma cases from controls based on individual SNPs, SNP types and SNP patterns. The method could be useful to identify potential biomarkers from the SNP data and complement existing methods for genotype analyses. C1 US FDA, Div Bioinformat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. US FDA, Ctr Toxicoinformat, Div syst Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. NCI, Genet Epidemiol Branch, DCEG, Rockville, MD 20852 USA. Shanxi Canc Hosp, Taiyuan 030013, Shanxi, Peoples R China. US FDA, Ctr Struct Genom, DPME, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Xie, Q (reprint author), US FDA, Div Bioinformat, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. EM QXie@nctr.fda.gov; LRatnasinghe@nctr.fda.gov; HHong@nctr.fda.gov; RPerkins@nctr.fda.gov; Zlyyjsi@public.ty.sx.cn; Hun@mail.nih.gov; PTaylor@dcpcepn.nci.nih.gov; WTong@nctr.fda.gov NR 19 TC 29 Z9 30 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD JUL 15 PY 2005 VL 6 SU 2 AR S4 DI 10.1186/1471-2105-6-S2-S4 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 022NC UT WOS:000236061500004 PM 16026601 ER EF