FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Li, Z Korzh, S Mudumana, SP Wan, H Korzh, V Gong, Z AF Li, Z. Korzh, S. Mudumana, S. P. Wan, H. Korzh, V Gong, Z. TI Generation of exocrine pancreas-specific GFP transgenic zebrafish and analyses of pancreas development SO MECHANISMS OF DEVELOPMENT LA English DT Meeting Abstract C1 [Li, Z.; Korzh, S.; Mudumana, S. P.; Wan, H.; Gong, Z.] Natl Univ Singapore, Dept Biol Sci, Singapore 117548, Singapore. [Mudumana, S. P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Charlestown, MA USA. [Wan, H.] NICHHD, NIH, Bethesda, MD 20892 USA. [Korzh, V] Natl Univ Singapore, Inst Mol & Cell Biol, Singapore 117548, Singapore. RI Gong, Zhiyuan/H-8794-2012 OI Gong, Zhiyuan/0000-0002-9660-5260 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD SEP PY 2005 VL 122 SU 1 BP S64 EP S65 PG 2 WC Developmental Biology SC Developmental Biology GA V11IA UT WOS:000207524100238 ER PT J AU Miura, S Davis, S Klingensmith, J Mishina, Y AF Miura, S. Davis, S. Klingensmith, J. Mishina, Y. TI BMP signaling through BMPRIA functions in the extraembryonic tissues to initiate gastrulation and in the epiblast to regulate mesoderm development in the mice SO MECHANISMS OF DEVELOPMENT LA English DT Meeting Abstract C1 [Miura, S.; Mishina, Y.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Davis, S.; Klingensmith, J.] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD SEP PY 2005 VL 122 SU 1 BP S18 EP S18 PG 1 WC Developmental Biology SC Developmental Biology GA V11IA UT WOS:000207524100064 ER PT J AU Nitta, KR Tanegashima, K Takahashi, S Asashima, M AF Nitta, K. R. Tanegashima, K. Takahashi, S. Asashima, M. TI XSIP1 is essential for early neural gene expression and neural differentiation by suppression of BMP signaling SO MECHANISMS OF DEVELOPMENT LA English DT Meeting Abstract C1 [Nitta, K. R.; Tanegashima, K.; Takahashi, S.; Asashima, M.] Univ Tokyo, Meguro Ku, Tokyo, Japan. [Tanegashima, K.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD SEP PY 2005 VL 122 SU 1 BP S35 EP S36 PG 2 WC Developmental Biology SC Developmental Biology GA V11IA UT WOS:000207524100124 ER PT J AU Rebustini, I Hoffman, MP AF Rebustini, I Hoffman, M. P. TI Fibroblast growth factor signaling regulates the expression and activity of laminin-alpha 5 and MMPs during branching morphogenesis of mouse submandibular glands SO MECHANISMS OF DEVELOPMENT LA English DT Meeting Abstract C1 [Rebustini, I; Hoffman, M. P.] NIDCR, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD SEP PY 2005 VL 122 SU 1 BP S85 EP S85 PG 1 WC Developmental Biology SC Developmental Biology GA V11IA UT WOS:000207524100315 ER PT J AU Sato, T Kida, Y Nakaya, MA Yamaguchi, TP Ogura, T AF Sato, T. Kida, Y. Nakaya, M. A. Yamaguchi, T. P. Ogura, T. TI Novel Dvl2 interacting protein Crip2 regulates notochord cell intercalation of zebrafish embryo SO MECHANISMS OF DEVELOPMENT LA English DT Meeting Abstract C1 [Sato, T.; Kida, Y.; Ogura, T.] Tohoku Univ, Inst Dev Aging & Canc, Sendai, Miyagi 980, Japan. [Nakaya, M. A.; Yamaguchi, T. P.] NCI Frederick, Canc & Dev Biol Lab, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD SEP PY 2005 VL 122 SU 1 BP S82 EP S82 PG 1 WC Developmental Biology SC Developmental Biology GA V11IA UT WOS:000207524100304 ER PT J AU Arora, NK Ayanian, JZ Guadagnoli, E AF Arora, NK Ayanian, JZ Guadagnoli, E TI Examining the relationship of patients' attitudes and beliefs with their self-reported level of participation in medical decision-making SO MEDICAL CARE LA English DT Article; Proceedings Paper CT Annual Research and Teaching Forum of the American-Academy-on-Physician-and-Patient CY OCT, 2003 CL Baltimore, MD SP Amer Acad Phys & Patient DE patient participation; medical decision-making; behavior change; scale development ID 12 PROBLEM BEHAVIORS; CANCER-PATIENTS; BREAST-CANCER; PHYSICIAN SCALE; PREFERENCES; EFFICACY; TRUST; INFORMATION; CARE; INVOLVEMENT AB Objective: We applied constructs from the transtheoretical model (TTM) of behavior change to identify modifiable determinants of patient participation in medical decision-making. Method: We surveyed a convenience sample of 621 primary care patients at one Boston hospital (response rate 60.6%). With a random half of the sample, we examined the factor structure of a new Patient Attitudes and Beliefs Scale (PABS) that focused on issues about participation in medical decision-making, and with the other half we confirmed the factor structure and examined the association of patients' stage of readiness to participate in decisionmaking with subscales of the PABS (pros, cons, and decisional balance), self-efficacy, and trust in physician. Results: Patients were classified into 4 stages: precontemplation (don't participate and don't intend to, 17.2%), contemplation (don't participate but contemplating participating, 6.9%), preparation (participate to some degree, 36.1%), and action (participate fully, 39.8%). Factor analysis of the PABS items indicated 2 factors representing pros and cons of participation. Scores on the pros increased and cons decreased significantly from precontemplation to action (P < 0.001). Significant nonlinear associations of stage of readiness with self-efficacy (P < 0.01) and trust in physician (P < 0.01) were evident; self-efficacy scores were highest for those in action whereas trust scores were highest for those in precontemplation. Conclusions: To move people from precontemplation towards action in participating in medical decision-making, interventions focusing on increasing the pros and decreasing the cons of participation may be needed. The challenge is to balance advocacy for an active patient role with individual patients' preference for participation. C1 NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Div Gen Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Arora, NK (reprint author), NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, 6130 Executive Blvd,MSC 7344, Bethesda, MD 20892 USA. EM aroran@mail.nih.gov NR 41 TC 34 Z9 37 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD SEP PY 2005 VL 43 IS 9 BP 865 EP 872 DI 10.1097/01.mlr.0000173560.18607.67 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 959BU UT WOS:000231492700004 PM 16116351 ER PT J AU Klabunde, CN Vernon, SW Nadel, MR Breen, N Seeff, LC Brown, ML AF Klabunde, CN Vernon, SW Nadel, MR Breen, N Seeff, LC Brown, ML TI Barriers to colorectal cancer screening: A comparison of reports from primary care physicians and average-risk adults SO MEDICAL CARE LA English DT Article DE colorectal cancer; screening; barriers; primary care; health behavior ID HEALTH INTERVIEW SURVEY; SIGMOIDOSCOPY; RECOMMENDATIONS; PARTICIPATION; GUIDELINES; RATIONALE; PROGRAMS; SERVICES; PATIENT; UPDATE AB Background: Barriers to colorectal cancer (CRC) screening are not well understood. Objectives: We sought to compare barriers to CRC screening reported by primary care physicians (PCPs) and by average-risk adults, and to examine characteristics of average-risk adults who identified lack of provider recommendation as a major barrier to CRC screening. Research Design: This was a comparative study using data from the 1999-2000 Survey of Colorectal Cancer Screening Practices and the 2000 National Health Interview Survey (NHIS). Subjects: We recruited nationally representative samples of PCPs (n = 1235) from the SCCSP and average-risk adults (n = 6497) from the NHIS. Measures: We measured barriers to CRC screening identified by PCPs and average-risk adults who were not current with screening. Results: Both PCPs and average-risk adults identified lack of patient awareness and physician recommendation as key barriers to obtaining CRC screening. PCPs also frequently cited patient embarrassment/ anxiety about testing and test cost/lack of insurance coverage, but few adults identified these as major barriers. Of adults not current with testing, those who had visited a doctor in the past year or had health insurance were more likely to report lack of physician recommendation as the main reason they were not up-to-date compared with their counterparts with no doctor visit or health insurance. Only 10% of adults not current with testing and who had a doctor visit in the past year reported receiving a screening recommendation. Conclusions: A need exists for continued efforts to educate the public about CRC and the important role of screening in preventing this disease. Practice-based strategies to systematically prompt health care providers to discuss CRC screening with eligible patients also are required. C1 NCI, Appl Res Program, Hlth Serv & Econ Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. Univ Texas, Ctr Hlth Promot & Prevent Res, Houston, TX USA. Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA USA. RP Klabunde, CN (reprint author), NCI, Appl Res Program, Hlth Serv & Econ Branch, Div Canc Control & Populat Sci, Execut Plaza N Room 4005,6130 Execut Blvd, Bethesda, MD 20892 USA. EM ck97b@nih.gov FU NCI NIH HHS [R01 CA76330, R21 CA89475, R01 CA97263] NR 31 TC 181 Z9 184 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD SEP PY 2005 VL 43 IS 9 BP 939 EP 944 DI 10.1097/01.mlr.0000173599.67470.ba PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 959BU UT WOS:000231492700013 PM 16116360 ER PT J AU Pelletier, R Alarie, I Lagace, R Walsh, TJ AF Pelletier, R Alarie, I Lagace, R Walsh, TJ TI Emergence of disseminated candidiasis caused by Candida krusei during treatment with caspofungin: Case report and review of literature SO MEDICAL MYCOLOGY LA English DT Review DE Caspofungin; Candida krusei; resistance; disseminated candidiasis ID INVASIVE CANDIDIASIS; ANTIFUNGAL AGENT; ALBICANS; SUSCEPTIBILITY; RESISTANCE; FLUCONAZOLE; INFECTION; MK-0991 AB Current data indicate that caspofungin has in vitro activity against virtually all Candida species. However, we report herein a case of disseminated candidiasis due to Candida krusei which emerged during caspofungin treatment. Lung and brain secondary sites were then successfully treated using a combination of amphotericin B plus flucytosine, amphotericin B lipid complex, and voriconazole, sequentially. Among the total of four well documented cases of refractory invasive candidiasis during caspofungin therapy, the common risk factors appear to involve prior abdominal surgery, persistent foreign body, and anatomical sites where drug concentrations may be sub-optimal for Candida species with increased MICs. Caspofungin failure should be suspected in patients with persistent or emergent signs and symptoms of deep-seated invasive candidiasis. C1 CHU Quebec, Hotel Dieu, Serv Microbiol & Infectiol, Quebec City, PQ G1R 2J6, Canada. NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. CHU Quebec, Hotel Dieu, Serv Pathol, Quebec City, PQ G1R 2J6, Canada. CHU Sherbrooke, Hop Fleurimont, Serv Microbiol & Infectiol, Sherbrooke, PQ J1H 5N4, Canada. RP Pelletier, R (reprint author), CHU Quebec, Hotel Dieu, Serv Microbiol & Infectiol, 11 Cote Palais, Quebec City, PQ G1R 2J6, Canada. EM rene.pelletier@chuq.qc.ca NR 21 TC 31 Z9 33 U1 0 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1369-3786 J9 MED MYCOL JI Med. Mycol. PD SEP PY 2005 VL 43 IS 6 BP 559 EP 564 DI 10.1080/13693780500220415 PG 6 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 984QV UT WOS:000233320300011 PM 16320498 ER PT J AU Gupta, S Ries, M Kotsopoulos, S Schiffmann, R AF Gupta, S Ries, M Kotsopoulos, S Schiffmann, R TI The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease a cross-sectional study of a large cohort of clinically affected heterozygous women SO MEDICINE LA English DT Article ID ENZYME REPLACEMENT THERAPY; ALPHA-GALACTOSIDASE; LIQUID-CHROMATOGRAPHY; PHENOTYPE; IDENTIFICATION; MUTATION; VARIANT; EFFICACY; PLASMA; GENE AB Fabry disease is a rare X-linked lysosomal storage disorder caused by deficient activity of alpha-galactosidase A (alpha-Gal A) resulting in the storage of glycosphingolipids, especially globotriaosylceramide (GbA in cells throughout the body, causing life-threatening renal, cardiac, and cerebrovascular complications in hemizygous males and some heterozygous females. Disease manifestations in heterozygotes are being recognized increasingly, but quantitative prospective data on their extent and severity are limited. Prospective clinical and laboratory assessments were performed in a 7-day study of 61 women with signs and symptoms of Fabry disease. Analyses included medical history and physical, neurologic, cardiac, and ophthalmologic assessments; laboratory assessments; renal function tests; magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the head; and Fabry-related blood and urine tests, including Gb(3) levels in blood and urine, skin biopsies, and DNA genotype analysis of the alpha-Gal A gene to identify causative mutations. Quality of life, pain and concomitant medication were documented using validated questionnaires and diaries. All patients had normal Gb3 levels in plasma; only 1 patient had visible storage material in the superficial dermal vascular endothelial cells. Cardiac, renal, or cerebrovascular abnormalities were documented in 52 of the 57 patients (91%) with confirmed Fabry genotypes. These included electrocardiographic abnormalities in 38 of 52 patients (73%), echocardiographic abnormalities in 8 of 57 (14%), proteinuria (> 150 g protein/24-h urine) in 23 of 3 8 (61%), low estimated glomerular filtration rate (< 90 mL/min per 1.73 m(2)) in 24 of 57 (42%), abnormal MRI in 4 of 54 (7%), and abnormal MRA in 10 of 50 patients (20%). Angiokeratomas and corneal epitheliopathy were documented in 63% and 82% of the 57 patients, respectively. Despite the virtual absence of storage material in plasma and skin vascular endothelial cells, this population of women with Fabry disease exhibited a wide spectrum of clinical abnormalities. Useful outcome measures for assessment of specific therapies need to be developed. Studies limited to homogeneously affected subjects may be possible. C1 Natl Inst Neurol Disorders & Dis, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Genzyme Corp, Cambridge, MA USA. RP Schiffmann, R (reprint author), Natl Inst Neurol Disorders & Dis, Dev & Metab Neurol Branch, NIH, Bldg 10,Room 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. EM RS4e@nih.gov OI Ries, Markus/0000-0002-5054-5741 FU Intramural NIH HHS; NINDS NIH HHS [NS002984-05] NR 30 TC 75 Z9 75 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0025-7974 J9 MEDICINE JI Medicine (Baltimore) PD SEP PY 2005 VL 84 IS 5 BP 261 EP 268 DI 10.1097/01.md.0000178976.62537.6b PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 966CE UT WOS:000231996400001 PM 16148726 ER PT J AU Wampler, NS Chen, Z Jacobsen, C Henderson, JA Howard, BV Rossouw, JE AF Wampler, NS Chen, Z Jacobsen, C Henderson, JA Howard, BV Rossouw, JE TI Bone mineral density of American Indian and Alaska Native women compared with non-Hispanic white women: results from the Women's Health Initiative Study SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE bone densitometry; postmenopausal women; American Indian; Alaska Native; racial differences ID POSTMENOPAUSAL WOMEN; OSTEOPOROTIC FRACTURES; RELIABILITY; METABOLISM; AFRICAN; TRIAL; MASS AB Objective: To compare bone mineral density (BMD) of American Indian/Alaska Native (AVAN) women with that of non-Hispanic white women. Design: This cross-sectional study compared mean BMD between AI/AN women and a random sample of non-Hispanic white women matched on geographic region in the Women's Health Initiative Study, a prospective study of postmenopausal women. We analyzed baseline BMD measurements for the total hip, spine, and whole body from 139 AI/AN women and 1,431 non-Hispanic white women. Results: Unadjusted mean spine and whole body BMDs were not significantly different between the two races. Controlling for age, education, and hormone therapy use, adjusted mean BMD was similar by race among women who were underweight, normal, or obese. We found a significant interaction of race by body mass index on spine (P = 0.003) and whole body (P = 0.0003) BMD; thus, analyses were stratified by body mass index. Overweight AVAN women had slightly lower adjusted mean whole body and spine BMD than overweight non-Hispanic white women (whole body: 0.97 vs 1.03 g/cm(2), p = 0.02; spine: 0.96 versus 1.03 g/cm(2), p = 0.001). Among extremely obese (body mass index: >= 40.0 kg/m(2)) women, adjusted mean total hip BMD was higher in the AI/AN women (1.07 vs 0.97 g/cm(2), respectively, P = 0.03). Conclusions: Overall, AI/AN and non-Hispanic white women had similar BMDs. This study suggests that extremely obese AI/AN women may have higher BMD at certain skeletal sites compared with extremely obese non-Hispanic white women. However, these results need to be confirmed by additional research. C1 Noqsi Res, Pine, CO USA. Univ Arizona, Div Epidemiol & Biostat, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA. Univ Washington, Sch Med, Seattle, WA 98195 USA. Black Hills Ctr Amer Indian Hlth, Rapid City, SD USA. MedStar Res Inst, Washington, DC USA. NHLBI, Womens Hlth Initiat, Bethesda, MD 20892 USA. RP Wampler, NS (reprint author), 2822 S Nova Rd, Pine, CO 80470 USA. EM nina.wampler@wispertel.net FU AHRQ HHS [P01 HS10854]; NIA NIH HHS [P30AG/15297] NR 20 TC 5 Z9 5 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 1072-3714 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD SEP-OCT PY 2005 VL 12 IS 5 BP 536 EP 544 DI 10.1097/01.gme.0000182161.88939.f0 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 009LU UT WOS:000235114300009 PM 16145307 ER PT J AU Phue, JN Shiloach, J AF Phue, JN Shiloach, J TI Impact of dissolved oxygen concentration on acetate accumulation and physiology of E coli BL21, evaluating transcription levels of key genes at different dissolved oxygen conditions SO METABOLIC ENGINEERING LA English DT Article DE Escherichia coli B; acetate; oxygen; glucose ID FOREIGN PROTEIN-PRODUCTION; DENSITY FERMENTATION; ENTERIC BACTERIA; ACETYL-COENZYME; METABOLISM; OXIDASE; RESPONSES; GROWTH; SYNTHETASE; OVERFLOW AB High density growth of Escherichia coli especially in large bioreactors may temporarily expose the cells to oxygen limitation as a result of a local inadequate oxygen supply or intermittently high concentrations of cells and nutrients. Although short, these periods can potentially alter bacterial metabolism, affecting both growth and recombinant proteins production capability, and thus lowering process productivity. When E coli B (BL21), a lower acetate producing strain, was grown aerobically on high glucose, acetate accumulation was found to be inversely correlated to the dissolved oxygen (DO) levels, reaching 10 g/L at 1%, 4g/L at 6%, and zero at 30% DO concentration at stationary growth phase. Time-course transcription analysis of several genes involved in glucose and acetate metabolism indicated that the enhanced acetate production at lower DO levels is the result of altered transcription of several key genes. These genes are: the acetate producing gene (poxB), the glyoxylate shunt gene (aceA) the acetate uptake gene (acs), the gluconeogensis and anaplerotic pathways genes, (pckA, ppsA, ppc, and sfcA), the TCA cycle gene (gltA), arld the sigma factors 70 and S (rpoD and rpoS). It is suggested that the catabolic repressor/activator Cra is responsible for the bacterial response to different oxygen levels. Oxygen limitation seems to repress the constitutive expression of the glyoxylate shunt and gluconeognesis. In this work, the concept of transition state is proposed to describe the bacterial response to the lower DO concentration. Published by Elsevier Inc. C1 NIDDK, Biotechnol Unit, Bethesda, MD 20892 USA. RP Shiloach, J (reprint author), NIDDK, Biotechnol Unit, Bldg 14A Room 173, Bethesda, MD 20892 USA. EM yossi@nih.gov NR 32 TC 30 Z9 35 U1 1 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7176 J9 METAB ENG JI Metab. Eng. PD SEP-NOV PY 2005 VL 7 IS 5-6 BP 353 EP 363 DI 10.1016/j.ymben.2005.06.003 PG 11 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 998TK UT WOS:000234342300003 PM 16099189 ER PT J AU Huang, X Blackman, MR Herreman, K Pabst, KM Harman, SM Caballero, B AF Huang, X Blackman, MR Herreman, K Pabst, KM Harman, SM Caballero, B TI Effects of growth hormone and/or sex steroid administration on whole-body protein turnover in healthy aged women and men SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID RANDOMIZED CONTROLLED TRIAL; FACTOR-I; POSTMENOPAUSAL WOMEN; ESTROGEN REPLACEMENT; THERAPY; MASS; METABOLISM; SECRETION; GH; ANABOLISM AB Aging is associated with reduced activities of the growth hormone (GH), insulin-like growth factor I (IGF-I), and sex steroid axes, and with decreased lean body mass and protein synthesis. Using a randomized, double-blinded, placebo-controlled design, we studied the effects of 6 months of administration of GH alone, sex hormone alone (hormone replacement therapy in women, testosterone enanthate [T] in men), or GH plus sex hormone on protein turnover in healthy men (n = 60) and women (n = 43), aged 65 to 88 years (mean, 71 +/- 4.4 years). Growth hormone administration significantly increased IGF-I levels in both sexes, more markedly in men. Sex steroid administration increased the levels of estrogen and testosterone in women and men, respectively (P = .05). Protein turnover was measured before and after the 26-week treatment period by means of a primed, constant L-[1-C-13]leucine infusion. In men, GH plus T administration increased leucine flux from 80.2 +/- 2.8 to 93.6 +/- 4.2 mu mol (.) h(-1) (.) kg(-1) (P = .02). Leucine oxidation did not change significantly after hormone treatment in either sex. Growth hormone treatment led to nonsignificant upward trends in nonoxidative leucine disposal in men (9.1 +/- 5.2 mol (.) h(-1) (.) kg(-1)) and women (7.6 +/- 7.1 mol (.) h(-1) (.) kg(-1)). Among all groups combined, changes in nonoxidative leucine disposal were directly related to those of serum IGF-I level (r = 0.248, P < .02). Whole-body protein turnover increased in GH plus T-treated men (0.6 +/- 0.2 g protein (.) kg(-1) (.) d(-1); P < .01). These data suggest that low-dose GH administration increases protein synthesis in healthy aged women and men, and that the coadministration of testosterone plus GH enhances this effect in elderly men. (c) 2005 Elsevier Inc. All rights reserved. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Human Nutr, Baltimore, MD 21205 USA. Johns Hopkins Bayview Med Ctr, Div Endocrinol & Metab, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. NIA, Endocrine Sect, Lab Clin Invest, Intramural Res Program,Nih, Baltimore, MD 21224 USA. RP Caballero, B (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Ctr Human Nutr, Baltimore, MD 21205 USA. EM bcaballe@jhsph.edu FU NCRR NIH HHS [M01-RR-02719]; NIA NIH HHS [R01-AG11005] NR 41 TC 12 Z9 13 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 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD SEP PY 2005 VL 54 IS 9 BP 1162 EP 1167 DI 10.1016/j.metabol.2005.03.023 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 965AY UT WOS:000231923300006 PM 16125527 ER PT J AU Jacobson, L Pacak, K AF Jacobson, L Pacak, K TI Combined corticotropin-releasing hormone and glucocorticoid deficiency does not enhance counterregulatory responses after recurrent hypoglycemia in mice SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID ANTECEDENT HYPOGLYCEMIA; SUBSEQUENT HYPOGLYCEMIA; AUTONOMIC FAILURE; FOOD-INTAKE; CORTISOL; RATS; NOREPINEPHRINE; CORTICOSTERONE; NEUROENDOCRINE; INSUFFICIENCY AB Glucocorticoids and corticotropin-releasing hormone (CRH) have been proposed to inhibit counterregulatory responses to recurrent hypoglycemia. We used the CRH knockout (CR-H KO) mouse to test the hypothesis that combined CRH and glucocorticoid deficiency would prevent development of counterregulatory deficits after repeated hypoglycemia. To develop a mouse model of recurrent hypoglycemia, we first tested the effects of daily lente insulin injection on counterregulatory responses to acute hypoglycemia in male C57BL/6 mice. Treatment with up to 250 U/kg per day lente insulin resulted in significantly greater decreases in plasma glucose, suggestive of impaired counterregulation, after hypoglycemia, induced by acute insulin injection. Plasma catecholamine responses to hypoglycemia in repeatedly hypoglycemic C57BL/6 mice were unexpectedly higher than in naive mice, which we interpreted as a compensatory response to the greater decreases in plasma glucose. Lente insulin doses had to be reduced (50-75 U/kg per day) for CRH KO mice to survive repeated hypoglycemia. Wild-type (WT) mice treated with 50 to 75 U/kg per day lente insulin exhibited enhanced sympathetic activity after hypoglycemia, resembling the compensatory responses associated with impaired glucose homeostasis in C57BL/6 mice treated with 250 U/kg per day lente insulin. During acute hypoglycemia, CRH KO mice maintained higher plasma glucose levels that correlated with higher plasma norepinephrine and greater glycogen mobilization. Recurrent hypoglycemia did not enhance liver glycogen depletion or the markedly impaired glucocorticoid and epinephrine responses to hypoglycemia in CRH KO mice. Previously hypoglycemic CRH KO mice also did not display the further increases in sympathetic activity that in WT mice were suggestive of compensation for impaired counterregulation. Despite the apparent resistance of CRH KO mice to the counterregulatory effects of repeated hypoglycemia, their greater mortality after hypoglycemia tolerated by WT mice indicates that combined CRH and glucocorticoid deficiency does not significantly improve counterregulation after repeated hypoglycemia. (c) 2005 Elsevier Inc. All rights reserved. C1 Albany Med Coll, Ctr Neuropharmacol & Neurosci, Albany, NY 12208 USA. NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Jacobson, L (reprint author), Albany Med Coll, Ctr Neuropharmacol & Neurosci, Albany, NY 12208 USA. EM jacobsl@mail.amc.edu FU NIDDK NIH HHS [R21 DK062442, DK 62442] NR 29 TC 6 Z9 6 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 SEP PY 2005 VL 54 IS 9 BP 1259 EP 1265 DI 10.1016/j.metabol.2005.04.013 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 965AY UT WOS:000231923300018 PM 16125539 ER PT J AU Rasooly, A AF Rasooly, A TI Biosensor technologies SO METHODS LA English DT Editorial Material C1 Natl Canc Inst, US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Biol Sci,Canc Diagnost Pr, Rockville, MD 20852 USA. RP Rasooly, A (reprint author), Natl Canc Inst, US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs,Div Biol Sci,Canc Diagnost Pr, 6130 Execut Blvd, Rockville, MD 20852 USA. EM rasoolya@mail.nih.gov NR 3 TC 7 Z9 7 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD SEP PY 2005 VL 37 IS 1 BP 1 EP 3 DI 10.1016/j.ymeth.2005.05.004 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 979MG UT WOS:000232945500001 PM 16199171 ER PT J AU Lapp, KG Bosworth, HB Strauss, JL Stechuchak, KM Horner, RD Calhoun, PS Meador, KG Lipper, S Butterfield, MI AF Lapp, KG Bosworth, HB Strauss, JL Stechuchak, KM Horner, RD Calhoun, PS Meador, KG Lipper, S Butterfield, MI TI Lifetime sexual and physical victimization among male veterans with combat-related post-traumatic stress disorder SO MILITARY MEDICINE LA English DT Article; Proceedings Paper CT 155th Annual Meeting of the American-Psychiatric-Association CY MAY 18-23, 2002 CL PHILADELPHIA, PA SP Amer Psychiat Assoc ID SEVERE MENTAL-ILLNESS; PSYCHIATRIC-INPATIENTS; VIETNAM VETERANS; VIOLENT BEHAVIOR; ABUSE; TRAUMA; PREVALENCE; WOMEN; SURVIVORS; HEALTH AB Because of the high prevalence of post-traumatic stress disorder (PTSD) among veteran men and the limited research on victimization in this group, we recruited 133 male veterans with combat-related PTSD from a psychiatric inpatient unit and assessed them for lifetime physical and sexual trauma. Results indicated that 96% of the sample had experienced some form of victimization over their lifetimes; 60% reported childhood physical abuse, 41% childhood sexual abuse, 93% adulthood physical assault, and 20% adulthood sexual assault. In the preceding year alone, 46% experienced either physical or sexual assault. These findings support the need for routine inquiry into the histories of noncombat victimization in this cohort. Determining the lifetime history of trauma exposure may have implications for vulnerability to subsequent development of PTSD and the risk of future violence. C1 Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Vet Affairs Med Ctr, Hlth Serv Res & Dev, Durham, NC 27705 USA. NINDS, Off Minor Hlth & Res, Bethesda, MD 20892 USA. RP Lapp, KG (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. NR 28 TC 18 Z9 19 U1 6 U2 11 PU ASSN MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 J9 MIL MED JI Milit. Med. PD SEP PY 2005 VL 170 IS 9 BP 787 EP 790 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 019JQ UT WOS:000235831800013 PM 16261985 ER PT J AU Hodges, M Yikilmaz, E Patterson, G Kasvosve, I Rouault, TA Gordeuk, VR Loyevsky, M AF Hodges, M Yikilmaz, E Patterson, G Kasvosve, I Rouault, TA Gordeuk, VR Loyevsky, M TI An iron regulatory-like protein expressed in Plasmodium falciparum displays aconitase activity SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE aconitase; Plasmodium falciparum; TCA cycle; iron ID RNA-BINDING PROTEIN; DEPENDENT ISOCITRATE DEHYDROGENASE; SUCCINATE-DEHYDROGENASE; OXIDATIVE-PHOSPHORYLATION; MALATE-DEHYDROGENASE; MALARIA PARASITES; ESCHERICHIA-COLI; MITOCHONDRIA; MUTATIONS; GENE AB Plasmodium falciparum iron regulatory-like protein (PfIRPa) has homology to both mammalian iron regulatory proteins and aconitases and is capable of binding RNA iron response elements. We examined the subcellular localization of PfIRPa and its enzymatic properties at low oxygen tension. Differential digitonin permeabilization of isolated trophozoites with subsequent Western blot analysis suggests that the localization of PfIRPa is predominantly in the membranous compartments of the parasite, such as the mitochondrion. Immunofluorescence analysis showed that PfIRPa colocalizes with heat shock protein 60 (Hsp60), a mitochondrial marker, and is also present in the parasitic cytosol/food vacuole. Under conditions favoring the formation of an iron-sulfur cluster, recombinant PfIRPa (rPfIRPa) had aconitase activity as detected by a colorimetric NADPH-MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay. As assessed by the hydration of cis-aconitate spectrophotometrically at 240 nm, rPfIRPa had high affinity for cis-aconitate (K-m =3.5 mu M) but a low turnover number (K-cat = 3.3 s(-1)). The overall catalytic efficiency (K-cat/K-m) of rPfIRPa was similar in magnitude to human cytosolic IRP1/aconitase and human mitochondrial aconitase. PfIRPa immunoprecipitated from parasite lysates also had aconitase activity, as assessed by an MTT-based assay. Our results provide evidence that PfIRPa localizes in the mitochondrion and in the cytosol/food vacuole and is able to demonstrate aconitase activity. Further understanding of the role of PfIRPa/aconitase in the regulation of P. falciparum homeostasis may contribute towards the development of novel antimalarial strategies against plasmodial species. (c) 2005 Elsevier B.V. All rights reserved. C1 Sanaria Inc, Rockville, MD 20852 USA. Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Loyevsky, M (reprint author), Sanaria Inc, 12115 Parklawn Dr,Suite L, Rockville, MD 20852 USA. EM mloyevsky@sanaria.com FU NCRR NIH HHS [M01-RR10284-06]; NHLBI NIH HHS [UHL-HL03679-07]; PHS HHS [R01-A144857-05] NR 44 TC 21 Z9 21 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 SEP PY 2005 VL 143 IS 1 BP 29 EP 38 DI 10.1016/j.molbiopara.2005.05.004 PG 10 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 956YK UT WOS:000231335800005 PM 15963579 ER PT J AU Eksi, S Haile, Y Furuya, T Ma, L Su, XZ Williamson, KC AF Eksi, S Haile, Y Furuya, T Ma, L Su, XZ Williamson, KC TI Identification of a subtelomeric gene family expressed during the asexual-sexual stage transition in Plasmodium falciparum SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE malaria; Plasmodium falciparum; gametocytogenesis; transmission-blocking; sexual differentiation; subtelomeric gene family ID GREEN FLUORESCENT PROTEIN; BLOCKING TARGET ANTIGEN; TRANSMISSION STAGES; MALARIA PARASITE; LIFE-CYCLE; GAMETOCYTOGENESIS; PFS230; PFS16; DIFFERENTIATION; SEQUESTRATION AB For malaria transmission, the parasite must undergo sexual differentiation into mature gametocytes. However, the molecular basis for this critical transition in the parasites life cycle is unknown. Six previously uncharacterized genes, Pfg14.744, Pfg14.745, Pfg14.748, Pfg14.763, Pfg14.752 and Pfg6.6 that are members of a 36 gene Plasmodium falciparum-specific subtelomeric superfamily were found to be expressed in parasites that are committed to sexual development as suggested by co-expression of Pfs16 and Pfg27. Northern blots demonstrated that Pfg14.744 and Pfg14.748 were first expressed before the parasites differentiated into morphologically distinct gametocytes, transcription continued to increase until stage II gametocytes were formed and then rapidly decreased. Immunofluorescence assays indicated that both proteins were only produced in the subpopulation of ring stage parasites that are committed to gametocytogenesis and both localized to the parasitophorous vacuole (PV)(b) of the early ring stage parasites. As the parasites continued to develop Pfg14.748 remained within the parasitophorous vacuole, while Pfg14.744 was detected in the erythrocyte. The 5' flanking region of either gene alone was sufficient to drive early gametocyte specific expression of green fluorescent protein (GFP). In parasites transfected with a plasmid containing the Pfg14.748 5' flanking region immediately upstream of GFP, fluorescence was observed in a small number of schizonts the cycle before stage I gametocytes were observed. This expression pattern is consistent with commitment to sexual differentiation prior to merozoite release and erythrocyte invasion. Further investigation into the role of these genes in the transition from asexual to sexual differentiation could provide new strategies to block malaria transmission. (c) 2005 Elsevier B.V. All rights reserved. C1 Loyola Univ, Dept Biol, Chicago, IL 60626 USA. NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Williamson, KC (reprint author), Loyola Univ, Dept Biol, 6525 N Sheridan Rd, Chicago, IL 60626 USA. EM kwilli4@luc.edu RI Furuya, Tetsuya/J-5916-2013; Furuya, Tetsuya/H-2412-2013; OI Furuya, Tetsuya/0000-0003-3979-7072; Su, Xinzhuan/0000-0003-3246-3248 FU NIAID NIH HHS [AI40592, R01 AI048826, R01 AI048826-04, AI48826] NR 35 TC 45 Z9 47 U1 1 U2 5 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 SEP PY 2005 VL 143 IS 1 BP 90 EP 99 DI 10.1016/j.molbiopara.2005.05.010 PG 10 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 956YK UT WOS:000231335800011 PM 15996767 ER PT J AU Thorslund, T von Kobbe, C Harrigan, JA Indig, FE Christiansen, M Stevnsner, T Bohr, VA AF Thorslund, T von Kobbe, C Harrigan, JA Indig, FE Christiansen, M Stevnsner, T Bohr, VA TI Cooperation of the Cockayne syndrome group B protein and poly(ADP-ribose) polymerase 1 in the response to oxidative stress SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID BASE EXCISION-REPAIR; TRANSCRIPTION-COUPLED REPAIR; INDUCED DNA-DAMAGE; CSB GENE-PRODUCT; HUMAN-CELLS; HELICASE DOMAIN; LIGASE-III; 8-OXOGUANINE; PARP-1; XRCC1 AB Cockayne syndrome (CS) is a rare genetic disorder characterized as a segmental premature-aging syndrome. The CS group B (CSB) protein has previously been implicated in transcription-coupled repair, transcriptional elongation, and restoration of RNA synthesis after DNA damage. Recently, evidence for a role of CSB in base excision repair of oxidative DNA lesions has accumulated. In our search to understand the molecular function of CSB in this process, we identify a physical and functional interaction between CSB and poly (ADP-ribose) polymerase-1 (PARP-1). PARP-1 is a nuclear enzyme that protects the integrity of the genome by responding to oxidative DNA damage and facilitating DNA repair. PARP-1 binds to single-strand DNA breaks which activate the catalytic ability of PARP-I to add polymers of ADP-ribose to various proteins. We find that CSB is present at sites of activated PARP-1 after oxidative stress, identify CSB as a new substrate of PARP-1, and demonstrate that poly(ADP-ribosyl)ation of CSB inhibits its DNA-dependent ATPase activity. Furthermore, we find that CSB-deficient cell lines are hypersensitive to inhibition of PARP. Our results implicate CSB in the PARP-1 poly(ADP-ribosyl)ation response after oxidative stress and thus suggest a novel role of CSB in the cellular response to oxidative damage. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Univ Aarhus, Dept Mol Biol, Danish Ctr Mol Gerontol, Aarhus, Denmark. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vbohr@nih.gov NR 49 TC 70 Z9 72 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 SEP PY 2005 VL 25 IS 17 BP 7625 EP 7636 DI 10.1128/MCB.25.17.7625-7636.2005 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 956VY UT WOS:000231329300021 PM 16107709 ER PT J AU Ying, H Furuya, F Willingham, MC Xu, JM O'Malley, BW Cheng, SY AF Ying, H Furuya, F Willingham, MC Xu, JM O'Malley, BW Cheng, SY TI Dual functions of the steroid hormone receptor coactivator 3 in modulating resistance to thyroid hormone SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TARGETED MUTATION; MOLECULAR-BASIS; CELL-GROWTH; BETA GENE; MICE; CARCINOMA; PATHWAY; SRC-3 AB Mutations of the thyroid hormone receptor beta (TR beta) gene cause resistance to thyroid hormone (RTH). RTH is characterized by increased serum thyroid hormone associated with nonsuppressible thyroid-stimulating hormone (TSH) and impaired growth. It is unclear how the actions of TR beta mutants are modulated in vivo to affect the manifestation of RTH. Using a mouse model of RTH that harbors a knockin mutation of the TR beta gene (TR beta PV mouse), we investigated the effect of the steroid hormone receptor coactivator 3 (SRC-3) on RTH. In TR beta PV mice deficient in SRC-3, dysfunction of the pituitary-thyroid axis and hypercholesterolemia was lessened, but growth impairment of RTH was worsened. The lessened dysfunction of the pituitary-thyroid axis was attributed to a significant decrease in growth of the thyroid and pituitary. Serum insulin-like growth factor 1 (IGF-1) was further reduced in TR beta PV mice deficient in SRC-3. This effect led to reduced signaling of the IGF-1/phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway that is known to mediate cell growth and proliferation. Thus, SRC-3 modulates RTH by at least two mechanisms, one via its role as a receptor coregulator and the other via its growth regulatory role through the IGF-1/PI3K/AKT/mTOR signaling. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Dept Pathol, Winston Salem, NC 27109 USA. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, NIH, 37 Convent Dr,Rm 5128, Bethesda, MD 20892 USA. EM sycheng@helix.nih.gov NR 26 TC 17 Z9 18 U1 0 U2 0 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 SEP PY 2005 VL 25 IS 17 BP 7687 EP 7695 DI 10.1128/MCB.25.17.7687-7695.2005 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 956VY UT WOS:000231329300027 PM 16107715 ER PT J AU Sasaki, S Mori, D Toyo-oka, K Chen, A Garrett-Beal, L Muramatsu, M Miyagawa, S Hiraiwa, N Yoshiki, A Wynshaw-Boris, A Hirotsune, S AF Sasaki, S Mori, D Toyo-oka, K Chen, A Garrett-Beal, L Muramatsu, M Miyagawa, S Hiraiwa, N Yoshiki, A Wynshaw-Boris, A Hirotsune, S TI Complete loss of Ndel1 results in neuronal migration defects and early embryonic lethality SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID DIEKER LISSENCEPHALY GENE; CYTOPLASMIC DYNEIN; ASPERGILLUS-NIDULANS; NUCLEAR MIGRATION; NEOCORTICAL DEVELOPMENT; CORTICAL DEVELOPMENT; CEREBRAL-CORTEX; MICE LACKING; HEAVY-CHAIN; LIS1 AB Regulation of cytoplasmic dynein and microtubule dynamics is crucial for both mitotic cell division and neuronal migration. NDEL1 was identified as a protein interacting with LIS1, the protein product of a gene mutated in the lissencephaly. To elucidate NDEL1 function in vivo, we generated null and hypomorphic alleles of Ndel1 in mice by targeted gene disruption. Ndel1(-/-) mice were embryonic lethal at the peri-implantation stage like null mutants of Lis1 and cytoplasmic dynein heavy chain. In addition, Ndel1(-/-) blastocysts failed to grow in culture and exhibited a cell proliferation defect in inner cell mass. Although Ndel1(-/-) mice displayed no obvious phenotypes, further reduction of NDEL1 by making null/hypomorph compound heterozygotes (Ndel1(cko/-)) resulted in histological defects consistent with mild neuronal migration defects. Double Lis1(cko/+)-Ndel1(+/-) mice or Lis1(+/-)-Ndel1(+/-) mice displayed more severe neuronal migration defects than Lis1(cko/+)-Ndel1(+/-) mice or Lis1(+/-)-Ndel1(+/+) mice, respectively. We demonstrated distinct abnormalities in microtubule organization and similar defects in the distribution of beta-COP-positive vesicles (to assess dynein function) between Ndel1 or Lis1-null MEFs, as well as similar neuronal migration defects in Ndel1- or Lis1-null granule cells. Rescue of these defects in mouse embryonic fibroblasts and granule cells by overexpressing LIS1, NDEL1, or NDE1 suggest that NDEL1, LIS1, and NDE1 act in a common pathway to regulate dynein but each has distinct roles in the regulation of microtubule organization and neuronal migration. C1 Osaka City Univ, Grad Sch Med, Dept Genet Dis Res, Osaka 5458586, Japan. Saitama Med Sch, Res Ctr Genom Med, Div Neurosci, Hidaka City, Saitama, Japan. Natl Ctr Human Genome Res, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. Osaka Univ, Grad Sch Med, Biomed Res Ctr, Div Organ Transplantat, Suita, Osaka 5650871, Japan. RIKEN, Tsukuba Inst, Bioresource Ctr, Dept Biol Syst,Expt Anim Div, Tsukuba, Ibaraki 3050074, Japan. Univ Calif San Diego, Ctr Canc, Dept Pediat, La Jolla, CA 92093 USA. Univ Calif San Diego, Ctr Canc, Dept Med, La Jolla, CA 92093 USA. RP Hirotsune, S (reprint author), Osaka City Univ, Grad Sch Med, Dept Genet Dis Res, Asahi Machi 1-4-3, Osaka 5458586, Japan. EM shinjih@med.osaka-cu.ac.jp RI Yoshiki, Atsushi/A-6036-2016 OI Yoshiki, Atsushi/0000-0002-9450-5151 FU NINDS NIH HHS [NS41030, R01 NS041030] NR 47 TC 97 Z9 102 U1 2 U2 8 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 SEP PY 2005 VL 25 IS 17 BP 7812 EP 7827 DI 10.1128/MCB.25.17.7812-7827.2005 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 956VY UT WOS:000231329300038 PM 16107726 ER PT J AU Zhang, Y Fatima, N Dufau, ML AF Zhang, Y Fatima, N Dufau, ML TI Coordinated changes in DNA methylation and histone modifications regulate silencing/derepression of luteinizing hormone receptor gene transcription SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CPG-BINDING-PROTEIN; FREQUENT EPIGENETIC INACTIVATION; NUCLEAR ORPHAN RECEPTORS; TUMOR-SUPPRESSOR GENE; DEACETYLASE INHIBITOR; CANCER-CELLS; PROMOTER; EXPRESSION; ACETYLATION; ACTIVATION AB We have previously demonstrated that transcription of the luteinizing hormone receptor (LHR) gene is subject to repression by histone deacetylation at its promoter region, where a histone deacetylase (HDAC)/ mSin3A complex is anchored at a proximal Sp1 site. The present studies have shown that epigenetic silencing and activation of the LHR gene is achieved through coordinated regulation at both the histone and DNA levels. The HDAC inhibitor trichostatin A (TSA) evoked robust but significantly lower activation of the LHR gene in JAR than in MCF-7 cells. This effect was localized to the 176-bp promoter region, which is highly methylated in JAR and lightly methylated in MCF-7 cells. Consequently, TSA and the DNA demethylating reagent 5-azacytidine (5-AzaC) caused marked synergistic activation of the LHR gene in JAR but not in MCF-7 cells. Multiple site-specific lysine acetylation of H3/H4 is associated with such LHR gene activation. Methylation or acetylation of H3 at K9 is present at the silenced and derepressed LHR promoter, respectively. While DNA methylation levels did not affect the histone code of the LHR gene promoter, demethylation of the promoter CpG sites was necessary for maximal stimulation of this gene. Mechanistically, the combined actions of TSA and 5-AzaC, but not either 5-AzaC or TSA alone, resulted in complete demethylation of the LHR gene promoter in JAR cells. Release of the repressive HDAC/mSin3A complex from the LHR gene promoter in both cell types required both TSA-induced changes of histone modifications and, concurrently, a demethylated promoter. Also, Dnmt1 was largely dissociated from the LHR gene promoter in the presence of TSA or TSA plus 5-AzaC, and binding of MBD2 in JAR cells was diminished upon conversion of the promoter to a demethylated state. Such changes induced a more permissive chromatin where recruitment of polymerase II and TFIIB to the promoter was significantly increased. The activated state of the LHR gene induced by TSA and 5-AzaC in JAR and MCF-7 cells was observed basally in LHR-expressing PLC cells, in which the promoter is unmethylated and associated with hyperacetylated histones. Consequently, PLC cells are unresponsive to drug treatment. These findings have elucidated a regulatory mechanism whereby concurrent dissociation of repressors and association of activators and basal transcriptional components, resulting from coordinated histone hyperacetylation and DNA demethylation, lead to derepression of the LHR gene expression. C1 NICHD, NIH, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), NICHD, NIH, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, Bldg 49,Rm 6A-36,49 Convent Dr,MSC 4510, Bethesda, MD 20892 USA. EM dufaum@mail.nih.gov NR 63 TC 56 Z9 61 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2005 VL 25 IS 18 BP 7929 EP 7939 DI 10.1128/MCB.25.18.7929-7939.2005 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 961GZ UT WOS:000231651200001 PM 16135786 ER PT J AU Kametaka, S Mattera, R Bonifacino, JS AF Kametaka, S Mattera, R Bonifacino, JS TI Epidermal growth factor-dependent phosphorylation of the GGA3 adaptor protein regulates its recruitment to membranes SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANS-GOLGI NETWORK; FACTOR-BINDING PROTEINS; TYROSINE PHOSPHORYLATION; VHS DOMAIN; UBIQUITIN BINDING; FACTOR RECEPTOR; SORTING SIGNAL; CLATHRIN; KINASE; MECHANISM AB The Golgi-localized, Gamma-ear-containing, Arf-binding (GGA) proteins are monomeric clathrin adaptors that mediate the sorting of transmembrane cargo at the traps-Golgi network and endosomes. Here we report that one of these proteins, GGA3, becomes transiently phosphorylated upon activation of the epidermal growth factor (EGF) receptor. This phosphorylation takes place on a previously unrecognized site in the "hinge" segment of the protein, S368, and is strictly dependent on the constitutive phosphorylation of another site, S372. The EGF-induced phosphorylation of 5368 does not require internalization of the EGF receptor or association of GGA3 with membranes. This phosphorylation can be blocked by inhibitors of both the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways that function downstream of the activated EGF receptor. Phosphorylation of GGA3 on 5368 causes an increase in the hydrodynamic radius of the protein, indicating a transition to a more asymmetric shape. Mutation of 5368 and 5372 to a phosphomimic aspartate residue decreases the association of GGA3 with membranes. These observations indicate that EGF signaling elicits phosphorylation events that regulate the association of GGA3 with organellar membranes. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Room 101, Bethesda, MD 20892 USA. EM Juan@helix.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 NR 49 TC 22 Z9 23 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2005 VL 25 IS 18 BP 7988 EP 8000 DI 10.1128/MCB.25.18.7988-8000.2005 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 961GZ UT WOS:000231651200006 PM 16135791 ER PT J AU Knodler, LA Steele-Mortimer, O AF Knodler, LA Steele-Mortimer, O TI The Salmonella effector PipB2 affects late endosome/lysosome distribution to mediate sif extension SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID LYSOSOMAL MEMBRANE-GLYCOPROTEINS; ENTERICA SEROVAR TYPHIMURIUM; III SECRETION SYSTEM; LATE ENDOCYTIC COMPARTMENTS; PATHOGENICITY ISLAND 2; CONTAINING VACUOLES; EPITHELIAL-CELLS; HOST-CELLS; FILAMENTOUS STRUCTURES; NONNEURONAL CELLS AB After internalization into mammalian cells, the bacterial pathogen Salmonella enterica resides within a membrane-bound compartment, the Salmonella-containing vacuole (SCV). During its maturation process, the SCV interacts extensively with host cell endocytic compartments, especially late endosomes/lysosomes (LE/Lys) at later stages. These interactions are mediated by the activities of multiple bacterial and host cell proteins. Here, we show that the Salmonella type III effector PipB2 reorganizes LE/Lys compartments in mammalian cells. This activity results in the centrifugal extension of lysosomal glycoprotein-rich membrane tubules, known as Salmonella-induced filaments, away from the SCV along microtubules. Salmonella overexpressing pipB2 induce the peripheral accumulation of LE/Lys compartments, reducing the frequency of LE/Lys tubulation. Furthermore, ectopic expression of pipB2 redistributes LE/Lys, but not other cellular organelles, to the cell periphery. In coexpression studies, PipB2 can overcome the effects of dominant-active Rab7 or Rab34 on LE/Lys positioning. Deletion of a C-terminal pentapeptide motif of PipB2, LFNEF, prevents its peripheral targeting and effect on organelle positioning. The PipB2 homologue PipB does not possess this motif or the same biological activity as PipB2. Therefore, it seems that a divergence in the biological functions of these two effectors can be accounted for by sequence divergence in their C termini. C1 NIAID, Rocky Mt Lab, Lab Intracellular Parasites, NIH, Hamilton, MT 59840 USA. RP Knodler, LA (reprint author), NIAID, Rocky Mt Lab, Lab Intracellular Parasites, NIH, Hamilton, MT 59840 USA. EM lknodler@niaid.nih.gov NR 64 TC 57 Z9 60 U1 0 U2 2 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 SEP PY 2005 VL 16 IS 9 BP 4108 EP 4123 DI 10.1091/mbc.E05-04-0367 PG 16 WC Cell Biology SC Cell Biology GA 959XO UT WOS:000231553000016 PM 15987736 ER PT J AU Janvier, K Bonifacino, JS AF Janvier, K Bonifacino, JS TI Role of the endocytic machinery in the sorting of lysosome-associated membrane proteins SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CLATHRIN-MEDIATED ENDOCYTOSIS; HERMANSKY-PUDLAK-SYNDROME; EPIDERMAL-GROWTH-FACTOR; AP-3 ADAPTER COMPLEX; TRANS-GOLGI NETWORK; PLASMA-MEMBRANE; CELL-SURFACE; MDCK CELLS; CYTOPLASMIC TAIL; COATED VESICLES AB The limiting membrane of the lysosome contains a group of transmembrane glycoproteins named lysosome-associated membrane proteins (Lamps). These proteins are targeted to lysosomes by virtue of tyrosine-based sorting signals in their cytosolic tails. Four adaptor protein (AP) complexes, AP-1, AP-2, AP-3, and AP-4, interact with such signals and are therefore candidates for mediating sorting of the Lamps to lysosomes. However, the role of these complexes and of the coat protein, clathrin, in sorting of the Lamps in vivo has either not been addressed or remains controversial. We have used RNA interference to show that AP-2 and clathrin-and to a lesser extent the other AP complexes-are required for efficient delivery of the Lamps to lysosomes. Because AP-2 is exclusively associated with plasma membrane clathrin coats, our observations imply that a significant population of Lamps traffic via the plasma membrane en route to lysosomes. C1 NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. EM bonifacinoj@mail.nih.gov OI Bonifacino, Juan S./0000-0002-5673-6370 NR 78 TC 120 Z9 122 U1 2 U2 5 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 SEP PY 2005 VL 16 IS 9 BP 4231 EP 4242 DI 10.1091/mbc.E05-03-0213 PG 12 WC Cell Biology SC Cell Biology GA 959XO UT WOS:000231553000026 PM 15987739 ER PT J AU Kim, JS Baek, SJ Bottone, FG Sali, T Eling, TE AF Kim, JS Baek, SJ Bottone, FG Sali, T Eling, TE TI Overexpression of 15-lipoxygenase-1 induces growth arrest through phosphorylation of p53 in human colorectal cancer cells SO MOLECULAR CANCER RESEARCH LA English DT Article ID DAMAGE-INDUCED PHOSPHORYLATION; DEPENDENT PROTEIN-KINASE; ACTIVATED RECEPTOR-GAMMA; MAMMALIAN LIPOXYGENASES; PROSTATE ADENOCARCINOMA; INDUCED APOPTOSIS; EXPRESSION; CARCINOMA; MDM2; CYCLOOXYGENASE-2 AB To investigate the function of 15-lipoxygenase-1 (15-LOX-1) in human colorectal cancer, we overexpressed 15-LOX-1 in HCT-116 human colorectal cancer cells. Clones expressing the highest levels of 15-LOX-1 displayed reduced viability compared with the HCT-116-Vector control cells. Further, by cell cycle gene array analyses, the cyclin-dependent kinase inhibitor p21 (WAF1/CIP1) and MDM2 genes were up-regulated in 15-LOX-1-overexpressing cells. The induction of p21 (WAF1/CIP1) and MDM2 were linked to activation of p53 by 15-LOX-1, as there was a dramatic induction of phosphorylated p53 (Ser 15) in 15-LOX-1-overesxpressing cells. However, the 15-LOX-1 metabolites 13(S)-hydroxyoctadecadienoic acid and 15(S)-hydroxyeicosatetraenoic acid failed to induce phosphorylation of p53 at Ser(15), and the 15-LOX-1 inhibitor PD146176 did not inhibit the phosphorylation of p53 at Ser(15) in 15-LOX-1-overexpressing cells. Nonetheless, the growth-inhibitory effects of 15-LOX-1 were p53 dependent, as 15-LOX-1 overexpression had no effect on cell growth in p53 (-/-) HCT-116 cells. Finally, treatment of HCT-116-15-LOX-1 cells with different kinase inhibitors suggested that the effects of 15-LOX-1 on p53 phosphorylation and activation were due to effects on DNA-dependent protein kinase. Collectively, these findings suggest a new mechanism to explain the biological activity of 15-LOX-1, where 15-LOX plays a stoichiometric role in activating a DNA-dependent protein kinase -dependent pathway that leads to p53-dependent growth arrest. C1 Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Tennessee, Coll Vet Med, Dept Pathobiol, Knoxville, TN USA. RP Eling, TE (reprint author), Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, NIH, MD E4-09,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM eling@niehs.nih.gov OI Baek, Seung/0000-0001-7866-7778 NR 29 TC 18 Z9 19 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD SEP PY 2005 VL 3 IS 9 BP 511 EP 517 DI 10.1158/1541-7786.MCR-05-0011 PG 7 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 967ZH UT WOS:000232129600005 PM 16179498 ER PT J AU Abi-Habib, RJ Urieto, JO Liu, SH Leppla, SH Duesbery, NS Frankel, AE AF Abi-Habib, RJ Urieto, JO Liu, SH Leppla, SH Duesbery, NS Frankel, AE TI BRAF status and mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 activity indicate sensitivity of melanoma cells to anthrax lethal toxin SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID MALIGNANT-MELANOMA; BACILLUS-ANTHRACIS; INACTIVATION; RECEPTOR; PROTEIN; TRANSFORMATION; MELANOCYTES; INHIBITION; MUTATIONS; APOPTOSIS AB Anthrax lethal toxin, composed of protective antigen and lethal factor, was tested for cytotoxicity to human melanoma cell lines and normal human cells. Eleven of 18 melanoma cell lines were sensitive to anthrax lethal toxin (IC50 < 400 pmol/L) and 10 of these 11 sensitive cell lines carried the V599E BRAF mutation. Most normal cell types (10 of 15) were not sensitive to anthrax lethal toxin and only 5 of 15 normal human cell types were sensitive to anthrax lethal toxin (IC50 < 400 pmol/L). These cells included monocytes and a subset of endothelial cells. In both melanoma cell lines and normal cells, anthrax toxin receptor expression levels did not correlate with anthrax lethal toxin cytotoxicity. Furthermore, an anthrax toxin receptor -deficient cell line (PR230) did not show any enhanced sensitivity to anthrax lethal toxin when transfected with anthrax toxin receptor. Anthrax lethal toxin toxicity correlated with elevated phosphorylation levels of mitogen -activated protein/extracellular signal-regulated kinase kinase [MEK) 1/2 in both melanoma cell lines and normal cells. Anthrax lethal toxin -sensitive melanoma cell lines and normal cells had higher phospho-MEK1/2 levels than anthrax lethal toxin-resistant melanoma cell lines and normal tissue types. UO126, a specific MEK1/2 inhibitor, was not toxic to anthrax lethal toxin resistant melanoma cell lines but was toxic to 8 of 11 anthrax lethal toxin-sensitive cell lines. These results show that anthrax lethal toxin toxicity correlates with elevated levels of active MEK1/2 pathway but not with anthrax toxin receptor expression levels in both normal and malignant tissues. Anthrax lethal toxin may be a useful therapeutic for melanoma patients, especially those carrying the V599E BRAF mutation with constitutive activation of the mitogen -activated protein kinase pathway. C1 Scott & White Mem Hosp & Clin, Hematol Oncol & Canc Res Inst, Temple, TX 76508 USA. Wake Forest Univ, Sch Med, Dept Biochem, Winston Salem, NC 27109 USA. Wake Forest Univ, Sch Med, Dept Mol Biol, Winston Salem, NC 27109 USA. NIAID, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. Van Andel Res Inst, Grand Rapids, MI USA. RP Frankel, AE (reprint author), Scott & White Mem Hosp & Clin, Hematol Oncol & Canc Res Inst, 2401 S 31st St, Temple, TX 76508 USA. EM afrankel@swmail.sw.org NR 25 TC 51 Z9 52 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD SEP PY 2005 VL 4 IS 9 BP 1303 EP 1310 DI 10.1158/1535-7163.MCT-05-0145 PG 8 WC Oncology SC Oncology GA 965BA UT WOS:000231923500003 PM 16170021 ER PT J AU Yin, Y Bai, R Russell, RG Beildeck, ME Xie, Z Kopelovich, L Glazer, RI AF Yin, Y Bai, R Russell, RG Beildeck, ME Xie, Z Kopelovich, L Glazer, RI TI Characterization of medroxyprogesterone and DMBA-induced multilineage mammary tumors by gene expression profiling SO MOLECULAR CARCINOGENESIS LA English DT Article DE carcinogenesis; DMBA; medroxyprogesterone; mammary; adenocarcinoma; adenosquamous; myoepithelial; squamous; gene microarray ID BREAST-CANCER; STEM-CELLS; EPITHELIAL-CELLS; RETINOIC ACID; GROWTH; CARCINOGENESIS; GLAND; CARCINOMAS; PROLACTIN; MICE AB Mouse mammary tumors arising during medroxyprogesterone-DMBA-mediated mammary carcinogenesis comprised three distinct phenotypes: adenocarcinoma, squamous cell carcinoma, and myoepithelial carcinoma. The molecular signature for each of the three tumor subsets was characterized by gene microarray analysis, and three distinct sets of gene expression profiles were obtained that were corroborated in part by quantitative RT-PCR and immunohistochemistry. These results suggest that this carcinogenesis and gene expression model will be useful for rapidly assessing the histopathological differences arising in mammary carcinogenesis and the effects of tumor promoting or chemoprevention agents. Published 2005 Wiley-Liss, Inc.(dagger) C1 Georgetown Univ, Dept Oncol, Washington, DC 20057 USA. Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. Chemoprevent Agent Dev Res Grp, Div Canc Prevent, NCI, Bethesda, MD USA. RP Glazer, RI (reprint author), Georgetown Univ, Dept Oncol, Washington, DC 20057 USA. FU NCI NIH HHS [N01-CN25101] NR 49 TC 21 Z9 22 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 SEP PY 2005 VL 44 IS 1 BP 42 EP 50 DI 10.1002/mc.20119 PG 9 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 959XK UT WOS:000231552600005 PM 15937957 ER PT J AU Park, SW Li, GJ Lin, YP Barrero, MJ Ge, K Roeder, RG Wei, LN AF Park, SW Li, GJ Lin, YP Barrero, MJ Ge, K Roeder, RG Wei, LN TI Thyroid hormone-induced juxtaposition of regulatory elements/factors and chromatin remodeling of Crabp1 dependent on MED1/TRAP220 SO MOLECULAR CELL LA English DT Article ID PROTEIN-I GENE; RNA-POLYMERASE-II; NUCLEAR RECEPTORS; COACTIVATOR COMPLEX; TRANSCRIPTIONAL REGULATION; TRAP220 COMPONENT; MEDIATOR; PROMOTER; VIVO; RECRUITMENT AB The cellular retinoic acid binding protein I gene is induced by thyroid hormone (T3) through a T3 response element (TRE) approximately 1 kb upstream of the basal promoter. The upstream region is organized into a positioned nucleosomal array with the N1 nucleosome spanning the GC box region. T3 induces apparent interactions between chromatin segments containing the THE and the GC box regions and the sliding of upstream nucleosomes toward N1 with concomitant N1 remodeling. Concurrently, the chromatin-remodeling factor BRIM is replaced by BRG1 and histones are hyperacetylated. All these events are abolished in Medl/Trap220 null cells, indicating a key role for TRAP/Mediator in these processes. A MED1/ TRAP220-containing Mediator complex constitutively occupies the GC box region but not the TRE, serving as a nexus for distal and proximal factors. This indicates new TRAP/Mediator functions in facilitating ultimate recruitment and function of RNA polymerase II and the general transcription machinery. C1 Univ Minnesota, Sch Med, Dept Pharmacol, Minneapolis, MN 55455 USA. Rockefeller Univ, Biochem & Mol Biol Lab, New York, NY 10021 USA. NIDDKD, Nucl Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. RP Wei, LN (reprint author), Univ Minnesota, Sch Med, Dept Pharmacol, Minneapolis, MN 55455 USA. EM weixx009@umn.edu OI Barrero, Maria/0000-0002-5990-7040; Ge, Kai/0000-0002-7442-5138 FU NIDA NIH HHS [DA11190, K02-DA13926]; NIDDK NIH HHS [DK54733, DK60521, DK71900] NR 41 TC 38 Z9 42 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD SEP PY 2005 VL 19 IS 5 BP 643 EP 653 DI 10.1016/j.molcel.2005.08.008 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 961WQ UT WOS:000231692900006 PM 16137621 ER PT J AU Oki, M Kamakaka, RT AF Oki, M Kamakaka, RT TI Barrier function at HMR SO MOLECULAR CELL LA English DT Article ID RNA-POLYMERASE-III; ACETYLTRANSFERASE ACTIVITY; SACCHAROMYCES-CEREVISIAE; TRANSCRIPTION; CHROMATIN; HETEROCHROMATIN; BOUNDARIES; COMPLEXES; YEAST; INSULATORS AB The silenced HMR domain is restricted from spreading by barrier elements, and the right barrier is a unique t-RNAT(THR) gene. We show that sequences immediately flanking the silenced domain were enriched in acetylated, but not methylated, histones, whereas the barrier element was associated with a nucleosome-free region. Surprisingly, the SAGA acetyltransferase resided across the entire region. We further demonstrate that a mutation in the barrier eliminated the nucleosome-free gap but only subtly altered the distribution of SAGA. Interestingly, neither reformation of the nucleosome nor mutations in chromatin-modifying enzymes alone led to an unrestricted spread of silenced chromatin. Double mutations in the t-RNA barrier and these complexes, on the other hand, led to a significant spread of Sir proteins. These results suggest two overlapping mechanisms function to restrict the spread of silencing: one of which involves a DNA binding element, whereas the other mechanism involves specific chromatin-modifying activities. C1 NICHHD, Unit Chromatin & Transcript, NIH, Bethesda, MD 20892 USA. RP Kamakaka, RT (reprint author), NICHHD, Unit Chromatin & Transcript, NIH, Bldg 18T,Room 106,18 Lib Dr, Bethesda, MD 20892 USA. EM rohinton@helix.nih.gov FU Intramural NIH HHS NR 30 TC 62 Z9 65 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD SEP PY 2005 VL 19 IS 5 BP 707 EP 716 DI 10.1016/j.molcel.2005.07.022 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 961WQ UT WOS:000231692900012 PM 16137626 ER PT J AU Conradas, KA Yi, M Simpson, KA Lucas, DA Camalier, CE Yu, LR Veenstra, TD Stephens, RM Conrads, TP Beck, GR AF Conradas, KA Yi, M Simpson, KA Lucas, DA Camalier, CE Yu, LR Veenstra, TD Stephens, RM Conrads, TP Beck, GR TI A combined proteome and microarray investigation of inorganic phosphate-induced pre-osteoblast cells SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID MESSENGER-RNA EXPRESSION; OXIDATIVE-PHOSPHORYLATION; SACCHAROMYCES-CEREVISIAE; METABOLIC NETWORK; MC3T3-E1 CELLS; DIFFERENTIATION; KINASE; FRA-1; MINERALIZATION; ACTIVATION AB Inorganic phosphate, which is generated during osteoblast differentiation and mineralization, has recently been identified as an important signaling molecule capable of altering signal transduction pathways and gene expression. A large scale quantitative proteomic investigation of pre-osteoblasts stimulated with inorganic phosphate for 24 h resulted in the identification of 2501 proteins, of which 410 (16%) had an altered abundance ratio of greater than or equal to 1.75-fold, either up or down, revealing both novel and previously defined osteoblast-regulated proteins. A pathway/function analysis of these proteins revealed an increase in cell cycle and proliferation that was subsequently verified by conventional biochemical means. To further analyze the mechanisms by which inorganic phosphate regulates cellular protein levels, we undertook a mRNA microarray analysis of preosteoblast cells at 18, 21, and 24 h after inorganic phosphate exposure. Comparison of the mRNA microarray data with the 24-hour quantitative proteomic data resulted in a generally weak overall correlation; the 21-hour RNA sample showed the highest correlation to the proteomic data. However, an analysis of osteoblast relevant proteins revealed a much higher correlation at all time points. A comparison of the microarray and proteomic datasets allowed for the identification of a number of candidate proteins that are post-transcriptionally regulated by elevated inorganic phosphate, including Fra-1, a member of the activator protein-1 family of transcription factors. The analysis of the data presented here not only sheds new light on the important roles of inorganic phosphate in osteoblast function but also begins to address the contribution of post-transcriptional and post-translational regulation to a cell's expressed proteome. The ability to accurately measure changes in both protein abundance and mRNA levels on a system-wide scale represents a novel means to extract data from previously one-dimensional datasets. C1 Ctr Canc Res, Lab Canc Prevent, Frederick, MD 21702 USA. SAIC Frederick Inc, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. SAIC Frederick Inc, Lab Prote & Analyt Technol, NCI, Frederick, MD 21702 USA. RP Beck, GR (reprint author), Ctr Canc Res, Lab Canc Prevent, Frederick, MD 21702 USA. EM gbeck@ncifcrf.gov FU NCI NIH HHS [CA84573, N01-CO12400] NR 39 TC 65 Z9 70 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 SEP PY 2005 VL 4 IS 9 BP 1284 EP 1296 DI 10.1074/mcp.M500082-MCP200 PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 963WE UT WOS:000231836100008 PM 15958391 ER PT J AU Perrot, V Rechler, MM AF Perrot, V Rechler, MM TI The coactivator p300 directly acetylates the Forkhead transcription factor Foxo1 and stimulates Foxo1-induced transcription SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID CREB-BINDING-PROTEIN; INSULIN-RESPONSE SEQUENCE; C-TERMINAL FRAGMENT; FACTOR FKHR; KINASE B; CAENORHABDITIS-ELEGANS; GENE-EXPRESSION; FACTOR AFX; HISTONE ACETYLTRANSFERASES; REGULATES TRANSCRIPTION AB The FOXO ( Forkhead box class O) subgroup of forkhead transcription factors controls the expression of many genes involved in fundamental cellular processes. Until recently, studies conducted on posttranslational modifications of Forkhead proteins were restricted to their phosphorylation. In this report, we show that the coactivator p300 directly acetylates lysines in the carboxyl-terminal region of Foxo1 in vivo and in vitro, and potently stimulates Foxo1-induced transcription of IGF-binding protein-1 in transient transfection experiments. The intrinsic acetyltransferase activity of p300 is required for both activities. Our results suggest that acetylation of Foxo1 by p300 is responsible, at least in part, for its increased transactivation potency, although acetylation of histones cannot be excluded. Insulin, the major negative regulator of Foxo1-stimulated transcription, potently enhances p300 acetylation of Foxo1. Three consensus protein kinase B/Akt phosphorylation sites whose phosphorylation is stimulated by insulin are required for insulin-induced acetylation of Foxo1. In contrast to its importance in regulating the transcriptional activity of Foxo1 in the absence of insulin, acetylation plays only a minor role compared with phosphorylation in insulin inhibition of Foxo1 transcriptional activity. C1 NIDDKD, Growth & Dev Sect, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Rechler, MM (reprint author), NIDDKD, Growth & Dev Sect, Diabet Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 8D12, Bethesda, MD 20892 USA. EM mrechler@helix.nih.gov NR 82 TC 68 Z9 70 U1 0 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD SEP PY 2005 VL 19 IS 9 BP 2283 EP 2298 DI 10.1210/me.2004-0292 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 958MY UT WOS:000231453600007 PM 15890677 ER PT J AU Liu, Y Yao, ZX Bendavid, C Borgmeyer, C Han, ZQ Cavalli, LR Chan, WY Folmer, J Zirkin, BR Haddad, BR Gallicano, GI Papadopoulos, V AF Liu, Y Yao, ZX Bendavid, C Borgmeyer, C Han, ZQ Cavalli, LR Chan, WY Folmer, J Zirkin, BR Haddad, BR Gallicano, GI Papadopoulos, V TI Haploinsufficiency of cytochrome P450 17 alpha-hydroxylase/17,20 lyase (CYP17) causes infertility in male mice SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID LEYDIG-CELLS; STEROIDOGENESIS; CHOLESTEROL; SPERMATOGENESIS; IDENTIFICATION; BIOSYNTHESIS; TESTOSTERONE; ALPHA; FSH AB Cytochrome P450 17 alpha-hydroxylase/17,20-lyase (CYP17) is critical in determining cortisol and sex steroid biosynthesis. To investigate how CYP17 functions in vivo, we generated mice with a targeted deletion of CYP17. Although in chimeric mice Leydig cell CYP17 mRNA and intratesticular and circulating testosterone levels were dramatically reduced (80%), the remaining testosterone was sufficient to support spermatogenesis as evidenced by the generation of phenotypical black C57BL/6 mice. However, male chimeras consistently failed to generate heterozygous CYP17 mice and after five matings chimeric mice stopped mating indicating a change in sexual behavior. These results suggested that CYP17 deletion caused a primary phenotype ( infertility), probably not due to the anticipated androgen imbalance and a secondary phenotype ( change in sexual behavior) due to the androgen imbalance. Surprisingly, CYP17 mRNA was found in mature sperm, and serial analysis of gene expression identified CYP17 mRNA in other testicular germ cells. CYP17 mRNA levels were directly related to percent chimerism. Moreover, more than 50% of the sperm from high-percentage chimeric mice were morphologically abnormal, and half of them failed the swim test. Furthermore, 60% of swimming abnormal sperm was devoid of CYP17. These results suggest that CYP17, in addition to its role in steroidogenesis and androgen formation, is present in germ cells where it is essential for sperm function, and deletion of one allele prevents genetic transmission of mutant and wild-type alleles causing infertility followed by change in sexual behavior due to androgen imbalance. C1 Georgetown Univ, Ctr Med, Dept Biochem & Mol Biol, Washington, DC 20057 USA. Georgetown Univ, Ctr Med, Dept Oncol, Washington, DC 20057 USA. Georgetown Univ, Ctr Med, Dept Cell Biol, Washington, DC 20057 USA. Georgetown Univ, Ctr Med, Dept Pediat, Washington, DC 20057 USA. NICHHD, Lab Clin Genom, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. RP Georgetown Univ, Ctr Med, Dept Biochem & Mol Biol, Washington, DC 20057 USA. EM papadopv@georgetown.edu RI Cavalli, Luciane/J-6100-2012 FU NCI NIH HHS [P30 CA51008-13] NR 33 TC 22 Z9 22 U1 1 U2 1 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD SEP PY 2005 VL 19 IS 9 BP 2380 EP 2389 DI 10.1210/me.2004-0418 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 958MY UT WOS:000231453600015 PM 15890676 ER PT J AU Zhang, Q Rubenstein, JN Jang, TL Pins, M Javonovic, B Yang, XM Kim, SJ Park, I Lee, C AF Zhang, Q Rubenstein, JN Jang, TL Pins, M Javonovic, B Yang, XM Kim, SJ Park, I Lee, C TI Insensitivity to transforming growth factor-beta results from promoter methylation of cognate receptors in human prostate cancer cells (LNCaP) SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID II RECEPTORS; GENE; EXPRESSION; TGF-BETA-1; PROLIFERATION; DIHYDROTESTOSTERONE; SENSITIVITY; ARREST; MODEL; LINES AB Prostate cancers often develop insensitivity to TGF-beta to gain a growth advantage. In this study, we explored the status of promoter methylation of TGF-beta receptors (T beta Rs) in a prostate cancer cell line, LNCaP, which is insensitive to TGF-beta. Sensitivity to TGF-beta was restored in cells treated with 5-Aza-2'-deoxycytidine (5-Aza), as indicated by an increase in the expression of phosphorylated Smad-2, type I (T beta RI), and type II (T beta RII) TGF-beta receptors, and a reduced rate of proliferation. The same treatment did not significantly affect a benign prostate cell line, RWPE-1, which is sensitive to TGF-beta. Mapping of methylation sites was performed by screening 82 potential CpG methylation sites in the promoter of T beta RI and 33 sites in T beta RII using methylation-specific PCR and sequence analysis. There were six methylation sites (-365, -356, -348, -251, -244, -231) in the promoter of T beta RI. The -244 site was located in an activator protein (AP)-2 box. There were three methylated sites (-140, +27, +32) in the T beta RII promoter and the -140 site was located in one of the Sp1 boxes. Chromatin immunoprecipitation analysis demonstrated DNA binding activity of AP-2 in the T beta RI promoter and of Sp1 in the T beta RII promoter after treatment with 5-Aza. To test whether promoter methylation is present in clinical specimens, we analyzed human prostate specimens that showed negative staining for either T beta RI or T beta RII in a tissue microarray system. DNA samples were isolated from the microarray after laser capture microdissection. Methylation-specific PCR was performed for T beta RI ( six sites) and T beta RII ( three sites) promoters as identified in LNCaP cells. A significant number of clinical prostate cancer specimens lacked expression of either T beta RI and/or T beta RII, especially those with high Gleason's scores. In those specimens showing a loss of T beta R expression, a promoter methylation pattern similar to that of LNCaP cells was a frequent event. These results demonstrate that insensitivity to TGF-beta in some prostate cancer cells is due to promoter methylation in T beta Rs. C1 Northwestern Univ, Feinberg Sch Med, Dept Urol, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Zhang, Q (reprint author), Northwestern Univ, Sch Med, 303 E Chicago Ave,Tarry 16-733, Chicago, IL 60611 USA. EM q-zhang2@northwestern.edu; c-lee7@northwestern.edu FU NCI NIH HHS [CA 60553, CA 90386] NR 28 TC 27 Z9 34 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD SEP PY 2005 VL 19 IS 9 BP 2390 EP 2399 DI 10.1210/me.2005-0096 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 958MY UT WOS:000231453600016 PM 15905358 ER PT J AU Gropman, AL AF Gropman, AL TI Expanding the diagnostic and research toolbox for inborn errors of metabolism: The role of magnetic resonance spectroscopy SO MOLECULAR GENETICS AND METABOLISM LA English DT Article ID PROTON MR SPECTROSCOPY; X-LINKED-ADRENOLEUKODYSTROPHY; VANISHING WHITE-MATTER; PELIZAEUS-MERZBACHER-DISEASE; SJOGREN-LARSSON-SYNDROME; SYRUP-URINE-DISEASE; IN-VIVO; HUMAN BRAIN; LACTIC-ACIDOSIS; CHILDHOOD ADRENOLEUKODYSTROPHY C1 Georgetown Univ, Dept Pediat & Neurol, Washington, DC 20057 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Gropman, AL (reprint author), Georgetown Univ, Dept Pediat & Neurol, Washington, DC 20057 USA. EM ag334@georgetown.edu FU NCRR NIH HHS [RR17613] NR 63 TC 15 Z9 15 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2005 VL 86 IS 1-2 BP 2 EP 9 DI 10.1016/j.ymgme.2005.07.009 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 976AT UT WOS:000232705900002 PM 16276565 ER PT J AU Chandler, RJ Venditti, CP AF Chandler, RJ Venditti, CP TI Genetic and genomic systems to study methylmalonic acidemia SO MOLECULAR GENETICS AND METABOLISM LA English DT Review DE methylmalonic acidemia; cobalamin deficiency; methylmalonyl-CoA mutase; MMAA; MMAB; Caenorhabditis elegans; mouse models; molecular genetics; genomics ID COA MUTASE; INBORN ERROR; ATP-COB(I)ALAMIN ADENOSYLTRANSFERASE; INTERALLELIC COMPLEMENTATION; SACCHAROMYCES-CEREVISIAE; PROPIONATE METABOLISM; CRYSTAL-STRUCTURE; COENZYME B-12; RAT-LIVER; ACIDURIA AB Methylmalonic acidemia (MMAemia) is the biochemical hallmark of a group of genetic metabolic disorders that share a common defect in the ability to convert methylmalonyl-CoA into succinyl-CoA. This disorder is due to either a mutant methylmalonyl-CoA mutase apoenzyme or impaired synthesis of adenosylcobalamin, the cofactor for this enzyme. In this article, we will provide an overview of the pathways disrupted in these disorders, discuss the known metabolic blocks with a particular focus on molecular genetics, and review the use of selected model organisms to study features of methylmalonic acidemia. Published by Elsevier Inc. C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Venditti, CP (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov FU Intramural NIH HHS [Z01 HG200318-04, Z99 HG999999] NR 62 TC 26 Z9 27 U1 3 U2 12 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 SEP-OCT PY 2005 VL 86 IS 1-2 BP 34 EP 43 DI 10.1016/j.ymgme.2005.07.020 PG 10 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 976AT UT WOS:000232705900006 PM 16182581 ER PT J AU Huizing, M Brooks, BP Anikster, Y AF Huizing, M Brooks, BP Anikster, Y TI Optic atrophies in metabolic disorders SO MOLECULAR GENETICS AND METABOLISM LA English DT Review DE eye; inborn error of metabolism; myelination; oligodendrocyte; ophthalmology; optic nerve pallor; optic neuropathy; reactive oxygen species; retina; retinal ganglion cell ID NEURONAL CEROID-LIPOFUSCINOSIS; MITOCHONDRIAL INNER MEMBRANE; NIEMANN-PICK-DISEASE; OCULAR MANIFESTATIONS; 3-METHYLGLUTACONIC ACIDURIA; STORAGE DISEASES; OPA3 GENE; OPHTHALMOLOGIC FINDINGS; TRANSMEMBRANE PROTEIN; ENDOPLASMIC-RETICULUM AB Optic nerve involvement in metabolic disorders often results from apoptosis of cells that form or support the optic nerve, the retinal ganglion cell (RGC) axons, the myelin-forming oligodendrocytes, or the supporting vascular system. Given their high energy demands and the long course of their axons, RGCs are particularly sensitive to intracellular metabolic defects. Defects in energy metabolism, formation of reactive oxygen species, and storage of metabolites can all cause apoptosis of RGCs, decreased myelin formation of oligodendrocytes and increased pressure on the optic nerve. Clinically, the loss of RGC axons manifests as pale optic nerves. In general, the ophthalmologist can identify the underlying cause of an optic atrophy by careful examination, neuro-imaging, and family history. In some cases, however, the diagnosis proves elusive. In these instances, and especially when optic atrophy is accompanied by other systemic involvement, a metabolic disorder should be considered. Here, we review the underlying mechanisms of optic atrophy and its significance in metabolic disorders. Early identification of optic atrophy aids the diagnosis and subsequent management of the underlying condition, including anticipation of symptoms, genetic counseling, and possible therapeutic interventions. For many metabolic disorders, molecular testing is available. Published by Elsevier Inc. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NEI, NIH, Bethesda, MD 20892 USA. Safra Children Hosp, Metab Dis Unit, Sheba Med Ctr, Tel Hashomer, Israel. Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. RP Huizing, M (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM mhuizing@mail.nih.gov FU Intramural NIH HHS NR 100 TC 10 Z9 11 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2005 VL 86 IS 1-2 BP 51 EP 60 DI 10.1016/j.ymgme.2005.07.034 PG 10 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 976AT UT WOS:000232705900008 PM 16194617 ER PT J AU Gottlieb, E Ciccone, C Darvish, D Naiem-Cohen, S Dalakas, MC Savelkoul, PJ Krasnewich, DM Gahl, WA Huizing, M AF Gottlieb, E Ciccone, C Darvish, D Naiem-Cohen, S Dalakas, MC Savelkoul, PJ Krasnewich, DM Gahl, WA Huizing, M TI Single nucleotide polymorphisms in the dystroglycan gene do not correlate with disease severity in hereditary inclusion body myopathy SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE dystroglycan; disease modifier; hereditary inclusion body myopathy; muscular dystrophy; single nucleotide polymorphism; sialic acid ID ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; RIMMED VACUOLES; DISTAL MYOPATHY; GNE GENE; MODIFIER LOCI; BIFUNCTIONAL ENZYME; ACID BIOSYNTHESIS; IRANIAN JEWS; MUTATIONS; QUADRICEPS AB Aberrant glycosylation of dystroglycan occurs in certain muscular dystrophies, including hereditary inclusion body myopathy (HIBM). HIBM harbors a widely varying clinical severity and age of onset, which raised the suspicion of the presence of disease modifier genes. We considered the highly polymorphic dystroglycan gene (DAG1) as a feasible candidate modifier gene. DAG1 genomic DNA was sequenced for 32 HIBM patients, mainly of Persian-Jewish descent. Five novel DAG1 single nucleotide polymorphisms (SNPs) were identified, bringing the total number of SNPs to 19. However, no direct correlation between DAG1 SNPs and clinical severity of HIBM could be detected. Several identified SNPs substitute an amino acid and might modulate dystroglycan function or glycosylation status, and deserve further research. These data are valuable for future studies on the role of DAG1 in HIBM and other muscular dystrophies, especially those dystrophies that involve abnormal glycosylation of dystroglycan. Published by Elsevier Inc. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. HIBM Res Grp, Encino, CA USA. City Hope Natl Med Ctr, Beckman Res Inst, Div Neurosci, Duarte, CA 91010 USA. NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. NIH, Off Rare Dis, Off Director, Bethesda, MD 20892 USA. RP Huizing, M (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM mhuizing@mail.nih.gov NR 42 TC 4 Z9 4 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2005 VL 86 IS 1-2 BP 244 EP 249 DI 10.1016/j.ymgme.2005.07.003 PG 6 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 976AT UT WOS:000232705900029 PM 16112887 ER PT J AU Ferguson, SS Chen, YP LeCluyse, EL Negishi, M Goldstein, JA AF Ferguson, SS Chen, YP LeCluyse, EL Negishi, M Goldstein, JA TI Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4 alpha SO MOLECULAR PHARMACOLOGY LA English DT Article ID DISTAL ENHANCER MODULE; HUMAN HEPATOCYTES; CLINICAL-RELEVANCE; RESPONSE ELEMENTS; DRUG-METABOLISM; GENE-EXPRESSION; INDUCTION; PROMOTER; IDENTIFICATION; ACTIVATION AB Cytochrome P450 (P450) enzymes play important roles in the metabolism of endogenous and xenobiotic substrates in humans. CYP2C8 is an important member of the CYP2C subfamily, which metabolizes both endogenous compounds (i.e., arachidonic acids and retinoic acid) and xenobiotics (e.g., paclitaxel). Induction of P450 enzymes by drugs can result in tolerance as well as drug-drug interactions. CYP2C8 is the most strongly inducible member of the CYP2C subfamily in human hepatocytes, but the mechanism of induction by xenobiotics has not been delineated. To determine the mechanisms controlling the regulation of this important P450, we cloned the 5'-flanking region of CYP2C8 and investigated its transcriptional regulation by nuclear factors such as the pregnane X receptor (PXR), constitutive androstane receptor (CAR), glucocorticoid receptor (GR), and hepatic nuclear factor 4 (HNF4 alpha) that are known to be involved in the induction of other P450 enzymes using both cell lines and primary hepatocyte models. We initially identified a distal PXR/CAR-binding site in the CYP2C8 promoter that confers inducibility of CYP2C8 via the PXR agonist/ligand rifampicin and the CAR agonist/ligand CITCO[6-(4-chlorophenyl) imidazo[2,1-b][1,3] thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl) oxime]. A glucocorticoid-responsive element was identified that mediates dexamethasone induction via the GR. We finally identified an HNF4 alpha-binding site within the CYP2C8 basal promoter region that is cis-activated by cotransfected HNF4 alpha. In summary, the present studies show that CAR, PXR, GR, and HNF4 alpha can regulate CYP2C8 expression and identify specific cis-elements within the promoter that control these regulatory pathways. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Pharm, Chapel Hill, NC USA. RP Goldstein, JA (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, Mail Drop A3-02,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM goldste1@niehs.nih.gov RI Goldstein, Joyce/A-6681-2012; OI LeCluyse, Edward/0000-0002-2149-8990 NR 35 TC 123 Z9 130 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD SEP PY 2005 VL 68 IS 3 BP 747 EP 757 DI 10.1124/mol.105.013169 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 957GQ UT WOS:000231358200022 PM 15933212 ER PT J AU Lievremont, JP Bird, GS Putney, JW AF Lievremont, JP Bird, GS Putney, JW TI Mechanism of inhibition of TRPC cation channels by 2-aminoethoxydiphenylborane SO MOLECULAR PHARMACOLOGY LA English DT Article ID CAPACITATIVE CALCIUM-ENTRY; INOSITOL 1,4,5-TRISPHOSPHATE RECEPTORS; ACTIVATED CA2+ CHANNELS; STORE-OPERATED CHANNEL; TRANSIENT RECEPTOR; TRISPHOSPHATE RECEPTOR; CELLS; RELEASE; BORATE; PATHWAY AB We investigated the actions of the organoborane, 2-amino-ethoxydiphenylborane (2APB), on Ca2+ signaling in wild-type human embryonic kidney (HEK) 293 cells and in HEK293 cells stably expressing canonical transient receptor potential (TRPC) channels. Previous reports have suggested that 2APB inhibits agonist activation of TRPC channels because of its ability to act as a membrane-permeant inhibitor of inositol 1,4,5-trisphosphate (IP3) receptors. 2APB was specifically said to inhibit TRPC3 channels when activated through a phospholipase Clinked receptor but not when activated more directly by a synthetic diacylglycerol, oleyl-acetyl-glycerol (OAG) [Science (Wash DC) 287: 1647-1651, 2000]. However, we subsequently reported that IP3 does not activate TRPC3; rather the mechanism of activation by phospholipase C-linked receptors seemed to result from diacylglycerol [J Biol Chem 278: 16244-16252, 2003]. Thus, the current study was carried out to address the mechanism of action of 2APB in inhibiting TRPC channels. We found that, although the release of Ca2+ by a muscarinic agonist was reduced by high concentrations of 2APB, this effect was indistinguishable from that seen when stores were discharged by thapsigargin, which does not involve IP3 receptors. This indicates that 2APB is incapable of significant inhibition of IP3 receptors when applied to intact cells. We found that 2APB partially inhibits divalent cation entry in cells expressing TRPC3, TRPC6, or TRPC7 and that this partial inhibition was observed whether the channels were activated by a muscarinic agonist or by OAG. Thus, as concluded for store-operated channels, 2APB seems to inhibit TRPC channels by a direct mechanism not involving IP3 receptors. C1 NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov NR 33 TC 68 Z9 73 U1 0 U2 6 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 SEP PY 2005 VL 68 IS 3 BP 758 EP 762 DI 10.1124/mol.105.012856 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 957GQ UT WOS:000231358200023 PM 15933213 ER PT J AU Lyons-Warren, A Chang, JJ Balkissoon, R Kamiya, A Garant, M Nurnberger, J Scheftner, W Reich, T McMahon, F Kelsoe, J Gershon, E Coryell, W Byerley, W Berrettini, W DePaulo, R McInnis, M Sawa, A AF Lyons-Warren, A Chang, JJ Balkissoon, R Kamiya, A Garant, M Nurnberger, J Scheftner, W Reich, T McMahon, F Kelsoe, J Gershon, E Coryell, W Byerley, W Berrettini, W DePaulo, R McInnis, M Sawa, A TI Evidence of association between bipolar disorder and Citron on chromosome 12q24 SO MOLECULAR PSYCHIATRY LA English DT Letter ID SUSCEPTIBILITY; PEDIGREES; LINKAGE; LOCI; SCHIZOPHRENIA; 12Q23-Q24; SCAN C1 Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21287 USA. Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. Indiana Univ, Indianapolis, IN 46204 USA. NIMH, Genet Initiat Bipolar Consortium, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Rush Presbyterian Med Ctr, Chicago, IL USA. Washington Univ, St Louis, MO USA. NIMH, Mood & Anxiety Program, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Calif San Diego, San Diego, CA 92103 USA. San Diego Vet Affairs Healthcare Syst, San Diego, CA USA. Univ Chicago, Chicago, IL 60637 USA. Univ Iowa, Iowa City, IA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. San Francisco VA Med Ctr, San Francisco, CA USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Sawa, A (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat, 600 N Wolfe St,Meyer 2-181, Baltimore, MD 21287 USA. EM asawa1@jhmi.edu RI McMahon, Francis/A-7290-2009; kamiya, atsushi/L-8550-2016 NR 10 TC 27 Z9 29 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2005 VL 10 IS 9 BP 807 EP 809 DI 10.1038/sj.mp.4001703 PG 4 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 958YD UT WOS:000231483200002 PM 15983625 ER PT J AU Li, Y Rowland, C Tacey, K Catanese, J Sninsky, J Hardy, J Powell, J Lovestone, S Morris, JC Thal, L Goate, A Owen, M Williams, J Grupe, A AF Li, Y Rowland, C Tacey, K Catanese, J Sninsky, J Hardy, J Powell, J Lovestone, S Morris, JC Thal, L Goate, A Owen, M Williams, J Grupe, A TI The BDNF val66met polymorphism is not associated with late onset Alzheimer's disease in three case-control samples SO MOLECULAR PSYCHIATRY LA English DT Letter ID NEUROTROPHIC FACTOR BDNF; GENETIC-VARIANTS C1 Celera Diagnost, Alameda, CA 94502 USA. NIA, Bethesda, MD 20892 USA. Kings Coll London, Inst Psychiat, Dept Neurosci, London WC2R 2LS, England. Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Cardiff Univ, Wales Coll Med, Dept Psychol Med, Cardiff, Wales. RP Grupe, A (reprint author), Celera Diagnost, 1401 Harbor Bay Pkwy, Alameda, CA 94502 USA. EM Andrew.grupe@celeradiagnostics.com RI Lovestone, Simon/E-8725-2010; turton, miranda/F-4682-2011; Powell, John/G-4412-2011; Hardy, John/C-2451-2009 OI Powell, John/0000-0001-6124-439X; FU NIA NIH HHS [U24 AG021886] NR 10 TC 26 Z9 26 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2005 VL 10 IS 9 BP 809 EP 810 DI 10.1038/sj.mp.4001702 PG 3 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 958YD UT WOS:000231483200003 PM 15970929 ER PT J AU Hasler, G Pine, DS Kleinbaum, DG Gamma, A Luckenbaugh, D Ajdacic, V Eich, D Rossler, W Angst, J AF Hasler, G Pine, DS Kleinbaum, DG Gamma, A Luckenbaugh, D Ajdacic, V Eich, D Rossler, W Angst, J TI Depressive symptoms during childhood and adult obesity: the Zurich Cohort Study SO MOLECULAR PSYCHIATRY LA English DT Article DE depression; child development; body weight ID BODY-MASS INDEX; WEIGHT CHANGE; MAJOR DEPRESSION; PSYCHIATRIC-SYMPTOMS; ATYPICAL DEPRESSION; YOUNG ADULTHOOD; DISORDER; PSYCHOPATHOLOGY; POPULATION; OVERWEIGHT AB Depression and obesity have become major health problems with increasing prevalence. Given the limited effectiveness of treatment for weight problems, the identification of novel, potentially modifiable risk factors may provide insights on new preventive approaches to obesity. The purpose of this study was to test the hypothesis that depressive symptoms during childhood are associated with weight gain and obesity during young adulthood. Participants were from a prospective community-based cohort study of young adults (N = 591) followed between ages 19 and 40 years. The sample was stratified to increase the probability of somatic and psychological syndromes. Information was derived from six subsequent semistructured diagnostic interviews conducted by professionals over 20 years. The outcome measures were body mass index (BMI) and obesity (BMI >30). Among women, depressive symptoms before age 17 years were associated with increased weight gain (4.8 vs 2.6% BMI increase per 10 years) representing greater risk for adult obesity (hazard ratio = 11.52, P < 0.05). Among men, only after controlling for confounders, depressive symptoms before age 17 years were associated with increased weight gain (6.6 vs 5.2% BMI increase per 10 years) in adulthood but not with occurrence of obesity. These associations between childhood depressive symptoms and adult body weight were adjusted for baseline body weight, a family history of weight problems, levels of physical activity, consumption of alcohol and nicotine, and demographic variables. As the magnitude of the associations was high, and depression during childhood is a prevalent and treatable condition, this finding may have important clinical implications for the prevention and treatment of obesity. Whether the results of this study are limited to populations with elevated levels of psychopathology remains to be tested. C1 NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Psychiat Univ Hosp, Zurich, Switzerland. Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. RP Hasler, G (reprint author), NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, NIH, 15K North Dr,Room 200,MSC 2670, Bethesda, MD 20892 USA. EM g.hasler@bluewin.ch RI Hasler, Gregor/E-4845-2012; OI Hasler, Gregor/0000-0002-8311-0138; Ajdacic-Gross, Vladeta/0000-0002-7032-9237 NR 48 TC 90 Z9 97 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2005 VL 10 IS 9 BP 842 EP 850 DI 10.1038/sj.mp.4001671 PG 9 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 958YD UT WOS:000231483200007 PM 15838533 ER PT J AU Zheng, CY Baum, BJ AF Zheng, CY Baum, BJ TI Evaluation of viral and mammalian promoters for use in gene delivery to salivary glands SO MOLECULAR THERAPY LA English DT Article DE promoter; salivary gland; gene therapy; adenoviral vectors ID RAT SUBMANDIBULAR-GLAND; IN-VIVO; TRANSGENE EXPRESSION; REGULATORY ELEMENTS; TISSUE KALLIKREIN; AMYLASE GENES; CELL LINE; ADENOVIRUS; DNA; LOCALIZATION AB To optimize vectors for salivary gland gene transfer, we screened viral [cytomegalovirus (CMV; human immediate early), Rous sarcoma virus (RSV), simian virus 40, and Moloney murine leukemia virus long terminal repeat] and mammalian [elongation factor 1 alpha (EF1 alpha), cytokeratin 18 (K18), cytokeratin 19 (K19), kallikrein (Kall), and amylase (AMY), all human, and rat aquaporin-5 (rAQP5), and derivative elements] promoters driving luciferase activity in vitro and in vivo. In adenoviral vectors, the CMV promoter showed highest activity, with the EF1 alpha and RSV promoters slightly less powerful, in rat submandibular glands (SMGs). The K18 2.5-kb, K19 3.0-kb, and rAQP5 0.4-kb and Kall promoters had intermediate activity, while the AMY promoter exhibited lowest activity. To localize transgene expression, enhanced green fluorescence protein was used. The CMV, RSV, EF1 alpha, K18 2.5-kb, K19 3.0-kb, rAQP5 0.4-kb, and AMY promoters were not cell-type specific in SMGs; however, the Kall promoter was primarily active in ductal cells. These data will facilitate optimal expression cassette design for salivary gland gene transfer. C1 NIDCR, GTTB, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), NIDCR, GTTB, Dept Hlth & Human Serv, NIH, Bldg 10,Room 1N113,MSC-1190,10 Ctr Dr, Bethesda, MD 20892 USA. EM bbaum@dir.nidcr.nih.gov NR 43 TC 25 Z9 26 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD SEP PY 2005 VL 12 IS 3 BP 528 EP 536 DI 10.1016/j.ymthe.2005.03.008 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 960LP UT WOS:000231592400021 PM 16099414 ER PT J AU Chan, CC Chew, EY Shen, DF Hackett, J Zhuang, ZP AF Chan, CC Chew, EY Shen, DF Hackett, J Zhuang, ZP TI Expression of stem cells markers in ocular hemangioblastoma associated with von Hippel-Lindau (VHL) Disease SO MOLECULAR VISION LA English DT Article ID HIPPEL-LINDAU-DISEASE; ENDOTHELIAL GROWTH-FACTOR; TUMOR-SUPPRESSOR GENE; RECEPTOR INHIBITOR SU5416; CENTRAL-NERVOUS-SYSTEM; VHL GENE; ERYTHROPOIETIN RECEPTOR; CONGENITAL POLYCYTHEMIA; SIGNAL-TRANSDUCTION; RETINAL ANGIOMA AB Purpose: To better understand the histogenesis of ocular hemangioblastomas associated with von Hippel-Lindau (VHL) disease. Methods: We found that co-expression of Epo and EpoR may mediate developmental stagnation and induce proliferation of hemangioblastoma. All lesions were frozen and/or fixed in formalin and embedded in paraffin. The specimens were sectioned and subjected to routine histology, immunohistochemistry and molecular analyses. Avidin-biotin-complex immunoperoxidase was used to evaluate the expression of erythropoietin (Epo), Epo receptor (EpoR), CD31, CD34, CD117, and CD133. Ocular hemangioblastoma cells were microdissected in order to determine expression of Epo and EpoR transcripts using reverse transcription-polymerase chain reaction. Results: Tumorlet-like cells were identified in retinal and optic nerve hemangioblastomas. Co-expression of Epo and EpoR at both protein and messenger levels was detected in many hemangioblastoma cells. In addition, ocular VHL lesions expressed several stem cell markers including CD133 to various degrees. Conclusions: The data suggest that VHL disease-associated ocular hemangioblastomas are comprised of developmentally arrested stem cells including hemangioblasts, endothelial, and neuronal progenitor cells. We found that co-expression of Epo and EpoR may not only mediate developmental stagnation, but may also induce proliferation. Suppression of the growth of AC133/CD133 positive stem cells might be considered as one of the therapeutic targets for VHL-associated hemangioblastoma. C1 NEI, NIH, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Strokes, NIH, Bethesda, MD USA. RP Chan, CC (reprint author), NEI, NIH, Bldg 10,Room 10N103,10 Ctr Dr, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov FU Intramural NIH HHS [Z01 EY000222-22, Z99 EY999999] NR 60 TC 25 Z9 28 U1 0 U2 4 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 SEP 1 PY 2005 VL 11 IS 80-82 BP 697 EP 704 PG 8 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 964MH UT WOS:000231884700003 PM 16163267 ER PT J AU Back, SA Tuohy, TMF Chen, H Wallingford, N Craig, A Struve, J Luo, NL Banine, F Liu, Y Chang, A Trapp, BD Bebo, BF Rao, MS Sherman, LS AF Back, SA Tuohy, TMF Chen, H Wallingford, N Craig, A Struve, J Luo, NL Banine, F Liu, Y Chang, A Trapp, BD Bebo, BF Rao, MS Sherman, LS TI Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 21st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis/10th Annual Meeting of Rehabilitation in MS CY SEP 28-OCT 01, 2005 CL Thessaloniki, GREECE SP European Comm Treatment & Res Multiple Sclerosis C1 Oregon Hlth & Sci Univ, Portland, OR 97201 USA. NIH, Baltimore, MD USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Oregon Hlth & Sci Univ, Beaverton, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU HODDER ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2005 VL 11 SU 1 BP S179 EP S179 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969QO UT WOS:000232249900649 ER PT J AU Bagnato, F Talagala', L Calabrese, A Moll, FT Ohayon, JM Ikonomidou, VN Condon, E Hill, R Calabrese, M Oh, U Riva, M McFarland, HF AF Bagnato, F Talagala', L Calabrese, A Moll, FT Ohayon, JM Ikonomidou, VN Condon, E Hill, R Calabrese, M Oh, U Riva, M McFarland, HF TI In vivo visualisation of cortical lesions by 3 Tesla magnetic resonance imaging in patients with multiple sclerosis SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 21st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis/10th Annual Meeting of Rehabilitation in MS CY SEP 28-OCT 01, 2005 CL Thessaloniki, GREECE SP European Comm Treatment & Res Multiple Sclerosis C1 NINDS, NIB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU HODDER ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2005 VL 11 SU 1 BP S178 EP S178 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969QO UT WOS:000232249900644 ER PT J AU Calabrese, M Cao, M Gupta, S Ohayon, J Tovar-Moll, F Finamore, L Reynolds, RC Quinn, BT Fischl, B McFarland, HF Bagnato, F AF Calabrese, M Cao, M Gupta, S Ohayon, J Tovar-Moll, F Finamore, L Reynolds, RC Quinn, BT Fischl, B McFarland, HF Bagnato, F TI Neocortical damage is early and diffuse in patients with multiple sclerosis SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 21st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis/10th Annual Meeting of Rehabilitation in MS CY SEP 28-OCT 01, 2005 CL Thessaloniki, GREECE SP European Comm Treatment & Res Multiple Sclerosis C1 NIH, Bethesda, MD 20892 USA. New York Med Coll, Valhalla, NY 10595 USA. MIT, Cambridge, MA 02139 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HODDER ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2005 VL 11 SU 1 BP S2 EP S2 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969QO UT WOS:000232249900006 ER PT J AU Cao, M Calabrese, M Gupta, S Ostuni, J Ohayon, J Finamore, L Tovar-Moll, F Richert, N McFarland, HF Bagnato, F AF Cao, M Calabrese, M Gupta, S Ostuni, J Ohayon, J Finamore, L Tovar-Moll, F Richert, N McFarland, HF Bagnato, F TI Deep grey matter disease in multiple sclerosis: a primary or secondary pathogenetic process? SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 21st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis/10th Annual Meeting of Rehabilitation in MS CY SEP 28-OCT 01, 2005 CL Thessaloniki, GREECE SP European Comm Treatment & Res Multiple Sclerosis C1 NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HODDER ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2005 VL 11 SU 1 BP S57 EP S58 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969QO UT WOS:000232249900207 ER PT J AU Durastanti, V Bagnato, F Gupta, S Onesti, E Sbardella, E Pozzilli, C AF Durastanti, V Bagnato, F Gupta, S Onesti, E Sbardella, E Pozzilli, C TI Fatigue, depression and quality of life in secondary progressive multiple sclerosis: comparative study between mitoxantrone and interferon beta-1b treated patients SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 21st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis/10th Annual Meeting of Rehabilitation in MS CY SEP 28-OCT 01, 2005 CL Thessaloniki, GREECE SP European Comm Treatment & Res Multiple Sclerosis C1 Univ Roma La Sapienza, Rome, Italy. NIH, Bethesda, MD 20892 USA. New York Med Coll, New York, NY USA. RI Sbardella, Emilia/K-2167-2016 OI Sbardella, Emilia/0000-0002-9129-9065 NR 0 TC 0 Z9 0 U1 0 U2 0 PU HODDER ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2005 VL 11 SU 1 BP S94 EP S94 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969QO UT WOS:000232249900340 ER PT J AU Finamore, L Ohayon, JM Calabrese, A Richert, ND McFarland, HF Bagnato, E AF Finamore, L Ohayon, JM Calabrese, A Richert, ND McFarland, HF Bagnato, E TI Yearly clinical and imaging follow-up of patients with multiple sclerosis: a 14-year study SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 21st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis/10th Annual Meeting of Rehabilitation in MS CY SEP 28-OCT 01, 2005 CL Thessaloniki, GREECE SP European Comm Treatment & Res Multiple Sclerosis C1 Univ Roma La Sapienza, Rome, Italy. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HODDER ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2005 VL 11 SU 1 BP S57 EP S57 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969QO UT WOS:000232249900206 ER PT J AU Ikonomidou, V van Gelderen, R Tovar-Moll, E de Zwart, J Horovitz, S Calabrese, M Ohayon, J Tasciyan, T McFarland, HE Duyn, J Bagnato, F AF Ikonomidou, V van Gelderen, R Tovar-Moll, E de Zwart, J Horovitz, S Calabrese, M Ohayon, J Tasciyan, T McFarland, HE Duyn, J Bagnato, F TI Visualisation of fluid accumulation in T1 black holes using double inversion recovery SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 21st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis/10th Annual Meeting of Rehabilitation in MS CY SEP 28-OCT 01, 2005 CL Thessaloniki, GREECE SP European Comm Treatment & Res Multiple Sclerosis C1 NINDS, NIH, Bethesda, MD 20892 USA. RI Duyn, Jozef/F-2483-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU HODDER ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2005 VL 11 SU 1 BP S57 EP S57 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969QO UT WOS:000232249900205 ER PT J AU Pomeroy, IM Matthews, PM Frank, J Jordan, EK Esiri, MM AF Pomeroy, IM Matthews, PM Frank, J Jordan, EK Esiri, MM TI Decreased neuronal density within cortical lesions in an animal model of multiple sclerosis SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 21st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis/10th Annual Meeting of Rehabilitation in MS CY SEP 28-OCT 01, 2005 CL Thessaloniki, GREECE SP European Comm Treatment & Res Multiple Sclerosis C1 Univ Oxford, Oxford, England. Natl Inst Hlth, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HODDER ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2005 VL 11 SU 1 BP S44 EP S44 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969QO UT WOS:000232249900159 ER PT J AU Scagnolari, C Bellomi, F Bagnato, F De Vito, G Casato, M Di Marco, P Bramanti, P Antonelli, G AF Scagnolari, C Bellomi, F Bagnato, F De Vito, G Casato, M Di Marco, P Bramanti, P Antonelli, G TI Expression of interferon type I induced markers in patients suffering from multiple sclerosis and other chronic diseases SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 21st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis/10th Annual Meeting of Rehabilitation in MS CY SEP 28-OCT 01, 2005 CL Thessaloniki, GREECE SP European Comm Treatment & Res Multiple Sclerosis C1 Univ Roma La Sapienza, Rome, Italy. NIH, Bethesda, MD 20892 USA. Univ Messina, Messina, Italy. RI SCAGNOLARI, CAROLINA/G-3837-2011 OI SCAGNOLARI, CAROLINA/0000-0003-1044-1478 NR 0 TC 0 Z9 0 U1 0 U2 0 PU HODDER ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2005 VL 11 SU 1 BP S175 EP S176 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969QO UT WOS:000232249900635 ER PT J AU Scagnolari, C Bellomi, E Bagnato, F De Vito, G Alberelli, A Trombetti, S Antonelli, G AF Scagnolari, C Bellomi, E Bagnato, F De Vito, G Alberelli, A Trombetti, S Antonelli, G TI Binding antibodies do not affect the expression of interferon-(IFN)-induced markers in relapsing-remitting multiple sclerosis treated patients SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 21st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis/10th Annual Meeting of Rehabilitation in MS CY SEP 28-OCT 01, 2005 CL Thessaloniki, GREECE SP European Comm Treatment & Res Multiple Sclerosis C1 Univ Roma La Sapienza, Rome, Italy. NIH, Bethesda, MD 20892 USA. RI SCAGNOLARI, CAROLINA/G-3837-2011 OI SCAGNOLARI, CAROLINA/0000-0003-1044-1478 NR 0 TC 0 Z9 0 U1 0 U2 0 PU HODDER ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2005 VL 11 SU 1 BP S175 EP S175 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969QO UT WOS:000232249900634 ER PT J AU Sospedra, M Zhao, Y zur Hansen, H Muraro, P Hamashin, C de Viliers, E Pinilla, C Martin, R AF Sospedra, M Zhao, Y zur Hansen, H Muraro, P Hamashin, C de Viliers, E Pinilla, C Martin, R TI Arginine-enriched protein domains from the non-pathogenic torque teno virus and other common viruses trigger autoreactive T cells in multiple sclerosis SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 21st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis/10th Annual Meeting of Rehabilitation in MS CY SEP 28-OCT 01, 2005 CL Thessaloniki, GREECE SP European Comm Treatment & Res Multiple Sclerosis C1 Vall Hebron Univ Hosp, Barcelona, Spain. NCI, NIH, Bethesda, MD 20892 USA. Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. NINDS, NIH, Bethesda, MD 20892 USA. Mixture Sci, San Diego, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU HODDER ARNOLD, HODDER HEADLINE PLC PI LONDON PA 338 EUSTON ROAD, LONDON NW1 3BH, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD SEP PY 2005 VL 11 SU 1 BP S135 EP S135 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969QO UT WOS:000232249900495 ER PT J AU Major, EO Ryschkewitsch, C Fahle, G Fischer, S Hou, J Curfman, B Clifford, D Yoursy, T AF Major, EO Ryschkewitsch, C Fahle, G Fischer, S Hou, J Curfman, B Clifford, D Yoursy, T TI The laboratory evaluation for JC Virus DNA in cerebrospinal fluid and plasma from multiple sclerosis patients participating in the phase III clinical trials of natalizumab SO MULTIPLE SCLEROSIS JOURNAL LA English DT Meeting Abstract CT 21st Congress of the European-Committee/10th Annual Meeting of the American-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis CY SEP 28-OCT 01, 2005 CL Thessaloniki, GREECE SP European Comm Treatment & Res Multiple Sclerosis C1 NINDS, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. Washington Univ, St Louis, MO USA. UCL, London, England. NR 0 TC 4 Z9 4 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER J JI Mult. Scler. J. PD SEP PY 2005 VL 11 SU 1 BP S181 EP S181 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 969QO UT WOS:000232249900653 ER PT J AU Cheng, Z Ventura, M She, XW Khaitovich, P Graves, T Osoegawa, K Church, D DeJong, P Wilson, RK Paabo, S Rocchi, M Eichler, EE AF Cheng, Z Ventura, M She, XW Khaitovich, P Graves, T Osoegawa, K Church, D DeJong, P Wilson, RK Paabo, S Rocchi, M Eichler, EE TI A genome-wide comparison of recent chimpanzee and human segmental duplications SO NATURE LA English DT Article ID HUMAN-CHROMOSOMES; GENE FAMILY; EVOLUTION; REGIONS; REARRANGEMENTS; SELECTION; PATTERNS; SEQUENCE; LINEAGE; MOUSE AB We present a global comparison of differences in content of segmental duplication between human and chimpanzee, and determine that 33% of human duplications (>94% sequence identity) are not duplicated in chimpanzee, including some human disease-causing duplications. Combining experimental and computational approaches, we estimate a genomic duplication rate of 4 - 5 megabases per million years since divergence. These changes have resulted in gene expression differences between the species. In terms of numbers of base pairs affected, we determine that de novo duplication has contributed most significantly to differences between the species, followed by deletion of ancestral duplications. Post-speciation gene conversion accounts for less than 10% of recent segmental duplication. Chimpanzee-specific hyperexpansion (. 100 copies) of particular segments of DNA have resulted in marked quantitative differences and alterations in the genome landscape between chimpanzee and human. Almost all of the most extreme differences relate to changes in chromosome structure, including the emergence of African great ape subterminal heterochromatin. Nevertheless, base per base, large segmental duplication events have had a greater impact (2.7%) in altering the genomic landscape of these two species than single-base-pair substitution (1.2%). C1 Univ Washington, Sch Med, Dept Genome Sci, Howard Hughes Med Inst, Seattle, WA 98195 USA. Univ Bari, Dept Genet & Microbiol, I-70126 Bari, Italy. Max Planck Inst Evolutionary Anthropol, D-04103 Leipzig, Germany. Washington Univ, Sch Med, St Louis, MO 63108 USA. Childrens Hosp Oakland, Res Inst, BACPAC Resources, Oakland, CA 94609 USA. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Eichler, EE (reprint author), Univ Washington, Sch Med, Dept Genome Sci, Howard Hughes Med Inst, 1705 NE Pacific St, Seattle, WA 98195 USA. EM eee@gs.washington.edu RI Ventura, Mario/E-6420-2011; OI Ventura, Mario/0000-0001-7762-8777; Rocchi, Mariano/0000-0002-9451-5616 NR 30 TC 227 Z9 243 U1 4 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 1 PY 2005 VL 437 IS 7055 BP 88 EP 93 DI 10.1038/nature04000 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 960AC UT WOS:000231560400046 PM 16136132 ER PT J AU Im, YJ Raychaudhuri, S Prinz, WA Hurley, JH AF Im, YJ Raychaudhuri, S Prinz, WA Hurley, JH TI Structural mechanism for sterol sensing and transport by OSBP-related proteins SO NATURE LA English DT Article ID OXYSTEROL-BINDING-PROTEIN; PHOSPHATIDYLINOSITOL-TRANSFER PROTEIN; TOCOPHEROL TRANSFER PROTEIN; CRYSTAL-STRUCTURE; LIGAND-BINDING; LIPID-BINDING; DOMAIN; PHOSPHATIDYLCHOLINE; MEMBRANES; HOMOLOGS AB The oxysterol-binding-protein (OSBP)-related proteins (ORPs) are conserved from yeast to humans(1,2), and are implicated in the regulation of sterol homeostasis(3,4) and in signal transduction pathways(5). Here we report the structure of the full-length yeast ORP Osh4 (also known as Kes1) at 1.5 - 1.9 angstrom resolution in complexes with ergosterol, cholesterol, and 7-, 20- and 25-hydroxycholesterol. We find that a single sterol molecule binds within a hydrophobic tunnel in a manner consistent with a transport function for ORPs. The entrance is blocked by a flexible amino-terminal lid and surrounded by basic residues that are critical for Osh4 function. The structure of the open state of a lid-truncated form of Osh4 was determined at 2.5 angstrom resolution. Structural analysis and limited proteolysis show that sterol binding closes the lid and stabilizes a conformation favouring transport across aqueous barriers and signal transmission. The structure of Osh4 in the absence of ligand exposes potential phospholipid-binding sites that are positioned for membrane docking and sterol exchange. On the basis of these observations, we propose a model in which sterol and membrane binding promote reciprocal conformational changes that facilitate a sterol transfer and signalling cycle. C1 NIDDKD, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIDDKD, Lab Cell Biochem & Biol, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Gwangju Inst Sci & Technol, Dept Life Sci, Gwangju City 500712, South Korea. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov OI Raychaudhuri, Sumana/0000-0002-3164-0057 FU Intramural NIH HHS; NIDDK NIH HHS [Z01 DK036118-12] NR 30 TC 205 Z9 209 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 1 PY 2005 VL 437 IS 7055 BP 154 EP 158 DI 10.1038/nature03923 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 960AC UT WOS:000231560400060 PM 16136145 ER PT J AU Veigel, C Schmitz, S Wang, F Sellers, JR AF Veigel, C Schmitz, S Wang, F Sellers, JR TI Load-dependent kinetics of myosin-V can explain its high processivity SO NATURE CELL BIOLOGY LA English DT Article ID SMOOTH-MUSCLE MYOSIN; STEPPING KINETICS; OPTICAL TWEEZERS; WORKING STROKE; MOTOR; FORCE; MECHANISM; MOVEMENT; BINDING; HEADS AB Recent studies provide strong evidence that single myosin class V molecules transport vesicles and organelles processively along F- actin, taking several 36- nm steps, ' hand over hand', for each diffusional encounter. The mechanisms regulating myosin- V's processivity remain unknown. Here, we have used an optical- tweezers- based transducer to measure the effect of load on the mechanical interactions between rabbit skeletal F- actin and a single head of mouse brain myosin- V, which produces its working stroke in two phases. We found that the lifetimes of the first phase of the working stroke changed exponentially and about 10-fold over a range of pushing and pulling forces of +/- 1.5 pN. Stiffness measurements suggest that intramolecular forces could approach 3.6 pN when both heads are bound to F- actin, in which case extrapolation would predict the detachment kinetics of the front head to slow down 50- fold and the kinetics of the rear head to accelerate respectively. This synchronizing effect on the chemo- mechanical cycles of the heads increases the probability of the trail head detaching first and causes a strong increase in the number of forward steps per diffusional encounter over a system with no strain dependence. C1 Natl Inst Med Res, London NW7 1AA, England. NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Veigel, C (reprint author), Natl Inst Med Res, Ridgeway,Mill Hill, London NW7 1AA, England. EM cveigel@nimr.mrc.ac.uk FU Medical Research Council [MC_U117570593] NR 41 TC 169 Z9 170 U1 1 U2 15 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 SEP PY 2005 VL 7 IS 9 BP 861 EP 869 DI 10.1038/ncb1287 PG 9 WC Cell Biology SC Cell Biology GA 960NY UT WOS:000231601600009 PM 16100513 ER PT J AU Meetei, AR Medhurst, AL Ling, C Xue, YT Singh, TR Bier, P Steltenpool, J Stone, S Dokal, I Mathew, CG Hoatlin, M Joenje, H de Winter, JP Wang, WD AF Meetei, AR Medhurst, AL Ling, C Xue, YT Singh, TR Bier, P Steltenpool, J Stone, S Dokal, I Mathew, CG Hoatlin, M Joenje, H de Winter, JP Wang, WD TI A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M SO NATURE GENETICS LA English DT Article ID HOMOLOGOUS RECOMBINATION; ENDONUCLEASE; HELICASE; NUCLEASE; DAMAGE; GENE; ATP; DEFICIENT; MUTATION; COMPLEX AB Fanconi anemia is a genetic disease characterized by genomic instability and cancer predisposition(1). Nine genes involved in Fanconi anemia have been identified; their products participate in a DNA damage - response network involving BRCA1 and BRCA2 ( refs. 2,3). We previously purified a Fanconi anemia core complex containing the FANCL ubiquitin ligase and six other Fanconi anemia associated proteins(4 - 6). Each protein in this complex is essential for monoubiquitination of FANCD2, a key reaction in the Fanconi anemia DNA damage - response pathway(2,7). Here we show that another component of this complex, FAAP250, is mutant in individuals with Fanconi anemia of a new complementation group ( FA- M). FAAP250 or FANCM has sequence similarity to known DNA- repair proteins, including archaeal Hef, yeast MPH1 and human ERCC4 or XPF. FANCM can dissociate DNA triplex, possibly owing to its ability to translocate on duplex DNA. FANCM is essential for monoubiquitination of FANCD2 and becomes hyperphosphorylated in response to DNA damage. Our data suggest an evolutionary link between Fanconi anemia associated proteins and DNA repair; FANCM may act as an engine that translocates the Fanconi anemia core complex along DNA. C1 VU Univ Med Ctr, Dept Clin Genet & Human Genet, NL-1081 BT Amsterdam, Netherlands. Cincinnati Childrens Hosp, Div Expt Hematol, Cincinnati, OH 45229 USA. Univ Cincinnati, Coll Med, Cincinnati, OH 45229 USA. NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. Oregon Hlth Sci Univ, Div Mol Med & Mol & Med Genet NRC3, Portland, OR 97239 USA. Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Haematol, London, England. Univ London Kings Coll, Guys Kings & St Thomas Sch Med, Dept Med & Mol Genet, London WC2R 2LS, England. RP de Winter, JP (reprint author), VU Univ Med Ctr, Dept Clin Genet & Human Genet, Van der Boechorststr 7, NL-1081 BT Amsterdam, Netherlands. EM j.dewinter@vumc.nl; wangw@grc.nia.nih.gov RI Mathew, Christopher/G-3434-2015 OI Mathew, Christopher/0000-0003-4178-1838 FU Intramural NIH HHS; NCI NIH HHS [R01 CA112775] NR 30 TC 278 Z9 296 U1 1 U2 12 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 SEP PY 2005 VL 37 IS 9 BP 958 EP 963 DI 10.1038/ng1626 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 960LK UT WOS:000231591900020 PM 16116422 ER PT J AU Metcalfe, DD AF Metcalfe, DD TI Genetically modified crops and allergenicity SO NATURE IMMUNOLOGY LA English DT Editorial Material ID FOOD ALLERGENS; PROTEINS; LIFE; SENSITIZATION; CHILDREN AB Among the concerns surrounding genetically modified crops has been the possibility of expressing within a plant new proteins that may be allergenic. Using available technology, practical approaches have been adopted to help prevent the creation of foods that are allergenic. