FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Visalli, RJ Fairhurst, J Srinivas, S Hu, W Feld, B DiGrandi, M Curran, K Ross, A Bloom, JD van Zeijl, M Jones, TR O'Connell, J Cohen, JI AF Visalli, RJ Fairhurst, J Srinivas, S Hu, W Feld, B DiGrandi, M Curran, K Ross, A Bloom, JD van Zeijl, M Jones, TR O'Connell, J Cohen, JI TI Identification of small molecule compounds that selectively inhibit varicella-zoster virus replication SO JOURNAL OF VIROLOGY LA English DT Article ID CYTOMEGALOVIRUS DNA MATURATION; UL6 GENE; RESISTANCE; TYPE-1; ACYCLOVIR; CLEAVAGE; MUTANTS; PRODUCT; THERAPY; UL89 AB A series of nonnucleoside, N-alpha-methylbenzyl-N'-arylthiourea analogs were identified which demonstrated selective activity against varicella-zoster virus (VZV) but were inactive against other human herpesviruses, including herpes simplex virus. Representative compounds had potent activity against VZV early-passage clinical isolates and an acyclovir-resistant isolate. Resistant viruses generated against one inhibitor were also resistant to other compounds in the series, suggesting that this group of related small molecules was acting on the same virus-specific target. Sequencing of the VZV ORF54 gene from two independently derived resistant viruses revealed mutations in ORF54 compared to the parental VZV strain Ellen sequence. Recombinant VZV in which the wild-type ORF54 sequence was replaced with the ORF54 gene from either of the resistant viruses became resistant to the series of inhibitor compounds. Treatment of VZV-infected cells with the inhibitor impaired morphogenesis of capsids. Inhibitor-treated cells lacked DNA-containing dense-core capsids in the nucleus, and only incomplete virions were present on the cell surface. These data suggest that the VZV-specific thiourea inhibitor series block virus replication by interfering with the function of the ORF54 protein and/or other proteins that interact with the ORF54 protein. C1 Wyeth Vaccines, Dept Mol Biol Virol, Infect Dis Sect, Pearl River, NY 10965 USA. Wyeth Vaccines, Dept Chem Sci, Pearl River, NY 10965 USA. NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Visalli, RJ (reprint author), Wyeth, Viral Vaccine Res, 401 N Middletown Rd, Pearl River, NY 10965 USA. NR 33 TC 31 Z9 33 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2003 VL 77 IS 4 BP 2349 EP 2358 DI 10.1128/JVI.77.4.2349-2358.2003 PG 10 WC Virology SC Virology GA 640WZ UT WOS:000180712700006 PM 12551972 ER PT J AU Napuli, AJ Alzhanova, DV Doneanu, CE Barofsky, DF Koonin, EV Dolja, VV AF Napuli, AJ Alzhanova, DV Doneanu, CE Barofsky, DF Koonin, EV Dolja, VV TI The 64-kilodalton capsid protein homolog of Beet yellows virus is required for assembly of virion tails SO JOURNAL OF VIROLOGY LA English DT Article ID CELL-TO-CELL; LONG-DISTANCE TRANSPORT; TOBACCO ETCH POTYVIRUS; CITRUS TRISTEZA VIRUS; HSP70 HOMOLOG; COAT PROTEIN; MOVEMENT PROTEIN; LIQUID-CHROMATOGRAPHY; READTHROUGH PROTEIN; PLANT CLOSTEROVIRUS AB The filamentous virion of the closterovirus Beet yellows virus (BYV) consists of a long body formed by the major capsid protein (CP) and a short tail composed of the minor capsid protein (CPm) and the virus-encoded Hsp70 homolog. By using nano-liquid chromatography-tandem mass spectrometry and biochemical analyses, we show here that the BYV 64-kDa protein (p64) is the fourth integral component of BYV virions. The N-terminal domain of p64 is exposed at the virion surface and is accessible to antibodies and mild trypsin digestion. In contrast, the C-terminal domain is embedded in the virion and is inaccessible to antibodies or trypsin. The C-terminal domain of p64 is shown to be homologous to CP and CPm. Mutation of the signature motifs of capsid proteins of filamentous RNA viruses in p64 results in the formation of tailless virions, which are unable to move from cell to cell. These results reveal the dual function of p64 in tail assembly and BYV motility and support the concept of the virion tail as a specialized device for BYV cell-to-cell movement. C1 Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. Oregon State Univ, Dept Chem, Corvallis, OR 97331 USA. Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Oregon State Univ, Dept Bot & Plant Pathol, Cordley Hall 2082, Corvallis, OR 97331 USA. EM doijav@science.oregonstate.edu FU NIGMS NIH HHS [R01 GM053190, R1 GM 53190 B] NR 50 TC 50 Z9 52 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD FEB PY 2003 VL 77 IS 4 BP 2377 EP 2384 DI 10.1128/JVI.77.4.2377-2384.2003 PG 8 WC Virology SC Virology GA 640WZ UT WOS:000180712700009 PM 12551975 ER PT J AU Evans, DT Chen, LM Gillis, J Lin, KC Harty, B Mazzara, GP Donis, RO Mansfield, KG Lifson, JD Desrosiers, RC Galan, JE Johnson, PR AF Evans, DT Chen, LM Gillis, J Lin, KC Harty, B Mazzara, GP Donis, RO Mansfield, KG Lifson, JD Desrosiers, RC Galan, JE Johnson, PR TI Mucosal priming of simian immunodeficiency virus-specific cytotoxic T-lymphocyte responses in rhesus macaques by the Salmonella type III secretion antigen delivery system SO JOURNAL OF VIROLOGY LA English DT Article ID VACCINE PROTECTION; SIV INFECTION; IN-VIVO; RECOMBINANT; AIDS; IMMUNIZATION; CELLS; TYPHIMURIUM; INDUCTION; CHALLENGE AB Nearly all human immunodeficiency virus (HIV) infections are acquired mucosally, and the gut-associated lymphoid tissues are important sites for early virus replication. Thus, vaccine strategies designed to prime virus-specific cytotoxic T lymphocyte (CTL) responses that home to mucosal compartments may be particularly effective at preventing or containing HIV infection. The Salmonella type III secretion system has been shown to be an effective approach for stimulating mucosal CTL responses in mice. We therefore tested DeltaphoP-phoQ attenuated strains of Salmonella enterica serovar Typhimurium and S. enterica serovar Typhi expressing fragments of the simian immunodeficiency virus (SIV) Gag protein fused to the type III-secreted SopE protein for the ability to prime virus-specific CTL responses in rhesus macaques. Mamu-A*01(+) macaques were inoculated with three oral doses of recombinant Salmonella, followed by a peripheral boost with modified vaccinia virus Ankara expressing SIV Gag (MVA Gag). Transient low-level CTL responses to the Mamu-A*01 Gag(181-189) epitope were detected following each dose of Salmonella. After boosting with MVA Gag, strong Gag-specific CTL responses were consistently detected, and tetramer staining revealed the expansion of Gag(181-189)-specific CD8(+) T-cell responses in peripheral blood. A significant percentage of the Gag(181-189)-specific T-cell population in each animal also expressed the intestinal homing receptor alpha4beta7. Additionally, Gag(181-189)-specific CD8(+) T cells were detected in lymphocytes isolated from the colon. Yet, despite these responses, Salmonella-primed/MVA-boosted animals did not exhibit improved control of virus replication following a rectal challenge with SIVmac239. Nevertheless, this study demonstrates the potential of mucosal priming by the Salmonella type III secretion system to direct SIV-specific cellular immune responses to the gastrointestinal mucosa in a primate model. C1 Harvard Univ, Sch Med, New England Reg Primate Res Ctr, Div Immunol, Southborough, MA 01772 USA. Yale Univ, Sch Med, Boyer Ctr Mol Med, Sect Microbial Pathogenesis, New Haven, CT 06536 USA. Therion Biol Corp, Cambridge, MA 02142 USA. Univ Nebraska, Dept Vet & Biomed Sci, Lincoln, NE 68583 USA. NCI Frederick, Retroviral Pathogenesis lab, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21702 USA. Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA 02115 USA. Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02115 USA. RP Johnson, PR (reprint author), Harvard Univ, Sch Med, New England Reg Primate Res Ctr, Div Immunol, 1 Pine Hill Dr, Southborough, MA 01772 USA. FU NCI NIH HHS [N01CO12400, N01 CO 12400]; NCRR NIH HHS [K26 RR000168, RR 00168, P51 RR000168]; NIAID NIH HHS [AI 35365, R01 AI046953, AI 45314, AI 10464, AI 46953, F32 AI010464, P01 AI035365, U01 AI035365] NR 43 TC 73 Z9 77 U1 1 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2003 VL 77 IS 4 BP 2400 EP 2409 DI 10.1128/JVI.77.4.2400-2409.2003 PG 10 WC Virology SC Virology GA 640WZ UT WOS:000180712700011 PM 12551977 ER PT J AU Xiang, Y Moss, B AF Xiang, Y Moss, B TI Molluscum contagiosum virus interleukin-18 (IL-18) binding protein is secreted as a full-lenath form that binds cell surface glycosaminoglycans through the C-terminal tail and a furin-cleaved form with only the IL-18 binding domain SO JOURNAL OF VIROLOGY LA English DT Article ID FIBROBLAST GROWTH-FACTORS; FUNCTIONAL EPITOPES; VACCINIA VIRUS; POXVIRUS; ENDOPROTEASE; INHIBITION; CYTOKINE; SEQUENCE; EVASION; FAMILY AB Some poxviruses and their mammalian hosts encode homologous proteins that bind interleukin-18 (IL-18) with high affinity and inhibit IL-18-mediated immune responses. MC54L, the IL-18 binding protein of the human poxvirus that causes molluscum contagiosum, is unique in having a C-terminal tail of nearly 100 amino acids that is dispensable for IL-18 binding. When recombinant MC54L was expressed and purified via a C-terminal six-histidine tag, a shorter fragment was detected in addition to the full-length protein. This C-terminal fragment resulted from the cleavage of MC54L by cellular furin, as it was greatly diminished when furin was specifically inhibited or when a furin-deficient cell line was used for expression. Furthermore, the Nand C-terminal fragments of MC54L were generated by cleavage of the recombinant protein with furin in vitro. The furin cleavage site was mapped within a 32-amino-acid segment that is C terminal to the IL-18 binding domain. Full-length MC54L, but not the N-terminal IL-18 binding fragment, bound to cells and to purified heparin and other glycosaminoglycans that are commonly found on the cell surface and in the extracellular matrix. MC54L bound to heparin with a nanomolar K-d and could simultaneously bind to IL-18. Their different glycosaminoglycan and cell binding properties may allow the long and short forms of MC54L to inactivate IL-18 near the site of infection and at more distal locations, respectively. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. NR 26 TC 23 Z9 23 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD FEB PY 2003 VL 77 IS 4 BP 2623 EP 2630 DI 10.1128/JVI.77.4.2623-2630.2003 PG 8 WC Virology SC Virology GA 640WZ UT WOS:000180712700035 PM 12552001 ER PT J AU Nelson, RG AF Nelson, RG TI Intrauterine determinants of diabetic kidney disease in disadvantaged populations SO KIDNEY INTERNATIONAL LA English DT Article; Proceedings Paper CT World Congress of Nephrology CY OCT 19-20, 2001 CL SANTA FE, NEW MEXICO DE birth weight; diabetic nephropathy; type 2 diabetes mellitus; vitamin A deficiency; intrauterine environment; neonate; nephron mass ID STAGE RENAL-DISEASE; LOW-BIRTH-WEIGHT; PIMA-INDIANS; GROWTH-RETARDATION; MELLITUS; CHILDREN; PREVALENCE; COMMUNITY; FAILURE; RATES AB Disadvantaged populations worldwide are experiencing an increasing incidence of kidney disease, much of which is attributable to diabetes. This report reviews the evidence that intrauterine exposure to growth retardation, diabetes, and vitamin A deficiency contribute disproportionately to the rising incidence of kidney disease in disadvantaged people, because they encounter these exposures more frequently than people from developed countries. These abnormal intrauterine exposures reduce nephron mass by impairing nephrogenesis, thereby increasing the susceptibility to kidney damage from diseases such as hypertension and diabetes that commonly affect disadvantaged people. C1 NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85014 USA. RP Nelson, RG (reprint author), NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. RI Nelson, Robert/B-1470-2012 NR 23 TC 3 Z9 3 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD FEB PY 2003 VL 63 SU 83 BP 13 EP 16 DI 10.1046/j.1523-1755.63.s83.4.x PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 635VE UT WOS:000180419700004 ER PT J AU Kopp, JB Winkler, C AF Kopp, JB Winkler, C TI HIV-associated nephropathy in African Americans SO KIDNEY INTERNATIONAL LA English DT Article; Proceedings Paper CT World Congress of Nephrology CY OCT 19-20, 2001 CL SANTA FE, NEW MEXICO DE viral infection; black Americans; focal segmental glomerulosclerosis; toxic HIV-1 accessory proteins; admixed population; MALD ID HUMAN-IMMUNODEFICIENCY-VIRUS; LINKAGE DISEQUILIBRIUM; ADMIXED POPULATIONS; TRANSGENIC MICE; RENAL EPITHELIUM; MESANGIAL CELLS; INFECTION; DISEASE; ADMIXTURE; GENES AB Human immunodeficiency virus-1 (HIV-1) infection is associated with several glomerular syndromes, the most prevalent of which is HIV-associated focal segmental glomerulosclerosis (FSGS). At present, HIV-associated FSGS may account for up to 30% of patients in the United States entering end-stage renal disease (ESRD) as a consequence of FSGS. The mechanisms responsible for HIV-associated FSGS are not well defined, but evidence has been presented in favor of direct infection of renal parenchymal cells and toxicity of HIV-1 accessory proteins. HIV-associated FSGS has a striking predilection for patients of African descent. This likely has a genetic basis, although the gene or genes responsible have not yet been identified. One approach is to examine candidate genes for polymorphisms that are associated with disease. Another approach uses a genome-wide scan, relying upon linkage disequilibrium between DNA markers and the disease gene, to identify the causal gene or genes. African Americans are an admixed population, with genetic contributions from African, European, and Native American populations. In admixed populations, linkage disequilibrium between disease genes and marker genes can be exploited to identify disease genes, using an approach termed mapping by admixture linkage disequilibrium (MALD). C1 NCI, Mol Genet Epidemiol Sect, Lab Genom Divers, Basic Res Program,SAIC Frederick Inc,NIH, Frederick, MD 21701 USA. NIDDKD, Kidney Dis Sect, Bethesda, MD 20892 USA. RP Kopp, JB (reprint author), 10-3N116 NIH, Bethesda, MD 20892 USA. NR 40 TC 19 Z9 19 U1 1 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD FEB PY 2003 VL 63 SU 83 BP 43 EP 49 DI 10.1046/j.1523-1755.63.s83.10.x PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 635VE UT WOS:000180419700010 ER PT J AU Douglas, JG Agodoa, L AF Douglas, JG Agodoa, L TI ACE inhibition is effective and renoprotective in hypertensive nephrosclerosis: The African American Study of Kidney Disease and Hypertension (AASK) trial SO KIDNEY INTERNATIONAL LA English DT Article; Proceedings Paper CT World Congress of Nephrology CY OCT 19-20, 2001 CL SANTA FE, NEW MEXICO DE ACE inhibition; AASK trial; NIDDK; ESRD AB An interim analysis of the AASK trial at three years demonstrates a renoprotective effect [slower decline in glomerular filtration rate (GFR), delayed onset of significant decrease in GFR, end-stage renal disease (ESRD) or death, and a decrease in urinary protein excretion] of the angiotensin converting enzyme (ACE) inhibitor, ramipril, as compared to the dihydropyridine calcium channel blocker (DHP-CCB), amlodipine, in patients with mild-to-moderate renal insufficiency. The beneficial effect occurred in the presence of similar levels of blood pressure control and was apparent in patients with proteinuric (beyond the threshold of "dipstick positive" proteinuria, 300 mg/day) and non-proteinuric hypertensive nephrosclerosis. At the time of the interim analysis, the effectiveness of the beta-blocker metoprolol was not significantly different from that of the ACE inhibitor. The data suggest that DHP-CCBs should be used with caution in the presence of mild-to-moderate renal insufficiency. C1 Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA. Univ Hosp, Cleveland, OH USA. NIDDKD, Off Minor Hlth Res Coordinat, NIH, Bethesda, MD 20892 USA. RP Douglas, JG (reprint author), Case Western Reserve Univ, Sch Med, Dept Med, W165,10900 Euclid, Cleveland, OH 44106 USA. NR 6 TC 4 Z9 4 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD FEB PY 2003 VL 63 SU 83 BP 74 EP 76 DI 10.1046/j.1523-1755.63.s83.15.x PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 635VE UT WOS:000180419700015 ER PT J AU Glanton, CW Kao, TC Cruess, D Agodoa, LYC Abbott, KC AF Glanton, CW Kao, TC Cruess, D Agodoa, LYC Abbott, KC TI Impact of renal transplantation on survival in end-stage renal disease patients with elevated body mass index SO KIDNEY INTERNATIONAL LA English DT Article DE obesity; body mass index; renal transplant; living donor; cadaveric organs; survival; wait list; dialysis; ESRD; USRDS ID RACIAL DISPARITIES; RECIPIENTS; MORTALITY; HEMODIALYSIS; OUTCOMES; DIALYSIS AB Background. Cadaveric renal transplantation is associated with a survival advantage compared with dialysis patients remaining on the renal transplantation waiting list, but this advantage has not been confirmed in obese end-stage renal disease (ESRD) patients. Methods. Using data from the USRDS, we studied 7521 patients who presented with ESRD from 1 April 1995 to 29 June 1999 and later enrolled on the renal transplantation waiting list with body mass indices (BMI) greater than or equal to30 kg/m(2) at the time of presentation to ESRD, and followed until 6 November 2000. Recipients of preemptive renal transplantation or organs other than kidneys were excluded. Cox non-proportional hazards regression models were used to calculate adjusted, time-dependent hazard ratios (HR) for time to death in a given patient during the study period, controlling for renal transplantation, demographics and comorbidities (Form 2728). Results. The incidence of mortality was 3.3 episodes per 100 patient-years (PY) in cadaveric renal transplantation and 1.9/100 PY in living donor renal transplantation compared with 6.6 episodes/100 PY in all patients on the transplant waiting list. In comparison to maintenance dialysis, both recipients of solitary cadaveric kidneys (HR 0.39, 95% CI 0.33 to 0.47), and recipients of living donor kidneys (HR 0.23, 95% CI 0.16 to 0.34) had statistically significant improved survival. A benefit of cadaveric renal transplantation did not apply to patients with BMI greater than or equal to41 kg/m(2) (HR 0.47, 95% CI, 0.17 to 1.25, P = 0.13). Conclusions. Obese patients on the renal transplant waiting list had a significantly lower risk of mortality after renal transplantation compared with those remaining on dialysis. C1 Walter Reed Army Med Ctr, MC Nephrol Serv, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NIDDK, NIH, Bethesda, MD USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, MC Nephrol Serv, Washington, DC 20307 USA. OI Abbott, Kevin/0000-0003-2111-7112 NR 21 TC 105 Z9 106 U1 0 U2 2 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD FEB PY 2003 VL 63 IS 2 BP 647 EP 653 DI 10.1046/j.1523-1755.2003.00761.x PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 635VB UT WOS:000180419300025 PM 12631130 ER PT J AU Nohammer, C Brunner, F Wolkart, G Staber, PB Steyrer, E Gonzalez, FJ Zechner, R Hoefler, G AF Nohammer, C Brunner, F Wolkart, G Staber, PB Steyrer, E Gonzalez, FJ Zechner, R Hoefler, G TI Myocardial dysfunction and male mortality in peroxisome proliferator-activated receptor alpha knockout mice overexpressing lipoprotein lipase in muscle SO LABORATORY INVESTIGATION LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; CHOLESTEROL LEVELS; MOUSE; METABOLISM; EXPRESSION; PLASMA; TISSUE; HYPERTRIGLYCERIDEMIA; FAMILY; HEART AB Free fatty acids (FFA) are liberated from triglyceride-rich lipoproteins by lipoprotein lipase (LPL) and are considered to be a principal energy source for the heart. The peroxisome proliferator-activated receptor alpha (PPARalpha) is a key regulator of FFA catabolism. To investigate its role in cardiac muscle metabolism, transgenic mice overexpressing LPL in skeletal and cardiac muscle were bred on a PPARalpha knockout background. Fifty-five percent of male animals lacking PPARalpha and overexpressing LPL died within 4 months after birth. In contrast, females of this genotype stayed alive. Deceased animals exhibited cardiopulmonary congestion but had no increase of neutral lipids in the heart. Changes in plasma glucose, FFA, lactate, and triglycerides did not clearly account for gender-specific differences in mortality; however, they indicated a critical role for PPARa during fasting. Analysis of cardiac function revealed that in isolated perfused hearts, left ventricular developed pressure (a measure of contractility) was markedly lower in PPARa knockout mice overexpressing LPL compared with controls. Glucose uptake of isolated perfused hearts was significantly higher in PPARalpha knockout mice with both normal or increased LPL expression. However, uptake of FFA was not different among genotypes. In contrast, fasted FFA levels were significantly lower in cardiac muscle of PPARalpha knockout mice with normal LPL expression (-26%) and PPARalpha knockout mice overexpressing LPL (-38%) compared with controls. Our results indicate a critical role for PPARalpha in myocardial pump function and suggest that mouse models combining different genetic effects such as PPARa knockout mice overexpressing muscle LPL may be useful to study cardiomyopathies. C1 Graz Univ, Dept Pathol, A-8036 Graz, Austria. Graz Univ, Dept Pharmacol & Toxicol, A-8036 Graz, Austria. Graz Univ, Dept Med Biochem, A-8036 Graz, Austria. Graz Univ, Dept Mol Biol Biochem & Microbiol, A-8036 Graz, Austria. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Hoefler, G (reprint author), Graz Univ, Dept Pathol, Auenbruggerpl 25, A-8036 Graz, Austria. RI Hoefler, Gerald/B-7006-2008; Hoefler, Gerald/H-1796-2016 OI Hoefler, Gerald/0000-0002-9056-3063 NR 27 TC 26 Z9 26 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD FEB PY 2003 VL 83 IS 2 BP 259 EP 269 DI 10.1097/01.LAB.0000053916.61772.CA PG 11 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 652QE UT WOS:000181389200011 PM 12594240 ER PT J AU Pommier, Y Kohn, KW AF Pommier, Y Kohn, KW TI New anticancer therapeutic targets in the cell cycle and cell cycle checkpoints SO M S-MEDECINE SCIENCES LA French DT Review ID DEPENDENT PROTEIN-KINASE; DNA-DAMAGE; P53 PATHWAY; C-MYC; CANCER; PEPTIDE; INHIBITION; ADENOVIRUS; MODULATORS; ONYX-015 AB Leland H. Hartwell, Paul M. Nurse et R. Timothy Hunt just received the Nobel price for their discovery of the molecular components of the cell cycle and cell cycle checkpoints. This review is an update of the molecular networks driving the cell cycle and its regulation, and of the importance of this knowledge for understanding the mechanisms driving oncogenesis and therapeutic developments. C1 NCI, Canc Res Ctr, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Canc Res Ctr, Mol Pharmacol Lab, NIH, Bldg 37,Room 5068, Bethesda, MD 20892 USA. NR 45 TC 13 Z9 19 U1 0 U2 7 PU MASSON EDITEUR PI PARIS 06 PA 120 BLVD SAINT-GERMAIN, 75280 PARIS 06, FRANCE SN 0767-0974 J9 M S-MED SCI JI M S-Med. Sci. PD FEB PY 2003 VL 19 IS 2 BP 173 EP 186 DI 10.1051/medsci/2003192173 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 644YH UT WOS:000180948600012 PM 12836612 ER PT J AU Peters, DC Lederman, RJ Dick, AJ Raman, VK Guttman, MA Derbyshire, JA McVeigh, ER AF Peters, DC Lederman, RJ Dick, AJ Raman, VK Guttman, MA Derbyshire, JA McVeigh, ER TI Undersampled projection reconstruction for active catheter imaging with adaptable temporal resolution and catheter-only views SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE catheter tracking; interventional MRI; projection reconstruction; radial imaging; real-time MRI; intravascular MRI; MR fluoroscopy; cardiac MRI ID REAL-TIME; MR FLUOROSCOPY; INTERVENTIONAL MRI; TRACKING; CONTRAST; ACQUISITION AB In this study undersampled projection reconstruction (PR) was, used for rapid catheter imaging in the heart, employing steady-state free precession (SSFP) contrast. Active catheters and phased-array coils were used for combined imaging of anatomy and catheter position in swine. Real-time imaging of catheter position was performed with relatively high spatial and temporal resolution, providing 2 x 2 x 8 mm spatial resolution and four to eight frames per second. Two interactive features were introduced. The number of projections (Np) was adjusted interactively to trade off imaging speed and artifact reduction, allowing acquisition of high-quality or high-frame-rate images. Thin-slice imaging was performed, with interactive requests for thick-slab projection images of the signal received solely from the active catheter. Briefly toggling on catheter-only projection images was valuable for verifying that the catheter tip was contained within the selected slice, or for locating the catheter when part of it was outside the selected slice. Published 2003 Wiley-Liss, Inc(dagger). C1 NIH, Cardiac Energet Lab, Bethesda, MD 20892 USA. RP Peters, DC (reprint author), NIH, Cardiac Energet Lab, 10 Ctr Dr,Bldg 10 B1D416, Bethesda, MD 20892 USA. OI lederman, robert/0000-0003-1202-6673 FU Intramural NIH HHS [Z01 HL005062-05, Z01 HL004608-08] NR 28 TC 27 Z9 27 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD FEB PY 2003 VL 49 IS 2 BP 216 EP 222 DI 10.1002/mrm.10390 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 642MA UT WOS:000180807100003 PM 12541240 ER PT J AU Herzka, DA Guttman, MA McVeigh, ER AF Herzka, DA Guttman, MA McVeigh, ER TI Myocardial tagging with SSFP SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE myocardial tagging; SSFP; FGRE; fast cardiac imaging; FISP ID STEADY-STATE PRECESSION; TAGGED MR-IMAGES; MAGNETIC-RESONANCE; BREATH-HOLD; VENTRICULAR-FUNCTION; HEART; MOTION; CONTRAST; TRUEFISP; TRACKING AB This work presents the first implementation of myocardial tagging with refocused steady-state free precession (SSFP) and magnetization preparation. The combination of myocardial tagging (a noninvasive method for quantitative measurement of regional and global cardiac function) with the high tissue signal-to-noise ratio (SNR) obtained with SSFP is shown to yield improvements in terms of the myocardium-tag contrast-to-noise ratio (CNR) and tag persistence When compared to the current standard fast gradient-echo (FGRE) tagging protocol. Myocardium-tag CNR and tag persistence were studied using numerical simulations as well as phantom and human experiments. Both quantities were found to decrease with increasing imaging flip angle (alpha) due to an increased tag decay rate and a decrease in myocardial steady-state signal. However, higher alpha yielded better blood-myocardium contrast, indicating that optimal alpha is dependent on the application: higher alpha for better blood-myocardium boundary visualization, and lower alpha for better tag persistence. SSFP tagging provided the same myocardium-tag CNR as FGRE tagging when acquired at four times the bandwidth and better tag- and blood-myocardium CNRs than FGRE tagging when acquired at equal or twice the receiver bandwidth (RBW). The increased acquisition efficiency of SSFP allowed decreases in breath-hold duration, or increases in temporal resolution, as compared to FGRE. Published 2003 Wiley-Liss, Inc.(dagger). C1 NHLBI, Lab Cardiac Energet, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. RP Herzka, DA (reprint author), NHLBI, Lab Cardiac Energet, NIH, 10 Ctr Dr,MSC-1061,Bldg 10,B1D416, Bethesda, MD 20892 USA. EM herzkad@nih.gov OI Herzka, Daniel/0000-0002-9400-7814 FU Intramural NIH HHS [Z01 HL004608-08] NR 40 TC 32 Z9 33 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD FEB PY 2003 VL 49 IS 2 BP 329 EP 340 DI 10.1002/mrm.10361 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 642MA UT WOS:000180807100017 PM 12541254 ER PT J AU Beauchamp, MS AF Beauchamp, MS TI Detection of eye movements from fMRI data SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE electrooculography; vitreous body; neuroimaging; physiological noise; BOLD ID IMAGE REGISTRATION; RF COIL; MOTION; ATTENTION; CORTEX; BRAIN AB Awake humans make eye movements with amplitudes and frequencies that depend on behavioral state and task. This poses two problems for functional magnetic resonance imaging (fMRI) studies that compare brain activity across tasks. First, motion of the eye in the orbit increases the variance of the MR signal in adjacent regions of the orbitofrontal cortex, hampering activation detection. Second, eye movements are associated with activity in a distributed network of brain areas, confounding comparisons of task activation. Direct measurement of eye movements in the scanner bore is possible with expensive and technically demanding equipment. A method is described that detects eye movements directly from MR data without the use of additional equipment. Changes in the MR time series from the vitreous of the eye were observed that correlated with eye movements, as measured directly with an infrared pupil tracking system. In each of 10 subjects, the variance of the MR time series from the eye vitreous was greater when the subject made eye movements than when the subject fixated centrally (average standard deviation (SD) 99.7 vs. 75.6, P = 0.001). The assessment of eye movements directly from fMRI data may be especially useful for retrospective and meta-analyses. Published 2003 Wiley-Liss, Inc.(dagger). C1 NIMH, LBC, Bethesda, MD 20892 USA. RP Beauchamp, MS (reprint author), NIMH, LBC, 10 Ctr Dr MSC 1366,Bldg 10,Rm 4C104, Bethesda, MD 20892 USA. OI Beauchamp, Michael/0000-0002-7599-9934 NR 19 TC 22 Z9 22 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD FEB PY 2003 VL 49 IS 2 BP 376 EP 380 DI 10.1002/mrm.10345 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 642MA UT WOS:000180807100022 PM 12541259 ER PT J AU Patel, S Kartasova, T Segre, JA AF Patel, S Kartasova, T Segre, JA TI Mouse Sprr locus: a tandem array of coordinately regulated genes SO MAMMALIAN GENOME LA English DT Article ID CORNIFIED ENVELOPE; BARRIER FUNCTION; EXPRESSION; FAMILY; SKIN; DIFFERENTIATION; PRECURSOR; COMPLEX; REGIONS; PROTEIN AB Small PRoline Rich (SPRR) proteins are primary constituents of the cornified cell envelope, necessary to create a permeability barrier across the body's surface. The family of murine Sprr genes has diversified, enabling the body to construct slightly different types of barriers as needed for backskin, mouth, tongue, etc. The Sprr genes have remained tandemly arrayed within 220 kb on mouse Chromosome (Chr) 3. On the basis of sequence similarity, we identified a novel member of the family, the murine ortholog of SPRR4. We present a sequence-verified physical map of the region and identify the complete coding sequence of the Sprr2 genes. Highly specific RNase protection assays based on the 3' untranslated sequences were used to query the expression of these genes in a model of barrier deficiency, mice with a targeted ablation of the transcription factor Kruppel-like factor 4 (Klf4-/-). Twelve of the 15 members of the Sprr family are upregulated in the Klf4-/- mice. The sequences upstream of the start of transcription of the Sprr2 genes contain common regulatory elements conserved with the human SPRR2 genes. The clustering of the genes and their misregulation suggest that these genes may be held together in a tandem array to allow coordinate regulation. C1 NHGRI, Epithelial Biol Sect, Bethesda, MD 20892 USA. RP Segre, JA (reprint author), NHGRI, Epithelial Biol Sect, Bethesda, MD 20892 USA. NR 25 TC 48 Z9 61 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD FEB PY 2003 VL 14 IS 2 BP 140 EP 148 DI 10.1007/s00335-002-2205-4 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 646WA UT WOS:000181057700006 PM 12584609 ER PT J AU Sidorov, IA Hirsch, KS Harley, CB Dimitrov, DS AF Sidorov, IA Hirsch, KS Harley, CB Dimitrov, DS TI Cancer treatment by telomerase inhibitors: predictions by a kinetic model SO MATHEMATICAL BIOSCIENCES LA English DT Article DE telomere; telomerase inhibitors; kinetic model ID MATHEMATICAL-MODELS; IMMORTAL CELLS; TUMOR-GROWTH; LENGTH; ASSOCIATION; LEUKEMIA AB The inhibition of telomerase activity in actively dividing cells leads to shortening of their telomeres and suppression of cell growth when the telomere lengths become smaller than a certain threshold value (typically about 1-2 kb of DNA). We evaluated the time (efficacy delay) required to reach the threshold telomeric DNA size after initiation of treatment, which is of critical importance for the efficacy of telomerase inhibitors. A model based on the solution of a system of differential equations was developed to analyze the efficacy delay and dynamics of tumor growth. The efficacy delay was strongly dependent on the size distribution of telomere lengths at the treatment initiation. An increase in the heterogeneity of telomere size resulted in shortening of the delay. However, the long-term dynamics of tumors with homogeneous populations of telomeres were more significantly affected by telomerase inhibitors compared to tumors with heterogeneous size distribution of telomeres. Size distribution of telomeres and tumor doubling times are of critical importance for the dynamics of tumor growth in presence of telomerase inhibitors. (C) 2003 Published by Elsevier Science Inc. C1 NCI, NIH, Frederick, MD 21702 USA. Emergent Biotechnol LLC, Redwood City, CA 94608 USA. Geron Corp, Menlo Pk, CA 94025 USA. RP Sidorov, IA (reprint author), NCI, NIH, POB B, Frederick, MD 21702 USA. NR 27 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-5564 J9 MATH BIOSCI JI Math. Biosci. PD FEB PY 2003 VL 181 IS 2 BP 209 EP 221 AR PII S0025-5564(02)00132-3 DI 10.1016/S0025-5564(02)00132-3 PG 13 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 624XH UT WOS:000179786800006 PM 12445762 ER PT J AU Hartmann, B Lee, PN Kang, YY Tomarev, S de Couet, HG Callaerts, P AF Hartmann, B Lee, PN Kang, YY Tomarev, S de Couet, HG Callaerts, P TI Pax6 in the sepiolid squid Euprymna scolopes: evidence for a role in eye, sensory organ and brain development SO MECHANISMS OF DEVELOPMENT LA English DT Article DE Pax6; squid; euprymna scolopes; eye; sensory organ; brain; development ID GENE; EXPRESSION; DROSOPHILA; HOMEOBOX; SEGMENTATION; EVOLUTION; ANIRIDIA; EYELESS; REGION AB The cloning of a Pax6 orthologue from the sepiolid squid Euprymna scolopes and its developmental expression pattern are described. The data are consistent with the presence of a single gene encoding a protein with highly conserved DNA-binding paired and homeodomains. A detailed expression analysis by in situ hybridization and immunodetection revealed Pax6 mRNA and protein with predominantly nuclear localization in the developing eye, olfactory organ, brain lobes (optic lobe, olfactory lobe, peduncle lobe, superior frontal lobe and dorsal basal lobe), arms and mantle, suggestive of a role in eye, brain, and sensory organ development. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Dept Biol & Biochem, Houston, TX 77204 USA. Univ Hawaii, Dept Zool, Honolulu, HI 96822 USA. NEI, NIH, Bethesda, MD 20892 USA. RP Callaerts, P (reprint author), Dept Biol & Biochem, Houston, TX 77204 USA. RI de Couet, Heinz/J-9522-2012 OI de Couet, Heinz/0000-0002-0307-2881 NR 22 TC 32 Z9 32 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD FEB PY 2003 VL 120 IS 2 BP 177 EP 183 DI 10.1016/S0925-4773(02)00456-2 PG 7 WC Developmental Biology SC Developmental Biology GA 648UP UT WOS:000181169200004 PM 12559490 ER PT J AU Lu, WQ Jablonski, KA Resnick, HE Jain, AK Jones, KL Gottlieb, AM Welty, TK Lee, ET Fabsitz, RR Howard, BV AF Lu, WQ Jablonski, KA Resnick, HE Jain, AK Jones, KL Gottlieb, AM Welty, TK Lee, ET Fabsitz, RR Howard, BV TI Alcohol intake and glycemia in American Indians: The Strong Heart Study SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID DEPENDENT DIABETES-MELLITUS; RISK-FACTORS; CARDIOVASCULAR-DISEASE; INSULIN SENSITIVITY; GLUCOSE-TOLERANCE; SWEDISH MEN; CONSUMPTION; POPULATION AB The goal of this study was to explore the relationship between alcohol intake and glycemia and type 2 diabetes in American Indians aged 45 to 74 years. Data were obtained from participants in the Strong Heart Study, a longitudinal study of 13 American Indian communities in 3 geographic areas in the United States. Alcohol consumption was determined by self-reported alcohol intake history. Participants previously diagnosed with diabetes were excluded from the analysis. Analysis of covariance (ANCOVA) was used to estimate the adjusted means of blood glucose for alcohol intake categories. Logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) to estimate the association between alcohol intake and type 2 diabetes in the cross-sectional analysis and between alcohol intake and glucose intolerance using longitudinal data. Fasting and 2-hour plasma glucose concentrations showed an inverse J-shaped curve across categories of alcohol intake. Using never drinkers as the referent group in cross-sectional analysis, light drinkers had a significantly lower risk of having diabetes (OR, 0.66; 95% CI, 0.44 to 0.99); among drinkers, heavy drinkers had a higher, although not significant, prevalence of diabetes. Longitudinal analysis showed no significant worsening of glucose tolerance across levels of alcohol intake. Subanalyses stratified by body mass index (BMI) did not show differences between obese and non-obese participants in the relationship between alcohol intake and glucose tolerance. Although plasma glucose concentration showed a shallow, inverse J-shaped association across levels of increasing alcohol intake in American Indians aged 45 to 74 years, alcohol intake did not appear to significantly increase the risk for worsening glucose tolerance. Thus, alcohol intake does not appear to be a determinant of diabetes risk in this population. Copyright 2003, Elsevier Science (USA). All rights reserved. C1 MedStar Res Inst, Adelphi, MD 20783 USA. Washington Hosp Ctr, Washington, DC 20010 USA. Aberdeen Area Tribal Chairmens Hlth Board, Rapid City, SD USA. Univ Oklahoma, Hlth Sci Ctr, Ctr Amer Indian Hlth Res, Oklahoma City, OK USA. NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. RP Howard, BV (reprint author), MedStar Res Inst, 6495 New Hampshire Ave,Suite 201, Adelphi, MD 20783 USA. FU NHLBI NIH HHS [U01-HL41642, UL01HL41654, U01HL41652] NR 34 TC 13 Z9 14 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 FEB PY 2003 VL 52 IS 2 BP 129 EP 135 DI 10.1053/meta.2003.50020 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 644MH UT WOS:000180921500001 PM 12601620 ER PT J AU Snyder, DS Small, PLC AF Snyder, DS Small, PLC TI Uptake and cellular actions of mycolactone, a virulence determinant for Mycobacterium ulcerans SO MICROBIAL PATHOGENESIS LA English DT Article DE mycolactone; confocal microscopy; signal transduction; macrolide; calcium ID APOPTOSIS; TOXIN; INHIBITOR; CELLS AB Mycolactone is a macrolide secreted by Mycobacterium ulcerans. Experimental evidence suggests that mycolactone plays a prominent role in the pathogenesis of Buruli ulcer by causing both tissue destruction and immunosuppression. To understand the cell biology of mycolactone activity, we have synthesized the fluorescent mycolactone derivativebodipymycolactone. Although derivatization resulted in a modest decrease in cytopathic activity, the derivatized and native molecules produce identical phenotypes in cultured cells. Confocal microscopy of bodipymycolactone added to cultured fibroblasts, shows that it is localized to the cytosol. Bodipymycolactone fails to bind to the cell membrane and is excluded from the nucleus. Uptake is both nonsaturable and noncompetitive with excess mycolactone, consistent with passive diffusion of this toxin through the cell membrane. These facts, combined with the inability of signal transduction inhibitors to inhibit mycolactone cytopathicity point towards the presence of an cytosolic target for mycolactone. A dose dependent increase in intracellular calcium levels at occurs upon mycolactone exposure, but chelation of intracellular calcium alters neither the cytopathicity nor the caspase induction profile of treated cells. Mitochondrial polarization is maintained in treated cells for up to 3 days arguing that the rise in intracellular calcium levels may be a result of cytoskeletal remodeling. Published by Elsevier Science Ltd. C1 Univ Tennessee, Dept Microbiol, Knoxville, TN 37996 USA. NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Small, PLC (reprint author), Univ Tennessee, Dept Microbiol, M409 Walters Life Sci Bldg, Knoxville, TN 37996 USA. EM psmall@tennessee.edu NR 24 TC 45 Z9 45 U1 0 U2 4 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0882-4010 J9 MICROB PATHOGENESIS JI Microb. Pathog. PD FEB PY 2003 VL 34 IS 2 BP 91 EP 101 DI 10.1016/S0882-4010(02)00210-3 PG 11 WC Immunology; Microbiology SC Immunology; Microbiology GA 659BU UT WOS:000181757900005 PM 12623277 ER PT J AU Bryant-Greenwood, P Sorbara, L Filie, AC Little, R Yarchoan, R Wilson, W Raffeld, M Abati, A AF Bryant-Greenwood, P Sorbara, L Filie, AC Little, R Yarchoan, R Wilson, W Raffeld, M Abati, A TI Infection of mesothelial cells with human herpes virus 8 in human immunodeficiency virus-infected patients with Kaposi's sarcoma, Castleman's disease, and recurrent pleural effusions SO MODERN PATHOLOGY LA English DT Article DE Castleman's disease; HHV 8; HIV; Kaposi's sarcoma; mesothelial cells; pleural effusions ID IMMUNE-DEFICIENCY-SYNDROME; DNA-SEQUENCES; VIRAL IL-6; LYMPHOMA; AIDS; EXPRESSION; CYTOKINE; INVOLVEMENT; KSHV AB Recurrent pleural effusions are common complications of hospitalized patients with human inummodeficiency virus (HIV) infection and may pose difficult diagnostic dilemmas. A common cause of recurrent pleural effusions in up to 30% of HIVseropositive patients is pulmonary involvement by Kaposi's sarcoma, a human herpesvirus 8 (HHV 8)related neoplasm. The pathogenesis of these effusions is unclear. These recurrent effusions, although benign, have shown significant mesothelial atypia/reactive changes of uncertain etiology. We attempted to evaluate these effusions morphologically and molecularly for the presence of HHV 8, with particular attention to mesothelial cells. All recurrent pleural effusions, as defined by any effusion tapped for cytological examination on more than two occasions, in HIV-positive patients at the National Institutes of Health were examined from 1998 to the present. Cases were stratified according to patients with and without histologically confirmed HHV 8 disease manifestations. Five patients with HHV 8 diseases (four with disseminated Kaposi's sarcoma and one with Castleman's disease) were identified. As a control group, five effusions from HIV-seropositive patients without known HHV 8-related diseases were identified. Cytological examination of effusions in patients with HHV 8-related diseases demonstrated atypical/markedly reactive mesothelial cells accompanied by a polymorphous background of lymphocytes. Molecular studies for B- and T-cell clonality in microdissected whole samples showed no definitive clones in these cases. Conversely, polymerase chain reaction (PCR) studies for the HHV 8 virus was positive in these samples. PCR studies on pure populations of microdissected mesothelial cells from the HHV 8-related effusions were positive for HHV 8 sequences, whereas those from HIV patients with non-HHV 8 related diseases were negative. Immunohistochemistry for HRV 8 (monoclonal antibody to latent nuclear antigen (LNA-1; ORF-73) on cellblock material demonstrated scattered positive mesothelial cells in three of the five cases of HHV 8-associated. effusions. HHV 8 has been recently implicated in the pathogenesis of Kaposi's sarcoma and primary effusion lymphoma. Mesothelial cells in recurrent pleural effusions from patients with Kaposi's sarcoma and Castleman's disease appear to be infected with HHV 8. Additional studies need to be done to define the role of mesothelial cell infection in the pathogenesis of these HHV 8-associated effusions and define the prognostic significance. C1 NCI, Cytopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Abati, A (reprint author), NCI, Cytopathol Sect, Pathol Lab, NIH, Bldg 10,Room 2A19, Bethesda, MD 20892 USA. NR 35 TC 12 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2003 VL 16 IS 2 BP 145 EP 153 DI 10.1097/01.MP.0000052374.61768.79 PG 9 WC Pathology SC Pathology GA 648ZC UT WOS:000181181400007 PM 12591967 ER PT J AU Taddesse-Heath, L Feldman, JI Fahle, GA Fischer, SH Sorbara, L Raffeld, M Jaffe, ES AF Taddesse-Heath, L Feldman, JI Fahle, GA Fischer, SH Sorbara, L Raffeld, M Jaffe, ES TI Florid CD4+, CD56+ T-Cell infiltrate associated with Herpes simplex infection simulating nasal NK-/T-Cell lymphoma SO MODERN PATHOLOGY LA English DT Article DE atypical lymphoid infiltrate; CD56; Herpes simplex virus; T/NK cell lymphoma ID LYMPHADENITIS; VIRUS; LYMPHOCYTES; MECHANISMS; EXPRESSION; LEUKEMIA; CLONES; LIVER; DNA AB We report a case of Herpes simplex virus (HSV) infection of the nasopharynx associated with a dense CD4+, CD56+ T-cell infiltrate that simulated lymphoma. on clinical, histologic, and immunophenotypic grounds. Histologic examination showed a tumorlike lymphoid infiltrate with extensive necrosis. Multinucleated giant cells with "ground-glass" nuclei characteristic of HSV were observed in necrotic areas but were not prominent. Immunohistochemical studies of the lymphoid infiltrate revealed a predominance of T cells, positive for CD3, CD4, CD5, and CD56. Immunohistochemical staining with HSV antibody was focally positive in the multinucleated giant cells. Molecular studies using PCR and Southern blot were positive for HSV Type H. PCR studies for T-cell receptor gamma and immunoglobulin heavy chain gene rearrangements showed no evidence of a clonal population. In situ hybridization studies for Epstein-Barr virus (EBV) were negative. The clinical presentation of a large fungating mass, the extent of the lymphoid infiltrate, and the expression of CD56 all raised the possibility of a nasal NK/T cell lymphoma. However, the presence of HSV, lack of angioinvasion and angiodestruction, absence of EBV, and polyclonal T-cell nature of the infiltrate argued against this diagnosis. Although prior studies have not fully characterized the immunophenotypic features of the lymphocyte response to HSV in infected tissues, we postulate that the CD56+, CD4+ T-ceff reaction represents a florid antiviral immune response. C1 NCI, Pathol Lab, Hematopathol Sect, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Microbiol Serv, Dept Lab Med, Bethesda, MD 20892 USA. Westerly Hosp, Westerly, RI USA. RP Jaffe, ES (reprint author), NCI, Pathol Lab, Hematopathol Sect, NIH, Bldg 10,Room 2N202,10 Ctr Dr,MSC-1500, Bethesda, MD 20892 USA. NR 28 TC 16 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD FEB PY 2003 VL 16 IS 2 BP 166 EP 172 DI 10.1097/01.MP.0000051680.14007.D7 PG 7 WC Pathology SC Pathology GA 648ZC UT WOS:000181181400010 PM 12591970 ER PT J AU Raghavan, N Miller, AN Gardner, M FitzGerald, PC Kerlavage, AR Johnston, DA Lewis, FA Knight, M AF Raghavan, N Miller, AN Gardner, M FitzGerald, PC Kerlavage, AR Johnston, DA Lewis, FA Knight, M TI Comparative gene analysis of Biomphalaria glabrata hemocytes pre- and post-exposure to miracidia of Schistosoma mansoni SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE Biomphalaria glabrata; EST; hemocytes; reverse transcriptase; Bge ID EXPRESSED SEQUENCE TAGS; TERMINAL REPEAT RETROTRANSPOSON; ORIENTAL BLOOD FLUKE; SNAIL HOST; IDENTIFICATION; GENOME; SUSCEPTIBILITY; SPOROCYSTS; INFECTION; JAPONICUM AB The internal defense mechanism of the snail Biomphalaria glabrata during a schistosome infection is activated and mediated via the immune effector cells known as hemocytes. Since resistance and susceptibility to schistosome infection is known to be genetically determined, our interest was to use the EST approach as a gene discovery tool to examine transcription profiles in hemocytes of resistant snails pre- and post-exposure to Schistosoma mansoni. Comparative analysis of the transcripts suggested that parasite exposure caused an active metabolic response in the hemocytes. The most abundant transcripts were those showing 23-74% similarity to known reverse transcriptases (RT). Further characterization by RT-PCR indicated the RT transcripts were expressed in normal snails, parasite exposed snails, and the embryonic cell line Bge. To determine whether the occurrence of RT transcripts correlates to the presence of functional enzyme activity in the snails, RT assays were performed from both resistant and susceptible snails, pre- and post-exposure to miracidia, using protein extracts from the head-foot and posterior region tissues. Results indicated that in the resistant snail, RT activity was greater in the posterior region than in the head-foot. After exposure, however, RT activity increased dramatically in the head-foot, with peak activity at 24 h post-exposure. The detection of RT activity in B. glabrata was unexpected and the role of this enzyme in the hemocyte-mediated killing of parasites is not yet known. However, identification of this and other transcripts from these cells by the EST approach provides a useful resource towards elucidating the molecular basis of resistance/susceptibility in this snail-host parasite relationship. (C) 2002 Published by Elsevier Science B.V. C1 Biomed Res Inst, Rockville, MD 20852 USA. Inst Genom Res, Rockville, MD 20850 USA. NCI, Genome Anal Unit, NIH, Bethesda, MD 20892 USA. Celera Genom Corp, Rockville, MD 20850 USA. Nat Hist Museum, Dept Zool, London SW7 5BD, England. RP Knight, M (reprint author), Biomed Res Inst, Rockville, MD 20852 USA. EM mknight@afbr-bri.com FU NIAID NIH HHS [AI-27777] NR 44 TC 59 Z9 63 U1 0 U2 6 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 FEB PY 2003 VL 126 IS 2 BP 181 EP 191 AR PII S0166-6851(02)00272-4 DI 10.1016/S0166-6851(02)00272-4 PG 11 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 659CV UT WOS:000181760700007 PM 12615317 ER PT J AU Loyevsky, M Mompoint, F Yikilmaz, E Altschul, SF Madden, T Wootton, JC Kurantsin-Mills, J Kassim, OO Gordeuk, VR Rouault, TA AF Loyevsky, M Mompoint, F Yikilmaz, E Altschul, SF Madden, T Wootton, JC Kurantsin-Mills, J Kassim, OO Gordeuk, VR Rouault, TA TI Expression of a recombinant IRP-like Plasmodium falciparum protein that specifically binds putative plasmodial IREs SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE malaria; Plasmodium falciparum; iron; IRE; IRP ID IRON-RESPONSIVE ELEMENT; MESSENGER-RNA; TRANSFERRIN RECEPTOR; REGULATORY PROTEIN-1; NITRIC-OXIDE; MOLECULAR CHARACTERIZATION; TRANSLATIONAL REGULATION; DROSOPHILA-MELANOGASTER; 5'-UNTRANSLATED REGION; HIGH-AFFINITY AB Plasmodium falciparum iron regulatory-like protein (PfIRPa, accession AJ012289) has homology to a family of iron-responsive element (IRE)-binding proteins (IRPs) found in different species. We have previously demonstrated that erythrocyte R falciparum PfIRPa binds a mammalian consensus IRE and that the binding activity is regulated by iron status. In the work we now report, we have cloned a C-terminus histidine-tagged PfIRPa and overexpressed it in a bacterial expression system in soluble form capable of binding IREs. To overexpress PfIRPa, we used the T7 promoter-driven vector, pET28a(+), in conjunction with the Rosetta(DE3)pLysS strain of E. coli, which carries extra copies of tRNA genes usually found in organisms such as R falciparum whose genome is (A + T)-rich. The histidine-tagged recombinant protein (rPfIRPa) in soluble form was partially purified using His-bind resin. We searched the plasmodial database, plasmoDB, to identify sequences capable of forming IRE loops using a specially developed algorithm, and found three plasmodial sequences matching the search criteria. In gel retardation assays, rPfIRPa bound three P-32-labeled putative plasmodial IREs with affinity exceeding the affinity for the mammalian consensus IRE. The binding was concentration-dependent and was not inhibited by heparin, an inhibitor of non-specific binding. Immunodepletion of rPfIRPa resulted in substantial inhibition of the signal intensity in the gel retardation assays and in Western blot-determinations of rPfIRPa protein levels. Endogenous PflRPa retained all three putative P-32-IREs at the same position on the gel as the recombinant PfIRPa. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. NICHD, NIH, Bethesda, MD USA. NIH, NCBI, Natl Lib Med, Bethesda, MD 20892 USA. Howard Univ, Dept Microbiol, Washington, DC 20059 USA. RP Loyevsky, M (reprint author), Howard Univ, Ctr Sickle Cell Dis, 2121 Georgia Ave NW, Washington, DC 20059 USA. EM mloyevsky@howard.edu FU NCRR NIH HHS [M01-RR10284]; NHLBI NIH HHS [UH1HL03679]; PHS HHS [A144857-03] NR 39 TC 21 Z9 21 U1 0 U2 1 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 FEB PY 2003 VL 126 IS 2 BP 231 EP 238 AR PII S0166-6851(02)00278-5 DI 10.1016/S0166-6851(02)00278-5 PG 8 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 659CV UT WOS:000181760700012 PM 12615322 ER PT J AU Hebbar, PB Archer, TK AF Hebbar, PB Archer, TK TI Nuclear factor 1 is required for both hormone-dependent chromatin remodeling and transcriptional activation of the mouse mammary tumor virus promoter SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID LONG TERMINAL REPEAT; ADENOVIRUS DNA-REPLICATION; GLUCOCORTICOID RECEPTOR; IN-VIVO; MMTV PROMOTER; PROGESTERONE-RECEPTOR; FACTOR ACCESS; HISTONE H1; BINDING; NUCLEOSOME AB The mouse mammary tumor virus (MMTV) promoter has been used as a model to study how the glucocorticoid receptor (GR) remodels chromatin to allow other transcription factors to bind and activate transcription. To dissect the precise role of nuclear factor 1 (NF1) in chromatin remodeling and transcriptional activation, we used linker-scanning mutants of transcription factor binding sites on the MMTV promoter. We compared the NF1 mutant MMTV promoter in the context of transiently transfected templates (transient transfection) and templates organized as chromatin (stable transfection) to understand the effect of chromatin on factor binding and transcription. We show that on a transiently transfected template, mutation in the NF1 binding site reduces both basal and hormone-dependent transcription. This suggests that NF1 is required for transcription in the absence of organized chromatin. We also found that binding of NF1 on a transiently transfected template is independent of mutation in hormone response elements or the octamer transcription factor (OTF) binding site. In contrast, the binding of OTF proteins to a transiently transfected template was found to be dependent on the binding of NF1, which may imply that NF1 has a stabilizing effect on OTF binding. On a chromatin template, mutation in the NF1 binding site does not affect the positioning of nucleosomes on the promoter. We also show that in the absence of NF1 binding, GR-mediated chromatin remodeling of nucleosome B is reduced and hormone-dependent activation of transcription is abolished. Further, we demonstrate that NF1 is required for both the association of BRG1 chromatin remodeling complex and the GR on the promoter in vivo. These results suggest the novel possibility that NF1 may participate in chromatin remodeling activities in addition to directly enhancing transcription and that in the absence of its binding site the GR is unable to effectively bind the promoter and recruit the remodeling complex. C1 NIEHS, Chromatin & Gene Express Sect, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), NIEHS, Chromatin & Gene Express Sect, Reprod & Dev Toxicol Lab, POB 12233,111 Alexander Dr,MD E4-06, Res Triangle Pk, NC 27709 USA. NR 56 TC 44 Z9 44 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 FEB PY 2003 VL 23 IS 3 BP 887 EP 898 DI 10.1128/MCB.23.3.887-898.2003 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 640DY UT WOS:000180673600012 PM 12529394 ER PT J AU Bi, XL Kajava, AV Jones, T Demidenko, ZN Mortin, MA AF Bi, XL Kajava, AV Jones, T Demidenko, ZN Mortin, MA TI The carboxy terminus of prospero regulates its subcellular localization SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HOMEODOMAIN-DNA INTERACTIONS; HOMEOBOX GENE PROX-1; SENSE ORGAN LINEAGE; SIBLING CELL FATE; NUCLEAR EXPORT; TRANSCRIPTION FACTOR; ASYMMETRIC LOCALIZATION; DROSOPHILA-PROSPERO; CRYSTAL-STRUCTURE; PROTEIN AB Subcellular localization of the transcription factor Prospero is dynamic. For example, the protein is cytoplasmic in neuroblasts, nuclear in sheath cells, and degraded in newly formed neurons. The carboxy terminus of Prospero, including the homeodomain and Prospero domain, plays roles in regulating these changes. The homeodomain has two distinct subdomains, which exclude proteins from the nucleus, while the intact homeo/Prospero domain masks this effect. One subdomain is an Exportin-dependent nuclear export signal requiring three conserved hydrophobic residues, which models onto helix 1. Another, including helices 2 and 3, requires proteasome activity to degrade nuclear protein. Finally, the Prospero domain is missing in pros(113) embryos, thus unmasking nuclear exclusion, resulting in constitutively cytoplasmic protein. Multiple processes direct Prospero regulation of cell fate in embryonic nervous system development. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NIH, Ctr Mol Modeling, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Mortin, MA (reprint author), NCI, Biochem Lab, NIH, Bldg 37,Rm 6134,37 Convent Dr, Bethesda, MD 20892 USA. RI Bi, Xiaolin/E-7469-2010; Mortin, Mark/B-4251-2008; Bi, Xiaolin/C-7038-2014; Kajava, Andrey/E-1107-2014 OI Bi, Xiaolin/0000-0002-7172-7851; Bi, Xiaolin/0000-0003-2837-9457; Kajava, Andrey/0000-0002-2342-6886 NR 38 TC 16 Z9 17 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD FEB PY 2003 VL 23 IS 3 BP 1014 EP 1024 DI 10.1128/MCB.23.3.1004-1024.2003 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 640DY UT WOS:000180673600023 PM 12529405 ER PT J AU Yamagoe, S Kanno, T Kanno, Y Sasaki, S Siegel, RM Lenardo, MJ Humphrey, G Wang, YH Nakatani, Y Howard, BH Ozato, K AF Yamagoe, S Kanno, T Kanno, Y Sasaki, S Siegel, RM Lenardo, MJ Humphrey, G Wang, YH Nakatani, Y Howard, BH Ozato, K TI Interaction of histone Acetylases and deacetylases in vivo SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-POLYMERASE-II; N-COR; TRANSCRIPTIONAL REPRESSION; DNA METHYLATION; ENERGY-TRANSFER; COMPLEX; PCAF; YEAST; COACTIVATOR; PROTEIN AB Having opposing enzymatic activities, histone acetylases (HATs) and deacetylases affect chromatin and regulate transcription. The activities of the two enzymes are thought to be balanced in the cell by an unknown mechanism that may involve their direct interaction. Using fluorescence resonance energy transfer analysis, we demonstrated that the acetylase PCAF and histone deacetylase 1 (HDAC1) are in close spatial proximity in living cells, compatible with their physical interaction. In agreement, coimmunoprecipitation assays demonstrated that endogenous HDACs are associated with PCAF and another acetylase, GCN5, in HeLa cells. We found by glycerol gradient sedimentation analysis that HATs are integrated into a large multiprotein HDAC complex that is distinct from the previously described HDAC complexes containing mSin3A, Mi-2/NRD, or CoREST. This HDAC-HAT association is partly accounted for by a direct protein-protein interaction observed in vitro. The HDAC-HAT complex may play a role in establishing a dynamic equilibrium of the two enzymes in vivo. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bldg 6,Rm 2A01, Bethesda, MD 20892 USA. RI Siegel, Richard/C-7592-2009; Kanno, Yuka/B-5802-2013; OI Siegel, Richard/0000-0001-5953-9893; Kanno, Yuka/0000-0001-5668-9319 NR 46 TC 58 Z9 60 U1 0 U2 3 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 FEB PY 2003 VL 23 IS 3 BP 1025 EP 1033 DI 10.1128/MCB.23.3.1025-1033.2003 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 640DY UT WOS:000180673600024 PM 12529406 ER PT J AU Naslavsky, N Weigert, R Donaldson, JG AF Naslavsky, N Weigert, R Donaldson, JG TI Convergence of non-clathrin-and clathrin-derived endosomes involves Arf6 inactivation and changes in phosphoinositides SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CLASS-I MOLECULES; MHC CLASS-II; PLASMA-MEMBRANE; INTERLEUKIN-2 RECEPTORS; ENDOCYTIC PATHWAY; CELL-SURFACE; CONSTITUTIVE MACROPINOCYTOSIS; DENDRITIC CELLS; DOWN-REGULATION; BETA-CHAIN AB The trafficking of two plasma membrane (PM) proteins that lack clathrin internalization sequences, major histocompatibility complex class I (MHCI), and interleukin 2 receptor a subunit (Tac) was compared with that of PM proteins internalized via clathrin. MHCI and Tac were internalized into endosomes that were distinct from those containing clathrin cargo. At later times, a fraction of these internalized membranes were observed in Arf6-associated, tubular recycling endosomes whereas another fraction acquired early endosomal autoantigen 1 (EEA1) before fusion with the "classical" early endosomes containing the clathrin-dependent cargo, LDL. After Convergence, cargo molecules from both pathways eventually arrived, in a Rab7-dependent manner, at late endosomes and were degraded. Expression of a constitutively active mutant of Arf6, Q67L, caused MHCI and Tac to accumulate in enlarged PIP2-enriched vacuoles, devoid of EEA1 and inhibited their fusion with clathrin cargo-containing endosomes and hence blocked degradation. By contrast, trafficking and degradation of clathrin-cargo was not affected. A similar block in transport of MHCI and Tac was reversibly induced by a PI3-kinase inhibitor, implying that inactivation of Arf6 and acquisition of PI3P are required for convergence of endosomes arising from these two pathways. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Donaldson, JG (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 40 TC 187 Z9 192 U1 1 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 FEB PY 2003 VL 14 IS 2 BP 417 EP 431 DI 10.1091/mbc.02-04-0053 PG 15 WC Cell Biology SC Cell Biology GA 666NX UT WOS:000182184300007 PM 12589044 ER PT J AU Wu, XF Zhao, XH Puertollano, R Bonifacino, JS Eisenberg, E Greene, LE AF Wu, XF Zhao, XH Puertollano, R Bonifacino, JS Eisenberg, E Greene, LE TI Adaptor and clathrin exchange at the plasma membrane and trans-golgi network SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID COATED VESICLE FORMATION; MEDIATED ENDOCYTOSIS; IN-VIVO; DYNAMIN FAMILY; LIVING CELLS; PROTEINS; COMPLEX; MUTANT; INTERNALIZATION; PHOSPHORYLATION AB We previously demonstrated, using fluorescence recovery after photobleaching, that clathrin in clathrin-coated pits at the plasma membrane exchanges with free clathrin in the cytosol, suggesting that clathrin-coated pits are dynamic structures. We now investigated whether clathrin at the trans-Golgi network as well as the clathrin adaptors AP2 and AP1 in clathrin-coated pits at the plasma membrane and trans-Golgi network, respectively, also exchange with free proteins in the cytosol. We found that when the budding of clathrin-coated vesicle is blocked without significantly affecting the structure of clathrin-coated pits, both clathrin and AP2 at the plasma membrane and clathrin and AP1 at the trans-Golgi network exchange rapidly with free proteins in the cytosol. In contrast, when budding of clathrin-coated vesicles was blocked at the plasma membrane or trans-Golgi network by hypertonic sucrose or K+ depletion, conditions that markedly affect the structure of clathrin-coated pits, clathrin exchange was blocked but AP2 at the plasma membrane and both AP1 and the GGA1 adaptor at the trans-Golgi network continue to rapidly exchange. We conclude that clathrin-coated pits are dynamic structures with rapid exchange of both clathrin and adaptors and that adaptors are able to exchange independently of clathrin when clathrin exchange is blocked. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Greene, LE (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. OI Bonifacino, Juan S./0000-0002-5673-6370 NR 32 TC 65 Z9 66 U1 0 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 FEB PY 2003 VL 14 IS 2 BP 516 EP 528 DI 10.1091/mbc.E02-06-0353 PG 13 WC Cell Biology SC Cell Biology GA 666NX UT WOS:000182184300014 PM 12589051 ER PT J AU Hodges, LC Cook, JD Lobenhofer, EK Li, LP Bennett, L Bushel, PR Aldaz, CM Afshari, CA Walker, CL AF Hodges, LC Cook, JD Lobenhofer, EK Li, LP Bennett, L Bushel, PR Aldaz, CM Afshari, CA Walker, CL TI Tamoxifen functions as a molecular agonist inducing cell cycle-associated genes in breast cancer cells SO MOLECULAR CANCER RESEARCH LA English DT Article ID HUMAN ESTROGEN-RECEPTOR; QUINONE REDUCTASE GENE; BONE-MINERAL DENSITY; POSTMENOPAUSAL WOMEN; MESSENGER-RNA; TRANSCRIPTIONAL ACTIVATION; ANTIESTROGEN TAMOXIFEN; E-CDK2 ACTIVATION; IN-VITRO; C-FOS AB Tamoxifen is a widely used breast cancer therapeutic and preventative agent. Although functioning as an estrogen antagonist at the cellular level, transcriptional profiling revealed that at the molecular level, tamoxifen functions largely as an agonist, virtually recapitulating the gene expression profile induced in breast cancer cells by estrogen. Remarkably, tamoxifen induces transcription factors and genes involved in promoting cell cycle progression including fos, myc, myb, cdc25a, cyclins E and A2, and stk15 with kinetics that paralleled that of cells cycling in response to estrogen, even though tamoxifen-treated cells are not transiting through the cell cycle. Induction of cell cycle-associated genes was specific for tamoxifen, and did not occur with raloxifene. However, cyclin D1 was a key estrogen-induced gene not expressed in response to tamoxifen or raloxifene but constitutively expressed in tamoxifen-resistant cells. C1 UT MD Anderson Canc Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USA. Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC USA. Natl Inst Environm Hlth Sci, Lab Mol Carcinogenesis, Res Triangle Pk, NC USA. RP Walker, CL (reprint author), UT MD Anderson Canc Ctr, Dept Carcinogenesis, Sci Pk Res Div, POB 389, Smithville, TX 78957 USA. EM cwalker@odin.mdacc.tmc.edu FU NIEHS NIH HHS [ES07784, ES98263] NR 52 TC 92 Z9 97 U1 0 U2 5 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 FEB PY 2003 VL 1 IS 4 BP 300 EP 311 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 761EX UT WOS:000187888800006 PM 12612058 ER PT J AU Burroughs, KD Oh, J Barrett, JC DiAugustine, RP AF Burroughs, KD Oh, J Barrett, JC DiAugustine, RP TI Phosphatidylinositol 3-kinase and Mek1/2 are necessary for insulin-like growth factor-I-induced vascular endothelial growth factor synthesis in prostate epithelial cells: A role for hypoxia-inducible factor-1? SO MOLECULAR CANCER RESEARCH LA English DT Article ID FACTOR VEGF EXPRESSION; DOMINANT-NEGATIVE MUTANT; SIGNAL-REGULATED KINASE; CANCER CELLS; FACTOR RECEPTOR; FACTOR 1-ALPHA; BREAST-CANCER; FACTOR GENE; ANTISENSE RNA; TRANSCRIPTIONAL ACTIVATION AB Due to the importance of vascular endothelial growth factor (VEGF) in the neovascularization of solid tumors, a clear understanding of how VEGF is regulated in normal and tumor cells is warranted. We investigated insulin-like growth factor (IGF)-I-stimulated signaling pathways that increase the rate of VEGF synthesis in primary cultures of normal prostate epithelial cells (PrEC). IGF-I increased the secretion of VEGF(165) into PrEC growth medium and stimulated transcription of a reporter gene driven by a 1.5-kb region of the VEGF promoter. Inhibition of either phosphatidylinositol 3-kinase (PI3-K) or Mek1/2 signaling pathways completely abrogated the IGF-I-induced increase in VEGF secretion and promoter activity, indicating a dependence on coordinate signaling from both pathways to produce this effect. Levels of the transcription factors hypoxia-inducible factor (HIF)-1 and Fos were elevated in response to IGF-I in a PI3-K-dependent and Mek1/2-dependent manner, respectively. The expression of an activator protein (AP)-1 dominant negative in an immortalized prostate epithelial cell line PZ-HPV-7 suppressed the IGF-I-induced increase in VEGF promoter activity. Mutation of the hypoxia response element (HRE), which mediates hypoxic stimulation of VEGF transcription, did not inhibit the effect of IGF-I on the VEGF promoter, despite the fact that this mutation inhibited PI3-K-stimulated VEGF promoter activity in prostate cancer cells. These data indicate that PI3-K signaling does not increase VEGF transcription through transactivation by HIF-1 at the HRE in normal PrEC. This work also suggests that an additional signal, not stimulated by IGF-I in PrEC, is needed for HIF-1 to stimulate transcription from the VEGF HRE. C1 Natl Inst Environm Hlth Sci, Hormones & Canc Grp, Lab Mol Carcinogenesis, Res Triangle Pk, NC 27709 USA. NCI, Ctr Canc Res, Bethesda, MD USA. RP DiAugustine, RP (reprint author), Natl Inst Environm Hlth Sci, Hormones & Canc Grp, Lab Mol Carcinogenesis, Mail Drop D4-04,POB 12233, Res Triangle Pk, NC 27709 USA. EM diaugus2@niehs.nih.gov NR 70 TC 43 Z9 46 U1 0 U2 0 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 FEB PY 2003 VL 1 IS 4 BP 312 EP 322 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 761EX UT WOS:000187888800007 PM 12612059 ER PT J AU Chiosis, G Huezo, H Rosen, N Mimnaugh, E Whitesell, L Neckers, L AF Chiosis, G Huezo, H Rosen, N Mimnaugh, E Whitesell, L Neckers, L TI 17AAG: Low target binding affinity and potent cell activity - Finding an explanation SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID HSP90 MOLECULAR CHAPERONE; BREAST-CANCER CELLS; MUTANT P53; ANSAMYCINS CAUSES; TYROSINE KINASE; ANTITUMOR AGENT; HERBIMYCIN-A; ATP BINDING; IN-VIVO; GELDANAMYCIN AB The ansamycin geldanamycin (GM) and its derivative, 17AAG, now in early clinical trials in cancer patients, have potent activity against several cancer cells at low nanomolar concentrations. The main target of these drugs is the molecular chaperone heat shock protein 90. Contrary to the high antitumor potency, the affinity of these drugs for the chaperone was determined to be similar to1 muM. We propose that this difference can partly be explained by the physicochemical characteristics of the ansamycins. GM and 17AAG accumulate in cells, producing higher intracellular concentrations than expected. We conclude that although apparent activity for ansamycins can be seen at low nanomolar concentration, their real activity correlates with the heat shock protein 90 binding affinity and is in the low micromolar concentration range. We suggest that in the clinic, micromolar concentrations of 17AAG must accumulate in the tumor cells to achieve antitumor effects in patients comparable with ones achieved in tissue culture settings. C1 Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Program Cell Biol, New York, NY 10021 USA. NCI, Cell & Canc Biol Branch, NIH, Rockville, MD 20850 USA. Univ Arizona, Steele Mem Childrens Res Ctr, Tucson, AZ 85724 USA. RP Chiosis, G (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave,Box 271, New York, NY 10021 USA. FU NCI NIH HHS [1U01CA91178-01] NR 53 TC 135 Z9 141 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD FEB PY 2003 VL 2 IS 2 BP 123 EP 129 PG 7 WC Oncology SC Oncology GA 645YF UT WOS:000181007500001 PM 12589029 ER PT J AU Porta, M Ayude, D Alguacil, J Jariod, M AF Porta, M Ayude, D Alguacil, J Jariod, M TI Exploring environmental causes of altered ras effects: Fragmentation plus integration? SO MOLECULAR CARCINOGENESIS LA English DT Review DE pancreas; neoplasms; ras genes; mutation spectra; organic chemicals; environment/chemistry ID EXOCRINE PANCREATIC-CANCER; NF-KAPPA-B; ACTIVATED PROTEIN-KINASE; INDUCED OXIDATIVE STRESS; HUMAN RSA CELLS; K-RAS; POLYCHLORINATED-BIPHENYLS; VINYL-CHLORIDE; MUTATION SPECTRA; HA-RAS AB Mutations in ras genes are the most common abnormality of oncogenes in human cancer and a major example of activation by point mutation. Experimental and epidemiological studies support the notion that Ki-ras activation and expression may be chemically related. We discuss the potential role of several environmental compounds in the induction or promotion of ras mutations in humans, with a focus on exocrine pancreatic cancer, the human tumor with the highest prevalence at diagnosis of Ki-ras mutations. Organochlorine compounds, organic solvents, and coffee compounds may play an indirect role in causing Ki-ras mutations, rather than as direct inducers of the mutations. Although for some organochlorine compounds the induction of point mutations in ras oncogenes cannot be excluded, it seems more likely that the effects of these compounds are mediated through nongenomic or indirectly genotoxic mechanisms of action. Organic solvents also may act via enzymatic induction of ras mutagens or by providing a proliferation advantage to ras-mutated cell clones. In exocrine pancreatic cancer, caffeine, other coffee compounds, or other factors with which coffee drinking is associated could modulate Ki-ras activation by interfering with DNA repair, cell-cycle checkpoints, and apoptosis. Asbestos, cigarette smoking, and some dietary factors also may be involved in the initiation or the promotion of Ki-ras mutations in lung and colon cancers. Further development of the mechanistic scenarios proposed here could contribute to a meaningful integration of biological, clinical, and environmental knowledge on the causes of altered ras effects. (C) 2003 Wiley-Liss, Inc. C1 Univ Autonoma Barcelona, Inst Municipal Invest Med, E-08003 Barcelona, Spain. NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Autonoma Barcelona, Catalonia, Spain. RP Porta, M (reprint author), Univ Autonoma Barcelona, Inst Municipal Invest Med, Carrer Dr Aiguader 80, E-08003 Barcelona, Spain. RI Porta, Miquel/B-5787-2008 OI Porta, Miquel/0000-0003-1684-7428 NR 127 TC 19 Z9 20 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD FEB PY 2003 VL 36 IS 2 BP 45 EP 52 DI 10.1002/mc.10093 PG 8 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 642RB UT WOS:000180817200001 PM 12557259 ER PT J AU Jazaeri, AA Lu, K Schmandt, R Harris, CP Rao, PH Sotiriou, C Chandramouli, GVR Gershenson, DM Liu, ET AF Jazaeri, AA Lu, K Schmandt, R Harris, CP Rao, PH Sotiriou, C Chandramouli, GVR Gershenson, DM Liu, ET TI Molecular determinants of tumor differentiation in papillary serous ovarian carcinoma SO MOLECULAR CARCINOGENESIS LA English DT Article DE ovarian cancer; grade; microarray; centrosome; 20q13 ID COMPARATIVE GENOMIC HYBRIDIZATION; GENE-EXPRESSION PROFILES; PROGNOSTIC-SIGNIFICANCE; CDNA MICROARRAY; DNA-PLOIDY; 20Q GAIN; CANCER; IMMORTALIZATION; PROLIFERATION; AMPLIFICATION AB In epithelial ovarian cancer, tumor grade is an independent prognosticator whose molecular determinants remain unknown. We investigated patterns of gene expression in well- and poorly differentiated serous papillary ovarian and peritoneal carcinomas with cDNA microarrays. A 6500-feature cDNA microarray was used for comparison of the molecular profiles of eight grade III and four grade I stage III serous papillary adenocarcinomas. With a modified F-test in conjunction with random permutations, 99 genes whose expression was significantly different between grade I and grade III tumors were identified (P < 0.01). A disproportionate number of these differentially expressed genes were located on the chromosomal regions 20q13 and all exhibited higher expression in grade III tumors. Interphase fluorescent in situ hybridization demonstrated 20q13 amplification in two of the four grade III and none of the three grade I tumors available for evaluation. Several centrosome-related genes also showed higher expression in grade III tumors. We propose a model in which tumor differentiation is inversely correlated with the overexpression of several oncogenes located on 20q13, a common amplicon in ovarian and numerous other cancers. Dysregulation of centrosome function is one potential mechanistic link between genetic/epigenetic changes and the poorly differentiated phenotype in ovarian cancer. Published 2003 Wiley-Liss, Inc. C1 Univ Texas, MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. Texas Childrens Canc Ctr, Dept Pediat, Houston, TX USA. NCI, Ctr Canc Res, Gaithersburg, MD USA. RP Jazaeri, AA (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Gynecol Oncol, 1515 Holcombe Blvd,Box 440, Houston, TX 77030 USA. RI Jazaeri, Amir/A-2400-2008; Liu, Edison/C-4141-2008; Jazaeri, Amir/I-3458-2015 OI Jazaeri, Amir/0000-0003-4335-4151 NR 36 TC 62 Z9 63 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD FEB PY 2003 VL 36 IS 2 BP 53 EP 59 DI 10.1002/mc.10098 PG 7 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 642RB UT WOS:000180817200002 PM 12557260 ER PT J AU Sandrini, F Stratakis, C AF Sandrini, F Stratakis, C TI Clinical and molecular genetics of Carney complex SO MOLECULAR GENETICS AND METABOLISM LA English DT Review ID NODULAR ADRENOCORTICAL DISEASE; PROTEIN-KINASE-A; SPOTTY SKIN PIGMENTATION; PSAMMOMATOUS MELANOTIC SCHWANNOMA; FAMILIAL CARDIAC MYXOMAS; ENDOCRINE OVERACTIVITY; REGULATORY SUBUNIT; ACTIVATING MUTATIONS; ATRIAL-MYXOMA; PRKAR1A GENE AB Carney complex (CNC) is a multiple endocrine neoplasia (MEN) syndrome characterized by lentigines, cardiac myxomas and tumors, including primary pigmented adrenocortical disease (PPNAD). In the present report we review the main clinical manifestations of this disorder. We also discuss some of the newest molecular information regarding CNC. The complex has been mapped to 2p16 and 17q22-24, and a third locus appears likely. The gene coding for the protein kinase A (PKA) type I-a regulatory subunit (RIa), PRKAR1A, had been mapped to 17q. Cloning of the PRKAP1A genomic structure and its sequencing showed mutations in CNC patients. So far, among 57 kindreds, PRKAR1A mutations. have been found in 28. In almost all the mutations, the sequence change is predicted to lead to a premature stop codon; 1 mutation altered the initiator ATG codon. Analysis of mRNA transcripts in patient lymphocytes treated with cycloheximide showed that mutant mRNAs containing a premature stop codon were degraded, due to nonsense-mediated mRNA decay-the predicted mtPRKAR1A protein products were absent in these cells. In CNC tumors, PKA activity showed increased stimulation by cAMP, whereas PKA activity ratio was decreased. To date, mutations in the PRKAR1A gene have been described in CNC patients and in some sporadic endocrine tumors. LOH of the normal allele and increased PKA activity in response to cAMP are found in these tumors, suggesting that normal PRKAR1A (largely responsible for PKA type I activity) is implicated more widely in endocrine tumorigenesis. CNC is the first human disease caused by mutations of one of the subunits of the PKA holoenzyme, a critical component of numerous cellular signaling systems. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NICHHD, Sect Endocrinol & Genet, Dev Endocrinol Branch, Bethesda, MD 20892 USA. RP Stratakis, C (reprint author), NICHHD, Sect Endocrinol & Genet, Dev Endocrinol Branch, Bldg 10,Room 10N262,10 Ctr Dr,MSC1862, Bethesda, MD 20892 USA. NR 55 TC 44 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD FEB PY 2003 VL 78 IS 2 BP 83 EP 92 DI 10.1016/S1096-7192(03)00006-4 PG 10 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 655XH UT WOS:000181577600001 PM 12666684 ER PT J AU Wolford, JK Gruber, JD Ossowski, VM Vozarova, B Tataranni, PA Bogardus, C Hanson, RL AF Wolford, JK Gruber, JD Ossowski, VM Vozarova, B Tataranni, PA Bogardus, C Hanson, RL TI A C-reactive protein promoter polymorphism is associated with type 2 diabetes mellitus in Pima Indians SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE 1q21; single nucleotide polymorphisms (SNPs); association analyses; candidate genes; positional cloning; complex disease; chronic inflammation; C-reactive protein; diabetes mellitus, type 2; type 2 diabetes mellitus; corrected insulin response ID SERUM SIALIC-ACID; INSULIN SENSITIVITY; INDEPENDENT REPLICATION; SUSCEPTIBILITY GENES; RISK; INFLAMMATION; LOCI; ATHEROSCLEROSIS; SECRETION; INDEXES AB Linkage analysis has identified a susceptibility locus for type 2 diabetes mellitus (T2DM) on chromosome 1q21-q23 in several populations. Results from recent prospective studies indicate that increased levels of C-reactive protein (CRP), a marker of immune system activation, are predictive of diabetes, independent of adiposity. Because CRP is located on 1q21, we considered it a potential positional candidate gene for T2DM. We therefore evaluated CRP and the nearby serum amyloid P-component, APCS, which is structurally similar to CRP, as candidate diabetes susceptibility genes. Approximately 10.9 kb of the CRP-APCS locus was screened for polymorphisms using denaturing high performance liquid chromatography and direct sequencing. We identified 27 informative polymorphisms, including 26 single nucleotide polymorphisms (SNPs) and 1 insertion/deletion, which were divided into 7 linkage disequilibrium clusters. We genotyped representative SNPs in similar to 1300 Pima samples and found a single variant in the CRP promoter (SNP 133552) that was associated with T2DM (P = 0.014), as well as a common haplotype (CGCG) that was associated with both T2DM (P = 0.029) and corrected insulin response, a surrogate measure of insulin secretion in non-diabetic subjects (P = 0.050). Linkage analyses that adjusted for the effect of these polymorphisms indicated that they do not in themselves account for the observed linkage with T2DM on chromosome 1q. However, these findings suggest that variation within the CRP locus may play a role in diabetes susceptibility in Pima Indians. (C) 2003 Elsevier Science (USA). All rights reserved. C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Res Branch, NIH, Phoenix, AZ 85016 USA. RP Wolford, JK (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Res Branch, NIH, 4212 N 16th St, Phoenix, AZ 85016 USA. RI Hanson, Robert/O-3238-2015; OI Hanson, Robert/0000-0002-4252-7068; de Courten, Barbora/0000-0001-8760-2511 NR 27 TC 63 Z9 64 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 FEB PY 2003 VL 78 IS 2 BP 136 EP 144 DI 10.1016/S1096-7192(02)00230-5 PG 9 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 655XH UT WOS:000181577600007 PM 12618085 ER PT J AU Bae, MA Song, BJ AF Bae, MA Song, BJ TI Critical role of c-Jun N-terminal protein kinase activation in troglitazone-induced apoptosis of human HepG2 hepatoma cells SO MOLECULAR PHARMACOLOGY LA English DT Article ID SMOOTH-MUSCLE CELLS; RECEPTOR-GAMMA; JNK ACTIVATION; DEATH PATHWAY; PC12 CELLS; THIAZOLIDINEDIONE; MITOCHONDRIAL; HEPATOCYTES; LIGAND; DIFFERENTIATION AB The peroxisome proliferator-activated receptor agonist troglitazone (TRO) was used for treatment of non-insulin-dependent diabetes until its removal from the market because of its severe hepatotoxicity. However, the mechanism for its hepatotoxicity is still poorly understood. In this study, we investigated whether TRO caused cell death by altering signaling pathways associated with cell damage and survival in human hepatoma cells. Our data reveal that TRO caused time- and concentration-dependent apoptosis of HepG2 and Chang liver human hepatoma cells, as evidenced by DNA fragmentation and staining with Hoechst 33342. In contrast, 50 or 100 muM rosiglitazone, a structural analog of TRO, did not cause apoptosis in these hepatoma cells. TRO activated both c-Jun N-terminal protein kinase (JNK) and p38 kinase about 5-fold between 0.5 and 8 h before they returned to control levels at 16 h in HepG2 cells. In contrast, TRO failed to activate the extracellular signal-regulated kinase. Furthermore, TRO increased the levels of proapoptotic proteins, Bad, Bax, release of cytochrome c, and cleavage of Bid in a time-dependent manner. The antiapoptotic Bcl-2 protein level decreased in hepatoma cells treated with TRO. Pretreatment of hepatoma cells with a selective JNK inhibitor, anthra[1,9-cd]pyrazol-6(28)-one (SP600125), significantly reduced the rate of TRO-induced cell death, whereas 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580), an inhibitor of p38 kinase, had little effect on apoptosis. Pretreatment with SP600125 also prevented JNK activation and c-Jun phosphorylation. In addition, rosiglitazone, which is not as toxic to hepatoma cells as TRO, did not stimulate JNK activity. Transfection of cDNA for the dominant-negative mutant JNK-KR (Lys-->Arg) or SEK1-KR (Lys-->Arg), an immediate upstream kinase of JNK, significantly reduced TRO-induced JNK activation and cell death rate. Furthermore, SP600125 pretreatment effectively prevented the TRO-mediated changes in Bad, Bax, Bid cleavage, and cytochrome c release. These data strongly suggest that hepatotoxic TRO causes apoptosis by activating the JNK-dependent cell death pathway accompanied by increased Bid cleavage and elevation of proapoptotic proteins. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Song, BJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr, Rockville, MD 20852 USA. NR 39 TC 93 Z9 97 U1 0 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD FEB PY 2003 VL 63 IS 2 BP 401 EP 408 DI 10.1124/mol.63.2.401 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 635JK UT WOS:000180395600017 PM 12527812 ER PT J AU Steele, VE Hawk, ET Viner, JL Lubet, RA AF Steele, VE Hawk, ET Viner, JL Lubet, RA TI Mechanisms and applications of non-steroidal anti-inflammatory drugs in the chemoprevention of cancer SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT Conference on Dietary and Medicinal Antimutagens and Anticarcinogens - Molecular Mechanisms and Chempreventive Potential CY OCT 17-19, 2001 CL SEOUL, SOUTH KOREA DE NSAID; anti-inflammatory; cChemoprevention; cyclooxygenase; lipoxygenase ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; FAMILIAL ADENOMATOUS POLYPOSIS; ARACHIDONIC-ACID METABOLISM; METHYL-N-NITROSOUREA; PROTEIN-KINASE-C; CYCLOOXYGENASE-2 INHIBITOR; COLON-CANCER; IN-VITRO; PROSTAGLANDIN SYNTHESIS; MAMMARY CARCINOGENESIS AB Biological and chemical irritants can be the cause of irritation in a variety of organ sites. It is becoming well understood that chronic irritation in any form can initiate and accelerate the cancer process in these same organs. This understanding comes in part from the many epidemiologic studies which point out that chronic inflammation correlates with increased risk of developing cancer in that organ which is affected. One of the hallmarks of chronic irritation is the increased activity in the arachidonic acid pathway which provides many of the necessary inflammatory biochemical mediators to this process. Arachidonic acid metabolism diverges down two main pathways, the cyclooxygenase (COX) and the lipoxygenase (LOX) pathways. The COX pathway leads to prostaglandin and thromboxane production and the LOX pathway leads to the leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs). These classes of inflammatory molecules exert profound biological effects which enhance the development and progression of human cancers. A large number of synthetic drugs and natural products have been discovered that block many of these key pathways. Much experimental evidence in animals has shown that inhibition of the key enzymes which drive these pathways can, in fact, prevent, slow or reverse the cancer process. The data are convincing in a number of organ sites including colon, breast, lung, bladder and skin. More recently, double-blinded randomize clinical trials in humans have shown the prevention of colonic polyps by anti-inflammatory agents. These studies have primarily used non-steroidal anti-inflammatory drugs (NSAIDS) which block the COX pathways. Recent preclinical studies indicate that the LOX pathway also may be an important target for cancer prevention strategy. The expression of high levels of these enzymes in cancerous tissues make them an obvious first target for cancer prevention strategies. As newer more specific drugs are developed with few adverse effects this important prevention strategy may become a reality. Published by Elsevier Science B.V. C1 NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. RP Steele, VE (reprint author), NCI, Div Canc Prevent, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM vsly@nih.gov NR 62 TC 64 Z9 70 U1 1 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 FEB-MAR PY 2003 VL 523 SI SI BP 137 EP 144 DI 10.1016/S0027-5107(02)00329-9 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 658RH UT WOS:000181733900014 PM 12628511 ER PT J AU De Flora, S D'Agostini, F Balansky, R Camoirano, A Bennicelli, C Bagnasco, M Cartiglia, C Tampa, E Longobardi, MG Lubet, RA Izzotti, A AF De Flora, S D'Agostini, F Balansky, R Camoirano, A Bennicelli, C Bagnasco, M Cartiglia, C Tampa, E Longobardi, MG Lubet, RA Izzotti, A TI Modulation of cigarette smoke-related end-points in mutagenesis and carcinogenesis SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article; Proceedings Paper CT Conference on Dietary and Medicinal Antimutagens and Anticarcinogens - Molecular Mechanisms and Chempreventive Potential CY OCT 17-19, 2001 CL SEOUL, SOUTH KOREA DE cigarette smoke; mutagenesis; carcinogenesis; lung cancer; chemoprevention; biomarkers; multigene expression; pharmacogenomics ID ORAL N-ACETYLCYSTEINE; ENVIRONMENTAL TOBACCO-SMOKE; DNA-ADDUCTS; LUNG-CANCER; CHEMOPREVENTIVE AGENTS; BACTERIAL MUTAGENICITY; DEGENERATIVE DISEASES; ALVEOLAR MACROPHAGES; CHRONIC INHALATION; EXPOSED MICE AB The epidemic of lung cancer and the increase of other tumours and chronic degenerative diseases associated with tobacco smoking have represented one of the most dramatic catastrophes of the 20th century. The control of this plague is one of the major challenges of preventive medicine for the next decades. The imperative goal is to refrain from smoking. However, chemoprevention by dietary and/or pharmacological agents provides a complementary strategy, which can be targeted not only to current smokers but also to former smokers and passive smokers. This article summarises the results of studies performed in our laboratories during the last 10 years, and provides new data generated in vitro, in experimental animals and in humans. We compared the ability of 63 putative chemopreventive agents to inhibit the bacterial mutagenicity of mainstream cigarette smoke. Modulation by ethanol and the mechanisms involved were also investigated both in vitro and in vivo. Several studies evaluated the effects of dietary chemopreventive agents towards smoke-related intermediate biomarkers in various cells, tissues and organs of rodents. The investigated end-points included metabolic parameters, adducts to haemoglobin, bulky adducts to nuclear DNA, oxidative DNA damage, adducts to mitochondrial DNA, apoptosis, cytogenetic damage in alveolar macrophages, bone marrow and peripheral blood erytrocytes, proliferation markers, and histopathological alterations. The agents tested in vivo included N-acetyl-L-cysteine, 1,2-dithiole-3-thione, oltipraz, phenethyl isothiocyanate, 5,6-benzoflavone, and sulindac. We started applying multigene expression analysis to chemoprevention research, and postulated that an optimal agent should not excessively alter per se the physiological background of gene expression but should be able to attenuate the alterations produced by cigarette smoke or other carcinogens. We are working to develop an animal model for the induction of lung tumours following exposure to cigarette smoke. The most encouraging results were so far obtained in models using A/J mice and Swiss albino mice. The same smoke-related biomarkers used in animal studies can conveniently be applied to human chemoprevention studies. We participated in trials evaluating the effects of N-acetyl-L-cysteine and oltipraz in smokers from Italy, The Netherlands, and the People's Republic of China. We are trying to develop a pharmacogenomic approach, e.g. based on genetic metabolic polymorphisms, aimed at predicting not only the risk of developing cancer but also the individual responsiveness to chemopreventive agents. (C) 2002 Elsevier Science B.V All rights reserved. C1 Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. Natl Oncol Ctr, BU-1157 Sofia, Bulgaria. NCI, Rockville, MD USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. EM sdf@unige.it OI izzotti, alberto/0000-0002-8588-0347 NR 68 TC 46 Z9 47 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 FEB-MAR PY 2003 VL 523 SI SI BP 237 EP 252 DI 10.1016/S0027-5107(02)00340-8 PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 658RH UT WOS:000181733900025 PM 12628522 ER PT J AU Latour, S Roncagalli, R Chen, RY Bakinowski, M Shi, XC Schwartzberg, PL Davidson, D Veillette, A AF Latour, S Roncagalli, R Chen, RY Bakinowski, M Shi, XC Schwartzberg, PL Davidson, D Veillette, A TI Binding of SAP SH2 domain to FynT SH3 domain reveals a novel mechanism of receptor signalling in immune regulation SO NATURE CELL BIOLOGY LA English DT Article ID LINKED LYMPHOPROLIFERATIVE-DISEASE; TYROSINE-PROTEIN-KINASE; NATURAL-KILLER-CELLS; GENE-PRODUCT; ENCODING GENE; CUTTING EDGE; PHOSPHATASE; RESPONSIVENESS; ACTIVATION; INABILITY AB SAP (or SH2D1A), an adaptor-like molecule expressed in immune cells, is composed almost exclusively of a Src homology 2 (SH2) domain(1-4). In humans, SAP is mutated and either absent or non-functional in X-linked lymphoproliferative (XLP) syndrome, a disease characterized by an inappropriate response to Epstein-Barr virus (EBV) infection(5). Through its SH2 domain, SAP associates with tyrosines in the cytoplasmic domain of the SLAM family of immune cell receptors, and is absolutely required for the function of these receptors(1,6-10). This property results from the ability of SAP to promote the selective recruitment and activation of FynT, a cytoplasmic Src-related protein tyrosine kinase (PTK)(8). Here, we demonstrate that SAP operates in this pathway by binding to the SH3 domain of FynT, through a second region in the SAP SH2 domain distinct from the phosphotyrosine-binding motif. We demonstrate that this interaction is essential for SAP-mediated signalling in T cells, and for the capacity of SAP to modulate immune cell function. These observations characterize a biologically important signalling mechanism in which an adaptor molecule composed only of an SH2 domain links a receptor devoid of intrinsic catalytic activity to the kinase required for its function. C1 Clin Res Inst Montreal, Oncol Mol Lab, Montreal, PQ H2W 1R7, Canada. Hop Necker Enfants Malad, INSERM, U429, Paris, France. Univ Montreal, Program Mol Biol, Montreal, PQ H2W 1R7, Canada. Univ Montreal, Dept Med, Montreal, PQ H2W 1R7, Canada. NHGRI, NIH, Bethesda, MD 20892 USA. McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada. McGill Univ, Dept Microbiol & Immunol, Montreal, PQ H3G 1Y6, Canada. McGill Univ, Dept Med, Montreal, PQ H3G 1Y6, Canada. RP Veillette, A (reprint author), Clin Res Inst Montreal, Oncol Mol Lab, 110 Pine Ave W, Montreal, PQ H2W 1R7, Canada. OI Roncagalli, Romain/0000-0001-7554-0552 NR 29 TC 181 Z9 191 U1 0 U2 2 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 FEB PY 2003 VL 5 IS 2 BP 149 EP 154 DI 10.1038/ncb919 PG 6 WC Cell Biology SC Cell Biology GA 642KF UT WOS:000180802100015 PM 12545173 ER PT J AU Zhang, Q Zhao, BH Li, W Oiso, N Novak, EK Rusiniak, ME Gautam, R Chintala, S O'Brien, EP Zhang, Y Roe, BA Elliott, RW Eicher, EM Liang, P Kratz, C Legius, E Spritz, RA O'Sullivan, TN Copeland, NG Jenkins, NA Swank, RT AF Zhang, Q Zhao, BH Li, W Oiso, N Novak, EK Rusiniak, ME Gautam, R Chintala, S O'Brien, EP Zhang, Y Roe, BA Elliott, RW Eicher, EM Liang, P Kratz, C Legius, E Spritz, RA O'Sullivan, TN Copeland, NG Jenkins, NA Swank, RT TI Ru2 and Ru encode mouse orthologs of the genes mutated in human Hermansky-Pudlak syndrome types 5 and 6 SO NATURE GENETICS LA English DT Article ID STORAGE POOL DEFICIENCY; PALE EAR EP; MUTATIONS; TRAFFICKING; MELANOSOMES; BIOGENESIS; DISORDERS; TRANSPORT; PROTEINS; ADAPTER AB Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous disease involving abnormalities of melanosomes, platelet dense granules and lysosomes. Here we have used positional candidate and transgenic rescue approaches to identify the genes mutated in ruby-eye 2 and ruby-eye mice (ru2 and ru, respectively), two 'mimic' mouse models of HPS. We also show that these genes are orthologs of the genes mutated in individuals with HPS types 5 and 6, respectively, and that their protein products directly interact. Both genes are previously unknown and are found only in higher eukaryotes, and together represent a new class of genes that have evolved in higher organisms to govern the synthesis of highly specialized lysosome-related organelles. C1 Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Buffalo, NY 14263 USA. Univ Colorado, Hlth Sci Ctr, Human Med Genet Program, Denver, CO 80262 USA. Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA. Jackson Lab, Bar Harbor, ME 04609 USA. Roswell Pk Canc Inst, Dept Canc Genet, Buffalo, NY 14263 USA. Univ Dusseldorf, Klin Padiat Hamatol & Onkol, D-4000 Dusseldorf, Germany. Univ Ziekenhuizen Leuven, Ctr Human Genet, Louvain, Belgium. Natl Canc Inst, Mouse Canc Genet Program, Frederick, MD USA. RP Swank, RT (reprint author), Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Buffalo, NY 14263 USA. RI Liang, Ping/D-2709-2009 OI Liang, Ping/0000-0003-4423-0636 NR 42 TC 102 Z9 109 U1 1 U2 3 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2003 VL 33 IS 2 BP 145 EP 153 DI 10.1038/ng1087 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 641YB UT WOS:000180773700011 PM 12548288 ER PT J AU Takeuchi, A Mishina, Y Miyaishi, O Kojima, E Hasegawa, T Isobe, K AF Takeuchi, A Mishina, Y Miyaishi, O Kojima, E Hasegawa, T Isobe, K TI Heterozygosity with respect to Zfp148 causes complete loss of fetal germ cells during mouse embryogenesis SO NATURE GENETICS LA English DT Article ID EMBRYONIC STEM-CELLS; TRANSCRIPTION FACTOR; BINDING PROTEIN; P53 PROTEIN; MICE; DISRUPTION; ZBP-89; GENE; EXPRESSION; DEFICIENT AB Zfp148 belongs to a large family of C2H2-type zinc-finger transcription factors. Zfp148 is expressed in fetal germ cells in 13.5-d-old (E13.5) mouse embryos. Germ-line transmission of mutations were not observed in chimeric Zfp148(+/-) mice, and some of these mice completely lacked spermatogonia. The number of primordial germ cells in Zfp148(+/-) tetraploid embryos was normal until E11.5, but declined from E11.5 to E13.5 and continued to decline until few germ cells were present at E18.5. This phenotype was not rescued by wild-type Sertoli or stromal cells, and is therefore a cell-autonomous phenotype. These results indicate that two functional alleles of Zfp148 are required for the normal development of fetal germ cells. Recent studies have shown that Zfp148 activates p53, which has an important role in cell-cycle regulation(1). Primordial germ cells stop proliferating at approximately E13.5, which correlates with induction of phosphorylation of p53 and its translocation to the nucleus. Phosphorylation of p53 is impaired in Zfp(148+/-) embryonic stem cells and in fetal germ cells from chimeric Zfp148(+/-) embryos. Thus, Zfp148 may be required for regulating p53 in the development of germ cells. C1 Natl Inst Longev Sci, Dept Basic Gerontol, Obu, Aichi 4748522, Japan. Natl Inst Environm Hlth Studies, Mol Dev Biol Grp, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC USA. RP Isobe, K (reprint author), Natl Inst Longev Sci, Dept Basic Gerontol, 36-3 Gengo,Morioka Cho, Obu, Aichi 4748522, Japan. RI isobe, ken-ichi/A-6685-2011 OI isobe, ken-ichi/0000-0002-8150-2496 NR 25 TC 67 Z9 83 U1 0 U2 4 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2003 VL 33 IS 2 BP 172 EP 176 DI 10.1038/ng1072 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 641YB UT WOS:000180773700015 PM 12524542 ER PT J AU Chen, WY Zeng, XB Carter, MG Morrell, CN Yen, RWC Esteller, M Watkins, DN Herman, JG Mankowski, JL Baylin, SB AF Chen, WY Zeng, XB Carter, MG Morrell, CN Yen, RWC Esteller, M Watkins, DN Herman, JG Mankowski, JL Baylin, SB TI Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors SO NATURE GENETICS LA English DT Article ID SUPPRESSOR GENE; DNA HYPERMETHYLATION; CANCER; TUMORIGENESIS; METHYLATION; P53; EXPRESSION; P16(INK4A); RETENTION AB The gene hypermethylated in cancer-1 (HIC1) encodes a zinc-finger transcription factor(1) that belongs to a group of proteins known as the POZ family(2). HIC1 is hypermethylated and transcriptionally silent in several types of human cancer(1,3-5). Homozygous disruption of Hic1 impairs development and results in embryonic and perinatal lethality in mice(6). Here we show that mice disrupted in the germ line for only one allele of Hic1 develop many different spontaneous malignant tumors, including a predominance of epithelial cancers in males and lymphomas and sarcomas in females. The complete loss of Hic1 function in the heterozygous mice seems to involve dense methylation of the promoter of the remaining wild-type allele. We conclude that HIC1 is a candidate tumor-suppressor gene for which loss of function in both mouse and human cancers is associated only with epigenetic modifications. C1 Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Div Tumor Biol, Baltimore, MD 21231 USA. NIA, Genet Lab, Dev Genom & Aging Sect, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Div Comparat Med, Baltimore, MD 21205 USA. Ctr Nacl Invest Oncol, Mol Pathol Program, Canc Epigenet Lab, Madrid, Spain. RP Baylin, SB (reprint author), Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Div Tumor Biol, 1650 Orleans St, Baltimore, MD 21231 USA. RI Carter, Mark/B-5089-2010; Watkins, David/I-6113-2013; Esteller, Manel/L-5956-2014 OI Esteller, Manel/0000-0003-4490-6093 NR 23 TC 146 Z9 163 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2003 VL 33 IS 2 BP 197 EP 202 DI 10.1038/ng1077 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 641YB UT WOS:000180773700020 PM 12539045 ER PT J AU Tonon, G Modi, S Wu, LZ Kubo, A Coxon, AB Komiya, T O'Neil, K Stover, K El-Naggar, A Griffin, JD Kirsch, IR Kaye, FJ AF Tonon, G Modi, S Wu, LZ Kubo, A Coxon, AB Komiya, T O'Neil, K Stover, K El-Naggar, A Griffin, JD Kirsch, IR Kaye, FJ TI t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway SO NATURE GENETICS LA English DT Article ID MINOR SALIVARY-GLAND; NEOPLASTIC TRANSFORMATION; CHROMOSOMAL TRANSLOCATIONS; HUMAN HOMOLOG; GENE; TUMOR; ACTIVATION; EXPRESSION; MASTERMIND; RECEPTORS AB Truncation of Notch1 has been shown to cause a subtype of acute leukemia(1), and activation of Notch4 has been associated with mammary and salivary gland carcinomas of mice(2). Here we identify a new mechanism for disrupting Notch signaling in human tumorigenesis, characterized by altered function of a new ortholog of the Drosophila melanogaster Notch co-activator molecule Mastermind. We cloned the t(11;19) translocation that underlies the most common type of human malignant salivary gland tumor. This rearrangement fuses exon 1 from a novel gene of unknown function at 19p13, termed mucoepidermoid carcinoma translocated 1 (MECT1), with exons 2-5 of a novel member of the Mastermind-like gene family (MAML2) at 11q21 (ref. 3). Similar to D. melanogaster Mastermind and MAML1 (refs. 4,5), full-length MAML2 functioned as a CSL (CBF-1, suppressor of hairless and Lag-1)-dependent transcriptional co-activator for ligand-stimulated Notch. In contrast, MECT1-MAML2 activated transcription of the Notch target gene HES1 independently of both Notch ligand and CSL binding sites. MECT1-MAML2 induced foci formation in RK3E epithelial cells, confirming a biological effect for the fusion product. These data suggest a new mechanism to disrupt the function of a Notch co-activator in a common type of malignant salivary gland tumor. C1 Natl Canc Inst, Genet Branch, Ctr Canc Res, Bethesda, MD 20889 USA. Natl Naval Med Res Inst, Bethesda, MD 20889 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Natl Naval Med Res Inst, Dept Med, Div Pulm, Bethesda, MD 20889 USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. RP Kaye, FJ (reprint author), Natl Canc Inst, Genet Branch, Ctr Canc Res, Bethesda, MD 20889 USA. EM fkaye@helix.nih.gov RI kaye, frederic/E-2437-2011 NR 30 TC 217 Z9 235 U1 4 U2 11 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD FEB PY 2003 VL 33 IS 2 BP 208 EP 213 DI 10.1038/ng1083 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 641YB UT WOS:000180773700022 PM 12539049 ER PT J AU Fan, ZS Beresford, PJ Zhang, D Xu, Z Novina, CD Yoshida, A Pommier, Y Lieberman, J AF Fan, ZS Beresford, PJ Zhang, D Xu, Z Novina, CD Yoshida, A Pommier, Y Lieberman, J TI Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A SO NATURE IMMUNOLOGY LA English DT Article ID HUMAN APURINIC ENDONUCLEASE; BASE EXCISION-REPAIR; APURINIC/APYRIMIDINIC ENDONUCLEASE; POLY(ADP-RIBOSE) POLYMERASE; REDOX REGULATION; MAMMALIAN-CELLS; DNA-BINDING; IN-VIVO; EXPRESSION; REF-1 AB The cytolytic T lymphocyte protease granzyme A (GzmA) initiates a caspase-independent cell death pathway. Here we report that the rate-limiting enzyme of DNA base excision repair, apurinic endonuclease-1 (Ape1), which is also known as redox factor-1 (Ref-1), binds to GzmA and is contained in the SET complex, a macromolecular complex of 270-420 kDa that is associated with the endoplasmic reticulum and is targeted by GzmA during cell-mediated death. GzmA cleaves Ape1 after Lys31 and destroys its known oxidative repair functions. In so doing, GzmA may block cellular repair and force apoptosis. In support of this, cells with silenced Ape1 expression are more sensitive, whereas cells overexpressing noncleavable Ape1 are more resistant, to GzmA-mediated death. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. MIT, Ctr Canc Res, Cambridge, MA 02139 USA. NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Lieberman, J (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RI Lieberman, Judy/A-2717-2015 NR 43 TC 172 Z9 178 U1 2 U2 4 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD FEB PY 2003 VL 4 IS 2 BP 145 EP 153 DI 10.1038/ni885 PG 9 WC Immunology SC Immunology GA 640JW UT WOS:000180686500014 PM 12524539 ER PT J AU Tirona, RG Lee, W Leake, BF Lan, LB Cline, CB Lamba, V Parviz, F Duncan, SA Inoue, Y Gonzalez, FJ Schuetz, EG Kim, RB AF Tirona, RG Lee, W Leake, BF Lan, LB Cline, CB Lamba, V Parviz, F Duncan, SA Inoue, Y Gonzalez, FJ Schuetz, EG Kim, RB TI The orphan nuclear receptor HNF4 alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4 SO NATURE MEDICINE LA English DT Article ID PREGNANE-X-RECEPTOR; HUMAN CYP2B6 GENE; TRANSCRIPTIONAL REGULATION; VISCERAL ENDODERM; ACTIVATION; EXPRESSION; HNF-4; GASTRULATION; REQUIRES; EMBRYOS AB The drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is thought to be involved in the metabolism of nearly 50% of all the drugs currently prescribed. Alteration in the activity or expression of this enzyme seems to be a key predictor of drug responsiveness and toxicity(1). Currently available studies indicate that the ligand-activated nuclear receptors pregnane X receptor (PXR; NR1I2) and constitutive androstane receptor (CAR; NR1I3) regulate CYP3A4 expression(2,3). However, in cell-based reporter assays, CYP3A4 promoter activity was most pronounced in liver-derived cells and minimal or modest in non-hepatic cells(2), indicating that a liver-specific factor is required for physiological transcriptional response. Here we show that the orphan nuclear receptor hepatocyte nuclear factor-4alpha (HNF4alpha; HNF4A) is critically involved in the PXR- and CAR-mediated transcriptional activation of CYP3A4. We identified a specific cis-acting element in the CYP3A4 gene enhancer that confers HNF4alpha binding and thereby permits PXR- and CAR-mediated gene activation. Fetal mice with conditional deletion of Hnf4alpha had reduced or absent expression of CYP3A. Furthermore, adult mice with conditional hepatic deletion of Hnf4alpha had reduced basal and inducible expression of CYP3A. These data identify HNF4alpha as an important regulator of coordinate nuclear-receptor-mediated response to xenobiotics. C1 Vanderbilt Univ, Sch Med, Div Clin Pharmacol, Nashville, TN 37212 USA. Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA. NCI, Lab Metab, Div Basic Sci, Bethesda, MD 20892 USA. St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. RP Kim, RB (reprint author), Vanderbilt Univ, Sch Med, Div Clin Pharmacol, Nashville, TN 37212 USA. EM richard.kim@vanderbilt.edu RI Cline, Cynthia/F-7065-2012; Lee, Wooin/K-7789-2012 OI Lee, Wooin/0000-0001-7805-869X FU NIEHS NIH HHS [ES08658]; NIGMS NIH HHS [GM54724, GM60346, GM31304] NR 23 TC 298 Z9 303 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD FEB PY 2003 VL 9 IS 2 BP 220 EP 224 DI 10.1038/nm815 PG 5 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 642KD UT WOS:000180801900027 PM 12514743 ER PT J AU Mattson, MP AF Mattson, MP TI Insulating axons via NF-kappa B SO NATURE NEUROSCIENCE LA English DT Editorial Material ID MYELINATION; SURVIVAL C1 NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 12 TC 11 Z9 11 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD FEB PY 2003 VL 6 IS 2 BP 105 EP 106 DI 10.1038/nn0203-105 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 640CL UT WOS:000180669100004 PM 12555100 ER PT J AU Bushara, KO Hanakawa, T Immisch, I Toma, K Kansaku, K Hallett, M AF Bushara, KO Hanakawa, T Immisch, I Toma, K Kansaku, K Hallett, M TI Neural correlates of cross-modal binding SO NATURE NEUROSCIENCE LA English DT Article ID HUMAN BRAIN; ATTENTION; CORTEX AB Little is known about how the brain binds together signals from multiple sensory modalities to produce unified percepts of objects and events in the external world. Using event-related functional magnetic resonance imaging (fMRI) in humans, we measured transient brain responses to auditory/visual binding, as evidenced by a sound-induced change in visual motion perception. Identical auditory and visual stimuli were presented in all trials, but in some trials they were perceived to be bound together and in others they were perceived as unbound unimodal events. Cross-modal binding was associated with higher activity in multimodal areas, but lower activity in predominantly unimodal areas. This activation pattern suggests that a reciprocal and 'competitive' interaction between multimodal and unimodal areas underlies the perceptual interpretation of simultaneous signals from multiple sensory modalities. C1 Minneapolis Vet Affairs Med Ctr, Serv Neurol, Minneapolis, MN 55417 USA. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Bushara, KO (reprint author), Minneapolis Vet Affairs Med Ctr, Serv Neurol, Room 4B135,1 Vet Dr, Minneapolis, MN 55417 USA. EM busha001@umn.edu NR 16 TC 117 Z9 119 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD FEB PY 2003 VL 6 IS 2 BP 190 EP 195 DI 10.1038/nn993 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 640CL UT WOS:000180669100020 PM 12496761 ER PT J AU Wood, JN Grafman, J AF Wood, JN Grafman, J TI Human prefrontal cortex: Processing and representational perspectives SO NATURE REVIEWS NEUROSCIENCE LA English DT Review ID FRONTAL-LOBE LESIONS; ANTERIOR CINGULATE CORTEX; DECISION-MAKING; FUNCTIONAL-MRI; ORBITOFRONTAL CORTEX; BRAIN ACTIVATION; GRASP REPRESENTATIONS; MENTAL REPRESENTATION; PARKINSONS-DISEASE; RECOGNITION MEMORY AB Through evolution, humans have acquired 'higher' cognitive skills-such as language, reasoning and planning-and complex social behaviour. Evidence from neuropsychological and neuroimaging research indicates that the prefrontal cortex (PFC) underlies much of this higher cognition. A number of theories have been proposed for how the PFC might achieve this. Although many of these theories focus on the types of 'process' that the PFC carries out, we argue for the validity of a representational approach to understanding PFC function. C1 NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov OI Grafman, Jordan H./0000-0001-8645-4457 NR 107 TC 306 Z9 316 U1 13 U2 41 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-003X J9 NAT REV NEUROSCI JI Nat. Rev. Neurosci. PD FEB PY 2003 VL 4 IS 2 BP 139 EP 147 DI 10.1038/nrn1033 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 642JB UT WOS:000180799500018 PM 12563285 ER PT J AU Arimoto, T Bing, GY AF Arimoto, T Bing, GY TI Up-regulation of inducible nitric oxide synthase in the substantia nigra by lipopolysaccharide causes microglial activation and neurodegeneration SO NEUROBIOLOGY OF DISEASE LA English DT Article DE inducible nitric oxide synthase; nitric oxide; inflammation; lipopolysaccharide; microglia; neurodegeneration ID TYROSINE-HYDROXYLASE ACTIVITY; SINGLE INTRANIGRAL INJECTION; TUMOR-NECROSIS-FACTOR; APOPTOTIC CELL-DEATH; PARKINSONS-DISEASE; GLIAL-CELLS; IN-VIVO; DOPAMINERGIC SYSTEM; ALZHEIMERS-DISEASE; INTERFERON-GAMMA AB The present study was designed to examine whether expression of iNOS was involved in LPS-induced neurodegeneration in rat substantia nigra (SN) and to study the role of NO in the loss of the SN dopaminergic neurons. In Western blot analysis, iNOS was induced in the SN after injection of LPS in a time- and dose-dependent manner. Immunofluorescence and immunohistochemical analyses revealed that the iNOS is located in a fully activated microglia with the characteristic amoeboid morphology. Furthermore, LPS-induced loss of dopaminergic neurons was significantly inhibited by the administration of L-N-G-nitroarginine, a selective inhibitor of NOS, and the glucocorticoid dexamethasone. These inhibiting agents for iNOS reduced LPS-induced microglial activation, suggesting that NO has a role in inflammatory-mediated microglial activation. These results demonstrate that LPS induces the expression of iNOS in activated microglia in the SN, and that NO and/or its metabolites may play a crucial role in inflammation-mediated degeneration of dopaminergic neurons. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Kentucky, Dept Anat & Neurobiol, Ctr Med, Lexington, KY 40536 USA. RP Arimoto, T (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI bing, guoying/F-7084-2012; OI Bing, Guoying/0000-0003-0609-8152 FU NINDS NIH HHS [NS39345] NR 71 TC 132 Z9 139 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 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD FEB PY 2003 VL 12 IS 1 BP 35 EP 45 DI 10.1016/S09869-9961(02)00017-7 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 652ZM UT WOS:000181410800004 PM 12609487 ER PT J AU Chung, MK Worsley, KJ Robbins, S Paus, T Taylor, J Giedd, JN Rapoport, JL Evans, AC AF Chung, MK Worsley, KJ Robbins, S Paus, T Taylor, J Giedd, JN Rapoport, JL Evans, AC TI Deformation-based surface morphometry applied to gray matter deformation SO NEUROIMAGE LA English DT Article DE cerebral cortex; cortical surface; brain development; cortical thickness; brain growth; brain atrophy; deformation; morphometry ID UNIFIED STATISTICAL APPROACH; HUMAN CORPUS-CALLOSUM; CORTICAL SURFACE; BRAIN-DEVELOPMENT; CEREBRAL-CORTEX; IN-VIVO; IMAGES; SEGMENTATION; ADOLESCENCE; ACTIVATION AB We present a unified statistical approach to deformation-based morphometry applied to the cortical surface. The cerebral cortex has the topology of a 2D highly convoluted sheet. As the brain develops over time, the cortical surface area, thickness, curvature, and total gray matter volume change. It is highly likely that such age-related surface changes are not uniform. By measuring how such surface metrics change over time, the regions of the most rapid structural changes can be localized. We avoided using surface flattening, which distorts the inherent geometry of the cortex in our analysis and it is only used in visualization. To increase the signal to noise ratio, diffusion smoothing, which generalizes Gaussian kernel smoothing to an arbitrary curved cortical surface, has been developed and applied to surface data. Afterward, statistical inference on the cortical surface will be performed via random fields theory. As an illustration, we demonstrate how this new surface-based morphometry can be applied in localizing the cortical regions of the gray matter tissue growth and loss in the brain images longitudinally collected in the group of children and adolescents. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Wisconsin, Dept Stat, Madison, WI 53706 USA. Univ Wisconsin, WM Keck Lab Funct Brain Imaging & Behav, Madison, WI 53706 USA. McGill Univ, Dept Math & Stat, Montreal, PQ H3A 2T5, Canada. McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2T5, Canada. Stanford Univ, Dept Stat, Stanford, CA 94305 USA. NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Chung, MK (reprint author), Univ Wisconsin, Dept Stat, 1210 W Dayton St, Madison, WI 53706 USA. RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 NR 54 TC 162 Z9 162 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB PY 2003 VL 18 IS 2 BP 198 EP 213 AR PII S1053-8119(02)00017-4 DI 10.1016/S1053-8119(02)00017-4 PG 16 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 648ZM UT WOS:000181182500002 PM 12595176 ER PT J AU Knutson, B Fong, GW Bennett, SM Adams, CM Homme, D AF Knutson, B Fong, GW Bennett, SM Adams, CM Homme, D TI A region of mesial prefrontal cortex tracks monetarily rewarding outcomes: characterization with rapid event-related fMRI SO NEUROIMAGE LA English DT Article DE reward; human; functional magnetic resonance imaging (FMRI); nucleus accumbens (NAcc); ventral striatum; mesial prefrontal cortex (MPFC); anticipation; outcome; money ID ANTERIOR CINGULATE CORTEX; ORBITOFRONTAL CORTEX; NUCLEUS-ACCUMBENS; NEURAL RESPONSES; DECISION-MAKING; WORKING-MEMORY; EMOTIONAL RESPONSES; FRONTAL-CORTEX; BRAIN ACTIVITY; BASAL GANGLIA AB The function of the mesial prefrontal cortex (MPFC: including Brodman areas 10/12/32) remains an enigma. Current theories suggest a role in representing internal information, including emotional introspection, autonomic control, and a "default state" of semantic processing. Recent evidence also suggests that parts of this region may also play a role in processing reward outcomes. In this study, we investigated the possibility that a region of the MPFC would be preferentially recruited by monetary reward outcomes using a parametric monetary incentive delay (MID) task. Twelve healthy volunteers participated in functional magnetic resonance scans while playing the MID task. Group analyses indicated that while the ventral striatum was recruited by anticipation of monetary reward, a region of the MPFC, instead responded to rewarding monetary outcomes. Specifically, volume-of-interest analyses indicated that when volunteers received $5.00 after anticipating a $5.00 win, MPFC activity increased, whereas when volunteers did not receive $5.00 after anticipating a $5.00 win, MPFC activity decreased, relative to outcomes with no incentive value. These findings suggest that in the context of processing monetary rewards, a region of the MPFC preferentially tracks rewarding outcomes. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. NIAAA, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Knutson, B (reprint author), Stanford Univ, Dept Psychol, Bldg 420,Jordan Hall, Stanford, CA 94305 USA. OI Knutson, Brian/0000-0002-7669-426X FU NIMH NIH HHS [MH 066923] NR 42 TC 451 Z9 457 U1 3 U2 37 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB PY 2003 VL 18 IS 2 BP 263 EP 272 DI 10.1016/S1053-8119(02)00057-5 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 648ZM UT WOS:000181182500007 PM 12595181 ER PT J AU Saad, ZS DeYoe, EA Ropella, KM AF Saad, ZS DeYoe, EA Ropella, KM TI Estimation of FMRI response delays SO NEUROIMAGE LA English DT Article DE functional magnetic resonance imaging; activation latency; Hilbert transform; spectral leakage; phase estimation ID FUNCTIONAL MRI; HEMODYNAMIC-RESPONSE; VISUAL AREAS; CORTEX; BRAIN AB We present an efficient algorithm using the Hilbert Transform for estimating the delay of the BOLD response to neuronal stimulation. With minimal additional computations, the algorithm estimates parameters generated in the widely used cross-correlation method and simplifies the interpolation required to estimate the response delay from the cross-correlation function. We examined errors in the Hilbert-based delay estimate associated with the use of DFT on short-duration discrete signals and proposed a method for minimizing these errors. Furthermore, we compared the delay estimates obtained with the Hilbert method to those obtained using the onset of the BOLD response. The Hilbert method resulted in less variance in the delay estimate despite the potential for higher variability in the latter part of the BOLD response. This improved delay estimate was attributed to the reduced sensitivity of the Hilbert method to noise contamination compared to the onset method. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Marquette Univ, Dept Biomed Engn, Milwaukee, WI 53233 USA. Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA. RP Saad, ZS (reprint author), NIMH, Stat & Sci Comp Core, Bldg 10,Room 1D80,10 Ctr Dr,MSC 1148, Bethesda, MD 20892 USA. FU NCRR NIH HHS [5M01 RR 00058]; NEI NIH HHS [EY 10244]; NIMH NIH HHS [MH 51358] NR 22 TC 25 Z9 25 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB PY 2003 VL 18 IS 2 BP 494 EP 504 DI 10.1016/S1053-8119(02)00024-1 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 648ZM UT WOS:000181182500028 PM 12595202 ER PT J AU Servitja, JM Masgrau, R Pardo, R Sarri, E von Eichel-Streiber, C Gutkind, JS Picatoste, F AF Servitja, JM Masgrau, R Pardo, R Sarri, E von Eichel-Streiber, C Gutkind, JS Picatoste, F TI Metabotropic glutamate receptors activate phospholipase D in astrocytes through a protein kinase C-dependent and Rho-independent pathway SO NEUROPHARMACOLOGY LA English DT Article DE phospholipase D; phospholipase C; protein kinase C; Arf; Rho; glutamate; astrocytes ID ADP-RIBOSYLATION-FACTOR; DIFFICILE TOXIN-B; RAT CULTURED ASTROCYTES; AMINO-ACIDS; CELLS; STIMULATION; AGONIST; ARF; INHIBITION; CALCIUM AB Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that mediate phospholipase D (PLD) activation in brain, but the mechanism underlying this response remains unclear. Here we used primary cultures of astrocytes as a cell model to explore the mechanism that links mGluRs to PLD. Glutamate activated both phospholipase C (PLC) and PLD with equal potency and this effect was mimicked by L-Cysteinesulfinic acid. a putative neurotransmitter previously shown to activate mGluRs coupled to PLD, but not PLC, in adult brain. PLD activation by glutamate was dependent on Ca2+ mobilization and fully blocked by both protein kinase C (PKC) inhibitors and PKC down-regulation, suggesting that PLD activation is secondary to PLC stimulation. Furthermore, brefeldin A. an inhibitor of ADP-ribosylation factor (ARF) activation, partially inhibited the activation of PLD by glutamate. By contrast, pretreatment of astrocytes with Clostridium difficile toxin B, which inactivates small G proteins of the Rho family (Rho, Rac, and Cdc42), had no effect on PLD stimulation by glutamate. Taken together, these results indicate that PLD activation by mGluRs in astrocytes is dependent on PKC and small G proteins of the ARF family, but does not require Rho proteins. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Univ Autonoma Barcelona, Fac Med, Dept Bioquim & Biol Mol, E-08193 Barcelona, Spain. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20817 USA. Univ Mainz, Inst Med Mikrobiol & Hyg, D-55101 Mainz, Germany. RP Picatoste, F (reprint author), Univ Autonoma Barcelona, Fac Med, Dept Bioquim & Biol Mol, E-08193 Barcelona, Spain. RI Gutkind, J. Silvio/A-1053-2009; Masgrau, Roser/D-3047-2011; OI Masgrau, Roser/0000-0002-6722-5939; SERVITJA DUQUE, JOAN-MARC/0000-0002-1241-8004; Sarri, Elisabet/0000-0002-2435-399X NR 39 TC 17 Z9 17 U1 0 U2 0 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 FEB PY 2003 VL 44 IS 2 BP 171 EP 180 DI 10.1016/S0028-3908(02)00361-1 PG 10 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 647DL UT WOS:000181077100003 PM 12623215 ER PT J AU Qu, Y Chang, L Klaff, J Balbo, A Rapoport, SI AF Qu, Y Chang, L Klaff, J Balbo, A Rapoport, SI TI Imaging brain phospholipase A(2) activation in awake rats in response to the 5-HT2A/2C agonist (+/-)2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI) SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE serotonin (5-HT); phospholipase A(2); DOI; mianserin; arachidonic acid; imaging; brain ID ATYPICAL ANTIPSYCHOTIC-DRUGS; NUCLEUS BASALIS MAGNOCELLULARIS; ARACHIDONIC-ACID INCORPORATION; 5-HT RECEPTOR AGONISTS; MESSENGER-RNA LEVELS; SIGNAL-TRANSDUCTION; CHOROID-PLEXUS; 1-(2,5-DIMETHOXY-4-IODOPHENYL)-2-AMINOPROPANE DOI; PHOSPHOINOSITIDE HYDROLYSIS; SEROTONIN RECEPTORS AB Incorporation coefficients k* of intravenously injected [H-3]arachidonic acid from blood into brain reflect the release from phospholipids of arachidonic acid by receptor-initiated activation of phospholipase A(2) (PLA(2)). In unanesthetized adult rats, 2.5 mg/kg intraperitoneally (i.p.) (+/-)2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), which is a 5-HT2A/2C receptor agonist, has been reported to produce the behavioral changes of what is known as the 5-HT2 syndrome, but only a few small regional decrements in brain glucose metabolism. In this study, 2.5 mg/kg i.p. DOI, when administered to unanesthetized rats, produced widespread and significant increases, of the order of 60%, in k* for arachidonate, particularly in neocortical brain regions reported to have high densities of 5-HT2A receptors. The increases could be entirely blocked by chronic pretreatment with mianserin, a 5-HT2 receptor antagonist. The results suggest that the 5-HT2 syndrome involves widespread brain activation of PLA(2) via 5-HT2A receptors, leading to the release of the second messenger, arachidonic acid. Chronic mianserin, a 5-HT2 antagonist, prevents this activation. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Qu, Y (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 10,Room 6N202, Bethesda, MD 20892 USA. NR 100 TC 41 Z9 41 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD FEB PY 2003 VL 28 IS 2 BP 244 EP 252 DI 10.1038/sj.npp.1300022 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 649XM UT WOS:000181233300006 PM 12589377 ER PT J AU Hashimoto, K Suehiro, K Kodaka, Y Miura, K Kawano, K AF Hashimoto, K Suehiro, K Kodaka, Y Miura, K Kawano, K TI Effect of target saliency on human smooth pursuit initiation: interocular transfer SO NEUROSCIENCE RESEARCH LA English DT Article DE eye movement; attention; human ID CORTICAL AREAS MT; EYE-MOVEMENTS; MST; ATTENTION; SELECTION; MECHANISMS; RESPONSES AB Our previous study showed that the saliency of a target increases the gain of smooth pursuit initiation. In this study, we examined the interocular transfer of this effect in five humans. A square red frame surrounding the target was used as a cue to indicate the initial target position. In the cue condition, the responses were similar, irrespective of the eye to which the cue was presented, and were significantly larger than in the no-cue condition. The result suggests that central pathways that receive input from both eyes mediate the effect of saliency on smooth pursuit initiation. (C) 2002 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved. C1 Natl Inst Adv Ind Sci & Technol, Neurosci Res Inst, Tsukuba, Ibaraki 3058568, Japan. Univ Tsukuba, Tsukuba, Ibaraki 3058575, Japan. NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Hashimoto, K (reprint author), Natl Inst Adv Ind Sci & Technol, Neurosci Res Inst, Cent 2,1-1-1 Umezono, Tsukuba, Ibaraki 3058568, Japan. NR 19 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0168-0102 J9 NEUROSCI RES JI Neurosci. Res. PD FEB PY 2003 VL 45 IS 2 BP 211 EP 217 AR PII S0168-0102(02)00227-4 DI 10.1016/S0168-0102(02)00227-4 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 647YG UT WOS:000181121200008 PM 12573467 ER PT J AU Smith, SS Jorenby, DE Leischow, SJ Nides, MA Rennard, SI Johnston, JA Jamerson, B Fiore, MC Baker, TB AF Smith, SS Jorenby, DE Leischow, SJ Nides, MA Rennard, SI Johnston, JA Jamerson, B Fiore, MC Baker, TB TI Targeting smokers at increased risk for relapse: treating women and those with a history of depression SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID SUSTAINED-RELEASE BUPROPION; SMOKING-CESSATION; GENDER DIFFERENCES; NICOTINE PATCH; TRANSDERMAL NICOTINE; MAJOR DEPRESSION; TOBACCO SMOKING; NEGATIVE AFFECT; DEPENDENCE; WITHDRAWAL AB Some studies have shown that female smokers and smokers with a history of depression have an increased risk of relapse following smoking cessation treatment. This study examined the efficacy of bupropion sustained-release (SR) and the nicotine patch for smoking cessation in subgroups of smokers at possible risk for relapse. Data for this study were from a previously published randomized, double-blind, placebo-controlled clinical trial in which 893 smokers were randomized to four treatment conditions:. placebo tablet + placebo patch, placebo tablet + 21 mg/24-hr nicotine patch, 300 mg bupropion SR + placebo patch, and 300 mg bupropion SR + 21 mg/24-hr nicotine patch. Study medication continued for 8 weeks after the quit day; brief individual cessation counseling was provided during weekly clinic visits. In comparison to the placebo tablet, bupropion SR approximately tripled I-year non-smoking rates among women and previously depressed individuals. In contrast, the nicotine patch did not significantly improve cessation rates for any group. We conclude that bupropion SR is a first-line treatment for smoking that has the potential to benefit all smokers, especially women and the previously depressed. C1 Univ Wisconsin, Sch Med, Dept Med, Ctr Tobacco Res & Intervent, Madison, WI USA. Univ Wisconsin, Dept Psychol, Madison, WI 53706 USA. NCI, Tobacco Control Res Branch, Bethesda, MD 20892 USA. Los Angeles Clin Trials, Los Angeles, CA USA. Univ Nebraska, Med Ctr, Omaha, NE USA. GlaxoSmithKline, Res Triangle Pk, NC USA. RP Smith, SS (reprint author), Univ Wisconsin, Sch Med, 1930 Monroe St,Suite 200, Madison, WI 53711 USA. NR 55 TC 58 Z9 59 U1 3 U2 5 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD FEB PY 2003 VL 5 IS 1 BP 99 EP 109 DI 10.1080/1462220021000060437 PG 11 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 716HA UT WOS:000185021700012 PM 12745511 ER PT J AU Arbab, AS Ueki, J Koizumi, K Araki, T AF Arbab, AS Ueki, J Koizumi, K Araki, T TI Effects of extracellular Na+ and Ca2+ ions and Ca2+ channel modulators on the cell-associated activity of Tc-99m-MIBI and Tc-99m-tetrofosmin in tumour cells SO NUCLEAR MEDICINE COMMUNICATIONS LA English DT Article DE Tc-99m-tetrofosmin; Verapamil; Flunarizine; dichlorobenzamil; Ca2+ channels; Na+ channels ID P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE; TECHNETIUM-99M-SESTAMIBI UPTAKE; CALCIUM-ANTAGONISTS; MYOCARDIAL-CELLS; HEART-CELLS; TL-201; TECHNETIUM-99M-TETROFOSMIN; MEMBRANE; EXCHANGE AB Our aim was to determine whether the Ca2+ ion or cell membrane Ca2+ and Na+/Ca2+, ion transport systems are involved in maintaining the cell-associated activity of technetium-99m-hexakis-methoxyisobutyl-isonitrile (Tc-99m-MIBI) and technetium-99m-ethylene-bis[bis(2-ethoxyethyl)phosphin] (Tc-99m-tetrofosmin) in tumour cell lines. The cell-associated activities of Tc-99m-MIBI and Tc-99m-tetrofosmin were assessed in various buffers, with or without Na+ and/or with different concentrations of Ca2+, in Lewi's murine lung cell carcinoma and human glioma cell lines. Different Ca2+ channel modulators, such as verapamil, flunarizine and 3,4-dichlorobenzamil (DCB), were used to assess the effect of Ca2+ channels on the cell-associated activity of Tc-99m-MIBI and Tc-99m-tetrofosmin. Despite significant differences between cell lines, the cell-associated activity of Tc-99m-MIBI was higher in buffers without extracellular Ca2+ and Na+. The cell-associated activity of Tc-99m-MIBI was significantly lower in all buffers containing high concentrations of Ca2+ in both cell lines. The cell-associated activity of Tc-99m-tetrofosmin was also significantly higher in buffers without Ca2+, and was significantly decreased in buffers with high concentrations of Ca2+. All modulators significantly increased the cell-associated activity of Tc-99m-MIBI in both cell lines in all buffers. All modulators increased the cell-associated activity of Tc-99m-tetrofosmin, particularly in buffers containing Ca2+. The cell-associated activities of both Tc-99m-MIBI and Tc-99m-tetrofosmin may be dependent on verapamil-, flunarizine- and DCB-sensitive Ca2+ channels. ((C) 2003 Lippincott Williams Wilkins). C1 Yamanashi Med Univ, Dept Radiol, Yamanashi, Japan. Tokyo Med Univ Hachioji Ctr, Dept Radiol, Tokyo, Japan. RP Arbab, AS (reprint author), NIH, LDRR CC, Bldg 10,Room B1N256, Bethesda, MD 20892 USA. NR 49 TC 12 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0143-3636 J9 NUCL MED COMMUN JI Nucl. Med. Commun. PD FEB PY 2003 VL 24 IS 2 BP 155 EP 166 DI 10.1097/01.mnm.0000057329.59072.11 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 650FH UT WOS:000181252000008 PM 12548040 ER PT J AU Kouprina, N Ebersole, T Koriabine, M Pak, E Rogozin, IB Katoh, M Oshimura, M Ogi, K Peredelchuk, M Solomon, G Brown, W Barrett, JC Larionov, V AF Kouprina, N Ebersole, T Koriabine, M Pak, E Rogozin, IB Katoh, M Oshimura, M Ogi, K Peredelchuk, M Solomon, G Brown, W Barrett, JC Larionov, V TI Cloning of human centromeres by transformation-associated recombination in yeast and generation of functional human artificial chromosomes SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN Y-CHROMOSOME; ALPHOID SATELLITE DNA; SACCHAROMYCES-CEREVISIAE; CONSENSUS SEQUENCE; MINICHROMOSOMES; HYBRIDIZATION; CONSTRUCTION; REPLICATION; EVOLUTION; FAMILIES AB Human centromeres remain poorly characterized regions of the human genome despite their importance for the maintenance of chromosomes. In part this is due to the difficulty of cloning of highly repetitive DNA fragments and distinguishing chromosome-specific clones in a genomic library. In this work we report the highly selective isolation of human centromeric DNA using transformation-associated recombination (TAR) cloning. A TAR vector with alphoid DNA monomers as targeting sequences was used to isolate large centromeric regions of human chromosomes 2, 5, 8, 11, 15, 19, 21 and 22 from human cells as well as monochromosomal hybrid cells. The alphoid DNA array was also isolated from the 12 Mb human mini-chromosome DeltaYq74 that contained the minimum amount of alphoid DNA required for proper chromosome segregation. Preliminary results of the structural analyses of different centromeres are reported in this paper. The ability of the cloned human centromeric regions to support human artificial chromosome (HAC) formation was assessed by transfection into human HT1080 cells. Centromeric clones from DeltaYq74 did not support the formation of HACs, indicating that the requirements for the existence of a functional centromere on an endogenous chromosome and those for forming a de novo centromere may be distinct. A construct with an alphoid DNA array from chromosome 22 with no detectable CENP-B motifs formed mitotically stable HACs in the absence of drug selection without detectable acquisition of host DNAs. In summary, our results demonstrated that TAR cloning is a useful tool for investigating human centromere organization and the structural requirements for formation of HAC vectors that might have a potential for therapeutic applications. C1 NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NHGRI, Lab Genet Dis Res, Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Tottori Univ, Fac Med, Dept Mol & Cellular Biol, Div Mol & Cell Genet, Yonago, Tottori 683, Japan. Takeda Chem Ind Ltd, Div Pharmaceut Res, Discovery Res Labs 1, Tsukuba, Ibaraki 3004293, Japan. NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Nottingham, Queens Med Ctr, Inst Genet, Nottingham NG7 2UH, England. RP Kouprina, N (reprint author), NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, Bldg 37,Room 5032, Bethesda, MD 20892 USA. NR 46 TC 40 Z9 42 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 1 PY 2003 VL 31 IS 3 BP 922 EP 934 DI 10.1093/nar/gkg182 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 647VJ UT WOS:000181114500020 PM 12560488 ER PT J AU Christiansen, M Stevnsner, T Modin, C Martensen, PM Brosh, RM Bohr, VA AF Christiansen, M Stevnsner, T Modin, C Martensen, PM Brosh, RM Bohr, VA TI Functional consequences of mutations in the conserved SF2 motifs and post-translational phosphorylation of the CSB protein SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RNA-POLYMERASE-II; NUCLEOTIDE EXCISION-REPAIR; COUPLING FACTOR CSB/ERCC6; INDUCED DNA-DAMAGE; GROUP-B PROTEIN; COCKAYNE-SYNDROME; ACIDIC REGION; GENE-PRODUCT; HELICASE; TRANSCRIPTION AB The rare inherited human genetic disorder Cockayne syndrome (CS) is characterized by developmental abnormalities, UV sensitivity and premature aging. The cellular and molecular phenotypes of CS include increased sensitivity to UV-induced and oxidative DNA lesions. Two genes are involved: CSA and CSB. The CS group B (CSB) protein has roles in transcription, transcription-coupled repair, and base excision repair. It is a DNA stimulated ATPase and remodels chromatin in vitro. Here, we have analyzed wild-type (wt) and motif II, V and VI mutant CSB proteins. We find that the mutant proteins display different degrees of ATPase activity deficiency, and in contrast to the in vivo complementation studies, the motif II mutant is more defective than motif V and VI CSB mutants. Furthermore, CSB wt ATPase activity was studied with different biologically important DNA cofactors: DNA with different secondary structures and damaged DNA. The results indicate that the state of DNA secondary structure affects the level of CSB ATPase activity. We find that the CSB protein is phosphorylated in untreated cells and that UV irradiation leads to its dephosphorylation. Importantly, dephosphorylation of the protein in vitro results in increased ATPase activity of the protein, suggesting that the activity of the CSB protein is subject to phosphorylation control in vivo. These observations may have significant implications for the function of CSB in vivo. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Univ Aarhus, Danish Ctr Mol Gerontol, DK-8000 Aarhus C, Denmark. Univ Aarhus, Dept Mol Biol, DK-8000 Aarhus C, Denmark. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Martensen, Pia/I-3996-2012 NR 48 TC 32 Z9 34 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD FEB 1 PY 2003 VL 31 IS 3 BP 963 EP 973 DI 10.1093/nar/gkg164 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 647VJ UT WOS:000181114500024 PM 12560492 ER PT J AU Chan, CC Shen, DF Hackett, JJ Buggage, RR Tuaillon, N AF Chan, CC Shen, DF Hackett, JJ Buggage, RR Tuaillon, N TI Expression of chemokine receptors, CXCR4 and CXCR5, and chemokines, BLC and SDF-1, in the eyes of patients with primary Intraocular lymphoma SO OPHTHALMOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NERVOUS-SYSTEM LYMPHOMA; PRIMARY CNS LYMPHOMA; FACTOR-I; OCULAR MANIFESTATIONS; FUNCTIONAL-RESPONSE; GENE REARRANGEMENT; CELL MATURATION; STROMAL CELLS; B-CELLS AB Objective: Chemokines have a range of biologic activities, including regulation of leukocyte trafficking, modulation of hematopoietic cell proliferation, and adhesion to extracellular matrix molecules. Specifically, B-lymphocyte chemoattractant (BLC); BCA-1; CXCL13, SCYB13) and stromal cell-derived factor-1 (SDF-1, CXCL12, SCYB12) are chemotactic for human B cells, and their ligands CXCR4 and CXCR5 are differentially expressed on B cells, including malignant B cells. We investigated the expression of these chemokine/chemokine receptors in eyes with primary intraocular B-cell lymphoma (PIOL). Design: Observational case series (human tissue study). Methods: Three freshly enucleated eyes with PIOL and a normal autopsied eye were frozen and sectioned. The sections were evaluated using immunohistochemistry (avid in-biotin-complex immunoperoxidase technique) for CXCR4, CXCR5, BLC, and SDF-1 to detect the expression and location. Reverse transcriptase-polymerase chain reaction was used to detect chemokine transcripts of CXCR4, CXCR5, BLC, and SDF-1 in PIOL and retinal pigment epithelium (RPE) cells after microdissection-either by laser capture (Arcturus) or by manual dissection-from frozen sections. Main Outcome Measures and Results: The three PIOL eyes showed similar pathology, with typical diffuse large B-lymphoma cells subjacent to the RPE. The eyes also demonstrated a similar chemokine profile. High expression levels of CXCR4 and CXCR5 were found limited to the lymphoma cells. In contrast, BLC protein was expressed in the RPE but not located in other ocular resident cells. SDF-1 was barely detected in a few RPE cells. CXCR4 and CXCR5 transcripts were detected abundantly in lymphoma cells, whereas BLC and SDF-1 transcripts were detected only in the RIPE and not the malignant cells. No chemokine expression was detected on the RIPE cells in the normal control eye. Conclusions: Chemokines and chemokine receptors selective for B cells were identified in RPE and malignant B cells, respectively. BLC, and possibly SDF-1, attracts both normal and malignant B-cells while promoting migration of only small numbers of T cells and macrophages. We propose that B-cell chemokines may be involved in the pathogenesis of PIOL by selectively attracting lymphoma cells to the RPE from the choroidal circulation. Our data suggest that inhibition of B-cell chemoattractants could be a future strategy for the treatment of PIOL. Ophthalmology 2003;110:421-426 (C) 2003 by the American Academy of Ophthalmology. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Rm 10N103,10 Ctr Dr, Bethesda, MD 20892 USA. NR 59 TC 47 Z9 50 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD FEB PY 2003 VL 110 IS 2 BP 421 EP 426 AR PII S0161-6420(02)01737-2 DI 10.1016/S0161-6420(02)01737-2 PG 6 WC Ophthalmology SC Ophthalmology GA 643TK UT WOS:000180876400039 PM 12578791 ER PT J AU Mellins, CA Smith, R O'Driscoll, P Magder, LS Brouwers, P Chase, C Blasini, I Hittleman, J Llorente, A Matzen, E AF Mellins, CA Smith, R O'Driscoll, P Magder, LS Brouwers, P Chase, C Blasini, I Hittleman, J Llorente, A Matzen, E CA NIH NIAID NICHD NIDA-Sponsored Wom TI High rates of behavioral problems in perinatally HIV-infected children are not linked to HIV disease SO PEDIATRICS LA English DT Article DE pediatric HIV infection; behavioral outcome; Conners' Parent Rating Scale ID HUMAN-IMMUNODEFICIENCY-VIRUS; SCHOOL-AGE-CHILDREN; PSYCHOLOGICAL ADJUSTMENT; UNINFECTED CHILDREN; INFANTS; ADOLESCENTS; HEMOPHILIA; PREGNANCY; CULTURE; COHORT AB Objective. Descriptive studies and clinical reports have suggested that human immunodeficiency virus (HIV)-positive children are at risk for behavioral problems. Inadequate control groups and sample sizes have limited the ability of investigators to consider multiple influences that place HIV-positive children at risk for poor behavioral outcomes. We examined the unique and combined influences of HIV, prenatal drug exposure, and environmental factors on behavior in children who were perinatally exposed to HIV. Methods. Participants included 307 children who were born to HIV-positive mothers (96 HIV infected and 211 seroreverters) and enrolled in a natural history, longitudinal study of women to infant HIV transmission. Caregivers completed parent behavioral rating scales, beginning when the children were 3 years old. Data were also collected on prenatal drug exposure; child age, gender, and ethnicity; caregiver relationship to child; and birth complications. Results. Multivariate analyses comparing the HIV-infected children with perinatally exposed but uninfected children from similar backgrounds failed to find an association between either HIV status or prenatal drug exposure and poor behavioral outcomes. The strongest correlates of increased behavioral symptoms were demographic characteristics. Conclusions. This study suggests that although a high prevalence of behavioral problems does exist among HIV-infected children, neither HIV infection nor prenatal drug exposure is the underlying cause. Rather, other biological and environmental factors are likely contributors toward poor behavioral outcomes. C1 Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. Univ Illinois, Chicago, IL USA. Inst Human Virol, Baltimore, MD USA. Baylor Coll Med, Houston, TX 77030 USA. Boston Med Ctr, Boston, MA USA. Univ Puerto Rico, San Juan, PR 00936 USA. SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Mellins, CA (reprint author), New York State Psychiat Inst & Hosp, Hiv Ctr Clin & Behav Studies, Box 15,1051 Riverside Dr, New York, NY 10032 USA. FU NCRR NIH HHS [RR00188, RR00645]; NIAID NIH HHS [1 U01 AI 50274-01, N01 AI 85339, U01 AI 34841, U01 AI 34858]; NICHD NIH HHS [HD-3-6117, U01 HD 41983]; NIDA NIH HHS [9U01 DA 15054, U01 DA 15053] NR 54 TC 66 Z9 67 U1 0 U2 4 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 FEB PY 2003 VL 111 IS 2 BP 384 EP 393 DI 10.1542/peds.111.2.384 PG 10 WC Pediatrics SC Pediatrics GA 640VR UT WOS:000180709100041 PM 12563068 ER PT J AU Suskauer, SJ Cintas, HL Marini, JC Gerber, LH AF Suskauer, SJ Cintas, HL Marini, JC Gerber, LH TI Temperament and physical performance in children with osteogenesis imperfecta SO PEDIATRICS LA English DT Article DE osteogenesis imperfecta; temperament; motor performance ID YOUNG-CHILDREN; PARENTAL OVERPROTECTION; RELATIONSHIP DISORDERS; DIABETES-MELLITUS; STABILITY; INFANCY; VULNERABILITY; PERCEPTIONS; MUTATIONS; SCALE AB Objective. Children with osteogenesis imperfecta (OI) must participate in therapy to achieve motor performance objectives. Their behavioral style may influence motor performance. For this reason, the temperament of children with types III or IV OI was assessed prospectively to 1) compare their temperament with that of nondisabled children, 2) investigate the relationship between temperament and gross motor performance, and 3) examine relationships among temperament, parental overprotection and coping, physical activity, muscle strength, and motor performance. Methods. Age-appropriate Carey Temperament Scales, Brief Assessment of Motor Function (BAMF), and the Vulnerable Child/Overprotecting Parents Scale were completed for 35 children 1 to 12 years old. Additional measures included the Childhood Health Assessment Questionnaire, Parent Daily Hassles Scale, manual muscle testing, Pediatric Activity Record, and a Summed Severity Score. Spearman correlations and multiple regression were used to identify and predict significant relationships. Results. Temperament of children with OI differed from age-based norms in only 1 domain: activity. Motor performance (BAMF) correlated significantly with 3 domains of temperament: persistence (r = -.48), approach (r =-.34), and activity (r =.40). Activity was also related to the ratio of head circumference to body length (r = -.45) and the number of fractures in the preceding year (r = -.35). Parents' reports of their daily hassles significantly correlated with several domains of the child's temperament. No significant relationships were identified between parental overprotection and temperament or motor performance. Conclusions. The temperament of children with types III and IV OI does not differ from that of their nondisabled peers, with the exception of lower activity scores. Although it is considered a biological attribute, the expression of temperament, specifically activity, may be influenced by learned behaviors. Because gross motor performance is related to activity, persistence, and approach/avoidance, knowledge of an individual's temperament may enhance the child's ability to benefit from interventions to improve motor skill and activity levels. C1 NIH, Dept Rehabil Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Univ Cincinnati, Med Ctr, Cincinnati Childrens Hosp, Cincinnati, OH 45267 USA. NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Cintas, HL (reprint author), NIH, Dept Rehabil Med, Warren G Magnuson Clin Ctr, Bldg 10,Rm 6 S 235, Bethesda, MD 20892 USA. NR 43 TC 11 Z9 11 U1 1 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD FEB PY 2003 VL 111 IS 2 AR e153 DI 10.1542/peds.111.2.e153 PG 9 WC Pediatrics SC Pediatrics GA 640VR UT WOS:000180709100008 PM 12563089 ER PT J AU Zhang, ZJ Russell, S Obeng, K Postma, T Obrocea, G Weiss, SRB Post, RM AF Zhang, ZJ Russell, S Obeng, K Postma, T Obrocea, G Weiss, SRB Post, RM TI Coadministration of gabapentin or MK-801 with lamotrigine slows tolerance to its anticonvulsant effects on kindled seizures SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE tolerance; lamotrigine; gabapentin; MK-801; amygdala kindling ID CYCLING BIPOLAR DISORDER; NMDA-RECEPTOR ANTAGONIST; CONTINGENT TOLERANCE; ANTIEPILEPTIC DRUGS; CROSS-TOLERANCE; CARBAMAZEPINE; DIAZEPAM; RATS; VALPROATE; EPILEPSY AB The development of tolerance to therapeutic effects of antiepileptic drugs can be a problem in the treatment of epilepsy, bipolar disorder, and pain syndromes. In the present study, acute treatment with the new antiepileptic drug lamotrigine (LTG, 15 mg/kg) markedly suppressed seizure stage and seizure duration in amygdala-kindled rats; but this antiseizure effect was rapidly lost following 4-8 days of repeated treatment. When gabapentin (GBP, 20 mg/kg) was coadministered with LTG, the ability of LTG to suppress seizure stage, seizure duration, and after-discharge (AD) duration was markedly extended. In addition, GBP coadministration with LTG decreased the number of animals that developed LTG-related running fits (Stage 6 seizures) and lengthened the number of days required to develop running fits or complete tolerance. Neither acute nor repeated treatment with MK-801 (0.3 mg/kg), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, had effects on kindled seizures. However, cotreatment with MK-801 markedly extended the anticonvulsant effects of LTG on the three seizure indices and reduced running fits. These data indicate that cotreatment with either GBP or MK-801 slows tolerance development to the anticonvulsant effects of LTG on kindled seizures. Therapeutic implications of the present study remain to be explored. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP Zhang, ZJ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Psychiat, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 48 TC 14 Z9 14 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD FEB PY 2003 VL 74 IS 3 BP 565 EP 571 AR PII S0091-3057(02)01035-3 DI 10.1016/S0091-3057(02)01035-3 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 641WE UT WOS:000180769400007 PM 12543220 ER PT J AU Malson, JL Lee, EM Murty, R Moolchan, ET Pickworth, WB AF Malson, JL Lee, EM Murty, R Moolchan, ET Pickworth, WB TI Clove cigarette smoking: biochemical, physiological, and subjective effects SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE kreteks; alternative cigarettes; nicotine; smoking ID TRANSDERMAL NICOTINE; BIDIS AB Alternative tobacco products such as clove (kreteks) and bidi cigarettes have become increasingly popular among US smokers. The nicotine content of a popular clove cigarette (Djarurn Special) filler averaged 7.4 mg; conventional cigarettes contained 13.0 mg. However, smoke yields from standardized machine-smoking analysis indicated it delivered more nicotine, carbon monoxide (CO), and tar than conventional cigarettes. In a clinical study, nicotine delivery, physiologic, and subjective effects of the clove cigarette were compared to their own brand of cigarette in 10 adult smokers (7 males). Average time to smoke the clove cigarette (549 s) and number of puffs (15.1) were significantly greater than own brand (314 s and 9.4 puffs). Increases in venous plasma nicotine and exhaled CO after smoking the clove cigarette (17.4 ng/ml; 6 ppm) were similar to those after own brand (17.6 ng/ml; 4.5 ppm). Maximal changes in heart rate (HR), systolic, and diastolic blood pressures (BP) did not differ significantly between the clove and own brand of cigarette. Compared to their own brand of cigarette, the clove cigarette was rated as better tasting and being distinctly different. Our findings indicate that clove cigarettes deliver significant quantities of nicotine, CO, and presumably other toxic components of tobacco smoke. Taste satisfaction, aromatic odor, and novelty may contribute to their appeal to young smokers. (C) 2002 Published by Elsevier Science Inc. C1 NIDA, Intramural Res Program, Baltimore, MD 21224 USA. Murty Pharmaceut Corp, Lexington, KY USA. RP Pickworth, WB (reprint author), NIDA, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NCI NIH HHS [P50CA84718] NR 32 TC 25 Z9 26 U1 2 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD FEB PY 2003 VL 74 IS 3 BP 739 EP 745 DI 10.1016/S0091-3057(02)01076-6 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 641WE UT WOS:000180769400027 PM 12543240 ER PT J AU Bence, AK Worthen, DR Stables, JP Crooks, PA AF Bence, AK Worthen, DR Stables, JP Crooks, PA TI An in vivo evaluation of the antiseizure activity and acute neurotoxicity of agmatine SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE agmatine; seizure; epilepsy; acute neurotoxicity; maximal electroshock; anticonvulsant activity ID IMIDAZOLINE BINDING-SITES; METHYL-D-ASPARTATE; RAT HIPPOCAMPUS; BRAIN; RECEPTORS; POLYAMINES; GLUTAMATE; EPILEPSY; INDUCTION; MICE AB Agmatine, an endogenous cationic amine, exerts a wide range of biological effects, including modulation of glutamate-activated N-methyl-D-aspartate (NMDA) receptor function in the central nervous system (CNS). Since glutamate and the NMDA receptor have been implicated in the initiation and spread of seizure activity, the capacity of agmatine to inhibit seizure spread was evaluated in vivo. Orally administered agmatine (30 mg/kg) protected against maximal electroshock seizure (MES)-induced seizure spread in rats as rapidly as 15 min and for as long as 6 h after administration. Inhibition of MES-induced seizure spread Was also observed when agmatine was administered intraperitoneally. Agmatine's antiseizure activity did not appear to be dose-dependent. An in vivo neurotoxicity screen indicated that agmatine was devoid of any acute neurological toxicity at the doses tested. These preliminary data suggest that agmatine has promising anticonvulsant activity. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Univ Kentucky, Coll Pharm, Div Pharmaceut Sci, Lexington, KY 40536 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Crooks, PA (reprint author), Univ Kentucky, Coll Pharm, Div Pharmaceut Sci, 800 Rose St, Lexington, KY 40536 USA. EM pcrooks@uky.edu NR 30 TC 35 Z9 35 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD FEB PY 2003 VL 74 IS 3 BP 771 EP 775 DI 10.1016/S0091-3057(02)01079-1 PG 5 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 641WE UT WOS:000180769400031 PM 12543244 ER PT J AU Lakhani, NJ Sarkar, MA Venitz, J Figg, WD AF Lakhani, NJ Sarkar, MA Venitz, J Figg, WD TI 2-methoxyestradiol, a promising anticancer agent SO PHARMACOTHERAPY LA English DT Review ID ENDOGENOUS ESTROGEN METABOLITE; INHIBITS TUBULIN POLYMERIZATION; VASCULAR INJURY RESPONSE; SMOOTH-MUSCLE CELLS; BREAST-CANCER; MAMMALIAN METABOLITE; UDP-GLUCURONOSYLTRANSFERASE; SUPEROXIDE-DISMUTASE; ESTRADIOL; ANGIOGENESIS AB Estrogens occurring naturally in the body are metabolized to catecholestrogens (2- and 4-hydroxyestradiol) by the cytochrome P450 enzymes. 2-Hydroxy catecholestrogens are further metabolized by catechol-O-methyltransferase to 2-methoxyestradiol, which is known to be protective against tumor formation. 2-Methoxyestradiol exhibits potent apoptotic activity against rapidly growing tumor cells. It also possesses antiangiogenic activity through a direct apoptotic effect on endothelial cells. Other molecular mechanisms, including microtubule stabilization by inhibition of the colchicine-binding site, have been reported. The exact mechanism of action of 2-methoxyestradiol is still unclear, but it has been shown to be effective in preventing tumor growth in a variety of cell lines. 2-Methoxyestradiol also possesses cardioprotective activity by inhibiting vascular smooth muscle cell growth in arteries. It has a lower binding affinity for estrogen receptor alpha compared with that of estradiol, and its affinity for estrogen receptor beta is even lower than that of estrogen receptor alpha, thus it has minimal estrogenic activity. 2-Methoxyestradiol is distinct because of its inability to engage estrogen receptors as an agonist, and its unique antiproliferative and apoptotic activities are mediated independently of estrogen receptors alpha and beta. A phase I clinical trial of 2-methoxyestradiol 200, 400, 600, 800, and 1000 mg/day in 15 patients with breast cancer showed significant reduction in bone pain and analgesic intake in some patients, with no significant adverse effects. Another phase I study of 2-methoxyestradiol 200-1000 mg/day in combination with docetaxel 35 mg/m(2)/week for 4-6 weeks performed in 15 patients with advanced refractory metastatic breast cancer showed no serious drug-related adverse effects. A phase II randomized, double-blind trial of 2-methoxyestradiol 400 and 1200 mg/day in 33 patients with hormone-refractory prostate cancer showed that it was well tolerated and showed prostate specific antigen stabilizations and declines. We have started a phase I clinical trial to explore dosages greater than 1000 mg/day. C1 NCI, Canc Res Ctr, Canc Therapeut Branch, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Canc Res Ctr, Canc Therapeut Branch, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 61 TC 169 Z9 178 U1 2 U2 15 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD FEB PY 2003 VL 23 IS 2 BP 165 EP 172 DI 10.1592/phco.23.2.165.32088 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 644FA UT WOS:000180906200007 PM 12587805 ER PT J AU Taraphder, S Hummer, G AF Taraphder, S Hummer, G TI Dynamic proton transfer pathways in proteins: role of sidechain conformational fluctuations SO PHYSICA A-STATISTICAL MECHANICS AND ITS APPLICATIONS LA English DT Article; Proceedings Paper CT International Conference on Statistical Physics CY JAN 14-16, 2002 CL KOLKATA, INDIA SP Variabale Energy Cyclotron Ctr, Saha Inst Nucl PHys, Indian Assoc Cultivat Sci, Satyendra Nath Bose Natl Ctr Basic Sci, Govt India, Dept Sci & Technol, Govt India Council Sci & Ind Res DE proton transfer; protein dynamics; P450cam ID CYTOCHROME-C-OXIDASE; ACTIVE-SITE; OXYGEN ACTIVATION; DISORDERED WATER; P450CAM; RESOLUTION; HYDRATION; CAVITY; ACID; CRYSTALLOGRAPHY AB Identification of proton-conducting pathways in a protein is a key to understanding the mechanisms of biomolecular proton transfer. Starting from a known protein structure, proton pathways are modeled here as hydrogen bonded networks of proton conducting groups, including proton-exchanging groups of amino acid sidechains and bound water molecules. The energy minimized static structure is often found to be inadequate to detect suitable proton transfer paths leading, e.g., from the protein surface to the active site buried inside the protein. A general method is developed to study the effect of sidechain rotations and change in internal hydration of the protein on the formation of dynamic connections in the networked path. Application to cytochrome P450cam shows that cooperative rotation of amino acids and motion of water molecules connects the protein surface to the molecular oxygen at the active site. Our observations emphasize the intrinsic dynamical nature of proton pathways. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Indian Inst Technol, Dept Chem, Kharagpur 721302, W Bengal, India. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Taraphder, S (reprint author), Indian Inst Technol, Dept Chem, Kharagpur 721302, W Bengal, India. RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 34 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4371 J9 PHYSICA A JI Physica A PD FEB 1 PY 2003 VL 318 IS 1-2 BP 293 EP 301 AR PII S0378-4371(02)01430-9 DI 10.1016/S0378-4371(02)01430-9 PG 9 WC Physics, Multidisciplinary SC Physics GA 642RE UT WOS:000180802700035 ER PT J AU Masoliver, J Montero, M Weiss, GH AF Masoliver, J Montero, M Weiss, GH TI Continuous-time random-walk model for financial distributions SO PHYSICAL REVIEW E LA English DT Article ID TURBID MEDIUM; FLUCTUATIONS; DYNAMICS AB We apply the formalism of the continuous-time random walk to the study of financial data. The entire distribution of prices can be obtained once two auxiliary densities are known. These are the probability densities for the pausing time between successive jumps and the corresponding probability density for the magnitude of a jump. We have applied the formalism to data on the U.S. dollar-deutsche mark future exchange, finding good agreement between theory and the observed data. C1 Univ Barcelona, Dept Fis Fonamental, E-08028 Barcelona, Spain. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Univ Barcelona, Dept Fis Fonamental, Diagonal 647, E-08028 Barcelona, Spain. RI Montero, Miquel/B-7107-2011; Masoliver, Jaume/F-7198-2016 OI Montero, Miquel/0000-0002-3221-1211; Masoliver, Jaume/0000-0002-5810-879X NR 28 TC 88 Z9 94 U1 0 U2 3 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 2470-0045 EI 2470-0053 J9 PHYS REV E JI Phys. Rev. E PD FEB PY 2003 VL 67 IS 2 AR 021112 DI 10.1103/PhysRevE.67.021112 PN 1 PG 10 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 654WP UT WOS:000181520200016 PM 12636658 ER PT J AU Noonan, FP Dudek, J Merlino, G De Fabo, EC AF Noonan, FP Dudek, J Merlino, G De Fabo, EC TI Animal models of melanoma: An HGF/SF transgenic mouse model may facilitate experimental access to UV initiating events SO PIGMENT CELL RESEARCH LA English DT Review DE melanoma; mouse models; ultraviolet radiation; hepatocyte growth factor/scatter factor ID CYCLOBUTANE PYRIMIDINE DIMERS; HEPATOCYTE GROWTH-FACTOR; ULTRAVIOLET-B RADIATION; FACTOR SCATTER FACTOR; MALIGNANT-MELANOMA; MONODELPHIS-DOMESTICA; HUMAN MELANOCYTES; DNA-DAMAGE; CUTANEOUS MELANOMA; SIGNAL-TRANSDUCTION AB Cutaneous malignant melanoma, the most lethal of the skin cancers, known for its intractability to current therapies, continues to increase in incidence, providing a significant public health challenge. There is a consensus that skin cancer is initiated by sunlight exposure. For non-melanoma skin cancer there is substantial evidence that chronic exposure to the ultraviolet B radiation (UVB) (280-320 nm) portion of the sunlight spectrum is responsible. Experimentally, UVB is mutagenic and chronic UVB exposure can cause non-melanoma skin cancer in laboratory animals. Non-melanoma tumors in animals and in humans show characteristic UVB signature lesions in the tumor suppressor p53 and/or in the patched (PTCH) gene. An action spectrum or wavelength dependence for squamous cell carcinoma in the mouse shows a major peak of efficacy in the UVB. For malignant melanoma, however, the situation is unclear and the critical direct target(s) of sunlight in initiating melanoma and even the wavelengths responsible are as yet unidentified. This lack of information is in major part a result of a paucity of animal models for melanoma which recapitulate the role of sunlight in initiating this disease. The epidemiology of melanoma differs significantly from non-melanoma skin cancer. Intense sporadic sunlight exposure in childhood, probably exacerbated by additional adult exposure, is associated with elevated melanoma risk. Melanoma is also a disease of gene-environment interactions with underlying genetic factors playing a significant role. These major differences indicate that extrapolation from information for nonmelanoma skin cancer to melanoma is unlikely to be useful. We summarize in this review the experimental information available on the role of UV radiation in melanoma and give an overview of animal melanoma models. A new model derived by neonatal UV irradiation of hepatocyte growth factor/scatter factor (HGF/SF) transgenic mice is described which recapitulates the etiology, the histopathology and molecular pathogenesis of human disease. It is anticipated that the HGF/SF transgenic model will provide a means to access the mechanism(s) by which sunlight initiates this lethal disease and provide an appropriate vehicle for derivation of appropriate therapeutic and preventive strategies. C1 George Washington Univ, Sch Med,Lab Photobiol & Photoimmunol, Sch Publ Hlth & Hlth Serv, Dept Environm & Occupat Hlth, Washington, DC 20037 USA. NCI, Mol Genet Sect, Mol Biol Lab, Bethesda, MD 20892 USA. RP Noonan, FP (reprint author), George Washington Univ, Sch Med,Lab Photobiol & Photoimmunol, Sch Publ Hlth & Hlth Serv, Dept Environm & Occupat Hlth, Ross Hall,Rm 113,2300 Eye St NW, Washington, DC 20037 USA. NR 134 TC 53 Z9 54 U1 0 U2 7 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PD FEB PY 2003 VL 16 IS 1 BP 16 EP 25 DI 10.1034/j.1600-0749.2003.00014.x PG 10 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 640HE UT WOS:000180682100002 PM 12519121 ER PT J AU Sunthitikawinsakul, A Kongkathip, N Kongkathip, B Phonnakhu, S Daly, JW Spande, TF Nimit, Y Rochanaruangrai, S AF Sunthitikawinsakul, A Kongkathip, N Kongkathip, B Phonnakhu, S Daly, JW Spande, TF Nimit, Y Rochanaruangrai, S TI Coumarins and carbazoles from Clausena excavata exhibited antimycobacterial and antifungal activities SO PLANTA MEDICA LA English DT Article ID ROOT BARK; ALKALOIDS; CONSTITUENTS; HARMANDIANA; ELUCIDATION; ASSAY AB Four known coumarins, dentatin (1), nor-dentatin (2), clausenidin (3) and xanthoxyletin (5), and six known carbazole derivatives, 3-formylcarbazole (6), mukonal (7), 3-methoxycarbonyl-carbazole (8), murrayanine (9), 2-hydroxy-3-formyl-7-methoxy-carbazole (10) and clauszoline J (11) were isolated from Clausena excavata. Compounds 1 and 6 were first isolated from the crude chloroform extract of the rhizomes. Compounds 1, 2, 3, 6, 7, 8, 10 and 11 showed anti- mycobacterial activity at a minimum inhibitory concentration (MIC) of 50,100, 200, 100, 200, 50, 100 and 100mug/mL, respectively. O-Methylated clausenidin (4), prepared from 3, exhibited anti mycobacterial activity at MIC 50 mug/mL. Compounds 6, 7, 8 and 10 showed antifungal activity with IC50 values of 13.6, 29.3, 9.5 and 2.8 mug/mL, respectively. All compounds demonstrated no cytotoxicity against KB and BC-1 cell lines. C1 Kasetsart Univ, Dept Chem, Fac Sci, Nat Prod & Organ Synth Res Unit, Bangkok 10900, Thailand. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NIH, Off Natl Advisory Council, Bethesda, MD 20892 USA. NSTDA, Natl Ctr Genet Engn & Biotechnol, Bangkok, Thailand. RP Kongkathip, N (reprint author), Kasetsart Univ, Dept Chem, Fac Sci, Nat Prod & Organ Synth Res Unit, Bangkok 10900, Thailand. EM fscinpk@ku.ac.th NR 17 TC 69 Z9 73 U1 0 U2 8 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0032-0943 J9 PLANTA MED JI Planta Med. PD FEB PY 2003 VL 69 IS 2 BP 155 EP 157 DI 10.1055/s-2003-37716 PG 3 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA 659UA UT WOS:000181794800011 PM 12624822 ER PT J AU Kalache, KD Romero, R Conoscenti, G Qureshi, F Jacques, SM Chaiworapongsa, T Treadwell, M Johnson, A AF Kalache, KD Romero, R Conoscenti, G Qureshi, F Jacques, SM Chaiworapongsa, T Treadwell, M Johnson, A TI Prenatal diagnosis of dilated coronary sinus with persistent left superior vena cava in a fetus with trisomy 18 SO PRENATAL DIAGNOSIS LA English DT Article DE coronary sinus; persistent left superior vena cava; trisomy 18; ultrasonography; prenatal diagnosis ID PULMONARY VENOUS CONNECTION; DEFECTS AB A case of dilated coronary sinus with persistent left superior vena cava diagnosed at 33 weeks in a fetus with trisomy 18 is reported. The features of this cardiac anomaly on prenatal ultrasonography and its association with trisomy 18 are discussed. Published in 2002 by John Wiley Sons, Ltd. C1 Wayne State Univ, Hutzel Hosp, DHHS,NIH, NICHD,Perinatol Res Branch,Dept Obstet & Gynecol, Detroit, MI 48201 USA. Wayne State Univ, Hutzel Hosp, Dept Pathol, Detroit, MI USA. RP Kalache, KD (reprint author), Wayne State Univ, Hutzel Hosp, DHHS,NIH, NICHD,Perinatol Res Branch,Dept Obstet & Gynecol, 4707 St Antoine Blvd, Detroit, MI 48201 USA. NR 14 TC 9 Z9 11 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0197-3851 J9 PRENATAL DIAG JI Prenat. Diagn. PD FEB PY 2003 VL 23 IS 2 BP 108 EP 110 DI 10.1002/pd.460 PG 3 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 650KG UT WOS:000181262100005 PM 12575015 ER PT J AU Lawrence, D Graber, JE Mills, SL Meissner, HI Warnecke, R AF Lawrence, D Graber, JE Mills, SL Meissner, HI Warnecke, R TI Smoking cessation interventions in US racial/ethnic minority populations: an assessment of the literature SO PREVENTIVE MEDICINE LA English DT Article DE smoking cessation; tobacco; intervention studies; program evaluation; ethnic groups; blacks; Asians; Hispanic Americans; Native Americans; American Indians ID AFRICAN-AMERICAN WOMEN; HISPANIC SMOKERS; IMPACT; PROJECT; CLINICS; PHYSICIAN; NICOTINE; PROGRAM; SPANISH; HARLEM AB Background. Smoking prevalence rates in some ethnic minority groups are elevated relative to the majority population. Thus, identifying cessation interventions that are effective for these groups is important. This article reviews published studies that examine effects of smoking cessation interventions relevant to racial ethnic minority populations. Methods. A literature search of tobacco interventions, reporting smoking cessation outcomes (including quit rates) in U.S. minority populations, was conducted for the period 1985 to 2001. Results. Thirty-six studies met preset criteria for inclusion. Twenty-three reported quit rates for African Americans, 4 for Asian/Pacific Islanders, 3 for Native Americans, and 10 for Hispanics. Conclusions. The disproportionate number of studies that focused on African American smokers compared with the other major racial/ethnic groups suggests the need for continued efforts to develop and evaluate the effectiveness of smoking cessation interventions for all ethnic minority populations. Abstinence rates varied considerably depending on study design and intervention strategy. Moreover, a relatively small percentage of studies that were randomized trials reported statistically significant findings, and most used intervention strategies that do not reflect the current state-of-the-art. These results strongly suggest that more research is needed to identify successful smoking cessation interventions in these populations. (C) 2003 American Health Foundation and Elsevier Science (USA). All rights reserved. C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Abt Associates Inc, Bethesda, MD 20814 USA. Univ Illinois, Policy Ctr, Chicago, IL 60607 USA. Univ Illinois, Hlth Res Ctr, Chicago, IL 60607 USA. RP Lawrence, D (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN Suite 4005 MSC 7344, Bethesda, MD 20892 USA. NR 52 TC 82 Z9 82 U1 8 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD FEB PY 2003 VL 36 IS 2 BP 204 EP 216 DI 10.1016/S0091-7435(02)00023-3 PG 13 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 650KD UT WOS:000181261700010 PM 12590996 ER PT J AU McClure, EB Kubiszyn, T Kaslow, NJ AF McClure, EB Kubiszyn, T Kaslow, NJ TI Evidence-based assessment of childhood mood disorders: Reply to Lee and Hunsley (2003) SO PROFESSIONAL PSYCHOLOGY-RESEARCH AND PRACTICE LA English DT Article ID PSYCHOLOGICAL-ASSESSMENT C1 NIMH, Bethesda, MD 20892 USA. Univ Texas, Austin, TX 78712 USA. Emory Univ, Sch Med, Atlanta, GA 30322 USA. RP McClure, EB (reprint author), NIMH, Bethesda, MD 20892 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7028 J9 PROF PSYCHOL-RES PR JI Prof. Psychol.