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Metcalfe, DD (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dmetcalfe@niaid.nih.gov NR 24 TC 17 Z9 17 U1 0 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 SEP PY 2005 VL 6 IS 9 BP 857 EP 860 DI 10.1038/ni0905-857 PG 4 WC Immunology SC Immunology GA 957KX UT WOS:000231369800003 PM 16116460 ER PT J AU Rogawski, MA AF Rogawski, MA TI Astrocytes get in the act in epilepsy SO NATURE MEDICINE LA English DT Editorial Material ID NEURONAL-ACTIVITY; EPILEPTOGENESIS AB Neurons in the brain of individuals with focal epilepsy exhibit sustained discharges, called paroxysmal depolarization shifts. Unexpected new evidence indicates that glutamate release from glia can generate these events, and may serve to synchronize the activity of neurons ( pages 973 - 981). C1 NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. RP Rogawski, MA (reprint author), NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. EM michael.rogawski@nih.gov RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 FU NINDS NIH HHS [Z01 NS002732-19] NR 13 TC 26 Z9 29 U1 0 U2 2 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 SEP PY 2005 VL 11 IS 9 BP 919 EP 920 DI 10.1038/nm0905-919 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 962IL UT WOS:000231724700011 PM 16145568 ER PT J AU DeLeo, FR Hinnebusch, BJ AF DeLeo, FR Hinnebusch, BJ TI A plague upon the phagocytes SO NATURE MEDICINE LA English DT Editorial Material ID RECOMBINANT V-ANTIGEN; YERSINIA-PESTIS; PROTECTS MICE; IMMUNITY; VACCINE; ROLES; CELLS AB Plague bacteria are renowned for causing some of the most devastating epidemics in human history. We are now closer to understanding why: the pathogen selectively disarms key cells of the innate immune system, weakening the front- line defenses of the body. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP DeLeo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.govor; jhinnebusch@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 NR 13 TC 5 Z9 5 U1 0 U2 1 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 SEP PY 2005 VL 11 IS 9 BP 927 EP 928 DI 10.1038/nm0905-925 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 962IL UT WOS:000231724700016 PM 16145573 ER PT J AU Back, SA Tuohy, TMF Chen, HQ Wallingford, N Craig, A Struve, J Luo, NL Banine, F Liu, Y Chang, A Trapp, BD Bebo, BF Rao, MS Sherman, LS AF Back, SA Tuohy, TMF Chen, HQ Wallingford, N Craig, A Struve, J Luo, NL Banine, F Liu, Y Chang, A Trapp, BD Bebo, BF Rao, MS Sherman, LS TI Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation SO NATURE MEDICINE LA English DT Article ID MULTIPLE-SCLEROSIS LESIONS; PRECURSOR CELLS; CD44 EXPRESSION; DENDRITIC CELLS; WHITE-MATTER; SPINAL-CORD; T-CELLS; ASTROCYTES; ADULT; BRAIN AB Demyelination is the hallmark of numerous neurodegenerative conditions, including multiple sclerosis. Oligodendrocyte progenitors ( OPCs), which normally mature into myelin- forming oligodendrocytes, are typically present around demyelinated lesions but do not remyelinate affected axons. Here, we find that the glycosaminoglycan hyaluronan accumulates in demyelinated lesions from individuals with multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. A high molecular weight ( HMW) form of hyaluronan synthesized by astrocytes accumulates in chronic demyelinated lesions. This form of hyaluronan inhibits remyelination after lysolecithin- induced white matter demyelination. OPCs accrue and do not mature into myelin- forming cells in demyelinating lesions where HMW hyaluronan is present. Furthermore, the addition of HMW hyaluronan to OPC cultures reversibly inhibits progenitor- cell maturation, whereas degrading hyaluronan in astrocyte- OPC cocultures promotes oligodendrocyte maturation. HMW hyaluronan may therefore contribute substantially to remyelination failure by preventing the maturation of OPCs that are recruited to demyelinating lesions. C1 Oregon Hlth Sci Univ, Oregon Natl Primate Res Ctr, Div Neurosci, Beaverton, OR 97006 USA. Oregon Hlth Sci Univ, Dept Pediat, Portland, OR 97239 USA. Oregon Hlth Sci Univ, Dept Neurol, Sch Med, Portland, OR 97239 USA. NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. Cleveland Clin Fdn, Lerner Res Inst, Dept Neurosci, Cleveland, OH 44195 USA. Oregon Hlth Sci Univ, Inst Neurol Sci, Beaverton, OR 97006 USA. RP Sherman, LS (reprint author), Oregon Hlth Sci Univ, Oregon Natl Primate Res Ctr, Div Neurosci, 505 NW 185th Ave, Beaverton, OR 97006 USA. EM shermanl@ohsu.edu RI Tuohy, Therese/A-8665-2009 FU NCCIH NIH HHS [AT001517]; NCRR NIH HHS [RR00163]; NINDS NIH HHS [NS39550] NR 46 TC 253 Z9 256 U1 2 U2 12 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 SEP PY 2005 VL 11 IS 9 BP 966 EP 972 DI 10.1038/nm1279 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 962IL UT WOS:000231724700024 PM 16086023 ER PT J AU Neelapu, SS Kwak, LW Kobrin, CB Reynolds, CW Janik, JE Dunleavy, K White, T Harvey, L Pennington, R Stetler-Stevenson, M Jaffe, ES Steinberg, SM Gress, R Hakim, F Wilson, WH AF Neelapu, SS Kwak, LW Kobrin, CB Reynolds, CW Janik, JE Dunleavy, K White, T Harvey, L Pennington, R Stetler-Stevenson, M Jaffe, ES Steinberg, SM Gress, R Hakim, F Wilson, WH TI Vaccine-induced tumor-specific immunity despite severe B-cell depletion in mantle cell lymphoma SO NATURE MEDICINE LA English DT Article ID COLONY-STIMULATING FACTOR; DOSE-ADJUSTED EPOCH; T-CELLS; RESPONSES; ANTIGEN; INDUCTION; MEMORY; GENERATION; RITUXIMAB; VARIANTS AB The role of B cells in T- cell priming is unclear, and the effects of B- cell depletion on immune responses to cancer vaccines are unknown. Although results from some mouse models suggest that B cells may inhibit induction of T cell - dependent immunity by competing with antigen- presenting cells for antigens, skewing T helper response toward a T helper 2 profile and/ or inducing T- cell tolerance(1-4), results from others suggest that B cells are necessary for priming as well as generation of T- cell memory(5-7). We assessed immune responses to a wellcharacterized idiotype vaccine in individuals with severe B- cell depletion but normal T cells after CD20- specific antibody based chemotherapy of mantle cell lymphoma in first remission. Humoral antigen- and tumor- specific responses were detectable but delayed, and they correlated with peripheral blood B- cell recovery. In contrast, vigorous CD4(+) and CD8(+) antitumor type I T- cell cytokine responses were induced in most individuals in the absence of circulating B cells. Analysis of relapsing tumors showed no mutations or change in expression of target antigen to explain escape from therapy. These results show that severe B- cell depletion does not impair T- cell priming in humans. Based on these results, it is justifiable to administer vaccines in the setting of B- cell depletion; however, vaccine boosts after B- cell recovery may be necessary for optimal humoral responses. C1 NCI, Expt & Transplantat Immunol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, SAIC, Frederick, MD 21702 USA. NCI, Off Sci Operat, Frederick, MD 21702 USA. NCI, Biostat & Data Management Sect, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Kwak, LW (reprint author), Univ Texas, MD Anderson Canc Ctr, Div Canc Med, Dept Lymphoma & Myeloma, 1515 Holcombe Blvd,Unit 429, Houston, TX 77030 USA. EM lkwak@mdanderson.org NR 31 TC 75 Z9 78 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 SEP PY 2005 VL 11 IS 9 BP 986 EP 991 DI 10.1038/nm1290 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 962IL UT WOS:000231724700027 PM 16116429 ER PT J AU Martin, A Gotts, SJ AF Martin, A Gotts, SJ TI Making the causal link: frontal cortex activity and repetition priming SO NATURE NEUROSCIENCE LA English DT Editorial Material ID INFERIOR PREFRONTAL CORTEX; MEMORY; MECHANISMS; KNOWLEDGE; BRAIN AB Object identification improves with repeated presentation, but neural activity decreases. In a new study, disrupting inferior frontal activity with transcranial magnetic stimulation during initial exposure to an object blocks later behavioral and neural changes. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Martin, A (reprint author), NIMH, Lab Brain & Cognit, Bldg 10 Room 4C-104, Bethesda, MD 20892 USA. EM alexmartin@mail.nih.gov RI martin, alex/B-6176-2009; Gotts, Stephen/J-4842-2012 NR 15 TC 6 Z9 6 U1 2 U2 4 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 SEP PY 2005 VL 8 IS 9 BP 1134 EP 1135 DI 10.1038/nn0905-1134 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 958YJ UT WOS:000231483800007 PM 16127445 ER PT J AU Chen, XK Wang, LC Zhou, Y Cai, Q Prakriya, M Duan, KL Sheng, ZH Lingle, C Zhou, Z AF Chen, XK Wang, LC Zhou, Y Cai, Q Prakriya, M Duan, KL Sheng, ZH Lingle, C Zhou, Z TI Activation of GPCRs modulates quantal size in chromaffin cells through G(beta gamma) and PKC SO NATURE NEUROSCIENCE LA English DT Article ID PROTEIN-KINASE-C; FUSION PORE KINETICS; BETA-GAMMA-SUBUNITS; TRANSMITTER RELEASE; NEUROTRANSMITTER RELEASE; PRESYNAPTIC INHIBITION; SECRETORY GRANULES; VESICLE FUSION; EXOCYTOSIS; RECEPTOR AB Exocytosis proceeds by either full fusion or 'kiss-and-run' between vesicle and plasma membrane. Switching between these two modes permits the cell to regulate the kinetics and amount of secretion. Here we show that ATP receptor activation reduces secretion downstream from cytosolic Ca2+ elevation in rat adrenal chromaffin cells. This reduction is mediated by activation of a pertussis toxin - sensitive G(i/o) protein, leading to activation of G(beta gamma) subunits, which promote the `kiss-and-run' mode by reducing the total open time of the fusion pore during a vesicle fusion event. Furthermore, parallel activation of the muscarinic acetylcholine receptor removes the inhibitory effects of ATP on secretion. This is mediated by a G(q) pathway through protein kinase C activation. The inhibitory effects of ATP and its reversal by protein kinase C activation are also shared by opioids and somatostatin. Thus, a variety of G protein pathways exist to modulate Ca2+-evoked secretion at specific steps in fusion pore formation. C1 Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Neurosci, Shanghai 200031, Peoples R China. Chinese Acad Sci, Grad Sch, Shanghai 200031, Peoples R China. Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. NINDS, Synapt Funct Unit, Bethesda, MD 20892 USA. Washington Univ, Dept Anesthesiol, St Louis, MO 63110 USA. Peking Univ, Coll Life Sci, State Key Lab Biomembrane Engn, Beijing 100871, Peoples R China. RP Zhou, Z (reprint author), Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Neurosci, Shanghai 200031, Peoples R China. EM zzhou@pku.edu.cn RI zhou, zhuan/A-8285-2011; chen, xiaoke/E-5385-2011 FU NIDDK NIH HHS [DK46564, R01 DK046564] NR 39 TC 59 Z9 59 U1 0 U2 6 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 SEP PY 2005 VL 8 IS 9 BP 1160 EP 1168 DI 10.1038/nn1529 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 958YJ UT WOS:000231483800015 PM 16116443 ER PT J AU Cryan, JF Holmes, A AF Cryan, JF Holmes, A TI The ascent of mouse: Advances in modelling human depression and anxiety SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID CONDITIONED TASTE-AVERSION; ASSESSING ANTIDEPRESSANT ACTIVITY; POTENTIATED STARTLE PARADIGM; STRESS-INDUCED HYPERTHERMIA; DRUG DEVELOPMENT COSTS; FORCED SWIMMING TEST; PROBE BURYING TEST; ANIMAL-MODELS; MICE LACKING; SEROTONIN TRANSPORTER AB Psychiatry has proven to be among the least penetrable clinical disciplines for the development of satisfactory in vivo model systems for evaluating novel treatment approaches. However, mood and anxiety disorders remain poorly understood and inadequately treated. With the explosion in the use of genetically modified mice, enormous research efforts have been focused on developing mouse models of psychiatric disorders. The success of this approach is largely contingent on the usefulness of available behavioural models of depression- and anxiety-related behaviours in mice. Here, we assess the current status of research into developing appropriate tests for assessing such behaviours. C1 Novartis Inst Biomed Res, CH-4055 Basel, Switzerland. NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. RP Cryan, JF (reprint author), Novartis Inst Biomed Res, CH-4055 Basel, Switzerland. EM johncryan@hotmail.com; holmesan@mail.nih.gov RI Cryan, John/A-6950-2013 OI Cryan, John/0000-0001-5887-2723 NR 181 TC 590 Z9 608 U1 14 U2 106 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD SEP PY 2005 VL 4 IS 9 BP 775 EP 790 DI 10.1038/nrd1825 PG 16 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 970VP UT WOS:000232340800025 PM 16138108 ER PT J AU Leonard, WJ Spolski, R AF Leonard, WJ Spolski, R TI Interleukin-21: A modulator of lymphoid proliferation, apoptosis and differentiation SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID SEVERE COMBINED IMMUNODEFICIENCY; RECEPTOR-GAMMA-CHAIN; T-CELL-ACTIVATION; VIVO ANTITUMOR-ACTIVITY; DNA-BINDING ACTIVITY; IN-VIVO; DEFICIENT MICE; NATURAL-KILLER; NK CELLS; B-CELLS AB The interleukin-21 (IL-21) - IL-21-receptor system was discovered in 2000. It was immediately of great interest because of the homology of IL-21 to IL-2, IL-4 and IL-15, and of the IL-21-receptor subunit IL-21R to the beta-subunit of the IL-2 receptor, and because the IL-21 receptor also contains the common cytokine-receptor gamma-chain, the protein that is mutated in X-linked severe combined immunodeficiency. As we discuss, IL-21 has pleiotropic actions, from augmenting the proliferation of T cells and driving the differentiation of B cells into memory cells and terminally differentiated plasma cells to augmenting the activity of natural killer cells. Moreover, it has antitumour activity and might have a role in the development of autoimmunity, so these findings have implications for the treatment of cancer and autoimmune diseases. C1 NHLBI, Lab Mol Immunol, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, Bldg 10, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov FU Intramural NIH HHS NR 93 TC 289 Z9 295 U1 0 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD SEP PY 2005 VL 5 IS 9 BP 688 EP 698 DI 10.1038/nri1688 PG 11 WC Immunology SC Immunology GA 960NW UT WOS:000231601400009 PM 16138102 ER PT J AU Hennighausen, L Robinson, GW AF Hennighausen, L Robinson, GW TI Information networks in the mammary gland SO NATURE REVIEWS MOLECULAR CELL BIOLOGY LA English DT Review ID ACIDIC PROTEIN GENE; ESTROGEN-RECEPTOR-ALPHA; GROWTH-FACTOR RECEPTOR; PROGESTERONE-RECEPTOR; PROLACTIN RECEPTOR; KNOCKOUT MICE; EPITHELIAL-CELLS; TRANSGENIC MICE; CYCLIN D1; LOBULOALVEOLAR DEVELOPMENT AB Unique developmental features during puberty, pregnancy, lactation and post-lactation make the mammary gland a prime object to explore genetic circuits that control the specification, proliferation, differentiation, survival and death of cells. Steroids and simple peptide hormones initiate and carry out complex developmental programmes, and reverse genetics has been used to define the underlying mechanistic connections. C1 NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Hennighausen, L (reprint author), NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. EM lotharh@amb.niddk.nih.gov RI Robinson, Gertraud/I-2136-2012 FU Intramural NIH HHS NR 80 TC 254 Z9 259 U1 3 U2 31 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 SEP PY 2005 VL 6 IS 9 BP 715 EP 725 DI 10.1038/nrm1714 PG 11 WC Cell Biology SC Cell Biology GA 960OA UT WOS:000231601800013 PM 16231422 ER PT J AU Adams, JP Dudek, SM AF Adams, JP Dudek, SM TI Opinion - Late-phase long-term potentiation: getting to the nucleus SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID IMMEDIATE-EARLY GENE; CULTURED HIPPOCAMPAL-NEURONS; D-ASPARTATE RECEPTORS; RAT DENTATE GYRUS; SYNAPTIC PLASTICITY; PROTEIN-KINASE; MESSENGER-RNA; CA1 REGION; IN-VIVO; LASTING POTENTIATION AB New mRNA must be transcribed in order to consolidate changes in synaptic strength. But how are events at the synapse communicated to the nucleus? Some research has shown that proteins can move from activated synapses to the nucleus. However, other work has shown that action potentials can directly inform the nucleus about cellular activation. Here we contend that action potential- induced signalling to the nucleus best meets the requirements of the consolidation of synapse- specific plasticity, which include both timing and stoichiometric constraints. C1 NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Dudek, SM (reprint author), NIEHS, Neurobiol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM dudek@niehs.nih.gov NR 83 TC 44 Z9 46 U1 3 U2 4 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 SEP PY 2005 VL 6 IS 9 BP 737 EP 743 DI 10.1038/nrn1749 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 960LJ UT WOS:000231591700016 PM 16136174 ER PT J AU Longo, A Leonard, CW Bassi, GS Berndt, D Krahn, JM Hall, TMT Weeks, KM AF Longo, A Leonard, CW Bassi, GS Berndt, D Krahn, JM Hall, TMT Weeks, KM TI Evolution from DNA to RNA recognition by the bI3 LAGLIDADG maturase SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID GROUP-I INTRON; HOMING-ENDONUCLEASE; CRYSTAL-STRUCTURE; SACCHAROMYCES-CEREVISIAE; ASPERGILLUS-NIDULANS; SPLICING ACTIVITY; ELECTRON-DENSITY; DIFFRACTION DATA; MESSENGER-RNA; PROTEINS AB LAGLIDADG endonucleases bind across adjacent major grooves via a saddle-shaped surface and catalyze DNA cleavage. Some LAGLIDADG proteins, called maturases, facilitate splicing by group I introns, raising the issue of how a DNA-binding protein and an RNA have evolved to function together. In this report, crystallographic analysis shows that the global architecture of the bI3 maturase is unchanged from its DNA-binding homologs; in contrast, the endonuclease active site, dispensable for splicing facilitation, is efficiently compromised by a lysine residue replacing essential catalytic groups. Biochemical experiments show that the maturase binds a peripheral RNA domain 50 A from the splicing active site, exemplifying long-distance structural communication in a ribonucleoprotein complex. The bI3 maturase nucleic acid recognition saddle interacts at the RNA minor groove; thus, evolution from DNA to RNA function has been mediated by a switch from major to minor groove interaction. C1 Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Hall, TMT (reprint author), Univ N Carolina, Dept Chem, CB 3290, Chapel Hill, NC 27599 USA. EM hall4@niehs.nih.gov FU Intramural NIH HHS; NIGMS NIH HHS [GM56222] NR 49 TC 21 Z9 22 U1 0 U2 3 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 SEP PY 2005 VL 12 IS 9 BP 779 EP 787 DI 10.1038/nsmb976 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 961WD UT WOS:000231691600017 PM 16116439 ER PT J AU Kernich, CA AF Kernich, CA TI Stem cell research SO NEUROLOGIST LA English DT Article C1 Univ Hosp Hlth Syst, Univ Hosp Fac Serv, Dept Med, Cleveland, OH USA. RP Kernich, CA (reprint author), NIH, 9000 Rockville Pike, 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 19106-3261 USA SN 1074-7931 J9 NEUROLOGIST JI Neurologist PD SEP PY 2005 VL 11 IS 5 BP 309 EP 310 DI 10.1097/01.nrl.0000178760.72695.9c PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 965NF UT WOS:000231956500007 PM 16148739 ER PT J AU Le Foll, B Goldberg, SR Sokoloff, P AF Le Foll, B Goldberg, SR Sokoloff, P TI The dopamine D-3 receptor and drug dependence: Effects on reward or beyond? SO NEUROPHARMACOLOGY LA English DT Review DE dopamine D-3 receptor; nucleus accumbens shell; conditioned place preference; reward; discrimination; sensitization; cocaine; drug-associated cues ID COCAINE-SEEKING BEHAVIOR; CONDITIONED PLACE PREFERENCE; SELF-ADMINISTERED COCAINE; NEUROTROPHIC FACTOR; NUCLEUS-ACCUMBENS; DISCRIMINATIVE-STIMULUS; DEFICIENT MICE; MESSENGER-RNA; MUTANT MICE; RAT-BRAIN AB Abused drugs (alcohol, heroin, cocaine, tetrahydrocannabinol and nicotine) elicit a variety of chronically relapsing disorders by interacting with brain reward systems. All of these drugs increase dopamine levels in the shell of nucleus accumbens, a structure that has been involved in their hedonic and reinforcing properties. Dopamine D-3 receptors (DRD3) are predominantly expressed in the nucleus accumbens, but also in the ventral tegmental area and in the amygdala, brain structures implicated in drug dependence. Moreover, converging pharmacological, human post-mortem and genetic studies have suggested the involvement of the DRD3 in drug dependence. Based on early studies using non-selective DRD3 ligands, the DRD3 was proposed as having a direct role in the rewarding effects of psychostimulants. However, recent studies using highly selective DRD3 ligands and the DRD3-deficient mice have revealed that the DRD3 is not implicated in the direct reinforcing effects of drugs of abuse. In contrast, the DRD3 appears to be implicated in the motivation to self-administer drugs under schedules where the response requirements are high. This is consistent with a behavioral economic analysis, with the effects of DRD3 ligands revealed only in situations with high prices for drug. Drug-self administration and relapse are strongly controlled by environmental stimuli. The DRD3 strongly modulates the influence of these environmental stimuli on drug-seeking behavior. DRD3 blockade disrupts the reactivity to drug-associated stimuli in various paradigms, such as second-order schedules of drug-self administration, conditioned place preference and Pavlovian conditioning procedures. In several paradigms, the involvement of the DRD3 has been confirmed by using DRD3-deficient mice. On the contrary, reactivity to stimuli associated with natural reinforcers, such as food, appears unaffected by modulation of the DRD3. All these findings suggest that DRD3 ligands may represent a useful strategy for decreasing relapse in abstinent drug-abusers. (c) 2005 Elsevier Ltd. All rights reserved. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. INSERM, Ctr Paul Broca, U573, Unite Neurobiol & Pharmacol Mol, F-75014 Paris, 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 129 TC 120 Z9 121 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP PY 2005 VL 49 IS 4 BP 525 EP 541 DI 10.1016/j.neuropharm.2005.04.022 PG 17 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 963BO UT WOS:000231778000010 PM 15963538 ER PT J AU Bergen, AW Yeager, M Welch, RA Haque, K Ganjei, JK van den Bree, MBM Mazzanti, C Nardi, I Fichter, MM Halmi, KA Kaplan, AS Strober, M Treasure, J Woodside, DB Bulik, CM Bacanu, SA Devlin, B Berrettini, WH Goldman, D Kaye, WH AF Bergen, AW Yeager, M Welch, RA Haque, K Ganjei, JK van den Bree, MBM Mazzanti, C Nardi, I Fichter, MM Halmi, KA Kaplan, AS Strober, M Treasure, J Woodside, DB Bulik, CM Bacanu, SA Devlin, B Berrettini, WH Goldman, D Kaye, WH TI Association of multiple DRD2 Polymorphisms with anorexia nervosa SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE anorexia nervosa; case-control studies; female; haplotypes; linkage disequilibrium; dopamine D2 ID DOPAMINE D2 RECEPTOR; FAMILY-BASED ASSOCIATION; POPULATION-BASED TWIN; BULIMIA-NERVOSA; HAPLOTYPE FREQUENCIES; EATING-DISORDERS; LINKAGE ANALYSIS; GENERAL-CLASS; BEHAVIOR; POWER AB To investigate whether the dopaminergic system plays a role in the etiology of anorexia nervosa (AN) via the dopamine D2 receptor, we investigated association and transmission disequilibrium at seven single-nucleotide polymorphisms (SNPs) spanning about 75 kbp of the gene DRD2. We studied 191 probands with a DSM-IV diagnosis of AN, 457 parents and affected relatives with a DSM-IV eating disorder diagnosis, and 98 unrelated, female, normal weight controls. The -141 C/- insertion/deletion (-141 Indel), previously shown to affect DRD2 transcription efficiency, and multiple exon seven polymorphisms, one of which has previously been shown to affect DRD2 transcript stability, exhibited statistically significant association with diagnosis in haplotype transmission disequilibrium and in haplotype case : control analyses. Significant linkage disequilibrium between the -141 Indel and two exon seven SNPs (939Y and 957Y) was observed over a distance of >50 kbp in the AN probands but not in the controls. Genetically transmitted variation in D2 dopamine receptor expression mediated by functional polymorphisms affecting transcription and translation efficiency may play a role in vulnerability to AN. C1 NCI, Core Genotyping Facil, Ctr Adv Technol, Gaithersburg, MD USA. TissueGene Inc, Gaithersburg, MD USA. Cardiff Univ, Dept Psychol Med, Cardiff, Wales. Canc Res UK, Lab Human Cytogenet, London, England. Univ Pisa, Lab Biol Cellulare & Sviluppo, Pisa, Italy. Univ Munich, Hosp Behav Med, Klin Roseneck, Prien Am Chiemsee, Germany. Cornell Univ, Weill Med Coll, New York Presbyterian hosp Westchester, White Plains, NY USA. Toronto Gen Hosp, Univ Hlth Network, Dept Psychiat, Toronto, ON, Canada. Univ Calif Los Angeles, Sch Med, Neuropsychiat Inst & Hosp, Los Angeles, CA USA. Univ London Kings Coll, Inst Psychiat, London WC2R 2LS, England. Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. Univ Penn Hlth Syst, Dept Psychiat, Ctr Neurobiol & Behav, Philadelphia, PA USA. NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RP Bergen, AW (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM bergena@mail.nih.gov RI turton, miranda/F-4682-2011; Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Bergen, Andrew/0000-0002-1237-7644; Treasure, Janet/0000-0003-0871-4596 FU NCRR NIH HHS [RR03655]; NIMH NIH HHS [MH57881] NR 56 TC 77 Z9 79 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD SEP PY 2005 VL 30 IS 9 BP 1703 EP 1710 DI 10.1038/sj.npp.1300719 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 955XR UT WOS:000231264000012 PM 15920508 ER PT J AU Wu, HE Schwasinger, ET Hong, JS Tseng, LF AF Wu, HE Schwasinger, ET Hong, JS Tseng, LF TI Pretreatment with antiserum against dynorphin, substance P, or cholecystokinin enhances the morphine-produced anti-allodynia in the sciatic nerve ligated mice SO NEUROSCIENCE LETTERS LA English DT Article DE opioid; cholecystokinin; substance P; neuropathic pain; spinal cord; mouse ID CONTROLLED-RELEASE OXYCODONE; RANDOMIZED CONTROLLED-TRIAL; NEUROPATHIC PAIN; SPINAL-CORD; PERIPHERAL NEUROPATHY; ANTIALLODYNIC EFFICACY; THERMAL HYPERALGESIA; DIABETIC-NEUROPATHY; INJURED RATS; MODEL AB It is generally accepted that neuropathic pain is resistant to. amelioration by morphine in clinical studies and insensitivity to intrathecal (i.t.) administered morphine in experimental models of neuropathic pain has been demonstrated. This study is to determine if endogenous dynorphin, substance P or cholecystokinin is involved in the lack of anti-allodynia of morphine in a partial sciatic nerve ligation (PSL) model of CD-1 mice. Mice exhibited tactile allodynia in the ipsilateral hind paw I day after PSL, and reached its maximal allodynic effect at 2 days and remained allodynic for 7 days. Morphine (3.0 nmol) given i.t. did not alter the tactile allodynic threshold in ipsilateral paw of mice pretreated i.t. with normal rabbit serum 2 days after PSL. However, the same dose of morphine (3.0 nmol) given i.t. reduced markedly allodynia in mice pretreated for 2 h with antiserum against dynorphin A(1-17) (200 mu g); the morphine-produced anti-allodynia developed slowly, reached its peak effect at 30 min and returned to an allodynic state in 60 min. Similarly, i.t. injection of morphine reduced the allodynia in PSL mice pretreated with antiserum against substance P (10 mu g) or cholecystokinin (200 mu g) for 2 h. Intrathecal pretreatment with antiserum against dynorphin A(1-17), substance P or cholecystokinin for 2 h injected alone did not affect the baseline mechanical tactile threshold in ipsilateral paw 2 days after PSL. The results indicate that endogenous dynorphin A(1-17), substance P and cholecystokinin are involved in PSL-induced neuropathic allodynia to attenuate the anti-allodynic effect of morphine. (C) 2005 Elsevier Ireland Ltd. All rights reserved. C1 Med Coll Wisconsin, Dept Anesthesiol, Milwaukee, WI 53226 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Tseng, LF (reprint author), Med Coll Wisconsin, Dept Anesthesiol, Med Educ Bldg,Room M4308,8701 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM ltseng@post.its.mcw.edu FU NIDA NIH HHS [DA12588] NR 35 TC 7 Z9 10 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP PY 2005 VL 386 IS 1 BP 46 EP 51 DI 10.1016/j.neulet.2005.05.052 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 955GR UT WOS:000231214300010 PM 15982809 ER PT J AU Brody, LC AF Brody, LC TI Treating cancer by targeting a weakness SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Brody, LC (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NR 3 TC 27 Z9 28 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 SEP 1 PY 2005 VL 353 IS 9 BP 949 EP 950 DI 10.1056/NEJMcibr052331 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 959WX UT WOS:000231551100017 PM 16135843 ER PT J AU Wang, T Iyer, LM Pancholy, R Shi, XY Hall, TC AF Wang, T Iyer, LM Pancholy, R Shi, XY Hall, TC TI Assessment of penetrance and expressivity of RNAi-mediated silencing of the Arabidopsis phytoene desaturase gene SO NEW PHYTOLOGIST LA English DT Article DE Arabidopsis thaliana; expressivity; gene silencing; penetrance; phytoene desaturase (PDS); relative RT-PCR; RNAi (RNA interference) ID DOUBLE-STRANDED-RNA; CAENORHABDITIS-ELEGANS; FUNCTIONAL GENOMICS; DNA; INTERFERENCE; THALIANA; PLANTS; EFFICIENT; BIOSYNTHESIS; METHYLATION AB RNA interference (RNAi) is of great value in plant functional genomics. However, the absence of RNAi phenotypes and the lack of uniform level of RNAi silencing has complicated gene identification. Here, the penetrance and expressivity of RNAi-mediated silencing of the phytoene desaturase (PDS) gene in Arabidopsis thaliana were examined quantitatively to provide a reference for the likely severity and distribution of silencing effects. Arabidopsis plants were transformed with an RNAi construct targeting PDS. Transgenic plants were examined for frequency of RNAi-mediated silencing and various silencing phenotypes. mRNA depletion level and RNAi expressivity were assayed by relative reverse transcription polymerase chain reaction (RT-PCR). High penetrance and variable expressivity of RNAi were demonstrated. An inverse correlation between PDS mRNA level and RNAi phenotype was seen. No direct relationship between copy number for the RNAi-generating transgene and phenotype was evident. Decreased RNAi penetrance in T(2) plants was observed. It is suggested that variability in RNAi expressivity and postmeiotic decrease in RNAi penetrance constitute barriers for high throughput plant gene characterization. C1 Texas A&M Univ, Inst Dev & Mol Biol, College Stn, TX 77843 USA. Texas A&M Univ, Dept Biol, College Stn, TX 77843 USA. NCBI, Natl Lib Med, NIH, Bethesda, MD 20894 USA. RP Hall, TC (reprint author), Texas A&M Univ, Inst Dev & Mol Biol, College Stn, TX 77843 USA. EM tim@idmb.tamu.edu NR 42 TC 18 Z9 20 U1 4 U2 18 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0028-646X J9 NEW PHYTOL JI New Phytol. PD SEP PY 2005 VL 167 IS 3 BP 751 EP 760 DI 10.1111/j.1469-8137.2005.01454.x PG 10 WC Plant Sciences SC Plant Sciences GA 952HQ UT WOS:000230995000011 PM 16101912 ER PT J AU Schmidt, PJ Rubinow, DR AF Schmidt, PJ Rubinow, DR TI Reproductive aging, hormone therapy, and mood disorders SO NORDIC JOURNAL OF PSYCHIATRY LA English DT Meeting Abstract C1 NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS AS PI OSLO PA PO BOX 12 POSTHUSET, NO-0051 OSLO, NORWAY SN 0803-9488 J9 NORD J PSYCHIAT JI Nord. J. Psychiatr. PD SEP PY 2005 VL 59 IS 5 BP 399 EP 399 PG 1 WC Psychiatry SC Psychiatry GA 992SU UT WOS:000233905100034 ER PT J AU Dizon-Townson, D Miller, C Sibai, B Spong, CY Thom, E Wendel, G Wenstrom, K Samuels, P Cotroneo, MA Moawad, A Sorokin, Y Meis, P Miodovnik, M O'Sullivan, M Conway, D Wapner, RJ Gabbe, SG AF Dizon-Townson, D Miller, C Sibai, B Spong, CY Thom, E Wendel, G Wenstrom, K Samuels, P Cotroneo, MA Moawad, A Sorokin, Y Meis, P Miodovnik, M O'Sullivan, M Conway, D Wapner, RJ Gabbe, SG CA Natl Inst Child Hlth Human Dev Mat TI The relationship of the factor v Leiden mutation and pregnancy outcomes for mother and fetus SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID ACTIVATED PROTEIN-C; VENOUS THROMBOEMBOLISM; RECURRENT MISCARRIAGE; UNITED-STATES; WOMEN; THROMBOPHILIA; RESISTANCE; THROMBOSIS; PREECLAMPSIA; PROTHROMBIN AB Objective: We sought to estimate the frequency of pregnancy-related thromboembolic events among carriers of the factor V Leiden (FVL) mutation without a personal history of thromboembolism, and to evaluate the impact of maternal and fetal FVL mutation carriage or other thrombophilias on the risk of adverse outcomes. Methods: Women with a singleton pregnancy and no history of thromboembolism were recruited at 13 clinical centers before 14 weeks of gestation from April 2000 to August 2001. Each was tested for the FVL mutation, as was the resultant conceptus after delivery or after miscarriage, when available. The incidence of thromboembolism (primary outcome), and of other adverse outcomes, was compared between FVL mutation carriers and noncarriers. We also compared adverse outcomes in a secondary nested carrier-control analysis of FVL mutation and other coagulation abnormalities. In this secondary analysis, we defined carriers as women having one or more of the following traits: carrier for FVL mutation, protein C deficiency, protein S deficiency, antithrombin III deficiency, activated protein C resistance, or lupus anticoagulant-positive, heterozygous for prothrombin G20210A or homozygous for the 5,10 methylenetetrahydrofolate reductase mutations. Carriers of the FVL mutation alone (with or without activated protein C resistance) were compared with those having one or more other coagulation abnormalities and with controls with no coagulation abnormality. Results: One hundred thirty-four FVL Mutation carriers were identified among 4,885 gravidas (2.7%), with both FVL mutation status and pregnancy outcomes available. No thromboembolic events occurred among the FVL mutation carriers (0%, 95% confidence interval 0-2.7%). Three pulmonary emboli and one deep venous thrombosis occurred (0.081%, 95% confidence interval 0.02-0.21%), all occurring in FVL mutation noncarriers. In the nested carrier-control analysis (n = 339), no differences in adverse pregnancy outcomes were observed between FVL mutation carriers, carriers of other coagulation disorders, and controls. Maternal FVL mutation carriage was not associated with increased pregnancy loss, preeclampsia, placental abruption, or small for gestational age births. However, fetal FVL mutation carriage was associated with more frequent preeclampsia among African-American (15.0%) and Hispanic (12.5%) women than white women (2.6%, P =.04), adjusted odds ratio 2.4 (95% confidence interval 1.0-5.2, P =.05). Conclusion: Among women with no history of thromboembolism, maternal heterozygous carriage of the FVL mutation is associated with a low risk of venous thromboembolism in pregnancy. Neither universal screening for the FVL mutation, nor treatment of low-risk carriers during pregnancy is indicated. C1 NICHHD, Maternal Fetal Med Units Network, Bethesda, MD 20892 USA. RP Dizon-Townson, D (reprint author), Univ Utah, Hlth Sci Ctr, Dept Obstet & Gynecol, 50 N Med Dr,Room 2B200, Salt Lake City, UT 84132 USA. EM uvddizon@ihc.com RI Samuels, Philip/E-4011-2011; OI Miller, Connie H/0000-0002-3989-7973 FU NICHD NIH HHS [U10-HD21410, U10-HD21414, U10-HD27860, U10-HD27861, U10-HD27869, U10-HD27905, U10-HD27915, U10-HD27917, U10-HD34116, U10-HD34122, U10-HD34136, U10-HD34208, U10-HD34210, U10-HD36801] NR 27 TC 136 Z9 140 U1 1 U2 5 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 SEP PY 2005 VL 106 IS 3 BP 517 EP 524 DI 10.1097/01.AOG.0000173986.32528.ca PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 959BW UT WOS:000231492900011 PM 16135581 ER PT J AU Massad, LS Evans, CT Strickler, HD Burk, RD Watts, DH Cashin, L Darragh, T Gange, S Lee, YC Moxley, M Levine, A Passaro, DJ AF Massad, LS Evans, CT Strickler, HD Burk, RD Watts, DH Cashin, L Darragh, T Gange, S Lee, YC Moxley, M Levine, A Passaro, DJ TI Outcome after negative colposcopy among human immunodeficiency virus-infected women with borderline cytologic abnormalities SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID CERVICAL INTRAEPITHELIAL NEOPLASIA; 2001 CONSENSUS GUIDELINES; INTERAGENCY HIV; RISK-FACTORS; FOLLOW-UP; PREVALENCE; MANAGEMENT; LESIONS; CANCER; SMEARS AB Objective: To estimate the risk of and risk factors for progression among human immunodeficiency virus (HIV)-seropositive women with abnormal cervical cytology but negative colposcopy. Methods: In a prospective cohort study, 391 HIV-seropositive and 103 seronegative women with cervical cytology read as atypical squamous cells (ASQ or low-grade squamous intraepithelial lesion (LSIL) but negative colposcopy were followed up for a mean of 4.0 years with cytology at 6-month intervals. Colposcopy was prescribed for any epithelial abnormality. Results: Progression to CIN2, CIN3, high-grade SIL/severe clysplasia, or cancer occurred in 47 (12%) HIV-seropositive women and 4 (4%) HIV-seronegative women (P =.02). Progression to CIN1 was seen in an additional 12 HIVseropositive women and I seronegative woman. In multivariate analysis, high-risk but not low-risk HPV detection (hazard ratio [HR] 2.46-95% confidence interval [01 1.18-5.12, P = .02 for high risk, HR 1.41, 95% CI 0.62-3.21, P.42 for low risk), satisfactory colposcopy (HR 2.01, 95% CI 1.11-3.65, P =.02), and non-Hispanic African-American ethnicity (HR 5.08, 95% CI 1.72-14.98, P =.003) were the only factors associated with progression, while HIV serostatus was marginally significant (HR 2.53, 95% CI 0.85-7.50, P =.09). Conclusion: Human immunodeficiency virus-seropositive women with negative colposcopy after borderline cytology face a higher risk of progression than seronegative women, but the absolute risk is low and becomes nonsignificant after controlling for HPV risk type, ethnicity, and colposcopic findings. Observation is appropriate. C1 So Illinois Univ, Sch Med, Springfield, IL USA. Univ Illinois, Chicago, IL USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. NICHHD, Bethesda, MD 20892 USA. Montefiore Med Ctr, Bronx, NY 10467 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. SUNY Brooklyn, Brooklyn, NY USA. Georgetown Univ, Sch Med, Washington, DC USA. Univ So Calif, Keck Sch Med, Los Angeles, CA USA. RP Massad, LS (reprint author), So Illinois Univ, Dept Obstet & Gynecol, POB 19640, Springfield, IL 62794 USA. EM LSMASSAD@ameritech.net OI Gange, Stephen/0000-0001-7842-512X FU NCI NIH HHS [CA85178-01]; NCRR NIH HHS [M01-RR00079, M01-RR00083]; NIAID NIH HHS [U01-AI-34989, U01-AI-35004, U01-AI-31834, U01-AI-34993, U01-AI-42590, U01-AI-34994]; NICHD NIH HHS [U01-HD-32632] NR 17 TC 9 Z9 10 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 SEP PY 2005 VL 106 IS 3 BP 525 EP 532 DI 10.1097/01.AOG.0000172429.45130.1f PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 959BW UT WOS:000231492900012 PM 16135582 ER PT J AU Meis, PJ Klebanoff, M Dombrowski, MP Sibai, BM Leindecker, S Moawad, AH Northen, A Iams, JD Varner, MW Caritis, SN O'Sullivan, MJ Miodovnik, M Leveno, K Conway, D Wapner, RJ Carpenter, M Mercer, B Ramin, SM Thorp, JM Peaceman, AM Gabbe, S AF Meis, PJ Klebanoff, M Dombrowski, MP Sibai, BM Leindecker, S Moawad, AH Northen, A Iams, JD Varner, MW Caritis, SN O'Sullivan, MJ Miodovnik, M Leveno, K Conway, D Wapner, RJ Carpenter, M Mercer, B Ramin, SM Thorp, JM Peaceman, AM Gabbe, S CA Natl Inst Child Hlth Human Dev Mat TI Does progesterone treatment influence risk factors for recurrent preterm delivery? SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID LOW-BIRTH-WEIGHT; REPETITION; PREDICTION; TERM AB Objective: To examine how demographic and pregnancy characteristics can affect the risk of recurrent preterm delivery and the how the effectiveness of progesterone treatment for prevention alters these relationships. Methods: This was a secondary analysis of a randomized trial of 17 alpha-hydroxyprogesterone caproate to prevent recurrent preterm delivery in women at risk. Associations of risk factors for preterm delivery (less than 37 completed weeks of gestation) were examined separately for the women in the 17 alpha-hydroxyprogesterone caproate (n = 310) and placebo (n = 153) groups. Results: Univariate analysis found that the number of previous preterm deliveries and whether the penultimate delivery was preterm were significant risk factors for preterm delivery in both the placebo and progesterone groups. High body mass index was protective of preterm birth in the placebo group. Multivariate analysis found progesterone treatment to cancel the risk of more than 1 previous preterm delivery, but not the risk associated with the penultimate pregnancy delivered preterm. Obesity was associated with lower risk for preterm delivery in the placebo group but not in the women treated with progesterone. Conclusion: The use of 17 alpha-hydroxyprogesterone caproate in women with a previous preterm delivery reduces the overall risk of preterm delivery and changes the epidemiology of risk factors for recurrent preterm delivery. in particular, these data suggest that 17 alpha-hydroxyprogesterone caproate reduces the risk of a history of more than 1 preterm delivery. C1 Wake Forest Univ, Sch Med, Dept Obstet & Gynecol, Winston Salem, NC 27157 USA. Wake Forest Univ, Sch Med, Div Maternal Fetal Med, Winston Salem, NC 27157 USA. NICHHD, Rockville, MD USA. George Washington Univ, Ctr Biostat, Rockville, MD USA. Univ Alabama, Div Maternal Fetal Med, Birmingham, AL USA. Univ Tennessee, Memphis, TN USA. Wayne State Univ, Detroit, MI USA. Univ Chicago, Chicago, IL 60637 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Utah, Salt Lake City, UT USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Miami, Miami, FL 33152 USA. Univ Cincinnati, Cincinnati, OH USA. Univ Texas, Dallas, TX 75230 USA. Univ Texas Antonio, San Antonio, TX USA. Drexel Univ, Philadelphia, PA 19104 USA. Brown Univ, Providence, RI 02912 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Texas, Houston, TX USA. Univ N Carolina, Chapel Hill, NC USA. NW Univ, Chicago, IL USA. Vanderbilt Univ, Nashville, TN USA. RP Meis, PJ (reprint author), Wake Forest Univ, Sch Med, Dept Obstet & Gynecol, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM pmeis@wfubmc.edu RI Varner, Michael/K-9890-2013; OI caritis, steve/0000-0002-2169-0712; Varner, Michael/0000-0001-9455-3973; Peaceman, Alan/0000-0002-4515-4850 FU NCRR NIH HHS [M01-RR-000080]; NICHD NIH HHS [HD40500, HD21410, HD21414, HD27860, HD27861, HD27869, HD27905, HD27915, HD27917, HD34116, HD34122, HD34136, HD34208, HD34210, HD36801, HD40512, HD40544, HD40560] NR 15 TC 25 Z9 25 U1 0 U2 1 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 SEP PY 2005 VL 106 IS 3 BP 557 EP 561 DI 10.1097/01.AOG.0000174582.79364.a7 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 959BW UT WOS:000231492900017 PM 16135587 ER PT J AU de Joode, BV Vermeulen, R van Hemmen, JJ Fransman, W Kromhout, H AF de Joode, BV Vermeulen, R van Hemmen, JJ Fransman, W Kromhout, H TI Accuracy of a semiquantitative method for dermal exposure assessment (DREAM) SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID RUBBER-MANUFACTURING-INDUSTRY; VIDEO IMAGING TECHNIQUE; OCCUPATIONAL EXPOSURES; SUBJECTIVE ASSESSMENT; MEASUREMENT ERROR; RELIABILITY; BENZENE; MODEL AB Background: The authors recently developed a Dermal Exposure Assessment Method (DREAM), an observational semiquantitative method to assess dermal exposures by systematically evaluating exposure determinants using pre-assigned default values. Aim: To explore the accuracy of the DREAM method by comparing its estimates with quantitative dermal exposure measurements in several occupational settings. Methods: Occupational hygienists observed workers performing a certain task, whose exposure to chemical agents on skin or clothing was measured quantitatively simultaneously, and filled in the DREAM questionnaire. DREAM estimates were compared with measurement data by estimating Spearman correlation coefficients for each task and for individual observations. In addition, mixed linear regression models were used to study the effect of DREAM estimates on the variability in measured exposures between tasks, between workers, and from day to day. Results: For skin exposures, spearman correlation coefficients for individual observations ranged from 0.19 to 0.82. DREAM estimates for exposure levels on hands and forearms showed a fixed effect between and within surveys, explaining mainly between-task variance. In general, exposure levels on clothing layer were only predicted in a meaningful way by detailed DREAM estimates, which comprised detailed information on the concentration of the agent in the formulation to which exposure occurred. Conclusions: The authors expect that the DREAM method can be successfully applied for semiquantitative dermal exposure assessment in epidemiological and occupational hygiene surveys of groups of workers with considerable contrast in dermal exposure levels (variability between groups >1.0). For surveys with less contrasting exposure levels, quantitative dermal exposure measurements are preferable. C1 Univ Utrecht, Inst Risk Assessment Sci, Environm & Occupat Hlth Div, NL-3508 TD Utrecht, Netherlands. NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Kromhout, H (reprint author), Univ Utrecht, Inst Risk Assessment Sci, Environm & Occupat Hlth Div, POB 80176, NL-3508 TD Utrecht, Netherlands. EM h.kromhout@iras.uu.nl RI Kromhout, Hans/A-9159-2008; Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 NR 34 TC 18 Z9 18 U1 0 U2 3 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD SEP PY 2005 VL 62 IS 9 BP 623 EP 632 DI 10.1136/oem.2004.018564 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 956JO UT WOS:000231296200008 ER PT J AU Kirk, GD Lesi, OA Mendy, M Szymanska, K Whittle, H Goedert, JJ Hainaut, P Montesano, R AF Kirk, GD Lesi, OA Mendy, M Szymanska, K Whittle, H Goedert, JJ Hainaut, P Montesano, R TI 249(ser) TP53 mutation in plasma DNA, hepatitis B viral infection, and risk of hepatocellular carcinoma SO ONCOGENE LA English DT Article DE hepatocellular carcinoma; aflatoxin; hepatitis B virus; TP53 gene; plasma DNA ID AFLATOXIN-ALBUMIN ADDUCTS; CIRCULATING NUCLEIC-ACIDS; LIVER-CANCER RISK; REPUBLIC-OF-CHINA; WEST-AFRICA; P53 GENE; MOLECULAR PATHOGENESIS; VIRUS-INFECTION; STEM-CELLS; E-ANTIGEN AB Hepatocellular carcinoma (HCC) from regions with high dietary exposure to aflatoxins and endemic for hepatitis B virus (HBV) often contain a specific mutation at codon 249 in TP53 (249(ser); AGG to AGT, Arg to Ser). This mutation is also detectable in circulating cell-free DNA from the plasma of HCC patients and healthy subjects in these regions. We have examined the joint effect of plasma 249(ser) and HBV infection in a case-control study design involving 348 control, 98 cirrhotic, and 186 HCC participants from The Gambia, West Africa, an area of high HCC incidence. The 249(ser) mutation was detected in 3.5% of controls, 15.3% of cirrhotics, and 39.8% of HCC cases (adjusted odds ratios (OR): 4.83, (95% confidence interval (CI): 1.71-13.7) for cirrhosis and 20.3 (8.19-50.0) for HCC). HBsAg positivity along with plasma 249(ser) was observed in 45/183 (24.6%) HCC cases compared to only one (0.3%) control. Risk for HCC was associated with markers of HBV alone (OR: 10.0, 95% CI: 5.16-19.6), 249(ser) alone (OR: 13.2, 95% CI: 4.99-35.0), and both markers present (OR: 399, 95% CI: 48.6-3270). These results suggest a multiplicative effect on HCC risk resulting from the mutational effect of aflatoxin on TP53, as monitored by detection of plasma 249(ser), with concomitant chronic infection with HBV. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Infect Dis Epidemiol Program, Dept Epidemiol, Baltimore, MD 21205 USA. Gambia Hepatitis Intervent Study, Banjul, Gambia. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. MRC Labs, Banjul, Gambia. Int Agcy Res Canc, F-69372 Lyon, France. RP Kirk, GD (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Infect Dis Epidemiol Program, Dept Epidemiol, 615 N Wolfe St,E-6533, Baltimore, MD 21205 USA. EM gkirk@jhsph.edu RI Kirk, Gregory/A-8484-2009; Hainaut, Pierre /B-6018-2012 OI Hainaut, Pierre /0000-0002-1303-1610 NR 64 TC 69 Z9 74 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP PY 2005 VL 24 IS 38 BP 5858 EP 5867 DI 10.1038/sj.onc.1208732 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 960KW UT WOS:000231590400008 PM 16007211 ER PT J AU Antman, K Hassan, R Eisner, M Ries, LAG Edwards, BK AF Antman, K Hassan, R Eisner, M Ries, LAG Edwards, BK TI Update on malignant mesothelioma SO ONCOLOGY-NEW YORK LA English DT Article ID HYPERTHERMIC INTRATHORACIC CHEMOTHERAPY; LEUKEMIA GROUP-B; PHASE-II TRIAL; PLEURAL MESOTHELIOMA; PERITONEAL MESOTHELIOMA; ASBESTOS EXPOSURE; RANDOMIZED-TRIAL; EXTRAPLEURAL PNEUMONECTOMY; LUNG-CANCER; PAPILLARY MESOTHELIOMA AB Mesothellomas are uncommon in the United States, with an incidence of about 3,000 new cases per year (or a risk of about 11 per million Americans per year). Incidence and mortality, however, are probably underestimated. Most are associated with asbestos, although some have arisen in ports of prior radiation, and a reported association with simian virus (S 17)40 remains controversial. About 85% of mesotheliomas arise in the pleura, about 9% in the, peritoneum, and a small percentage in the pericardium or tunica vaginalis testis. The histology of about half of mesotheliomas is epithelial (tubular papillary), with the remainder sarcomatous or mixed Multicystic mesotheliomas and well-differentiated papillary mesotheliomas are associated with long survival in the absence of treatment and should be excluded from clinical trials intended for the usual rapidly lethal histologic variants of the disease. The median survival is under a year, although. longer median survivals for selected patients, particularly those with epithelial histology, have been reported in some combined-modality studies. Recent randomized trials have shown significant improvement in time to progression and survival for the addition of new antifolates to platinum-based chemotherapy. C1 Boston Univ, Sch Med, Boston, MA 02118 USA. NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Mesothelin Expressing Canc Unit, Mol Biol Lab, Bethesda, MD 20892 USA. NCI, Surveillance Res Program, Canc Stat Branch, Bethesda, MD 20892 USA. RP Antman, K (reprint author), Boston Univ, Sch Med, 715 Albany St,A, Boston, MA 02118 USA. EM kha4@bu.edu NR 69 TC 15 Z9 17 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 SEP PY 2005 VL 19 IS 10 BP 1301 EP 1309 PG 9 WC Oncology SC Oncology GA 052EP UT WOS:000238214600005 PM 16285225 ER PT J AU Ben-David, M Ilev, IK Waynant, RW Gannot, I AF Ben-David, M Ilev, IK Waynant, RW Gannot, I TI Pulse dispersion in hollow optical waveguides SO OPTICAL ENGINEERING LA English DT Article DE waveguides; dispersion; pulses ID DELIVERY; PROPAGATION; LASER; FIBERS; TAPER AB A study of laser (near- and mid-infrared) pulse dispersion in hollow waveguides is presented, We developed an analytical model to describe the pulse dispersion in hollow waveguides and compared our theoretical calculations with measurements done by us and also by two other groups. The pulse dispersion was experimentally measured for a short Q-switched Er:YAG laser in the nanosecond range and for femtosecond Ti:sapphire laser pulses transmitted by hollow optical waveguides. For analytical calculation of the pulse dispersion in these waveguides, a refined ray tracing program was developed. This approach took into account roughness of the internal reflecting and refracting inner layers. A comparison analysis between the measurements and calculations conducted at identical parameters demonstrates good correlation between theoretical and experimental results. (c) 2005 society of Photo-Optical Instrumentation Engineers. C1 Tel Aviv Univ, Fac Exact Sci, Dept Appl Phys, IL-69978 Tel Aviv, Israel. US FDA, Off Sci & Engn Labs, Ctr Devices & Radiol Hlth, Rockville, MD 20857 USA. Tel Aviv Univ, Fac Engn, Dept Biomed Engn, IL-69978 Tel Aviv, Israel. Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Ben-David, M (reprint author), Tel Aviv Univ, Fac Exact Sci, Dept Appl Phys, IL-69978 Tel Aviv, Israel. EM moshe@glucon.com NR 19 TC 1 Z9 1 U1 1 U2 4 PU SPIE-INT SOCIETY OPTICAL ENGINEERING PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 0091-3286 J9 OPT ENG JI Opt. Eng. PD SEP PY 2005 VL 44 IS 9 AR 095001 DI 10.1117/1.2042967 PG 6 WC Optics SC Optics GA 981NG UT WOS:000233094700025 ER PT J AU Mash, C Dobson, V AF Mash, Clay Dobson, Velma TI Intraobserver Reliability of the Teller Acuity Card Procedure in Infants With Perinatal Complications SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE grating acuity; intraobserver reliability; infants; children; perinatal complications AB Purpose. Intraobserver test-retest reliability of the Teller Acuity Card (TAC) procedure for estimating grating acuity was assessed in 79 infants who had been treated in a neonatal intensive care unit for preterm birth and/or other perinatal complications. Methods. Subjects were tested monocularly at one or more of four different age intervals that ranged between 2.5 and 18.5 mo corrected age. Testers were masked to the location and spatial frequency of the grating on each card. Results. Of the intraobserver test-retest scores, 91% differed by no more than one octave and 68% differed by no more than 0.5 octave. Intraobserver agreement was similar to that reported previously for healthy, preterm infants. Reliability was uniform between infants of differing levels of risk for abnormal visual development but bore effects of low tester ratings of confidence. Conclusions. The results demonstrate the reliability of the TAC procedure but suggest that test sessions should be repeated when tester confidence in validity of results is low. C1 [Mash, Clay] NICHHD, Sect Child & Family Res, Bethesda, MD 20892 USA. [Dobson, Velma] Univ Arizona, Dept Ophthalmol, Tucson, AZ USA. [Dobson, Velma] Univ Arizona, Dept Psychol, Tucson, AZ 85721 USA. RP Mash, C (reprint author), 6705 Rockledge Dr,Suite 8030, Bethesda, MD 20892 USA. EM mashc@mail.nih.gov FU National Eye Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland [R01 EY05804] FX This work was supported by grant R01 EY05804 from the National Eye Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, awarded to VD. The authors thank the parents of infants who participated in this study, and Lisa Getz and Beatriz Luna, PhD, who served as testers. The authors thank Robert D. Guthrie, MD, and the staff of Magee-Women's Hospital for subject recruitment, and Lisa Getz, and Beatriz Luna, PhD, for assistance with testing participants. A preliminary report of this study was presented at the annual meeting of the Association for Research in Vision and Ophthalmology, Ft. Lauderdale, Florida, May 14 to 19, 1995. NR 13 TC 4 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1040-5488 EI 1538-9235 J9 OPTOMETRY VISION SCI JI Optom. Vis. Sci. PD SEP PY 2005 VL 82 IS 9 BP 817 EP 822 DI 10.1097/01.opx.0000177809.75080.41 PG 6 WC Ophthalmology SC Ophthalmology GA V40NH UT WOS:000209484800004 PM 16189491 ER PT J AU Wadhwa, S Embree, MC Kilts, T Young, MF Ameye, LG AF Wadhwa, S Embree, MC Kilts, T Young, MF Ameye, LG TI Accelerated osteoarthritis in the temporomandibular joint of biglycan/fibromodulin double-deficient mice SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE temporomandibular joint (TMJ); biglycan; fibromodulin; proliferation; osteoarthritis; mice ID EXTRACELLULAR-MATRIX; ARTICULAR-CARTILAGE; SMALL PROTEOGLYCANS; EXPERIMENTAL-MODEL; BIGLYCAN; DECORIN; DISC; LOCALIZATION; RABBIT; FIBROMODULIN AB Objective: To investigate whether the absence of biglycan and fibromodulin, two proteoglycans expressed in cartilage, bone and tendon, resulted in accelerated osteoarthritis in the temporomandibular joint (TMJ). Methods: Histological sections of TMJ from 3-, 6-, 9- and 18-month-old wild-type (WT) and biglycan/fibromodulin double-deficient (DKO) mice were compared. Immunostainings for biglycan, fibromodulin and proliferating cell nuclear antigen (PCNA) were performed. Results: Biglycan and fibromodulin were highly expressed in the disc and articular cartilage of the TMJ. At 3 months of age, both WT and DKO presented early signs of cartilage degeneration visible as small acellular areas under the articular surfaces and superficial waving. From 6 months of age, DKOs developed accelerated osteoarthritis compared to WT. At 6 months, small vertical clefts in the condylar cartilage and partial disruption of the disk were visible in the DKO. In addition, chondrocytes had lost their regular columnar organization to form clusters. At 9 months, these differences were even more pronounced. At 18 months, extended cartilage erosion was visible in DKOs when by comparison the thickness of the articular cartilage in WT controls was basically intact. PCNA staining was stronger in 3-month-old WT TMJ fibrocartilage than in 3-month-old DKO TMJ fibrocartilage suggesting that chondrocyte proliferation might be impaired in DKOs. Conclusion: The biglycan/fibromodulin double knock-out mouse constitutes a useful animal model to decipher the pathobiology of osteoarthritis in the TMJ. (c) 2005 OsteoArthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 Nestle Res Ctr, Dept Nutr & Hlth, CH-1026 Lausanne, Switzerland. NIDCR, Mol Biol Bones & Teeth Univ, Craniofacial & Skeletal Dis Branch, NIH,DHHS, Bethesda, MD 20892 USA. RP Ameye, LG (reprint author), Nestle Res Ctr, Dept Nutr & Hlth, Vers Chez Blanc,POB 44, CH-1026 Lausanne, Switzerland. EM laurent.ameye@rdls.nestle.com NR 39 TC 43 Z9 43 U1 1 U2 5 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD SEP PY 2005 VL 13 IS 9 BP 817 EP 827 DI 10.1016/j.joca.2005.04.016 PG 11 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 969RJ UT WOS:000232252100009 PM 16006154 ER PT J AU Biesecker, LG Cohen, MM AF Biesecker, LG Cohen, MM TI Misdiagnosis of neurofibromatosis type 1 as Proteus syndrome SO PANMINERVA MEDICA LA English DT Letter ID DIAGNOSTIC-CRITERIA C1 NHGRI, Bethesda, MD 20892 USA. Dalhousie Univ, Halifax, NS, Canada. RP Biesecker, LG (reprint author), NHGRI, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 0 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 0031-0808 EI 1827-1898 J9 PANMINERVA MED JI Panminerva Medica PD SEP PY 2005 VL 47 IS 3 BP 197 EP 197 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 023RW UT WOS:000236144900009 PM 16462730 ER PT J AU Finlayson, TL Siefert, K Ismail, AI Delva, J Sohn, W AF Finlayson, TL Siefert, K Ismail, AI Delva, J Sohn, W TI Reliability and validity of brief measures of oral health-related knowledge, fatalism, and self-efficacy in mothers of African American children SO PEDIATRIC DENTISTRY LA English DT Article DE child; oral health; African American; self-efficacy; measures ID DENTAL-CARIES; BEHAVIOR AB Purpose: Low-income African American children experience high rates of dental caries compared to the general population. Knowledgeable and efficacious caregivers can play an important role in caries prevention. The purpose of this study was to develop and evaluate 4 brief measures reflecting mothers' potentially modifiable cognitions associated with African American children's oral health: (1) knowledge about appropriate bottle use (KBU); (2) knowledge about children's oral hygiene (KCOH); (3) oral health-related fatalism (OHF); and (4) oral health-related self-efficacy (OHSE). Methods: Questions were selected based on reviews of the health promotion and oral health literature, with input from low-income African American caregivers of young children. Reliability and validity were evaluated using survey and dental examination data from 719 low-income African American mothers and their 1- to 5-year-old children. Results: Alpha reliabilities ranged from 0.76 to 0.91. KCOH was significantly associated with mothers' oral health perceptions and children's caries status. OHSE was significantly positively correlated with children's brushing frequency and with mothers' subjective perceptions of children's oral health, which was, in turn, significantly associated with children's caries status. Conclusions: Results support the reliability and validity of the new measures. If confirmed by further research, these measures can be used to develop tailored educational and cognitive-behavioral interventions to reduce oral health disparities. C1 Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. Univ Michigan, Sch Social Work, NIMH, Res Ctr Poverty Risk & Ment Hlth, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Dent, Ann Arbor, MI 48109 USA. RP Finlayson, TL (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. EM tracyf@berkeley.edu FU NIDCR NIH HHS [U-54 DE 14261-01, U54 DE014261]; NIMH NIH HHS [T32 MH016806] NR 33 TC 45 Z9 47 U1 0 U2 6 PU AMER ACAD PEDIATRIC DENTISTRY PI CHICAGO PA 211 E CHICAGO AVENUE SUITE 1036, CHICAGO, IL 60611-2616 USA SN 0164-1263 J9 PEDIATR DENT JI Pediatr. Dent. PD SEP-OCT PY 2005 VL 27 IS 5 BP 422 EP 428 PG 7 WC Dentistry, Oral Surgery & Medicine; Pediatrics SC Dentistry, Oral Surgery & Medicine; Pediatrics GA 001OU UT WOS:000234547000014 PM 16435644 ER PT J AU Jang, HS Jo, JH Oh, CK Kim, MB Lee, JB Chang, CL Kwon, YW Kwon, KS AF Jang, HS Jo, JH Oh, CK Kim, MB Lee, JB Chang, CL Kwon, YW Kwon, KS TI Successful treatment of localized cutaneous infection caused by Mycobacterium scrofulaceum with clarithromycin SO PEDIATRIC DERMATOLOGY LA English DT Article ID SKIN; LYMPHADENITIS; CHILDREN; DISEASE AB Cutaneous infection arising from Mycobacterium scrofulaceum, a nontuberculous mycobacteria, has rarely been reported, and most of the reported infections were disseminated forms in patients with AIDS or other immunocompromising illness. We describe an occurrence of localized mycobacterial skin infection caused by M. scrofulaceum in a previously healthy child that manifested as a red nodule on the cheek. A biopsy specimen of the lesion demonstrated granulomatous infiltration in the dermis. M. scrofulaceum was isolated from culture of a tissue specimen. Polymerase chain reaction amplified specific fragments for M. scrofulaceum. The patient was treated successfully with clarithromycin as monotherapy for 6 months, leading to complete healing without recurrence during a follow-up period of 2 years. C1 Pusan Natl Univ, Coll Med, Dept Dermatol, Pusan 602739, South Korea. Pusan Natl Univ, Dept Clin Pathol, Pusan 602739, South Korea. NIAID, Mol Pathol Sect, Lab Immunopathol, NIH, Rockville, MD USA. RP Jang, HS (reprint author), Pusan Natl Univ, Coll Med, Dept Dermatol, 1-10 Ami Dong, Pusan 602739, South Korea. EM hsjang@pusan.ac.kr NR 19 TC 5 Z9 7 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0736-8046 J9 PEDIATR DERMATOL JI Pediatr. Dermatol. PD SEP-OCT PY 2005 VL 22 IS 5 BP 476 EP 479 DI 10.1111/j.1525-1470.2005.00120.x PG 4 WC Dermatology; Pediatrics SC Dermatology; Pediatrics GA 966VM UT WOS:000232050600019 PM 16191006 ER PT J AU Zimmerman, AW Jyonouchi, H Comi, AM Connors, SL Milstien, S Varsou, A Heyes, MP AF Zimmerman, AW Jyonouchi, H Comi, AM Connors, SL Milstien, S Varsou, A Heyes, MP TI Cerebrospinal fluid and serum markers of inflammation in autism SO PEDIATRIC NEUROLOGY LA English DT Article ID QUINOLINIC ACID; CYTOKINE PRODUCTION; INFANTILE-AUTISM; HUMAN MICROGLIA; NITRIC-OXIDE; BIOPTERIN; NEOPTERIN; CHILDREN; METABOLITES; TRYPTOPHAN AB Systemic immune abnormalities have no known relevance to brain dysfunction in autism. In order to find evidence for neuroinflammation, we compared levels of sensitive indicators of immune activation: quinolinic acid, neopterin, and biopterin, as well as multiple cytokines and cytokine receptors, in cerebrospinal fluid and serum from children with autism, to control subjects with other neurologic disorders. In cerebrospinal fluid from 12 children with autism, quinolinic acid (P = 0.037) and neopterin (P = 0.003) were decreased, and biopterin (P = 0.040) was elevated, compared with control subjects. In sera from 35 persons with autism, among cytokines, only tumor necrosis factor receptor II was elevated compared with controls (P < 0.02). Decreased quinolinic acid and neopterin in cerebrospinal fluid are paradoxical and suggest dysmaturation of metabolic pathways and absence of concurrent infection, respectively, in autism. Alternatively, they may be produced by microglia but remain localized and not expressed in cerebrospinal fluid. (c) 2005 by Elsevier Inc. All rights reserved. C1 Kennedy Krieger Inst, Dept Neurol & Dev Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Pediat, Newark, NJ 07103 USA. NIMH, Bethesda, MD 20892 USA. Univ Athens, Sch Med, GR-11527 Athens, Greece. PsychoGen Inc, Hawthorne, NY USA. RP Zimmerman, AW (reprint author), Kennedy Krieger Inst, Dept Neurol & Dev Med, 707 N Broadway, Baltimore, MD 21205 USA. NR 37 TC 132 Z9 135 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD SEP PY 2005 VL 33 IS 3 BP 195 EP 201 DI 10.1016/j.pediatrneurol.2005.03.014 PG 7 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 967TN UT WOS:000232114200007 PM 16139734 ER PT J AU Vohr, BR Wright, LL Poole, K McDonald, SA AF Vohr, BR Wright, LL Poole, K McDonald, SA CA NICHD Neonatal Res Network Follow TI Neurodevelopmental outcomes of extremely low birth weight infants < 32 weeks' gestation between 1993 and 1998 SO PEDIATRICS LA English DT Article; Proceedings Paper CT Annual Meeting of the Pediatric-Research-Societies CY MAY 01, 2001 CL BALTIMORE, MD SP Pediat Res Soc DE extremely low birth weight; neurologic outcome; impairment; cerebral palsy; Bayley; antenatal steroids ID ASSISTED REPRODUCTIVE TECHNOLOGY; NEONATAL RESEARCH NETWORK; RESPIRATORY-DISTRESS SYNDROME; NATIONAL-INSTITUTE; CHILD-HEALTH; UNITED-STATES; AMERICAN SOCIETY; PRETERM INFANTS; CORTICOSTEROIDS; PREVENTION AB Objective. This study evaluated the impact of changes in perinatal management on neurodevelopmental impairment (NDI) at 18 to 22 months ' corrected age of low gestation (22 - 26 weeks) and higher gestation (27 - 32 weeks) extremely low birth weight infants (401 1000 g birth weight) who were cared for in the National Institute of Child Health and Human Development Neonatal Research Network during 3 epochs (1993 - 1994, 1995 - 1996, and 1997 - 1998). It was hypothesized that outcomes would improve over the 3 epochs. Methods. A multicenter cohort study was conducted of the outcomes of 3785 infants with assessments at 18 to 22 months ' corrected age. Regression analyses were completed to evaluate for epoch effects, gestational age effects, and time plus gestational age interaction. Regression analyses were also performed to identify the independent associations of epoch and 4 study perinatal interventions: antenatal steroids (yes, no), high- frequency ventilation (yes, no), number of days to regain birth weight as a marker of nutritional intake, and postnatal steroids for treatment of bronchopulmonary dysplasia (yes, no) with outcomes. Results. Survival improved for both the low (55% 61%) and higher (82% - 86%) gestational age groups during the 3 epochs. Regression analyses indicated that the decreased risk for adverse outcome was significantly lower in epoch 2 compared with epoch 1 with decreased rates of low Bayley Mental Development Index (MDI) and neurodevelopmental impairment (NDI). Antenatal steroids were associated with decreased risk for moderate to severe cerebral palsy (CP) and low Bayley Psychomotor Development Index. High- frequency ventilation was associated with a low Bayley MDI and NDI, and postnatal steroids were associated with moderate to severe CP, any CP, low Bayley MDI, low Bayley Psychomotor Development Index, and increased NDI. Conclusion. Survival of extremely low birth weight infants improved between 1993 and 1998. Although some outcomes remained unchanged, the rates of low Bayley MDI scores and NDI improved. Antenatal steroid administration was the only study intervention associated with improved outcomes. C1 Women & Infants Hosp Rhode Isl, Dept Pediat, Providence, RI 02905 USA. NICHHD, Ctr Res Mothers & Children, Bethesda, MD 20892 USA. SRTI Int, Res Triangle Pk, NC USA. RP Vohr, BR (reprint author), Women & Infants Hosp Rhode Isl, Dept Pediat, 101 Dudley St, Providence, RI 02905 USA. EM Betty_Vohr@brown.edu FU NICHD NIH HHS [U10 HD27853, HD27904, U01 HD36790, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD21415, U10 HD27851, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881] NR 34 TC 223 Z9 234 U1 0 U2 16 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 SEP PY 2005 VL 116 IS 3 BP 635 EP 643 DI 10.1542/peds.2004-2247 PG 9 WC Pediatrics SC Pediatrics GA 960FW UT WOS:000231576600036 PM 16143580 ER PT J AU Raju, TNK AF Raju, TNK TI William Sealy Gosset and William A. Silverman: Two "students" of science SO PEDIATRICS LA English DT Biographical-Item DE ethics; history of medicine; history of statistics; neonatal intensive care; society and medicine ID COMPASSION AB In 1908, William Sealy Gosset, a chemist in an Irish brewery, published his second article on statistics in Biometrika under the pseudonym "Student." He chose this pseudonym because his company did not allow its scientists to publish confidential data. In the article, Gosset described a procedure to assess population means by using small samples. This was the origin of the "Student's t test." Dr William Silverman(1917-2004), a pioneer neonatologist, also used the pseudonym "Student." He sent thousands of notes, clippings, anecdotes, and quotations to Pediatrics with the signature line "Submitted by Student" that appeared as blurbs at the ends of articles since 1977. Both Gosset and Silverman were rigorous students of science. Silverman chose pseudonyms to seek readers' responses to the message rather than the messenger. He also wished that one would remain a perpetual student, ready to say "I don't know," and strive to understand the human side of medicine. This brief article provides a perspective on these 2 "students" of science. C1 NICHHD, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, Bethesda, MD 20892 USA. RP Raju, TNK (reprint author), NICHD, NIH, PPB, 6100 Execut Blvd,Room 4B03, Gaithersburg, MD 20878 USA. EM rajut@mail.nih.gov NR 22 TC 12 Z9 13 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD SEP PY 2005 VL 116 IS 3 BP 732 EP 735 DI 10.1542/peds.2005-1134 PG 4 WC Pediatrics SC Pediatrics GA 960FW UT WOS:000231576600049 PM 16140715 ER PT J AU Moody, TW Fuselier, J Coy, DH Mantey, S Pradhan, T Nakagawa, T Jensen, RT AF Moody, TW Fuselier, J Coy, DH Mantey, S Pradhan, T Nakagawa, T Jensen, RT TI Camptothecin-somatostatin conjugates inhibit the growth of small cell lung cancer cells SO PEPTIDES LA English DT Article DE camptothecin; somatostatin; conjugates; small cell lung cancer; proliferation ID RECEPTOR SUBTYPES; MEDIATED ENDOCYTOSIS; RADIONUCLIDE THERAPY; CARCINOMA NCI-H69; HIGH-DENSITY; CYCLIC-AMP; TUMORS; ANALOGS; EXPRESSION; CYTOCHROME-P450 AB The effects of camptothecin-somatostatin (CPT-SS) conjugates were investigated on small cell lung cancer (SCLC) cells. CPT was coupled to a SS agonist (SSA), c(Cys-Phe-DTrp-Lys-Thr-Cys)Thr-NH2 using the built in nucleophile assisted-releasing group (L1) N-methyl-aminoethyl-Gly-Dser-Nle-Dtyr-Dser or (L2) aminoethyl-Gly-Dser-Nle-Dtyr-Dser. The resulting CPT-L1-SSA and CPT-L2-SSA inhibited the specific binding of [I-125-Tyr(11)]SS to NCI-H69 cell membranes with IC50 values of 0.2 and 2.1 nM, respectively. [I-125]CPT-L1-SSA was internalized by SCLC cells at 37 degrees C but not at 4 degrees C. CPT-L1-SSA and CPT-L2-SSA inhibited in a dose-dependent manner the increase in adenylylcyclase activity caused by 25 mu M forskolin. In vitro, 0.3 mu M CPT-L1-SSA half-maximally inhibited the clonal growth of SCLC cells and 1 mu M CPT-L1-SSA strongly inhibited H-3-thymidine incorporation into DNA and trypan-blue exclusion. These results suggest that CPT conjugated peptides such as CPT-L1-SSA may prove useful for exploring the efficacy of receptor-directed cytotoxicity to inhibit the proliferation of SCLC cells. Published by Elsevier Inc. C1 NCI, DHHS, NIH, Off Director,CCR, Bethesda, MD 20892 USA. Tulane Univ, Sch Med, New Orleans, LA 70112 USA. NIDDK, Digest Dis Branch, Bethesda, MD 20892 USA. RP Moody, TW (reprint author), NCI, DHHS, NIH, Off Director,CCR, 31 Ctr Dr, Bethesda, MD 20892 USA. EM moodyt@mail.nih.gov NR 41 TC 17 Z9 23 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD SEP PY 2005 VL 26 IS 9 BP 1560 EP 1566 DI 10.1016/j.peptides.2005.02.025 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 966RU UT WOS:000232039600004 PM 16112393 ER PT J AU Brody, H Miller, FG Bogdan-Lovis, E AF Brody, H Miller, FG Bogdan-Lovis, E TI Evidence-based medicine - watching out for its friends SO PERSPECTIVES IN BIOLOGY AND MEDICINE LA English DT Article ID PHARMACEUTICAL-INDUSTRY; CONTROLLED-TRIAL; QUALITY; PATIENT; SCIENCE; ETHICS; DRUG AB An old joke states that one need not worry about one's enemies, but may be in danger from one's friends. We review a number of "enemies" and "friends" of evidence-based medicine (EBM). To understand where these enemies and friends have come from, it is important to see how the rise of EBM has created shifts in power, especially within academic medicine. Attacks from "enemies"-especially the criticism that EBM amounts to overturning a medicine of the individual in favor of an undesirable population medicine-tend to reflect misunderstandings of EBM, or of the degrees of uncertainty inherent in medicine itself, rather than substantive criticisms. The activities of three categories of so-called friends might well give EBM an undesirable reputation. These "friends" are the practitioners of a crude version of EBM (uncritical acceptance of randomized controlled trials while rejecting all other forms of evidence), commercial sponsors of clinical trials whose biases distort the available evidentiary base, and bureaucrats who employ EBM practices in the service of inequitable rationing of health resources. C1 Michigan State Univ, Dept Family Practice, E Lansing, MI 48824 USA. Michigan State Univ, Ctr Eth & Humanities Life Sci, E Lansing, MI 48824 USA. NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. Michigan State Univ, Ctr Eth & Humanities, E Lansing, MI 48824 USA. RP Brody, H (reprint author), Michigan State Univ, Dept Family Practice, B-100 Clin Ctr, E Lansing, MI 48824 USA. EM brody@msu.edu NR 42 TC 14 Z9 14 U1 0 U2 1 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0031-5982 J9 PERSPECT BIOL MED JI Perspect. Biol. Med. PD FAL PY 2005 VL 48 IS 4 BP 570 EP 584 DI 10.1353/pbm.2005.0085 PG 15 WC History & Philosophy Of Science; Medicine, Research & Experimental SC History & Philosophy of Science; Research & Experimental Medicine GA 981MG UT WOS:000233092100009 PM 16227668 ER PT J AU Kim, H Kong, HS Choi, B Yang, YW Kim, Y Lim, MJ Neckers, L Jung, YJ AF Kim, H Kong, HS Choi, B Yang, YW Kim, Y Lim, MJ Neckers, L Jung, YJ TI Metabolic and pharmacological properties of rutin, a dietary quercetin glycoside, for treatment of inflammatory bowel disease SO PHARMACEUTICAL RESEARCH LA English DT Article DE inflammatory bowel disease; nuclear factor kappa B; quercetin; quercetin deliverer; rutin ID NF-KAPPA-B; 5-AMINOSALICYLIC ACID; DRUG; INHIBITION; ABSORPTION; FLAVONOIDS; COLITIS; BINDING; ALPHA; CELLS AB Purpose. Orally administered rutin reportedly ameliorates 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis of rats. We investigated the metabolic and pharmacological properties of rutin underlying the rutin-mediated amelioration of the rat colitis. Methods. Apparent partition coefficients of rutin and its aglycone quercetin were compared. The biochemical/chemical stability of rutin was examined in the contents of various segments of gastrointestinal tracts of rats. Inflammatory indices were determined in the colitis rats after oral administration of rutin or rectal administration of quercetin. In human colon epithelial cells, the effect of quercetin on tumor necrosis factor-alpha (TNF-alpha)-induced nuclear factor kappa B (NF kappa B) activation was examined. Results The sugar residue in rutin greatly lowered the apparent partition coefficient and was rapidly deglycosylated to liberate quercetin in the cecal contents, whereas it was stable in the contents of the upper intestine. Not only oral administration of rutin but also rectal administration of quercetin remarkably ameliorated TNBS-induced colitis rats, indicating that quercetin liberated from rutin is therapeutically active. Furthermore, quercetin dose-dependently inhibited an inflammatory signal TNF-alpha-dependent NF kappa B activation. Conclusions. Our data suggest that rutin acted as a quercetin deliverer to the large intestine and its anti-inflammatory action in TNBS-induced colitis rats may be through quercetin-mediated inhibition of TNF-alpha-induced NF kappa B activation. C1 Pusan Natl Univ, Coll Pharm, Lab Biomed Chem, Pusan 609735, South Korea. NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Cell & Canc Biol Branch, Rockville, MD 20850 USA. RP Jung, YJ (reprint author), Pusan Natl Univ, Coll Pharm, Lab Biomed Chem, Pusan 609735, South Korea. EM jungy@pusan.ac.kr NR 37 TC 66 Z9 71 U1 0 U2 12 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARM RES JI Pharm. Res. PD SEP PY 2005 VL 22 IS 9 BP 1499 EP 1509 DI 10.1007/s11095-005-6250-z PG 11 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 958TW UT WOS:000231472100009 PM 16132362 ER PT J AU Allan, JM Rabkin, CS AF Allan, JM Rabkin, CS TI Genetic susceptibility to iatrogenic malignancy SO PHARMACOGENOMICS LA English DT Review DE anthracycline; ataxia telangiectasia; chemotherapy; cytochrome P450; epipodophyllotoxin; Fanconi anemia; glutathione S-transferase; Li-Fraumeni syndrome; neurofibromatosis; Nijmegen breakage syndrome; pharmacogenetics; radiotherapy; single nucleotide polymorphism; thiopurine methyltransferase; xeroderma pigmentosum ID GLUTATHIONE-S-TRANSFERASE; ACUTE MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; NUCLEOTIDE EXCISION-REPAIR; NON-HODGKINS-LYMPHOMA; LI-FRAUMENI-SYNDROME; DE-NOVO AML; ATAXIA-TELANGIECTASIA; BREAST-CANCER; THIOPURINE METHYLTRANSFERASE AB Iatrogenic malignancies represent a devastating and often fatal long-term effect of therapy administered for a prior condition, usually a primary cancer. Earlier diagnosis and the development of more effective cancer treatments over the last 30 years have considerably improved the long-term survival of patients. However, the burgeoning number of cancer survivors has led to a parallel increase in the number of cases of iatrogenic malignancy. Consequently, understanding host susceptibility factors, such that high-risk patients can be identified, has become a priority. However, this task is made difficult by the heterogeneity of iatrogenic malignancies. Nevertheless, the identification of polymorphic loci and pathways predicted to modify dose (e.g., glutathione S-transferases, nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase, cytochrome P450, and thiopurine S-methyltransferase) or determine cellular outcome (e.g., nucleotide excision DNA repair, base excision DNA repair, DNA mismatch repair, and cell death signaling) after therapy has provided insight into how host genetics may impact on the risk of developing iatrogenic malignancy. C1 Univ York, Epidemiol & Genet Unit, Dept Biol, York YO10 5DD, N Yorkshire, England. NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Allan, JM (reprint author), Univ York, Epidemiol & Genet Unit, Dept Biol, York YO10 5DD, N Yorkshire, England. EM jim.allan@egu.york.ac.uk RI Allan, James/B-4448-2009 FU Intramural NIH HHS NR 103 TC 9 Z9 9 U1 0 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD SEP PY 2005 VL 6 IS 6 BP 615 EP 628 DI 10.2217/14622416.6.6.615 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 965NV UT WOS:000231958300011 PM 16143001 ER PT J AU Simpkins, F Czechowicz, JA Liotta, L Kohn, EC AF Simpkins, F Czechowicz, JA Liotta, L Kohn, EC TI SELDI-TOF mass spectrometry for cancer biomarker discovery and serum proteomic diagnostics SO PHARMACOGENOMICS LA English DT Article DE biomarker; mass spectrometry; proteomics; SELDI-TOF ID LASER DESORPTION/IONIZATION-TIME; OVARIAN-CANCER; PROSTATE-CANCER; NONCANCER PATIENTS; COLORECTAL-CANCER; PANCREATIC-CANCER; BREAST-CANCER; TREE ANALYSIS; IDENTIFICATION; PATTERNS AB Proteomics is more than the identification of proteins that are altered in expression as a consequence of disease. Among the tools critical for the detection, treatment and monitoring of disease are biomarkers. The necessity for new methods to identify and validate biomarkers is underscored by the increased survival of patients diagnosed at early stages of cancer. Serum proteomic pattern diagnostics is a new technique in which proteomic signatures are used as a diagnostic classifier. Surf ace-enhanced laser desorption/ionization time-of-flight mass spectrometry has shown promise as a modality for biomarker discovery of early-stage cancers. Mass spectrometry-derived protein signatures have been modeled and are now moving into validation. Further sequencing of these key features can lead to new insights into disease etiology and intervention. C1 NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, FDA, Clin Proteom Program, Bethesda, MD 20892 USA. RP Kohn, EC (reprint author), NCI, Pathol Lab, Ctr Canc Res, Bldg 10 Rm 12N226,10 Ctr Dr,MSC 1500, Bethesda, MD 20892 USA. EM kohne@mail.nih.gov NR 51 TC 29 Z9 32 U1 1 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD SEP PY 2005 VL 6 IS 6 BP 647 EP 653 DI 10.2217/14622416.6.6.647 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 965NV UT WOS:000231958300014 PM 16143004 ER PT J AU Born, C Dittmann, S Post, RM Grunze, H AF Born, C Dittmann, S Post, RM Grunze, H TI Newer prophylactic agents for bipolar disorder and their influence on suicidality SO PHARMACOPSYCHIATRY LA English DT Meeting Abstract CT 24th Symposium of the Arbeitsgemeinschaft-fur-Neuropsychopharmakologie-und-Pharmakopsychiatrie (AGNP) CY OCT 05-08, 2005 CL Munich, GERMANY SP Arbeitsgemeinsch Neuropsychopharmakol & Pharmakopsychiatr C1 Univ Munich, Klin & Poliklin Psychiat & Psychotherapie, Munich, Germany. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0176-3679 J9 PHARMACOPSYCHIATRY JI Pharmacopsychiatry PD SEP PY 2005 VL 38 IS 5 BP 231 EP 231 PG 1 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 974LB UT WOS:000232591900029 ER PT J AU Giegling, I Goldman, D Zhou, Z Dietrich, I Hartmann, AM Moller, HJ Rujescu, D AF Giegling, I Goldman, D Zhou, Z Dietrich, I Hartmann, AM Moller, HJ Rujescu, D TI Association of suicidal behavior with the TPH2 gene SO PHARMACOPSYCHIATRY LA English DT Meeting Abstract CT 24th Symposium of the Arbeitsgemeinschaft-fur-Neuropsychopharmakologie-und-Pharmakopsychiatrie (AGNP) CY OCT 05-08, 2005 CL Munich, GERMANY SP Arbeitsgemeinsch Neuropsychopharmakol & Pharmakopsychiatr C1 Univ Munich, Klin & Poliklin Psychiat & Psychotherapie, Munich, Germany. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0176-3679 J9 PHARMACOPSYCHIATRY JI Pharmacopsychiatry PD SEP PY 2005 VL 38 IS 5 BP 243 EP 243 PG 1 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 974LB UT WOS:000232591900079 ER PT J AU Hondo, E Kiso, Y Stewart, CL AF Hondo, E Kiso, Y Stewart, CL TI LIF regulated genes in the luminal epithelium at embryo implantation SO PLACENTA LA English DT Meeting Abstract C1 Yamaguchi Univ, Fac Agr, Dept Vet Anat, Yamaguchi 7538515, Japan. NCI, Canc & Dev Biol Lab, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD SEP-OCT PY 2005 VL 26 IS 8-9 BP A19 EP A19 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 959DG UT WOS:000231496500077 ER PT J AU Holmes, EC Ghedin, E Miller, N Taylor, J Bao, YM St George, K Grenfell, BT Salzberg, SL Fraser, CM Lipman, DJ Taubenberger, JK AF Holmes, EC Ghedin, E Miller, N Taylor, J Bao, YM St George, K Grenfell, BT Salzberg, SL Fraser, CM Lipman, DJ Taubenberger, JK TI Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses SO PLOS BIOLOGY LA English DT Article ID PANDEMIC INFLUENZA; GENETIC-VARIATION; ANTIGENIC DRIFT; UNITED-STATES; AMINO-ACID; B VIRUSES; EVOLUTION; HEMAGGLUTININ; NEURAMINIDASE; RECOMBINATION AB Understanding the evolution of influenza A viruses in humans is important for surveillance and vaccine strain selection. We performed a phylogenetic analysis of 156 complete genomes of human H3N2 influenza A viruses collected between 1999 and 2004 from New York State, United States, and observed multiple co-circulating clades with different population frequencies. Strikingly, phylogenies inferred for individual gene segments revealed that multiple reassortment events had occurred among these clades, such that one clade of H3N2 viruses present at least since 2000 had provided the hemagglutinin gene for all those H3N2 viruses sampled after the 2002 - 2003 influenza season. This reassortment event was the likely progenitor of the antigenically variant influenza strains that caused the A/Fujian/411/ 2002-like epidemic of the 2003 - 2004 influenza season. However, despite sharing the same hemagglutinin, these phylogenetically distinct lineages of viruses continue to co-circulate in the same population. These data, derived from the first large-scale analysis of H3N2 viruses, convincingly demonstrate that multiple lineages can co-circulate, persist, and reassort in epidemiologically significant ways, and underscore the importance of genomic analyses for future influenza surveillance. C1 US Dept HHS, Natl Ctr Biotechnol Informat, Natl Lib Med, NIH, Bethesda, MD 20892 USA. Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. Inst Genom Res, Rockville, MD USA. New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. Armed Forces Inst Pathol, Dept Mol Pathol, Rockville, MD USA. RP Lipman, DJ (reprint author), US Dept HHS, Natl Ctr Biotechnol Informat, Natl Lib Med, NIH, Bethesda, MD 20892 USA. EM lipman@ncbi.nlm.nih.gov RI Salzberg, Steven/F-6162-2011; OI Salzberg, Steven/0000-0002-8859-7432; Fraser, Claire/0000-0003-1462-2428; Holmes, Edward/0000-0001-9596-3552 FU NIAID NIH HHS [N01AI30071]; ODCDC CDC HHS [U50/CCU223671] NR 63 TC 214 Z9 227 U1 0 U2 26 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD SEP PY 2005 VL 3 IS 9 BP 1579 EP 1589 AR e300 DI 10.1371/journal.pbio.0030300 PG 11 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 963RF UT WOS:000231820900009 PM 16026181 ER PT J AU Loftus, SK Cannons, JL Incao, A Pak, E Chen, A Zerfas, PM Bryant, MA Biesecker, LG Schwartzberg, PL Pavan, WJ AF Loftus, SK Cannons, JL Incao, A Pak, E Chen, A Zerfas, PM Bryant, MA Biesecker, LG Schwartzberg, PL Pavan, WJ TI Acinar cell apoptosis in Serpini2-deficient mice models pancreatic insufficiency SO PLOS GENETICS LA English DT Article ID SHWACHMAN-DIAMOND-SYNDROME; B-CELLS; GENE; MUTATIONS; SBDS; RAT; HYBRIDIZATION; SUPPRESSION; DYSFUNCTION; INHIBITOR AB Pancreatic insufficiency (PI) when left untreated results in a state of malnutrition due to an inability to absorb nutrients. Frequently, PI is diagnosed as part of a larger clinical presentation in cystic fibrosis or Shwachman-Diamond syndrome. In this study, a mouse model for isolated exocrine PI was identified in a mouse line generated by a transgene insertion. The trait is inherited in an autosomal recessive pattern, and homozygous animals are growth retarded, have abnormal immunity, and have reduced life span. Mice with the disease locus, named pequeno (pq), exhibit progressive apoptosis of pancreatic acinar cells with severe exocrine acinar cell loss by 8 wk of age, while the islets and ductal tissue persist. The mutation in pq/pq mice results from a random transgene insertion. Molecular characterization of the transgene insertion site by fluorescent in situ hybridization and genomic deletion mapping identified an approximately 210-kb deletion on Chromosome 3, deleting two genes. One of these genes, Serpini2, encodes a protein that is a member of the serpin family of protease inhibitors. Reintroduction of only the Serpini2 gene by bacterial artificial chromosome transgenic complementation corrected the acinar cell defect as well as body weight and immune phenotypes, showing that deletion of Serpini2 causes the pequeno phenotype. Dietary supplementation of pancreatic enzymes also corrected body size, body weight, and immunodeficiency, and increased the life span of Serpini2-deficient mice, despite continued acinar cell loss. To our knowledge, this study describes the first characterized genetic animal model for isolated P1. Genetic complementation of the transgene insertion mutant demonstrates that Serpini2 deficiency directly results in the acinar cell apoptosis, malabsorption, and malnutrition observed in pq/pq mice. The rescue of growth retardation, immunodeficiency, and mortality by either Serpini2 bacterial artificial chromosome transgenic expression or by pancreatic enzyme supplementation demonstrates that these phenotypes are secondary to malnutrition in pq/pq mice. C1 NIH, Genet Dis Res Branch, NHGRI, Bethesda, MD 20892 USA. NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. RP Loftus, SK (reprint author), NIH, Genet Dis Res Branch, NHGRI, Bldg 10, Bethesda, MD 20892 USA. EM sloftus@mail.nih.gov FU Intramural NIH HHS NR 38 TC 10 Z9 10 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD SEP PY 2005 VL 1 IS 3 BP 369 EP 379 AR e38 DI 10.1371/journal.pgen.0010038 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 003XA UT WOS:000234714300011 PM 16184191 ER PT J AU Miller, FG Wendler, D Swartzman, LC AF Miller, FG Wendler, D Swartzman, LC TI Deception in research on the placebo effect SO PLOS MEDICINE LA English DT Editorial Material ID INFORMED-CONSENT; ETHICAL ISSUES; EXPECTANCY; SUGGESTION; PSYCHOLOGY; EXPERIENCE; ALCOHOL; TRIALS; BLIND C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. Univ Western Ontario, Dept Psychol, London, ON N6A 3K7, Canada. RP Miller, FG (reprint author), NIH, Dept Clin Bioeth, Bldg 10, Bethesda, MD 20892 USA. EM fmiller@nih.gov NR 46 TC 51 Z9 52 U1 3 U2 15 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 SEP PY 2005 VL 2 IS 9 BP 853 EP 859 AR e262 DI 10.1371/journal.pmed.0020262 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 972DG UT WOS:000232433600012 PM 16173830 ER PT J AU Longo, DL AF Longo, Dan L. TI Risk of breast cancer after a biopsy showing benign disease SO POSTGRADUATE MEDICINE LA English DT Editorial Material C1 Natl Inst Hlth, Bethesda, MD 20892 USA. RP Longo, DL (reprint author), Natl Inst Hlth, Bethesda, MD 20892 USA. NR 2 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 SEP PY 2005 VL 118 IS 3 BP 6 EP 6 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA V44DO UT WOS:000202983600003 ER PT J AU Han, JY Song, KD Shin, JH Han, BK Park, TS Park, HJ Kim, JK Lillehoj, HS Lim, JM Kim, H AF Han, JY Song, KD Shin, JH Han, BK Park, TS Park, HJ Kim, JK Lillehoj, HS Lim, JM Kim, H TI Identification and characterization of the peroxiredoxin gene family in chickens SO POULTRY SCIENCE LA English DT Article DE chicken; oxidative damage; antioxidant activity; peroxiredoxin ID NONSELENIUM GLUTATHIONE-PEROXIDASE; OXIDATIVE STRESS; MAMMALIAN PEROXIREDOXIN; CANCER-CELLS; DISEASE; EXPRESSION; MICE; MECHANISM; ALIGNMENT; PROTEIN AB Peroxiredoxin (PRX) is a crucial antioxidant protein that protects against endogenously produced peroxides in prokaryotes, to eukaryotes. To date, 6 different isoforms have been identified in mammals. In this study, we describe the first members of the PRX protein family to be characterized in Chicken. Through bioinformatics: analysis, we observed that at least 4 different classes of PRX protein have been evolutionarily conserved in chickens. Furthermore, in vitro functional assays of the candidate chicken PRX proteins demonstrated that they had levels of antioxidant activity similar to those of the mammalian enzymes. The expression patterns of the PRX transcript in several chicken tissues were not tissue specific, Suggesting that they might play an essential role as a housekeeping gene in all tissues to protect against oxidative damage, In conclusion, the sequences of the putative members of this functional gene family in chickens could be effectively retrieved in silico through bioinformatics analysis, and the functionality of their gene products evaluated by in vitro comparative assay. C1 Seoul Natl Univ, Div Anim Genet Engn, Dept Food & Anim Biotechnol, Seoul 151921, South Korea. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. Avicore Biotechnol Inst Inc, Gunpo City 435050, Gyeonggi Do, South Korea. Seoul Natl Univ, Ctr Agr Biomat, Seoul 151921, South Korea. Changwon Natl Univ, Dept Microbiol, Coll Nat Sci, Chang Won 641773, South Korea. USDA, Anim Parasit Dis Lab, ANRI, Beltsville, MD 20705 USA. RP Han, JY (reprint author), Seoul Natl Univ, Div Anim Genet Engn, Dept Food & Anim Biotechnol, Seoul 151921, South Korea. EM jaehan@snu.ac.kr OI Kim, Heebal/0000-0003-3064-1303 NR 32 TC 10 Z9 12 U1 0 U2 1 PU POULTRY SCIENCE ASSOC INC PI SAVOY PA 1111 N DUNLAP AVE, SAVOY, IL 61874-9604 USA SN 0032-5791 J9 POULTRY SCI JI Poult. Sci. PD SEP PY 2005 VL 84 IS 9 BP 1432 EP 1438 PG 7 WC Agriculture, Dairy & Animal Science SC Agriculture GA 956VN UT WOS:000231328100014 PM 16206565 ER PT J AU Flay, BR Biglan, A Boruch, RF Castro, FG Gottfredson, D Kellam, S Moscicki, EK Schinke, S Valentine, JC Ji, P AF Flay, BR Biglan, A Boruch, RF Castro, FG Gottfredson, D Kellam, S Moscicki, EK Schinke, S Valentine, JC Ji, P TI Standards of evidence: Criteria for efficacy, effectiveness and dissemination SO PREVENTION SCIENCE LA English DT Review DE standards; efficacy; effectiveness; dissemination ID SCHOOL-BASED PREVENTION; RANDOMIZED CONTROLLED-TRIAL; DRUG-ABUSE PREVENTION; FOLLOW-UP; REDUCING VIOLENCE; ELEMENTARY-SCHOOL; PROPENSITY SCORE; AMERICAN YOUTH; MENTAL-HEALTH; DRINKING AGE AB Ever increasing demands for accountability, together with the proliferation of lists of evidence-based prevention programs and policies, led the Society for Prevention Research to charge a committee with establishing standards for identifying effective prevention programs and policies. Recognizing that interventions that are effective and ready for dissemination are a subset of effective programs and policies, and that effective programs and policies are a subset of efficacious interventions, SPR's Standards Committee developed overlapping sets of standards. We designed these Standards to assist practitioners, policy makers, and administrators to determine which interventions are efficacious, which are effective, and which are ready for dissemination. Under these Standards, an efficacious intervention will have been tested in at least two rigorous trials that (1) involved defined samples from defined populations, (2) used psychometrically sound measures and data collection procedures; (3) analyzed their data with rigorous statistical approaches; (4) showed consistent positive effects (without serious iatrogenic effects); and (5) reported at least one significant long-term follow-up. An effective intervention under these Standards will not only meet all standards for efficacious interventions, but also will have (1) manuals, appropriate training, and technical support available to allow third parties to adopt and implement the intervention; (2) been evaluated under real-world conditions in studies that included sound measurement of the level of implementation and engagement of the target audience (in both the intervention and control conditions); (3) indicated the practical importance of intervention outcome effects; and (4) clearly demonstrated to whom intervention findings can be generalized. An intervention recognized as ready for broad dissemination under these Standards will not only meet all standards for efficacious and effective interventions, but will also provide (1) evidence of the ability to "go to scale"; (2) clear cost information; and (3) monitoring and evaluation tools so that adopting agencies can monitor or evaluate how well the intervention works in their settings. Finally, the Standards Committee identified possible standards desirable for current and future areas of prevention science as the field develops. If successful, these Standards will inform efforts in the field to find prevention programs and policies that are of proven efficacy, effectiveness, or readiness for adoption and will guide prevention scientists as they seek to discover, research, and bring to the field new prevention programs and policies. C1 Univ Illinois, Inst Hlth Res & Policy, Chicago, IL 60608 USA. Oregon Res Inst, Eugene, OR 97403 USA. Univ Penn, Philadelphia, PA 19104 USA. Arizona State Univ, Tempe, AZ 85287 USA. Univ Maryland, College Pk, MD 20742 USA. Amer Inst Res, Washington, DC USA. NIMH, Bethesda, MD 20892 USA. Columbia Univ, New York, NY 10027 USA. Duke Univ, Durham, NC 27706 USA. RP Flay, BR (reprint author), Univ Illinois, Inst Hlth Res & Policy, 1747 W Roosevelt Rd,Suite 500,M-C 275, Chicago, IL 60608 USA. EM bflay@uic.edu RI Valentine, Jeffrey/D-8583-2011; Flay, Brian/A-8517-2008 OI Flay, Brian/0000-0002-5209-2766 NR 121 TC 446 Z9 453 U1 14 U2 67 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 J9 PREV SCI JI Prev. Sci. PD SEP PY 2005 VL 6 IS 3 BP 151 EP 175 DI 10.1007/s11121-005-5553-y PG 25 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 990XF UT WOS:000233776000001 PM 16365954 ER PT J AU Beck, KH Hartos, JL Simons-Morton, BG AF Beck, KH Hartos, JL Simons-Morton, BG TI Parent-teen disagreement of parent-imposed restrictions on teen driving after one month of licensure: Is discordance related to risky teen driving? SO PREVENTION SCIENCE LA English DT Article DE adolescent driving; parenting; driving restrictions or limits; concordance ID BRIEF INTERVENTION; DRIVERS; PASSENGERS; 16-YEAR-OLD; BEHAVIOR AB The purpose of the investigation was to determine if parent-teen discordance for parent-imposed restrictions on driving conditions, driving rules, and the consequences for driving rule violations were related to risky teen driving. A total of 579 parents and their newly licensed teens were interviewed by telephone, 1 month after teens obtained provisional licenses. In multiple regression analyses, the degree of disagreement with parent restrictions on driving conditions and parent-imposed consequences for driving rule violations were negatively associated with a composite measure of teen risky driving. Female parents were negatively associated and male teens were positively associated with risky driving, but discordance with restricted driving conditions was the most important predictor. Discordance may reflect poor parent-teen relations or inadequate communication about parental expectations. The findings suggest that increasing parent-teen concordance on parent-imposed driving restrictions may help reduce risky teen driving. C1 Univ Maryland, Dept Publ & Community Hlth, College Pk, MD 20742 USA. Univ N Carolina, Coll Hlth & Human Serv, Dept Hlth Behav & Adm, Charlotte, NC 28223 USA. NICHD, Prevent Res Branch, DESPR, NIH, Bethesda, MD 20892 USA. RP Beck, KH (reprint author), Univ Maryland, Dept Publ & Community Hlth, 2366 Hlth & Human Perf Bldg, College Pk, MD 20742 USA. EM kbeck1@umd.edu; jlhartos@email.unce.edu; mortonb@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 NR 32 TC 20 Z9 20 U1 2 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 J9 PREV SCI JI Prev. Sci. PD SEP PY 2005 VL 6 IS 3 BP 177 EP 185 DI 10.1007/s11121-005-0001-6 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 990XF UT WOS:000233776000002 PM 16044210 ER PT J AU Simons-Morton, B Haynie, D Saylor, K Crump, AD Chen, RA AF Simons-Morton, B Haynie, D Saylor, K Crump, AD Chen, RA TI The effects of the going places program on early adolescent substance use and antisocial behavior SO PREVENTION SCIENCE LA English DT Article DE adolescents; intervention; problem behavior; schools ID PREVENTION PROGRAMS; ALCOHOL-USE; SCHOOL ADJUSTMENT; SOCIAL COMPETENCE; ABUSE PREVENTION; DRUG-ABUSE; ASSOCIATION; SMOKING; YOUTH; PEER AB This study evaluated the effects of a school-based intervention on growth trajectories of smoking, drinking, and antisocial behavior among early adolescents. Seven middle schools were randomized to intervention or comparison conditions and students in two successive cohorts (n = 1484) provided five waves of data from sixth to ninth grade. The Going Places Program, included classroom curricula, parent education, and school environment components. Latent growth curve analyses demonstrated significant treatment group effects, including reducing increases in friends who smoke, outcome expectations for smoking, and smoking progression, but had non-significant effects on drinking or antisocial behavior. The Going Places Program was effective in preventing increases in smoking progression, but its efficacy as a more cross-cutting problem behavior preventive intervention was not confirmed. C1 NICHD, Prevent Res Branch, DESPR, NIH, Rockville, MD 20852 USA. NeuroSci Inc, Bethesda, MD USA. NIDA, Prevent Res Branch, NIH, Rockville, MD USA. Georgetown Univ, Washington, DC 20057 USA. RP Simons-Morton, B (reprint author), NICHD, Prevent Res Branch, DESPR, NIH, 6100 Execut Blvd 7B13M, Rockville, MD 20852 USA. EM Mortonb@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079 NR 49 TC 20 Z9 20 U1 2 U2 8 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 J9 PREV SCI JI Prev. Sci. PD SEP PY 2005 VL 6 IS 3 BP 187 EP 197 DI 10.1007/s11121-005-0005-2 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 990XF UT WOS:000233776000003 PM 16091854 ER PT J AU Aliberti, J Bafica, A AF Aliberti, J Bafica, A TI Anti-inflammatory pathways as a host evasion mechanism for pathogens SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS INFECTION; TOXOPLASMA-GONDII; IL-12 PRODUCTION; LIPOXIN A(4); IMMUNE-RESPONSE; HUMAN MONOCYTES; INFLAMMATION; RECEPTOR; MICE; CELLS AB Lipoxins play a key role in controlling potent pro-inflammatory responses triggered by infection with pathogens, such as Toxoplasma gondii and Mycobacterium tuberculosis. In order to contain microbial dissemination, infected hosts must mount a powerful immune response to prevent mortality. The onset of the chronic phase of infection is characterized by continuous cell-mediated immunity. Such potent responses are kept under tight control by a class of anti-inflammatory eicosanoids, the lipoxins. Here, we review such immune-containment strategies from the host's perspective, to keep pro-inflammatory responses under control during chronic disease, as well as from the perspective of the pathogen, which pirates the host's lipoxygenase machinery to its own advantage as a probable immune-escape mechanism. (c) 2005 Published by Elsevier Ltd. C1 Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27705 USA. NIAID, Parasit Dis Lab, Immunobiol Sect, NIH, Bethesda, MD 20892 USA. Fiocruz MS, Ctr Pesquisas Goncalo Moniz, LIMI, Bahia Blanca, Argentina. RP Aliberti, J (reprint author), Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27705 USA. EM julio.aliberti@duke.edu RI Aliberti, Julio/I-7354-2013 OI Aliberti, Julio/0000-0003-3420-8478 NR 46 TC 15 Z9 17 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD SEP-OCT PY 2005 VL 73 IS 3-4 BP 283 EP 288 DI 10.1016/j.plefa.2005.05.018 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 968OF UT WOS:000232171100018 PM 15982863 ER PT J AU Rapaka, RS Hla, T Dey, SK AF Rapaka, RS Hla, T Dey, SK TI The dawn of lipidomics SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Editorial Material C1 NIDA, Chem & Physiol Syst Res Branch, Div Basic Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. Univ Connecticut, Ctr Hlth, Ctr Vasc Biol, Dept Physiol, Farmington, CT 06030 USA. Vanderbilt Univ, Ctr Med, Div Reprod & Dev Biol, Nashville, TN 37232 USA. Vanderbilt Univ, Ctr Med, Dept Pediat, Nashville, TN 37232 USA. Vanderbilt Univ, Ctr Med, Dept Cell & Dev Biol, Nashville, TN 37232 USA. RP Rapaka, RS (reprint author), NIDA, Chem & Physiol Syst Res Branch, Div Basic Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. EM rr82u@nih.gov RI Hla, Timothy/G-5873-2012 OI Hla, Timothy/0000-0001-8355-4065 NR 0 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD SEP PY 2005 VL 77 IS 1-4 BP 1 EP 3 DI 10.1016/j.prostaglandins.2005.06.001 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 962YT UT WOS:000231770200001 PM 16099385 ER PT J AU Maceyka, M Milstien, S Spiegel, S AF Maceyka, M Milstien, S Spiegel, S TI Sphingosine kinases, sphingosine-1-phosphate and sphingolipidomics SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Article; Proceedings Paper CT Workshop on Target Lipidomics - Signaling Lipids and Drugs of Abuse CY APR, 2004 CL Washington, DC SP Natl Natl Inst Drug Abuse DE sphingolipid; ceramide; LC-MS; sphingosine; sphingosine-1-phosphate ID TANDEM MASS-SPECTROMETRY; PROTEIN-COUPLED RECEPTOR; VASCULAR MATURATION; CERAMIDE; 1-PHOSPHATE; APOPTOSIS; CELLS; EDG-1; GLYCOLIPIDS; METABOLITES AB It has become abundantly clear over the past decade that sphingolipids and their metabolites are key signaling molecules. Ceramide, the backbone of all sphingolipids, predominantly inhibits cell growth and induces apoptosis, while its metabolite, sphingosine-1-phosphate promotes growth and survival. Given the interconvertibility of these two opposing signaling molecules, it is essential that any study that examines the effects of one also look at the other. The newly available technology of liquid chromatography-tandem mass spectroscopy (LC-MS/MS) is increasingly being applied for this purpose, as it can quickly identify and measure many different sphingolipids simultaneously. An added benefit of LC-MS/MS is that it is several orders of magnitude more sensitive than enzymatic methods or more traditional chromatographic techniques, allowing smaller sample sizes and increased throughput. Here, we briefly discuss the importance of LC-MS/MS for measuring sphingolipid metabolites and some future directions researchers may take given the increasingly accessibility to this technology. (c) 2004 Elsevier Inc. All rights reserved. C1 Virginia Commonwealth Univ, Sch Med, Dept Biochem, Richmond, VA 23298 USA. NIMH, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biochem, Med Coll Virginia Campus, Richmond, VA 23298 USA. EM sspiegel@vcu.edu RI Maceyka, Michael/B-9277-2008 FU NCI NIH HHS [R01CA61774] NR 38 TC 25 Z9 27 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD SEP PY 2005 VL 77 IS 1-4 BP 15 EP 22 DI 10.1016/j.prostaglandins.2004.09.010 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 962YT UT WOS:000231770200003 PM 16099387 ER PT J AU Rapoport, SI AF Rapoport, SI TI In vivo approaches and rationale for quantifying kinetics and imaging brain lipid metabolic pathways SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Article; Proceedings Paper CT Workshop on Target Lipidomics - Signaling Lipids and Drugs of Abuse CY APR, 2004 CL Washington, DC SP Natl Natl Inst Drug Abuse DE phospholipid; ether; imaging; kinetics; brain; turnover; phospholipase A(2); PET; lipidomics; hexadecanol; myo-inositol; docosahexaenoic; arachidonic ID DOCOSAHEXAENOIC ACID METABOLISM; POSITRON-EMISSION-TOMOGRAPHY; RAT-BRAIN; SIGNAL-TRANSDUCTION; PHOSPHOLIPASE A(2); AWAKE RATS; MAMMALIAN BRAIN; CHRONIC LITHIUM; UNANESTHETIZED RATS; NERVOUS-SYSTEM AB Developing a kinetic strategy to examine rates of lipid metabolic pathways can help to elucidate the roles that lipids play in tissue function and structure in health and disease. This review summarizes such a strategy, and shows how it has been applied to quantify different kinetic aspects of brain lipid metabolism in animals and humans. Methods involve injecting intravenously a radioactive or heavy isotope labeled substrate that will be incorporated into a lipid metabolic pathway, and using chemical analytical and/or imaging procedures (e.g., quantitative autoradiography or positron emission tomography) to determine tracer distribution in brain regions and their lipid compartments as a function of time. From the measurements, fluxes, turnover rates, half-lives and ATP consumption rates can be calculated, and incorporation rates can be imaged. Experimental changes in these kinetic parameters can help to identify changes in the expression of regulatory enzymes, and thus aid in drug targeting. Cases that are discussed are arachidonic acid turnover and imaging of neuroreceptor-initiated phospholipase, A(2) activation, ether phospholipid biosynthesis, and kinetics of the phosphatidylinositol cycle. Published by Elsevier Inc. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. EM sir@helix.nih.gov NR 56 TC 24 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 1098-8823 EI 2212-196X J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD SEP PY 2005 VL 77 IS 1-4 BP 185 EP 196 DI 10.1016/j.prostaglandins.2004.09.015 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 962YT UT WOS:000231770200019 PM 16099403 ER PT J AU Rapaka, RS AF Rapaka, RS TI Targeted lipidomics and drug abuse research SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Article; Proceedings Paper CT Workshop on Target Lipidomics - Signaling Lipids and Drugs of Abuse CY APR, 2004 CL Washington, DC SP Natl Natl Inst Drug Abuse DE lipidomics; drug abuse; addiction AB Contemporaneously with genomics and proteomics technologies, lipidomics may be recognized as the next important emerging technology. The emergence of this important area of "omics" could very well mark the beginning of "the decade of the lipids." A workshop on lipidomics was held in Washington, DC, by the National Institute on Drug Abuse (NIDA) in April 2004. The goal of the workshop was to bring together scientists working at the frontier of lipid research, to discuss their findings in this area and to promote "lipidomics," in general, but also with a special focus on its application to drug abuse research and development of therapies to treat addiction. (c) 2005 Elsevier Inc. All rights reserved. C1 NIDA, Chem & Physiol Syst Res Branch, Div Basic Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. RP Rapaka, RS (reprint author), NIDA, Chem & Physiol Syst Res Branch, Div Basic Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. EM rr82u@nih.gov NR 2 TC 4 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD SEP PY 2005 VL 77 IS 1-4 BP 219 EP 222 DI 10.1016/j.prostaglandins.2005.06.007 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 962YT UT WOS:000231770200022 PM 16099406 ER PT J AU Rapaka, RS Piomelli, D Spiegel, S Bazan, N Dennis, EA AF Rapaka, RS Piomelli, D Spiegel, S Bazan, N Dennis, EA TI Targeted lipidomics: Signaling lipids and drugs of abuse SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Article; Proceedings Paper CT Workshop on Target Lipidomics - Signaling Lipids and Drugs of Abuse CY APR, 2004 CL Washington, DC SP Natl Natl Inst Drug Abuse DE lipidomics; HPLC-MS; MALDI-TOF C1 NIDA, Chem & Physiol Syst Res Branch, Div Basic Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92697 USA. Virginia Commonwealth Univ, Sch Med, Dept Biochem, Richmond, VA 23298 USA. Louisiana State Univ, Hlth Sci Ctr, Neurosci Ctr Excellence, New Orleans, LA 70112 USA. Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. RP Rapaka, RS (reprint author), NIDA, Chem & Physiol Syst Res Branch, Div Basic Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. EM rr82u@nih.gov OI Dennis, Edward A/0000-0003-3738-3140 NR 0 TC 9 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD SEP PY 2005 VL 77 IS 1-4 BP 223 EP 234 DI 10.1016/j.prostaglandins.2005.06.005 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 962YT UT WOS:000231770200023 PM 16099407 ER PT J AU Chang, BL Isaacs, SD Wiley, KE Gillanders, EM Zheng, SL Meyers, DA Walsh, PC Trent, JM Xu, JF Isaacs, WB AF Chang, BL Isaacs, SD Wiley, KE Gillanders, EM Zheng, SL Meyers, DA Walsh, PC Trent, JM Xu, JF Isaacs, WB TI Genome-wide screen for prostate cancer susceptibility genes in men with clinically significant disease SO PROSTATE LA English DT Article DE aggressive; prostate cancer; linkage; genome-wide scan; hereditary ID LINKAGE ANALYSIS; LOCUS HPCX; FAMILIES; HETEROGENEITY AB BACKGROUND. One of the difficulties confronting genetic studies of prostate cancer is the complex and heterogeneous etiology. Given the high population frequency of lesions meeting the histological definition of prostate cancer, a significant portion of men with a positive family history may be diagnosed due to increased surveillance and associated higher likelihood of biopsy. Over diagnosis decreases power to detect genes that increase susceptibility to a clinically significant prostate cancer. METHODS. We re-evaluated all 623 men with prostate cancer in our 188 hereditary prostate cancer families and identified a subset of 244 men with more aggressive disease based upon meeting at least one of the following clinical and/or pathologic criteria: tumor grade Gleason score >= 7, tumor stage T2c or higher, pretreatment PSA >= 20 ng/ml, rising PSA after treatment, evidence of metastasis, or death from prostate cancer. RESULTS. Genome-wide screens were re-performed by defining men as affected only if they met the criteria for clinically significant disease. The new analyses identified stronger evidence for linkage in Xq27-28 and 22q, as well as several novel loci, including 3p and 9p. CONCLUSIONS. Although, these results need to be confirmed in independent studies, our approach represents an important step to overcome the impact of over diagnosis in genetic studies of prostate cancer. Larger studies that incorporate this approach are needed. C1 Wake Forest Univ, Sch Med, Ctr Human Genet, Winston Salem, NC 27157 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. RP Xu, JF (reprint author), Wake Forest Univ, Sch Med, Ctr Human Genet, Med Ctr Bldg, Winston Salem, NC 27157 USA. EM jxu@wfubmc.edu FU NCI NIH HHS [CA89600, CA105055, CA58236, CA95052, CA106523] NR 20 TC 35 Z9 36 U1 0 U2 0 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 SEP 1 PY 2005 VL 64 IS 4 BP 356 EP 361 DI 10.1002/pros.20249 PG 6 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 957KQ UT WOS:000231369100005 PM 15754351 ER PT J AU Street, TO Bradley, CM Barrick, D AF Street, TO Bradley, CM Barrick, D TI An improved experimental system for determining small folding entropy changes resulting from proline to alanine substitutions SO PROTEIN SCIENCE LA English DT Article DE unfolding entropy; proline substitution; Notch ankyrin domain; chemical denaturation ID ALPHA-CHYMOTRYPSIN; REPEATS; PROTEIN; COOPERATIVITY; SEQUENCE AB Changes in protein stability can be achieved by making substitutions that increase or decrease the available conformations of the unfolded protein without altering the conformational freedom of the folded protein. Matthews and coworkers (1987) proposed that proline to alanine (P -> A) substitution would achieve this type of entropic destabilization. By comparing the Ramachandran area associated with alanine and proline residues, Matthews et al. estimated the unfolding entropy change resulting from P -> A substitution to be 4.8 cal mol(-1) K-1. Although such an entropy difference would produce a substantial free energy change, accurately resolving such free energy changes into entropic and enthalpic components has been difficult. Here, we attempt to quantify the unfolding entropy change produced by P -> A substitution by amplifying the effect through multiple substitutions, and by decreasing the uncertainty in determining the unfolding entropy. Variants of a repeat protein, the Drosophila Notch ankyrin domain, were constructed with a varying number of P -> A substitutions at structurally conserved positions. Unfolding entropy values of the variants were determined from free energy measurements taken over a common temperature range using chemical denaturation. Our findings confirm the prediction that increasing the number of proline residues present in similar local environments increases the unfolding entropy. The average value of this increase in unfolding entropy is 7.7 +/- 4.2 cat mol(-1) K-1, which is within error of the value estimated by Matthews et al. (1987). C1 Johns Hopkins Univ, TC Jenkins Dept Biophys, Baltimore, MD 21218 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Barrick, D (reprint author), Johns Hopkins Univ, TC Jenkins Dept Biophys, 204 Jenkins Hall,3400 N Charles St, Baltimore, MD 21218 USA. EM barrick@jhu.edu FU NIGMS NIH HHS [GM068642, GM60001, R01 GM060001, R01 GM068462] NR 12 TC 8 Z9 8 U1 0 U2 1 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 SEP PY 2005 VL 14 IS 9 BP 2429 EP 2435 DI 10.1110/ps.051505705 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 960QF UT WOS:000231607500024 PM 16131666 ER PT J AU Terracciano, A McCrae, RR Brant, LJ Costa, PT AF Terracciano, A McCrae, RR Brant, LJ Costa, PT TI Hierarchical linear modeling analyses of the NEO-PI-R scales in the Baltimore longitudinal study of aging SO PSYCHOLOGY AND AGING LA English DT Article; Proceedings Paper CT Annual Convention of the Gerontological-Society-America CY NOV, 2004 CL Washington, DC SP Gerontol Soc Amer DE five-factor model; personality change; aging; longitudinal study; HLM ID PERSONALITY-CHANGE; ALZHEIMERS-DISEASE; AGE-DIFFERENCES; SELF-REPORTS; ADULT PERSONALITY; GENETIC-ANALYSIS; 5-FACTOR MODEL; SPOUSE RATINGS; OLDER-ADULTS; LIFE-SPAN AB The authors examined age trends in the 5 factors and 30 facets assessed by the Revised NEO Personality Inventory in Baltimore Longitudinal Study of Aging data (N = 1,944; 5,027 assessments) collected between 1989 and 2004. Consistent with cross-sectional results, hierarchical linear modeling analyses showed gradual personality changes in adulthood: a decline in Neuroticism up to age 80, stability and then decline in Extraversion, decline in Openness, increase in Agreeableness, and increase in Conscientiousness up to age 70. Some facets showed different curves from the factor they define. Birth cohort effects were modest, and there were no consistent Gender X Age interactions. Significant nonnormative changes were found for all 5 factors; they were not explained by attrition but might be due to genetic factors, disease, or life experience. C1 NIA, Lab Personal & Cognit, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. NIA, Res Resources Bracnh, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Terracciano, A (reprint author), Gerontol Res Ctr, Box 03,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM terraccianoa@grc.nia.nih.gov RI terracciano, antonio/B-1884-2008; OI Costa, Paul/0000-0003-4375-1712 FU Intramural NIH HHS [Z99 AG999999, ZIA AG000183-22, ZIA AG000183-23, ZIA AG000197-03, ZIA AG000197-04] NR 68 TC 197 Z9 198 U1 6 U2 33 PU AMER PSYCHOLOGICAL ASSOC/EDUCATIONAL PUBLISHING FOUNDATION PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD SEP PY 2005 VL 20 IS 3 BP 493 EP 506 DI 10.1037/0882-7974.20.3.493 PG 14 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 980ML UT WOS:000233022500012 PM 16248708 ER PT J AU Brown, PL Kiyatkin, EA AF Brown, PL Kiyatkin, EA TI Brain temperature change and movement activation induced by intravenous cocaine delivered at various injection speeds in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE brain metabolism; vasoconstriction; locomotion; ventral tegmental area; nucleus accumbens; brain hyperthermia ID DOPAMINE UPTAKE; SENSITIZATION; INHIBITION; RELEASE; FLUCTUATIONS; AMPHETAMINE; ADDICTION; RESPONSES; BINDING; SYSTEM AB Rationale: Speed of intravenous (i.v.) injection presumably affects the rewarding effects of cocaine in humans. Work with animals has shown alterations in the behavioral and neurochemical effects of cocaine based on delivery speed. Objectives: We studied the effects of cocaine (1 mg/kg) as both a single i.v. injection and a series of five repeated injections (8-min intervals) delivered at different speeds (4, 16, and 64 s) on brain, muscle, and skin temperatures, and locomotion in awake, unrestrained rats. Since cocaine has a distinctive action on temperature, any enhancement of cocaine's properties by injection speed should readily be seen. Results: When given as a single injection, cocaine increased brain temperature and locomotion, but transiently decreased skin and muscle temperatures; these effects were augmented by a high injection speed. Regardless of injection speed, however, changes in brain temperature and locomotion were strongly correlated with basal brain temperatures; higher temperatures were associated with less change after cocaine injection. When given as a series of five injections, cocaine increased brain temperature and locomotion. Although skin temperature initially decreased, it increased after successive cocaine injections. With each successive cocaine injection in the series, measures of temperature and movement parameters increased to a plateau and brain temperature change became biphasic. Conclusions: While confirming the results. of others that rapid injection speed enhances cocaine-induced locomotor activation, our study suggests that delivery rate also affects the basic physiological actions of cocaine. 