-Res. Pract. PD FEB PY 2003 VL 34 IS 1 BP 113 EP 114 PG 2 WC Psychology, Multidisciplinary SC Psychology GA 639ZH UT WOS:000180660300017 ER PT J AU Pezawas, L Angst, J Gamma, A Ajdacic, V Eich, D Rossler, W AF Pezawas, L Angst, J Gamma, A Ajdacic, V Eich, D Rossler, W TI Recurrent brief depression - past and future SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE depression; mood disorder; recurrent brief depression; subthreshold; therapy ID GENERAL HEALTH-CARE; AFFECTIVE-ILLNESS; PSYCHOLOGICAL-PROBLEMS; PSYCHIATRIC-DISORDERS; SUICIDAL-BEHAVIOR; CONTROLLED TRIAL; MOOD SWINGS; PREVALENCE; ZURICH; FLUOXETINE AB Recurrent brief depressive disorder (RBD) is. a well-defined and significantly prevalent affective disorder with an increased risk of suicidal behavior and significant clinical impairment in the community and general practice. RBD is characterized by depressive episodes occurring at least once a month and lasting for only a few days. The lifetime co-occurrence of both RBD and major depressive disorder (MDD), called combined depression (CD), increases substantially the risk for suicide attempts, even more than is known for "pure" MDD. Diagnostic criteria for RBD can be found in the ICD-10 and DSM-IV and are helpful in both, research and clinical routine. Furthermore, several methodological issues are covered in this paper, which make clinical diagnostic and drug response evaluation of RBD very different from MDD. However, clinical procedures rather bear a resemblance to those used in the treatment of migraine or epilepsy. Formal differences in the course of RBD and MDD create different needs concerning the design of drug treatment studies. Absence of special methodological requirements and highly selected patient samples has probably been responsible for false negative results in double-blind, placebo-controlled treatment studies. Although several authors reported successful treatment of RBD with different compounds in about 60 patients, it is still not possible to deduce a treatment algorithm for RBD to date. Obviously, future treatment studies without the limitations of previous studies are clearly required for RBD. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Univ Vienna, Dept Gen Psychiat, Vienna, Austria. Univ Zurich, Hosp Psychiat, Zurich, Switzerland. RP Pezawas, L (reprint author), NIMH, Clin Brain Disorders Branch, NIH, 10 Ctr Dr 4S235, Bethesda, MD 20892 USA. OI Pezawas, Lukas/0000-0002-1329-6352; Ajdacic-Gross, Vladeta/0000-0002-7032-9237 NR 57 TC 12 Z9 13 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD FEB PY 2003 VL 27 IS 1 BP 75 EP 83 AR PII S0278-5846(02)00318-4 DI 10.1016/S0278-5846(02)00318-4 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 644ZL UT WOS:000180951700011 PM 12551729 ER PT J AU Saroff, HA AF Saroff, HA TI Structure of deoxyhemoglobin: Ionizable groups and polyethylene glycol SO PROTEINS-STRUCTURE FUNCTION AND GENETICS LA English DT Article DE X-ray; models; dimer interface; Bohr effect; cooperativity ID HEMOGLOBIN; RESOLUTION; CRYSTALS; BINDING AB X-ray studies on deoxy-hemoglobin have been reported on crystals grown under conditions of high (about 2.5 M) and low salt (about 0.1 M). The high-salt crystals were grown in water, whereas the low-salt crystals were prepared in polyethylene glycol solutions (m.w. 6000-8000 Da, 10-30% w/v). Oxygen-binding characteristics of hemoglobin in these two environments differ radically. In salt solutions, hemoglobin binds oxygen with a p50 value of about 5 torr of oxygen and in a cooperative manner characterized with an n value of Hill varying from two to three. In polyethylene glycol solutions, hemoglobin crystals are oxygenated with a p50 value of about 270 torr of oxygen, without exhibiting a cooperative effect. I report on a detailed study of the X-ray data defining the dimer interface (alpha1beta2) of these two forms of hemoglobin. The study reveals that the main difference between the two structures lies in the number and arrangement of the water molecules and in distances between ionizable side chains in the dimer interface. I propose that these differences lead to significant shifts in the pK values of the ionizable groups in the dimer interface. (C) 2002 Wiley-Liss, Inc*. C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Saroff, HA (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NR 24 TC 2 Z9 2 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-3585 J9 PROTEINS JI Proteins PD FEB 1 PY 2003 VL 50 IS 2 BP 329 EP 340 DI 10.1002/prot.10258 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 632EA UT WOS:000180209700016 PM 12486726 ER PT J AU Medjahed, D Smythers, GW Powell, DA Stephens, RM Lemkin, PF Munroe, DJ AF Medjahed, D Smythers, GW Powell, DA Stephens, RM Lemkin, PF Munroe, DJ TI VIRTUAL2D: A web-accessible predictive database for proteomics analysis SO PROTEOMICS LA English DT Article DE expressed sequence tags; protein expression map; two-dimensional gel electrophoresis; VIRTUAL2D ID RESOLUTION 2-DIMENSIONAL ELECTROPHORESIS; PROTEINS AB The available archive of sequence databases compiled from whole genome projects and budding proteomics efforts have enabled us to develop VIRTUAL2D, an interactive system for the assembly of virtual protein expression maps computed on the basis of theoretical isoelectric focusing point, molecular weight, tissue specificity and relative abundance for any set of proteins currently catalogued. This tool will assist in the preliminary, albeit putative, prediction of the identity and location of unknown and/or low abundance proteins in experimentally derived two-dimensional polyacrylamide gel electrophoresis maps. C1 NCI, Lab Mol Technol, Frederick, MD 21702 USA. NCI, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. NCI, Data Management Serv, Frederick, MD 21702 USA. NCI, Lab Computat & Expt Biol, CCR, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21702 USA. RP Medjahed, D (reprint author), NCI, Lab Mol Technol, POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 23 TC 12 Z9 13 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD FEB PY 2003 VL 3 IS 2 BP 129 EP 138 DI 10.1002/pmic.200390021 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 650TX UT WOS:000181280400003 PM 12601805 ER PT J AU Wyatt, RJ Henter, ID Mojtabai, R Bartko, JJ AF Wyatt, RJ Henter, ID Mojtabai, R Bartko, JJ TI Height, weight and body mass index (BMI) in psychiatrically ill US Armed Forces personnel SO PSYCHOLOGICAL MEDICINE LA English DT Article ID DUTCH-HUNGER-WINTER; PRENATAL EXPOSURE; SCHIZOPHRENIA; METAANALYSIS; BRAIN; RISK; SIZE AB Background. In both psychiatrically ill and psychiatrically healthy adults, the connection between health and individuals' height and weight has long been examined. Specifically, research on the idea that individuals with certain body types were prone to particular psychiatric diseases has been explored sporadically for centuries. The hypothesis that psychiatrically ill individuals were shorter and weighed less than psychiatrically healthy counterparts would correspond with the neurodevelopmental model of psychiatric disease. Method. To evaluate possible links between psychiatric illness and physique, the height, weight and BMI of 7514 patients and 85 940 controls were compared. All subjects were part of the National Collaborative Study of Early Psychosis and Suicide (NCSEPS). Patients were US military active duty personnel hospitalized for either bipolar disorder, major depressive disorder, or schizophrenia and controls were psychiatrically-healthy US military active duty personnel matched for date of entry into the service. Results. No consistent differences in height, weight or BMI were found between patients and controls, or between patient groups. Some weak ANOVA differences were found between age at the time of entering active duty and weight, as well as BMI, but not height. Conclusions. Unlike most previous studies that have looked at the links between height and psychiatric illness, this study of the NCSEPS cohort found that, at entry into the US Armed Forces, there were no consistent decreases in height for patients with bipolar disorder, major depressive disorder or schizophrenia compared with a large control group. Furthermore, there were no consistent differences for weight or BMI. C1 NIMH, Neuropsychiat Branch, NIH, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. RP Wyatt, RJ (reprint author), NIMH, Neuropsychiat Branch, NIH, 5415 W Cedar Lane,MSC 2610,Suite 106B, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 MH999999] NR 24 TC 16 Z9 17 U1 0 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD FEB PY 2003 VL 33 IS 2 BP 363 EP 368 DI 10.1017/S0033291702006694 PG 6 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 671RZ UT WOS:000182479000019 PM 12622316 ER PT J AU Gilbert, ES Stovall, M Gospodarowicz, M van Leeuwen, FE Andersson, M Glimelius, B Joensuu, T Lynch, CF Curtis, RE Holowaty, E Storm, H Pukkala, E van't Veer, MB Fraumeni, JE Boice, JD Clarke, EA Travis, LB AF Gilbert, ES Stovall, M Gospodarowicz, M van Leeuwen, FE Andersson, M Glimelius, B Joensuu, T Lynch, CF Curtis, RE Holowaty, E Storm, H Pukkala, E van't Veer, MB Fraumeni, JE Boice, JD Clarke, EA Travis, LB TI Lung cancer after treatment for Hodgkin's disease: Focus on radiation effects SO RADIATION RESEARCH LA English DT Article ID ATOMIC-BOMB SURVIVORS; BREAST-CANCER; MORTALITY; RISK; EXPOSURE; FIBROSIS; THERAPY; SMOKING; COHORT; DNA AB Aspects of radiation-induced lung cancer were evaluated in an international study of Hodgkin's disease. The study population consisted of 227 patients with lung cancer and 455 matched controls. Unique features included dose determinations to the specific location in the lung where each cancer developed and quantitative data on both chemotherapy and tobacco use obtained from medical records. The estimated excess relative risk (ERR) per Gy was 0.15 (95% CI: 0.06-0.39), and there was little evidence of departure from linearity even though lung doses for the majority of Hodgkin's disease patients treated with radiotherapy exceeded 30 Gy. The interaction of radiation and chemotherapy that included alkylating agents was almost exactly additive, and a multiplicative relationship could be rejected (P = 0.017). Conversely, the interaction of radiation and smoking was consistent with a multiplicative relationship, but not with an additive relationship (P < 0.001). The ERR/Gy for males was about four times that for females, although the difference was not statistically significant. There was little evidence of modification of the ERR/Gy by time since exposure (after a 5-year minimum latent period), age at exposure, or attained age. Because of the very high radiation doses received by Hodgkin's disease patients and the immunodeficiency inherent to this lymphoma and that associated with chemotherapy, generalizing these findings to other populations receiving considerably lower doses of radiation should be done cautiously. (C) 2003 by Radiation Research Society. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. Netherlands Canc Inst, Amsterdam, Netherlands. Danish Canc Soc, Copenhagen, Denmark. Uppsala Univ, Stockholm, Sweden. Univ Helsinki, Cent Hosp, FIN-00014 Helsinki, Finland. Univ Iowa, Iowa City, IA USA. Canc Care Ontario, Toronto, ON, Canada. Finnish Canc Registry, FIN-00170 Helsinki, Finland. Dr Daniel Den Hoed Canc Ctr, NL-3008 AE Rotterdam, Netherlands. Vanderbilt Univ, Nashville, TN USA. Int Epidemiol Inst, Rockville, MD USA. RP Gilbert, ES (reprint author), Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, 6120 Execut Blvd,Room 7050, Rockville, MD 20852 USA. NR 36 TC 113 Z9 115 U1 0 U2 2 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 FEB PY 2003 VL 159 IS 2 BP 161 EP 173 DI 10.1667/0033-7587(2003)159[0161:LCATFH]2.0.CO;2 PG 13 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 642BU UT WOS:000180785100004 PM 12537521 ER PT J AU Pastwa, E Neumann, RD Mezhevaya, K Winters, TA AF Pastwa, E Neumann, RD Mezhevaya, K Winters, TA TI Repair of radiation-induced DNA double-strand breaks is dependent upon radiation quality and the structural complexity of double-strand breaks SO RADIATION RESEARCH LA English DT Article ID HUMAN CELL-EXTRACTS; IN-VITRO REPAIR; GROUP NO 6; IONIZING-RADIATION; ESCHERICHIA-COLI; SINGLE-STRAND; 3'-PHOSPHOGLYCOLATE TERMINI; MAMMALIAN-CELLS; TRACK STRUCTURE; CHO-CELLS AB Mammalian cells primarily repair DSBs by nonhomologous end joining (NHEJ). To assess the ability of human cells to mediate end joining of complex DSBs such as those produced by chemicals, oxidative events, or high- and low-LET radiation, we employed an in vitro double-strand break repair assay using plasmid DNA linearized by these various agents. We found that human HeLa cell extracts support end joining of complex DSBs and form multimeric plasmid products from substrates produced by the radiomimetic drug bleomycin, (60)Co gamma rays, and the effects of (125)I decay in DNA. End joining was found to be dependent on the type of DSB-damaging agent, and it decreased as the cytotoxicity of the DSB-inducing agent increased. In addition to the inhibitory effects of DSB end-group structures on repair, NHEJ was found to be strongly inhibited by lesions proximal to DSB ends. The initial repair rate for complex non-ligatable bleomycin-induced DSBs was sixfold less than that of similarly configured (blunt-ended) but less complex (ligatable) restriction enzyme-induced DSBs. Repair of DSBs produced by gamma rays was 15-fold less efficient than repair of restriction enzyme-induced DSBs. Repair of the DSBs produced by (125)I was near the lower limit of detection in our assay and was at least twofold lower than that of gamma-ray-induced DSBs. In addition, DSB ends produced by (125)I were shown to be blocked by 3'-nucleotide fragments: the removal of these by E. coli endonuclease IV permitted ligation. (C) 2003 by Radiation Research Society. C1 NIH, Dept Nucl Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. Med Univ Lodz, Dept Gen Chem, Inst Physiol & Biochem, Lodz, Poland. RP Winters, TA (reprint author), NIH, Dept Nucl Med, Warren Grant Magnuson Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. EM twinters@mail.cc.nih.gov NR 60 TC 69 Z9 71 U1 1 U2 4 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD FEB PY 2003 VL 159 IS 2 BP 251 EP 261 DI 10.1667/0033-7587(2003)159[0251:RORIDD]2.0.CO;2 PG 11 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 642BU UT WOS:000180785100014 PM 12537531 ER PT J AU Hewitt, SC Korach, KS AF Hewitt, SC Korach, KS TI Oestrogen receptor knockout mice: roles for oestrogen receptors alpha and beta in reproductive tissues SO REPRODUCTION LA English DT Review ID EPIDERMAL GROWTH-FACTOR; HUMAN ESTROGEN-RECEPTOR; ER-BETA; TARGETED DISRUPTION; CHROMOSOMAL LOCALIZATION; PROGESTERONE ACTION; SIGNALING PATHWAYS; SEXUAL DEVELOPMENT; OVARIAN PHENOTYPE; MOLECULAR-BIOLOGY AB Oestrogen is an essential component of female reproduction, with well-characterized functions in the uterus, ovaries, mammary gland and hypothalamic-pituitary axis. The mechanism of oestrogen action involves mediation of the rate of transcription by nuclear-localized oestrogen receptor molecules. Two oestrogen receptors are present in mouse tissues, oestrogen receptors alpha and beta. Each receptor exhibits differential tissue expression patterns. Mouse models with genetically engineered disruption or 'knockout' of the oestrogen receptors have been developed. Characterization of the resulting defects in reproductive tissues as well as alterations in physiological and genomic responses has given insight into the receptor-mediated effects of oestrogen in reproduction. Oestrogen receptor alpha knockout females are infertile because they are anovulatory, have disruption in LH regulation and have uteri that are insensitive to oestrogen. In contrast, oestrogen receptor beta knockout females are sub-fertile and primarily lack efficient ovulatory function. Mice with deletion of both oestrogen receptors alpha and beta are similar to those lacking oestrogen receptor alpha only, but exhibit a unique ovarian pathology. These observed phenotypes elucidate the relative roles of the oestrogen receptors in reproductive functions of female rodents. C1 NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Hewitt, SC (reprint author), NIEHS, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. OI Korach, Kenneth/0000-0002-7765-418X NR 53 TC 157 Z9 168 U1 1 U2 17 PU SOC REPRODUCTION FERTILITY PI CAMBRIDGE PA 22 NEWMARKET RD, CAMBRIDGE CB5 8DT, ENGLAND SN 1470-1626 J9 REPRODUCTION JI Reproduction PD FEB PY 2003 VL 125 IS 2 BP 143 EP 149 PG 7 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA 656CC UT WOS:000181590400001 PM 12578528 ER PT J AU Luke, BT AF Luke, BT TI Fuzzy structure-activity relationships SO SAR AND QSAR IN ENVIRONMENTAL RESEARCH LA English DT Article DE Fuzzy classifiers; Fuzzy structure-activity relationship; Selwood data; K nearest neighbor (KNN) ID STRUCTURE-PROPERTY RELATIONSHIPS; NEURAL NETWORKS; SELECTION; QSAR; OPTIMIZATION AB While quantitative structure-activity relationships attempt to predict the numerical value of the activities, it is found that statistically good predictors do not always do a good job of qualitatively determining the activity. This study shows how Fuzzy classifiers can be used to generate Fuzzy structure-activity relationships which can more accurately determine whether or not a compound will be highly inactive, moderately inactive or active, or highly active. Four examples of these classifiers are presented and applied to a well-studied activity dataset. C1 NCI, Adv Biomed Comp Ctr, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Luke, BT (reprint author), NCI, Adv Biomed Comp Ctr, SAIC Frederick Inc, POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 28 TC 0 Z9 0 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1062-936X J9 SAR QSAR ENVIRON RES JI SAR QSAR Environ. Res. PD FEB PY 2003 VL 14 IS 1 BP 41 EP 57 DI 10.1080/1062936021000058773 PG 17 WC Chemistry, Multidisciplinary; Computer Science, Interdisciplinary Applications; Environmental Sciences; Mathematical & Computational Biology; Toxicology SC Chemistry; Computer Science; Environmental Sciences & Ecology; Mathematical & Computational Biology; Toxicology GA 643JH UT WOS:000180857800005 PM 12688415 ER PT J AU Elvevag, B Fisher, JE Goldberg, TE AF Elvevag, B Fisher, JE Goldberg, TE TI Probed recall for serial order deficits in short-term memory in schizophrenic patients SO SCHIZOPHRENIA RESEARCH LA English DT Article DE probed recall; short-term memory; schizophrenia ID POSITRON-EMISSION-TOMOGRAPHY; WORKING-MEMORY; TEMPORAL-ORDER; TIME; REHEARSAL; STORAGE AB Background: Patients with schizophrenia frequently display problems in tasks demanding working memory. In a previous study, we examined short-term memory (STM) for serial order by having participants recall lists of letters from the first item to the last item in the order in which they were presented, and we examined the types of errors made (e.g., omissions, intrusions and movements; [Neuropsychology 15 (2001) 128]). We found that the disproportionate errors schizophrenic patients made were omissions at the end of six-item lists, a finding we suggested might reflect patients' longer output times, which adds to information maintenance demands. If this is the case, we predicted that the group difference in the terminal positions could be eliminated through the use of a probed recall paradigm. Method: In the current study, 26 schizophrenic patients and 33 control participants were tested on a probed recall task that was similar to our previous serial recall task except that instead of recalling the whole sequence of letters, participants were probed as to which letter appeared in a specific position in the sequence. Results: We found that when participants were probed for later positions, recall was equivalent in the groups (i.e., recency), but disproportionately worse in patients for earlier positions. Conclusions: We suggest that schizophrenic patients' limited STM span for serial order is not attributable to a selective deficit in memory for serial order. Rather, we propose that it may be explicable in terms of impaired information maintenance and thus this becomes evident in conditions involving longer sequences of stimuli. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Elvevag, B (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Room 4S235,MSC 1379,Bldg 10, Bethesda, MD 20892 USA. NR 37 TC 14 Z9 14 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD FEB 1 PY 2003 VL 59 IS 2-3 BP 127 EP 135 AR PII S0920-9964(01)00384-X DI 10.1016/S0920-9964(01)00384-X PG 9 WC Psychiatry SC Psychiatry GA 646PJ UT WOS:000181043200003 PM 12414069 ER PT J AU Fang, S Lorick, KL Jensen, JP Weissman, AM AF Fang, S Lorick, KL Jensen, JP Weissman, AM TI RING finger ubiquitin protein ligases: implications for tumorigenesis, metastasis and for molecular targets in cancer SO SEMINARS IN CANCER BIOLOGY LA English DT Review DE ubiquitin; ubiquitin protein ligase; E3; RING finger; proteasome; molecular target; metastasis; ERAD; autocrine motility factor receptor; BRCA1 ID AUTOCRINE MOTILITY FACTOR; RETICULUM-ASSOCIATED DEGRADATION; TUMOR-SUPPRESSOR COMPLEX; CELL RECEPTOR SUBUNITS; F-BOX PROTEIN; ENDOPLASMIC-RETICULUM; CONJUGATING ENZYME; INVERSE RELATION; U-BOX; PROTEASOME INHIBITION AB Covalent modification of proteins with ubiquitin regulates almost all aspects of eukaryotic cellular function. Ubiquitin protein ligases (E3s) play central regulatory roles in that they provide substrate specificity to this process and therefore, represent attractive molecular targets for disease therapy. We summarize recent advances in our understanding of RING finger and RING finger-related E3s with emphasis on BRCA1 and the tumor autocrine motility factor receptor (gp78), as well as discuss the potential for components of the ubiquitin pathway for proteasomal degradation as molecular targets. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NCI, Regulat Prot Funct Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Weissman, AM (reprint author), NCI, Regulat Prot Funct Lab, Ctr Canc Res, Bldg 560,Room 22-95,1050 Boyles St, Frederick, MD 21702 USA. RI Fang, Shengyun/H-3802-2011 NR 123 TC 99 Z9 102 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD FEB PY 2003 VL 13 IS 1 BP 5 EP 14 AR PII S1044-579X(02)00095-0 DI 10.1016/S1044-579X(02)00095-0 PG 10 WC Oncology SC Oncology GA 639EC UT WOS:000180613800002 PM 12507552 ER PT J AU Rehermann, B AF Rehermann, B TI Immune responses in hepatitis B virus infection SO SEMINARS IN LIVER DISEASE LA English DT Review DE liver; hepatitis B virus; T cell; immune response; cytokine ID CYTOTOXIC T-LYMPHOCYTES; NECROSIS-FACTOR-ALPHA; TRANSGENIC MOUSE MODEL; ACUTE VIRAL-HEPATITIS; NF-KAPPA-B; DNA-MEDIATED IMMUNIZATION; IFN-INDUCIBLE PROTEIN-10; CHRONIC ACTIVE HEPATITIS; PERFORIN-DEFICIENT MICE; CHRONIC HBV INFECTION AB Hepatitis B virus infection is one of the most frequent causes of chronic liver disease worldwide. Even though a preventive vaccine is available, the search for a cure for chronically infected patients remains a high priority to reduce the morbidity and mortality from liver cirrhosis and hepatocellular carcinoma. This review summarizes the immune response in acute, self-limited and chronic hepatitis B; its differential effects on viral replication and liver injury; and prospects for immunotherapy. C1 NIDDK, Liver Dis Sect, HHS, NIH, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDK, Liver Dis Sect, HHS, NIH, HHS Bldg 10,Room 9B16,10 Ctr Dr, Bethesda, MD 20892 USA. NR 174 TC 65 Z9 73 U1 0 U2 3 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0272-8087 J9 SEMIN LIVER DIS JI Semin. Liver Dis. PD FEB PY 2003 VL 23 IS 1 BP 21 EP 37 DI 10.1055/s-2003-37586 PG 17 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 651DD UT WOS:000181304400003 PM 12616448 ER PT J AU Paiva, CN Pyrrho, AS Lannes-Vieira, J Vacchio, M Soares, MBP Gattass, CR AF Paiva, CN Pyrrho, AS Lannes-Vieira, J Vacchio, M Soares, MBP Gattass, CR TI Trypanosoma cruzi sensitizes mice to fulminant SEB-induced shock: Overrelease of inflammatory cytokines and independence of Chagas' disease or TCR V beta-usage SO SHOCK LA English DT Article DE repertoire; clone CL-14; CL strain; staphylococcal enterotoxin B; sepsis; T lymphocyte; TNF-alpha; IFN-gamma ID STAPHYLOCOCCAL-ENTEROTOXIN-B; TUMOR-NECROSIS-FACTOR; T-CELL; LETHAL SHOCK; BACTERIAL SUPERANTIGEN; TOXIC-SHOCK; MONOCLONAL-ANTIBODY; INTERFERON-GAMMA; IN-VIVO; INFECTION AB Trypanosoma cruzi-infected mice display increased susceptibility to shock induced by injection of lipopolysaccharide (LPS), anti-CD3, or resulting from interleukin (IL)-10-defective response to the parasite itself, but the basis of such susceptibility remains unknown. Herein, we tested the susceptibility of mice inoculated with virulent and avirulent T. cruzi to staphylococcal enterotoxins (SE), potent inducers of inflammatory cytokine secretion. Mice infected with T. cruzi CL-strain or inoculated with the avirulent clone CL-14, a clone that does not induce disease or polyclonal lymphocyte activation, succumb suddenly to low doses of staphylococcal enterotoxin B (SEB), but not to staphylococcal enterotoxin A (SEA). High plasma levels of TNF, IFN-gamma, and liver transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were found in these mice, indicating lethal toxic shock. Sensitization to shock required inoculation of live avirulent trypomastigotes and a time interval before challenge with SEB. We found no prior skewing of T cell receptor (TCR) Vbeta-repertoire in CL-14-inoculated mice that could be responsible for sensitization. Splenocytes from CL-14-inoculated mice proliferated more under anti-Vbeta8 than anti-TCRbeta stimulation when compared with normal mice, but were suppressed to SEB stimulation. Both SEB and anti-Vbeta8 antibodies stimulated splenocytes from T. cruzi-inoculated mice to secrete higher levels of inflammatory cytokines than normal controls. Taken together, our results show that T. cruzi inoculation can sensitize mice to lethal SEB-induced shock even in the absence of tissue damage, polyclonal lymphocyte activation, or previously increased levels of inflammatory cytokines, and they suggest that altered reactivity of Vbeta8 lymphocytes may be involved in the phenomenon. C1 Fed Univ Rio De Janeiro, Lab Imunoparasitol, Inst Biofis Carlos Chagas Filho, BR-21941900 Rio De Janeiro, Brazil. Fed Univ Rio De Janeiro, Dept Anal Clin & Toxicol, Fac Farm, BR-21941900 Rio De Janeiro, Brazil. Fiocruz MS, Inst Oswaldo Cruz, BR-21045900 Rio De Janeiro, Brazil. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Fiocruz MS, Ctr Pesquisas Goncalo Moniz, BR-40295001 Salvador, BA, Brazil. RP Gattass, CR (reprint author), Fed Univ Rio De Janeiro, Lab Imunoparasitol, Inst Biofis Carlos Chagas Filho, BR-21941900 Rio De Janeiro, Brazil. NR 35 TC 7 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 J9 SHOCK JI Shock PD FEB PY 2003 VL 19 IS 2 BP 163 EP 168 DI 10.1097/01.SHK.0000054747.80210.e9 PG 6 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 640CG UT WOS:000180668600013 PM 12578126 ER PT J AU Prato, N Banderali, A Neumaier, CE Dahmane, M Martinoli, C Derchi, LE AF Prato, N Banderali, A Neumaier, CE Dahmane, M Martinoli, C Derchi, LE TI Calcific tendinitis of the rotator cuff as a cause of drooping shoulder SO SKELETAL RADIOLOGY LA English DT Article DE drooping shoulder; glenohumeral joint subluxation; calcification; rotator cuff; radiographs; MRI ID INFERIOR SUBLUXATION AB We describe a case of inferior glenohumeral subluxation or drooping shoulder secondary to acute calcific tendinitis of the rotator cuff. The various etiologies of drooping shoulder and the specific causes determining glenohumeral widening in our report are discussed. The importance in recognizing this uncommon complication of a common abnormal finding and correction by aspiration is stressed. C1 Univ Genoa, Dept Radiol, I-16132 Genoa, Italy. San Carlo Hosp, Dept Radiol, I-16158 Genoa, Italy. Natl Canc Inst, Dept Radiol, I-16132 Genoa, Italy. RP Derchi, LE (reprint author), Univ Genoa, Dept Radiol, Viale Benedetto 15 10, I-16132 Genoa, Italy. NR 13 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0364-2348 J9 SKELETAL RADIOL JI Skeletal Radiol. PD FEB PY 2003 VL 32 IS 2 BP 82 EP 85 DI 10.1007/s00256-002-0554-4 PG 4 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA 655WV UT WOS:000181576400005 PM 12589486 ER PT J AU Georgieva, DN Genov, N Nikolov, P Aleksiev, B Rajashankar, KR Voelter, W Betzel, C AF Georgieva, DN Genov, N Nikolov, P Aleksiev, B Rajashankar, KR Voelter, W Betzel, C TI Structure-function relationships in the neurotoxin Vipoxin from the venom of Vipera ammodytes meridionalis SO SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY LA English DT Article DE snake venom; phospholipase A(2); toxicity ID PHOSPHOLIPASE A(2) AB The neurotoxic complex Vipoxin is the lethal component of the venom of Vipera ammodytes meridionalis, the most toxic snake in Europe. It is a complex between a toxic phospholipase A(2) (PLA(2)) and a non-toxic and catalytically inactive protein, stabilizing the enzyme and reducing the activity and toxicity. Structure-function relationships in this complex were studied by spectroscopic methods. A good correlation between the ionization behaviour and accessible surface area (ASA) of the tyrosyl residues was observed. In the toxic PLA2 subunit phenolic groups participate in H-bonding network that stabilizes the catalytically and pharmacologically active conformation. The tryptophan fluorescence decay of Vipoxin is well fitted by two exponentials with lifetimes of 0.1 (54%) and 2.5 (46%) ns. W20P, W31P and W31I are located in the interface between the two subunits and participate in hydrophobic interactions stabilizing the complex. Dissociation of the complex leads to a transition of the tryptophans from hydrophobic to hydrophilic environment, which influences mainly tau(2). The longer lifetime is more sensitive to the polarity of the environment. Circular dichroism measurements demonstrate that the two components of the neurotoxin preserve their secondary structure after dissociation of the complex. The results of the spectroscopic studies are in accordance with a mechanism of blockade of transmission across the neuromuscular junctions of the breathing muscles by interaction of a dissociated toxic PLA(2) with a membrane. The loss of toxicity is connected with slight changes in the secondary structure of PLA2. CD studies also show a substantial contribution of disulfide bonds to the stability of the neurotoxic complex and its components. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Bulgarian Acad Sci, Inst Organ Chem, BU-1113 Sofia, Bulgaria. Univ Chem Technol & Met, Sofia, Bulgaria. NCI, Frederick & Brookhaven Natl Lab, Upton, NY 11973 USA. Univ Tubingen, Phys Biochem Abt, Inst Physiol Chem, D-72076 Tubingen, Germany. Univ Klinikum Hamburg Eppendorf, Inst Med Biochem & Mol Biol, DESY, D-22603 Hamburg, Germany. RP Genov, N (reprint author), Bulgarian Acad Sci, Inst Organ Chem, BU-1113 Sofia, Bulgaria. NR 19 TC 2 Z9 2 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1386-1425 J9 SPECTROCHIM ACTA A JI Spectroc. Acta Pt. A-Molec. Biomolec. Spectr. PD FEB PY 2003 VL 59 IS 3 BP 617 EP 627 AR PII S1386-1425(02)00212-3 DI 10.1016/S1386-1425(02)00212-3 PG 11 WC Spectroscopy SC Spectroscopy GA 639EZ UT WOS:000180615800023 PM 12524132 ER PT J AU Albert, PS Follmann, DA AF Albert, PS Follmann, DA TI A random effects transition model for longitudinal binary data with informative missingness SO STATISTICA NEERLANDICA LA English DT Article DE repeated binary data; non-ignorable missing data; repeated measures; Markov models ID DATA SUBJECT; LINEAR-MODEL; DROPOUT; PANEL AB Understanding the transitions between disease states is often the goal in studying chronic disease. These studies, however, are typically subject to a large amount of missingness either due to patient dropout or intermittent missed visits. The missing data is often informative since missingness and dropout are usually related to either an individual's underlying disease process or the actual value of the missed observation. Our motivating example is a study of opiate addiction that examined the effect of a new treatment on thrice-weekly binary urine tests to assess opiate use over follow-up. The interest in this opiate addiction clinical trial was to characterize the transition pattern of opiate use (in each treatment arm) as well as to compare both the marginal probability of a positive urine test over follow-up and the time until the first positive urine test between the treatment arms. We develop a shared random effects model that links together the propensity of transition between states and the probability of either an intermittent missed observation or dropout. This approach allows for heterogeneous transition and missing data patterns between individuals as well as incorporating informative intermittent missing data and dropout. We compare this new approach with other approaches proposed for the analysis of longitudinal binary data with informative missingness. C1 NCI, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. RP Albert, PS (reprint author), NCI, 6130 Execut Blvd,MSC 7434, Bethesda, MD 20892 USA. NR 20 TC 20 Z9 20 U1 0 U2 4 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 0039-0402 J9 STAT NEERL JI Stat. Neerl. PD FEB PY 2003 VL 57 IS 1 BP 100 EP 111 DI 10.1111/1467-9574.00223 PG 12 WC Statistics & Probability SC Mathematics GA 690JD UT WOS:000183544000008 ER PT J AU Warach, S AF Warach, S TI Stroke neuroimaging SO STROKE LA English DT Editorial Material C1 Natl Inst Neurol Disorders & Stroke, Stroke Branch, Bethesda, MD 20892 USA. RP Warach, S (reprint author), Natl Inst Neurol Disorders & Stroke, Stroke Branch, 36 Convent Dr,MSC 4129,Rm 4A03, Bethesda, MD 20892 USA. NR 20 TC 18 Z9 19 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2003 VL 34 IS 2 BP 345 EP 347 DI 10.1161/01.STR.0000054262.69831.24 PG 3 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 645AT UT WOS:000180954600009 PM 12574531 ER PT J AU Fox, CS Polak, JF Chazaro, I Cupples, A Wolf, PA D'Agostino, RA O'Donnell, CJ AF Fox, CS Polak, JF Chazaro, I Cupples, A Wolf, PA D'Agostino, RA O'Donnell, CJ TI Genetic and environmental contributions to atherosclerosis phenotypes in men and women - Heritability of carotid intima-media thickness in the Framingham Heart Study SO STROKE LA English DT Article DE epidemiology; genetics; intima-media thickness ID WALL SHEAR-STRESS; CONVERTING-ENZYME GENOTYPES; NHLBI FAMILY HEART; RISK-FACTORS; MYOCARDIAL-INFARCTION; CARDIOVASCULAR HEALTH; OLDER ADULTS; GENOME SCAN; ARTERY; DISEASE AB Background and Purpose-Carotid intima-media thickness (IMT) is a quantitative measure of subclinical atherosclerosis that is predictive of subsequent myocardial infarction and stroke. There is controversy regarding the proportion of variability in IMT explained by genetic factors. Thus, it is uncertain whether carotid IMT is a heritable trait that can be used in genetic studies. Methods-From 1996 to 1998, we measured carotid IMT in 906 men (mean age, 56.7 years) and 980 women (mean age, 57.4 years) from 586 extended families (1630 sib pairs) in the Framingham Offspring cohort. B-mode carotid ultrasonography was used to define mean and maximum IMT of the common carotid artery (CCA) and internal carotid artery (ICA). Correlation coefficients were calculated in pairs of siblings. Variance component methods were used to estimate heritability with crude, age-and sex-adjusted, and multivariable-adjusted normalized deviates. Results-Multivariable-adjusted correlation coefficients for mean CCA and ICA IMT were 0.16 and 0.16, respectively. Crude, age-and sex-adjusted, and multivariable-adjusted heritabilities were 0.67, 0.44, and 0.38 for the mean CCA IMT (all P<0.001) and 0.43, 0.37, and 0.35 for the mean ICA IMT (all P<0.001). For CCA IMT, 27% of the overall variance was due to measured covariates; 38% was due to heritable factors. Conclusions-These data suggest that a substantial proportion of the variability in carotid IMT is explained by genetic factors. Further studies of genetic linkage and candidate gene association are warranted to identify specific genetic variants predisposing to subclinical atherosclerosis and stroke. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Epidemiol, Boston, MA 02215 USA. Boston Univ, Dept Biostat & Epidemiol, Boston, MA 02215 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP O'Donnell, CJ (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. FU NHLBI NIH HHS [N01-HC-25195]; NINDS NIH HHS [5R01-NS17950-20] NR 44 TC 134 Z9 136 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2003 VL 34 IS 2 BP 397 EP 401 DI 10.1161/01.STR.0000048214.56981.6F PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 645AT UT WOS:000180954600031 PM 12574549 ER PT J AU Lamb, SE Ferrucci, L Volapto, S Fried, LP Guralnik, JM AF Lamb, SE Ferrucci, L Volapto, S Fried, LP Guralnik, JM CA Women's Hlth Aging Study TI Risk factors for falling in home-dwelling older women with stroke - The women's health and aging study SO STROKE LA English DT Article DE epidemiology; rehabilitation; stroke ID ELDERLY PEOPLE; STOPS WALKING; REHABILITATION; BALANCE; DISABILITY; FRACTURES; STRENGTH; TALKING; PREDICT; INDEX AB Background and Purpose-Much of our knowledge of risk factors for falls comes from studies of the general population. The aim of this study was to estimate the risk of falling associated with commonly accepted and stroke-specific factors in a home-dwelling stroke population. Methods-This study included an analysis of prospective fall reports in 124 women with confirmed stroke over 1 year. Variables relating to physical and mental health, history of falls, stroke symptoms, self-reported difficulties in activities of daily living, and physical performance tests were collected during home assessments. Results-Risk factors for falling commonly reported in the general population, including performance tests of balance, incontinence, previous falls, and sedative/hypnotic medications, did not predict falls in multivariate analyses. Frequent balance problems while dressing were the strongest risk factor for falls (odds ratio, 7.0). Residual balance, dizziness, or spinning stroke symptoms were also a strong risk factor for falling (odds ratio, 5.2). Residual motor symptoms were not associated with an increased risk of falling. Conclusions-Interventions to reduce the frequency of balance problems during complex tasks may play a significant role in reducing falls in stroke. Clinicians should be aware of the increased risk of falling in women with residual balance, dizziness, or spinning stroke symptoms and recognize that risk assessments developed for use in the general population may not be appropriate for stroke patients. C1 Coventry Univ, Sch Hlth & Social Sci, Interdisciplinary Res Ctr Hlth, Warwick W Midlands Primary Care Network, Coventry CV1 5FB, W Midlands, England. INRCA, Dept Geriatr, Lab Clin Epidemiol, Florence, Italy. Univ Ferrara, Sez Med Interna, I-44100 Ferrara, Italy. Johns Hopkins Univ, Inst Med, Baltimore, MD 21218 USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. RP Lamb, SE (reprint author), Coventry Univ, Sch Hlth & Social Sci, Interdisciplinary Res Ctr Hlth, Warwick W Midlands Primary Care Network, Priory St, Coventry CV1 5FB, W Midlands, England. NR 31 TC 137 Z9 142 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2003 VL 34 IS 2 BP 494 EP 500 DI 10.1161/01.STR.0000053444.00582.B7 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 645AT UT WOS:000180954600049 PM 12574566 ER PT J AU Chang, CF Lin, SZ Chiang, YH Morales, M Chou, J Lein, P Chen, HL Hoffer, BJ Wang, Y AF Chang, CF Lin, SZ Chiang, YH Morales, M Chou, J Lein, P Chen, HL Hoffer, BJ Wang, Y TI Intravenous administration of bone morphogenetic protein-7 after ischemia improves motor function in stroke rats SO STROKE LA English DT Article DE bone morphogenetic proteins; growth factors; nerve regeneration; stroke ID FOCAL CEREBRAL-ISCHEMIA; ELECTROPHYSIOLOGICAL TRANSCORTICAL DIASCHISIS; INTRACISTERNAL OSTEOGENIC PROTEIN-1; HUMAN EMBRYONIC-DEVELOPMENT; NERVOUS-SYSTEM; INJURY; BRAIN; RECOVERY; LOCALIZATION; EXPRESSION AB Background and Purpose-We and others have previously reported that bone morphogenetic protein-7 (BMP-7), given before middle cerebral artery occlusion (MCAO), reduces ischemic injury in brain. Recent studies have indicated that receptors for BMP are upregulated after brain ischemia. It is possible that this upregulation may facilitate endogenous neurorepair in the ischemic brain. The purpose of this study was to determine the neuroregenerative effects of BMP-7 given parenterally after ischemia/reperfusion injury. Methods-Adult Sprague-Dawley rats were anesthetized with chloral hydrate. The middle cerebral artery was transiently occluded by a filament inserted through the right internal carotid artery. The filament was removed after 60-minute ischemia to allow reperfusion. Some animals were killed 24 hours after MCAO to examine BMP-7 mRNA expression. Other animals received a single dose of intravenous BMP-7 or vehicle at 24 hours after MCAO and were used for subsequent behavioral studies and BMP-7 immunostaining. Results-BMP-7 mRNA was upregulated 24 hours after MCAO in untreated animals. BMP-7 immunoreactivity was dose-dependently increased on the ischemic side of the hippocampus/dentate on day 6 after MCAO in animals receiving intravenous injection of BMP-7. Animals receiving BMP-7 also showed a decrease in body asymmetry from day 7 to day 14 and an increase in locomotor activity on day 14 after MCAO. Conclusions-Our data indicate that BMP-7, given parenterally after stroke, can pass through the blood-brain barrier on the ischemic side and induce behavioral recovery in stroke animals at longer testing times. C1 NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Natl Def Med Ctr, Grad Inst Life Sci, Taipei, Taiwan. Johns Hopkins Univ, Dept Environm Hlth Sci, Baltimore, MD 21218 USA. RP Wang, Y (reprint author), NIDA, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 26 TC 85 Z9 99 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD FEB PY 2003 VL 34 IS 2 BP 558 EP 564 DI 10.1161/01.STR.0000051507.64423.00 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 645AT UT WOS:000180954600059 PM 12574575 ER PT J AU Ikemoto, S Witkin, BM AF Ikemoto, S Witkin, BM TI Locomotor inhibition induced by procaine injections into the nucleus accumbens core, but not the medial ventral striatum: Implication for cocaine-induced locomotion SO SYNAPSE LA English DT Article DE olfactory tubercle; shell; local anesthesia; sodium channels; dopamine transporters ID LOCAL-ANESTHETICS; DOPAMINE TRANSPORTER; SEROTONIN; RECEPTORS; CONGENERS; BINDING; POTENCY; NEURONS; CORTEX; RATS AB We examined whether injections of the local anesthesia procaine into the nucleus accumbens core disrupts locomotion more readily than those into the medial ventral striatum. Spontaneous locomotion decreased during the first 10 min immediately following injections of procaine into the core. When procaine was co-administered with d-amphetamine into the core, the injections also decreased amphetamine-induced locomotion during the initial 10 min. On the other hand, no detectable effect on spontaneous or amphetamine-induced locomotion was found when procaine was injected into the medial ventral striatum, including the medial shell and medial olfactory tubercle. We replicated our recent finding that cocaine injections into the core induced delayed, modest locomotion, while cocaine injections into the medial ventral striatum induced immediate, vigorous locomotion. Injections of amphetamine into the core induced as equally vigorous locomotion as that of the medial ventral striatum. These results show that the neurons of the core involved in locomotion are more vulnerable to local anesthesia than the neurons of the medial ventral striatum. In other words, cocaine at the doses inducing vigorous locomotion in the medial ventral striatum induces local anesthesia when applied to the core. C1 NIDA, Behav Neurosci Branch, NIH, Baltimore, MD 21224 USA. RP Ikemoto, S (reprint author), NIDA, Behav Neurosci Branch, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Ikemoto, Satoshi/0000-0002-0732-7386 NR 21 TC 13 Z9 13 U1 1 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD FEB PY 2003 VL 47 IS 2 BP 117 EP 122 DI 10.1002/syn.10151 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 630RP UT WOS:000180122900004 PM 12454949 ER PT J AU Ress, NB Hailey, JR Maronpot, RR Bucher, JR Travlos, GS Haseman, JK Orzech, DP Johnson, JD Hejtmancik, MR AF Ress, NB Hailey, JR Maronpot, RR Bucher, JR Travlos, GS Haseman, JK Orzech, DP Johnson, JD Hejtmancik, MR TI Toxicology and carcinogenesis studies of microencapsulated citral in rats and mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE food additives; fragrance additives; GRAS list; microencapsulation; toxicity; malignant lymphoma; vinyl aldehyde; rats; mice; nephropathy ID ZERO DOSE CONTROL; CORN-OIL GAVAGE; PROSTATIC HYPERPLASIA; VENTRAL PROSTATE; TOXICITY; CINNAMALDEHYDE; BENIGN; TESTS; FEED AB Citral, a widely used natural ingredient, is added to foods and cosmetics as a flavoring and fragrance agent. Male and female F344/N rats and B6C3F1 mice were exposed to microencapsulated citral in the feed for 14 weeks or two years. All studies included untreated and vehicle control groups. In the 14-week studies, rats and mice were given diets containing 3900, 7800, 15,600, or 31,300 ppm citral. In rats, food consumption was reduced in the two highest dose groups. In mice an apparent increase in food consumption was observed, but was due to mice scattering the feed. Body weights of all treated animals were less than controls. All rats and four male mice were killed moribund in the high dose groups. In rats, forestomach and kidney lesions were observed. At the higher doses, lesions observed in the bone marrow, testes, and thymus in rats and in the ovary in mice were considered related to inanition and resultant moribundity. In the two-year studies, rats were exposed to 1000, 2000, or 4000 ppm citral. Body weights were reduced in the 4000 ppm rats. Mice were exposed to 500, 1000, or 2000 ppm citral. Body weights in the 1000 and 2000 ppm groups were reduced. No neoplasms were attributed to citral in rats or mice. Malignant lymphoma occurred with a positive trend and was significantly greater than controls in female mice in the 2000 ppm group. However, the incidences were within the NTP historical control range and could not be clearly related to citral administration. C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. Battelle Labs, Columbus, OH 43201 USA. RP Bucher, JR (reprint author), Natl Inst Environm Hlth Sci, 79 Alexander Dr,Mail Drop EC-34, Res Triangle Pk, NC 27709 USA. NR 31 TC 20 Z9 21 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2003 VL 71 IS 2 BP 198 EP 206 DI 10.1093/toxsci/71.2.198 PG 9 WC Toxicology SC Toxicology GA 642XT UT WOS:000180832200009 PM 12563105 ER PT J AU Kodavanti, UP Moyer, CF Ledbetter, AD Schladweiler, MC Costa, DL Hauser, R Christiani, DC Nyska, A AF Kodavanti, UP Moyer, CF Ledbetter, AD Schladweiler, MC Costa, DL Hauser, R Christiani, DC Nyska, A TI Inhaled environmental combustion particles cause myocardial injury in the Wistar Kyoto rat SO TOXICOLOGICAL SCIENCES LA English DT Article DE inhaled particulate matter; myocardial injury; Wistar Kyoto rats; bioavailable zinc; cardiovascular disease ID OIL FLY-ASH; SPONTANEOUSLY HYPERTENSIVE RAT; PARTICULATE AIR-POLLUTION; ACUTE PULMONARY TOXICITY; CARDIOVASCULAR-DISEASE; AMBIENT AIR; EXPOSURE; MATTER; METALS; MODEL AB Epidemiologists have associated particulate matter (PM) air pollution with cardiovascular morbidity and premature mortality worldwide. However, experimental evidence demonstrating causality and pathogenesis of particulate matter (PM)-induced cardiovascular damage has been insufficient. We hypothesized that protracted, repeated inhalation by rats of oil combustion-derived, fugitive emission PM (EPM), similar in metal composition to selected sources of urban air PM, causes exposure duration- and dose-dependent myocardial injury in susceptible rat strains. Zinc was the only primary water-leachable/bioavailable element of this EPM. Male Sprague-Dawley (SD), Wistar Kyoto (WKY), and spontaneously hypertensive (SH) rats were exposed nose-only to EPM (2, 5, or 10 mg/m(3), 6 h/day for 4 consecutive days or 10 mg/m(3), 6 h/day, 1 day/week for 4 or 16 consecutive weeks). Two days following the last EPM exposure, cardiac and pulmonary tissues were examined histologically. The results showed that particle-laden alveolar macrophages were the only pulmonary lesions observed in all three rat strains. However, WKY rats exposed to EPM (10 mg/m(3) 6 h/day, 1 day/week for 16 weeks) demonstrated cardiac lesions with inflammation and degeneration. To further characterize the nature of EPM-associated lesions, more rigorous histopathological and histochemical techniques were employed for WKY and SD rats. We examined the hearts for myocardial degeneration, inflammation, fibrosis, calcium deposits, apoptosis, and the presence of mast cells. Decreased numbers of granulated mast cells, and multifocal myocardial degeneration, chronic-active inflammation, and fibrosis were present in 5 of 6 WKY rats exposed to EPM for 16 weeks. None of these lesions were present in WKY exposed to clean air. EPM-related cardiac lesions were indistinguishable from air-exposed controls in SD and SH rats. This study demonstrates that long-term inhalation exposures to environmentally relevant PM containing bioavailable zinc can cause myocardial injury in sensitive rats. These findings provide supportive evidence for the epidemiological associations of cardiovascular morbidity and ambient PM. C1 US EPA, Pulm Toxicol Branch, Expt Toxicol Div, Natl Hlth & Environm Effects Res Lab,Off Res & De, Res Triangle Pk, NC 27709 USA. Pathol Associates Inc, Raleigh, NC USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Natl Inst Environm Hlth & Sci, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. RP Kodavanti, UP (reprint author), US EPA, Pulm Toxicol Branch, Expt Toxicol Div, Natl Hlth & Environm Effects Res Lab,Off Res & De, 109 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. NR 36 TC 67 Z9 71 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD FEB PY 2003 VL 71 IS 2 BP 237 EP 245 DI 10.1093/toxsci/71.2.237 PG 9 WC Toxicology SC Toxicology GA 642XT UT WOS:000180832200013 PM 12563109 ER PT J AU Dunnick, JK Burka, LT Mahler, J Sills, R AF Dunnick, JK Burka, LT Mahler, J Sills, R TI Carcinogenic potential of o-nitrotoluene and p-nitrotoluene SO TOXICOLOGY LA English DT Article DE o-nitrotoluene; neoplasms; carcinogenic metabolites ID FISCHER-344 RATS; INVIVO; MONONITROTOLUENES; GENOTOXICITY; HEPATOCYTES; METABOLISM; OXIDATION; ASSAY AB The potential of o-nitrotoluene and p-nitrotoluene to cause cancer in mammalian species was studied in male and female F344/N rats and B6C3F1 mice. These chemicals are on the EPA list of high production chemicals and there is potential for human exposure (High Production Volume Chemical List (2000) http://oaspub.cpa.gov/opptintr/chemrtk/ volchall.htm.). o-Nitrotoluene, administered in the feed for up to 2 years, caused clear evidence for cancer at multiple sites in rats and mice. Male rats, receiving o-nitrotoluene in the feed (similar to0, 25, 50, or 90 mg/kg per day), developed treatment-related mesotheliomas, subcutaneous skin neoplasms, mammary gland fibroadenomas, and liver neoplasms. By 2 years, mesotheliomas, skin, liver, mammary gland and liver tumors also occurred in 'stop-study' male rats that received o-nitrotoluene at 125 or 315 mg/kg per day for only the first 3 months of study. These 'stop-studies' showed that the critical events leading to tumor formation occurred after 3 months of dosing, and these events were irreversible and eventually led to cancer at multiple sites. o-Nitrotoluene given in the feed to female rats (similar to0, 30, 60, or 100 mg/kg per day) and to male and female mice (similar to0, 150, 320, or 700 mg/kg per day) also caused a carcinogenic response. In female rats, treatment-related subcutaneous skin neoplasms and mammary gland fibroadenomas occurred. Hemangiosarcomas and carcinomas of the large intestine (cecum) were seen in treated male and female mice. In contrast to o-nitrotoluene, p-nitrotoluene given in the feed over approximately the same exposure. levels caused only equivocal evidence of carcinogenic activity in male rats (subcutaneous skin neoplasms); some evidence of carcinogenic activity in female rats (clitoral gland neoplasms); equivocal evidence of carcinogenic activity in male mice (lung neoplasms); and no evidence of carcinogenic activity in female mice. Differences in the o-nitrotoluene and p-nitrotoluene carcinogenic activity may be due to differences in the metabolism of the parent compound to carcinogenic metabolites. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Dunnick, JK (reprint author), NIEHS, NIH, 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. NR 36 TC 17 Z9 17 U1 1 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD FEB 1 PY 2003 VL 183 IS 1-3 BP 221 EP 234 AR PII S0300-483X(02)00543-7 DI 10.1016/S0300-483X(02)00543-7 PG 14 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 642HX UT WOS:000180799100016 PM 12504353 ER PT J AU Gunasekaran, K Tsai, CJ Kumar, S Zanuy, D Nussinov, R AF Gunasekaran, K Tsai, CJ Kumar, S Zanuy, D Nussinov, R TI Extended disordered proteins: targeting function with less scaffold SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Editorial Material ID INTRINSICALLY UNSTRUCTURED PROTEINS; PHYSIOLOGICAL CONDITIONS; RECOGNITION; STATE AB It has been estimated that a large fraction of cellular proteins are natively disordered. Current opinion largely holds that natively disordered proteins are more 'adaptive', leading to advantages in regulation and in binding diverse ligands. Here, we argue for another, simple, physically based reason. Disordered proteins often have large intermolecular interfaces, the size of which is dictated by protein function. For proteins to be stable as monomers with extensive interfaces, protein size would need to be 2-3 times larger. This would either increase cellular crowding or enlarge the size of the cell by 15-30%, owing to the increase in the sequence length. Smaller sizes of cells, proteins, DNA and RNA conserve energy. Thus, disordered proteins provide a simple yet elegant solution to having large intermolecular interfaces, but with smaller protein, genome and cell sizes. C1 NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Frederick, MD 21702 USA. NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Nussinov, R (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Bldg 469,Rm 151, Frederick, MD 21702 USA. RI Zanuy, David/G-3930-2014 OI Zanuy, David/0000-0001-7704-2178 FU NCI NIH HHS [N01-CO-12400] NR 32 TC 245 Z9 251 U1 1 U2 13 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD FEB PY 2003 VL 28 IS 2 BP 81 EP 85 DI 10.1016/S0968-0004(03)00003-3 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 648MK UT WOS:000181155000006 PM 12575995 ER PT J AU Boheler, KR Stern, MD AF Boheler, KR Stern, MD TI The new role of SAGE in gene discovery SO TRENDS IN BIOTECHNOLOGY LA English DT Article ID SERIAL ANALYSIS; HUMAN GENOME; IDENTIFICATION; TAGS; TRANSCRIPTS; EXPRESSION; SEQUENCE; CELLS AB The sequencing of the human genome has led to in silico predictions of far fewer genes than anticipated. Recent studies using serial analysis of gene expression have cast doubt on this finding. One study predicts the presence of many unidentified low abundance transcripts, whereas two others have mapped unique tags to previously unpredicted exons. Genome and transcriptome complexity is thus greater than predicted and many of the missing genes are probably expressed in low copy numbers or only in early embryonic tissues. C1 NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Boheler, KR (reprint author), NIA, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM bohelerk@grc.nia.nih.gov NR 13 TC 26 Z9 31 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0167-7799 J9 TRENDS BIOTECHNOL JI Trends Biotechnol. PD FEB PY 2003 VL 21 IS 2 BP 55 EP 57 AR PII S0167-7799(02)00031-8 DI 10.1016/S0167-7799(02)00031-8 PG 3 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 648MJ UT WOS:000181154900002 PM 12573851 ER PT J AU Jordan, IK Rogozin, IB Glazko, GV Koonin, EV AF Jordan, IK Rogozin, IB Glazko, GV Koonin, EV TI Origin of a substantial fraction of human regulatory sequences from transposable elements SO TRENDS IN GENETICS LA English DT Article ID SCAFFOLD/MATRIX-ATTACHED REGIONS; LOCUS-CONTROL REGIONS; GENOME EVOLUTION; GLOBIN GENE; SELFISH DNA; CLUSTERS; PARASITE AB Transposable elements (TEs) are abundant in mammalian genomes and have potentially contributed to their hosts' evolution by providing novel regulatory or coding sequences. We surveyed different classes of regulatory region in the human genome to assess systematically the potential contribution of TEs to gene regulation. Almost 25% of the analyzed promoter regions contain TE-derived sequences, including many experimentally characterized cis-regulatory elements. Scaffold/matrix attachment regions (S/MARs) and locus control regions (LCRs) that are involved in the simultaneous regulation of multiple genes also contain numerous TE-derived sequences. Thus, TEs have probably contributed substantially to the evolution of both gene-specific and global patterns of human gene regulation. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Penn State Univ, Inst Mol Evolut Genet, Mueller Lab 328, University Pk, PA 16802 USA. Penn State Univ, Dept Biol, Mueller Lab 328, University Pk, PA 16802 USA. RP Jordan, IK (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bldg 38A Room N511M,8600 Rockville Pike, Bethesda, MD 20894 USA. EM jordan@ncbi.nlm.nih.gov RI Phelps, Steve/H-2263-2011 FU NIGMS NIH HHS [GM-20293] NR 22 TC 318 Z9 331 U1 3 U2 14 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD FEB PY 2003 VL 19 IS 2 BP 68 EP 72 AR PII S0168-9525(02)00006-9 DI 10.1016/S0168-9525(02)00006-9 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 643DD UT WOS:000180845900005 PM 12547512 ER PT J AU Freed, EO AF Freed, EO TI The HIV-TSG101 interface: recent advances in a budding field SO TRENDS IN MICROBIOLOGY LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; TSG101 UEV DOMAIN; PROTEIN; UBIQUITIN; HIV-1; RELEASE; COMPLEX; RECOGNITION; RECEPTOR; HOMOLOG AB Efficient budding of HIV from the plasma membrane requires a small peptide motif, Pro-Thr/Ser-Ala-Pro (PTAP), located near the amino terminus of the p6 Gag protein. Studies from several laboratories have demonstrated that the ability of p6 to stimulate HIV budding requires a direct interaction between the PTAP motif and the host endosomal sorting protein TSG101. The structure of the PTAP-TSG101 binding site has recently been solved, providing valuable insights into this crucial protein-protein interaction. C1 NIAID, Lab Mol Microbiol, NIH, Bethesda, MD 20892 USA. RP Freed, EO (reprint author), NIAID, Lab Mol Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 25 TC 52 Z9 56 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0966-842X J9 TRENDS MICROBIOL JI Trends Microbiol. PD FEB PY 2003 VL 11 IS 2 BP 56 EP 59 DI 10.1016/S0966-842X(02)00013-6 PG 4 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 652FX UT WOS:000181370100002 PM 12598123 ER PT J AU Rickard, AH Gilbert, P High, NJ Kolenbrander, PE Handley, PS AF Rickard, AH Gilbert, P High, NJ Kolenbrander, PE Handley, PS TI Bacterial coaggregation: an integral process in the development of multi-species biofilms SO TRENDS IN MICROBIOLOGY LA English DT Review ID STREPTOCOCCUS-GORDONII DL1; AGGREGATION-PROMOTING FACTOR; ORAL MICROBIAL COMMUNITIES; PORPHYROMONAS-GINGIVALIS; FUSOBACTERIUM-NUCLEATUM; ACTINOMYCES-NAESLUNDII; LACTOBACILLUS STRAINS; ESCHERICHIA-COLI; ANTIGEN-I/II; ADHESION AB Coaggregation is a process by which genetically distinct bacteria become attached to one another via specific molecules. Cumulative evidence suggests that such adhesion influences the development of complex multi-species biofilms. Once thought to occur exclusively between dental plaque bacteria, there are increasing reports of coaggregation between bacteria from other biofilm communities in several diverse habitats. A general role for coaggregation in the formation of multi-species biofilms is discussed. C1 Univ Manchester, Sch Pharm, Manchester M13 9PL, Lancs, England. Univ Manchester, Sch Biol Sci, Manchester M13 9PT, Lancs, England. NIDCR, Oral Biofilm Commun Unit, NIH, Bethesda, MD 20892 USA. RP Rickard, AH (reprint author), Univ Manchester, Sch Pharm, Coupland 3 Bldg,Oxford Rd, Manchester M13 9PL, Lancs, England. NR 63 TC 265 Z9 277 U1 3 U2 61 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0966-842X J9 TRENDS MICROBIOL JI Trends Microbiol. PD FEB PY 2003 VL 11 IS 2 BP 94 EP 100 DI 10.1016/S0966-842X(02)00034-3 PG 7 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 652FX UT WOS:000181370100011 PM 12598132 ER PT J AU Abbracchio, MP Boeynaems, JM Barnard, EA Boyer, JL Kennedy, C Miras-Portugal, MT King, BF Gachet, C Jacobson, KA Weisman, GA Burnstock, G AF Abbracchio, MP Boeynaems, JM Barnard, EA Boyer, JL Kennedy, C Miras-Portugal, MT King, BF Gachet, C Jacobson, KA Weisman, GA Burnstock, G TI Characterization of the UDP-glucose receptor (re-named here the P2Y(14) receptor) adds diversity to the P2Y receptor family SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Article ID PROTEIN-COUPLED RECEPTOR; ADP RECEPTOR; IDENTIFICATION; PURINOCEPTORS; NUCLEOTIDES AB The cloning of a human G-protein-coupled receptor (GPCR) that specifically responds to UDP-glucose and related sugar-nucleotides has been reported recently. This receptor has important structural similarities to known members of the P2Y receptor family but also shows a distinctly different pharmacological response profile. Here, the IUPHAR Subcommittee for P2Y receptor nomenclature and classification review the current knowledge of this receptor and present their reasons for including this receptor in the P2Y receptor family as the P2Y(14) receptor. C1 UCL Royal Free & Univ Coll Med Sch, Auton Neurosci Inst, London NW3 2PF, England. Univ Complutense Madrid, Dept Bioquim, Madrid, Spain. Univ Strathclyde, Dept Physiol & Pharmacol, Glasgow G1 1XQ, Lanark, Scotland. Inspire Pharmaceut Inc, Mol Pharmacol, Durham, NC USA. Univ Cambridge, Dept Pharmacol, Cambridge CB2 1QJ, England. Free Univ Brussels, Erasme Hosp, IRIBHM, Brussels, Belgium. Free Univ Brussels, Erasme Hosp, Dept Med Chem, Brussels, Belgium. Univ Milan, Dept Pharmacol Sci, Milan, Italy. EFS Alsace, INSERM U311, Strasbourg, France. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD USA. Univ Missouri, Dept Biochem, Columbia, MO USA. RP Burnstock, G (reprint author), UCL Royal Free & Univ Coll Med Sch, Auton Neurosci Inst, Rowland Hill St, London NW3 2PF, England. EM g.burnstock@ucl.ac.uk RI Jacobson, Kenneth/A-1530-2009; Miras-Portugal, Maria Teresa/L-7137-2014; Abbracchio, Maria Pia/B-9342-2014; Gachet, Christian/H-9156-2016 OI Jacobson, Kenneth/0000-0001-8104-1493; Abbracchio, Maria Pia/0000-0002-7833-3388; FU Intramural NIH HHS [Z01 DK031116-20] NR 22 TC 275 Z9 284 U1 1 U2 9 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD FEB PY 2003 VL 24 IS 2 BP 52 EP 55 AR PII S0165-6147(02)00038-X DI 10.1016/S0165-6147(02)00038-X PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 645CH UT WOS:000180958300002 PM 12559763 ER PT J AU Necela, BM Cidlowski, JA AF Necela, BM Cidlowski, JA TI Crystallization of the human glucocorticoid receptor ligand binding domain: a step towards selective glucocorticoids SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Article ID NUCLEAR RECEPTOR; COACTIVATORS; MECHANISMS AB The crystal structure of the glucocorticoid receptor (GR) ligand binding domain in a ternary complex with dexamethasone and a TIF2 coactivator peptide has been determined recently. The structure reveals several distinct features not found in other nuclear receptors, such as a novel dimerization interface and a second charge clamp that might be important in determining coactivator binding selectivity. The GR ligand binding domain also has a steroid binding pocket that is distinct from other nuclear receptors and might explain its selectivity for glucocorticoids and its diversity of responses. C1 NIEHS, Dept Hlth & Human Serv, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Dept Hlth & Human Serv, Lab Signal Transduct, NIH, Bldg 101,MD F3-07, Res Triangle Pk, NC 27709 USA. NR 19 TC 18 Z9 18 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD FEB PY 2003 VL 24 IS 2 BP 58 EP 61 AR PII S016(56)14702-000469 DI 10.1016/S0165-6147(02)00046-9 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 645CH UT WOS:000180958300004 PM 12559765 ER PT J AU Kalache, KD Espinoza, J Chaiworapongsa, T Londono, J Schoen, ML Treadwell, MC Lee, W Romero, R AF Kalache, KD Espinoza, J Chaiworapongsa, T Londono, J Schoen, ML Treadwell, MC Lee, W Romero, R TI Three-dimensional ultrasound fetal lung volume measurement: a systematic study comparing the multiplanar method with the rotational (VOCAL) technique SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE lung volume; pulmonary hypoplasia; three-dimensional ultrasonography; VOCAL ID LETHAL PULMONARY HYPOPLASIA; 3-DIMENSIONAL ULTRASOUND; PREDICTION; DIAGNOSIS; ULTRASONOGRAPHY; CIRCUMFERENCE; CHEST AB Objectives This study was designed to compare a conventional multiplanar technique for three-dimensional (3D) ultrasound measurement of fetal lung volume with a rotational method using VOCAL(TM) (Virtual Organ Computer-aided AnaLysis). Methods Thirty-two fetuses with, a variety of conditions at risk for pulmonary hypoplasia were studied. 3D volume data sets of the fetal lungs were acquired using a commercially available ultrasound system. The right and left lung volumes were calculated separately using VOCAL and the multiplanar technique. The level of agreement between two independent observers in categorizing the 3D volume data set as measurable or non-measurable was determined. The interobserver and intermethod variabilities were also evaluated for both, methods. Results The intermethod variability was excellent (correlation r = 0.93 and r = 0.96 for the left and right lung, respectively), and there was substantial agreement between the results of both, approaches (limits of agreement - 4.4 to 8.9 and - 3.4 to 4.8 mL for the right and left lung, respectively). Fetal lung estimation with VOCAL bad a significantly higher interobserver variability than the multiplanar technique. Interobserver agreement in categorizing lung volume data sets as measurable or non-measurable was lower when VOCAL was used. Conclusion Fetal lung volume measurements can be undertaken interchangeably using the multiplanar technique or the rotational method with VOCAL. However, the latter was less reproducible (lower degree of agreement and significantly higher interobserver variability) than the former. Copyrigbt (C) 2003 ISUOG. Published by John Wiley Sons, Ltd. C1 Wayne State Univ, Hutzel Hosp, Perinatal Res Branch, NICHD,NIH,DHHS,Dept Obstet & Gynecol, Detroit, MI 48201 USA. NICHHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, Royal Oak, MI 48072 USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Hosp, Perinatal Res Branch, NICHD,NIH,DHHS,Dept Obstet & Gynecol, 4707 St Antoine Blvd, Detroit, MI 48201 USA. NR 22 TC 87 Z9 96 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD FEB PY 2003 VL 21 IS 2 BP 111 EP 118 DI 10.1002/uog.39 PG 8 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 653NQ UT WOS:000181442900003 PM 12601829 ER PT J AU Kalache, KD Espinoza, J Chaiworapongsa, T Londono, J Schoen, ML Treadwell, MC Lee, W Romero, R AF Kalache, KD Espinoza, J Chaiworapongsa, T Londono, J Schoen, ML Treadwell, MC Lee, W Romero, R TI Three-dimensional reconstructed fetal lung using VOCAL SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article C1 Wayne State Univ, Dept Obstet & Gynecol, Perinatal Res Branch, NICHD,NIH,DHHS,Hutzel Hosp, Detroit, MI 48201 USA. NICHHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, Royal Oak, MI 48072 USA. RP Romero, R (reprint author), Wayne State Univ, Dept Obstet & Gynecol, Perinatal Res Branch, NICHD,NIH,DHHS,Hutzel Hosp, 4707 St Antoine Blvd, Detroit, MI 48201 USA. NR 0 TC 6 Z9 6 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD FEB PY 2003 VL 21 IS 2 BP 205 EP 205 DI 10.1002/uog.66 PG 1 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 653NQ UT WOS:000181442900025 PM 12601851 ER PT J AU Maranchie, JK Linehan, WM AF Maranchie, JK Linehan, WM TI Genetic disorders and renal cell carcinoma SO UROLOGIC CLINICS OF NORTH AMERICA LA English DT Article ID HIPPEL-LINDAU-DISEASE; TUMOR-SUPPRESSOR GENE; HOGG-DUBE-SYNDROME; VHL GENE; GERMLINE MUTATIONS; KIDNEY NEOPLASIA; BETA-DOMAIN; PROTEIN; PRODUCT; COMPLEX AB Familial syndromes have been described for each of the common renal cell carcinoma histologies. Analysis of affected families led to the identification of genes that are involved in sporadic renal cell carcinoma, and continues to provide insight into the cellular pathways that are associated with tumorigenesis. Because hereditary renal carcinoma frequently has an early-onset and is multi-focal, patient management involves life-long screening and measures to minimize the frequency of invasive procedures and preserve renal parenchyma. An awareness of the nonrenal manifestations of these genetic disorders may facilitate prompt diagnosis and appropriate intervention. C1 NCI, Urol Oncol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Canc Res Ctr, NIH, 9000 Rockville Pike,Bldg 10-2B47, Bethesda, MD 20892 USA. OI Maranchie, Jodi/0000-0002-8534-9468 NR 49 TC 5 Z9 6 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 0094-0143 J9 UROL CLIN N AM JI Urol. Clin. N. Am. PD FEB PY 2003 VL 30 IS 1 BP 133 EP + AR PII S0094-0143(02)00120-9 DI 10.1016/S0094-0143(02)00120-9 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 641CZ UT WOS:000180728000013 PM 12580565 ER PT J AU Hsieh, LJ Carter, HB Landis, PK Tucker, KL Metter, EJ Newschaffer, CJ Platz, EA AF Hsieh, LJ Carter, HB Landis, PK Tucker, KL Metter, EJ Newschaffer, CJ Platz, EA TI Association of energy intake with prostate cancer in a long-term aging study: Baltimore longitudinal study of aging (United States) SO UROLOGY LA English DT Article ID GROWTH-FACTOR-I; FAT INTAKE; RISK; COHORT; WOMEN AB Objectives. To examine the association of total energy intake and macronutrient contributors to energy with prostate cancer risk among men in the Baltimore Longitudinal Study of Aging. Methods. In the Baltimore Longitudinal Study of Aging cohort, 444 men completed at least one food frequency questionnaire (FFQ). At their earliest FFQ completion, men were 45 to 92 years old. The total number of prostate cancer cases (n = 68) consisted of men who were diagnosed with cancer before their FFQ completion (n = 46) and those who were diagnosed after their FFQ completion (n = 22). Multiple logistic regression analysis was used to calculate the odds ratio of prostate. cancer and its 95% confidence interval. Results. Total energy intake was positively associated with prostate cancer. Compared with the lowest quintile of energy intake, the odds ratio for the highest quintile was 3.79 (95% confidence interval 1.52 to 9.48, P trend = 0.002). Energy-adjusted intakes of protein, fat, and carbohydrates were not statistically significantly associated with prostate cancer risk. Conclusions. This analysis, in which we used current energy intake as a surrogate for past prediagnostic intake, suggests a higher risk of prostate cancer with increased energy intake. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. Tufts Univ, Human Nutr Res Ctr Aging, Jean Mayer USDA, Boston, MA 02111 USA. NIA, Clin Invest Lab, Longitudinal Studies Sect, Baltimore, MD 21224 USA. RP Platz, EA (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St, Baltimore, MD 21205 USA. RI Tucker, Katherine/A-4545-2010; OI Tucker, Katherine/0000-0001-7640-662X FU NCI NIH HHS [CA58236] NR 20 TC 25 Z9 26 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD FEB PY 2003 VL 61 IS 2 BP 297 EP 301 DI 10.1016/S0090-4295(02)02120-9 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 648NN UT WOS:000181157600008 PM 12597934 ER PT J AU Leonard, GD Zhuang, SH Dahut, W AF Leonard, GD Zhuang, SH Dahut, W TI Prostate cancer metastatic to skin SO UROLOGY LA English DT Article C1 NCI, Med Oncol Clin Res Inst, Ctr Canc Res, Natl Naval Med Ctr, Bethesda, MD 20889 USA. RP Leonard, GD (reprint author), NCI, Med Oncol Clin Res Inst, Ctr Canc Res, Natl Naval Med Ctr, 8901 Wisconsin Ave,Bldg 8,Rm 5101, Bethesda, MD 20889 USA. NR 5 TC 3 Z9 3 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 FEB PY 2003 VL 61 IS 2 BP 456 EP 457 DI 10.1016/S0090-4295(02)02161-1 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 648NN UT WOS:000181157600043 PM 12597969 ER PT J AU Kaludov, N Padron, E Govindasamy, L McKenna, R Chiorini, JA Agbandje-McKenna, M AF Kaludov, N Padron, E Govindasamy, L McKenna, R Chiorini, JA Agbandje-McKenna, M TI Production, purification and preliminary X-ray crystallographic studies of adeno-associated virus serotype 4 SO VIROLOGY LA English DT Article DE adeno-associated virus; gene therapy; parvovirus; crystallization; virus structure ID TRANSDUCTION; TYPE-2; SPECIFICITY; PARVOVIRUS; VECTORS; SYSTEM; AAV4 AB Adeno-associated virus (AAV) serotypes 1 to 5 are currently under development as clinical gene delivery vectors for the treatment of human diseases. However, the ubiquitous nature of their cell surface receptors, heparin sulfate (AAV2 and 3) and sialic acids (AAV4 and 5), can preclude specific tissue targeting in vivo. Structural studies of AAV4 were initiated to characterize its capsid surface for re-targeting manipulations. Crystals obtained diffracted synchrotron radiation to 3.2 Angstrom resolution. The unit cell is body-centered orthorhombic, 1222, with a = 339.6, b = 319.2 and c = 285.0 Angstrom. The virus particle orientation and position have been determined. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Univ Florida, Coll Med, McKnight Brain Inst, Ctr Struct Biol,Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. NIDCR, GTTB, NIH, Bethesda, MD 20892 USA. RP Chiorini, JA (reprint author), Univ Florida, Coll Med, McKnight Brain Inst, Ctr Struct Biol,Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. NR 20 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 0042-6822 J9 VIROLOGY JI Virology PD FEB 1 PY 2003 VL 306 IS 1 BP 1 EP 6 AR PII S0042-6822(02)000347-5 DI 10.1016/S0042-6822(02)00037-5 PG 6 WC Virology SC Virology GA 654TA UT WOS:000181511100001 PM 12620791 ER PT J AU Yang, DS FitzGibbon, EJ Miles, FA AF Yang, DS FitzGibbon, EJ Miles, FA TI Short-latency disparity-vergence eye movements in humans: sensitivity to simulated orthogonal tropias SO VISION RESEARCH LA English DT Article DE disparity vergence; tropia; anomalous retinal correspondence ID PERIPHERAL VISUAL-FIELD; RETINAL CORRESPONDENCE; ORIENTATION DISPARITY; BINOCULAR RESPONSES; VERTICAL VERGENCE; DEPTH-PERCEPTION; STRIATE CORTEX; STRABISMUS; AMBLYOPIA; AREA AB Small disparity stimuli applied to large random-dot patterns elicit machine-like vergence eye movements at short latency. We have examined the sensitivity of these eye movements to simulated orthogonal tropias in three normal subjects by recording (1) the effects of vertical disparities on the initial horizontal vergence responses elicited by 2degrees crossed and uncrossed (horizontal) disparity stimuli, and (2) the effects of horizontal disparities on the initial vertical vergence responses elicited by 1.2degrees left-hyper and 0.8degrees right-hyper (vertical) disparity stimuli. Initial vergence responses were strongest when the orthogonal disparity was close to zero, and decreased to zero as the orthogonal disparity increased to 3degrees-5degrees, i.e., there was only a limited tolerance for orthogonal disparity. Tuning curves describing the dependence of the initial change in the vergence angle on the orthogonal disparity were well fit by a Gaussian function. An additional subject, who had an esotropia of similar to10degrees in our experimental setup, showed almost no horizontal vergence responses but did show vertical vergence responses to vertical disparity stimuli at short latency (albeit slightly longer than normal) despite the fact that her esotropia resulted in uncrossed disparities that would have totally disabled the vertical vergence mechanism of a normal subject, cf., anomalous retinal correspondence. Published by Elsevier Science Ltd. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Miles, FA (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50,49 Convent Dr, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 EY000153-24] NR 62 TC 29 Z9 29 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD FEB PY 2003 VL 43 IS 4 BP 431 EP 443 AR PII S0042-6989(02)00572-2 DI 10.1016/S0042-6989(02)00572-2 PG 13 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 641DJ UT WOS:000180728900008 PM 12536000 ER PT J AU Izumikawa, K Kakeya, H Tsai, HF Grimberg, B Bennett, JE AF Izumikawa, K Kakeya, H Tsai, HF Grimberg, B Bennett, JE TI Function of Candida glabrata ABC transporter gene, PDH1 SO YEAST LA English DT Article DE ATP binding cassette transporters; drug resistance; PDR5; yeast ID YEAST MULTIDRUG-RESISTANCE; AZOLE ANTIFUNGAL AGENTS; SACCHAROMYCES-CEREVISIAE; FLUCONAZOLE RESISTANCE; DRUG-RESISTANCE; ALBICANS; SUSCEPTIBILITY; DELETION; CLONING; EFFLUX AB The rapid increase in azole resistance during treatment of patients infected with Candida glabrata may be due to increased azole efflux mediated by ABC transporters, as occurs with increased expression of PDR5 in Saccharomyces cerevisiae. Two known C glabrata homologues of PDR5 influencing azole susceptibility are PDH1 (CgCDR2) and CgCDR1. Disruption of PDH1 in a cgcdr1::ura3 strain increased susceptibility to rhodamine 6G, cycloheximide and chloramphenicol, and also increased rhodamine 6G accumulation, all properties of pdr5 null mutants. Overexpression of PDH1 in S. cerevisiae complemented the pdr5 mutation by reversing susceptibility to rhodamine 6G, chloramphenicol and cycloheximide, as well as by decreasing rhodamine 6G intracellular concentration. Expression of PDH1 in a C glabrata cgcdr1::ura3 pdh1Delta::ura3 mutant using a multicopy plasmid almost completely restored the wild-type phenotype, showing that PDH1 at higher levels of expression can replace CgCDR1. Because PDH1 and CgCDR1 have both been reported to have upstream sequences similar to the Pdr1p- and Pdr3p-binding elements of PDR5, we sought similarities in regulation between the three genes. Abundance of PDH1 and CgCDR1 mRNA in C glabrata was increased by rhodamine 6G, cycloheximide and oligomycin, properties in common with PDR5. PDH1, CgCDR1 and PDR5 have striking similarities in function and regulation. Published in 2003 by John Wiley Sons, Ltd. C1 NIAID, Clin Invest Lab, Clin Mycol Sect, NIH, Bethesda, MD 20892 USA. RP Bennett, JE (reprint author), Bldg 10,Room 11C304,10 Ctr Dr, Bethesda, MD 20892 USA. RI Grimberg, Brian/I-1251-2013 OI Grimberg, Brian/0000-0002-6015-4912 NR 33 TC 36 Z9 39 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0749-503X J9 YEAST JI Yeast PD FEB PY 2003 VL 20 IS 3 BP 249 EP 261 DI 10.1002/yea.962 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 646WR UT WOS:000181059400005 PM 12557277 ER PT J AU Oz, M Alptekin, A Dinc, M AF Oz, M Alptekin, A Dinc, M TI A closed chamber method for performing biochemical experiments at accurate concentrations of volatile agents SO JOURNAL OF BIOCHEMICAL AND BIOPHYSICAL METHODS LA English DT Article DE volatile agents; desflurane; biochemical methods; headspace ID CHANNELS AB Experiments with volatile agents such as general anesthetics present difficulties in maintaining defined concentrations of these agents during in-vitro experimental conditions. In conventional filtration apparatuses, due to their partition between liquid and vapor phases (to open air or headspaces of the incubation vehicles), some degree of inaccuracy in calculated concentrations of these agents may occur in experiments using these types of chambers. In the present study, a method is described which permits the performance of biochemical experiments in a closed system in which the concentrations of a volatile agent, desflurane, in the liquid phase of the assay environment can be maintained constant for a relatively long time period. Published by Elsevier Science B.V. C1 NIDA, IRP, Cellular Neurobiol Sect, Baltimore, MD 21224 USA. SSK Ankara Training Hosp, Dept Anesthesiol & Reanimat, Ankara, Turkey. Oncol Hosp, Dept Pulm Disorders, TR-06514 Ankara, Turkey. RP Oz, M (reprint author), NIDA, IRP, Cellular Neurobiol Sect, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Oz, Murat/E-2148-2012 NR 5 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-022X J9 J BIOCHEM BIOPH METH JI J. Biochem. Biophys. Methods PD JAN 31 PY 2003 VL 55 IS 1 BP 95 EP 100 AR PII S0165-022X(02)00115-X DI 10.1016/S0165-022X(02)00115-X PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 649ZX UT WOS:000181238800009 PM 12559592 ER PT J AU Steele, VE AF Steele, VE TI Current mechanistic approaches to the chemoprevention of cancer SO JOURNAL OF BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Review DE anticancer; anti mutagenesis; chemoprevention; chemoprotection; nonsteroidal antiinflammatory drugs ID PROSTAGLANDIN-H SYNTHASE-2; INTRAEPITHELIAL NEOPLASIA; ANGIOGENESIS; INHIBITION; CALCIUM AB The prevention of cancer is one of the most important public health and medical practices of the 21(st) century. We have made much progress in this new emerging field, but so much remains to be accomplished before widespread use and practice become common place. Cancer chemoprevention encompasses the concepts of inhibition, reversal, and retardation of the cancer process. This process, called carcinogenesis, requires 20-40 years to reach the endpoint called invasive cancer. It typically follows multiple, diverse and complex pathways in a stochastic process of clonal evolution. These pathways appear amenable to inhibition, reversal or retardation at various points. We must therefore identify key pathways in the evolution of the cancer cell that can be exploited to prevent this carcinogenesis process. Basic research is identifying many genetic lesions and epigenetic processes associated with the progression of precancer to invasive disease. Many of these early precancerous lesions favor cell division over quiescence and protect cells against apoptosis when signals are present. Many oncogenes are active during early development and are reactivated in adulthood by aberrant gene promoting errors. Normal regulatory genes are mutated, making them insensitive to normal regulatory signals. Tumor suppressor genes are deleted or mutated rendering them inactive. Thus there is a wide range of defects in cellular machinery which can lead to evolution of the cancer phenotype. Mistakes may not have to appear in a certain order for cells to progress along the cancer pathway. To conquer this diverse disease, we must attack multiple key pathways at once for a predetermined period of time. Thus, agent combination prevention strategies are essential to decrease cancer morbidity. Furthermore, each cancer type may require custom combination of prevention strategies to be successful. C1 NCI, Chemoprevent Agent Dev Res Grp, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. RP Steele, VE (reprint author), NCI, Chemoprevent Agent Dev Res Grp, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. NR 27 TC 25 Z9 26 U1 0 U2 1 PU SPRINGER-VERLAG SINGAPORE PTE LTD PI SINGAPORE PA #04-01 CENCON I, 1 TANNERY RD, SINGAPORE 347719, SINGAPORE SN 1225-8687 J9 J BIOCHEM MOL BIOL JI J. Biochem. Mol. Biol. PD JAN 31 PY 2003 VL 36 IS 1 BP 78 EP 81 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 638RN UT WOS:000180584200010 PM 12542978 ER PT J AU Shah, BH Soh, JW Catt, KJ AF Shah, BH Soh, JW Catt, KJ TI Dependence of gonadotropin-releasing hormone-induced neuronal MAPK signaling on epidermal growth factor receptor transactivation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; TYROSINE KINASE PYK2; ALPHA-T3-1 CELL-LINE; SMOOTH-MUSCLE CELLS; EGF RECEPTOR; ANGIOTENSIN-II; REGULATED KINASE; MESANGIAL CELLS; NEUROPEPTIDE RELEASE; RAS ACTIVATION AB The hypothalamic decapeptide, gonadotropin-releasing hormone (GnRH), utilizes multiple signaling pathways to activate extracellularly regulated mitogen-activated protein kinases (ERK1/2) in normal and immortalized pituitary gonadotrophs and transfected cells expressing the GnRH receptor. In immortalized hypothalamic GnRH neurons (GT1-7 cells), which also express GnRH receptors, GnRH, epidermal growth factor (EGF), and phorbol 12-myristate 13-acetate (PMA) caused marked phosphorylation of ERK1/2. This action of GnRH and PMA but not that of EGF, was primarily dependent on activation of protein kinase C (PKC), and the ERK1/2 responses to all three agents were abolished by the selective EGF receptor kinase inhibitor, AG1478. Consistent with this, both GnRH and EGF increased tyrosine phosphorylation of the EGF receptor. GnRH and PMA, but not EGF, caused rapid phosphorylation of the proline-rich tyrosine kinase, Pyk2, at Tyr(402). This was reduced by Ca2+ chelation and inhibition of PKC, but not by AG1478. GnRH stimulation caused translocation of PKCalpha and -epsilon to the cell membrane and enhanced the association of Src with PKCalpha and PKCepsilon, Pyk2, and the EGF receptor. The Src inhibitor, PP2, the C-terminal Src kinase (Csk), and dominant-negative Pyk2 attenuated ERK1/2 activation by GnRH and PMA but not by EGF. These findings indicate that Src and Pyk2 act upstream of the EGF receptor to mediate its transactivation, which is essential for GnRH-induced ERK1/2 phosphorylation in hypothalamic GnRH neurons. C1 NICHD, ERRB, NIH, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA. RP Catt, KJ (reprint author), NICHD, ERRB, NIH, Bldg 49,Rm 6A36, Bethesda, MD 20892 USA. NR 58 TC 52 Z9 52 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 JAN 31 PY 2003 VL 278 IS 5 BP 2866 EP 2875 DI 10.1074/jbc.m208783200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 644JW UT WOS:000180915000015 PM 12446705 ER PT J AU Kino, T Chrousos, GP AF Kino, T Chrousos, GP TI Tumor necrosis factor alpha receptor- and Fas-associated FLASH inhibit transcriptional activity of the glucocorticoid receptor by binding to and interfering with its interaction with p160 type nuclear receptor coactivators SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FACTOR-KAPPA-B; INDUCED APOPTOSIS; PROTEIN-1 GRIP1; CELLS; ESTROGEN; SENSITIVITY; LYMPHOCYTES; BIOLOGY; GROWTH; TNF AB Tumor necrosis factor alpha (TNFalpha) and its downstream transcription factor nuclear factor kappaB (NF-kappaB) suppress glucocorticoid action, contributing to tissue resistance to glucocorticoids in several pathologic inflammatory states. p160 nuclear receptor coactivators on the other hand, contribute to the transcriptional signal of the glucocorticoid receptor (GR) through interaction with it via LXXLL motifs in their nuclear receptor-binding (NRB) domain. To discover TNFalpha-induced factors that regulate GR activity at the coactivator level, we performed yeast two-hybrid screening using the NRB domain of the glucocorticoid receptor-interacting protein 1 (GRIP1) as bait. We found that FLICE-associated huge protein (FLASH), which transduces, TNFalpha and Fas ligand signals, bound the NRB domain of GRIP1 at a region between the second and third LXXLL motifs. FLASH suppressed both GR transactivation and GRIP1 enhancement of the glucocorticoid signal and inhibited the physical interaction between GR and the GRIP1 NRB domain. Transfected green fluorescent protein-fused FLASH was located in both the cytoplasm and nucleus, while endogenous FLASH shifted its subcellular localization from the cytoplasm into the nucleus in response to TNFalpha. FLASH antisense and super-repressor IkappaBalpha inhibited the action of TNFalpha independently of each other and additively. These findings indicate that FLASH participates in TNFalpha-induced blockade of GR transactivation at the nuclear receptor coactivator level, upstream and independently of NF-kappaB. C1 NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Kino, T (reprint author), NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Rm 9D42,10 Ctr Dr,MSC 1583, Bethesda, MD 20892 USA. NR 46 TC 46 Z9 52 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 JAN 31 PY 2003 VL 278 IS 5 BP 3023 EP 3029 DI 10.1074/jbc.M209234200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 644JW UT WOS:000180915000034 PM 12477726 ER PT J AU Fukuda, M Kanno, E Ogata, Y Saegusa, C Kim, T Loh, YP Yamamoto, A AF Fukuda, M Kanno, E Ogata, Y Saegusa, C Kim, T Loh, YP Yamamoto, A TI Nerve growth factor-dependent sorting of synaptotagmin IV protein to mature dense-core vesicles that undergo calcium-dependent exocytosis in PC12 cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SQUID GIANT SYNAPSE; CONSERVED WHXL MOTIF; C2B DOMAIN; REGULATED EXOCYTOSIS; DEVELOPMENTAL REGULATION; ENDOPLASMIC-RETICULUM; ANTIBODY INJECTION; MESSENGER-RNAS; CA2+ BINDING; C-TERMINUS AB Synaptotagmin IV (Syt IV) is a fourth member of the Syt family and has been shown to regulate some forms of memory and learning by analysis of Syt]IV null mutant mice (Ferguson, G. D., Anagnostaras, S. G., Silva, A. J., and Herschman, H. R. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 5598-5603). However, the involvement of Syt IV protein in vesicular trafficking and even its localization in secretory vesicles are still matters of controversy. Here we present several lines of evidence showing that the Syt IV protein in PC12 cells is normally localized in the Golgi or immature vesicles at the cell periphery and is sorted to fusioncompetent mature dense-core vesicles in response to short nerve growth factor (NGF) stimulation. (i) In undifferentiated PC12 cells, Syt IV protein is mainly localized in the Golgi and small amounts are also present at the cell periphery, but according to the results of an immunocytochemical analysis, they do not colocalize with conventional secretory vesicle markers (Syt I, Syt IX, Rab3A, Rab27A, vesicle-associated membrane protein 2, and synaptophysin) at all. By contrast, limited colocalization of Syt IV protein with dense-core vesicle markers is found in the distal parts of the neurites of NGF-differentiated PC12 cells. (ii) Immunoelectron microscopy with highly specific anti-Syt IV antibody revealed that the Syt IV protein in undifferentiated PC12 cells is mainly present on the Golgi membranes and immature secretory vesicles, whereas after NGF stimulation Syt IV protein is also present on the mature dense-core vesicles. (iii) An N-terminal antibody-uptake experiment indicated that Syt IV-containing vesicles in the neurites of NGF-differentiated PC12 cells undergo Ca2+-dependent exocytosis, whereas no uptake of the anti-Syt IV-N antibody was observed in undifferentiated PC12 cells. Our results suggest that Syt IV is a stimulus (e.g. NGF)-dependent regulator for exocytosis of dense-core vesicles. C1 RIKEN, Inst Phys & Chem Res, Fukuda Initiat Res Unit, Wako, Saitama 3510198, Japan. NICHD, Dev Neurobiol Lab, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. Kansai Med Univ, Dept Physiol, Moriguchi, Osaka 5708506, Japan. RP Fukuda, M (reprint author), RIKEN, Inst Phys & Chem Res, Fukuda Initiat Res Unit, 2-1 Hirosawa, Wako, Saitama 3510198, Japan. RI Fukuda, MItsunori/I-1511-2015 NR 69 TC 26 Z9 27 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 JAN 31 PY 2003 VL 278 IS 5 BP 3220 EP 3226 DI 10.1074/jbc.M208323200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 644JW UT WOS:000180915000058 PM 12446703 ER PT J AU Chang, CS Magracheva, E Kozlov, S Fong, S Tobin, G Kotenko, S Wlodawer, A Zdanov, A AF Chang, CS Magracheva, E Kozlov, S Fong, S Tobin, G Kotenko, S Wlodawer, A Zdanov, A TI Crystal structure of interleukin-19 defines a new subfamily of helical cytokines SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTERFERON-GAMMA; RECEPTOR COMPLEXES; HOMOLOG; REVEALS; IDENTIFICATION; IL-19; CHAIN AB Interleukin-19 (IL-19) is a novel cytokine that was initially identified during a sequence data base search aimed at finding potential IL-10 homologs. IL-19 shares a receptor complex with IL-20, indicating that the biological activities of these two cytokines overlap and that both may play an important role in regulating development and proper functioning of the skin. We determined the crystal structure of human recombinant IL-19 and refined it at 1.95-Angstrom resolution to an R-factor of 0.157. Unlike IL-10, which forms an intercalated dimer, the molecule of IL-19 is a monomer made of seven amphipathic helices, A-G, creating a unique helical bundle. On the basis of the observed structure, we propose that IL-19, IL-20, and other putative members of the proposed IL-10 family together form a distinct subfamily of helical cytokines. C1 NCI, Ctr Canc Res, Macromol Crystallog Lab, Prot Struct Sect,NIH, Frederick, MD 21702 USA. SAIC Frederick Inc, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Canc & Dev Biol Lab, NIH, Frederick, MD 21702 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Biochem & Mol Biol, Newark, NJ 07103 USA. RP Zdanov, A (reprint author), NCI, Ctr Canc Res, Macromol Crystallog Lab, Prot Struct Sect,NIH, POB B, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-12400] NR 30 TC 55 Z9 64 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 JAN 31 PY 2003 VL 278 IS 5 BP 3308 EP 3313 DI 10.1074/jbc.M208602200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 644JW UT WOS:000180915000069 PM 12403790 ER PT J AU Pal, D Vuthoori, M Pande, S Wheeler, D Hinton, DM AF Pal, D Vuthoori, M Pande, S Wheeler, D Hinton, DM TI Analysis of regions within the bacteriophage T4 AsiA protein involved in its binding to the sigma(70) subunit of E-coli RNA polymerase and its role as a transcriptional inhibitor and co-activator SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE T4; AsiA; transcription; inhibition; sigma(70) ID AROMATIC-AMINO-ACIDS; ESCHERICHIA-COLI; MIDDLE PROMOTER; MOTA PROTEIN; EXPRESSED PROTEIN; SIGMA-70 SUBUNIT; OPEN COMPLEX; DNA; GENE; DOMAIN AB Bacteriophage T4 AsiA, a protein of 90 amino acid residues, binds to the sigma(70) subunit of Escherichia coli RNA polymerase and inhibits host or T4 early transcription or, together with the T4 MotA protein, activates T4 middle transcription. To investigate which regions within AsiA are involved in forming a complex with sigma(70) and in providing transcriptional functions we generated random mutations throughout AsiA and targeted mutations within the C-terminal region. We tested mutant proteins for nontheir ability to complement the growth of T4 asiA am phage under non-suppressing conditions, to inhibit E. coli growth, to interact with sigma(70) region 4 in a two-hybrid assay, to bind to sigma(70) in a native protein gel, and to inhibit or activate transcription in vitro using a T4 middle promoter that is active with RNA polymerase alone, is inhibited by AsiA, and is activated by MotA/AsiA. We find that substitutions within the N-terminal half of of AsiA, at amino acid residues V14, L18, and 140, rendered the protein defective for binding to sigma(70). These residues reside at the monomer-monomer interface in recent NMR structures of the AsiA dimer. In contrast, AsiA missing the C-terminal 44 amino acid residues interacted well with sigma(70) region 4 in the two-hybrid assay, and AsiA missing the C-terminal 17 amino acid residues (Delta74-90) bound to sigma(70) and was fully competent in standard in vitro transcription assays. However, the presence of the C-terminal region delayed formation of transcriptionally competent species when the AsiA/polymerase complex was pre-incubated with the promoter in the absence of MotA. Our results suggest that amino acid residues within the N-terminal half of AsiA are involved in forming or maintaining the AsiA/sigma(70) complex. The C-terminal region of AsiA, while not absolutely required for inhibition or co-activation, aids inhibition by slowing the formation of transcription complexes between a promoter and the AsiA/polymerase complex. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 NIDDKD, Mol & Cellular Biol Lab, Bethesda, MD 20892 USA. Natl Ctr Biotechnol Informat, NIH, Bethesda, MD USA. RP Hinton, DM (reprint author), NIDDKD, Mol & Cellular Biol Lab, Bethesda, MD 20892 USA. NR 64 TC 19 Z9 19 U1 0 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 31 PY 2003 VL 325 IS 5 BP 827 EP 841 DI 10.1016/S0022-2836(02)01307-4 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 640EY UT WOS:000180676300001 PM 12527294 ER PT J AU Chen, SY Simons, SS AF Chen, SY Simons, SS TI A second pathway for modulating glucocorticoid receptor transactivation properties SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE glucocorticoid receptor; modulation of dose-response curve; partial agonist activity; E1A; hSur2 ID POLYMERASE-II HOLOENZYME; TYROSINE AMINOTRANSFERASE GENE; NUCLEAR HORMONE RECEPTORS; PARTIAL AGONIST ACTIVITY; TRANSCRIPTION FACTOR; INDUCTION PROPERTIES; COACTIVATOR COMPLEX; ESTROGEN-RECEPTOR; PROMOTER-CONTEXT; FUNCTIONAL-GROUP AB We recently reported that three factors (a cis-acting element and changing concentrations of receptor or coactivator TIF2) act at a common rate-limiting step to modulate the position of the dose-response curve and the partial agonist activity of glucocorticoid receptors (GRs). The ability of saturating levels of GR, and added inhibitors, to prevent the actions of the three modulators (cis-acting element, GR, and TIF2) but not the currently investigated C-terminal fragment of E1A-13S (E1A-133C) indicates that E1A-133C alters GR properties via a second pathway that is downstream of the common step for the original three modulators. hSur2 binds to E1A-133C. We find that hSur2 modulates GR transactivation properties, thus suggesting that the effects of E1A-133C are due to the recruitment of hSur2. hSur2 also modifies GR activities in the presence of saturating GR concentrations, which is consistent with hSur2 acting downstream of the common step for the original three modulators. The H160Y mutation, which eliminates hSur2 binding to E1A, blocks most of the activity of E1A-133C. This suggests that the modulatory activity of E1A-133C is largely due to the binding of hSur2, which is a component of the Mediator complex. Collectively, these data support the existence of a new pathway for modulating GR transactivation processes, thereby increasing the number of cellular mechanisms that permit differential control of gene expression by endogenous levels of glucocorticoid hormones. Published by Elsevier Science Ireland Ltd. C1 NIDDK, Steroid Hormones Sect, LMCB, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, Steroid Hormones Sect, LMCB, NIH, Bldg 8,Room B2A-07, Bethesda, MD 20892 USA. NR 66 TC 7 Z9 8 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JAN 31 PY 2003 VL 199 IS 1-2 BP 129 EP 142 AR PII S0303-7207(02)00333-7 DI 10.1016/S0303-7207(02)00333-7 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 650HA UT WOS:000181256400012 PM 12581885 ER PT J AU Abasolo, I Yang, LP Haleem, R Xiao, WH Pio, R Cuttitta, F Montuenga, LM Kozlowski, JM Calvo, A Wang, Z AF Abasolo, I Yang, LP Haleem, R Xiao, WH Pio, R Cuttitta, F Montuenga, LM Kozlowski, JM Calvo, A Wang, Z TI Overexpression of adrenomedullin gene markedly inhibits proliferation of PC3 prostate cancer cells in vitro and in vivo SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE adrenomedullin; prostate cancer; growth inhibition; xenograft; PC3 ID PROADRENOMEDULLIN N-TERMINAL-20 PEPTIDE; SMOOTH-MUSCLE CELLS; RAT VENTRAL PROSTATE; HYPOTENSIVE PEPTIDE; MESANGIAL CELLS; HUMAN PLASMA; CYCLIC-AMP; LINE PC-3; EXPRESSION; RECEPTOR AB The expression of the gene encoding adrenomedullin (AM), a multifunctional peptide hormone, in the prostate is localized to the epithelial cells. Prostate cancer cells are derived from prostatic epithelial cells. To elucidate the potential role of the AM gene in prostate cancer progression, we have stably-transfected the PC3 human prostate cancer cell line with an AM gene expression vector. The AM-transfected PC3 sublines were studied along with parental and empty vector transfected PC3 cells as controls. The average level of AM in the conditioned media of AM-transfected cells was 0.959 +/- 0.113 nM, a physiologically relevant concentration. The ectopic expression of AM gene inhibited the proliferation of PC3 cells in culture dishes. In addition, anchorage-independent growth of the transfected sublines was virtually abolished in soft agar assays. Flow cytometry studies showed that overexpression of AM gene caused a very significant G(1)/G(0) cell cycle arrest. In vivo experiments demonstrated that AM gene expression markedly inhibited the growth of xenograft tumors in nude mice. Our in vivo and in vitro studies suggest that AM could strongly suppress the malignancy of prostate cancer cells, via autocrine and/or paracrine mechanisms. (C) 2002 Published by Elsevier Science Ireland Ltd. C1 Northwestern Univ, Sch Med, Dept Urol, Chicago, IL 60611 USA. Northwestern Univ, Sch Med, Dept Mol Pharmacol & Biol Chem, Chicago, IL 60611 USA. Northwestern Univ, Sch Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. Univ Navarra, Dept Histol & Pathol, Pamplona 31008, Spain. NCI, Dept Cell & Canc Biol, Med Branch, Bethesda, MD 20892 USA. RP Wang, Z (reprint author), Northwestern Univ, Sch Med, Dept Urol, 11-715,303 E Chicago Ave, Chicago, IL 60611 USA. RI Abasolo, Ibane/H-7741-2012; Pio, Ruben/F-5353-2017 OI Abasolo, Ibane/0000-0001-5970-6276; Pio, Ruben/0000-0002-6831-6111 FU NCI NIH HHS [P50 CA90386]; NIDDK NIH HHS [R01 DK51193] NR 54 TC 15 Z9 15 U1 3 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JAN 31 PY 2003 VL 199 IS 1-2 BP 179 EP 187 AR PII S0303-7207(02)00229-0 DI 10.1016/S0303-7207(02)00229-0 PG 9 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 650HA UT WOS:000181256400016 PM 12581889 ER PT J AU Nomura, M Korach, KS Pfaff, DW Ogawa, S AF Nomura, M Korach, KS Pfaff, DW Ogawa, S TI Estrogen receptor beta (ER beta) protein levels in neurons depend on estrogen receptor alpha, (ER alpha) gene expression and on its ligand in a brain region-specific manner SO MOLECULAR BRAIN RESEARCH LA English DT Article DE estrogen receptor alpha; estrogen receptor beta; androgen receptor; testosterone; estrogen; sexual behavior; aggression; immunocytochemistry; knockout mouse ID MESSENGER-RIBONUCLEIC-ACID; FEMALE RAT-BRAIN; MALE-MICE; AGGRESSIVE-BEHAVIOR; PROGESTIN RECEPTORS; TISSUE DISTRIBUTION; HORMONAL-REGULATION; KNOCKOUT MOUSE; RNA; IMMUNOREACTIVITY AB Estrogen receptors (ERs) alpha and beta are very similar estrogen-binding proteins, perhaps gene duplication products, which act as ligand-dependent transcription factors. While the estrogenic regulation of ERalpha has been well documented, little is known about how estrogen regulates ERbeta and whether ERalpha plays a role in the expression and estrogenic regulation of ERbeta. In the present study, we examined the effects of gonadectomy and estrogen replacement on ERbeta immunoreactivity (ir) in wild-type (WT) and ERalpha knockout (alphaERKO) adult male mice in six brain regions, the medial preoptic area (MPOA), the bed nucleus of the stria terminalis (BNST), the paraventricular nucleus (PVN), the ventromedial nucleus of hypothalamus (VMH), the medial amygdala nucleus (MeAMY) and the dorsal raphe nucleus (DRN). Mice were divided into four different treatment groups: gonadally intact, gonadectomized (GDX), GDX+short-term treatment with estrogen (s.c. injection of estradiol benzoate (EB), 5 mug, at 48 h before perfusion) or GDX+long-term treatment with estrogen (implant of an EB pellet, 2.5 mug/day, for 10 days). In intact alphaERKO mice, the number of ERbeta expressing cells was significantly decreased in the MPOA and increased in the BNST, compared to WT mice. Both in the MPOA and BNST, steroid hormone regulation of ERbeta protein (an increase by GDX and a decline to intact levels by EB) was found only in WT, not in alphaERKO mice. In the VMH, GDX significantly increased the number of ERbeta ir expressing cells in both genotypes. EB treatment tended to decrease the number of ERbeta it cells in WT mice, whereas EB treatment tended to increase ERbeta ir cell counts in alphaERKO mice. No effects of GDX or EB treatment were found in the DRN and MeAMY regardless of genotype. These results suggest that gonadal steroid hormones may regulate ERbeta protein in male mice and ERalpha may be involved in the expression and regulation of ERbeta in a region-specific manner. Published by Elsevier Science B.V. C1 Rockefeller Univ, Neurobiol & Behav Lab, New York, NY 10021 USA. NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Ogawa, S (reprint author), Rockefeller Univ, Neurobiol & Behav Lab, Box 275,1230 York Ave, New York, NY 10021 USA. OI Korach, Kenneth/0000-0002-7765-418X NR 39 TC 27 Z9 27 U1 0 U2 2 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 JAN 31 PY 2003 VL 110 IS 1 BP 7 EP 14 AR PII S0169-328X(02)00544-2 DI 10.1016/S0169-328X(02)00544-2 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 703WX UT WOS:000184306100002 ER PT J AU Parisi, M Nuttall, R Naiman, D Bouffard, G Malley, J Andrews, J Eastman, S Oliver, B AF Parisi, M Nuttall, R Naiman, D Bouffard, G Malley, J Andrews, J Eastman, S Oliver, B TI Paucity of genes on the Drosophila X chromosome showing male-biased expression SO SCIENCE LA English DT Article ID MELANOGASTER; SPERMATOGENESIS; EVOLUTION; SEX AB Sex chromosomes are primary determinants of sexual dimorphism in many organisms. These chromosomes are thought to arise via the divergence of an ancestral autosome pair and are almost certainly influenced by differing selection in mates and females. Exploring how sex chromosomes differ from autosomes is highly amenable to genomic analysis. We examined global gene expression in Drosophila melanogaster and report a dramatic underrepresentation of X-chromosome genes showing high relative expression in mates. Using comparative genomics, we find that these same X-chromosome genes are exceptionally poorly conserved in the mosquito Anopheles gambiae. These data indicate that the X chromosome is a disfavored location for genes selectively expressed in males. C1 NIDDKD, Cellular & Dev Biol Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. Incyte Genom, Palo Alto, CA 94304 USA. Johns Hopkins Univ, Dept Math Sci, Baltimore, MD 21218 USA. NHGRI, Natl Inst Hlth Intramural Sequencing Ctr, NIH, US Dept HHS, Gaithersburg, MD 20877 USA. NIH, Ctr Informat Technol, US Dept HHS, Bethesda, MD 20892 USA. RP Oliver, B (reprint author), NIDDKD, Cellular & Dev Biol Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. RI Naiman, Daniel/A-3304-2010; Marion-Poll, Frederic/D-8882-2011 OI Naiman, Daniel/0000-0001-6504-9081; Marion-Poll, Frederic/0000-0001-6824-0180 FU NIDDK NIH HHS [Z01 DK015600-10] NR 20 TC 344 Z9 350 U1 1 U2 24 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 JAN 31 PY 2003 VL 299 IS 5607 BP 697 EP 700 DI 10.1126/science.1079190 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 640KH UT WOS:000180687700044 PM 12511656 ER PT J AU Cheutin, T McNairn, AJ Jenuwein, T Gilbert, DM Singh, PB Misteli, T AF Cheutin, T McNairn, AJ Jenuwein, T Gilbert, DM Singh, PB Misteli, T TI Maintenance of stable heterochromatin domains by dynamic HP1 binding SO SCIENCE LA English DT Article ID MAMMALIAN-CELLS; HISTONE H3; LYSINE 9; CHROMATIN; PROTEINS; DROSOPHILA; YEAST; RNA AB One function of heterochromatin is the epigenetic silencing by sequestration of genes into transcriptionally repressed nuclear neighborhoods. Heterochromatin protein 1 (HP1) is a major component of heterochromatin and thus is a candidate for establishing and maintaining the transcriptionally repressive heterochromatin structure. Here we demonstrate that maintenance of stable heterochromatin domains in living cells involves the transient binding and dynamic exchange of HP1 from chromatin. HP1 exchange kinetics correlate with the condensation level of chromatin and are dependent on the histone methyltransferase Suv39h. The chromodomain and the chromoshadow domain of HP1 are both required for binding to native chromatin in vivo, but they contribute differentially to binding in euchromatin and heterochromatin. These data argue against HP1 repression of transcription by formation of static, higher order oligomeric networks but support a dynamic competition model, and they demonstrate that heterochromatin is accessible to regulatory factors. C1 NCI, NIH, Bethesda, MD 20892 USA. SUNY Upstate Med Univ, Syracuse, NY 13210 USA. Inst Mol Pathol, A-1030 Vienna, Austria. Roslin Inst, Roslin EH25 9PS, Midlothian, Scotland. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. RI Singh, Prim/G-1088-2014; OI McNairn, Adrian/0000-0003-4727-3770 NR 24 TC 384 Z9 388 U1 1 U2 11 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 JAN 31 PY 2003 VL 299 IS 5607 BP 721 EP 725 DI 10.1126/science.1078572 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 640KH UT WOS:000180687700052 PM 12560555 ER PT J AU Schimmenti, LA de la Cruz, J Lewis, RA Karkera, JD Manligas, GS Roessler, E Muenke, M AF Schimmenti, LA de la Cruz, J Lewis, RA Karkera, JD Manligas, GS Roessler, E Muenke, M TI Novel mutation in sonic hedgehog in non-syndromic colobomatous microphthalmia SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE coloboma; sonic hedgehog; PAX2; microphthalmia ID CONGENITAL EYE MALFORMATIONS; SIMPLE MENDELIAN DISORDERS; PAX2 GENE; CONSECUTIVE BIRTHS; COMPLEX TRAITS; OPTIC FISSURE; EXPRESSION; ANOMALIES; MORPHOGENESIS; MOUSE AB Ocular (uveoretinal) colobomas occur in one in 10,000 individuals and present a substantive cause of congenital poor vision. The genetic bases of most forms of uveoretinal coloboma are elusive; mutations in PAX2 are found in only a few cases of coloboma of the retina and optic nerve that occur with renal anomalies as part of the renal-coloboma syndrome (MIM#120330; #167409). From experimental data that upstream expression of sonic hedgehog (SHH) controls Pax2 expression in mice and zebrafish, and from clinical experience that colobomas are observed frequently in patients with holoprosencephaly, we hypothesized that SHH could be a candidate for non-syndromic ocular colobomas (NSOC). We identified a three-generation family in which both a proband and his mother presented with iris and uveoretinal colobomas without optic nerve involvement. A novel 24 bp deletion in the gene SHH was identified in these affected family members, and cosegregated with the phenotype. This is the first report of the association of SHH mutations and uveoretinal coloboma. Published 2002 Wiley-Liss, Inc.(dagger). C1 Univ Calif Los Angeles, Dept Human Genet, Jules Stein Eye Inst, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Human Genet, Mental Retardat Res Ctr, Los Angeles, CA USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. RP Schimmenti, LA (reprint author), Univ Minnesota, Dept Pediat, Div Genet & Metabolism, 420 Delaware St, Minneapolis, MN 55455 USA. FU NHLBI NIH HHS [K08 HL03515] NR 37 TC 87 Z9 93 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JAN 30 PY 2003 VL 116A IS 3 BP 215 EP 221 DI 10.1002/ajmg.a.10884 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 670HD UT WOS:000182400700001 PM 12503095 ER PT J AU Basso, G Nichelli, P Wharton, CM Peterson, M Grafman, J AF Basso, G Nichelli, P Wharton, CM Peterson, M Grafman, J TI Distributed neural systems for temporal production: A functional MRI study SO BRAIN RESEARCH BULLETIN LA English DT Article DE time production; functional MRI; inferior parietal lobule; short-term memory ID VISUAL WORKING-MEMORY; TIME PERCEPTION; SELECTIVE ATTENTION; PARKINSONS-DISEASE; MENTAL CALCULATION; STIMULUS RATE; CORTEX; ACTIVATION; DURATION; PET AB Using functional magnetic resonance imaging (fMRI), we investigated the neural substrates for computing time intervals. Five right-handed males were asked to judge if a digit probe belonged to a string of digits presented immediately before but to provide their response only after 1.5s had elapsed. This time estimation condition, compared with control working memory and motor tasks, was associated with increased activity in the middle occipital gyri, in the right inferior parietal lobe, and bilaterally in the prefrontal cortex. We argue that activity elicited in the occipital lobe provides duration information about visual stimuli that can be quantified at the level of the inferior parietal lobe. Comparison with time reference information depends on the bilateral prefrontal cortex. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Univ Modena, Dipartimento Neurosci TCR, I-41100 Modena, Italy. NINDS, Cognit Neurosci Sect, MNB, NIH, Bethesda, MD 20892 USA. RP Nichelli, P (reprint author), Univ Modena, Dipartimento Neurosci TCR, Via Pozzo 71, I-41100 Modena, Italy. RI Basso, Gianpaolo/A-9208-2012; Nichelli, Paolo/F-7336-2015; OI Basso, Gianpaolo/0000-0002-6245-9402; Nichelli, Paolo/0000-0001-9756-6796; Grafman, Jordan H./0000-0001-8645-4457 NR 47 TC 36 Z9 38 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD JAN 30 PY 2003 VL 59 IS 5 BP 405 EP 411 AR PII S0361-9230(02)00941-3 DI 10.1016/S0361-9230(02)00941-3 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 635YR UT WOS:000180428200011 PM 12507693 ER PT J AU Lee, SH Kim, YM Yajima, S Ha, JM Ha, BJ Kim, OS Ohsawa, K Mouradian, MM AF Lee, SH Kim, YM Yajima, S Ha, JM Ha, BJ Kim, OS Ohsawa, K Mouradian, MM TI Genomic organization and promoter characterization of the murine dopamine receptor regulating factor (DRRF) gene SO GENE LA English DT Article DE TATA-less; transcription factor; regulation; Sp1 ID TRANSCRIPTION FACTOR; REGION AB To study the transcriptional mechanisms by which expression of the dopamine receptor regulating factor (DRRF) gene is regulated, a murine genomic clone was isolated using a DRRF cDNA as probe. A 24 kb genomic fragment which comprises 13 kb upstrearn of the transcription initiation site was sequenced. The promoter region lacks a TATA box and CAAT box, is rich in G + C content, and has multiple putative binding sites for the transcription factor Sp1. The DRRF gene also has consensus sequences for AP1 and AP2 binding sites. The transcriptional activity of five deletion mutants of a 1.5 kb fragment was analyzed by modulating transcription of the heterologous chloramphenicol acetyltransferase (CAT) gene in the promoterless plasmid pCAT-Basic. All mutants showed significant transcriptional activity in the murine neuroblastoma cell line NB41A3, except the construct stretching from -901 to + 17. These transient expression assays suggested the presence of positive regulators between -1153 and -901 and between -118 and -93 while a negative regulator was found in the region between -901 and -118. Comparison among cell types revealed strong transcriptional activity of the DRRF promoter in neuronal NB41A3 cells and moderate activity in hepatic HepG2 and renal OK cells, but none in skeletal muscle C2C12 or glial C6 cells. These findings confirm the tissue-specific activity of the DRRF promoter and suggest that this gene shares structural and functional similarities with the dopamine receptor genes that it regulates. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Silla Univ, Dept Biosci & Biotechnol, Sasang Gu, Pusan 617736, South Korea. NINDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Tokyo Univ Agr, Dept Biosci, Setagaya Ku, Tokyo 1568502, Japan. RP Lee, SH (reprint author), Silla Univ, Dept Biosci & Biotechnol, Sasang Gu, San 1-1 Kwaebop Dong, Pusan 617736, South Korea. EM slee@silla.ac.kr; mouradianm@ninds.nih.gov OI Mouradian, M. Maral/0000-0002-9937-412X NR 19 TC 5 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JAN 30 PY 2003 VL 304 BP 193 EP 199 DI 10.1016/S0378-1119(02)01209-X PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 647ZT UT WOS:000181124500019 PM 12568728 ER PT J AU Petrella, RJ Andricioaei, I Brooks, BR Karplus, M AF Petrella, RJ Andricioaei, I Brooks, BR Karplus, M TI An improved method for nonbonded list generation: Rapid determination of near-neighbor pairs SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE nonbonded list; neighborlist; pair distribution; molecular dynamics; cutoff distance; energy calculations ID ELECTROSTATIC INTERACTIONS; PROTEIN DYNAMICS; SIMULATION; PROGRAM; ENERGY AB Generation of the list of near-neighbor pairs of atoms not bonded to each other is it key feature of many programs for calculating the energy and energy derivatives for large molecules, Because this step can take a significant amount of CPU time, more efficient nonbonded list generation can speed up the energy Calculations, In this article, a novel nonbonded list generation algorithm, BYCC, is introduced. It combines certain feature,, of other algorithms and achieves more rapid nonbonded list generations a factor of approximate to2.5 for a molecule of 5000 atoms with a cutoff in the 10 Angstrom range is obtained on Hewlett-Packard (HP) and Alpha processors, without greatly increasing memory requirements. (C) 2002 Wiley Periodicals, Inc. C1 Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD USA. Univ Strasbourg 1, Inst Le Bel, F-67070 Strasbourg, France. RP Petrella, RJ (reprint author), Harvard Univ, Dept Chem & Biol Chem, 12 Oxford St, Cambridge, MA 02138 USA. NR 26 TC 16 Z9 17 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD JAN 30 PY 2003 VL 24 IS 2 BP 222 EP 231 DI 10.1002/jcc.10123 PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA 632PX UT WOS:000180233000008 PM 12497601 ER PT J AU Kozikowski, AP Nowak, I Petukhov, PA Etcheberrigaray, R Mohamed, A Tan, M Lewin, N Hennings, H Pearce, LL Blumberg, PM AF Kozikowski, AP Nowak, I Petukhov, PA Etcheberrigaray, R Mohamed, A Tan, M Lewin, N Hennings, H Pearce, LL Blumberg, PM TI New amide-bearing benzolactam-based protein kinase C modulators induce enhanced secretion of the amyloid precursor protein metabolite sAPP alpha SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ALZHEIMERS-DISEASE PATIENTS; ACTIVATOR-BINDING DOMAIN; PHORBOL ESTER; BETA-SECRETASE; LIGAND INTERACTIONS; MOLECULAR-DYNAMICS; GENETIC ALGORITHM; FLEXIBLE DOCKING; SCORING FUNCTION; TUMOR PROMOTION AB Protein kinase C (PKC) is known to participate in the processing of the amyloid precursor protein (APP). Abnormal processing of APP through the action of the beta- and gamma-secretases leads to the production of the 39-43 amino acid Abeta fragment, which is neurotoxic and which is believed to play an important role in the etiology of Alzheimer's disease. PKC activation enhances alpha-secretase activity, which results in a decrease of the amyloidogenic products of beta-secretase. In this article, we describe the synthesis of 10 new benzolactam V8 based PKC activators having side chains of varied saturation and lipophilicity linked to the aromatic ring through an amide group. The K-i values measured for the inhibition of phorbol ester binding to PKCalpha are in the nanomolar range and show some correlation with their lipophilicity. Compounds 5g and 5h show the best binding affinity among the 10 benzolactams that were synthesized. By use of a cell line derived from an AD patient, significant enhancement of sAPPalpha secretion was achieved at 1 muM concentration for most of the compounds studied and at 0.1 muM for compounds 5e and 5f. At 1 muM the enhancement of sAPPalpha secretion for compounds 5c-h is higher than that observed for the control compound 8-(1-decynyl)benzolactam (BL). Of interest is the absence of activity found for the highly lipophilic ligand 5i, which has a K-i of 11 nM. On the other hand, its saturated counterpart 5i, which possesses a comparable K-i and ClogP, retains activity in the secretase assay. In the hyperplasia studies, 5f showed a modest response at 100 mug and 5e at 300 mug, suggesting that 5f was approximately 30-fold less potent than the PKC activator mezerein and 100-fold less potent than TPA. 5e was approximately 3-fold less active than 5f. On the basis of the effect of unsaturation for other potent PKC ligands, we would predict that 5e would retain biological activity in most assays but would show a marked loss of tumor-promoting activity. Compound 5e thus becomes a viable candidate compound in the search for Alzheimer's therapeutics capable of modulating amyloid processing. C1 Georgetown Univ, Med Ctr, Dept Neurol, Drug Discovery Program, Washington, DC 20007 USA. NeuroLog Inc, Rockville, MD 20850 USA. NIH, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. RP Kozikowski, AP (reprint author), Georgetown Univ, Med Ctr, Dept Neurol, Drug Discovery Program, 3970 Reservoir Rd NW, Washington, DC 20007 USA. EM kozikowa@georgetown.edu FU NCI NIH HHS [CA79601] NR 70 TC 41 Z9 43 U1 1 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 JAN 30 PY 2003 VL 46 IS 3 BP 364 EP 373 DI 10.1021/jm020350r PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 638PD UT WOS:000180578700007 PM 12540236 ER PT J AU Breman, JG Arita, I Fenner, F AF Breman, JG Arita, I Fenner, F TI Preventing the return of smallpox SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 Fogarty Int Ctr, Bethesda, MD 20892 USA. Agcy Cooperat Int Hlth, Kumamoto, Japan. Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT 2601, Australia. RP Breman, JG (reprint author), Fogarty Int Ctr, Bldg 16,Rm 214,16 Ctr Dr, Bethesda, MD 20892 USA. NR 18 TC 14 Z9 18 U1 0 U2 5 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JAN 30 PY 2003 VL 348 IS 5 BP 463 EP 466 DI 10.1056/NEJMp025175 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 639RU UT WOS:000180643800015 PM 12556549 ER PT J AU Tuomala, RE Shapiro, DE Mofenson, LM AF Tuomala, RE Shapiro, DE Mofenson, LM TI Antiretroviral therapy during pregnancy and the risk of an adverse outcome - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. NIH, Rockville, MD 20852 USA. RP Tuomala, RE (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JAN 30 PY 2003 VL 348 IS 5 BP 471 EP 472 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 639RU UT WOS:000180643800023 ER PT J AU Bachelier, R Xu, XL Wang, XY Li, WM Naramura, M Gu, H Deng, CX AF Bachelier, R Xu, XL Wang, XY Li, WM Naramura, M Gu, H Deng, CX TI Normal lymphocyte development and thymic lymphoma formation in Brca1 exon-11-deficient mice SO ONCOGENE LA English DT Article DE T-lymphoma; Brca1; p53; tumorigenesis ID DNA-DAMAGE RESPONSE; DOUBLE-STRAND BREAKS; MAMMARY EPITHELIAL-CELLS; MURINE BRCA1; CANCER SUSCEPTIBILITY; SUBCELLULAR-LOCALIZATION; ATAXIA-TELANGIECTASIA; CHROMOSOME STABILITY; GENETIC INSTABILITY; REPAIR AB Breast-cancer-associated gene 1 (BRCA1) is highly expressed in thymus and spleen. In this paper, we have studied lymphocyte development and tumorigenesis in mice carrying mutations in Brca1 and p53. We show that the deletion of Brca1 exon 11 (Brca1-Delta11), which disrupts the full-length isoform, but not the short isoform of Brcal, does not interfere with lymphocyte development. This is true irrespective of p53 status, that is, whether it is wild type, heterozygous or homozygous for a null mutation. These data suggest that the expression of Brcal short isoform alone is enough to maintain normal development of lymphocytes. However, it cannot suppress tumorigenesis as about 30% of Brca1(Delta11/Delta11)p53(+/-) mice develop thymic lymphoma between 3 and 7 months of age. We demonstrate that p53 plays an essential role in Brca1-associated lymphoma, as all the tumors from Brca1(Delta11/Delta11)p53(+/-) mice exhibit LOH of p53 and Brca1(Delta11/Delta)11p53(-/-) mice exhibited accelerated tumorigenesis. We further demonstrate that the Brca1-Delta11 deficiency does not affect thymocyte proliferation; however, it increases genetic instability and triggers gamma-irradiation-induced apoptosis. The loss of p53 attenuates apoptosis and allows accumulation of further mutations in Brca1-Delta11 thymocytes, eventually leading to thymic lymphoma formation. C1 NIDDK, Genet Dev & Dis Branch, Lab Immunol, Bethesda, MD 20892 USA. NIAID, Lab Immunol, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, Lab Immunol, 10-9N105,10 Ctr Dr, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016; OI Naramura, Mayumi/0000-0003-3658-0767 NR 66 TC 21 Z9 22 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 30 PY 2003 VL 22 IS 4 BP 528 EP 537 DI 10.1038/sj.onc.1206208 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 637XC UT WOS:000180538200006 PM 12555066 ER PT J AU Muthumani, K Bagarazzi, M Conway, D Hwang, DS Manson, K Ciccarelli, R Israel, Z Montefiori, DC Ugen, K Miller, N Kim, J Boyer, J Weiner, DB AF Muthumani, K Bagarazzi, M Conway, D Hwang, DS Manson, K Ciccarelli, R Israel, Z Montefiori, DC Ugen, K Miller, N Kim, J Boyer, J Weiner, DB TI A Gag-Pol/Env-Rev SIV239 DNA vaccine improves CD4 counts, and reduce viral loads after pathogenic intrarectal SIV(mac)251 challenge in Rhesus Macaques SO VACCINE LA English DT Article; Proceedings Paper CT 3rd World Congress on Vaccines and Immunisation CY JUN 04-09, 2002 CL OPATIJA, CROATIA DE DNA vaccines; HIV 1Gag/Pol; HIV-1Env/REV; CD4/CD8; CD29w; neutralizing antibody ID IMMUNODEFICIENCY VIRUS CHALLENGES; IMMUNE-RESPONSES; IN-VIVO; MONKEYS; PROTECTION; AIDS; LYMPHOCYTES; PREVENTION; TYPE-1; RNA AB DNA vaccines are an important vaccine approach for many infectious diseases including human immunodeficiency virus (HIV). Recently, there have been exciting results reported for plasmid vaccination in pathogenic SHIV model systems. In these studies, plasmid vaccines supplemented by IL-2 Ig cytokine gene adjuvants or boosted by recombinant MVA vectors expressing relevant SIV and HIV antigens prevented CD4(+) T-cell loss and lowered viral loads following pathogenic challenge. However, similar results have not been reported in a direct pathogenic macaque challenge model. Here we report on a study of the ability of a multiplasmid SIV DNA vaccine in a pathogenic SIV251 rhesus mucosal challenge study. We observed that pGag/Pol + pEnv/Rev plasmid vaccines could not prevent SIV infection; however, vaccinated animals exhibited significant improvement in control of viral challenge compared to control animals. Furthermore, vaccinated animals exhibited protection against CD4+ T-cell loss. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Merck & Co Inc, W Point, PA 19486 USA. Med Coll Penn & Hahnemann Univ, Philadelphia, PA USA. Primedica Inc, Worcester, MA USA. Wyeth Lederle, Vaccine, NY USA. Duke Med Univ, Dept Surg, Duke, NC 27710 USA. Univ S Florida, Tampa, FL 33612 USA. NIAID, Bethesda, MD 20892 USA. Viraol Genomix, Philadelphia, PA 19104 USA. RP Weiner, DB (reprint author), Univ Penn, Dept Pathol & Lab Med, 505 Stellar Chance Labs,422 Curie Blvd, Philadelphia, PA 19104 USA. RI Ugen, Kenneth/H-6544-2011; Muthumani, Karuppiah/D-1092-2009; Weiner, David/H-8579-2014 NR 25 TC 25 Z9 28 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JAN 30 PY 2003 VL 21 IS 7-8 BP 629 EP 637 AR PII S0264-410X(02)00571-6 DI 10.1016/S0264-410X(02)00571-6 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 645BQ UT WOS:000180956700013 PM 12531331 ER PT J AU Pari, K Mueller, GA DeRose, EF Kirby, TW London, RE AF Pari, K Mueller, GA DeRose, EF Kirby, TW London, RE TI Solution structure of the RNase H domain of the HIV-1 reverse transcriptase in the presence of magnesium SO BIOCHEMISTRY LA English DT Article ID PROTEIN SECONDARY STRUCTURE; CHEMICAL-SHIFT INDEX; RIBONUCLEASE-H; ESCHERICHIA-COLI; INOSITOL MONOPHOSPHATASE; RESONANCE SPECTROSCOPY; EXONUCLEASE ACTIVITY; CRYSTAL-STRUCTURE; DRUG-RESISTANCE; NMR EXPERIMENTS AB This paper presents the first solution structure of the RNase H domain of HIV-1 reverse transcriptase (RT) determined by NMR methods. The solution conditions in this study were at physiological pH in the presence of Mg2+. An investigation of the dependence of the H-1-N-15 HSQC spectrum of the RNase H domain on [Mg2+] indicates that Mg2+ produces significant, global effects on the amide chemical shifts, implying that divalent metal ion binding is important for stabilizing the structure of the isolated domain in solution. Analysis of amide shift data as a function of MgCl2 concentration using either a single- or two-site binding model indicated that the latter provided a significantly improved fit, with the K-D for site A = 2.7-3.2 mM and K-D for site B similar to 35 mM, calculated on the assumption that site A is already occupied. Resonances of the [U-C-13,N-15]RNase H domain, measured at pH 6.8, in 80 MM MgCl2, were assigned and NOESY data collected in order to determine the structure. Assignment of the NOESY spectra using the ARIA program resulted in a high-resolution structure for residues 6-114 which was similar to the crystal structure of the isolated domain, (HRH)-H-1. The data were insufficient to define a compact structure for the C-terminal residues after 114. Residues I134-L138 located at the C-terminus are highly disordered and give rise to relatively sharp and intense amide resonances, while the amide resonances for the segment from E124 to A132 appear to be largely absent and are presumably subject to significant exchange broadening between different conformational states. Comparisons with crystal structure data for the full reverse transcriptase molecule indicate that the corresponding region is absent in nearly all of the crystal structures determined for the P2(1)2(1)2(1) space group, while these residues adopt an alpha-helix in structures determined for other symmetry groups. This structural heterogeneity indicates that significant conformational variability exists for this segment of the full reverse transcriptase enzyme as well, and the structure of the C-terminal peptide can be selected or deselected, depending on crystallization conditions. This analysis, along with the structural characterization contained herein, challenges the previous paradigm that the dynamic behavior of the isolated RNase H domain differs substantially from the behavior in the intact enzyme. The poor Mg2+ binding and conformational flexibility of residues located near the active site indicate that substrate binding is a precondition for metal ion binding and for selecting the active site conformation of the RNase H domain. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 52 TC 47 Z9 51 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 28 PY 2003 VL 42 IS 3 BP 639 EP 650 DI 10.1021/bi0204894 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 638JY UT WOS:000180568900006 PM 12534276 ER PT J AU Lu, N Hu, N Li, WJ Roth, MJ Wang, CY Su, H Wang, QH Taylor, PR Dawsey, SM AF Lu, N Hu, N Li, WJ Roth, MJ Wang, CY Su, H Wang, QH Taylor, PR Dawsey, SM TI Microsatellite alterations in esophageal dysplasia and squamous cell carcinoma from laser capture microdissected endoscopic biopsies SO CANCER LETTERS LA English DT Article DE allelic loss; esophageal cancer; precursor lesion; microdissection ID GENETIC ALTERATIONS; BARRETT-ESOPHAGUS; ALLELIC LOSS; CANCER; INSTABILITY; CHINA; PROGRESSION; EVOLUTION; LINXIAN; RISK AB Esophageal squamous cell carcinoma (ESCC), with a 5 year survival below 15%, is one of the most common fatal cancers worldwide. Significant reduction in mortality may be achieved by detecting and treating asymptomatic precursor lesions and curable early cancers. To explore this possibility and look for potential early detection markers, we examined alterations in 16 microsatellite markers in laser capture microdissected (LCM) endoscopic biopsies from the esophagus, including 15 dysplasias and 22 ESCCs, in patients from Shanxi Province, a region in north-central China. We found a significant increase in the total frequency of allelic loss with increasing disease severity. Allelic loss was seen in 2% of the markers in patients with low grade dysplasia (LGD), 15% of the markers in patients with high grade dysplasia (HGD), and 35% of the markers in patients with ESCC. Ten different markers (D3S4513, D5S2501, D8S1106, D9S118, D9S910, D13S1493, D13S894, D13S796, D15S655, and D17S1303) showed allelic loss in one or more of the premalignant lesions tested. The frequency of microsatellite instability (MSI) also increased with histological severity, from 22% in LGD to 33% in HGD and 59% in ESCC. These results indicate that the development of ESCC is associated with genetic instability, that this instability can be detected in endoscopic biopsies of recognized precursor lesions in patients without invasive cancer, and that these markers may be useful as predictive markers in the early detection of ESCC. Finally, we also report methodologic/technical modifications that enhance the use of LCM for screening endoscopic biopsies. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. Chinese Acad Med Sci, Canc Inst & Hosp, Beijing 100021, Peoples R China. Shanxi Canc Hosp & Inst, Taiyuan 030013, Shanxi, Peoples R China. Natl Vaccine & Serun Inst, Beijing 100024, Peoples R China. RP Taylor, PR (reprint author), NCI, Canc Prevent Studies Branch, 6116 Execut Blvd,Rm 705, Bethesda, MD 20892 USA. NR 28 TC 13 Z9 14 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD JAN 28 PY 2003 VL 189 IS 2 BP 137 EP 145 AR PII S0304-3835(02)00555-4 DI 10.1016/S0304-3835(02)00555-4 PG 9 WC Oncology SC Oncology GA 636BW UT WOS:000180435500003 PM 12490306 ER PT J AU Rutter, MK Parise, H Benjamin, EJ Levy, D Larson, MG Meigs, JB Nesto, RW Wilson, PWF Vasan, RS AF Rutter, MK Parise, H Benjamin, EJ Levy, D Larson, MG Meigs, JB Nesto, RW Wilson, PWF Vasan, RS TI Impact of glucose intolerance and insulin resistance on cardiac structure and function - Sex-related differences in the Framingham Heart Study SO CIRCULATION LA English DT Article DE insulin; echocardiography; ventricle, left; hypertrophy, ventricular ID LEFT-VENTRICULAR MASS; DIABETES-MELLITUS; ELDERLY MEN; HYPERTENSION; CARDIOMYOPATHY; TOLERANCE; GEOMETRY; HYPERTROPHY; OBESITY; DISEASE AB Background-Although insulin resistance has been implicated in the pathogenesis of left ventricular (LV) hypertrophy, previous studies have yielded inconsistent results and are limited by referral bias. Methods and Results-We examined the relations between echocardiographic LV measurements and glucose tolerance status in 2623 Framingham Study subjects (1514 women, mean age 53 years) free of myocardial infarction and heart failure. We also evaluated the relations of insulin resistance (homeostasis model, HOMA-IR) and LV and left atrial (LA) measures within the normal and abnormal glucose tolerance categories (the latter included impaired glucose tolerance, impaired fasting glucose, and newly diagnosed diabetes). LV mass (adjusted for age, height, heart rate, and systolic blood pressure) increased across categories of worsening glucose tolerance; the trend was more striking in women (P<0.001) compared with men (P=0.054). In subjects with normal (n=2022) and abnormal glucose tolerance (n=327), covariate-adjusted LV mass and LV wall thickness increased across HOMA-IR quartiles in women (P<0.001) but not men. In contrast, covariate-adjusted LA size increased with worsening glucose tolerance and across HOMA-IR quartiles in the normal and abnormal glucose tolerance groups in both sexes. Adjustment for body mass index considerably attenuated the relations of LV/LA measures and HOMA-IR, rendering them statistically nonsignificant in the normal glucose tolerance group. Conclusions-In our large community-based sample, LV mass and wall thickness increased with worsening glucose intolerance, an effect that was more striking in women compared with men. Insulin resistance was associated with increased LV mass in women alone, but this relation was largely accounted for by obesity. C1 Lahey Clin Fdn, Burlington, MA USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Epidemiol & Prevent Med, Boston, MA 02118 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Clin Epidemiol, Boston, MA 02215 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Cardiol, Boston, MA 02215 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NHLBI, Bethesda, MD 20892 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. OI Larson, Martin/0000-0002-9631-1254; Rutter, Martin/0000-0001-6380-539X; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [1K24 HL04334, N01-HC-25195]; NINDS NIH HHS [5R01-NS-17950] NR 26 TC 273 Z9 289 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 28 PY 2003 VL 107 IS 3 BP 448 EP 454 DI 10.1161/01.CIR.0000045671.62860.98 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 642CE UT WOS:000180786100033 PM 12551870 ER PT J AU Lakatta, EG AF Lakatta, EG TI Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises - Part III: Cellular and molecular clues to heart and arterial aging SO CIRCULATION LA English DT Article DE aging; calcium; cardiovascular diseases; endothelium; remodeling ID SMOOTH-MUSCLE CELLS; GROWTH-FACTOR EXPRESSION; INTIMA-MEDIA THICKNESS; AGE-ASSOCIATED CHANGES; GENE-EXPRESSION; RAT MYOCARDIUM; MATRIX METALLOPROTEINASE-2; FIBRONECTIN EXPRESSION; EXCITATION-CONTRACTION; COLLAGENASE ACTIVITY C1 NIA, Gerontol Res Ctr, Intramural Res Program, Lab Cardiovasc Sci,NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Gerontol Res Ctr, Intramural Res Program, Lab Cardiovasc Sci,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 83 TC 412 Z9 439 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 28 PY 2003 VL 107 IS 3 BP 490 EP 497 DI 10.1161/01.CIR.0000048894.99865.02 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 642CE UT WOS:000180786100039 PM 12551876 ER PT J AU Lenfant, C AF Lenfant, C TI The SPARK that burns me up - Response SO CIRCULATION LA English DT Letter C1 NHLBI, Bethesda, MD 20892 USA. RP Lenfant, C (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 28 PY 2003 VL 107 IS 3 BP E28 EP E28 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 642CE UT WOS:000180786100013 ER PT J AU Presciuttini, S Ciampini, F Alu, M Cerri, N Dobosz, M Domenici, R Peloso, G Pelotti, S Piccinini, A Ponzano, E Ricci, U Tagliabracci, A Baley-Wilson, JE De Stefano, F Pascali, V AF Presciuttini, S Ciampini, F Alu, M Cerri, N Dobosz, M Domenici, R Peloso, G Pelotti, S Piccinini, A Ponzano, E Ricci, U Tagliabracci, A Baley-Wilson, JE De Stefano, F Pascali, V TI Allele sharing in first-degree and unrelated pairs of individuals in the Ge.FI AmpFlSTR (R) Profiler Plus (TM) database SO FORENSIC SCIENCE INTERNATIONAL LA English DT Article DE allele sharing; Profiler Plus (TM); validation study; population structure ID TANDEM REPEAT LOCI; POPULATION AB Eleven Italian forensic laboratories participated in a population study based on the AB Profiler plus(TM) loci with proficiency testing. The validated database, including 1340 individuals, is available on-line. Tests for Hardy-Weinberg equilibrium, gametic unbalance, and heterogeneity of gene frequency were generally not significant. Gene frequencies at each locus were consistent with those of two previously published Italian studies, but different from a third. Individuals of each subsample were paired, and the total number of alleles shared across the nine loci was determined in each pair. The analysis was replicated over the total sample. In addition, two samples of mother-child pairs (N = 315) and full-sib pairs (N = 91) were subjected to allele sharing analysis. The resulting distributions were sufficiently distinct from the sample of unrelated pairs as to be of practical usefulness. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Pisa, Ctr Retrovirus, Dept Biomed, I-56127 Pisa, Italy. Univ Modena & Reggio Emilia, Dept Morphol & Forens Sci, Modena, Italy. Univ Brescia, Chair Legal Med, Brescia, Italy. Univ Sacred Heart, Inst Med Legale, I-00168 Rome, Italy. Univ Pisa, Chair Legal Med, Pisa, Italy. Univ Pavia, Dept Legal Med & Publ Hlth, I-27100 Pavia, Italy. Univ Bologna, Dept Hyg & Publ Hlth, Bologna, Italy. Univ Milan, Inst Med Legale, Milan, Italy. Univ Padua, Dept Med & Publ Hlth, Sect Legal Med, Padua, Italy. Hosp A Meyer, Ctr Med & Mol Genet, Florence, Italy. Univ Ancona, Inst Med Legale, Ancona, Italy. NHGRI, Inherited Dis Res Branch, Baltimore, MD USA. Univ Cagliari, Inst Med Legale, Cagliari, Italy. RP Presciuttini, S (reprint author), Univ Pisa, Ctr Retrovirus, Dept Biomed, SS Abetone & Brennero 2, I-56127 Pisa, Italy. RI Piccinini, Andrea/L-6533-2016; OI Piccinini, Andrea/0000-0001-8017-7065; Peloso, Gabriella/0000-0002-6601-630X; Tagliabracci, Adriano/0000-0002-4434-0475; Dobosz, Marina/0000-0003-3680-6279 NR 17 TC 15 Z9 16 U1 0 U2 5 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0379-0738 J9 FORENSIC SCI INT JI Forensic Sci.Int. PD JAN 28 PY 2003 VL 131 IS 2-3 BP 85 EP 89 AR PII S0379-0738(02)00399-7 DI 10.1016/S0379-0738(02)00399-7 PG 5 WC Medicine, Legal SC Legal Medicine GA 652LR UT WOS:000181381100001 PM 12590044 ER PT J AU Felix, K Rolink, A Melchers, F Janz, S AF Felix, K Rolink, A Melchers, F Janz, S TI Bcl-2 reduces mutant rates in a transgenic lacZ reporter gene in mouse pre-B lymphocytes SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE in vivo mutagenesis assay; shuttle vector; pUR288; ionizing radiation ID IN-VIVO MUTATIONS; POSITIVE SELECTION; HYDROGEN-PEROXIDE; COLOR MUTANTS; MICE; GLUTATHIONE; APOPTOSIS; SYSTEM; MODEL; BRAIN AB To assess mutagenesis during early B-lymphocyte development in vitro, progenitor B cells (pre-B cells) were obtained from fetal livers of BALB/c mice and DBA/2N mice that harbored the transgenic shuttle vector, pUR288, with a lacZ reporter gene for the determination of mutant frequencies (MFs). Differentiation-arrested pre-B cells demonstrated a marked dose-dependent increase in lacZ mutant levels after exposure to gamma-irradiation with a peak MF of 250 x 10(-5) at 2.5 Gy. Without genotoxic treatment, pre-B cells undergoing spontaneous differentiation into surface IgM expressing immature B cells exhibited lacZ mutant levels of up to 95 x 10(-5). The mutational pattern was dominated in both experiments by illegitimate recombination mutations of lacZ, not point mutations. Likewise, in both experiments, the enforced expression of Bcl-2 resulted in a striking reduction of lacZ mutations. These findings indicated that mouse pre-B cells are prone to accumulate induced and self-inflicted mutations, particularly recombinations. Additionally, our studies revealed a heretofore unknown role of Bcl-2 in inhibiting mutagenesis during early B-cell development in mice. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NCI, Genet Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Basel Inst Immunol, Basel, Switzerland. RP Janz, S (reprint author), NCI, Genet Lab, Ctr Canc Res, NIH, Room 2B10,Bldg 37, Bethesda, MD 20892 USA. NR 41 TC 3 Z9 4 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 JAN 28 PY 2003 VL 522 IS 1-2 BP 135 EP 144 AR PII S0027-5107(02)00309-3 DI 10.1016/S0027-5107(02)00309-3 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 642BR UT WOS:000180784900015 PM 12517419 ER PT J AU Hirtz, D Berg, A Bettis, D Camfield, C Camfield, P Crumrine, P Gaillard, WD Schneider, S Shinnar, S AF Hirtz, D Berg, A Bettis, D Camfield, C Camfield, P Crumrine, P Gaillard, WD Schneider, S Shinnar, S TI Practice parameter: Treatment of the child with a first unprovoked seizure - Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society SO NEUROLOGY LA English DT Article ID TONIC-CLONIC SEIZURE; EXTENDED FOLLOW-UP; SODIUM VALPROATE; ANTIEPILEPTIC DRUGS; DEVELOPING BRAIN; PSYCHOMOTOR PERFORMANCE; RECURRENT SEIZURES; STATUS EPILEPTICUS; EPILEPSY; CARBAMAZEPINE AB The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society develop practice parameters as strategies for patient management based on analysis of evidence regarding risks and benefits. This parameter reviews published literature relevant to the decision to begin treatment after a child or adolescent experiences a first unprovoked seizure and presents evidence-based practice recommendations. Reasons why treatment may be considered are discussed. Evidence is reviewed concerning risk of recurrence as well as effect of treatment on prevention of recurrence and development of chronic epilepsy. Studies of side effects of anticonvulsants commonly used to treat seizures in children are also reviewed. Relevant articles are classified according to the Quality Standards Subcommittee classification scheme. Treatment after a first unprovoked seizure appears to decrease the risk of a second seizure, but there are few data from studies involving only children. There appears to be no benefit of treatment with regard to the prognosis for long-term seizure remission. Antiepileptic drugs (AED) carry risks of side effects that are particularly important in children. The decision as to whether or not to treat children and adolescents who have experienced a first unprovoked seizure must be based on a risk-benefit assessment that weighs the risk of having another seizure against the risk of chronic AED therapy. The decision should be individualized and take into account both medical issues and patient and family preference. C1 NINDS, NIH, Bethesda, MD USA. No Illinois Univ, Dept Biol Sci, Boise, ID USA. IWK Hlth Ctr, Dept Pediat Neurol, Halifax, NS, Canada. Childrens Hosp Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. Childrens Natl Med Ctr, Riverside, CA USA. No Illinois Univ, Dept Biol Sci, De Kalb, IL 60115 USA. Albert Einstein Coll Med, Dept Neurol, Montefiore Med Ctr, New York, NY USA. Albert Einstein Coll Med, Dept Pediat, Montefiore Med Ctr, New York, NY USA. RP Hirtz, D (reprint author), Amer Acad Neurol, 1080 Montreal Ave, St Paul, MN 55116 USA. NR 66 TC 83 Z9 88 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 28 PY 2003 VL 60 IS 2 BP 166 EP 175 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 639ET UT WOS:000180615200003 PM 12552027 ER PT J AU Bian, J Oddone, EZ Samsa, GP Lipscomb, J Matchar, DB AF Bian, J Oddone, EZ Samsa, GP Lipscomb, J Matchar, DB TI Racial differences in survival post cerebral infarction among the elderly SO NEUROLOGY LA English DT Article ID STROKE; BLACKS; POPULATION; WHITES AB Objective: To investigate whether there are differences in poststroke survival between African American and white patients, aged 65 and over, in the United States. Methods: A biracial cohort of patients was selected from a random 20% national sample of Medicare patients (age 65 and over) hospitalized with cerebral infarction in 1991, and was followed up to a period of 3 years. The Cox regression model was used for covariate adjustment. Results: A total of 47,045 patients (including 5,324 African Americans) were identified for our analysis. Compared to white patients, African American patients on average were 6% more likely to die post cerebral infarction. The subpopulation analyses further suggest that African Americans age 65 to 74 had much lower 3-year survival probabilities (15 to 20%) than their white counterparts. Conclusions: The authors find evidence of racial disparities in survival post cerebral infarction among the elderly, although the differences by race are not as great as reported elsewhere for stroke incidence and mortality. Future analyses, using more clinically detailed data, should focus especially on whether survival differences by race persist in the young-old (age 65 to 74) population. C1 Univ N Carolina, Dept Hlth Policy & Adm, Chapel Hill, NC USA. Duke Univ, Dept Med, Durham, NC USA. Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA. Vet Affairs Med Ctr, Durham, NC USA. NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Samsa, GP (reprint author), Duke Univ, Med Ctr, Ctr Clin Hlth Policy Res, 2200 W Main St,Suite 220, Durham, NC 27705 USA. OI Matchar, David/0000-0003-3020-2108 FU AHRQ HHS [HS 290-91-0028] NR 20 TC 19 Z9 19 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 28 PY 2003 VL 60 IS 2 BP 285 EP 290 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 639ET UT WOS:000180615200024 PM 12552046 ER PT J AU Colaizzo-Anas, T Aplan, PD AF Colaizzo-Anas, T Aplan, PD TI Cloning and characterization of the SIL promoter SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE T cell ALL; chromosomal translocation; immediate early response gene; SIL transcription; midline defect; SIL sequence ID ACUTE LYMPHOBLASTIC-LEUKEMIA; SCL GENE-PRODUCT; T-CELL LEUKEMIA; DNA METHYLATION; DIFFERENTIATION; EXPRESSION; LOCUS AB The SIL gene undergoes a site-specific rearrangement with the SCL gene in 25% of patients with T cell acute lymphoblastic leukemia (ALL). The functional result of this rearrangement is that the SIL regulatory elements aberrantly drive expression of the SCL gene. We have cloned and sequenced the human SIL promoter, cloned a murine homolog, found the sequence to be highly conserved, and defined a minimal promoter region. Both the cloned murine and human sequences were found to be highly active in either human or murine cells. SCL mRNA, driven by a cloned SIL promoter, could be downregulated by DMSO in stably transfected F4-6 murine erythroleukemia cells. The SIL promoter was found to be partially unmethylated in proliferating tissues, in which it is highly expressed, and more highly methylated in post-mitotic tissues, in which SIL is not expressed. The isolation of the SIL promoter provides an important tool for the study of both the SIL gene expression as well as the role of the SIL promoter in leukemogenesis. Published by Elsevier Science B.V. C1 SUNY Coll Buffalo, Buffalo, NY 14222 USA. Natl Canc Inst, Ctr Canc Res, Genet Branch, Gaithersburg, MD USA. RP SUNY Coll Buffalo, 210 Caudell Hall, Buffalo, NY 14222 USA. EM tcolaizzo@aol.com RI Aplan, Peter/K-9064-2016 NR 23 TC 4 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD JAN 27 PY 2003 VL 1625 IS 2 BP 207 EP 213 DI 10.1016/S0167-4781(02)00597-3 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 640MN UT WOS:000180692700011 PM 12531481 ER PT J AU Ho, GYF Melman, A Liu, SM Li, M Yu, H Negassa, A Burk, R Hsing, AW Ghavamian, R Chua, SC AF Ho, GYF Melman, A Liu, SM Li, M Yu, H Negassa, A Burk, R Hsing, AW Ghavamian, R Chua, SC TI Polymorphism of the insulin gene is associated with increased prostate cancer risk SO BRITISH JOURNAL OF CANCER LA English DT Article DE prostate cancer; insulin; polymorphism ID GROWTH-FACTOR-I; HORMONE-BINDING GLOBULIN; BREAST-CANCER; DIABETES SUSCEPTIBILITY; LINKAGE DISEQUILIBRIUM; COLORECTAL-CANCER; FASTING INSULIN; SERUM LEVELS; C-PEPTIDE; WEIGHT AB High insulin levels are linked with increased cancer risk, including prostate cancer. We examined the associations between prostate cancer with polymorphisms of the insulin gene (INS) and its neighbouring genes, tyrosine-hydroxylase and IGF-II (TH and IGF2). In this study, 126 case-control pairs matched on age, race, and countries of origin were genotyped for +1127 INS-Pstl in INS, -4217 TH-Pstl in TH, and +3580 IGF2-Mspl in IGF2. The homozygous CC genotype of +1127 INS-Pstl occurred in over 60% of the population. It was associated with an increased risk of prostate cancer in nondiabetic Blacks and Caucasians (OR = 3.14, P = 0.008). The CC genotype was also associated with a low Gleason score <7 (OR=2.60, P=0.022) and a late age of diagnosis (OR=2.10, P=0.046). Markers in the neighbouring genes of INS showed only null to modest associations with prostate cancer. The polymorphism of INS may play a role in the aetiology of prostate cancer. Given the high prevalence of the CC genotype and its association with late age of onset of low-grade tumours, this polymorphism may contribute to the unique characteristics of prostate cancer, namely a high prevalence of indolent cancers and the dramatic increase in incidence with age. (C) 2003 Cancer Research UK. C1 Yeshiva Univ Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Urol, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10461 USA. Columbia Univ, Dept Pediat, Div Mol Genet, New York, NY 10032 USA. Yale Univ, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Ho, GYF (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Epidemiol & Social Med, 1300 Morris Pk Ave,Belfer Bldg,Room 1312, Bronx, NY 10461 USA. FU NCI NIH HHS [P30 CA13330, P30 CA013330, R01 CA064247, R01 CA64247]; NCRR NIH HHS [M01 RR012248, RR-12248] NR 47 TC 41 Z9 45 U1 0 U2 1 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 JAN 27 PY 2003 VL 88 IS 2 BP 263 EP 269 DI 10.1038/sj.bjc.6600747 PG 7 WC Oncology SC Oncology GA 651ZU UT WOS:000181354700017 PM 12610512 ER PT J AU Cannon, MJ Dollard, SC Black, JB Edlin, BR Hannah, C Hogan, SE Patel, MM Jaffe, HW Offermann, MK Spira, TJ Pellett, PE Gunthel, CJ AF Cannon, MJ Dollard, SC Black, JB Edlin, BR Hannah, C Hogan, SE Patel, MM Jaffe, HW Offermann, MK Spira, TJ Pellett, PE Gunthel, CJ TI Risk factors for Kaposi's sarcoma in men seropositive for both human herpesvirus 8 and human immunodeficiency virus SO AIDS LA English DT Article DE Kaposi's sarcoma; herpesvirus; epidemiology; opportunistic infections; risk factors; homosexual men ID HUMAN-HERPESVIRUS-8 DNA; PERIPHERAL-BLOOD; SEROLOGIC ASSAYS; INFECTION; ANTIBODIES; TYPE-1; SEROCONVERSION; INDIVIDUALS; SEQUENCES AB Objective: To identify risk factors for Kaposi's sarcoma (KS) among men seropositive for both human herpesvirus 8 (HHV-8) and HIV. Design: Cross-sectional study of 91 HHV-8 seropositive, HIV seropositive men who have sex with men (57 with KS), and 70 controls at lower risk for KS. Methods: Patients received clinical evaluations. Blood, oral fluids, semen, rectal brush, rectal swab, and urine were collected, and tests for HHV-8 were performed. Results: Men with KS were more likely to have HHV-8 DNA in peripheral blood mononuclear cells (PBMC) than men without KS [35.1 versus 5.9%, odds ratio (OR), 8.6, 95% confidence interval (CI), 1.9-39.9]. The prevalence of HHV-8 DNA in oral fluids was similar for the two groups (37.0 versus 32.4%; OR, 1.2; 95% CI, 0.5-3.0). HHV-8 DNA was rarely detected in specimens of other types from these men, or in any specimens from the 70 controls. Among men with KS, HHV-8 DNA in PBMC was associated with new KS lesions (OR, 4.5; 95% CI, 1.4-14.5), and HHV-8 DNA in oral fluids was associated with oropharyngeal KS lesions (OR, 3.1; 95% CI, 1.0-10.1). Men with high HHV-8 antibody titers were more likely to have KS (OR, 9.6; 95% CI, 1.2-78.2), but were less likely to have new KS lesions (OR, 0.2; 95% CI, 0.0-1.1) or HHV-8 DNA in PBMC (OR, 0.2; 95% CI, 0.0-1.6) or oral fluids (OR, undefined; P=0.001). Conclusions: In HHV-8- and HIV-seropositive men, HHV-8 DNA is associated with KS. Among men without KS, HHV-8 DNA is most commonly found in oral fluids. High HHV-8 antibody titers may protect against circulating HHV-8 and new KS lesions. (C) 2003 Lippincott Williams Wilkins. C1 Emory Univ, Atlanta, GA 30322 USA. Ctr Dis Control & Prevent CDC, Atlanta, GA USA. NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. DeKalb Cty Board Hlth, STD Clin Cent Hlth Ctr, Atlanta, GA USA. RP Cannon, MJ (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd,Mailstop A-15, Atlanta, GA 30333 USA. RI Cannon, Michael/E-5894-2011; OI Cannon, Michael/0000-0001-5776-5010; Edlin, Brian/0000-0001-8172-8797 NR 30 TC 63 Z9 65 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JAN 24 PY 2003 VL 17 IS 2 BP 215 EP 222 DI 10.1097/01.aids.0000042943.55529.48 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 643HN UT WOS:000180856000010 PM 12545082 ER PT J AU Bonifacino, JS Jackson, CL AF Bonifacino, JS Jackson, CL TI Endosome-specific localization and function of the ARF activator GNOM SO CELL LA English DT Article ID NUCLEOTIDE EXCHANGE FACTOR; MDCK CELLS; COMPLEX; BIG2 AB ARF GTPases act at multiple steps of the secretory and vacuolar/lysosomal trafficking pathways, but little is known about the spatial regulation of ARF activation. In this issue of Cell, Geldner et al. demonstrate that the Arabidopsis ARF activator GNOM localizes to endosomes where it controls the polarized trafficking of the auxin efflux carrier PIN1 to the basal plasma membrane. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RI Jackson, Catherine/A-3421-2013; OI Jackson, Catherine/0000-0002-0843-145X; Bonifacino, Juan S./0000-0002-5673-6370 NR 10 TC 18 Z9 18 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JAN 24 PY 2003 VL 112 IS 2 BP 141 EP 142 DI 10.1016/S0092-8674(03)00038-2 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 649DL UT WOS:000181191600001 PM 12553900 ER PT J AU Epstein, ND Davis, JS AF Epstein, ND Davis, JS TI Sensing stretch is fundamental SO CELL LA English DT Review ID DILATED CARDIOMYOPATHY; SKELETAL-MUSCLE; TITIN; CALCIUM; PROTEIN AB Stretch induces changes in cardiomyocyte biology that are implicated in heart failure, but the mechanism by which stretch is sensed and signals are transduced is unknown. New understanding of the Z disc elements of contractile units are beginning to elucidate the mechanism of stretch sensing and its relation to cardiac adaptation and disease. C1 NHLBI, Mol Physiol Sect, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Epstein, ND (reprint author), NHLBI, Mol Physiol Sect, Mol Cardiol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 20 TC 67 Z9 68 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JAN 24 PY 2003 VL 112 IS 2 BP 147 EP 150 DI 10.1016/S0092-8674(03)00037-0 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 649DL UT WOS:000181191600004 PM 12553903 ER PT J AU Egan, MF Kojima, M Callicott, JH Goldberg, TE Kolachana, BS Bertolino, A Zaitsev, E Gold, B Goldman, D Dean, M Lu, B Weinberger, DR AF Egan, MF Kojima, M Callicott, JH Goldberg, TE Kolachana, BS Bertolino, A Zaitsev, E Gold, B Goldman, D Dean, M Lu, B Weinberger, DR TI The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function SO CELL LA English DT Article ID LONG-TERM POTENTIATION; HIGH-FREQUENCY STIMULATION; N-ACETYL ASPARTATE; NEUROTROPHIC FACTOR; SYNAPTIC TRANSMISSION; ALZHEIMERS-DISEASE; WORKING-MEMORY; RELATIVE RISK; KNOCKOUT MICE; SCHIZOPHRENIA AB Brain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity and hippocampal-dependent memory in cell models and in animals. We examined the effects of a valine (val) to methionine (met) substitution in the 5' pro-region of the human BDNF protein. In human subjects, the met allele was associated with poorer episodic memory, abnormal hippocampal activation assayed with fMRI, and lower hippocampal n-acetyl aspartate (NAA), assayed with MRI spectroscopy. Neurons transfected with met-BDNF-GFP showed lower depolarization-induced secretion, while constitutive secretion was unchanged. Furthermore, met-BDNF-GFP failed to localize to secretory granules or synapses. These results demonstrate a role for BDNF C1 NICHHD, Sect Neural Dev & Plast, NIH, DHHS, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, Rockville, MD 20857 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Natl Inst AIST, Cell Dynam Res Grp, Osaka 5638577, Japan. Japan Sci & Technol Corp, CREST, Kawaguchi 3320012, Japan. RP Lu, B (reprint author), NICHHD, Sect Neural Dev & Plast, NIH, DHHS, Bldg 49-6A67, Bethesda, MD 20892 USA. RI Lu, Bai/A-4018-2012; Dean, Michael/G-8172-2012; Callicott, Joseph/C-9102-2009; Goldman, David/F-9772-2010 OI Dean, Michael/0000-0003-2234-0631; Callicott, Joseph/0000-0003-1298-3334; Goldman, David/0000-0002-1724-5405 NR 52 TC 1915 Z9 1993 U1 13 U2 155 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JAN 24 PY 2003 VL 112 IS 2 BP 257 EP 269 DI 10.1016/S0092-8674(03)00035-7 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 649DL UT WOS:000181191600014 PM 12553913 ER PT J AU Freebern, WJ Smith, JL Chaudhry, SS Haggerty, CM Gardner, K AF Freebern, WJ Smith, JL Chaudhry, SS Haggerty, CM Gardner, K TI Novel cell-specific and dominant negative anti-apoptotic roles of p73 in transformed leukemia cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN BLADDER-CANCER; P53-RELATED PROTEIN; MUTATION ANALYSIS; SPLICE VARIANTS; GENE-EXPRESSION; LUNG-CANCER; MDM2 GENE; P53; VIRUS; OVEREXPRESSION AB Although extensive homology exists between related genes p53 and p 73, recent data suggest that the family members have divergent roles. We demonstrate that the differential regulatory roles of p53 family member p73 are highly cell-context and promoter-specific. Full-length p73 expressed in the transformed leukemia cell line Jurkat behaves as a specific dominant negative transcriptional repressor of the cell cycle inhibitor gene p21 and blocks p53-mediated apoptosis. These findings provide evidence for a new mechanism in oncogenesis through which the functional properties of p73 can be altered in an inheritable and cell-specific fashion independent of transcriptional coding. C1 NCI, Lab Receptor Biol & Gene Express, Adv Technol Ctr, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Howard Univ, Dept Microbiol, Washington, DC 20001 USA. RP Gardner, K (reprint author), NCI, Lab Receptor Biol & Gene Express, Adv Technol Ctr, NIH, Rm 134C,8717 Grovemont Circle, Bethesda, MD 20892 USA. NR 52 TC 11 Z9 12 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 JAN 24 PY 2003 VL 278 IS 4 BP 2249 EP 2255 DI 10.1074/jbc.M208517200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 638FY UT WOS:000180562000025 PM 12427762 ER PT J AU Xiong, HB Zhu, C Li, HX Chen, F Mayer, L Ozato, K Unkeless, JC Plevy, SE AF Xiong, HB Zhu, C Li, HX Chen, F Mayer, L Ozato, K Unkeless, JC Plevy, SE TI Complex formation of the interferon (IFN) consensus sequence-binding protein with IRF-1 is essential for murine macrophage IFN-gamma-induced iNOS gene expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NITRIC-OXIDE SYNTHASE; MOUSE PERITONEAL-MACROPHAGES; REGULATORY FACTOR FAMILY; TRANSCRIPTION FACTOR; ANTIMICROBIAL ACTIVITY; REACTIVE OXYGEN; FACTOR PU.1; KAPPA-B; ACTIVATION; INDUCTION AB This study describes the role of the interferon (IFN) consensus sequence-binding protein (ICSBP or IRF-8) in iNOS gene expression by murine macrophages. An ICSBP binding site in the iNOS promoter region (-923 to -913) was identified using an electrophoretic mobility shift assay and chromatin co-immunoprecipitation. Overexpression of ICSBP greatly enhanced IFN-gamma-induced iNOS promoter activation in RAW264.7 cells, and IFN-gamma-induced iNOS promoter activation was abolished in ICSBP-/- macrophages. Furthermore, transduction of retrovirus-ICSBP in ICSBP-/- macrophages rescued IFN-gamma-induced iNOS gene expression. However, transduction of retrovirus-ICSBP in the absence of IFN-/- activation did not induce iNOS expression in either RAW264.7 cells or ICSBP-/- macrophages. Interestingly, ICSBP alone transduced into ICSBP-/- macrophages did not bind to IFN-stimulated response element site (-923 to -913) of the iNOS promoter region, although following activation with IFN-gamma, a DNA(.)protein complex was formed that contains ICSBP and IRF-1. Co-transduction of ICSBP with IRF-1 clearly induces nitric oxide production. In addition, interleukin-4 inhibits IFN-gamma-induced iNOS gene expression by attenuating the physical interaction of ICSBP with IRF-1. Complex formation of ICSBP with IRF-1 is essential for iNOS expression, and interleulkin-4 attenuates the physical interaction of ICSBP with IRF-1 resulting in the inhibition of INOS gene expression. C1 Mt Sinai Sch Med, Immunobiol Ctr, New York, NY 10029 USA. Mt Sinai Sch Med, Dept Pediat, New York, NY 10029 USA. NICHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15261 USA. RP Xiong, HB (reprint author), Mt Sinai Sch Med, Immunobiol Ctr, Box 1630,1 Gustave L Levy Pl, New York, NY 10029 USA. NR 53 TC 49 Z9 49 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 24 PY 2003 VL 278 IS 4 BP 2271 EP 2277 DI 10.1074/jbc.M209583200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 638FY UT WOS:000180562000028 PM 12429737 ER PT J AU Lambert, G Amar, MJA Guo, G Brewer, HB Gonzalez, FJ Sinal, CJ AF Lambert, G Amar, MJA Guo, G Brewer, HB Gonzalez, FJ Sinal, CJ TI The farnesoid X-receptor is an essential regulator of cholesterol homeostasis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DENSITY-LIPOPROTEIN RECEPTOR; BILE-ACID; NUCLEAR RECEPTOR; TRANSGENIC MICE; TARGETED DISRUPTION; SELECTIVE UPTAKE; UP-REGULATION; PROTEIN GENE; LXR-ALPHA; IN-VIVO AB To address the importance of the farnesoid X-receptor (FXR; NR1H4) for normall. cholesterol homeostasis, we evaluated the major pathways of cholesterol metabolism in the FXR-deficient (-/-) mouse model. Compared with wild-type, FXR(-/-) mice have increased plasma high density lipoprotein (HDL cholesterol and a markedly reduced rate of plasma HDL cholesterol ester clearance. Concomitantly, FXR(-/-) mice exhibit reduced expression of hepatic genes involved in reverse cholesterol transport, most notably, that for scavenger receptor BI. FXR(-/-) mice also have increased: W plasma non-HDL cholesterol and triglyceride levels, (ii) apolipoprotein B-containing lipoprotein synthesis, and (iii) intestinal cholesterol absorption. Surprisingly, biliary cholesterol elimination was increased in FXR(-/-) mice, despite decreased expression of hepatic genes thought to be involved in this process. These data demonstrate that FXR is a critical regulator, of normal cholesterol metabolism and that genetic changes affecting FXR function have the potential to be pro-atherogenic. C1 Dalhousie Univ, Dept Pharmacol, Halifax, NS B3H 4H7, Canada. NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Sinal, CJ (reprint author), Dalhousie Univ, Dept Pharmacol, Sir Charles Tupper Med Bldg,5859 Univ Ave, Halifax, NS B3H 4H7, Canada. NR 54 TC 186 Z9 195 U1 1 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 24 PY 2003 VL 278 IS 4 BP 2563 EP 2570 DI 10.1074/jbc.M209525200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 638FY UT WOS:000180562000066 PM 12421815 ER PT J AU D'Sa, RA Wang, YH Ruane, PH Showalter, BM Saavedra, JE Davies, KM Citro, ML Booth, MN Keefer, LK Toscano, JP AF D'Sa, RA Wang, YH Ruane, PH Showalter, BM Saavedra, JE Davies, KM Citro, ML Booth, MN Keefer, LK Toscano, JP TI Preparation and reactivity of O-2-sulfonated diazeniumdiolates SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID FACILE; OXIDE AB We report the facile preparation of O-2-sulfonated diazeniumdiolates and mechanistic investigation of their reactions with representative nucleophiles. This new class of compounds extends the range of O-2-substituted diazeniumdiolates available for potential applications in research and medicine. C1 Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. George Mason Univ, Dept Chem, Fairfax, VA 22030 USA. NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA. RP Toscano, JP (reprint author), Johns Hopkins Univ, Dept Chem, 3400 N Charles St, Baltimore, MD 21218 USA. EM jtoscano@jhu.edu RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU NCI NIH HHS [N01-CO12400]; NIGMS NIH HHS [R01 GM58109] NR 12 TC 2 Z9 2 U1 0 U2 2 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 JAN 24 PY 2003 VL 68 IS 2 BP 656 EP 657 DI 10.1021/jo026656n PG 2 WC Chemistry, Organic SC Chemistry GA 637YC UT WOS:000180540500066 PM 12530906 ER PT J AU Acar, C Mears, A Yashar, B Maheshwary, A Andreasson, S Baldi, A Sieving, P Iannaccone, A Musarella, M Jacobson, S Swaroop, A AF Acar, C Mears, A Yashar, B Maheshwary, A Andreasson, S Baldi, A Sieving, P Iannaccone, A Musarella, M Jacobson, S Swaroop, A TI Mutation screening of patients with Leber congenital amaurosis or the enhanced S-cone syndrome reveals a lack of sequence variations in the NRL gene SO MOLECULAR VISION LA English DT Article ID TRANSCRIPTION-FACTOR GENE; RETINAL DEGENERATION; RETINITIS-PIGMENTOSA; LEUCINE-ZIPPER; ROD DYSTROPHY; HOMEOBOX GENE; FACTOR CRX; PHOTORECEPTOR; HOMEODOMAIN; INVOLVEMENT AB Purpose: To determine if mutations in the retinal transcription factor gene NRL are associated with retinopathies other than autosomal dominant retinitis pigmentosa (adRP). Methods: Genomic DNA was isolated from blood samples obtained from 50 patients with Leber Congenital Amaurosis (LCA), 17 patients with the Enhanced S-Cone Syndrome (ESCS), and a patient with an atypical retinal degeneration that causes photoreceptor rosettes with blue cone opsin. The 5' upstream region (putative promoter), untranslated exon 1, coding exons 2 and 3, and exon-intron boundaries of the NRL gene were analyzed by direct sequencing of the PCR-amplified products. Results: Complete sequencing of the NRL gene in DNA samples from this cohort of patients revealed only one nucleotide change. The C->G transversion at nucleotide 711 of NRL exon 3 was detected in one LCA patient; however, this change did not alter the amino acid (L237L). Conclusions: No potential disease causing mutation was identified in the NRL gene in patients with LCA, ESCS, or the atypical retinal degeneration. Together with previous studies, our results demonstrate that mutations in the NRL gene are not a major cause of retinopathy. To date, only missense changes have been reported in adRP patients, and sequence variations are rare. It is possible that the loss of NRL function in humans is associated with a more complex clinical phenotype due to its expression in pineal gland in addition to rod photoreceptors. C1 Univ Michigan, WK Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. Univ Michigan, Dept Human Genet, Ann Arbor, MI 48105 USA. Univ Hacettepe, Dept Biol, TR-06100 Ankara, Turkey. Lund Univ, Dept Ophthalmol, Lund, Sweden. Univ Naples 2, Dept Biochem, Sect Mol Pathol, Naples, Italy. NEI, Bethesda, MD 20892 USA. Univ Tennessee, Ctr Hlth Sci, Dept Ophthalmol, Memphis, TN 38163 USA. SUNY Downstate Med Ctr, Dept Ophthalmol, Brooklyn, NY 11203 USA. Univ Penn, Scheie Eye Inst, Philadelphia, PA 19104 USA. RP Swaroop, A (reprint author), Univ Michigan, WK Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, 1000 Wall St, Ann Arbor, MI 48105 USA. RI Acar, Ceren/B-5758-2008; OI Baldi, Alfonso/0000-0002-8693-3842; Swaroop, Anand/0000-0002-1975-1141 FU NEI NIH HHS [EY13729, EY11115, EY13385] NR 29 TC 5 Z9 5 U1 0 U2 0 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 JAN 24 PY 2003 VL 9 IS 3-4 BP 14 EP 17 PG 4 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 640BB UT WOS:000180665100001 PM 12552256 ER PT J AU Poremba, A Saunders, RC Crane, AM Cook, M Sokoloff, L Mishkin, M AF Poremba, A Saunders, RC Crane, AM Cook, M Sokoloff, L Mishkin, M TI Functional mapping of the primate auditory system SO SCIENCE LA English DT Article ID CEREBRAL GLUCOSE-UTILIZATION; PREFRONTAL CORTEX; COMPLEX SOUNDS; MACAQUE; MONKEYS; AREA; ORGANIZATION; LOCALIZATION; AFFERENTS; PATHWAYS AB Cerebral auditory areas were delineated in the awake, passively listening, rhesus monkey by comparing the rates of glucose utilization in an intact hemisphere and in an acoustically isolated contralateral hemisphere of the same animal. The auditory system defined in this way occupied large portions of cerebral tissue, an extent probably second only to that of the visual system. Cortically, the activated areas included the entire superior temporal gyrus and large portions of the parietal, prefrontal, and limbic lobes. Several auditory areas overlapped with previously identified visual areas, suggesting that the auditory system, like the visual system, contains separate pathways for processing stimulus quality, location, and motion. C1 Univ Iowa, Dept Psychol, Iowa City, IA 52242 USA. Univ Iowa, Neurosci Program, Iowa City, IA 52242 USA. NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. Univ Texas, Ctr Perceptual Syst, Austin, TX 78712 USA. NIMH, Cerebral Metab Lab, Bethesda, MD 20892 USA. RP Poremba, A (reprint author), Univ Iowa, Dept Psychol, Iowa City, IA 52242 USA. NR 45 TC 144 Z9 145 U1 3 U2 13 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 24 PY 2003 VL 299 IS 5606 BP 568 EP 572 DI 10.1126/science.1078900 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 638EZ UT WOS:000180559800051 PM 12543977 ER PT J AU Tang, Y Katuri, V Dillner, A Mishra, B Deng, CX Mishra, L AF Tang, Y Katuri, V Dillner, A Mishra, B Deng, CX Mishra, L TI Disruption of transforming growth factor-beta signaling in ELF beta-spectrin-deficient mice SO SCIENCE LA English DT Article ID TGF-BETA; LIVER DEVELOPMENT; EPITHELIAL-CELLS; SMAD PROTEINS; PATHWAY; CANCER AB Disruption of the adaptor protein ELF, a beta-spectrin, leads to disruption of transforming growth factor-beta (TGF-beta) signaling by Smad proteins in mice. Elf(-/-) mice exhibit a phenotype similar to smad2(+/-)/smad3(+/-) mutant mice of midgestational death due to gastrointestinal, liver, neural, and heart defects. We show that TGF-beta triggers phosphorylation and association of ELF with Smad3 and Smad4, followed by nuclear translocation. ELF deficiency results in mislocalization of Smad3 and Smad4 and loss of the TGF-beta-dependent transcriptional response, which could be rescued by overexpression of the COOH-terminal region of ELF. This study reveals an unexpected molecular link between a major dynamic scaffolding protein and a key signaling pathway. C1 NIDDKD, Genet Dev & Dis Branch, NIH, US Dept HHS, Bethesda, MD 20878 USA. Georgetown Univ, Dept Med, Dev Biol Lab, Washington, DC 20007 USA. Dept Vet Affairs, Washington, DC 20422 USA. Temple Univ, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19140 USA. RP Mishra, B (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, US Dept HHS, Bethesda, MD 20878 USA. RI deng, chuxia/N-6713-2016 FU NIDDK NIH HHS [R01 DK56111, R01 DK58637, R03 DK53861] NR 22 TC 161 Z9 169 U1 0 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 JAN 24 PY 2003 VL 299 IS 5606 BP 574 EP 577 DI 10.1126/science.1075994 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 638EZ UT WOS:000180559800053 PM 12543979 ER PT J AU Felsenfeld, G Groudine, M AF Felsenfeld, G Groudine, M TI Controlling the double helix SO NATURE LA English DT Article ID NUCLEAR ARCHITECTURE; ORDERED RECRUITMENT; NUCLEOSOME CORE; HISTONE H3; LYSINE 9; CHROMATIN; TRANSCRIPTION; METHYLATION; EXPRESSION; PROTEINS AB Chromatin is the complex of DNA and proteins in which the genetic material is packaged inside the cells of organisms with nuclei. Chromatin structure is dynamic and exerts profound control over gene expression and other fundamental cellular processes. Changes in its structure can be inherited by the next generation, independent of the DNA sequence itself. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98109 USA. Univ Washington, Sch Med, Dept Radiat Oncol, Seattle, WA 98195 USA. RP Felsenfeld, G (reprint author), NIDDKD, Mol Biol Lab, NIH, Bldg 5,Room 212, Bethesda, MD 20892 USA. NR 51 TC 657 Z9 677 U1 7 U2 79 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 23 PY 2003 VL 421 IS 6921 BP 448 EP 453 DI 10.1038/nature01411 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 637UW UT WOS:000180533000062 PM 12540921 ER PT J AU Hirshberg, B Conn, PM Uwaifo, GI Blauer, KL Clark, BD Nieman, LK AF Hirshberg, B Conn, PM Uwaifo, GI Blauer, KL Clark, BD Nieman, LK TI Ectopic luteinizing hormone secretion and anovulation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HUMAN CHORIONIC-GONADOTROPIN; CARCINOMA; CHILDHOOD; CANCER; HCG C1 NIDDKD, Transplantat & Autoimmun Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Oregon Hlth & Sci Univ, Beaverton, OR USA. Genet & IVF Inst, Fairfax, VA USA. RP Nieman, LK (reprint author), Bldg 10,Rm 9D42,10 Ctr Dr,MSC 1583, Bethesda, MD 20892 USA. RI Uwaifo, Gabriel/M-2361-2016 OI Uwaifo, Gabriel/0000-0002-6962-9304 FU NCRR NIH HHS [RR-00163]; NICHD NIH HHS [HD-19899] NR 27 TC 8 Z9 9 U1 0 U2 4 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JAN 23 PY 2003 VL 348 IS 4 BP 312 EP 317 DI 10.1056/NEJMoa022384 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 637JD UT WOS:000180507200006 PM 12540644 ER PT J AU Nagashima, M Shiseki, M Pedeux, RM Okamura, S Kitahama-Shiseki, M Miura, K Yokota, J Harris, CC AF Nagashima, M Shiseki, M Pedeux, RM Okamura, S Kitahama-Shiseki, M Miura, K Yokota, J Harris, CC TI A novel PHD-finger motif protein, p47ING3, modulates p53-mediated transcription, cell cycle control, and apoptosis SO ONCOGENE LA English DT Article DE PHD-finger motif; ING1; ING3; p53 ID CANDIDATE TUMOR-SUPPRESSOR; DNA-DAMAGE; ALTERNATIVE TRANSCRIPTS; P53; P33(ING1); GENE; ACETYLATION; EXPRESSION; MUTATIONS; BINDING AB A candidate tumor suppressor gene, p33ING1, was previously identified by using the genetic suppressor element methodology. p33ING1 cooperates with p53 and plays a significant role in p53-mediated cellular processes. Recently, we have identified p33ING2, which shows a sequence homology similar to p33ING1 and modulates p53 function. In the present study, we identified and characterized another 'ING family' gene. The estimated molecular weight of the encoded protein is 46.8 kDa, thus, we named it p47ING3. The p47ING3 gene is located at chromosome 7q31.3 and consists of 12 exons that encode 418 amino acids. A computational domain search revealed a C-terminal PHD-finger motif. Such motifs are common in proteins involved in chromatin remodeling. p47ING3 is highly expressed in some normal human tissues or organs, including the spleen, testis, skeletal muscle, and heart. p47ING3 expression levels varied among cancer cell lines. p47ING3 overexpression resulted in a decreased population of cells in S phase, a diminished colony-forming efficiency, and induced apoptosis in RKO cells, but not in RKO-E6 cells with inactivated p53. p47ING3 activates p53-transactivated promoters, including promoters of p21/waf1 and bax. Thus, we have isolated a novel ING family gene, p47ING3, which modulates p53-mediated transcription, cell cycle control, and apoptosis. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Natl Canc Ctr, Res Inst, Div Biol, Chuo Ku, Tokyo 104, Japan. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, 37 Convent Dr,Bldg 37,Rm 2C05, Bethesda, MD 20892 USA. OI Miura, Koh/0000-0001-7303-9430 NR 26 TC 98 Z9 105 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 JAN 23 PY 2003 VL 22 IS 3 BP 343 EP 350 DI 10.1038/sj.onc.1206115 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 635CB UT WOS:000180379100003 PM 12545155 ER PT J AU Arsura, M Panta, GR Bilyeu, JD Cavin, LG Sovak, MA Oliver, AA Factor, V Heuchel, R MErcurio, F Thorgeirsson, SS Sonenshein, GE AF Arsura, M Panta, GR Bilyeu, JD Cavin, LG Sovak, MA Oliver, AA Factor, V Heuchel, R MErcurio, F Thorgeirsson, SS Sonenshein, GE TI Transient activation of NF-kappa B through a TAK1/IKK kinase pathway by TGF-beta 1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation SO ONCOGENE LA English DT Article DE NF-kappa B; IKK; TGF-beta 1; JNK; AP-1; apoptosis ID GROWTH-FACTOR-BETA; MICE LACKING; IKK-ALPHA; EMBRYONIC LETHALITY; TRANSGENIC MICE; HEPATOCELLULAR CARCINOMAS; MEDIATED TRANSCRIPTION; TERMINAL KINASE; ADAPTER PROTEIN; JNK ACTIVATION AB NF-kappaB has been implicated in the regulation of apoptosis, a key mechanism of normal and malignant growth control. Previously, we demonstrated that inhibition of NF-kappaB activity by TGF-beta1 leads directly to induction of apoptosis of murine B-cell lymphomas and hepatocytes. Thus, we were surprised to determine that NF-kappaB is transiently activated in response to TGF-beta1 treatment. Here we elucidate the mechanism of TGF-beta1-mediated regulation of NF-kappaB and induction of apoptosis in epithelial cells. We report that TGF-beta1 activates IKK kinase, which mediates IkappaB-alpha phosphorylation. In turn, the activation of IKK following TGF-beta1 treatment is mediated by the TAK1 kinase. As a result of NF-kappaB activation, IkappaB-alpha mRNA and protein levels are increased leading to postrepression of NF-kappaB and induction of cell death. Inhibition of NF-kappaB following TGF-beta1 treatment increased AP-1 complex transcriptional activity through sustained c-Jun phosphorylation, thereby potentiating AP-1/SMADs-mediated cell killing. Furthermore, TGF-beta1-mediated upregulation of Smad7 appeared independent of NF-kappaB. In hepatocellular carcinomas of TGF-beta1 or TGF-alpha/c-myc transgenic mice, we observed constitutive activation of NF-kappaB that led to inhibition of JNK signaling. Overall, our data illustrate an autocrine mechanism based on the ability of IKK/NF-kappaB/IkappaB-alpha signaling to negatively regulate NF-kappaB levels thereby permitting TGF-beta1-induced apoptosis through AP-1 activity. C1 Univ Tennessee, Coll Med, Dept Pharmacol, Memphis, TN 38163 USA. Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. NCI, CCR, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. Celgene Signal Res Div, San Diego, CA 92121 USA. Ludwig Inst Canc Res, S-75124 Uppsala, Sweden. RP Arsura, M (reprint author), Univ Tennessee, Coll Med, Dept Pharmacol, 874 Union Ave, Memphis, TN 38163 USA. FU NCI NIH HHS [CA78616-S1, CA36355, CA78616, CA82742] NR 73 TC 96 Z9 102 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 23 PY 2003 VL 22 IS 3 BP 412 EP 425 DI 10.1038/sj.onc.1206132 PG 14 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 635CB UT WOS:000180379100010 PM 12545162 ER PT J AU Yuan, BZ Zhou, XL Durkin, ME Zimonjic, DB Gumundsdottir, K Eyfjord, JE Thorgeirsson, SS Popescu, NC AF Yuan, BZ Zhou, XL Durkin, ME Zimonjic, DB Gumundsdottir, K Eyfjord, JE Thorgeirsson, SS Popescu, NC TI DLC-1 gene inhibits human breast cancer cell growth and in vivo tumorigenicity SO ONCOGENE LA English DT Article DE tumor suppressor gene; breast cancer; colon cancer; prostate cancer; tumorigenicity; metastasis ID TUMOR-SUPPRESSOR GENE; HUMAN HEPATOCELLULAR-CARCINOMA; CHROMOSOME 8P DELETION; PROSTATE-CANCER; ASSOCIATION; METASTASIS; 8P22-23; PROTEIN; CLONING; RHOGAP AB The human DLC-1 (deleted in liver cancer 1) gene was cloned from a primary human hepatocellular carcinoma (HCC) and mapped to the chromosome 8p21-22 region frequently deleted in common human cancers and suspected to harbor tumor suppressor genes. DLC-1 was found to be deleted or downregulated in a significant number of HCCs. We expanded our investigations to other cancers with recurrent deletions of 8p22, and in this study examined alterations of DLC-1 in primary human breast tumors, human breast, colon, and prostate tumor cell lines. Genomic deletion of DLC-1 was observed in 40% of primary breast tumors, whereas reduced or undetectable levels of DLC-1 mRNA were seen in 70% of breast, 70% of colon, and 50% of prostate tumor cell lines To see whether DLC-1 expression affects cell growth and tumorigenicity, two breast carcinoma cell lines lacking the expression of endogenous gene were transfected with the DLC-1 cDNA. In both cell lines, DLC-1 transfection caused significant growth inhibition and reduction of colony formation. Furthermore, introduction of the DLC-1 cDNA abolished the in vivo tumorigenicity in nude mice, suggesting that the DLC-1 gene plays a role in breast cancer by acting as a bona fide tumor suppressor gene. C1 NCI, Expt Carcinogenesis Lab, Canc Res Ctr, Bethesda, MD 20892 USA. Iceland Canc Soc, Reykjavik, Iceland. RP Popescu, NC (reprint author), NCI, Expt Carcinogenesis Lab, Canc Res Ctr, Bethesda, MD 20892 USA. NR 29 TC 113 Z9 122 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 23 PY 2003 VL 22 IS 3 BP 445 EP 450 DI 10.1038/sj.onc.1206064 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 635CB UT WOS:000180379100013 PM 12545165 ER PT J AU Ni, YJ Goldman, D Hoffman, B Brooks, PJ AF Ni, YJ Goldman, D Hoffman, B Brooks, PJ TI Overexpression of an epitope-tagged serotonin transporter in serotonin neurons of the dorsal raphe nucleus using a defective HSV-1 vector SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE serotonin transporter; dorsal raphe nuclei; herpes simplex virus vector; autoradiography ID CENTRAL-NERVOUS-SYSTEM; REGULATORY REGION POLYMORPHISM; DIRECT GENE-TRANSFER; PROTEIN-KINASE-C; IN-VIVO; MAJOR DEPRESSION; RAT-BRAIN; ASSOCIATION; BEHAVIOR; PROMOTER AB The serotonin transporter (5HTT) plays a central role in serotonin neurotransmission. Abnormalities of 5HTT function have been implicated in depression, anxiety and alcohol intake. To better understand the functional role of this important molecule, we have utilized a viral vector approach to overexpress the 5HTT in regions of the rat brain. We have constructed a bicistronic defective herpes virus (HSV-1) vector that expresses both an epitope-tagged 5HTT as well as beta-galactosidase (beta-GAL) as a marker for infected cells. The vector was capable of conferring serotonin uptake activity to Vero cells in culture, indicating transfer of a functional 5HTT. Injection of the 5HTT virus into the rat brain resulted in a dense focus of specific I-125 RTI-55 binding at the injection site, indicating that the virally expressed 5HTT can also bind ligand when expressed in the brain. We were also able to overexpress an epitope tagged 5HTT in serotonergic neurons in the dorsal raphe nucleus (DRN) using this approach. These data demonstrate that the levels of the 5HTT in 5HT neurons can be manipulated in the adult rodent brain using an HSV-1 vector. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIAAA, Mol Neurobiol Sect, Neurogenet Lab, Rockville, MD 20892 USA. NIMH, Unit Mol Pharmacol, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Ni, YJ (reprint author), VIRXSYS Corp, Sect Vector Dev, 200 Perry Pkwy Suite 1A, Gaithersburg, MD 20877 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 61 TC 1 Z9 2 U1 2 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD JAN 22 PY 2003 VL 138 IS 2 BP 133 EP 143 AR PII S0166-4328(02)00239-5 DI 10.1016/S0166-4328(02)00239-5 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 639CA UT WOS:000180609000003 PM 12527444 ER PT J AU Pinn, VW AF Pinn, VW TI Sex and gender factors in medical studies - Implications for health and clinical practice SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID CORONARY HEART-DISEASE; WOMENS HEALTH; UNITED-STATES; PRIMARY-CARE; TRIALS; MEN; REPRESENTATION; PROLONGATION; DELIVERY; TRENDS C1 NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. RP Pinn, VW (reprint author), NIH, Off Res Womens Hlth, 9000 Rockville Pike,Bldg 1,Room 201, Bethesda, MD 20892 USA. NR 59 TC 68 Z9 72 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 JAN 22 PY 2003 VL 289 IS 4 BP 397 EP 400 DI 10.1001/jama.289.4.397 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 636TD UT WOS:000180472300001 PM 12533102 ER PT J AU Sachs, JN Petrache, HI Zuckerman, DM Woolf, TB AF Sachs, JN Petrache, HI Zuckerman, DM Woolf, TB TI Molecular dynamics simulations of ionic concentration gradients across model bilayers SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID INTERFACIAL ELECTRIC-FIELDS; LONG-RANGE FORCES; LIPID BILAYERS; SURFACE-CHARGE; ALAMETHICIN CHANNEL; ELECTROLYTE SYSTEMS; COMPUTER-SIMULATION; BOUNDARY-CONDITIONS; MEMBRANE SURFACES; AQUEOUS-SOLUTIONS AB To model a concentration gradient across a biomembrane, we have performed all-atom molecular dynamics simulations of NaCl solutions separated by two oppositely charged plates. We have employed the recently formulated three-dimensional Ewald summation with correction (EW3DC) technique for calculations of long-range electrostatics in two-dimensionally periodic systems, allowing for different salt concentrations on the two sides of the plates. Six simulations were run, varying the salt concentrations and plate surface charge density in a biologically relevant range. The simulations reveal well-defined, atomic-level asymmetries between the two sides: distinct translational and rotational orderings of water molecules; differing ion residency times; a clear wetting layer adjacent only to the negative plate; and marked differences in charge density/potential profiles which reflect the microscopic behavior. These phenomena, which may play important roles in membrane and ion channel physiology, result primarily from the electrostatics and asymmetry of water molecules, and not from the salt ions. In order to establish that EW3DC can accurately capture fundamental electrostatic interactions important to asymmetric biomembrane systems, the CHARMM force-field (with the corrected Ewald sum) has been used. Comparison of the results with previously published simulations of electrolyte near charged surfaces, which employed different force-fields, shows the robustness of the CHARMM potential and gives confidence in future all-atom bilayer simulations using EW3DC and CHARMM. (C) 2003 American Institute of Physics. C1 Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Ctr Computat Biol & Bioinformat, Pittsburgh, PA 15213 USA. Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA. RP Sachs, JN (reprint author), Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA. OI Zuckerman, Daniel/0000-0001-7662-2031 NR 69 TC 7 Z9 7 U1 1 U2 10 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 JAN 22 PY 2003 VL 118 IS 4 BP 1957 EP 1969 DI 10.1063/1.1531589 PG 13 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 634AD UT WOS:000180317000049 ER PT J AU Huang, HB Spande, TF Panek, JS AF Huang, HB Spande, TF Panek, JS TI Highly enantioenriched tetrahydropyridines from chiral organosilanes: Application to the synthesis of quinolizidine alkaloid (-)-217A SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID STEREOSELECTIVE SYNTHESIS; IMINIUM ION; PIPERIDINES; SILICON; CYCLIZATIONS; HETEROCYCLES; MANTELLA; CARBON C1 Boston Univ, Dept Chem, Boston, MA 02215 USA. Boston Univ, Ctr Chem Methodol & Lib Dev, Boston, MA 02215 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Panek, JS (reprint author), Boston Univ, Dept Chem, 590 Commonwealth Ave, Boston, MA 02215 USA. EM Panek@chem.bu.edu FU NCI NIH HHS [CA56304]; NIGMS NIH HHS [P50 GM067041] NR 22 TC 44 Z9 44 U1 0 U2 1 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 JAN 22 PY 2003 VL 125 IS 3 BP 626 EP 627 DI 10.1021/ja028937i PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 636QY UT WOS:000180468900008 PM 12526650 ER PT J AU Goldstein, S Merenyi, G Russo, A Samuni, A AF Goldstein, S Merenyi, G Russo, A Samuni, A TI The role of oxoammonium cation in the SOD-Mimic activity of cyclic nitroxides SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SUPEROXIDE; RADICALS; ANTIOXIDANTS; TOXICITY; TEMPOL; RAT AB Cyclic nitroxides (RNO.) mimic the activity of superoxide dismutase (SOD) and demonstrate antioxidant properties in numerous in vitro and in vivo models. Their broad antioxidant activity may involve the participation of their reduced and oxidized forms, that is, hydroxylamine (RNO-H) and oxoammonium cation (RNO+). To examine this possibility we studied the reactions of RNO+ and RNO+ with HO2./O-2(.-) and with several reductants by pulse radiolysis and rapid-mixing stopped-flow techniques. The oxoammonium cations were generated by electrochemical and radiolytic oxidation of 2,2,6,6-tetramethylpiperidinoxyl (TPO) and 3-carbamoyl-2,2,5,5-tetramethylpyrrolidinoxyl (3-CP). The rate constant for the reaction of RNO. with HO2. to form RNO+ was determined to be (1.2 +/- 0.1) x 10(8) for TPO and (1.3 +/- 0.1) x 10(6) M-1 s(-1) for 3-CP. The kinetics results demonstrate that the reaction of RNO. with HO2. proceeds via an inner-sphere electron-transfer mechanism. The rate constant for the reaction of RNO. with O-2(.-) is lower than 1 x 10(3) M-1 s(-1). The rate constant for the reaction of RNO+ with O-2(.-) was determined to be (3.4 +/- 0.2) x 10(9) for TPO+ and (5.0 +/- 0.2) x 10(9) M-1 s(-1) for 3-CP+. Hence, both nitroxides catalyze the dismutation of superoxide through the RNO./RNO+ redox couple, and the dependence of the catalytic rate constant, k(cat), on pH displayed a bell-shaped curve having a maximum around pH 4. The oxoammonium cation oxidized ferrocyanide and HO2- by a one-electron transfer, whereas the oxidation of methanol, formate, and NADH proceeded through a two-electron-transfer reaction. The redox potential of RNO./RNO+ couple was calculated to be 0.75 and 0.89 V for 3-CP and TPO, respectively. The elucidated mechanism provides a clearer insight into the biological antioxidant properties of cyclic nitroxides that should permit design of even more effective antioxidants. C1 Hebrew Univ Jerusalem, Dept Phys Chem, IL-91904 Jerusalem, Israel. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Royal Inst Technol, Dept Chem, S-10044 Stockholm 70, Sweden. Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Mol Biol, IL-91120 Jerusalem, Israel. RP Hebrew Univ Jerusalem, Dept Phys Chem, IL-91904 Jerusalem, Israel. EM sarag@vms.huji.ac.il NR 24 TC 96 Z9 97 U1 2 U2 8 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 JAN 22 PY 2003 VL 125 IS 3 BP 789 EP 795 DI 10.1021/ja028190w PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 636QY UT WOS:000180468900038 PM 12526680 ER PT J AU Meacci, E Nuti, F Catarzi, S Vasta, V Donati, C Bourgoin, S Bruni, P Moss, J Vaughan, M AF Meacci, E Nuti, F Catarzi, S Vasta, V Donati, C Bourgoin, S Bruni, P Moss, J Vaughan, M TI Activation of phospholipase D by bradykinin and sphingosine 1-phosphate in A549 human lung adenocarcinoma cells via different GTP-binding proteins and protein kinase C delta signaling pathways SO BIOCHEMISTRY LA English DT Article ID ADP-RIBOSYLATION FACTOR; PHOSPHATIDIC-ACID; MEDIATED ACTIVATION; COUPLED RECEPTOR; PLASMA-MEMBRANE; C2C12 MYOBLASTS; GENE FAMILY; ALPHA; SPHINGOSINE-1-PHOSPHATE; CASCADE AB Phospholipase D (PLD) is involved in the signaling by many extracellular ligands, and its regulation appears to be quite complex. We investigated the signaling pathways initiated by bradykinin (BK) or sphingosine 1-phosphate (S1P) in A549 cells to define molecular mechanisms responsible for their additive effects on PLD activity. BK and S I P each elicited a sustained increase in phosphatidic acid content through a rapid and transient activation of PLD. The two pathways demonstrated rapid homologous downregulation, but heterologous desensitization was not observed. Action of both agonists required protein kinase C (PKC) activation and Ca2+ influx but was mediated by different heterotrimeric G proteins. In membranes, inhibition of PKCdelta by rottlerin enhanced BK activation of PLD but inhibited that by SIP. Rottlerin inhibited activation of PLD in nuclei by both BK and SIP. By in situ immunofluorescence or cell fractionation followed by immunoblotting, PLD1 was concentrated primarily in nuclei, whereas the membrane fraction contained PLD2 and PLD1. Moreover, PKCdelta specifically phosphorylated recombinant PLD2, but not PLD1 BK and SIP similarly enhanced RhoA translocation to nuclei, whereas BK was less efficacious than SIP on RhoA relocalization to membranes. Effects of both agonists on the nuclear fraction, which contains only PLD1, are compatible with a RhoA- and PKCdelta-dependent process. In membranes, which contain both PLD1 and PLD2, the stimulatory effect of S1P on PLD activity can best be explained by RhoA- and PKCdelta-dependent activation of PLD 1; in contrast, the effects of BK on RhoA translocation and enhancement of BK-stimulated PLD activity by PKC inhibition are both consistent with PLD2 serving as its primary target. C1 Univ Florence, Dipartimento Sci Biochim, I-50134 Florence, Italy. CHUL, Ctr Rech, Ctr Rech Rheumatol & Immunol, St Foy, PQ, Canada. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Bruni, P (reprint author), Univ Florence, Dipartimento Sci Biochim, Viale GB Morgagni 50, I-50134 Florence, Italy. RI Bruni, Paola/A-1151-2008; OI Bruni, Paola/0000-0002-1151-3413 FU Telethon [1086] NR 51 TC 19 Z9 21 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 JAN 21 PY 2003 VL 42 IS 2 BP 284 EP 292 DI 10.1021/bio026350a PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 636TK UT WOS:000180472900006 PM 12525155 ER PT J AU Xu, S Offer, G Gu, J White, HD Yu, LC AF Xu, S Offer, G Gu, J White, HD Yu, LC TI Temperature and ligand dependence of conformation and helical order in myosin filaments SO BIOCHEMISTRY LA English DT Article ID X-RAY STRUCTURES; LIGHT-CHAIN PHOSPHORYLATION; MUSCLE THICK FILAMENTS; RABBIT SKELETAL-MUSCLE; SPIN-LABELED MYOSIN; HEAD-TAIL JUNCTION; MOTOR DOMAIN; ADENOSINE-TRIPHOSPHATE; ATP HYDROLYSIS; PSOAS MUSCLE AB Mammalian myosin filaments are helically ordered only at higher temperatures (> 20 degreesC) and become progressively more disordered as the temperature is decreased. It had previously been suggested that this was a consequence of the dependence of the hydrolytic step of myosin ATPase on temperature and the requirement that hydrolysis products (e.g., ADP(.)P(i)) be bound at the active site. An alternative hypothesis is that temperature directly affects the conformation of the myosin heads and that they need to be in a particular conformation for helical order in the filament. To discriminate between these two hypotheses, we have studied the effect of temperature on the helical order of myosin heads in rabbit psoas muscle in the presence of nonhydrolyzable ligands. The muscle fibers were overstretched to nonoverlap such that myosin affinity for nucleotides was not influenced by the interaction of myosin with the thin filament. We show that with bound ADP(.)vanadate, which mimics the transition state between ATP and hydrolysis products, or with the ATP analogues AMP-PNP or ADP-BeFx the myosin filaments are substantially ordered at higher temperatures but are reversibly disordered by cooling. These results reinforce recent studies in solution showing that temperature as well as ligand influence the equilibrium between multiple myosin conformations [Malnasi-Csizmadia, A., Pearson, D. S., Kovacs, M., Woolley, R. J., Geeves, M. A., and Bagshaw, C. R. (2001) Biochemistry 40, 12727-12737; Malnasi-Csizmadia, A., Woolley, R. J., and Bagshaw, C. R. (2000) Biochemistry 39, 16135-16146; Urbanke, C., and Wray, J. (2001) Biochem. J. 358, 165-173] and indicate that helical order requires the myosin heads to be in the closed conformation. Our results suggest that most of the heads in the closed conformation are ordered, and that order is not produced in a separate step. Hence, helical order can be used as a signature of the closed conformation in relaxed muscle. Analysis of the dependence on temperature of helical order and myosin conformation shows that in the presence of these analogues one ordered (closed) conformation and two disordered conformations with distinct thermodynamic properties coexist. Low temperatures favor one disordered conformation, while high temperatures favor the ordered (closed) conformation together with a second disordered conformation. C1 NIAMSD, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Bristol, Dept Physiol, Bristol BS8 1TD, Avon, England. Eastern Virginia Med Sch, Dept Physiol Sci, Norfolk, VA 23501 USA. RP Yu, LC (reprint author), NIAMSD, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. NR 71 TC 41 Z9 41 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 21 PY 2003 VL 42 IS 2 BP 390 EP 401 DI 10.1021/bi026085t PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 636TK UT WOS:000180472900017 PM 12525166 ER PT J AU Gladwin, MT Schechter, AN Ognibene, FP Coles, WA Reiter, CD Schenke, WH Csako, G Waclawiw, MA Panza, JA Cannon, RO AF Gladwin, MT Schechter, AN Ognibene, FP Coles, WA Reiter, CD Schenke, WH Csako, G Waclawiw, MA Panza, JA Cannon, RO TI Divergent nitric oxide bioavailability in men and women with sickle cell disease SO CIRCULATION LA English DT Article DE nitric oxide; endothelium; anemia, sickle cell; acetylcholine; cell adhesion molecules ID LEUKOCYTE ADHESION MOLECULE; ACUTE CHEST SYNDROME; REGIONAL BLOOD-FLOW; POSTMENOPAUSAL WOMEN; RISK-FACTORS; MEDIATED VASODILATION; VASOOCCLUSIVE CRISIS; POTENTIAL ROLE; ESTROGEN; ATHEROSCLEROSIS AB Background-Although reduced endothelial nitric oxide (NO) bioavailability has been demonstrated in arteriosclerotic vascular disease, the integrity of this system in sickle cell disease remains uncertain. Methods and Results-We measured forearm blood flow in 21 patients with sickle cell disease (hemoglobin SS genotype) and 18 black control subjects before and after intra-arterial infusions of acetylcholine, nitroprusside, and the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). Endothelium-dependent vasodilation, measured by the percent increase in flow induced by acetylcholine infusion, was significantly greater than in controls (252 +/- 37% for patients versus 134-124% for controls; P<0.0001). However, there was a large sex difference in blood flow responses between female and male patients (340 +/- 46% versus 173+/-41%; P=0.035). Similarly, basal NO bioactivity, as measured by the percent decrease in flow induced by L-NMMA, was depressed in male compared with female patients (-17 +/- 5% versus -34 +/- 4%; P=0.01), as was the response to nitroprusside (86 +/- 21% versus 171 +/- 22%; P=0.008). L-NMMA reduced the blood flow response to acetylcholine in women, but not in men. Sex differences in vascular cell adhesion molecule-1 were appreciated, with significant correlations between levels of soluble vascular cell adhesion molecule-1 and blood flow responses to L-NMMA and nitroprusside (r=0.53, P=0.004 and r=-0.66, P<0.001, respectively). Conclusions-NO bioavailability and NO responsiveness are greater in women than in men with sickle cell disease and determines adhesion molecule expression. Endothelium-dependent blood flows are largely non-NO mediated in male patients. These results provide a possible mechanism for reported sex differences in sickle cell disease morbidity and mortality-and provide a basis for novel pharmacological interventions. C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Lab Med, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), NIDDKD, Biol Chem Lab, NIH, Bldg 10,Room 7D-43,10 Ctr Dr, Bethesda, MD 20892 USA. OI Schechter, Alan N/0000-0002-5235-9408 NR 49 TC 118 Z9 120 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 21 PY 2003 VL 107 IS 2 BP 271 EP 278 DI 10.1161/01.CIR.0000044943.12533.A8 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 642CA UT WOS:000180785700013 PM 12538427 ER PT J AU Lakatta, EG Levy, D AF Lakatta, EG Levy, D TI Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises - Part II: The aging heart in health: Links to heart disease SO CIRCULATION LA English DT Review ID LEFT-VENTRICULAR MASS; AGE-ASSOCIATED CHANGES; AMBULATORY ELECTROCARDIOGRAPHY; PROGNOSTIC-SIGNIFICANCE; EXERCISE; FAILURE; PERFORMANCE; PREVALENCE; POPULATION; MEN C1 NIA, Intramural Res Program, Gerontol Res Ctr, Cardiovasc Sci Lab,NIH, Baltimore, MD 21224 USA. NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. RP Lakatta, EG (reprint author), NIA, Intramural Res Program, Gerontol Res Ctr, Cardiovasc Sci Lab,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 38 TC 464 Z9 489 U1 1 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 21 PY 2003 VL 107 IS 2 BP 346 EP 354 DI 10.1161/01.CIR.0000048893.62841.F7 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 642CA UT WOS:000180785700025 PM 12538439 ER PT J AU Fusco, D Accornero, N Lavoie, B Shenoy, SM Blanchard, JM Singer, RH Bertrand, E AF Fusco, D Accornero, N Lavoie, B Shenoy, SM Blanchard, JM Singer, RH Bertrand, E TI Single mRNA molecules demonstrate probabilistic movement in living mammalian cells SO CURRENT BIOLOGY LA English DT Article ID MESSENGER-RNA LOCALIZATION; IN-SITU; PROTEIN; TRANSPORT; VISUALIZATION; PARTICLES; SEQUENCES; ORGANIZATION; FILAMENTS; DIFFUSION AB Cytoplasmic mRNA movements ultimately determine the spatial distribution of protein synthesis. Although some mRNAs are compartmentalized in cytoplasmic regions, most mRNAs, such as housekeeping mRNAs or the poly-adenylated mRNA population, are believed to be distributed throughout the cytoplasm [1-4]. The general mechanism by which all mRNAs may move, and how this may be related to localization, is unknown. Here, we report a method to visualize single mRNA molecules in living mammalian cells, and we report that, regardless of any specific cytoplasmic distribution, individual mRNA molecules exhibit rapid and directional movements on microtubules. Importantly, the beta-actin mRNA zipcode increased both the frequency and length of these movements, providing a common mechanistic basis for both localized and nonlocalized mRNAs. Disruption of the cytoskeleton with drugs showed that microtubules and microfilaments are involved in the types of mRNA movements we have observed, which included complete immobility and corralled and nonrestricted diffusion. Individual mRNA molecules switched frequently among these movements, suggesting that mRNAs undergo continuous cycles of anchoring, diffusion, and active transport. C1 CNRS, Inst Genet Mol Montpellier, UMR 5535, IFR 24, Montpellier 5, France. Yeshiva Univ Albert Einstein Coll Med, Dept Anat & Struct Biol, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10461 USA. NINDS, NIH, Mol Plast Sect, Bethesda, MD 20892 USA. RP Singer, RH (reprint author), CNRS, Inst Genet Mol Montpellier, UMR 5535, IFR 24, 1919 Route de Mende, Montpellier 5, France. FU NIBIB NIH HHS [R01 EB002060]; NIGMS NIH HHS [GM54887] NR 29 TC 320 Z9 327 U1 7 U2 27 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 21 PY 2003 VL 13 IS 2 BP 161 EP 167 AR PII S0960-9822(02)01436-7 DI 10.1016/S0960-9822(02)01436-7 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 645DE UT WOS:000180960300028 PM 12546792 ER PT J AU Krylov, DM Nasmyth, K Koonin, EV AF Krylov, DM Nasmyth, K Koonin, EV TI Evolution of eukaryotic cell cycle regulation: Stepwise addition of regulatory kinases and late advent of the CDKs SO CURRENT BIOLOGY LA English DT Article ID MEIOTIC GENE-EXPRESSION; PROTEIN-KINASE; BUDDING YEAST; SACCHAROMYCES-CEREVISIAE; LIKELIHOOD METHODS; ENCODES; PARSIMONY; HOMOLOG AB Protein kinases regulate a number of critical events in mitosis and meiosis. A study of the evolution of kinases involved in cell cycle control (CCC) might shed light on the evolution of the eukaryotic cell cycle. In particular, applying quantitative phylogenetic methods to key CCC kinases could provide information on the relative timing of gene duplication events. To investigate the evolution of CCC kinases, we constructed phylogenetic trees for the CDC28 family and performed statistical tests of the tree topology. This family includes the cyclin-dependent kinases (CDKs), which are key regulators of the eukaryotic cell cycle, as well as other CCC kinases. We found that CDKs and, in particular, the principal cell cycle regulator Cdc28p, branch off the phylogenetic tree at a late stage, after several other kinases involved in either mitosis or meiosis regulation. On the basis of this tree topology, it is proposed that, at early stages of evolution, the eukaryotic cell cycle was not controlled by CDKs and that only a subset of extant kinases, notably the DNA damage checkpoint kinase Chk1p, were in place. During subsequent evolution, a series of duplications of kinase genes occurred, gradually adding more kinases to the CCC system, the CDKs being among the last major additions. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Res Inst Mol Pathol, A-1030 Vienna, Austria. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. NR 31 TC 36 Z9 38 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 21 PY 2003 VL 13 IS 2 BP 173 EP 177 AR PII S0960-9822(03)00008-3 DI 10.1016/S0960-9822(03)00008-3 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 645DE UT WOS:000180960300030 PM 12546794 ER PT J AU Hirano, T Hou, YC Jiao, XN Gu, XX AF Hirano, T Hou, YC Jiao, XN Gu, XX TI Intranasal immunization with a lipooligosaccharide-based conjugate vaccine from nontypeable Haemophilus influenzae enhances bacterial clearance in mouse nasopharynx SO FEMS IMMUNOLOGY AND MEDICAL MICROBIOLOGY LA English DT Article DE intranasal immunization; conjugate vaccine; lipooligosaccharide; nontypeable Haemophilus influenzae ID NONTYPABLE HEMOPHILUS-INFLUENZAE; OUTER-MEMBRANE PROTEIN; ACUTE OTITIS-MEDIA; MIDDLE-EAR; DETOXIFIED LIPOOLIGOSACCHARIDE; STRUCTURAL-ANALYSIS; RAT MODEL; MONOCLONAL-ANTIBODIES; MUCOSAL IMMUNIZATION; PULMONARY CLEARANCE AB Nontypeable Haemophilus influenzae (NTHi) is a major cause of otitis media in children. We investigated whether intranasal immunization with a detoxified lipooligosaccharide-tetanus toxoid (dLOS-TT) conjugate vaccine would generate protective immunity against NTHi in a mouse model of nasopharyngeal clearance. The results demonstrated that intranasal immunization with dLOS-TT plus adjuvant cholera toxin (CT) significantly induced LOS-specific IgA antibodies in mouse external secretions, especially in nasal wash (90-fold), bronchoalveolar lavage fluid (25-fold), saliva (13-fold) and fecal extract (three-fold). LOS-specific IgA antibody-forming cells were also found in mucosal and lymphoid tissues with their highest numbers in the nasal passage (528 per 106 cells). In addition, the intranasal immunization elicited a significant rise in LOS-specific IgG (32-fold) and IgA (13-fold) in serum. For the immunized mice which had been challenged through the nose with 10(7) live NTHi strain 9274 cells, the vaccine group showed a significant reduction (74-77%) of NTHi, compared to that of control groups with CT alone or dLOS plus CT (P < 0.05). Negative correlations were found between bacterial counts and the levels of nasal wash IgA or IgG, saliva IgA and serum IgG. The clearance of five heterologous strains was investigated and revealed a significant clearance of strains 3198, 5657 and 7502 but not of strains 1479 and 2019. These data suggest that intranasal immunization with dLOS-TT vaccine elicits both mucosal and systemic immunity against NTHi and enhances bacterial clearance from nasopharynx. in mice. Such a vaccine and vaccination regime may be applicable to humans with an appropriate formulation. (C) 2002 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved. C1 Natl Inst Deafness & Other Commun Disorders, NIH, Rockville, MD 20850 USA. RP Gu, XX (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, 5 Res Court, Rockville, MD 20850 USA. NR 44 TC 23 Z9 26 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0928-8244 J9 FEMS IMMUNOL MED MIC JI FEMS Immunol. Med. Microbiol. PD JAN 21 PY 2003 VL 35 IS 1 BP 1 EP 10 AR PII S0928-8244(02)00457-1 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 649RJ UT WOS:000181221500001 PM 12589951 ER PT J AU Banwell, MG Edwards, AJ Jolliffe, KA Smith, JA Hamel, E Verdier-Pinard, P AF Banwell, MG Edwards, AJ Jolliffe, KA Smith, JA Hamel, E Verdier-Pinard, P TI Total synthesis of (+/-)-rhazinal, an alkaloidal spindle toxin from Kopsia teoi SO ORGANIC & BIOMOLECULAR CHEMISTRY LA English DT Article ID RHAZINILAM ANALOGS; COUPLING REACTIONS; TUBULIN; (-)-RHAZINILAM; CONVERSION; BIPHENYLS; PYRROLE; AMIDES; AGENTS AB The title alkaloid I and its B-nor-congener 3, both of which display potent and unusual anti-mitotic properties, have been synthesized in racemic form and characterised by single-crystal X-ray analysis. C1 Australian Natl Univ, Inst Adv Studies, Res Sch Chem, Canberra, ACT 0200, Australia. Univ Sydney, Sch Chem, Sydney, NSW 2006, Australia. NCI, Div Canc Treatment & Diagnosis, NIH, Screening Technol Branch,Dev Therapeut Program, Frederick, MD 21702 USA. RP Banwell, MG (reprint author), Australian Natl Univ, Inst Adv Studies, Res Sch Chem, Canberra, ACT 0200, Australia. EM mgb@rsc.anu.edu.au RI Jolliffe, Katrina/E-3834-2010; smith, jason/J-7391-2014; Banwell, Martin/H-8354-2014 OI Jolliffe, Katrina/0000-0003-1100-4544; smith, jason/0000-0001-6313-3298; NR 49 TC 60 Z9 60 U1 2 U2 4 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1477-0520 J9 ORG BIOMOL CHEM JI Org. Biomol. Chem. PD JAN 21 PY 2003 VL 1 IS 2 BP 296 EP 305 DI 10.1039/b209992f PG 10 WC Chemistry, Organic SC Chemistry GA 655MU UT WOS:000181557300012 PM 12929425 ER PT J AU Leuba, SH Karymov, MA Tomschik, M Ramjit, R Smith, P Zlatanova, J AF Leuba, SH Karymov, MA Tomschik, M Ramjit, R Smith, P Zlatanova, J TI Assembly of single chromatin fibers depends on the tension in the DNA molecule: Magnetic tweezers study SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SCANNING FORCE MICROSCOPY; NUCLEOSOME CORE PARTICLE; HIGHER-ORDER STRUCTURE; POLYMERASE; PROTEIN-1; CLEAVAGE; NAP-1 AB We have used magnetic tweezers to study in real time chaperonemediated chromatin assembly/disassembly at the level of single chromatin fibers. We find a strong dependence of the rate of assembly on the exerted force, with strong inhibition of assembly at forces exceeding 10 pN. During assembly, and especially at higher forces, occasional abrupt increases in the length of the fiber were observed, giving a clear indication of reversibility of the assembly process. This result is a clear demonstration of the dynamic equilibrium between nucleosome assembly and disassembly at the single chromatin fiber level. C1 Univ Pittsburgh, Canc Inst Res Pavilion, Hillman Canc Ctr, Sch Med,Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA. NCI, NIH, Bethesda, MD 20892 USA. NIH, Div Bioengn Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. Polytech Univ, Dept Chem & Chem Engn, Brooklyn, NY 11201 USA. RP Zlatanova, J (reprint author), Univ Pittsburgh, Canc Inst Res Pavilion, Hillman Canc Ctr, Sch Med,Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA. RI Zlatanova, Jordanka/B-3273-2009 NR 36 TC 62 Z9 64 U1 1 U2 17 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 21 PY 2003 VL 100 IS 2 BP 495 EP 500 DI 10.1073/pnas.0136890100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 638UE UT WOS:000180589000022 PM 12522259 ER PT J AU Lukin, JA Kontaxis, G Simplaceanu, V Yuan, Y Bax, A Ho, C AF Lukin, JA Kontaxis, G Simplaceanu, V Yuan, Y Bax, A Ho, C TI Quaternary structure of hemoglobin in solution SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; NMR STRUCTURES; ASPARTATE TRANSCARBAMOYLASE; LIGANDED HEMOGLOBIN; RELAXATION; PROTEINS; MACROMOLECULES; RESOLUTION; ALIGNMENT; BINDING AB Many important proteins perform their physiological functions under allosteric control, whereby the binding of a ligand at a specific site influences the binding affinity at a different site. Allosteric regulation usually involves a switch in protein conformation upon ligand binding. The energies of the corresponding structures are comparable, and, therefore, the possibility that a structure determined by x-ray diffraction in the crystalline state is influenced by its intermolecular contacts, and thus differs from the solution structure, cannot be excluded. Here, we demonstrate that the quaternary structure of tetrameric human normal adult carbonmonoxy-hemoglobin can readily be determined in solution at near-physiological conditions of pH, ionic strength, and temperature by NMR measurement of N-15-H-1 residual dipolar couplings in weakly oriented samples. The structure is found to be a dynamic intermediate between two previously solved crystal structures, known as the R and R2 states. Exchange broadening at the subunit interface points to a rapid equilibrium between different structures that presumably include the crystallographically observed states. C1 Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Ho, C (reprint author), Carnegie Mellon Univ, Dept Biol Sci, 4400 5th Ave, Pittsburgh, PA 15213 USA. RI Ho, Chien/O-6112-2016 OI Ho, Chien/0000-0002-4094-9232 FU NCRR NIH HHS [S10 RR 11248]; NHLBI NIH HHS [R01 HL 24525, R01 HL024525] NR 29 TC 137 Z9 138 U1 3 U2 25 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 JAN 21 PY 2003 VL 100 IS 2 BP 517 EP 520 DI 10.1073/pnas.232715799 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 638UE UT WOS:000180589000026 PM 12525687 ER PT J AU Luo, T Lee, YH Saint-Jeannet, JP Sargent, TD AF Luo, T Lee, YH Saint-Jeannet, JP Sargent, TD TI Induction of neural crest in Xenopus by transcription factor AP2 alpha SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bone morphogenetic protein; Wnt; Sox9; Slug; morpholino antisense oligonucleotides ID FACTOR AP-2; MOUSE EMBRYOGENESIS; EXPRESSION; PLATE; GENES; MESODERM; ECTODERM; EMBRYOS; CLONING; DLX3 AB We report experiments with Xenopus laevis, using both intact embryos and ectodermal explants, showing that the transcription factor AP2alpha is positively regulated by bone morphogenetic protein (EIMP) and Writ signaling, and that this activation is an essential step in the induction of neural crest (NC). Ectopic expression of AP2alpha is sufficient to activate high-level expression of NC-specific genes such as Slug and Sox9, which can occur as isolated domains within the neural plate as well as by expansion of endogenous NC territories. AP2alpha also has the property of inducing NC in isolated ectoderm in which Writ signaling is provided but BMP signaling is minimized by overexpression of chordin. Like other NC regulatory factors, activation of AP2alpha requires some attenuation of endogenous BMP signaling; however, this process occurs at a lower threshold for AP2alpha. Furthermore, AP2alpha expression domains are larger than for other NC factors. Loss-of-function experiments with antisense AP2alpha morpholino oligonucleotides result in severe reduction in the INC territory. These results support a central role for AP2alpha in NC induction. We propose a model in which AP2alpha expression, along with inactivation of INC inhibitory factors such as Dlx3, establish a feedback loop comprising AP2alpha, Sox9, and Slug, leading to and maintaining NC spcification. C1 NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Vet Med, Dept Anim Biol, Philadelphia, PA 19104 USA. RP Sargent, TD (reprint author), NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. FU NIDCR NIH HHS [DE 014212, R01 DE014212] NR 56 TC 129 Z9 130 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 21 PY 2003 VL 100 IS 2 BP 532 EP 537 DI 10.1073/pnas.0237226100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 638UE UT WOS:000180589000029 PM 12511599 ER PT J AU Rouzine, IM Wakeley, J Coffin, JM AF Rouzine, IM Wakeley, J Coffin, JM TI The solitary wave of asexual evolution SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MULLERS RATCHET; RNA VIRUS; SMALL POPULATIONS; SELECTION; FITNESS; RECOMBINATION; MUTATIONS; ACCUMULATION; ADVANTAGE AB Using a previously undescribed approach, we develop an analytic model that predicts whether an asexual population accumulates advantageous or deleterious mutations over time and the rate at which either process occurs. The model considers a large number of linked identical loci, or nucleotide sites; assumes that the selection coefficient per site is much less than the mutation rate per genome; and includes back and compensating mutations. Using analysis and Monte Carlo simulations, we demonstrate the accuracy of our results over almost the entire range of population sizes. Two limiting cases of our results, when either deleterious or advantageous mutations can be neglected, correspond to the Fisher-Muller effect and Muller's ratchet, respectively. By comparing predictions of our model (no recombination) to those of simple single-locus models (strong recombination), we show that the accumulation of advantageous mutations is slowed by linkage over a broad, finite range of population size. This supports the view of Fisher and Muller, who argued in the 1930s that progressive evolution of organisms is slowed because loci at which beneficial mutations can occur are often linked together on the same chromosome. These results follow from our main finding, that distribution of sequences over the mutation number evolves as a traveling wave whose speed and width depend on population size and other parameters. The model explains a logarithmic dependence of steady-state fitness on the population size reported recently for an RNA virus. C1 Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Rouzine, IM (reprint author), Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. FU NCI NIH HHS [CA 89441, R01 CA089441, R35 CA 44385, R37 CA089441]; NIAID NIH HHS [K25 AI 01811, K25 AI001811] NR 44 TC 124 Z9 125 U1 1 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 21 PY 2003 VL 100 IS 2 BP 587 EP 592 DI 10.1073/pnas.242719299 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 638UE UT WOS:000180589000039 PM 12525686 ER PT J AU Qi, CF Martensson, A Mattioli, M Dalla-Favera, R Lobanenkov, VV Morse, HC AF Qi, CF Martensson, A Mattioli, M Dalla-Favera, R Lobanenkov, VV Morse, HC TI CTCF functions as a critical regulator of cell-cycle arrest and death after ligation of the B cell receptor on immature B cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID C-MYC ONCOGENE; TUMOR-SUPPRESSOR; LYMPHOMA-CELLS; GROWTH ARREST; APOPTOSIS; P53; EXPRESSION; GENE; ACTIVATION; INHIBITION AB The WEHI 231 B cell lymphoma is used as a model of self-tolerance by clonal deletion because B cell receptor (BCR) ligation results in apoptosis. Two critical events precede cell death: an early rise and fall in expression of MYC and cell-cycle arrest associated with enhanced expression of p21, p27, and p53. CTCF is a transcription factor identified as a repressor of MYC recently shown to cause cell growth inhibition. The present studies demonstrate that BCR ligation of WEHI 231 as well as of normal immature B cells greatly increased expression of CTCF in association with down-regulation of MYC followed by growth arrest and cell death. Conditional expression of CTCF in WEHI 231 mimicked BCR ligation with activated cells showing repressed expression of MYC, enhanced expression of p27, p21, p53, and pj9ARF, and inhibition of cell growth and induction of apoptosis. In keeping with a central role for CTCF in control of B cell death, conditional expression of a CTCF antisense construct in WEHI 231 resulted in inhibition of p27, p21, p53, and p19(ARF) in association with enhanced expression of MYC. Activation of the endogenous CTCF locus by BCR ligation was also mimicked by three other routes to apoptotic death in WEHI 231: inhibition of the phosphoinositide 3-kinase or mTOR/FRAP signaling cascades and treatment with transforming growth factor (TGF)-beta. Rapid activation of CTCF by BCR ligation or treatment with TGF-beta was suppressed by ligation of CD40. These results demonstrate that CTCF is a common determinant to different pathways of death signaling in immature B cells. C1 NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. Scripps Res Inst, La Jolla, CA 92037 USA. Columbia Univ, Inst Canc Genet, New York, NY 10032 USA. Columbia Univ, Dept Pathol, New York, NY 10032 USA. Columbia Univ, Dept Genet & Dev, New York, NY 10032 USA. RP Morse, HC (reprint author), NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. RI Mattioli, Michela/K-3951-2013; OI Mattioli, Michela/0000-0002-1692-9178; Lobanenkov, Victor/0000-0001-6665-3635; Morse, Herbert/0000-0002-9331-3705 NR 40 TC 49 Z9 54 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 21 PY 2003 VL 100 IS 2 BP 633 EP 638 DI 10.1073/pnas.0237127100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 638UE UT