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 31 TC 18 Z9 18 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2005 VL 181 IS 2 BP 299 EP 308 DI 10.1007/s000213-005-2244-0 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 966VU UT WOS:000232051700012 PM 15778873 ER PT J AU Fantegrossi, WE Harrington, AW Eckler, JR Arshad, S Rabin, RA Winter, JC Coop, A Rice, KC Woods, JH AF Fantegrossi, WE Harrington, AW Eckler, JR Arshad, S Rabin, RA Winter, JC Coop, A Rice, KC Woods, JH TI Hallucinogen-like actions of 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7) in mice and rats SO PSYCHOPHARMACOLOGY LA English DT Article DE 2C-T-7; hallucinogens; phenethylamines; drug discrimination; head twitch response; 5-HT2A receptor; mice; rats ID HEAD-TWITCH RESPONSE; RECEPTOR ACTIVATION; 5-HT2 RECEPTORS; STIMULUS; ANTAGONISTS; LSD; 5-HYDROXYTRYPTAMINE; SEROTONIN; BEHAVIOR; DRUGS AB Rationale: Few studies have examined the effects of 2,5-dimethoxy-4-(n)-propylthiophenethylamine (2C-T-7) in vivo. Objectives: 2C-T-7 was tested in a drug-elicited head twitch assay in mice and in several drug discrimination assays in rats; 2C-T-7 was compared to the phenylisopropylamine hallucinogen R(-)-1-(2,5-dimethoxy4-methylphenyl)-2-aminopropane (DOM) in both assays, with or without pretreatment with the selective 5-HT2A antagonist (+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907). Finally, the affinity of 2C-T-7 for three distinct 5-HT receptors was determined in rat brain. Methods: Drug-elicited head twitches were quantified for 10 min following administration of various doses of either 2C-T-7 or R(-)-DOM, with and without pretreatments of 0.01 mg/kg M100907. In rats trained to discriminate lysergic acid diethylamide (LSD), 2C-T-7 and R(-)-DOM were tested for generalization. In further studies, rats were trained to discriminate 2C-T-7 from saline, then challenged with 0.05 mg/kg M100907. In competition binding studies, the affinity of 2C-T-7 was assessed at 5-HT2A receptors, 5-HT1A receptors, and 5-HT2C receptors. Results: 2C-T-7 and R(-)-DOM induced similar head twitch responses in the mouse that were antagonized by M100907. In the rat, 2C-T-7 produced an intermediate degree of generalization (75%) to the LSD cue and served as a discriminative stimulus; these interoceptive effects were attenuated by M100907. Finally, 2C-T-7 had nanomolar affinity for 5-HT2A and 5-HT2C receptors and lower affinity for 5-HT1A receptors. Conclusions: 2C-T-7 is effective in two rodent models of 5-HT2 agonist activity and has affinity at receptors relevant to hallucinogen effects. The effectiveness with which M 100907 antagonizes the behavioral actions of 2C-T-7 strongly suggests that the 5-HT2A receptor is an important site of action for this compound. C1 Emory Univ, Yerkes Natl Primate Res Ctr, Div Neurosci, Atlanta, GA 30322 USA. Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. SUNY Buffalo, Sch Med & Biomed Sci, Dept Pharmacol, Buffalo, NY 14214 USA. Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. NIDDK, Lab Med Chem, NIH, Bethesda, MD 20892 USA. RP Fantegrossi, WE (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, Div Neurosci, 954 Gatewood Dr, Atlanta, GA 30322 USA. EM wfanteg@emory.edu NR 41 TC 40 Z9 41 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2005 VL 181 IS 3 BP 496 EP 503 DI 10.1007/s00213-005-0009-4 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 975BE UT WOS:000232635200008 PM 15983786 ER PT J AU Eaker, ED Sullivan, LM Kelly-Hayes, M D'Agostino, RB Benjamin, EJ AF Eaker, ED Sullivan, LM Kelly-Hayes, M D'Agostino, RB Benjamin, EJ TI Tension and anxiety and the prediction of the 10-year incidence of coronary heart disease, atrial fibrillation, and total mortality: The Framingham Offspring Study SO PSYCHOSOMATIC MEDICINE LA English DT Article DE tension; anxiety; coronary heart disease; atrial fibrillation; mortality ID PSYCHOSOCIAL FACTORS; PHOBIC ANXIETY; RISK; MEN; DEATH AB Objective: Conflicting research findings regarding the ability of tension or anxiety to predict incident coronary heart disease (CHD) have created uncertainty in the literature. In addition, there are no prospective studies relating these characteristics to the development of atrial fibrillation (AF). Methods: From 1984 to 1987, 3682 participants (mean age 48.5 +/- 10.1 year; 52% women) of the Framingham Offspring Study were examined and followed for 10 years for the incidence of CHD, AF, and total mortality. Measures of tension, anxiety, and risk factors for CHD and AF were collected at the baseline examination. Results: After adjusting for age, systolic blood pressure, body mass index, current cigarette smoking, diabetes, and total cholesterol/high-density cholesterol in Cox proportional hazards models, increased tension was predictive of 10-year incidence of definite CHD (relative risk (RR) = 1.25 relative to a one SD difference; 95% confidence interval (CI), 1.05-1.49) and total mortality (RR = 1.23; 95% Cl, 1.06-1.42) in men. After adjusting for AF risk factors, tension also predicted AF in men (RR = 1.24; 95% CI, 1.04-1.48). Anxiety in men (RR = 1.22; 95% CI, 1.08-1.38), and in women (RR = 1.27; 95% CI, 1.05-1.55) was significantly related to total mortality. Conclusions: Tension was observed to be an independent risk factor for incident CHD, AF, and mortality in men. Anxiety was a risk factor for total mortality in men and women. Our findings suggest that further research into the pathophysiology of the excess morbidity and mortality observed with tension and anxiety is merited. C1 Eaker Epidemiol Enterprises LLC, Chili, WI 54420 USA. Boston Univ, Sch Publ Hlth, Dept Math & Stat, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Cardiol, Boston, MA 02215 USA. Framingham Heart Dis Epidemiol Study, Natl Heart Lung & Blood Inst, Bethesda, MD USA. RP Eaker, ED (reprint author), Eaker Epidemiol Enterprises LLC, 8975 Cty Rd 5, Chili, WI 54420 USA. EM eakerepi@tznet.com OI Benjamin, Emelia/0000-0003-4076-2336; Sullivan, Lisa/0000-0003-0726-7149 FU NHLBI NIH HHS [1 R03 HL 67426-01, N01-HC-25195] NR 18 TC 80 Z9 84 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD SEP-OCT PY 2005 VL 67 IS 5 BP 692 EP 696 DI 10.1097/01.psy.0000174050.87193.96 PG 5 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 970GT UT WOS:000232294000003 PM 16204425 ER PT J AU Wulsin, LR Evans, JC Vasan, RS Murabito, JM Kelly-Hayes, M Benjamin, EJ AF Wulsin, LR Evans, JC Vasan, RS Murabito, JM Kelly-Hayes, M Benjamin, EJ TI Depressive symptoms, coronary heart disease, and overall mortality in the Framingham Heart Study SO PSYCHOSOMATIC MEDICINE LA English DT Article DE depressive symptoms; epidemiology; incidence; coronary heart disease; mortality; Framingham Heart Study ID CARDIAC MORTALITY; RISK-FACTOR; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; MAJOR DEPRESSION; ARTERY-DISEASE; COMMUNITY; SEVERITY; EVENTS; SAMPLE AB Objective: Although a substantial number of studies have shown that depressive symptoms predict worse cardiac outcome for patients with existing coronary disease, relatively few methodologically rigorous studies have examined the relation of depressive symptoms to coronary disease incidence in individuals initially free of heart disease in the community. Methods: Using multivariable-adjusted sex-stratified Cox proportional hazards regression, we examined the association between depressive symptoms and incident coronary disease and all-cause mortality in 3634 Framingham Heart Study original and offspring cohort participants (mean age 52 years, 55% women) attending a routine study examination between 1983 and 1994. Results: Over 6 years, of follow-up, 83 participants had a hard coronary heart disease event (myocardial infarction or coronary death), and 133 died. Depressive symptoms (Center for Epidemiologic Studies Depression Scale (CES-D) >= 16) did not predict hard coronary disease events. All-cause mortality, however, was directly associated with depressive symptoms. Compared with the lowest tertile of CES-D score, multivariable-adjusted risks of death in the second and third tertiles were 33% and 88% higher, respectively (hazards ratio per tertile increment = 1.37, 95% confidence interval 1.10-1.71, p for trend = 0.005). Conclusion: These findings underscore the importance of further research into the pathogenesis and prevention of excess mortality experienced with depressive symptoms. C1 Univ Cincinnati, Dept Psychiat, Cincinnati, OH 45221 USA. Univ Cincinnati, Dept Family Med, Cincinnati, OH 45221 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Med Ctr, Div Cardiol & Prevent Med & Neurol, Boston, MA USA. Boston Med Ctr, Gen Internal Med Sect, Boston, MA USA. RP Wulsin, LR (reprint author), 231 Albert Sabin Way,ML 559, Cincinnati, OH 45267 USA. EM Lawson.wulsin@uc.edu OI Murabito, Joanne/0000-0002-0192-7516; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K24-HL-04334, N01-HC-25195]; NINDS NIH HHS [5R01-NS-17950] NR 28 TC 70 Z9 71 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD SEP-OCT PY 2005 VL 67 IS 5 BP 697 EP 702 DI 10.1097/01.psy.0000181274.56785.28 PG 6 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 970GT UT WOS:000232294000004 PM 16204426 ER PT J AU Weiss, A Costa, PT AF Weiss, A Costa, PT TI Domain and facet personality predictors of all-cause mortality among medicare patients aged 65 to 100 SO PSYCHOSOMATIC MEDICINE LA English DT Article DE mortality; conscientiousness; neuroticism; agreeableness; Five-Factor Model; elderly ID CORONARY HEART-DISEASE; CHD INCIDENCE; HOSTILITY; RISK; VALIDATION; PHYSICIANS; BEHAVIORS; HEALTH; DEATH AB Objectives: Our objectives were to test whether Conscientiousness, the other 4 domains of the Five-Factor Model, and their facets predicted mortality in older, frail individuals. Methods: Controlling for demographic and health measures, we used Cox regression to test whether the NEO Five-Factor Inventory (NEO-FFI) Neuroticism, Extraversion, Openness to Experience, Agreeableness, and Conscientiousness domains predicted all-cause mortality over 5 years in 1076 65- to 100-year-old participants who took part in a Medicare Demonstration study. Supplementary analyses on 597 participants aged 66 to 102 who were reassessed 2 years later were conducted to determine whether any of the Revised NEO Personality Inventory (NEO-PI-R) facets were related to mortality. Results: When personality domains were treated as continuous variables, NEO-FFI Neuroticism and Agreeableness were significant protective factors. When personality domains were trichotomized, NEO-FFI Conscientiousness was a protective factor. In a third analysis, Agreeableness was not a significant predictor in a model that included the continuous Neuroticism and trichotomized Conscientiousness variables. Analysis of the NEO-PI-R Neuroticism, Agreeableness, and Conscientiousness factors showed that Agreeableness and Conscientiousness were protective and that there was a trend for a similar effect of Neuroticism. Facet-level analyses revealed that the Impulsiveness, Straightforwardness, and Self-Discipline facets of Neuroticism, Agreeableness, and Conscientiousness, respectively, were prospectively related to greater survival over a 3-year interval. Conclusion: The effects of Neuroticism and Agreeableness on mortality are inconsistent across previous studies. This study indicates that, in a sample of older, frail participants, high Neuroticism and Agreeableness scores are protective and that more specific effects are primarily the result of the Impulsiveness and Straightforwardness facet scales. The Conscientiousness findings are consistent with those in earlier studies and demonstrate the importance of the Self-Discipline facet. C1 NIA, Lab Personal & Cognit, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Weiss, A (reprint author), NIA, Lab Personal & Cognit, NIH, Dept Hlth & Human Serv, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM weissal@grc.nia.nih.gov OI Costa, Paul/0000-0003-4375-1712 NR 36 TC 129 Z9 132 U1 5 U2 23 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3261 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD SEP-OCT PY 2005 VL 67 IS 5 BP 724 EP 733 DI 10.1097/01.psy.0000181272.58103.18 PG 10 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 970GT UT WOS:000232294000008 PM 16204430 ER PT J AU Miller, RW Zanzonico, PB AF Miller, RW Zanzonico, PB TI Radioiodine fallout and breast-feeding SO RADIATION RESEARCH LA English DT Editorial Material ID MILK; EXCRETION; RADIOPHARMACEUTICALS; IODINE C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, Clin Genet Branch, Bethesda, MD 20892 USA. RP Zanzonico, PB (reprint author), Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. EM ZanzoniP@MSKCC.ORG NR 12 TC 2 Z9 2 U1 0 U2 0 PU RADIATION RESEARCH SOC PI OAK BROOK PA 820 JORIE BOULEVARD, OAK BROOK, IL 60523 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD SEP PY 2005 VL 164 IS 3 BP 339 EP 340 DI 10.1667/RR3437.1 PG 2 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 959XB UT WOS:000231551500016 PM 16137209 ER PT J AU Natanzon, A Aletras, AH Hsu, LY Arai, AE AF Natanzon, A Aletras, AH Hsu, LY Arai, AE TI Determining canine myocardial area at risk with manganese-enhanced MR imaging SO RADIOLOGY LA English DT Article ID NUCLEAR MAGNETIC-RESONANCE; EMISSION-COMPUTED-TOMOGRAPHY; INFARCT SIZE; MN-DPDP; CONTRAST ENHANCEMENT; HEART; QUANTIFICATION; ISONITRILE; PERFUSION; MNDPDP AB PURPOSE: To test whether manganese-enhanced magnetic resonance (MR) imaging can safely depict the myocardial area at risk both during coronary artery occlusion and for at least 2 hours after reperfusion in dogs. MATERIALS AND METHODS: All procedures were performed in accordance with the animal care and use committee of the National Institutes of Health. In eight dogs, the left anterior descending (LAD) coronary artery was occluded for 90 minutes, and 15 mu mol of MnCl2, per kilogram of body weight was intravenously infused for 12 minutes. Phase-sensitive inversion-recovery MR imaging of the LAD arterial territory was performed before occlusion, during MnCl2 infusion, and for at least 2 hours after reperfusion. Hemodynamic responses were monitored continuously. Fluorescent microsphere enhancement was used as the reference standard for determining the area at risk ex vivo. Results are reported as percentages of left ventricular area. Correlation, Bland-Altman, and t test analyses were performed. RESULTS: Significant differences in manganese-induced contrast enhancement of the area at risk, the normal myocardium, and the blood (P <.01) were measured during LAD artery occlusion and at least 2 hours after reperfusion. No significant changes in heart rate or blood pressure were detected during or after MnCl2 infusion. Measurements of the area at risk obtained with manganese-enhanced MR imaging during LAD artery occlusion and 2 hours after reperfusion correlated well with the size of the at-risk area demarcated by the fluorescent microspheres (during occlusion: y = 0.81x, R = 0.90; during reperfusion: y = 0.83x, R = 0.89). BlandAltman analysis revealed small systematic errors in measurements at both occlusion and reperfusion. CONCLUSION: Manganese-enhanced MR imaging can depict the area at risk during LAD artery occlusion and at least 2 hours after reperfusion without hemodynamic compromise. (c) RSNA, 2005. C1 NHLBI, Cardiac Energet Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. Mt Sinai Sch Med, New York, NY USA. RP Arai, AE (reprint author), NHLBI, Cardiac Energet Lab, NIH, US Dept HHS, 10 Ctr Dr,MSC 1061,Bldg 10,Room B1D-416, Bethesda, MD 20892 USA. EM araia@nih.gov OI Aletras, Anthony/0000-0002-3786-3817 NR 57 TC 19 Z9 20 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD SEP PY 2005 VL 236 IS 3 BP 859 EP 866 DI 10.1148/radiol.2363040413 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 957ZR UT WOS:000231412600016 PM 16118166 ER PT J AU Muanza, T Cotrim, A Baum, B McAuliffe, M Feldchtein, F Amazeen, P Coleman, N Sowers, A Cook, J Mitchell, J AF Muanza, T Cotrim, A Baum, B McAuliffe, M Feldchtein, F Amazeen, P Coleman, N Sowers, A Cook, J Mitchell, J TI Evaluation of radiation-induced oral mucositis by optical coherence tomography SO RADIOTHERAPY AND ONCOLOGY LA English DT Meeting Abstract CT Annual Scientific Meeting of the Canadian-Association-of-Radiation-Oncology CY SEP 07-10, 2005 CL Victoria, CANADA SP Canadian Assoc Radiat Oncol C1 McGill Univ, Ctr Hlth, Montreal, PQ, Canada. Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. NIH, Biomed Imaging Res Serv, Bethesda, MD 20892 USA. Imalux Corp, Cleveland, OH USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-8140 J9 RADIOTHER ONCOL JI Radiother. Oncol. PD SEP PY 2005 VL 76 SU 1 MA 63 BP S19 EP S20 DI 10.1016/S0167-8140(05)80224-5 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 984RS UT WOS:000233322600064 ER PT J AU Atienza, AA King, AC AF Atienza, AA King, AC TI Comparing self-reported versus objectively measured physical activity behavior: A preliminary investigation of older Filipino American women SO RESEARCH QUARTERLY FOR EXERCISE AND SPORT LA English DT Article DE ethnic minority; exercise; gerontology; measurement ID RECALL; ADULTS; HEALTH; RELIABILITY C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA. RP Atienza, AA (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM atienzaa@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999]; NHLBI NIH HHS [5T32-HL07034]; NIA NIH HHS [AG-12358] NR 24 TC 13 Z9 13 U1 2 U2 5 PU AMER ALLIANCE HEALTH PHYS EDUC REC & DANCE PI RESTON PA 1900 ASSOCIATION DRIVE, RESTON, VA 22091 USA SN 0270-1367 J9 RES Q EXERCISE SPORT JI Res. Q. Exerc. Sport PD SEP PY 2005 VL 76 IS 3 BP 358 EP 362 PG 5 WC Hospitality, Leisure, Sport & Tourism; Psychology, Applied; Psychology; Sport Sciences SC Social Sciences - Other Topics; Psychology; Sport Sciences GA 969VP UT WOS:000232263800013 PM 16270713 ER PT J AU Rouhani, FN Meitin, CA Kaler, M Miskinis-Hilligoss, D Stylianou, M Levine, SJ AF Rouhani, FN Meitin, CA Kaler, M Miskinis-Hilligoss, D Stylianou, M Levine, SJ TI Effect of tumor necrosis factor antagonism on allergen-mediated asthmatic airway inflammation SO RESPIRATORY MEDICINE LA English DT Article DE asthma; airway inflammation; tumor necrosis factor; TNF antagonists ID SEGMENTAL ANTIGEN CHALLENGE; BRONCHIAL EPITHELIAL-CELLS; FACTOR-ALPHA; TNF-ALPHA; IN-VITRO; RHEUMATOID-ARTHRITIS; GENE-EXPRESSION; MAST-CELL; CYTOKINES; INTERLEUKIN-6 AB Objective: To assess whether tumor necrosis factor (TNF) antagonism can attenuate eosinophilic airway inflammation in patients with mild-to-moderate allergic asthma. Design: Randomized, double-blind, placebo-controlled trial. Setting: National Institutes of Health (NIH) Clinical Center. Patients: Twenty-six patients with mild-to-moderate allergic asthma, receiving only inhaled beta-2-agonists, who demonstrated both an early and late phase response to inhalational allergen challenge. Intervention: Injection of a soluble TNF receptor (TNFR:Fc, etanercept, Enbrel) or placebo, 25 mg subcutaneously, twice weekly for 2 weeks, followed by a bronchoscopic segmental allergen challenge. Measurements: The primary outcome measure was whether TNFR:Fc can access the lung and inhibit TNF bioactivity. Secondary outcome measures included pulmonary eosinophilia, Th2-type cytokines, and airway hyperresponsiveness. Results: Anti-TNF therapy was associated with transient hemiplegia in one patient, which resulted in suspension of the study. Data from the 21 participants who completed the study were analyzed. Following treatment, patients receiving anti-TNF therapy had significantly increased TNFR2 levels in epithelial lining fluid (ELF) (P<0.001), consistent with delivery of TNFR:Fc to the lung. TNF antagonism did not attenuate pulmonary eosinophilia and was associated with an increase in ELF IL-4 levels (P = 0.033) at 24 h following segmental allergen challenge. TNF antagonism was not associated with a change in airway hyperresponsiveness to methacholine. Conclusions: TNF antagonism may not be effective for preventing allergen-mediated eosinophilic airway inflammation in mild-to-moderate asthmatics. Transient hemiplegia, which may mimic an evolving stroke, may be a potential toxicity of anti-TNF therapy. Published by Elsevier Ltd. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,Room 6D03,MSC 1590, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov FU Intramural NIH HHS NR 48 TC 42 Z9 44 U1 1 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 J9 RESP MED JI Respir. Med. PD SEP PY 2005 VL 99 IS 9 BP 1175 EP 1182 DI 10.1016/j.rmed.2005.02.031 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA 961HM UT WOS:000231652500014 PM 16085220 ER PT J AU Calvo-Alen, J Alarcon, GS Campbell, R Fernandez, M Reveille, JD Cooper, GS AF Calvo-Alen, J Alarcon, GS Campbell, R Fernandez, M Reveille, JD Cooper, GS TI Lack of recording of systemic lupus erythematosus in the death certificates of lupus patients SO RHEUMATOLOGY LA English DT Article DE systemic lupus erythematosus; epidemiology; vital statistics ID MORTALITY; DISEASE; ATHEROSCLEROSIS; MORBIDITY; FEATURES AB Objective. To determine to what extent the diagnosis of systemic lupus erythematosus (SLE) in deceased lupus patients is under-reported in death certificates, and the patient characteristics associated with such an occurrence. Methods. The death certificates of 76 of the 81 deceased SLE patients from two US lupus cohorts (LUMINA for Lupus in Minorities: Nature vs Nurture and CLU for Carolina Lupus Study), including 570 and 265 patients, respectively, were obtained from the Offices of Vital Statistics of the states where the patients died (Alabama, Georgia, North Carolina, South Carolina, Tennessee and Texas). Both cohorts included patients with SLE as per the American College of Rheumatology criteria, aged >= 16 yr, and disease duration at enrolment of <= 5 yr. The median duration of follow-up in each cohort at the time of these analyses ranged from 38.1 to 53.0 months. Standard univariable analyses were performed comparing patients with SLE recorded anywhere in the death certificate and those without it. A multivariable logistic regression model was performed to identify the variables independently associated with not recording SLE in death certificates. Results. In 30 (40%) death certificates, SLE was not recorded anywhere in the death certificate. In univariable analyses, older age was associated with lack of recording of SLE in death certificates [mean age (standard deviation) 50.9 (15.6) years and 39.1 (18.6) yr among those for whom SLE was omitted and included on the death certificates, respectively, P = 0.005]. Patients without health insurance, those dying of a cardiovascular event and those of Caucasian ethnicity were also more likely to be in the non-recorded group. In the multivariable analysis, variables independently associated with not recording SLE as cause of death were older age [odds ratio = (95% confidence interval) 1.043 (1.005-1.083 per yr increase); P = 0.023] and lack of health insurance [4.649 (1.152-18.768); P = 0.031]. Conclusions. A high proportion of SLE diagnoses are not recorded in death certificates. Older patients and those without health insurance are more prone to have SLE not recorded. These findings do have implications for the assessment of the impact of this disease in epidemiological studies conducted using vital statistics records. C1 Univ Alabama, Birmingham, AL USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Texas, Hlth Sci Ctr, Houston, TX USA. NIEHS, Durham, NC USA. RP Alarcon, GS (reprint author), 830 Fac Off Tower,510 20th St S, Birmingham, AL 35294 USA. EM graciela.alarcon@ccc.uab.edu FU NCRR NIH HHS [M01-RR00032, M01-RR02558]; NIAMS NIH HHS [R01-AR42503] NR 14 TC 14 Z9 14 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD SEP PY 2005 VL 44 IS 9 BP 1186 EP 1189 DI 10.1093/rheumatology/keh717 PG 4 WC Rheumatology SC Rheumatology GA 958UB UT WOS:000231472600020 PM 15956088 ER PT J AU Sato, N AF Sato, N TI Signal transduction pathways regulating pluripotency in human embryonic stem cells SO SEIKAGAKU LA Japanese DT Review ID SELF-RENEWAL; MOUSE EMBRYOS; ES CELLS; DIFFERENTIATION; MAINTENANCE; ACTIVATION; INDUCTION; STAT3 C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Sato, N (reprint author), NIEHS, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 24 TC 0 Z9 0 U1 0 U2 1 PU JAPANESE BIOCHEMICAL SOC PI TOKYO PA ISHIKAWA BLDG-3F, 25-16 HONGO-5-CHOME, BUNKYO-KU, TOKYO, 113, JAPAN SN 0037-1017 J9 SEIKAGAKU JI Seikagaku PD SEP PY 2005 VL 77 IS 9 BP 1192 EP 1196 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 973JW UT WOS:000232519700009 PM 16241008 ER PT J AU Gomes, J Chalela, JA AF Gomes, J Chalela, JA TI Stroke in the tropics SO SEMINARS IN NEUROLOGY LA English DT Review DE cerebral infarction; intracranial hemorrhages; tropics; nonatherosclerotic stroke mechanisms ID TRYPANOSOMIASIS CHAGAS-DISEASE; ARGENTINE HEMORRHAGIC-FEVER; SEVERE FALCIPARUM-MALARIA; CEREBRAL MALARIA; MOYAMOYA-DISEASE; TUBERCULOUS MENINGITIS; CLINICAL-FEATURES; BEHCETS SYNDROME; SOUTH-AMERICA; MENINGOVASCULAR SYPHILIS AB Similar to northern developed countries, cerebrovascular disease is a leading cause of morbidity and mortality in tropical countries. The epidemiology of stroke in the tropics is different from one tropical region to another and from the tropics to northern latitudes. In tropical regions, stroke is due to the conventional mechanisms encountered in other latitudes, as well as unusual causative mechanisms unique to the tropics. In tropical regions, infectious causes of stroke and nonatherosclerotic mechanisms are more common than in nontropical areas. Our current knowledge of stroke in the tropics is limited by the financial restrictions existing in such regions limiting health care delivery and epidemiological research. C1 NINDS, Sect Stroke Diagnost & Therapeut, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Neurosci Crit Care Dept, Baltimore, MD USA. RP Chalela, JA (reprint author), NINDS, Sect Stroke Diagnost & Therapeut, NIH, 10 Ctr Dr,Room B1D733, Bethesda, MD 20892 USA. NR 111 TC 0 Z9 3 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 J9 SEMIN NEUROL JI Semin. Neurol. PD SEP PY 2005 VL 25 IS 3 BP 290 EP 299 DI 10.1055/s-2005-917665 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 969UI UT WOS:000232260100006 PM 16170741 ER PT J AU Bachelder, EM Ainslie, KM Pishko, MV AF Bachelder, EM Ainslie, KM Pishko, MV TI Utilizing a quartz crystal microbalance for quantifying CD4(+) T cell counts SO SENSOR LETTERS LA English DT Article DE immunosensor; biosensor; HIV/AIDS sensor; inexpensive; cell sensor ID PIEZOELECTRIC IMMUNOSENSOR; HIV-INFECTION; HUMAN ERYTHROCYTES; LYMPHOCYTE COUNTS; DNA; INDIVIDUALS; PROTEIN; BIOSENSOR; ALBUMIN; MARKERS AB Acquired immune deficiency syndrome (AIDS) is a world wide epidemic. Third world countries, especially in Africa, suffer the most from AIDS. The progression of HIV/AIDS is monitored by the change in blood concentration of CD4(+) T cells. However, the most common technology used to measure CD4(+) counts, flow cytometry, has a high cost of capital, and is incapable of measuring in remote villages. An alternative method of measurement must be developed to help properly treat the individuals most affected in resource poor areas. In this paper, by using a self-assembled monolayer, we were able to attach anti-CD4 antibodies to the surface of a gold coated quartz crystal for use in a quartz crystal microbalance (QCM). The antibody coated QCM crystal was able to quantify the amount of CD4(+) T cells in phosphate buffer solution (PBS). Furthermore, the functionalized crystal did not respond to CD4(+) T cell controls in identical conditions. With these results we propose that QCM technology can be used to quantify CD4(+) T cells in patients who are HIV positive. C1 Penn State Univ, Dept Chem Engn, University Pk, PA 16802 USA. Penn State Univ, Dept Chem & Mat Sci & Engn, University Pk, PA 16802 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Nebraska, Dept Chem Engn, Lincoln, NE 68588 USA. RP Pishko, MV (reprint author), Penn State Univ, Dept Chem Engn, University Pk, PA 16802 USA. EM mpishko@engr.psu.edu NR 51 TC 8 Z9 8 U1 0 U2 2 PU AMER SCIENTIFIC PUBLISHERS PI STEVENSON RANCH PA 25650 NORTH LEWIS WAY, STEVENSON RANCH, CA 91381-1439 USA SN 1546-198X J9 SENS LETT JI Sens. Lett. PD SEP PY 2005 VL 3 IS 3 BP 211 EP 215 DI 10.1166/sl.2005.029 PG 5 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation; Physics, Applied SC Chemistry; Electrochemistry; Instruments & Instrumentation; Physics GA 004QH UT WOS:000234766800004 ER PT J AU Konda, KA Klausner, JD Lescano, AG Leon, S Jones, FR Pajuelo, J Caceres, CF Coates, TJ AF Konda, KA Klausner, JD Lescano, AG Leon, S Jones, FR Pajuelo, J Caceres, CF Coates, TJ CA NIMH Collaborative HIV STI TI The epidemiology of herpes simplex virus type 2 infection in low-income urban populations in coastal Peru SO SEXUALLY TRANSMITTED DISEASES LA English DT Article; Proceedings Paper CT 15th International AIDS Conference CY JUL 11-17, 2004 CL Bangkok, THAILAND ID HUMAN-IMMUNODEFICIENCY-VIRUS; GENITAL HERPES; TRANSMISSION; RISK; VALACYCLOVIR; MANAGEMENT; DISEASE AB Objective: The objective of this study was to determine the epidemiology of herpes simplex virus type 2 (HSV-2) in general and socially marginalized populations of low-income, urban, coastal Peru. Study: Two low-income populations were administered an epidemiologic survey and serologic tests, determining risk behavior, HSV-2, and HIV prevalence. Results: In the socially marginalized population, HSV-2 prevalence was 72.3% in men who have sex only with men (MSOM), 42.5% in women, and 20.7% in men. In the general population, HSV-2 prevalence was 20.5% in women and 7.1% in men. In all groups except the male general population, HSV-2 prevalence increased with age or number of sexually active years (both P < 0.001). HSV-2 infection was associated with HIV infection in MSOM (P < 0.023) and other socially marginalized men (P < 0.01). Conclusion: HSV-2 was common in both low-income populations, and control programs are needed in Peru given high prevalence and association with HIV infection. Prevention of HSV-2 infection should target individuals before they become sexually active. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. San Francisco Dept Publ Hlth, San Francisco, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Peruana Cayetano Heredia, Lima, Peru. USN, Med Res Ctr Detachment, Lima, Peru. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA USA. NIMH, Multisite Int Grp, Bethesda, MD 20892 USA. RP Klausner, JD (reprint author), STD Prevent & Control Serv, 1360 Misson St,Suite 401, San Francisco, CA 94103 USA. EM jeff.klausner@sfdph.org RI Lescano, Andres/B-8479-2008; OI Lescano, Andres/0000-0001-9779-633X; Caceres, Carlos/0000-0002-8101-0790 FU NIMH NIH HHS [U10 MH061536, U10 MH61536] NR 28 TC 27 Z9 29 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD SEP PY 2005 VL 32 IS 9 BP 534 EP 541 DI 10.1097/01.olq.0000175413.89733.ae PG 8 WC Infectious Diseases SC Infectious Diseases GA 960GU UT WOS:000231579400004 PM 16118601 ER PT J AU White, KJC AF White, KJC TI Women in the great migration - Economic activity of black and white southern-born female migrants in 1920, 1940, and 1970 SO SOCIAL SCIENCE HISTORY LA English DT Article ID LABOR-FORCE PARTICIPATION; HEADING HOUSEHOLDS; NORTH; RACE; ACHIEVEMENT; NONMIGRANTS; PERSPECTIVE; INEQUALITY; RESIDENCE; PATTERNS AB Using data from the Integrated Public Use Microdata Series (IPUMS), this analysis examines the economic activity of black and white southern-born female migrants participating in the Great Migration. Labor,force participation and occupational SEI scores are investigated with specific focus on racial differences within and between migrant groups. Black migrants had a higher probability of participating in the labor force, yet their employment was concentrated among the, lower SEI occupations throughout the period. Racial differences also were observed among the influence of personal, household, and location characteristics on economic activity such that the positive associations were less pronounced, while the negative impacts were differentially felt among black migrant women; education was less beneficial, and the deterring effects of marital status mere less pronounced for black migrants. Racial differences narrowed at the end of the Great Migration for the southern migrants, reflecting a pattern most similar to nonmigrant northerners and more advantageous than that observed for nonmigrant southern women. C1 Univ Wisconsin, NICHHD, Madison, WI 53706 USA. Univ Wisconsin, Ctr Demog & Ecol, Madison, WI 53706 USA. RP White, KJC (reprint author), Univ Wisconsin, NICHHD, Madison, WI 53706 USA. NR 72 TC 6 Z9 6 U1 1 U2 3 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 0145-5532 J9 SOC SCI HIST JI Soc. Sci. Hist. PD FAL PY 2005 VL 29 IS 3 BP 413 EP 455 DI 10.1215/01455532-29-3-413 PG 43 WC History; History Of Social Sciences SC History; Social Sciences - Other Topics GA 993BX UT WOS:000233928800003 ER PT J AU Dawson, L Kass, NE AF Dawson, L Kass, NE TI Views of US researchers about informed consent in international collaborative research SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE ethics; informed consent; developing countries; qualitative research; USA ID PROTECTING COMMUNITIES; BIOMEDICAL-RESEARCH; RANDOM ALLOCATION; RESEARCH ETHICS; CLINICAL-TRIAL; COMPREHENSION AB Informed consent poses challenges in all settings. Challenges may be particularly great in international collaborative research, where cultural perspectives may differ, and where education levels and language may be barriers to participant understanding. We conducted a written survey and focus groups with US health researchers doing research in developing countries, asking about informed consent and other ethical issues in their research. We present here both qualitative and quantitative data relevant to informed consent. Qualitative data revealed that researchers' experiences and beliefs about informed consent fell into three paradigms: regulatory, community, and individual. The regulatory paradigm refers to researchers' views and practices relating to informed consent requirements of institutional review boards and other oversight bodies. The community paradigm refers to researchers' approach to the content and methodology of informed consent in the context of long-term relationships between research teams and study communities. Researchers emphasized the importance of these relationships for creating and maintaining communication fundamental to the informed consent process. Finally, the individual paradigm refers to researchers' views about individual participants' understanding and decision-making process regarding research. Researchers described community-level influences on participants' decision-making, but stressed the need for individual comprehension and voluntary participation. While these paradigms are distinct, they also are intertwined. Quantitative data supported the existence of these three paradigms in respondents' characterization of informed consent. Researchers frequently stated that legal language on the consent forms was meaningless (52%). Forty-four percent of researchers had consulted with community leaders, and 23% believed the consent process focuses too much on the individual, rather than on family or community. Most researchers (82%) reported that the consent process was an important means of educating participants about the study. Fifty-four percent of researchers believed participants did not understand placebos. Further research is needed to understand how culture and relationships affect research participation, and to provide information and dialogue among researchers, oversight bodies and community representatives about appropriate ways to approach informed consent in international research. (c) 2005 Elsevier Ltd. All rights reserved. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21218 USA. NIH, Kevric Corp, Off Biotechnol Act, Bethesda, MD 20892 USA. Johns Hopkins Univ, Phoebe R Berman Bioeth Inst, Baltimore, MD 21218 USA. RP Dawson, L (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21218 USA. EM lizadawson2004@yahoo.com; nkass@jhsph.edu NR 21 TC 47 Z9 48 U1 2 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD SEP PY 2005 VL 61 IS 6 BP 1211 EP 1222 DI 10.1016/j.socscimed.2005.02.004 PG 12 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 946FG UT WOS:000230557200008 PM 15970232 ER PT J AU Wu, CWH Bichot, NP Kaas, JH AF Wu, CWH Bichot, NP Kaas, JH TI Somatosensory areas S2 and PV project to the superior colliculus of a prosimian primate, Galago garnetti SO SOMATOSENSORY AND MOTOR RESEARCH LA English DT Article DE area 3b; multisensory; parietal cortex; tectum; visuomotor ID CORTICAL AREAS; MULTISENSORY INTEGRATION; LATERAL SULCUS; GOLDEN-HAMSTER; BRAIN-STEM; ORGANIZATION; CORTEX; CAT; NEURONS; MACAQUE AB As part of an effort to describe the connections of the somatosensory system in Galago garnetti, a small prosimian primate, injections of tracers into cortex revealed that two somatosensory areas, the second somatosensory area (S2) and the parietal ventral somatosensory area (PV), project densely to the ipsilateral superior colliculus, while the primary somatosensory area (S1 or area 3b) does not. The three cortical areas were defined in microelectrode mapping experiments and recordings were used to identify appropriate injection sites in the same cases. Injections of wheat germ agglutinin conjugated with horseradish peroxidase (WGA-HRP) were placed in S1 in different mediolateral locations representing body regions from toes to face in five galagos, and none of these injections labeled projections to the superior colliculus. In contrast, each of the two injections in the face representation of S2 in two galagos and three injections in face and forelimb representations of PV in three galagos produced dense patches of labeled terminations and axons in the intermediate gray ( layer IV) over the full extent of the superior colliculus. The results suggest that the higher-order somatosensory areas, PV and S2, are directly involved in the visuomotor functions of the superior colliculus in prosimian primates, while S1 is not. The somatosensory inputs appear to be too widespread to contribute to a detailed somatotopic representation in the superior colliculus, but they may be a source of somatosensory modulation of retinotopically guided oculomotor instructions. C1 Vanderbilt Univ, Dept Psychol, Nashville, TN 37240 USA. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Kaas, JH (reprint author), Vanderbilt Univ, Dept Psychol, 301 Wilson Hall, Nashville, TN 37240 USA. EM jon.h.kaas@vanderbilt.edu FU NINDS NIH HHS [R01 NS016446, NS16446] NR 45 TC 2 Z9 2 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0899-0220 J9 SOMATOSENS MOT RES JI Somatosens. Mot. Res. PD SEP PY 2005 VL 22 IS 3 BP 221 EP 231 DI 10.1080/08990220500262661 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 993AK UT WOS:000233924900012 PM 16338830 ER PT J AU Wagner, W Laufs, S Blake, J Schwager, C Wu, XL Zeller, JW Ho, AD Fruehauf, S AF Wagner, W Laufs, S Blake, J Schwager, C Wu, XL Zeller, JW Ho, AD Fruehauf, S TI Retroviral integration sites correlate with expressed genes in hematopoietic stem cells SO STEM CELLS LA English DT Article DE hematopoietic stem cell; microarray; retroviral vector integration; CD34(+); gene expression; gene targeting ID RESISTANCE 1 GENE; TRANSCRIPT PROFILING ANALYSIS; MOBILIZED PERIPHERAL-BLOOD; PROGENITOR CELLS; BONE-MARROW; IMMUNODEFICIENT MICE; REPOPULATING CELLS; START REGIONS; CD34(+) CELLS; HUMAN GENOME AB In this study, we analyzed whether retroviral integration sites in repopulating hematopoietic cells correlate with genes expressed in fractions enriched in hematopoietic stem cells (HSCs). We have previously described microarray studies of two populations enriched in HSCs: CD34(+)/CD38(-) and the slow dividing fraction of CD34(+)/CD38(-) cells (SDF). Furthermore, we demonstrated that oncoretroviral integrations in severe combined immunodeficient repopulating cells are preferentially located near the transcription start. Here, we have identified 117 corresponding cDNA clones on our microarray representing genes with retroviral integration sites. These genes revealed a higher mean signal intensity in comparison with either all genes on the array or a subset of control genes with retroviral integrations in HeLa cells. Furthermore, these genes demonstrated a higher expression in CD34(+)/CD38(-) cells and SDF. The association of gene expression and retrovirally targeted genes observed here will help to elucidate the molecular characteristics of primitive repopulating hematopoietic cells. C1 Univ Heidelberg, Dept Internal Med 5, D-69120 Heidelberg, Germany. German Canc Res Ctr, D-6900 Heidelberg, Germany. European Mol Biol Lab, Biochem Instrumentat Programme, D-6900 Heidelberg, Germany. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Ho, AD (reprint author), Univ Heidelberg, Dept Internal Med 5, Neuenheimer Feld 410, D-69120 Heidelberg, Germany. EM anthony_dick.ho@urz.uni-heidelberg.de NR 50 TC 13 Z9 13 U1 0 U2 0 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 SEP PY 2005 VL 23 IS 8 BP 1050 EP 1058 DI 10.1634/stemcells.2005-0006 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 969EM UT WOS:000232216200005 PM 16140869 ER PT J AU Shen, H Chen, GJ Harvey, B Wang, Y AF Shen, H Chen, GJ Harvey, B Wang, Y TI Inosine, calcium channels, and neuroprotection against ischemic brain injury - Response SO STROKE LA English DT Letter C1 Natl Inst Drug Abuse, Neural Protect & Regenerat Sect, Baltimore, MD 21224 USA. RP Shen, H (reprint author), Natl Inst Drug Abuse, Neural Protect & Regenerat Sect, Baltimore, MD 21224 USA. NR 2 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD SEP PY 2005 VL 36 IS 9 BP 1823 EP 1823 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 958JR UT WOS:000231441200005 ER PT J AU Kang, DW Chalela, JA Dunn, W Warach, S AF Kang, DW Chalela, JA Dunn, W Warach, S CA NIH-Suburban Stroke Ctr Investigators TI MRI screening before standard tissue plasminogen activator therapy is feasible and safe SO STROKE LA English DT Article DE magnetic resonance imaging; stroke, acute; thrombolysis ID ACUTE ISCHEMIC-STROKE; RT-PA STROKE; INTRACEREBRAL HEMORRHAGE; THROMBOLYSIS; DIFFUSION; PERFUSION; ALTEPLASE AB Background and Purpose - MRI screening for thrombolytic therapy may improve patient selection. Alternatively, it may excessively delay treatment and thereby lead to worse outcomes. We hypothesized that times to treatment and outcomes in a stroke center with immediate MRI access and interpretation would not differ from those of the typical clinical practice. Methods - We compared the results of 120 consecutive patients treated with intravenous tissue plasminogen activator (tPA) within 3 hours of onset at our center with those of the 2 largest multicenter registries of tPA use. 5,6 In addition to standard criteria, MRI specific eligibility criteria were applied in 97 patients. MRI was not performed in 23 patients because of contraindications to MRI or late patient arrival (>2.5 hours). Outcomes were the modified Rankin Scale (mRS) obtained at 3 months. Results - Times to treatment (median door-to-needle time 81.5 minutes; median onset-to-needle time 135 minutes) and outcomes (mRS 0 to 1, 40.8%; mRS 0 to 2, 47.5%) were not inferior to those of the typical clinical practice. Door-to-needle time was shorter in computed tomography (CT) screening (67.5 +/- 22.5 minutes; n = 23) than in MRI screening (86.8 +/- 21.5 minutes; n = 97; P<0.001). However, outcomes were not different between MRI screening (mRS 0 to 1, 42.3%; mRS 0 to 2, 49.5%) and CT screening (mRS 0 to 1, 34.8%; mRS 0 to 2, 39.1%). Neither times to treatment nor MRI screening was predictive of outcomes. Conclusion - These data demonstrate that MRI screening before tPA therapy is feasible and not associated with unacceptable times to treatment or outcomes. C1 NINDS, Sect Stroke Diagnost & Therapeut, Stroke Branch, NIH, Bethesda, MD 20892 USA. Univ Ulsan, Asan Med Ctr, Dept Neurol, Seoul, South Korea. RP Warach, S (reprint author), NINDS, Sect Stroke Diagnost & Therapeut, Stroke Branch, NIH, 10 Ctr Dr,Room B1D733, Bethesda, MD 20892 USA. EM WarachS@ninds.nih.gov NR 15 TC 63 Z9 64 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD SEP PY 2005 VL 36 IS 9 BP 1939 EP 1943 DI 10.1161/01.STR.00001775.39.72071.f0 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 958JR UT WOS:000231441200032 PM 16081864 ER PT J AU Tsai, SY Hayashi, T Su, TP AF Tsai, SY Hayashi, T Su, TP TI Picomolar concentrations of hibernation induction delta opioid peptide [D-Ala2,D-Leu5]Enkephalin increase the nerve growth factor in NG-108 cells SO SYNAPSE LA English DT Article DE DADLE; opioid; NG-108; NGF; c-jun; c-fos ID MESSENGER-RNA; NEUROPROTECTION; ENKEPHALIN; EXPRESSION; RECEPTORS; BLOCKS AB The delta opioid peptide [D-Ala2,D-Leu5]enkephalin (DADLE) has been shown to be a neuroprotective agent via mechanisms that are not totally understood. We previously demonstrated that the i.p. injection of DADLE in mice causes an increase of nerve growth factor (NGF) in the brain. To further clarify the NGF-increasing action of DADLE, we examined here the NGF-increasing effect of DADLE in vitro, using cultured NG-108 cells. DADLE dose-dependently increases the immunoreactive level of NGF in NG-108 cells in a bell-shape manner, with the effective DADLE concentrations in the picomolar range (0.01-100 pM). Also, DADLE at 1 pM selectively increases c-Jun and c-Fos, but not c-Rel. These results indicate that DADLE is one of the most potent agents in increasing the NGF in the biological system and that this action of DADLE involves selective increases of c-Jun and c-Fos, transcription factors that promote the NGF expression. Published 2005 Wiley-Liss, Inc.dagger C1 NIDA, Cellular Pathobiol Unit, DPS CNRB IRP, NIH DHHS, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Unit, DPS CNRB IRP, NIH DHHS, Triad Room 3304,333 Cassell Dr, Baltimore, MD 21224 USA. EM TSU@intra.nida.nih.gov RI Hayashi, Teruo/A-9690-2008 NR 16 TC 3 Z9 4 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD SEP 1 PY 2005 VL 57 IS 3 BP 179 EP 181 DI 10.1002/syn.20167 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 947SK UT WOS:000230666400007 PM 15945062 ER PT J AU Wellner, RB Hong, SH Cotrim, AP Swaim, WD Baum, BJ AF Wellner, RB Hong, SH Cotrim, AP Swaim, WD Baum, BJ TI Modifying the NH2 and COOH termini of aquaporin-5: Effects on localization in polarized epithelial cells SO TISSUE ENGINEERING LA English DT Article ID WATER CHANNELS; GENE-TRANSFER; SJOGRENS-SYNDROME; LACRIMAL GLANDS; SWEAT GLANDS; SALIVARY; IMMUNOLOCALIZATION; TRAFFICKING; EXPRESSION; DISEASE AB To reengineer polarized epithelial cell functions directly in situ, or ex vivo in the fabrication of an artificial organ, it is necessary to understand mechanisms that account for polarized membrane sorting. We have used the aquaporins ( AQPs), a family of homotetrameric water channel proteins, as model membrane proteins for this purpose. AQP monomers contain six transmembrane-spanning domains linked by five interconnecting loops, with the NH2 and COOH termini residing in the cytosol. AQP5 is localized in the apical membranes of several different epithelia in vivo, and in stably transfected MDCK-II cells grown as a polarized monolayer. We wished to identify a structural region( s) within rat AQP5 ( rAQP5) important for apical localization, and to study the MDCK-II cell localization of rAQP5s modified in either their NH2 or COOH terminus. We show that the NH2-terminal region does not play a major role in apical localization as deletion of the NH2 terminus produced a modified rAQP5 construct ( AQP5-NTdel) that was stably expressed and localized primarily to the apical membranes of MDCK-II cells. Attachment of a FLAG epitope to the NH2 terminus of AQP5 ( AQP5(flag) construct) also did not perturb apical localization. In addition, we found that the exchange of NH2-terminal regions between rAQP5 and human AQP1 ( hAQP1; a nonpolarized AQP isoform) produced a modified rAQP5 construct ( AQP5-1NT) and a modified hAQP1 construct ( AQP1-5NT), each of which localized as the parental AQP ( apically, and to both apical and basolateral membranes, respectively). In contrast, we found that deletion of the COOH terminus resulted in a modified rAQP5 construct ( AQP5-CTdel) that was unstably expressed and localized to intracellular site( s) in MDCK-II cells. Substitution of the COOH terminus of AQP1 with the COOH terminus of AQP5 also produced a construct ( AQP1-5CT) transiently expressed in intracellular compartment( s). However, substitution of the COOH terminus of rAQP5 with the COOH terminus of hAQP1 produced a modified rAQP5 construct ( AQP5-1CT) that was stably expressed and localized to basolateral membranes, suggesting the loss of an apical targeting/ retention signal from rAQP5, the gain of a basolateral targeting/ retention signal from hAQP1, or a combination of these two possibilities. C1 Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, Gene Transfer Sect, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Receptors & Signal Transduct Sect, Oral Infect & Immun Branch, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, Gene Transfer Sect, NIH, Bldg 10,Room 1N113,10 Ctr Dr,MSC 1190, Bethesda, MD 20892 USA. EM bbaum@dir.nidcr.nih.gov NR 35 TC 17 Z9 17 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD SEP PY 2005 VL 11 IS 9-10 BP 1449 EP 1458 DI 10.1089/ten.2005.11.1449 PG 10 WC Cell & Tissue Engineering SC Cell Biology GA 985AA UT WOS:000233347300016 PM 16259600 ER PT J AU Song, SU Cha, YD Han, JU Oh, IS Choi, KB Yi, YS Hyun, JP Lee, HY Chi, GF Lim, CL Ganjei, JK Noh, MJ Kim, SJ Lee, DK Lee, KH AF Song, SU Cha, YD Han, JU Oh, IS Choi, KB Yi, YS Hyun, JP Lee, HY Chi, GF Lim, CL Ganjei, JK Noh, MJ Kim, SJ Lee, DK Lee, KH TI Hyaline cartilage regeneration using mixed human chondrocytes and transforming growth factor-beta(1)-producing chondrocytes SO TISSUE ENGINEERING LA English DT Article ID PERIOSTEUM-DERIVED CELLS; ARTICULAR-CARTILAGE; THICKNESS DEFECTS; JOINT SURFACES; TGF-BETA; CULTURE; DIFFERENTIATION; CHONDROGENESIS; PROTEOGLYCANS; IMPLANTATION AB The purpose of this study was to investigate the efficacy of cartilage regeneration when using a mixture of transforming growth factor-beta(1) ( TGF-beta(1))-producing human chondrocytes ( hChon-TGF-beta(1)) and primary human chondrocytes ( hChon) ("mixed cells"), compared with either hChon-TGF-beta(1) or hChon cells alone. Specifically, mixed cells or hChon cells were first injected intradermally into the backs of immune-deficient nude mice to test the feasibility of cartilage formation in vivo. Both the mixed cells and the hChon-TGF-beta(1) cells alone induced cartilage formation in nude mice, whereas hChon cells alone did not. To further test the efficacy of the cells in generating cartilage, an artificially induced partial thickness defect of the femoral condyle of a rabbit knee joint was loaded with hChon-TGF-beta(1) cells with or without mixing additional untransduced hChon cells, and hyaline cartilage regeneration was observed at 4 or 6 weeks. The efficiency of complete filling of the defect and the quality of tissue generated after implanting were evaluated on the basis of a histological grading system modified from O'Driscoll et al. ( J.Bone Joint Surg. 70A, 595, 1988). Significantly, mixed cells ( 14.2 +/- 0.9) produced significantly better results than hChon-TGF-beta(1) ( 9.0 +/- 1.7) or hChon ( 8.0 +/- 1.8) cells alone. Histological and immunohistochemical staining of the newly repaired tissues produced after treatment with either mixed cells or hChon-TGF-beta(1) cells alone showed hyaline cartilage-like characteristics. These results suggest that the implantation of mixed cells may be a clinically efficient method of regenerating hyaline articular cartilage. C1 Inha Univ, Coll Med, Clin Res Ctr, Inchon, South Korea. Inha Univ, Coll Med, Dept Orthoped Surg, Inchon, South Korea. TissueGene Asia, Inchon, South Korea. TissueGene, Gaithersburg, MD USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Gaithersburg, MD USA. RP Lee, DK (reprint author), Inha Univ, Coll Med, Clin Res Ctr, Inchon, South Korea. EM dklee@tissuegene.com NR 24 TC 25 Z9 26 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD SEP PY 2005 VL 11 IS 9-10 BP 1516 EP 1526 DI 10.1089/ten.2005.11.1516 PG 11 WC Cell & Tissue Engineering SC Cell Biology GA 985AA UT WOS:000233347300022 PM 16259606 ER PT J AU Wexler, P AF Wexler, P TI Web alerts SO TOXICOLOGY LA English DT Article C1 Natl Lib Med, Toxicol & Environm Hlth Informat Program, NIH, Bethesda, MD 20892 USA. RP Wexler, P (reprint author), Natl Lib Med, Toxicol & Environm Hlth Informat Program, NIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. EM wexlerp@mail.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD SEP 1 PY 2005 VL 212 IS 2-3 BP 239 EP 242 DI 10.1016/j.tox.2005.05.019 PG 4 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 954MI UT WOS:000231158800016 ER PT J AU Howard, AS Bucelli, R Jett, DA Bruun, D Yang, DR Lein, PJ AF Howard, AS Bucelli, R Jett, DA Bruun, D Yang, DR Lein, PJ TI Chlorpyrifos exerts opposing effects on axonal and dendritic growth in primary neuronal cultures SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE organophosphate pesticides; chlorpyrifos; axon outgrowth; dendritogenesis; acetylcholinesterase; developmental neurotoxicity; in vitro models ID RAT SYMPATHETIC NEURONS; ROOT GANGLION NEURONS; ACETYLCHOLINESTERASE INHIBITOR TREATMENT; NUCLEAR TRANSCRIPTION FACTORS; SUPERIOR CERVICAL-GANGLION; GENDER-RELATED DIFFERENCES; DEVELOPMENTAL NEUROTOXICITY; MORPHOLOGICAL-DIFFERENTIATION; IN-VITRO; ORGANOPHOSPHATE PESTICIDES AB Evidence that children are widely exposed to organophosphorus pesticides (OPs) and that ON cause developmental neurotoxicity in animal models raises significant concerns about the risks these compounds pose to the developing human nervous system. Critical to assessing this risk is identifying specific neurodevelopmental events targeted by OPs. Observations that OPs alter brain morphometry in developing rodents and inhibit neurite outgrowth in neural cell lines suggest that OPs perturb neuronal morphogenesis. However, an important question yet to be answered is whether the dysmorphogenic effect of OPs reflects perturbation of axonal or dendritic growth. We addressed this question by quantifying axonal and dendritic growth in primary cultures of embryonic rat sympathetic neurons derived from superior cervical ganglia (SCG) following in vitro exposure to chlorpyrifos (CPF) or its metabolites CPF-oxon (CPFO) and trichloropyridinol (TCP). Axon outgrowth was significantly inhibited by CPF or CPFO, but not TCP, at concentrations >= 0.001 mu M or 0.001 nM, respectively. In contrast, all three compounds enhanced BMP-induced dendritic growth. Acetylcholinesterase was inhibited only by the highest concentrations of CPF (>= 1 mu M) and CPFO (>= 1 nM); TCP had no effect on this parameter. In summary, these compounds perturb neuronal morphogenesis via opposing effects on axonal and dendritic growth, and both effects are independent of acetylcholinesterase inhibition. These findings have important implications for current risk assessment practices of using acetylcholinesterase inhibition as a biomarker of OP neurotoxicity and suggest that OPs may disrupt normal patterns of neuronal connectivity in the developing nervous system. (c) 2004 Elsevier Inc. All rights reserved. C1 Oregon Hlth Sci Univ, CROET, Portland, OR 97239 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. NINDS, Bethesda, MD 20892 USA. RP Lein, PJ (reprint author), Oregon Hlth Sci Univ, CROET, 3181 SW Sam Jackson Pk Rd,L606, Portland, OR 97239 USA. EM leinp@ohsu.edu FU NIEHS NIH HHS [2 P30 ES03819, R21 ES011771, 1 R21 ES011771, 2 T32 ES00714, 5 T35 ES007308] NR 84 TC 95 Z9 98 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 1 PY 2005 VL 207 IS 2 BP 112 EP 124 DI 10.1016/j.taap.2005.12.008 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 958ZB UT WOS:000231485600003 PM 16102564 ER PT J AU Jin, H Hwang, SK Lee, YS Lee, KH Prats, AC Morello, D Beck, GR Cho, MH AF Jin, H. Hwang, S. K. Lee, Y. S. Lee, K. H. Prats, A. C. Morello, D. Beck, G. R. Jr . Cho, M. H. TI Effects of excess dietary inorganic phosphate on the brain of young transgenic mice expressing bicistronic LUCR-C-MYC-IRES-LUCF reporter gene SO TOXICOLOGY LETTERS LA English DT Meeting Abstract C1 Seoul Natl Univ, Toxicol Lab, Coll Vet Med, Seoul 151742, South Korea. Seoul Natl Univ, Sch Agr Biotechnol, Seoul 151742, South Korea. Seoul Natl Univ, Coll Human Ecol, Dept Food & Nutr, Seoul 151742, South Korea. Korea Inst Radiol & Med Sci, Mol Oncol Lab, Seoul 139240, South Korea. CHU Rangueil, INSERM U397, F-31403 Toulouse 04, France. Univ Toulouse 3, Ctr Biol Dev, CNRS UMR5547, IFR 109, F-31062 Toulouse, France. NCI, Lab Canc Prevent, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD SEP PY 2005 VL 158 SU 1 BP S96 EP S97 PG 2 WC Toxicology SC Toxicology GA V44GT UT WOS:000202991900208 ER PT J AU Thorgeirsson, SS AF Thorgeirsson, S. S. TI Role of oval cells in hepatocarcinogenesis SO TOXICOLOGY LETTERS LA English DT Meeting Abstract C1 Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD SEP PY 2005 VL 158 SU 1 BP S22 EP S23 PG 2 WC Toxicology SC Toxicology GA V44GT UT WOS:000202991900041 ER PT J AU Huff, J Chan, P AF Huff, J Chan, P TI Is marihuana [THC] anti-carcinogenic? SO TOXICON LA English DT Letter ID NATIONAL TOXICOLOGY PROGRAM; B6C3F1 MICE; BODY-WEIGHT; F344/N RATS; CARCINOGENESIS BIOASSAYS; CHEMICAL CARCINOGENESIS; RAMAZZINI-FOUNDATION; RODENT BIOASSAY; TUMOR-INCIDENCE; CANNABINOIDS C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM huff1@niehs.nih.gov; chanp@mail.nih.gov NR 32 TC 1 Z9 1 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0041-0101 J9 TOXICON JI Toxicon PD SEP 1 PY 2005 VL 46 IS 3 BP 357 EP 359 DI 10.1016/j.toxicon.2005.04.001 PG 3 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 957XE UT WOS:000231405900015 PM 15990141 ER PT J AU Stevens, WT Childs, RW Leitman, SF Stroncek, DF Bolan, CD AF Stevens, WT Childs, RW Leitman, SF Stroncek, DF Bolan, CD TI Passenger lymphocyte associated hemolysis in an Rh-D positive patient after peripheral blood stem cell (PBSC) transplantation from an Rh-D negative sibling donor SO TRANSFUSION LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 15-18, 2005 CL Seattle, WA SP Amer Assoc Blood Banks C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, Bethesda, MD 20892 USA. EM wstevens@cc.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2005 VL 45 IS 3 SU S BP 4A EP 5A PG 2 WC Hematology SC Hematology GA 963ME UT WOS:000231807600014 ER PT J AU Ronquillo, JG Alvandi, F Reynolds, JC Cecco, SA Wesley, RA Yau, Y Oblitas, JM Collins, MT Rehak, NN Leitman, SF Bolan, CD AF Ronquillo, JG Alvandi, F Reynolds, JC Cecco, SA Wesley, RA Yau, Y Oblitas, JM Collins, MT Rehak, NN Leitman, SF Bolan, CD TI Citrate effects and bone mineral density (BMD) in serial long-term apheresis donors SO TRANSFUSION LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 15-18, 2005 CL Seattle, WA SP Amer Assoc Blood Banks C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. EM ronquillojg@cc.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2005 VL 45 IS 3 SU S BP 15A EP 15A PG 1 WC Hematology SC Hematology GA 963ME UT WOS:000231807600048 ER PT J AU Harding, AJ Watson, RS Haas, CB Bolan, C Popovsky, M Hollis-Perry, KM AF Harding, AJ Watson, RS Haas, CB Bolan, C Popovsky, M Hollis-Perry, KM TI Prospective, randomized trial of 2-red cell collection by apheresis vs. whole blood donation: Cardiovascular performance SO TRANSFUSION LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 15-18, 2005 CL Seattle, WA SP Amer Assoc Blood Banks C1 Naval Hosp Camp Lejeune, Lejeune, NC USA. Naval Med Ctr San Diego, San Diego, CA USA. NIH, Bethesda, MD 20892 USA. Haemonet Corp, Braintree, MA USA. EM ajharding@nhcl.med.navy.mil NR 0 TC 2 Z9 2 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2005 VL 45 IS 3 SU S BP 16A EP 16A PG 1 WC Hematology SC Hematology GA 963ME UT WOS:000231807600052 ER PT J AU Grose, HL Byrne, KM Stroncek, DF Salata, JM Rentas, FJ AF Grose, HL Byrne, KM Stroncek, DF Salata, JM Rentas, FJ TI Freezing RBC collected by apheresis after 6 days of collection SO TRANSFUSION LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 15-18, 2005 CL Seattle, WA SP Amer Assoc Blood Banks C1 NIH, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Silver Spring, MD USA. EM kbyrne@mail.cc.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2005 VL 45 IS 3 SU S BP 19A EP 19A PG 1 WC Hematology SC Hematology GA 963ME UT WOS:000231807600063 ER PT J AU Helmberg, W Feolo, M Dunivin, R AF Helmberg, W Feolo, M Dunivin, R TI dbRBC, a new specialised sequence database and tool for red blood cell research SO TRANSFUSION LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 15-18, 2005 CL Seattle, WA SP Amer Assoc Blood Banks C1 UBT, Graz, Austria. NCBI, NIH, Bethesda, MD USA. EM helmberg@ncbi.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2005 VL 45 IS 3 SU S BP 123A EP 123A PG 1 WC Hematology SC Hematology GA 963ME UT WOS:000231807600431 ER PT J AU Caruccio, L Lee, AH Byrne, K Stroncek, DF AF Caruccio, L Lee, AH Byrne, K Stroncek, DF TI A modified elution method that can be used for phenotyping red cells as well as for antibody and complement elution SO TRANSFUSION LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 15-18, 2005 CL Seattle, WA SP Amer Assoc Blood Banks C1 NIH, Bethesda, MD 20892 USA. EM lcaruccio@mail.cc.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2005 VL 45 IS 3 SU S BP 125A EP 125A PG 1 WC Hematology SC Hematology GA 963ME UT WOS:000231807600440 ER PT J AU Renoud, K Barracchini, K Adams, S Byrne, KM Caruccio, L Stroncek, D AF Renoud, K Barracchini, K Adams, S Byrne, KM Caruccio, L Stroncek, D TI Development of a sequence specific primer (SSP-PCR) assay for Js(a)/Js(a), Js(a)/Js(b), and Js(b)/Js(b) genotyping SO TRANSFUSION LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 15-18, 2005 CL Seattle, WA SP Amer Assoc Blood Banks C1 NIH, Bethesda, MD 20892 USA. EM kbyrne@mail.cc.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2005 VL 45 IS 3 SU S BP 127A EP 127A PG 1 WC Hematology SC Hematology GA 963ME UT WOS:000231807600446 ER PT J AU Gildner, JF David-Ocampo, V Khuu, HM Procter, JL Carter, CS Read, EJ AF Gildner, JF David-Ocampo, V Khuu, HM Procter, JL Carter, CS Read, EJ TI Design and implementation of a training program in a high volume, high complexity cell processing facility SO TRANSFUSION LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 15-18, 2005 CL Seattle, WA SP Amer Assoc Blood Banks C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. EM jgildner@mail.cc.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2005 VL 45 IS 3 SU S BP 178A EP 179A PG 2 WC Hematology SC Hematology GA 963ME UT WOS:000231807600622 ER PT J AU McGann, MJ Khuu, HM Read, EJ AF McGann, MJ Khuu, HM Read, EJ TI Electronic documentation of cell therapy product issue and infusion using SoftBank SO TRANSFUSION LA English DT Meeting Abstract CT 58th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 15-18, 2005 CL Seattle, WA SP Amer Assoc Blood Banks C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. EM MMcGann@mail.cc.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2005 VL 45 IS 3 SU S BP 182A EP 182A PG 1 WC Hematology SC Hematology GA 963ME UT WOS:000231807600633 ER PT J AU Konkle, BA Nemo, GJ AF Konkle, BA Nemo, GJ TI The clinical trials network in transfusion medicine and hemostasis (TMH) SO TRANSFUSION LA English DT Editorial Material ID FRESH-FROZEN PLASMA; LIVER-DISEASE; ABNORMALITIES; COAGULOPATHY; RISKS C1 Univ Penn, Sch Med, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Konkle, BA (reprint author), Univ Penn, Sch Med, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. EM barbara.konkle@uphs.upenn.edu NR 14 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2005 VL 45 IS 9 BP 1405 EP 1406 PG 2 WC Hematology SC Hematology GA 957SD UT WOS:000231392700003 ER PT J AU Balla, T AF Balla, T TI Found in the crystal: phospholipid ligands for nuclear orphan receptors SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID STEROIDOGENIC FACTOR-I; LRH-1; ACTIVATION; SF-1 AB Phospholipids are important components of cellular membranes, contributing to their structural integrity and regulatory functions. Because of these functional properties, phospholipids are often the subject of cell biology and signal transduction studies. Proteins that bind and transport phospholipids between membranes have been described and investigated but few scientists would have entertained the thought of phospholipids acting as ligands for transcription factors. However, the surprising results of recent crystallization studies revealed phospholipid ligands in the binding pockets of members of the,nuclear orphan receptor family 5. Their ability to alter transcriptional activity by acting as bona fide ligands has been inspirational not only for the transcription factor community, but also for phospholipid researchers. C1 NICHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Balla, T (reprint author), NICHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. EM tambal@box-t.nih.gov OI Balla, Tamas/0000-0002-9077-3335 NR 12 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD SEP PY 2005 VL 16 IS 7 BP 289 EP 290 DI 10.1016/j.tem.2005.07.006 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 967LI UT WOS:000232092300001 PM 16054837 ER PT J AU Goodman, M Grossman, LI Wildman, DE AF Goodman, M Grossman, LI Wildman, DE TI Moving primate genomics beyond the chimpanzee genome SO TRENDS IN GENETICS LA English DT Review ID CYTOCHROME-C-OXIDASE; EPSILON-GLOBIN GENE; HUMAN BRAIN SIZE; ANTHROPOID PRIMATES; ADAPTIVE EVOLUTION; ACCELERATED EVOLUTION; MOLECULAR EVOLUTION; MAJOR DETERMINANT; DNA EVIDENCE; PHYLOGENY AB The comparative DNA sequence data that already exist on individual genomic loci depict the phylogenetic relationships of nearly all extant primate genera. Such a phylogenetic representation of the primates, validated by many sequenced primate genomes, and encompassing the full adaptive diversity of the order, is a prerequisite for identifying the genetic basis of humankind, and for testing the proposed human uniqueness of these traits. Some of these traits have been discovered recently, particularly in genes encoding proteins that are important for brain function. C1 Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. NICHHD, Serv Support Perinatol Res Branch, NIH, DHHS, Detroit, MI 48201 USA. RP Goodman, M (reprint author), Wayne State Univ, Sch Med, Dept Anat & Cell Biol, 540 E Canfield Ave, Detroit, MI 48201 USA. EM mgoodwayne@aol.com FU NIDDK NIH HHS [DK-56927]; NIGMS NIH HHS [GM-65580] NR 52 TC 68 Z9 70 U1 1 U2 11 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD SEP PY 2005 VL 21 IS 9 BP 511 EP 517 DI 10.1016/j.tig.2005.06.012 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 963DK UT WOS:000231783300009 PM 16009448 ER PT J AU Kern, F LiPira, G Gratama, JW Manca, F Roederer, M AF Kern, F LiPira, G Gratama, JW Manca, F Roederer, M TI Measuring Ag-specific immune responses: understanding immunopathogenesis and improving diagnostics in infectious disease, autoimmunity and cancer SO TRENDS IN IMMUNOLOGY LA English DT Review ID CD8(+) T-CELLS; MEMORY B-CELLS; FLOW-CYTOMETRY; PERIPHERAL-BLOOD; IN-VIVO; HIV-1 INFECTION; SECRETING CELLS; ANTIGEN; IDENTIFICATION; CYTOMEGALOVIRUS AB Characterization of antigen-specific immune responses at the single-cell level has been made possible by recent advancements in reagent and technology development, combined with increasing knowledge of molecular mechanisms. Fluorescently labelled MHC-peptide multimers and antigens identify directly specific T and B cells, respectively, whereas dynamic assays exploit mediator production or secretion, or the changes in surface expression of other proteins, to identify specific lymphocytes some techniques enabling the recovery of viable cells. Meanwhile, multiparameter flow cytometry has emerged as the most versatile platform for integrating most of these methods. As the complexity of experimental data increases, so does the level of technical sophistication required for analysis and interpretation, both in terms of basic research and modern medicine, with new applications for infectious diseases, autoimmunity and cancer. C1 Free Univ Berlin, Inst Med Immunol, D-10098 Berlin, Germany. Ist Giannina Gaslini, Clin & Expt Immunol Lab, I-16148 Genoa, Italy. Erasmus Univ, Dr Daniel Den Hoed Canc Ctr, Dept Med Oncol, Lab Clin & Tumor Immunol, NL-3075 EA Rotterdam, Netherlands. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Kern, F (reprint author), Free Univ Berlin, Inst Med Immunol, Campus Mitte, D-10098 Berlin, Germany. EM florian.kern@charite.de RI Roederer, Mario/G-1887-2011; Li Pira, Giuseppina/H-1973-2012 NR 68 TC 48 Z9 48 U1 0 U2 6 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 SEP PY 2005 VL 26 IS 9 BP 477 EP 484 DI 10.1016/j.it.2005.07.005 PG 8 WC Immunology SC Immunology GA 966BB UT WOS:000231993500004 PM 16039158 ER PT J AU Goldstein, AL Hannappel, E Kleinman, HK AF Goldstein, AL Hannappel, E Kleinman, HK TI Thymosin beta(4): actin-sequestering protein moonlights to repair injured tissues SO TRENDS IN MOLECULAR MEDICINE LA English DT Review ID ASPARTYL-LYSYL-PROLINE; NUCLEAR-MAGNETIC-RESONANCE; VEIN ENDOTHELIAL-CELLS; IN-VIVO; DEVELOPMENTAL REGULATION; INFLAMMATORY MEDIATORS; CONVERTING ENZYME; CARCINOMA CELLS; BETA-THYMOSINS; ALKALI INJURY AB Here, we review the biochemical and molecular properties of thymosin beta(4) (T beta(4)), the major actin-sequestering molecule in eukaryotic cells, and its key role in dermal-and corneal-wound healing. T beta(4) has several, novel, potential clinical applications in the repair and remodeling of ulcerated tissues and solid organs following hypoxic injuries, such as myocardial infarction and stroke. It might also have important repair functions in the pathophysiologic sequelae that are associated with actin toxicity and with septic shock, such as respiratory distress syndrome, multi-organ failure and severe tissue trauma. C1 George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Washington, DC 20037 USA. Univ Erlangen Nurnberg, Inst F Biochem, D-91054 Erlangen, Germany. NIDCR, Cell Biol Sect, NIH, Bethesda, MD 20892 USA. RP Goldstein, AL (reprint author), George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, 2300 1 St,NW, Washington, DC 20037 USA. EM bcmalg@gwumc.edu NR 70 TC 164 Z9 184 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 J9 TRENDS MOL MED JI Trends Mol. Med PD SEP PY 2005 VL 11 IS 9 BP 421 EP 429 DI 10.1016/j.molmed.2005.07.004 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 970UB UT WOS:000232334200006 PM 16099219 ER PT J AU Nagappan, G Lu, B AF Nagappan, G Lu, B TI Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications SO TRENDS IN NEUROSCIENCES LA English DT Review ID LONG-TERM POTENTIATION; NEUROTROPHIC FACTOR BDNF; INDUCED SYNAPTIC POTENTIATION; MESSENGER-RNA EXPRESSION; RETINAL GANGLION-CELLS; LIPID RAFTS; HIPPOCAMPAL-NEURONS; TYROSINE KINASE; SIGNAL-TRANSDUCTION; RAT HIPPOCAMPUS AB Although brain-derived neurotrophic factor (BDNF) has emerged as a key regulator of activity-dependent synaptic plasticity, a conceptually challenging question is how this diffusible molecule achieves local and synapse-specific modulation. One hypothesis is that neuronal activity enhances BDNF signaling by selectively modulating TrkB receptors at active neurons or synapses without affecting receptors on neighboring, less-active ones. Growing evidence suggests that neuronal activity facilitates cell-surface expression of TrkB. BDNF secreted from active synapses and neurons recruits TrkB from extrasynaptic sites into lipid rafts, microdomains of membrane that are enriched at synapses. Postsynaptic rises in cAMP concentrations facilitate translocation of TrkB into the postsynaptic density. Finally, neuronal activity promotes BDNF-induced TrkB endocytosis, a signaling event important for many long-term BDNF functions. These mechanisms could collectively underlie synapse-specific regulation by BDNF. C1 NICHHD, Sect Neural Dev & Plast, NIH, Bethesda, MD 20892 USA. NIH, Gene Cognit & Psychosis Program, GCAP, Bethesda, MD 20892 USA. RP Lu, B (reprint author), NICHHD, Sect Neural Dev & Plast, NIH, 35 Lincoln Dr,MSC 3714, Bethesda, MD 20892 USA. EM bailu@mail.nih.gov RI Lu, Bai/A-4018-2012 NR 91 TC 155 Z9 160 U1 2 U2 14 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD SEP PY 2005 VL 28 IS 9 BP 464 EP 471 DI 10.1016/j.tins.2005.07.003 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 966LV UT WOS:000232022300003 PM 16040136 ER PT J AU Miller, LH Saul, A Mahanty, S AF Miller, LH Saul, A Mahanty, S TI Revisiting Freund's incomplete adjuvant for vaccines in the developing world SO TRENDS IN PARASITOLOGY LA English DT Article ID APICAL MEMBRANE ANTIGEN-1; FREE FATTY ACIDS; CLINICAL-TRIAL; ARLACEL; MALARIA; PROTECTION; TOXICITY; DISEASES AB The rightful emphasis on collaboration between the public and private sectors in solving the world's health problems, especially those of the poor in the developing world, relies on industry developing new technologies with the support of government and foundations. However, certain products, despite their potential to have a great impact on disease in the developing world, will not be developed by industry because they carry the risk of lawsuits owing to possible severe adverse reactions risks that are not counterbalanced by potential profit of products that are of limited use in the developed world. Freund's incomplete adjuvant (FIA) is one such example that is better developed in the public sector. In this article, we present the evidence that has led to our interest in FIA, evidence of its potential benefit in vaccines against blood-stage malaria, and the way forward to make safe, effective and affordable vaccines for malaria and other serious diseases in the developing world. C1 NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20818 USA. RP Miller, LH (reprint author), NIAID, Malaria Vaccine Dev Branch, NIH, Twinbrook 1,5640 Fishers Lane, Rockville, MD 20818 USA. EM lmiller@niaid.nih.gov RI Saul, Allan/I-6968-2013; OI Saul, Allan/0000-0003-0665-4091; Mahanty, Siddhartha/0000-0003-1068-0524 NR 20 TC 18 Z9 18 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 J9 TRENDS PARASITOL JI Trends Parasitol. PD SEP PY 2005 VL 21 IS 9 BP 412 EP 414 DI 10.1016/j.pt.2005.07.005 PG 3 WC Parasitology SC Parasitology GA 963CK UT WOS:000231780300007 PM 16043410 ER PT J AU Romero, R AF Romero, R TI Imaging: A discovery tool in obstetrics and gynecology SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Editorial Material ID FUNCTIONAL MAGNETIC-RESONANCE; FETAL-BRAIN ACTIVITY; VELOCITY WAVE-FORMS; INFERIOR VENA-CAVA; INTRAUTERINE GROWTH RESTRICTION; GESTATIONAL-AGE FETUSES; CROWN-RUMP LENGTH; BLOOD-FLOW; 3-DIMENSIONAL ULTRASONOGRAPHY; PRENATAL-DIAGNOSIS C1 Wayne State Univ, Perinatol Res Branch, NICHD,Hutzel Womens Hosp, NIH,DHHS, Detroit, MI 48201 USA. RP Romero, R (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD,Hutzel Womens Hosp, NIH,DHHS, 3990 John R,4th Floor, Detroit, MI 48201 USA. EM warfiela@mail.nih.gov NR 98 TC 3 Z9 3 U1 3 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD SEP PY 2005 VL 26 IS 3 BP 207 EP 213 DI 10.1002/uog.1988 PG 7 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 968FQ UT WOS:000232147700001 PM 16116559 ER PT J AU D'Amico, AV Chen, MH Cox, MC Dahut, W Figg, WD AF D'Amico, AV Chen, MH Cox, MC Dahut, W Figg, WD TI Prostate-specific antigen response duration and risk of death for patients with hormone-refractory metastatic prostate cancer SO UROLOGY LA English DT Article ID PHASE-II TRIAL; PLACEBO-CONTROLLED TRIAL; THALIDOMIDE; SURVIVAL; MEN AB Objectives. To evaluate whether the time to return to the baseline prostate-specific antigen (PSA) level (PSA response duration) is significantly associated with the time to death after randomization for men with hormone-refractory metastatic prostate cancer. Methods. The study (n = 213) and validation (n = 281) cohorts constituted 494 men with hormone-refractory metastatic prostate cancer treated in four prospective randomized Phase II studies between February 1996 and October 2001. Cox regression analysis was used to evaluate whether a significant association existed between the PSA response duration and the time to death after randomization, controlling for treatment and known prognostic factors. Results. A decreasing PSA response duration was significantly associated with a shorter survival after randomization in the study (P = 0.001) and validation (P = 0.02) cohorts, controlling for treatment and known prognostic factors, which included serum PSA, lactate dehydrogenase, alkaline phosphatase, and hemoglobin levels and the Eastern Cooperative Oncology Group performance status. The adjusted hazard ratio for death was 1.9 (95% confidence interval 1.4 to 2.6; P = 0.0002) and 2.1 (95% Cl 1.2 to 3.5; P = 0.01) for men in the study and validation cohorts, respectively, whose PSA response duration was shorter than the median value of 3 months. The PSA response duration dichotomized about the median remained significantly associated with death whether patients in the validation cohort experienced at least a 50% reduction (P = 0.05) in the PSA level or not (P = 0.03). Conclusions. The duration of the PSA response to treatment is significantly associated with length of survival for men with hormone-refractory metastatic prostate cancer. C1 Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. NCI, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. RP D'Amico, AV (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,L-2 Level, Boston, MA 02215 USA. EM adamico@lroc.harvard.edu RI Figg Sr, William/M-2411-2016 NR 13 TC 9 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD SEP PY 2005 VL 66 IS 3 BP 571 EP 576 DI 10.1016/j.urology.2005.03.083 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 968JC UT WOS:000232157700021 PM 16140080 ER PT J AU Louder, MK Sambor, A Chertova, E Hunte, T Barrett, S Ojong, F Sanders-Buell, E Zolla-Pazner, S McCutchan, FE Roser, JD Gabuzda, D Lifson, JD Mascola, JR AF Louder, MK Sambor, A Chertova, E Hunte, T Barrett, S Ojong, F Sanders-Buell, E Zolla-Pazner, S McCutchan, FE Roser, JD Gabuzda, D Lifson, JD Mascola, JR TI HIV-1 envelope pseudotyped viral vectors and infectious molecular clones expressing the same envelope glycoprotein have a similar neutralization phenotype, but culture in peripheral blood mononuclear cells is associated with decreased neutralization sensitivity SO VIROLOGY LA English DT Article DE HIV-1; vaccines; neutralizing antibodies; pseudovirus ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODY; HUMAN LYMPHOID-TISSUE; TYPE-1 INFECTION; HOST ICAM-1; PRIMARY ISOLATE; CHIMERIC VIRUS; ENV GENES; T-CELLS; HLA-DR AB Recombinant lentiviral vectors pseudotyped with heterologous HIV-1 envelope glycoproteins allow rapid and accurate measurement of antibody-mediated HIV-1 neutralization. However, the neutralization phenotypes of envelope pseudoviruses have not been directly compared to isogenic replication competent HIV-1. We produced pseudoviruses expressing three different HIV-1 envelope glycoproteins and subdoned the same three env genes into a replication competent NL4-3 molecular clone. For each of the antibodies tested, the neutralization dose-response curves of pseudoviruses and corresponding replication competent viruses were similar. Thus, envelope pseudoviruses can be used to study the anti-HIV-1 neutralizing antibody response. A single passage of replication competent virus derived from 293T cells through peripheral blood mononuclear cells (PBMC) caused a substantial decrease in sensitivity to neutralizing antibodies. This was associated with an increase in average virion envelope glycoprotein content of the PBMC-derived virus. Replication competent HIV-1 and isogenic envelope pseudoviruses have similar neutralization characteristics, but passage into PBMC is associated with decreased sensitivity to neutralization. Published by Elsevier Inc. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, AIDS Vaccine Program, SAIC Frederick Inc, Frederick, MD 21702 USA. Henry M Jackson Fdn, Rockville, MD 20850 USA. New York Vet Affairs Med Ctr, New York, NY USA. NYU, Sch Med, New York, NY USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. EM jmascola@nih.gov FU NCI NIH HHS [N01-CO-124000]; NINDS NIH HHS [NS37277] NR 59 TC 54 Z9 55 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 1 PY 2005 VL 339 IS 2 BP 226 EP 238 DI 10.1016/j.virol.2005.06.003 PG 13 WC Virology SC Virology GA 960ZO UT WOS:000231631900008 PM 16005039 ER PT J AU Witkin, AL Milburn, NG Rotheram-Borus, MJ Batterham, P May, S Brooks, R AF Witkin, AL Milburn, NG Rotheram-Borus, MJ Batterham, P May, S Brooks, R TI Finding homeless youth - Patterns based on geographical area and number of homeless episodes SO YOUTH & SOCIETY LA English DT Article DE homelessness; homeless youth; cruise area; Los Angeles homeless ID NEW-YORK-CITY; HIV RISK BEHAVIORS; STREET YOUTH; RUNAWAY ADOLESCENTS; SUBSTANCE USE; HEALTH-CARE; NORTHERN CALIFORNIA; LOS-ANGELES; DRUG-USE; PROFILE AB A census of homeless youth was conducted in locations across Los Angeles County, California. Building on previous research that has focused on homeless youth in cruise areas, the authors examined demographic and behavioral differences between homeless youth in cruise and noncruise areas. Youth in cruise areas were more likely than youth in noncruise areas to be older to have been away from home longer to have recently visited community-based agencies, and were likely to have resided in shelters and less likely to attend school. These data suggest possible selection bias in earlier studies that relied primarily on homeless youth from cruise areas. C1 Univ Calif Los Angeles, Inst Neuropsychiat, Ctr Community Hlth, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Treatment Serv Core, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, NIMH, Ctr HIV Identificat Prevent & Treatment Serv, Inst Neuropsychiat, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, AIDS Inst, Los Angeles, CA 90024 USA. RP Witkin, AL (reprint author), Univ Calif Los Angeles, Inst Neuropsychiat, Ctr Community Hlth, 760 Westwood Plaza, Los Angeles, CA 90024 USA. NR 44 TC 19 Z9 19 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0044-118X J9 YOUTH SOC JI Youth Soc. PD SEP PY 2005 VL 37 IS 1 BP 62 EP 84 DI 10.1177/0044118X04272811 PG 23 WC Social Issues; Social Sciences, Interdisciplinary; Sociology SC Social Issues; Social Sciences - Other Topics; Sociology GA 955SH UT WOS:000231247400003 ER PT J AU Joung, YH Lim, EJ Lee, MY Parka, JH Ye, SK Park, EU Kim, SY Zhang, Z Lee, KJ Park, DK Park, T Moon, WK Young, MY AF Joung, YH Lim, EJ Lee, MY Parka, JH Ye, SK Park, EU Kim, SY Zhang, Z Lee, KJ Park, DK Park, T Moon, WK Young, MY TI Hypoxia activates the cyclin D1 promoter via the Jak2/STAT5b pathway in breast cancer cells SO EXPERIMENTAL AND MOLECULAR MEDICINE LA English DT Article DE breast neoplasms; cell hypoxia; cyclin D1; Janus kinase 2; Stat5 protein; trans-activation ID SIGNAL-REGULATED KINASE; GENE-EXPRESSION; HEPG2 CELLS; SERINE PHOSPHORYLATION; EPITHELIAL-CELLS; BINDING-PROTEIN; STAT5B; GROWTH; TRANSDUCER; PROLACTIN AB Hypoxia, a common consequence of solid tumor growth in breast cancer or other cancers, serves to propagate a cascade of molecular pathways which include angiogenesis, glycolysis, and various cell cycle control proteins. As we have shown previously, hypoxia activates STAT5 (signal transducer and activator of transcription 5) and increases its binding activity to the GAS element in mammary epithelial cells. In this study we attempted to elucidate the mechanism by which cyclin D1 is regulated by the STAT5 protein under hypoxic conditions. Our data demonstrate that hypoxia (2% O-2) or desferrioxamine (DFO) induces tyrosine and serine phosphorylation of STAT5 in human breast cancer cells (MCF-7) and mammary epithelial cells (HC11). Imunoprecipitation and subsequent Western analysis showed that Jak2 leads to the tyrosine phosphorylation and activation of STAT5a or STAT5b under hypoxic conditions. Using a transfected COS-7 cell model system, we demonstrate that the activity of a cyclin D1 promoter-luciferase construct increased under hypoxic conditions or DFO treatment. The activity of the STAT5b/cyclin D1 promoter increased significantly by 12 h of hypoxia, whereas the activity of the STAT5a/cyclin D1 promoter was unaffected under hypoxic conditions. These increases in promoter activity are predominantly mediated by the Jak2/STAT5b signaling pathway. We have shown by EMSA that hypoxia induces STAT5 to bind to the cyclin D1 promoter (GAS-1) in MCF-7 and HC11 cells. These data suggest that STAT5b may mediate the transcriptional activation of cyclin D1 after hypoxic stimulation. C1 Konkuk Univ, Dept Pathol, Coll Med, Chungju 380701, South Korea. Konkuk Univ, Bio Food Drug Res Ctr, Dept Biotechnol, Coll Biomed & Hlth Sci, Chungju 380701, South Korea. NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Seoul Natl Univ, Dept Pharmacol, Coll Med, Seoul 110799, South Korea. NHLBI, Lab Kidney & Electrolyte Metab, NIH, Bethesda, MD 20892 USA. Konkuk Univ, Dept Anim Biotechnol, Coll Anim Husb, Seoul 143701, South Korea. Konkuk Univ, Dept Appl Biol & Chem, Seoul 143701, South Korea. Nat F&P Corp, Chongwon 363883, South Korea. RP Young, MY (reprint author), Konkuk Univ, Dept Pathol, Coll Med, Chungju 380701, South Korea. EM ymyang@kku.ac.kr RI Ye, Sang Kyu/J-2768-2012 NR 42 TC 28 Z9 28 U1 0 U2 0 PU KOREAN SOC MED BIOCHEMISTRY MOLECULAR BIOLOGY PI SEOUL PA #812 KOFST, 635-4 YOKSAM-DONG KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1226-3613 J9 EXP MOL MED JI Exp. Mol. Med. PD AUG 31 PY 2005 VL 37 IS 4 BP 353 EP 364 PG 12 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 965FO UT WOS:000231936000011 PM 16155412 ER PT J AU Edler, MC Buey, RM Gussio, R Marcus, AI Vanderwal, CD Sorensen, EJ Diaz, JF Giannakakou, P Ernest, H AF Edler, MC Buey, RM Gussio, R Marcus, AI Vanderwal, CD Sorensen, EJ Diaz, JF Giannakakou, P Ernest, H TI Cyclostreptin (FR182877), an antitumor tubulin-polymerizing agent deficient in enhancing tubulin assembly despite its high affinity for the taxoid site SO BIOCHEMISTRY LA English DT Article ID MICROTUBULE-STABILIZING AGENTS; ANTIMITOTIC SUBSTANCE; PACLITAXEL TAXOL; PURIFIED TUBULIN; CELLS RESISTANT; EPOTHILONE-B; CANCER-CELLS; BINDING-SITE; ANALOGS; LAULIMALIDE AB Cyclostreptin (FR182877), a bacterial natural product, was reported to have weak paclitaxel-like activity with tubulin but antitumor activity in vivo. We used synthetic cyclostreptin in studies of its mechanism of action. Although less potent than paclitaxel in several human cancer cell lines, cyclostreptin was active against cells resistant to paclitaxel and epothilone A. At equitoxic concentrations with paclitaxel, cyclostreptin was more effective in arresting MCF-7 cells in mitosis and equivalent in bundling microtubules in PtK2 cells. Tubulin assembly with paclitaxel occurs at low temperatures and in the absence of GTP or microtubule-associated proteins (MAPs). Brisk assembly with cyclostreptin required MAPs, GTP, and higher reaction temperatures. On the basis of turbidimetry, cyclostreptin-induced microtubules were more stable in the cold than the paclitaxel-induced polymer. Moreover, at 37 degrees C cyclostreptin was a strong competitive inhibitor of the binding of radiolabeled paclitaxel to tubulin polymer, with an apparent K-i value of 88 nM. Competition studies versus a fluorescent taxoid across a temperature range, in comparison with paclitaxel and docetaxel, showed that only the binding of cyclostreptin to microtubules was markedly reduced at 4 degrees C versus temperatures over 30 degrees C. The binding of cyclostreptin to microtubules was characterized by a relatively greater endothermic and entropic profile as compared with those of the taxoid binding reactions, which are characterized more by exothermic and enthalpic interactions. Molecular modeling showed that cyclostreptin formed a pharmacophore with taxoids but formed hydrogen bonds only with the S9-S10 and M loops in the taxoid site. Initial studies also indicate that, relative to paclitaxel, cyclostreptin is more deficient in nucleation than elongation of polymer. C1 NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Ft Detrick, MD 21702 USA. CSIC, Ctr Invest Biol, E-28040 Madrid, Spain. NCI, Informat Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Ft Detrick, MD 21702 USA. Emory Univ, Sch Med, Winship Canc Inst, Atlanta, GA 30322 USA. Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. Univ Calif San Diego, La Jolla, CA 92037 USA. RP Ernest, H (reprint author), NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Bldg 469,Room 104, Ft Detrick, MD 21702 USA. EM hamele@mail.nih.gov RI Martinez-Buey, Ruben/K-4296-2014; OI Martinez-Buey, Ruben/0000-0003-1263-0221; Giannakakou, Paraskevi/0000-0001-7378-262X; Diaz, J. Fernando/0000-0003-2743-3319 NR 47 TC 38 Z9 40 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 30 PY 2005 VL 44 IS 34 BP 11525 EP 11538 DI 10.1021/bi050660m PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 960JZ UT WOS:000231587900023 PM 16114889 ER PT J AU Koenig, BW Gawrisch, K AF Koenig, BW Gawrisch, K TI Specific volumes of unsaturated phosphatidylcholines in the liquid crystalline lamellar phase SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE specific volume; lipid; polyunsaturated fatty acid; DHA; neutral buoyancy method ID POLYUNSATURATED FATTY-ACIDS; MOLECULAR-DYNAMICS SIMULATIONS; HYDRATED BILAYER DISPERSIONS; X-RAY-DIFFRACTION; LIPID-BILAYERS; H-2 NMR; PHOSPHOLIPID-BILAYERS; STRUCTURAL-PROPERTIES; CHAIN-LENGTH; ACYL-CHAIN AB The specific volumes of seven 1,2-diacyl-sn-glycero-3-phosphocliolines with symmetric, unbranched acyl chains containing one, four, or six cis double bonds per chain, or with a saturated sn-1 chain and one, four, or six cis double bonds in the sn-2 chain were determined by the neutral buoyancy method. Experiments were conducted in the liquid crystalline lamellar phase over the temperature range from 5 to 35 degrees C. It is demonstrated that the molecular volume of phosphatidylcholines can be well approximated as the sum of a constant volume of the polar lipid head region and the temperature-dependent volumes of hydrocarbon chain -CH(2), CH, and terminal CH(3) groups. A linear dependence of chain segment volumes on temperature was observed. A self-consistent set of partially temperature-dependent volumes is obtained that allows prediction of phosphatidylcholine molecular volumes within very tight error margins. (c) 2005 Elsevier B.V. All rights reserved. C1 Forschungszentrum Julich, IBI2, NMR,Struct Biol Inst, D-52425 Julich, Germany. Univ Dusseldorf, Inst Biol Phys, D-40225 Dusseldorf, Germany. NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Koenig, BW (reprint author), Forschungszentrum Julich, IBI2, NMR,Struct Biol Inst, D-52425 Julich, Germany. EM b.koenig@fz-juelich.de RI Koenig, Bernd/B-4315-2008 OI Koenig, Bernd/0000-0002-5300-6276 NR 39 TC 44 Z9 45 U1 3 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD AUG 30 PY 2005 VL 1715 IS 1 BP 65 EP 70 DI 10.1016/j.bbamem.2005.07.006 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 960JI UT WOS:000231586100008 PM 16109383 ER PT J AU Best, LG Zhang, Y Lee, ET Yeh, JL Cowan, L Palmieri, V Roman, M Devereux, RB Fabsitz, RR Tracy, RP Robbins, D Davidson, M Ahmed, A Howard, BV AF Best, LG Zhang, Y Lee, ET Yeh, JL Cowan, L Palmieri, V Roman, M Devereux, RB Fabsitz, RR Tracy, RP Robbins, D Davidson, M Ahmed, A Howard, BV TI C-reactive protein as a predictor of cardiovascular risk in a population with a high prevalence of diabetes - The Strong Heart Study SO CIRCULATION LA English DT Article DE inflammation; epidemiology; risk factors; cardiovascular diseases; diabetes mellitus ID HORMONE REPLACEMENT THERAPY; NESTED CASE-CONTROL; AMERICAN-INDIANS; MYOCARDIAL-INFARCTION; PLASMA-CONCENTRATION; ANGINA-PECTORIS; ALL-CAUSE; DISEASE; INFLAMMATION; WOMEN AB Background - High- sensitivity C-reactive protein (CRP) has been investigated extensively as a marker for predicting the risk of cardiovascular disease (CVD). CVD accounts for a large proportion of mortality and morbidity in American Indians; we sought to test the association of CRP and CVD in a population- based American Indian cohort 45 to 74 years old. Methods and Results - Of 3277 participants who were CVD-free at baseline, 542 had CRP > 10 mg/L and were excluded from analysis; 50.1% of those included had diabetes. There were 343 CVD events among this cohort during a median follow- up of 6.2 years. Multiple CVD risk factors were used as covariates in Cox proportional- hazard models. After exclusions, the median CRP (3.2 mg/ L) was higher than reported in many other populations. CRP predicted CVD in models adjusted for traditional risk factors, but not when albuminuria and fibrinogen were included. In subgroup analysis, CRP was strongly related to incident CVD among nondiabetic women participants, even after adjustment for traditional CVD risk factors and other indicators of inflammation. Conversely, CRP was elevated beyond the useful range of the American Heart Association/Centers for Disease Control and Prevention clinical guidelines in 16% of this population, and CRP was not predictive of CVD in important subgroups, such as those with diabetes. Conclusions - CRP was a predictor of CVD in this American Indian population with a high prevalence of diabetes and other risk factors. The predictive ability of CRP varies considerably among subgroups with different risk factor profiles. C1 Missouri Breaks Ind Res Inc, Timber Lake, SD USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. Cornell Med Ctr, New York, NY USA. NHLBI, Bethesda, MD 20892 USA. Univ Vermont, Lab Clin Biochem Res, Burlington, VT USA. Medstar Res Inst, Washington, DC USA. RP Best, LG (reprint author), 1 Airport Rd,RRI,Box 88, Rolette, ND 58366 USA. EM sbest@utma.com OI Palmieri, Vittorio/0000-0003-3732-524X FU NHLBI NIH HHS [U01-HL-41642, U01-HL-41652, U01-HL-41654, U01-HL-65520, U01-HL-65521] NR 37 TC 57 Z9 61 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 30 PY 2005 VL 112 IS 9 BP 1289 EP 1295 DI 10.1161/CIRCULATIONAHA.104.489260 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 959IJ UT WOS:000231511100009 PM 16116058 ER PT J AU Sandberg, MB Fridriksson, J Madsen, L Rishi, V Vinson, C Holmsen, H Berge, RK Mandrup, S AF Sandberg, MB Fridriksson, J Madsen, L Rishi, V Vinson, C Holmsen, H Berge, RK Mandrup, S TI Glucose-induced lipogenesis in pancreatic beta-cells is dependent on SREBP-1 SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE INS-IE cells; transduction; adenovirus; dominant negative SREBP; lipid accumulation; glucolipotoxicity ID STEROL REGULATORY-ELEMENT; ACETYL-COA CARBOXYLASE; HELIX-LOOP-HELIX; BINDING PROTEIN-1C EXPRESSION; FATTY-ACID METABOLISM; DE-NOVO LIPOGENESIS; GENE-EXPRESSION; TRANSCRIPTION FACTOR; INSULIN-SECRETION; ADIPOCYTE DIFFERENTIATION AB High concentrations of glucose induce de novo fatty acid synthesis in pancreatic beta-cells and chronic exposure of elevated glucose and fatty acids synergize to induce accumulation of triglycerides, a phenomenon termed glucolipotoxicity. Here we investigate the role of sterol-regulatory element binding proteins in glucose-induced lipogenesis in the pancreatic beta-cell line INS-1E. We show that glucose induces SREBP- l c expression and SREBP-1 activity independent of insulin secretion and signaling. Using adenoviral expression of SREBP-1c and a SREBP-mutant we show that lipogenic gene expression, de novo fatty acid synthesis and lipid accumulation are induced primarily through sterol-regulatory elements (SREs) and not E-Boxes. Adenoviral expression of a dominant negative SREBP compromises glucose induction of some lipogenic genes and significantly reduces glucose-induction of de novo fatty acid synthesis. Thus, we demonstrate for the first time that SREBP activity is necessary for full glucose induction of de novo fatty acid synthesis in pancreatic beta-cells. (c) 2005 Elsevier Ireland Ltd. All rights reserved. C1 Univ So Denmark, Dept Biochem & Mol Biol, DK-5230 Odense, Denmark. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Univ Bergen, Dept Biomed, N-5009 Bergen, Norway. Univ Bergen, Haukeland Hosp, Dept Clin Biochem, N-5021 Bergen, Norway. RP Mandrup, S (reprint author), Univ So Denmark, Dept Biochem & Mol Biol, Campusvej 55, DK-5230 Odense, Denmark. EM s.mandrup@bmb.sdu.dk RI Mandrup, Susanne/B-6693-2008; Madsen, Lise/C-6246-2012; OI Madsen, Lise/0000-0003-4468-1947; Mandrup, Susanne/0000-0002-0961-5787 NR 58 TC 17 Z9 20 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD AUG 30 PY 2005 VL 240 IS 1-2 BP 94 EP 106 DI 10.1016/j.mce.2005.05.005 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 963WM UT WOS:000231836900011 PM 16002205 ER PT J AU Vasireddy, V Vijayasarathy, C Huang, JB Wang, XFF Jablonski, MM Petty, HR Sieving, PA Ayyagari, R AF Vasireddy, V Vijayasarathy, C Huang, JB Wang, XFF Jablonski, MM Petty, HR Sieving, PA Ayyagari, R TI Stargardt-like macular dystrophy protein ELOVL4 exerts a dominant negative effect by recruiting wild-type protein into aggresomes SO MOLECULAR VISION LA English DT Article ID GENE; ELECTROPHORESIS; IMPAIRMENT; EXPRESSION; INHIBITORS; COMPLEXES; MUTATION AB Purpose: Mutations in the gene Elongation of very long-chain fatty acids-4 (ELOVL4) have been shown to be associated with autosomal dominant Stargardt-like macular dystrophy (STGD3). ELOVL4 is expressed in photoreceptors and encodes a putative transmembrane protein of 314 amino acids with an endoplasmic reticulum (ER) retention signal. A 5 bp deletion in exon 6 of ELOVL4 observed in some STGD3 patients results in the truncation of the protein and loss of the ER retention signal. To understand the disease mechanism underlying STGD3 we studied the intracellular trafficking of the wild-type and a 5 bp deletion mutant of ELOVL4. Methods: Wild-type and mutant ELOVL4 proteins with the N-terminal GFP/V5 tags were expressed in COS-7 cells. Expression and the intracellular localization of the wild-type and mutant proteins were characterized by immunocytochemistry and western blot analysis using tag- and organelle-specific antibodies. Interaction between the wild-type and mutant proteins was studied by two-dimensional gel electrophoresis and fluorescence resonance energy transfer (FRET) analysis. Results: The mutant ELOVL4 protein exerted a dominant negative effect when the wild-type and 5 bp deletion mutant ELOVL4 proteins were co-expressed in COS-7 cells. Immunocytochemical analysis, two-dimensional gel electrophoresis and FRET revealed that the mutant ELOVL4 interacts with the wild-type protein, forming higher molecular mass complexes that accumulate in aggresomes. Conclusions: In the presence of mutant ELOVL4 protein, the wild-type protein was recruited into perinuclear cytoplasmic inclusions that resemble aggresomes. The interaction between the wild-type and mutant forms of ELOVL4 and the resultant alteration in the trafficking of the wild-type ELOVL4 protein suggest a mechanism for the pathogenicity observed in patients with autosomal dominant STGD3. C1 Univ Michigan, WK Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. NEI, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. Univ Tennessee, Ctr Hlth Sci, Hamilton Eye Inst, Memphis, TN 38163 USA. RP Ayyagari, R (reprint author), Univ Michigan, WK Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, 1000 Wall St,Room 325, Ann Arbor, MI 48105 USA. EM ayyagari@umich.edu FU NEI NIH HHS [P30EY07060, R01EY13198, P30EY007003, P30EY13080] NR 23 TC 46 Z9 48 U1 0 U2 1 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 AUG 30 PY 2005 VL 11 IS 78-79 BP 665 EP 676 PG 12 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 964MF UT WOS:000231884500002 PM 16163264 ER PT J AU Lagenaur, LA Berger, EA AF Lagenaur, LA Berger, EA TI An anti-HIV microbicide comes alive SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID TRANSMISSION; CD4; INFECTIONS; INHIBITION; PREVENTION; MACAQUES; PROTEIN; GP120 C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. OSEL Inc, Santa Clara, CA 95054 USA. RP Berger, EA (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM edward_berger@nih.gov NR 12 TC 12 Z9 13 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 30 PY 2005 VL 102 IS 35 BP 12294 EP 12295 DI 10.1073/pnas.0505960102 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 961QC UT WOS:000231675900003 PM 16118279 ER PT J AU Jia, YZ Guo, GL Surapureddi, S Sarkar, J Qi, C Guo, DS Xia, J Kashireddi, P Yu, ST Cho, YW Rao, S Kemper, B Ge, K Gonzalez, FJ Reddy, JK AF Jia, YZ Guo, GL Surapureddi, S Sarkar, J Qi, C Guo, DS Xia, J Kashireddi, P Yu, ST Cho, YW Rao, S Kemper, B Ge, K Gonzalez, FJ Reddy, JK TI Transcription coactivator peroxisome proliferator-activated receptor-binding protein/mediator 1 deficiency abrogates acetaminophen hepatotoxicity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE constitutive androstane receptor ID CONSTITUTIVE ANDROSTANE RECEPTOR; REGULATED GENE-EXPRESSION; NUCLEAR RECEPTORS; EMBRYONIC-DEVELOPMENT; XENOBIOTIC INDUCTION; TRAP220 COMPONENT; DRUG-METABOLISM; HORMONE ACTION; X RECEPTOR; PROTEIN AB Peroxisome proliferator-activated receptor-binding protein (PBP), also known as thyroid hormone receptor-associated protein 220/vitamin D receptor-interacting protein 205/mediator 1, an anchor for multisubunit mediator transcription complex, functions as a transcription coactivator for nuclear receptors. Disruption of the PBP gene results in embryonic lethality around embryonic day 11.5 by affecting placental and multiorgan development. Here, we report that targeted deletion of PBP in liver parenchymal cells (PBPLiv-/-) results in the abrogation of hypertrophic and hyperplastic influences in liver mediated by constitutive androstane receptor (CAR) ligands phenobarbital (PB) and 1,4-bis-[2-(3,5-di-chloropyridyloxy)] benzene, and of acetaminophen-induced hepatotoxicity. CAR interacts with the two nuclear receptor-interacting LXXLL (L, leucine; X, any amino acid) motifs in PBP in a ligand-dependent manner. We also show that PBP interacts with the C-terminal portion of CAR, suggesting that PBP is involved in the regulation of CAR function. Although the full-length PBP only minimally increased CAR transcriptional activity, a truncated form of PBP (amino acids 487-735) functioned as a dominant negative repressor, establishing that P8P functions as a coactivator for CAR. A reduction in CAR mRNA and protein level observed in PBP(Liv-/-)mouse liver suggests that PBP may regulate hepatic CAR expression. PBP-deficient hepatocytes in liver failed to reveal PB-dependent translocation of CAR to the nucleus. Adenoviral reconstitution of PBP in PBPLiv-/- mouse livers restored PB-mediated nuclear translocation of CAR as well as inducibility of CYP1A2, CYP2B10, CYP3A11, and CYP7A1 expression. We conclude that transcription coactivator PBP/TRAP220/MED1 is involved in the regulation of hepatic CAR function and that PBP deficiency in liver abrogates acetaminophen hepatotoxicity. C1 Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA. NCI, Lab Metab, Canc Res Ctr, Bethesda, MD 20892 USA. NIDDKD, Nucl Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. Univ Illinois, Dept Cell & Struct Biol, Urbana, IL 61801 USA. RP Reddy, JK (reprint author), Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA. EM jkreddy@northwestern.edu RI guo, Dongsheng/A-2196-2010; Cho, Young-Wook /F-8269-2011; OI Ge, Kai/0000-0002-7442-5138 FU Intramural NIH HHS [Z99 DK999999, Z01 DK047055-01]; NCI NIH HHS [CA104578, R01 CA104578]; NIGMS NIH HHS [GM23750, R01 GM023750, R37 GM023750] NR 37 TC 41 Z9 44 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 30 PY 2005 VL 102 IS 35 BP 12531 EP 12536 DI 10.1073/pnas.0506000102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 961QC UT WOS:000231675900045 PM 16109766 ER PT J AU Van Boven, RW Ingeholm, JE Beauchamp, MS Bikle, PC Ungerleider, LG AF Van Boven, RW Ingeholm, JE Beauchamp, MS Bikle, PC Ungerleider, LG TI Tactile form and location processing in the human brain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE brain imaging; functional MRI; somatosensory ID ORIENTATION DISCRIMINATION; FMRI DATA; CORTEX; SHAPE; TASK; VISUALIZATION; MANIPULATION; MECHANISMS; DOMINANCE; COGNITION AB To elucidate the neural basis of the recognition of tactile form and location, we used functional MRI while subjects discriminated gratings delivered to the fingertip of either the right or left hand. Subjects were required to selectively attend to either grating orientation or grating location under identical stimulus conditions. Independent of the hand that was stimulated, grating orientation discrimination selectively activated the left intraparietal sulcus, whereas grating location discrimination selectively activated the right temporoparietal junction. Hence, hemispheric dominance appears to be an organizing principle for cortical processing of tactile form and location. C1 NIMH, Lab Brain & Cognit, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Ungerleider, LG (reprint author), NIMH, Lab Brain & Cognit, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM ungerlel@mail.nih.gov OI Beauchamp, Michael/0000-0002-7599-9934 FU Intramural NIH HHS NR 36 TC 66 Z9 68 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 30 PY 2005 VL 102 IS 35 BP 12601 EP 12605 DI 10.1073/pnas.0505907102 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 961QC UT WOS:000231675900057 PM 16116098 ER PT J AU Nguyen, AD Pan, CJ Shieh, JJ Chou, JY AF Nguyen, AD Pan, CJ Shieh, JJ Chou, JY TI Increased cellular cholesterol efflux in glycogen storage disease type Ia mice: A potential mechanism that protects against premature atherosclerosis SO FEBS LETTERS LA English DT Article DE glycogen storage disease type I; atherosclerosis; scavenger receptor class B type I; ATP-binding cassette transporter A1; cholesterol efflux; phospholipid ID RECEPTOR CLASS-B; APOLIPOPROTEIN A-IV; SCAVENGER RECEPTOR; DEFICIENT MICE; SERUM; HDL; LIPOPROTEINS; LIPIDS; MOUSE; OVEREXPRESSION AB Glycogen storage disease type la (GSD-Ia) patients manifest a pro-atherogenic lipid profile but are not at elevated risk for developing atherosclerosis. Serum phospholipid, which correlates positively with the scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux, and apolipoprotein A-IV and E, acceptors for ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol transport, are increased in GSD-Ia mice. Importantly, sera from GSD-Ia mice are more efficient than sera from control littermates in promoting SRBI- and ABCA1-mediated cholesterol effluxes. As the first step in reverse cholesterol transport, essential for cholesterol homeostasis, these observations provide one explanation why GSD-Ia patients are apparently protected against premature atherosclerosis. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 NICHHD, Sect Cellular Differentiat, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Chou, JY (reprint author), NICHHD, Sect Cellular Differentiat, Heritable Disorders Branch, NIH, Bldg 10,Room 9D42,NIH 9000,Rockville Pike, Bethesda, MD 20892 USA. EM chouja@mail.nih.gov NR 36 TC 2 Z9 2 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 29 PY 2005 VL 579 IS 21 BP 4713 EP 4718 DI 10.1016/j.febslet.2005.07.042 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 960XF UT WOS:000231625800026 PM 16098970 ER PT J AU Lammerding, J Hsiao, J Schulze, PC Kozlov, S Stewart, CL Lee, RT AF Lammerding, J Hsiao, J Schulze, PC Kozlov, S Stewart, CL Lee, RT TI Abnormal nuclear shape and impaired mechanotransduction in emerin-deficient cells SO JOURNAL OF CELL BIOLOGY LA English DT Article ID DREIFUSS MUSCULAR-DYSTROPHY; HUTCHINSON-GILFORD-PROGERIA; ENCODING LAMIN A/C; PROMOTING TRANSCRIPTIONAL REPRESSOR; SMOOTH-MUSCLE-CELLS; RNA-POLYMERASE-II; DILATED CARDIOMYOPATHY; PARTIAL LIPODYSTROPHY; IN-VITRO; ACTIN CYTOSKELETON AB Emery-Dreifuss muscular dystrophy can be caused by mutations in the nuclear envelope proteins lamin A/C and emerin. We recently demonstrated that A-type lamin-deficient cells have impaired nuclear mechanics and altered mechanotransduction, suggesting two potential disease mechanisms (Lammerding, J., P. C. Schulze, T. Takahashi, S. Kozlov, T. Sullivan, R. D. Kamm, C. L. Stewart, and R. T. Lee. 2004. J. Clin. Invest. 113: 370 - 378). Here, we examined the function of emerin on nuclear mechanics and strain-induced signaling. Emerin-deficient mouse embryo fibroblasts have abnormal nuclear shape, but in contrast to A-type lamin-deficient cells, exhibit nuclear deformations comparable to wild type cells in cellular strain experiments, and the integrity of emerin-deficient nuclear envelopes appeared normal in a nuclear microinjection assay. Interestingly, expression of mechanosensitive genes in response to mechanical strain was impaired in emerin-deficient cells, and prolonged mechanical stimulation increased apoptosis in emerin-deficient cells. Thus, emerin-deficient mouse embryo fibroblasts have apparently normal nuclear mechanics but impaired expression of mechanosensitive genes in response to strain, suggesting that emerin mutations may act through altered transcriptional regulation and not by increasing nuclear fragility. C1 Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. MIT, HST Div, Cambridge, MA 02139 USA. NCI, Canc & Dev Biol Lab, Ft Detrick, MD 21702 USA. RP Lammerding, J (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM jlammerding@rics.bwh.harvard.edu RI Lammerding, Jan/A-9498-2016 OI Lammerding, Jan/0000-0003-4335-8611 FU NHLBI NIH HHS [HL073809, HL64858, P01 HL064858, R01 HL073809] NR 50 TC 172 Z9 174 U1 2 U2 19 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 AUG 29 PY 2005 VL 170 IS 5 BP 781 EP 791 DI 10.1083/jcb.200502148 PG 11 WC Cell Biology SC Cell Biology GA 959IB UT WOS:000231510300012 PM 16115958 ER PT J AU Pankov, R Endo, Y Even-Ram, S Araki, M Clark, K Cukierman, E Matsumoto, K Yamada, KM AF Pankov, R Endo, Y Even-Ram, S Araki, M Clark, K Cukierman, E Matsumoto, K Yamada, KM TI A Rac switch regulates random versus directionally persistent cell migration SO JOURNAL OF CELL BIOLOGY LA English DT Article ID NEUTROPHIL CHEMOTAXIS; RHO-GTPASES; PHOSPHATIDYLINOSITOL 3-KINASE; EUKARYOTIC CHEMOTAXIS; TISSUE-CULTURE; LEADING-EDGE; LIVING CELLS; CDC42; ACTIVATION; POLARITY AB Directional migration moves cells rapidly between points, whereas random migration allows cells to explore their local environments. We describe a Rac1 mechanism for determining whether cell patterns of migration are intrinsically random or directionally persistent. Rac activity promoted the formation of peripheral lamellae that mediated random migration. Decreasing Rac activity suppressed peripheral lamellae and switched the cell migration patterns of fibroblasts and epithelial cells from random to directionally persistent. In three dimensional rather than traditional two-dimensional cell culture, cells had a lower level of Rac activity that was associated with rapid, directional migration. In contrast to the directed migration of chemotaxis, this intrinsic directional persistence of migration was not mediated by phosphatidylinositol 3'-kinase lipid signaling. Total Rac1 activity can therefore provide a regulatory switch between patterns of cell migration by a mechanism distinct from chemotaxis. C1 Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Div Basic Sci, Philadelphia, PA 19111 USA. RP Yamada, KM (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. EM kenneth.yamada@nih.gov RI Pankov, Roumen/B-3284-2014; OI Pankov, Roumen/0000-0002-3157-3659; Even-Ram, Sharona/0000-0002-5540-3822; Yamada, Kenneth/0000-0003-1512-6805 NR 56 TC 282 Z9 286 U1 1 U2 19 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 AUG 29 PY 2005 VL 170 IS 5 BP 793 EP 802 DI 10.1083/jcb.200503152 PG 10 WC Cell Biology SC Cell Biology GA 959IB UT WOS:000231510300013 PM 16129786 ER PT J AU Roberts, A Mishra, L AF Roberts, A Mishra, L TI Role of TGF-beta in stem cells and cancer SO ONCOGENE LA English DT Editorial Material C1 Georgetown Univ, Washington, DC 20007 USA. DVAMC, Washington, DC 20007 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Georgetown Univ, Lab GI Dev Biol, Dept Surg, Washington, DC USA. Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. RP Mishra, L (reprint author), Georgetown Univ, Med Dent Bldg,NW 210-12 3900 Reservoir Rd,NW, Washington, DC 20007 USA. EM Lopamishra@yahoo.com NR 0 TC 12 Z9 13 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 29 PY 2005 VL 24 IS 37 BP 5667 EP 5667 DI 10.1038/sj.onc.1208915 PG 1 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 958MQ UT WOS:000231452800001 ER PT J AU Letterio, JJ AF Letterio, JJ TI TGF-beta signaling in T cells: roles in lymphoid and epithelial neoplasia SO ONCOGENE LA English DT Review DE transforming growth factor beta ( TGF-beta); lymphocyte; neoplasia; leukemia; inflammation; Smad3 ID TRANSFORMING-GROWTH-FACTOR; HEMATOPOIETIC STEM-CELLS; SMAD3 MUTANT MICE; DOWN-REGULATION; IN-VIVO; TUMOR-SUPPRESSOR; THYMOCYTE PROLIFERATION; LYMPHOBLASTIC-LEUKEMIA; INFLAMMATORY RESPONSE; IL-12 RESPONSIVENESS AB Transforming growth factor-beta (TGF-beta) plays an essential role in regulating the homeostasis of cells in the lymphoid lineage. TGF-beta signaling is not required for normal thymopoiesis, but is essential for regulating the expansion, activation, and effector function of the mature CD4(+) and CD8(+) T cells in the peripheral lymphoid organs and target tissues. Recent studies in both mice and humans have elucidated an important and complex role for TGF-beta in regulatory T-cell biology. Disruption of TGF-beta signaling in T cells impairs the maintenance of regulatory T cells, results in the expansion of activated effector T cells, and is associated with the production of cytokines that have major effects on cells in their environment. While autoimmunity and inflammation are the principal phenotypes associated with the abrogation of TGF-beta signaling in T cells in mice, emerging evidence now also directly links Smad-dependent TGF-beta signaling in T cells to the suppression of epithelial neoplasia. The TGF-beta receptor-activated Smad3 plays a critical role in mediating many of the inhibitory effects of TGF-beta signaling in T cells, and has now been established as an important suppressor of leukemogenesis. These studies are increasing our awareness of the many complex mechanisms through which TGF-beta signaling controls the pathogenesis of cancer. C1 NCI, Lab Cell Regulat & Carcinogenesis, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Letterio, JJ (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Canc Res Ctr, NIH, Bldg 41,Room C629,41 Lib Dr, Bethesda, MD 20892 USA. EM letterij@mail.nih.gov NR 127 TC 49 Z9 56 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 29 PY 2005 VL 24 IS 37 BP 5701 EP 5712 DI 10.1038/sj.onc.1208922 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 958MQ UT WOS:000231452800005 PM 16123803 ER PT J AU Strizzi, L Bianco, C Normanno, N Salomon, D AF Strizzi, L Bianco, C Normanno, N Salomon, D TI Cripto-1: A multifunctional modulator during embryogenesis and oncogenesis SO ONCOGENE LA English DT Review DE Cripto-1; embryogenesis; oncogenesis; EHT; engiogenesis; therapy ID MAMMARY EPITHELIAL-CELLS; EMBRYONIC STEM-CELLS; GROWTH-FACTOR-ALPHA; ONE-EYED-PINHEAD; EGF-CFC FAMILY; DIFFERENTIAL IMMUNOHISTOCHEMICAL DETECTION; CERVICAL-CARCINOMA CELLS; HUMAN BREAST CARCINOMAS; FACTOR-RELATED PROTEINS; TRANSGENIC MICE AB It is increasingly evident that genes known to perform critical roles during early embryogenesis, particularly during stem cell renewal, pluripotentiality and survival, are also expressed during the development of cancer. In this regard, oncogenesis may be considered as the recapitulation of embryogenesis in an inappropriate temporal and spatial manner. The epidermal growth factor-Cripto-1/FRL1/cryptic family of proteins consists of extracellular and cell-associated proteins that have been identified in several vertebrate species. During early embryogenesis, epidermal growth factor-Cripto-1/FRL1/ cryptic proteins perform an obligatory role as coreceptors for the transforming growth factor-beta subfamily of proteins, which includes Nodal. Cripto-1 has also been shown to function as a ligand through a Nodal/Alk4-independent signaling pathway that involves binding to glypican-1 and the subsequent activation through src of phosphoinositol-3 kinase/Akt and ras/mitogen-activated protein kinase intracellular pathways. Expression of Cripto-1 is increased in several human cancers and its overexpression is associated with the development of mammary tumors in mice. Here, we review the role of Cripto-1 during embryogenesis, cell migration, invasion and angiogenesis and how these activities may relate to cellular transformation and tumorigenesis. We also briefly discuss evidence suggesting that Cripto-1 may be involved in stem cell maintenance. C1 NCI, Tumor Growth Factor Sect, Mammary Biol & Tumorigenesis Lab, NIH,Ctr Canc Res, Bethesda, MD 20892 USA. ITN Fdn Pascale, Div Haematol Oncol, I-80131 Naples, Italy. ITN Fdn Pascale, Dept Expt Oncol, I-80131 Naples, Italy. RP Salomon, D (reprint author), NCI, Tumor Growth Factor Sect, Mammary Biol & Tumorigenesis Lab, NIH,Ctr Canc Res, Bldg 37,Room 118B, Bethesda, MD 20892 USA. EM salomond@mail.nih.gov OI Normanno, Nicola/0000-0002-7158-2605 NR 136 TC 94 Z9 106 U1 2 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 AUG 29 PY 2005 VL 24 IS 37 BP 5731 EP 5741 DI 10.1038/sj.onc.1208918 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 958MQ UT WOS:000231452800008 PM 16123806 ER PT J AU Ruscetti, FW Akel, S Bartelmez, SH AF Ruscetti, FW Akel, S Bartelmez, SH TI Autocrine transforming growth factor-beta regulation of hematopoiesis: many outcomes that depend on the context SO ONCOGENE LA English DT Review DE transforming growth factor-beta 1; hematopoiesis; autocrine; stem cells ID PROTEIN-KINASE PATHWAY; UMBILICAL-CORD BLOOD; ACUTE MYELOBLASTIC-LEUKEMIA; HUMAN MARROW CULTURES; STEM-CELL QUIESCENCE; TRANS-RETINOIC ACID; HUMAN-BONE-MARROW; RECEPTOR-TYPE-II; TGF-BETA; PROGENITOR CELLS AB Transforming growth factor-beta (TGF-beta) is a pleiotropic regulator of all stages of hematopoieis. The three mammalian isoforms (TGF-beta 1, 2 and 3) have distinct but overlapping effects on hematopoiesis. Depending on the differentiation stage of the target cell, the local environment and the concentration and isoform of TGF-beta, in vivo or in vitro, TGF-beta can be pro- or antiproliferative, pro- or antiapoptotic, pro- or antidifferentiative and can inhibit or increase terminally differentiated cell function. TGF-beta is a major regulator of stem cell quiescence, at least in vitro. TGF-beta can act directly or indirectly through effects on the bone marrow microenvironment. In addition, paracrine and autocrine actions of TGF-beta have overlapping but distinct regulatory effects on hematopoietic stem/progenitor cells. Since TGF-beta can act in numerous steps in the hematopoietic cascade, loss of function mutations in hematopoeitic stem cells (HSC) have different effects on hematopoiesis than transient blockade of autocrine TGF-beta 1. Transient neutralization of autocrine TGF-beta in HSC has therapeutic potential. In myeloid and erythroid leukemic cells, autocrine TGF-beta 1 and/or its Smad signals controls the ability of these cells to respond to various differentiation inducers, suggesting that this pathway plays a role in determining the cell fate of leukemic cells. C1 NCI, Expt Immunol Lab, Leukocyte Biol Sect, Canc Res Ctr, Frederick, MD 21702 USA. Hashemite Univ, Dept Med Lab Sci, Zarqa, Jordan. Hemogenix Inc, Colorado Springs, CO USA. RP Ruscetti, FW (reprint author), NCI, Expt Immunol Lab, Leukocyte Biol Sect, Canc Res Ctr, Bldg 567,RM 251, Frederick, MD 21702 USA. EM Ruscettif@ncifcrf.gov FU NCI NIH HHS [N01-CO-56000] NR 141 TC 60 Z9 67 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 29 PY 2005 VL 24 IS 37 BP 5751 EP 5763 DI 10.1038/sj.onc.1208921 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 958MQ UT WOS:000231452800010 PM 16123808 ER PT J AU Alam, R Liu, ST Majumdar, A Puri, N Shahid, KA Miller, P AF Alam, R Liu, ST Majumdar, A Puri, N Shahid, KA Miller, P TI Bioactive triplex forming oligonucleotides containing RNA analogue sugar residues SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIA, Lab Mol Gerontol, Sect Gene Targeting, Baltimore, MD 21224 USA. Johns Hopkins Univ, Dept Biochem & Mol Biol, Baltimore, MD 21218 USA. EM AlamRo@grc.nia.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 54-CARB BP U679 EP U679 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797301349 ER PT J AU Appella, DH AF Appella, DH TI New paradigms for the reactivation of mutant p53 SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIDDK, DHHS, NIH, Bioorgan Chem Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 519-ORGN BP U3337 EP U3338 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797306514 ER PT J AU Appella, DH AF Appella, DH TI Functionalized polyamines that bind folded RNA SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIDDK, Bioorgan Chem Lab, US Dept HHS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 231-ORGN BP U3147 EP U3147 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797306229 ER PT J AU Barchi, JJ AF Barchi, JJ TI Progress in the synthesis and biological applications of sugar coated nanoparticles SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Natl Canc Inst, Frederick, MD 21702 USA. EM barchi@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 83-CARB BP U693 EP U694 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797301378 ER PT J AU Bash, R Wang, HD Hager, GL Yodh, J Lindsay, SM Lohr, D AF Bash, Ralph Wang, Hongda Hager, Gorden L. Yodh, Jaya Lindsay, Stuart M. Lohr, Dennis TI Tracking histones during chromatin remodeling with recognition imaging AFM SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC SP Amer Chem Soc C1 Arizona State Univ, Biodesign Inst, Tempe, AZ 85287 USA. NCI, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. Arizona State Univ, Biodesign Inst, Tempe, AZ 85287 USA. Arizona State Univ, Dept Chem & Biochem, Tempe, AZ 85287 USA. EM ralph.bash@asu.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 17-BIOL BP U511 EP U511 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797301017 ER PT J AU Bear, S AF Bear, S TI Text search anomalies and how to cope with the "tough" searches in Pubmed for your just-in-time knowledge needs SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Natl Lib Med, NIH, Bethesda, MD 20894 USA. EM soaringbear@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 15-CINF BP U1005 EP U1006 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302015 ER PT J AU Betz, JM AF Betz, JM TI Challenges in identifying and characterizing biological activity in botanical products SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. EM betzj@od.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 13-AGFD BP U9 EP U9 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797300014 ER PT J AU Brooks, BR Woodcock, HL AF Brooks, BR Woodcock, HL TI Examining reaction processes in macromollecullar systems SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM brb@nih.gov RI Woodc, Henry/D-9275-2011 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 210-PHYS BP U2868 EP U2868 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305668 ER PT J AU Bryant, SH AF Bryant, SH TI PubChem SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, NIH, Bethesda, MD 20894 USA. EM bryant@ncbi.nlm.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 22-CINF BP U1008 EP U1009 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302022 ER PT J AU Burke, TR Kang, SU Choi, WJ Shi, ZD Karki, R Phan, J Worthy, KM Bindu, L Nicklaus, MC Waugh, DS Fisher, RJ AF Burke, TR Kang, SU Choi, WJ Shi, ZD Karki, R Phan, J Worthy, KM Bindu, L Nicklaus, MC Waugh, DS Fisher, RJ TI Application of phenylphosphate mimetics to the design and synthesis of olefin metathesis-derived Grb2 SH2 domain-binding macrocycles SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA. NCI, Macromol Crystallog Lab, CCR, NIH, Frederick, MD 21702 USA. SAIC, Prot Chem Lab, Frederick, MD USA. RI Fisher, Robert/B-1431-2009 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 BP U2605 EP U2605 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305166 ER PT J AU Cai, LS Nichols, L Cuevas, J Temme, S Herman, MM Innis, RB Pike, VW AF Cai, LS Nichols, L Cuevas, J Temme, S Herman, MM Innis, RB Pike, VW TI Structure-activity relationship study of IMPY derivatives as candidate radioligands for beta-amyloid SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIMH, PET Radiopharmaceut Sci, Mol Imaging Branch, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. EM cail@intra.nimh.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 455-MEDI BP U2758 EP U2758 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305438 ER PT J AU Chan, K Isaaq, HJ Veenstra, TD AF Chan, K Isaaq, HJ Veenstra, TD TI Multidimensional separation schemes for proteomic research SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, Lab Proteom & Analyt Technol, SAIC Frederick, Frederick, MD 21702 USA. EM chan@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 313-ANYL BP U326 EP U326 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797300629 ER PT J AU Che, Y Brooks, BR Marshall, GR AF Che, Y Brooks, BR Marshall, GR TI Development of small molecules designed to modulate protein-protein interactions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63130 USA. EM chey@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 136-COMP BP U1316 EP U1316 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302648 ER PT J AU Chernomordik, LV AF Chernomordik, LV TI Membrane fusion: Universal pathways and universal inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NICHD, Lab Cellular & Mol Biophys, Sect Membrane Biol, NIH, Bethesda, MD 20878 USA. EM chemoml@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 80-COLL BP U1076 EP U1076 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302160 ER PT J AU Chinigo, GM Leal, R Elder, M Hamel, E Mooberry, SL Brown, ML AF Chinigo, GM Leal, R Elder, M Hamel, E Mooberry, SL Brown, ML TI Dihydroquinazolinones: Dual action inhibitors of cancer cell proliferation and angiogenesis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Univ Virginia, Dept Chem, Charlottesville, VA 22904 USA. Natl Canc Inst, Frederick Canc Res, Div Canc Treatment & Diagnosis, Dev Therapeut Program, Frederick, MD 21701 USA. EM gmc8s@virginia.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 372-MEDI BP U2712 EP U2713 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305356 ER PT J AU Choi, WJ Kang, SU Worthy, KM Bindu, L Fisher, R Burke, TR AF Choi, WJ Kang, SU Worthy, KM Bindu, L Fisher, R Burke, TR TI Examination of methoxy- and hydroxy-containing phosphonomethylphenylalanine residues in Grb2 SH2 domain-binding peptides SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, Med Chem Lab, CCR, Frederick, MD 21702 USA. SAIC Frederick, Prot Chem Lab, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 419-MEDI BP U2739 EP U2740 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305402 ER PT J AU Colina, CM Venkateswarlu, D Duke, RE Perera, L Darden, T Pedersen, LG AF Colina, CM Venkateswarlu, D Duke, RE Perera, L Darden, T Pedersen, LG TI Complete structural and dynamical solution equilibrated model for Tissue Factor/Factor VIIa SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. N Carolina Agr & Tech State Univ, Dept Chem, Greensboro, NC 27411 USA. Univ N Carolina, Dept Chem, Chapel Hill, NC USA. Univ N Carolina, High Performance Comp Grp, Informat Technol Serv, Chapel Hill, NC USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. EM ccolina@email.unc.edu RI Pedersen, Lee/E-3405-2013; Venkateswarlu, Divi/K-1815-2014 OI Pedersen, Lee/0000-0003-1262-9861; Venkateswarlu, Divi/0000-0003-2481-7480 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 298-COMP BP U1392 EP U1392 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302807 ER PT J AU Comin, MJ Marquez, VE AF Comin, MJ Marquez, VE TI Synthesis of functionalized bicyclo[3.1.0]hexanes by cross metathesis and intramolecular cyclopropanation: Application to the synthesis of conformationally locked carbocyclic nucleosides SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, Lab Med Chem, Canc Res Ctr, Frederick, MD 21702 USA. EM jcomin@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 678-ORGN BP U3432 EP U3432 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797306671 ER PT J AU Conforti, PF Yingling, YG Garrison, BJ AF Conforti, PF Yingling, YG Garrison, BJ TI Simulations of laser ablation of polymers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Penn State Univ, Dept Chem, University Pk, PA 16802 USA. NIH, Canc Res Ctr, Bethesda, MD 20892 USA. EM pat@chem.psu.edu RI Garrison, Barbara/P-1807-2014 OI Garrison, Barbara/0000-0002-7053-5284 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 273-PHYS BP U2899 EP U2899 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305731 ER PT J AU Costanzi, S Besada, P Joshi, BV Maddileti, S Mamedova, L Shin, DH Gonzalez-Moa, MJ Marquez, VE Jacobson, K AF Costanzi, S Besada, P Joshi, BV Maddileti, S Mamedova, L Shin, DH Gonzalez-Moa, MJ Marquez, VE Jacobson, K TI Human P2Y(6) receptor: Molecular modeling and structure-based drug design SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIDDK, Computat Chem Core Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Med, Chapel Hill, NC USA. NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. EM stefanoc@intra.niddk.nih.gov RI Jacobson, Kenneth/A-1530-2009; Besada Pereira, Pedro/E-6051-2012 OI Jacobson, Kenneth/0000-0001-8104-1493; Besada Pereira, Pedro/0000-0002-9985-9063 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA MEDI-79 BP U2551 EP U2551 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305076 ER PT J AU Dan, N AF Dan, N TI Domain formation in mixed cholesterol/lipid bilayers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Drexel Univ, Dept Chem & Biol Engn, Philadelphia, PA 19104 USA. NICHHD, Lab Cellular & Mol Biophys, Bethesda, MD 20892 USA. EM dan@cbis.ece.drexel.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 304-COLL BP U1185 EP U1185 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302382 ER PT J AU Duan, DH Lai, CC Kelley, JA Lewin, N Blumberg, PM Marquez, VE AF Duan, DH Lai, CC Kelley, JA Lewin, N Blumberg, PM Marquez, VE TI Design of C1 domain-containing isozyme-specific ligands guided by the bioassay of diacylglycerol lactone libraries SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, Canc Res Ctr, Med Chem Lab, Ft Detrick, MD 21702 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. EM dhduan1129@yahoo.com NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 221-MEDI BP U2631 EP U2632 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305211 ER PT J AU Englund, EA Appella, DH AF Englund, EA Appella, DH TI Nucleic acid molecular beacons based on Y substituted PNA SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIDDK, Bioorgan Chem Lab, US Dept HHS, NIH, Bethesda, MD 20892 USA. EM e-englund@northwestern.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 230-ORGN BP U3146 EP U3147 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797306228 ER PT J AU Etzion, Y Hinshaw, JE Danino, D AF Etzion, Y Hinshaw, JE Danino, D TI Dynamic structural transformations of dynamin assemblies upon GTP binding and hydrolysis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Technion Israel Inst Technol, Dept Biotechnol & Food Engn, Haifa, Israel. NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. Technion Israel Inst Technol, Dept Biotechnol & Food Engn, IL-32000 Haifa, Israel. EM dganitd@technion.ac.il NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 281-COLL BP U1173 EP U1174 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302359 ER PT J AU Farber, GK AF Farber, GK TI Funding opportunities in instrument and technology development at NIH SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIH, Natl Ctr Res Resources, DHHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 400-ANYL BP U367 EP U367 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797300715 ER PT J AU Francis, A Burnett, CA Shen, ZM Li, KC Danthi, N AF Francis, A Burnett, CA Shen, ZM Li, KC Danthi, N TI Novel bivalent integrin antagonist compounds SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIH, Mol Imaging Lab, Clin Ctr, Bethesda, MD 20892 USA. EM ndanthi@cc.nih.gov RI Danthi, Simhan/B-7639-2014 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA MEDI-55 BP U2537 EP U2538 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305053 ER PT J AU Gallahan, D AF Gallahan, D TI The National Cancer Institute (NCI) Alliance for Nanotechnology in Cancer SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, Div Canc Biol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 58-ANYL BP U202 EP U203 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797300384 ER PT J AU Goodwin, MB Boshoff, H Dowd, CS Barry, CE AF Goodwin, MB Boshoff, H Dowd, CS Barry, CE TI Quantification of cellular small molecule organic acids from mycobacterium tuberculosis using ion exclusion LC/MS SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIAID, TB Res Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM mgoodwin@niaid.nih.gov RI Barry, III, Clifton/H-3839-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 159-ANYL BP U251 EP U251 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797300482 ER PT J AU Gorczynski, MJ Newman, M Grembecka, J Zhou, Y Corpora, T Jeon, JP Liu, PP Sridharan, M Lilien, R Donald, BR Bushweller, JH Brown, ML AF Gorczynski, MJ Newman, M Grembecka, J Zhou, Y Corpora, T Jeon, JP Liu, PP Sridharan, M Lilien, R Donald, BR Bushweller, JH Brown, ML TI Development of an allosteric inhibitor of the protein-protein interaction between RUNX1 and CBF beta SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Univ Virginia, Dept Chem, Charlottesville, VA 22904 USA. Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22903 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Dartmouth Coll, Dept Comp Sci, Hanover, NH 03755 USA. EM mjg6d@virginia.edu RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 413-MEDI BP U2736 EP U2737 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305396 ER PT J AU Grigorenko, B Nemukhin, A Topol, IA Burt, SK AF Grigorenko, B Nemukhin, A Topol, IA Burt, SK TI Modeling dioxygen activation by nonheme iron containing enzymes SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119992, Russia. NCI, Adv Biomed Comp Ctr, Frederick, MD 21701 USA. EM bella@lcc.chem.msu.ru RI Nemukhin, Alexander/P-9662-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 358-PHYS BP U2938 EP U2938 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305816 ER PT J AU Gronenborn, AM Mangold, SL Morgan, JR Schlick, KH Strohmeyer, GC Udelhoven, RA Cloninger, MJ AF Gronenborn, AM Mangold, SL Morgan, JR Schlick, KH Strohmeyer, GC Udelhoven, RA Cloninger, MJ TI The effect of shape complementarity and affinity on interactions between carbohydrate functionalized dendrimers and lectins SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIDDK, LCP, NIH, Bethesda, MD 20892 USA. Montana State Univ, Dept Chem & Biochem, Bozeman, MT 59717 USA. Montana State Univ, Ctr Bioinspired Nanomat, Bozeman, MT 59717 USA. EM gronenborn@nih.gov; mcloninger@chemistry.montana.edu NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 263-POLY BP U4120 EP U4120 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797308260 ER PT J AU Horkay, F Basser, PJ Hecht, AM Geissler, E AF Horkay, F Basser, PJ Hecht, AM Geissler, E TI Effect of calcium ions on the structure of synthetic and biopolymer gels SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. Univ Grenoble 1, CNRS, UMR 5588, Lab Spectrometie Phys, F-38041 Grenoble, France. EM horkay@helix.nih.gov RI Basser, Peter/H-5477-2011 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 61-PMSE BP U3530 EP U3530 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797307059 ER PT J AU Horkay, F Horkayne-Szakaly, I Basser, PJ AF Horkay, F Horkayne-Szakaly, I Basser, PJ TI Compressive properties of tissue-engineered cartilage SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. EM horkay@helix.nih.gov RI Basser, Peter/H-5477-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 164-BIOL BP U579 EP U580 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797301163 ER PT J AU Hsin, LW Chang, LT Dersch, CM Rothman, RB AF Hsin, LW Chang, LT Dersch, CM Rothman, RB TI Synthesis and opioid binding affinity of (-)-octahydro-1H-benzofuro[3,2-e]isoquinolines SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Natl Taiwan Univ, Inst Pharmaceut Sci, Taipei 10018, Taiwan. NIDA, Clin Psychopharmacol Sect, IRP, NIH, Bethesda, MD 20892 USA. EM lwh@ntumc.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 163-MEDI BP U2599 EP U2599 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305156 ER PT J AU Hummer, G AF Hummer, G TI Water in hydrophobic confinement: Structure, dynamics, and function SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM Gerhard.Hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 7-COMP BP U1254 EP U1254 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302521 ER PT J AU Iera, JA Zambetti, GP Appella, DH AF Iera, JA Zambetti, GP Appella, DH TI A new family of small molecules to probe the reactivation of mutant p53 SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Northwestern Univ, Dept Chem, Bioorgan Chem Lab, NIDDK,DHHS,NIH, Bethesda, MD 20892 USA. St Jude Childrens Hosp, Dept Biochem, Memphis, TN 38101 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 434-ORGN BP U3277 EP U3278 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797306429 ER PT J AU Ito, Y AF Ito, Y TI pH-Zone-refining countercurrent chromatography: An efficient preparative separation technique for natural products SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NHLBI, Ctr Biochem & Biophys, NIH, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov NR 0 TC 0 Z9 0 U1 2 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 34-AGFD BP U20 EP U20 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797300035 ER PT J AU Jacobson, KA AF Jacobson, KA TI Neoceptor approach to unraveling microscopic interactions between G protein-coupled receptors and their agonists SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 263-MEDI BP U2653 EP U2653 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305252 ER PT J AU Jiang, S Li, P Long, YQ Lee, SL Lin, CY Dickson, RB Roller, PP AF Jiang, S Li, P Long, YQ Lee, SL Lin, CY Dickson, RB Roller, PP TI Synthesis and evaluation of analogs of sfti-1, potent inhibitors of the type II transmembrane serine protease, matriptase SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, Med Chem Lab, NIH, Ft Detrick, MD 21702 USA. NIH, NC, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20057 USA. NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. EM sjiang@ncifcrf.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 335-MEDI BP U2692 EP U2693 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305321 ER PT J AU Kang, JH Peach, ML Pu, YM Lewin, NE Blumberg, PM Marquez, VE AF Kang, JH Peach, ML Pu, YM Lewin, NE Blumberg, PM Marquez, VE TI Exploration of the sn-1 and sn-2 carbonyl functionalities reveals the essential role of the sn-1 carbonyl at the lipid interface in the binding of DAG-lactones to protein kinase C SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, Med Chem Lab, NIH, Ft Detrick, MD 21702 USA. NIH, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. EM jhkang@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 416-MEDI BP U2738 EP U2738 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305399 ER PT J AU Kang, SU Worthy, KM Bindu, L Karki, RG Nicklaus, MC Fisher, RJ Burke, TR AF Kang, SU Worthy, KM Bindu, L Karki, RG Nicklaus, MC Fisher, RJ Burke, TR TI Design and synthesis of beta-aminomethylene phosphotyrosyl mimetics and their use in the preparation of macrocyclic Grb2 SH2 domain binding inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA. SAIC Frederick, Prot Chem Lab, Frederick, MD USA. RI Fisher, Robert/B-1431-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 421-MEDI BP U2740 EP U2740 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305404 ER PT J AU Kasianowicz, JJ Stanford, VM Misakian, MM Henrickson, SE Nguyen, T Gussio, R Halverson, KM Bavari, S Panchal, RG AF Kasianowicz, JJ Stanford, VM Misakian, MM Henrickson, SE Nguyen, T Gussio, R Halverson, KM Bavari, S Panchal, RG TI Structure-function relationships of transmembrane nanopore toxins: Mechanisms of action and new applications SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Natl Inst Stand & Technol, Gaithersburg, MD 20899 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 429-ANYL BP U380 EP U381 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797300743 ER PT J AU Kelly, L Abraham, B Mullan, M AF Kelly, L Abraham, B Mullan, M TI Probing protein structure and interactions using functionalized naphthalimides SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. NIDDK, NIH, Bethesda, MD 20892 USA. EM lkelly@umbc.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 21-PHYS BP U2780 EP U2780 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305480 ER PT J AU Kim, P Zhang, YM Shenoy, G Manjunatha, U Boshoff, H Nguyen, QA Goodwin, M Miller, D White, S Duncan, K Rock, CO Barry, CE Dowd, CS AF Kim, P Zhang, YM Shenoy, G Manjunatha, U Boshoff, H Nguyen, QA Goodwin, M Miller, D White, S Duncan, K Rock, CO Barry, CE Dowd, CS TI Synthesis of 4-position hydrophilic derivatives of thiolactomycin as antitubercular agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIAID, TB Res Sect, NIH, Rockville, MD 20852 USA. St Jude Childrens Hosp, Dept Infect Dis, Memphis, TN 38101 USA. St Jude Childrens Hosp, Dept Biol Struct, Memphis, TN 38101 USA. EM pkim@niaid.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 457-MEDI BP U2759 EP U2760 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305440 ER PT J AU Kim, SK Jacobson, KA AF Kim, SK Jacobson, KA TI Computational prediction of adenosine receptor homodimerization SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. EM SooKyungK@intra.niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 241-COMP BP U1365 EP U1366 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302750 ER PT J AU Kim, YC Lee, LS Sak, K Marteau, F Mamedova, L Boeynaems, LM Jacobson, KA AF Kim, YC Lee, LS Sak, K Marteau, F Mamedova, L Boeynaems, LM Jacobson, KA TI Synthesis of pyridoxall phosphate derivatives with antagonist activity at the P2Y(13) receptor SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Gwangju Inst Sci & Technol, Dept Life Sci, Kwangju 500712, South Korea. Free Univ Brussels, Inst Interdisciplinary Res, Brussels, Belgium. NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. Erasme Univ Hosp, Dept Clin Pathol, Brussels, Belgium. EM yongchul@gist.ac.kr NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA MEDI-81 BP U2554 EP U2554 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305079 ER PT J AU Kirk, KL Cramer, J Hajduch, J Hayakawa, Y Heredia-Moya, J Narayanan, J Ye, S AF Kirk, KL Cramer, J Hajduch, J Hayakawa, Y Heredia-Moya, J Narayanan, J Ye, S TI New approaches to fluorinated heterocyclic compounds SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIDDK, Bioorgan Chem Lab, US Dept HHS, NIH, Bethesda, MD 20892 USA. EM kennethk@bdg8.niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 11-FLUO BP U1618 EP U1618 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797303237 ER PT J AU Kisker, C Truglio, JJ Rhau, B Karakas, E Croteau, DL Van Houten, B AF Kisker, C Truglio, JJ Rhau, B Karakas, E Croteau, DL Van Houten, B TI How does it cut? Insights into the incisions reactions during nucleotide excision repair SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 SUNY Stony Brook, Dept Pharmacol, Stony Brook, NY 11795 USA. NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. EM kisker@pharm.stonybrook.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 5-TOXI BP U1831 EP U1832 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797303673 ER PT J AU Klauda, JB Pastor, RW Kucerka, N Brooks, BR AF Klauda, JB Pastor, RW Kucerka, N Brooks, BR TI Refining the structure of lipid bilayers with insight from molecular dynamics simulations SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. US FDA, Biophys Lab, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. Carnegie Mellon Univ, Dept Phys, Pittsburgh, PA 15213 USA. Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA. EM klauda@helix.nih.gov RI Klauda, Jeffery/A-4345-2008 NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 296-COMP BP U1391 EP U1391 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302805 ER PT J AU Kong, YL Grembecka, J Edler, MC Hamel, E Brown, ML AF Kong, YL Grembecka, J Edler, MC Hamel, E Brown, ML TI Synthesis and structure-activity relationships of boronic acid chalcone bioisosteres of combretastatin A-4 SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Univ Virginia, Dept Chem, Charlottesville, VA 22904 USA. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis, Frederick, MD 21701 USA. EM yk4n@virginia.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 359-MEDI BP U2706 EP U2706 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305344 ER PT J AU Korte, BJ AF Korte, BJ TI Funding opportunities in biomedical imaging and bioengineering at the NIH SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIH, Div Discovery Sci & Technol, Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. EM kortebr@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 434-ANYL BP U382 EP U383 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797300747 ER PT J AU Krajewski, K Marchand, C Pommier, Y Roller, PP AF Krajewski, K Marchand, C Pommier, Y Roller, PP TI HIV-1 integrase inhibitory peptides: Cyclization, dimerization, tetramerization and peptide inhibitory potency SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. NCI, Mol Pharmacol Lab, NIH, Frederick, MD 21702 USA. EM krajewsk@helix.nih.gov RI Marchand, Christophe/D-8559-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 186-MEDI BP U2613 EP U2614 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305178 ER PT J AU Kulkarni, SS Nightingale, B Dersch, CM Rothman, RB Newman, AH AF Kulkarni, SS Nightingale, B Dersch, CM Rothman, RB Newman, AH TI Design and synthesis of novel rnGluR5 antagonists SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIDA, IRP, NIH, DHHS,Clin Psychopharmacol Sect, Baltimore, MD 21224 USA. EM Skulkami@intra.nida.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 51-MEDI BP U2533 EP U2534 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305049 ER PT J AU Lewis, CD AF Lewis, CD TI NIH Programs in single molecule biophysics, cellular imaging, and nanoscience SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Natl Inst Gen Med Sci, NIH, Bethesda, MD 20892 USA. EM lewisc@nigms.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 276-ANYL BP U308 EP U308 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797300593 ER PT J AU Liang, HJ Harries, D Wong, GCL AF Liang, HJ Harries, D Wong, GCL TI Self-assembly between DNA and anionic membranes SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Univ Illinois, Dept Mat Sci & Engn, Urbana, IL 61801 USA. Univ Illinois, Dept Phys & Bioengn, Urbana, IL 61801 USA. NIH, Lab Phys & Struct Biol, Bethesda, MD 20892 USA. EM gclwong@uiuc.edu RI Liang, Hongjun/K-2460-2012 OI Liang, Hongjun/0000-0003-0864-9106 NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 75-PMSE BP U3537 EP U3537 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797307073 ER PT J AU Liu, F Oishi, S Karki, RG Shi, ZD Worthy, KM Bindu, L Maderia, M Nicklaus, MC Barchi, JJ Fisher, RJ Burke, TR AF Liu, F Oishi, S Karki, RG Shi, ZD Worthy, KM Bindu, L Maderia, M Nicklaus, MC Barchi, JJ Fisher, RJ Burke, TR TI High affinity Grb2 SH2 domain-binding macrocycles derived from ring-closing metathesis of alkenylglycine residues with beta-vinyl phosphotyrosyl mimetics SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, Med Chem Lab, CCR, Frederick, MD 21702 USA. NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. SAIC Frederick, Prot Chem Lab, Frederick, MD USA. EM liuf@ncifcrf.gov RI Fisher, Robert/B-1431-2009 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 420-MEDI BP U2740 EP U2740 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305403 ER PT J AU Manimala, JC Li, ZT Roach, T Gildersleeve, JC AF Manimala, JC Li, ZT Roach, T Gildersleeve, JC TI Carbohydrate microarrays in cancer research SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, Med Chem Lab, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 4-CARB BP U654 EP U655 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797301301 ER PT J AU McCloud, TG AF McCloud, TG TI High throughput extraction of plants for preservation of biologically active molecules SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, SAIC Frederick, Appl Dev Res Support Program, Frederick, MD 21702 USA. EM mccloud@dtpax2.ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 49-AGFD BP U27 EP U27 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797300049 ER PT J AU Michelman-Ribeiro, A Boukari, H Nossal, R Horkay, F AF Michelman-Ribeiro, A Boukari, H Nossal, R Horkay, F TI Probe diffusion in PVA solutions and gels studied by fluorescence correlation spectroscopy SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Integrat & Med Biophys, Bethesda, MD 20892 USA. EM michelma@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 345-POLY BP U4158 EP U4158 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797308342 ER PT J AU Moore, S Jaeschke, H Neumann, S Jiang, JK Thomas, CJ Krause, G Pashke, R Raaka, BM Gershengorn, MC AF Moore, S Jaeschke, H Neumann, S Jiang, JK Thomas, CJ Krause, G Pashke, R Raaka, BM Gershengorn, MC TI Identification of the first low molecular weight antagonists for the thyroid stimulating hormone receptor with therapeutic potential for hyperthyroidism SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Chem Biol Core Facil, NIH, Bethesda, MD 20892 USA. NIDDK, Chem Biol Core, NIH, Bethesda, MD 20892 USA. Univ Leipzig, Med Klin & Poliklin 3, D-7010 Leipzig, Germany. EM mooresu@niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 111-BIOL BP U554 EP U554 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797301110 ER PT J AU Nemukhin, A Grigorenko, B Topol, IA Burt, SK AF Nemukhin, A Grigorenko, B Topol, IA Burt, SK TI QM/MM potential energy surfaces for modeling mechanisms of enzymatic reactions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119992, Russia. NCI, Adv Biomed Comp Ctr, Frederick, MD 21701 USA. EM anem@lcc.chem.msu.ru RI Nemukhin, Alexander/P-9662-2015 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 383-PHYS BP U2949 EP U2949 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305840 ER PT J AU Nicklaus, MC Sitzmann, M Filippov, IV AF Nicklaus, MC Sitzmann, M Filippov, IV TI Open access chemical-information and computer-aided drug design resources SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, CCR, Med Chem Lab, NIH,US Dept HHS, Frederick, MD 21702 USA. EM mnl@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 25-CINF BP U1009 EP U1010 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302024 ER PT J AU Parsons, LM Orban, J AF Parsons, LM Orban, J TI Solution structure of peptidoglycan associated lipoprotein from Haemophilus influenzae bound to UDP-N-acetylmuramyl pentapeptide SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIH, Phys Chem Lab, Bethesda, MD 20892 USA. Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, College Pk, MD 20742 USA. EM lmp123@gmail.com NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 204-BIOL BP U597 EP U597 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797301200 ER PT J AU Peach, ML Kang, JH Pu, YM Lewin, NE Blumberg, PM Nicklaus, MC Marquez, VE AF Peach, ML Kang, JH Pu, YM Lewin, NE Blumberg, PM Nicklaus, MC Marquez, VE TI Modeling the binding of DAG-lactones to protein kinase C at the lipid interface SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, SAIC Frederick Inc, Basic Res Program, Ft Detrick, MD 21702 USA. NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. EM mpeach@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 415-MEDI BP U2737 EP U2738 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305398 ER PT J AU Petrache, HI Brown, MF AF Petrache, HI Brown, MF TI Universal features of lipid packing as determined by solid state 2H NMR spectroscopy SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIH, Lab Phys & Struct Biol, Bethesda, MD 20892 USA. Univ Arizona, Dept Chem, Tucson, AZ 85721 USA. EM petrachh@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 394-COLL BP U1229 EP U1229 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302472 ER PT J AU Pike, VW Briard, E Simeon, FG Shetty, HU Lee, YS AF Pike, VW Briard, E Simeon, FG Shetty, HU Lee, YS TI Rotational barriers in the peripheral benzodiazepine receptor ligand, PK 11195: Determination by quantum chemistry and NMR SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. EM pikev@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 38-MEDI BP U2525 EP U2525 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305036 ER PT J AU Pokorski, JK Appella, DH AF Pokorski, JK Appella, DH TI (S,S)-trans-cyclopentane PNA: An optimized probe for nucleic acid detection SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIDDK, Bioorgan Chem Lab, US Dept HHS, NIH, Bethesda, MD 20892 USA. EM pokorskij@niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 298-ORGN BP U3193 EP U3194 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797306296 ER PT J AU Rasaiah, JC Vaitheeswaran, S Yin, H Hummer, G AF Rasaiah, JC Vaitheeswaran, S Yin, H Hummer, G TI Water clusters in nonpolar cavities SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Univ Maine, Orono, ME 04469 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM rasaiah@maine.edu RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 278-PHYS BP U2901 EP U2902 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305736 ER PT J AU Rau, EH AF Rau, EH TI Howard Faucett Award. Potential applications of strategies from an institutional mercury reduction campaign to develop a national public health initiative for reducing human exposure SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIH, Environm Protect Branch, US Dept HHS, Bethesda, MD 20892 USA. EM erau@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 5-CHAS BP U718 EP U719 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797301437 ER PT J AU Rispin, A AF Rispin, Amy TI Performance standards for quality assurance of validated alternative test methods SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC SP Amer Chem Soc C1 US EPA, OPP, Washington, DC 20460 USA. NIEHS, Div Intramural Res, Res Triangle Pk, NC 27709 USA. EM rispin.amy@epa.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 64-CINF BP U1027 EP U1027 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302061 ER PT J AU Schloss, JA AF Schloss, JA TI Programs in nanotechnology at NIH and single molecule analysis at NHGRI SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NHGRI, NIH, Bethesda, MD 20892 USA. EM jeff_schloss@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 307-ANYL BP U322 EP U323 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797300623 ER PT J AU Simeon, FG Patterson, VM Chin, FT Innis, RB Pike, VW AF Simeon, FG Patterson, VM Chin, FT Innis, RB Pike, VW TI Synthesis of an easily F-18-labeled and high affinity candidate radioligand for PET imaging of brain mGluR5 receptors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. EM simeonf@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 49-MEDI BP U2532 EP U2533 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305047 ER PT J AU Stern, JV Knight, J Horkay, F Basser, PJ AF Stern, JV Knight, J Horkay, F Basser, PJ TI Ion-exchange in charged deformable polymer gels: A theoretical modeling framework SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA. SUNY Stony Brook, Dept Phys, Stony Brook, NY 11794 USA. Australian Natl Univ, CSIRO Land & Water, Canberra, ACT, Australia. NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. EM jvstern@aol.com RI Basser, Peter/H-5477-2011; Knight, John/A-3795-2008 OI Knight, John/0000-0001-7170-7482 NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 259-PHYS BP U2892 EP U2892 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305717 ER PT J AU Sun, GY AF Sun, GY TI Linear-response study on the binding affinity of non-nucleoside RT inhibitors with HIV-1 reverse transcriptase SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 BP U2611 EP U2611 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305174 ER PT J AU Sun, GY Nicklaus, MC Simmons, DP Lai, LY AF Sun, GY Nicklaus, MC Simmons, DP Lai, LY TI Molecular modeling study of binding between DNA and CC-1065 analogue SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, Med Chem Lab, CCR, NIH, Ft Detrick, MD 21702 USA. NCI, Lab Cellular Carcinogenesis & Tumor Promot, CCR, NIH, Ft Detrick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 191-COMP BP U1342 EP U1342 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302701 ER PT J AU Sun, HY Qin, DG Nikolovska-Coleska, Z Yang, CY Kumar, S Gao, W Qiu, S Lu, JF Tomita, Y Roller, PP Wang, SM AF Sun, HY Qin, DG Nikolovska-Coleska, Z Yang, CY Kumar, S Gao, W Qiu, S Lu, JF Tomita, Y Roller, PP Wang, SM TI Design, synthesis and evaluation of conformationally restricted Smac mimetics as inhibitors of IAP family proteins SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA. Georgetown Univ, Vincent T Lombardi Canc Res Ctr, Washington, DC 20057 USA. NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 446-MEDI BP U2753 EP U2754 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305429 ER PT J AU Sweedler, JV Jurchen, JC Monroe, E Rubakhin, S AF Sweedler, JV Jurchen, JC Monroe, E Rubakhin, S TI Mass spectrometry in the brain: From single cells to imaging SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIH, Div Discovery Sci & Technol, Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. EM sweedler@scs.uiuc.edu RI Rubakhin, Stanislav/E-6685-2017 OI Rubakhin, Stanislav/0000-0003-0437-1493 NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 433-ANYL BP U382 EP U382 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797300746 ER PT J AU Talanova, GG Vedernikova, EY Staunton, EA Talanov, VS AF Talanova, GG Vedernikova, EY Staunton, EA Talanov, VS TI Application of dye-calix[4]arene supramolecular complexes in optical recognition of metal ions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Howard Univ, Dept Chem, Washington, DC 20059 USA. NCI, Radiat Oncol Branch, Ctr Res, NIH, Bethesda, MD 20892 USA. EM gtalanova@howard.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 110-INOR BP U2065 EP U2066 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797304110 ER PT J AU Talanova, GG Buie, NM Talanov, VS AF Talanova, GG Buie, NM Talanov, VS TI New fluorogenic dansyl-containing calix[4]arene in paco conformation for selective recognition of Pb2+ SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Howard Univ, Dept Chem, Washington, DC 20059 USA. NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gtalanova@howard.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 108-INOR BP U2064 EP U2065 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797304108 ER PT J AU Talanova, GG Buie, NM Roper, ED Gorbunova, MG Bartsch, RA Talanov, VS AF Talanova, GG Buie, NM Roper, ED Gorbunova, MG Bartsch, RA Talanov, VS TI New fluorogenic calixarene- and calixcrown-based ionophores for optical sensing of hazardous metal ions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Howard Univ, Dept Chem, Washington, DC 20059 USA. Texas Tech Univ, Oak Ridge Natl Lab, Lubbock, TX USA. Texas Tech Univ, Dept Chem & Biochem, Lubbock, TX 79409 USA. NCI, Radiat Oncol Branch, Canc Res Ctr, NIH, Bethesda, MD USA. EM gtalanova@howard.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 14-INOR BP U2006 EP U2006 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797304014 ER PT J AU Wang, SM Ding, K Lu, YP Nikolovska-Coleska, Z Qiu, S Kumar, S Roller, PP Tomita, Y Krajewski, K Deschamps, JR AF Wang, SM Ding, K Lu, YP Nikolovska-Coleska, Z Qiu, S Kumar, S Roller, PP Tomita, Y Krajewski, K Deschamps, JR TI Structure-based design of potent, non-peptide small-molecule inhibitors of the MDM2-p53 interaction starting from an inactive lead SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA. NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Lombardi Canc Ctr, Washington, DC 20057 USA. EM shaomeng@umich.edu RI Ding, Ke/B-3257-2010 NR 0 TC 1 Z9 2 U1 1 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 349-MEDI BP U2700 EP U2700 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305335 ER PT J AU Witschi, MA Appella, DH AF Witschi, MA Appella, DH TI Cyclopentane-modified peptide nucleic acids (PNA): Synthesis and properties SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIDDK, Lab Bioorgan Chem, DHHS, NIH, Bethesda, MD 20892 USA. EM witschim@niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 735-ORGN BP U3460 EP U3461 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797306728 ER PT J AU Yadavalli, VK Forbes, JG Wang, K AF Yadavalli, VK Forbes, JG Wang, K TI Studying the elasticity and structure of single muscle proteins on self-assembled monolayers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIAMS, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. EM yadavalv@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 282-COLL BP U1174 EP U1174 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302360 ER PT J AU Yang, W AF Yang, W TI Translesion DNA synthesis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIH, Mol Biol Lab, Bethesda, MD 20892 USA. EM wei.yang@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 7-TOXI BP U1832 EP U1833 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797303675 ER PT J AU Zaharevitz, DW AF Zaharevitz, DW TI Chemical and biological data from DTP/NCI SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NCI, Informat Technol Branch, Dev Therapeut Program, EPN, Bethesda, MD 20892 USA. EM zaharevitz@dtpax2.ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 34-CINF BP U1014 EP U1014 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797302032 ER PT J AU Zou, MF Cao, JJ Kopajtic, T Desai, R Katz, JL Newman, AH AF Zou, MF Cao, JJ Kopajtic, T Desai, R Katz, JL Newman, AH TI Synthesis and binding profile of a novel series of (S)-2 beta-substituted-4 ',4 '' difluorobenztropine analogs SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 230th National Meeting of the American-Chemical-Society CY AUG 28-SEP 01, 2005 CL Washington, DC C1 NIDA, Med Chem Sect, IRP, NIH,DHHS, Baltimore, MD 21224 USA. NIDA, Psychobiol Sect, IRP, NIH,DHHS, Baltimore, MD 21224 USA. EM mzou@intra.nida.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 28 PY 2005 VL 230 MA 458-MEDI BP U2760 EP U2760 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 032TJ UT WOS:000236797305441 ER PT J AU Miyoshi, N Naniwa, K Kumagai, T Uchida, K Osawa, T Nakamura, Y AF Miyoshi, N Naniwa, K Kumagai, T Uchida, K Osawa, T Nakamura, Y TI alpha-Tocopherol-mediated caspase-3 up-regulation enhances susceptibility to apoptotic stimuli SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE alpha-tocopherol; caspase-3; apoptosis; Sp 1; etoposide ID LOW-DENSITY-LIPOPROTEIN; VITAMIN-E-SUCCINATE; SMOOTH-MUSCLE-CELL; PROTEIN-KINASE-C; NEURONAL APOPTOSIS; CANCER CELLS; EXPRESSION; ACTIVATION; PROLIFERATION; MITOCHONDRIA AB Although alpha-tocopherol is known as an essential micronutrient involved in various oxidative stress-related processes, its non-antioxidant activities have only been characterized in recent years. In this study, we reveal that (+)-alpha-tocopherol [RRR-alpha-tocopherol] enhances cellular susceptibility to both oxidative and non-oxidative apoptosis-inducing stimuli through up-regulation of caspase-3/ CPP32 expression in several human cell lines. Exposure of (+)-alpha-tocopherol pretreated cells to known apoptosis-inducing stimuli, such as Fas, H2O2, or etoposide, resulted in an increase in cellular apoptotsis. In addition, (+)-alpha-tocopherol also elevated the procaspase-3 protein level and mRNA expression in a time- and dose-dependent manner, while other tocopherol analogues showed no effect. Experiments using a GC-specific DNA binding agent, mithramycin A, and an electrophoretic mobility shift assay demonstrated that Sp1 might mediate the enhanced expression of caspase-3. Our results also confirmed that (+)-a-tocopherol promotes the expression, but not the activation, of caspase-3 in various human cell lines. These findings provide biological evidence showing that (+)-alpha-tocopherol can amplify the apoptotic response by up-regulating the expression of pro-caspase-3. (c) 2005 Elsevier Inc. All rights reserved. C1 Nagoya Univ, Grad Sch Bioagr Sci, Lab Food & Biodynam, Nagoya, Aichi 4648601, Japan. NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Kitasato Univ, Sch Pharmaceut Sci, Lab Hyg Chem, Tokyo 1088641, Japan. Okayama Univ, Grad Sch Nat Sci & Technol, Div Biosci, Dept Biofunct Chem, Okayama 7008530, Japan. RP Nakamura, Y (reprint author), Nagoya Univ, Grad Sch Bioagr Sci, Lab Food & Biodynam, Nagoya, Aichi 4648601, Japan. EM yossan@cc.okayama-u.ac.jp RI Miyoshi, Noriyuki/F-4554-2010 NR 31 TC 16 Z9 17 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 26 PY 2005 VL 334 IS 2 BP 466 EP 473 DI 10.1016/j.bbrc.2005.06.113 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 950TI UT WOS:000230880200024 PM 16009347 ER PT J AU Bibillo, A Lener, D Tewari, A Le Grice, SFJ AF Bibillo, A Lener, D Tewari, A Le Grice, SFJ TI Interaction of the Ty3 reverse transcriptase thumb subdomain with template-primer SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; DOUBLE-STRANDED DNA; POLYMERASE ACTIVE-SITE; GROOVE-BINDING TRACK; VERTICAL-SCANNING MUTAGENESIS; NUCLEIC ACID INTERACTIONS; MURINE LEUKEMIA-VIRUS; RNASE-H DOMAIN; POLYPURINE TRACT; MINOR-GROOVE AB Amino acid sequence alignment was used to identify the putative thumb subdomain of reverse transcriptase ( RT) from the Saccharomyces cerevisiae long terminal repeat-containing retrotransposon Ty3. The counterpart to helix alpha H of human immunodeficiency virus type 1 ( HIV-1) RT, which mediates important interactions with a duplex nucleic acid similar to 3 - 6 bp behind the DNA polymerase catalytic center, was identified between amino acids 290 and 298 of the Ty3 enzyme. The consequences of substituting Ty3 RT Gln(290), Phe(292), Gly(294), Asn(297), and Tyr(298) ( the counterparts of HIV-1 RT Gln(258), Leu(260), Gly(262), Asn(265), and Trp(266), respectively) for both DNA polymerase and RNase H activities were examined. DNA-dependent DNA synthesis was evaluated on unmodified substrates and on duplexes containing targeted insertion of locked nucleic acid analogs and abasic lesions in either the template or primer. Based on this combined strategy, our data suggest an interaction of Ty3 RT Tyr298 with primer nucleotide - 3, Gly294 with primer nucleotide - 4, and Asn297 with template nucleotide - 6. Substitution of Ala for Gln290 was well tolerated, despite the high degree of conservation at this position. Mutations in the thumb subdomain of Ty3 also affected RNase H activity, suggesting a closer spatial relationship between its N- and C-terminal catalytic centers compared with HIV-1 RT. C1 NCI, Reverse Transcriptase Biochem Sect, Resistance Mech Lab, HIV Drug Resistance Program,NIH, Frederick, MD 21702 USA. RP Le Grice, SFJ (reprint author), NCI, Reverse Transcriptase Biochem Sect, Resistance Mech Lab, HIV Drug Resistance Program,NIH, Bldg 535, Frederick, MD 21702 USA. EM slegrice@ncifcrf.gov NR 59 TC 9 Z9 9 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 AUG 26 PY 2005 VL 280 IS 34 BP 30282 EP 30290 DI 10.1074/jbc.M502457200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 957IC UT WOS:000231362500037 PM 15944162 ER PT J AU Bi, YM Stuelten, CH Kilts, T Wadhwa, S Iozzo, RV Robey, PG Chen, XD Young, MF AF Bi, YM Stuelten, CH Kilts, T Wadhwa, S Iozzo, RV Robey, PG Chen, XD Young, MF TI Extracellular matrix proteoglycans control the fate of bone marrow stromal cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR-BETA; OSTEOPOROSIS-LIKE PHENOTYPE; TGF-BETA; STEM-CELLS; IN-VITRO; TARGETED DISRUPTION; NEGATIVE REGULATION; DEFICIENT MICE; DECORIN; EXPRESSION AB Extracellular matrix glycoproteins and proteoglycans bind a variety of growth factors and cytokines thereby regulating matrix assembly as well as bone formation. However, little is known about the mechanisms by which extracellular matrix molecules modulate osteogenic stem cells and bone formation. Using mice deficient in two members of the small leucine-rich proteoglycans, biglycan and decorin, we uncovered a role for these two extracellular matrix proteoglycans in modulating bone formation from bone marrow stromal cells. Our studies showed that the absence of the critical transforming growth factor-beta (TGF-beta)-binding proteoglycans, biglycan and decorin, prevents TGF-beta from proper sequestration within the extracellular matrix. The excess TGF-beta directly binds to its receptors on bone marrow stromal cells and overactivates its signaling transduction pathway. Overall, the predominant effect of the increased TGF-beta signaling in bgn/dcn-deficient bone marrow stromal cells is a "switch in fate" from growth to apoptosis, leading to decreased numbers of osteoprogenitor cells and subsequently reduced bone formation. Thus, biglycan and decorin appear to be essential for maintaining an appropriate number of mature osteoblasts by modulating the proliferation and survival of bone marrow stromal cells. These findings underscore the importance of the micro-environment in controlling the fate of adult stem cells and reveal a novel cellular and molecular basis for the physiological and pathological control of bone mass. C1 NIDCR, Craniofacial & Skeletal Dis Branch, Bethesda, MD 20892 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Pathol, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Anat, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Cell Biol, Philadelphia, PA 19107 USA. RP Chen, XD (reprint author), Univ Arkansas, Coll Med, 4301 W Markam Str,Slot 587, Little Rock, AR 72205 USA. EM xdchen@uams.edu; myoung@dir.nidcr.nih.gov RI Robey, Pamela/H-1429-2011; OI Robey, Pamela/0000-0002-5316-5576; Iozzo, Renato/0000-0002-5908-5112 NR 67 TC 153 Z9 161 U1 1 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 26 PY 2005 VL 280 IS 34 BP 30481 EP 30489 DI 10.1074/jbc.M500573200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 957IC UT WOS:000231362500061 PM 15964849 ER PT J AU Toth, J Kovacs, M Wang, F Nyitray, L Sellers, JR AF Toth, J Kovacs, M Wang, F Nyitray, L Sellers, JR TI Myosin V from Drosophila reveals diversity of motor mechanisms within the myosin V family SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID KINETIC MECHANISM; 50/20-KDA JUNCTION; NUCLEOTIDE-BINDING; FLUORESCENT-PROBE; MOLECULAR MOTOR; ATPASE ACTIVITY; REAL-TIME; ACTIN; ACTOMYOSIN; DOMAIN AB Myosin V is the best characterized vesicle transporter in vertebrates, but it has been unknown as to whether all members of the myosin V family share a common, evolutionarily conserved mechanism of action. Here we show that myosin V from Drosophila has a strikingly different motor mechanism from that of vertebrate myosin Va, and it is a nonprocessive, ensemble motor. Our steady-state and transient kinetic measurements on single-headed constructs reveal that a single Drosophila myosin V molecule spends most of its mechanochemical cycle time detached from actin, therefore it has to function in processive units that comprise several molecules. Accordingly, in in vitro motility assays, double-headed Drosophila myosin V requires high surface concentrations to exhibit a continuous translocation of actin filaments. Our comparison between vertebrate and fly myosin V demonstrates that the well preserved function of myosin V motors in cytoplasmic transport can be accomplished by markedly different underlying mechanisms. C1 NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. Eotvos Lorand Univ, Dept Biochem, H-1117 Budapest, Hungary. RP Sellers, JR (reprint author), NHLBI, Lab Mol Physiol, NIH, 9000 Rockville Pike,Bldg 10,Rm 8N202,MSC 1762, Bethesda, MD 20892 USA. EM sellersj@nhlbi.nih.gov RI Kovacs, Mihaly/A-6841-2011 NR 48 TC 35 Z9 35 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 AUG 26 PY 2005 VL 280 IS 34 BP 30594 EP 30603 DI 10.1074/jbc.M505209200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 957IC UT WOS:000231362500076 PM 15980429 ER PT J AU Balboni, G Cocco, MT Salvadori, S Romagnoli, R Sasaki, Y Okada, Y Bryant, SD Jinsmaa, Y Lazarus, LH AF Balboni, G Cocco, MT Salvadori, S Romagnoli, R Sasaki, Y Okada, Y Bryant, SD Jinsmaa, Y Lazarus, LH TI From the potent and selective mu opioid receptor agonist H-Dmt-D-Arg-Phe-Lys-NH2 to the potent delta antagonist H-Dmt-Tic-Phe-Lys(Z)-OH SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DMT-TIC PHARMACOPHORE; HIGHLY POTENT; ANALOGS; MICE; NALTRINDOLE; DERMORPHIN; DEPENDENCE; TOLERANCE; ANALGESIA; PEPTIDES AB H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt(1)]DALDA) binds with high affinity and selectivity to the mu opioid receptor and is a potent and long-acting analgesic. Substitution of D-Arg in position 2 with Tic and masking of the lysine amine side chain by Z protection and of the C-terminal carboxylic function instead of the amide function transform a potent and selective mu agonist into a potent and selective delta antagonist H-Dmt-Tic-Phe-Lys(Z)-OH. Such a delta antagonist could be used as a pharmacological tool. C1 Univ Cagliari, Dept Toxicol, I-09124 Cagliari, Italy. Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy. Tohoku Pharmaceut Univ, Aoba Ku, Sendai, Miyagi 9818558, Japan. Kobe Gakuin Univ, Fac Pharmaceut Sci, Dept Med Chem, Kobe, Hyogo 6512180, Japan. Kobe Gakuin Univ, High Technol Res Ctr, Kobe, Hyogo 6512180, Japan. NIEHS, Lab Pharmacol & Chem, Med Chem Grp, Res Triangle Pk, NC 27709 USA. RP Balboni, G (reprint author), Univ Cagliari, Dept Toxicol, I-09124 Cagliari, Italy. EM gbalboni@unica.it RI Romagnoli, Romeo/G-9887-2015 NR 22 TC 5 Z9 5 U1 0 U2 1 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 AUG 25 PY 2005 VL 48 IS 17 BP 5608 EP 5611 DI 10.1021/jm0504959 PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 958PG UT WOS:000231459600027 PM 16107162 ER PT J AU Klauda, JB Pastor, RW Brooks, BR AF Klauda, JB Pastor, RW Brooks, BR TI Adjacent gauche stabilization in linear alkanes: Implications for polymer models and conformational analysis SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Letter ID MOLECULAR SIMULATIONS; AB-INITIO; ENERGIES AB High-level ab initio quantum mechanical calculations are used to study various gauche conformational energies of n-pentane to n-decane. The destabilizing "pentane effect" (adjacent gauche states of opposite sign) for alkanes is confirmed, but the energies were found to depend slightly on chain length. In contrast, introducing an adjacent gauche of the same sign requires only 0.22-0.37 kcal/mol, approximately half of the single gauche state energy. This adjacent gauche stabilization should be taken into account when formulating or analyzing rotational isomeric models, carrying out conformational analysis, and developing force fields for alkanes, lipids, and related polymers. C1 NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. US FDA, Biophys Lab, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Klauda, JB (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM klauda@helix.nih.gov RI Klauda, Jeffery/A-4345-2008 FU NHLBI NIH HHS [Z01 HL001051-08] NR 13 TC 42 Z9 43 U1 2 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD AUG 25 PY 2005 VL 109 IS 33 BP 15684 EP 15686 DI 10.1021/jp0527608 PG 3 WC Chemistry, Physical SC Chemistry GA 958DX UT WOS:000231426000005 PM 16852989 ER PT J AU Donehower, LA French, JE Hursting, SD AF Donehower, LA French, JE Hursting, SD TI The utility of genetically altered mouse models for cancer research SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Editorial Material C1 Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. NIEHS, Res Triangle Pk, NC 27709 USA. NCI, Bethesda, MD 20892 USA. RP Donehower, LA (reprint author), Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. EM larryd@bcm.tmc.edu NR 4 TC 1 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD AUG 25 PY 2005 VL 576 IS 1-2 BP 1 EP 3 DI 10.1016/j.mrfmmm.2005.04.007 PG 3 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 953SN UT WOS:000231100900001 PM 15982676 ER PT J AU Calvo, A Gonzalez-Moreno, O Yoon, CY Huh, JI Desai, K Nguyen, QT Green, JE AF Calvo, A Gonzalez-Moreno, O Yoon, CY Huh, JI Desai, K Nguyen, QT Green, JE TI Prostate cancer and the genomic revolution: Advances using microarray analyses SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Review DE cDNA microarrays; prostate cancer; gene expression profiling ID LASER-CAPTURE-MICRODISSECTION; GENE-EXPRESSION PROFILES; ANDROGEN-RESPONSIVE GENES; INTRAEPITHELIAL NEOPLASIA; VENTRAL PROSTATE; BREAST-CANCER; UP-REGULATION; COA RACEMASE; CPG ISLAND; NOBLE RAT AB The emerging technology of microarray analysis allows the establishment of molecular portraits of prostate cancer and the discovery of novel genes involved in the carcinogenesis process. Many novel genes have already been identified using this technique, and functional analyses of these genes are currently being tested. The combination of microarray analysis with other recently developed high-throughput techniques, such as protcomics, tissue arrays, and gene promoter-methylation, especially using tissue microdissection methods, will provide us with more comprehensive insights into how prostate cancer develops and responds to gene-targeted therapies. Animal models of prostate cancer are being characterized by high throughput techniques to better define the similarities and differences between those models and the human disease, and to determine whether particular models may be useful for specific targeted therapies in pre-clinical studies. Although profiling of mRNA expression provides important information of gene expression, the development of proteomic technologies will allow for an even more precise global insight into cellular signaling and structural alterations during prostate carcinogenesis. Not only will the "omic" revolution change basic science, but it will lead to a new era of molecular medicine. Published by Elsevier B.V. C1 NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Univ Navarra, Ctr Appl Med Res, Div Oncol, E-31080 Pamplona, Spain. Univ Navarra, Dept Histol & Pathol, E-31080 Pamplona, Spain. Korea Univ, Coll Med, Dept Urol, Seoul 136701, South Korea. RP Green, JE (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bldg 41,Room C629,41 Lib Dr, Bethesda, MD 20892 USA. EM jegreen@nih.gov NR 82 TC 10 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD AUG 25 PY 2005 VL 576 IS 1-2 BP 66 EP 79 DI 10.1016/j.mrfmmm.2004.08.019 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 953SN UT WOS:000231100900006 PM 15950992 ER PT J AU Hursting, SD Nunez, NP Patel, AC Perkins, SN Lubet, RA Barrett, JC AF Hursting, SD Nunez, NP Patel, AC Perkins, SN Lubet, RA Barrett, JC TI The utility of genetically altered mouse models for nutrition and cancer chemoprevention research SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Review DE chemoprevention; mouse models; cancer-related genes; molecular targets; diet; energy balance ID SELECTIVE CYCLOOXYGENASE-2 INHIBITOR; INTESTINAL POLYP DEVELOPMENT; TUMOR-SUPPRESSOR GENES; TRANSGENIC MICE; CALORIE RESTRICTION; P53-DEFICIENT MICE; PROSTATE-CANCER; BREAST-CANCER; SPONTANEOUS TUMORIGENESIS; DIETARY RESTRICTION AB The development of effective cancer preventive interventions is being enhanced by the use of relevant animal models to confirm, refine, and extend potential leads from clinical and epidemiologic studies. In particular, genetically altered mice, with specific cancer-related genes modulated, are providing powerful tools for studying carcinogenesis, as well as important conduits for translating basic research findings from the laboratory bench to the bedside. This review explores the utility of genetically altered mice for developing cancer preventive strategies that can offset increased cancer susceptibility resulting from specific genetic lesions. Examples will focus on preventing cancer by dietary interventions, particularly obesity prevention/energy balance modulation, as well as chemoprevention, in mice with alterations in genes such as the p53 or Apc tumor suppressors, components of the ErbB pathway, and other pathways frequently altered in human cancer. Published by Elsevier B.V. C1 NCI, Off Prevent Oncol, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Hursting, SD (reprint author), NCI, Off Prevent Oncol, Div Canc Prevent, 6130 Execut Blvd, Bethesda, MD 20892 USA. EM hurstins@mail.nih.gov NR 86 TC 17 Z9 17 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD AUG 25 PY 2005 VL 576 IS 1-2 BP 80 EP 92 DI 10.1016/j.mrfmmm.2004.11.019 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 953SN UT WOS:000231100900007 PM 15990122 ER PT J AU Letterio, JJ AF Letterio, JJ TI Disruption of the TGF-beta pathway and modeling human cancer in mice SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Review DE TGF-beta; cancer; SMAD; signaling; inflammation ID GROWTH-FACTOR-BETA; TUMOR-SUPPRESSOR SMAD4/DPC4; SMAD3 MUTANT MICE; COLON-CANCER; T-CELLS; TRANSFORMING GROWTH-FACTOR-BETA-1; KNOCKOUT MICE; GASTROINTESTINAL TUMORIGENESIS; LYMPHOBLASTIC-LEUKEMIA; TARGETED DISRUPTION AB There is considerable complexity underlying the mechanisms through which the TGF-beta signaling pathway regulates the initiation and progression of cancer. Analysis of this pathway and the role that it plays in human malignancy continues to elucidate novel mechanisms through which various genetic and epigenetic events subvert the controls that TGF-beta exerts over cell growth, differentiation, and malignant transformation. Modeling these events in the mouse represents an important goal, as the relevant preclinical models are essential not only for improving our understanding of the role of the TGF-beta pathway in the molecular pathogenesis of cancer, but also as tools for evaluating the impact of novel therapeutics on TGF-beta signaling and the role they may play in the prevention and treatment of malignancies. Here, we consider highlights from a number of in vivo murine model systems and relate a few of the significant observations to what we know about TGF-beta signaling in human cancer. (c) 2005 Published by Elsevier B.V. C1 NCI, Ctr Canc Res, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Letterio, JJ (reprint author), NCI, Ctr Canc Res, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. EM letterij@mail.nih.gov NR 75 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD AUG 25 PY 2005 VL 576 IS 1-2 BP 120 EP 131 DI 10.1016/j.mrfmmm.2005.03.004 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 953SN UT WOS:000231100900010 PM 15935406 ER PT J AU Hance, KW Zeytin, HE Greiner, JW AF Hance, KW Zeytin, HE Greiner, JW TI Mouse models expressing human carcinoembryonic antigen (CEA) as a transgene: Evaluation of CEA-based cancer vaccines SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Review DE carcinoembryonic antigen; poxvirus cancer vaccines; gastrointestinal cancer ID COLONY-STIMULATING FACTOR; FAMILIAL ADENOMATOUS POLYPOSIS; TRANSFORMING-GROWTH-FACTOR; DNA MISMATCH REPAIR; CYCLOOXYGENASE-2 INHIBITOR CELECOXIB; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; MULTIPLE INTESTINAL NEOPLASIA; PREVENT COLORECTAL ADENOMAS; CROSS-REACTING ANTIGEN; REGIONAL LYMPH-NODES AB In recent years, investigators have carried out several studies designed to evaluate whether human tumor-associated antigens might be exploited as targets for active specific immunotherapy, specifically human cancer vaccines. Not too long ago such an approach would have been met with considerable skepticism because the immune system was believed to be a rigid discriminator between self and non-self which, in turn, protected the host from a variety of pathogens. That viewpoint has been challenged in recent years by a series of studies indicating that antigenic determinants of self have not induced absolute host immune tolerance. Moreover, under specific conditions that evoke danger signals, peptides from self-antigen can be processed by the antigen-presenting cellular machinery, loaded onto the major histocompatibility antigen groove to serve as targets for immune intervention. Those findings provide the rationale to investigate a wide range of tumor-associated antigens, including differentiation antigens, oncogenes, and tumor suppressor genes as possible immune-based targets. One of those tumor-associated antigens is the carcinoembryonic antigen (CEA). Described almost 40 years ago, CEA is a M-r 180-200,000 oncofetal antigen that is one of the more widely studied human tumor-associated antigens. This review will provide: (i) a brief overview of the CEA gene family, (ii) a summary of early preclinical findings on overcoming immune tolerance to CEA, and (iii) the rationale to develop mouse models which spontaneously develop gastrointestinal tumors and express the CEA transgene. Those models have been used extensively in the study of overcoming host immune tolerance to CEA, a self, tumor-associated antigen, and the experimental findings have served as the rationale for the design of early clinical trials to evaluate CEA-based cancer vaccines. (c) 2005 Elsevier B.V. All rights reserved. C1 NCI, Lab Tumor Immunol & Biol, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Canc Prevent Fellowship Program, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. RP Greiner, JW (reprint author), NCI, Lab Tumor Immunol & Biol, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. EM jg117s@nih.gov FU Intramural NIH HHS [NIH0011268250]; PHS HHS [NIH0011268250] NR 130 TC 17 Z9 17 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD AUG 25 PY 2005 VL 576 IS 1-2 BP 132 EP 154 DI 10.1016/j.mrfmmm.2004.10.014 PG 23 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 953SN UT WOS:000231100900011 PM 15888344 ER PT J AU Zhang, J Gilles, JM Barnhart, K Creinin, MD Westhoff, C Frederick, MM AF Zhang, J Gilles, JM Barnhart, K Creinin, MD Westhoff, C Frederick, MM CA NICHD Management Early Pregnancy F TI A comparison of medical management with misoprostol and surgical management for early pregnancy failure SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID EXPECTANT MANAGEMENT; ENDOMETRIAL THICKNESS; MISCARRIAGE; ABORTION; ULTRASOUND; CURETTAGE; TRIAL AB Background: Misoprostol is increasingly used to treat women who have a failed pregnancy in the first trimester. We assessed the efficacy, safety, and acceptability of this treatment in a large, randomized trial. Methods: A total of 652 women with a first-trimester pregnancy failure (anembryonic gestation, embryonic or fetal death, or incomplete or inevitable spontaneous abortion) were randomly assigned to receive 800 microg of misoprostol vaginally or to undergo vacuum aspiration (standard of care) in a 3:1 ratio. The misoprostol group received treatment on day 1, a second dose on day 3 if expulsion was incomplete, and vacuum aspiration on day 8 if expulsion was still incomplete. Surgical treatment (for the misoprostol group) or repeated aspiration (for the vacuum-aspiration group) within 30 days after the initial treatment constituted treatment failure. Results: Of the 491 women assigned to receive misoprostol, 71 percent had complete expulsion by day 3 and 84 percent by day 8 (95 percent confidence interval, 81 to 87 percent). Treatment failed in 16 percent of the misoprostol group and 3 percent of the surgical group (absolute difference, 12 percent; 95 percent confidence interval, 9 to 16 percent) by day 30. Hemorrhage or endometritis requiring hospitalization was rare (1 percent or less in each group), with no significant differences between the groups. In the misoprostol group, 78 percent of the women stated that they would use misoprostol again if the need arose and 83 percent stated that they would recommend it to others. Conclusions: Treatment of early pregnancy failure with 800 microg of misoprostol vaginally is a safe and acceptable approach, with a success rate of approximately 84 percent. C1 NICHD, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Univ Miami, Miami, FL 33152 USA. Univ Penn, Philadelphia, PA 19104 USA. Columbia Univ, New York, NY USA. Clin Trials & Surveys Corp, Baltimore, MD USA. RP Zhang, J (reprint author), NICHD, Epidemiol Branch, NIH, Bldg 6100,Rm 7B03, Bethesda, MD 20892 USA. EM zhangj@mail.nih.gov FU NCRR NIH HHS [M01 RR000056]; NICHD NIH HHS [N01-HD-1-3321, N01-HD-3322, N01-HD-3323, N01-HD-3324, N01-HD-3325] NR 23 TC 93 Z9 95 U1 4 U2 7 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 AUG 25 PY 2005 VL 353 IS 8 BP 761 EP 769 DI 10.1056/NEJMoa044064 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 957YK UT WOS:000231409300005 PM 16120856 ER PT J AU Perkins, BA Nelson, RG Krolewski, AS AF Perkins, BA Nelson, RG Krolewski, AS TI Cystatin C and the risk of death SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Univ Toronto, Toronto, ON M5G 2C4, Canada. Natl Inst Hlth, Phoenix, AZ 85014 USA. Harvard Univ, Boston, MA 02215 USA. RP Perkins, BA (reprint author), Univ Toronto, 100 Coll St, Toronto, ON M5G 2C4, Canada. EM bruce.perkins@uhn.on.ca RI Nelson, Robert/B-1470-2012 NR 2 TC 2 Z9 2 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 25 PY 2005 VL 353 IS 8 BP 843 EP 843 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 957YK UT WOS:000231409300019 ER PT J AU Kippenhan, JS Olsen, RK Mervis, CB Morris, CA Kohn, P Lindenberg, AM Berman, KF AF Kippenhan, JS Olsen, RK Mervis, CB Morris, CA Kohn, P Lindenberg, AM Berman, KF TI Genetic contributions to human gyrification: Sulcal morphometry in Williams syndrome SO JOURNAL OF NEUROSCIENCE LA English DT Article DE Williams syndrome; brain imaging; sulcal depth; visuospatial construction; intraparietal sulcus; MRI; cortical surface models ID SURFACE-BASED ANALYSIS; CORTICAL SURFACE; COORDINATE SYSTEM; BRAIN STRUCTURE; THICKNESS; COGNITION; BEHAVIOR; CORTEX; MRI; NEUROANATOMY AB Although gyral and sulcal patterns are highly heritable, and emerge in a tightly controlled sequence during development, very little is known about specific genetic contributions to abnormal gyrification or the resulting functional consequences. Williams syndrome (WS), a genetic disorder caused by hemizygous microdeletion on chromosome 7q11.23 and characterized by abnormal brain structure and striking cognitive ( impairment in visuospatial construction) and behavioral (hypersocial/anxious) phenotypes, offers a unique opportunity to study these issues. We performed a detailed analysis of sulcal depth based on geometric cortical surface representations constructed from high-resolution magnetic resonance imaging scans acquired from participants with WS and from healthy controls who were matched for age, sex, and intelligence quotient, and compared between-group differences with those obtained from a voxel-based morphometry analysis. We found bilateral reductions in sulcal depth in the intraparietal/occipitoparietal sulcus ( PS) in the brains of participants with WS, as well as in the collateral sulcus and the orbitofrontal region in the left hemisphere. The left-hemisphere PS in the WS group averaged 8.5mm shallower than in controls. Sulcal depth findings in the PS corresponded closely to measures of reduced gray matter volume in the same area, providing evidence that the gray matter volume loss and abnormal sulcal geometry may be related. In the context of previous functional neuroimaging findings demonstrating functional alterations in the same cortical regions, our results further define the neural endophenotype underlying visuoconstructive deficits in WS, set the stage for defining the effects of specific genes, and offer insight into genetic mechanisms of cortical gyrification. C1 NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch, NIH,Dept Hlth & Human Serv, 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 Kippenhan, JS (reprint author), NIMH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch, NIH,Dept Hlth & Human Serv, Bldg 10,Room 4C101, Bethesda, MD 20892 USA. EM shane_kippenhan@nih.gov OI Olsen, Rosanna/0000-0002-2918-4152; Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU Intramural NIH HHS; NINDS NIH HHS [NS35102, R01 NS035102] NR 54 TC 83 Z9 85 U1 4 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 24 PY 2005 VL 25 IS 34 BP 7840 EP 7846 DI 10.1523/JNEUROSCI.1722-05.2005 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 958JA UT WOS:000231439300016 PM 16120786 ER PT J AU Petrache, HI Kimchi, I Harries, D Parsegian, VA AF Petrache, HI Kimchi, I Harries, D Parsegian, VA TI Measured depletion of ions at the biomembrane interface SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID LIPID-BILAYERS; HOFMEISTER; ANIONS; WATER; SIMULATIONS; VOLUMES; SALT C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Petrache, HI (reprint author), NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. EM petrachh@mail.nih.gov RI Harries, Daniel/F-7016-2012 OI Harries, Daniel/0000-0002-3057-9485 NR 20 TC 33 Z9 34 U1 2 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD AUG 24 PY 2005 VL 127 IS 33 BP 11546 EP 11547 DI 10.1021/ja052549+ PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 958ND UT WOS:000231454100007 PM 16104699 ER PT J AU McDermott, DH Yang, Q Kathiresan, S Cupples, LA Massaro, JM Keaney, JF Larson, MG Vasan, RS Hirschhorn, JN O'Donnell, CJ Murphy, PM Benjamin, EJ AF McDermott, DH Yang, Q Kathiresan, S Cupples, LA Massaro, JM Keaney, JF Larson, MG Vasan, RS Hirschhorn, JN O'Donnell, CJ Murphy, PM Benjamin, EJ TI CCL2 polymorphisms are associated with serum monocyte chemoattractant protein-1 levels and myocardial infarction in the framingham heart study SO CIRCULATION LA English DT Article DE epidemiology; genetics; inflammation; myocardial infarction; risk factors ID CORONARY-ARTERY DISEASE; E-DEFICIENT MICE; MCP-1 GENE; ATHEROSCLEROTIC LESIONS; REDUCES ATHEROSCLEROSIS; PLASMA-LEVELS; EXPRESSION; RESTENOSIS; ALLELE; RISK AB Background - Monocyte chemoattractant protein-1 (MCP-1) is a chemokine strongly implicated in promoting atherosclerosis in animal models, but human genetic evidence is contradictory. Methods and Results - We analyzed the association of genetic variation in the MCP-1 gene (CCL2) with prevalent myocardial infarction and serum MCP-1 levels in the community-based Framingham Heart Study Offspring Cohort (50% women; mean age, 62 years). MCP-1 levels and CCL2 genotypes were determined in 3236 and 1797 individuals, respectively. Significant clinical correlates of MCP-1 levels were age, cigarette smoking, triglycerides, body mass index, and waist-to-hip ratio. The MCP-1-2578G allele located in the CCL2 regulatory region was significantly associated with both higher serum MCP-1 levels in a recessive genetic model (358 +/- 10 versus 328 +/- 3 pg/mL; P = 0.002) and higher prevalence of myocardial infarction in a dominant genetic model (adjusted odds ratio, 2.0; 95% CI, 1.2 to 3.3; P = 0.005). We also defined the linkage disequilibrium structure at the CCL2 locus and observed 6 common haplotypes in whites. We performed haplotype-based association analysis and found that only the most frequent haplotype, defined by the MCP-1-2578G allele, was associated with prevalent MI. Conclusions - Our data are consistent with the hypothesis that MCP-1 is involved in the pathogenesis of human atherosclerosis and myocardial infarction. C1 NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Dept Math, Boston, MA 02215 USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02115 USA. Broad Inst, Cambridge, MA USA. NHLBI, NIH, Bethesda, MD 20892 USA. Framingham Heart Dis Epidemiol Study, NHLBI, Framingham, MA USA. RP McDermott, DH (reprint author), NIAID, Lab Mol Immunol, NIH, Bldg 10,Room 11N111, Bethesda, MD 20892 USA. EM dmcdermott@niaid.nih.gov; emelia@bu.edu RI Yang, Qiong/G-5438-2014; OI Massaro, Joseph/0000-0002-2682-4812; Cupples, L. Adrienne/0000-0003-0273-7965; Larson, Martin/0000-0002-9631-1254; McDermott, David/0000-0001-6978-0867; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [R01 HL-64753, N01-HC 25195, R01 HL-076784, U01 HL-66582] NR 42 TC 143 Z9 155 U1 0 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 23 PY 2005 VL 112 IS 8 BP 1113 EP 1120 DI 10.1161/CIRCULATIONAHA.105.543579 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 957LM UT WOS:000231371300010 PM 16116069 ER PT J AU Rao, S Hu, S McHugh, L Lueders, K Henry, K Zhao, Q Fekete, RA Kar, S Adhya, S Hamer, DH AF Rao, S Hu, S McHugh, L Lueders, K Henry, K Zhao, Q Fekete, RA Kar, S Adhya, S Hamer, DH TI Toward a live microbial microbicide for HIV: Commensal bacteria secreting an HIV fusion inhibitor peptide SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bacterial; microbicide; Nissle 1917; AIDS prevention ID ESCHERICHIA-COLI STRAIN; ULCERATIVE-COLITIS; GASTROINTESTINAL-TRACT; MAINTAINING REMISSION; NISSLE 1917; INFECTION; DISEASE; MESALAZINE; SYSTEM; COLONIZATION AB Most HIV transmission occurs on the mucosal surfaces of the gastrointestinal and cervicovaginal tracts, both of which are normally coated by a biofilm of nonpathogenic commensal bacteria. We propose to genetically engineer such naturally occurring bacteria to protect against HIV infection by secreting antiviral peptides. Here we describe the development and characterization of Nissle 1917, a highly colonizing probiotic strain of Escherichia coli, secreting HIV-gp41-hemolysin A hybrid peptides that block HIV fusion and entry into target cells. By using an appropriate combination of cis- and transacting secretory and regulatory signals, micromolar secretion levels of the anti-HIV peptides were achieved. The genetically engineered Nissle 1917 were capable of colonizing mice for periods of weeks to months, predominantly in the colon and cecum, with lower concentrations of bacteria present in the rectum, vagina, and small intestine. Histological and immunocytochemical examination of the colon revealed bacterial growth and peptide secretion throughout the luminal mucosa and in association with epithelial surfaces. The use of genetically engineered live microbes as anti-HIV microbicides has important potential advantages in economy, efficacy, and durability. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Hamer, DH (reprint author), NCI, Biochem Lab, NIH, 9000 Rockville Pike,Bldg 37,Room 6002, Bethesda, MD 20892 USA. EM deanh@helix.nih.gov NR 37 TC 82 Z9 96 U1 2 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 23 PY 2005 VL 102 IS 34 BP 11993 EP 11998 DI 10.1073/pnas.0504881102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 958VO UT WOS:000231476500009 PM 16040799 ER PT J AU Patteson, KG Trivedi, N Stadtman, TC AF Patteson, KG Trivedi, N Stadtman, TC TI Methanococcus vannielii selenium-binding protein (SeBP): Chemical reactivity of recombinant SeBP produced in Escherichia coli SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE buried SH group; cysteine alkylation; essential thiol group; hydrophobic protein; protein folding ID SELENOPHOSPHATE SYNTHETASE; SELENOCYSTEINE LYASE; SULFHYDRYL GROUPS; GLUTATHIONE; PURIFICATION; PERSELENIDE; JANNASCHII; REDUCTION; TOXICITY; CLONING AB A selenium-binding protein (SeBP) from Methanococcus vannielii was recently identified, and its gene was isolated and overexpressed in Escherichia coli [Self, W. T., Pierce, R. & Stadtman, T. C. (2004) IUBMB Life 56,501-507]. SeBP and recombinant SeBP(rSeBP) migrated as approximate to 42-kDa species on native gels and as approximate to 33-kDa species on SIDS gels. rSeBP consists of identical 8.8-kDa subunits, each containing a single cysteine residue. rSeBP isolated in the absence of reducing agents contained oxidized cysteine (89%) and very little bound selenium (0.05 eq or less per subunit). Complete reduction of the oxidized cysteine residues in rSeBP with Tris(2-carboxyethyl)phosphine required addition of a denaturant, such as 1 M guanidine-hydrochloride. With selenite as the selenium source and the isolated reduced protein as sole reductant, binding of one selenium per tetramer under anaerobic conditions required four cysteine thiol groups, one on each subunit. In the corresponding reaction, with reduced glutathione (GSH), equimolar amounts of selenodiglutathione (GSSeSG) and glutathione disulfide are formed from selenite and 4 GSH. At GSH-to-selenite ratios >4:1, conversion of GSSeSG to a perselenide derivative, GSSe(-), occurs. However, with the reduced rSeBP as sole electron donor in the reaction with selenite, further conversion of the R-SSeS-R product apparently did not occur. Prior alkylation of the cysteine thiol groups in reduced rSeBP prevented selenite reduction and selenium binding under comparable conditions. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, TC (reprint author), NHLBI, Biochem Lab, NIH, Bldg 50,Room 2120,50 South Dr,MSC-8012, Bethesda, MD 20892 USA. EM tcstadtman@nih.gov NR 27 TC 11 Z9 15 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 23 PY 2005 VL 102 IS 34 BP 12029 EP 12034 DI 10.1073/pnas.0505650102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 958VO UT WOS:000231476500015 PM 16103372 ER PT J AU Ouyang, KF Zheng, H Qin, XM Zhang, C Yang, DM Wang, X Wu, CH Zhou, Z Cheng, HP AF Ouyang, KF Zheng, H Qin, XM Zhang, C Yang, DM Wang, X Wu, CH Zhou, Z Cheng, HP TI Ca2+ sparks and secretion in dorsal root ganglion neurons SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE endoplasmic reticulum; ryanodine receptor; exocytosis ID RAT SENSORY NEURONS; INDUCED CALCIUM-RELEASE; SKELETAL-MUSCLE; RYANODINE RECEPTORS; TRANSMITTER RELEASE; CELLS; EXOCYTOSIS; AMPLITUDE; VOLTAGE; TERMINATION AB Ca2+ sparks as the elementary intracellular Ca2+ release events are instrumental to local control of Ca2+ signaling in many types of cells. Here, we visualized neural Ca2+ sparks in dorsal root ganglion (DRG) sensory neurons and investigated possible role of DRG sparks in the regulation of secretion from the somata of the cell. DRG sparks arose mainly from type 3 ryanodine receptor Ca2+ release channels on subsurface cisternae of the endoplasmic reticulum, rendering a striking subsurface localization. Caffeine- or 3,7-dimethyl-1-(2-propynyl)xanthine-induced store Ca2+ release, in the form of Ca2+ sparks, triggered exocytosis, independently of membrane depolarization and external Ca2+. The spark-secretion coupling probability was estimated to be between 1 vesicle per 6.6 sparks and 1 vesicle per 11.4 sparks. During excitation, subsurface sparks were evoked by physiological Ca2+ entry via the Ca2+- induced Ca2+ release mechanism, and their synergistic interaction with Ca2+ influx accounted for approximate to 60% of the Ca2+-dependent exocytosis. Furthermore, inhibition of Ca2+-induced Ca2+ release abolished endotoxin-induced secretion of pain-related neuropeptides. These findings underscore an important role for Ca2+ sparks in the amplification of surface Ca2+ influx and regulation of neural secretion. C1 Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. Peking Univ, Natl Lab Biomembrane & Membrane Biotechnol, Beijing 100871, Peoples R China. Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Neurosci, Shanghai 200031, Peoples R China. Peking Univ, Dept Physiol, Hlth Sci Ctr, Beijing 100083, Peoples R China. NIA, Cardiovasc Sci Lab, NIH, Bethesda, MD 20892 USA. RP Zhou, Z (reprint author), Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. EM zzhou@pku.edu.cn; chengp@grc.nia.nih.gov RI zhou, zhuan/A-8285-2011; ouyang, kunfu/B-3073-2011; zheng, Hui/I-3573-2013 OI ouyang, kunfu/0000-0003-0292-375X; zheng, Hui/0000-0002-2504-9092 FU Intramural NIH HHS NR 39 TC 38 Z9 39 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 23 PY 2005 VL 102 IS 34 BP 12259 EP 12264 DI 10.1073/pnas.0408494102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 958VO UT WOS:000231476500054 PM 16103366 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 tumour MARKer prognostic studies (REMARK) SO BRITISH JOURNAL OF CANCER LA English DT Article DE tumour marker; guidelines; REMARK; NCI; EORTC; 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 methodological 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 the study results. The development of guidelines for the reporting of tumour marker studies was a major recommendation of the US National Cancer Institute and the European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. Similar to the successful CONSORT initiative for randomised trials and 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 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. C1 US NCI, Bethesda, MD 20892 USA. Canc Res UK, Med Stat Grp, Ctr Stat Med, Wolfson Coll, Oxford OX2 6UD, England. Univ Freiburg Klinikum, Inst Med Biometrie & Med Informat, D-79104 Freiburg, Germany. Osped Civile, Ctr Reg Indicatori Biochim Tumoure, I-30122 Venice, Italy. OSI Pharmaceut Inc, Boulder, CO 80301 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 353 Z9 357 U1 1 U2 11 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 AUG 22 PY 2005 VL 93 IS 4 BP 387 EP 391 DI 10.1038/sj.bjc.6602678 PG 5 WC Oncology SC Oncology GA 955XD UT WOS:000231260400002 PM 16106245 ER PT J AU Cragg, GM Newman, DJ AF Cragg, GM Newman, DJ TI Plants as a source of anti-cancer agents SO JOURNAL OF ETHNOPHARMACOLOGY LA English DT Article DE camptothecins; combretastatins; flavopiridol; podophyllotoxins; taxanes; vinca alkaloids; cell cycle target inhibitor ID NATURAL-PRODUCTS; CANCER; TUBULIN; ACID AB Plant-derived compounds have been an important source of several clinically useful anti-cancer agents. These include vinblastine, vincristine, the camptothecin derivatives, topotecan and irinotecan, etoposide. derived froth epipodophyllotoxin, and paclitaxel (taxol(R)). A number of promising new agents are in clinical development based on selective activity against cancer-related molecular targets, including flavopiridol and combretastin A4 phosphate, while some agents which failed in earlier clinical studies are stimulating renewed interest. (C) 2005 Elsevier Ireland Ltd. All rights reserved. C1 NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Cragg, GM (reprint author), NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag, POB B, Frederick, MD 21702 USA. EM cragg@mail.nih.gov NR 28 TC 610 Z9 629 U1 9 U2 102 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-8741 J9 J ETHNOPHARMACOL JI J. Ethnopharmacol. PD AUG 22 PY 2005 VL 100 IS 1-2 BP 72 EP 79 DI 10.1016/j.jep.2005.05.011 PG 8 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA 955FW UT WOS:000231211900015 PM 16009521 ER PT J AU Liu, H AF Liu, H TI Oleanolic acid and ursolic acid: Research perspectives SO JOURNAL OF ETHNOPHARMACOLOGY LA English DT Article DE oleanolic acid; oleanolic acid derivatives; pharmacology; toxicology ID PROTECTION; APOPTOSIS; INDUCTION AB Oleanolic acid and ursolic acid are ubiquitous triterpenoids in plant kingdom. medicinal herbs, and are integral part of the human diet. During the last decade over 700 research articles have been published on their research, reflecting tremendous interest and progress in our understanding of these triterpenoids. This included the isolation and purification of these tritepernoids from various plants and herb,, the chemical modifications to make more effective and water soluble derivatives, the pharmacological research on their beneficial effects, the toxicity studies. and the clinical use of these triterpenoids in various diseases including anticancer chemotherapies, A briefly commentary is attempted here for their research perspectives. C1 NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. RP Liu, H (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Liu6@niehs.nih.gov NR 15 TC 191 Z9 210 U1 6 U2 53 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-8741 J9 J ETHNOPHARMACOL JI J. Ethnopharmacol. PD AUG 22 PY 2005 VL 100 IS 1-2 BP 92 EP 94 DI 10.1016/j.jep.2005.05.024 PG 3 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA 955FW UT WOS:000231211900018 PM 15994040 ER PT J AU Burdick, KE Hodgkinson, CA Szeszko, PR Lencz, T Ekholm, JM Kane, JM Goldman, D Malhotra, AK AF Burdick, KE Hodgkinson, CA Szeszko, PR Lencz, T Ekholm, JM Kane, JM Goldman, D Malhotra, AK TI DISC1 and neurocognitive function in schizophrenia SO NEUROREPORT LA English DT Article DE DISC1; genetics; neurocognition; schizophrenia ID ASSOCIATION; GENES; TRANSLOCATION; CORTEX; FAMILY; MATTER; P300; LOCI AB We recently reported an association between DISC1 and schizophrenia, schizoaffective disorder, and bipolar disorder. Convergent evidence suggests that DISC1 has a direct effect on central nervous system functioning. However, there is a paucity of data investigating the effects of DISC1 on neurocognition. Thus, we analyzed the relationship between five single-nucleotide polymorphisms that influenced risk for schizophrenia in our previous study and neurocognition in 250 patients with schizophrenia. DISC1 genotype was related to neurocognitive performance on measures of rapid visual search and verbal working memory, when controlling for age and premorbid intellectual capacity, and explained 3%-4% of the variance. These data suggest that DISC1 is associated with neurocognitive functioning in schizophrenia. C1 N Shore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Dept Psychiat Res, Glen Oaks, NY USA. NIAAA, Neurogenet Lab, Bethesda, MD USA. RP Burdick, KE (reprint author), N Shore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Dept Psychiat Res, Glen Oaks, NY USA. EM kburdick@lij.edu RI Burdick, Katherine/G-6124-2012; Szeszko, Philip/G-9336-2013; Goldman, David/F-9772-2010; Lencz, Todd/J-3418-2014 OI Goldman, David/0000-0002-1724-5405; Lencz, Todd/0000-0001-8586-338X FU Intramural NIH HHS; NIMH NIH HHS [K23MH001760] NR 17 TC 79 Z9 82 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 22 PY 2005 VL 16 IS 12 BP 1399 EP 1402 DI 10.1097/01.wnr.0000175248.25535.f6 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 959BT UT WOS:000231492600028 PM 16056147 ER PT J AU Patel, AA Kajdacsy-Balla, A Berman, JJ Bosland, M Datta, MW Dhir, R Gilbertson, J Melamed, J Orenstein, J Tai, KF Becich, MJ AF Patel, AA Kajdacsy-Balla, A Berman, JJ Bosland, M Datta, MW Dhir, R Gilbertson, J Melamed, J Orenstein, J Tai, KF Becich, MJ TI The development of common data elements for a multi-institute prostate cancer tissue bank: The Cooperative Prostate Cancer Tissue Resource (CPCTR) experience SO BMC CANCER LA English DT Article ID BIOBANK AB Background: The Cooperative Prostate Cancer Tissue Resource (CPCTR) is a consortium of four geographically dispersed institutions that are funded by the U. S. National Cancer Institute (NCI) to provide clinically annotated prostate cancer tissue samples to researchers. To facilitate this effort, it was critical to arrive at agreed upon common data elements (CDEs) that could be used to collect demographic, pathologic, treatment and clinical outcome data. Methods: The CPCTR investigators convened a CDE curation subcommittee to develop and implement CDEs for the annotation of collected prostate tissues. The draft CDEs were refined and progressively annotated to make them ISO 11179 compliant. The CDEs were implemented in the CPCTR database and tested using software query tools developed by the investigators. Results: By collaborative consensus the CPCTR CDE subcommittee developed 145 data elements to annotate the tissue samples collected. These included for each case: 1) demographic data, 2) clinical history, 3) pathology specimen level elements to describe the staging, grading and other characteristics of individual surgical pathology cases, 4) tissue block level annotation critical to managing a virtual inventory of cases and facilitating case selection, and 5) clinical outcome data including treatment, recurrence and vital status. These elements have been used successfully to respond to over 60 requests by end-users for tissue, including paraffin blocks from cases with 5 to 10 years of follow up, tissue microarrays (TMAs), as well as frozen tissue collected prospectively for genomic profiling and genetic studies. The CPCTR CDEs have been fully implemented in two major tissue banks and have been shared with dozens of other tissue banking efforts. Conclusion: The freely available CDEs developed by the CPCTR are robust, based on "best practices" for tissue resources, and are ISO 11179 compliant. The process for CDE development described in this manuscript provides a framework model for other organ sites and has been used as a model for breast and melanoma tissue banking efforts. C1 Univ Pittsburgh, Dept Pathol, Ctr Pathol Informat, Benedum Oncol Informat Ctr, Pittsburgh, PA USA. Univ Illinois, Dept Pathol, Chicago, IL USA. NCI, Canc Diag Program, Bethesda, MD 20892 USA. NYU, Dept Pathol, New York, NY 10016 USA. NYU, Dept Environm Med, New York, NY 10016 USA. NYU, Dept Urol, New York, NY USA. Emory Univ, Dept Pathol, Atlanta, GA 30322 USA. Emory Univ, Dept Urol, Atlanta, GA 30322 USA. George Washington Univ, Dept Pathol, Washington, DC USA. Med Coll Wisconsin, Human & Mol Genet Ctr, Bioinformat Program, Milwaukee, WI 53226 USA. RP Becich, MJ (reprint author), Univ Pittsburgh, Dept Pathol, Ctr Pathol Informat, Benedum Oncol Informat Ctr, Pittsburgh, PA USA. EM patelaa@upmc.edu; aballa@uic.edu; jjbermanj@alum.mit.edu; maarten.bosland@med.nyu.edu; mdatta@emory.edu; dhirr@upmc.edu; gilbertsonjr@upmc.edu; jonathan.melamed@med.nyu.edu; jorenstein@mfa.gwu.edu; ktai@mcw.edu; becich@pitt.edu FU NCI NIH HHS [U01 CA86743, P30 CA13343, U01 CA086735, U01 CA086739, U01 CA086743, U01 CA086772, U01 CA86735, U01 CA86739, U01 CA86772] NR 14 TC 21 Z9 22 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD AUG 21 PY 2005 VL 5 AR 108 DI 10.1186/1471-2407-5-108 PG 14 WC Oncology SC Oncology GA 968LV UT WOS:000232164900001 PM 16111498 ER PT J AU Nolte, G Dassios, G AF Nolte, G Dassios, G TI Analytic expansion of the EEG lead field for realistic volume conductors SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID BOUNDARY-ELEMENT METHOD; HEAD SHAPE; MAGNETOENCEPHALOGRAPHY; ELECTROENCEPHALOGRAPHY; POTENTIALS; ACCURACY; MODEL AB EEG forward calculation in realistic volume conductors using the boundary element method suffers from the fact that the solutions become inaccurate for superficial sources. Here we propose to correct an analytical approximation of the respective lead fields with series of spherical harmonics with respect to multiple expansion points. The necessary correction depends very much on the chosen analytical approximation. We constructed the latter such that the correction can be modelled adequately within the chosen basis. Simulations for a 3-shell prolate spheroid demonstrate the accurate modelling of the lead fields. Explicit comparison with analytically known solutions was done for the 3-shell spherical volume conductor showing that relative errors are mostly far below 1% even for the most superficial sources placed directly on the innermost surface. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Fraunhofer Gesell First, Berlin, Germany. Univ Patras, Dept Chem Engn, Div Appl Math, GR-26110 Patras, Greece. RP Nolte, G (reprint author), NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. EM nolte@first.fhg.de; gdassios@chemeng.upatras.gr NR 20 TC 39 Z9 39 U1 0 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD AUG 21 PY 2005 VL 50 IS 16 BP 3807 EP 3823 DI 10.1088/0031-9155/50/16/010 PG 17 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 962YU UT WOS:000231770300010 PM 16077228 ER PT J AU O'Connell, MJ AF O'Connell, MJ TI Combined-modality neoadjuvant therapy for rectal cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID ADJUVANT THERAPY; RADIATION-THERAPY; FLUOROURACIL; CARCINOMA; TRIAL C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Allegheny Gen Hosp, Ctr Canc, Pittsburgh, PA USA. RP O'Connell, MJ (reprint author), Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. NR 16 TC 2 Z9 2 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 20 PY 2005 VL 23 IS 24 BP 5450 EP 5451 DI 10.1200/JCO.2005.04.904 PG 2 WC Oncology SC Oncology GA 957LQ UT WOS:000231371700012 PM 16009954 ER PT J AU Camphausen, K Citrin, D Krishna, MC Mitchell, JB AF Camphausen, K Citrin, D Krishna, MC Mitchell, JB TI Implications for tumor control during protection of normal tissues with antioxidants SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID OXIDATIVE STRESS; BETA-CAROTENE; DOUBLE-BLIND; RADIATION; PREVENTION; TRIAL; MUCOSITIS; CANCER C1 NCI, Radiat Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Radiol Biol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. NR 12 TC 17 Z9 17 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 20 PY 2005 VL 23 IS 24 BP 5455 EP 5457 DI 10.1200/JCO.2005.05.903 PG 3 WC Oncology SC Oncology GA 957LQ UT WOS:000231371700014 PM 16027436 ER PT J AU McGlynn, KA Devesa, SS Graubard, BI Castle, PE AF McGlynn, KA Devesa, SS Graubard, BI Castle, PE TI Increasing incidence of testicular germ cell tumors among black men in the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TRENDS; CANCER AB Purpose There has been marked disparity in the incidence of testicular germ cell tumors (TGCT) among white and black men for a number of decades in the United States. Since at least the beginning of the Surveillance, Epidemiology, and End Results (SEER) Program in 1973, incidence rates among white men have been five times higher than rates among black men. In addition, rates among white men have been increasing, whereas rates among black men have remained stable. However, a recent examination of ethnic-specific rates suggested that the incidence among black men may have begun to change in the 1990s. Patients and Methods TGCT incidence data from nine registries of the SEER Program were analyzed for the years 1973 to 2001. Trends were examined separately for seminoma and nonseminoma. Results Analyses found that the incidence of TGCT began to increase among black men between the 1988 to 1992 and 1993 to 1997 periods. Before that time, incidence among black men had decreased by 14.8%. Between 1988 to 1992 and 1998 to 2001, however, the incidence increased by 100%, with the incidence of seminoma increasing twice as much (124.4%) as the incidence of nonseminoma (64.3%). Over the 29-year time period, there was no evidence of a change in the proportion of tumors diagnosed at earlier stages among black men. In contrast, the proportion of tumors diagnosed at localized stages significantly increased among white men. Conclusion The incidence of TGCT among black men has increased since 1988 to 1992. Although the reasons for this increase are unclear, screening and earlier diagnosis of TGCT do not seem to be factors. C1 Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Rockville, MD 20852 USA. RP McGlynn, KA (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, US Dept HHS, 6120 Execut Blvd,Rm 7060, Rockville, MD 20852 USA. EM mcglynnk@mail.nih.gov NR 15 TC 71 Z9 73 U1 0 U2 2 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 20 PY 2005 VL 23 IS 24 BP 5757 EP 5761 DI 10.1200/JCO.2005.08.227 PG 5 WC Oncology SC Oncology GA 957LQ UT WOS:000231371700050 PM 16110032 ER PT J AU Pavletic, SZ Khouri, IF Haagenson, M King, RJ Bierman, PJ Bishop, MR Carston, M Giralt, S Molina, A Copelan, EA Ringden, O Roy, V Ballen, K Adkins, DR McCarthy, P Weisdorf, D Montserrat, E Anasetti, C AF Pavletic, SZ Khouri, IF Haagenson, M King, RJ Bierman, PJ Bishop, MR Carston, M Giralt, S Molina, A Copelan, EA Ringden, O Roy, V Ballen, K Adkins, DR McCarthy, P Weisdorf, D Montserrat, E Anasetti, C TI Unrelated donor marrow transplantation for B-Cell chronic lymphocytic leukemia after using myeloablative conditioning: Results from the center for international blood and marrow transplant research SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 36th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 19-23, 2000 CL NEW ORLEANS, LA SP Amer Soc Clin Oncol ID GRAFT-VERSUS-LEUKEMIA; MINIMAL RESIDUAL DISEASE; BONE-MARROW; HOST-DISEASE; LYMPHOID MALIGNANCIES; PERIPHERAL-BLOOD; ALLOGENEIC BLOOD; SALVAGE THERAPY; FLUDARABINE; PROGRAM AB Purpose To determine the role of myeloablative conditioning and unrelated donor (URD) bone marrow transplantation in the treatment of patients with advanced B-cell chronic lymphocytic leukemia (CLL). Patients and Methods A total of 38 CLL patients received a matched URD transplant using bone marrow procured by the National Marrow Donor Program. The median age was 45 years (range, 26 to 57 years), the median time from diagnosis was 51 months, and the median number of prior chemotherapy regimens was three. Fifty-five percent of patients were chemotherapy refractory and 89% had received fludarabine. Conditioning included total-body irradiation in 92% of patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate with cyclosporine or tacrolimus for 82% of patients. Results Twenty-one patients (58%) achieved complete response and six (17%) achieved partial response. Incidences of grades 2 to 4 acute GVHD were 45% at 100 days and incidences of chronic GVHD were 85% at 5 years. Eleven patients are alive and disease free at a median of 6 years (range, 3.0 to 9.0 years). Five-year overall survival, failure-free survival, disease progression rates, and treatment-related mortality (TRM) were 33%, 30%, 32%, and 38% respectively. Conclusion These data demonstrate that lasting remissions can be achieved after URD transplantation in patients with advanced CLL. High TRIM suggest that myeloablative conditioning and HLA-mismatched donors should be avoided in future protocols, and it is mandatory to investigate transplant strategies with a lower morbidity and mortality, including the use of nonmyeloablative regimens. C1 NCI, Graft Versus Host & Autoimmuni Unit, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Minnesota, Ctr Int Blood & Marrow Transplant Res, Natl Marrow Donor Program, Minneapolis, MN 55455 USA. Univ Nebraska Med Ctr, Coll Nursing, Omaha, NE 68198 USA. City Hope Natl Canc Ctr, Duarte, CA USA. Ohio State Univ, Columbus, OH 43210 USA. Karolinska Univ Hosp, Huddinge, Sweden. Massachusetts Gen Hosp, Boston, MA 02114 USA. Mayo Clin, Jacksonville, FL USA. Washington Univ, Sch Med, St Louis, MO 63130 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Univ Barcelona, IDIBAPS, Hosp & Clin, Barcelona, Spain. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. RP Pavletic, SZ (reprint author), NCI, Graft Versus Host & Autoimmuni Unit, Expt Transplantat & Immunol Branch, 9000 Rockville Pike,Bldg 10,Room CRC 3-3330, Bethesda, MD 20892 USA. EM pavletis@mail.nih.gov NR 42 TC 61 Z9 63 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 20 PY 2005 VL 23 IS 24 BP 5788 EP 5794 DI 10.1200/JCO.2005.03.962 PG 7 WC Oncology SC Oncology GA 957LQ UT WOS:000231371700054 PM 16043827 ER PT J AU Demark-Wahnefried, W Aziz, NM Rowland, JH Pinto, BM AF Demark-Wahnefried, W Aziz, NM Rowland, JH Pinto, BM TI Riding the crest of the teachable moment: Promoting long-term health after the diagnosis of cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID QUALITY-OF-LIFE; POSTMENOPAUSAL BREAST-CANCER; RANDOMIZED CONTROLLED-TRIAL; BONE-MINERAL DENSITY; ANDROGEN-DEPRIVATION THERAPY; FAT DIETARY INTERVENTION; HIGH-DOSE CHEMOTHERAPY; PHYSICAL-ACTIVITY; PRIMARY-CARE; NECK-CANCER AB Purpose Cancer survivors are at increased risk for several comorbid conditions, and many seek lifestyle change to reduce dysfunction and improve long-term health. To better understand the impact of cancer on adult survivors' health and health behaviors, a review was conducted to determine (1) prevalent physical health conditions, (2) persistent lifestyle changes, and (3) outcomes of previous lifestyle interventions aimed at improving health within this population. Methods Relevant studies from 1966 and beyond were identified through MEDLINE and PubMed searches. Results Cancer survivors are at increased risk for progressive disease but also for second primaries, osteoporosis, obesity, cardiovascular disease, diabetes, and functional decline. To improve overall health, survivors frequently initiate diet, exercise, and other lifestyle changes after diagnosis. However, those who are male, older, and less educated are less likely to adopt these changes. There also is selective uptake of messages, as evidenced by findings that only 25% to 42% of survivors consume adequate amounts of fruits and vegetables, and approximately 70% of breast and prostate cancer survivors are overweight or obese. Several behavioral interventions show promise for improving survivors' health-related outcomes. Oncologists can play a pivotal role in health promotion, yet only 20% provide such guidance. Conclusion With 64% of cancer patients surviving > 5 years beyond diagnosis, oncologists are challenged to expand their focus from acute care to managing the long-term health consequences of cancer. Although more research is needed, opportunities exist for oncologists to promote lifestyle changes that may improve the length and quality of life of their patients. C1 Duke Univ, Med Ctr, Duke Comprehens Canc Ctr, Program Canc Prevent, Durham, NC 27710 USA. NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. Brown Univ, Miriam Hosp, Lifespan Acad Med Ctr, Ctr Behav & Prevent Med, Providence, RI 02912 USA. RP Demark-Wahnefried, W (reprint author), Duke Univ, Med Ctr, Box 3707, Durham, NC 27710 USA. EM demar001@mc.duke.edu FU NCI NIH HHS [R01 CA081191, CA106919, CA81191, CA92468, R01 CA106919, R21 CA092468] NR 154 TC 451 Z9 455 U1 8 U2 42 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 20 PY 2005 VL 23 IS 24 BP 5814 EP 5830 DI 10.1200/JCO.2005.01.230 PG 17 WC Oncology SC Oncology GA 957LQ UT WOS:000231371700057 PM 16043830 ER PT J AU Korn, EL Hunsberger, S Freidlin, B Smith, MA Abrams, JS AF Korn, EL Hunsberger, S Freidlin, B Smith, MA Abrams, JS TI Preliminary data release for randomized clinical trials of noninferiority: A new proposal SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article AB Noninferiority trials often require a long follow-up period for the data to reach the maturity needed for definitive analysis. A proposal is presented that allows for early release of outcome data from a carefully specified subset of noninferiority trials. This subset is defined so that the early release of the data will be potentially useful to patients who face a treatment decision but will not compromise the integrity of the trial or interfere with the completion of the trial to its definitive analysis. In particular, the release of the data will only occur after the last participant has been randomly assigned and is off treatment-arm-specific therapy and only if it is unlikely that subsequent treatment and/or follow-up practices will change based on the knowledge of released data. In contrast to standard interim monitoring, (1) the release of the data would be automatic and independent of the observed data, and (2) the trial would continue on to its planned final analysis and not be stopped. Examples are given demonstrating how the proposal would work, along with a discussion of possible objections to the proposal. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NCI, Clin Invest Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Korn, EL (reprint author), NCI, Res Branch, EPN-8128, Bethesda, MD 20892 USA. EM korne@ctep.rci.nih.gov NR 10 TC 16 Z9 16 U1 0 U2 2 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 20 PY 2005 VL 23 IS 24 BP 5831 EP 5836 DI 10.1200/JCO.2005.02.105 PG 6 WC Oncology SC Oncology GA 957LQ UT WOS:000231371700058 PM 16027441 ER PT J AU Garcia-Closas, M Malats, N Silverman, D Dosemeci, M Kogevinas, M Hein, DW Tardon, A Serra, C Carrato, A Garcia-Closas, R Lloreta, J Castano-Vinyals, G Yeager, M Welch, R Chanock, S Chatterjee, N Wacholder, S Samanic, C Tora, M Fernandez, F Real, FX Rothman, N AF Garcia-Closas, M Malats, N Silverman, D Dosemeci, M Kogevinas, M Hein, DW Tardon, A Serra, C Carrato, A Garcia-Closas, R Lloreta, J Castano-Vinyals, G Yeager, M Welch, R Chanock, S Chatterjee, N Wacholder, S Samanic, C Tora, M Fernandez, F Real, FX Rothman, N TI NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses SO LANCET LA English DT Article ID GLUTATHIONE-S-TRANSFERASE; N-ACETYLTRANSFERASE 2; GENE-ENVIRONMENT INTERACTION; CIGARETTE-SMOKING; AROMATIC-AMINES; URINARY-BLADDER; POOLED ANALYSIS; POLYMORPHISMS; M1; SUSCEPTIBILITY AB Background Many reported associations between common genetic polymorphisms and complex diseases have not been confirmed in subsequent studies. An exception could be the association between NAT2 slow acetylation, GSTM1 null genotype, and bladder-cancer risk. However, current evidence is based on meta-analyses of relatively small studies (range 23-374 cases) with some evidence of publication bias and study heterogeneity. Associations between polymorphisms in other NAT and GST genes and bladder-cancer risk have been inconsistent. Methods We investigated polymorphisms in NAT2, GSTM1, NAT1, GSTT1, GSTM3, and GSTP1 in 1150 patients with transitional-cell carcinoma of the urinary bladder and 1149 controls in Spain; all the participants were white. We also carried out meta-analyses of NAT2, GSTM1, and bladder cancer that included more than twice as many cases as in previous reports. Findings In our study, the odds ratios for bladder cancer for individuals with deletion of one or two copies of the GSTM1 gene were 1.2 (95% CI 0.8-1.7)and 1.9 (1.4-2.7) respectively (p for trend <0.0001). Compared with NAT2 rapid or intermediate acetylators, NAT2 slow acetylators had an increased overall risk of bladder cancer (1.4 [1.2-1.7]) that was stronger for cigarette smokers than for never smokers (p for interaction 0.008). No significant associations were found with the other polymorphisms. Meta-analyses showed that the overall association for NAT2 was robust (p<0.0001), and case-only meta-analyses provided support for an interaction between NAT2 and king (p for interaction 0.009). The overall association for GSTM1 was also robust (p<0.0001) and was not smoking modified by smoking status (p=0.86). Interpretation The GSTM1 null genotype increases the overall risk of bladder cancer, and the NAT2 slow-acetylator genotype increases risk particularly among cigarette smokers. These findings provide compelling evidence for the role of common polymorphisms in the aetiology of cancer. Relevance to practice Although the relative risks are modest, these polymorphisms could account for up to 31% of bladder cancers because of their high prevalence. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Core Genotype Facil, Ctr Adv Technol, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Inst Municipal Invest Med, E-08003 Barcelona, Spain. Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. Univ Louisville, Sch Med, James Graham Brown Canc Ctr, Louisville, KY 40292 USA. Univ Oviedo, Oviedo, Spain. Consorci Hosp Parc Tauli, Sabadell, Spain. Univ Pompeu Fabra, Barcelona, Spain. Hosp Gen Elche, Elche, Spain. Hosp Univ Canarias, Unidad Invest, San Cristobal la Laguna, Spain. Univ Autonoma Barcelona, Hosp Mar, IMAS, Dept Pathol, Barcelona, Spain. RP Garcia-Closas, M (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 7076,MSC 7234, Rockville, MD 20852 USA. EM montse@nih.gov RI Hein, David/A-9707-2008; Serra, C/E-6879-2014; Lloreta, J/I-2112-2014; Garcia-Closas, Montserrat /F-3871-2015; Osborne, Nicholas/N-4915-2015; Kogevinas, Manolis/C-3918-2017; OI Serra, C/0000-0001-8337-8356; Lloreta, J/0000-0003-1644-9470; Garcia-Closas, Montserrat /0000-0003-1033-2650; Osborne, Nicholas/0000-0002-6700-2284; Castano-Vinyals, Gemma/0000-0003-4468-1816 FU NCI NIH HHS [CA34627, N02CP11015, R01 CA034627] NR 61 TC 375 Z9 388 U1 0 U2 39 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD AUG 20 PY 2005 VL 366 IS 9486 BP 649 EP 659 DI 10.1016/S0140-6736(05)67137-1 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 958EB UT WOS:000231426400028 PM 16112301 ER PT J AU Lenders, JWM Eisenhofer, G Mannelli, M Pacak, K AF Lenders, JWM Eisenhofer, G Mannelli, M Pacak, K TI Phaeochromocytoma SO LANCET LA English DT Review ID ENDOCRINE NEOPLASIA TYPE-2; HIPPEL-LINDAU-DISEASE; POSITRON-EMISSION-TOMOGRAPHY; ADRENAL-SPARING SURGERY; LAPAROSCOPIC ADRENALECTOMY; MALIGNANT PHEOCHROMOCYTOMA; HEREDITARY PHEOCHROMOCYTOMA; PLASMA METANEPHRINES; CHROMOGRANIN-A; EXTRAADRENAL PHEOCHROMOCYTOMA AB Phaeochromocytomas are rare neuroendocrine tumours with a highly variable clinical presentation but most commonly presenting with episodes of headaches, sweating, palpitations, and hypertension. The serious and potentially lethal cardiovascular complications of these tumours are due to the potent effects of secreted catecholamines. Biochemical testing for phaeochromocytoma is indicated not only in symptomatic patients, but also in patients with adrenal incidentalomas or identified genetic predispositions (eg, multiple endocrine neoplasia type 2, von Hippel-Lindau syndrome, neurofibromatosis type 1, and mutations of the succinate dehydrogenase genes). Imaging techniques such as CT or MRI and functional ligands such as I-123-MIBG are used to localise biochemically proven tumours. After the use of appropriate preoperative treatment to block the effects of secreted catecholamines, laparoscopic tumour removal is the preferred procedure. If removal of phaeochromocytoma is timely, prognosis is excellent. However, prognosis is poor in patients with metastases, which especially occur in patients with large, extra-adrenal tumours. C1 Radboud Univ Nijmegen Med Ctr, Dept Internal Med, Div Gen Internal Med, NL-6525 GA Nijmegen, Netherlands. Univ Florence, Dept Clin Pathophysiol, I-50121 Florence, Italy. NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, NIH, Bethesda, MD USA. RP Lenders, JWM (reprint author), Radboud Univ Nijmegen Med Ctr, Dept Internal Med, Div Gen Internal Med, NL-6525 GA Nijmegen, Netherlands. EM j.lenders@aig.umcn.nl RI Lenders, J.W.M./L-4487-2015; OI Mannelli, Massimo/0000-0002-8001-9857 NR 133 TC 612 Z9 655 U1 7 U2 54 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD AUG 20 PY 2005 VL 366 IS 9486 BP 665 EP 675 DI 10.1016/S0140-6736(05)67139-5 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 958EB UT WOS:000231426400031 PM 16112304 ER PT J AU Hait, NC Sarkar, S Le Stunff, H Mikami, A Maceyka, M Milstien, S Spiegel, S AF Hait, NC Sarkar, S Le Stunff, H Mikami, A Maceyka, M Milstien, S Spiegel, S TI Role of sphingosine kinase 2 in cell migration toward epidermal growth factor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; FUNCTIONAL-CHARACTERIZATION; MOLECULAR-CLONING; SPHINGOSINE-1-PHOSPHATE RECEPTORS; LYMPHOCYTE RECIRCULATION; DEPENDENT ACTIVATION; VASCULAR MATURATION; PLASMA-MEMBRANE; KINASE TYPE-2; 1-PHOSPHATE AB Sphingosine 1-phosphate (S1P), produced by two sphingosine kinase isoenzymes, denoted SphK1 and SphK2, is the ligand for a family of five specific G protein-coupled receptors that regulate cytoskeletal rearrangements and cell motility. Whereas many growth factors stimulate SphK1, much less is known of the regulation of SphK2. Here we report that epidermal growth factor (EGF) stimulated SphK2 in HEK 293 cells. This is the first example of an agonist-dependent regulation of SphK2. Chemotaxis of HEK 293 cells toward EGF was inhibited by N,N-dimethylsphingosine, a competitive inhibitor of both SphKs, implicating S1P generation in this process. Down-regulating expression of SphK1 in HEK 293 cells with a specific siRNA abrogated migration toward EGF, whereas decreasing SphK2 expression had no effect. EGF contributes to the invasiveness of human breast cancer cells, and EGF receptor expression is associated with poor prognosis. EGF also stimulated SphK2 in MDA-MB-453 breast cancer cells. Surprisingly, however, down-regulation of SphK2 in these cells completely eliminated migration toward EGF without affecting fibronectin-induced haptotaxis. Our results suggest that SphK2 plays an important role in migration of MDA-MB-453 cells toward EGF. C1 Virginia Commonwealth Univ, Sch Med, Dept Biochem, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Sch Med, Massey Canc Ctr, Richmond, VA 23298 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biochem, Med Coll Virginia Campus, Richmond, VA 23298 USA. EM sspiegel@vcu.edu RI Maceyka, Michael/B-9277-2008 FU NCI NIH HHS [R01CA61774] NR 59 TC 99 Z9 101 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 AUG 19 PY 2005 VL 280 IS 33 BP 29462 EP 29469 DI 10.1074/jbc.M502922200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 954SX UT WOS:000231176200011 PM 15951439 ER PT J AU Doherty, KM Sommers, JA Gray, MD Lee, JW von Kobbe, C Thoma, NH Kureekattil, RP Kenny, MK Brosh, RM AF Doherty, KM Sommers, JA Gray, MD Lee, JW von Kobbe, C Thoma, NH Kureekattil, RP Kenny, MK Brosh, RM TI Physical and functional mapping of the replication protein A interaction domain of the Werner and Bloom syndrome helicases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SYNDROME GENE-PRODUCT; DNA-REPLICATION; RECQ HELICASES; HUMAN-DISEASES; WRN HELICASE; S-PHASE; SUBUNIT; COMPLEX; ARREST; GENOME AB The single-stranded DNA-binding protein replication protein A (RPA) interacts with several human RecQ DNA helicases that have important roles in maintaining genomic stability; however, the mechanism for RPA stimulation of DNA unwinding is not well understood. To map regions of Werner syndrome helicase (WRN) that interact with RPA, yeast two-hybrid studies, WRN affinity pull-down experiments and enzyme-linked immunosorbent assays with purified recombinant WRN protein fragments were performed. The results indicated that WRN has two RPA binding sites, a high affinity N-terminal site, and a lower affinity C-terminal site. Based on results from mapping studies, we sought to determine if the WRN N-terminal region harboring the high affinity RPA interaction site was important for RPA stimulation of WRN helicase activity. To accomplish this, we tested a catalytically active WRN helicase domain fragment (WRNH-R) that lacked the N-terminal RPA interaction site for its ability to unwind long DNA duplex substrates, which the wild-type enzyme can efficiently unwind only in the presence of RPA. WRNH-R helicase activity was significantly reduced on RPA-dependent partial duplex substrates compared with full-length WRN despite the presence of RPA. These results clearly demonstrate that, although WRNH-R had comparable helicase activity to full-length WRN on short duplex substrates, its ability to unwind RPA-dependent WRN helicase substrates was significantly impaired. Similarly, a Bloom syndrome helicase (BLM) domain fragment, BLM642-1290, that lacked its N-terminal RPA interaction site also unwound short DNA duplex substrates similar to wild-type BLM, but was severely compromised in its ability to unwind long DNA substrates that full-length BLM helicase could unwind in the presence of RPA. These results suggest that the physical interaction between RPA and WRN or BLM helicases plays an important role in the mechanism for RPA stimulation of helicase-catalyzed DNA unwinding. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. MDG Assoicates, Seattle, WA 98126 USA. Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, Struct Biol Program, New York, NY 10021 USA. Montefiore Med Ctr, Albert Einstein Coll Med, Dept Emergency Med, Bronx, NY 10467 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM BroshR@grc.nia.nih.gov NR 50 TC 68 Z9 69 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 AUG 19 PY 2005 VL 280 IS 33 BP 29494 EP 29505 DI 10.1074/jbc.M500653200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 954SX UT WOS:000231176200015 PM 15965237 ER PT J AU Golding, H Khurana, S Yarovinsky, F King, LR Abdoulaeva, G Antonsson, L Owman, C Platt, EJ Kabat, D Andersen, JF Sher, A AF Golding, H Khurana, S Yarovinsky, F King, LR Abdoulaeva, G Antonsson, L Owman, C Platt, EJ Kabat, D Andersen, JF Sher, A TI CCR5 N-terminal region plays a critical role in HIV-1 inhibition by Toxoplasma gondii-derived cyclophilin-18 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE GLYCOPROTEIN; AMINO-TERMINUS; GASTROINTESTINAL-TRACT; CHEMOKINE RECEPTORS; ENTRY INHIBITORS; GP120 BINDING; CELL-LINE; INFECTION; DOMAIN AB Molecular mimicry of chemokine ligands has been described for several pathogens. Toxoplasma gondii produces a protein, cyclophilin-18 (C-18), which binds to the human immunodeficiency virus (HIV) co-receptor CCR5 and inhibits fusion and infection of T cells and macrophages by R5 viruses but not by X4 viruses. We recently identified structural determinants of C-18 required for anti-HIV activity (Yarovinsky, F., Andersen, J. F., King, L. R., Caspar, P., Aliberti, J., Golding, H., and Sher, A. ( 2004) J. Biol. Chem. 279, 53635 - 53642). Here we have elucidated the fine specificity of CCR5 residues involved in binding and HIV inhibitory potential of C-18. To delineate the regions of CCR5 involved in C-18 binding, we analyzed C-18 inhibition of cells expressing CXCR4/CCR5 chimeric receptors and CCR5 with a truncated N terminus (Delta 2-19). These experiments identified a critical role for the N terminus of CCR5 in C-18 binding and anti-HIV activity. Studies with a large panel of CCR5 N-terminal peptides, including Tyr-sulfated analogues, truncated peptides, and alanine-scanning mutants, suggested that each of the 12 - 17 amino acids in the N terminus of CCR5 are essential for C-18 binding and inhibitory activity. Tyr sulfation did not improve C-18 reactivity. This finding is of interest because the same CCR5 N-terminal region was shown previously to play a key role in binding of HIV-1 envelope glycoproteins. The elucidation of the functional C-18-binding mechanism may help in the rational design of novel antiviral agents against HIV. C1 US FDA, Div Viral Prodat & Res, Bethesda, MD 20892 USA. US FDA, Core Facil, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. Div Mol Neurobiol, SE-22184 Lund, Sweden. Oregon Hlth Sci Univ, Portland, OR 97239 USA. RP Golding, H (reprint author), US FDA, Div Viral Prodat & Res, Bethesda, MD 20892 USA. EM goldingh@cber.FDA.gov NR 40 TC 7 Z9 8 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 AUG 19 PY 2005 VL 280 IS 33 BP 29570 EP 29577 DI 10.1074/jbc.M500236200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 954SX UT WOS:000231176200024 PM 15975927 ER PT J AU Duran-Sandoval, D Cariou, B Percevault, F Hennuyer, N Grefhorst, A van Dijk, TH Gonzalez, FJ Fruchart, JC Kuipers, F Staels, B AF Duran-Sandoval, D Cariou, B Percevault, F Hennuyer, N Grefhorst, A van Dijk, TH Gonzalez, FJ Fruchart, JC Kuipers, F Staels, B TI The farnesoid X receptor modulates hepatic carbohydrate metabolism during the fasting-refeeding transition SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOENOLPYRUVATE CARBOXYKINASE GENE; REQUIRES GLUCOSE-METABOLISM; BILE-ACIDS; NUCLEAR RECEPTOR; RESPONSE ELEMENT; TRANSCRIPTION FACTOR; EXPRESSION; INSULIN; BINDING; LIVER AB The liver plays a central role in the control of blood glucose homeostasis by maintaining a balance between glucose production and utilization. The farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor. Hepatic FXR expression is regulated by glucose and insulin. Here we identify a role for FXR in the control of hepatic carbohydrate metabolism. When submitted to a controlled fasting-refeeding schedule, FXR-/- mice displayed an accelerated response to high carbohydrate refeeding with an accelerated induction of glycolytic and lipogenic genes and a more pronounced repression of gluconeogenic genes. Plasma insulin and glucose levels were lower in FXR-/- mice upon refeeding the high-carbohydrate diet. These alterations were paralleled by decreased hepatic glycogen content. Hepatic insulin sensitivity was unchanged in FXR-/- mice. Treatment of isolated primary hepatocytes with a synthetic FXR agonist attenuated glucose-induced mRNA expression as well as promoter activity of L-type pyruvate kinase, acetyl-CoA carboxylase 1, and Spot14. Moreover, activated FXR interfered negatively with the carbohydrate response elements regions. These results identify a novel role for FXR as a modulator of hepatic carbohydrate metabolism. C1 Inst Pasteur, INSERM, UR 545, F-59019 Lille, France. Univ Lille, Fac Pharm, F-59019 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), Inst Pasteur, INSERM, UR 545, 1 Rue Prof Calmette-BP245, F-59019 Lille, France. EM bart.staels@pasteur-lille.fr RI percevault, frederic/K-1836-2015 NR 41 TC 120 Z9 126 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 19 PY 2005 VL 280 IS 33 BP 29971 EP 29979 DI 10.1074/jbc.M501931200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 954SX UT WOS:000231176200070 PM 15899888 ER PT J AU Fortune, JM Pavlov, YI Welch, CM Johansson, E Burgers, PMJ Kunkel, TA AF Fortune, JM Pavlov, YI Welch, CM Johansson, E Burgers, PMJ Kunkel, TA TI Saccharomyces cerevisiae DNA polymerase delta - High fidelity for base substitutions but lower fidelity for single- and multi-base deletions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CALF THYMUS; REPLICATION; EPSILON; MUTAGENESIS; HOLOENZYME; ERRORS; PROCESSIVITY; INSTABILITY; FRAMESHIFT; SUBUNIT AB Eukaryotic DNA polymerase delta ( Pol delta) plays an essential role in replicating large nuclear genomes, a process that must be accurate to maintain stability over many generations. Based on kinetic studies of insertion of individual dNTPs opposite a template guanine, Pol delta is believed to have high selectivity for inserting correct nucleotides. This high selectivity, in conjunction with an intrinsic 3'-exonuclease activity, implies that Pol delta should have high base substitution fidelity. Here we demonstrate that the wild type Saccharomyces cerevisiae three-subunit Pol delta does indeed have high base substitution fidelity for the 12 possible base-base mismatches, producing on average less than 1.3 stable misincorporations/ 100,000 nucleotides polymerized. Measurements with exonuclease-deficient Pol delta confirm the high nucleotide selectivity of the polymerase and further indicate that proofreading enhances the base substitution fidelity of the wild type enzyme by at least 60-fold. However, Pol delta inefficiently proofreads single nucleotide deletion mismatches in homopolymeric runs, such that the error rate is 30 single nucleotide deletions/ 100,000 nucleotides polymerized. Moreover, wild type Pol delta frequently deletes larger numbers of nucleotides between distantly spaced direct repeats of three or more base pairs. Although wild type Pol delta and Pol delta both have high base substitution fidelity, Pol delta is much less accurate than Pol epsilon for deletions involving repetitive sequences. Thus, strand slippage during replication by wild type Pol delta may be a primary source of insertion and deletion mutagenesis in eukaryotic genomes. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Washington Univ, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. Umea Univ, Dept Med Biochem & Biophys, SE-90187 Umea, Sweden. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, POB 12233,MD E-3-01, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU NIGMS NIH HHS [R01 GM032431] NR 36 TC 75 Z9 75 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 19 PY 2005 VL 280 IS 33 BP 29980 EP 29987 DI 10.1074/jbc.M505236200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 954SX UT WOS:000231176200071 PM 15964835 ER PT J AU Oku, N Krishnamoorthy, R Benson, AG Ferguson, RL Lipton, MA Phillips, LR Gustafson, KR McMahon, JB AF Oku, N Krishnamoorthy, R Benson, AG Ferguson, RL Lipton, MA Phillips, LR Gustafson, KR McMahon, JB TI Complete stereochemistry of neamphamide A and absolute configuration of the beta-methoxytyrosine residue in papuamide B SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID SPONGE CALLIPELTA SP; STEREOSELECTIVE-SYNTHESIS; ASYMMETRIC-SYNTHESIS; (2R,3R,4S)-3-HYDROXY-2,4,6-TRIMETHYLHEPTANOIC ACID; ENANTIOSELECTIVE SYNTHESIS; CYCLIC DEPSIPEPTIDE; NATURAL PRODUCT; NEW-GUINEA; STEREOISOMERS; DERIVATIVES AB [GRAPHICS] The absolute stereochemistry of the three unresolved structural components in neamphamide A (1) was determined to be (R)-beta-methoxy-L-tyrosine, (2R,3R,4S)-4-amino-7-guanidino-2,3-dihydroxyheptanoic acid, and (2R,3R,4R)-3-hydroxy-2,4,6-trimethylheptanoic acid. Stereochemical assignments were made by chemical degradation of 1, derivatization of the resulting products, and then spectroscopic and chromatographic comparison of the derivatives with synthetically prepared standards. Using the same analytical protocol developed for 1, the beta-methoxytyrosine residue in papuamide B (2) was found to be (R)-beta-methoxy-D-tyrosine. This represents a rare example of divergent stereochemistry in an unusual amino acid residue that is present in two closely related classes of peptides. C1 NCI, Mol Targets Dev Program, Canc Res Ctr, Ft Detrick, MD 21702 USA. Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. NCI, Dev Therapeut Program, Biol Testing Branch, Frederick, MD 21701 USA. RP Gustafson, KR (reprint author), NCI, Mol Targets Dev Program, Canc Res Ctr, Bldg 1052,Room 121, Ft Detrick, MD 21702 USA. EM manuscripts@ncifcrf.gov FU Intramural NIH HHS [Z99 CA999999]; NIAID NIH HHS [AI 50888, R01 AI050888] NR 24 TC 21 Z9 21 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD AUG 19 PY 2005 VL 70 IS 17 BP 6842 EP 6847 DI 10.1021/jo0508853 PG 6 WC Chemistry, Organic SC Chemistry GA 954VK UT WOS:000231183000034 PM 16095304 ER PT J AU Kubler-Kielb, J Pozsgay, V AF Kubler-Kielb, J Pozsgay, V TI A new method for conjugation of carbohydrates to proteins using an aminooxy-thiol heterobifunctional linker SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID INFLUENZAE TYPE-B; CHEMOSELECTIVE LIGATION; PEPTIDE; IMMUNOGENICITY; POLYSACCHARIDE; BIOCONJUGATION; CYCLOADDITION; VACCINE AB [GRAPHICS] A new, efficient, and mild protocol is presented for the coupling of saccharides to proteins. First, a heterobifunctional aminooxy-thiol linker is coupled to the bromoacylated protein to introduce aminooxy groups through thioether linkages. Condensation of the aminooxylated protein and aldehydo/keto-derivatized carbohydrates affords covalent saccharide-protein constructs. Uncoupled saccharide can be recovered in its original form. The scope of our protocol is exemplified by the coupling of neutral mono- and tetrasaccharides and a negatively charged ribitol-phosphate construct to BSA. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Pozsgay, V (reprint author), NICHHD, NIH, 31 Ctr Dr MSC 2423, Bethesda, MD 20892 USA. EM pozsgayv@mail.nih.gov NR 29 TC 31 Z9 31 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD AUG 19 PY 2005 VL 70 IS 17 BP 6987 EP 6990 DI 10.1021/jo050934b PG 4 WC Chemistry, Organic SC Chemistry GA 954VK UT WOS:000231183000063 PM 16095333 ER PT J AU Rapaka, RS Makriyannis, A Di Marzo, V Piomelli, D AF Rapaka, RS Makriyannis, A Di Marzo, V Piomelli, D TI Targeted lipidomics: endocannabinoids and other endolipid modulators - Preface SO LIFE SCIENCES LA English DT Editorial Material C1 NIDA, Bethesda, MD 20892 USA. Northeastern Univ, Boston, MA 02115 USA. CNR, Inst Chim Biomol, Pozzuoli, NA, Italy. Univ Calif Irvine, Gillespie Nanosci Facil, Irvine, CA USA. RP Rapaka, RS (reprint author), NIDA, Bethesda, MD 20892 USA. EM rrapaka@nida.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD AUG 19 PY 2005 VL 77 IS 14 BP 1517 EP 1518 DI 10.1016/j.lfs.2005.05.001 PG 2 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 961DH UT WOS:000231641600001 ER PT J AU Rapaka, RS AF Rapaka, RS TI Lipidomics, drugs of abuse and NIDA - Introduction SO LIFE SCIENCES LA English DT Editorial Material C1 Natl Inst Drug Abuse, Chem & Physiol Syst Res Branch, Div Basic Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. RP Rapaka, RS (reprint author), Natl Inst Drug Abuse, Chem & Physiol Syst Res Branch, Div Basic Neurosci & Behav Res, NIH, Bethesda, MD 20892 USA. EM rr82u@nih.gov NR 0 TC 1 Z9 1 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD AUG 19 PY 2005 VL 77 IS 14 BP 1519 EP 1521 DI 10.1016/j.lfs.2005.05.002 PG 3 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 961DH UT WOS:000231641600002 PM 15961116 ER PT J AU Hayashi, T Su, TP AF Hayashi, T Su, TP TI The potential role of sigma-1 receptors in lipid transport and lipid raft reconstitution in the brain: Implication for drug abuse SO LIFE SCIENCES LA English DT Article; Proceedings Paper CT Workshop on Targeted Lipidomics CY JUN 22, 2004 CL Paestum, ITALY DE raft; microdomain; ganglioside; cholesterol; lipid; sigma; sigma receptor; sigma ligand; cocaine; methamphetamine; trophic factor; PC12; NG108; (+)pentazocine; neuritogenesis; cytoskeleton ID CENTRAL-NERVOUS-SYSTEM; CONDITIONED PLACE PREFERENCE; SIGMA(1) BINDING-SITES; GROWTH-FACTOR RECEPTOR; IMMUNOHISTOCHEMICAL LOCALIZATION; OLIGODENDROCYTE DEVELOPMENT; CHOLESTEROL-METABOLISM; ENDOPLASMIC-RETICULUM; STEROL ISOMERASE; OPIOID RECEPTOR AB The brain is highly enriched in lipids. However, the molecular biological roles of lipids in the brain have been largely unexplored. Although, in 1990s, several studies have demonstrated the roles of lipids in a variety of neuronal functions and certain neurological diseases, the involvement of lipids in drug dependence, if any, is almost totally unknown. Sigma-1 receptors are brain-enriched proteins that interact with psychostimulants such as cocaine and methamphetamine. Sigma-1 receptors possess a putative sterol-binding pocket and are predominantly expressed on the endoplasmic reticulum (ER) where most lipids and their precursors are synthesized. Sigma-1 receptors are involved in drug-seeking behaviors and in psychostimulant-induced behavioral sensitization. Recent studies demonstrated that sigma-1 receptors target the lipid-storing subcompartments of the ER and are colocalized with cholesterol and neutral lipids. Sigma-1 receptors form detergent-insoluble lipid microdomains (lipid rafts) on the ER subcompartments and can translocate on the ER when stimulated. Upregulation of sigma-1 receptors affect the levels of plasma membrane lipid rafts by changing the lipid components therein. The membrane reconstitution thus induced by sigma-1 receptors in turn affects functions of proteins residing in plasma membrane lipid rafts including tropic factor receptors and tyrosine kinases. Specifically, we recently found that sigma-1 receptors modulate MAP kinase activation induced by tropic factors, neuritegenesis and oligodendrocyte differentiation-all related to lipid raft reconstitution. Sigma-1 receptors may thus play a role in psychostimulant-induced long-lasting morphological changes in the brain via the capacity of sigma-1 receptors in regulating ER lipid transport and the resultant plasma membrane lipid raft reconstitution. Published by Elsevier Inc. C1 NIH, Cellular Pathobiol Unit, Dev & Plastic Sect,Cellular Neurobiol Res Branch, IRP,Natl Inst Drug Abuse,DHHS, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIH, Cellular Pathobiol Unit, Dev & Plastic Sect,Cellular Neurobiol Res Branch, IRP,Natl Inst Drug Abuse,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM TSU@intra.nida.nih.gov RI Hayashi, Teruo/A-9690-2008 NR 73 TC 52 Z9 58 U1 2 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD AUG 19 PY 2005 VL 77 IS 14 BP 1612 EP 1624 DI 10.1016/j.lfs.2005.05.009 PG 13 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 961DH UT WOS:000231641600010 PM 16002098 ER PT J AU Jang, MK Mochizuki, K Zhou, MS Jeong, HS Brady, JN Ozato, K AF Jang, MK Mochizuki, K Zhou, MS Jeong, HS Brady, JN Ozato, K TI The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription SO MOLECULAR CELL LA English DT Article ID TERMINAL DOMAIN; LIVING CELLS; KINASE; BINDS; CDK9; ELONGATION; COMPLEX; LOCALIZATION; INTERACTS; SUBUNITS AB Brd4 is a mammalian bromodomain protein that binds to acetylated chromatin. Proteomic analysis revealed that Brd4 interacts with cyclinT1 and Cdk9 that constitutes core positive transcription elongation factor b (P-TEFb). Brd4 interacted with P-TEFb in the living nucleus through its bromodomain. About half of P-TEFb was bound to the inhibitory subunit and functionally inactive. Brd4 interacted with P-TEFb that was free of the inhibitory subunit. An increase in Brd4 expression led to increased P-TEFb-dependent phosphorylation of RNA polymerase II (RNAPII) CTD and stimulation of transcription from promoters in vivo. Conversely, a reduction in Brd4 expression by siRNA reduced CTD phosphorylation and transcription, revealing that Brd4 is a positive regulatory component of P-TEFb. In chromatin immunoprecipitation (ChIP) assays, the recruitment of P-TEFb to a promoter was dependent on Brd4 and was enhanced by an increase in chromatin acetylation. Together, P-TEFb alternately interacts with Brd4 and the inhibitory subunit to maintain functional equilibrium in the cell. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. NCI, Tumor Virus Biol Sect, Basic Res Lab, NIH, Bethesda, MD 20892 USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. EM ozatok@nih.gov NR 39 TC 443 Z9 456 U1 7 U2 30 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD AUG 19 PY 2005 VL 19 IS 4 BP 523 EP 534 DI 10.1016/j.molcel.2005.06.027 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 958OQ UT WOS:000231458000011 PM 16109376 ER PT J AU Yang, ZY Yik, JHN Chen, RC He, NH Jang, MK Ozato, K Zhou, Q AF Yang, ZY Yik, JHN Chen, RC He, NH Jang, MK Ozato, K Zhou, Q TI Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein brd4 SO MOLECULAR CELL LA English DT Article ID RNA-POLYMERASE-II; C-TERMINAL DOMAIN; HIV-1 TAT; 7SK SNRNA; BINDING DOMAIN; HIGH-AFFINITY; IN-VITRO; KINASE; ACTIVATION; IDENTIFICATION AB The cyclinT1/Cdk9 heterodimer that constitutes core P-TEFb is generally presumed to be the transcriptionally active form for stimulating RNA polymerase 11 elongation. About half of cellular P-TEFb also exists in an inactive complex with the 7SK snRNA and the HEXIM1 protein. Here, we show that the remaining half associates with the bromodomain protein Brd4. In stress-induced cells, the 7SK/HEXIM1-bound P-TEFb is quantitatively converted into the Brd4-associated form. The association with Brd4 is necessary to form the transcriptionally active P-TEFb, recruits P-TEFb to a promoter, and enables P-TEFb to contact the Mediator complex, a potential target for the Brd4-mediated recruitment. Although generally required for transcription, the P-TEFb-recruitment function of Brd4 can be substituted by that of HIV-1 Tat, which recruits P-TEFb directly for activated HIV-1 transcription. Brd4, HEXIM1, and 7SK are all implicated in regulating cell growth, which may result from their dynamic control of the general transcription factor P-TEFb. C1 Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. Xiamen Univ, Sch Life Sci, Xiamen 361005, Peoples R China. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Zhou, Q (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. EM qzhou@berkeley.edu RI Yik, Jasper/C-7343-2009; Chen, Ruichuan/G-4618-2010; Yang, Zhiyuan/C-9543-2012 OI Yik, Jasper/0000-0001-7532-629X; Yang, Zhiyuan/0000-0002-1175-4188 FU NIAID NIH HHS [AI058400, AI41757] NR 42 TC 414 Z9 432 U1 5 U2 30 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD AUG 19 PY 2005 VL 19 IS 4 BP 535 EP 545 DI 10.1016/j.molcel.2005.06.029 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 958OQ UT WOS:000231458000012 PM 16109377 ER PT J AU Anfinrud, P Schotte, F AF Anfinrud, P Schotte, F TI X-ray fingerprinting of chemical intermediates in solution SO SCIENCE LA English DT Editorial Material ID CRYSTALLOGRAPHY; PROTEIN; TIME; DIFFRACTION; MYOGLOBIN C1 NIH, Chem Phys Lab, Bethesda, MD 20892 USA. RP Anfinrud, P (reprint author), NIH, Chem Phys Lab, Bldg 10, Bethesda, MD 20892 USA. EM anfinrud@nih.gov FU Intramural NIH HHS NR 16 TC 5 Z9 6 U1 2 U2 5 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 AUG 19 PY 2005 VL 309 IS 5738 BP 1192 EP 1193 DI 10.1126/science.1117325 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 957TE UT WOS:000231395400029 PM 16109869 ER PT J AU Talbot, LA Musiol, RJ Witham, EK Metter, EJ AF Talbot, LA Musiol, RJ Witham, EK Metter, EJ TI Falls in young, middle-aged and older community dwelling adults: perceived cause, environmental factors and injury SO BMC PUBLIC HEALTH LA English DT Article ID ELDERLY PEOPLE; RISK-FACTORS; HOME; POPULATION; WOMEN; MEN; PREVALENCE AB Background: Falls in older people have been characterized extensively in the literature, however little has been reported regarding falls in middle-aged and younger adults. The objective of this paper is to describe the perceived cause, environmental influences and resultant injuries of falls in 1497 young (20-45 years), middle-aged (46-65 years) and older (>65 years) men and women from the Baltimore Longitudinal Study on Aging. Methods: A descriptive study where participants completed a fall history questionnaire describing the circumstances surrounding falls in the previous two years. Results: The reporting of falls increased with age from 18% in young, to 21% in middle-aged and 35% in older adults, with higher rates in women than men. Ambulation was cited as the cause of the fall most frequently in all gender and age groups. Our population reported a higher percentage of injuries (70.5%) than previous studies. The young group reported injuries most frequently to wrist/hand, knees and ankles; the middle-aged to their knees and the older group to their head and knees. Women reported a higher percentage of injuries in all age groups. Conclusion: This is the first study to compare falls in young, middle and older aged men and women. Significant differences were found between the three age groups with respect to number of falls, activities engaged in prior to falling, perceived causes of the fall and where they fell. C1 Uniformed Serv Univ Hlth Sci, Grad Sch Nursing, Silver Spring, MD 20910 USA. Holy Cross Hosp, Silver Spring, MD 20910 USA. Henry M Jackson Fdn, Rockville, MD 20852 USA. Harbor Hosp, NIH, Intramural Res Program, NIH, Baltimore, MD 21225 USA. RP Talbot, LA (reprint author), Uniformed Serv Univ Hlth Sci, Grad Sch Nursing, 1335 East West Highway, Silver Spring, MD 20910 USA. EM ltalbot@usuhs.mil; robinmusiol@hotmail.com; ewitham@usuhs.mil; MetterJ@grc.nia.nih.gov FU Intramural NIH HHS NR 38 TC 119 Z9 124 U1 1 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD AUG 18 PY 2005 VL 5 AR 86 DI 10.1186/1471-2458-5-86 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 964KQ UT WOS:000231880400002 PM 16109159 ER PT J AU Dietz, BM Mahady, GB Pauli, GF Farnsworth, NR AF Dietz, BM Mahady, GB Pauli, GF Farnsworth, NR TI Valerian extract and valerenic acid are partial agonists of the 5-HT5a receptor in vitro SO MOLECULAR BRAIN RESEARCH LA English DT Article DE circadian rhythm; insomnia; serotonin; 5-HT5A; valerian; valerenic acid ID SEROTONIN RECEPTOR; RAT-BRAIN; SLEEP; BINDING; CLONING; STRESS; LOCALIZATION; VOLUNTEERS; EXPRESSION; INSOMNIA AB Insomnia is the most frequently encountered sleep complaint worldwide. While many prescription drugs are used to treat insomnia, extracts of valerian (Valeriana officinalis L., Valerianaceae) are also used for the treatment of insomnia and restlessness. To determine novel mechanisms of action, radioligand binding studies were performed with valerian extracts (100% methanol, 50% methanol, dichloromethane [DCM], and petroleum ether [PE]) at the melatonin, glutamate, and GABA(A) receptors, and 8 serotonin receptor subtypes. Both DCM and PE extracts had strong binding affinity to the 5-HT5a receptor, but only weak binding affinity to the 5-HT2b and the serotonin transporter. Subsequent binding studies focused on the 5-HT5a receptor due to the distribution of this receptor in the suprachiasmatic nucleus of the brain, which is implicated in the sleep-wake cycle. The PE extract inhibited [H-3]lysergic acid diethylamide (LSD) binding to the human 5-HT5a receptor (86% at 50 mu g/ml) and the DCM extract inhibited LSD binding by 51%. Generation of an IC50 curve for the PE extract produced a biphasic curve, thus GTP shift experiments were also performed. In the absence of GTP, the competition curve was biphasic (two affinity sites) with an IC50 of 15.7 ng/ml for the high-affinity state and 27.7 mu g/ml for the low-affinity state. The addition of GTP (100 AM) resulted in a right-hand shift of the binding curve with an IC50 of 11.4 mu g/ml. Valerenic acid, the active constituent of both extracts, had an IC50 of 17.2 mu M. These results indicate that valerian and valerenic acid are new partial agonists of the 5-HT5a receptor. (c) 2005 Elsevier B.V. All rights reserved. C1 Univ Illinois, Coll Pharm, Dept Pharm Practice, Chicago, IL 60612 USA. Univ Illinois, Coll Pharm, NIH, Ctr Bot Dietary Supplements Res, Chicago, IL 60612 USA. RP Mahady, GB (reprint author), Univ Illinois, Coll Pharm, Dept Pharm Practice, Rm 122,833 S Wood St,MC 886, Chicago, IL 60612 USA. EM mahady@uic.edu OI Pauli, Guido/0000-0003-1022-4326 NR 48 TC 36 Z9 36 U1 0 U2 8 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 AUG 18 PY 2005 VL 138 IS 2 BP 191 EP 197 DI 10.1016/j.molbrainres.2005.04.009 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 958VH UT WOS:000231475800010 ER PT J AU Feld, JJ Hoofnagle, JH AF Feld, JJ Hoofnagle, JH TI Mechanism of action of interferon and ribavirin in treatment of hepatitis C SO NATURE LA English DT Review ID NONSTRUCTURAL 5A PROTEIN; INDUCED ANTIVIRAL RESPONSE; VIRUS-INFECTION; GENE-EXPRESSION; ALPHA-INTERFERON; PEGINTERFERON ALPHA-2A; MICROARRAY ANALYSIS; INITIAL TREATMENT; RNA REPLICATION; PLUS RIBAVIRIN AB Since the identification of the hepatitis C virus, great strides have been made in the development of an antiviral therapy. As a crucial mediator of the innate antiviral immune response, interferon-alpha (IFN-alpha) was a natural choice for treatment. Whereas treatment with IFN-alpha alone achieved only modest success, the addition of the broad-spectrum antiviral agent ribavirin greatly improved responses. However, half of the infected individuals with chronic disease do not achieve sustained clearance of hepatitis C virus. To optimize current therapeutic strategies and to develop new therapies, a better understanding of the mechanism of action of IFN and ribavirin will be essential. C1 NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Hoofnagle, JH (reprint author), NIDDKD, Liver Dis Branch, NIH, Bldg 31,Room 9A27,31 Ctr Dr, Bethesda, MD 20892 USA. EM Hoofnagle@extra.niddk.nih.gov RI Yang, Chen/G-1379-2010 NR 91 TC 617 Z9 656 U1 8 U2 51 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 18 PY 2005 VL 436 IS 7053 BP 967 EP 972 DI 10.1038/nature04082 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 955XQ UT WOS:000231263900039 PM 16107837 ER PT J AU Jorgensen, R Merrill, AR Yates, SP Marquez, VE Schwan, AL Boesen, T Andersen, GR AF Jorgensen, R Merrill, AR Yates, SP Marquez, VE Schwan, AL Boesen, T Andersen, GR TI Exotoxin A-eEF2 complex structure indicates ADP ribosylation by ribosome mimicry SO NATURE LA English DT Article ID PSEUDOMONAS-AERUGINOSA EXOTOXIN; NICOTINAMIDE ADENINE-DINUCLEOTIDE; ELONGATION-FACTOR EEF2; DIPHTHERIA-TOXIN; CRYSTAL-STRUCTURE; CONFORMATIONAL-CHANGES; CLOSTRIDIUM-BOTULINUM; CATALYTIC MECHANISM; C3 EXOENZYME; TRANSFER-RNA AB The bacteria causing diphtheria, whooping cough, cholera and other diseases secrete mono-ADP-ribosylating toxins that modify intracellular proteins. Here, we describe four structures of a catalytically active complex between a fragment of Pseudomonas aeruginosa exotoxin A (ETA) and its protein substrate, translation elongation factor 2 (eEF2). The target residue in eEF2, diphthamide (a modified histidine), spans across a cleft and faces the two phosphates and a ribose of the non-hydrolysable NAD(+) analogue, beta TAD. This suggests that the diphthamide is involved in triggering NAD(+) cleavage and interacting with the proposed oxacarbenium intermediate during the nucleophilic substitution reaction, explaining the requirement of diphthamide for ADP ribosylation. Diphtheria toxin may recognize eEF2 in a manner similar to ETA. Notably, the toxin-bound beta TAD phosphates mimic the phosphate backbone of two nucleotides in a conformational switch of 18S rRNA, thereby achieving universal recognition of eEF2 by ETA. C1 Aarhus Univ, Ctr Struct Biol, Dept Mol Biol, DK-8000 Aarhus, Denmark. Univ Guelph, Dept Mol & Cellular Biol, Guelph, ON N1G 2W1, Canada. Univ Guelph, Dept Chem, Guelph, ON N1G 2W1, Canada. NCI, Med Chem Lab, Canc Res Ctr, NIH, Frederick, MD 21702 USA. RP Andersen, GR (reprint author), Aarhus Univ, Ctr Struct Biol, Dept Mol Biol, Gustav Wieds Vej 10C, DK-8000 Aarhus, Denmark. EM rmerrill@uoguelph.ca; gra@mb.au.dk RI Jorgensen, Rene/P-5619-2014; OI Jorgensen, Rene/0000-0003-0672-466X; Andersen, Gregers Rom/0000-0001-6292-3319 NR 38 TC 76 Z9 76 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 18 PY 2005 VL 436 IS 7053 BP 979 EP 984 DI 10.1038/nature03871 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 955XQ UT WOS:000231263900041 PM 16107839 ER PT J AU Palmer, CL Lim, W Hastie, PGR Toward, M Korolchuk, VI Burbidge, SA Banting, G Collingridge, GL Isaac, JTR Henley, JM AF Palmer, CL Lim, W Hastie, PGR Toward, M Korolchuk, VI Burbidge, SA Banting, G Collingridge, GL Isaac, JTR Henley, JM TI Hippocalcin functions as a calcium sensor in hippocampal LTD SO NEURON LA English DT Article ID AMPA RECEPTOR TRAFFICKING; SYNAPTIC-TRANSMISSION; GLUTAMATE RECEPTORS; TYROSINE MOTIFS; 2-HYBRID SYSTEM; CLATHRIN; PROTEIN; ENDOCYTOSIS; BINDING; BRAIN AB It is not fully understood how NMDAR-dependent LTD causes Ca2+-dependent endocytosis of AMPARs. Here we show that the neuronal Ca2+ sensor hippocalcin binds the beta 2-adaptin subunit of the AP2 adaptor complex and that along with GluR2 these coimmunoprecipitate in a Ca2+-sensitive manner. Infusion of a truncated mutant of hippocalcin (HIP2-72) that lacks the Ca2+ binding domains prevents synaptically evoked LTD but has no effect on LTR These data indicate that the AP2-hippocalcin complex acts as a Ca2+ sensor that couples NMDAR-dependent activation to regulated endocytosis of AMPARs during LTD. C1 Univ Bristol, Sch Med Sci, Dept Anat, MRC Ctr Synapt Plast, Bristol BS8 1TD, Avon, England. Univ Bristol, Sch Med Sci, Dept Biochem, Bristol BS8 1TD, Avon, England. GlaxoSmithKline Inc, Neurol Ctr Excellence Drug Discovery, Harlow CM19 5AW, Essex, England. NINDS, NIH, Bethesda, MD 20892 USA. RP Henley, JM (reprint author), Univ Bristol, Sch Med Sci, Dept Anat, MRC Ctr Synapt Plast, Bristol BS8 1TD, Avon, England. EM j.m.henley@bris.ac.uk RI Henley, Jeremy/A-2776-2009; Collingridge, Graham/C-4605-2015; OI Collingridge, Graham/0000-0002-9572-5359; Korolchuk, Viktor/0000-0002-4071-592X; Banting, George/0000-0001-8249-1621; Henley, Jeremy/0000-0003-3589-8335 FU Medical Research Council [G9532377, G9629038]; Wellcome Trust [, 059917] NR 40 TC 74 Z9 79 U1 2 U2 11 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 18 PY 2005 VL 47 IS 4 BP 487 EP 494 DI 10.1016/j.neuron.2005.06.014 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 957ZC UT WOS:000231411100006 PM 16102532 ER PT J AU Bielsky, IF Hu, SB Ren, XH Terwilliger, EF Young, LJ AF Bielsky, IF Hu, SB Ren, XH Terwilliger, EF Young, LJ TI The V1a vasopressin receptor is necessary and sufficient for normal social recognition: A gene replacement study SO NEURON LA English DT Article ID ANXIETY-RELATED BEHAVIOR; LATERAL SEPTAL VASOPRESSIN; PAIR-BOND FORMATION; AGGRESSIVE-BEHAVIOR; PATERNAL BEHAVIOR; MONOGAMOUS VOLE; GOLDEN-HAMSTERS; MEADOW VOLES; RAT-BRAIN; MEMORY AB Vasopressin modulates many social and nonsocial behaviors, including emotionality. We have previously reported that male mice with a null mutation in the V1a receptor (V1aR) exhibit a profound impairment in social recognition and changes in anxiety-like behavior. Using site-specific injections of a V1aR-specific antagonist, we demonstrate that the lateral septum, but not the medial amygdala, is critical for social recognition. Reexpressing V1aR in the lateral septum of V1aR knockout mice (V1aRKO) using a viral vector resulted in a complete rescue of social recognition. Furthermore, overexpression of the V1aR in the lateral septum of wild-type (wt) mice resulted in a potentiation of social recognition behavior and a mild increase in anxiety-related behavior. These results demonstrate that the V1aR in the lateral septum plays a critical role in the neural processing of social stimuli required for complex social behavior. C1 Emory Univ, Dept Psychiat, Atlanta, GA 30329 USA. Emory Univ, Ctr Behav Neurosci, Atlanta, GA 30329 USA. NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. Harvard Univ, Inst Med, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. RP Bielsky, IF (reprint author), Emory Univ, Dept Psychiat, Atlanta, GA 30329 USA. EM alanwithisa@yahoo.com FU NCRR NIH HHS [RR00165]; NIMH NIH HHS [MH64692, MH056538, MH070112, MH56897] NR 60 TC 193 Z9 200 U1 6 U2 17 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 18 PY 2005 VL 47 IS 4 BP 503 EP 513 DI 10.1016/j.neuron.2005.06.031 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 957ZC UT WOS:000231411100008 PM 16102534 ER PT J AU Yoo, E Kim, BU Lee, SY Cho, CH Chung, JH Lee, CH AF Yoo, E Kim, BU Lee, SY Cho, CH Chung, JH Lee, CH TI 53BP1 is associated with replication protein A and is required for RPA2 hyperphosphorylation following DNA damage SO ONCOGENE LA English DT Article DE 53BP1; replication protein A; camptothecin ID DOUBLE-STRAND BREAKS; BINDING PROTEIN; ATAXIA-TELANGIECTASIA; P34 SUBUNIT; HELA-CELLS; PHOSPHORYLATION; CHECKPOINT; KINASE; CAMPTOTHECIN; SENSITIVITY AB p53-binding protein 1 (53BP1) acts as an 'adaptor/mediator' for transducing DNA damage signals, especially following detection of DNA double-strand breaks. In an effort to broaden our understanding of the protein network surrounding 53BP1, we isolated possible 53BP1 binding partners by co-immunoprecipitation, and identified them via tandem mass spectrometric analysis. The 53BP1-associated proteins included RPA1 and RPA2, two components of the replication protein A (RPA) complex. The presence of RPA components in the immunoprecipitates was confirmed by immunoblotting, and we found that the association between 53BP1 and RPA2 was disrupted following DNA damage induced by treatment with camptothecin, a topoisomerase I inhibitor. To investigate the functional meaning of the 53BP1 and RPA interaction, we established U2OS osteosarcoma cell lines stably expressing dominant-negative fragments of 53BP1. We found that camptothecin-induced RPA2 phosphorylation was inhibited in these cells, and also following 53BP1 knockdown by siRNA transfection. On the cellular level, camptothecin-induced apoptosis was augmented in the dominant-negative cell lines, resulting in increased chemosensitivity to this drug. Taken together, these results suggest that 53BP1 is involved in DNA damage-induced RPA2 hyperphosphorylation, and inhibition of 53BP1 function may sensitize cancer cells to camptothecin treatment. C1 Natl Canc Ctr, Res Inst, Gyeonggi 411769, South Korea. NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Lee, CH (reprint author), Natl Canc Ctr, Res Inst, 809 Madu Dong, Gyeonggi 411769, South Korea. EM chlee@ncc.re.kr NR 35 TC 21 Z9 23 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 AUG 18 PY 2005 VL 24 IS 35 BP 5423 EP 5430 DI 10.1038/sj.onc.1208710 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 955JN UT WOS:000231222300003 PM 15856006 ER PT J AU Wendler, D Belsky, L Thompson, KM Emanuel, EJ AF Wendler, D Belsky, L Thompson, KM Emanuel, EJ TI Quantifying the federal minimal risk standard - Implications for pediatric research without a prospect of direct benefit SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CHILDREN; EXPERIMENTATION; VENIPUNCTURE; HEALTH; BIASES AB United States federal regulations allow institutional review boards (IRBs) to approve pediatric research that does not offer participants a "prospect of direct" benefit only when, the risks are minimal or a "minor" increase over minimal. The federal regulations define minimal risks based on the risks "ordinarily encountered in daily life or during routine physical or psychological examinations or tests." In the absence of empirical data, IRB members may assume they are familiar with the risks of daily life and with the risks of routine examinations and tests and rely on their own intuitive judgment to make these assessments. Yet intuitive judgment of risk is subject to systematic errors, highlighting the need for empirical data to guide IRB review and approval of pediatric research. Current data reveal that car trips pose the highest risk of mortality ordinarily encountered by healthy children. On average, these risks are approximately 0.06 per million for children aged 14 years and younger, and approximately 0.4 per million for children aged 15 through 19 years. Riskier, but still ordinary, car trips pose an approximately 0.6 per million chance of death for children aged 14 years and younger and an approximately 4 per million chance of,death for children aged 15 through 19 years. Participation in sports represents the upper end of the range of morbidity risks for healthy children. For every million instances of playing basketball, approximately 1900 individuals will sustain injuries, including 180 broken bones and 58 permanent disabilities. These findings suggest IRBs are implementing the federal minimal risk standard too cautiously in many cases. These data also raise the question of whether the federal minimal risk standard may sometimes fail to provide sufficient protection for children, prompting the need to consider alternative standards. C1 NIH, Dept Clin Bioeth, NIH Clin Ctr, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Kids Risk Project, Boston, MA 02115 USA. RP Wendler, D (reprint author), NIH, Dept Clin Bioeth, NIH Clin Ctr, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov NR 37 TC 68 Z9 68 U1 2 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 17 PY 2005 VL 294 IS 7 BP 826 EP 832 DI 10.1001/jama.294.7.826 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 955LI UT WOS:000231227000023 PM 16106008 ER PT J AU Cai, HB Lin, X Xie, CS Laird, FM Lai, C Wen, HJ Chiang, HC Shim, H Farah, MH Hoke, A Price, DL Wong, PC AF Cai, HB Lin, X Xie, CS Laird, FM Lai, C Wen, HJ Chiang, HC Shim, H Farah, MH Hoke, A Price, DL Wong, PC TI Loss of ALS2 function is insufficient to trigger motor neuron degeneration in knock-out mice but predisposes neurons to oxidative stress SO JOURNAL OF NEUROSCIENCE LA English DT Article DE ALS2; knock-out mouse; motor neuron; motor coordination; motor learning; oxidative stress ID NUCLEOTIDE EXCHANGE FACTOR; AMYOTROPHIC-LATERAL-SCLEROSIS; CU/ZN-SUPEROXIDE-DISMUTASE; SPASTIC PARALYSIS; SPINAL-CORD; GENE; DISEASE; PROTEIN; RAB5; PHENOTYPE AB Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, is caused by a selective loss of motor neurons in the CNS. Mutations in the ALS2 gene have been linked to one form of autosomal recessive juvenile onset ALS ( ALS2). To investigate the pathogenic mechanisms of ALS2, we generated ALS2 knock-out (ALS2(-/-)) mice. Although ALS2(-/-) mice lacked obvious developmental abnormalities, they exhibited age-dependent deficits in motor coordination and motor learning. Moreover, ALS2(-/-) mice showed a higher anxiety response in the open-field and elevated plus-maze tasks. Although they failed to recapitulate clinical or neuropathological phenotypes consistent with motor neuron disease by 20 months of age, ALS2(-/-) mice or primary cultured neurons derived from these mice were more susceptible to oxidative stress compared with wild-type controls. These observations suggest that loss of ALS2 function is insufficient to cause major motor deficits or motor neuron degeneration in a mouse model but predisposes neurons to oxidative stress. C1 NIA, Sect Transgenesis, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. RP Cai, HB (reprint author), NIA, Sect Transgenesis, Neurogenet Lab, NIH, Bldg 35,Room 1A116,MSC 3707,35 Convent Dr, Bethesda, MD 20892 USA. EM caih@mail.nih.gov RI Cai, Huaibin/H-3359-2013; OI Cai, Huaibin/0000-0002-8596-6108; Hoke, Ahmet/0000-0003-1215-3373 FU Intramural NIH HHS [Z01 AG000959-04, Z99 AG999999]; NINDS NIH HHS [R01 NS040014, R01 NS40014] NR 28 TC 76 Z9 80 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 AUG 17 PY 2005 VL 25 IS 33 BP 7567 EP 7574 DI 10.1523/JNEUROSCI.1645-05.2005 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 955XW UT WOS:000231264500010 PM 16107644 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 NCI EORTC Working Grp Canc Diagnos TI Reporting recommendations for tumor marker prognostic studies (REMARK) SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material 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 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 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 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. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NCI, Canc Diag Program, Bethesda, MD 20892 USA. Univ Oxford Wolfson Coll, Ctr Stat Med, Med Stat Grp, Oxford OX2 6UD, England. Univ Freiburg Klinikum, Inst Med Biometrie & Med Informat, Freiburg, Germany. Osped Civile Venezia, Ctr Reg Indicatori Biochim Tumore, Venice, Italy. OSI Pharmaceut Inc, Boulder, CO USA. RP McShane, LM (reprint author), NCI, Biometr Res Branch, DCTD,Rm 8126,Execut Plaza N,MSC 7434,6130 Execut, Bethesda, MD 20892 USA. EM lm5h@nih.gov NR 42 TC 730 Z9 741 U1 4 U2 24 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 AUG 17 PY 2005 VL 97 IS 16 BP 1180 EP 1184 DI 10.1093/jnci/dji237 PG 5 WC Oncology SC Oncology GA 969YT UT WOS:000232272800007 PM 16106022 ER PT J AU Baldwin, LM Dobie, SA Billingsley, K Cai, Y Wright, GE Dominitz, JA Barlow, W Warren, JL Taplin, SH AF Baldwin, LM Dobie, SA Billingsley, K Cai, Y Wright, GE Dominitz, JA Barlow, W Warren, JL Taplin, SH TI Explaining black-white differences in receipt of recommended colon cancer treatment SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID AFRICAN-AMERICAN WOMEN; SEER-MEDICARE DATA; QUALITY-OF-CARE; RACIAL-DIFFERENCES; COLORECTAL-CANCER; LUNG-CANCER; ADJUVANT CHEMOTHERAPY; UNITED-STATES; RENAL-TRANSPLANTATION; PROSTATE CARCINOMA AB Background. Black-white disparities exist in receipt of recommended medical care, including colorectal cancer treatment. This retrospective cohort study examines the degree to which health systems (e.g., physician, hospital) factors explain black-white disparities in colon cancer care. Methods: Data from the Surveillance, Epidemiology, and End Results program; Medicare claims; the American Medical Association Masterfile; and hospital surveys were linked to examine chemotherapy receipt after stage III colon cancer resection among 5294 elderly ( >= 66 years of age) black and white Medicare-insured patients. Logistic regression analysis was used to identify factors associated with black-white differences in chemotherapy use. All statistical tests were two-sided. Results: Black and white patients were equally likely to consult with a medical oncologist, but among patients who had such a consultation, black patients were less likely than white patients (59.3% versus 70.4%, difference = 10.9%, 95% confidence interval [CI] = 5.1% to 16.4%, P < .001) to receive chemotherapy. This black-white disparity was highest among patients aged 66-70 years (black patients 65.7%, white patients 86.3%, difference = 20.6%, 95% CI = 10.7% to 30.4%, P < .001) and decreased with age. The disparity among patients aged 66-70 years also remained statistically significant in the regression analysis. Overall, patient, physician, hospital, and environmental factors accounted for approximately 50% of the disparity in chemotherapy receipt among patients aged 66-70 years; surgical length of stay and neighborhood socioeconomic status accounted for approximately 27% of the disparity in this age group, and health systems factors accounted for 12%. Conclusions: Black and white Medicare-insured colon cancer patients have an equal opportunity to learn about adjuvant chemotherapy from a medical oncologist but do not receive chemotherapy equally. Little disparity was explained by health systems; more was explained by illness severity, social support, and environment. Further qualitative research is needed to understand the factors that influence the lower receipt of chemotherapy by black patients. C1 Univ Washington, Dept Family Med, Seattle, WA 98195 USA. Oregon Hlth Sci Univ, Dept Surg, Portland, OR 97201 USA. VA Puget Sound Hlth Care Syst, NW Ctr Outcomes Res Older Adults, Ctr Excellence, Seattle, WA USA. Univ Washington, Dept Med, Div Gastroenterol, Seattle, WA 98195 USA. Canc Res & Biostat, Seattle, WA USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Baldwin, LM (reprint author), Univ Washington, Dept Family Med, Box 354982, Seattle, WA 98195 USA. EM lmb@fammed.washington.edu OI Dominitz, Jason/0000-0002-8070-7086 FU NCI NIH HHS [R01 CA089544, R01 CA089544-01, R01CA089544] NR 71 TC 124 Z9 125 U1 2 U2 4 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 AUG 17 PY 2005 VL 97 IS 16 BP 1211 EP 1220 DI 10.1093/jnci/dji241 PG 10 WC Oncology SC Oncology GA 969YT UT WOS:000232272800011 PM 16106026 ER PT J AU Adler, V Qu, YX Smith, SJ Izotova, L Pestka, S Kung, HF Lin, M Friedman, FK Chie, L Chung, D Boutjdir, M Pincus, MR AF Adler, V Qu, YX Smith, SJ Izotova, L Pestka, S Kung, HF Lin, M Friedman, FK Chie, L Chung, D Boutjdir, M Pincus, MR TI Functional interactions of Raf and MEK with jun-N-terminal kinase (JNK) result in a positive feedback loop on the oncogenic ras signaling pathway SO BIOCHEMISTRY LA English DT Article ID LAEVIS OOCYTE MATURATION; RAS-P21 PROTEIN; XENOPUS-LAEVIS; CHEMOTHERAPEUTIC-AGENTS; EFFECTOR PEPTIDE; MAP KINASE; INDUCTION; IDENTIFICATION; TRANSFORMATION; INHIBITION AB In previous studies we have found that oncogenic (Val 12)-ras-p21 induces Xenopus laevis oocyte maturation that is selectively blocked by two ras-p21 peptides, 35-47, also called PNC-7, that blocks its interaction with raf, and 96-110, also called PNC-2, that blocks its interaction with jun-N-terminal kinase (INK). Each peptide blocks activation of both JNK and MAP kinase (MAPK or ERK) suggesting interaction between the raf-MEK-ERK and JNK-jun pathways. We further found that dominant negative raf blocks JNK induction of oocyte maturation, again suggesting cross-talk between pathways. In this study, we have undertaken to determine where these points of cross-talk occur. First, we have immunoprecipitated injected Val 12-Ha-ras-p21 from oocytes and found that a complex forms between ras-p21 raf, MEK, MAPK, and JNK. Co-injection of either peptide, but not a control peptide, causes diminished binding of ras-p21, raf, and JNK. Thus, one site of interaction is cooperative binding of Val 12-ras-p21 to raf and JNK. Second, we have injected JNK, c-raf, and MEK into oocytes alone and in the presence of raf and MEK inhibitors and found that JNK activation is independent of the raf-MEK-MAPK pathway but that activated JNK activates raf, allowing for activation of ERK. Furthermore, we have found that constitutively activated MEK activates JNK. We have corroborated these findings in studies with isolated protein components from a human astrocyte (U-251) cell line; that is, JNK phosphorylates raf but not the reverse; MEK phosphorylates JNK but not the reverse. We further have found that JNK does not phosphorylate MAPK and that MAPK does not phosphorylate JNK. The stress-inducing agent, anisomycin, causes activation of JNK, raf, MEK, and ERK in this cell line; activation of JNK is not inhibitable by the MEK inhibitor, U0126, while activation of raf, MEK, and ERK are blocked by this agent. These results suggest that activated JNK can, in turn, activate not only jun but also raf that, in turn, activates MEK that can then cross-activate JNK in a positive feedback loop. C1 New York Harbor VA Med Ctr, Dept Pathol & Lab Med 113, Brooklyn, NY 11209 USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. QRNA Corp, New York, NY 10032 USA. Suny Downstate Med Ctr, Dept Pathol, Brooklyn, NY 11203 USA. Univ Med & Dent New Jersey, Dept Microbiol & Human Genet, Robert Wood Johnson Med Ctr, Piscataway, NJ 08854 USA. NCI, Lab Expt & Computat Biol, Bethesda, MD 20892 USA. Chinese Univ Hong Kong, Dept Virol, Hong Kong, Hong Kong, Peoples R China. Long Isl Univ, Dept Chem & Biol, Brooklyn, NY 11201 USA. Canc Inst New Jersey, New Brunswick, NJ 08901 USA. RP Pincus, MR (reprint author), New York Harbor VA Med Ctr, Dept Pathol & Lab Med 113, 800 Poly Pl, Brooklyn, NY 11209 USA. EM matthew.pincus2@med.va.gov RI Friedman, Fred/D-4208-2016 FU NCI NIH HHS [R01CA42500, R01-CA46465]; NIAID NIH HHS [R01-AI43369, R01-AI36450] NR 33 TC 22 Z9 22 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 16 PY 2005 VL 44 IS 32 BP 10784 EP 10795 DI 10.1021/bi050619j PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 956ZT UT WOS:000231339600005 PM 16086581 ER PT J AU Yin, SM Guan, Z Tang, YY Zhao, J Honga, JS Zhang, WQ AF Yin, SM Guan, Z Tang, YY Zhao, J Honga, JS Zhang, WQ TI Abnormal expression of epilepsy-related gene ERG1/NSF in the spontaneous recurrent seizure rats with spatial learning memory deficits induced by kainic acid SO BRAIN RESEARCH LA English DT Article DE epilepsy-related gene; spontaneous recurrent seizure; N-ethylmaleimide-sensitive fusion protein; kainic acid; spatial learning memory; ventral tegmental area ID LONG-TERM POTENTIATION; NEUROTRANSMITTER RELEASE; SYNAPTIC-TRANSMISSION; HIPPOCAMPAL LTD; LOBE EPILEPSY; AMPA; NSF; PLASTICITY; IMPAIRMENT; ACTIVATION AB Previous epilepsy-related gene screen identified a spontaneous recurrent seizure (SRS)-related gene named epilepsy-related gene (ERG1) that encodes N-ethylmaleimide-sensitive fusion protein (NSF). To explore whether spatial learning memory deficits are relevant to SRS and whether hippocampal NSF expression is altered by SRS, we used the kainic acid (KA)-induced epilepsy animal model. SRS was monitored for 3 weeks after injection of a single convulsive dose of KA. KA-treated rats with SRS, KA-treated rats without SRS, and saline-treated rats were then measured in Morris water maze. In this spatial learning task, KA-treated rats with SRS performed poorer compared to those without SRS and those treated with saline. During the subsequent probe trials, KA-treated rats with SRS spent less swim path and time in the target quadrant but more swim path and time in the opposite quadrant, and showed fewer platform crossings. Moreover, in situ hybridization and immunohistochemistry showed that both ERG1/NSF mRNA and NSF immunoreactive expression were down-regulated in the CA1 and dorsal dentate gyrus cells (dDGCs) of the hippocampus, and interestingly, tyrosine hydroxylase (TH) immunoreactive dopamine (DA) neurons were lost in ventral tegmental area (VTA) in the KA rats with SRS. These data demonstrate that SRS impairs spatial learning memory and suggest that the down-regulation of NSF expression pattern in the hippocampus and the loss of DA neurons in VTA might contribute to the spatial learning memory deficits induced by SRS. (c) 2005 Elsevier B.V. All rights reserved. C1 Dalian Med Univ, Dept Physiol, Dalian 116027, Peoples R China. Dalian Univ Technol, Inst Neuroinformat, Dalian 116024, Peoples R China. Natl Inst Environm Hlth Sci, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Tang, YY (reprint author), Dalian Med Univ, Dept Physiol, Dalian 116027, Peoples R China. EM shengmingyin@yahoo.com.cn; yy2100@163.net; wanqinzhang100@yahoo.com.cn NR 41 TC 11 Z9 12 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD AUG 16 PY 2005 VL 1053 IS 1-2 BP 195 EP 202 DI 10.1016/j.brainres.2005.06.054 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 959YM UT WOS:000231555500023 PM 16039622 ER PT J AU Arnlov, J Evans, JC Meigs, JB Wang, TJ Fox, CS Levy, D Benjamin, EJ D'Agostino, RB Vasan, RS AF Arnlov, J Evans, JC Meigs, JB Wang, TJ Fox, CS Levy, D Benjamin, EJ D'Agostino, RB Vasan, RS TI Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals - The Framingham heart study SO CIRCULATION LA English DT Article DE endothelium; epidemiology; mortality; risk factors ID CLINICALLY HEALTHY-SUBJECTS; DEPENDENT DIABETES-MELLITUS; BLOOD-PRESSURE; ESSENTIAL-HYPERTENSION; ARTERIAL-HYPERTENSION; KIDNEY-DISEASE; FOLLOW-UP; MICROALBUMINURIA; EXCRETION; RISK AB Background - Data are limited with regard to the relations of low-grade albuminuria ( below the microalbuminuria threshold) and incidence of cardiovascular disease (CVD) events in nondiabetic, nonhypertensive individuals. Methods and Results - We examined the association of urinary albumin excretion ( spot urine albumin indexed to creatinine [UACR]) and the incidence of CVD events and all-cause mortality in 1568 nonhypertensive, nondiabetic Framingham Offspring Study participants ( mean age, 55 years; 58% women) free of CVD. On follow-up ( median, 6 years), 54 participants ( 20 women) developed a first CVD event, and 49 ( 19 women) died. After adjustment for established risk factors, increasing UACR was associated with greater risk of CVD ( hazards ratio [HR] per SD increment in log UACR, 1.36; 95% CI, 1.00 to 1.87) and death ( HR per SD increment in log UACR, 1.55; 95% CI, 1.10 to 2.20). Participants with UACR greater than or equal to the sex-specific median (>= 3.9 mu g/ mg for men, >= 7.5 mu g/mg for women) experienced a nearly 3-fold risk of CVD ( adjusted HR, 2.92; 95% CI, 1.57 to 5.44; P < 0.001) and a borderline significantly increased risk of death ( adjusted HR, 1.75; 95% CI, 0.95 to 3.22; P = 0.08) compared with those with UACR below the median. The increased CVD risk associated with UACR at or above the median remained robust in analyses restricted to individuals without microalbuminuria (n = 1470) and in subgroups with intermediate ( n = 1469) and low ( n = 1186) pretest probabilities of CVD. Conclusions - In our community-based sample of middle-aged nonhypertensive, nondiabetic individuals, low levels of urinary albumin excretion well below the current microalbuminuria threshold predicted the development of CVD. Our observations add to the growing body of evidence that challenges the notion that UACR < 30 mu g/mg indicates "normal" albumin excretion. C1 Framingham Heart Dis Epidemiol Study, NHLBI, Framingham, MA 01702 USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. Boston Univ, Dept Math, Boston, MA 02118 USA. Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Endocrinol Hypertens & Diabet, Boston, MA 02114 USA. Uppsala Univ, Dept Publ Hlth & Caring Sci, Sect Geriatr, S-75105 Uppsala, Sweden. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, NHLBI, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@bu.edu RI Arnlov, Johan/N-9886-2013; OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [2K24-HL-04334, K23-HL-074077, N01-HC-25195] NR 50 TC 422 Z9 442 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 16 PY 2005 VL 112 IS 7 BP 969 EP 975 DI 10.1161/CIRCULATIONAHA.105.538132 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 955OM UT WOS:000231235600007 PM 16087792 ER PT J AU Liu, QR Drgon, T Walther, D Johnson, C Poleskaya, O Hess, J Uhl, GR AF Liu, QR Drgon, T Walther, D Johnson, C Poleskaya, O Hess, J Uhl, GR TI Pooled association genome scanning: Validation and use to identify addiction vulnerability loci in two samples SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE complex genetics; drug dependence; linkage disequilibrium; microarray; SNP ID SUBSTANCE-ABUSE VULNERABILITY; DRUG-ABUSE; LINKAGE DISEQUILIBRIUM; POLYSUBSTANCE ABUSERS; MOLECULAR-GENETICS; CORDON-BLEU; TWIN PAIRS; DEPENDENCE; GENES; DNA AB Association genome scanning is of increasing interest for identifying the chromosomal regions that contain gene variants that contribute to vulnerability to complex disorders, including addictions. To improve the power and feasibility of this approach, we have validated "10k" microarray-based allelic frequency assessments in pooled DNA samples and have used this approach to seek allelic frequency differences between heavy polysubstance abusers and well characterized control individuals. Thirty-eight loci contain SNPs that display robust allele frequency differences between abusers and controls in both European- and African-American samples. These loci identify an alcohol/acetaldehyde dehydrogenase gene cluster and genes implicated in cellular signaling, gene regulation, development, "cell adhesion," and Mendelian disorders. The results converge with previous linkage and association results for addictions. Pooled association genome-scanning provides a useful tool for elucidating molecular genetic underpinnings of complex disorders and identifies both previously understood and previously unanticipated mechanisms for addiction vulnerability. C1 NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Uhl, GR (reprint author), NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, POB 5180, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov RI Liu, Qing-Rong/A-3059-2012 OI Liu, Qing-Rong/0000-0001-8477-6452 FU Intramural NIH HHS NR 48 TC 68 Z9 68 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 16 PY 2005 VL 102 IS 33 BP 11864 EP 11869 DI 10.1073/pnas.0500329102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 956RH UT WOS:000231317000053 PM 16091475 ER PT J AU Ioannidis, JPA Bernstein, J Boffetta, P Danesh, J Dolan, S Hartge, P Hunter, D Inskip, P Jarvelin, MR Little, J Maraganore, DM Bishop, JAN O'Brien, TR Petersen, G Riboli, E Seminara, D Taioli, E Uitterlinden, AG Vineis, P Winn, DM Salanti, G Higgins, JPT Khoury, MJ AF Ioannidis, JPA Bernstein, J Boffetta, P Danesh, J Dolan, S Hartge, P Hunter, D Inskip, P Jarvelin, MR Little, J Maraganore, DM Bishop, JAN O'Brien, TR Petersen, G Riboli, E Seminara, D Taioli, E Uitterlinden, AG Vineis, P Winn, DM Salanti, G Higgins, JPT Khoury, MJ TI A network of investigator networks in human genome epidemiology SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE epidemiology; genome; meta-analysis; multicenter studies ID GENETIC ASSOCIATION; METAANALYSIS; PUBLICATION; TRIALS AB The task of identifying genetic determinants for complex, multigenetic diseases is hampered by small studies, publication and reporting biases, and lack of common standards worldwide. The authors propose the creation of a network of networks that include groups of investigators collecting data for human genome epidemiology research. Twenty-three networks of investigators addressing specific diseases or research topics and representing several hundreds of teams have already joined this initiative. For each field, the authors are currently creating a core registry of teams already participating in the respective network. A wider international registry will include all other teams also working in the same field. Independent investigators are invited to join the registries and existing networks and to join forces in creating additional ones as needed. The network of networks aims to register these networks, teams, and investigators; be a resource for information about or connections to the many networks; off er methodological support; promote sound design and standardization of analytical practices; generate inclusive overviews of fields at large; facilitate rapid confirmation of findings; and avoid duplication of effort. C1 Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Clin & Mol Epidemiol Unit, GR-45110 Ioannina, Greece. Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. Int Agcy Res Canc, Gene Environm Epidemiol Grp, F-69372 Lyon, France. Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. March Dimes, White Plains, NY USA. NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Univ London Imperial Coll Sci & Technol, Dept Epidemiol & Publ Hlth, London, England. Univ Oulu, Dept Publ Hlth Sci & Gen Practice, Oulu, Finland. Univ Ottawa, Dept Epidemiol & Community Hlth, Ottawa, ON, Canada. Mayo Clin, Dept Neurol, Rochester, MN USA. CR UK Clin Ctr, Genet Epidemiol Div, Leeds, W Yorkshire, England. Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. Int Agcy Res Canc, Unit Nutr & Canc, F-69372 Lyon, France. NCI, Div Canc Control & Populat Sci, Rockville, MD USA. Osped Policlin, IRCCS, Mol & Genet Epidemiol Unit, Milan, Italy. Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. Erasmus MC, Dept Epidemiol & Biostat, Rotterdam, Netherlands. ISI Fdn, Turin, Italy. Univ Cambridge, Biostat Unit, MRC, Cambridge, England. Strangeways Res Lab, Publ Hlth Genet Unit, Cambridge CB1 4RN, England. Ctr Dis Control & Prevent, Off Genom & Dis Prevent, Atlanta, GA USA. RP Ioannidis, JPA (reprint author), Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, Clin & Mol Epidemiol Unit, GR-45110 Ioannina, Greece. EM jioannid@cc.uoi.gr RI Ioannidis, John/G-9836-2011; Higgins, Julian/H-4008-2011; OI Higgins, Julian/0000-0002-8323-2514; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Newton Bishop, Julia/0000-0001-9147-6802 NR 11 TC 81 Z9 82 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2005 VL 162 IS 4 BP 302 EP 304 DI 10.1093/aje/kwi201 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 954JE UT WOS:000231150600002 PM 16014777 ER PT J AU Calvert, RJ Kammouni, W Kikawa, KD AF Calvert, RJ Kammouni, W Kikawa, KD TI Optimization of a nonradioactive method for consistent and sensitive determination of activated K-ras protein SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE K-ras; lung; activity assay ID ESCHERICHIA-COLI; HEAT-SHOCK; EXPRESSION; CELLS; PURIFICATION; MOUSE; LUNG; REDUCTASE; PATHWAY; CLONING AB Accurate measurement of activity of wild-type K-ras protein is important due to its tumor suppressor action in tissues such as lung. A published method by Taylor and co-workers uses plasmid-containing Escherichia coli cells to produce a glutathione-S-transferase/raf-1 ras binding domain (GST-RBD) fusion protein attached to glutathione beads to isolate activated ras protein. We systematically optimized the method before use on lung tissues. Changing the GST-RBD protein induction temperature from the original 37 to 30 degrees C produced a consistently greater yield of fusion protein. To improve stability of the GST-RBD beads so as to perform large-scale experiments, 0.1% NaN3 was added. NaN3-treated beads retained full affinity for at least 24 days. Sensitivity was improved by using a polyvinylidene difluoride membrane rather than nitrocellulose for immunoblotting. We also compared our GST-RBD beads with two commercial assay kits and found that our beads had both superior sensitivity and reduced variability. In summary, our modification of the GST-RBD affinity method to recover activated K-ras greatly increased the yield of fusion protein, prolonged the useful life of GST-RBD beads to at least 24 days, and enhanced detection sensitivity. Published by Elsevier Inc. C1 US FDA, Off Nutr Prod Labeling & Dietary Supplements, Div Res & Appl Technol, College Pk, MD 20740 USA. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Calvert, RJ (reprint author), US FDA, Off Nutr Prod Labeling & Dietary Supplements, Div Res & Appl Technol, College Pk, MD 20740 USA. EM calvert@mail.ncifcrf.gov NR 26 TC 3 Z9 3 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD AUG 15 PY 2005 VL 343 IS 2 BP 283 EP 292 DI 10.1016/j.ab.2005.06.008 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 954OH UT WOS:000231163900012 PM 16018961 ER PT J AU Moaddel, R Jozwiak, K Yamaguchi, R Wainer, IW AF Moaddel, R Jozwiak, K Yamaguchi, R Wainer, IW TI Direct chromatographic determination of dissociation rate constants of ligand-receptor complexes: Assessment of the interaction of noncompetitive inhibitors with an immobilized nicotinic acetylcholine receptor-based liquid chromatography stationary phase SO ANALYTICAL CHEMISTRY LA English DT Article ID AFFINITY-CHROMATOGRAPHY; BINDING-KINETICS; L-TRYPTOPHAN; ALPHA-3-BETA-4; ALBUMIN AB A liquid chromatographic stationary phase containing immobilized membranes from a cell line expressing the alpha 3 beta 4 subtype of the neuronal nicotinic acetylcholine receptor (nAChR) has been used to assess dissociation rate constants (k(d)) of 12 noncompetitive inhibitor-nAChR complexes. The pharmacological effects of the noncompetitive inhibitors, expressed as percent recovery of activity at 7 min and 4 h postexposure to the inhibitor, were also determined. The results demonstrate that the k(d) values correlated with the pharmacological effect and that this approach can be used to identify molecular structures associated with differences in k(d) values. The method can be adapted for use with membrane-bound receptors, ion channels, and transporters and represents a direct and facile technique for the assessment of dissociation rate constants (k(d)) of ligand-receptor complexes. C1 NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Wainer, IW (reprint author), NIA, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Wainerir@grc.nia.nih.gov NR 17 TC 24 Z9 24 U1 1 U2 7 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 AUG 15 PY 2005 VL 77 IS 16 BP 5421 EP 5426 DI 10.1021/ac0504464 PG 6 WC Chemistry, Analytical SC Chemistry GA 955OT UT WOS:000231236300049 PM 16097790 ER PT J AU Veauvy, CM McDonald, MD Van Audekerke, J Vanhoutte, G Van Camp, N Van der Linden, A Walsh, PJ AF Veauvy, CM McDonald, MD Van Audekerke, J Vanhoutte, G Van Camp, N Van der Linden, A Walsh, PJ TI Ammonia affects brain nitrogen metabolism but not hydration status in the Gulf toadfish (Opsanus beta) SO AQUATIC TOXICOLOGY LA English DT Article DE ammonia; Opsanus beta; glutamine glutamine synthetase; methionine sulfoximine; MRI ID GLUTAMINE-SYNTHETASE; HYPERAMMONEMIC ENCEPHALOPATHY; IN-VIVO; FISH; PHYSIOLOGY; EXCRETION; TOXICITY; RATS AB Laboratory rodents made hyperammonemic by infusing ammonia into the blood show symptoms of brain cell swelling and increased intracranial pressure. These symptoms could be caused in part by an increase in brain glutamine formed when brain glutamine synthetase (GS) naturally detoxifies ammonia to glutamine. Previous studies on the Gulf toadfish (Opsanus beta) demonstrated that it is resistant to high ammonia exposure (HAE) (96 h LC50 = 10 mM) despite an increase in brain glutamine. This study attempts to resolve whether the resistance of O. beta is mediated by special handling of brain water in the face of changing glutamine concentrations. Methionine sulfoximine (MSO), an inhibitor of GS, was used to pharmacologically manipulate glutamine concentrations, and magnetic resonance imaging (MRI) was used to assess the status of brain water. Ammonia or MSO treatment did not substantially affect blood acid-base parameters. Exposure to 3.5 mM ammonium chloride in seawater for 16 or 40 h resulted in a parallel increase in brain ammonia (3-fold) and glutamine (2-fold) and a decrease in brain glutamate (1.3-fold). Pre-treatment with MSO prevented ammonia-induced changes in glutamine and glutamate concentrations. HAE also induced an increase in plasma osmolality (by 7%) which was probably due to a disturbance of osmoregulatory processes but which did not result in broader whole body dehydration as indicated by muscle water analysis. The increase in brain glutamine was not associated with any changes in brain water in toadfish exposed to 3.5 mM ammonia for up to 40 h or even at 10, 20 and 30 mM ammonia consecutively and for one hour in each concentration. The lack of brain water accumulation implies that ammonia toxicity in toadfish appears to be via pathways other than cerebral swelling. Furthermore, toadfish pre-treated with MSO did not survive a normally sub-lethal exposure to 3.5 mM ammonia for 40 h. The enhancement of ammonia toxicity by MSO suggests that GS function is critical to ammonia tolerance in this species. (c) 2005 Elsevier B.V. All rights reserved. C1 Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, Div Marine Biol & Fisheries, NIEHS,Marine & Freshwater Biomed Sci Ctr, Miami, FL 33149 USA. Univ Antwerp, RUCA, BioImaging Lab, B-2020 Antwerp, Belgium. RP Veauvy, CM (reprint author), Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, Div Marine Biol & Fisheries, NIEHS,Marine & Freshwater Biomed Sci Ctr, 4600 Rickenbacker Causeway, Miami, FL 33149 USA. EM eveauvy@rsmas.miami.edu FU NIEHS NIH HHS [(ES 05705), PJW (ES 11005)] NR 29 TC 23 Z9 24 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-445X J9 AQUAT TOXICOL JI Aquat. Toxicol. PD AUG 15 PY 2005 VL 74 IS 1 BP 32 EP 46 DI 10.1016/j.aquatox.2005.05.003 PG 15 WC Marine & Freshwater Biology; Toxicology SC Marine & Freshwater Biology; Toxicology GA 952XQ UT WOS:000231039800003 PM 15927282 ER PT J AU Chung, YL Rider, LG Bell, JD Summers, RM Zemel, LS Rennebohm, RM Passo, MH Hicks, J Miller, FW Scott, DL AF Chung, YL Rider, LG Bell, JD Summers, RM Zemel, LS Rennebohm, RM Passo, MH Hicks, J Miller, FW Scott, DL CA Juvenile Dermatomyositis Dis Activ TI Muscle metabolites, detected in urine by proton spectroscopy, correlate with disease damage in juvenile idiopathic inflammatory myopathies SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article DE magnetic resonance spectroscopy; creatine; myositis; muscle damage ID MAGNETIC-RESONANCE SPECTROSCOPY; HEALTH ASSESSMENT QUESTIONNAIRE; DERMATOMYOSITIS; POLYMYOSITIS; CREATINE; ABNORMALITIES; VALIDATION; DIAGNOSIS; CHILDREN; EXERCISE AB Objective. To assess for novel markers of muscle damage using urinary muscle metabolites by H-1 magnetic resonance spectroscopy in patients with juvenile idiopathic inflammatory myopathy (IIM). Methods. Creatine (Cr), choline (Cho), betaine (Bet), glycine (Gly), trimethylamine oxide (TMAO), and several other metabolites were measured in first morning void urine samples from 45 patients with juvenile IIM and from 35 healthy age-matched controls, and correlated with measures of myositis disease activity and damage. Urinary metabolite to age-adjusted creatinine (Cn) ratios were examined. Results. Age-adjusted initial Cr:Cn, Cho:Cn, Bet:Cn, Gly:Cn, and TMAO:Cn ratios were higher in patients with juvenile IIM than controls (P < 0.01). Cr:Cn ratios showed significant correlations with physician-assessed global disease damage (Spearman r(s), = 0.37; P = 0.01), Steinbrocker functional class (r(s) = 0.35; P = 0.02), serum Cr (r(s) 0.72; P = 0.001), and lactate dehydrogenase (r(s) = 0.34; P = 0.03) levels. Cho:Cn (r(s), = 0.3; P = 0.05), Gly:Cn (r(s) = 0.33; P 0.03), and TMAO:Cn (r(s), = 0.36; P = 0.02) ratios showed a significant correlation with serum aldolase levels. Cho:Cn ratios also showed a significant correlation with aspartate aminotransferase levels (r. = 0.35; P = 0.02). A linear regression model was used to evaluate the factors influencing urinary Cr:Cn ratios in the 43 patients with data sets available at the initial visit. The regression model explained 73% of the variation in Cr:Cn ratios. The most significant factor was the physician-assessed global disease damage (R-2 = 0.50, P = 0.015). Conclusion. Urinary Cr:Cn, Cho:Cn, Bet:Cn, Gly:Cn, and TMAO:Cn ratios are elevated in juvenile IIM and Cr:Cn correlates strongly with global disease damage. The Cr:Cn ratio may have potential utility as a marker of myositis disease damage. C1 Imperial Coll Sch Med, GKT Sch Med, London, England. NIEHS, Environm Autoimmun Grp, NIH, Bethesda, MD USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. Connecticut Childrens Med Ctr, Hartford, CT USA. Ohio State Univ, Childrens Hosp, Columbus, OH 43210 USA. Univ Cincinnati, Childrens Hosp, Cincinnati, OH USA. RP Chung, YL (reprint author), St George Hosp, Sch Med, Dept Basic Med Sci, Canc Res UK Biomed Magnet Resonance Res Grp, Cranmer Terrace, London SW17 0RE, England. EM ychung@sghms.ac.uk OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 FU Medical Research Council [MC_U120061305] NR 37 TC 11 Z9 11 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD AUG 15 PY 2005 VL 53 IS 4 BP 565 EP 570 DI 10.1002/art.21331 PG 6 WC Rheumatology SC Rheumatology GA 952YI UT WOS:000231041900014 PM 16082628 ER PT J AU Salvioli, R Tatti, M Scarpa, S Moavero, SM Ciaffoni, F Felicetti, F Kaneski, CR Brady, RO Vaccaro, AM AF Salvioli, R Tatti, M Scarpa, S Moavero, SM Ciaffoni, F Felicetti, F Kaneski, CR Brady, RO Vaccaro, AM TI The N370S (Asn(370)-> Ser) mutation affects the capacity of glucosylceramidase to interact with anionic phospholipid-containing membranes and saposin C SO BIOCHEMICAL JOURNAL LA English DT Article DE anionic phospholipid; Gaucher fibroblast; glucosylceramidase; large unilamellar vesicles; lysobisphosphatidic acid (LBPA); saposin C ID ACID-BETA-GLUCOSIDASE; NIEMANN-PICK-DISEASE; SPHINGOLIPID ACTIVATOR PROTEIN-2; SITE-DIRECTED MUTAGENESIS; TYPE-1 GAUCHER-DISEASE; HUMAN GLUCOCEREBROSIDASE; CATALYTIC-ACTIVITY; RECONSTITUTION; FIBROBLASTS; CHOLESTEROL AB The properties of the endolysosomal enzyme GCase (glucosylceramidase), carrying the most prevalent mutation observed in Gaucher patients, namely substitution of an asparagine residue with a serine at amino acid position 370 [N370S (Asn(371) -> Ser) GCase], were investigated in the present study. We previously demonstrated that Sap (saposin) C, the physiological GCase activator, promotes the association of GCase with anionic phospholipid-containing membranes, reconstituting in this way the enzyme activity. In the present study, we show that, in the presence of Sap C and membranes containing high levels of anionic phospholipids, both normal and N370S GCases are able to associate with the lipid surface and to express their activity. Conversely, when the amount of anionic phospholipids in the membrane is reduced (similar to 20% of total lipids), Sap C is still able to promote binding and activation of the normal enzyme, but not of N370S GCase. The altered interaction of the mutated enzyme with anionic phospholipid-containing membranes and Sap C was further demonstrated in Gaucher fibroblasts by confocal microscopy, which revealed poor co-localization of N370S GCase with Sap C and lysobisphosphatidic acid, the most abundant anionic phospholipid in endolysosomes. Moreover, we found that N370S Gaucher fibroblasts accumulate endolysosomal free cholesterol, a lipid that might further interfere with the interaction of the enzyme with Sap C and lysobisphosphatidic acid-containing membranes. In summary, our results show that the N370S mutation primarily affects the interaction of GCase with its physiological activators, namely Sap C and anionic phospholipid-containing membranes. We thus propose that the poor contact between N370S GCase and its activators may be responsible for the low activity of the mutant enzyme in vivo. C1 Ist Super Sanita, Dept Hematol Oncol & Mol Med, I-00161 Rome, Italy. Univ Roma La Sapienza, Dept Expt Med & Pathol, I-00161 Rome, Italy. NINDS, Dev & Metabol Neurol Branch, NIH, Bethesda, MD USA. RP Vaccaro, AM (reprint author), Ist Super Sanita, Dept Hematol Oncol & Mol Med, Viale Regina Elena 299, I-00161 Rome, Italy. EM annamaria.vaccaro@iss.it OI Kaneski, Christine/0000-0003-1453-2502 NR 44 TC 20 Z9 21 U1 0 U2 3 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 AUG 15 PY 2005 VL 390 BP 95 EP 103 DI 10.1042/BJ20050325 PN 1 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 959BV UT WOS:000231492800011 PM 15826241 ER PT J AU Szabo, R Netzel-Arnett, S Hobson, JP Antalis, TM Bugge, TH AF Szabo, R Netzel-Arnett, S Hobson, JP Antalis, TM Bugge, TH TI Matriptase-3 is a novel phylogenetically preserved membrane-anchored serine protease with broad serpin reactivity SO BIOCHEMICAL JOURNAL LA English DT Article DE extracellular protease; inhibitor complex; matriptase-3; pericellular proteolysis; serpin; type II transmembrane serine protease (TTSP) ID SURFACE PROTEOLYTIC-ENZYMES; BREAST-CANCER CELLS; MATRIX METALLOPROTEINASES; OVARIAN-CANCER; PLASMINOGEN ACTIVATION; EXPRESSION; IDENTIFICATION; PROGRESSION; INHIBITOR; DIAGNOSIS AB We report in the present study the bioinformatic identification, molecular cloning and biological characterization of matriptase-3, a novel membrane-anchored serine protease that is phylogenetically preserved in fish, birds, rodents, canines and primates. The gene encoding matriptase-3 is located on syntenic regions of human chromosome 3q13.2, mouse chromosome 16B5, rat chromosome 11q21 and chicken chromosome 1. Bioinformatic analysis combined with cDNA cloning predicts a functional TTSP (type II transmembrane serine protease) with 31% amino acid identity with both matriptase/MT-SP1 and matriptase-2. This novel protease is composed of a short N-terminal cytoplasmic region followed by a transmembrane domain, a stem region with one SEA, two CUB and three LDLRa (low-density lipoprotein receptor domain class A) domains and a C-terminal catalytic serine protease domain. Transcript analysis revealed restricted. species-conserved expression of matriptuse-3, with the highest mRNA levels in brain, skin, reproductive and oropharyngeal tissues. The full-length matriptase-3 cDNA directed the expression of a 90 kDa N-glycosylated protein that localized to the cell surface, as assessed by cell-surface biotin labelling. The purified activated matriptase-3 serine protease domain expressed in insect cells hydrolysed synthetic peptide substrates, with a strong preference for Arg at position P-1, and showed proteolytic activity towards several macromolecular substrates, including gelatin, casein and albumin. Interestingly, activated matriptase-3 formed stable inhibitor complexes with an array of serpins, including plasminogen activator inhibitor-1, protein C inhibitor, alpha 1-proteinase inhibitor, alpha 2-antiplasmin and antithrombin III. Our study identifies matriptase-3 as a novel biologically active TTSP of the matriptase subfamily having a unique expression pattern and post-translational regulation. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Proteases & Tissue Remodelling Unit, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Physiol, Rockville, MD 20855 USA. Univ Maryland, Sch Med, Dept Surg, Rockville, MD 20855 USA. RP Bugge, TH (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Proteases & Tissue Remodelling Unit, NIH, 30 Convent Dr, Bethesda, MD 20892 USA. EM thomas.bugge@nih.gov FU NCI NIH HHS [P30 CA134274, CA098369, R01 CA098369, R56 CA098369]; NHLBI NIH HHS [R01 HL084387] NR 48 TC 48 Z9 55 U1 2 U2 4 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD AUG 15 PY 2005 VL 390 BP 231 EP 242 DI 10.1042/BJ20050299 PN 1 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 959BV UT WOS:000231492800025 PM 15853774 ER PT J AU Wu, CP Klokouzas, A Hladky, SB Ambudkar, SV Barrand, MA AF Wu, CP Klokouzas, A Hladky, SB Ambudkar, SV Barrand, MA TI Interactions of mefloquine with ABC proteins, MRP1 (ABCC1) and MRP4 (ABCC4) that are present in human red cell membranes SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE ATP hydrolysis; mefloquine; multidrug resistance-associated proteins 1 and 4; MK-571; erythrocyte membranes ID MULTIDRUG-RESISTANCE PROTEIN; HUMAN P-GLYCOPROTEIN; GUANOSINE 3',5'-CYCLIC-MONOPHOSPHATE CGMP; CONJUGATE EXPORT PUMP; ATP HYDROLYSIS; HUMAN ERYTHROCYTES; TUMOR-CELLS; TRANSITION-STATE; PLASMODIUM-FALCIPARUM; GLUTATHIONE-CONJUGATE AB Human erythrocyte membranes express the multidrug resistance-associated proteins, MRPI, MRP4 and 5, that collectively can efflux oxidised glutathione, glutathione conjugates and cyclic nucleotides. It is already known that the quinoline derivative, MK-571, is a potent inhibitor of MRP-mediated transport. We here examine whether the quinoline-based antimalarial drugs, amodiaquine, chloroquine, mefloquine, primaquine, quinidine and quinine, also interact with erythrocyte MRPs with consequences for their access to the intracellular parasites or for efflux of oxidised glutathione from infected cells. Using inside-out vesicles prepared from human erythrocytes we have shown that mefloquine and MK-571 inhibit transport of 3 mu M [H-3]DNP-SG known to be mediated by MRPl (IC50 127 and 1.1 mu M, respectively) and of 3.3 mu M [H-3]cGMP thought but not proven to be mediated primarily by MRP4 IC50 21 and 0.41 mu M). They also inhibited transport in membrane vesicles prepared from tumour cells expressing MRP1 or MRP4 and blocked calcein efflux from MRP1 over-expressing cells and BCECF efflux from MRP4-overexpressin- cells. Both stimulated ATPase activity in membranes prepared from MRP1 and MRP4-overexpressing cells and inhibited activity stimulated by quercetin or PGE1, respectively. Neither inhibited [alpha-P-32]8azidoATP binding confirming that the interactions are not at the ATP binding site. These results demonstrate that mefloquine and MK-571 both inhibit transport of other substrates and stimulate ATPase activity and thus may themselves be substrates for transport. But at concentrations achieved clinically mefloquine is unlikely to affect the MRP1-mediated transport of GSSG across the erythrocyte membrane. (c) 2005 Elsevier Inc. All rights reserved. C1 Univ Cambridge, Dept Pharmacol, Cambridge CB2 1QJ, England. NCI, Cell Biol Labs, NIH, DHHS, Bethesda, MD 20892 USA. RP Barrand, MA (reprint author), Univ Cambridge, Dept Pharmacol, Tennis Court Rd, Cambridge CB2 1QJ, England. EM mb10002@cam.ac.uk RI Ambudkar, Suresh/B-5964-2008 FU NCI NIH HHS [Z01 BC010030-10] NR 47 TC 36 Z9 40 U1 0 U2 1 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 AUG 15 PY 2005 VL 70 IS 4 BP 500 EP 510 DI 10.1016/j.bcp.2005.05.022 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 951RY UT WOS:000230949700002 PM 16004972 ER PT J AU Durinck, S Moreau, Y Kasprzyk, A Davis, S De Moor, B Brazma, A Huber, W AF Durinck, S Moreau, Y Kasprzyk, A Davis, S De Moor, B Brazma, A Huber, W TI BioMart and Bioconductor: a powerful link between biological databases and microarray data analysis SO BIOINFORMATICS LA English DT Article ID ANNOTATION AB biomaRt is a new Bioconductor package that integrates BioMart data resources with data analysis software in Bioconductor. It can annotate a wide range of gene or gene product identifiers (e.g. Entrez-Gene and Affymetrix probe identifiers) with information such as gene symbol, chromosomal coordinates, Gene Ontology and OMIM annotation. Furthermore biomaRt enables retrieval of genomic sequences and single nucleotide polymorphism information, which can be used in data analysis. Fast and up-to-date data retrieval is possible as the package executes direct SOL queries to the BioMart databases (e.g. Ensembl). The biomaRt package provides a tight integration of large, public or locally installed BioMart databases with data analysis in Bioconductor creating a powerful environment for biological data mining. C1 Katholieke Univ Leuven, SCD, ESAT, Dept Elect Engn, Heverlee, Belgium. EBI, Cambridge CB10 1SD, England. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Durinck, S (reprint author), Katholieke Univ Leuven, SCD, ESAT, Dept Elect Engn, Kasteelpk Arenberg 10, Heverlee, Belgium. EM steffen.durinck@esat.kuleuven.ac.be OI Huber, Wolfgang/0000-0002-0474-2218; Davis, Sean/0000-0002-8991-6458; Brazma, Alvis/0000-0001-5988-7409 NR 7 TC 338 Z9 343 U1 0 U2 27 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD AUG 15 PY 2005 VL 21 IS 16 BP 3439 EP 3440 DI 10.1093/bioinformatics/bti525 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 957HJ UT WOS:000231360600020 PM 16082012 ER PT J AU Sunderland, T AF Sunderland, T TI Geriatric psychiatry: Coming of age in America SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID ALZHEIMERS-DISEASE; RISK-FACTORS; LATE-LIFE; DEPRESSION; SCHIZOPHRENIA; DISORDERS; ONSET; GENES; APOE C1 Natl Inst Mental Hlth, Bethesda, MD 20892 USA. RP Sunderland, T (reprint author), Natl Inst Mental Hlth, 9000 Rockville Pike,Bldg 10,Room 3N228, Bethesda, MD 20892 USA. EM trey@mail.nih.gov FU NIMH NIH HHS [Z01 MH00330-14] NR 18 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 15 PY 2005 VL 58 IS 4 BP 263 EP 264 DI 10.1016/j.biopsych.2005.06.023 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 954WZ UT WOS:000231187300001 PM 16102543 ER PT J AU Sunderland, T Gur, RE Arnold, SE AF Sunderland, T Gur, RE Arnold, SE TI The use of biomarkers in the elderly: Current and future challenges SO BIOLOGICAL PSYCHIATRY LA English DT Review DE Alzheimer disease; APOE; beta-amyloid; biomarker; cerebrospinal fluid ID MILD COGNITIVE IMPAIRMENT; FAMILIAL ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E GENOTYPE; LATE-LIFE DEPRESSION; PHOSPHORYLATED TAU-PROTEIN; PLACEBO-CONTROLLED TRIAL; CEREBROSPINAL-FLUID TAU; HIPPOCAMPAL VOLUME LOSS; CEREBRAL BLOOD-FLOW; CSF TOTAL TAU AB Biomarkers are hypothesized but not frequently used in research with the elderly because of a general paucity of supportive scientific data. However, there is an obvious need for greater diagnostic specificity and sensitivity across many diagnoses in the elderly, as well as good targets for therapeutic trials, The authors reviewed the available information in this field aspart of a general review of geriatric research for the American Psychiatric Association. Potential biomarkers with pathophysiologic significance have been studied in the field of Alzheimer disease research with some success, especially in the area of genetic markers (apolipoprotein E [APOE] epsilon 4 allele), neuroimaging, and cerebrospinal fluid markers (beta-amyloid and tau). While some progress has been made in the search for adequate biomarkers in the elderly, in particular with Alzheimer disease, much more work is needed before these potential biomarkers can be reliably used in clinical practice. C1 Natl Inst Mental Hlth, Geriatr Psychiat Branch, Bethesda, MD 20892 USA. Univ Penn, Dept Psychiat, Philadelphia, PA USA. RP Sunderland, T (reprint author), Natl Inst Mental Hlth, Geriatr Psychiat Branch, Bldg 10,Room 3N228,9000 Rockville Pike, Bethesda, MD 20892 USA. EM trey@mail.nih.gov RI Arnold, Steven/J-7546-2012 FU NIA NIH HHS [AG-10125, AG-15819, AG-17917]; NIMH NIH HHS [MH-04045, MH-059852, MH-42191, MH-60722, MH-64045, Z01 MH00330-14] NR 85 TC 23 Z9 24 U1 3 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 15 PY 2005 VL 58 IS 4 BP 272 EP 276 DI 10.1016/j.biopsych.2005.05.016 PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 954WZ UT WOS:000231187300003 PM 16018985 ER PT J AU Alexopoulos, GS Schultz, SK Lebowitz, BD AF Alexopoulos, GS Schultz, SK Lebowitz, BD TI Late-life depression: A model for medical classification SO BIOLOGICAL PSYCHIATRY LA English DT Review ID EXECUTIVE DYSFUNCTION SYNDROME; SUBGENUAL PREFRONTAL CORTEX; DEFINED VASCULAR DEPRESSION; RECURRENT MAJOR DEPRESSION; WHITE-MATTER LESIONS; GERIATRIC DEPRESSION; MOOD DISORDERS; ANTERIOR CINGULATE; HIPPOCAMPAL VOLUME; SUBCORTICAL HYPERINTENSITIES AB Geriatric psychiatric syndromes might serve as the stalling point for a medical classification of psychiatric disorders, because their medical and neurological comorbidity and their clinical, neuropsychological, and neuroimaging features often reflect specific brain abnormalities. Geriatric syndromes, however, consist of complex behaviors that are unlikely to be caused by single lesions. We propose a model in which aging-related changes in specific brain structures increase the propensity for the development of certain psychiatric syndromes. The predisposing factors are distinct from the mechanisms mediating the expression of a syndromic state, much like hypertension is distinct from stroke, but constitutes a morbid vulnerability. We argue that research seeking to identify both brain abnormalities conferring vulnerability as well as the mediating mechanisms of symptomatology has the potential to lead to a medical classification of psychiatric disorders. In addition, a medical classification call guide the effort to improve treatment and prevention of psychiatric disorders as it can direct therapeutic efforts to the underlying predisposing, abnormalities, the syndrome-mediating mechanisms, and to development of behavioral skills needed for coping with adversity and disability. C1 Cornell Univ, Weill Med Coll, Cornell Inst Geriatr Psychiat, White Plains, NY 10605 USA. Univ Iowa, Coll Med, Iowa City, IA USA. Natl Inst Mental Hlth, Geriat Treatment & Prevent Intervent Res Branch, Bethesda, MD USA. RP Alexopoulos, GS (reprint author), Cornell Univ, Weill Med Coll, Cornell Inst Geriatr Psychiat, 21 Bloomingdale Rd, White Plains, NY 10605 USA. EM gsalexop@med.cornell.edu OI Alexopoulos, George/0000-0001-5677-7001 FU NIMH NIH HHS [R01 MH65652, P30 MH 68638] NR 73 TC 41 Z9 44 U1 6 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 15 PY 2005 VL 58 IS 4 BP 283 EP 289 DI 10.1016/j.biopsych.2005.04.055 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 954WZ UT WOS:000231187300005 PM 16026764 ER PT J AU Winkler, D Pjrek, E Praschak-Rieder, N Willeit, M Pezawas, L Konstantinidis, A Stastny, J Kasper, S AF Winkler, D Pjrek, E Praschak-Rieder, N Willeit, M Pezawas, L Konstantinidis, A Stastny, J Kasper, S TI Actigraphy in patients with seasonal affective disorder and healthy control subjects treated with light therapy SO BIOLOGICAL PSYCHIATRY LA English DT Article DE depression; seasonal affective disorder; light therapy; activity; actigraphy; circadian rhythms ID REST-ACTIVITY DISTURBANCES; BRIGHT-LIGHT; WINTER DEPRESSION; MOTOR-ACTIVITY; CIRCADIAN-RHYTHMS; SEROTONIN UPTAKE; CONTROLLED-TRIAL; SLEEP; PHOTOTHERAPY; CHILDREN AB Background: Abnormalities of the circadian rest-activity cycle are hypothesized to accompany the clinical picture of seasonal affective disorder (SAD). The purpose of this study was to investigate if bright light therapy (BLT) is able to reverse these disturbances. Methods. Seventeen SAD outpatients and 17 sex- and age-matched healthy control subjects were treated with BLT administered in the morning for 4 weeks. Activity levels were measured with wrist actigraphy. Results: SAD patients had 3396 lower total (p = .031) and 43% lower daylight activity (p = .006) in week I compared with control subjects. The relative amplitude of the sleep-wake cycle was attenuated by 6916 inpatients (p = .025); they were phase delayed by 55 minutes(p = .023) and bad significantly lower sleep efficiency (p = .030). Total(p = .002) and daylight activity (p = .001)increased after 4 weeks of treatment in SAD patients. Moreover, BLT led to increase of relative amplitude (p = .005), advance of delayed rhythms (p = .036), and improved sleep efficiency (p = .011) inpatients. Intradaily stability, measuring the strength of coupling of the rhythm to external zeitgebers, increased by 9% both in patients and healthy control subjects (p = .032). Conclusions: Treatment with BLT normalizes disturbed activity patterns and restores circadian rhythms in SAD patients. BLT migth also stabilize the circadian rhythm in nondepressed individuals during the fall-winter season. C1 Med Univ Vienna, Dept Gen Psychiat, Vienna, Austria. Ctr Addicat & Mental Hlth, Toronto, ON, Canada. Natl Inst Mental Hlth, Clin Brain Disorders Branch, Bethesda, MD USA. RP Winkler, D (reprint author), Med Univ Vienna, Dept Gen Psychiat, Wahringer Gurtel 18-20,A-1090, Vienna, Austria. EM dietmar.winkler@meduniwien.ac.at OI Pezawas, Lukas/0000-0002-1329-6352 NR 50 TC 32 Z9 32 U1 2 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 15 PY 2005 VL 58 IS 4 BP 331 EP 336 DI 10.1016/j.biopsych.2005.01.031 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 954WZ UT WOS:000231187300011 PM 16102546 ER PT J AU Shen, YH Xie, Q Norberg, M Sausville, E Woude, GV Wenkert, D AF Shen, YH Xie, Q Norberg, M Sausville, E Woude, GV Wenkert, D TI Geldanamycin derivative inhibition of HGF/SF-mediated Met tyrosine kinase receptor-dependent urokinase-plasminogen activation SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE geldanamycin; hepatocyte growth factor/scatter factor; urokinase-plasminogen activation; Met tyrosine kinase receptor ID IMPORTANT BIOLOGIC ACTIVITIES; HEPATOCYTE GROWTH-FACTOR; C-MET; IN-VITRO; ANTITUMOR-ACTIVITY; PROTEIN CHAPERONE; CRYSTAL-STRUCTURE; TERMINAL DOMAIN; HSP90; CANCER AB Ansamycins including geldanamycin and the derivative 17-allylamino-17-demethoxygeldanamyein, and radicicol are known for their ability to tightly bind to the ATP-binding site of the amino-terminal domain region of heat shock protein 90. We have found that geldanamycin and some of its derivatives can inhibit hepatocyte growth factor/scatter factor-mediated Met tyrosine kinase receptor-dependent urokinase-plasminogen activation at femtomolar levels. Assessment is made of structural requirements for such an activity and evidence is given that distinguishes the target of Such all activity from that of heat shock protein 90. (c) 2005 Elsevier Ltd. All rights reserved. C1 Michigan State Univ, Dept Physiol, E Lansing, MI 48864 USA. Van Andel Res Inst, Grand Rapids, MI 49503 USA. NCI, Div Canc Treatment & Diagnosis, Bethesda, MD 20892 USA. RP Wenkert, D (reprint author), Michigan State Univ, Dept Physiol, E Lansing, MI 48864 USA. EM wenkert@msu.edu RI Shen, Yuehai/J-7829-2012 NR 62 TC 15 Z9 17 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD AUG 15 PY 2005 VL 13 IS 16 BP 4960 EP 4971 DI 10.1016/j.bmc.2005.05.038 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 949JF UT WOS:000230780600017 PM 15978816 ER PT J AU Peretti, S Shaw, A Blanchard, J Bohm, R Morrow, G Lifson, JD Gettie, A Pope, M AF Peretti, S Shaw, A Blanchard, J Bohm, R Morrow, G Lifson, JD Gettie, A Pope, M TI Immunomodulatory effects of HSV-2 infection on immature macaque dendritic cells modify innate and adaptive responses SO BLOOD LA English DT Article ID HERPES-SIMPLEX-VIRUS; SIMIAN IMMUNODEFICIENCY VIRUS; T-CELLS; RETROVIRAL INFECTIVITY; INDUCED MATURATION; IMMUNE-RESPONSES; IN-VITRO; ACTIVATION; TYPE-1; LESIONS AB Herpes simplex viruses (HSV) infect human and murine dendritic cells (DCs) and interfere with their immunostimulatory functions in culture. HSV-2 infection increases human immunodeficiency virus (HIV) spread in patients, and DCs also promote HIV infection. We have studied these topics in rhesus macaque monocyte-derived DCs (moDCs) to set the stage for future studies of these issues in animals. We provide the first evidence that macaque DCs become infected by HSV-2. Structural viral proteins (ICP5 [infected cell protein 5], glycoprotein D [gD], envelope) were detected in the cell periphery, and a functional protein (infected cell protein 8 [ICP8]) was predominantly found in the nucleus after infection. Infectious HSV-2 induced apoptotic death, decreased expression of HLA-DR, CD40, CD80, CD83, and CD86, and increased release of interleukin-6 (IL-6), tumor necrosis factor-a. (TNF-alpha), macrophage inflammatory protein-la (MIP-1 alpha) (CCL3), and RANTES (regulated on activation normal T cells expressed and secreted) (CCL5) but not IL-12 or interferon-alpha (IFN-alpha) by macaque DCs. This coincided with HSV-2-infected DCs stimulating weak T-cell responses, including impaired SIV-specific responses. Comparable HSV-2 protein expression, DC apoptosis, as well as membrane immunophenotype and functional modifications were observed in HSV-2-exposed human moDCs. Such HSV-2-induced modifications of macaque and human DCs could augment DC-driven immunodeficiency virus infection. This work affords the basis for future macaque studies to explore how HSV-2 impacts the efficacy of strategies being developed to prevent HIV transmission. C1 Populat Council, Ctr Biomed Res, New York, NY 10021 USA. Tulane Univ, Tulane Natl Primate Res Ctr, Covington, LA USA. NCI, AIDS Vaccine Program, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. Aaron Diamond AIDS Res Ctr, New York, NY USA. RP Pope, M (reprint author), Populat Council, Ctr Biomed Res, 1230 York Ave, New York, NY 10021 USA. EM mpope@popcouncil.org FU NCI NIH HHS [N01-CO-12400]; NCRR NIH HHS [RR00164]; NIAID NIH HHS [R01 AI040877]; NICHD NIH HHS [P01 HD041752] NR 49 TC 20 Z9 22 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 15 PY 2005 VL 106 IS 4 BP 1305 EP 1313 DI 10.1182/blood-2004-12-4899 PG 9 WC Hematology SC Hematology GA 954PT UT WOS:000231167700033 PM 15845898 ER PT J AU Halin, C Scimone, ML Bonasio, R Gauguet, JM Mempel, TR Quackenbush, E Proia, RL Mandala, S von Andrian, UH AF Halin, C Scimone, ML Bonasio, R Gauguet, JM Mempel, TR Quackenbush, E Proia, RL Mandala, S von Andrian, UH TI The S1P-analog FTY720 differentially modulates T-cell homing via HEV: T-cell-expressed S1P(1) amplifies integrin activation in peripheral lymph nodes but not in Peyer patches SO BLOOD LA English DT Article ID SPHINGOSINE 1-PHOSPHATE RECEPTORS; CIRCULATING MATURE LYMPHOCYTES; PROTEIN-COUPLED RECEPTOR; HIGH ENDOTHELIAL VENULES; SKIN ALLOGRAFT SURVIVAL; VASCULAR MATURATION; IN-VIVO; SPHINGOSINE-1-PHOSPHATE; IMMUNOSUPPRESSANT; CHEMOKINE AB Sphingosine-1-phosphate (S1P) and its receptor S1P, control T-cell egress from thymus and secondary lymphoid organs (SLOs). To further define the role of S1P, in lymphocyte trafficking, we performed adoptive transfer experiments and intravital microscopy (IVM) using both S1P(1)(-/-) lymphocytes and recipient wild-type (WT) mice treated with FTY720, an immunosuppressant that downmodulates S1P receptors. S1P, deficiency and FTY720 caused rapid disappearance of T cells from blood, prolonged retention in SLOs, and accumulation in bone marrow, but did not alter interstitial T-cell motility in peripheral lymph nodes (PLNs) as assessed by multiphoton IVM. However, S1P(1)(-/-) lymphocytes displayed reduced short-term homing to PLNs due to attenuated integrin-mediated firm arrest in high endothelial venules (HEVs). By contrast, S1P(1)(-/-) T cells homed normally to Peyer patches (PPs), whereas S1P(1)(-/-) B cells had a marked defect in homing to PPs and arrested poorly in PP HEVs. Therefore, S1P, not only controls lymphocyte egress from SLOs, but also facilitates in a tissue- and subset-specific fashion integrin activation during homing. Interestingly, FTY720 treatment enhanced accumulation of both S1P(1) sufficient and S1P(1)(-/-) T cells in PPs by enhancing integrin-mediated arrest in HEVs. Thus, FTY720 exerts unique effects on T-cell traffic in PPs that are independent of T-cell-expressed S1P(1). C1 CBR Inst Biomed Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Merck Res Labs, Dept Immunol & Rheumatol, Rahway, NJ USA. NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP von Andrian, UH (reprint author), CBR Inst Biomed Res, 200 Longwood Ave, Boston, MA 02115 USA. EM uva@cbr.med.harvard.edu RI Proia, Richard/A-7908-2012; von Andrian, Ulrich/A-5775-2008; Bonasio, Roberto/P-1356-2014 OI Bonasio, Roberto/0000-0002-0767-0889 FU NHLBI NIH HHS [HL48675, HL54936, HL56949, P01 HL056949] NR 43 TC 68 Z9 70 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2005 VL 106 IS 4 BP 1314 EP 1322 DI 10.1182/blood-2004-09-3687 PG 9 WC Hematology SC Hematology GA 954PT UT WOS:000231167700034 PM 15870184 ER PT J AU He, QC Madsen, M Kilkenney, A Gregory, B Christensen, EI Vorum, H Hojrup, P Schaffer, AA Kirkness, EF Tanner, SM de la Chapelle, A Giger, U Moestrup, SK Fyfe, JC AF He, QC Madsen, M Kilkenney, A Gregory, B Christensen, EI Vorum, H Hojrup, P Schaffer, AA Kirkness, EF Tanner, SM de la Chapelle, A Giger, U Moestrup, SK Fyfe, JC TI Amnionless function is required for cubilin brush-border expression and intrinsic factor-cobalamin (vitamin B-12) absorption in vivo SO BLOOD LA English DT Article ID HEREDITARY MEGALOBLASTIC-ANEMIA; KIDNEY PROXIMAL TUBULES; MOUSE GASTRULATION; VISCERAL-ENDODERM; LINKAGE ANALYSIS; B-12 RECEPTOR; PROTEIN; MALABSORPTION; ENDOCYTOSIS; MEGALIN AB Amnionless (AMN) and cubilin gene products appear to be essential functional subunits of an endocytic receptor called cubam. Mutation of either gene causes autosomal recessive Imerslund-Grasbeck syndrome (I-GS, OMIM no. 261100) in humans, a disorder characterized by selective intestinal malabsorption of cobalamin (vitamin B-12) and urinary loss of several specific low-molecular-weight proteins. Vital insight into the molecular pathology of I-GS has been obtained from studies of dogs with a similar syndrome. In this work, we show that I-GS segregates in a large canine kindred due to an in-frame deletion of 33 nucleotides in exon 10 of AMN. In a second, unrelated I-GS kindred, affected dogs exhibit a homozygous substitution in the AMN translation initiation codon. Studies in vivo demonstrated that both mutations abrogate AMN expression and block cubilin processing and targeting to the apical membrane. The essential features of AMN dysfunction observed in vivo are recapitulated in a heterologous cell-transfection system, thus validating the system for analysis of AMN-cubilin interactions. Characterization of canine AMN mutations that cause I-GS establishes the canine model as an ortholog of the human disorder well suited to studies of AMN function and coevolution with cubilin. C1 Michigan State Univ, Coll Vet Med, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. Univ Aarhus, Dept Biochem Med, Aarhus, Denmark. Univ Aarhus, Inst Anat, Dept Cell Biol, Aarhus, Denmark. Odense Univ, Dept Biochem & Mol Biol, Odense, Denmark. NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Inst Genome Res, Rockville, MD USA. Ohio State Univ, Ctr Comprehens Canc, Human Canc Genet Program, Columbus, OH 43210 USA. Univ Penn, Vet Hosp, Med Genet Sect, Philadelphia, PA 19104 USA. RP Fyfe, JC (reprint author), Michigan State Univ, Coll Vet Med, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. EM fyfe@cvm.msu.edu RI Schaffer, Alejandro/F-2902-2012; Moestrup, Soren Kragh/A-1403-2014 OI Moestrup, Soren Kragh/0000-0003-3862-2107 FU NCI NIH HHS [CA16058]; NCRR NIH HHS [RR02512]; NIDDK NIH HHS [DK064161] NR 43 TC 61 Z9 62 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 15 PY 2005 VL 106 IS 4 BP 1447 EP 1453 DI 10.1182/blood-2005-03-1197 PG 7 WC Hematology SC Hematology GA 954PT UT WOS:000231167700053 PM 15845892 ER PT J AU Goh, SH Lee, YT Bhanu, NV Cam, MC Desper, R Martin, BM Moharram, R Gherman, RB Miller, JL AF Goh, SH Lee, YT Bhanu, NV Cam, MC Desper, R Martin, BM Moharram, R Gherman, RB Miller, JL TI A newly discovered human alpha-globin gene SO BLOOD LA English DT Article ID MINOR HEMOGLOBIN COMPONENT; HIGH-ALTITUDE RESPIRATION; AMINO-ACID-SEQUENCES; D-CHAINS; EXPRESSION; PSEUDOGENE; ALIGNMENT; CLUSTER; PROTEINS; BIRDS AB A previously undefined transcript with significant homology to the pseudo-alpha 2 region of the at-globin locus on human chromosome 16 was detected as part of an effort to better define the transcriptional profiles of human reticulocytes. Cloning and sequencing of that transcript (GenBank AY698022; named mu-globin) revealed an insert with a 423-nucleotide open reading frame. BLASTP and ClustalW and phylogenetic analyses of the predicted protein demonstrated a high level of homology with the avian alpha-D globin. In addition, the heme- and globin-binding amino acids of mu-globin and avian alpha-D globin are largely conserved. Using quantitative real-time polymerase chain reaction (PC:R), mu-globin was detected at a level of approximately 0.1% that measured for alpha-globin in erythroid tissues. Erythroid-specific expression was detected by Northern blot analysis, and maximal expression during the erythroblast terminal differentiation was also detected. Despite this highly regulated pattern of mu-globin gene transcription, mu-globin protein was not detected by mass spectrometry. These results suggest the human genome encodes a previously unrecognized globin member of the avian alpha-D family that is transcribed in a highly regulated pattern in erythroid cells. C1 NIDDKD, Mol Med Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Microarray Core Facil, NIH, Bethesda, MD 20892 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. NIMH, Lab Neurotoxicol, NIH, Bethesda, MD 20892 USA. Natl Naval Hosp, Bethesda, MD USA. RP Miller, JL (reprint author), NIDDKD, Mol Med Branch, NIH, Bldg 10 Rm 9B17,10 Ctr Dr, Bethesda, MD 20892 USA. EM jm7f@nih.gov NR 45 TC 37 Z9 38 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 15 PY 2005 VL 106 IS 4 BP 1466 EP 1472 DI 10.1182/blood-2005-03-0948 PG 7 WC Hematology SC Hematology GA 954PT UT WOS:000231167700056 PM 15855277 ER PT J AU Cahn, JY Klein, JP Lee, SJ Milpied, N Blaise, D Antin, JH Leblond, V Ifrah, N Jouet, JP Loberiza, F Ringden, O Barrett, AJ Horowitz, MM Socie, G AF Cahn, JY Klein, JP Lee, SJ Milpied, N Blaise, D Antin, JH Leblond, V Ifrah, N Jouet, JP Loberiza, F Ringden, O Barrett, AJ Horowitz, MM Socie, G TI Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Societe Francaise de Greffe de Moelle et Therapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study SO BLOOD LA English DT Article ID SEVERITY INDEX; DISEASE AB The most commonly used grading system for acute graft-versus-host disease (aGVHD) was introduced 30 years ago by Glucksberg; a revised system was developed by the International Bone Marrow Transplant Registry (IBMTR) in 1997. To prospectively compare the 2 classifications and to evaluate the effect of duration and severity of aGVHD on survival, we conducted a multicenter study of 607 patients receiving T-cell-replete allografts, scored weekly for aGVHD in 18 transplantation centers. Sixty-nine percent of donors were HLA-identical siblings and 28% were unrelated donors. The conditioning regimen included total body irradiation in 442 (73%) patients. The 2 classifications performed similarly in explaining variability in survival by aGVHD grade, although the Glucksberg classification predicted early survival better. There was less physician bias or error in assigning grades with the IBMTR scoring system. With either system, only the maximum observed grade had prognostic significance for survival; neither time of onset nor progression from an initially lower grade of aGVHD was associated with survival once maximum grade was considered. Regardless of scoring system, aGVHD severity accounted for only a small percentage of observed variation in survival. Validity of these results in populations receiving peripheral blood transplants or nommyeloalblative conditioning regimens remains to be tested. C1 CHU Grenoble, Dept Hematol, F-38043 Grenoble, France. Med Coll Wisconsin, Int Bone Marrow Transplant Registry, Milwaukee, WI 53226 USA. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. CHU Nantes, Dept Hematol, F-44035 Nantes, France. Inst J Paoli I Calmettes, Dept Hematol, F-13009 Marseille, France. Hop La Pitie Salpetriere, Dept Hematol, Paris, France. Dept Hematol, Angers, France. Dept Hematol, Lille, France. Huddinge Univ Hosp, Stockholm, Sweden. NIH, Bethesda, MD 20892 USA. Hop St Louis, Paris, France. RP Cahn, JY (reprint author), CHU Grenoble, INSERM,EMI 353, Hop Michallon, Dept Oncohematol, F-38700 Grenoble, France. EM jycahn@chu-grenoble.fr RI Cahn, Jean-Yves/M-6493-2014 FU NCI NIH HHS [U24-CA76518] NR 9 TC 83 Z9 86 U1 2 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 15 PY 2005 VL 106 IS 4 BP 1495 EP 1500 DI 10.1182/blood-2004-11-4557 PG 6 WC Hematology SC Hematology GA 954PT UT WOS:000231167700060 PM 15878974 ER PT J AU Evelhoch, J Garwood, N Vigneron, D Knopp, N Sullivan, D Menkens, A Clarke, L Liu, GY AF Evelhoch, J Garwood, N Vigneron, D Knopp, N Sullivan, D Menkens, A Clarke, L Liu, GY TI Expanding the use of magnetic resonance in the assessment of tumor response to therapy: Workshop report SO CANCER RESEARCH LA English DT Article ID BRAIN-TUMORS; PHASE-I; SPECTROSCOPY; PHOSPHATE; CANCER AB Although dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and magnetic resonance spectroscopy (MRS) have great potential to provide routine assessment of cancer treatment response, their widespread application has been hampered by a lack of standards for use. Thus, the National Cancer Institute convened a workshop to assess developments and applications of these methods, develop standards for methodology, and engage relevant partners (drug and device industries, researchers, clinicians, and government) to encourage sharing of data and methodologies. Consensus recommendations were reached for DCE-MRI methodologies and the focus for initial multicenter trials of MRS. In this meeting report, we outline the presentations, the topics discussed, the ongoing challenges identified, and the recommendations made by workshop participants for the use of DCE-MRI and H-1 MRS in the clinical assessment of antitumor therapies. C1 NCI, Canc Imaging Program, NIH, Bethesda, MD 20892 USA. Amgen Inc, Thousand Oaks, CA 91320 USA. Univ Minnesota, Minneapolis, MN USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Ohio State Univ, Columbus, OH 43210 USA. RP Liu, GY (reprint author), NCI, Canc Imaging Program, NIH, 6130 Execut Blvd,Suite 6000, Bethesda, MD 20892 USA. EM liug@mail.nih.gov RI Liu, Gary/A-6200-2009 NR 18 TC 67 Z9 69 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 15 PY 2005 VL 65 IS 16 BP 7041 EP 7044 DI 10.1158/0008-5472.CAN-05-0674 PG 4 WC Oncology SC Oncology GA 954XK UT WOS:000231188600003 PM 16103049 ER PT J AU Worden, B Yang, XP Lee, TL Bagain, L Yeh, NT Cohen, JG Van Waes, C Chen, Z AF Worden, B Yang, XP Lee, TL Bagain, L Yeh, NT Cohen, JG Van Waes, C Chen, Z TI Hepatocyte growth factor/scatter factor differentially regulates expression of proangiogenic factors through Egr-1 in head and neck squamous cell carcinoma SO CANCER RESEARCH LA English DT Article ID PROTEIN-KINASE-C; FACTOR-A-CHAIN; NF-KAPPA-B; TRANSCRIPTION FACTOR EGR-1; ENDOTHELIAL-CELLS; GENE-EXPRESSION; SIGNAL PATHWAYS; FACTOR RECEPTOR; MELANOMA-CELLS; TUMOR-GROWTH AB Hepatocyte growth factor/scatter factor (HGF) and the angiogenesis factors platelet-derived growth factors (PDGF), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) are found in elevated concentrations in serum or tumor tissue of patients with head and neck squamous cell carcinomas (HNSCC), suggesting these factors may be coregulated. A cDNA microarray analysis for HGF-inducible genes revealed that HGF also modulates PDGFA expression, a gene recently shown to be inducible by the transcription factor, early growth response-1 (Egr-1). In the present study, we investigated the potential role of HGF-induced Egr-1 in expression of PDGF, VEGF, and IL-8. HGF induced expression of all three factors and Egr-1 expression and DNA-binding activity. The analysis of promoter sequences showed putative Egr-1 binding sites in the PDGFA or VEGF but not in the IL-8 promoter, and HGF-induced Egr-1-binding activity was confirmed by chromatin immunoprecipitation (ChIP) assay. The maximal basal and HGF-induced promoter activity for the PDGFA gene existed within -630 bp of the promoter region, and overexpression of Egr-1 significantly increased such activity. Consistent with this, expression of PDGFA and VEGF but not IL-8 showed corresponding differences with Egr-1 expression in HNSCC tumor specimens and were strongly suppressed by transfection of Egr-1-antisense or small interference RNA (siRNA) oligonucleotides. HGF-induced expression of Egr-1, PDGFA, and VEGF was suppressed by pharmacologic and siRNA inhibitors of mitogen-activated protein kinase kinase 1/2 (MEK1/2) and protein kinase C (PKC) pathways. We conclude that the HGF-induced activation of transcription factor Egr-1 by MEK1/2- and PKC-dependent mechanisms differentially contributes to expression of PDGF and VEGF, which are important angiogenesis factors and targets for HNSCC therapy. C1 Natl Inst Deafness & Other Communicable Disorders, NIH, Head & Neck Surg Branch, Tumor Biol Sect, Bethesda, MD 20892 USA. RP Chen, Z (reprint author), Natl Inst Deafness & Other Communicable Disorders, NIH, Head & Neck Surg Branch, Tumor Biol Sect, 10-5D55,MSC-1419, Bethesda, MD 20892 USA. EM chenz@nidcd.nih.gov RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU NIDCD NIH HHS [DC-00016] NR 48 TC 61 Z9 64 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 15 PY 2005 VL 65 IS 16 BP 7071 EP 7080 DI 10.1158/008-5472.CAN-04-0989 PG 10 WC Oncology SC Oncology GA 954XK UT WOS:000231188600008 PM 16103054 ER PT J AU Coxon, A Rozenblum, E Park, YS Joshi, N Tsurutani, J Dennis, PA Kirsch, IR Kaye, FJ AF Coxon, A Rozenblum, E Park, YS Joshi, N Tsurutani, J Dennis, PA Kirsch, IR Kaye, FJ TI Mect1-maml2 fusion oncogene linked to the aberrant activation of cyclic AMP/CREB regulated genes SO CANCER RESEARCH LA English DT Article ID SALIVARY-GLAND TUMORS; GENOME-WIDE ANALYSIS; CELL LUNG-CANCER; MUCOEPIDERMOID CARCINOMA; TRANSCRIPTIONAL REGULATION; CHROMOSOME-ABERRATIONS; C-ERBB-2 ONCOPROTEIN; EPITHELIAL-CELLS; MAMMALIAN-CELLS; IN-VIVO AB Malignant salivary gland tumors can arise from a t(11;19) translocation that fuses 42 residues from Mect1/Torc1, a cyclic AMP (cAMP)/cAMP-responsive element binding protein (CREB)-dependent transcriptional coactivator, with 982 residues from Mam12, a NOTCH receptor coactivator. To determine if the Mect1-Mam12 fusion oncogene mediates tumorigenicity by disrupting cAMP/CREB signaling, we have generated in-frame deletions within the CREB-binding domain of Mect1/Torc1 for testing transformation activity and have also developed a doxycycline-regulated Mect1-Mam12 mammalian expression vector for global gene expression profiling. We observed that small deletions within the CREB-binding domain completely abolished transforming activity in RK3E epithelial cells. Further, we have shown that the ectopic induction of Mect1-Mam12 in HeLa cells strongly activated the expression (of a group of known cAMP/CREB-regulated genes. In addition, we detected candidate cAMP-responsive element sites within 100 nucleotides of the transcriptional start sites of other genes activated by Mect1-Mam12 expression. In contrast, we did not observe alterations of known Notch-regulated target genes in these expression array profile experiments. We validated the results by reverse transcription-PCR in transfected HeLa, RK3E, and H2009 lung tumor cells and in mucoepidermoid cancer cells that endogenously express the fusion oncopeptide. Whereas overexpression of components of the cAMP pathway has been associated with a subset of human carcinomas, these data provide a direct genetic link between deregulation of cAMP/CREB pathways and epithelial tumorigenesis and suggest future therapeutic strategies for this group of salivary gland tumors. C1 Natl Naval Med Res Inst, Gaithersburg, MD 20899 USA. Natl Canc Inst, Canc Res Ctr, Genet Branch, Bethesda, MD USA. Natl Canc Inst, Canc Res Ctr, Canc Therapeut Branch, Bethesda, MD USA. RP Kaye, FJ (reprint author), Natl Naval Med Res Inst, Bldg 8,Room 5101, Gaithersburg, MD 20899 USA. EM fkaye@helix.nih.gov RI kaye, frederic/E-2437-2011 NR 50 TC 70 Z9 71 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2005 VL 65 IS 16 BP 7137 EP 7144 DI 10.1158/0008-5472.CAN-05-1125 PG 8 WC Oncology SC Oncology GA 954XK UT WOS:000231188600017 PM 16103063 ER PT J AU Lin, YW Deveney, R Barbara, M Iscove, NN Nimer, SD Slape, C Aplan, PD AF Lin, YW Deveney, R Barbara, M Iscove, NN Nimer, SD Slape, C Aplan, PD TI OLIG2 (BHLHB1), a bHLH transcription factor, contributes to leukemogenesis in concert with LMO1 SO CANCER RESEARCH LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; T-CELL MALIGNANCIES; LOOP-HELIX PROTEINS; SCL GENE-PRODUCT; TRANSGENIC MICE; STEM-CELLS; IN-VIVO; OLIGODENDROCYTE DIFFERENTIATION; BETHESDA PROPOSALS; PROGENITOR CELLS AB OLIG2 (originally designated BHLHB1) encodes a transcription factor that contains the basic helix-loop-helix motif. Although expression of OLIG2 is normally restricted to neural tissues, overexpression of OLIG2 has been shown in patients with precursor T-cell lymphoblastic lymphoma/leukemia (pre-T LBL). In the current study, we found that overexpression of OLIG2 was not only found in oligodendroglioma samples and normal neural tissue but also in a wide spectrum of malignant cell lines including leukemia, non-small cell lung carcinoma, melanoma, and breast cancer cell lines. To investigate whether enforced expression of OLIG2 is oncogenic, we generated transgenic mice that overexpressed OLIG2 in the thymus. Ectopic OLIG2 expression in the thymus was only weakly oncogenic as only 2 of 85 mice developed pre-T LBL. However, almost 60% of transgenic mice that overexpressed both OLIG2 and LMO1 developed pre-T LBL with large thymic tumor masses. Gene expression profiling of thymic tumors that developed in OLIG2/LMO1 mice revealed up-regulation of Notch1 as well as Deltex1 (Dtx1) and pre T-cell antigen receptor alpha (Ptcra), two genes that are considered to be downstream of Notch1. Of note, we found mutations in the Notch1 heterodimerization or proline-, glutamic acid-, serine-, and threonine-rich domain in three of six primary thymic tumors. In addition, growth of leukemic cell lines established from OLIG2/LMO1 transgenic mice was suppressed by a gamma-secretase inhibitor, suggesting that Notch1 up-regulation is important for the proliferation of OLIG2/LMO1 leukemic cells. C1 Natl Canc Inst, Genet Branch, Ctr Canc Res, NIH, Gaithersburg, MD 20899 USA. Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. Mem Sloan Kettering Canc Ctr, Dept Med, Div Hematol Oncol, Serv Hematol, New York, NY 10021 USA. RP Aplan, PD (reprint author), Natl Canc Inst, Genet Branch, Ctr Canc Res, NIH, 8901 Wisconsin Ave, Gaithersburg, MD 20899 USA. EM aptanp@mail.nih.gov RI Slape, Christopher/H-8586-2016; Aplan, Peter/K-9064-2016 OI Slape, Christopher/0000-0002-8407-3092; NR 47 TC 14 Z9 14 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2005 VL 65 IS 16 BP 7151 EP 7158 DI 10.1158/0008-55472.CAN-05-1400 PG 8 WC Oncology SC Oncology GA 954XK UT WOS:000231188600019 PM 16103065 ER PT J AU Bar-Sinai, A Bassa, N Fischette, M Gottesman, MM Love, DC Hanover, JA Hochman, J AF Bar-Sinai, A Bassa, N Fischette, M Gottesman, MM Love, DC Hanover, JA Hochman, J TI Mouse mammary tumor virus env-derived peptide associates with nucleolar targets in lymphoma, mammary carcinoma, and human breast cancer SO CANCER RESEARCH LA English DT Article ID T-CELL LYMPHOMAS; GENE-SEQUENCES; P-32 PROTEIN; DNA-DAMAGE; LOCALIZATION; TUMORIGENICITY; IDENTIFICATION; AGENTS AB We have previously shown that the leader peptide (p14) of the Env-precursor of mouse mammary tumor virus is translocated into the nucleoli of murine T cell lymphomas that harbor this virus. Using a polyclonal antibody against recombinant p14, we show here that p14 is also localized to the nucleoli of murine mammary carcinomas and some human breast cancer samples. Affinity purification studies define a number of proteins, mostly nucleolar, that hind p14. Taken together, these findings point towards a more general involvement of p14 in lymphomagenesis and mammary carcinogenesis. C1 Hebrew Univ Jerusalem, Inst Life Sci, Dept Cell & Anim Biol, IL-91904 Jerusalem, Israel. NIDDK, NHLBI, Bethesda, MD USA. NIDDK, Cell Biol Lab, Ctr Canc Res, NCI, Bethesda, MD USA. NIDDK, Lab Cell Biochem & Biol, Bethesda, MD USA. RP Hochman, J (reprint author), Hebrew Univ Jerusalem, Inst Life Sci, Dept Cell & Anim Biol, IL-91904 Jerusalem, Israel. EM hochman@vms.huji.ac.il NR 32 TC 9 Z9 12 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2005 VL 65 IS 16 BP 7223 EP 7230 DI 10.1158/0008-5472.CAN-04-3879 PG 8 WC Oncology SC Oncology GA 954XK UT WOS:000231188600027 PM 16103073 ER PT J AU Koblinski, JE Kaplan-Singer, BR VanOsdol, SJ Wu, M Engbring, JA Wang, SL Goldsmith, CM Piper, JT Vostal, JG Harms, JF Welch, DR Kleinman, HK AF Koblinski, JE Kaplan-Singer, BR VanOsdol, SJ Wu, M Engbring, JA Wang, SL Goldsmith, CM Piper, JT Vostal, JG Harms, JF Welch, DR Kleinman, HK TI Endogenous osteonectin/SPARC/BM-40 expression inhibits MDA-MB-231 breast cancer cell metastasis SO CANCER RESEARCH LA English DT Article ID EXTRACELLULAR-MATRIX PROTEIN; HUMAN-MELANOMA CELLS; SPARC-NULL MICE; GENE-EXPRESSION; ENHANCED GROWTH; BONE METASTASIS; TUMOR-GROWTH; IN-VIVO; OSTEONECTIN; PLATELET AB Skeletal metastases occur with high incidence in patients with breast cancer and cause long-term skeletal morbidity. Osteonectin (SPARC, BM-40) is a bone matrix factor that is an in vitro chemoattractant for breast and prostate cancer cells. Increased expression of osteonectin is found in malignant breast tumors. We infected MDA-231 breast cancer cells with an adenovirus expressing osteonectin to examine the role of osteonectin expression in breast cancer cells and its effect on metastasis, in particular to bone. Expression of osteonectin did not affect MDA-231 cell proliferation, apoptosis, migration, cell aggregation, or protease cleavage of collagen IV. However, in vitro invasion of these osteonectin-infected cells through Matrigel and colony formation on Matrigel was decreased. Interestingly, high osteonectin expression in MDA-231 cells inhibited metastasis in a dose-dependent manner to many different organs including bone. The reduction in metastasis may be due to decreased platelet-tumor cell aggregation, because exogenous osteonectin inhibited platelet aggregation in vitro and the high osteonectin expression in MDA-231 cells reduced tumor cell-induced thrombocytopenia in vivo compared with control-infected cells. These studies suggest that high endogenous expression of osteonectin in breast cancer cells may reduce metastasis via reduced invasive activity and reduced tumor cell-platelet aggregation. C1 Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Genet Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. Capital Univ Med Sci, Fac Stomatol, Beijing, Peoples R China. US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. Penn State Univ, Coll Med, Jake Gittlen Canc Res Inst, Hershey, PA USA. Univ Alabama, Dept Pathol, Ctr Comprehens Canc, Birmingham, AL 35294 USA. RP Kleinman, HK (reprint author), Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Room 433,Bldg 30,30 Convent Dr, Bethesda, MD 20892 USA. EM hkleinma@mail.nih.gov RI Welch, Danny/B-7310-2009; OI Welch, Danny/0000-0002-1951-4947; Wu, Michael C./0000-0002-3357-6570 FU NCI NIH HHS [CA-91572, CA87728] NR 56 TC 74 Z9 75 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 15 PY 2005 VL 65 IS 16 BP 7370 EP 7377 DI 10.1158/0008-5472.CAN-05-0807 PG 8 WC Oncology SC Oncology GA 954XK UT WOS:000231188600044 PM 16103089 ER PT J AU Agarwal, R D'Souza, T Morin, P AF Agarwal, R D'Souza, T Morin, P TI Claudin-3 and claudin-4 expression in ovarian epithelial cells enhances invasion and is associated with increased matrix metalloproteinase-2 activity SO CANCER RESEARCH LA English DT Article ID CLOSTRIDIUM-PERFRINGENS ENTEROTOXIN; JUNCTION PROTEINS CLAUDIN-3; TIGHT JUNCTIONS; PANCREATIC-CANCER; MOLECULAR MARKERS; MEMBRANE-PROTEINS; TUMOR-SUPPRESSOR; CARCINOMA-CELLS; PDZ DOMAIN; GENE AB Claudin proteins form a large family of integral membrane proteins crucial for tight junction formation and function. Our previous studies have revealed that claudin-3 and claudin-4 proteins are highly overexpressed in ovarian cancer. To clarify the roles of claudins in ovarian tumorigenesis, we have generated human ovarian surface epithelial (HOSE) cells constitutively expressing wild-type claudin-3 and claudin-4. Expression of these claudins in HOSE cells increased cell invasion and motility as measured by Boyden chamber assays and wound-healing experiments. Conversely, small interfering RNA (siRNA)-mediated knockdown of claudin-3 and claudin-4 expression in ovarian cancer cell lines reduced invasion. Claudin expression also increased cell survival in HOSE cells but did not significantly affect cell proliferation. Moreover, the claudin-expressing ovarian epithelial cells were found to have increased matrix metalloproteinase-2 (MMP-2) activity indicating that claudin-mediated increased invasion might be mediated through the activation of MMP proteins. However, siRNA inactivation of claudins in ovarian cancer cell lines did not have a significant effect on the high endogenous MMP-2 activity present in these cells, showing that malignant cells have alternative or additional pathways to fully activate MMP-2. Taken together, our results suggest that claudin overexpression may promote ovarian tumorigenesis and metastasis through increased invasion and survival of tumor cells. C1 NIA, Gerontol Res Ctr, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. RP Morin, P (reprint author), NIA, Gerontol Res Ctr, Cellular & Mol Biol Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM morinp@grc.nia.nih.gov NR 48 TC 211 Z9 225 U1 2 U2 12 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 15 PY 2005 VL 65 IS 16 BP 7378 EP 7385 DI 10.1158/0008-5472.CAN-05-1036 PG 8 WC Oncology SC Oncology GA 954XK UT WOS:000231188600045 PM 16103090 ER PT J AU Blagosklonny, MV Trostel, S Kayastha, G Demidenko, ZN Vassilev, LT Romanova, LY Bates, S Fojo, T AF Blagosklonny, MV Trostel, S Kayastha, G Demidenko, ZN Vassilev, LT Romanova, LY Bates, S Fojo, T TI Depletion of mutant p53 and cytotoxicity of histone deacetylase inhibitors SO CANCER RESEARCH LA English DT Article ID SUBEROYLANILIDE HYDROXAMIC ACID; SMALL-MOLECULE ANTAGONISTS; PSEUDO-NULL P53; DEPSIPEPTIDE FR901228; MITOTIC ARREST; CANCER-CELLS; ACTIVATION; EXPRESSION; TRANSCRIPTION; APOPTOSIS AB Mutant p53 is a cancer-specific target for pharmacologic intervention. We show that histone deacetylase inhibitors such as FR901228 and trichostatin A completely depleted mutant p53 in cancer cell lines. This depletion was preceded by induction of p53-regulated transcription. In cells with mutant p53 pretreated with historic deacetylase inhibitors, DNA damage further enhanced the p53 trans-function. Furthermore, histone deacetylase inhibitors were preferentially cytotoxic to cells with mutant p53 rather than to cells lacking wild-type p53. We suggest that, by either restoring or mimicking p53 trans-functions, historic deacetylase inhibitors initiate degradation of mutant p53. Because mutant p53 is highly expressed, a sudden restoration of p53-like functions is highly cytotoxic to cells with mutant p53. In a broader perspective, this shows how selectivity may be achieved by targeting a non-cancer-specific target, such as histone deacetylases, in the presence of a cancer-specific alteration, such as mutant p53. C1 Ctr Canc, Ordway Res Inst, Albany, NY 12208 USA. New York Med Coll, Valhalla, NY 10595 USA. NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Hoffmann La Roche Inc, Discovery Oncol, Roche Res Ctr, Nutley, NJ 07110 USA. Harvard Univ, Sch Med, Dept Radiat Oncol, Charlestown, MA USA. RP Blagosklonny, MV (reprint author), Ctr Canc, Ordway Res Inst, 150 New Scotland Ave, Albany, NY 12208 USA. EM blagnsklonny@hotmail.com NR 36 TC 57 Z9 59 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 15 PY 2005 VL 65 IS 16 BP 7386 EP 7392 DI 10.1158/0008-5472.CAN-04-3433 PG 7 WC Oncology SC Oncology GA 954XK UT WOS:000231188600046 PM 16103091 ER PT J AU Jensen, LH Thougaard, AV Grauslund, M Sokilde, B Carstensen, EV Dvinge, HK Scudiero, DA Jensen, PB Shoemaker, RH Sehested, M AF Jensen, LH Thougaard, AV Grauslund, M Sokilde, B Carstensen, EV Dvinge, HK Scudiero, DA Jensen, PB Shoemaker, RH Sehested, M TI Substituted purine analogues define a novel structural class of catalytic topoisomerase II inhibitors SO CANCER RESEARCH LA English DT Article ID HAMSTER OVARY CELLS; DNA TOPOISOMERASE; LUNG-CANCER; MAMMALIAN-CELLS; ATP HYDROLYSIS; STEADY-STATE; HISTONE H1; IN-VIVO; ALPHA; ETOPOSIDE AB By screening 1,990 compounds from the National Cancer Institute diversity set library against human topoisomerase II alpha, we identified a novel catalytic topoisomerase II inhibitor NSC35866, a S-6-substituted analogue of thioguanine. In addition to inhibiting the DNA strand passage reaction of human topoisomerase II alpha, NSC35866 also inhibited its ATPase reaction. NSC35866 primarily inhibited DNA-stimulated ATPase activity, whereas DNA-independent ATPase activity was less sensitive to inhibition. We compared the mode of topoisomerase II ATPase inhibition induced by NSC35866 with that of 12 other substituted purine analogues of different chemical classes. The ability of thiopurines with free SH functionalities to inhibit topoisomerase II ATPase activity was completely abolished by DTT, suggesting that these thiopur- ines inhibit topoisomerase II ATPase activity by covalently modifying free cysteine residues. In contrast, NSC35866 as well as two O-6-substituted guanine analogues, O-6-benzylguanine and NU2058, could inhibit topoisomerase II ATPase activity in the presence of DTT, indicating that they have a different mechanism of inhibition. NSC35866 did not increase the level of topoisomerase II covalent cleavable complexes with DNA, indicating that it is a catalytic inhibitor and not a poison. NSC35866 was also capable of inducing a salt-stable complex of topoisomerase II on closed circular DNA. In accordance with these biochemical data, NSC35866 could antagonize etoposide-induced cytotoxicity and DNA breaks in human and murine cancer cells, confirming that NSC35866 also functions as a catalytic topoisomerase II inhibitor in cells. C1 Natl Univ Hosp Copenhagen, Ctr Diagnost, Dept Pathol, Copenhagen, Denmark. TopoTarget AS, Copenhagen, Denmark. Natl Univ Hosp Copenhagen, Finsen Ctr, Lab Expt Med Oncol, Copenhagen, Denmark. Sci Applicat Int Corp, Frederick, MD USA. NCI, Dev Therapeut Program, Frederick, MD 21701 USA. RP Jensen, LH (reprint author), Rigshosp, Ctr Diagnost, Dept Pathol, 5444,Frederik Vs Vej 11, DK-2100 Copenhagen, Denmark. EM lhjenscn@rh.dk NR 53 TC 21 Z9 23 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 15 PY 2005 VL 65 IS 16 BP 7470 EP 7477 DI 10.1158/0008-5472.CAN-05-0707 PG 8 WC Oncology SC Oncology GA 954XK UT WOS:000231188600056 PM 16103101 ER PT J AU Wu, W Ginsburg, E Vonderhaar, BK Walker, AM AF Wu, W Ginsburg, E Vonderhaar, BK Walker, AM TI S179D prolactin increases vitamin D receptor and p21 through up-regulation of short 1b prolactin receptor in human prostate cancer cells SO CANCER RESEARCH LA English DT Article ID PHOSPHORYLATED PROLACTIN; UNMODIFIED PROLACTIN; BREAST-CANCER; BINDING PROTEIN; KNOCKOUT MICE; SHORT FORMS; LONG-FORM; EXPRESSION; ACTIVATION; KINASE AB In this study, we further investigated the mechanisms by which pseudophosphorylated prolactin (S179D PRL) inhibits the growth of human prostate cancer cells. When treated with S179D PRL for 3 days, LnCAP cells responded by increasing expression of the vitamin D receptor (VDR) and the cell cycle regulatory molecule, p21, whereas PC3 and DU145 cells did not. After 5 days of treatment, both PC3 and DU145 cells responded. Untreated LnCAP cells express the short 1b form (SF1b) of the human prolactin receptor, but DU145 and PC3 cells express only low amounts of this receptor until elevated by treatment with S179D PRL. DU145 and PC3 cells become sensitive to the negative effects of S179D PRL on cell number after induction of the SF1b. Transfection of either SF1b or SF1a into PC3 or DU145 cells made them sensitive to S179D PRL in the 3-day time frame, a finding that was not duplicated by transfection with the long form of the receptor. Treatment of LnCAP cells with S179D PRL increased long-term activation of extracellular signal-regulated kinase 1/2 (ERK1/2). This did not occur in PC3 and DU145 cells until transfection with SF1a/SF1b. Blockade of ERK signaling eliminated S179D PRL-stimulated expression of the VDR and p21 in LnCAP cells and transfected PC3 and DU145 cells. We conclude that initiation of alternative splicing to produce SF1b, and subsequent altered signaling, contribute to the growth inhibitory mechanisms of S179D PRL. This is the first indication of a role for short prolactin receptors in the regulation of cell proliferation. C1 Univ Calif Riverside, Div Biomed Sci, Riverside, CA 92521 USA. NCI, Mammary Biol & Tumorigenesis Lab, Bethesda, MD 20892 USA. RP Walker, AM (reprint author), Univ Calif Riverside, Div Biomed Sci, Riverside, CA 92521 USA. EM ameae.walker@ucr.edu FU NIDDK NIH HHS [DK 61005, R01 DK061005] NR 55 TC 35 Z9 35 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2005 VL 65 IS 16 BP 7509 EP 7515 DI 10.1158/0008-5472.CAN-04-3350 PG 7 WC Oncology SC Oncology GA 954XK UT WOS:000231188600061 PM 16103106 ER PT J AU Onda, M Willingham, M Nagata, S Bera, TK Beers, R Ho, M Hassan, R Kreitman, RJ Pastan, I AF Onda, M Willingham, M Nagata, S Bera, TK Beers, R Ho, M Hassan, R Kreitman, RJ Pastan, I TI New monoclonal antibodies to mesothelin useful for immunohistochemistry, fluorescence-activated cell sorting,Western blotting, and ELISA SO CLINICAL CANCER RESEARCH LA English DT Article ID ANTITUMOR-ACTIVITY; RECOMBINANT IMMUNOTOXINS; OVARIAN-CARCINOMA; PHAGE DISPLAY; ANTIGEN; DIAGNOSIS; CANCERS; K1; ADENOCARCINOMAS; EXPRESSION AB Purpose: Mesothelin is a cell surface protein that is highly expressed in some malignant tumors, and is a promising target for immunotherapy. Recent data suggests that mesothelin is an adhesive. protein and may have a role in the metastases of ovarian cancer. Although a few monoclonal antibodies (MAb) to mesothelin have been produced, they have limitations for the study of expression of native mesothelin because of their low affinity or reactivity only with denatured mesothelin protein. We have produced novel MAbs to mesothelin to help study mesothelin function and to develop improved diagnosis and immunotherapy of mesothelin-expressing tumors. Experimental Design: Mesothelin-deficient mice were immunized with plasmid cDNA encoding mesothelin, and boosted with a mesothelin-rabbit IgG Fc fusion protein prior to cell fusion. Hybridomas were screened by an ELISA using plates coated with mesothelin-Fc protein. Results: Seventeen hybridomas producing anti-mesothelin antibodies were established and shown to react with two epitopes on mesothelin. One group reacts with the same epitope as the low-affinity antibody K1 that was originally used to identify mesothelin. The other is a new group that reacts with a new epitope. One antibody from each group was chosen for further study and shown to react strongly on ELISA, on immunohistochemistry, and by fluorescence-activated cell sorting on living cells. Conclusion: Our two newly established MAbs, MN and MB, have different and useful properties compared with current antibodies used for the detection of mesothelin by immunohistochemistry, fluorescence-activated cell sorting, ELISA, and Western blotting. C1 NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Dept Pathol, Winston Salem, NC 27109 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov RI Ho, Mitchell/F-5059-2015 NR 29 TC 47 Z9 50 U1 1 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2005 VL 11 IS 16 BP 5840 EP 5846 DI 10.1158/1078-0432.CCR-05-0578 PG 7 WC Oncology SC Oncology GA 956SL UT WOS:000231320000027 PM 16115924 ER PT J AU Gulmann, C Espina, V Petricoin, E Longo, DL Santi, M Knutsen, T Raffeld, M Jaffe, ES Liotta, LA Feldman, AL AF Gulmann, C Espina, V Petricoin, E Longo, DL Santi, M Knutsen, T Raffeld, M Jaffe, ES Liotta, LA Feldman, AL TI Proteomic analysis of apoptotic pathways reveals prognostic factors in follicular lymphoma SO CLINICAL CANCER RESEARCH LA English DT Article ID NON-HODGKINS-LYMPHOMA; LASER CAPTURE MICRODISSECTION; PHASE PROTEIN MICROARRAYS; BCL-2 FAMILY-MEMBERS; B-CELL LYMPHOMA; EXPRESSION PATTERNS; PROSTATE-CANCER; OVARIAN-CANCER; SURVIVAL; PHOSPHORYLATION AB Follicular lymphoma (FL) is the second most common non-Hodgkin's lymphoma and generally is incurable. Reliable prognostic markers to differentiate patients who progress rapidly from those who survive for years with indolent disease have not been established. Most cases overexpress Bcl-2, but the pathogenesis of FL remains incompletely understood. To determine whether a proteomic approach could help overcome these obstacles, we procured lymphoid follicles from 20 cases of FL and 15 cases of benign follicular hyperplasia (FH) using laser capture microdissection. Lysates were spotted on reverse-phase protein microarrays and probed with 21 antibodies to proteins in the intrinsic apoptotic pathway, including those specific for posttranslational modifications such as phosphorylation. A panel of three antibodies [phospho-Akt(Ser473), Bcl-2, and cleaved poly (ADP-ribose) polymerase] segregated most cases of FL from FH. Phospho-Akt(Ser473) and Bcl-2 were significantly increased in FL (P=0.001 and P<0.0001, respectively). Additionally, the Bcl-2/Bak ratio completely segregated FL from FH, High ratios of Bcl-2/Bak and Bcl-2/Bax were associated with early death from disease with differences in median survival times of 7.3 years (P=0.0085) and 3.8 years (P=0.018), respectively. Using protein microarrays, we identified candidate proteins that may signify clinically relevant molecular events in FL. This approach showed significant changes at the posttranslational level, including Akt phosphorylation, and suggested new prognostic markers, including the Bcl-2/Bak and Bcl-2/Bax ratios. Proteomic end points should be incorporated in larger, multicenter trials to validate the clinical utility of these protein microarray findings. C1 NCI, Pathol Lab, Food & Drug Adm, Clin Proteom Program, Bethesda, MD 20892 USA. NCI, Genet Branch, Bethesda, MD 20892 USA. US FDA, Tissue Proteom Unit, Div Therapeut Prot, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. NIA, Baltimore, MD 21224 USA. Childrens Natl Med Ctr, Dept Pathol, Washington, DC 20010 USA. RP Feldman, AL (reprint author), NCI, Pathol Lab, Food & Drug Adm, Clin Proteom Program, Room 2A33,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM feldmana@mail.nih.gov RI Feldman, Andrew/D-5028-2012; OI Espina, Virginia/0000-0001-5080-5972 NR 50 TC 77 Z9 81 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 15 PY 2005 VL 11 IS 16 BP 5847 EP 5855 DI 10.1158/1078-0432.CCR-05-0637 PG 9 WC Oncology SC Oncology GA 956SL UT WOS:000231320000028 PM 16115925 ER PT J AU Nesterova, MV Johnson, NR Stewart, T Abrams, S Cho-Chung, YS AF Nesterova, MV Johnson, NR Stewart, T Abrams, S Cho-Chung, YS TI CpG immunomer DNA enhances antisense protein kinase a RI alpha inhibition of multidrug-resistant colon carcinoma growth in nude mice: Molecular basis for combinatorial therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID MYCOBACTERIUM-BOVIS BCG; BREAST-CANCER CELLS; BACTERIAL-DNA; TUMOR-GROWTH; IN-VITRO; SUBUNIT; OLIGONUCLEOTIDES; GENE; RECEPTOR; MOTIFS AB Purpose: CpG DNAs induce cytokines, activate natural killer cells, and elicit vigorous T-cell response leading to antitumor effects. Antisense oligodeoxynucleotides targeted against the RI alpha subunit of protein kinase A (antisense PKA RI alpha induce growth arrest, apoptosis, and differentiation in a variety of cancer cell lines in vitro and in vivo. This study investigated the use of a combinatorial therapy consisting of the RNA-DNA second-generation antisense PKA RI alpha and the CpG immunomer (CpG DNA linked through 3'-3' linkage containing two accessible 5' ends). Experimental Design: HCT-15 multidrug-resistant colon carcinoma growth in nude mice was used as an experimental model. The inhibitory effect on tumor growth and apoptotic activity of antisense RI alpha and CpG immunomer, singly and in combination, were measured by tumor grow levels of RI alpha subunit, and antiapoptotic and proapoptotic proteins. Effect on host-immune system was measured by mouse spleen size, interleukin-6 (IL-6) levels in mouse blood, and nuclear factor-kappa B (NF-kappa B) transcription activity in mouse spleen cells. Results: In combination, CpG immunomer and antisense PKA Riot induced additive/supra-additive effect on the inhibition of tumor growth. Antisense RI alpha but not CpG immunomer increased Bax and Bak proapoptotic protein levels and decreased Bcl-2 and RI alpha protein levels in tumor cells. CpG immunomer but not antisense Riot induced an enlargement of mouse spleen, increased IL-6 levels in mouse blood, and increased NF-kappa B transcription activity in mouse spleen cells. Conclusions: These results show that type I PKA down-regulation and induction of apoptosis in tumor cells by antisense PKA RI alpha and host-immune stimulation by CpG immunomer are responsible at the molecular level for the supra-additive effects of tumor growth inhibition. Thus, antisense PKA RI alpha and CpG immunomer in combination work cooperatively and as tumor-targeted therapeutics to treat human cancer. C1 NCI, Basic Res Lab, Cellular Biochem Sect, Bethesda, MD 20892 USA. NCI, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. RP Cho-Chung, YS (reprint author), NCI, Basic Res Lab, Cellular Biochem Sect, Bldt 10,Room 5B05,9000 Rockville Pike, Bethesda, MD 20892 USA. EM yc12b@nih.gov RI Stewart, Trina/F-5967-2012 OI Stewart, Trina/0000-0003-3220-9231 NR 45 TC 5 Z9 5 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2005 VL 11 IS 16 BP 5950 EP 5955 DI 10.1158/1078-0432.CCR-05-0624 PG 6 WC Oncology SC Oncology GA 956SL UT WOS:000231320000041 PM 16115938 ER PT J AU Zerbe, CS Holland, SM AF Zerbe, CS Holland, SM TI Disseminated histoplasmosis in persons with interferon-gamma receptor 1 deficiency SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HYPER-IGE SYNDROME; JOBS SYNDROME; PATIENT; IMMUNODEFICIENCY; CAPSULATUM; DISEASE; INFECTIONS; DOMINANT; FEATURES; DEFECTS AB Mutations in the interferon (IFN)-gamma receptor predispose to infection with bacille Calmette-Guerin, nontuberculous mycobacteria, and Salmonella organisms. We identified a patient with recurrent disseminated Histoplasma capsulatum osteomyelitis who had an autosomal dominant form of IFN-gamma receptor 1 deficiency (i.e., a 4-bp deletion at or near base 818). IFN-gamma-mediated immunity is important in the control of histoplasmosis. C1 Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. Natl Inst Allergy & Infect Dis, Lab Clin Infect Dis, NIH, Bethesda, MD USA. RP Holland, SM (reprint author), Univ Maryland, Dept Med, Bldg 10,CRC B3-4141,10 Ctr Dr,MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov NR 34 TC 58 Z9 59 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2005 VL 41 IS 4 BP E38 EP E41 DI 10.1086/432120 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 946ZE UT WOS:000230611000039 PM 16028145 ER PT J AU Walker, DL Vacha, SJ Kirby, ML Lo, CW AF Walker, DL Vacha, SJ Kirby, ML Lo, CW TI Connexin43 deficiency causes dysregulation of coronary vasculogenesis SO DEVELOPMENTAL BIOLOGY LA English DT Article DE coronary vessels; connexin43; knockout; VEGF; vascular smooth muscle; endothelial cells; heart development ID SMOOTH-MUSCLE-CELLS; GAP JUNCTIONAL COMMUNICATION; NEURAL CREST CELLS; GROWTH-FACTOR-BETA; CARDIAC OUTFLOW TRACT; CDNA CLONE SET; HEART DEVELOPMENT; GENE-EXPRESSION; AVIAN HEART; MESENCHYMAL TRANSFORMATION AB The connexin43 knockout (Cx43 alpha 1 KO) mouse dies at birth from outflow obstruction associated with infundibular pouches. To elucidate the origin of the infundibular pouches, we used microarray analysis to investigate gene expression changes in the pouch tissue. We found elevated expression of many genes encoding markers for vascular smooth muscle (VSM), endothelial cells, and fibroblasts, cell types that are epicardially derived and essential for coronary vasculogenesis. This was accompanied by increased expression of VEGF and genes in the TGF beta and VEGF/Notch/Eph cell-signaling pathways known to regulate vasculogenesis/angiogenesis. Using immunohistochemistry and a VSM lacZ reporter gene, we confirmed an abundance of ectopic VSM and endothelial cells in the infundibular pouch and in some regions of the right ventricle fort-ning secondary pouches. This was associated with distinct thinning of the compact myocardium. TUNEL labeling showed increased apoptosis in the pouch tissue, in agreement with the finding of altered expression of many apoptotic genes. Defects in vascular remodeling were indicated by a marked reduction in the branching complexity of the distal coronary arteries. In the near term KO mouse, we also observed a profusion of large coronary vascular plexuses subepicardially. This was associated with elevated epicardial expression of VEGF and abnormal epicardial cell morphology. Together, these observations indicate that dysregulated coronary vasculogenesis plays a pivotal role in formation of the infundibular pouches and suggests an essential role for Cx43 alpha 1 gap junctions in coronary vasculogenesis and vascular remodeling. Published by Elsevier Inc. C1 NHLBI, Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Agilent Technol, Palo Alto, CA 94304 USA. Duke Univ, Neonatal Perinatal Res Inst, Med Ctr, Div Neonatol, Durham, NC 27710 USA. RP Lo, CW (reprint author), NHLBI, Dev Biol Lab, NIH, Bldg 50-Room 4537,9000 Rockville Pike, Bethesda, MD 20892 USA. EM LoC@nhlbi.nih.gov FU NHLBI NIH HHS [HL36059, Z01-HL005701] NR 94 TC 41 Z9 47 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD AUG 15 PY 2005 VL 284 IS 2 BP 479 EP 498 DI 10.1016/j.ydbio.2005.06.004 PG 20 WC Developmental Biology SC Developmental Biology GA 960OI UT WOS:000231602600017 PM 16039638 ER PT J AU Varga, T Aplan, PD AF Varga, T Aplan, PD TI Chromosomal aberrations induced by double strand DNA breaks SO DNA REPAIR LA English DT Article DE chromosomal rearrangement; double strand DNA break; non-homologous end joining; insertion; I-SceI ID ILLEGITIMATE RECOMBINATION; MAMMALIAN CHROMOSOME; HOMOLOGOUS RECOMBINATION; SEQUENCE HOMOLOGIES; HUMAN-CELLS; REPAIR; RETROTRANSPOSITION; TRANSLOCATIONS; MECHANISM; PATHWAY AB It has been suggested that introduction of double strand DNA breaks (DSBs) into mammalian chromosomes can lead to gross chromosomal rearrangements through improper DNA repair. To study this phenomenon, we employed a model system in which a double strand DNA break can be produced in human cells in vivo at a predetermined location. The ensuing chromosomal changes flanking the breakage site can then be cloned and characterized. In this system, the recognition site for the I-SceI endonuclease, whose 18 by recognition sequence is not normally found in the human genome, is placed between a strong constitutive promoter and the Herpes simplex virus thymidine kinase (HSV-tk) gene, which serves as a negative selectable marker. We found that the most common mutation following aberrant DSB repair was an interstitial deletion; these deletions typically showed features of non-homologous end joining (NHEJ), such as microhomologies and insertions of direct or inverted repeat sequences. We also detected more complex rearrangements, including large insertions from adjacent or distant genomic regions. The insertion events that involved distant genomic regions typically represented transcribed sequences, and included both L1 LINE elements and sequences known to be involved in genomic rearrangements. This type of aberrant repair could potentially lead to gene inactivation via deletion of coding or regulatory sequences, or production of oncogenic fusion genes via insertion of coding sequences. Published by Elsevier B.V. C1 NCI, NIH, Genet Branch, Ctr Canc Res, Bethesda, MD 20889 USA. RP Aplan, PD (reprint author), NCI, NIH, Genet Branch, Ctr Canc Res, Navy 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM aplanp@mail.nih.gov RI Varga, Tamas/B-2413-2012; Aplan, Peter/K-9064-2016 NR 32 TC 41 Z9 41 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD AUG 15 PY 2005 VL 4 IS 9 BP 1038 EP 1046 DI 10.1016/j.dnarep.2005.05.004 PG 9 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 950QO UT WOS:000230872400009 PM 15935739 ER PT J AU McNairn, AJ Okuno, Y Misteli, T Gilbert, DM AF McNairn, AJ Okuno, Y Misteli, T Gilbert, DM TI Chinese hamster ORC subunits dynamically associate with chromatin throughout the cell-cycle SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE cell-cycle; DNA replication; GFP; origin recognition complex; photobleaching ID ORIGIN RECOGNITION COMPLEX; S-PHASE CHECKPOINT; MINICHROMOSOME MAINTENANCE PROTEINS; EUKARYOTIC DNA-REPLICATION; LIVING HUMAN-CELLS; IN-VIVO; SACCHAROMYCES-CEREVISIAE; GLUCOCORTICOID-RECEPTOR; HISTONE H1; RAPID EXCHANGE AB In yeast, the Origin Recognition Complex (ORC) is bound to replication origins throughout the cell-cycle, but in animal cells, there are conflicting data as to whether and when ORC is removed from chromatin. We find ORC1, 2 and ORC4 to be metabolically stable proteins that co-fractionate with chromatin throughout the cell-cycle in Chinese hamster fibroblasts. Since cellular extraction methods cannot directly examine the chromatin binding properties of proteins in vivo, we examined ORC:chromatin interactions in living cells. Fluorescence loss in photobleaching (FLIP) studies revealed ORC1 and ORC4 to be highly dynamic proteins during the cell-cycle with exchange kinetics similar to other regulatory chromatin proteins. In vivo interaction with chromatin was not significantly altered throughout the cell-cycle, including S-phase. These data support a model in which ORC subunits dynamically interact with chromatin throughout the cell-cycle. (c) 2005 Elsevier Inc. All rights reserved. C1 SUNY Upstate Med Univ, Dept Biochem & Mol Biol, Syracuse, NY 13210 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Gilbert, DM (reprint author), SUNY Upstate Med Univ, Dept Biochem & Mol Biol, 750 E Adams St, Syracuse, NY 13210 USA. EM gilbertd@upstate.edu OI McNairn, Adrian/0000-0003-4727-3770 FU NIGMS NIH HHS [GM-57233-01, R01 GM057233] NR 82 TC 29 Z9 30 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 15 PY 2005 VL 308 IS 2 BP 345 EP 356 DI 10.1016/j.yexcr.2005.05.009 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 953RV UT WOS:000231099100011 PM 15950218 ER PT J AU Huang, SM Litt, M Felsenfeld, G AF Huang, SM Litt, M Felsenfeld, G TI Methylation of histone H4 by arginine methyltransferase PRMT1 is essential in vivo for many subsequent histone modifications SO GENES & DEVELOPMENT LA English DT Article DE chromatin; histone H4 Arg3 methylation; PRMT1; chicken beta-globin locus ID H3 LYSINE-27 METHYLATION; EPIGENETIC CONTROL; ACETYLATION; GENE; CHROMATIN; H2B; UBIQUITINATION; TRANSCRIPTION; CODE; ACETYLTRANSFERASE AB PRMT1 is a histone methyltransferase that methylates Arg3 on histone H4. When we used siRNA to knock down PRMT1 in an erythroid cell line, it resulted in nearly complete loss of H4 Arg3 methylation across the chicken beta-globin domain, which we use as a model system for studying the relationship of gene activity to histone modification. We observed furthermore a domain-wide loss of histone acetylation on both histones H3 and H4, as well as an increase in H3 Lys9 and Lys27 methylation, both marks associated with inactive chromatin. To determine whether the effect on acetylation was directly related to the loss of H4 Arg3 methylation, we performed an in vitro acetylation reaction on chromatin isolated from PRMT1-depleted cells. We found that nucleosomes purified from these cells, and depleted in methylation at Arg3, are readily acetylated by nuclear extracts from the same cells, if and only if the nucleosomes are incubated with PRMT1 beforehand. Thus, methylation of histones by PRMT1 was sufficient to permit subsequent acetylation. Consistent with earlier reports of experiments in vitro, H4 Arg3 methylation by PRMT1 appears to be essential in vivo for the establishment or maintenance of a wide range of "active" chromatin modifications. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM Gary.felsenfeld@nih.gov NR 42 TC 123 Z9 126 U1 1 U2 10 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD AUG 15 PY 2005 VL 19 IS 16 BP 1885 EP 1893 DI 10.1101/gad.1333905 PG 9 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 956CX UT WOS:000231277600008 PM 16103216 ER PT J AU List, K Szabo, R Molinolo, A Sriuranpong, V Redeye, V Murdock, T Burke, B Nielsen, BS Gutkind, JS Bugge, TH AF List, K Szabo, R Molinolo, A Sriuranpong, V Redeye, V Murdock, T Burke, B Nielsen, BS Gutkind, JS Bugge, TH TI Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation SO GENES & DEVELOPMENT LA English DT Article DE transmembrane serine protease; cell surface protease; oncogenic proteolysis; carcinoma; multistage carcinogenesis; ras ID MEMBRANE SERINE-PROTEASE; MOUSE SKIN CARCINOGENESIS; HAIR FOLLICLE DEVELOPMENT; HEPATOCYTE GROWTH-FACTOR; PLASMINOGEN-ACTIVATOR; OVARIAN-CANCER; EXTRACELLULAR-MATRIX; BREAST-CANCER; STROMAL CELLS; EXPRESSION AB Overexpression of the type II transmembrane serine protease matriptase is a highly consistent feature of human epithelial tumors. Here we show that matriptase possesses a strong oncogenic potential when unopposed by its endogenous inhibitor, HAI-1. Modest orthotopic overexpression of matriptase in the skin of transgenic mice caused spontaneous squamous cell carcinoma and dramatically potentiated carcinogen-induced tumor formation. Matriptase-induced malignant conversion was preceded by progressive interfollicular hyperplasia, dysplasia, follicular transdifferentiation, fibrosis, and dermal inflammation. Furthermore, matriptase induced activation of the pro-tumorigenic PI3K-Akt signaling pathway. This activation was frequently accompanied by H-ras or K-ras mutations in carcinogen-induced tumors, whereas matriptase-induced spontaneous carcinoma formation occurred independently of ras activation. Increasing epidermal HAI-1 expression completely negated the oncogenic effects of matriptase. The data implicate dysregulated matriptase expression in malignant epithelial transformation. C1 Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Mol Carcinogenesis Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Finsen Inst, DK-2100 Copenhagen, Denmark. RP Bugge, TH (reprint author), Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, NIH, Bethesda, MD 20892 USA. EM thomas.bugge@nih.gov RI Gutkind, J. Silvio/A-1053-2009; Tang, Amy/L-3226-2016 OI Tang, Amy/0000-0002-5772-2878 NR 52 TC 146 Z9 152 U1 2 U2 11 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD AUG 15 PY 2005 VL 19 IS 16 BP 1934 EP 1950 DI 10.1101/gad.1300705 PG 17 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 956CX UT WOS:000231277600012 PM 16103220 ER PT J AU Wang, J Xu, GL Li, H Gonzales, V Fromholt, D Karch, C Copeland, NG Jenkins, NA Borchelt, DR AF Wang, J Xu, GL Li, H Gonzales, V Fromholt, D Karch, C Copeland, NG Jenkins, NA Borchelt, DR TI Somatodendritic accumulation of misfolded SOD1-L126Z in motor neurons mediates degeneration: alpha B-crystallin modulates aggregation SO HUMAN MOLECULAR GENETICS LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; ALS-LINKED SOD1; SUPEROXIDE-DISMUTASE 1; MOLECULAR-WEIGHT COMPLEXES; HEAT-SHOCK PROTEINS; COPPER-BINDING-SITE; TRANSGENIC MICE; CU,ZN-SUPEROXIDE DISMUTASE; HYDROGEN-PEROXIDE; MUTANT SOD1 AB Mice expressing variants of superoxide dismutase-1 (SOD1) encoding C-terminal truncation mutations linked to familial amyotrophic lateral sclerosis (FALS) have begun to define the role of misfolding and aggregation in the pathogenesis of disease. Here, we examine transgenic mice expressing SOD1-L126Z (Z = stop-truncation of last 28 amino acids), finding that detergent-insoluble mutant protein specifically accumulates in somatodendritic compartments. Soluble forms of the SOD1-L126Z were virtually undetectable in spinal cord at any age and the levels of accumulated protein directly correlated with disease symptoms. Neither soluble nor insoluble forms of SOD1-L126Z were transported to distal axons. In vitro, small heat shock protein (Hsp) alpha B-crystallin suppressed the in vitro aggregation of SOD1-L126Z. In vivo, alpha B-crystallin immunoreactivity was most abundant in oligodendrocytes and up-regulated in astrocytes of symptomatic mice; neither of these cell-types accumulated mutant SOD1 immunoreactivity. These results suggest that damage to motor neuron cell bodies and dendrites within the spinal cord can be sufficient to induce motor neuron disease and that the activities of chaperones may modulate the cellular specificity of mutant SOD1 accumulation. C1 NCI, Mouse Canc Genet Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Borchelt, DR (reprint author), Univ Florida, Coll Med, Dept Neurosci, McKnight Brain Inst, 100 Newell Dr,Room L1-100H,POB 100244, Gainesville, FL 32610 USA. EM borchelt@mbi.ufl.edu FU NINDS NIH HHS [R01 NS 047225, R01 NS 37225] NR 49 TC 82 Z9 83 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2005 VL 14 IS 16 BP 2335 EP 2347 DI 10.1093/hmg/ddi236 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 957RJ UT WOS:000231390700004 PM 16000321 ER PT J AU Myers, AJ Kaleem, M Marlowe, L Pittman, AM Lees, AJ Fung, HC Duckworth, J Leung, D Gibson, A Morris, CM de Silva, R Hardy, J AF Myers, AJ Kaleem, M Marlowe, L Pittman, AM Lees, AJ Fung, HC Duckworth, J Leung, D Gibson, A Morris, CM de Silva, R Hardy, J TI The H1c haplotype at the MAPT locus is associated with Alzheimer's disease SO HUMAN MOLECULAR GENETICS LA English DT Article ID PROGRESSIVE SUPRANUCLEAR PALSY; TAU GENE; LINKAGE DISEQUILIBRIUM; POLYMORPHISMS; DEGENERATION; HYPOTHESIS; DEMENTIAS; BETA AB Although it is clear that microtubule associated protein tau (MAPT) is involved in Alzheimer's disease (AD) pathology, it has not been clear whether it is involved genetically. We have recently examined the MAPT locus in progressive supranuclear palsy and found that a haplotype (H1c) on the background of the well-described H1 clade is associated with PSP. Here we report that the same haplotype is associated with the risk of AD in two autopsy confirmed series of cases with ages at death >65 years. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Newcastle Gen Hosp, Inst Ageing & Hlth, Newcastle Upon Tyne NE4 6BE, Tyne & Wear, England. Chang Gung Univ, Dept Neurol 2, Chang Gung Mem Hosp, Taipei 10591, Taiwan. Chang Gung Univ, Coll Med, Taipei 10591, Taiwan. Inst Neurol, Sara Koe PSP Res Ctr, London WC1N 1PJ, England. Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. UCL, Reta Lila Weston Inst Neurol Studies, London W1T 4JF, England. RP Hardy, J (reprint author), NIA, Neurogenet Lab, NIH, Porter Neurosci Bldg,35 Convent Dr, Bethesda, MD 20892 USA. EM hardyj@mail.nih.gov RI de Silva, Rohan/C-1734-2008; Myers, Amanda/B-1796-2010; Hardy, John/C-2451-2009; Pittman, Alan/D-6231-2012; Lees, Andrew/A-6605-2009; Leung, Doris/R-5447-2016 OI de Silva, Rohan/0000-0002-5052-5775; Myers, Amanda/0000-0002-3100-9396; Leung, Doris/0000-0002-2558-7798 FU Intramural NIH HHS; NIA NIH HHS [AG 05146, AG05128, P50 AG16570, P50-AG08671]; NIMH NIH HHS [MH60451]; NINDS NIH HHS [NS39764] NR 20 TC 125 Z9 129 U1 2 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 15 PY 2005 VL 14 IS 16 BP 2399 EP 2404 DI 10.1093/hmg/ddi241 PG 6 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 957RJ UT WOS:000231390700009 PM 16000317 ER PT J AU Shebzukhov, YV Koroleva, EP Khlgatian, SV Lagarkova, MA Meshcheryakov, AA Lichinitser, MR Karbach, J Jager, E Kuprash, DV Nedospasov, SA AF Shebzukhov, YV Koroleva, EP Khlgatian, SV Lagarkova, MA Meshcheryakov, AA Lichinitser, MR Karbach, J Jager, E Kuprash, DV Nedospasov, SA TI Humoral immune response to thymidylate synthase in colon cancer patients after 5-FU chemotherapy SO IMMUNOLOGY LETTERS LA English DT Article DE antibodies; serology; thymidylate synthase (TYMS); 5-fluorouracil (5-FU) ID COLORECTAL-CANCER; TUMOR-ANTIGENS; EXPRESSION; 5-FLUOROURACIL; IDENTIFICATION; MECHANISMS; ENZYME AB Thymidylate synthase (TYMS), the critical enzyme for DNA synthesis and a target for chemotherapy, was recently characterized as an oncogene and a potential target for specific immunotherapy. Here we report TYMS-specific antibody response in a fraction of colon cancer patients. Humoral immune response to TYMS is induced by chemotherapy using TYMS inhibitors, such as 5-fluorouracil (5-FU), and may be associated with tumor burden. Therefore, TYMS may serve as a useful serological biomarker for monitoring the course of disease and treatment in cancer patients. (c) 2005 Elsevier B.V. All rights reserved. C1 Moscow MV Lomonosov State Univ, Belozersky Inst PhysicoChem Biol, Dept Mol Immunol, Moscow 119899, Russia. SAIC Frederick Inc, Basic Res Program, NCI Frederick, Frederick, MD 21702 USA. Russian Acad Sci, Lab Mol Immunol, VA Engelhardt Mol Biol Inst, Moscow 119991, Russia. Russian Acad Med Sci, NN Blokhin Canc Res Ctr, Moscow 115478, Russia. Krankenhaus Nordw, Med Klin 2, D-60488 Frankfurt, Germany. RP Nedospasov, SA (reprint author), Moscow MV Lomonosov State Univ, Belozersky Inst PhysicoChem Biol, Dept Mol Immunol, Vorobjovy Gory, Moscow 119899, Russia. EM snedos@online.ru RI Kuprash, Dmitry/O-4899-2015; Nedospasov, Sergei/Q-7319-2016; Nedospasov, Sergei/J-5936-2013; Nedospasov, Sergei/L-1990-2015 OI Kuprash, Dmitry/0000-0002-1488-4148; FU NCI NIH HHS [N01 CO 12400] NR 19 TC 9 Z9 13 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD AUG 15 PY 2005 VL 100 IS 1 BP 88 EP 93 DI 10.1016/j.imlet.2005.06.011 PG 6 WC Immunology SC Immunology GA 971ZC UT WOS:000232422600014 PM 16055198 ER PT J AU Matthews, JNA Yim, PB Jacobs, DT Forbes, JG Peters, ND Greer, SC AF Matthews, JNA Yim, PB Jacobs, DT Forbes, JG Peters, ND Greer, SC TI The polymerization of actin: Extent of polymerization under pressure, volume change of polymerization, and relaxation after temperature jumps SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID AMINO-ACID SEQUENCE; LIVING POLYMERIZATION; HYDROSTATIC-PRESSURE; F TRANSFORMATION; LATTICE MODEL; MUSCLE ACTIN; EQUILIBRIUM POLYMERIZATION; SKELETAL-MUSCLE; SMOOTH-MUSCLE; MECHANISM AB The protein actin can polymerize from monomeric globular G-actin to polymeric filamentary F-actin, under the regulation of thermodynamic variables such as temperature, pressure, and compositions of G-actin and salts. We present here new measurements of the extent of polymerization (phi) of actin under pressure (P), for rabbit skeletal muscle actin in H2O buffer in the presence of adenosine triposphate and calcium ions and at low (5-15 mM) KCl concentrations. We measured phi using pyrene-labeled actin, as a function of time (t) and temperature (T), for samples of fixed concentrations of initial G-actin and KCl and at fixed pressure. The phi(T,P) measurements at equilibrium have the same form as reported previously at 1 atm: low levels of polymerization at low temperatures, representing dimerization of the actin; an increase in phi at the polymerization temperature (T-p); a maximum in phi(T) above T-p with a decrease in phi(T) beyond the maximum, indicating a depolymerization at higher T. From phi(T,P) at temperatures below T-p, we estimate the change in volume for the dimerization of actin, Delta V-dim, to be -307 +/- 10 ml/mol at 279 K. The change of T-p with pressure dT(p)/dP=(0.3015 +/- 0.0009) K/MPa=(30.15 +/- 0.09) mK/atm. The phi(T,P) data at higher T indicate the change in volume on propagation, Delta V-prop, to be +401 +/- 48 ml/mol at 301 K. The phi(t) measurements yield initial relaxation times r(p)(T) that reflect the behavior of phi(T) and support the presence of a depolymerization temperature. We also measured the density of polymerizing actin with a vibrating tube density meter, the results of which confirm that the data from this instrument are affected by viscosity changes and can be erroneous. (c) 2005 American Institute of Physics. C1 Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. Coll Wooster, Dept Phys, Wooster, OH 44691 USA. NIAMSD, Proteom & Nanotechnol Sect, Muscle Biol Lab, NIH,DHHS, Bethesda, MD 20892 USA. RP Greer, SC (reprint author), Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. EM sgreer@umd.edu FU NIAMS NIH HHS [AR45191] NR 69 TC 8 Z9 8 U1 0 U2 6 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 AUG 15 PY 2005 VL 123 IS 7 AR 074904 DI 10.1063/1.2001635 PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 958LL UT WOS:000231449700065 PM 16229617 ER PT J AU Dobolyi, A Irwin, S Makara, G Usdin, TB Palkovits, M AF Dobolyi, A Irwin, S Makara, G Usdin, TB Palkovits, M TI Calcitonin gene-related peptide-containing pathways in the rat forebrain SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE CGRP immunocytochemistry; electrolytic lesion; neuronal pathway transection; parabrachial nuclei ID CENTRAL-NERVOUS-SYSTEM; CORTICOTROPIN-RELEASING FACTOR; SUBPARAFASCICULAR THALAMIC NUCLEUS; MEDIAL GENICULATE-NUCLEUS; LATERAL SEPTAL AREA; CGRP MESSENGER-RNA; STRIA TERMINALIS; BINDING-SITES; IMMUNOHISTOCHEMICAL ANALYSIS; PARABRACHIAL NUCLEUS AB The present study focuses on the topographical distribution of calcitonin gene-related peptide (CGRP)-containing cell bodies and fibers and their connections and pathways in the rat forebrain. We confirm previously reported CGRP projections from the perifornical area of the hypothalamus to the lateral septum, from the posterior thalamus to the caudate putamen and cerebral cortex, and from the parabrachial nuclei to the central extended amygdala, lateral hypothalamus, and ventromedial thalamus. Despite previous descriptions of CGRP in the central nervous system, important neuroanatomical aspects of the forebrain CGRP system remained obscure, which we addressed by using brain lesion techniques combined with modern immunohistology. We first report CGRP terminal fields in the olfactory-anterior septal region and also CGRP projections from the parabrachial nuclei to the olfactory-anterior septal region, the medial prefrontal cortex, the interstitial nucleus of the anterior commissure, the nucleus of the lateral olfactory tract, the anterior amygdaloid area, the posterolateral cortical amygdaloid nucleus, and the dorsolateral part of the lateral amygdaloid nucleus. In addition, we identified a CGRP cell group in the premamillary nuclei and showed that it projects to the medial CGRP layer of the lateral septum. CGRP fibers usually join other pathways rather than forming bundles. They run along the fornix from the hypothalamus, along the supraoptic decussations or the inferior thalamic peduncle-stria terminalis pathway from the posterior thalamus, and along the superior cerebellar peduncle, thalamic fasciculus, and ansa peduncularis from the parabrachial nuclei. This description of the forebrain CGRP system will facilitate investigation of its role in higher brain functions. Published 2005 Wiley-Liss, Inc. C1 Semmelweis Univ, Sch Med, Neuromorphol Lab, H-1094 Budapest, Hungary. Hungarian Acad Sci, H-1094 Budapest, Hungary. Hungarian Acad Sci, Inst Expt Med, H-1450 Budapest, Hungary. NIMH, Genet Lab, Bethesda, MD 20892 USA. RP Palkovits, M (reprint author), Semmelweis Univ, Sch Med, Neuromorphol Lab, Tuzolto 58, H-1094 Budapest, Hungary. EM palkovits@ana.sote.hu RI Dobolyi, Arpad/B-9089-2008; Palkovits, Miklos/F-2707-2013; Makara, Gabor/H-8397-2013; OI Makara, Gabor/0000-0001-9220-0373; Palkovits, Miklos/0000-0003-0578-0387 FU Intramural NIH HHS NR 90 TC 49 Z9 50 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD AUG 15 PY 2005 VL 489 IS 1 BP 92 EP 119 DI 10.1002/cne.20618 PG 28 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 941PJ UT WOS:000230226400007 PM 15977170 ER PT J AU Asselin-Paturel, C Trinchieri, G AF Asselin-Paturel, C Trinchieri, G TI Production of type I interferons: plasmacytoid dendritic cells and beyond SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID TOLL-LIKE RECEPTORS; POSITIVE FEEDBACK; ALPHA INDUCTION; VIRUS-INFECTION; CPG-A; IFN; ACTIVATION; RESPONSES; IRF-7; EXPRESSION AB Plasmacytoid dendritic cells (pDCs) are specialized producers of type I interferons (IFNs) that respond to most viruses. Because of their antiviral activity and regulatory functions in innate and adaptive immunity, type I IFNs are important not only for antiviral resistance but also in other types of infections and in immune pathology. Here we discuss recent data that begin to reveal the unique molecular mechanisms underlying the remarkably rapid and efficient type I IFN production by pDCs. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Asselin-Paturel, C (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM carine.paturel@free.fr; trinchig@niaid.nih.gov NR 28 TC 166 Z9 178 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 15 PY 2005 VL 202 IS 4 BP 461 EP 465 DI 10.1084/jem.20051395 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 955RF UT WOS:000231244000002 PM 16103406 ER PT J AU Corn, RA Hunter, C Liou, HC Siebenlist, U Boothby, MR AF Corn, RA Hunter, C Liou, HC Siebenlist, U Boothby, MR TI Opposing roles for RelB and Bcl-3 in regulation of T-box expressed in T cells, GATA-3, and Th effector differentiation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; TRANSCRIPTION FACTOR; IMMUNE-RESPONSES; TOXOPLASMA-GONDII; FAMILY-MEMBERS; C-REL; LYMPHOCYTE-PROLIFERATION; TARGETED DISRUPTION; IL-12R-BETA-2 CHAIN; DENDRITIC CELLS AB CD4(+) T cells with a block in the NF-kappa B signaling pathway exhibit decreases in Th1 responses and diminished nuclear levels of multiple transactivating NF-kappa B/Rel/I kappa B proteins. To determine the lineage-intrinsic contributions of these transactivators to Th differentiation, T cells from mice deficient in specific subunits were cultured in exogenous cytokines promoting either Th1 or Th2 differentiation. Relli-deficient cells exhibited dramatic defects in Th1 differentiation and IFN-gamma production, whereas no consistent defect in either Th1 or Th2 responses was observed with c-Rel-deficient cells. In sharp contrast, Bcl-3-null T cells displayed no defect in IFN-gamma production, but their Th2 differentiation and IL-4, IL-5, and IL-13 production were significantly impaired. The absence of ROB led to a dramatic decrease in the expression of, T-box expressed in T cells and Stat4. In contrast, Bcl-3-deficient cells exhibited decreased GATA-3, consistent with evidence that Bcl-3 can transactivate a gata3 promoter. These data indicate that Bcl-3 and RelB exert distinct and opposing effects on the expression of subset-determining transcription factors, suggesting that the characteristics of Th cell responses may be regulated by titrating the stoichiometry of transactivating NF-kappa B[ReVIKB complexes in the nuclei of developing helper effector cells. C1 Vanderbilt Univ, Sch Med, Dept Microbiol & Immunol, Nashville, TN 37232 USA. Meharry Med Coll, Dept Microbiol, Nashville, TN 37208 USA. Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. Cornell Univ, Div Immunol, Coll Med, Dept Med, New York, NY 10021 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Vanderbilt Univ, Sch Med, Dept Microbiol & Immunol, MCN AA4220,1161 21st Ave S, Nashville, TN 37232 USA. EM mark.boothby@vanderbilt.edu RI Hunter, Christopher/H-1970-2011; minor, radiah/B-6412-2012 FU NCI NIH HHS [CA68485]; NHLBI NIH HHS [HL68744, P01 HL68744]; NIAID NIH HHS [AI49460, AI49460-02S1-04S1]; NIDDK NIH HHS [P60 DK20593]; NIGMS NIH HHS [R25 GM62459] NR 61 TC 49 Z9 55 U1 1 U2 7 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2005 VL 175 IS 4 BP 2102 EP 2110 PG 9 WC Immunology SC Immunology GA 966HJ UT WOS:000232010400013 PM 16081776 ER PT J AU Prlic, M Gibbs, J Jameson, SC AF Prlic, M Gibbs, J Jameson, SC TI Characteristics of NK cell migration early after vaccinia infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; LARGE ANTIGRANULOCYTES LYMPHOCYTES; CD8(+) T-CELLS; IN-VIVO; MURINE CYTOMEGALOVIRUS; DENDRITIC CELLS; PERTUSSIS-TOXIN; VIRUS-INFECTION; ACCUMULATION; INVIVO AB NK cells are critical components in innate immunity, yet little is known about their migration and proliferation during infection. In this report we study the early NK response toward vaccinia. We observed NK migration into the infected peritoneum as early as 6 h after vaccinia inoculation. Interestingly, although NK trafficking to the infected peritoneum depended on G alpha(i) protein-coupled receptors, trafficking to other tissues (including lung, liver, spleen, and bone marrow) did not. We found that despite a dramatic increase in NK numbers at the primary site of infection, their in situ proliferation was low compared with that at other tissue locations. These features are similar to those found for Ag-experienced T cells, suggesting similar patterns of trafficking and proliferation for these lymphocyte subsets. C1 Univ Minnesota, Ctr Immunol, Minneapolis, MN 55455 USA. Univ Minnesota, Ctr Canc, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Univ Minnesota, Ctr Immunol, 6-110 NHH,312 Church St, Minneapolis, MN 55455 USA. EM james024@umn.edu RI Jameson, Stephen/D-9892-2013 FU NCPDCID CDC HHS [R01-CI00100]; NIAID NIH HHS [R01AI38903] NR 27 TC 21 Z9 21 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2005 VL 175 IS 4 BP 2152 EP 2157 PG 6 WC Immunology SC Immunology GA 966HJ UT WOS:000232010400018 PM 16081781 ER PT J AU Houtman, JCD Houghtling, RA Barda-Saad, M Toda, Y Samelson, LE AF Houtman, JCD Houghtling, RA Barda-Saad, M Toda, Y Samelson, LE TI Early phosphorylation kinetics of proteins involved in proximal TCR-mediated signaling pathways SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; ANTIGEN RECEPTOR; PHOSPHOLIPASE C-GAMMA-1; NEGATIVE REGULATION; TYROSINE RESIDUES; ADAPTER PROTEIN; FAMILY KINASES; SLP-76 DOMAINS; ACTIVATION; LAT AB Activation of T cells via the stimulation of the TCR plays a central role in the adaptive immunological response. Although much is known about TCR-stimulated signaling pathways, there are still gaps in our knowledge about the kinetics and sequence of events during early activation and about the in vivo specificity of kinases involved in these proximal signaling pathways. This information is important not only for understanding the activation of signaling pathways important for T cell function but also for the development of drug targets and computer-based molecular models. In this study, phospho-specific Abs directed toward individual sites on signaling proteins were used to investigate the early phosphorylation kinetics of proteins involved in proximal TCR-induced pathways. These studies indicate that linker for activation of T cells' tyrosines have substantially different phosphorylation kinetics and that Src homology 2 domain-containing leukocyte protein of 76 kDa has rapid, transient phosphorylation kinetics compared to other proteins. In additions, we provide evidence that ZAP-70 is the primary in vivo kinase for LAT tyrosine 191 and that Itk plays a role in the phosphorylation of tyrosine 783 on phospholipase C-gamma 1. In total, these studies give new insight into the sequence, kinetics and specificity of early TCR-mediated signaling events that are vital for T cell activation. C1 NCI, Lab Cellular & Mol Biol, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP NCI, Lab Cellular & Mol Biol, 37 Convent Dr,MSC 4255,Bldg 37,Room 2066, Bethesda, MD 20892 USA. EM samelson@helix.nih.gov FU NCI NIH HHS [Z01 BC010304-07] NR 46 TC 65 Z9 69 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2005 VL 175 IS 4 BP 2449 EP 2458 PG 10 WC Immunology SC Immunology GA 966HJ UT WOS:000232010400053 PM 16081816 ER PT J AU Zhao, AP Morimoto, M Dawson, H Elfrey, JE Madden, KB Gause, WC Min, B Finkelman, FA Urban, JF Shea-Donohue, T AF Zhao, AP Morimoto, M Dawson, H Elfrey, JE Madden, KB Gause, WC Min, B Finkelman, FA Urban, JF Shea-Donohue, T TI Immune regulation of protease-activated receptor-1 expression in murine small intestine during Nippostrongylus brasiliensis infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SMOOTH-MUSCLE; THROMBIN; RESPONSES; CELLS; STAT6; IL-13; INTERLEUKIN-13; INFLAMMATION; PARASITISM; SECRETION AB Infection with gastrointestinal nematodes exerts profound effects on both immune and physiological responses of the host. Helminth infection induces a hypercontractility of intestinal smooth muscle that is dependent on the Th2 cytokines, IL-4 and IL-13, and may contribute to worm expulsion. Protease-activated receptors (PARs) are expressed throughout the gut, and activation of PAR-1 was observed in asthma, a Th2-driven pathology. In the current study we investigated the physiologic and immunologic regulation of PAR-I in the murine small intestine, specifically 1) the effect of PAR-1 agonists on small intestinal smooth muscle contractility, 2) the effects of Nippostrongylus brasiliensis infection on PAR-1 responses, 3) the roles of IL-13 and IL-4 in N. brasiliensis infection-induced alterations in PAR-I responses, and 4) the STAT6 dependence of these responses. We demonstrate that PAR-I activation induces contraction of murine intestinal smooth muscle that is enhanced during helminth infection. This hypercontractility is associated with an elevated expression of PAR-I mRNA and protein. N. brasiliensis-induced changes in PAR-1 function and expression were seen in IL-4-deficient mice, but not in IL-13- or STAT6-deficient mice, indicating the dependence of IL-13 on the STAT6 signaling pathway independent of IL-4. C1 Univ Maryland, Sch Med, Mucosal Biol Res Ctr, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. USDA ARS, Nutr Requirements & Funct Lab, Beltsville Human Nutr Res Ctr, Beltsville, MD 20705 USA. Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Univ Cincinnati, Dept Med, Cincinnati, OH 45267 USA. Univ Cincinnati, Dept Pediat, Cincinnati, OH 45267 USA. Cincinnati Vet Adm Med Ctr, Cincinnati, OH 45220 USA. RP Univ Maryland, Sch Med, Mucosal Biol Res Ctr, 20 Penn St, Baltimore, MD 21201 USA. EM tdonohue@mbrc.umaryl.edu RI Dawson, Harry/H-8242-2013; OI Urban, Joseph/0000-0002-1590-8869 FU NIAID NIH HHS [R01 AI031678, R01 AI031678-06, R01 AI031678-07, R01 AI031678-08, R01 AI031678-09, R01 AI031678-10, R01 AI031678-11, R01 AI031678-12, R01 AI049316, R01 AI052099, R01AI/DK49316, R01AI052099, R01AI35987]; NIDDK NIH HHS [R01 DK049316] NR 32 TC 29 Z9 31 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2005 VL 175 IS 4 BP 2563 EP 2569 PG 7 WC Immunology SC Immunology GA 966HJ UT WOS:000232010400067 PM 16081830 ER PT J AU Chrousos, GP Kino, T AF Chrousos, GP Kino, T TI Interactive functional specificity of the stress and immune responses: The ying, the yang, and the defense against 2 major classes of bacteria SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID GLUCOCORTICOIDS; INFLAMMATION; SYSTEM C1 Univ Athens, Dept Pediat 1, Athens, Greece. NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. RP Chrousos, GP (reprint author), Univ Athens, Sch Med, Dept Pediat 1, Childrens Hosp Aghia Sophia, GR-11527 Athens, Greece. EM chrousge@med.uoa.gr NR 10 TC 8 Z9 9 U1 2 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2005 VL 192 IS 4 BP 551 EP 555 DI 10.1086/432135 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 952QB UT WOS:000231019500001 PM 16028122 ER PT J AU Barczak, AK Domenech, P Boshoff, HIM Reed, MB Manca, C Kaplan, G Barry, CE AF Barczak, AK Domenech, P Boshoff, HIM Reed, MB Manca, C Kaplan, G Barry, CE TI In vivo phenotypic dominance in mouse mixed infections with Mycobacterium tuberculosis clinical isolates SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Keystone Symposia on Tuberculosis - Integrating Host and Pathogen Biology CY JAN 25-30, 2003 CL Taos, NM ID LABORATORY STRAINS; SPREAD; VIRULENCE; OUTBREAK; RUSSIA AB Clinical isolates of Mycobacterium tuberculosis demonstrate significant heterogeneity in virulence potential in animal models of infection. Isolate CDC1551, for example, has previously been described in mouse survival studies as being hypovirulent, and isolate HN878 has been described as being hypervirulent. Observed differences in this mouse infection experiment have been proposed to reflect differential engagement of the host immune response. To assess whether this is a local or a systemic effect, C57BL/6 mice were infected simultaneously with mixtures of CDC1551 and HN878 in varying ratios and were monitored for mycobacterial growth kinetics, strain proportions during infection, and mouse survival. Strain mixtures that contained primarily HN878 grew more quickly during the first 5 weeks of infection and were more lethal for mice, and HN878 was enriched during in vivo growth. The absolute number of implanted HN878 bacilli at infection correlated inversely with mouse survival and was independent of concomitant infection with CDC1551. In infections of nonactivated mouse macrophages, HN878 grew more quickly. However, phagocyte preactivation reduced and equalized the growth rate of both strains. These results suggest that HN878 exerts a dominant immunosuppressive effect limited to the granuloma in which it is contained. C1 NIAID, TB Res Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. NIH, Res Scholars Program, Howard Hughes Med Inst, Bethesda, MD USA. Publ Hlth Res Inst, TB Res Ctr, Lab Mycobacterial Immun & Pathogenesis, Newark, NJ USA. RP Barry, CE (reprint author), NIAID, TB Res Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM cbarry@niaid.nih.gov RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000734-12]; NIAID NIH HHS [AI54338, AI54361, R01 AI054338] NR 20 TC 41 Z9 42 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2005 VL 192 IS 4 BP 600 EP 606 DI 10.1086/432006 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 952QB UT WOS:000231019500007 PM 16028128 ER PT J AU Hope, WW Warn, PA Sharp, A Reed, P Keevil, B Louie, A Denning, DW Drusano, GL AF Hope, WW Warn, PA Sharp, A Reed, P Keevil, B Louie, A Denning, DW Drusano, GL TI Surface response modeling to examine the combination of amphotericin B deoxycholate and 5-fluorocytosine for treatment of invasive candidiasis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 44th Interscience Conference on Antimicrobial Agents and Chemotherapy CY OCT 30-NOV 02, 2004 CL Washington, DC ID ATTRIBUTABLE MORTALITY; COMPARING FLUCONAZOLE; ANTIFUNGAL THERAPY; IN-VITRO; CANDIDEMIA; FLUCYTOSINE; ALBICANS; TRIAL; PHARMACODYNAMICS; ASPERGILLOSIS AB The strategy of combining antifungal drugs in a treatment regimen may improve the outcome of invasive candidiasis. Using a well-validated pharmacodynamic murine model of invasive candidiasis, we defined the effect of the combination of amphotericin B deoxycholate (AmB) and 5-fluorocytosine (5FC) by use of the Greco model of drug interaction. The combination was additive, meaning that the experimental effect did not deviate in a statistically significant manner from the null reference model (or additive surface) of the combined effect. From a clinical perspective, the addition of 5FC to a regimen of AmB may enable the near-maximum effect to be reached in circumstances in which the administration of a given dose of AmB alone produces a submaximum effect but an increase in the dose is not possible, because of dose-related toxicity. Our methods provide a way in which some of the complex issues surrounding antifungal combination treatment can be addressed. C1 Univ Manchester, Dept Med, Manchester M13 9PL, Lancs, England. Hope Hosp, Dept Biochem, Manchester, Lancs, England. Wythenshawe Hosp, Dept Biochem, Manchester M23 9LT, Lancs, England. Ordway Res Inst, Albany, NY USA. RP NCI, Pediat Oncol Branch, NIH, Rm 1-5750,10 Ctr Dr,MSC 1100, Bethesda, MD 20892 USA. EM hopew@mail.nih.gov OI Denning, David/0000-0001-5626-2251; Hope, William/0000-0001-6187-878X NR 29 TC 13 Z9 14 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2005 VL 192 IS 4 BP 673 EP 680 DI 10.1086/432069 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 952QB UT WOS:000231019500016 PM 16028137 ER PT J AU Maingret, F Lauri, SE Taira, T Isaac, JTR AF Maingret, F Lauri, SE Taira, T Isaac, JTR TI Profound regulation of neonatal CA1 rat hippocampal GABAergic transmission by functionally distinct kainate receptor populations SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID LONG-TERM POTENTIATION; SYNAPTIC-TRANSMISSION; AMPA RECEPTORS; IN-VIVO; NETWORK OSCILLATIONS; MEDIATED RESPONSES; PYRAMIDAL CELLS; INTERNEURONS; SYNAPSES; ACTIVATION AB Neonatal hippocampus exhibits distinct patterns of network activity that are dependent on the interaction between inhibitory and excitatory transmission. Kainate receptors are ideally positioned to regulate this activity by virtue of their ability to regulate presynaptic function in GABAergic interneurones. Indeed, kainate receptors are highly expressed in neonatal hippocampal interneurones, yet the role and mechanisms by which they might regulate neonatal circuitry are unexplored. To address this we investigated the kainate receptor-dependent regulation of GABAergic transmission onto neonatal CA I pyramidal neurones. Kainate receptor activation produced two distinct opposing effects, a very large increase in the frequency of spontaneous IPSCs, and a robust depression of evoked GABAergic transmission. The up-regulation of spontaneous transmission was due to activation of somatodendritic and axonal receptors while the depression of evoked transmission could be fully accounted for by a direct regulation of GABA release by kainate receptors located at the terminals. None of the effects of kainate receptor agonists were sensitive to GABA(B) receptor antagonists, nor was there any postsynaptic kainate receptor-dependent effects observed in CA1 pyramidal cells that could account for our findings. Our data demonstrate that kainate receptors profoundly regulate neonatal CA1 GABAergic circuitry by two distinct opposing mechanisms, and indicate that these two effects are mediated by functionally distinct populations of receptors. Thus kainate receptors are strategically located to play a critical role in shaping early hippocampal network activity and by virtue of this have a key role in hippocampal development. C1 NINDS, NIH, Bethesda, MD 20892 USA. Univ Bristol, Dept Anat, MRC, Ctr Synapt Plast, Bristol BS8 1TD, Avon, England. Univ Helsinki, Ctr Neurosci, FIN-00014 Helsinki, Finland. Univ Helsinki, Dept Biosci, FIN-00014 Helsinki, Finland. RP Isaac, JTR (reprint author), NINDS, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM isaacj@ninds.nih.gov OI Lauri, Sari/0000-0002-5895-1357 FU Wellcome Trust NR 47 TC 29 Z9 31 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 15 PY 2005 VL 567 IS 1 BP 131 EP 142 DI 10.1111/jphysiol.2005.089474 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 958VX UT WOS:000231477400016 PM 15946969 ER PT J AU Gregoriou, GG Luppino, G Matelli, M Savaki, HE AF Gregoriou, GG Luppino, G Matelli, M Savaki, HE TI Frontal cortical areas of the monkey brain engaged in reaching behavior: A (14)C-deoxyglucose imaging study SO NEUROIMAGE LA English DT Article DE frontal cortical area; monkey brain; (14)C-deoxyglucose ID SUPPLEMENTARY MOTOR AREA; VENTRAL PREMOTOR CORTEX; ADJACENT CINGULATE CORTEX; SACCADIC EYE-MOVEMENTS; MACAQUE MONKEY; NEURONAL-ACTIVITY; CORTICOSPINAL PROJECTIONS; INFERIOR AREA-6; TOPOGRAPHIC ORGANIZATION; FUNCTIONAL-ORGANIZATION AB The ((14)C)-deoxyglucose method was employed to study whether different areas of the primate frontal lobe are involved in different aspects of reaching behavior. To this end, we mapped the functional activity of the frontal motor cortical areas in three monkeys performing reaching movements with one forelimb. The first monkey had to capture a peripheral visual target with a saccade and a forelimb-reach together, the second monkey had to reach a peripheral visual target with one forelimb while fixating a central target, and the third one had to reach a peripheral memorized target with one forelimb in complete darkness while the eyes maintained a straight ahead direction. The extent and intensity of activations were compared to those of three respective control monkeys: a saccadecontrol, a fixation-control, and a dark-control. The primary somatosensory (SI) and motor (F1) forelimb representation, the S1 and F1-trunk representation, the F2-dimple region, areas F3-forelimb, F4, F5-bank of arcuate sulcus, F7-ridge, the dorsal bank of cingulate sulcus, and 24c were activated in all reaching monkeys regardless of accompanying visual stimulation and oculomotor behavior. Interestingly, the SI-forelimb activation in the monkey reaching to memorized targets in complete darkness was more pronounced than that in the monkeys reaching to visual targets in the light, indicating that increased somatosensory processing compensates for the absence of visual feedback. On the other hand, areas F2-periarcuate, F5-convexity, F6, and 23 were preferentially activated by reaching to visual targets and remained unaffected during reaching to memorized targets when no visual feedback was available. (c) 2005 Elsevier Inc. All rights reserved. C1 NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. Univ Crete, Sch Hlth Sci, Fac Med, Dept Basic Sci,FORTH,Inst Appl & Computat Math, Iraklion 71003, Crete, Greece. Univ Parma, Fac Med, Dipartimento Neurosci, Parma, Italy. RP Savaki, HE (reprint author), NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. EM savaki@med.uoc.gr RI Gregoriou, Georgia/F-7759-2011 OI Gregoriou, Georgia/0000-0002-4002-6657 NR 71 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 15 PY 2005 VL 27 IS 2 BP 442 EP 464 DI 10.1016/j.neuroimage.2005.02.038 PG 23 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 954KV UT WOS:000231154900018 PM 16061153 ER PT J AU Doerr, TP Alves, G Yu, YK AF Doerr, TP Alves, G Yu, YK TI Ranked solutions to a class of combinatorial optimizations - with applications in mass spectrometry based peptide sequencing and a variant of directed paths in random media SO PHYSICA A-STATISTICAL MECHANICS AND ITS APPLICATIONS LA English DT Article DE statistical significance; combinatorial optimization; dynamic programming; directed paths in random media ID RANDOM IMPURITIES AB Typical combinatorial optimizations are NP-hard; however, for a particular class of cost functions the corresponding combinatorial optimizations can be solved in polynomial time using the transfer matrix technique or, equivalently, the dynamic programming approach. This suggests a way to efficiently find approximate solutions-find a transformation that makes the cost function as similar as possible to that of the solvable class. After keeping many high-ranking solutions using the approximate cost function, one may then re-assess these solutions with the full cost function to find the best approximate solution. Under this approach, it is important to be able to assess the quality of the solutions obtained, e.g., by finding the true ranking of the kth best approximate solution when all possible solutions are considered exhaustively. To tackle this statistical issue, we provide a systematic method starting with a scaling function generated from the finite number of high-ranking solutions followed by a convergent iterative mapping. This method, useful in a variant of the directed paths in random media problem proposed here, can also provide a statistical significance assessment for one of the most important proteomic tasks-peptide sequencing using tandem mass spectrometry data. For directed paths in random media, the scaling function depends on the particular realization of randomness; in the mass spectrometry case, the scaling function is spectrum-specific. (c) 2005 Elsevier B.V. All rights reserved. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Yu, YK (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM yyu@ncbi.nlm.nih.gov NR 6 TC 3 Z9 3 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4371 J9 PHYSICA A JI Physica A PD AUG 15 PY 2005 VL 354 BP 558 EP 570 DI 10.1016/j.physa.2005.03.004 PG 13 WC Physics, Multidisciplinary SC Physics GA 937TP UT WOS:000229948900046 ER PT J AU Li, XF Hassan, SA Mehler, EL AF Li, XF Hassan, SA Mehler, EL TI Long dynamics simulations of proteins using atomistic force fields and a continuum representation of solvent effects: Calculation of structural and dynamic properties SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Review ID PANCREATIC TRYPSIN-INHIBITOR; NUCLEAR-MAGNETIC-RESONANCE; IMMUNOGLOBULIN-BINDING DOMAIN; DISTRIBUTED MULTIPOLE ANALYSIS; SCREENED COULOMB POTENTIALS; OVOMUCOID 3RD DOMAIN; POLAR GROUP BURIAL; MOLECULAR-DYNAMICS; ELECTROSTATIC INTERACTIONS; PK(A) VALUES AB Long dynamics simulations were carried out on the B1 immunoglobulin-binding domain of streptococcal. protein G (ProtG) and bovine pancreatic trypsin inhibitor (BPTI) using atomistic descriptions of the proteins and a continuum representation of solvent effects. To mimic frictional and random collision effects, Langevin dynamics (LD) were used. The main goal of the calculations was to explore the stability of tens-of-nanosecond trajectories as generated by this molecular mechanics approximation and to analyze in detail structural and dynamical properties. Conformational fluctuations, order parameters, cross correlation matrices, residue solvent accessibilities, pKa values of titratable groups, and hydrogen-bonding (HB) patterns were calculated from all of the trajectories and compared with available experimental data. The simulations comprised over 40 ns per trajectory for ProtG and over 30 ns per trajectory for BPTL For comparison, explicit water molecular dynamics simulations (EW/MD) of 3 ns and 4 ns, respectively, were also carried out. Two continuum simulations were performed on each protein using the CHARNM program, one with the all-atom PAR22 representation of the protein force field (here referred to as PAR22/LD simulations) and the other with the modifications introduced by the recently developed CMAP potential (CMAP/LD simulations). The explicit solvent simulations were performed with PAR22 only. Solvent effects are described by a continuum model based on screened Coulomb potentials (SCP) reported earlier, i.e., the SCP-based implicit solvent model (SCP-ISM). For ProtG, both the PAR22/LD and the CMAP/LD 40-ns trajectories were stable, yielding C-alpha root mean square deviations (RMSD) of about 1.0 and 0.8 angstrom respectively along the entire simulation time, compared to 0.8 angstrom for the EW/MD simulation. For BPTI, only the CMAPALD trajectory was stable for the entire 30-ns simulation, with a C. RMSD of approximate to 1.4 angstrom, while the PAR22/LD trajectory became unstable early in the simulation, reaching a C-alpha RMSD of about 2.7 angstrom and remaining at this value until the end of the simulation; the C. RMSD of the EW/MD simulation was about 1.5 angstrom. The source of the instabilities of the BPTI trajectories in the PAR22/LD simulations was explored by an analysis of the backbone torsion angles. To further validate the findings from this analysis of BPTI, a 35-ns SCP-ISM simulation of Ubiquitin (Ubq) was carried out. For this protein, the CMAP/LD simulation was stable for the entire simulation time (C. RMSD of approximate to 1.0 angstrom), while the PAR22/LD trajectory showed a trend similar to that in BPTI, reaching a C. RMSD of approximate to 1.5 angstrom at 7 ns. All the calculated properties were found to be in agreement with the corresponding experimental values, although local deviations were also observed. HB patterns were also well reproduced by all the continuum solvent simulations with the exception of solvent-exposed side chain-side chain (sc-sc) HB in ProtG, where several of the HB interactions observed in the crystal structure and in the EW/MD simulation were lost. The overall analysis reported in this work suggests that the combination of an atomistic representation of a protein with a CMAP/CHARMM force field and a continuum representation of solvent effects such as the SCP-ISM provides a good description of structural and dynamic properties obtained from long computer simulations. Although the SCP-ISM simulations (CMAP/LD) reported here were shown to be stable and the properties well reproduced, further refinement isneeded to attain a level of accuracy suitable for more challenging biological applications, particularly the study of protein-protein interactions. C1 Natl Inst Hlth, Ctr Mol Modeling, Div Computat Biosci, CIT,DHHS, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, Ithaca, NY 14853 USA. RP Hassan, SA (reprint author), Natl Inst Hlth, Ctr Mol Modeling, Div Computat Biosci, CIT,DHHS, Bethesda, MD 20892 USA. EM mago@helix.nih.gov FU NIDA NIH HHS [R01 DA015170, R01 DA15170] NR 151 TC 48 Z9 48 U1 1 U2 22 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 15 PY 2005 VL 60 IS 3 BP 464 EP 484 DI 10.1002/prot.20470 PG 21 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 949II UT WOS:000230778100013 PM 15959866 ER PT J AU Grigorenko, BL Nemukhin, AV Topol, IA Cachau, RE Burt, SK AF Grigorenko, BL Nemukhin, AV Topol, IA Cachau, RE Burt, SK TI QM/MM modeling the Ras-GAP catalyzed hydrolysis of guanosine triphosphate SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE G-proteins; Ras-GAP; GTP hydrolysis; QM/MM modeling ID GTP-HYDROLYSIS; ARGININE-FINGER; MOLECULAR-DYNAMICS; MECHANICAL METHOD; PROTON-TRANSFER; G-PROTEINS; AB-INITIO; WATER; COMPLEX; P21 AB The mechanism of the hydrolysis reaction of guanosine triphosphate (GTP) by the protein complex Ras-GAP (p21(ras) - p120(GAP)) has been modeled by the quantum mechanical-molecular mechanical (QM/MM) and ab initio quantum calculations. Initial geometry configurations have been prompted by atomic coordinates of a structural analog (PDBID:1WQ1). It is shown that the minimum energy reaction path is consistent with an assumption of two-step chemical transformations. At the first stage, a unified motion of Arg789 of GAP, Gln61, Thr35 of Ras, and the lytic water molecule results in a substantial spatial separation of the gamma-phosphate group of GTP from the rest of the molecule (GDP). This phase of hydrolysis process proceeds through the low-barrier transition state TS1. At the second stage, Gln61 abstracts and releases protons within the subsystem including Gln61, the lytic water molecule and the T-phosphate group of GTP through the corresponding transition state TS2. Direct quantum calculations show that, in this particular environment, the reaction GTP + H(2)O -> GDP + H(2)PO(4)(-) can proceed with reasonable activation barriers of less than 15 kcal/mol at every stage. This conclusion leads to a better understanding of the anticatalytic effect of cancer-causing mutations of Ras, which has been debated in recent years. C1 Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119992, Russia. NCI, SAIC Frederick, Adv Biomed Comp Ctr, Frederick, MD 21701 USA. RP Nemukhin, AV (reprint author), Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119992, Russia. EM nemukhin@ncifcrf.gov RI Nemukhin, Alexander/P-9662-2015 FU NCI NIH HHS [N01-CO-12400] NR 43 TC 62 Z9 66 U1 1 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0887-3585 J9 PROTEINS JI Proteins PD AUG 15 PY 2005 VL 60 IS 3 BP 495 EP 503 DI 10.1002/prot.20472 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 949II UT WOS:000230778100015 PM 15906320 ER PT J AU Neal, R Aykin-Burns, N Ercal, N Zigler, JS AF Neal, R Aykin-Burns, N Ercal, N Zigler, JS TI Pb2+ exposure alters the lens alpha A-crystallin protein profile in vivo and induces cataract formation in lens organ culture SO TOXICOLOGY LA English DT Article DE Pb2+; lens; cataract; alpha-crystallin ID LEAD-EXPOSURE; MOLECULAR CHAPERONE; B-CRYSTALLIN; RAT LENSES; COPPER; MEN; IDENTIFICATION; HYPERTENSION; ANTIOXIDANTS; CHILDHOOD AB Epidemiological data supports lead exposure as a risk factor for cataract development. Previous studies which demonstrated oxidative imbalances in the lens following in vivo Pb2+ exposure support the idea that lead exposure can alter the lens biochemical homeostasis which may ultimately lead to loss of lens clarity with time. alpha-Crystallin, a major lens structural protein and molecular chaperone, undergoes various post-translational modifications upon aging which may contribute to decreased chaperone function and contribute to loss of lens clarity. This study evaluated the impact of 5 weeks of oral Pb2+ exposure (peripheral Pb2+ level similar to 30 mu g/dL) on the alpha A-crystallin protein profile of the lens from Fisher 344 rats. Decreases in relative protein spot intensity of more acidic forms of alpha A- and beta A(4)-crystallin and of truncated forms of alpha A-crystallin were noted. This data indicates that changes in post-translational processing of crystalline do occur in vivo following short courses of clinically relevant Pb2+-exposure. In addition, organ culture of lenses from 4.5-month-old rats in 5 mu M Pb2+ resulted in opacities, demonstrating that lead is toxic to the lens and can induce a loss of lens clarity. Published by Elsevier Ireland Ltd. C1 NEI, Lab Mechan Ocular Dis, Prot Biochem Sect, NIH, Bethesda, MD 20892 USA. Univ Missouri, Dept Chem, Rolla, MO 65401 USA. RP Neal, R (reprint author), NEI, Lab Mechan Ocular Dis, Prot Biochem Sect, NIH, 9000 Rockville Pike,NIH Campus Bldg 7,Room 229, Bethesda, MD 20892 USA. EM nealr@nei.nih.gov NR 40 TC 14 Z9 17 U1 0 U2 1 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 15 PY 2005 VL 212 IS 1 BP 1 EP 9 DI 10.1016/j.tox.2005.03.015 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 947JH UT WOS:000230639000001 PM 15905016 ER PT J AU Benbrahim-Tallaa, L Waterland, RA Styblo, M Achanzar, WE Webber, MM Waalkes, MP AF Benbrahim-Tallaa, L Waterland, RA Styblo, M Achanzar, WE Webber, MM Waalkes, MP TI Molecular events associated with arsenic-induced malignant transformation of human prostatic epithelial cells: aberrant genomic DNA methylation and K-ras oncogene activation SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE arsenic; chronic exposure; DNA methylation; K-ras ID GLUTATHIONE-S-TRANSFERASE; DRINKING-WATER; DIMETHYLARSINIC ACID; GENE-EXPRESSION; HA-RAS; N-RAS; CANCER; HYPOMETHYLATION; MUTATIONS; CARCINOMA AB Numerous studies link arsenic exposure to human cancers in a variety of tissues, including the prostate. Our prior work showed that chronic arsenic exposure of the non-tumorigenic, human prostate epithelial cell line, RWPE-1, to low levels of (5 mu M) sodium arsenite for 29 weeks resulted in malignant transformation and produced the tumorigenic CAsE-PE cell line. The present work focuses on the molecular events occurring during this arsenic-induced malignant transformation. Genomic DNA methylation was significantly reduced in CAsE-PE cells. A time course experiment showed that during malignant transformation DNA methyltransferase activity was markedly reduced by arsenic. However, DNA methyltransferase mRNA levels were not affected by arsenic exposure. Microarray screening showed that K-ras was highly overexpressed in CAsE-PE cells, a result further confirmed by Northern blot and Western blot analyses. Since ras activation is thought to be a critical event in prostate cancer progression, further detailed study was performed. Time course experiments also showed that increased K-ras expression preceded malignant transformation. Mutational analysis of codons 12, 13, and 61 indicated the absence of K-ras mutations. The K-ras gene can be activated by hypomethylation, but our study showed that CpG methylation in K-ras promoter region was not altered by arsenic exposure. Arsenic metabolism studies showed RWPE-1, CAsE-PE, and primary human prostate cells all had a very poor capacity for arsenic methylation. Thus, inorganic arsenic-induced transformation in human cells is associated with genomic DNA hypomethylation and K-ras overexpression. However, overexpression of K-ras occurred without mutations and through a mechanism other than promoter region hypomethylation. Published by Elsevier Inc. C1 NIEHS, NCI, Comparat Carcinogenesis Lab, Inorgan Carcinogenesis Sect, Res Triangle Pk, NC 27709 USA. Baylor Coll Med, Childrens Nutr Res Ctr, Dept Pediat, Houston, TX 77030 USA. Baylor Coll Med, Childrens Nutr Res Ctr, Dept Mol Genet, Houston, TX 77030 USA. Baylor Coll Med, Childrens Nutr Res Ctr, Dept Human Genet, Houston, TX 77030 USA. Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC 27599 USA. Michigan State Univ, Dept Med, E Lansing, MI 48824 USA. Michigan State Univ, Dept Zool, E Lansing, MI 48824 USA. RP Waalkes, MP (reprint author), NIEHS, NCI, Comparat Carcinogenesis Lab, Inorgan Carcinogenesis Sect, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov NR 62 TC 80 Z9 87 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD AUG 15 PY 2005 VL 206 IS 3 BP 288 EP 298 DI 10.1016/j.taap.2004.11.017 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 953NY UT WOS:000231084500002 PM 16039940 ER PT J AU Burlak, C Twining, LM Rees, MA AF Burlak, C Twining, LM Rees, MA TI Terminal sialic acid residues on human glycophorin A are recognized by porcine Kupffer cells SO TRANSPLANTATION LA English DT Article DE extracorporeal perfusion; glycophorin A; xenogeneic; N-acetylneuraminic acid; sialic acid ID HUMAN-ERYTHROCYTE-MEMBRANE; N-GLYCOLYLNEURAMINIC ACID; RAT-LIVER MACROPHAGES; BLOOD-GROUP; ANTI-GAL; GLYCOPROTEINS; RECEPTORS; EPITOPES; SIALOGLYCOPROTEINS; HETEROGENEITY AB Background. We have previously shown that recognition of human erythrocytes by porcine Kupffer cells is mediated by a carbohydrate-dependent mechanism. The present study explores the possible ligands existing on human glycophorin A and tests their ability to inhibit erythrocyte rosette formation. Methods. Human erythrocytes were tested for ABO and MN specificity and used as targets in a (51)Chromium quantitative erythrocyte rosette assay. Monosaccharides present on human glycophorin A, neuraminyl lactoses, bovine and porcine submaxillary mucins (BSM and PSM), and hyaluronic acid as well as proteoglycan N-linked glycosidase F(PNGaseF)- and sialidase A-treated human erythrocyte glycoproteins (hEGP) and human erythrocytes were all tested for inhibitory potential in the rosetting assay. Results. Porcine Kupffer-cell recognition of human erythrocytes was insensitive to differences in blood groups A, B, 0, or MN. At 30 mM, the monosaccharide, N-acetylneuraminic acid, and the trisaccharide mixture, neuraminyl lactoses, disrupted human erythrocyte recognition by 25% and 30%, respectively. A dilution of BSM but not PSM inhibited the rosetting assay by 17% (.2 mg/mL), 33% (1 mg/mL), and 53% (2 mg/mL). The same dilution of hyaluronic acid had no effect on rosetting. Removal of N-linked oligosaccharides from hEGP with PNGaseF did not impair its ability to inhibit the rosetting assay. In contrast, removal of sialic acid completely abrogated its inhibitory ability. Treatment of whole human erythrocytes with sialidase A likewise prevented recognition by porcine Kupffer cells. Conclusions. Terminal sialic acid on human erythrocytes is a target recognized by porcine Kupffer cells, suggesting a role for a sialic-acid receptor in innate cellular recognition of xenogeneic epitopes. Inasmuch as this work reveals a carbohydrate-recognition mechanism for cellular rejection, we shed light on a potential new boundary that will need to be overcome within xenotransplantation. C1 Med Coll Ohio, Dept Urol, Toledo, OH 43699 USA. RP Burlak, C (reprint author), NIH, Rocky Mt Lab, 903 S 4th St, Hamilton, MT 59840 USA. EM Cburlak@niaid.nih.gov NR 47 TC 23 Z9 24 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD AUG 15 PY 2005 VL 80 IS 3 BP 344 EP 352 DI 10.1097/01.TP.0000162974.94890.9F PG 9 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 952UA UT WOS:000231029800010 PM 16082330 ER PT J AU Xiong, CY Hixson, PM Mendoza, LH Smith, CW AF Xiong, CY Hixson, PM Mendoza, LH Smith, CW TI Cloning and expression of rabbit interleukin-15 SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article DE cloning; gene expression; interleukin-15; rabbit; RT-PCR (reverse tianscriptase polymerase chain reaction); Western blotting ID IL-15 MESSENGER-RNA; NATURAL-KILLER; RECEPTOR COMPLEX; ALPHA-CHAIN; IN-VIVO; CELL; SECRETION; ISOFORMS; PHAGOCYTOSIS; TRAFFICKING AB In order to understand the inflammatory mechanisms related to rabbit interleukin-15 (RIL-15), we cloned and expressed RIL-15 cDNA gene. A cDNA encoding RIL-15 was cloned from heart mRNA by reverse transcriptase polymerase chain reaction (RT-PCR) amplification using hIL-15 primers. The RIL-15 cDNA contains an open reading frame (ORF) of 162 amino acids (aa) with a 48 aa leader sequence. The predicted molecular weight of the encoded protein (12.5 kDa) matched the size of recombinant IL-15 on Western blotting in an Escherichia coli (pET32a) expression system. Amino acid and nucleotide sequence analyses of RIL-15 revealed 82.7% and 87% homology with human IL-15 (hIL-15), respectively. RIL-15 is similar to the hIL-15 (hlL-15) in that it contains seven cysteine residues. RT-PCR showed that IL-15 is expressed in many tissues in the rabbit, including heart, spleen, lung, liver, muscle and kidney. Expressed and purified recombinant RIL-15, in the absence of the 48 aa leader sequence, stimulated the proliferation of cells of the mouse T cell line, CTLL-2, and its activity is comparable to hIL-15. Western blotting demonstrated that recombinant RIL-15 can be recognized by anti-IL-15 neutralization antibody. Western blotting also confirmed that IL-15 is present in many tissues including heart, spleen, lung, liver, muscle and kidney. (C) 2005 Elsevier B.V. All rights reserved. C1 Baylor Coll Med, Dept Pediat, Sect Leukocyte Biol, Childrens Nutr Res Ctr, Houston, TX 77030 USA. NCI, NIH, Frederick, MD 21701 USA. Baylor Coll Med, Dept Med, Cardiovasc Sci Sect, Houston, TX 77030 USA. RP Smith, CW (reprint author), Baylor Coll Med, Dept Pediat, Sect Leukocyte Biol, Childrens Nutr Res Ctr, 1100 Bates St,Suite 6014, Houston, TX 77030 USA. EM cwsmith@bcm.tmc.edu FU NHLBI NIH HHS [HL42550] NR 31 TC 7 Z9 8 U1 3 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD AUG 15 PY 2005 VL 107 IS 1-2 BP 131 EP 141 DI 10.1016/j.vetimm.2005.04.013 PG 11 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 944QV UT WOS:000230444800013 PM 15978671 ER PT J AU O'Meara, WP Breman, JG McKenzie, FE AF O'Meara, WP Breman, JG McKenzie, FE TI Intermittent preventive malaria treatment in Tanzanian infants SO LANCET LA English DT Letter ID PLACEBO-CONTROLLED TRIAL; ANEMIA C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP O'Meara, WP (reprint author), NIH, Fogarty Int Ctr, Bldg 16, Bethesda, MD 20892 USA. EM prudhomw@mail.nih.gov NR 3 TC 1 Z9 1 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 AUG 13 PY 2005 VL 366 IS 9485 BP 545 EP 545 DI 10.1016/S0140-6736(05)67092-4 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 955LL UT WOS:000231227300020 PM 16099286 ER PT J AU Lehrman, G Hogue, IB Palmer, S Jennings, C Spina, CA Wiegand, A Landay, AL Coombs, RW Richman, DD Mellors, JW Coffin, JM Bosch, RJ Margolis, DM AF Lehrman, G Hogue, IB Palmer, S Jennings, C Spina, CA Wiegand, A Landay, AL Coombs, RW Richman, DD Mellors, JW Coffin, JM Bosch, RJ Margolis, DM TI Depletion of latent HIV-1 infection in vivo: a proof-of-concept study SO LANCET LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; CD4(+) T-CELLS; LONG TERMINAL REPEAT; HUMAN-FACTORS YY1; CELLULAR RESERVOIRS; HIV-1-INFECTED PATIENTS; IMMUNE-ACTIVATION; VALPROIC ACID; TYPE-1 HIV-1 AB Background Persistent infection in resting CD4+ T cells prevents eradication of HIV-1. Since the chromatin remodeling enzyme histone deacetylase 1 (HDAC1) maintains latency of integrated HIV, we tested the ability of the HDAC inhibitor valproic acid to deplete persistent, latent infection in resting CD4+ T cells. Procedures We did a proof-of-concept study in four volunteers infected with HIV and on highly-active antiretroviral therapy (HAART). After intensifying the effect of HAART with subcutaneous enfuvirtide 90 mu g twice daily for 4-6 weeks to prevent the spread of HIV, we added oral valproic acid 500-750 mg twice daily to their treatment regimen for 3 months. We quantified latent infection of resting CD4+ T cells before and after augmented treatment by limiting-dilution culture of resting CD4+ T cells after ex-vivo activation. Findings The frequency of resting cell infection was stable before addition of enfuvirtide and valproic acid, but declined thereafter. This decline was significant in three of four patients (mean reduction 75%, range 68% to >84%). Patients had slight reactions to enfuvirtide at the injection site, but otherwise tolerated treatment well. Interpretation Combination therapy with an HDAC inhibitor and intensified HAART safely accelerates clearance of HIV from resting CD4+ T cells in vivo, suggesting a new and practical approach to eliminate HIV infection in this persistent reservoir. This finding, though not definitive, suggests that new approaches will allow the cure of HIV in the future. C1 Univ Texas, SW Med Ctr, Dept Med, Div Infect Dis, Dallas, TX 75390 USA. NCI, HIV Drug Resistance Program, NIH, Frederick, MD USA. Rush Presbyterian St Lukes Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Vet Affairs Med Ctr, San Diego, CA 92161 USA. Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. N Texas Vet Hlth Care Syst, Dallas, TX USA. RP Margolis, DM (reprint author), Univ Texas, SW Med Ctr, Dept Med, Div Infect Dis, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM dmargo@med.unc.edu OI Margolis, David/0000-0001-5714-0002 FU NIAID NIH HHS [U01 AI038858, AI-043638, AI-047745, AI-27670, AI-27757, AI-29164, AI-36214, AI-38858, N01-AI-85354, N01AI85354, P30 AI027757, P30 AI036214, R01 AI-45297, R01 AI045297, R01 AI047745, R01 AI064074, R21 AI047745, R37 AI029164, R56 AI047745, U01 AI-38858, U01 AI027670, U01 AI043638]; NIDDK NIH HHS [DK-49477]; PHS HHS [20XS190A] NR 36 TC 333 Z9 352 U1 2 U2 29 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD AUG 13 PY 2005 VL 366 IS 9485 BP 549 EP 555 DI 10.1016/S0140-6736(05)67098-5 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 955LL UT WOS:000231227300026 PM 16099290 ER PT J AU Meshorer, E Misteli, T AF Meshorer, E Misteli, T TI Splicing misplaced SO CELL LA English DT Editorial Material ID TRANSLATION C1 NCI, NIH, Bethesda, MD 20892 USA. RP Meshorer, E (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 9 TC 11 Z9 12 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD AUG 12 PY 2005 VL 122 IS 3 BP 317 EP 318 DI 10.1016/j.cell.2005.07.016 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 955UZ UT WOS:000231254400001 PM 16096050 ER PT J AU Gunton, JE Kulkarni, RN Yim, SH Okada, T Hawthorne, WJ Tseng, YH Roberson, RS Ricordi, C O'Connell, PJ Gonzalez, FJ Kahn, CR AF Gunton, JE Kulkarni, RN Yim, SH Okada, T Hawthorne, WJ Tseng, YH Roberson, RS Ricordi, C O'Connell, PJ Gonzalez, FJ Kahn, CR TI Loss of ARNT/HIF1 beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes SO CELL LA English DT Article ID ARYL-HYDROCARBON RECEPTOR; INSULIN-RESISTANCE; BETA-CELLS; SKELETAL-MUSCLE; MICE LACKING; MELLITUS; TRANSCRIPTION; PATHOGENESIS; HYPOXIA; GLUCOSE AB beta cell dysfunction is a central component of the pathogenesis of type 2 diabetes. Using oligonucleotide microarrays and real-time PCR of pancreatic islets isolated from humans with type 2 diabetes versus normal glucose-tolerant controls, we identified multiple changes in expression of genes known to be important in beta cell function, including major decreases in expression of HNF4 alpha, insulin receptor, IRS2, Akt2, and several glucose-metabolic-pathway genes. There was also a 90% decrease in expression of the transcription factor ARNT Reducing ARNT levels in Min6 cells with small interfering RNA (siRNA) resulted in markedly impaired glucose-stimulated insulin release and changes in gene expression similar to those in human type 2 islets. Likewise, beta cell-specific ARNT knockout mice exhibited abnormal glucose tolerance, impaired insulin secretion, and changes in islet gene expression that mimicked those in human diabetic islets. Together, these data suggest an important role for decreased ARNT and altered gene expression in the impaired islet function of human type 2 diabetes. C1 Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. NCI, Lab Metab, Bethesda, MD 20892 USA. Univ Sydney, Westmead Hosp, Natl Pancreas Transplant Unit, Sydney, NSW 2145, Australia. Univ Miami, Diabet Res Inst, Miami, FL 33136 USA. RP Kahn, CR (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM c.ronald.kahn@joslin.harvard.edu OI Ricordi, Camillo/0000-0001-8092-7153 FU NCRR NIH HHS [RR16603]; NIDDK NIH HHS [DK60837-02, K08 DK02885, R01 DK33201, R01 DK67536] NR 56 TC 280 Z9 284 U1 4 U2 28 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD AUG 12 PY 2005 VL 122 IS 3 BP 337 EP 349 DI 10.1016/j.cell.2005.05.027 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 955UZ UT WOS:000231254400007 PM 16096055 ER PT J AU Lavoie, JF LeSauteur, L Kohn, J Wong, J Furtoss, O Thiele, CJ Miller, FD Kaplan, DR AF Lavoie, JF LeSauteur, L Kohn, J Wong, J Furtoss, O Thiele, CJ Miller, FD Kaplan, DR TI TrkA induces apoptosis of neuroblastoma cells and does so via a p53-dependent mechanism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NERVE GROWTH-FACTOR; FACTOR-INDUCED DIFFERENTIATION; DRUG-INDUCED APOPTOSIS; NEUROTROPHIC FACTOR; SIGNAL-TRANSDUCTION; TYROSINE KINASE; CYTOPLASMIC SEQUESTRATION; SYMPATHETIC NEURONS; PROMOTES SURVIVAL; FACTOR RECEPTOR AB Neuroblastoma (NB) is the most frequent solid extracranial tumor in children. Its clinical prognosis correlates with the expression of members of the Trk neurotrophin receptor family, which includes TrkA and TrkB. TrkA expression is associated with favorable prognosis, whereas TrkB expression is associated with poor prognosis. Here we show that TrkA expression induces the apoptosis of NB cells and does so by modulating the levels or activities of a number of proteins involved in regulating cell survival and apoptosis, including p53, Bcl-2, and caspase-3. TrkA increased the expression of p53 target proteins and failed to induce apoptosis in cells where p53 was inactivated by mutation or via expression of dominant inhibitory p53 or E1B55K, indicating that TrkA mediates apoptosis, at least in part, through p53. Treatment with a caspase inhibitor or overexpression of Bcl-X-L also prevented TrkA from inducing apoptosis. In contrast, elevated expression of TrkA in non-transformed sympathetic neurons resulted in the suppression of p53 levels and enhanced survival. These results identify apoptosis as a novel biological response of TrkA in NB cells and imply that TrkA is a good prognosis marker for NB due in part to its ability to mediate apoptosis when expressed at sufficient levels. C1 Hosp Sick Children, Canc Res Program, Toronto, ON M5G 1X8, Canada. Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A8, Canada. Univ Toronto, Dept Med Genet & Microbiol, Toronto, ON M5S 1A8, Canada. McGill Univ, Brain Tumor Res Ctr, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada. McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada. NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kaplan, DR (reprint author), Hosp Sick Children, Canc Res Program, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM dkaplan@sickkids.ca NR 63 TC 35 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 AUG 12 PY 2005 VL 280 IS 32 BP 29199 EP 29207 DI 10.1074/jbc.M502364200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 952QT UT WOS:000231021300048 PM 15961390 ER PT J AU Poliakov, E Gentleman, S Cunningham, FX Miller-Ihli, NJ Redmond, TM AF Poliakov, E Gentleman, S Cunningham, FX Miller-Ihli, NJ Redmond, TM TI Key role of conserved histidines in recombinant mouse beta-carotene 15,15 '-monooxygenase-1 activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PSEUDOMONAS-PAUCIMOBILIS TMY1009; LIGNOSTILBENE-ALPHA,BETA-DIOXYGENASE GENE; SUBSTRATE-SPECIFICITY; ENZYMATIC CLEAVAGE; OXIDATIVE CLEAVAGE; ENZYMES; EXPRESSION; CLONING; 15,15'-DIOXYGENASE; IDENTIFICATION AB Alignment of sequences of vertebrate beta-carotene 15,15'-monooxygenase-1 (BCMO1) and related oxygenases revealed four perfectly conserved histidines and five acidic residues (His(172), His(237), His(308), His(514), Asp(52), Glu(140), Glu(314), Glu(405), and Glu(457) in mouse BCMO1). Because BCMO1 activity is iron-dependent, we propose that these residues participate in iron coordination and therefore are essential for catalytic activity. To test this hypothesis, we produced mutant forms of mouse BCMO1 by replacing the conserved histidines and acidic residues as well as four histidines and one glutamate nonconserved in the overall family with alanines by site-directed mutagenesis. Our in vitro and in vivo data showed that mutation of any of the four conserved histidines and Glu405 caused total loss of activity. However, mutations of non-conserved histidines or any of the other conserved acidic residues produced impaired although enzymatically active proteins, with a decrease in activity mostly due to changes in V-max. The iron bound to protein was determined by inductively coupled plasma atomic emission spectrometry. Bound iron was much lower in preparations of inactive mutants than in the wild-type protein. Therefore, the conserved histidines and Glu405 are absolutely required for the catalytic mechanism of BCMO1. Because the mutant proteins are impaired in iron binding, these residues are concluded to coordinate iron required for catalytic activity. These data are discussed in the context of the predicted structure for the related eubacterial apocarotenal oxygenase. C1 NEI, LRCMB, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. USDA ARS, Food Composit Lab, Beltsville, MD 20705 USA. RP Redmond, TM (reprint author), NEI, LRCMB, NIH, Bldg 7,Rm 303,7 Mem Dr,MSC 0706, Bethesda, MD 20892 USA. EM Redmond@helix.nih.gov OI Redmond, T. Michael/0000-0002-1813-5291 NR 37 TC 52 Z9 54 U1 2 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 12 PY 2005 VL 280 IS 32 BP 29217 EP 29223 DI 10.1074/jbc.M500409200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 952QT UT WOS:000231021300050 PM 15951442 ER PT J AU Williams, DC Lee, JY Cai, ML Bewley, CA Clore, GM AF Williams, DC Lee, JY Cai, ML Bewley, CA Clore, GM TI Crystal structures of the HIV-1 inhibitory cyanobacterial protein MVL free and bound to Man(3)GlcNAc(2) - Structural basis for specificity and high-affinity binding to the core pentasaccharide from N-linked oligomannoside SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MACROMOLECULAR STRUCTURE DETERMINATION; ENVELOPE GLYCOPROTEIN GP120; CYANOVIRIN-N; INACTIVATING PROTEIN; NMR; ALIGNMENT; ANTIBODY; OLIGOSACCHARIDES; CRYSTALLOGRAPHY; MATRICES AB The cyanobacterial protein MVL inhibits HIV-1 envelope-mediated cell fusion at nanomolar concentrations by binding to high mannose N-linked carbohydrate on the surface of the envelope glycoprotein gp120. Although a number of other carbohydrate-binding proteins have been shown to inhibit HIV-1 envelope-mediated cell fusion, the specificity of MVL is unique in that its minimal target comprises the Man alpha(136)Man beta(1 -> 4)GlcNAc beta(1 -> 4) GlcNAc tetrasaccharide core of oligomannosides. We have solved the crystal structures of MVL free and bound to the pentasaccharide Man(3)GlcNAc(2) at 1.9- and 1.8-angstrom resolution, respectively. MVL is a homodimer stabilized by an extensive intermolecular interface between monomers. Each monomer contains two structurally homologous domains with high sequence similarity connected by a short five-amino acid residue linker. Intriguingly, a water-filled channel is observed between the two monomers. Residual dipolar coupling measurements indicate that the structure of the MVL dimer in solution is identical to that in the crystal. Man(3)GlcNAc(2) binds to a preformed cleft at the distal end of each domain such that a total of four independent carbohydrate molecules associate with each homodimer. The binding cleft provides shape complementarity, including the presence of a deep hydrophobic hole that accommodates the N-acetyl methyl at the reducing end of the carbohydrate, and specificity arises from 7-8 intermolecular hydrogen bonds. The structures of MVL and the MVL-Man(3)GlcNAc(2) complex further our understanding of the molecular basis of high affinity and specificity in protein-carbohydrate recognition. C1 NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Phys Chem Lab, NIH, Bldg 5,Rm B1-301, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural NIH HHS NR 36 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 AUG 12 PY 2005 VL 280 IS 32 BP 29269 EP 29276 DI 10.1074/jbc.M504642200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 952QT UT WOS:000231021300057 PM 15937331 ER PT J AU Padyana, AK Qiu, HF Roll-Mecak, A Hinnebusch, AG Burley, SK AF Padyana, AK Qiu, HF Roll-Mecak, A Hinnebusch, AG Burley, SK TI Structural basis for autoinhibition and mutational activation of eukaryotic initiation factor 2 alpha protein kinase GCN2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSFER-RNA SYNTHETASE; UNCHARGED TRANSFER-RNA; CRYSTAL-STRUCTURE; CATALYTIC SUBUNIT; BINDING DOMAIN; TRANSLATION; YEAST; PHOSPHORYLATION; DIMERIZATION; CELLS AB The GCN2 protein kinase coordinates protein synthesis with levels of amino acid stores by phosphorylating eukaryotic translation initiation factor 2. The autoinhibited form of GCN2 is activated in cells starved of amino acids by binding of uncharged tRNA to a histidyl-tRNA synthetase-like domain. Replacement of Arg-794 with Gly in the PK domain (R794G) activates GCN2 independently of tRNA binding. Crystal structures of the GCN2 protein kinase domain have been determined for wild-type and R794G mutant forms in the apo state and bound to ATP/AMPPNP. These structures reveal that GCN2 autoinhibition results from stabilization of a closed conformation that restricts ATP binding. The R794G mutant shows increased flexibility in the hinge region connecting the N- and C- lobes, resulting from loss of multiple interactions involving Arg(794). This conformational change is associated with intradomain movement that enhances ATP binding and hydrolysis. We propose that intramolecular interactions following tRNA binding remodel the hinge region in a manner similar to the mechanism of enzyme activation elicited by the R794G mutation. C1 Struct GenomiX Inc, San Diego, CA 92121 USA. Rockefeller Univ, Lab Mol Biophys, New York, NY 10021 USA. Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94107 USA. RP Burley, SK (reprint author), Struct GenomiX Inc, 10505 Roselle St, San Diego, CA 92121 USA. EM sburley@stromix.com FU NIGMS NIH HHS [R01 GM061262-05] NR 53 TC 65 Z9 67 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 AUG 12 PY 2005 VL 280 IS 32 BP 29289 EP 29299 DI 10.1074/jbc.M504096200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 952QT UT WOS:000231021300060 PM 15964839 ER PT J AU Li, M Craigie, R AF Li, M Craigie, R TI Processing of viral DNA ends channels the HIV-1 integration reaction to concerted integration SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; RETROVIRUS-LIKE DNA; IN-VITRO; CRYSTAL-STRUCTURE; CATALYTIC DOMAIN; ACTIVE-SITE; PREINTEGRATION COMPLEXES; TERMINAL DOMAINS; PROTEIN; INVITRO AB Retroviral DNA made by reverse transcription is blunt-ended, and the viral integrase protein must remove two nucleotides from each 3' end prior to integration into chromosomal DNA. Under most reaction conditions for integration in vitro, the majority of the reaction products are "half-site" products that result from integration of only one viral DNA end into one strand of the target DNA. Preprocessed DNA substrates are more efficient substrates for half-site reactions than are blunt-ended substrates, which require the removal of two nucleotides prior to integration. In contrast, we find that blunt-ended DNA is a better substrate for the biologically relevant reaction of concerted integration of pairs of viral DNA ends. The reaction pathway is channeled to concerted integration, and half-site integration products are reduced with blunt-ended DNA substrate that must first be processed by integrase. In addition, the terminal nucleotide requirements for concerted integration are more stringent than for the half-site reaction. Longer DNA is more efficient for the concerted reaction than is shorter DNA that is capable of efficient half-site integration. This suggests that nonspecific interactions of integrase with viral DNA distant from the termini contribute to the assembly of a complex that is competent for concerted integration. Finally, differential effects of mutation of a residue in the C-terminal domain of integrase on concerted versus half-site integration implicate protein-protein interactions involving this domain as important for concerted integration. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Craigie, R (reprint author), NIDDK, Mol Biol Lab, NIH, Bldg 5,Rm 301,5 Ctr Dr MSC 0560, Bethesda, MD 20892 USA. EM bobc@helix.nih.gov NR 48 TC 72 Z9 73 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 12 PY 2005 VL 280 IS 32 BP 29334 EP 29339 DI 10.1074/jbc.M505367200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 952QT UT WOS:000231021300064 PM 15958388 ER PT J AU Handa, V Yeh, HJC McPhie, P Usdin, K AF Handa, V Yeh, HJC McPhie, P Usdin, K TI The AUUCU repeats responsible for spinocerebellar ataxia type 10 form unusual RNA hairpins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MYOTONIC-DYSTROPHY; HUNTINGTONS-DISEASE; PROTEIN-KINASE; CUG REPEATS; EXPANSION; MISMATCHES; APOPTOSIS; SCA10; PKR AB Spinocerebellar ataxia type 10 is an autosomal dominant disorder caused by expansion of a pentameric repeat tract (ATTCT center dot AGAAT)(n) in intron 9 of the gene that encodes ataxin-10. We have analyzed duplex DNA containing the repeat, the individual DNA strands, and the RNA that would be generated by transcription of the repeat. Circular dichroism and UV absorbance measurements suggest that the previously reported tendency of the repeat to unpair when supercoiled is probably related simply to GC content rather than reflecting any unusual property of the duplex. DNA containing d(AT-TCT) 9 forms a folded structure at relatively low temperatures, whereas the antisense strand, d(AGAAT)(9), does not form a structure even at 0 degrees C. In contrast r(AUUCU)(9) forms a folded structure under physiologically reasonable conditions. S1 nuclease analysis reveals a single region of hypersensitivity in the middle of the repeat tract, whereas V1 digestion is consistent with a hydrogen bonded or well stacked structure. CD spectroscopy shows that the structure is unimolecular and hydrogen bonded and has a significant amount of A-form helix. NMR spectroscopy demonstrates that these hydrogen bonds comprise an equal number of A center dot U and U center dot U base pairs. Our data thus suggest that the repeat forms an unusual RNA hairpin. Thus the ability to form an RNA hairpin seems to be a common property of those Repeat Expansion Diseases that are not recessively inherited and are caused by repeats that are transcribed but not translated. C1 NIDDK, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Usdin, K (reprint author), NIDDK, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. EM ku@helix.nih.gov NR 33 TC 11 Z9 12 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 12 PY 2005 VL 280 IS 32 BP 29340 EP 29345 DI 10.1074/jbc.M503495200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 952QT UT WOS:000231021300065 PM 15970586 ER PT J AU Zhao, XJ Russell, P AF Zhao, XJ Russell, P TI Versican splice variants in human trabecular meshwork and ciliary muscle SO MOLECULAR VISION LA English DT Article ID CHONDROITIN SULFATE PROTEOGLYCANS; EXTRACELLULAR-MATRIX PROTEOGLYCAN; GROWTH-FACTOR-BETA; PG-M/VERSICAN; JUXTACANALICULAR TISSUE; DIFFERENTIAL REGULATION; HUMAN EYES; EXPRESSION; COMPONENTS; MIGRATION AB Purpose: Versican, chondroitin sulfate glycoprotein 2, is thought to play a role in regulating aqueous humor outflow and intraocular pressure via the human trabecular meshwork (HTM) of the eye. This protein was upregulated in HTM cells when they were treated with TGF-beta. There are four splice variant forms of versican (V0-V3) with different numbers of glycoaminoglycan (GAG) attachment domains. In this study, we investigated the various isoforms of versican from ocular tissues and cultured cells. Methods: HTM and human ciliary muscle (HCM) tissues were dissected from three pairs of donors eyes with no histories of eye disease. Cultures of HTM and HCM cells were established from five donor eyes, and HTM cells were treated for 72 h with 1 ng/ml of either with hrTGF-beta 1 or hrTGF-beta 2. Total RNA was isolated from cells and tissues from each of the samples. Relative quantitation of gene expression of each variant was detected by real-time PCR with SYBR Green dye. Results: All four variants of versican existed in each sample. In cultured HTM cells, the two variants with the largest number of GAG domains predominate. The V1 form is about 20% greater than the V0 form. There is an upregulation, particularly in the V0 form, when the cells are cultured. In tissue, the V1 form is about five fold greater than the other three. In the ocular ciliary muscle, the V1 form is the most prominent, but with this tissue, the relative amount of the V0 form did not change when cells were cultured. There was an upregulation of all splice variants in HTM cells when they were cultured with either TGF-beta 1 or TGF-beta 2. The increase in expression in the HTM with TGF-beta treatments were greatest with the V0 and V2 forms. Conclusions: This is the first report about the presence of various forms of versican in the anterior segment of the eye and the alterations in the mRNA patterns of these forms when cells are placed in culture. The results indicate the variants with the largest numbers of GAG attachment domains are the most prominent in the HTM and HCM. The increases in these forms that have the most GAG domains would be consistent with the increases in chondroitin sulfate reported in glaucoma. C1 NEI, Sect Aging & Ocular Dis, NIH, Bethesda, MD 20892 USA. RP Russell, P (reprint author), 7 Mem Dr,MSC 0703, Bethesda, MD 20892 USA. EM russellp@nei.nih.gov NR 24 TC 38 Z9 39 U1 0 U2 1 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 AUG 12 PY 2005 VL 11 IS 71-72 BP 603 EP 608 PG 6 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 956GU UT WOS:000231289000001 PM 16110303 ER PT J AU Kang, SU Worthy, KM Bindu, LK Zhang, MC Yang, DJ Fisher, RJ Burke, TR AF Kang, SU Worthy, KM Bindu, LK Zhang, MC Yang, DJ Fisher, RJ Burke, TR TI Design and synthesis of 4-(alpha-hydroxymalonyl)phenylalanine as a new phosphotyrosyl mimetic and its use in growth factor receptor bound 2 Src-homology 2 (Grb2 SH2) domain-binding peptides SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PHOSPHATE-CONTAINING LIGANDS; INHIBITION AB A new phosphotyrosyl mimetic 4-(alpha-hydroxymalonyl)phenylalanine and its incorporation into a Grb2 SH2 domain-binding tripeptide are presented. In whole-cell studies using malonyl ethyl ester prodrug derivatives, it was observed that the 4-(alpha-hydroxymalonyl)phenylalanyl-containing peptide exhibited greater efficacy than the nonhydroxylated 4-(malonyl)phenylalanyl-containing congener in blocking the association of Grb2 with activated erbB-2 tyrosine kinase. These results are consistent with de-esterification and at least partial intracellular decarboxylation. C1 NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA. SAIC Frederick, Prot Chem Lab, Frederick, MD 21702 USA. Univ Michigan, Sch Med, Ann Arbor, MI 48109 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA. EM tburke@helix.nih.gov RI Fisher, Robert/B-1431-2009; Burke, Terrence/N-2601-2014 NR 11 TC 8 Z9 8 U1 0 U2 3 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 AUG 11 PY 2005 VL 48 IS 16 BP 5369 EP 5372 DI 10.1021/jm050154v PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 953DB UT WOS:000231055300031 PM 16078854 ER PT J AU Phillips, LR Milescu, M Li-Smerin, YY Mindell, JA Kim, JI Swartz, KJ AF Phillips, LR Milescu, M Li-Smerin, YY Mindell, JA Kim, JI Swartz, KJ TI Voltage-sensor activation with a tarantula toxin as cargo SO NATURE LA English DT Article ID DEPENDENT K+ CHANNEL; POTASSIUM CHANNELS; GATING MODIFIER; SCORPION TOXIN; MOLECULAR DETERMINANTS; CHARGE MOVEMENT; SODIUM-CHANNELS; BINDING; HANATOXIN; FLUORESCENCE AB The opening and closing of voltage-activated Na+, Ca2+ and K+ (Kv) channels underlies electrical and chemical signalling throughout biology, yet the structural basis of voltage sensing is unknown. Hanatoxin is a tarantula toxin that inhibits Kv channels by binding to voltage-sensor paddles(1-5), crucial helix-turn-helix motifs within the voltage-sensing domains that are composed of S3b and S4 helices(6). The active surface of the toxin is amphipathic(7,8), and related toxins have been shown to partition into membranes(9-12), raising the possibility that the toxin is concentrated in the membrane and interacts only weakly and transiently with the voltage sensors. Here we examine the kinetics and state dependence of the toxin - channel interaction and the physical location of the toxin in the membrane. We find that hanatoxin forms a strong and stable complex with the voltage sensors, far outlasting fluctuations of the voltage sensors between resting ( closed) conformations at negative voltages and activated ( open) conformations at positive voltages. Toxin affinity is reduced by voltage-sensor activation, explaining why the toxin stabilizes the resting conformation. We also find that when hanatoxin partitions into membranes it is localized to an interfacial region, with Trp 30 positioned about 8.5 angstrom from the centre of the bilayer. These results demonstrate that voltage-sensor paddles activate with a toxin as cargo, and suggest that the paddles traverse no more than the outer half of the bilayer during activation. C1 Natl Inst Neurol Disorders & Stroke, Mol Physiol & Biophys Sect, NIH, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, Membrane Transport Biophys Unit, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. Gwangju Inst Sci & Technol, Dept Life Sci, Kwangju 500712, South Korea. RP Swartz, KJ (reprint author), Natl Inst Neurol Disorders & Stroke, Mol Physiol & Biophys Sect, NIH, 35 Convent Dr,MSC 3701, Bethesda, MD 20892 USA. EM swartzk@ninds.nih.gov OI Mindell, Joseph/0000-0002-6952-8247 FU Intramural NIH HHS [ZIA NS002945-13] NR 30 TC 125 Z9 131 U1 0 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 11 PY 2005 VL 436 IS 7052 BP 857 EP 860 DI 10.1038/nature03873 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 953XG UT WOS:000231116500048 PM 16094370 ER PT J AU Black, DM Bilezikian, JP Ensrud, KE Greenspan, SL Palermo, L Hue, T Lang, TF McGowan, JA Rosen, CJ AF Black, DM Bilezikian, JP Ensrud, KE Greenspan, SL Palermo, L Hue, T Lang, TF McGowan, JA Rosen, CJ CA PaTH Study Investigators TI One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BONE-MINERAL DENSITY; VERTEBRAL FRACTURES; POSTMENOPAUSAL WOMEN; RISK; MASS; TERIPARATIDE; TRIAL; REDUCTION; STRENGTH; THERAPY AB BACKGROUND: Since the use of parathyroid hormone as a treatment for osteoporosis is limited to two years or less, the question of whether antiresorptive therapy should follow parathyroid hormone therapy is important. We previously reported results after the first year of this randomized trial comparing the use of full-length parathyroid hormone (1-84) alone, alendronate alone, or both combined. In the continuation of this trial, we asked whether antiresorptive therapy is required to maintain gains in bone mineral density after one year of therapy with parathyroid hormone (1-84). METHODS: In the data reported here, women who had received parathyroid hormone (1-84) monotherapy (100 microg daily) in year 1 were randomly reassigned to one additional year with either placebo (60 subjects) or alendronate (59 subjects). Subjects who had received combination therapy in year 1 received alendronate in year 2; those who had received alendronate monotherapy in year 1 continued with alendronate in year 2. Bone mineral density at the spine and hip was assessed with the use of dual-energy x-ray absorptiometry and quantitative computed tomography (CT). RESULTS: Over two years, alendronate therapy after parathyroid hormone therapy led to significant increases in bone mineral density in comparison with the results for placebo after parathyroid hormone therapy, a difference particularly evident for bone mineral density in trabecular bone at the spine on quantitative CT (an increase of 31 percent in the parathyroid hormone-alendronate group as compared with 14 percent in the parathyroid hormone-placebo group). During year 2, subjects receiving placebo lost substantial bone mineral density. CONCLUSIONS: After one year of parathyroid hormone (1-84), densitometric gains appear to be maintained or increased with alendronate but lost if parathyroid hormone is not followed by an antiresorptive agent. These results have clinical implications for therapeutic choices after the discontinuation of parathyroid hormone. C1 Univ Calif San Francisco, San Francisco Coordinating Ctr, Dept Epidemiol, San Francisco, CA 94105 USA. Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94105 USA. Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94105 USA. Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY USA. Minneapolis Vet Affairs Med Ctr, Dept Med, Minneapolis, MN USA. Minneapolis Vet Affairs Med Ctr, Dept Epidemiol, Minneapolis, MN USA. Univ Minnesota, Minneapolis, MN USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. NIAMSD, NIH, Bethesda, MD 20892 USA. St Joseph Hosp, Maine Ctr Osteoporosis Res, Bangor, ME USA. RP Black, DM (reprint author), Univ Calif San Francisco, San Francisco Coordinating Ctr, Dept Epidemiol, 74 New Montgomery St,Suite 600, San Francisco, CA 94105 USA. EM dblack@psg.ucsf.edu RI Lang, Thomas/B-2685-2012 OI Lang, Thomas/0000-0002-3720-8038 FU NCRR NIH HHS [M01-RR000056]; NIAMS NIH HHS [N01-AR-9-2245] NR 16 TC 287 Z9 302 U1 0 U2 7 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 AUG 11 PY 2005 VL 353 IS 6 BP 555 EP 565 DI 10.1056/NEJMoa050336 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 953ST UT WOS:000231101500006 PM 16093464 ER PT J AU Sun, YP Lowther, W Kato, K Bianco, C Kenney, N Strizzi, L Raafat, D Hirota, M Khan, NI Bargo, S Jones, B Salomon, D Callahan, R AF Sun, YP Lowther, W Kato, K Bianco, C Kenney, N Strizzi, L Raafat, D Hirota, M Khan, NI Bargo, S Jones, B Salomon, D Callahan, R TI Notch4 intracellular domain binding to Smad3 and inhibition of the TGF-beta signaling SO ONCOGENE LA English DT Article DE Notch4ICD; Smad3; TGF-beta ID GROWTH-FACTOR-BETA; MAMMARY EPITHELIAL-CELLS; TRUNCATED INT3 GENE; NEOPLASTIC TRANSFORMATION; BRANCHING MORPHOGENESIS; TUMOR-SUPPRESSOR; MAMMALIAN NOTCH; CROSS-TALK; EXPRESSION; RECEPTORS AB We present evidence that Notch4ICD attenuates TGF-beta signaling. Cells expressing the activated form of the Notch4 receptor (ICD4) were resistant to the growth-inhibitory effects of TGF-beta. Notch4ICD was found to bind to Smad2, Smad3 and Smad4 but with higher affinity to Smad3. Deletion analysis showed that binding of Smad3 to ICD4 was mediated by its MH2 domain and was not dependent on the presence of the RAM23 region in ICD4. Using two TGF-beta/Activin reporter luciferase assays, RT-PCR and Western blot analysis, we demonstrate that ICD4 and ICD4 delta RAM23 inhibit Smad-binding element and 3TP luciferase reporter activity and PAI-1 gene expression. MCF-7 human breast cancer cells express Notch4ICD (ICD4) and are resistant to the growth-inhibitory effects of TGF-beta. Blockage of Notch4 processing to ICD4 by gamma-secretase inhibitor renders MCF-7 cells sensitive to growth inhibition by TGF-beta. The interplay between these two signaling pathways may be a significant determinant during mammary tumorigenesis. C1 NCI, Tumor Growth Factor Sect, Mammary Biol & Tumorigenesis Lab, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. NCI, Oncogenesis Sect, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Salomon, D (reprint author), NCI, Tumor Growth Factor Sect, Mammary Biol & Tumorigenesis Lab, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. EM salomond@mail.nih.gov; Callahro@mail.nih.gov NR 54 TC 53 Z9 58 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 11 PY 2005 VL 24 IS 34 BP 5365 EP 5374 DI 10.1038/sj.onc.1208528 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 954MF UT WOS:000231158500010 PM 16007227 ER PT J AU Berman, J AF Berman, J TI Modern classification of neoplasms: reconciling differences between morphologic and molecular approaches SO BMC CANCER LA English DT Article ID CLEAR-CELL SARCOMA; NONEPITHELIAL TUMORS; MALIGNANT-MELANOMA; FUSION TRANSCRIPTS; STROMAL TUMORS; GENE FUSION; STEM-CELLS; GERM-CELLS; CANCER; MUTATIONS AB Background: For over 150 years, pathologists have relied on histomorphology to classify and diagnose neoplasms. Their success has been stunning, permitting the accurate diagnosis of thousands of different types of neoplasms using only a microscope and a trained eye. In the past two decades, cancer genomics has challenged the supremacy of histomorphology by identifying genetic alterations shared by morphologically diverse tumors and by finding genetic features that distinguish subgroups of morphologically homogeneous tumors. Discussion: The Developmental Lineage Classification and Taxonomy of Neoplasms groups neoplasms by their embryologic origin. The putative value of this classification is based on the expectation that tumors of a common developmental lineage will share common metabolic pathways and common responses to drugs that target these pathways. The purpose of this manuscript is to show that grouping tumors according to their developmental lineage can reconcile certain fundamental discrepancies resulting from morphologic and molecular approaches to neoplasm classification. In this study, six issues in tumor classification are described that exemplify the growing rift between morphologic and molecular approaches to tumor classification: 1) the morphologic separation between epithelial and non-epithelial tumors; 2) the grouping of tumors based on shared cellular functions; 3) the distinction between germ cell tumors and pluripotent tumors of non-germ cell origin; 4) the distinction between tumors that have lost their differentiation and tumors that arise from uncommitted stem cells; 5) the molecular properties shared by morphologically disparate tumors that have a common developmental lineage, and 6) the problem of re-classifying morphologically identical but clinically distinct subsets of tumors. The discussion of these issues in the context of describing different methods of tumor classification is intended to underscore the clinical value of a robust tumor classification. Summary: A classification of neoplasms should guide the rational design and selection of a new generation of cancer medications targeted to metabolic pathways. Without a scientifically sound neoplasm classification, biological measurements on individual tumor samples cannot be generalized to class-related tumors, and constitutive properties common to a class of tumors cannot be distinguished from uninformative data in complex and chaotic biological systems. This paper discusses the importance of biological classification and examines several different approaches to the specific problem of tumor classification. C1 US Natl Canc Inst, Canc Diag Program, Bethesda, MD 20892 USA. RP Berman, J (reprint author), US Natl Canc Inst, Canc Diag Program, Bethesda, MD 20892 USA. EM jjberman@alum.mit.edu NR 64 TC 4 Z9 4 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD AUG 10 PY 2005 VL 5 AR 100 DI 10.1186/1471-2407-5-100 PG 12 WC Oncology SC Oncology GA 964BZ UT WOS:000231855000001 PM 16092965 ER PT J AU Pi, JB He, YY Bortner, C Huang, JL Liu, J Zhou, T Qu, W North, SL Kasprzak, KS Diwan, BA Chignell, CF Waalkes, MP AF Pi, JB He, YY Bortner, C Huang, JL Liu, J Zhou, T Qu, W North, SL Kasprzak, KS Diwan, BA Chignell, CF Waalkes, MP TI Low level, long-term inorganic arsenite exposure causes generalized resistance to apoptosis in cultured human keratinocytes: Potential role in skin co-carcinogenesis SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE arsenite; apoptosis; ultraviolet; carcinogenesis; PKB ID FORKHEAD TRANSCRIPTION FACTOR; MALIGNANT-TRANSFORMATION; DRINKING-WATER; GLUTATHIONE; CANCER; MICE; EXPRESSION; INDUCTION; PULMONARY; SURVIVAL AB Inorganic arsenic is a human carcinogen that targets the skin. Carcinogenesis is a multistep process in which acquired apoptotic resistance is a common event and prior work in non-skin cells shows acquired resistance to apoptosis occurs with chronic arsenite exposure. In the present study, when HaCaT cells, an immortalized, non-tumorigenic human keratinocyte cell line, were continuously exposed to low-level inorganic arsenite (as sodium arsenite; 100 nM) for 28 weeks, the cells acquired a generalized resistance to apoptosis. This included resistance to apoptosis induced by acute high concentrations of arsenite, ultraviolet A (UVA) irradiation, and several chemotherapeutic compounds (cisplatin, etoposide and doxorubicin). These arsenite-tolerant (As-TL) cells showed similar levels of UVA-induced reactive oxygen species (ROS) and oxidative DNA damage when compared to passage match control cells. Because cellular apoptosis is dependent on the balance between proapoptotic and survival pathways, the roles of protein kinase B (PKB), a key antiapoptotic molecule, in this acquired apoptotic resistance were investigated. Stimulation of apoptosis markedly decreased nuclear phosphorylated PKB (P-PKB) levels in control cells, but As-TL cells showed greatly increased stability of nuclear P-PKB. Pretreatment of the As-TL cells with LY294002 or Wortmannin, which specifically inhibit PKB phosphorylation, completely blocked apoptotic resistance in As-TL cells, indicating acquired apoptotic resistance is associated with increased stability of nuclear P-PKB. Because arsenic and UV irradiation are co-carcinogenic in mouse skin, resistance to UV-induced apoptosis in As-TL cells may allow UV-damaged cells to escape normal cell population controls and initiate the carcinogenic cascade. The observation that As-TL cells show no lessening of UV-induced genotoxicity supports this possibility. (c) 2005 Wiley-Liss, Inc. C1 NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC USA. NIEHS, Lab Signal Transduct, Res Triangle Pk, NC USA. Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21701 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, POB 12233,Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU NCI NIH HHS [N01-CO-12400] NR 30 TC 49 Z9 52 U1 0 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD AUG 10 PY 2005 VL 116 IS 1 BP 20 EP 26 DI 10.1002/ijc.20990 PG 7 WC Oncology SC Oncology GA 935FW UT WOS:000229766100004 PM 15756686 ER PT J AU Miller, FG Wendler, D AF Miller, FG Wendler, D TI Direct-to-consumer advertising and physician prescribing SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Clin Bioeth, Bldg 10, Bethesda, MD 20892 USA. EM dwendler@nih.gov NR 4 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 10 PY 2005 VL 294 IS 6 BP 678 EP 678 DI 10.1001/jama.294.6.678-a PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 953IA UT WOS:000231068600013 PM 16091566 ER PT J AU Kritchevsky, SB Nicklas, BJ Visser, M Simonsick, EM Newman, AB Harris, TB Lange, EM Penninx, BW Goodpaster, BH Satterfield, S Colbert, LH Rubin, SM Pahor, M AF Kritchevsky, SB Nicklas, BJ Visser, M Simonsick, EM Newman, AB Harris, TB Lange, EM Penninx, BW Goodpaster, BH Satterfield, S Colbert, LH Rubin, SM Pahor, M TI Angiotensin-converting enzyme insertion/deletion genotype, exercise, and physical decline SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HUMAN SKELETAL-MUSCLE; BODY-COMPOSITION; OLDER PERSONS; ACE GENE; DELETION POLYMORPHISM; I/D POLYMORPHISM; BLOOD-PRESSURE; I ALLELE; PERFORMANCE; MEN AB Context Physical performance in response to exercise appears to be influenced by the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) genotype in young adults, but whether this relationship could help explain variation in older individuals' response to exercise has not been well studied. Objective To determine whether the ACE genotype interacts with significant physical activity to affect the incidence of mobility limitation in well-functioning older adults. Design, Setting, and Participants The Health Aging and Body Composition (Health ABC) Cohort Study, conducted in the metropolitan areas of Memphis, Tenn, and Pittsburgh, Pa. A total of 3075 well-functioning community-dwelling adults aged 70 through 79 years were enrolled from 1997 to 1998 and had a mean of 4.1 years of follow-up. Main Outcome Measure Incident mobility limitation defined as the report of difficulty walking a quarter of a mile (0.4 km) or walking up 10 steps on 2 consecutive semiannual interviews (n=1204). Results Physically active participants (those reporting expending >= 1000 kcal/wk in exercise, walking, and stair climbing) were less likely to develop mobility limitation regardless of genotype. However, activity level interacted significantly with the ACE genotype (P=.002). In the inactive group, the ACE genotype was not associated with limitation (P=.46). In the active group, those with the II genotype were more likely to develop mobility limitation after adjusting for potential confounders compared with those with ID/DD genotypes (adjusted rate ratio, 1.45, 95% confidence interval, 1.08-1.94). The gene association was especially strong among participants reporting weightlifting. Exploration of possible physiological correlates revealed that among active participants, those with the II genotype had higher percentage of body fat (P=.02) and more intermuscular thigh fat (P=.02) but had similar quadriceps strength as those with ID/DD. Conclusions Among older individuals who exercised, those with the ACE DD or ID genotypes were less likely to develop mobility limitation than those with the II genotype. Regardless of genotype, individuals who exercised were less likely to develop mobility limitation than those who did not exercise. C1 Wake Forest Univ, Bowman Gray Sch Med,Sticht Ctr Aging, Dept Internal Med, Sect Gerontol & Geriatr Med, Winston Salem, NC 27157 USA. Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Dept Internal Med, Winston Salem, NC 27157 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27157 USA. Vrije Univ Amsterdam, Dept Psychiat, Amsterdam, Netherlands. Vrije Univ Amsterdam, Inst Hlth Sci, Amsterdam, Netherlands. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. Univ Wisconsin, Dept Kinesiol, Madison, WI USA. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94143 USA. Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL USA. RP Kritchevsky, SB (reprint author), Wake Forest Univ, Bowman Gray Sch Med,Sticht Ctr Aging, Dept Internal Med, Sect Gerontol & Geriatr Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM skritche@wfubmc.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, P30 AG-021332, R01 AG-18702] NR 62 TC 62 Z9 62 U1 4 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 10 PY 2005 VL 294 IS 6 BP 691 EP 698 DI 10.1001/jama.294.6.691 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 953IA UT WOS:000231068600022 PM 16091571 ER PT J AU Shalowitz, DI Miller, FG AF Shalowitz, DI Miller, FG TI Disclosing individual results of clinical research - Implications of respect for participants SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CHILDRENS ONCOLOGY GROUP; IMPACT; ATTITUDES; TRIAL; RISK C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Clin Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@cc.nih.gov RI Shalowitz, David/A-7432-2009; OI Shalowitz, David/0000-0002-5189-4687 NR 25 TC 140 Z9 140 U1 1 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 10 PY 2005 VL 294 IS 6 BP 737 EP 740 DI 10.1001/jama.294.6.737 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 953IA UT WOS:000231068600028 PM 16091577 ER PT J AU Overk, CR Yao, P Chadwick, LR Nikolic, D Sun, YK Cuendet, MA Deng, YF Hedayat, AS Pauli, GF Farnsworth, NR van Breemen, RB Bolton, JL AF Overk, CR Yao, P Chadwick, LR Nikolic, D Sun, YK Cuendet, MA Deng, YF Hedayat, AS Pauli, GF Farnsworth, NR van Breemen, RB Bolton, JL TI Comparison of the in vitro estrogenic activities of compounds from hops (Humulus lupulus) and red clover (Trifolium pratense) SO JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY LA English DT Article DE alkaline phosphatase; estrogen receptor; hops; Humulus lupulus; menopause; progesterone receptor; red clover; Trifolium pratense ID HORMONE-REPLACEMENT THERAPY; RANDOMIZED CONTROLLED-TRIAL; ENDOMETRIAL CANCER-CELLS; POSTMENOPAUSAL WOMEN; PLUS PROGESTIN; BREAST-CANCER; MENOPAUSAL SYMPTOMS; DIETARY-SUPPLEMENTS; ER-ALPHA; 8-PRENYLNARINGENIN AB Because the prevailing form of hormone replacement therapy is associated with the development of cancer in breast and endometrial tissues, alternatives are needed for the management of menopausal symptoms. Formulations of Trifiolium pratense L. (red clover) are being used to alleviate menopause-associated hot flashes but have shown mixed results in clinical trials. The strobiles of Humulus Iupulus L. (hops) have been reported to contain the prenylflavanone, 8-prenylnaringenin (8-PN), as the most estrogenic constituent, and this was confirmed using an estrogen receptor ligand screening assay utilizing ultrafiltration mass spectrometry. Extracts of hops and red clover and their individual constituents including 8-PN, 6-prenylnaringenin (6-PN), isoxanthohumol (IX), and xanthohumol (XN) from hops and daidzein, formononetin, biochanin A, and genistein from red clover were compared using a variety of in vitro estrogenic assays. The IC50 values for the estrogen receptor alpha and beta binding assays were 15 and 27,mu g/mL, respectively, for hops and 18.0 and 2.0 mu g/mL, respectively, for the red clover extract. Both of the extracts, genistein, and 8-PN activated the estrogen response element (ERE) in Ishikawa cells while the extracts, biochanin A, genistein, and 8-PN, significantly induced ERE-luciferase expression in MCF-7 cells. Hop and red clover extracts as well as 8-PN up-regulated progesterone receptor (PR) mRNA in the Ishikawa cell line. In the MCF-7 cell line, PR mRNA was significantly up-regulated by the extracts, biochanin A, genistein, 8-PN, and IX. The two extracts had EC50 values of 1.1 and 1.9 mu g/mL, respectively, in the alkaline phosphatase induction assay, On the basis of these data, hops and red clover could be attractive for the development as herbal dietary supplements to alleviate menopause-associated symptoms. C1 Univ Illinois, Dept Med Chem & Pharmacognosy, Program Collaborat Res Pharmaceut Sci, UIC,NIH,Ctr Bot Dietary Supplements,Coll Pharm, Chicago, IL 60612 USA. Univ Illinois, Dept Math Stat & Comp Sci, Chicago, IL 60607 USA. RP Bolton, JL (reprint author), Univ Illinois, Dept Med Chem & Pharmacognosy, Program Collaborat Res Pharmaceut Sci, UIC,NIH,Ctr Bot Dietary Supplements,Coll Pharm, M-C 781,833 S Wood St, Chicago, IL 60612 USA. EM Judy.bolton@uic.edu OI Pauli, Guido/0000-0003-1022-4326 FU NCCIH NIH HHS [F31 AT002423, F31 AT24232, P50 AT000155, P50 AT00155] NR 47 TC 68 Z9 73 U1 1 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0021-8561 J9 J AGR FOOD CHEM JI J. Agric. Food Chem. PD AUG 10 PY 2005 VL 53 IS 16 BP 6246 EP 6253 DI 10.1021/jf050448p PG 8 WC Agriculture, Multidisciplinary; Chemistry, Applied; Food Science & Technology SC Agriculture; Chemistry; Food Science & Technology GA 953AF UT WOS:000231047100012 PM 16076101 ER PT J AU Galanis, E Buckner, JC Maurer, MJ Kreisberg, JL Ballman, K Boni, J Peralba, JM Jenkins, RB Dakhil, SR Morton, RF Jaeckle, KA Scheithauer, BW Dancey, J Hidalgo, M Walsh, DJ AF Galanis, E Buckner, JC Maurer, MJ Kreisberg, JL Ballman, K Boni, J Peralba, JM Jenkins, RB Dakhil, SR Morton, RF Jaeckle, KA Scheithauer, BW Dancey, J Hidalgo, M Walsh, DJ TI Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: A north central cancer treatment group study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MESSENGER-RNA TRANSLATION; MAMMALIAN TARGET; PHOSPHATIDYLINOSITOL 3-KINASE; CELL-PROLIFERATION; MALIGNANT GLIOMAS; PROSTATE-CANCER; RAPAMYCIN; INHIBITOR; PHOSPHORYLATION; PATHWAY AB Background Temsirolimus (CCI-779) is a small-molecule inhibitor of the mammalian target of rapamycin (mTOR) and represents a rational therapeutic target against glioblastoma multiforme (GBM). Methods Recurrent GBM patients with <= 1 chemotherapy regimen for progressive disease were eligible. Temsirolimus was administered in a 250-mg intravenous dose weekly. Results Sixty-five patients were treated. The incidence of grade 3 or higher nonhematologic toxicity was 51% and consisted mostly of hypercholesterolemia (11%) hypertriglyceridemia (8%), and hyperglycemia (8%). Grade 3 hematologic toxicity was observed in 11% of patients. Temsirolimus peak concentration (C-max), and sirolimus C-max and area under the concentration-time curve were decreased in patients receiving p450 enzyme-inducing anticonvulsants (EIACs) by 73%, 47%, and 50%, respectively, but were still within the therapeutic range of preclinical models. Twenty patients (36%) had evidence of improvement in neuroimaging, consisting of decrease in T2 signal abnormality +/- decrease in T1 gadolinium enhancement, on stable or reduced steroid doses. Progression-free survival at 6 months was 7.8% and median overall survival was 4.4 months. Median time to progression (TTP) for all patients was 2.3 months and was significantly longer for responders (5.4 months) versus nonresponders (1.9 months). Development of grade 2 or higher hyperlipidemia in the first two treatment cycles was associated with a higher percentage of radiographic response (71% v 31%; P =.04). Significant correlation was observed between radiographic improvement and high levels of phosphorylated p70s6 kinase in baseline tumor samples (P =.04). Conclusion Temsirolimus is well tolerated in recurrent GBM patients. Despite the effect of EIACs on temsirolimus metabolism, therapeutic levels were achieved. Radiographic improvement was observed in 36% of temsirolimus-treated patients, and was associated with significantly longer TTP. High levels of phosphorylated p70s6 kinase in baseline tumor samples appear to predict a patient population more likely to derive benefit from treatment. These findings should be validated in other studies of mTOR inhibitors. C1 Mayo Clin, Coll Med, N Cent Canc Treatment Grp, Rochester, MN USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Wyeth, Collegeville, PA USA. NCI, Canc Therapy Evaluat Program, Invest Drug Branch, Rockville, MD USA. Wichita Community Clin Oncol Program, Wichita, KS USA. Iowa Oncol Res Assoc CCOP, Des Moines, IA USA. Mayo Clin Jacksonville, Jacksonville, FL 32224 USA. RP Galanis, E (reprint author), Mayo Clin & Mayo Fdn, 200 1st St SW, Rochester, MN 55905 USA. EM galanis.evanthia@mayo.edu RI HIDALGO, MANUEL/I-4995-2015 OI HIDALGO, MANUEL/0000-0002-3765-3318 FU NCI NIH HHS [CA25224, R21 CA99209]; NCRR NIH HHS [M01 RR00585-34] NR 40 TC 446 Z9 458 U1 1 U2 11 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 10 PY 2005 VL 23 IS 23 BP 5294 EP 5304 DI 10.1200/JCO.2005.23.622 PG 11 WC Oncology SC Oncology GA 955NG UT WOS:000231232100003 PM 15998902 ER PT J AU Ou, W Silver, J AF Ou, W Silver, J TI Efficient trapping of HIV-1 envelope protein by hetero-oligomerization with an N-helix chimera SO RETROVIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; FUSION INHIBITOR T-20; COILED-COIL POCKET; MEMBRANE-FUSION; INTERHELICAL INTERACTIONS; PEPTIDE INHIBITOR; SYNTHETIC PEPTIDE; ATOMIC-STRUCTURE; CORE STRUCTURE; GP41 CORE AB Background: The N-heptad repeat region of the HIV-1 Transmembrane Envelope protein is a trimerization domain that forms part of a "six helix bundle" crucial to Envelope-mediated membrane fusion. N-heptad repeat peptides have been used as extracellular reagents to inhibit virus fusion. Results: When expressed intracellularly with wild-type HIV-1 Envelope protein, the N-heptad repeat domain efficiently hetero-oligomerized with Envelope and trapped it in the endoplasmic reticulum or early Golgi, as indicated by lack of transport to the cell surface, absent proteolytic processing, and aberrant glycosylation. Conclusion: Post-translational processing of HIV Envelope is very sensitive to an agent that binds to the N-heptad repeat during synthesis, suggesting that it might be possible to modify drugs that bind to this region to have transport-blocking properties. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Silver, J (reprint author), NIAID, Mol Microbiol Lab, NIH, Bldg 4,Room 336, Bethesda, MD 20892 USA. EM wou@niaid.nih.gov; jsilver@nih.gov NR 48 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD AUG 10 PY 2005 VL 2 AR 51 DI 10.1186/1742-4690-2-51 PG 8 WC Virology SC Virology GA 033EA UT WOS:000236828200002 PM 16092970 ER PT J AU Chan, JCC Oyler, NA Yau, WM Tycko, R AF Chan, JCC Oyler, NA Yau, WM Tycko, R TI Parallel beta-sheets and polar zippers in amyloid fibrils formed by residues 10-39 of the yeast prion protein Ure2p SO BIOCHEMISTRY LA English DT Article ID SOLID-STATE NMR; NUCLEAR-MAGNETIC-RESONANCE; INHERITED NEURODEGENERATIVE DISEASES; CORE STRUCTURE; AMINO-ACIDS; C-13 NMR; SACCHAROMYCES-CEREVISIAE; STRUCTURAL CONSTRAINTS; HUMAN CALCITONIN; CHEMICAL-SHIFTS AB We report the results of solid-state nuclear magnetic resonance (NMR) and atomic force microscopy measurements on amyloid fibrils formed by residues 10-39 of the yeast prion protein Ure2p (Ure2p(10-39)). Measurements of intermolecular C-13-C-13 nuclear magnetic dipole-dipole couplings indicate that Ure2p(10-39) fibrils contain in-register parallel beta-sheets. Measurements of intermolecular N-15-C-13 dipole-dipole couplings, using a new solid-state NMR technique called DSQ-REDOR, are consistent with hydrogen bonds between side chain amide groups of GIn18 residues. Such side chain hydrogen bonding interactions have been called "polar zippers" by M. F. Perutz and have been proposed to stabilize amyloid fibrils formed by peptides with glutamine- and asparagine-rich sequences, such as Ure2p(10-39). We propose that polar zipper interactions account for the in-register parallel beta-sheet structure in Ure2p(10-39) fibrils and that similar peptides will also exhibit parallel beta-sheet structures in amyloid fibrils. We present molecular models for Ure2p(10-39) fibrils that are consistent with available experimental data. Finally, we show that solid-state C-13 NMR chemical shifts for C-13-labeled Ure2p(10-39) fibrils are insensitive to hydration level, indicating that the fibril structure is not affected by the presence or absence of bulk water. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov RI Chan, Jerry/F-8075-2010 OI Chan, Jerry/0000-0002-5108-4166 FU NIDDK NIH HHS [Z01 DK029029-09] NR 95 TC 103 Z9 106 U1 0 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 9 PY 2005 VL 44 IS 31 BP 10669 EP 10680 DI 10.1021/bi050724t PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 951ZX UT WOS:000230972000024 PM 16060675 ER PT J AU Burchfiel, CM Skelton, TN Andrew, ME Garrison, RJ Arnett, DK Jones, DW Taylor, HA AF Burchfiel, CM Skelton, TN Andrew, ME Garrison, RJ Arnett, DK Jones, DW Taylor, HA TI Metabolic syndrome and echocardiographic left ventricular mass in blacks - The Atherosclerosis Risk in Communities (ARIC) Study SO CIRCULATION LA English DT Article DE diabetes mellitus; echocardiography; hypertension; hypertrophy; lipids ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; DEPENDENT DIABETIC-PATIENTS; CONGESTIVE-HEART-FAILURE; SERUM-INSULIN LEVELS; BLOOD-PRESSURE; AFRICAN-AMERICANS; CARDIAC STRUCTURE; ESSENTIAL-HYPERTENSION; CARDIOVASCULAR HEALTH AB Background - The metabolic syndrome has been associated with cardiovascular disease, but few studies have examined its relationship with subclinical measures such as echocardiographic left ventricular (LV) mass. This relationship is likely to be of particular importance in blacks, in whom both the metabolic syndrome and LV hypertrophy are common. Methods and Results - Echocardiography, performed at 1 of 4 sites in the Atherosclerosis Risk in Communities (ARIC) Study, was used to assess LV dimensions in 1572 black women and men aged 49 to 75 years in 1993-1996. Participants were categorized by number of metabolic syndrome characteristics ( hypertension, dyslipidemia [ low HDL cholesterol or high triglycerides], and glucose intolerance). Age-adjusted mean LV mass indexed by height (g/m) increased in a stepwise gradient with increasing number of metabolic syndrome disorders ( none, any 1, any 2, all 3) in both women and men ( 125.1, 143.9, 153.7, 169.3 and 130.5, 148.7, 160.8, 170.2, respectively; P < 0.001, tests for trend). Associations were diminished slightly by adjustment for smoking, alcohol intake, and education; additional adjustment for waist circumference resulted in some attenuation, but associations remained statistically significant. Analyses focusing on components of LV mass revealed that posterior wall and interventricular septal thickness, but not LV chamber size, were significantly and independently associated in general with the number of metabolic syndrome disorders. Consistent with these findings, relative wall thickness was also associated with number of disorders. Associations were similar across age and central adiposity. Hypertension had a strong influence on LV mass with additional contributions from dyslipidemia and glucose intolerance; strong synergistic effects of the syndrome beyond its individual components were not observed. Conclusions - In this cross-sectional population-based study of black women and men, the degree of metabolic syndrome clustering was strongly related to LV mass and its wall thickness components. These associations are consistent with a possible influence of underlying factors such as insulin resistance or other vascular processes on myocardial thickening and not on chamber size. C1 NIOSH, Hlth Effects Lab Div, Biostat & Epidemiol Branch, Morgantown, WV 26505 USA. NHLBI, Jackson Heart Study, Jackson, MS USA. Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. Univ Mississippi, Med Ctr, Dept Prevent Med, Jackson, MS 39216 USA. Jackson State Univ, Jackson Heart Study Coordinating Ctr, Jackson, MS 39217 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. RP Burchfiel, CM (reprint author), NIOSH, Hlth Effects Lab Div, Biostat & Epidemiol Branch, 1095 Willowdale Rd,M-S 4020, Morgantown, WV 26505 USA. EM cburchfiel@cdc.gov FU NHLBI NIH HHS [N01-HC-95170, N01-HC-95171, N01-HC-955015, N01-HC-955022, N01-HC-955019, N01-HC-955016, N01-HC-95172, N01-HC-955020, N01-HC-955018] NR 70 TC 50 Z9 58 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 9 PY 2005 VL 112 IS 6 BP 819 EP 827 DI 10.1161/CIRCULATIONAHA.104.518498 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 953HN UT WOS:000231067300008 PM 16061739 ER PT J AU Thornton, AM AF Thornton, AM TI T regulatory cells SO CURRENT BIOLOGY LA English DT Editorial Material C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Thornton, AM (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM athornton@niaid.nih.gov NR 3 TC 4 Z9 4 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 9 PY 2005 VL 15 IS 15 BP R582 EP R582 DI 10.1016/j.cub.2005.07.048 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 955MO UT WOS:000231230200007 PM 16085474 ER PT J AU Floel, A Hummel, F Breitenstein, C Knecht, S Cohen, LG AF Floel, A Hummel, F Breitenstein, C Knecht, S Cohen, LG TI Dopaminergic effects on encoding of a motor memory in chronic stroke SO NEUROLOGY LA English DT Article ID RECOVERY; LEVODOPA; AGE AB The effects of a single oral dose of levodopa administered in a randomized, double-blind, placebo-controlled cross-over design on formation of a motor memory were studied by a training protocol in patients with chronic stroke. Levodopa enhanced the ability of motor training to encode an elementary motor memory relative to placebo. Up-regulation of dopaminergic function may enhance motor memory formation, crucial for successful rehabilitative treatments in patients with chronic stroke. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20817 USA. Univ Munster, Dept Neurol, D-4400 Munster, Germany. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20817 USA. EM cohenl@ninds.nih.gov RI Floel, Agnes/A-9426-2017; OI Knecht, Stefan/0000-0003-1056-9228 NR 10 TC 70 Z9 71 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 9 PY 2005 VL 65 IS 3 BP 472 EP 474 DI 10.1212/01.wnl.0000172340.56307.5e PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 953HM UT WOS:000231067200029 PM 16087920 ER PT J AU Liang, HJ Harries, D Wong, GCL AF Liang, HJ Harries, D Wong, GCL TI Polymorphism of DNA-anionic liposome complexes reveals hierarchy of ion-mediated interactions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE colloids; like-charge attraction; membrane; self-assembly; x-ray ID INVERTED-HEXAGONAL PHASE; LIPID COMPLEXES; CATIONIC LIPOSOMES; GENE DELIVERY; TRANSFECTION; INSTABILITY; EXPRESSION; MICROSCOPY; STABILITY; MEMBRANES AB Self-assembled DNA delivery systems based on anionic lipids (ALs) complexed with DNA mediated by divalent cations have been recently introduced as an alternative to cationic lipid-DNA complexes because of their low cytotoxicity. We investigate AL-DNA complexes induced by different cations by using synchrotron small angle x-ray scattering and confocal microscopy to show how different ion-mediated interactions are expressed in the self-assembled structures and phase behavior of AL-DNA complexes. The governing interactions in AL-DNA systems are complex: divalent ions can mediate strong attractions between different combinations of the components (such as DNA-DNA and membrane-membrane). Moreover, divalent cations can coordinate nonelectrostatically with lipids and modify the resultant membrane structure. We find that at low membrane charge densities AL-DNA complexes organize into a lamellar structure of alternating DNA and membrane layers crosslinked by ions. At high membrane charge densities, a new phase with no analog in cationic lipid-DNA systems is observed: DNA is expelled from the complex, and a lamellar stack of membranes and intercalated ions is formed. For a subset of the ionic species, high ion concentrations generate an inverted hexagonal phase comprised of DNA strands wrapped by ion-coated lipid tubes. A simple theoretical model that takes into account the electrostatic and membrane elastic contributions to the free energy shows that this transition is consistent with an ion-induced change in the membrane spontaneous curvature, c(0). Moreover, the crossover between the lamellar and inverted hexagonal phases occurs at a critical c(0) that agrees well with experimental values. C1 Univ Illinois, Dept Mat Sci & Engn, Urbana, IL 61801 USA. Univ Illinois, Dept Phys, Urbana, IL 61801 USA. Univ Illinois, Dept Bioengn, Urbana, IL 61801 USA. NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Wong, GCL (reprint author), Univ Illinois, Dept Mat Sci & Engn, Urbana, IL 61801 USA. EM gclwong@uiuc.edu RI Harries, Daniel/F-7016-2012; Liang, Hongjun/K-2460-2012 OI Harries, Daniel/0000-0002-3057-9485; Liang, Hongjun/0000-0003-0864-9106 NR 39 TC 55 Z9 56 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 AUG 9 PY 2005 VL 102 IS 32 BP 11173 EP 11178 DI 10.1073/pnas.0502416102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 955UP UT WOS:000231253400011 PM 16061807 ER PT J AU Hanover, JA Forsythe, ME Hennessey, PT Brodigan, TM Love, DC Ashwell, G Krause, M AF Hanover, JA Forsythe, ME Hennessey, PT Brodigan, TM Love, DC Ashwell, G Krause, M TI A Caenorhabditis elegans model of insulin resistance: Altered macronutrient storage and dauer formation in an OGT-1 knockout SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE nutrients; O-GlcNAc; signaling; diabetes mellitus ID LINKED GLCNAC TRANSFERASE; BETA-N-ACETYLGLUCOSAMINIDASE; DYNAMIC O-GLYCOSYLATION; PROGRAMMED CELL-DEATH; C-ELEGANS; CYTOSOLIC PROTEINS; LIFE-SPAN; TETRATRICOPEPTIDE REPEATS; SIGNAL-TRANSDUCTION; GLYCOGEN-SYNTHASE AB O-linked N-acetylglucosamine (O-GlcNAc) is an evolutionarily conserved modification of nuclear pore proteins, signaling kinases, and transcription factors. The O-GlcNAc transferase (OGT) catalyzing O-GlcNAc addition is essential in mammals and mediates the last step in a nutrient-sensing "hexosamine-signaling pathway." This pathway may be deregulated in diabetes and neurodegenerative disease. To examine the function of O-GlcNAc in a genetically amenable organism, we describe a putative null allele of OGT in Caenorhabditis elegans that is viable and fertile. We demonstrate that, whereas nuclear pore proteins of the homozygous deletion strain are devoid of O-GlcNAc, nuclear transport of transcription factors appears normal. However, the OGT mutant exhibits striking metabolic changes manifested in a approximate to 3-fold elevation in trehalose levels and glycogen stores with a concomitant approximate to 3-fold decrease in triglycericles levels. In nematodes, a highly conserved insulin-like signaling cascade regulates macronutrient storage, longevity, and dauer formation. The OGT knockout suppresses dauer larvae formation induced by a temperature-sensitive allele of the insulin-like receptor gene daf-2. Our findings demonstrate that OGT modulates macronutrient storage and dauer formation in C elegans, providing a unique genetic model for examining the role of O-GlcNAc in cellular signaling and insulin resistance. C1 NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hanover, JA (reprint author), NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. EM jah@helix.nih.gov OI Krause, Michael/0000-0001-6127-3940 NR 67 TC 119 Z9 130 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 AUG 9 PY 2005 VL 102 IS 32 BP 11266 EP 11271 DI 10.1073/pnas.0408771102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 955UP UT WOS:000231253400027 PM 16051707 ER PT J AU Ahmed, SH Lutjens, R van der Stap, LD Lekic, D Romano-Spica, V Morales, M Koob, GF Repunte-Canonigo, V Sanna, PP AF Ahmed, SH Lutjens, R van der Stap, LD Lekic, D Romano-Spica, V Morales, M Koob, GF Repunte-Canonigo, V Sanna, PP TI Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE release machinery; delta-catenin; Glu receptor-interacting protein 2; PKC gamma; fractalkine ID BRAIN REWARD FUNCTION; OLIGONUCLEOTIDE ARRAY DATA; VENTRAL TEGMENTAL AREA; PROTEIN BETA-SUBUNIT; SELF-STIMULATION; NUCLEUS-ACCUMBENS; NMDA RECEPTORS; NEUROFIBROMATOSIS TYPE-1; ETHANOL WITHDRAWAL; INTRINSIC NEURONS AB By using high-density oligonucleotide arrays, we profiled gene expression in reward-related brain regions of rats that developed escalated cocaine intake after extended access to cocaine (6 h per day). Rats allowed restricted daily access to cocaine (only 1 h) that displayed a stable level of cocaine intake and cocaine naive rats were used for controls. Four analysis methods were compared: Affymetrix MICROARRAY SUITE 4 and MICROARRAY SUITE 5, Which use perfect-match-minus-mismatch models, and DCHIP and RMA, which use perfect-match-only models to generate expression values. Results were validated by RT-PCR in individual animals from an independent replication of the experiment. A small number of genes was associated with escalated cocaine intake (ESC genes). Unexpectedly, of the brain regions examined [prefrontal cortex, nucleus accumbens, septum, lateral hypothalamus (LH), amygdala, and ventral tegmental area], the LH was the most transcriptionally responsive in escalation of cocaine intake. Most of the ESC genes identified are also expressed during synaptogenesis and synaptic plasticity and include genes that code for several presynaptic and postsynaptic proteins involved in neurotransmission. These results suggest that LH intrinsic circuitry undergoes a structural reorganization during escalation of cocaine use. This remodeling of LH circuitry could contribute to the chronic deficit in reward function that has been hypothesized to drive the transition to drug addiction. Results also support the value of using multiple analysis strategies to identify the most robust changes in gene expression and to compensate for the biases that affect each strategy. C1 Scripps Res Inst, Dept Neuropharmacol, La Jolla, CA 92103 USA. Univ Victor Segalen Bordeaux 2, CNRS, UMR 5541, Lab Neuropsychobiol & Desadaptat, F-33076 Bordeaux, France. Univ Rome, Inst Sci Motorie, Dipartimento Sci Salute, I-00194 Rome, Italy. Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Sanna, PP (reprint author), Scripps Res Inst, Dept Neuropharmacol, 10550 N Torrey Pines Rd,CVN 12, La Jolla, CA 92037 USA. EM psanna@scripps.edu RI Ahmed, Serge/D-5236-2014; koob, george/P-8791-2016 FU NIAAA NIH HHS [AA007456, T32 AA007456]; NIDA NIH HHS [R01 DA004398, DA004398, DA017208, DA13821, R01 DA013821, R21 DA017208] NR 78 TC 64 Z9 64 U1 2 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 AUG 9 PY 2005 VL 102 IS 32 BP 11533 EP 11538 DI 10.1073/pnas.0504438102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 955UP UT WOS:000231253400072 PM 16076954 ER PT J AU Chen, XB Vinade, L Leapman, RD Petersen, JD Nakagawa, T Phillips, TM Sheng, M Reese, TS AF Chen, XB Vinade, L Leapman, RD Petersen, JD Nakagawa, T Phillips, TM Sheng, M Reese, TS TI Mass of the postsynaptic density and enumeration of three key molecules SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mass measurements; PSD-95; SAP97; CaMKII ID PROTEIN-KINASE-II; LONG-TERM POTENTIATION; TUMOR-SUPPRESSOR PROTEIN; RECEPTOR GLUR1 SUBUNIT; DENDRITIC SPINES; PROTEOMIC ANALYSIS; SYNAPTIC PHYSIOLOGY; HIPPOCAMPAL-NEURONS; RAT HIPPOCAMPUS; CEREBRAL-CORTEX AB The total molecular mass of individual postsynaptic densities (PSDs) isolated from rat forebrain was measured by scanning transmission EM. PSDs had a mean diameter of 360 nm and molecular mass of 1.10 +/- 0.36 GDa. Because the mass represents the sum of the molecular masses of all of the molecules comprising a PSD, it becomes possible to derive the number of copies of each protein, once its relative mass contribution is known. Mass contributions of PSD-95, synapse-associated protein (SAP)97, and alpha-Ca2+/calmodulin-dependent protein kinase 11 (CaMKII) were determined by quantitative gel electrophoresis of PSD fractions. The number of PSD-95 molecules per average PSD, contributing 2.3% of the mass of the PSD, was calculated to be 300, whereas the number of SAP97 molecules, contributing 0.9% of the mass of the PSD, was 90. The alpha-CaMKII holoenzymes, which contribute 6% of the mass when brains are homogenized within 2 min of interrupting blood flow, have 80 holoenzymes associated with a typical PSD. When blood flow is interrupted 15 min before homogenization, the average mass of PSDs increases by approximate to 40%. The additional a-CaMKII associated with PSDs accounts for up to 20% of this mass increase, representing the addition of 100-200 alpha-CaMKII holoenzymes. C1 Natl Inst Neurol Diorders & Stroke, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Univ Fed Rio Grande Sul, Dept Bioquim, Fdn Support Res State Rio Grande do Sul, BR-90035003 Porto Alegre, RS, Brazil. NIH, Div Bioengn & Phys Sci, Off Res Serv, Off Director, Bethesda, MD 20892 USA. MIT, Howard Hughes Med Inst, Picower Ctr Learning & Memory, Cambridge, MA 02139 USA. RP Reese, TS (reprint author), Natl Inst Neurol Diorders & Stroke, Neurobiol Lab, NIH, 36 Convent Dr,MSC 4062, Bethesda, MD 20892 USA. EM treese@mbl.edu OI Petersen, Jennifer/0000-0003-1107-8535 FU Intramural NIH HHS NR 52 TC 103 Z9 108 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 AUG 9 PY 2005 VL 102 IS 32 BP 11551 EP 11556 DI 10.1073/pnas.0505359102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 955UP UT WOS:000231253400075 PM 16061821 ER PT J AU Ursin, G Bernstein, L Lord, SJ Karim, R Deapen, D Press, MF Daling, JR Norman, SA Liff, JM Marchbanks, PA Folger, SG Simon, MS Strom, BL Burkman, RT Weiss, LK Spirtas, R AF Ursin, G Bernstein, L Lord, SJ Karim, R Deapen, D Press, MF Daling, JR Norman, SA Liff, JM Marchbanks, PA Folger, SG Simon, MS Strom, BL Burkman, RT Weiss, LK Spirtas, R TI Reproductive factors and subtypes of breast cancer defined by hormone receptor and histology SO BRITISH JOURNAL OF CANCER LA English DT Article DE breast cancer; reproductive factors; hormone receptors; histology ID ESTROGEN-RECEPTOR; RISK-FACTORS; REPLACEMENT THERAPY; PREMENOPAUSAL WOMEN; PROGESTERONE; CARCINOMA; AGE; PREVENTION; REGIMENS; SERUM AB Reproductive factors are associated with reduced risk of breast cancer, but less is known about whether there is differential protection against subtypes of breast cancer. Assuming reproductive factors act through hormonal mechanisms they should protect predominantly against cancers expressing oestrogen (ER) and progesterone (PR) receptors. We examined the effect of reproductive factors on subgroups of tumours defined by hormone receptor status as well as histology using data from the NIHCD Women's Contraceptive and Reproductive Experiences (CARE) Study, a multicenter case-control study of breast cancer. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) as measures of relative risk using multivariate unconditional logistic regression methods. Multiparity and early age at first birth were associated with reduced relative risk of ER+PR+tumours (P for trend = 0.0001 and 0.01, respectively), but not of ER-PR-tumours (P for trend = 0.27 and 0.85), whereas duration of breastfeeding was associated with lower relative risk of both receptor-positive (P for trend = 0.0002) and receptor-negative tumours (P = 0.0004). Our results were consistent across subgroups of women based on age and ethnicity. We found few significant differences by histologic subtype, although the strongest protective effect of multiparity was seen for mixed ductolobular tumours. Our results indicate that parity and age at first birth are associated with reduced risk of receptor-positive tumours only, while lactation is associated with reduced risk of both receptor-positive and -negative tumours. This suggests that parity and lactation act through different mechanisms. This study also suggests that reproductive factors have similar protective effects on breast tumours of lobular and ductal origin. C1 Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90089 USA. Univ Oslo, Dept Nutr Res, Oslo, Norway. Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90089 USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Div Publ Hlth, Seattle, WA 98195 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA USA. Wayne State Univ, Dept Internal Med, Karmanos Canc Inst, Detroit, MI 48202 USA. Baystate Med Ctr, Dept Obstet & Gynecol, Springfield, MA USA. NCI, Canc Ctr Branch, Bethesda, MD 20892 USA. NICHHD, Contracept & Reprod Hlth Branch, Populat Res Ctr, US Dept HHS,NIH, Bethesda, MD USA. RP Ursin, G (reprint author), Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, 1441 Eastlake Ave, Los Angeles, CA 90089 USA. EM gursin@usc.edu OI Lord, Sarah J/0000-0003-2763-5949 FU NCI NIH HHS [N01-PC-67006, N01 CN065064, N01 PC067006, N01-CN-0532, N01-CN-65064, N01-CN-67010]; NICHD NIH HHS [N01 HD 2-3166, N01 HD 3-3168, N01 HD 3-3174, N01 HD 3-3175, N01 HD-3-3176, Y01 HD007022] NR 29 TC 84 Z9 85 U1 1 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 AUG 8 PY 2005 VL 93 IS 3 BP 364 EP 371 DI 10.1038/sj.bjc.6602712 PG 8 WC Oncology SC Oncology GA 951RN UT WOS:000230948500013 PM 16079783 ER PT J AU Okabe, M Unno, M Harigae, H Kaku, M Okitsu, Y Sasaki, T Mizoi, T Shiiba, K Takanaga, H Terasaki, T Matsuno, S Sasaki, I Ito, S Abe, T AF Okabe, M Unno, M Harigae, H Kaku, M Okitsu, Y Sasaki, T Mizoi, T Shiiba, K Takanaga, H Terasaki, T Matsuno, S Sasaki, I Ito, S Abe, T TI Characterization of the organic cation transporter SLC22A16: A doxorubicin importer SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE SLC22A 16; organic cation transporter; influx transporter; doxorubicin; leukemia; drug resistance; molecular targets for therapy ID ACUTE MYELOID-LEUKEMIA; ASCITES TUMOR-CELLS; MULTIDRUG-RESISTANCE; FUNCTIONAL EXPRESSION; ANION TRANSPORTER; DRUG-RESISTANCE; ADRIAMYCIN; DAUNORUBICIN; IDENTIFICATION; ACCUMULATION AB Specific efflux transporters, such as P-glycoprotein, have been shown to confer drug resistance by decreasing the intracellular accumulation of anticancer drugs. Understanding influx transporters, as well as efflux transporters, is essential to overcome this resistance. We report the expression profile and pharmacological characterization of an organic cation transporter, SLC22A16. The results of our experiments indicate that SLC22A16 is a mediator of doxorubicin uptake in cancer cells. Quantitative real-time RT-PCR analyses show that SLC22A16 is expressed in primary samples taken from patients with acute leukemia. Xenopus oocytes injected with SLC22A16 cRNA import doxorubicin, a widely used anticancer drug for hematological malignancies, in a saturable and dose-dependent manner. The apparent K-m value for doxorubicin import was 5.2 +/- 0.4 mu M. In cytotoxic assays, stable transfectants of leukemic Jurkat cells overexpressing SLC22A16 cells became significantly more sensitive to doxorubicin (2 mu M) treatment. Characterization of SLC22A16 will help in designing novel therapies targeting hematological malignancies. (c) 2005 Elsevier Inc. All rights reserved. C1 Tohoku Univ, Sch Med, Dept Surg, Div Gen & Alimentary Tract Surg, Sendai, Miyagi 980, Japan. Tohoku Univ, Sch Med, Dept Surg, Div Gastroenterol Surg, Sendai, Miyagi 980, Japan. Tohoku Univ, Sch Med, Dept Mol Diagnost, Sendai, Miyagi 980, Japan. Tohoku Univ, Sch Med, Dept Med, Div Rheumatol & Hematol, Sendai, Miyagi 980, Japan. Tohoku Univ, Sch Med, Dept Mol Biopharm & Genet, Sendai, Miyagi 980, Japan. Tohoku Univ, Sch Med, Dept Med, Div Nephrol Endocrinol & Vasc Med, Sendai, Miyagi 980, Japan. RP Okabe, M (reprint author), NCI, Cell Biol Lab, Canc Res Ctr, NIH, 37 Convent Dr,Bldg 37,Room 2112, Bethesda, MD 20892 USA. EM okabem@mail.nih.gov RI Terasaki, Tetsuya/K-6730-2012; Ito, Sadayoshi/A-3933-2015; Unno, Michiaki/A-8633-2010; Kaku, Mitsuo/E-5811-2017 OI Terasaki, Tetsuya/0000-0002-6332-7575; Unno, Michiaki/0000-0002-2145-6416; NR 40 TC 64 Z9 67 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 5 PY 2005 VL 333 IS 3 BP 754 EP 762 DI 10.1016/j.bbrc.2005.05.174 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 944HV UT WOS:000230418800014 PM 15963465 ER PT J AU Gaussin, V Morley, GE Cox, L Zwijsen, A Vance, KM Emile, L Tian, YM Liu, J Hong, C Myers, D Conway, SJ Depre, C Mishina, Y Behringer, RR Hanks, MC Schneider, MD Huylebroeck, D Fishman, GI Burch, JBE Vatner, SF AF Gaussin, V Morley, GE Cox, L Zwijsen, A Vance, KM Emile, L Tian, YM Liu, J Hong, C Myers, D Conway, SJ Depre, C Mishina, Y Behringer, RR Hanks, MC Schneider, MD Huylebroeck, D Fishman, GI Burch, JBE Vatner, SF TI Alk3/Bmpr1a receptor is required for development of the atrioventricular canal into valves and annulus fibrosus SO CIRCULATION RESEARCH LA English DT Article DE bone morphogenetic protein signaling; heart development; atrioventricular canal; Cre-lox system ID PARKINSON-WHITE-SYNDROME; MORPHOGENETIC PROTEIN-RECEPTOR; TRANSGENIC MICE; KNOCKOUT MICE; HEART DEVELOPMENT; MOUSE EMBRYOS; PERIOSTIN; EXPRESSION; CONDUCTION; CUSHION AB Endocardial cushions are precursors of mature atrioventricular (AV) valves. Their formation is induced by signaling molecules originating from the AV myocardium, including bone morphogenetic proteins (BMPs). Here, we hypothesized that BMP signaling plays an important role in the AV myocardium during the maturation of AV valves from the cushions. To test our hypothesis, we used a unique Cre/lox system to target the deletion of a floxed Alk3 allele, the type IA receptor for BMPs, to cardiac myocytes of the AV canal (AVC). Lineage analysis indicated that cardiac myocytes of the AVC contributed to the tricuspid mural and posterior leaflets, the mitral septal leaflet, and the atrial border of the annulus fibrosus. When Alk3 was deleted in these cells, defects were seen in the same leaflets, ie, the tricuspid mural leaflet and mitral septal leaflet were longer, the tricuspid posterior leaflet was displaced and adherent to the ventricular wall, and the annulus fibrosus was disrupted resulting in ventricular preexcitation. The defects seen in mice with AVC-targeted deletion of Alk3 provide strong support for a role of Alk3 in human congenital heart diseases, such as Ebstein's anomaly. In conclusion, our mouse model demonstrated critical roles for Alk3 signaling in the AV myocardium during the development of AV valves and the annulus fibrosus. C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Cell Biol & Mol Med, Cardiovasc Res Inst, Newark, NJ 07103 USA. NYU, Sch Med, Div Cardiol, New York, NY USA. Univ Louvain VIB, Dept Dev Biol, Louvain, Belgium. Univ Louvain, Dept Dev Biol, Mol Biol Lab, Louvain, Belgium. Indiana Univ, Sch Med, Wells Ctr Pediat Res, Cardiovasc Dev Grp, Indianapolis, IN USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Procter & Gamble Pharmaceut Hlth Care Res Ctr, Mason, OH USA. Baylor Coll Med, Dept Med, Ctr Cardiovasc Dev, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Cellular Biol, Ctr Cardiovasc Dev, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol Physiol & Biophys, Ctr Cardiovasc Dev, Houston, TX 77030 USA. Fox Chase Canc Ctr, Program Cell & Dev Biol, Philadelphia, PA 19111 USA. RP Gaussin, V (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Cell Biol & Mol Med, Cardiovasc Res Inst, 185 S Orange Ave,MSB Room G-609, Newark, NJ 07103 USA. EM gaussivi@umdnj.edu OI Huylebroeck, Danny/0000-0003-4862-1079; Schneider, Michael/0000-0001-9645-1938 FU NHLBI NIH HHS [R01 HL076751-04, 1P01HL69020, 2P01HL59139, 2R01HL33107, HL55373, P01 HL059139, P01 HL069020, R01 HL033107, R01 HL055373, R01 HL064757, R01 HL064757-09, R01 HL076751, R01 HL076751-01A1, R01 HL076751-02, R01 HL076751-03]; NIA NIH HHS [2R01AG14121, R01 AG014121]; NIAMS NIH HHS [AR42919, P01 AR042919] NR 35 TC 80 Z9 83 U1 0 U2 7 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 AUG 5 PY 2005 VL 97 IS 3 BP 219 EP 226 DI 10.1161/01.RES.0000177862.85474.63 PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 952HR UT WOS:000230995100005 PM 16037571 ER PT J AU Zhu, WZ Chakir, K Zhang, SJ Yang, DM Lavoie, C Bouvier, M Hebert, TE Lakatta, EG Cheng, HP Xiao, RP AF Zhu, WZ Chakir, K Zhang, SJ Yang, DM Lavoie, C Bouvier, M Hebert, TE Lakatta, EG Cheng, HP Xiao, RP TI Heterodimerization of beta(1)- and beta(2)-adrenergic receptor subtypes optimizes beta-adrenergic modulation of cardiac contractility SO CIRCULATION RESEARCH LA English DT Article DE receptor dimerization; beta-adrenergic receptor; G protein-coupled receptors; cardiac contractility; ligand binding ID RESONANCE ENERGY-TRANSFER; G-PROTEIN; HETEROMERIC COMPLEXES; TRANSGENIC MICE; HEART-FAILURE; CELL-SURFACE; MYOCYTES; ACTIVATION; OLIGOMERIZATION; DIMERIZATION AB Intermolecular interactions between members of both similar and divergent G protein-coupled receptor subfamilies have been shown in various experimental systems. Here, we demonstrate heterodimerization of predominant beta-adrenergic receptor (beta AR) subtypes expressed in the heart, beta(1)AR, and beta(2)AR, and its physiological relevance. In intact adult-mouse cardiac myocyte slacking native beta(1)AR and beta(2)AR, coexpression of both beta AR subtypes led to receptor heterodimerization, as evidenced by their coimmunoprecipitation, colocalization at optical resolution, and markedly increased binding affinity for subtype-selective ligands. As a result, the dose-response curve of myocyte contraction to beta AR agonist stimulation with isoproterenol (ISO) was shifted leftward by approximate to 1.5 orders of magnitude, and the response of cellular cAMP formation to ISO was enhanced concomitantly, indicating that intermolecular interactions of beta AR subtypes resulted in sensitization of these receptors in response to agonist stimulation. In contrast, the presence of beta(1)AR greatly suppressed ligand-independent spontaneous activity of coexisting beta(2)ARs. Thus, heterodimerization of beta(1)AR and beta(2)AR in intact cardiac myocytes creates a novel population of beta ARs with distinct functional and pharmacological properties, resulting in enhanced signaling efficiency in response to agonist stimulation while silencing ligand-independent receptor activation, thereby optimizing beta-adrenergic modulation of cardiac contractility. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Ctr Rech, Inst Cardiol Montreal, Montreal, PQ, Canada. Univ Montreal, Dept Biochim, Montreal, PQ H3C 3J7, Canada. Peking Univ, Inst Mol Med, Beijing, Peoples R China. RP Xiao, RP (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM xiaor@grc.nia.nih.gov RI Bouvier, Michel/H-2758-2014 OI Bouvier, Michel/0000-0003-1128-0100 NR 40 TC 73 Z9 78 U1 0 U2 8 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 AUG 5 PY 2005 VL 97 IS 3 BP 244 EP 251 DI 10.1161/01.RES.0000176764.38934.86 PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 952HR UT WOS:000230995100008 PM 16002745 ER PT J AU Tykocinski, LO Hajkova, P Chang, HD Stamm, T Sozeri, O Lohning, M Hu-Li, J Niesner, U Kreher, S Friedrich, B Pannetier, C Grutz, G Walter, J Paul, WE Radbruch, A AF Tykocinski, LO Hajkova, P Chang, HD Stamm, T Sozeri, O Lohning, M Hu-Li, J Niesner, U Kreher, S Friedrich, B Pannetier, C Grutz, G Walter, J Paul, WE Radbruch, A TI A critical control element for interleukin-4 memory expression in T helper lymphocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYTOKINE GENE-EXPRESSION; TRANSCRIPTION FACTOR GATA-1; IL-4 GENE; CUTTING EDGE; TH2 CELLS; TH2-SPECIFIC EXPRESSION; HISTONE ACETYLATION; REGULATORY ELEMENTS; BINDING PROTEIN; P300 PROTEIN AB Naive T helper (Th) lymphocytes are induced to express the il4 (interleukin-4) gene by simultaneous signaling through the T cell receptor and the interleukin (IL)-4 receptor. Upon restimulation with antigen, such preactivated Th lymphocytes can reexpress the il4 gene independent of IL-4 receptor signaling. This memory for expression of the il4 gene depends on epigenetic modification of the il4 gene locus and an increased expression of GATA-3, the key transcription factor for Th2 differentiation. Here, we have identified a phylogenetically conserved sequence, the conserved intronic regulatory element, in the first intron of the il4 gene containing a tandem GATA-3 binding site. We show that GATA-3 binds to this sequence in a position-and orientation-dependent manner, in vitro and in vivo. DNA demethylation and histone acetylation of this region occurs early and selectively in differentiating, IL-4-secreting Th2 lymphocytes. Deletion of the conserved element by replacement of the first exon and part of the first intron of the il4 gene with gfp leads to a defect in the establishment of memory for expression of IL-4, in that reexpression of IL-4 still requires costimulation by exogenous IL-4. The conserved intronic regulatory element thus links the initial epigenetic modification of the il4 gene to GATA-3 and serves as a genetic control element for memory expression of IL-4. C1 Deutsch Rheumaforschungszentrum Berlin, D-10117 Berlin, Germany. Wellcome Trust CR UK Inst, Cambridge CB2 1QR, England. Univ Zurich Hosp, Inst Expt Immunol, CH-8091 Zurich, Switzerland. NIH, Immunol Lab, Bethesda, MD 20892 USA. Max Delbruck Ctr Mol Med, D-13122 Berlin, Germany. Humboldt Univ, Univ Hosp Charite, D-10117 Berlin, Germany. Univ Saarland, D-66041 Saarbrucken, Germany. RP Radbruch, A (reprint author), Deutsch Rheumaforschungszentrum Berlin, Schumannstr 21-22, D-10117 Berlin, Germany. EM radbruch@drfz.de OI Hajkova, Petra/0000-0003-4145-1468 NR 61 TC 44 Z9 45 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 5 PY 2005 VL 280 IS 31 BP 28177 EP 28185 DI 10.1074/jbc.M502038200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 950KZ UT WOS:000230857300003 PM 15941711 ER PT J AU Pereira, CM Sattlegger, E Jiang, HY Longo, BM Jaqueta, CB Hinnebusch, AG Wek, RC Mello, LEAM Castilho, BA AF Pereira, CM Sattlegger, E Jiang, HY Longo, BM Jaqueta, CB Hinnebusch, AG Wek, RC Mello, LEAM Castilho, BA TI IMPACT, a protein preferentially expressed in the mouse brain, binds GCN1 and inhibits GCN2 activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTEGRATED STRESS-RESPONSE; UNCHARGED TRANSFER-RNA; AMINO-ACID DEFICIENCY; FACTOR 2-ALPHA KINASE; TRANSLATIONAL CONTROL; GENE-EXPRESSION; INITIATION FACTOR-2-ALPHA; SYNAPTIC PLASTICITY; EIF2-ALPHA KINASE; MAMMALIAN-CELLS AB Translational control directed by the eukaryotic translation initiation factor 2 alpha-subunit (eIF2 alpha) kinase GCN2 is important for coordinating gene expression programs in response to nutritional deprivation. The GCN2 stress response, conserved from yeast to mammals, is critical for resistance to nutritional deficiencies and for the control of feeding behaviors in rodents. The mouse protein IMPACT has sequence similarities to the yeast YIH1 protein, an inhibitor of GCN2. YIH1 competes with GCN2 for binding to a positive regulator, GCN1. Here, we present evidence that IMPACT is the functional counterpart of YIH1. Overexpression of IMPACT in yeast lowered both basal and amino acid starvation-induced levels of phosphorylated eIF2 alpha, as described for YIH1 (31). Overexpression of IMPACT in mouse embryonic fibroblasts inhibited phosphorylation of eIF2 alpha by GCN2 under leucine starvation conditions, abolishing expression of its downstream target genes, ATF4 (CREB-2) and CHOP (GADD153). IMPACT bound to the minimal yeast GCN1 segment required for interaction with yeast GCN2 and YIH1 and to native mouse GCN1. At the protein level, IMPACT was detected mainly in the brain. IMPACT was found to be abundant in the majority of hypothalamic neurons. Scattered neurons expressing this protein at higher levels were detected in other regions such as the hippocampus and piriform cortex. The abundance of IMPACT correlated inversely with phosphorylated eIF2 alpha levels in different brain areas. These results suggest that IMPACT ensures constant high levels of translation and low levels of ATF4 and CHOP in specific neuronal cells under amino acid starvation conditions. C1 Univ Fed Sao Paulo, Dept Microbiol Immunol & Parasitol, BR-04023062 Sao Paulo, Brazil. Univ Fed Sao Paulo, Dept Fisiol, BR-04023062 Sao Paulo, Brazil. NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. RP Univ Fed Sao Paulo, Dept Microbiol Immunol & Parasitol, Rua Botucatu 862, BR-04023062 Sao Paulo, Brazil. EM bac@ecb.epm.br RI Castilho, Beatriz/C-2503-2012; Mello, Luiz/B-4177-2009; OI Castilho, Beatriz/0000-0003-4509-5237; Mello, Luiz/0000-0002-6969-1108 NR 37 TC 33 Z9 35 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 5 PY 2005 VL 280 IS 31 BP 28316 EP 28323 DI 10.1074/jbc.M408571200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 950KZ UT WOS:000230857300018 PM 15937339 ER PT J AU Minor, KH Schar, CR Blouse, GE Shores, JD Lawrence, DA Schuck, P Peterson, CB AF Minor, KH Schar, CR Blouse, GE Shores, JD Lawrence, DA Schuck, P Peterson, CB TI A mechanism for assembly of complexes of vitronectin and plasminogen activator inhibitor-1 from sedimentation velocity analysis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SOMATOMEDIN-B DOMAIN; REACTIVE-CENTER LOOP; SIZE-DISTRIBUTION ANALYSIS; HUMAN PLASMA VITRONECTIN; UROKINASE RECEPTOR; CELL-ADHESION; ANALYTICAL ULTRACENTRIFUGATION; ENDOTHELIAL-CELLS; SELF-ASSOCIATION; LIGAND-BINDING AB Plasminogen activator inhibitor-1 ( PAI-1) and vitronectin are cofactors involved in pathological conditions such as injury, inflammation, and cancer, during which local levels of PAI-1 are increased and the active serpin forms complexes with vitronectin. These complexes become deposited into surrounding tissue matrices, where they regulate cell adhesion and pericellular proteolysis. The mechanism for their co- localization has not been elucidated. We hypothesize that PAI-1-vitronectin complexes form in a stepwise and concentration-dependent fashion via 1: 1 and 2: 1 intermediates, with the 2: 1 complex serving a key role in assembly of higher order complexes. To test this hypothesis, sedimentation velocity experiments in the analytical ultracentrifuge were performed to identify different PAI-1-vitronectin complexes. Analysis of sedimentation data invoked a novel multisignal method to discern the stoichiometry of the two proteins in the higher-order complexes formed ( Balbo, A., Minor, K. H., Velikovsky, C. A., Mariuzza, R. A., Peterson, C. B., and Schuck, P. ( 2005) Proc. Natl. Acad. Sci. U. S. A. 102, 81-86). Our results demonstrate that PAI-1 and vitronectin assemble into higher order forms via a pathway that is triggered upon saturation of the two PAI-1-binding sites of vitronectin to form the 2: 1 complex. This 2: 1 PAI-1-vitronectin complex, with a sedimentation coefficient of 6.5 S, is the key intermediate for the assembly of higher order complexes. C1 Univ Tennessee, Dept Biochem Cellular & Mol Biol, Knoxville, TN 37996 USA. Univ Tennessee, Ctr Excellence Struct Biol, Knoxville, TN 37996 USA. Henry Ford Hlth Syst, Dept Pathol, Div Biochem Res, Detroit, MI 48202 USA. Wayne State Univ, Sch Med, Dept Pharmacol, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Barbara Ann Karmanos Canc Inst, Detroit, MI 48201 USA. Univ Maryland, Sch Med, Dept Surg, Rockville, MD 20855 USA. Univ Maryland, Sch Med, Dept Physiol, Rockville, MD 20855 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Off Director, Bethesda, MD 20892 USA. RP Univ Tennessee, Dept Biochem Cellular & Mol Biol, M407 Walters Life Sci Bldg, Knoxville, TN 37996 USA. EM cynthia_peterson@utk.edu OI Schuck, Peter/0000-0002-8859-6966 FU NHLBI NIH HHS [R01 HL050676, HL50676] NR 79 TC 11 Z9 11 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 5 PY 2005 VL 280 IS 31 BP 28711 EP 28720 DI 10.1074/jbc.M500478200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 950KZ UT WOS:000230857300062 PM 15905170 ER PT J AU Cheung, A Struble, E He, JY Yang, C Wang, E Thurston, DE Liu, P AF Cheung, A Struble, E He, JY Yang, C Wang, E Thurston, DE Liu, P TI Direct liquid chromatography determination of the reactive imine SJG-136 (NSC 694501) SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE SJG-136; NSC 694501; benzodiazepine; water adducts; NMR; HPLC assay; development; validation ID CROSS-LINKING AGENT; SPECTRUM ANTITUMOR-ACTIVITY; DNA-BINDING; IN-VITRO; BENZODIAZEPINES; CYTOTOXICITY; POTENT; COLUMN; PHARMACOLOGY; METABOLITES AB SJG-136 (NSC 694501), 8,8 '- [[(propane-1,3-diyl)dioxy]bis[(11aS)-7-methoxy-2-methylidene- 1,2,3,11 a-tetrahydro-5H-pyrrolo[2,1 -c] 1,4] benzodiazepin-5 -one], which is being developed as a DNA-interactive antitumor agent, contains highly reactive imines in the diazepinone portions of the molecule. Water or alcohol adds readily to the imino moiety to form the corresponding carbinolamine or its alkyl ether, respectively. This sensitivity to protic substances poses a formidable challenge to the formulation and HPLC assay development for the compound. After studying the solution chemistry of SJG-136 and its potential interaction with various stationary phases, two reversed-phase liquid chromatographic assays for the compound have been developed. A direct assay that separates SJG-136 from its water or methanol adducts and an indirect assay that quantifies SJG-136 as its dihydrate adduct are reported. The latter method, which is more practical for drug development, has been validated. It is reproducible (R.S.D. < 2%), linear (r(2) = 0.9999) and accurate (within 98-102% recovery), with a lower detection limit of 2.5 ng. (c) 2005 Elsevier B.V. All rights reserved. C1 SRI Int, Dept Analyt Chem, Menlo Pk, CA 94025 USA. Univ London, Sch Pharm, Canc Res UK Gene Targeted Drug Design Res Grp, London WC1N 1AX, England. NCI, Pharmaceut Resources Branch, DCTD, Bethesda, MD 20892 USA. RP He, JY (reprint author), SRI Int, Dept Analyt Chem, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. EM jingyi.he@sri.com FU NCI NIH HHS [N01-CM-77104, N02-CM-27134] NR 15 TC 9 Z9 9 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD AUG 5 PY 2005 VL 822 IS 1-2 BP 10 EP 20 DI 10.1016/j.jchromb.2005.04.027 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 952MU UT WOS:000231008900002 PM 15994138 ER PT J AU Botos, I Melnikov, EE Cherry, S Kozov, S Makhovskaya, OV Tropea, JE Gustchina, A Rotanova, TV Wlodawer, A AF Botos, I Melnikov, EE Cherry, S Kozov, S Makhovskaya, OV Tropea, JE Gustchina, A Rotanova, TV Wlodawer, A TI Atomic-resolution crystal structure of the proteolytic domain of Archaeoglobus fulgidus Lon reveals the conformational variability in the active sites of Lon proteases SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE active site; ATP-dependent proteases; atomic resolution; catalytic dyad; structure comparisons ID ATP-DEPENDENT PROTEASE; BETA-CARBONIC ANHYDRASE; ESCHERICHIA-COLI LON; SER-LYS DYAD; THERMOPLASMA-ACIDOPHILUM; MOLECULAR REPLACEMENT; CATALYTIC DOMAIN; DNA-BINDING; REFINEMENT; BACTERIAL AB The atomic-resolution crystal structure of the proteolytic domain (P-domain, residues 415-621) of Archaeoglobusfulgidus B-type Lon protease (wtAfLonB) and the structures of several mutants have revealed significant differences in the conformation of the active-site residues when compared to other known Lon P-domains, despite the conservation of the overall fold. The catalytic Ser509 is facing the solvent and is distant from Lys552, the other member of the catalytic dyad. Instead, the adjacent Asp508 forms an ion pair with the catalytic lysine residue. Glu506, an analog of the putative third catalytic residue from a related Methanococcus jannaschii LonB, also faces the solvent and does not interact with the catalytic dyad. We have established that full-length wtAfLonB is proteolytically active in an ATP-dependent manner. The loss of enzymatic activity of the S509A mutant confirms the functional significance of this residue, while retention of considerable level of activity by the D508A and E506A mutants rules out their critical involvement in catalysis. In contrast to the full-length enzymes, all individually purified P-domains (wild-type and mutants) were inactive, and the mutations had no influence on the active-site structure. These findings raise the possibility that, although isolated proteolytic domains of both AfLonB and E. coli LonA are able to assemble into expected functional hexamers, the presence of the other domains, as well as substrate binding, may be needed to stabilize the productive conformation of their active sites. Thus, the observed conformational variability may reflect the differences in the stability of active-site structures for the proteolytic counterparts of single-chain Lon versus independently folded proteolytic subunits of two-chain AAA(+) proteases. Published by Elsevier Ltd. C1 NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia. NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM wlodawer@ncifcrf.gov NR 60 TC 34 Z9 37 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD AUG 5 PY 2005 VL 351 IS 1 BP 144 EP 157 DI 10.1016/j.jmb.2005.06.008 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 949QL UT WOS:000230803100014 PM 16002085 ER PT J AU Luo, WM Yu, QS Holloway, HW Parrish, D Greig, NH Brossi, A AF Luo, WM Yu, QS Holloway, HW Parrish, D Greig, NH Brossi, A TI Syntheses of tetrahydrofurobenzofurans and dihydromethanobenzodioxepines from 5-hydroxy-3-methyl-3H-benzofuran-2-one. Rearrangement and ring expansion under reductive conditions on treatment with hydrides SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID RACEMIC AFLATOXIN B1; BIOSYNTHESIS; ANALOGS AB 5-Hydroxy-3-methyl-3H-benzofuran-2-one, 5, easily obtained from pyruvic acid and 1,4-cyclohexanedione, was used as a starting material to prepare ()-5-hydroxy-3a-methyl-2,3,3a,8a-tetrahydrofuro[2,3-b]benzofuran, 10, and ()-7-hydroxy-5-methyl-4,5-dihydro-2,5-methano-1,3-benzodioxepine, 14. Reduced reactivity relative to 5-hydroxy-3-methoxycarbonylmethylene-3-methyl-3H-benzofuran2-one, 6, was preliminarily studied. Meanwhile, a plausible mechanism with regard to the formation of 10 and 14, which included cyclization, rearrangement, and ring expansion of hemiacetal, 15, is proposed. Specific carbamates of phenols, 10 and 14, have shown impressive inhibitory activities against human acetyleholinesterase (AChE) and butyrylcholinesterase (BChE) ex vivo. C1 NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. USN, Res Lab, Dept Navy, Struct Matter Lab, Washington, DC 20375 USA. Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. RP Greig, NH (reprint author), NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM greign@grc.nia.nih.gov NR 12 TC 12 Z9 12 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD AUG 5 PY 2005 VL 70 IS 16 BP 6171 EP 6176 DI 10.1021/jo0503052 PG 6 WC Chemistry, Organic SC Chemistry GA 951DK UT WOS:000230909100005 PM 16050674 ER PT J AU McElhinny, SAN Havener, JM Garcia-Diaz, M Juarez, R Bebenek, K Kee, BL Blanco, L Kunkel, TA Ramsden, DA AF McElhinny, SAN Havener, JM Garcia-Diaz, M Juarez, R Bebenek, K Kee, BL Blanco, L Kunkel, TA Ramsden, DA TI A gradient of template dependence defines distinct biological roles for family X polymerases in nonhomologous end joining SO MOLECULAR CELL LA English DT Article ID MU POL-MU; CHAIN GENE REARRANGEMENT; DNA-POLYMERASE; V(D)J RECOMBINATION; LESION BYPASS; LAMBDA; REPAIR; CELLS; DEFICIENT; PATHWAY AB Three Pol X family members have been linked to nonhomologous end joining (NHEJ) in mammals. Template-independent TdT promotes diversity during NHEJ-dependent repair of V(D)J recombination intermediates, but the roles of the template-dependent polymerases mu and lambda in NHEJ remain unclear. We show here that pol mu and pol lambda are similarly recruited by NHEJ factors to fill gaps when ends have partially complementary overhangs, suggesting equivalent roles promoting accuracy in NHEJ. However, only pol mu promotes accuracy during immunoglobulin kappa recombination. This distinctive in vivo role correlates with the TdT-like ability of pol mu, but not pol lambda, to act when primer termini lack complementary bases in the template strand. However, unlike TdT, synthesis by pol mu in this context is primarily instructed by a template from another DNA molecule. This apparent gradient of template dependence is largely attributable to a small structural element that is present but different in all three polymerases. C1 Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. Univ N Carolina, Curr Genet & Mol Biol, Chapel Hill, NC 27599 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Univ Autonoma Madrid, CSIC, E-28049 Madrid, Spain. Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. RP Ramsden, DA (reprint author), Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. EM dale_ramsden@med.uno.edu NR 43 TC 168 Z9 170 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD AUG 5 PY 2005 VL 19 IS 3 BP 357 EP 366 DI 10.1016/j.molcel.2005.06.012 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 953ME UT WOS:000231079600010 ER PT J AU Yuan, YR Pei, Y Ma, JB Kuryavyi, V Zhadina, M Meister, G Chen, HY Dauter, Z Tuschl, T Patel, DJ AF Yuan, YR Pei, Y Ma, JB Kuryavyi, V Zhadina, M Meister, G Chen, HY Dauter, Z Tuschl, T Patel, DJ TI Crystal structure of A-aeolicus Argonaute, a site-specific DNA-guided endoribonuclease, provides insights into RISC-mediated mRNA cleavage SO MOLECULAR CELL LA English DT Article; Proceedings Paper CT Banbury Symposium on RNAi-Related Processes in Plants - Chromatin, Development and Defense CY AUG 15-18, 2004 CL Cold Spring Harbor Labs, Cold Spring Harbor, NY HO Cold Spring Harbor Labs ID DOUBLE-STRANDED-RNA; PAZ DOMAIN; MICRORNA TARGETS; ISOMORPHOUS REPLACEMENT; SLICER ACTIVITY; ENZYME COMPLEX; PIWI PROTEIN; RECOGNITION; SIRNAS; BINDING AB Argonaute (Ago) proteins constitute a key component of the RNA-induced silencing complex (RISC). We report the crystal structure of Aquifex aeolicus Ago (Aa-Ago) together with binding and cleavage studies, which establish this eubacterial Ago as a bona fide guide DNA strand-mediated site-specific RNA endonuclease. We have generated a stereochemically robust model of the complex, where the guide DNA-mRNA duplex is positioned within a basic channel spanning the bilobal interface, such that the 5 ' phosphate of the guide strand can be anchored in a basic pocket, and the mRNA can be positioned for site-specific cleavage by RNase H-type divalent cation-coordinated catalytic Asp residues of the PIWI domain. Domain swap experiments involving chimeras of human Ago (hAgo1) and cleavage-competent hAgo2 reinforce the role of the PIWI domain in '' slicer '' activity. We propose a four-step Ago-mediated catalytic cleavage cycle model, which provides distinct perspectives into the mechanism of guide strand-mediated mRNA cleavage within the RISC. C1 Mem Sloan Kettering Canc Ctr, Struct Biol Program, New York, NY 10021 USA. Rockefeller Univ, Lab RNA Mol Biol, New York, NY 10021 USA. NCI, Argonne Natl Lab, Synchrotron Radiat Res Sect, Argonne, IL 60439 USA. RP Tuschl, T (reprint author), Mem Sloan Kettering Canc Ctr, Struct Biol Program, New York, NY 10021 USA. EM ttuschl@mail.rockefeller.edu; pateld@mskcc.org RI Pei, Yi/D-8998-2011 OI Pei, Yi/0000-0002-3466-760X FU NCI NIH HHS [P30 CA008748]; NIAID NIH HHS [R01 AI068776]; NIGMS NIH HHS [R01 GM068476-01, R01 GM068476] NR 55 TC 196 Z9 212 U1 5 U2 21 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD AUG 5 PY 2005 VL 19 IS 3 BP 405 EP 419 DI 10.1016/j.molcel.2005.07.011 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 953ME UT WOS:000231079600014 PM 16061186 ER PT J AU Bandopadhyay, R Miller, DW Kingsbury, AE Jowett, TP Kaleem, MM Pittman, AM de Silva, R Cookson, MR Lees, AJ AF Bandopadhyay, R Miller, DW Kingsbury, AE Jowett, TP Kaleem, MM Pittman, AM de Silva, R Cookson, MR Lees, AJ TI Development, characterisation and epitope mapping of novel monoclonal antibodies for DJ-1 (PARK7) protein SO NEUROSCIENCE LETTERS LA English DT Article DE DJ-1; PARK7; epitope mapping; Parkinson's disease; immunohistochemistry; human brain ID ONSET PARKINSONS-DISEASE; MUTATIONS; GENE; BRAIN AB Mutations in DJ-1 (PARk7) were recently identified as the cause for an autosomal recessive early onset form of familial Parkinson's disease, however, the function of the protein in the brain is yet to be elucidated. Here we report on the development, characterisation and epitope mapping, of two novel monoclonal antibodies to DJ-1. One of them (DJ-1 "clone 16") has its epitope between amino acids 56-78 of the human DJ-1 protein and has very similar properties to a commercially available DJ-1 antibody clone 3E8. The second antibody recognised both the rat and human DJ-1 (DJ-1 "clone 48") and its epitope is between amino acids 26-56. We have used immunohistochemistry with these two antibodies to compare the distribution of DJ-1 in human and rat brain tissue. Both antibodies gave similar patterns of labelling in human brain with marked astrocytic expression. Neuronal labelling was weak or absent and the antibodies did not label Lewy bodies or Lewy neurites. In the rat brain, DJ-1 was ubiquitously expressed in neurones but exhibited low expression in astrocytes. These antibodies could be exploited as important tools in dissecting out DJ-1 expression in different species and examination of the role of DJ-1 in Parkinson's disease. (c) 2005 Elsevier Ireland Ltd. All rights reserved. C1 Royal Free & UCL Med Sch, Reta Lila Weston Inst Neurol Studies, London W1T 4JF, England. NIA, Neurogenet Lab, NIH, Cell Biol & Gene Express Unit, Bethesda, MD 20892 USA. Royal Free & UCL Med Sch, Rayne Inst, Dept Med, Monoclonal Antibodies Unit, London WC1E 6JJ, England. RP Bandopadhyay, R (reprint author), Royal Free & UCL Med Sch, Reta Lila Weston Inst Neurol Studies, Winedeyer Bldg,46,Cleveland St, London W1T 4JF, England. EM regtrib@ucl.ac.uk RI de Silva, Rohan/C-1734-2008; Pittman, Alan/D-6231-2012; Lees, Andrew/A-6605-2009; Bandopadhyay, Rina /C-7926-2009 OI de Silva, Rohan/0000-0002-5052-5775; FU Parkinson's UK [G-4056] NR 19 TC 8 Z9 8 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD AUG 5 PY 2005 VL 383 IS 3 BP 225 EP 230 DI 10.1016/j.neulet.2005.04.024 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 940LJ UT WOS:000230145700006 PM 15955416 ER PT J AU Wickner, RB AF Wickner, RB TI Scrapie in ancient China? SO SCIENCE LA English DT Letter C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDKD, Lab Biochem & Genet, NIH, 8 Ctr Dr,MSC0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov NR 1 TC 6 Z9 6 U1 0 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD AUG 5 PY 2005 VL 309 IS 5736 BP 874 EP 874 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 953SS UT WOS:000231101400017 PM 16081716 ER PT J AU Kravchenko, JE Rogozin, IB Koonin, EV Chumakov, PM AF Kravchenko, JE Rogozin, IB Koonin, EV Chumakov, PM TI Transcription of mammalian messenger RNAs by a nuclear RNA polymerase of mitochondrial origin SO NATURE LA English DT Article ID DNA; CELLS; MTDNA; TOOL; SEQUENCES; ALIGNMENT; PATTERNS; B1 AB Transcription of eukaryotic genes is performed by three nuclear RNA polymerases, of which RNA polymerase II is thought to be solely responsible for the synthesis of messenger RNAs1. Here we show that transcription of some mRNAs in humans and rodents is mediated by a previously unknown single-polypeptide nuclear RNA polymerase (spRNAP-IV). spRNAP-IV is expressed from an alternative transcript of the mitochondrial RNA polymerase gene (POLRMT). The spRNAP-IV lacks 262 amino-terminal amino acids of mitochondrial RNA polymerase, including the mitochondrial-targeting signal, and localizes to the nucleus. Transcription by spRNAP-IV is resistant to the RNA polymease II inhibitor alpha-amanitin but is sensitive to short interfering RNA specific for the POLRMT gene. The promoters for spRNAP-IV differ substantially from those used by RNA polymerase II, do not respond to transcriptional enhancers and contain a common functional sequence motif. C1 Cleveland Clin Fdn, Lerner Res Inst, Cleveland, OH 44195 USA. VA Engelhardt Mol Biol Inst, Moscow 119991, Russia. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Chumakov, PM (reprint author), Cleveland Clin Fdn, Lerner Res Inst, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM chumakp@ccf.org OI Chumakov, Peter/0000-0002-8078-2908 FU NCI NIH HHS [R01 CA104903]; NIA NIH HHS [R01 AG025278, R01 AG025278-01A1] NR 30 TC 37 Z9 40 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 4 PY 2005 VL 436 IS 7051 BP 735 EP 739 DI 10.1038/nature03848 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 951XA UT WOS:000230964500051 PM 16079853 ER PT J AU Englund, EA Appella, DH AF Englund, EA Appella, DH TI Synthesis of gamma-substituted peptide nucleic acids: A new place to attach fluorophores without affecting DNA binding SO ORGANIC LETTERS LA English DT Article ID PNA MOLECULAR BEACONS; HYBRIDIZATION; PROBES AB [GRAPHICS] Molecular beacon strategies using PNA are currently restricted to fluorophore attachment to the ends of the PNA. We report the synthesis of PNA oligomers wherein fluorophores can be attached to the PNA backbone from novel gamma-lysine PNA monomers. Oligomers incorporating the modified PNA showed comparable thermal stability to the corresponding aegPNA oligomer with DNA. When the modified PNA oligomer was annealed with complementary DNA, the fluorescence intensity increased 4-fold over the unbound PNA. C1 NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. Northwestern Univ, Evanston, IL 60208 USA. RP Appella, DH (reprint author), NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. EM appellad@niddk.nih.gov NR 16 TC 53 Z9 53 U1 0 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 EI 1523-7052 J9 ORG LETT JI Org. Lett. PD AUG 4 PY 2005 VL 7 IS 16 BP 3465 EP 3467 DI 10.1021/ol051143z PG 3 WC Chemistry, Organic SC Chemistry GA 950LL UT WOS:000230858500019 PM 16048318 ER PT J AU Flegal, KM Graubard, BI Williamson, DF AF Flegal, KM Graubard, BI Williamson, DF TI Underweight, overweight, obesity, and excess deaths - In reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. RP Flegal, KM (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. EM kflegal@cdc.gov RI Flegal, Katherine/A-4608-2013 NR 2 TC 6 Z9 6 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 3 PY 2005 VL 294 IS 5 BP 552 EP 553 DI 10.1001/jama.294.5.552-c PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 951NN UT WOS:000230937500011 ER PT J AU Fleg, JL Morrell, CH Bos, AG Brant, LJ Talbot, LA Wright, JG Lakatta, EG AF Fleg, JL Morrell, CH Bos, AG Brant, LJ Talbot, LA Wright, JG Lakatta, EG TI Accelerated longitudinal decline of aerobic capacity in healthy older adults SO CIRCULATION LA English DT Article DE aging; exercise; follow-up studies ID AGE-ASSOCIATED DECLINE; CARDIOVASCULAR-RESPONSE; MEN; EXERCISE; WOMEN; ENDURANCE; FITNESS; MUSCLE; POWER; METAANALYSIS AB Background - The ability of older persons to function independently is dependent largely on the maintenance of sufficient aerobic capacity and strength to perform daily activities. Although peak aerobic capacity is widely recognized to decline with age, its rate of decline has been estimated primarily from cross-sectional studies that may provide misleading, overly optimistic estimates of aging changes. Methods and Results - To determine longitudinal rate of change in aerobic capacity and the influence of age, gender, and physical activity on these changes, we performed serial measurements of peak treadmill oxygen consumption ( peak V. O-2) in 375 women and 435 men ages 21 to 87 years from the Baltimore Longitudinal Study of Aging, a community-dwelling cohort free of clinical heart disease, over a median follow-up period of 7.9 years. A linear mixed-effects regression model was used to calculate the predicted longitudinal 10-year rate of change in peak V. O-2, expressed in milliliters per minute, for each age decade from the 20s through the 70s after adjustment for self-reported leisure-time physical activity. A longitudinal decline in peak V. O2 was observed in each of the 6 age decades in both sexes; however, the rate of decline accelerated from 3% to 6% per 10 years in the 20s and 30s to > 20% per 10 years in the 70s and beyond. The rate of decline for each decade was larger in men than in women from the 40s onward. Similar longitudinal rates of decline prevailed when peak V. O2 was indexed per kilogram of body weight or per kilogram of fat-free mass and in all quartiles of self-reported leisure-time physical activity. When the components of peak V. O2 were examined, the rate of longitudinal decline of the oxygen pulse ( ie, the O-2 utilization per heart beat) mirrored that of peak V. O2, whereas the longitudinal rate of heart rate decline averaged only 4% to 6% per 10 years, and accelerated only minimally with age. Conclusions - The longitudinal rate of decline in peak V. O2 in healthy adults is not constant across the age span in healthy persons, as assumed by cross-sectional studies, but accelerates markedly with each successive age decade, especially in men, regardless of physical activity habits. The accelerated rate of decline of peak aerobic capacity has substantial implications with regard to functional independence and quality of life, not only in healthy older persons, but particularly when disease-related deficits are superimposed. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. NIA, Clin Invest Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. NIA, Res Resources Branch, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Loyola Coll, Dept Math Sci, Baltimore, MD 21210 USA. Uniformed Serv Univ Hlth Sci, Grad Sch Nursing, Bethesda, MD 20814 USA. RP Fleg, JL (reprint author), NHLBI, 6701 Rockledge Dr,Room 8112, Bethesda, MD 20892 USA. EM flegj@nhlbi.nih.gov NR 35 TC 280 Z9 289 U1 3 U2 26 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 2 PY 2005 VL 112 IS 5 BP 674 EP 682 DI 10.1161/CIRCULATIONAHA.105.545459 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 950YM UT WOS:000230895200009 PM 16043637 ER PT J AU Raval, AN Telep, JD Guttman, MA Ozturk, C Jones, M Thompson, RB Wright, VJ Schenke, WH DeSilva, R Aviles, RJ Raman, VK Slack, MC Lederman, RJ AF Raval, AN Telep, JD Guttman, MA Ozturk, C Jones, M Thompson, RB Wright, VJ Schenke, WH DeSilva, R Aviles, RJ Raman, VK Slack, MC Lederman, RJ TI Real-time magnetic resonance imaging-guided stenting of aortic coarctation with commercially available catheter devices in swine SO CIRCULATION LA English DT Article DE angioplasty; catheterization; coarctation; heart defects, congenital; stents ID VENA-CAVA FILTER; CARDIAC-CATHETERIZATION; RADIATION-EXPOSURE; ANIMAL-MODEL; FOLLOW-UP; ENDOVASCULAR STENTS; FEASIBILITY; PLACEMENT; CHILDREN; CANCER AB Background - Real-time MR imaging (rtMRI) is now technically capable of guiding catheter-based cardiovascular interventions. Compared with x-ray, rtMRI offers superior tissue imaging in any orientation without ionizing radiation. Translation to clinical trials has awaited the availability of clinical-grade catheter devices that are both MRI visible and safe. We report a preclinical safety and feasibility study of rtMRI-guided stenting in a porcine model of aortic coarctation using only commercially available catheter devices. Method and Results - Coarctation stenting was performed wholly under rtMRI guidance in 13 swine. rtMRI permitted procedure planning, device tracking, and accurate stent deployment. "Active" guidewires, incorporating MRI antennas, improved device visualization compared with unmodified "passive" nitinol guidewires and shortened procedure time ( 26 +/- 11 versus 106 +/- 42 minutes; P = 0.008). Follow-up catheterization and necropsy showed accurate stent deployment, durable gradient reduction, and appropriate neointimal formation. MRI immediately identified aortic rupture when oversized devices were tested. Conclusions - This experience demonstrates preclinical safety and feasibility of rtMRI-guided aortic coarctation stenting using commercially available catheter devices. Patients may benefit from rtMRI in the future because of combined device and tissue imaging, freedom from ionizing radiation, and the ability to identify serious complications promptly. C1 NHLBI, Cardiovasc Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiac Energet Lab, Div Intramural Res, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Div Pediat Cardiol, Washington, DC 20010 USA. Univ Alberta, Dept Biomed Engn, Edmonton, AB, Canada. RP Lederman, RJ (reprint author), NHLBI, Cardiovasc Branch, Div Intramural Res, NIH, Bldg 10,Room 2c713,MSC 1538, Bethesda, MD 20892 USA. EM lederman@nih.gov RI Thompson, Richard/E-9821-2011; Ozturk, Cengizhan/A-6177-2016 OI Ozturk, Cengizhan/0000-0002-6966-0774 FU NHLBI NIH HHS [Z01 HL005062, Z01 HL005062-03, Z01-HL005062-01] NR 54 TC 43 Z9 44 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 2 PY 2005 VL 112 IS 5 BP 699 EP 706 DI 10.1161/CIRCULATIONAHA.105.542647 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 950YM UT WOS:000230895200012 PM 16043639 ER PT J AU Akbar, M Calderon, F Wen, ZM Kim, HY AF Akbar, M Calderon, F Wen, ZM Kim, HY TI Docosahexaenoic acid: A positive modulator of Akt signaling in neuronal survival SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE apoptosis; phosphatidylserine; hippocampus; docosapentaenoic acid; n-3 fatty acid deficiency ID PROTEIN-KINASE-B; MOLECULAR-SPECIES COMPOSITION; POLYUNSATURATED FATTY-ACIDS; PHOSPHATIDYLSERINE BIOSYNTHESIS; PHOSPHATIDYLINOSITOL 3-KINASE; PEROXISOMAL DISORDERS; SUBSTRATE PREFERENCE; DEFICIENCY; CELLS; TRANSLOCATION AB Phosphatidylinositol 3-kinase [PI (3)K]/Akt signaling is a critical pathway in cell survival. Here, we demonstrate a mechanism where membrane alteration by the n-3 fatty acid status affects Akt signaling, impacting neuronal survival. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid highly enriched in neuronal membranes, promotes neuronal survival by facilitating membrane translocation/activation of Akt through its capacity to increase phosphatidylserine (PS), the major acidic phospholipid in cell membranes. The activation of PI (3)K and phosphatidylsinositol triphosphate formation were not affected by DHA, indicating that membrane interaction of Akt is the event responsible for the DHA effect. Docosapentaenoic acid, which replaces DHA during n-3 fatty acid deficiency, was less effective in accumulating PS and translocating Akt and thus less effective in preventing apoptosis. Consistently, in vivo reduction of DHA by dietary depletion of n-3 fatty acids decreased hippocampal PS and increased neuronal susceptibility to apoptosis in cultures. This mechanism may contribute to neurological deficits associated with n-3 fatty acid deficiency and support protective effects of DHA in pathological models such as brain ischemia or Alzheimer's disease. C1 NIAAA, Sect Mass Spectrometry, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20952 USA. RP Kim, HY (reprint author), NIAAA, Sect Mass Spectrometry, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20952 USA. EM hykim@mail.nih.gov FU NIAAA NIH HHS [Z01 AA000284-16] NR 49 TC 254 Z9 272 U1 2 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 2 PY 2005 VL 102 IS 31 BP 10858 EP 10863 DI 10.1073/pnas.0502903102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 953TC UT WOS:000231102400024 PM 16040805 ER PT J AU Chintala, S Li, W Lamoreux, ML Ito, S Wakamatsu, K Sviderskaya, EV Bennett, DC Park, YM Gahl, WA Huizing, M Spritz, RA Ben, S Novak, EK Tan, J Swank, RT AF Chintala, S Li, W Lamoreux, ML Ito, S Wakamatsu, K Sviderskaya, EV Bennett, DC Park, YM Gahl, WA Huizing, M Spritz, RA Ben, S Novak, EK Tan, J Swank, RT TI Slc7a11 gene controls production of pheomelanin pigment and proliferation of cultured cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE glutathione; melanin; pigmentation; cystine; melanocyte ID HERMANSKY-PUDLAK-SYNDROME; GREY-LETHAL; MOUSE; MICE; MELANOCYTES; TRAFFICKING; PROTEIN; DEFICIENCY; TRANSPORT; MUTATION AB In mammals, > 100 genes regulate pigmentation by means of a wide variety of developmental, cellular, and enzymatic mechanisms. Nevertheless, genes that directly regulate pheomelanin production have not been described. Here, we demonstrate that the subtle gray (sut) mouse pigmentation mutant arose by means of a mutation in the Slc7a11 gene, encoding the plasma membrane cystine/glutamate exchanger xCT [Kanai, Y. & Endou, H. (2001) Curr. Drug Metab. 2, 339-354]. A resulting low rate of extracellular cystine transport into sut melanocytes reduces pheomelanin production. We show that Slc7a11 is a major genetic regulator of pheomelanin pigment in hair and melanocytes, with minimal or no effects on eumelanin. Furthermore, transport of cystine by xCT is critical for normal proliferation, glutathione production, and protection from oxidative stress in cultured cells. Thus, we have found that the Slc7a11 gene controls the production of pheomelanin pigment directly. Cells from sut mice provide a model for oxidative stress-related diseases and their therapies. C1 Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Buffalo, NY 14263 USA. Roswell Pk Canc Inst, Dept Cellular Stress Biol, Buffalo, NY 14263 USA. Chinese Acad Sci, Inst Genet & Dev Biol, Mol & Dev Biol Lab, Beijing 100080, Peoples R China. Texas A&M Univ, Comparat Med Program, College Stn, TX 77843 USA. St George Hosp, Sch Med, Dept Basic Med Sci, London SW17 0RE, England. Fujita Hlth Univ, Sch Hlth Sci, Dept Chem, Toyoake, Aichi 4701192, Japan. NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Colorado, Hlth Sci Ctr, Human Med Genet Program, Denver, CO 80262 USA. RP Swank, RT (reprint author), Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Elm & Carlton St, Buffalo, NY 14263 USA. EM richard.swank@roswellpark.org RI Bennett, Dorothy/C-2418-2008; Sviderskaya, Elena/D-2419-2009; OI Bennett, Dorothy/0000-0002-3639-7527; Ito, Shosuke/0000-0001-9182-5144; Wakamatsu, Kazumasa/0000-0003-1748-9001 FU NCI NIH HHS [CA 10948, CA 16056, P30 CA016056]; NEI NIH HHS [EY 12104, R01 EY012104]; NHLBI NIH HHS [HL 31698, HL 51480, R01 HL031698, R01 HL051480]; NIAMS NIH HHS [AR 39892, R01 AR039892]; Wellcome Trust NR 32 TC 82 Z9 87 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 AUG 2 PY 2005 VL 102 IS 31 BP 10964 EP 10969 DI 10.1073/pnas.0502856102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 953TC UT WOS:000231102400043 PM 16037214 ER PT J AU Bell, JK Botos, I Hall, PR Askins, J Shiloach, J Segal, DM Davies, DR AF Bell, JK Botos, I Hall, PR Askins, J Shiloach, J Segal, DM Davies, DR TI The molecular structure of the Toll-like receptor 3 ligand-binding domain SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE dsRNA; innate immunity; pathogen recognition receptor ID LEUCINE-RICH REPEATS; CRYSTAL-STRUCTURE; PROTEIN; RECOGNITION; ACTIVATION; COMPLEX; GENE; RNA; CELLS AB Innate immunity is the first line of defense against invading pathogens. Toll-like receptors (TLRs) act as sentinels of the innate immune system, sensing a variety of ligands from lipopolysaccharide to flagellin to dsRNA through their ligand-binding domain that is composed of leucine-rich repeats (LRRs). Ligand binding initiates a signaling cascade that leads to the up-regulation of inflammation mediators. In this study, we have expressed and crystallized the ectodomain (ECD) of human TLR3, which recognizes dsRNA, a molecular signature of viruses, and have determined the molecular structure to 2.4-angstrom resolution. The overall horseshoe-shaped structure of the TLR3-ECD is formed by 23 repeating LRRs that are capped at each end by specialized non-LRR domains. The extensive beta-sheet on the molecule's concave surface forms a platform for several modifications, including insertions in the LRRs and 11 Winked glycans. The TLR3-ECD structure indicates how LRR loops can establish distinct pathogen recognition receptors. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Biotechnol Unit, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Davies, DR (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM david.davies@nih.gov RI Bell, Jessica/I-3893-2013; Hall, Pamela/O-5402-2016 OI Bell, Jessica/0000-0003-1455-3274; Hall, Pamela/0000-0003-2367-3382 NR 43 TC 244 Z9 259 U1 4 U2 20 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 AUG 2 PY 2005 VL 102 IS 31 BP 10976 EP 10980 DI 10.1073/pnas.0505077102 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 953TC UT WOS:000231102400045 PM 16043704 ER PT J AU Olson, DR Simonsen, L Edelson, PJ Morse, SS AF Olson, DR Simonsen, L Edelson, PJ Morse, SS TI Epidemiological evidence of an early wave of the 1918 influenza pandemic in New York City SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE age-specific mortality; epidemic; herald wave; Spanish flu ID UNITED-STATES; EXCESS MORTALITY; VIRUS; EPIDEMICS; HEMAGGLUTININ; PNEUMONIA; ORIGIN; IMPACT; DEATHS; FRANCE AB The 1918 "Spanish flu" was the fastest spreading and most deadly influenza pandemic in recorded history. Hypotheses of its origin have been based on a limited collection of case and outbreak reports from before its recognized European emergence in the summer of 1918. These anecdotal accounts, however, remain insufficient for determining the early diffusion and impact of the pandemic virus. Using routinely collected monthly age-stratified mortality data, we show that an unmistakable shift in the age distribution of epidemic deaths occurred during the 1917/1918 influenza season in New York City. The timing, magnitude,and age distribution of this mortality shift provide strong evidence that an early wave of the pandemic virus was present in New York City during February-April 1918. C1 Columbia Univ, Dept Epidemiol, New York, NY 10032 USA. Columbia Univ, Dept Pediat, New York, NY 10032 USA. Columbia Univ, Ctr Publ Hlth Preparedness, New York, NY 10032 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Olson, DR (reprint author), Columbia Univ, Dept Epidemiol, New York, NY 10032 USA. EM dro7@columbia.edu OI Simonsen, Lone/0000-0003-1535-8526 FU NIAID NIH HHS [AI 01321-21]; ODCDC CDC HHS [U90 CCU 224241] NR 41 TC 123 Z9 126 U1 0 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 2 PY 2005 VL 102 IS 31 BP 11059 EP 11063 DI 10.1073/pnas.0408290102 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 953TC UT WOS:000231102400059 PM 16046546 ER PT J AU Saikrishnan, K Manjunath, GP Singh, P Jeyakanthan, J Dauter, Z Sekar, K Muniyappa, K Vijayan, M AF Saikrishnan, K Manjunath, GP Singh, P Jeyakanthan, J Dauter, Z Sekar, K Muniyappa, K Vijayan, M TI Structure of Mycobacterium smegmatis single-stranded DNA-binding protein and a comparative study involving homologus SSBs: biological implications of structural plasticity and variability in quaternary association SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID X-RAY-DIFFRACTION; ESCHERICHIA-COLI; TUBERCULOSIS RECA; CRYSTAL-STRUCTURE; TERMINAL DOMAIN; CRYSTALLOGRAPHY; GLYCOSYLASES; RESOLUTION; MOLECULES AB The structure of Mycobacterium smegmatis single-stranded DNA-binding protein (SSB) has been determined using three data sets collected from related crystals. The structure is similar to that of its homologue from Mycobacterium tuberculosis, indicating that the clamp arrangement that stabilizes the dimer and the ellipsoidal shape of the tetramer are characteristic features of mycobacterial SSBs. The central OB fold is conserved in mycobacterial SSBs as well as those from Escherichia coli, Deinococcus radiodurans and human mitochondria. However, the quaternary structure exhibits considerable variability. The observed plasticity of the subunit is related to this variability. The crystal structures and modelling provide a rationale for the variability. The strand involved in the clamp mechanism, which leads to higher stability of the tetramer, appears to occur in all high-G+C Gram-positive bacteria. The higher stability is perhaps required by these organisms. The mode of DNA binding of mycobacterial SSBs is different from that of E. coli SSB partly on account of the difference in the shape of the tetramers. Another difference between the two modes is that the former contains additional ionic interactions and is more susceptible to salt concentration. C1 Indian Inst Sci, Mol Biophys Unit, Bangalore 560012, Karnataka, India. Indian Inst Sci, Dept Biochem, Bangalore 560012, Karnataka, India. Brookhaven Natl Lab, NCI, Synchrotron Radiat Res Sect, MCL, Upton, NY 11973 USA. Indian Inst Sci, Bioinformat Ctr, Bangalore 560012, Karnataka, India. RP Indian Inst Sci, Mol Biophys Unit, Bangalore 560012, Karnataka, India. NR 45 TC 32 Z9 35 U1 0 U2 4 PU INT UNION CRYSTALLOGRAPHY PI CHESTER PA 2 ABBEY SQ, CHESTER, CH1 2HU, ENGLAND SN 1399-0047 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD AUG PY 2005 VL 61 BP 1140 EP 1148 DI 10.1107/S0907444905016896 PN 8 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 947CU UT WOS:000230621500016 PM 16041080 ER PT J AU Ling, W Amass, L Shoptaw, S Annon, JJ Hillhouse, M Babcock, D Brigham, G Harrer, J Reid, M Muir, J Buchan, B Orr, D Woody, G Krejci, J Ziedonis, D AF Ling, W Amass, L Shoptaw, S Annon, JJ Hillhouse, M Babcock, D Brigham, G Harrer, J Reid, M Muir, J Buchan, B Orr, D Woody, G Krejci, J Ziedonis, D CA Buprenorphine Study Protocol Group TI A multi-center randomized trial of buprenorphine-naloxone versus clonidine for opioid, detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network SO ADDICTION LA English DT Article DE buprenorphine; clonidine; detoxification; opiate dependence; treatment ID OPIATE WITHDRAWAL; ADDICTS AB Aims The clinical effectiveness of buprenorphine-naloxone (bup-nx) and clonidine for opioid detoxification in in-patient and out-patient community treatment programs was investigated in the first studies of the National Institute of Drug Abuse Clinical Trials Network. Design Diagnostic and Statistical Manual version IV (DSM IV)-diagnosed opioid-dependent individuals seeking short-term treatment were randomly assigned, in a 2 : 1 ratio favoring bup-nx, to a 13-day detoxification using bup-nx or clonidine. Methods A total of 113 in-patients (77 bup-nx, 36 clonidine) and 231 out-patients (157 bup-nx, 74 clonidine) participated. Supportive interventions included appropriate ancillary medications and standard counseling procedures guided by a self-help handbook. The criterion for treatment success was defined as the proportion of participants in each condition who were both retained in the study for the entire duration and provided an opioid-free urine sample on the last day of clinic attendance. Secondary outcome measures included use of ancillary medications, number of side effects reported and withdrawal and craving ratings. Findings A total of 59 of the 77 (77%) in-patients assigned to the bup-nx condition achieved the treatment success criterion compared to eight of the 36 (22%) assigned to clonidine, whereas 46 of the 157 (29%) out-patients assigned to the bup-nx condition achieved the treatment success criterion, compared to four of the 74 (5%) assigned to clonidine. Conclusions The benefits of bup-nx for opioid detoxification are supported and illustrate important ways in which clinical research can be conducted in community treatment programs. C1 Univ Calif Los Angeles, ISAP, David Geffen Sch Med, NPI Integrated Subst Abuse Program, Los Angeles, CA 90025 USA. Friends Res Inst, Los Angeles, CA USA. Midtown Community Mental Hlth Ctr, Indianapolis, IN USA. Maryhaven Inc, Columbus, OH USA. Vet Adm Med Ctr, Cincinnati, OH USA. NYU, Sch Med, New York, NY USA. Univ Miami, Miami, FL 33152 USA. Ctr Drug Free Living, Orlando, FL USA. Univ Penn, Philadelphia, PA 19104 USA. Mercer Trenton Addict Sci Ctr, Trenton, NJ USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Newark, NJ 07103 USA. NIDA, Ctr Clin Trials Network, Buprenorphine Study Protocol Grp Steering Comm, Bethesda, MD 20892 USA. RP Ling, W (reprint author), Univ Calif Los Angeles, ISAP, David Geffen Sch Med, NPI Integrated Subst Abuse Program, 11075 Santa Monica Blvd,Suite 200, Los Angeles, CA 90025 USA. EM lwalter@lx.netcom.com OI Brigham, Gregory/0000-0003-1150-4493 FU NIDA NIH HHS [U10 DA013732, U10 DA013035, U10 DA013036, U10 DA013043, U10 DA013045, U10 DA013046, U10 DA013710, U10 DA013720, U10 DA13035, U10 DA13036, U10 DA13043, U10 DA13045, U10 DA13046, U10 DA13710, U10 DA13720, U10 DA13732] NR 27 TC 121 Z9 123 U1 1 U2 6 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD AUG PY 2005 VL 100 IS 8 BP 1090 EP 1100 DI 10.1111/j.1360-0443.2005.01154.x PG 11 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 949FC UT WOS:000230769400017 PM 16042639 ER PT J AU de Grey, ADNJ Alvarez, PJJ Brady, RO Cuervo, AM Jerome, WG McCarty, PL Nixon, RA Rittmann, BE Sparrow, JR AF de Grey, ADNJ Alvarez, PJJ Brady, RO Cuervo, AM Jerome, WG McCarty, PL Nixon, RA Rittmann, BE Sparrow, JR TI Medical bioremediation: Prospects for the application of microbial catabolic diversity to aging and several major age-related diseases SO AGEING RESEARCH REVIEWS LA English DT Review DE aggregates; lysosomes; bioremediation; bacteria; catabolism; atherosclerosis; neurodegeneration; macular degeneration ID LOW-DENSITY-LIPOPROTEIN; ENZYME-REPLACEMENT THERAPY; PICK TYPE-C; CHAPERONE-MEDIATED AUTOPHAGY; PIGMENTED EPITHELIAL-CELLS; LYSOSOMAL STORAGE DISEASE; LIGHT-INDUCED DAMAGE; ALZHEIMERS-DISEASE; ATHEROSCLEROTIC LESIONS; LIPOFUSCIN FLUOROPHORE AB Several major diseases of old age, including atherosclerosis, macular degeneration and neuro-degenerative diseases are associated with the intracellular accumulation of substances that impair cellular function and viability. Moreover, the accumulation of lipofuscin, a substance that may have similarly deleterious effects, is one of the most universal markers of aging in postmitotic cells. Reversing this accumulation may thus be valuable, but has proven challenging, doubtless because substances resistant to cellular catabolism are inherently hard to degrade. We suggest a radically new approach: augmenting humans' natural catabolic machinery with microbial enzymes. Many recalcitrant organic molecules are naturally degraded in the soil. Since the soil in certain environments graveyards, for example - is enriched in human remains but does not accumulate these substances, it presumably harbours microbes that degrade them. The enzymes responsible could be identified and engineered to metabolise these substances in vivo. Here, we survey a range of such substances, their putative roles in age-related diseases and the possible benefits of their removal. We discuss how microbes capable of degrading them can be isolated, characterised and their relevant enzymes engineered for this purpose and ways to avoid potential side-effects. (c) 2005 Elsevier Ireland Ltd. All rights reserved. C1 Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. Rice Univ, Houston, TX 77251 USA. NINDS, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Vanderbilt Univ, Nashville, TN USA. Stanford Univ, Stanford, CA 94305 USA. Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. Arizona State Univ, Tempe, AZ USA. Columbia Univ, New York, NY USA. RP de Grey, ADNJ (reprint author), Univ Cambridge, Dept Genet, Downing St, Cambridge CB2 3EH, England. EM ag24@gen.cam.ac.uk RI McCarty, Perry/H-1132-2011 FU NHLBI NIH HHS [R01 HL48148] NR 109 TC 19 Z9 22 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1568-1637 J9 AGEING RES REV JI Ageing Res. Rev. PD AUG PY 2005 VL 4 IS 3 BP 315 EP 338 DI 10.1016/j.arr.2005.03.008 PG 24 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 967OM UT WOS:000232100700001 PM 16040282 ER PT J AU Brazel, CY Limke, TL Osborne, JK Miura, T Cai, JL Pevny, L Rao, MS AF Brazel, CY Limke, TL Osborne, JK Miura, T Cai, JL Pevny, L Rao, MS TI Sox2 expression defines a heterogeneous population of neurosphere-forming cells in the adult murine brain SO AGING CELL LA English DT Article DE aging; neural stem cell; neurogenesis; Sox2; subgranular layer; subventricular zone ID NEURAL STEM-CELL; CENTRAL-NERVOUS-SYSTEM; PROGENITOR CELLS; MOUSE BRAIN; SUBVENTRICULAR ZONE; MULTIPOTENT; DIFFERENTIATION; IDENTIFICATION; MICE; CNS AB The identification of neural stem cells (NSCs) in situ has been prevented by the inability to identify a marker consistently expressed in all adult NSCs and is thus generally accomplished using the in vitro neurosphere-forming assay. The high-mobility group transcription factor Sox2 is expressed in embryonic neural epithelial stem cells; because these cells are thought to give rise to the adult NSC population, we hypothesized that Sox2 may continue to be expressed in adult NSCs. Using Sox2:EGFP transgenic mice, we show that Sox2 is expressed in neurogenic regions along the rostral-caudal axis of the central nervous system throughout life. Furthermore, all neurospheres derived from these neurogenic regions express Sox2, suggesting that Sox2 is indeed expressed in adult NSCs. We demonstrate that NSCs are heterogeneous within the adult brain, with differing capacities for cell production. In vitro, all neurospheres express Sox2, but the expression of markers common to early progenitor cells within individual neurospheres varies; this heterogeneity of NSCs is mirrored in vivo. For example, both glial fibrillary acidic protein and NG2 are expressed within individual neurospheres, but their expression is mutually exclusive; likewise, these two markers show distinct staining patterns within the Sox2+ regions of the brain's neurogenic regions. Thus, we propose that the expression of Sox2 is a unifying characteristic of NSCs in the adult brain, but that not all NSCs maintain the ability to form all neural cell types in vivo. C1 NIA, Neurosci Lab, Baltimore, MD 21224 USA. NIGMS, Pharmacol Res Associate PRAT Program, Bethesda, MD 20892 USA. Univ N Carolina, Ctr Neurosci, Dept Genet, Chapel Hill, NC 27599 USA. RP Rao, MS (reprint author), NIA, Neurosci Lab, 333 Cassell Dr,Triad 406A, Baltimore, MD 21224 USA. EM raomah@mail.nih.gov NR 39 TC 102 Z9 111 U1 0 U2 6 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1474-9718 J9 AGING CELL JI Aging Cell PD AUG PY 2005 VL 4 IS 4 BP 197 EP 207 DI 10.1111/j.1474-9726.2005.00158.x PG 11 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 952OL UT WOS:000231015300004 PM 16026334 ER PT J AU MacGregor, RR Hafner, R Wu, JW Murphy, RL Perlman, DC Bermudez, LE Inderlied, CB Picker, LJ Wallis, RS Andersen, JW Mahon, LF Koletar, SL Peterson, DM AF MacGregor, RR Hafner, R Wu, JW Murphy, RL Perlman, DC Bermudez, LE Inderlied, CB Picker, LJ Wallis, RS Andersen, JW Mahon, LF Koletar, SL Peterson, DM CA ACTG Protocol 341 Team TI Clinical, microbiological, and immunological characteristics in HIV-Infected subjects at risk for disseminated Mycobacterium avium complex disease: An AACTG study SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; MEMORY/EFFECTOR T-CELLS; FLOW-CYTOMETRY; BONE-MARROW; ANTIRETROVIRAL THERAPY; CYTOKINE SYNTHESIS; AIDS PATIENTS; IN-VITRO; BACTEREMIA; C-18-CARBOXYPROPYLBETAINE AB The clinical, microbiologic, and immunologic parameters in HIV-infected subjects first presenting with disseminated Mycobacterium avium complex (DMAC) were determined. Four HIV-positive groups not yet on DMAC treatment were enrolled: 19 subjects with CD4 lymphocyte counts <= 50/mu l thought to have DMAC on clinical grounds; 18 subjects newly found to have a positive blood culture for MAC; 25 asymptomatic controls (CD4 cell counts <= 50); and 25 asymptomatic controls (CD4 counts 100-250/mu l). Outcome measures include comparisons between groups for clinical characteristics; results of cultures from blood, marrow, and gastrointestinal and respiratory tracts; immunological markers from staining of marrow and flow cytometry of circulating lymphocytes; and cytokine production of PBMCs. Only 21% of the 19 patients entered on suspicion of having DMAC grew MAC from blood or marrow. Neither clinical presentation nor laboratory tests differentiated those culture-positive from those culture-negative patients. However, prior PCP or multiple other opportunistic infections were more common in the DMAC group. MAC was isolated from 82% of marrow and 50% of blood specimens from the DMAC group. Respiratory or gastrointestinal colonization was present in 36% of DMAC subjects, but only 5% of non-DMAC subjects with CD4 counts <50 cells/mu l. CD8(+) cells were more frequent in bone marrow, and CD4 cells recognizing MAC antigen were more frequent in blood from DMAC subjects vs. controls. Results suggest an early stage of tissue dissemination preceding persistent bacteremia, and mucosal entry without persistence of colonization. MAC-specific T cell responses apparently develop and persist during DMAC, but are dysfunctional or too infrequent to prevent persistence. C1 Univ Penn, Div Infect Dis, Philadelphia, PA 19104 USA. NIAID, Treatment Res Program, Div Aids, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, SDAC, Boston, MA 02115 USA. Northwestern Univ, Chicago, IL 60611 USA. Beth Israel Med Ctr, New York, NY 10038 USA. Oregon State Univ, Coll Vet Med, Dept Biomed Sci, Corvallis, OR 97331 USA. Univ So Calif, Childrens Hosp, Keck Sch Med, Dept Pathol, Los Angeles, CA 90027 USA. Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Beaverton, OR 97005 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. AACTG Operat Ctr, Silver Spring, MD 20910 USA. Ohio State Univ Hosp, Columbus, OH 43210 USA. Univ Texas, SW Med Sch, Dallas, TX 75390 USA. RP MacGregor, RR (reprint author), Univ Penn, Div Infect Dis, 502 Johnson Pavil 6073, Philadelphia, PA 19104 USA. EM macgregr@mail.med.upenn.edu RI Wallis, Robert/A-8018-2009; OI Wallis, Robert/0000-0001-6152-5183; Murphy, Robert/0000-0003-3936-2052 FU NIAID NIH HHS [U01 AI38858, U01 AI046370] NR 32 TC 7 Z9 7 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD AUG PY 2005 VL 21 IS 8 BP 689 EP 695 DI 10.1089/aid.2005.21.689 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 963LM UT WOS:000231805800002 PM 16131307 ER PT J AU Johnson, BA Mann, K Willenbring, ML Litten, RZ Swift, RM Lesch, OM Berglund, M AF Johnson, BA Mann, K Willenbring, ML Litten, RZ Swift, RM Lesch, OM Berglund, M TI Challenges and opportunities for medications development in alcoholism: An international perspective on collaborations between academia and industry SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article; Proceedings Paper CT 12th International Congress of the International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 29-OCT 02, 2004 CL Mannheim, GERMANY SP Int Soc Biomed Res Alcoholism DE alcohol; topiramate; ondansetron; naltrexone; acamprosate; cannabinoid antagonist ID RANDOMIZED CONTROLLED-TRIAL; OPIOID RECEPTOR GENE; ADDICTION TREATMENT; DEPENDENT SUBJECTS; TREAT ALCOHOLISM; ORAL TOPIRAMATE; UNITED-STATES; NALTREXONE; SUBTYPES; PHARMACOTHERAPIES AB This article represents the proceedings of a symposium presented at the 12th Congress of the International Society for Biomedical Research on Alcoholism held in Heidelberg/Mannheim, Germany, on September 30, 2004. The organizers and cochairs were Bankole A. Johnson, DSc, MD, PhD, and Karl Mann, MD. The presentations included the following: (1) A Perspective from Academia, by Bankole A. Johnson, DSc, MD, PhD; (2) A Perspective from NIAAA, by Mark L. Willenbring, MD; (3) A Perspective from US Clinical Practice, by Robert M. Swift, MD, PhD; (4) A European Perspective on Medications Development, by Otto M. Lesch, MD, PhD, and (5) A Scandinavian Perspective on Evidence-Based Addiction Treatment, by Mats Berglund, MD. C1 Univ Virginia, Dept Psychiat Med, Charlottesville, VA 22908 USA. Univ Heidelberg, Cent Inst Mental Hlth, Dept Addict Behav & Addict Med, Heidelberg, Germany. NIAAA, Div Treatment & Recovery Res, NIH, Bethesda, MD USA. Brown Univ, Dept Psychiat & Human Behav, Providence, RI 02912 USA. Med Univ Vienna, Dept Psychiat, Vienna, Austria. Lund Univ, Malmo Univ Hosp, Dept Clin Alcohol Res, Malmo, Sweden. RP Johnson, BA (reprint author), Univ Virginia, Dept Psychiat Med, POB 800623, Charlottesville, VA 22908 USA. EM bankolejohnson@virginia.edu NR 49 TC 11 Z9 11 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2005 VL 29 IS 8 BP 1528 EP 1540 DI 10.1097/01.alc.0000174690.63787.fc PG 13 WC Substance Abuse SC Substance Abuse GA 962XY UT WOS:000231767900021 PM 16156050 ER PT J AU Wattendorf, DJ Hadley, DW AF Wattendorf, DJ Hadley, DW TI Family history: The three-generation pedigree SO AMERICAN FAMILY PHYSICIAN LA English DT Article ID PRIMARY-CARE; COLORECTAL-CANCER; RATIONALE; RECOMMENDATION; GENETICS; SUSCEPTIBILITY; PREVENTION; MEDICINE AB The collection of a family history ranges from simply asking patients if family members have the same presenting illness to diagramming complex medical and psychosocial relationships as part of a family genogram. The three-generation pedigree provides a pictorial representation of diseases within a family and is the most efficient way to assess hereditary influences on disease. Two recent events have made family history assessment more important than ever: the completion of the Human Genome Project with resultant identification of the inherited causes of many diseases, and the establishment of national clinical practice guidelines based on systematic reviews of preventive interventions. The family history is useful in stratifying a patient's risk for rare single-gene disorders and more common diseases with multiple genetic and environmental contributions. Major organizations have endorsed using standardized symbols in pedigrees to identify inherited contributions to disease. C1 USAF, NHGRI, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, F Edward Hebert Sch Med, Dept Family Med, Bethesda, MD 20814 USA. RP Wattendorf, DJ (reprint author), USAF, NHGRI, NIH, Bldg 31,Room 4B09, Bethesda, MD 20892 USA. EM dwatten@mail.nih.gov NR 29 TC 47 Z9 47 U1 1 U2 8 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 AUG 1 PY 2005 VL 72 IS 3 BP 441 EP 448 PG 8 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 953EL UT WOS:000231059300011 PM 16100858 ER PT J AU Havlik, RJ Phillips, CL Brock, DB Lohman, K Haskell, W Snell, P O'Toole, M Ribisl, P Vaitkevicius, P Spurgeon, HA Lakatta, EG Pullen, P AF Havlik, RJ Phillips, CL Brock, DB Lohman, K Haskell, W Snell, P O'Toole, M Ribisl, P Vaitkevicius, P Spurgeon, HA Lakatta, EG Pullen, P TI Walking may be related to less vascular stiffness in the Activity Counseling Trial (ACT) SO AMERICAN HEART JOURNAL LA English DT Article ID CARDIOVASCULAR-DISEASE ENTERPRISES; ARTERIAL COMPLIANCE; PHYSICAL-ACTIVITY; INDEPENDENT PREDICTOR; HYPERTENSIVE PATIENTS; MAJOR SHAREHOLDERS; VIGOROUS EXERCISE; AORTIC STIFFNESS; PREVENTION; EVENTS AB Background The ACT was a clinical trial of-various patient education and counseling interventions to increase physical activity in sedentary primary care populations. It provided the opportunity to measure the effect of increasing physical activity on aortic pulse wave velocity (APWV), a measure of vascular stiffness, in a relatively healthy middle-aged population. The effects of the interventions, as well as the impact of walking and correlates such as older age and maximal oxygen uptake ((V)over dot O(2)max), on APWV were assessed. Methods The participants in this study were a subset of the 874 persons recruited for the ACT. Information about self-reported physical activity and disease status was collected at baseline (464 persons), 6-month (528 persons), and 24-month (555 persons) intervals. Physiological measures included APWV, systolic blood pressure, and other correlates. Results In multivariate analyses, the various treatment arms did not have a significant effect on APWV. However, walking in hours per day was associated with slower APWV times or less stiffness (P = .03). This was significant for women and consistent but not significant for men. In addition, age, clinic site, race, systolic blood pressure, and (V)over dot O(2)max were independently associated with APWV. Conclusions Increased walking frequency over a 24-month period was predictive of reduced vascular stiffness in ACT. The more significant result for walking frequency in women than in men might be caused by the presence of a low (V)over dot O(2)max Or. physical activity threshold for an effect of walking on APWV, which most women achieved but most men had surpassed at the start of the study. Although needing confirmation because this was a secondary analysis, modest physical activity may. have a beneficial effect on large vessel structure. C1 NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. WESTAT Corp, Rockville, MD 20850 USA. Wake Forest Univ, Bowman Gray Sch Med, ACT Coordinating Ctr, Winston Salem, NC USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Univ Texas, SW Med Ctr Dallas, Cooper Inst Aerob Res, Dallas, TX 75235 USA. St Louis Univ, Sch Med, St Louis, MO USA. Univ Michigan, Dept Vet Affairs, Ann Arbor, MI 48109 USA. NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. Univ Tennessee, Sch Med, Memphis, TN USA. Johns Hopkins Sch Med, Dept Geriatr, Baltimore, MD USA. RP Phillips, CL (reprint author), NIA, Lab Epidemiol Demog & Biometry, Gateway Bldg,Suite 3C309,7201 Wisconsin Ave, Bethesda, MD 20892 USA. EM phillipc@gw.nia.nih.gov FU NHLBI NIH HHS [N01-HC-45136, N01-HC-45137, N01-HC-45135, N01-HC-45138] NR 21 TC 9 Z9 10 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD AUG PY 2005 VL 150 IS 2 BP 270 EP 275 DI 10.1016/j.ahj.2004.09.006 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 969YW UT WOS:000232273100014 PM 16086929 ER PT J AU McDermott, MM Guralnik, JM Corsi, A Albay, M Macchi, C Bandinelli, S Ferrucci, L AF McDermott, MM Guralnik, JM Corsi, A Albay, M Macchi, C Bandinelli, S Ferrucci, L TI Patterns of inflammation associated with peripheral arterial disease: The InCHIANTI study SO AMERICAN HEART JOURNAL LA English DT Article ID C-REACTIVE PROTEIN; UNSTABLE ANGINA; PHYSICAL-ACTIVITY; ATHEROSCLEROSIS; POPULATION; FIBRINOGEN; RUPTURE; MARKERS; WALKING; HEALTH AB Objective To determine whether peripheral arterial disease is associated with high circulating levels of pro-inflammatory cytokines, independent of confounders. Methods Participants were 955 men and women aged 60 years and older representative of the population in 2 Italian communities (107 with peripheral arterial disease). Measurements included the ankle brachial index, comorbidities, total cholesterol and high-density lipoprotein cholesterol (HDL-C) levels, and these inflammatory factors: albumin, alpha-2 macroglobulin, C-reactive protein, fibrinogen, interleukin (IL)-1 beta, IL-1 receptor antagonist, IL-6, IL-6 receptor, IL-1 0, IL-1 8, tumor necrosis factor a, and transforming growth factor beta. Results Adjusting for age, sex, body mass index, smoking, comorbidifies, HDL-C, and total cholesterol participants with peripheral arterial disease had higher levels of IL-1 receptor antagonist (147.97 vs 131.24 pg/mL, P = .002), IL-6 (1.65 vs 1.37 pg/mL, P = .026), fibrinogen (362.49 vs 345.50 mg/dL, P = .039), and C-reactive protein (3.18 vs 2.56 mg/dL, P = .043) compared with those without peripheral arterial disease. These associations were attenuated after additional adjustment for physical activity. Conclusion In a community population, peripheral arterial disease is associated with increased circulating levels of IL-6, IL-1 receptor antagonist, fibrinogen, and C-reactive protein compared to persons without peripheral arterial disease. Further study is needed to determine whether reducing levels of certain inflammatory factors lowers the incidence and progression of peripheral arterial disease. C1 Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. IRCCS, INRCA, Dept Geriatr, Lab Clin Epidemiol, Florence, Italy. NIA, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA. RP McDermott, MM (reprint author), 675 N St Clair,Suite 18-200, Chicago, IL 60611 USA. EM mdm608@northwestern.edu NR 28 TC 59 Z9 62 U1 1 U2 3 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD AUG PY 2005 VL 150 IS 2 BP 276 EP 281 DI 10.1016/j.ahj.2004.09.032 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 969YW UT WOS:000232273100015 PM 16086930 ER PT J AU Gori, AM Corsi, AM Fedi, S Gazzini, A Sofi, F Bartali, B Bandinelli, S Gensini, GF Abbate, R Ferrucci, L AF Gori, AM Corsi, AM Fedi, S Gazzini, A Sofi, F Bartali, B Bandinelli, S Gensini, GF Abbate, R Ferrucci, L TI A proinflammatory state is associated with hyperhomocysteinemia in the elderly SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE homocysteine; inflammation; cytokines; macronutrients; micronutrients; vitamin concentrations; InCHIANTI Study ID C-REACTIVE PROTEIN; ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY-DISEASE; APPARENTLY HEALTHY-MEN; CARDIOVASCULAR-DISEASE; ACUTE-PHASE; PLASMA HOMOCYSTEINE; RISK; HOMOCYST(E)INE; INFLAMMATION AB Background: The mechanism by which high circulating homocysteine concentrations are a risk factor for atherothrombosis is incompletely understood. A proinflammatory state is related to atherosclerosis, and recent studies suggest that acute phase reactants correlate with circulating concentrations of homocysteine. Objective: We determined whether high concentrations of inflammatory markers are associated with hyperhomocysteinemia independently of dietary vitamin intakes, vitamin concentrations, and cardiovascular disease risk factors in a large, representative sample of the general population. Design: Five hundred eighty-six men and 734 women were randomly selected from the inhabitants of 2 small towns near Florence, Italy. Results: After adjustment for multiple potential confounders, interleukin I receptor antagonist (IL-Ira) and interleukin 6 (IL-6) concentrations were significantly (P < 0.001) associated with plasma homocysteine concentrations in older (> 65 y) populations. Compared with participants in the lowest IL-6 tertile, those in the highest tertile had a higher risk of having homocysteine concentrations that were high (> 30 mu mol/L; odds ratio: 2.6; 95% Cl: 1.1, 5.6; P = 0.024) or in the intermediate range 15-30 mu mol/L (odds ratio: 1.6; 95% Cl: 1.2, 2.2; P = 0.0014). Sedentary state, intakes of vitamin B-6 and folic acid, and serum folate, vitamin B-12, vitamin B-6, and a-tocopherol concentrations were significant independent correlates of homocysteine. Conclusions: High circulating concentrations of IL-Ira and IL-6 are independent correlates of hyperhomocysteinemia and may explain, at least in part, the association between homocysteine and atherosclerosis. C1 Univ Florence, Ctr Study Mol & Clin Level Chron Degenerat & Neop, Dept Med, Cardiol Sect, I-50134 Florence, Italy. Univ Florence, Surg Crit Area, Cardiol Sect, I-50134 Florence, Italy. Univ Florence, Ctr Study Mol & Clin Level Chron Degenerat & Neop, Surg Crit Area, I-50134 Florence, Italy. Natl Inst Res & Care Aging, Dept Geriatr, Lab Clin Epidemiol, Florence, Italy. Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. NIA, Longitudinal Studies Sect, NIH, Baltimore, MD 21224 USA. RP Gori, AM (reprint author), Univ Florence, Ctr Study Mol & Clin Level Chron Degenerat & Neop, Dept Med, Cardiol Sect, Viale Morgagni 85, I-50134 Florence, Italy. EM am.gori@dac.unifi.it OI Gori, annamaria.gori@unifi.it/0000-0001-6857-5861 NR 45 TC 56 Z9 58 U1 1 U2 4 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG PY 2005 VL 82 IS 2 BP 335 EP 341 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 956IJ UT WOS:000231293100010 PM 16087976 ER PT J AU Li, HX Zhang, LR Lou, H Ding, I Kim, S Wang, LP Huang, JT Sant'Agnese, PA Lei, JY AF Li, HX Zhang, LR Lou, H Ding, I Kim, S Wang, LP Huang, JT Sant'Agnese, PA Lei, JY TI Overexpression of decoy receptor 3 in precancerous lesions and adenocarcinoma of the esophagus SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE decoy receptor 3; Barrett esophagus; esophageal cancer; immunohistochemistry ID BARRETTS METAPLASIA; GENE AMPLIFICATION; CANCER-CELLS; FAS LIGAND; EXPRESSION; APOPTOSIS; CARCINOGENESIS; DYSPLASIA; PROTEINS; SEQUENCE AB Overexpression of decoy receptor (DcR) 3 protein, a recently discovered member of the tumor necrosis factor receptor superfamily, was examined in 40 esophagogastrectomy specimens containing areas of Barrett esophagus (n = 27), low-grade dysplasia (n = 27), high-grade dysplasia or carcinoma in situ (n = 22), and esophageal adenocarcinoina (EAC; n = 28) with immunohistochemical analysis. The results revealed significantly, more overexpression of DcR3 in high-grade dysplasia or carcinoma in situ and EAC than in benign esophageal mucosa (both P < .0001), Barrett esophagus (both P < .001), and low-grade dysplasia (P < .01 and P = .033, respectively). Low-grade dysplasia also showed significant overexpression of DcR3 compared with benign esophagus (P < .05) but not with Barrett esophagus (P > .05). DcR3 overexpression seems to negatively correlate with the grade of EAC Our results suggest that overexpression of DcR3 protein might aid in the diagnosis of high-grade dysplasia or carcinoma in situ and EAC and also might serve as a potential therapeutic target. C1 Zhengzhou Univ, Sch Med, Dept Pathol, Henan, Peoples R China. Univ Rochester, Dept Pathol & Radiat Oncol, Rochester, NY USA. NIH, Bethesda, MD USA. RP Lei, JY (reprint author), 715 Mamaroneck Ave, Mamaroneck, NY 10543 USA. NR 22 TC 25 Z9 37 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD AUG PY 2005 VL 124 IS 2 BP 282 EP 287 DI 10.1309/XK594E4B5WU82QR6 PG 6 WC Pathology SC Pathology GA 949FK UT WOS:000230770200016 PM 16040301 ER PT J AU Weinberg, CR AF Weinberg, CR TI Re: "Why evidence for the fetal origins of adult disease might be a statistical artifact: The 'reversal paradox' for the relation between birth weight and blood pressure in later life" - Reply SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 NIEHS, Environm Dis & Med Program, Res Triangle Pk, NC 27709 USA. RP Weinberg, CR (reprint author), NIEHS, Environm Dis & Med Program, POB 12233, Res Triangle Pk, NC 27709 USA. NR 3 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2005 VL 162 IS 3 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 948NZ UT WOS:000230724300012 ER PT J AU Panza, F D'Introno, A Colacicco, AM Capurso, C Del Parigi, A Caselli, RJ Pilotto, A Argentieri, G Scapicchio, PL Scafato, E Capurso, A Solfrizzi, V AF Panza, F D'Introno, A Colacicco, AM Capurso, C Del Parigi, A Caselli, RJ Pilotto, A Argentieri, G Scapicchio, PL Scafato, E Capurso, A Solfrizzi, V TI Current epidemiology of mild cognitive impairment and other predementia syndromes SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article ID VASCULAR RISK-FACTORS; PROBABLE ALZHEIMERS-DISEASE; 3-YEAR FOLLOW-UP; MEMORY IMPAIRMENT; SENESCENT FORGETFULNESS; ELDERLY POPULATION; SEVERE DEMENTIA; PREVALENCE; COMMUNITY; CRITERIA AB A variety of clinically-defined predementia syndromes, with differing diagnostic criteria and nomenclature, have been proposed to describe nondisabling symptomatic cognitive deficits arising in elderly persons. Incidence and prevalence of different predementia syndromes vary as a result of different diagnostic criteria, sampling, and assessment procedures. The incidence rates of all predementia syndromes increase with age and are higher in subjects with less education; but age, educational background, and gender are not consistently related to prevalence rates. There is particular interest in "Mild Cognitive Impairment (MCI)" because this predementia syndrome is thought to be a prodromal phase of Alzheimer disease ( AD). Several studies have suggested that most patients who meet MCI criteria will progress to AD, but rates of conversion to AD and dementia vary widely among studies. Furthermore, MCI definition is less consistent in population-based studies than clinical studies, in which progression to AD is also more consistent. To clarify the sources of discrepant findings in the literature, this review summarizes existing epidemiological studies of the defined clinical predementia syndromes and their progression to dementia. C1 Univ Bari, Ctr Aging Brain, Memory Unit, Dept Geriatr, I-70124 Bari, Italy. Univ Foggia, Dept Geriatr, Foggia, Italy. NIDDKD, NIH, Phoenix, AZ 85016 USA. Mayo Clin, Dept Neurol, Scottsdale, AZ USA. IRCCS, Dept Geriatr, Foggia, Italy. Univ Sacred Heart, I-00168 Rome, Italy. Ist Super Sanita, Natl Ctr Epidemiol Surveillance & Hlth Promot, I-00161 Rome, Italy. RP Panza, F (reprint author), Univ Bari, Ctr Aging Brain, Memory Unit, Dept Geriatr, Piazza Giulio Cesare,11, I-70124 Bari, Italy. EM geriat.dot@geriatria.uniba.it OI Capurso, Cristiano/0000-0002-1152-3371; Panza, Francesco/0000-0002-7220-0656 NR 81 TC 147 Z9 160 U1 1 U2 9 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD AUG PY 2005 VL 13 IS 8 BP 633 EP 644 DI 10.1176/appi.ajgp.13.8.633 PG 12 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 952QN UT WOS:000231020700002 PM 16085779 ER PT J AU Fogarty, PF Stetler-Stevenson, M Pereira, A Dunbar, CE AF Fogarty, PF Stetler-Stevenson, M Pereira, A Dunbar, CE TI Large granular lymphocytic proliferation-associated cyclic thrombocytopenia SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article DE cyclic thrombocytopenia; large granular lymphocyte; platelets ID PURPURA; PATIENT AB Cyclic thrombocytopenia is a rare condition characterized by regular fluctuations in the platelet count, resulting in bleeding at the time of platelet count nadir. We evaluated a male patient whose platelet count cycled between < 10 x 10(9)/L and a maximum of > 1300 x 10(9)/L over a median of every 42 days (range, 28-57 days). Antiplatelet antibodies were present at highest titer just prior to platelet nadirs. A pathologic expansion of CD3(+)CD57(+) large granular lymphocytes (LGLs) along with a clonal rearrangement of the T-cell receptor (TCR) gamma gene in circulating T cells was detected. LGLs decreased in response to treatment with cyclosporine-A (CsA), but the cycling of the platelet count continued. This is the first report of cyclic thrombocytopenia associated with a T-LGL lymphoproliferative disorder. C1 NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. Kaiser Permanente Oncol, Fair Oaks, VA USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Fogarty, PF (reprint author), Univ Calif San Francisco, 505 Parnassus Ave,Box 1270, San Francisco, CA 94143 USA. EM pfogarty@medicine.ucsf.edu NR 8 TC 12 Z9 13 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD AUG PY 2005 VL 79 IS 4 BP 334 EP 336 DI 10.1002/ajh.20375 PG 3 WC Hematology SC Hematology GA 951TE UT WOS:000230953100019 PM 16044437 ER PT J AU Xu, JF Dimitrov, L Chang, BL Adams, TS Turner, AR Meyers, DA Eeles, RA Easton, DF Foulkes, WD Simard, J Giles, GG Hopper, JL Mahle, L Moller, P Bishop, T Evans, C Edwards, S Meitz, J Bullock, S Hope, Q Hsieh, CL Halpern, J Balise, RN Oakley-Girvan, I Whittemore, AS Ewing, CM Gielzak, M Isaacs, SD Walsh, PC Wiley, KE Isaacs, WB Thibodeau, SN McDonnell, SK Cunningham, JM Zarfas, KE Hebbring, S Schaid, DJ Friedrichsen, DM Deutsch, K Kolb, S Badzioch, M Jarvik, GP Janer, M Hood, L Ostrander, EA Stanford, JL Lange, EM Beebe-Dimmer, JL Mohai, CE Cooney, KA Ikonen, T Baffoe-Bonnie, A Fredriksson, H Matikainen, MP Tammela, TLJ Bailey-Wilson, J Schleutker, J Maier, C Herkommer, K Hoegel, JJ Vogel, W Paiss, T Wiklund, F Emanuelsson, M Stenman, E Jonsson, BA Gronberg, H Camp, NJ Farnham, J Cannon-Albright, LA Seminara, D AF Xu, JF Dimitrov, L Chang, BL Adams, TS Turner, AR Meyers, DA Eeles, RA Easton, DF Foulkes, WD Simard, J Giles, GG Hopper, JL Mahle, L Moller, P Bishop, T Evans, C Edwards, S Meitz, J Bullock, S Hope, Q Hsieh, CL Halpern, J Balise, RN Oakley-Girvan, I Whittemore, AS Ewing, CM Gielzak, M Isaacs, SD Walsh, PC Wiley, KE Isaacs, WB Thibodeau, SN McDonnell, SK Cunningham, JM Zarfas, KE Hebbring, S Schaid, DJ Friedrichsen, DM Deutsch, K Kolb, S Badzioch, M Jarvik, GP Janer, M Hood, L Ostrander, EA Stanford, JL Lange, EM Beebe-Dimmer, JL Mohai, CE Cooney, KA Ikonen, T Baffoe-Bonnie, A Fredriksson, H Matikainen, MP Tammela, TLJ Bailey-Wilson, J Schleutker, J Maier, C Herkommer, K Hoegel, JJ Vogel, W Paiss, T Wiklund, F Emanuelsson, M Stenman, E Jonsson, BA Gronberg, H Camp, NJ Farnham, J Cannon-Albright, LA Seminara, D CA ACTANE Consortium TI A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID WIDE SCAN; GERMLINE MUTATIONS; MODELS; SCREEN; BREAST; TESTS; LOCI; MAP AB Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric ( dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score > 1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of <= 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study. C1 Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. Mayo Clin, Rochester, MN 55905 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Tampere, FIN-33101 Tampere, Finland. Tampere Univ Hosp, FIN-33101 Tampere, Finland. Univ Ulm, D-89069 Ulm, Germany. Umea Univ, S-90187 Umea, Sweden. Univ Utah, Salt Lake City, UT 84112 USA. NCI, Bethesda, MD 20892 USA. RP Isaacs, WB (reprint author), Johns Hopkins Univ Hosp, Marburg 115,600 N Wolfe St, Baltimore, MD 21287 USA. EM wisaacs@jhmi.edu RI Jarvik, Gail/N-6476-2014; Meitz-Hopkins, Julia/M-3938-2016; OI Jarvik, Gail/0000-0002-6710-8708; Meitz-Hopkins, Julia/0000-0002-8127-6978; Ostrander, Elaine/0000-0001-6075-9738; Bailey-Wilson, Joan/0000-0002-9153-2920; Farnham, James/0000-0002-8213-949X; Bishop, Tim/0000-0002-8752-8785; albright, lisa/0000-0003-2602-3668; Giles, Graham/0000-0003-4946-9099 FU NCI NIH HHS [CA079596, CA080122, CA106523-01A1, CA58236, CA67044, CA72818, CA78835, CA89600, CA95052-01, K07 CA098364, K07 CA98364, N01-PC-35141, N01PC35141, P50 CA058236, R01 CA067044, R01 CA072818, R01 CA079596, R01 CA080122, R01 CA090752, R01 CA095052, R01 CA106523, R01 CA89600, R01 CA90752, T32 CA080416, U01 CA067044, U01 CA089600]; NCRR NIH HHS [M01 RR000064, M01-RR00064]; NHGRI NIH HHS [N01HG65403] NR 32 TC 98 Z9 102 U1 1 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG PY 2005 VL 77 IS 2 BP 219 EP 229 DI 10.1086/432377 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 943WW UT WOS:000230387200004 PM 15988677 ER PT J AU Farina, A LeShane, ES Romero, R Gomez, R Chaiworapongsa, T Rizzo, N Bianchi, DW AF Farina, A LeShane, ES Romero, R Gomez, R Chaiworapongsa, T Rizzo, N Bianchi, DW TI High levels of fetal cell-free DNA in maternal serum: A risk factor for spontaneous preterm delivery SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE fetal cell-free DNA; cell trafficking; prematurity; premature labor ID PLASMA; LABOR; ORIGIN AB Objective: This study was conducted to determine whether there is a relationship between the concentration of fetal cell-free DNA in maternal serum and the duration of pregnancy in women who are at high risk for preterm delivery because of either preterm labor or preterm premature rupture of the membranes. Study design: Sera were collected and frozen from 71 women with a male fetus. Maternal serum fetal cell-free DNA concentration was measured with the use of real-time polymerase chain reaction amplification of DYS1. Fetal cell-free DNA concentrations were converted to multiples of the median. The following groups were studied: group 1: women with preterm labor and intact membranes who were delivered at >= 36 weeks of gestation (n = 21); group 2: women with preterm labor who were delivered at < 36 weeks of gestation (n = 29); and group 3: women with preterm premature rupture of the membranes in labor (n = 20) or not in labor (n = 1) who were delivered prematurely (< 36 weeks of gestation). Kaplan-Meier and Cox regression analyses were used to analyze the relationship between fetal cell-free DNA concentrations and the likelihood of preterm delivery. Results: A cut-off value for fetal cell-free DNA of 1.82 multiples of the median was chosen for analysis. The cumulative rate of early preterm delivery (< 30 weeks of gestation) was significantly higher for women with fetal cell-free DNA concentrations of >= 1.82 multiples of the median than those with fetal cell-free DNA concentrations below this cut-off (45% [95% Cl, 36%-74%] vs 18% [95% CI, 11%-25%]; P = .008]. The cumulative rate of preterm delivery (< 36 weeks of gestation) was also significantly higher at >= 1.82 multiples of the median (73% [95% Cl, 52%-93%] vs 66% [95% CI, 54%-79%]; P = .02). After adjustment for covariates. Cox analysis showed that fetal cell-free DNA at >= 1.82 multiples of the mechanisms of disease that are associated with a mean hazard rate of delivery of 1.57 (P = .005). Conclusion: High concentrations of fetal cell-free DNA in maternal serum are associated with an increased risk of spontaneous preterm delivery. This observation may have implications for the understanding of the mechanisms of disease that is associated with preterm labor. (c) 2005 Elsevier Inc. All rights reserved. C1 Tufts Univ, New England Med Ctr, Dept Pediat, Div Genet, Boston, MA 02111 USA. Tufts Univ, New England Med Ctr, Dept Obstet & Gynecol, Boston, MA 02111 USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. Univ Bologna, Dept Embryol Obstetr & Gynecol, Prenatal Med Unit, Bologna, Italy. NICHHD, Perinatol Res Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Bianchi, DW (reprint author), Tufts Univ, New England Med Ctr, Dept Pediat, Div Genet, 750 Washington St,Box 394, Boston, MA 02111 USA. EM Dbianchi@tufts-nemc.org OI Farina, Antonio/0000-0002-6862-1810 FU NICHD NIH HHS [HD43204] NR 11 TC 61 Z9 73 U1 0 U2 5 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD AUG PY 2005 VL 193 IS 2 BP 421 EP 425 DI 10.1016/j.ajog.2004.12.023 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 955RA UT WOS:000231243500017 PM 16098864 ER PT J AU Dai, CS Huh, CG Thorgeirsson, SS Liu, YH AF Dai, CS Huh, CG Thorgeirsson, SS Liu, YH TI beta-Cell-specific ablation of the hepatocyte growth factor receptor results in reduced islet size, impaired insulin secretion, and glucose intolerance SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID RENAL INTERSTITIAL FIBROSIS; INDUCED DIABETIC MICE; C-MET; FACTOR/SCATTER FACTOR; LIVER-REGENERATION; MOUSE ISLETS; MASS; HYPERGLYCEMIA; KNOCKOUT; OVEREXPRESSION AB Hepatocyte growth factor (HGF) and its c-met receptor consist of a paired signaling system that has been implicated in the regulation of pancreatic beta-cell survival, proliferation, and function. To define the role of HGF/c-met signaling in beta-cell biology in vivo, we have generated conditional knockout mice in which the c-met receptor gene was specifically inactivated in pancreatic 0 cells by the Cre-loxP system. Mice with)beta-cell-specific deletion of the c-met receptor (beta met(-/-)) displayed slight growth retardation, mild hyperglycemia, and decreased serum insulin levels at 6 months of age when compared with their control littermates. Deficiency of the c-met receptor in 0 cells resulted in a complete loss of acute-phase insulin secretion in response to glucose and an impaired glucose tolerance. Glucose transporter-2 expression was down-regulated in the beta cells of beta met(-/-) mice. Compared to controls, beta met(-/-) mice exhibited reduced islet size and decreased insulin content in the pancreas, but displayed normal islet morphology. Therefore, HGF/c-met signaling plays an imperative role in controlling islet growth, in regulating beta-cell function, and in maintaining glucose homeostasis. C1 Univ Pittsburgh, Dept Pathol, Sch Med, Pittsburgh, PA 15261 USA. Natl Canc Inst, Expt Carcinogenesis Lab, NIH, Bethesda, MD USA. Natl Canc Inst, Ctr Canc Res, NIH, Bethesda, MD USA. RP Liu, YH (reprint author), Univ Pittsburgh, Dept Pathol, Sch Med, S-405 Biomed Sci Tower,200 Longthrop St, Pittsburgh, PA 15261 USA. EM liuy@upmc.edu FU NIDDK NIH HHS [DK054922, DK061408, DK064005, R01 DK054922, R01 DK061408, R01 DK064005] NR 36 TC 37 Z9 42 U1 1 U2 4 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2005 VL 167 IS 2 BP 429 EP 436 DI 10.1016/S0002-9440(10)62987-2 PG 8 WC Pathology SC Pathology GA 951GN UT WOS:000230917600014 PM 16049329 ER PT J AU Kumar-Singh, S Pirici, D McGowan, E Serneels, S Ceuterick, C Hardy, J Duff, K Dickson, D Van Broeckhoven, C AF Kumar-Singh, S Pirici, D McGowan, E Serneels, S Ceuterick, C Hardy, J Duff, K Dickson, D Van Broeckhoven, C TI Dense-core plaques in Tg2576 and PSAPP mouse models of Alzheimer's disease are centered on vessel walls SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID AMYLOID-PRECURSOR-PROTEIN; BLOOD-BRAIN-BARRIER; TRANSGENIC MICE; SENILE PLAQUES; BETA-PROTEIN; A-BETA; PRESENILIN-1 TRANSGENES; MUTANT PRESENILIN-1; BASEMENT-MEMBRANE; ANGIOPATHY AB Occurrence of amyloid 13 (A beta) dense-core plaques in the brain is one of the chief hallmarks of Alzheimer's disease (AD). It is not yet clear what factors are responsible for the aggregation of A beta in the formation of these plaques. Using Tg2576 and PSAPP mouse models that exhibit age-related development of amyloid plaques similar to that observed in AD, we showed that approximate to 95% of dense plaques in Tg2576 and approximate to 85% in PSAPP mice are centered on vessel walls or in the immediate perivascular regions. Stereoscopy and simulation studies focusing on smaller plaques suggested that vascular associations for both Tg2576 and PSAPP mice were dramatically higher than those encountered by chance alone. We further identified ultrastructural microvascular abnormalities occurring in association with dense plaques. Although occurrence of gross cerebral hemorrhage was infrequent, we identified considerable infiltration of the serum proteins immunoglobulin and albumin in association with dense plaques. Together with earlier evidence of vascular clearance of A beta, our data suggest that perturbed vascular transport and/or perivascular enrichment of A beta leads to the formation of vasocentric dense plaques in Tg2576 and PSAPP mouse models of AD. C1 Univ Antwerp VIB, Dept Mol Genet, Neurodegenerat Brain Dis Res Grp, Mol Neuropathol Project, B-2610 Antwerp, Belgium. Inst Born Bunge, Electron Microscopy Lab, Antwerp, Belgium. Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. Mayo Clin, Dept Pathol, Jacksonville, FL 32224 USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Nathan S Kline Inst Psychiat Res, Ctr Dementia Res, Orangeburg, NY 10962 USA. RP Kumar-Singh, S (reprint author), Univ Antwerp VIB, Dept Mol Genet, Neurodegenerat Brain Dis Res Grp, Mol Neuropathol Project, Univ Pl 1, B-2610 Antwerp, Belgium. EM samir.kumarsingh@ua.ac.be RI Pirici, Daniel/C-5760-2012; Hardy, John/C-2451-2009; Kumar-Singh, Samir/G-6280-2012; Kumar, Shaji/A-9853-2008; OI Kumar-Singh, Samir/0000-0001-9466-6732; Kumar, Shaji/0000-0001-5392-9284; Dickson, Dennis W/0000-0001-7189-7917 NR 61 TC 117 Z9 118 U1 0 U2 8 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2005 VL 167 IS 2 BP 527 EP 543 DI 10.1016/S0002-9440(10)62995-1 PG 17 WC Pathology SC Pathology GA 951GN UT WOS:000230917600022 PM 16049337 ER PT J AU Sun, Y Strizzi, L Raafat, A Hirota, M Bianco, C Feigenbaum, L Kenney, N Wechselberger, C Callahan, R Salomon, DS AF Sun, Y Strizzi, L Raafat, A Hirota, M Bianco, C Feigenbaum, L Kenney, N Wechselberger, C Callahan, R Salomon, DS TI Overexpression of human Cripto-1 in transgenic mice delays mammary gland development and differentiation and induces mammary tumorigenesis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID EPITHELIAL-CELLS; GROWTH-FACTOR; VERTEBRATE DEVELOPMENT; TUMOR PROGRESSION; GENE-EXPRESSION; AMPHIREGULIN; ACTIVATION; PATHWAY; TRANSFORMATION; INVOLUTION AB Overexpression of Cripto-1 has been reported in several types of human cancers including breast cancer. To investigate the role of human Cripto-1 (CR-1) in mammary gland development and tumorigenesis, we developed transgenic mice that express the human CR-1 transgene under the regulation of the whey acidic protein (WAP) promoter in the FVB/N mouse background. The CR-1 transgene was detected in the mammary gland of 15-week-old virgin WAP-CR-1 female mice that eventually developed hyperplastic lesions. From mid-pregnancy to early lactation, mammary lobulo-alveolar structures in WAP-CR-1 mice were less differentiated and delayed in their development due to decreased cell proliferation as compared to FVB/N mice. Early involution, due to increased apoptosis, was observed in the mammary glands of WAP-CR-1 mice. Higher levels of phosphorylated AKT and MAPK were detected in mammary glands of multiparous WAP-CR-1 mice as compared to multiparous FVB/N mice suggesting increased cell proliferation and survival of the transgenic mammary gland. in addition, more than half (15 of 29) of the WAP-CR-1 multiparous female mice developed multifocal mammary tumors of mixed histological subtypes. These results demonstrate that overexpression of CR-1 during pregnancy and lactation can lead to alterations in mammary gland development and to production of mammary tumors in multiparous mice. C1 NCI, Tumor Growth Factor Sect, Mammary Biol & Tumorigenesis Lab, Bethesda, MD 20892 USA. NCI, Oncogenet Sect, Mammary Biol & Tumorigenesis Lab, Bethesda, MD 20892 USA. SAIC Inc, Lab Anim Sci Program, Frederick, MD USA. Upper Austrian Res GmbH Linz, Linz, Austria. RP Salomon, DS (reprint author), NCI, Tumor Growth Factor Sect, Mammary Biol & Tumorigenesis Lab, 10 Ctr Dr,Bldg 37,Room 1106, Bethesda, MD 20892 USA. EM salomond@mail.nih.gov NR 49 TC 38 Z9 40 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2005 VL 167 IS 2 BP 585 EP 597 DI 10.1016/S0002-9440(10)63000-3 PG 13 WC Pathology SC Pathology GA 951GN UT WOS:000230917600027 PM 16049342 ER PT J AU Scuteri, A Najjar, SS Muller, D Andres, R Morrell, CH Zonderman, AB Lakatta, EG AF Scuteri, A Najjar, SS Muller, D Andres, R Morrell, CH Zonderman, AB Lakatta, EG TI ApoE4 allele and the natural history of cardiovascular risk factors SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE apolipoprotein E4; genetics of vascular disorders; population studies; longitudinal studies; risk factors; glucose ID APOLIPOPROTEIN-E POLYMORPHISM; CORONARY-HEART-DISEASE; ISLET AMYLOID POLYPEPTIDE; E-DEFICIENT MICE; DIABETES-MELLITUS; E GENOTYPE; E GENE; ATHEROSCLEROSIS; MEN; POPULATION AB The aims of the present study were to compare the longitudinal changes in traditional cardiovascular (CV) risk factors (blood pressure, BMI, total and HDL-cholesterol, triglycerides, and blood glucose) in men with and without the apolipoprotein (apo)E4 allele. Three hundred six men from the Baltimore Longitudinal Study of Aging, ranging in age from 20 to 92 yr, were studied. Repeated measurements of CV risk factors were performed over a median follow-up time of 7 yr (maximum 14.3 yr) for men. Longitudinal changes in these CV risk factors were analyzed by linear mixed-effects models. The prevalence of the apoE4 allele was 25.5%. apoE4 was independently associated with accelerated changes over time in fasting plasma glucose (+9.5% vs. no change in those without apoE4 in the 6th age-decade over 10 yr). No significant effect of apoE4 on longitudinal changes in total or HDL-cholesterol, triglycerides, or blood pressures was observed. In conclusion, apoE4 influences fasting plasma glucose and its changes over time. This could explain, in part, the increased CV risk associated with the apoE4 genotype observed in men. C1 NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. NIA, Clin Res Branch, NIH, Baltimore, MD 21224 USA. NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. Ist Nazl Ricovero & Cura Anziani, Unita Operat Geriatria, Rome, Italy. Loyola Coll, Baltimore, MD 21210 USA. RP Scuteri, A (reprint author), NIA, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Scuterian@mail.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 NR 42 TC 23 Z9 23 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD AUG PY 2005 VL 289 IS 2 BP E322 EP E327 DI 10.1152/ajpendo.00408.2004 PG 6 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 945CA UT WOS:000230477700020 PM 15769795 ER PT J AU Pacher, P Batkai, S Osei-Hyiaman, D Offertaler, L Liu, J Harvey-White, J Brassai, A Jarai, Z Cravatt, BF Kunos, G AF Pacher, P Batkai, S Osei-Hyiaman, D Offertaler, L Liu, J Harvey-White, J Brassai, A Jarai, Z Cravatt, BF Kunos, G TI Hemodynamic profile, responsiveness to anandamide, and baroreflex sensitivity of mice lacking fatty acid amide hydrolase SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE contractility; hypertension; cannabinoids; endocannabinoids ID CB1 CANNABINOID RECEPTORS; MOLECULAR CHARACTERIZATION; ENDOGENOUS CANNABINOIDS; ENDOCANNABINOID SYSTEM; INDUCED HYPOTENSION; HYPERTENSIVE-RATS; BRAIN; HYDROLYSIS; ANTAGONIST; ENZYME AB The endocannabinoid anandamide exerts neurobehavioral, cardiovascular, and immune-regulatory effects through cannabinoid receptors ( CB). Fatty acid amide hydrolase ( FAAH) is an enzyme responsible for the in vivo degradation of anandamide. Recent experimental studies have suggested that targeting the endocannabinergic system by FAAH inhibitors is a promising novel approach for the treatment of anxiety, inflammation, and hypertension. In this study, we compared the cardiac performance of FAAH knockout (FAAH(-/-)) mice and their wild-type (FAAH(+/+)) littermates and analyzed the hemodynamic effects of anandamide using the Millar pressure-volume conductance catheter system. Baseline cardiovascular parameters, systolic and diastolic function at different preloads, and baroreflex sensitivity were similar in FAAH(-/-) and FAAH(+/+) mice. FAAH(-/-) mice displayed increased sensitivity to anandamide-induced, CB1-mediated hypotension and decreased cardiac contractility compared with FAAH(+/+) littermates. In contrast, the hypotensive potency of synthetic CB1 agonist HU-210 and the level of expression of myocardial CB1 were similar in the two strains. The myocardial levels of anandamide and oleoylethanolamide, but not 2-arachidonylglycerol, were increased in FAAH(+/+) mice compared with FAAH(+/+) mice. These results indicate that mice lacking FAAH have a normal hemodynamic profile, and their increased responsiveness to anandamide-induced hypotension and cardiodepression is due to the decreased degradation of anandamide rather than an increase in target organ sensitivity to CB1 agonists. C1 NIAAA, NIH, Lab Physiol Studies, Bethesda, MD 20892 USA. Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA USA. Scripps Res Inst, Dept Cell Biol, La Jolla, CA USA. RP Pacher, P (reprint author), NIAAA, NIH, Lab Physiol Studies, 5625 Fishers Lane MSC 9413,Rm 2S24, Bethesda, MD 20892 USA. EM pacher@mail.nih.gov; gkunos@mail.nih.gov RI Batkai, Sandor/G-3889-2010; Pacher, Pal/B-6378-2008; Batkai, Sandor/H-7983-2014 OI Pacher, Pal/0000-0001-7036-8108; FU Intramural NIH HHS [Z01 AA000375-02] NR 47 TC 55 Z9 57 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD AUG PY 2005 VL 289 IS 2 BP H533 EP H541 DI 10.1152/ajpheart.00107.2005 PG 9 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 944VO UT WOS:000230458800007 PM 15821037 ER PT J AU Potenza, MA Marasciulo, FL Chieppa, DM Brigiani, GS Formoso, G Quon, MJ Montagnani, M AF Potenza, MA Marasciulo, FL Chieppa, DM Brigiani, GS Formoso, G Quon, MJ Montagnani, M TI Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE hypertension; endothelin-1; nitric oxide ID INTESTINAL BLOOD-FLOW; NITRIC-OXIDE; SIGNALING PATHWAYS; VASCULAR-TONE; STIMULATED PRODUCTION; MESENTERIC-ARTERIES; GROWTH-FACTOR; K+ CHANNELS; CELLS; MUSCLE AB Insulin stimulates production of NO in vascular endothelium via activation of phosphatidylinositol (PI)3-kinase, Akt, and endothelial NO synthase. We hypothesized that insulin resistance may cause imbalance between endothelial vasodilators and vasoconstrictors (e.g., NO and ET-1), leading to hypertension. Twelve-week-old male spontaneously hypertensive rats (SHR) were hypertensive and insulin resistant compared with control Wistar-Kyoto (WKY) rats (systolic blood pressure 202 +/- 11 vs. 132 +/- 10 mmHg; fasting plasma insulin 5 +/- 1 vs. 0.9 +/- 0.1 ng/ml; P<0.001). In WKY rats, insulin stimulated dose-dependent relaxation of mesenteric arteries precontracted with norepinephrine (NE) ex vivo. This depended on intact endothelium and was blocked by genistein, wortmannin, or N-omega-nitro-L-arginine methyl ester (inhibitors of tyrosine kinase, PI3-kinase, and NO synthases, respectively). Vasodilation in response to insulin (but not ACh) was impaired by 20% in SHR (vs. WKY, P<0.005). Preincubation of arteries with insulin significantly reduced the contractile effect of NE by 20% in WKY but not SHR rats. In SHR, the effect of insulin to reduce NE-mediated vasoconstriction became evident when insulin pretreatment was accompanied by ET-1 receptor blockade (BQ-123, BQ-788). Similar results were observed during treatment with the MEK inhibitor PD-98059. In addition, insulin-stimulated secretion of ET-1 from primary endothelial cells was significantly reduced by pretreatment of cells with PD-98059 (but not wortmannin). We conclude that insulin resistance in SHR is accompanied by endothelial dysfunction in mesenteric vessels with impaired PI3-kinase-dependent NO production and enhanced MAPK-dependent ET-1 secretion. These results may reflect pathophysiology in other vascular beds that directly contribute to elevated peripheral vascular resistance and hypertension. C1 Univ Bari, Sch Med, Policlin, Dept Pharmacol & Human Physiol,Sect Pharmacol, I-70124 Bari, Italy. NIH, Diabet Unit, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Montagnani, M (reprint author), Univ Bari, Sch Med, Policlin, Dept Pharmacol & Human Physiol,Sect Pharmacol, Piazza G Cesare 11, I-70124 Bari, Italy. EM monica@farmacol.uniba.it RI Quon, Michael/B-1970-2008; OI Potenza, Maria Assunta/0000-0002-9995-1468; Quon, Michael/0000-0002-9601-9915; montagnani, monica/0000-0002-5697-8185; Quon , Michael /0000-0002-5289-3707 NR 61 TC 164 Z9 175 U1 1 U2 10 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD AUG PY 2005 VL 289 IS 2 BP H813 EP H822 DI 10.1152/ajpheart.00092.2005 PG 10 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 944VO UT WOS:000230458800041 PM 15792994 ER PT J AU Levine, SJ Adamik, B Hawari, FI Islam, A Yu, ZX Liao, DW Zhang, J Cui, XL Rouhani, FN AF Levine, SJ Adamik, B Hawari, FI Islam, A Yu, ZX Liao, DW Zhang, J Cui, XL Rouhani, FN TI Proteasome inhibition induces TNFR1 shedding from human airway epithelial (NCI-H292) cells SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE soluble tumor necrosis factor receptors; vesicular trafficking ID TUMOR-NECROSIS-FACTOR; FACTOR-BINDING-PROTEIN; ACUTE LUNG INJURY; FACTOR RECEPTORS; HUMAN-URINE; LACTACYSTIN; APOPTOSIS; SURFACE; DEGRADATION; ACTIVATION AB The type 1 55-kDa TNF receptor (TNFR1) is an important modulator of lung inflammation. Here, we hypothesized that the proteasome might regulate TNFR1 shedding from human airway epithelial cells. Treatment of NCI-H292 human airway epithelial cells for 2 h with the specific proteasome inhibitor clasto-lactacystin beta-lactone induced the shedding of proteolytically cleaved TNFR1 ectodomains. Clasto-lactacystin beta-lactone also induced soluble TNFR1 (sTNFR1) release from the A549 pulmonary epithelial cell line, as well as from primary cultures of human small airway epithelial cells and human umbilical vein endothelial cells. Furthermore, sTNFR1 release induced by clasto-lactacystin beta-lactone was not a consequence of apoptosis or the extracellular release of TNFR1 exosome-like vesicles. The clasto-lactacystin beta-lactone-induced increase in TNFR1 shedding was associated with reductions in cell surface receptors and intracytoplasmic TNFR1 stores that were primarily localized to vesicular structures. As expected, the broad-spectrum zinc metalloprotease inhibitor TNF-alpha protease inhibitor 2 (TAPI-2) attenuated clasto-lactacystin beta-lactone-mediated TNFR1 shedding, which is consistent with its ability to inhibit the zinc metalloprotease-catalyzed cleavage of TNFR1 ectodomains. TAPI-2 also reduced TNFR1 on the cell surface and attenuated the clasto-lactacystin beta-lactone-induced reduction of intracytoplasmic TNFR1 vesicles. This suggests that TNFR1 shedding induced by clasto-lactacystin beta-lactone involves the zinc metalloprotease-dependent trafficking of intracytoplasmic TNFR1 vesicles to the cell surface. Together, these data are consistent with the conclusion that proteasomal activity negatively regulates TNFR1 shedding from human airway epithelial cells, thus identifying previously unrecognized roles for the proteasome and zinc metalloproteases in modulating the generation of sTNFRs. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Pathol Core Facil, NIH, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,Rm 6D03,MSC 1590, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov NR 46 TC 13 Z9 13 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD AUG PY 2005 VL 289 IS 2 BP L233 EP L243 DI 10.1152/ajplung.00469.2004 PG 11 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 943BY UT WOS:000230328000009 PM 15821012 ER PT J AU Savov, JD Brass, DM Lawson, BL McElvania-Tekippe, E Walker, JKL Schwartz, DA AF Savov, JD Brass, DM Lawson, BL McElvania-Tekippe, E Walker, JKL Schwartz, DA TI Toll-like receptor 4 antagonist (E5564) prevents the chronic airway response to inhaled lipopolysaccharide SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE endotoxin; asthma; airway inflammation; airway remodeling; airway pressure-time index; lipid A ID TOLL-LIKE RECEPTOR-4; ENDOTOXIN RESPONSIVENESS; BINDING-PROTEIN; CUTTING EDGE; DISEASE; DUST; ACTIVATION; EXPRESSION; CELLS; MD-2 AB Although chronic inhalation of endotoxin or lipopolysaccharide (LPS) causes all of the classic features of asthma, including airway hyperreactivity, airway inflammation, and airway remodeling, the mechanisms involved in this process are not clearly understood. The objective of this study was to determine whether intratracheal treatment with LPS antagonist (E5564, a lipid A analog) prevented the development of chronic endotoxin-induced airway disease in a mouse model of environmental airway disease. Pretreatment with 10 and 100 mu g of E5564 was found to inhibit the airway response ( hyperreactivity and inflammation) for up to 48 h after the administration of the compound. Repeated dosing with 50 mu g of E5564 intratracheally did not cause any measurable toxicity. Therefore, in a chronic experiment, mice were treated with either E5564 (50 mu g) or vehicle three times weekly for 5 wk and simultaneously daily exposed to either LPS (4.65 +/- 0.30 mu g/m(3)) or saline aerosol. E5564 was effective in decreasing the airway hyperreactivity to methacholine, the air space neutrophilia, the interleukin-6 in the lung lavage fluid, and the neutrophil infiltration of the airways 36 h after 5 wk of LPS inhalation. Less collagen deposition was observed in the airways of E5564-treated mice compared with vehicle-treated mice after a 4-wk recovery period. Our results indicate that E5564, a Toll-like receptor 4 antagonist, minimizes the physiological and biological effects of chronic LPS inhalation, suggesting a therapeutic role for competitive LPS antagonists in preventing or reducing endotoxin-induced environmental airway disease. C1 Duke Univ, Ctr Med, Div Pulm Allergy & Crit Care Med, Durham, NC USA. Vet Affairs Med Ctr, Durham, NC USA. RP Brass, DM (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM brassd@niehs.nih.gov FU NIEHS NIH HHS [ES-012496, ES-11375, ES-011961, ES-07498] NR 34 TC 40 Z9 47 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD AUG PY 2005 VL 289 IS 2 BP L329 EP L337 DI 10.1152/ajplung.00014.2005 PG 9 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 943BY UT WOS:000230328000021 PM 15833764 ER PT J AU Steiner, AA Chakravarty, S Robbins, JR Dragic, AS Pan, J Herkenham, M Romanovsky, AA AF Steiner, AA Chakravarty, S Robbins, JR Dragic, AS Pan, J Herkenham, M Romanovsky, AA TI Thermoregulatory responses of rats to conventional preparations of lipopolysaccharide are caused by lipopolysaccharide per se not by lipoprotein contaminants SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE body temperature; fever; hypothermia; inflammation; Toll-like receptors; TLR2; TLR4; LPS ID EARLY GENE-EXPRESSION; TOLL-LIKE RECEPTOR-4; A-ASSOCIATED PROTEINS; MURAMYL DIPEPTIDE; CUTTING EDGE; SYSTEMIC INFLAMMATION; SCAVENGER RECEPTORS; ENDOTOXIN PROTEIN; INNATE IMMUNITY; GUINEA-PIGS AB LPS preparations cause a variety of body temperature (T(b)) responses: monophasic fever, different phases of polyphasic fever, and hypothermia. Conventional (c) LPS preparations contain highly active lipoprotein contaminants (endotoxin proteins). Whereas LPS signals predominantly via the Toll-like receptor (TLR) 4, endotoxin proteins signal via TLR2. Several TLR2-dependent responses of immunocytes to cLPS in vitro are triggered by endotoxin proteins and not by LPS itself. We tested whether any T(b) response to cLPS from Escherichia coli 055:B5 is triggered by non-TLR4-signaling contaminants. A decontaminated (d) LPS preparation (free of endotoxin proteins) was produced by subjecting cLPS to phenol-water reextraction. The presence of non-TLR4-signaling contaminants in cLPS (and their absence in dLPS) was confirmed by showing that cLPS (but not dLPS) induced IL-1 beta expression in the spleen and increased serum levels of TNF-alpha and IL-1 beta of C3H/HeJ mice; these mice bear a nonfunctional TLR4. Yet, both cLPS and dLPS caused cytokine responses in C3H/HeOuJ mice; these mice bear a fully functional TLR4. We then studied the T(b) responses to cLPS and dLPS in Wistar rats preimplanted with jugular catheters. At a neutral ambient temperature (30 degrees C), a low (0.1 mu g/kg iv) dose of cLPS caused a monophasic fever, whereas a moderate ( 10 mu g/kg iv) dose produced a polyphasic fever. In the cold (20 degrees C), a high (500 mu g/kg iv) dose of cLPS caused hypothermia. All T(b) responses to dLPS were identical to those of cLPS. We conclude that all known T(b) responses to LPS preparations are triggered by LPS per se and not by non-TLR4-signaling contaminants of such preparations. C1 St Josephs Hosp, Systemic Inflammat Lab, Phoenix, AZ USA. NIMH, Funct Neuroanat Sect, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Romanovsky, AA (reprint author), St Josephs Hosp, 350 W Thomas Rd, Phoenix, AZ 85013 USA. EM aromano@chw.edu RI Steiner, Alexandre/G-1288-2012; OI Steiner, Alexandre/0000-0002-0802-4619; Herkenham, Miles/0000-0003-2228-4238 FU NINDS NIH HHS [R01 NS 41233] NR 43 TC 24 Z9 24 U1 2 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD AUG PY 2005 VL 289 IS 2 BP R348 EP R352 DI 10.1152/ajpregu.00223.2005 PG 5 WC Physiology SC Physiology GA 944UJ UT WOS:000230455400011 PM 15860647 ER PT J AU Norregaard, R Jensen, BL Li, CL Wang, WD Knepper, MA Nielsen, S Frokiaer, J AF Norregaard, R Jensen, BL Li, CL Wang, WD Knepper, MA Nielsen, S Frokiaer, J TI COX-2 inhibition prevents downregulation of key renal water and sodium transport proteins in response to bilateral ureteral obstruction SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE cyclooxygenase; PGE(2); parecoxib; AQP2 ID THICK ASCENDING LIMB; MEDULLARY INTERSTITIAL-CELLS; DIETARY SALT INTAKE; RAT-KIDNEY; CYCLOOXYGENASE-2 INHIBITOR; DIFFERENTIAL REGULATION; COLLECTING DUCT; ALTERED EXPRESSION; CHANNEL EXPRESSION; NEPHROTIC SYNDROME AB Bilateral ureteral obstruction (BUO) is associated with marked changes in the expression of renal aquaporins (AQPs) and sodium transport proteins. To examine the role of prostaglandin in this response, we investigated whether 24-h BUO changed the expression of cyclooxygenases (COX-1 and -2) in the kidney and tested the effect of the selective COX-2 inhibitor parecoxib (5 mg(.)kg(-1.)day(-1) via osmotic minipumps) on AQPs and sodium transport. Sham and BUO kidneys were analyzed by semiquantitative immunoblotting, and a subset of kidneys was perfusion fixed for immunocytochemistry. BUO caused a significant 14-fold induction of inner medullary COX-2 (14.40 +/- 1.8 vs. 1.0 +/- 0.4, n = 6; P < 0.0001) and a reduction in medullary tissue osmolality, whereas COX-1 did not change. Immunohistochemistry confirmed increased COX-2 labeling associated with medullary interstitial cells. COX isoforms did not change in cortex/ outer medulla after 24-h BUO. In BUO kidneys, inner medullary AQP2 expression was reduced, and this decrease was prevented by parecoxib. In the inner stripe of outer medulla, the type 3 Na(+)/H(+) exchanger (NHE3) and apical Na(+)-K(+)-2Cl(-) cotransporter (BSC-1) were significantly reduced by BUO, and this decrease was significantly attenuated by parecoxib. Immunohistochemistry for AQP2, NHE3, and BSC-1 confirmed the effect of parecoxib. Parecoxib had no significant effect on the Na-K-ATPase alpha(1)-subunit, type II Na-P(i) cotransporter, or AQP3. In conclusion, acute BUO leads to marked upregulation of COX- 2 in inner medulla and selective COX- 2 inhibition prevents dysregulation of AQP2, BSC-1, and NHE3 in response to BUO. These data indicate that COX- 2 may be an important factor contributing to the impaired renal water and sodium handling in response to BUO. C1 Univ Aarhus, Hosp Skejby, Dept Clin Physiol & Nucl Med, Water & Salt Res Ctr, DK-8200 Aarhus, Denmark. Univ Aarhus, Inst Anat, Aarhus C, Denmark. Univ Aarhus, Inst Clin Med, Aarhus C, Denmark. Univ Aarhus, Water & Salt Res Ctr, Aarhus C, Denmark. Univ So Denmark, Dept Physiol & Pharmacol, Odense, Denmark. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Frokiaer, J (reprint author), Univ Aarhus, Hosp Skejby, Dept Clin Physiol & Nucl Med, Water & Salt Res Ctr, Brendstrupgaardsvej, DK-8200 Aarhus, Denmark. EM JF@KI.AU.DK FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 50 TC 57 Z9 57 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD AUG PY 2005 VL 289 IS 2 BP F322 EP F333 DI 10.1152/ajprenal.00061.2005 PG 12 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 943WN UT WOS:000230385900013 PM 15840770 ER PT J AU Zhou, XM Ferraris, JD Cai, Q Agarwal, A Burg, MB AF Zhou, XM Ferraris, JD Cai, Q Agarwal, A Burg, MB TI Increased reactive oxygen species contribute to high NaCl-induced activation of the osmoregulatory transcription factor TonEBP/OREBP SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE superoxides; nitric oxide; ouabain; transactivation; nuclear translocation ID NITRIC-OXIDE SYNTHASE; NF-KAPPA-B; SUPEROXIDE-DISMUTASE; OXIDATIVE STRESS; IN-VIVO; TRANSACTIVATION DOMAIN; HYDROGEN-PEROXIDE; BINDING PROTEIN; RENAL-CELLS; P38 MAPK AB The signaling pathways leading to high NaCl-induced activation of the transcription factor tonicity-responsive enhancer binding protein/osmotic response element binding protein (TonEBP/OREBP) remain incompletely understood. High NaCl has been reported to produce oxidative stress. Reactive oxygen species (ROS), which are a component of oxidative stress, contribute to regulation of transcription factors. The present study was undertaken to test whether the high NaCl-induced increase in ROS contributes to tonicity-dependent activation of TonEBP/OREBP. Human embryonic kidney 293 cells were used as a model. We find that raising NaCl increases ROS, including superoxide. N-acetylcysteine (NAC), an antioxidant, and MnTBAP, an inhibitor of superoxide, reduce high NaCl-induced superoxide activity and suppress both high NaCl-induced increase in TonEBP/OREBP transcriptional activity and high NaCl-induced increase in expression of BGT1mRNA, a transcriptional target of TonEBP/OREBP. Catalase, which decomposes hydrogen peroxide, does not have these effects, whether applied exogenously or overexpressed within the cells. Furthermore, NAC and MnTBAP, but not catalase, blunt high NaCl-induced increase in TonEBP/OREBP transactivation. N(G)-monomethyl-L-arginine, a general inhibitor of nitric oxide synthase, has no significant effect on either high NaCl-induced increase in superoxide or TonEBP/OREBP transcriptional activity, suggesting that the effects of ROS do not involve nitric oxide. Ouabain, an inhibitor of Na-K-ATPase, attenuates high NaCl-induced superoxide activity and inhibits TonEBP/OREBP transcriptional activity. We conclude that the high NaCl-induced increase in ROS, including superoxide, contributes to activation of TonEBP/OREBP by increasing its transactivation. C1 Uniformed Serv Univ Hlth Sci, Dept Med, Div Nephrol, Bethesda, MD 20814 USA. NHLBI, Lab Kidney & Electrolyte Metab, NIH, Bethesda, MD 20892 USA. Univ Alabama, Div Nephrol & Hypertens, Birmingham, AL USA. RP Zhou, XM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med, Div Nephrol, Bethesda, MD 20814 USA. EM xiazhou@usuhs.mil NR 54 TC 38 Z9 38 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD AUG PY 2005 VL 289 IS 2 BP F377 EP F385 DI 10.1152/ajprenal.00463.2004 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 943WN UT WOS:000230385900018 PM 15769933 ER PT J AU Volkow, ND AF Volkow, ND TI What do we know about drug addiction? SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material C1 Natl Inst Drug Abuse, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), Natl Inst Drug Abuse, 6001 Execut Blvd,Room 5274, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov NR 0 TC 35 Z9 37 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2005 VL 162 IS 8 BP 1401 EP 1402 DI 10.1176/appi.ajp.162.8.1401 PG 2 WC Psychiatry SC Psychiatry GA 950LA UT WOS:000230857400001 PM 16055760 ER PT J AU Kalivas, PW Volkow, ND AF Kalivas, PW Volkow, ND TI The neural basis of addiction: A pathology of motivation and choice SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 157th Annual Meeting of the American-Psychiatric-Association CY MAY 01-06, 2004 CL New York, NY SP Amer Psychiat Assoc ID COCAINE-SEEKING BEHAVIOR; NUCLEUS-ACCUMBENS CORE; PREFRONTAL CORTEX NEURONS; INDUCED REINSTATEMENT; BASOLATERAL AMYGDALA; ANTERIOR CINGULATE; DRUG-SEEKING; GLUTAMATE TRANSMISSION; SYNAPTIC PLASTICITY; CONDITIONED REWARD AB Objective: A primary behavioral pathology in drug addiction is the overpowering motivational strength and decreased ability to control the desire to obtain drugs. In this review the authors explore how advances in neurobiology are approaching an understanding of the cellular and circuitry underpinnings of addiction, and they describe the novel pharmacotherapeutic targets emerging from this understanding. Method: Findings from neuroimaging of addicts are integrated with cellular studies in animal models of drug seeking. Results: While dopamine is critical for acute reward and initiation of addiction, end-stage addiction results primarily from cellular adaptations in anterior cingulate and orbitofrontal glutamatergic projections to the nucleus accumbens. Pathophysiological plasticity in excitatory transmission reduces the capacity of the prefrontal cortex to initiate behaviors in response to biological rewards and to provide executive control over drug seeking. Simultaneously, the prefrontal cortex is hyperresponsive to stimuli predicting drug availability, resulting in supraphysiological glutamatergic drive in the nucleus accumbens, where excitatory synapses have a reduced capacity to regulate neurotransmission. Conclusions: Cellular adaptations in prefrontal glutamatergic innervation of the accumbens promote the compulsive character of drug seeking in addicts by decreasing the value of natural rewards, diminishing cognitive control ( choice), and enhancing glutamatergic drive in response to drug-associated stimuli. C1 Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. Natl Inst Drug Abuse, Bethesda, MD USA. RP Kalivas, PW (reprint author), Med Univ S Carolina, Dept Neurosci, 173 Ashley Ave,BSB-403, Charleston, SC 29425 USA. EM kalivasp@musc.edu FU NIDA NIH HHS [DA-03906, DA-05369, DA-12513] NR 112 TC 1289 Z9 1330 U1 34 U2 253 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2005 VL 162 IS 8 BP 1403 EP 1413 DI 10.1176/appi.ajp.162.8.1403 PG 11 WC Psychiatry SC Psychiatry GA 950LA UT WOS:000230857400002 PM 16055761 ER PT J AU Vocci, FJ Acri, J Elkashef, A AF Vocci, FJ Acri, J Elkashef, A TI Medication development for addictive disorders: The state of the science SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 157th Annual Meeting of the American-Psychiatric-Association CY MAY 01-06, 2004 CL New York, NY SP Amer Psychiat Assoc ID COCAINE-SEEKING BEHAVIOR; CORTICOTROPIN-RELEASING-FACTOR; DOPAMINE AUTORECEPTOR ANTAGONIST; RANDOMIZED CLINICAL-TRIAL; PLACEBO-CONTROLLED TRIAL; STRESS-INDUCED RELAPSE; RAT NUCLEUS-ACCUMBENS; OPIOID DEPENDENCE; DRUG-SEEKING; EXTRACELLULAR DOPAMINE AB In 1989, the National Institute on Drug Abuse ( NIDA) established its Medications Development Program. This program has concentrated on developing pharmacotherapies for opiate and cocaine dependence and, more recently, for methamphetamine and cannabis dependence. The major goals of this program are to optimize existing treatments and to expand treatment options for physicians and patients. This review will concentrate on the development of pharmacotherapies for the following substance abuse disorders: opiate, cocaine, methamphetamine, and cannabis dependence. Left untreated, opiate and stimulant dependence are responsible for significant morbidity and mortality. For example, use of illicit opiates is associated with an increased risk of hepatitis C infection, HIV infection, and other medical consequences, e. g., an overdose. The NIDA Medications Development Program has had success in developing, with pharmaceutical partners, levomethadyl acetate, buprenorphine, and buprenorphine/naloxone for opiate dependence. Moreover, several marketed medications have shown promise in reducing cocaine use. Of interest, these medications likely operate through diverse neurochemical mechanisms, suggesting that combination therapy may be a rational next step that could increase treatment gains further in cocaine-dependent patients. The Medications Development Program has also identified multiple neuronal mechanisms that are altered by chronic administration of drugs of abuse. Advances in neuroscience have identified changes in conditioned cueing, drug priming, stress-induced increases in drug intake, and reduced frontal inhibitory mechanisms as all being possible for the development of, maintenance of, and possible relapse to addiction. Potential medications that modulate these mechanisms are highlighted. C1 Natl Inst Drug Abuse, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Vocci, FJ (reprint author), Natl Inst Drug Abuse, Div Pharmacotherapies & Med Consequences Drug Abu, NIH, Dept Hlth & Human Serv, 6001 Execut Blvd,Rm 4133,MSC 9551, Bethesda, MD 20892 USA. EM fv6k@nih.gov NR 124 TC 110 Z9 113 U1 7 U2 13 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2005 VL 162 IS 8 BP 1432 EP 1440 DI 10.1176/appi.ajp.162.8.1432 PG 9 WC Psychiatry SC Psychiatry GA 950LA UT WOS:000230857400005 PM 16055764 ER PT J AU Carroll, KM Onken, LS AF Carroll, KM Onken, LS TI Behavioral therapies for drug abuse SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Review ID RANDOMIZED CLINICAL-TRIAL; METHADONE-MAINTENANCE PATIENTS; ADOLESCENT SUBSTANCE-ABUSE; ENHANCE NALTREXONE TREATMENT; SERIOUS JUVENILE-OFFENDERS; AMBULATORY COCAINE ABUSERS; COPING SKILLS TREATMENT; CONTINGENCY MANAGEMENT; FAMILY-THERAPY; FOLLOW-UP AB The past three decades have been marked by tremendous progress in behavioral therapies for drug abuse and dependence, as well as advances in the conceptualization of approaches to development of behavioral therapies. Cognitive behavior therapy, contingency management, couples and family therapy, and a variety of other types of behavioral treatment have been shown to be potent interventions for several forms of drug addiction, and scientific progress has also been greatly facilitated by the articulation of a systematic approach to the development, evaluation, and dissemination of behavioral therapies. The authors review recent progress in strategies for the development of behavioral therapies for drug and alcohol abuse and dependence and discuss the range of effective behavioral therapies that are currently available. C1 Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. Natl Inst Drug Abuse, Bethesda, MD USA. RP Carroll, KM (reprint author), Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. EM kathleen.carroll@yale.edu RI Carroll, Kathleen/A-7526-2009; OI Carroll, Kathleen/0000-0003-3263-3374 FU NIDA NIH HHS [P50 DA-09241, K05 DA-00457, R01 DA-10679, K05 DA000457, R01 DA015969, P50 DA009241] NR 105 TC 149 Z9 154 U1 4 U2 38 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2005 VL 162 IS 8 BP 1452 EP 1460 DI 10.1176/appi.ajp.162.8.1452 PG 9 WC Psychiatry SC Psychiatry GA 950LA UT WOS:000230857400007 PM 16055766 ER PT J AU Compton, WM Thomas, YF Conway, KP Colliver, JD AF Compton, WM Thomas, YF Conway, KP Colliver, JD TI Developments in the epidemiology of drug use and drug use disorders SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 157th Annual Meeting of the American-Psychiatric-Association CY MAY 01-06, 2004 CL New York, NY SP Amer Psychiat Assoc ID SUBSTANCE USE DISORDERS; ENVIRONMENTAL RISK-FACTORS; UNITED-STATES; FAMILIAL TRANSMISSION; SOCIAL EPIDEMIOLOGY; ANXIETY DISORDERS; MENTAL-DISORDERS; MARIJUANA USE; ABUSE; ALCOHOL AB The past 30 years of research on the epidemiology of drug use, drug use disorders, and related conditions, such as HIV, has provided major insight into these conditions. Drug use peaked in the late 1970s, decreased across the 1980s, increased in the 1990s, and has remained stable during the past few years. Within this broad pattern, specific epidemics of crack cocaine, amphetamines, club drugs (such as Ecstasy), heroin, and prescription opioids and associated epidemics of HIV and other infectious diseases have been identified and tracked. Besides major accomplishments in surveillance, the epidemiology of drug use and drug use disorders has traditionally focused on identifying risk factors at the individual (genetic factors, high-risk behaviors), family (child abuse), neighborhood (high availability of drugs), and societal (policies and laws) levels as domains of influence, not as components of interrelated processes. Research includes careful cross-sectional and longitudinal observational studies as well as clinical epidemiological experiments in which prevention interventions test specific etiological theories. Building on this background, the next challenges for the epidemiology of drug use and drug use disorders will be to link individual vulnerabilities with specific environmental factors by using multilevel methodological approaches. For example, what are the environmental factors that interact with individual vulnerabilities to produce drug addictions and drug consequences such as HIV? Research in genetic epidemiology has demonstrated the potential for studies of interactions of genetic and environmental factors. The field needs to focus on linking science with epidemiology to make progress in understanding these complex health conditions. C1 Natl Inst Drug Abuse, Div Epidemiol, Serv & Prevent Res, NIH, Bethesda, MD 20892 USA. US Dept HHS, Off Appl Stat, Substance Abuse & Mental Helth Serv Adm, Bethesda, MD USA. RP Compton, WM (reprint author), Natl Inst Drug Abuse, Div Epidemiol, Serv & Prevent Res, NIH, 6001 Execut Blvd,MSC 9589, Bethesda, MD 20892 USA. EM wcompton@nida.nih.gov RI Reis, Aline/G-9573-2012; OI Conway, Kevin/0000-0002-7638-339X NR 74 TC 60 Z9 64 U1 8 U2 20 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2005 VL 162 IS 8 BP 1494 EP 1502 DI 10.1176/appi.ajp.162.8.1494 PG 9 WC Psychiatry SC Psychiatry GA 950LA UT WOS:000230857400011 PM 16055770 ER PT J AU Nabel, EG AF Nabel, EG TI Notes from the NHLBI director - A vision for the future: Opportunities and challenges SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG 1 PY 2005 VL 172 IS 3 BP 266 EP 267 DI 10.1164/rccm.2506010 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 949IM UT WOS:000230778600004 PM 16040790 ER PT J AU Schrager, JA Pittaluga, S Raffeld, M Jaffe, ES AF Schrager, JA Pittaluga, S Raffeld, M Jaffe, ES TI Granulomatous reaction in Burkitt lymphoma: Correlation with EBV positivity and clinical outcome SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Letter ID EPSTEIN-BARR-VIRUS; T-CELLS C1 NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Schrager, JA (reprint author), NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. NR 8 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD AUG PY 2005 VL 29 IS 8 BP 1115 EP 1116 PG 2 WC Pathology; Surgery SC Pathology; Surgery GA 949EU UT WOS:000230768500018 PM 16006809 ER PT J AU Troendle, JF AF Troendle, JF TI A bootstrap test of stochastic equality of two populations - Comment SO AMERICAN STATISTICIAN LA English DT Letter ID BEHRENS-FISHER PROBLEM C1 NIH, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Troendle, JF (reprint author), NIH, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. NR 3 TC 1 Z9 1 U1 0 U2 2 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0003-1305 J9 AM STAT JI Am. Stat. PD AUG PY 2005 VL 59 IS 3 BP 279 EP 279 DI 10.1198/000313005X56052 PG 1 WC Statistics & Probability SC Mathematics GA 947RV UT WOS:000230664900013 ER PT J AU McCutcheon, B White, K Kotwall, C Germolic, D Rebolloso, Y Hamann, MS Stiles, A AF McCutcheon, B White, K Kotwall, C Germolic, D Rebolloso, Y Hamann, MS Stiles, A TI A preliminary study of imiquimod treatment in variants of basal cell carcinoma SO AMERICAN SURGEON LA English DT Article; Proceedings Paper CT Annual Meeting of the Southeastern-Surgical-Congress CY FEB 11-15, 2005 CL New Orleans, LA SP SE Surg Congress ID 5-PERCENT CREAM; TOPICAL IMIQUIMOD; IMMUNE-RESPONSE; MELANOMA; INTERLEUKIN-8 AB Imiquimod is a topical immune response modifier that has proved efficacious in the treatment of the superficial variant of basal cell carcinoma. The nodular variant of basal cell carcinoma has shown moderate response to imiquimod; other variants have not been tested. The mechanism of action is largely unknown; however, studies indicate the mechanism involves alteration of local cytokine production. The objective of this study is to evaluate the cytokine response of imiquimod in all variants of basal cell carcinoma. Ten patients were selected who had clinically and histologically proven basal cell carcinoma. All lesions were treated with imiquimod once a day, 5 days a week, for 3 weeks. After a 3-week rest period, the lesions were rebiopsied. All biopsy specimens were analyzed via polymerase chain reaction (PCR) for various cytokines. Nine of 10 lesions resolved clinically, which included nodular, superficial, infiltrative, adenoid, and micronodular variants. The cytokine with the greatest change pre- and post-treatment was IL-8, which decreased an average of 44 per cent (P = 0.06). We concluded that topical 5 per cent imiquimod is an effective treatment of various subtypes of basal cell carcinoma. IL-8, which plays an important role in the development and metastasis of melanoma, may be involved in the mechanism of action of imiquimod on cutaneous malignancies. Larger studies are needed to prove the efficacy of imiquimod on nonsuperficial variants of basal cell carcinoma and cutaneous melanoma metastasis. C1 Coastal Area Hlth Educ Ctr, Dept Surg, Wilmington, NC 28401 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP McCutcheon, B (reprint author), Coastal Area Hlth Educ Ctr, Dept Surg, 2131 S 17th St, Wilmington, NC 28401 USA. NR 16 TC 4 Z9 4 U1 0 U2 0 PU SOUTHEASTERN SURGICAL CONGRESS PI ATLANTA PA 141 WEST WIEUCA RD, STE B100, ATLANTA, GA 30342 USA SN 0003-1348 J9 AM SURGEON JI Am. Surg. PD AUG PY 2005 VL 71 IS 8 BP 662 EP 665 PG 4 WC Surgery SC Surgery GA 959VO UT WOS:000231547600015 PM 16217949 ER PT J AU Vahratian, A Siega-Riz, AM Savitz, DA Zhang, J AF Vahratian, A Siega-Riz, AM Savitz, DA Zhang, J TI Maternal pre-pregnancy overweight and obesity and the risk of cesarean delivery in nulliparous women SO ANNALS OF EPIDEMIOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-for-Pediatric-and-Perinatal-Epidemiologic-Research/37th Annual Meeting of the Society-for-Epidemiologic-Research CY JUN 15-18, 2004 CL Salt Lake City, UT SP Soc Pediatr & Perinatal Epidemiol Res, Soc Epidemiol Res DE body mass index; delivery; obstetric; epidemiologic methods; labor; obstetric; obesity ID BODY-MASS INDEX; WEIGHT-GAIN RECOMMENDATIONS; ADVERSE PREGNANCY OUTCOMES; HEIGHT; COMPLICATIONS; POPULATION; AGE; DETERMINANTS; PREVALENCE; RATES AB PURPOSE: To examine the effect of maternal pre-pregnancy overweight and obesity on the risk of term cesarean delivery in nulliparous women. METHODS: The authors examined data from 641 nulliparous women with a term pregnancy that participated in the Pregnancy, Infection, and Nutrition Study from 1995 to 2002. Unadjusted and adjusted risk ratios and 95% confidence intervals (CI) were computed for normal weight (BMI 19.8-26.0 kg/m(2)), overweight (BMI 26.1-29.0 kg/m(2)), and obese (BMI > 29.0 kg/m(2)) women. Normal weight women served as the referent population. RESULTS: The unadjusted risk ratio for cesarean delivery for overweight women compared with normal weight women was 1.4 (95% Cl, 0.97, 2.1) and for obese women compared with normal weight women was 1.4 (95% Cl, 1.03, 2.0). After controlling for maternal height, education, weight gain during pregnancy, and labor induction, the adjusted risk ratio for cesarean delivery among overweight women was 1.2 (95% Cl, 0.8, 1.8). The adjusted risk ratio for obese women was 1.5 (95% Cl, 1.05, 2.0). CONCLUSION: Our analysis confirms that there is a moderate association between maternal pre-pregnancy obesity and an unplanned term cesarean delivery. However, the risk is not as large as previously reported. C1 Univ N Carolina, Sch Publ Hlth, Dept Maternal & Child Hlth, Chapel Hill, NC USA. NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. RP Vahratian, A (reprint author), Univ Michigan, Dept Obstet & Gynecol, L4000 Womens Hosp,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM amv@med.umich.edu RI Vahratian, Anjel/A-1182-2011 FU NCRR NIH HHS [RR00046]; NICHD NIH HHS [HD05798, HD28684, HD37584] NR 43 TC 58 Z9 59 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2005 VL 15 IS 7 BP 467 EP 474 DI 10.1016/j.annepidem.2005.02.005 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 952WX UT WOS:000231037800001 PM 15921926 ER PT J AU Gradishar, WJ Wedam, SB Jahanzeb, M Erban, J Limentani, SA Tsai, KT Olsen, SR Swain, SM AF Gradishar, WJ Wedam, SB Jahanzeb, M Erban, J Limentani, SA Tsai, KT Olsen, SR Swain, SM TI Neoadjuvant docetaxel followed by adjuvant doxorubicin and cyclophosphamide in patients with stage III breast cancer SO ANNALS OF ONCOLOGY LA English DT Article; Proceedings Paper CT 39th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 31-JUN 03, 2003 CL CHICAGO, IL SP Amer Soc Clin Oncol DE neoadjuvant docetaxel; stage II breast cancer ID PROSPECTIVE RANDOMIZED-TRIAL; PREOPERATIVE CHEMOTHERAPY; DOSE-DENSE; INDUCTION CHEMOTHERAPY; PATHOLOGICAL RESPONSE; EUROPEAN-ORGANIZATION; THERAPY; COMBINATION; VINORELBINE; CARCINOMA AB Background: To evaluate clinical and pathologic response to neoadjuvant docetaxel therapy in patients with stage III breast cancer. Patients and methods: Forty-five patients were planned to receive four cycles of docetaxel 100 mg/m(2) every 3 weeks, followed by surgery, four cycles of doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) (AC) every 3 weeks, radiation therapy (RT), and tamoxifen when indicated. Results: After four cycles of neoadjuvant docetaxel, the clinical response rate within the breast was 59% (95% CI 42% to 73%) and overall (breast and axilla) was 49% (95% Cl 38% to 72%) in the intention-to- treat (ITT) population. At the time of surgery, 10% (n=4) of patients had a pathologic complete response (pCR) in the breast, 27% (n = 11) had a pCR within the axillary lymph nodes, and 7% (n=3) had a pCR in the breast and axilla (95% CI 2% to 21%). An additional 5% (n=2) had minimal residual invasive tumor (<5 mm). The 5-year overall survival rate was 80%. The percentage of patients with grade 3/4 neutropenia was similar during docetaxel (93%) and AC (86%), while a greater percentage of patients had febrile neutropenia during docetaxel treatment (27%) compared with AC treatment (7%). Conclusions: Neoadjuvant docetaxel followed by surgery, adjuvant AC, hormonal therapy where indicated. and RT is an active regimen for patients with stage III breast cancer. C1 Natl Canc Inst, Canc Therapeut Branch, Ctr Canc Res, DHHS Bethesda, Bethesda, MD 20892 USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Univ Tennessee, Inst Canc, Memphis, TN USA. Tufts New England Med Ctr, Boston, MA USA. Carolinas Hematol Oncol Associates, Charlotte, NC USA. Blumenthal Canc Ctr, Charlotte, NC USA. Aventis Pharmaceut, Bridgewater, NJ USA. RP Swain, SM (reprint author), Natl Canc Inst, Canc Therapeut Branch, Ctr Canc Res, DHHS Bethesda, Bethesda, MD 20892 USA. EM swains@mail.nih.gov OI Swain, Sandra/0000-0002-1320-3830 NR 41 TC 24 Z9 24 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD AUG PY 2005 VL 16 IS 8 BP 1297 EP 1304 DI 10.1093/annonc/mdi254 PG 8 WC Oncology SC Oncology GA 955LX UT WOS:000231228500012 PM 15905305 ER PT J AU Seibel, NL Schwartz, C Arrieta, A Flynn, P Shad, A Albano, E Keirns, J Lau, WM Facklam, DP Buell, DN Walsh, TJ AF Seibel, NL Schwartz, C Arrieta, A Flynn, P Shad, A Albano, E Keirns, J Lau, WM Facklam, DP Buell, DN Walsh, TJ TI Safety, tolerability, and pharmacokinetics of micafungin (FK463) in febrile neutropenic pediatric patients SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID LIPOPEPTIDE ANTIFUNGAL AGENT; INVASIVE FUNGAL-INFECTIONS; MARROW TRANSPLANT RECIPIENTS; DISSEMINATED CANDIDIASIS; PULMONARY ASPERGILLOSIS; UNITED-STATES; MOUSE MODELS; SURVIVAL; LEUKEMIA; EPIDEMIOLOGY AB Micafungin (FK463) is a new parenteral echinocandin. A multicenter, phase I, open-label, sequential-group dose escalation study was conducted to assess the safety, tolerability, and pharmacokinetics of micafungin in neutropenic pediatric patients. A total of 77 patients stratified by age (2 to 12 and 13 to 17 years) received micafungin. Therapy was initiated at 0.5 mg/kg per day and escalated to higher dose levels of 1.0, 1.5, 2.0, 3.0, and 4.0 mg/kg per day. Micafungin was administered within 24 h of initiating broad-spectrum antibacterial antibiotics for the new onset of fever and neutropenia. The most common overall adverse events in the study population were diarrhea (19.5%), epistaxis (18.2%), abdominal pain (16.9%), and headache (16.9%). Nine patients (12%) experienced adverse events considered by the investigator to be possibly related to the study drug. The most common related events were diarrhea, vomiting, and headache, all occurring in two patients each. There was no evidence of a dose-limiting toxicity as defined within the prespecified criteria of this clinical protocol. There was one death during the study due to septic shock. The pharmacokinetic profiles for micafungin over the 0.5- to 4.0-mg/kg dose range demonstrated dose linearity. Clearance, volume of distribution, and half-life remained relatively constant over the dose range and did not change with repeated administration. The overall plasma pharmacokinetic profile was similar to that observed in adults. However, there was an inverse relation between age and clearance. For patients 2 to 8 years old, clearance was approximately 1.35 times that of patients >= 9 years of age. In summary, micafungin over a dosage range between 0.5 and 4.0 mg/kg/day in 77 febrile neutropenic pediatric patients displayed linear pharmacokinetics and increased clearance as a function of decreasing age. C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. George Washington Univ, Sch Med, Childrens Natl Med Ctr, Washington, DC 20010 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. Childrens Hosp Orange Cty, Orange, CA 92868 USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Georgetown Univ Hosp, Washington, DC 20007 USA. Univ Colorado, Childrens Hosp, Denver, CO 80218 USA. Fujisawa Healthcare Inc, Deerfield, IL 60015 USA. RP Walsh, TJ (reprint author), NCI, Pediat Oncol Branch, Bldg 10,Rm 13N-240,10 Ctr Dr, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov NR 28 TC 138 Z9 146 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2005 VL 49 IS 8 BP 3317 EP 3324 DI 10.1128/AAC.49.8.3317-3324.2005 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 951SI UT WOS:000230950700033 PM 16048942 ER PT J AU Smith, PF Robbins, GK Shafer, RW Wu, HL Yu, S Hirsch, MS Merigan, TC Park, JG Forrest, A Fischl, MA Morse, GD AF Smith, PF Robbins, GK Shafer, RW Wu, HL Yu, S Hirsch, MS Merigan, TC Park, JG Forrest, A Fischl, MA Morse, GD CA ACTG 384-5006 Team TI Pharmacokinetics of nelfinavir and efavirenz in antiretroviral-naive, human immunodeficiency virus-infected subjects when administered alone or in combination with nucleoside analog reverse transcriptase inhibitors SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID SEQUENTIAL 3-DRUG REGIMENS; INITIAL THERAPY; HIV-1 INFECTION; INDINAVIR AB Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiving efavirenz, nelfinavir, or both agents at weeks 4 and 32. Reductions of 25% and 45% were observed in the mean nelfinavir area under the concentration-time curve and minimum concentration of the drug in serum, and there was a 31% more rapid half-life for patients receiving both drugs compared to patients receiving nelfinavir alone. There were no significant differences in efavirenz pharmacokinetics. C1 SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Dept Pharm Practice, Adult ACTG Pharmacol Support,Lab Antiviral Res, Buffalo, NY 12460 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Stanford Univ, Sch Med, Palo Alto, CA 94304 USA. Rochester Sch Med & Dent, Rochester, NY USA. Univ Miami, Sch Med, Miami, FL 33152 USA. NIAID, Adult AIDS Clin Trials Grp, Bethesda, MD 20892 USA. RP Smith, PF (reprint author), SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Dept Pharm Practice, Adult ACTG Pharmacol Support,Lab Antiviral Res, 219 Cooke Hall, Buffalo, NY 12460 USA. EM pfsmith@buffalo.edu RI Robbins, Gregory/F-7988-2011 FU NCRR NIH HHS [M01 RR000070, M01RR0884, M01RR00047, M01-RR-00071, M01 RR000071, P20 RR011126, M01 RR000037, M01 RR000750, M01-RR00070, 1P20RR11126, RR00044, RR00046, M01 RR000046, M01 RR000425, M01-RR00425, M01-RR-00037, M01 RR000047, M01 RR000056, M01-RR00056, M01 RR000400, MO1RR00750, M01RR00400, M01 RR000044]; NIAID NIH HHS [AI25859, 5U01-AI46383, AI27661, AI27664, U01 AI025868, AI-27659, U01 AI027673, U01-AI-27667, AI27670, U01 AI046386, U01 AI027659, U01 AI027670, U01 AI027664, AI35162, UO1-AI38858, AI25868, AI27659, U01 AI025859, U01 AI046383, U01 AI038858, AI27666, AI46386, U01 AI027661, P30 AI050410, AI50410, U01 AI027665, AI34832, U01 AI025897, U01 AI034832, AI27660, AI27658, U01 AI027660, U01 AI027658, AI27665, U01 AI027666, AI27673, AI25897]; PHS HHS [M01-R00096] NR 11 TC 7 Z9 8 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2005 VL 49 IS 8 BP 3558 EP 3561 DI 10.1128/AAC.49.8.3558-3561.2005 PG 4 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 951SI UT WOS:000230950700074 PM 16048984 ER PT J AU Polianova, MT Ruscetti, FW Pert, CB Ruff, MR AF Polianova, MT Ruscetti, FW Pert, CB Ruff, MR TI Chemokine receptor-5 (CCR5) is a receptor for the HIV entry inhibitor peptide T (DAPTA) SO ANTIVIRAL RESEARCH LA English DT Article DE envelope; gp120; binding; CCR5; chemokine; receptor; HIV-1; entry; treatments ID HUMAN-IMMUNODEFICIENCY-VIRUS; MACROPHAGE-TROPIC HIV-1; CHEMOKINE RECEPTORS; GP120 BINDING; FUNCTIONAL EXPRESSION; ENVELOPE GLYCOPROTEIN; MOLECULAR-CLONING; CO-RECEPTORS; RHESUS CCR5; MIP-1 ALPHA AB The chemokine receptor CCR5 plays a crucial role in transmission of HIV isolates, which predominate in the early and middle stages of infection, as well as those, which populate the brain and cause neuro-AIDS. CCR5 is therefore an attractive therapeutic target for design of entry inhibitors. Specific rapid filtration binding assays have been useful for almost 30 years both for drug discovery and understanding molecular mechanisms of drug action. Reported in 1986, prior to discovery of chemokine co-receptors and so thought to act at CD4, peptide T (DAPTA) appears to greatly reduce cellular viral reservoirs in both HAART experienced and treatment naive patients, without toxicities. We here report that DAPTA potently inhibits specific CD4-dependent binding of gp120 Bal (IC50 = 0.06 nM) and CM235 (IC50 = 0.32 nM) to CCR5. In co-immunoprecipitation studies, DAPTA (I nM) blocks formation of the gp120/sCD4 complex with CCR5. Confocal microscopic studies of direct FITC-DAPTA binding to CCR5+, but not CCR5-, cells show that CCR5 is a DAPTA receptor. The capability of DAPTA to potently block gp120-CD4 binding to the major co-receptor CCR5 explains its molecular and therapeutic mechanism of action as a selective antiviral entry inhibitor for R5 tropic HIV-1 isolates. (c) 2005 Elsevier B.V. All rights reserved. C1 Georgetown Univ, Sch Med, Dept Physiol & Biosci, Washington, DC 20007 USA. NCI, Frederick Canc Res & Dev Ctr, Expt Immunol Lab, Canc Res Ctr, Frederick, MD 21701 USA. RP Ruff, MR (reprint author), Georgetown Univ, Sch Med, Dept Physiol & Biosci, Room 215,3900 Reservoir Rd NW, Washington, DC 20007 USA. EM ruffm@georgetown.edu NR 60 TC 12 Z9 14 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD AUG PY 2005 VL 67 IS 2 BP 83 EP 92 DI 10.1016/j.antiviral.2005.03.007 PG 10 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 958YV UT WOS:000231485000003 PM 16002156 ER PT J AU Scholl, D Adhya, S Merril, C AF Scholl, D Adhya, S Merril, C TI Escherichia coli K1's capsule is a barrier to bacteriophage T7 SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID TAIL-FIBER; DEGRADATION; EXPRESSION; PROTEINS; STRAINS; SYSTEM; PHAGE; DNA AB Escherichia coli strains that produce the K1 polysaccharide capsule have long been associated with pathogenesis. This capsule is believed to increase the cell's invasiveness, allowing the bacteria to avoid phagocytosis and inactivation by complement. It is also recognized as a receptor by some phages, such as K1F and K1-5, which have virion-associated enzymes that degrade the polysaccharide. In this report we show that expression of the K1 capsule in E. coli physically blocks infection by T7, a phage that recognizes lipopolysaccharide as the primary receptor. Enzymatic removal of the K1 antigen from the cell allows T7 to adsorb and replicate. This observation suggests that the capsule plays an important role as a defense against some phages that recognize structures beneath it and that the K1-specific phages evolved to counter this physical barrier. C1 NIMH, Sect Biochem Genet, NIH, Bethesda, MD 20892 USA. NCI, Sect Dev Genet, NIH, Bethesda, MD 20892 USA. RP Scholl, D (reprint author), NIMH, Sect Biochem Genet, NIH, Bldg 36,Room 3D20,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dscholl@usa.net NR 24 TC 65 Z9 66 U1 3 U2 20 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD AUG PY 2005 VL 71 IS 8 BP 4872 EP 4874 DI 10.1128/AEM.71.8.4872-4874.2005 PG 3 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 954OX UT WOS:000231165500089 PM 16085886 ER PT J AU Sarkar, K Weinberg, CR Oddis, CV Medsger, TA Plotz, PH Reveille, JD Arnett, FC Targoff, IN Genth, E Love, LA Miller, FW AF Sarkar, K Weinberg, CR Oddis, CV Medsger, TA Plotz, PH Reveille, JD Arnett, FC Targoff, IN Genth, E Love, LA Miller, FW TI Seasonal influence on the onset of idiopathic inflammatory myopathies in serologically defined groups SO ARTHRITIS AND RHEUMATISM LA English DT Article ID JUVENILE DERMATOMYOSITIS; HEALTHY-SUBJECTS; SKELETAL-MUSCLE; POLYMYOSITIS; MYOSITIS; AUTOANTIBODIES; IMPLANTS; CHILDREN; DISEASE AB Objective. To assess possible seasonal patterns in the onset of polymyositis (PM) and dermatomyositis (PM). Methods. The study group comprised 503 patients who met the criteria for probable or definite PM or DM and for whom detailed data on the time of myositis onset were available. Statistical analyses were performed using a Poisson model that assessed associations of ethnicity, sex, autoantibody presence, and month of onset of muscle weakness. Results. There were no significant seasonal patterns of disease onset in myositis patients as a whole or in the total PM or DM populations. Significant seasonal associations were present, however, in the serologically defined groups. In the 131 patients with antisynthetase autoantibodies who were categorized as non-black, myositis onset peaked in March-April (P = 0.03). Among the anti synthetase-positive patients, the association was predominantly in those with PM (n = 85; P = 0.05) and in men (n = 51; P = 0.042). Patients with anti-signal recognition particle autoantibodies, however, did not have a significant seasonal onset, which is in contrast to previous findings. Patients without myositis-specific antoantibodies showed a significant peak in summer, with myositis onset in June-July (n = 252; P = 0.03); this seasonal association was significant in women (n = 182; P = 0.005), whereas there was no seasonal pattern in men (P = 0.9). Conclusion. These findings, in conjunction with other data, suggest that diverse environmental agents, acting upon different immunogenetic backgrounds, result in distinct immune responses and clinical syndromes in the idiopathic inflammatory myopathies. Our results emphasize the importance of considering more homogeneous disease groups, based on clinicopathologic features, immune responses, ethnicity, and sex, when attempting to decipher the pathogeneses of autoimmune disorders. C1 Natl Inst Hlth Sci, DHHS, NIH, Bethesda, MD USA. Univ Pittsburgh, Pittsburgh, PA USA. NIAMSD, DHHS, NIH, Bethesda, MD 20892 USA. Univ Texas, Houston, TX USA. Univ Oklahoma, Hlth Sci Ctr, Vet Adm Med Ctr, Oklahoma City, OK USA. OMRF, Oklahoma City, OK USA. Clin & Res Inst Rheumat Dis, Aachen, Germany. RP Sarkar, K (reprint author), NIEHS, Environm Autoimmun Grp, NIH, 9000 Rockville Pike,Bldg 9,Room 1W107,MSC 0958, Bethesda, MD 20892 USA. EM sarkark@mail.nih.gov OI Miller, Frederick/0000-0003-2831-9593 NR 39 TC 26 Z9 26 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2005 VL 52 IS 8 BP 2433 EP 2438 DI 10.1002/art.21198 PG 6 WC Rheumatology SC Rheumatology GA 953LW UT WOS:000231078800028 PM 16052581 ER PT J AU Solly, K Mundt, SS Zokian, HJ Ding, GJF Hermanowski-Vosatka, A Strulovici, B Zheng, W AF Solly, K Mundt, SS Zokian, HJ Ding, GJF Hermanowski-Vosatka, A Strulovici, B Zheng, W TI High-throughput screening of 11 beta-hydroxysteroid dehydrogenase type 1 in scintillation proximity assay format SO ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES LA English DT Article ID HEPATIC INSULIN SENSITIVITY; DEHYDROGENASE TYPE-1; GLUCOCORTICOID ACTION; MICE; REDUCTASE; OBESITY; CLONING; ENZYME AB 11 beta-Hydroxysteroid dehydrogenase type-1 ( 11 beta-HSD1) is a potential target for the treatment of diabetes, obesity, and hyperlipidemia. This enzyme is mainly responsible for reactivating glucocorticoid hormone inside cells such as adipose cells and liver cells by converting the inactive cortisone to active cortisol. Enzyme assays for 11 beta-HSD1 involve either a thin-layer chromatography or high-performance liquid chromatography step to separate cortisol from the substrate cortisone. This additional step is labor intensive and increases the assay time, which limits assay throughput. A homogenous scintillation proximity assay-based method has been recently developed that enables high-throughput screening of 11 beta-HSD1 inhibitors. We have applied this novel 11 beta-HSD1 assay to screening a large-size compound collection and identified several structural classes of lead compounds that selectively inhibit the activity of 11 beta-HSD1. C1 Merck & Co Inc, Dept Automated Biotechnol, N Wales, PA USA. Merck & Co Inc, Dept Cardiovasc Dis, Rahway, NJ 07065 USA. RP Zheng, W (reprint author), NHGRI, NIH, Chem Genom Ctr, 9800 Med Ctr Dr,MSC 3370, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov OI Zheng, Wei/0000-0003-1034-0757 NR 15 TC 13 Z9 13 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-658X J9 ASSAY DRUG DEV TECHN JI ASSAY DRUG DEV. TECHNOL. PD AUG PY 2005 VL 3 IS 4 BP 377 EP 384 DI 10.1089/adt.2005.3.377 PG 8 WC Biochemical Research Methods; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 969IY UT WOS:000232229000003 PM 16180992 ER PT J AU Adeyemo, AA Johnson, T Acheampong, J Oli, J Okafor, G Amoah, A Owusu, S Agyenim-Boateng, K Eghan, BA Abbiyesuku, F Fasanmade, O Rufus, T Doumatey, A Chen, GJ Zhou, J Chen, YX Furbert-Harris, P Dunston, G Collins, F Rotimi, C AF Adeyemo, AA Johnson, T Acheampong, J Oli, J Okafor, G Amoah, A Owusu, S Agyenim-Boateng, K Eghan, BA Abbiyesuku, F Fasanmade, O Rufus, T Doumatey, A Chen, GJ Zhou, J Chen, YX Furbert-Harris, P Dunston, G Collins, F Rotimi, C TI A genome wide quantitative trait linkage analysis for serum lipids in type 2 diabetes in an African population SO ATHEROSCLEROSIS LA English DT Article DE genome scan; lipids; cholesterol; type 2 diabetes; Africa ID CORONARY-HEART-DISEASE; CARDIOVASCULAR-DISEASE; SUSCEPTIBILITY GENES; INSULIN-RESISTANCE; METABOLIC SYNDROME; MEXICAN-AMERICANS; HDL CHOLESTEROL; RISK-FACTORS; LIPOPROTEIN; PHENOTYPES AB Lipid abnormalities are strongly linked with coronary heart disease and are common in type 2 diabetes. However, little is known about the genetic determinants of serum lipids in African populations. An autosomal genome scan was performed for linkage to five plasma lipid phenotypes (total cholesterol, triglycerides (TG), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C) and VLDL-cholesterol (VLDL-C)) in the Africa-America Diabetes Mellitus (AADM) study. Two hundred and ninety-five affected sibling pairs with type 2 diabetes mellitus enrolled from Ghana and Nigeria were genotyped for 390 microsatellite markers with an average inter-marker distance of 9 cM. Multipoint variance components linkage analysis showed that HDL-C had a LOD score of 4.34 near marker D7S3061 and 3.00 near marker D7S513. Some clustering of linkage evidence to several lipid phenotypes was observed on chromosomes 5 (LDL-C, total cholesterol, VLDL-C), chromosome 7 (HDL-C, TG) and chromosome 19 (total cholesterol, LDL-C, TG). Principal component analysis of the five phenotypes yielded two factors, one (TG, HDL-C and VLDL) of which was linked to QTLs on chromosomes 2, 5 and 7, while the other (total cholesterol and LDL-C) was linked to a different set of QTLs on chromosomes 2, 5 and 18. Several of these regions have been reported to be linked to lipids in other studies. Follow up investigations are warranted in view of the central role serum lipids play in the aetiopathogenesis of cardiovascular disease. (c) 2005 Elsevier Ireland Ltd. All rights reserved. C1 Howard Univ, Coll Med, Natl Human Genome Ctr, Washington, DC 20059 USA. Univ Ibadan, Coll Med, Ibadan, Nigeria. Univ Lagos, Coll Med Endocrine & Metab Unit, Lagos, Nigeria. Univ Sci & Technol, Dept Med, Kumasi, Ghana. Univ Nigeria, Teaching Hosp, Dept Med, Enugu, Nigeria. Univ Ghana, Med Sch, Dept Med, Accra, Ghana. Natl Inst Hlth, Natl Human Genome Res Inst, Bethesda, MD USA. RP Rotimi, C (reprint author), Howard Univ, Coll Med, Natl Human Genome Ctr, 2216 6th St, Washington, DC 20059 USA. EM crotimi@howard.edu OI Adeyemo, Adebowale/0000-0002-3105-3231 FU FIC NIH HHS [3T37TW00041-03S2]; NIDDK NIH HHS [DK-54001] NR 42 TC 23 Z9 26 U1 1 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD AUG PY 2005 VL 181 IS 2 BP 389 EP 397 DI 10.1016/j.atherosclerosis.2004.12.049 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 956WP UT WOS:000231331100022 PM 16039295 ER PT J AU Feil, EG Small, JW Forness, SR Serna, LA Kaiser, AP Hancock, TB Brooks-Gunn, J Bryant, D Kuperschmidt, J Burchinal, MR Boyce, CA Lopez, ML AF Feil, Edward G. Small, Jason W. Forness, Steven R. Serna, Loretta A. Kaiser, Ann P. Hancock, Terry B. Brooks-Gunn, Jeanne Bryant, Donna Kuperschmidt, Janis Burchinal, Margaret R. Boyce, Cheryl A. Lopez, Michael L. TI Using different measures, informants, and clinical cut-off points to estimate prevalence of emotional or behavioral disorder's in preschoolers: Effects on age, gender, and ethnicity SO BEHAVIORAL DISORDERS LA English DT Article ID HEAD-START; PSYCHIATRIC-DISORDERS; LOW-INCOME; MULTIPLE INFORMANTS; CONDUCT DISORDER; YOUNG-CHILDREN; PARENT; COMMUNITY; SYMPTOMS; SAMPLE AB The early identification and remediation of emotional or behavior disorders are high priorities for early-childhood researchers and are based on the assumption that problems such as school failure can be averted with early screening, prevention, and intervention. Presently, prevalence, severity, and topography of mental health needs among low-income preschoolers and their families have not been well documented. Tools for screening and intervention for behavior problems in preschool children are few and many of those tools have not been studied within diverse Head Start systems. In this study, five instruments of symptoms and functional impairment, completed by teachers and two completed by parents, were obtained on a sample of 1,781 Head Start children from diverse racial and ethnic backgrounds from the Head Start Mental Health Research Consortium. Clinical cut-off scores were used to identify children who could be considered at relatively serious risk for emotional or behavioral disorders. At-risk classifications using clinical cut-offs at both 1.0 and 1.5 standard deviations for each measure were examined singly and in combination and then compared to the overall sample for age, gender, and ethnicity. Identification of children considered at risk ranged from a low of 1% to a high of 38%, with evidence of differential effects on age, gender, or ethnicity for some individual measures, but these tended to diminish when combinations of symptom and impairment measures were used. Implications for choosing instruments to establish eligibility for emotional or behavioral disorders in preschoolers are discussed. C1 Oregon Res Inst, Eugene, OR 97403 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ New Mexico, Albuquerque, NM 87131 USA. Vanderbilt Univ, Nashville, TN USA. Columbia Univ, New York, NY 10027 USA. Univ N Carolina, Chapel Hill, NC 27515 USA. NIMH, Bethesda, MD 20892 USA. RP Feil, EG (reprint author), Oregon Res Inst, 1715 Franklin Blvd, Eugene, OR 97403 USA. EM edf@ori.org NR 57 TC 31 Z9 31 U1 4 U2 11 PU COUNCIL CHILDREN BEHAVIORAL DISORDERS PI ARLINGTON PA COUNCIL EXCEPTIONAL CHILDREN, 1110 NORTH GLEBE RD, ARLINGTON, VA 22201-5704 USA SN 0198-7429 J9 BEHAV DISORDERS JI Behav. Disord. PD AUG PY 2005 VL 30 IS 4 BP 375 EP 391 PG 17 WC Psychology, Clinical; Psychology, Educational SC Psychology GA 107BT UT WOS:000242146400006 ER PT J AU Zhu, YX Li, XM McVie-Wylie, A Jiang, CW Thurberg, BL Raben, N Mattaliano, RJ Cheng, SH AF Zhu, YX Li, XM McVie-Wylie, A Jiang, CW Thurberg, BL Raben, N Mattaliano, RJ Cheng, SH TI Carbohydrate-remodel led acid alpha-glucosidase with higher affinity for the cation-independent mannose 6-phosphate receptor demonstrates improved delivery to muscles of Pompe mice SO BIOCHEMICAL JOURNAL LA English DT Article DE acid alpha-glucosidase; carbohydrate remodel ling; cation-independent mannose 6-phosphate receptor; enzyme replacement therapy; lysosomal storage disorders; Pompe disease ID DISEASE TYPE-II; ENZYME REPLACEMENT THERAPY; HAMSTER OVARY CELLS; LYSINE-BASED STRUCTURE; HIGH-LEVEL PRODUCTION; LYSOSOMAL-ENZYME; LINKED OLIGOSACCHARIDES; MALTASE DEFICIENCY; RABBIT MILK; DNASE-I AB To enhance the delivery of rhGAA (recombinant GAA, where GAA stands for acid alpha-glucosidase) to the affected muscles in Pompe disease, the carbohydrate moieties on the enzyme were remodelled to exhibit a high affinity ligand for the CI-MPR (cation-independent M6P receptor, where M6P stands for mannose 6-phosphate). This was achieved by chemically conjugating on to rhGAA, a synthetic oligosaccharide ligand bearing M61? residues in the optimal configuration for binding the receptor. The carbonyl chemistry used resulted in the conjugation of approx. six synthetic ligands on to each enzyme. The resulting modified enzyme [neo-rhGAA (modified recombinant human GAA harbouring synthetic oligosaccharide ligands)] displayed near-normal specific activity and significantly increased affinity for the CI-MPR. However, binding to the mannose receptor was unaffected despite the introduction of additional mannose residues in neo-rhGAA. Uptake studies using L6 myoblasts showed neorhGAA was internalized approx. 20-fold more efficiently than the unmodified enzyme. Administration of neo-rhGAA into Pompe mice also resulted in greater clearance of glycogen from all the affected muscles when compared with the unmodified rhGAA. Comparable reductions in tissue glycogen levels in the Pompe mice were realized using an approx. 8-fold lower dose of neorhGAA in the heart and diaphragm and an approx. 4-fold lower dose in the skeletal muscles. Treatment of older Pompe mice, which are more refractory to enzyme therapy, with 40 mg/kg neorhGAA resulted in near-complete clearance of glycogen from all the affected muscles as opposed to only partial correction with the unmodified rhGAA. These results demonstrate that remodelling the carbohydrate of rhGAA to improve its affinity for the CI-MPR represents a feasible approach to enhance the efficacy of enzyme replacement therapy for Pompe disease. C1 Genzyme Corp, Framingham, MA 01701 USA. NIH, Bethesda, MD 20892 USA. RP Cheng, SH (reprint author), Genzyme Corp, 31 New York Ave, Framingham, MA 01701 USA. EM seng.cheng@genzyme.com NR 55 TC 50 Z9 50 U1 0 U2 3 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 AUG 1 PY 2005 VL 389 BP 619 EP 628 PN 3 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 954WQ UT WOS:000231186400003 PM 15839836 ER PT J AU Tchilibon, S Zhang, J Yang, QF Eidelman, O Kim, H Caohuy, H Jacobson, KA Pollard, BS Pollard, HB AF Tchilibon, S Zhang, J Yang, QF Eidelman, O Kim, H Caohuy, H Jacobson, KA Pollard, BS Pollard, HB TI Amphiphilic pyridinium salts block TNF alpha/NF kappa B signaling and constitutive hypersecretion of interleukin-8 (IL-8) from cystic fibrosis lung epithelial cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE cystic fibrosis; inflammation; lung; interleukin 8; epithelium; NF kappa B; AP-1 ID TRANSMEMBRANE CONDUCTANCE REGULATOR; CHLORIDE EFFLUX; GENE-EXPRESSION; INFLAMMATION; ACTIVATION; CFTR; 8-CYCLOPENTYL-1,3-DIPROPYLXANTHINE; DELTA-F508-CFTR; ANTAGONISTS; XANTHINES AB Cystic fibrosis (CF) is a common, lethal genetic disease, which is due to mutations in the CFTR gene. The CF lung expresses a profoundly proinflammatory phenotype, due to constitutive hypersecretion of IL-8 from epithelial cells lining the airways. In a systematic search for candidate drugs that might be used therapeutically to suppress IL-8 secretion from these cells, we have identified a potent and efficacious series of amphiphilic pyridinium salts. The most potent of these salts is MRS2481, an (R)-1-phenylpropionic acid ester, with an IC50 of ca. 1 mu M. We have synthesized 21 analogues of MRS2481, which have proven sufficient to develop a preliminary structure-activity relationship (SAR). For optimal activity, we have found that the ester must be connected to the pyridinium derivative by an eight-carbon chain. An optical isomer of the lead compound, containing an (S)-1-phenylpropionic acid ester, has been found to be a much less active. The mechanism of action of MRS2481 appears to involve inhibition of signaling of the NF kappa B and AP- I transcription factors to the IL-8 promoter. MRS2481 is a potent inhibitor of TNF alpha-induced phosphorylation and proteosomal destruction Of I kappa B alpha. Inasmuch as I kappa B alpha is the principal inhibitor of the NF kappa B signaling pathway, preservation of intact I kappa B alpha would serve to keep the IL-8 promoter silent. We also find that MRS2481 blocks TNF alpha-activated phosphorylation of JNK, the c-JUN kinase. The IL-8 promoter is also activated by an AP- I site, which requires a phospho-c-JUN/c-FOS dimer for activity. We therefore interpret these data to suggest that the mechanism of MRS2481 action is to inhibit both NF kappa B and AP-1 signaling on the IL-8 promoter. Given the medicinally promising properties of water-solubility, potency in the low mu M concentration range, and high efficacy, we anticipate that MRS2481, or a further optimized derivative, may find an important place in the armamentarium of pharmaceutical strategies yet to be arrayed against the inflammatory phenotype of the CF lung. Published by Elsevier Inc. C1 Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, F Edward Herbert Sch Med, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Inst Mol Med, F Edward Herbert Sch Med, Bethesda, MD 20814 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Equal Employment Opportun Commiss Headquarters, Off Informat Technol, Washington, DC 20507 USA. RP Pollard, HB (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, F Edward Herbert Sch Med, Bethesda, MD 20814 USA. EM hpollard@usuhs.mil RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NHLBI NIH HHS [N01-HV-28187]; NIDDK NIH HHS [R01-DK53051] NR 35 TC 18 Z9 19 U1 0 U2 1 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 AUG 1 PY 2005 VL 70 IS 3 BP 381 EP 393 DI 10.1016/j.bcp.2005.05.002 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 946WW UT WOS:000230605000007 PM 15963954 ER PT J AU Dar, DE Mayo, C Uhl, GR AF Dar, DE Mayo, C Uhl, GR TI The interaction of methylphenidate and benztropine with the dopamine transporter is different than other substrates and ligands SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE dopamine; cocaine; transporter; uptake; substrates; ligands ID MAZINDOL BINDING; H-3 MAZINDOL; UPTAKE SITES; UPTAKE INHIBITORS; COCAINE BINDING; MOUSE STRIATUM; RAT STRIATUM; COS CELLS; ANALOGS; AMPHETAMINE AB A substantial body of evidence suggests that the dopamine transporter (DAT) is the principal site for cocaine-induced reward and euphoria. Interactions between the DAT and its substrates and ligands may therefore be of clinical relevance. The pharmacological characteristics of DAT compounds were compared in wild type (WT) and mutant DATs. The DAT mutants chosen for study were those with reduced binding and uptake activities (aspartic acid 79 mutated to alanine, termed D79A), reduced binding but normal uptake (tyrosine 251 mutated to alanine, termed Y251A; tyrosine 273 mutated to alanine, termed, Y273A), and normal binding but reduced uptake (a double mutation: serines 356 and 359 mutated to alanine, termed S356,359A). The WT and mutant DATs were transfected into COS-7 cells, and their pharmacological activities were examined 3 days later. Different patterns of pharmacological activity emerged. GBR 12909. cocaine, and mazindol each showed reduced affinity for the Y251A and the Y273A mutants, but their affinity for the S356,359A mutant was similar to that of the WT DAT. d-Amphetamine, MPP+, and dopamine each showed reduced affinity for the S356,359A mutant. Benztropine and methylphenidate had a different effect. Relative to the WT DAT, they both showed reduced affinity for the S356,359A mutant when displacing radioactive carboxyfluorotropane (CFT) binding, but similar affinity when inhibiting radioactive dopamine uptake. These results indicate that methylphenidate and benztropine may interact with the DAT in a different fashion then other substrates and ligands. (c) 2005 Elsevier Inc. All rights reserved. C1 NIDA, Mol Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA. Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. RP Dar, DE (reprint author), NIDA, Mol Neurobiol Branch, Intramural Res Program, Baltimore, MD 21224 USA. EM dalit.dar@weizmann.ac.il FU Intramural NIH HHS NR 37 TC 16 Z9 16 U1 2 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 AUG 1 PY 2005 VL 70 IS 3 BP 461 EP 469 DI 10.1016/j.bcp.2005.04.032 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 946WW UT WOS:000230605000015 PM 15950948 ER PT J AU Hardy, J AF Hardy, J TI Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: 'permissive templating' as a general mechanism underlying neurodegeneration SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Conference on Moleclar Mechanisms of Neurodegeneration CY MAR 14-16, 2005 CL Univ Coll Dublin, Dublin, IRELAND HO Univ Coll Dublin DE A beta; neurodegeneration; permissive templating; prion; tau; alpha-synuclein ID CREUTZFELDT-JAKOB-DISEASE; ONSET ALZHEIMERS-DISEASE; ALPHA-SYNUCLEIN GENE; PRION PROTEIN; PARKINSONS-DISEASE; LOCUS TRIPLICATION; VARIANT CJD; HYPOTHESIS; SCRAPIE; BRAIN AB Loci underlying autosomal dominant forms of most neurodegenerative disease have been identified: prion mutations cause Gerstmann Straussler syndrome and hereditary Creutzfeldt-Jakob disease, tau mutations cause autosomal dominant frontal temporal dementia and alpha-synuclein mutations cause autosomal dominant Parkinson's disease. In these cases, the pathogenic mutation is in the protein that is deposited in the diseased tissue and the whole protein is deposited. in Alzheimer's disease, mutations in amyloid precursor protein or in the presenilins cause autosomal dominant disease. These are the substrate and proteases responsible for the production of the deposited peptide A beta. Thus, in all the cases, the mutations lead to the disease by a mechanism that involves the deposition process. Furthermore, sporadic forms of all these diseases are predisposed by genetic variability at the same loci, implying that the quantity of the normal protein influences the risk of this form of disease. These results show that the amount of pathogenic protein expression is a key factor in determining disease initiation. Recent work on transgenic models of these diseases is consistent with the view that there are two stages of pathogenesis: a concentration-dependent formation of a pathogenic protein oligomer followed by aggregation on to this oligomeric template by a process that is less dependent on the concentration of the protein. C1 NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), NIA, Neurogenet Lab, Porter Neurosci Bldg,35 Convent Dr, Bethesda, MD 20892 USA. EM hardyj@mail.nih.gov RI Hardy, John/C-2451-2009 NR 32 TC 60 Z9 60 U1 0 U2 6 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD AUG PY 2005 VL 33 BP 578 EP 581 PN 4 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 957BZ UT WOS:000231345700009 PM 16042548 ER PT J AU Hardy, J Pittman, A Myers, A Gwinn-Hardy, K Fung, HC de Silva, R Hutton, M Duckworth, J AF Hardy, J Pittman, A Myers, A Gwinn-Hardy, K Fung, HC de Silva, R Hutton, M Duckworth, J TI Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Conference on Molecular Mechanisms of Neurodegeneration CY MAR 14-16, 2005 CL Univ Coll Dublin, Dublin, IRELAND HO Univ Coll Dublin DE genome; H2 haplotype; Homo sapiens; human genetics; MAPT gene; Neanderthal man ID PROGRESSIVE SUPRANUCLEAR PALSY; PARKINSONISM-DEMENTIA COMPLEX; TAU HAPLOTYPE; LATERAL-SCLEROSIS; HUMAN-POPULATIONS; GENE; GUAM; ASSOCIATION; ARCHAEOLOGY; SELECTION AB The tau (MAPT) locus exists as two distinct clades, H1 and H2. The H1 clade has a normal linkage disequilibrium structure and is the only haplotype found in all populations except those derived from Caucasians. The H2 haplotype is the minor haplotype in Caucasian populations and is not found in other populations. it shows no recombination over a region of 2 Mb with the more common H1 haplotype. The distribution of the haplotype and analysis of the slippage of dinucleotide repeat markers within the haplotype suggest that it entered Homo sapiens populations between approx. 10000 and 30000 years ago. However, sequence comparison of the H2 haplotype with the H1 haplotype and with the chimp sequence suggests that the common founder of the H1 and H2 haplotypes was far earlier than this. We suggest that the H2 haplotype is derived from Homo neanderthalensis and entered H. sapiens populations during the coexistence of these species in Europe from approx. 45000 to 18000 years ago and that the H2 haplotype has been under selection pressure since that time, possibly because of the role of this H1 haplotype in neurodegenerative disease. C1 NIA, Neurogenet Lab, Porter Neurosci Ctr, NIH, Bethesda, MD 20852 USA. NINDS, NIH, Bethesda, MD 20892 USA. UCL, Reta Lila Weston Inst Neurol Studies, London W1T 4JF, England. Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. RP Hardy, J (reprint author), NIA, Neurogenet Lab, Porter Neurosci Ctr, NIH, 35 Convent Dr, Bethesda, MD 20852 USA. EM hardyj@mail.nih.gov RI de Silva, Rohan/C-1734-2008; Gwinn, Katrina/C-2508-2009; Myers, Amanda/B-1796-2010; Hardy, John/C-2451-2009; Pittman, Alan/D-6231-2012 OI de Silva, Rohan/0000-0002-5052-5775; Myers, Amanda/0000-0002-3100-9396; NR 25 TC 50 Z9 53 U1 4 U2 18 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD AUG PY 2005 VL 33 BP 582 EP 585 PN 4 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 957BZ UT WOS:000231345700010 PM 16042549 ER PT J AU Donaldson, JG Honda, A AF Donaldson, JG Honda, A TI Localization and function of Arf family GTPases SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Conference on Localization and Activation of Ras-Like GTPases CY MAR 21-23, 2005 CL Royal Agr Coll, Cirencester, ENGLAND HO Royal Agr Coll DE Arf1; coat protein; Golgi; GTPase; SNARE; targeting ID GUANINE-NUCLEOTIDE-EXCHANGE; ADP-RIBOSYLATION FACTOR; PHOSPHOLIPASE-D; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; DOWNSTREAM EFFECTOR; VESICLE FORMATION; PLASMA-MEMBRANE; GOLGI MEMBRANES; GGA PROTEINS; COPI COAT AB Arfs are a family of Ras-related GTP-binding proteins that function in the regulation of membrane trafficking and structure. The six mammalian Arf proteins are expressed ubiquitously and so it is anticipated that each will have a distinct localization and function within the cell. it has been assumed that much of this specificity will be defined by determining which regulators of Arfs, the GEFs (guanine nucleotide-exchange factors) and GAPS (GTPase-activating proteins) function with which Arf proteins. Although in vitro assays may indicate Arf preferences for the numerous Arf GEFs and GAPS that have been identified, in the cell the different Arfs, GEFs and GAPS are targeted to specific compartments where they carry out their functions. We have embarked on studies to define regions of the Arf1 and Arf6 proteins that determine their sites of action and specific activities at the Golgi and plasma membrane respectively. Chimaeras were made between Arf1 and Arf6 in order to identify regions of the protein that contributed to targeting and function. Whereas Arf6 is targeted to the plasma membrane through multiple regions along the protein, we have found a Golgi-targeting region in Arf1 that is sufficient to target Arf6 to the Goigi complex. C1 NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Donaldson, JG (reprint author), NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. EM jdonalds@helix.nih.gov NR 34 TC 93 Z9 100 U1 0 U2 7 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD AUG PY 2005 VL 33 BP 639 EP 642 PN 4 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 957BZ UT WOS:000231345700023 PM 16042562 ER PT J AU Biessmann, H Prasad, S Walter, MF Mason, JM AF Biessmann, H Prasad, S Walter, MF Mason, JM TI Euchromatic and heterochromatic domains at Drosophila telomeres SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Article; Proceedings Paper CT 26th International West Coast Chromatin and Chromosomes Conference CY DEC 09-12, 2004 CL Pacific Grove, CA DE Drosophila; telomere; gene silencing; position effect; heterochromatin ID MELANOGASTER POLYTENE CHROMOSOMES; POSITION-EFFECT VARIEGATION; HET-A RETROPOSONS; INTERCALARY HETEROCHROMATIN; P-ELEMENT; CHROMATIN-STRUCTURE; PERICENTRIC HETEROCHROMATIN; SACCHAROMYCES TELOMERES; DIFFERENT MECHANISMS; DNA-SEQUENCES AB Noncoding repetitive sequences make up a large portion of eukaryotic genomes, but their function is not well understood. Large blocks of repetitive DNA-forming heterochromatin around the centromeres are required for this region to function properly, but are difficult to analyze. The smaller regions of heterochromatin at the telomeres provide an opportunity to study their DNA and protein composition. Drosophila telomere length is maintained through the targeted transposition of specific non-long terminal repeat retrotransposons to chromosome ends, where they form long tandem arrays. A subterminal telomere-associated sequence (TAS) lies immediately proximal to the terminal-retrotransposon array. Here, we review the experimental support for the heterochromatic features of Drosophila telomeres, and provide evidence that telomeric regions contain 2 distinct chromatin subdomains: TAS, which exhibits features that resemble beta heterochromatin; and the terminal array of retrotransposons, which appears euchromatic. This organization is significantly different from the telomeric organization of other eukaryotes, where the terminal telomerase-generated repeats are often folded in a t-loop structure and become part of the heterochromatin protein complex. C1 Univ Calif Irvine, Ctr Dev Biol, Irvine, CA 92697 USA. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Biessmann, H (reprint author), Univ Calif Irvine, Ctr Dev Biol, Irvine, CA 92697 USA. EM hbiessma@uci.edu FU FIC NIH HHS [TW-05653]; NIGMS NIH HHS [GM-56729] NR 99 TC 13 Z9 14 U1 0 U2 0 PU NATL RESEARCH COUNCIL CANADA PI OTTAWA PA RESEARCH JOURNALS, MONTREAL RD, OTTAWA, ONTARIO K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD AUG PY 2005 VL 83 IS 4 BP 477 EP 485 DI 10.1139/O05-053 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 958RV UT WOS:000231466300008 PM 16094451 ER PT J AU Zhao, H Dean, A AF Zhao, H Dean, A TI Organizing the genome: enhancers and insulators SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Article; Proceedings Paper CT 26th International West Coast Chromatin and Chromosomes Conference CY DEC 09-12, 2004 CL Pacific Grove, CA DE enhancer; locus control region; insulator; chromatin; intergenic transcription; nucleus ID BETA-GLOBIN LOCUS; RNA-POLYMERASE-II; DROSOPHILA BITHORAX COMPLEX; HISTONE ACETYLATION PATTERN; ELEMENTS IN-VIVO; CONTROL REGION; INTERGENIC TRANSCRIPTION; BLOCKING ACTIVITY; GENE ACTIVATION; CHROMATIN-STRUCTURE AB Enhancers can activate their target genes over large linear distances. Insulators can delimit the influence of an enhancer to an appropriate target. There are a number of intertwined mechanisms by which the regulatory functions of enhancers and insulators might be carried out at the level of the chromatin fiber. Recent evidence suggests that both enhancers and insulators participate in higher-order organization of chromatin in the nucleus and in localization of their regulated sequences to both subnuclear structures and compartments. Novel experimental approaches are helping to reveal the mechanisms underlying nuclear organization of developmentally regulated genes. C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Dean, A (reprint author), Bldg 50,50 S Dr,MSC 8028, Bethesda, MD 20892 USA. EM anndean@helix.nih.gov NR 88 TC 17 Z9 17 U1 0 U2 3 PU NATL RESEARCH COUNCIL CANADA PI OTTAWA PA RESEARCH JOURNALS, MONTREAL RD, OTTAWA, ONTARIO K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD AUG PY 2005 VL 83 IS 4 BP 516 EP 524 DI 10.1139/O05-054 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 958RV UT WOS:000231466300012 PM 16094455 ER PT J AU Muegge, K AF Muegge, K TI Lsh, a guardian of heterochromatin at repeat elements SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Article; Proceedings Paper CT 26th International West Coast Chromatin and Chromosomes Conference CY DEC 09-12, 2004 CL Pacific Grove, CA DE chromatin; methylation; Lsh; DNA repeats ID H3 LYSINE-9 METHYLATION; DNA METHYLATION; SNF2 FAMILY; HUMAN-CELLS; GENE; CHROMATIN; PROLIFERATION; HELICASES; MEMBER; LOCALIZATION AB Lymphoid-specific helicase (Lsh) is a crucial factor for normal embryonic development; targeted deletion of Lsh is lethal. Lsh belongs to a family of chromatin-remodeling proteins and is closely associated with pericentromeric heterochromatin. Lsh deficiency leads to abnormal heterochromatin organization, with a loss of DNA methylation, and an altered pattern of histone-tail acetylation and methylation. As a functional consequence of perturbed heterochromatin, aberrant reactivation of parasitic retroviral elements in the genome and abnormal mitosis with amplified centrosomes and genomic instability were observed. Thus, Lsh is a major epigenetic regulator crucial for normal heterochromatin structure and function. C1 NCI, Lab Canc Prevent, SAIC, FCRDC, Frederick, MD 21701 USA. RP Muegge, K (reprint author), NCI, Lab Canc Prevent, SAIC, FCRDC, Bldg 469,Rm 243, Frederick, MD 21701 USA. EM muegge@mail.ncifcrf.gov FU PHS HHS [N01-C0-12400] NR 39 TC 30 Z9 31 U1 0 U2 1 PU NATL RESEARCH COUNCIL CANADA PI OTTAWA PA RESEARCH JOURNALS, MONTREAL RD, OTTAWA, ONTARIO K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD AUG PY 2005 VL 83 IS 4 BP 548 EP 554 DI 10.1139/O05-119 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 958RV UT WOS:000231466300015 PM 16094458 ER EF