WOS:000180589000047 PM 12524457 ER PT J AU Broxmeyer, HE Srour, EF Hangoc, G Cooper, S Anderson, SA Bodine, DM AF Broxmeyer, HE Srour, EF Hangoc, G Cooper, S Anderson, SA Bodine, DM TI High-efficiency recovery of functional hematopoietic progenitor and stem cells from human cord blood cryopreserved for 15 years SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID COMBINED IMMUNODEFICIENT MICE; VERSUS-HOST DISEASE; UNRELATED DONORS; EX-VIVO; SELF-RENEWAL; BONE-MARROW; IN-VITRO; TRANSPLANTATION; ENGRAFTMENT; GROWTH AB Transplanted cord blood (CB) hematopoietic stem cells (HSC) and progenitor cells (HPC) can treat malignant and nonmalignant disorders. Because long-term cryopreservation is critical for C8 banking and transplantation, we assessed the efficiency of recovery of viable HSC/HPC from individual CBs stored frozen for 15 yr. Average recoveries (+/-1 SD) of defrosted nucleated cells, colony-forming unit-granulocyte, -macrophage (CFU-GM), burst-forming unit-erythroid (BFU-E), and colony-forming unit-granulocyte, -erythrocyte, -monocyte, and -megakaryocyte (CFU-GEMM) were, respectively, 83 +/- 12, 95 +/- 16, 84 +/- 25, and 85 +/- 25 using the same culture conditions as for prefreeze samples. Proliferative capacities of CFU-GM, BFU-E, and CFU-GEMM were intact as colonies generated respectively contained up to 22,500,182,500, and 292,500 cells. Self-renewal of CFU-GEMM was also retained as replating efficiency of single CFU-GEMM colonies into 2degrees dishes was >96% and yielded 2degrees colonies of CFU-GM, BFU-E, and CFU-GEMM. Moreover, CD34(+)CD38(-) cells isolated by FACS after thawing yielded >250-fold ex vivo expansion of HPC. To assess HSC capability, defrosts from single collections were bead-separated into CD34(+) cells and infused into sublethally irradiated nonobese diabetic (NOD)/severe combined immunodeficient (SCID) mice. CD45(+) human cell engraftment with multilineage phenotypes was detected in mice after 11-13 wk; engrafting levels were comparable to that reported with fresh CB. Thus, immature human CB cells with high proliferative, replating, ex vivo expansion and mouse NOD/SCID engrafting ability can be stored frozen for > 15 yr, can be efficiently retrieved, and most likely remain effective for clinical transplantation. C1 Indiana Univ, Sch Med, Walther Oncol Ctr, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Wells Ctr Pediat Res, Indianapolis, IN 46202 USA. Walther Canc Inst, Indianapolis, IN 46208 USA. NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Broxmeyer, HE (reprint author), Indiana Univ, Sch Med, Walther Oncol Ctr, 1044 W Walnut St,R4-302, Indianapolis, IN 46202 USA. FU NHLBI NIH HHS [HL 55716, R01 HL 56416, R01 HL 67384, R01 HL055716, R01 HL056416, R01 HL067384]; NIDDK NIH HHS [R01 DK 53674, R01 DK053674] NR 41 TC 118 Z9 131 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 JAN 21 PY 2003 VL 100 IS 2 BP 645 EP 650 DI 10.1073/pnas.0237086100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 638UE UT WOS:000180589000049 PM 12518050 ER PT J AU Liu, SH Aaronson, H Mitola, DJ Leppla, SH Bugge, TH AF Liu, SH Aaronson, H Mitola, DJ Leppla, SH Bugge, TH TI Potent antitumor activity of a urokinase-activated engineered anthrax toxin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PLASMINOGEN-DEFICIENT MICE; PROTECTIVE ANTIGEN; LETHAL FACTOR; TUMOR-GROWTH; RECEPTOR; PROTEASE; CELLS; FURIN; GENE; IDENTIFICATION AB The acquisition of cell-surface urokinase plasminogen activator activity is a hallmark of malignancy. We generated an engineered anthrax toxin that is activated by cell-surface urokinase in vivo and displays limited toxicity to normal tissue but broad and potent tumoricidal activity. Native anthrax toxin protective antigen, when administered with a chimeric anthrax toxin lethal factor, Pseudomonas exotoxin fusion protein, was extremely toxic to mice, causing rapid and fatal organ damage. Replacing the furin activation sequence in anthrax toxin protective antigen with an artificial peptide sequence efficiently activated by urokinase greatly attenuated toxicity to mice. In addition, the mutation conferred cell-surface urokinase-dependent toxin activation in vivo, as determined by using a panel of plasminogen, plasminogen activator, plasminogen activator receptor, and plasminogen activator inhibitor-deficient mice. Surprisingly, toxin activation critically depended on both urokinase plasminogen activator receptor and plasminogen in vivo, showing that both proteins are essential cofactors for the generation of cell-surface urokinase. The engineered toxin displayed potent tumor cell cytotoxicity to a spectrum of transplanted tumors of diverse origin and could eradicate established solid tumors. This tumoricidal activity depended strictly on tumor cell-surface plasminogen activation. The data show that a simple change of protease activation specificity converts anthrax toxin from a highly lethal to a potent tumoricidal agent. C1 Natl Inst Dent & Craniofacial Res, NIH, Oral Infect & Immun Branch, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, NIH, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. RP Leppla, SH (reprint author), 30 Convent Dr, Bethesda, MD 20892 USA. NR 41 TC 85 Z9 93 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 21 PY 2003 VL 100 IS 2 BP 657 EP 662 DI 10.1073/pnas.0236849100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 638UE UT WOS:000180589000051 PM 12525700 ER PT J AU Dobolyi, A Palkovits, M Usdin, TB AF Dobolyi, A Palkovits, M Usdin, TB TI Expression and distribution of tuberoinfundibular peptide of 39 residues in the rat central nervous system SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE tuberoinfundibular peptide of 39 residues (TIP39); parathyroid hormone 2 (PTH2) receptor; paralemniscal nucleus; subparafascicular area; intralaminar complex of the thalamus; hypothalamus ID SUBPARAFASCICULAR THALAMIC NUCLEUS; MEDIAL GENICULATE-BODY; COCHLEAR ROOT NEURONS; SPINAL-CORD; BRAIN-STEM; PTH2 RECEPTOR; EFFERENT CONNECTIONS; INFERIOR COLLICULUS; RETICULAR-FORMATION; AUDIOGENIC STRESS AB Tuberoinfundibular peptide of 39 residues (TIP39) has been recently purified and identified as a selective ligand for the parathyroid hormone 2 receptor. As a next step toward understanding its functions, we report the expression and distribution of TIP39 in the rat central nervous system. In situ hybridization histochemistry and immunocytochemistry revealed TIP39-containing cell bodies in three distinct areas. The major one comprises the subparafascicular area posterior through the intralaminar nucleus of the thalamus; a second is the medial paralemniscal nucleus at the pontomesencephalic junction; and a third is in the dorsal and dorsolateral hypothalamic areas, which contained a few, scattered cell bodies. We found, in contrast to the highly restricted localization of TIP39-containing cell bodies, a much more widespread localization of TIP39-containing fibers. The highest density of fibers was observed in limbic areas such as the septum, the amygdala, and the bed nucleus of the stria terminalis; in areas involved in endocrine regulation, such as the hypothalamic dorsomedial, paraventricular, periventricular, and arcuate nuclei; in auditory areas, such as the ectorhinal and temporal cortices, inferior colliculus, medial geniculate body, and some of the nuclei of the superior olivary complex; and in the dorsolateral funiculus of the spinal cord. The localization of TIP39-containing nuclei and fibers provides an anatomical basis for previously demonstrated endocrine and nociceptive effects of TIP39 and suggests additional functions for TIP39, one apparent candidate being the regulation of auditory information processing. C1 NIMH, Genet Lab, Bethesda, MD 20892 USA. RP Usdin, TB (reprint author), NIMH, Genet Lab, 36 Convent Dr, Bethesda, MD 20892 USA. RI Dobolyi, Arpad/B-9089-2008; Palkovits, Miklos/F-2707-2013; OI Palkovits, Miklos/0000-0003-0578-0387 NR 67 TC 45 Z9 46 U1 1 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JAN 20 PY 2003 VL 455 IS 4 BP 547 EP 566 DI 10.1002/cne.10515 PG 20 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 630QD UT WOS:000180118800010 PM 12508326 ER PT J AU Chan, HW Kurago, ZB Stewart, CA Wilson, MJ Martin, MP Mace, BE Carrington, M Trowsdale, J Lutz, CT AF Chan, HW Kurago, ZB Stewart, CA Wilson, MJ Martin, MP Mace, BE Carrington, M Trowsdale, J Lutz, CT TI DNA methylation maintains allele-specific KTR gene expression in human natural killer cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE killer cells, natural; killer inhibitory receptor; alleles; DNA methylation; gene expression regulation ID NUCLEOTIDE PRIMER EXTENSION; IFN-GAMMA PRODUCTION; CD4(+) T-CELLS; CYTOSINE METHYLATION; INTERFERON-GAMMA; NK CELLS; RECEPTOR; TRANSCRIPTION; LOCUS; HYPOMETHYLATION AB Killer immunoglobulin-like receptors (KIR) bind self-major histocompatibility complex class I molecules, allowing natural killer (NK) cells to recognize aberrant cells that have down-regulated class I. NK cells express variable numbers and combinations of highly homologous clonally restricted KIR genes, but uniformly express KIR2DL4. We show that NK clones express both 2DL4 alleles and either one or both alleles of the clonally restricted KIR 3DL1 and 3DL2 genes. Despite allele-independent expression, 3DL1 alleles differed in the core promoter by only one or two nucleotides. Allele-specific 3DL1 gene expression correlated with promoter and 5' gene DNA hypomethylation in NK cells in vitro and in vivo. The DNA methylase inhibitor, 5-aza-2'-deoxycytidine, induced KIR DNA hypomethylation and heterogeneous expression of multiple KIR genes. Thus, NK cells use DNA methylation to maintain clonally restricted expression of highly homologous KIR genes and alleles. C1 Univ Iowa, Dept Pathol, Iowa City, IA 52242 USA. Univ Iowa, Dept Oral Pathol Oral Radiol & Oral Med, Iowa City, IA 52242 USA. Univ Iowa, Grad Program Immunol, Iowa City, IA 52242 USA. Univ Iowa, Grad Program Mol Biol, Iowa City, IA 52242 USA. Univ Cambridge, Dept Pathol, Div Immunol, Cambridge CB2 1QP, England. NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. RP Lutz, CT (reprint author), Univ Iowa, Dept Pathol, Iowa City, IA 52242 USA. RI Stewart, Charles/G-2470-2012 NR 59 TC 134 Z9 140 U1 2 U2 6 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 JAN 20 PY 2003 VL 197 IS 2 BP 245 EP 255 DI 10.1084/jem.20021127 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 640KW UT WOS:000180688900011 PM 12538663 ER PT J AU Agartz, I Shoaf, S Rawlings, RR Momenan, R Hommer, DW AF Agartz, I Shoaf, S Rawlings, RR Momenan, R Hommer, DW TI CSF monoamine metabolites and MRI brain volumes in alcohol dependence SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE magnetic resonance imaging; tissue segmentation; 5-hydroxyindoleacetic acid; homovanillic acid; 3-methoxy-4-hydroxyphenylethyleneglycol; cerebrospinal fluid ID CEREBROSPINAL-FLUID VARIABLES; 5-HYDROXYINDOLEACETIC ACID; HOMOVANILLIC-ACID; M-CHLOROPHENYLPIPERAZINE; SCHIZOPHRENIC-PATIENTS; HIPPOCAMPAL VOLUME; HEALTHY-VOLUNTEERS; PREFRONTAL CORTEX; CEREBRAL-CORTEX; SIZE AB Correlations between cerebrospinal fluid (CSF) concentrations of monoamine metabolites (MAM) and brain structure have been described in schizophrenia, but not in alcoholism. To investigate the relationship between monoaminergic transmission and brain structure in alcoholism, the metabolites of dopamine (homovanillic acid, HVA), norepineptirenine (3-methoxy-4-hydroxyphenylethyleneglycol, MHPG) and serotonin (5-hydroxyindoleacetic acid, 5-HIAA) were measured in lumbar CSF in 54 alcohol-dependent patients and 20 healthy subjects. The volumes of the cerebrum, total grey and white matter, total and ventricular CSF, left and right hippocampus, and corpus callosum area were measured with MRI. MHPG and age were positively correlated in alcoholic women. The MAM concentrations were not significantly correlated with the MRI volumes in the subject categories. There were no differences in MAM across subjects defined by diagnosis and gender, age of onset of alcoholism or comorbidity of psychiatric disorders. Total CSF, cerebrum, and white and grey matter tissue volumes differed between patients and healthy subjects. The greatest difference was the white matter reduction in alcoholic women. In alcoholic women and men, monoaminergic neurotransmission measured by the CSF MAM HVA, MHPG, and 5-HIAA is not significantly correlated with the size of different brain structures. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 NIAAA, Sect Electrophysiol & Brain Imaging, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. Karolinska Hosp, Dept Clin Neurosci, Clin Alcohol & Drug Addict Res Sect & Human Brain, SE-17176 Stockholm, Sweden. RP Agartz, I (reprint author), Karolinska Hosp, Dept Clin Neurosci, Psychiat Sect, S-17176 Stockholm, Sweden. NR 73 TC 17 Z9 17 U1 1 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD JAN 20 PY 2003 VL 122 IS 1 BP 21 EP 35 AR PII S0925-4927(02)00084-7 DI 10.1016/S0925-4927(02)00084-7 PG 15 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 653NY UT WOS:000181443900003 PM 12589880 ER PT J AU Bonne, O Louzoun, Y Aharon, I Krausz, Y Karger, H Lerer, B Bocher, M Freedman, N Chisin, R AF Bonne, O Louzoun, Y Aharon, I Krausz, Y Karger, H Lerer, B Bocher, M Freedman, N Chisin, R TI Cerebral blood flow in depressed patients: a methodological comparison of statistical parametric mapping and region of interest analyses SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE single photon emission computed tomography (SPECT); regional cerebral blood flow (rCBF); depression; region of interest (ROI); statistical parametric mapping (SPM) ID POSITRON-EMISSION-TOMOGRAPHY; CHILDHOOD SEXUAL ABUSE; GLUCOSE-METABOLISM; BRAIN; SCHIZOPHRENIA; DISORDER; PET; DISEASE; SPECT; ABNORMALITIES AB Functional brain imaging has assumed a leading role in neuropsychiatric research. However, findings reported for mental disorders often vary. Whether this reflects diversity in pathophysiology or heterogeneity of imaging techniques and data-analytic procedures is still unknown. This study compares region of interest (ROI) and statistical parametric mapping (SPM) analyses of a Tc99m-HMPAO single photon emission computed tomography (SPECT) imaging study of 23 depressed and 21 control subjects. Reduced regional cerebral blood flow (rCBF) was demonstrated by both methods in the right parietal and occipital lobes, but additional regions were identified only on ROI analysis (left temporal) and only on SPM analysis (left parietal). To investigate the contribution of SPM spatial normalization to these discrepancies, further ROI analyses were performed, applying the original ROI templates to normalized images, and applying regions identified by SPM to the original images. This study demonstrated considerable. overlap in findings of SPM and ROI analyses. Differences between these methods may be mostly related to subjective placement of ROIs in ROI analysis, and standardized warping inherent in normalization in SPM. Given the advantages and drawbacks of each procedure, the choice of methodology should be determined in accordance with the study design, and complementary use of both methods may be considered. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Hadassah Univ Hosp, Dept Psychiat, IL-91120 Jerusalem, Israel. Hadassah Univ Hosp, Dept Med Biophys & Nucl Med, IL-91120 Jerusalem, Israel. RP Bonne, O (reprint author), NIMH, Mood & Anxiety Disorders Program, 15K North Dr,Room 200, Bethesda, MD 20892 USA. RI louzoun, yoram/F-5874-2011 OI louzoun, yoram/0000-0003-1714-6148 NR 35 TC 18 Z9 18 U1 1 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD JAN 20 PY 2003 VL 122 IS 1 BP 49 EP 57 AR PII S0925-4927(02)00103-8 DI 10.1016/S0925-4927(02)00103-8 PG 9 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 653NY UT WOS:000181443900005 PM 12589882 ER PT J AU Tan, SH Baker, CC Stunkel, W Bernard, HU AF Tan, SH Baker, CC Stunkel, W Bernard, HU TI A transcriptional initiator overlaps with a conserved YY1 binding site in the long control region of human papillomavirus type 16 SO VIROLOGY LA English DT Article ID RNA-POLYMERASE-II; UPSTREAM REGULATORY REGION; CCAAT DISPLACEMENT PROTEIN; TATA-LESS PROMOTER; DEPENDENT TRANSCRIPTION; BOVINE PAPILLOMAVIRUS; GENE CONTAINS; E6 PROMOTER; TFII-I; DNA AB A single promoter has so far been found in the long control region (LCRs) of human papillomavirus-16 (HPV-16). Multiple promoters exist in the LCRs of several other papillomaviruses, which are spliced to become mRNAs for late and some early genes. Here we have investigated whether such promoters exist in the LCR of HPV-16. In in vitro transcription experiments, we detected a strong transcript starting 280 bp downstream from the 3' end of the L1 gene between a nuclear matrix attachment region and the epithelia I-specific enhancer. Promoter activity coincides with a GCCATTTT motif, which binds the transcription factor YY1 (YY1 -7436). The A of this motif is the first nucleotide of the transcripts and identifies YY1 -7436 as an initiator. Genomic segments with YYI-7436 initiate expression of a luciferase reporter gene in transfection experiments. Mutational analysis of YY1 -7436 suggests, however, that promoter function originates from another factor but YY1, which can contact overlapping sequences. Promoter activity of YY1 -7436 is modulated by upstream A-T-rich sequences, which bind the basal transcription factor TFIID, and it is stimulated by the viral E2 protein binding to a downstream E2 binding site. In differentiating W12 cells, which contain episomal HPV-16 copies, we detected transcripts including LCR sequences downstream of YY1 -7436, which were differentially spliced to early and late genes. However, we could not detect 5' ends mapping to YY1-7436, but we detected two novel HPV-16 promoters within the L1 gene. Conservation of the arrangement of the YY1 and E2 binding sites suggests a role in important biological functions, which, however, is difficult to confirm in every type of cell culture. The study of W12 cells complements the examination of YY1-7436 and points to yet undetected promoters upstream of the LCR. (C) 2003 Elsevier Science (USA). C1 Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. Inst Mol & Cell Biol, Singapore 117609, Singapore. NCI, Basic Res Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bernard, HU (reprint author), Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. RI ASTAR, IMCB/E-2320-2012; Tan, Shyh-Han/I-7037-2013 OI Tan, Shyh-Han/0000-0001-8250-7005 FU NCI NIH HHS [R01CA91964] NR 63 TC 12 Z9 14 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 20 PY 2003 VL 305 IS 2 BP 486 EP 501 DI 10.1006/viro.2002.1779 PG 16 WC Virology SC Virology GA 641DK UT WOS:000180729000025 PM 12573593 ER PT J AU Lederman, RJ Annex, BH AF Lederman, RJ Annex, BH CA TRAFFIC Investigators TI Angiogenesis with recombinant fibroblast growth factor-2 for claudication - Reply SO LANCET LA English DT Letter ID PERIPHERAL ARTERIAL-DISEASE C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Div Cardiol, Durham, NC 27710 USA. RP Lederman, RJ (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10,Room 2C713, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 2 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JAN 18 PY 2003 VL 361 IS 9353 BP 256 EP 256 DI 10.1016/S0140-6736(03)12284-2 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 637VX UT WOS:000180535400037 ER PT J AU Holmes, A Rodgers, RJ AF Holmes, A Rodgers, RJ TI Prior exposure to the elevated plus-maze sensitizes mice to the acute behavioral effects of fluoxetine and phenelzine SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE elevated plus-maze; test experience; anxiety; antidepressant; benzodiazepine; (Mouse) ID ONE-TRIAL TOLERANCE; MONOAMINE-OXIDASE INHIBITORS; GABA(A) RECEPTOR COMPLEX; BENZODIAZEPINE RECEPTOR; ANXIOLYTIC EFFICACY; MAJOR DEPRESSION; RAT-BRAIN; ANTIDEPRESSANT DRUGS; ANXIETY DISORDERS; RISK ASSESSMENT AB A single undrugged experience of the elevated plus-maze modifies future drug responses in the test. The present study investigated the effects of maze-experience on the acute behavioral effects of the monoamine oxidase inhibitor phenelzine and the serotonin reuptake inhibitor fluoxetine. Phenelzine (2.5 - 12.5 mg/kg) had no clear effect on plus-maze behavior in test-naive Swiss Webster mice, but dose-dependently increased anxiety-like behavior in maze-experienced subjects. Similarly, fluoxetine (5-20 mg/kg) produced non-significant trends for increased anxiety-like behavior in maze-naive mice, but significantly and dose-dependently increased anxiety-like behavior and suppressed locomotor activity in maze-experienced mice. The anxiogenic effects of the benzodiazepine receptor inverse agonist N-methyl-beta-carboline-3-carboxamide (FG 7142) (20 mg/kg) was abolished by prior test experience, suggesting an alteration in gamma-aminobutyric acid (GABA), benzodiazepine receptor function with maze-experience, However, the benzodiazepine receptor antagonist flumazenil (5-20 mg/kg) produced a silent profile regardless of maze-experience. Present findings provide further evidence demonstrating that prior test history is a critical consideration in mouse studies of anxiety-related behavior. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Leeds, Behav Pharmacol Lab, Sch Psychol, Leeds LS2 9JT, W Yorkshire, England. RP Holmes, A (reprint author), NIMH, Sect Behav Genom, Bldg 10,Room 4D11, Bethesda, MD 20892 USA. NR 73 TC 51 Z9 52 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JAN 17 PY 2003 VL 459 IS 2-3 BP 221 EP 230 DI 10.1016/S0014-2999(02)02874-1 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 637FY UT WOS:000180502000015 PM 12524150 ER PT J AU Fu, DX Kuo, YL Liu, BY Jeang, KT Giam, CZ AF Fu, DX Kuo, YL Liu, BY Jeang, KT Giam, CZ TI Human T-lymphotropic virus type I Tax activates I-kappa B kinase by inhibiting I-kappa B kinase-associated serine/threonine protein phosphatase 2A SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; CELL-GROWTH; PERSISTENT ACTIVATION; TRANSCRIPTION FACTORS; TRANSFORMING PROTEIN; MEDIATED ACTIVATION; CATALYTIC SUBUNIT; IKK-ALPHA; S6 KINASE; PHOSPHORYLATION AB I-kappaB kinase (IKK) is a serine/threonine kinase that phosphorylates I-kappaBalpha and I-kappaBbeta and targets them for polyubiquitination and proteasome-mediated degradation. IKK consists of two highly related catalytic subunits, alpha and beta, and a regulatory gamma subunit, which becomes activated after serine phosphorylation of the activation loops of the catalytic domains. The human T-lymphotropic retrovirus type-I trans-activator, Tax, has been shown to interact directly with IKKgamma and activates IKK via a mechanism not fully understood. Here we demonstrate that IKK binds serine/threonine protein phosphatase 2A (PP2A), and via a tripartite protein-protein interaction, Tax, IKKgamma, and PP2A form a stable ternary complex. In vitro, PP2A down-regulates active IKK prepared from Tax-producing MT4 cells. In the presence of Tax, however, the ability of PP2A to inactivate IKK is diminished. Despite their interaction with IKKgamma, PP2A-interaction-defective Tax mutants failed to activate NF-kappaB. Our data support the notion that IKKgamma-associated PP2A is responsible for the rapid deactivation of IKK, and inhibition of PP2A by Tax in the context of IKK.PP2A.Tax ternary complex leads to constitutive IKK and NF-kappaB activation. C1 Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Giam, CZ (reprint author), Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. RI Jeang, Kuan-Teh/A-2424-2008 FU NCI NIH HHS [R01 CA/GM 75688, R01 CA48709] NR 45 TC 76 Z9 76 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 JAN 17 PY 2003 VL 278 IS 3 BP 1487 EP 1493 DI 10.1074/jbc.M210631200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 636NK UT WOS:000180462200017 PM 12419799 ER PT J AU Ayyagari, R Gomes, XV Gordenin, DA Burgers, PMJ AF Ayyagari, R Gomes, XV Gordenin, DA Burgers, PMJ TI Okazaki fragment maturation in yeast - I. Distribution of functions between FEN1 AND DNA2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL NUCLEAR ANTIGEN; REPLICATION PROTEIN-A; BASE-EXCISION-REPAIR; SINGLE-STRANDED-DNA; SACCHAROMYCES-CEREVISIAE; POLYMERASE-DELTA; LIGASE-I; FLAP ENDONUCLEASE-1; MUTATION AVOIDANCE; PURIFIED PROTEINS AB In the presence of proliferating cell nuclear antigen, yeast DNA polymerase delta (Pol delta) replicated DNA at a rate of 40-60 nt/s. When downstream double-stranded DNA was encountered, Pol 8 paused, but most replication complexes proceeded to carry out strand-displacement synthesis at a rate of 1.5 nt/s. In the presence of the flap endonuclease FEN1 (Rad27), the complex carried out nick translation (1.7 nt/s). The Dna2 nuclease/helicase alone did not efficiently promote nick translation, nor did it affect nick translation with FEN1. Maturation in the presence of DNA ligase was studied with various downstream primers. Downstream DNA primers, RNA primers, and small 5'-flaps were efficiently matured by Pol 5 and FEN1, and Dna2 did not stimulate maturation. However, maturation of long 5'-flaps to which replication protein A can bind required both DNA2 and FEN1. The maturation kinetics were optimal with a slight molar excess over DNA of Pol delta, FEN1, and proliferating cell nuclear antigen. A large molar excess of DNA ligase substantially enhanced the rate of maturation and shortened the nick-translation patch (nucleotides excised past the RNA/DNA junction before ligation) to 4-6 nt from 8-12 nt with equimolar ligase. These results suggest that FEN1, but not DNA ligase, is a stable component of the maturation complex. C1 Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. Lindenwood Univ, St Charles, MO 63301 USA. RP Burgers, PMJ (reprint author), Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. OI Gordenin, Dmitry/0000-0002-8399-1836 FU NIGMS NIH HHS [GM58534, R01 GM032431] NR 62 TC 155 Z9 159 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 17 PY 2003 VL 278 IS 3 BP 1618 EP 1625 DI 10.1074/jbc.M209801200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 636NK UT WOS:000180462200034 PM 12424238 ER PT J AU Jin, YH Ayyagari, R Resnick, MA Gordenin, DA Burgers, PMJ AF Jin, YH Ayyagari, R Resnick, MA Gordenin, DA Burgers, PMJ TI Okazaki fragment maturation in yeast - II. Cooperation between the polymerase and 3 '-5 '-exonuclease activities of Pol delta in the creation of a ligatable nick SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE EXCISION-REPAIR; DOUBLE-STRAND BREAKS; ESSENTIAL IN-VIVO; DNA-POLYMERASE; SACCHAROMYCES-CEREVISIAE; DEOXYRIBONUCLEIC-ACID; 2 FORMS; REPLICATION; PCNA; HELICASE AB To address the different functions of Pol delta and FEN1 (Rad27) in Okazaki fragment maturation, exonuclease-deficient polymerase Pol delta-01 and Pol delta-5DV (corresponding to alleles pol3-01-(D321A, E323A) and pol3-5DV-(D520V), respectively) were purified and characterized in this process. In the presence of the replication clamp PCNA, both wild-type and exo(-) Poldelta carried out strand displacement synthesis with similar rates; however, initiation of strand displacement synthesis was much more efficient with Pol delta-exo(-). When Pol delta-exo(-) encountered a downstream primer, it paused with 3-5 nucleotides of the primer displaced, whereas the wild type carried out precise gap filling. Consequently, in the absence of FEN1, Pol 5 exonuclease activity was essential for closure of simple gaps by DNA ligase. Compared with wild type, Okazaki fragment maturation with Pol delta-exo(-) proceeded with an increased duration of nick translation prior to ligation. Maturation was efficient in the absence of Dna2 and required Dna2 only when FEN1 activity was compromised. In agreement with these results, the proposed generation of double strand breaks in pol3-exo(-) rad27 mutants was suppressed by the overexpression of DNA2. Further genetic studies showed that pol3-exo- rad27 double mutants were sensitive to alkylation damage consistent with an in vivo defect in gap filling by exonuclease-deficient Pol delta. C1 Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. Lindenwood Univ, St Charles, MO 63301 USA. RP Burgers, PMJ (reprint author), Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. FU NIGMS NIH HHS [R01 GM032431] NR 33 TC 99 Z9 101 U1 2 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 17 PY 2003 VL 278 IS 3 BP 1626 EP 1633 DI 10.1074/jbc.M209803200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 636NK UT WOS:000180462200035 PM 12424237 ER PT J AU Santos, JH Hunakova, L Chen, YM Bortner, C Van Houten, B AF Santos, JH Hunakova, L Chen, YM Bortner, C Van Houten, B TI Cell sorting experiments link persistent mitochondrial DNA damage with loss of mitochondrial membrane potential and apoptotic cell death SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NORMAL HUMAN FIBROBLASTS; BASE EXCISION-REPAIR; OXIDATIVE STRESS; GROWTH ARREST; HYDROGEN-PEROXIDE; OXYGEN-TOXICITY; SENESCENCE; ENZYME; H2O2; P53 AB In order to understand the molecular events following oxidative stress, which lead to persistence of lesions in the mtDNA, experiments were performed on normal human fibroblast (NHF) expressing human telomerase reverse transcriptase (hTERT). The formation and repair of H2O2-induced DNA lesions were examined using quantitative PCR. It was found that NHF hTERTs show extensive mtDNA damage (similar to4 lesions/10 kb) after exposure to 200 muM H2O2, which is partially repaired during a recovery period of 6 h. At the same time, the nDNA seemed to be completely resistant to damage. Cell sorting experiments revealed persistent mtDNA damage at 24 h only in the fraction of cells with low mitochondrial membrane potential (DeltaPsim). Further analysis also showed increased production of H2O2 by these cells, which subsequently undergo apoptosis. This work supports a hypothesis for a feed-forward cascade of reactive oxygen species generation and mtDNA damage and also suggested a possible mechanism for persistence of lesions in the mtDNA involving a drop in DeltaPsim, compromised protein import, secondary reactive oxygen species generation, and loss of repair capacity. C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Canc Res Inst, Bratislava 83391, Slovakia. RP Van Houten, B (reprint author), NIEHS, Mol Genet Lab, NIH, 111 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. RI Hunakova, Luba/E-4523-2015 NR 50 TC 102 Z9 108 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 JAN 17 PY 2003 VL 278 IS 3 BP 1728 EP 1734 DI 10.1074/jbc.M208752200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 636NK UT WOS:000180462200049 PM 12424245 ER PT J AU Wei, SJ Trempus, CS Cannon, RE Bortner, CD Tennant, RW AF Wei, SJ Trempus, CS Cannon, RE Bortner, CD Tennant, RW TI Identification of Dss1 as a 12-O-tetradecanoylphorbol-13-acetate-responsive gene expressed in keratinocyte progenitor cells, with possible involvement in early skin tumorigenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSGENIC TG.AC MICE; STEM-CELLS; MOUSE SKIN; P53 HOMOLOG; PAPILLOMA DEVELOPMENT; SURFACE PHENOTYPE; EPIDERMAL-CELLS; CANDIDATE GENE; BETA-CATENIN; HAIR CYCLE AB This study identifies genes expressed early in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin carcinogenesis in genetically initiated Tg.AC nu-Ha-ras transgenic mice. Keratinocyte progenitor cells from TPA-treated Tg.AC mice were isolated with fluorescence-activated cell sorting and expression was analyzed using cDNA microarray technology. Eleven genes were identified whose expression changed significantly in response to carcinogen treatment. Deleted in split hand/split foot 1 (Dss1) is a gene associated with a heterogeneous limb developmental disorder called split hand/split foot malformation. cDNA microarray expression analysis showed that the mouse homologue of Dss1 is induced by TPA. Dss1 overexpression was detected by Northern blot analysis in early TPA-treated hyperplastic skins and in JB6 Cl 41-5a epidermal cells. Interestingly, Dss1 expression was also shown to be elevated in skin papillomas relative to normal skins, and further increased in squamous cell malignancies. Functional studies by ectopically constitutive expression of Dss1 in JB6 Cl 41-5a preneoplastic cells strongly increased focus formation and proliferation of these cells and enhanced efficiency of neoplastic transformation of the cells in soft agar. These results strongly suggest that Dss1 is a TPA-inducible gene that may play an important role in the early stages of skin carcinogenesis. C1 NIEHS, Natl Ctr Toxicogenomics, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Wei, SJ (reprint author), NIEHS, Natl Ctr Toxicogenomics, NIH, Bldg 101,Rm F-149,MD F1-05,POB 12233, Res Triangle Pk, NC 27709 USA. NR 48 TC 27 Z9 27 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 JAN 17 PY 2003 VL 278 IS 3 BP 1758 EP 1768 DI 10.1074/jbc.M206328200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 636NK UT WOS:000180462200053 PM 12419822 ER PT J AU Zhu, YJ Crawford, SE Stellmach, V Dwivedi, RS Rao, MS Gonzalez, FJ Qi, C Reddy, JK AF Zhu, YJ Crawford, SE Stellmach, V Dwivedi, RS Rao, MS Gonzalez, FJ Qi, C Reddy, JK TI Coactivator PRIP, the peroxisome proliferator-activated receptor-interacting protein, is a modulator of placental, cardiac, hepatic, and embryonic development SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID THYROID-HORMONE RECEPTOR; NUCLEAR RECEPTORS; BINDING PROTEIN; TRAP220 COMPONENT; GENE; COMPLEX; CBP; DISRUPTION; CLONING; CANCER AB Nuclear receptor coactivator PRIP (peroxisome proliferator-activated receptor (PPARgamma)-interacting protein) and PRIP-interacting protein with methyltransferase activity, designated PIMT, appear to serve as linkers between cAMP response element-binding protein-binding protein (CBP)/p300-anchored and PBP (PPARgamma-binding protein)-anchored coactivator complexes involved in the transcriptional activity of nuclear receptors. To assess the biological significance of PRIP, we disrupted the PRIP gene in mice by homologous recombination. Mice nullizygous for PRIP died between embryonic day 11.5 and 12.5 (postcoitum) due in most part to defects in the development of placenta, heart, liver, nervous system, and retardation of embryonic growth. Transient transfection assays using fibroblasts isolated from PRIP-/- embryos revealed a significant decrease in the capacity for ligand-dependent transcriptional activation of retinoid X receptor a and to a lesser effect on PPARgamma transcriptional activity. These observations indicate that PRIP like PBP, CBP, and p300 is an essential and nonredundant coactivator. C1 Northwestern Univ, Feinberg Sch Med, Dept Pathol, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Pediat, Chicago, IL 60611 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Reddy, JK (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Pathol, 303 W Chicago Ave, Chicago, IL 60611 USA. FU NCI NIH HHS [CA84472, CA64239, CA88898]; NIEHS NIH HHS [K08 ES00356]; NIGMS NIH HHS [GM23750] NR 40 TC 58 Z9 60 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 17 PY 2003 VL 278 IS 3 BP 1986 EP 1990 DI 10.1074/jbc.C200634200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 636NK UT WOS:000180462200082 PM 12446700 ER PT J AU Fisher, TS Darden, T Prasad, VR AF Fisher, TS Darden, T Prasad, VR TI Substitutions at Phe61 in the beta 3-beta 4 hairpin of HIV-1 reverse transcriptase reveal a role for the fingers subdomain in strand displacement DNA synthesis SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE human immunodeficiency virus; reverse transcriptase; displacement DNA synthesis; fingers subdomain; processivity ID HUMAN-IMMUNODEFICIENCY-VIRUS; CRYSTAL-STRUCTURE; RESISTANCE MUTATIONS; ANGSTROM RESOLUTION; TEMPLATE BINDING; THUMB SUBDOMAIN; K65R MUTATION; MINOR-GROOVE; IN-VITRO; TYPE-1 AB Unlike most DNA polymerases, retroviral reverse transcriptases (RTs) are capable of strand displacement DNA synthesis in vitro, unassisted by other proteins. While human immunodeficiency virus type 1 (HIV-1) RT has been shown to possess this rare ability, the structural determinants responsible are unknown. X-Ray crystallographic and biochemical studies have indicated that the beta3-beta4 hairpin of the fingers subdomain of HIV-1 RT contains key contacts for the incoming template strand. In order to assess the possible role of the fingers subdomain in strand displacement synthesis, a set of substitutions was created at the highly conserved Phe61 residue, which is thought to contact the template strand immediately ahead of the dNTP-binding site. Purified heterodimeric RTs containing Phe61 substitutions displayed altered degrees of strand displacement synthesis on nicked and gapped duplex DNA templates with the relative order being: F61Y greater than or equal to F61L > wild-type = F61A > F61W. In order to verify that the effects on strand displacement synthesis were not an indirect effect of alterations in processivity, all Phe61. mutants were tested for processive polymerization. While the strand displacement activity of F61W RT variant was affected severely, it displayed a wild-type-like processivity. In contrast, both F61L and F61Y substitutions, despite showing enhanced strand displacement synthesis, displayed reduced processivity. In contrast, the processivity of F61A mutant, which had displayed nearly wild-type-like strand displacement synthesis, was affected most. These results showed that the effects of Phe61 substitutions on strand displacement are not due to global changes in polymerase processivity. Analysis of pause sites during DNA polymerization on double-stranded templates revealed that the wild-type and the Phe61 mutant RTs interact with the template quite differently. Modeling a 5 nt duplex DNA ahead of the dNTP-binding site of HIV-1 RT suggested a correlation between the ability of the side-chain of the amino acid residue at position 61 to stabilize the first base-pair of the DNA duplex to be melted and the degree of strand displacement synthesis. Our results confirm a role for F61 residue in processive synthesis and indicate that the fingers subdomain harbors a structural determinant of strand displacement synthesis by HIV-1 RT. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Yeshiva Univ Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Prasad, VR (reprint author), Yeshiva Univ Albert Einstein Coll Med, Dept Microbiol & Immunol, Golding Bldg 401,1300 Morris Pk Ave, Bronx, NY 10461 USA. FU NIAID NIH HHS [R01 AI30861]; NIGMS NIH HHS [T32-GM07491] NR 52 TC 25 Z9 25 U1 0 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 17 PY 2003 VL 325 IS 3 BP 443 EP 459 DI 10.1016/S0022-2836(02)01225-1 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 637ZZ UT WOS:000180544700004 PM 12498795 ER PT J AU Hyman, SE Fenton, WS AF Hyman, SE Fenton, WS TI Medicine: What are the right targets for psychopharmacology? SO SCIENCE LA English DT Editorial Material ID SCHIZOPHRENIA; DYSFUNCTION C1 NIMH, Nihon Univ, US Dept HHS, Bethesda, MD 20896 USA. Harvard Univ, Cambridge, MA 02138 USA. RP Fenton, WS (reprint author), NIMH, Nihon Univ, US Dept HHS, Bethesda, MD 20896 USA. NR 22 TC 177 Z9 179 U1 2 U2 7 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 JAN 17 PY 2003 VL 299 IS 5605 BP 350 EP 351 DI 10.1126/science.1077141 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 635YB UT WOS:000180426800028 PM 12532001 ER PT J AU Berger, VW Bears, JD AF Berger, VW Bears, JD TI When can a clinical trial be called 'randomized'? SO VACCINE LA English DT Article DE allocation concealment; alternation; selection bias ID ACELLULAR PERTUSSIS VACCINES; HEPATITIS-A; ANTIBODY-RESPONSE; DOUBLE-BLIND; QUALITY; EFFICACY; IMMUNOGENICITY; VACCINATION; CHILDREN; POLYSACCHARIDE AB It is widely recognized that, in the context of the evaluation of medical interventions, randomized clinical trials constitute the gold standard. This is because randomization tends to balance both measured and unmeasured baseline characteristics, allows for masking, and provides a basis for inference. It is understandable, then, that investigators would wish to utilize this methodology whenever it is feasible to do so. Unfortunately, come studies are labeled as randomized when in fact they are not. These studies then receive more credibility, and influence medical practice, more than they deserve to. After reviewing the benefits of randomization, paying particular attention to the specific aspects of randomization that confer each benefit, we will explore the issue of what constitutes a randomized study. Published by Elsevier Science Ltd. C1 NCI, EPN, Bethesda, MD 20892 USA. Univ Maryland Baltimore Cty, Dept Math & Stat, Baltimore, MD 21250 USA. Colby Coll, Dept Math, Waterville, ME 04901 USA. RP Berger, VW (reprint author), NCI, EPN, Suite 3131,6130 Execut Blvd,MSC-7354, Bethesda, MD 20892 USA. NR 56 TC 23 Z9 25 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JAN 17 PY 2003 VL 21 IS 5-6 BP 468 EP 472 AR PII S0264-410X(02)00475-9 DI 10.1016/S0264-410X(02)00475-9 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 645BM UT WOS:000180956400018 PM 12531645 ER PT J AU Shan, ZH Haaf, T Popescu, NC AF Shan, ZH Haaf, T Popescu, NC TI Identification and characterization of a gene encoding a putative mouse Rho GTPase activating protein gene 8, Arhgap8 SO GENE LA English DT Article DE chromosome 15; Rho GAP ID CLONING; REGION AB Rho GTPase activating proteins promote the intrinsic GTP hydrolysis activity of Rho family proteins. We isolated a putative mouse ortholog of the human Rho GTPase activating protein 8, ARHGAP8. The open reading frame encodes a peptide of 3 87 amino. acids with high homology to human ARHGAP8 in its N-terminal domain. Both radiation hybrid mapping and fluorescent in situ hybridization localized the gene to mouse chromosome 15E. The 23 kb genomic Arhgap8 sequence consists of eight exons and seven introns. Northern blot and RT-PCR analyses showed that a transcript of approximately 1.9 kb is ubiquitously expressed in various adult mouse tissues with particularly strong expression in kidney. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NCI, Expt Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Mainz, Sch Med, Inst Human Genet, D-55101 Mainz, Germany. RP Popescu, NC (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, Bldg 37,Room 4128,37 Convent Dr,MSC4258, Bethesda, MD 20892 USA. NR 15 TC 6 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD JAN 16 PY 2003 VL 303 BP 55 EP 61 DI 10.1016/S0378-1119(02)01143-5 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 647ZP UT WOS:000181124200005 PM 12559566 ER PT J AU Wei, CQ Gao, Y Lee, K Guo, R Li, BH Zhang, MC Yang, DJ Burke, TR AF Wei, CQ Gao, Y Lee, K Guo, R Li, BH Zhang, MC Yang, DJ Burke, TR TI Macrocyclization in the design of Grb2 SH2 domain-binding ligands exhibiting high potency in whole-cell systems SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PHOSPHATE-CONTAINING LIGANDS; TYROSINE KINASE INHIBITORS; RING-CLOSING METATHESIS; ALPHA-AMINO-ACIDS; SIGNAL-TRANSDUCTION; OLEFIN METATHESIS; GROWTH-FACTOR; ANTAGONISTS; PEPTIDES; CATALYSTS AB While most SH2 domains bind phosphotyrosyl (pTyr) containing peptides in extended fashion, the growth factor receptor-bound protein 2 (Grb2) SH2 domain preferentially binds ligands in bend conformations. Accordingly, incorporation of bend-inducing functionality into synthetic ligands could potentially enhance their affinity for this SH2 domain. A macrocyclic tripeptide mimetic that contains a simplified pTyr surrogate lacking an alpha-nitrogen has recently been shown to exhibit high Grb2 SH2 domain-binding affinity in extracellular ELISA-based assays. However, the same compound is largely ineffective in whole-cell assays. It is known that acidic functionality originating from the alpha-nitrogen of pTyr residues or from the alpha-position of P-0 pTyr mimetics not only increases binding affinity of peptides to Grb2 SH2 domains in extracellular assays but also enhances potency in cell-based systems. Such functionality is absent from the previously reported macrocycle. Therefore, the current study was undertaken to examine the effects of introducing carboxylic functionality at the pTyr mimetic alpha-position of macrocyclic ligands. It was found that such a modification not only enhanced Grb2 SH2 domain binding in extracellular assays but also conferred high efficacy in whole-cell systems. The most potent compound of the current study exhibited an IC50 value of 0.002 muM in an extracellular ELISA-based assay, and in MDA-MB-453 cells, it both inhibited the association of Grb2 with p185(erbB-2) and exhibited antimitogenic effects with submicromolar IC50 values. C1 NCI, Ctr Canc Res, Med Chem Lab, NIH, Ft Detrick, MD 21702 USA. Univ Michigan, Sch Med, Dept Hematol Oncol, Ann Arbor, MI 48109 USA. RP Burke, TR (reprint author), NCI, Ctr Canc Res, Med Chem Lab, NIH, POB B,Bldg 376,Boyles St, Ft Detrick, MD 21702 USA. EM tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014 NR 28 TC 45 Z9 46 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JAN 16 PY 2003 VL 46 IS 2 BP 244 EP 254 DI 10.1021/jm0203635 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 633WF UT WOS:000180307000008 PM 12519063 ER PT J AU Crotty, S Kersh, EN Cannons, J Schwartzberg, PL Ahmed, R AF Crotty, S Kersh, EN Cannons, J Schwartzberg, PL Ahmed, R TI SAP is required for generating long-term humoral immunity SO NATURE LA English DT Article ID LINKED LYMPHOPROLIFERATIVE-DISEASE; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; T-CELLS; VIRAL-INFECTION; ENCODING GENE; PLASMA-CELLS; BONE-MARROW; B-CELLS; MUTATIONS; MEMORY AB Long-lived plasma cells and memory B cells are the primary cellular components of long-term humoral immunity and as such are vitally important for the protection afforded by most vaccines. The SAP gene has been identified as the genetic locus responsible for X-linked lymphoproliferative disease, a fatal immunodeficiency(1-4). Mutations in SAP have also been identified in some cases of severe common variable immunodeficiency disease(5,6). The underlying cellular basis of this genetic disorder remains unclear. We have used a SAP knockout mouse model system to explore the role of SAP in immune responses. Here we report that mice lacking expression of SAP generate strong acute IgG antibody responses after viral infection, but show a near complete absence of virus-specific long-lived plasma cells and memory B cells, despite the presence of virus-specific memory CD4(+) T cells. Adoptive transfer experiments show that SAP-deficient B cells are normal and the defect is in CD4(+) T cells. Thus, SAP has a crucial role in CD4(+) T-cell function: it is essential for late B-cell help and the development of long-term humoral immunity but is not required for early B-cell help and class switching. C1 Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Ahmed, R (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. NR 30 TC 266 Z9 278 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JAN 16 PY 2003 VL 421 IS 6920 BP 282 EP 287 DI 10.1038/nature01318 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 635KG UT WOS:000180397600051 PM 12529646 ER PT J AU Srinivasan, A Wolfenden, LL Song, XY Mackie, K Hartsell, TL Jones, HD Diette, GB Orens, JB Yung, RC Ross, TL Merz, W Scheel, PJ Haponik, EF Perl, TM AF Srinivasan, A Wolfenden, LL Song, XY Mackie, K Hartsell, TL Jones, HD Diette, GB Orens, JB Yung, RC Ross, TL Merz, W Scheel, PJ Haponik, EF Perl, TM TI An outbreak of Pseudomonas aeruginosa infections associated with flexible bronchoscopes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS; TRANSMISSION; CONTAMINATION; ENDOSCOPY AB Background: Endoscopes, including bronchoscopes, are the medical devices most frequently associated with outbreaks of nosocomial infections. We investigated an outbreak of Pseudomonas aeruginosa infections after bronchoscopic procedures. Methods: Microbiologic results were reviewed to determine the rates of recovery of P. aeruginosa from bronchoalveolar-lavage specimens. Environmental samples from endoscopes and the endoscopy suite were cultured. Medical records were reviewed to identify infections in the 14 days after a bronchoscopy. Results: The rate of recovery of P. aeruginosa from bronchoalveolar-lavage specimens obtained with use of endoscopy-suite bronchoscopes increased from 10.4 percent at base line to 31.0 percent during the outbreak (relative risk, 2.97; 95 percent confidence interval, 2.28 to 3.90). Cultures of samples from three bronchoscopes grew P. aeruginosa, whereas cultures of samples from the environment, instrument-cleaning machines, and gastrointestinal endoscopes did not. The three bronchoscopes had been part of a nationwide recall. A total of 414 patients underwent bronchoscopy during the outbreak, and there were 48 respiratory tract and bloodstream infections among 39 of these patients (9.4 percent). In 32 infections (66.7 percent), P. aeruginosa was confirmed as a potentially causative organism. Exposure to a potentially contaminated bronchoscope may have had a role in the death of three patients. The rate of recovery of P. aeruginosa returned to base line after the instruments were removed from service. Conclusions: This large outbreak of P. aeruginosa infections related to bronchoscopy was apparently caused by a loose biopsy-port cap in the bronchoscopes. Instrument safety and surveillance methods for bronchoscopy must be improved, and better recall procedures are needed for medical devices. C1 Johns Hopkins Med Inst, Dept Hosp Epidemiol & Infect Control, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Div Infect Dis, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Div Pulm & Crit Care Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Div Nephrol, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Srinivasan, A (reprint author), Johns Hopkins Univ Hosp, Off Antibiot Management, 600 N Wolfe St,Carnegie Bldg,Rm 284, Baltimore, MD 21287 USA. FU ODCDC CDC HHS [UR8/CCU315092] NR 20 TC 99 Z9 108 U1 1 U2 3 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 JAN 16 PY 2003 VL 348 IS 3 BP 221 EP 227 DI 10.1056/NEJMoa021808 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 635GJ UT WOS:000180390600006 PM 12529462 ER PT J AU Yawata, T Kamino, H Kugoh, H Katoh, M Nomura, N Oishi, M Horikawa, I Barrett, JC Oshimura, M AF Yawata, T Kamino, H Kugoh, H Katoh, M Nomura, N Oishi, M Horikawa, I Barrett, JC Oshimura, M TI Identification of a <= 600-kb region on human chromosome 1q42.3 inducing cellular senescence SO ONCOGENE LA English DT Article DE cellular senescence; chromosome transfer; chromosome 1; telomerase; mouse melanoma ID TELOMERASE REPRESSOR GENE; HAMSTER EMBRYO CELLS; HUMAN-BREAST-CANCER; IMMORTAL CELLS; INDEPENDENT SENESCENCE; SUPPRESSES TELOMERASE; MULTIPLE PATHWAYS; EPITHELIAL-CELLS; GROWTH ARREST; HUMAN TUMOR AB The introduction of a human chromosome 1 via microcell-mediated chromosome transfer (MMCT) induces the cellular senescence in mouse melanoma B16-F10 cells. The senescent cells maintained still the telomerase activity, which is frequently associated with immortal growth of human cells, suggesting that a telomerase-independent mechanism is involved in the senescence observed in this mouse cell line. To map the senescence-inducing gene to a specific chromosomal region, we took two experimental approaches: identification of a minimal region with the senescence-inducing activity via MMCT of a series of subchromosomal transferrable fragments (STFs), each consisting of a different profile of human chromosome 1-derived regions, and identification of a region commonly deleted from the transferred chromosome 1 in the revertant clones that escaped cellular senescence. These approaches identified a 2.7-3.0 Mb of senescence-inducing region shared among the active STFs and a 2.4-3.0 Mb of commonly deleted region in the revertant clones. These two regions overlapped each other to map the responsible gene at the 450 to 600-kb interval between UniSTS93710 and D1S3542 on chromosome 1q42.3. This study provides essential information and materials for cloning and characterization of a novel senescence-inducing gene that functions in a telomerase-independent pathway, which is likely to be conserved between mice and humans. C1 Tottori Univ, Fac Med, Sch Life Sci, Dept Mol & Cell Genet, Yonago, Tottori 6838503, Japan. NCI, Lab Biosyst & Canc, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Tottori Univ, Dept Human Genome Sci, Div Life Sci, Grad Sch Med, Yonago, Tottori 6838503, Japan. Kazusa DNA Res Inst, Chiba, Japan. RP Oshimura, M (reprint author), Tottori Univ, Fac Med, Sch Life Sci, Dept Mol & Cell Genet, 86 Nishimachi, Yonago, Tottori 6838503, Japan. NR 49 TC 7 Z9 7 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 16 PY 2003 VL 22 IS 2 BP 281 EP 290 DI 10.1038/sj.onc.1206143 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 634CL UT WOS:000180322400013 PM 12527897 ER PT J AU Li, WJ Hu, N Su, F Wang, CY Goldstein, AM Wang, Y Emmert-Buck, MR Roth, MJ Guo, WJ Taylor, PR AF Li, WJ Hu, N Su, F Wang, CY Goldstein, AM Wang, Y Emmert-Buck, MR Roth, MJ Guo, WJ Taylor, PR TI Allelic loss on chromosome 13q14 and mutation in deleted in cancer 1 gene in esophageal squamous cell carcinoma SO ONCOGENE LA English DT Article DE DICE1; LOH; SSCP; mutation; polymorphism; esophagus ID TUMOR-SUPPRESSOR GENES; SUSCEPTIBILITY GENE; HETEROZYGOSITY; IDENTIFICATION; CHINA; POPULATION; REGIONS AB Previous studies have shown frequent allelic loss on chromosome 13 in esophageal squamous cell carcinoma (ESCC). We assessed the frequency of allelic loss on chromosome 13q14 and mutations of deleted in cancer 1 (DICE1) (also found on 13q14) in ESCC patients to determine if this candidate tumor suppressor gene has a role in the development of ESCC, and whether this gene was an inactivation target for allelic loss on chromosome 13q14. Initially, we examined allelic loss at five markers flanking DICE1 in 56 ESCC patients from Shanxi Province, China, and then examined the entire coding sequence of this gene for mutations using polymerase chain reaction-single-strand confirmation polymorphism (PCR-SSCP) analysis and DNA sequencing. Subsequently, we extended our evaluation to an additional 80 ESCC patients and 232 healthy individuals to confirm the germline variant found in the initial 56 ESCC patients. The frequencies of allelic loss were 71, 58, and 75% for D13S325, D13S757, and D13S887, respectively, in the initial 56 ESCC patients studied. Overall, 73% of informative patients had loss of heterozygosity (LOH) for at least one of these three markers. Somatic mutations were identified in three patients (3/56, 5%), and one novel polymorphism was identified in 3% of ESCC patients (4/ 136) and 3% of healthy individuals (6/232). We conclude that DICE1 mutations occur in ESCC but are infrequent. The candidate tumor suppressor gene corresponding to the frequent allelic loss on chromosome 13q14 in ESCC remains unknown. C1 NCI, Canc Prevent Studies Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Shanxi Canc Hosp & Inst, Taiyuan 030013, Shanxi, Peoples R China. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Taylor, PR (reprint author), NCI, Canc Prevent Studies Branch, Ctr Canc Res, 6116 Execut Blvd,Suite 705, Bethesda, MD 20892 USA. NR 20 TC 17 Z9 19 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JAN 16 PY 2003 VL 22 IS 2 BP 314 EP 318 DI 10.1038/sj.onc.1206098 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 634CL UT WOS:000180322400017 PM 12527901 ER PT J AU Plato, CC Garruto, RM Galasko, D Craig, UK Plato, M Gamst, A Torres, JM Wiederholt, W AF Plato, CC Garruto, RM Galasko, D Craig, UK Plato, M Gamst, A Torres, JM Wiederholt, W TI Amyotrophic lateral sclerosis and parkinsonism-dementia complex of Guam: Changing incidence rates during the past 60 years SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE amyotrophic lateral sclerosis; dementia; parkinsonian disorders AB In the 1950s, the incidence of amyotrophic lateral sclerosis (ALS, or Lytico) and parkinsonism-dementia complex (PDC, or Bodig) on the island of Guam was much higher than anywhere else in the world. From the late 1960s to the early 1980s, the incidence of both disorders has decreased. The objective of the present study was to ascertain whether the decreasing incidence continued until the end of the century (1999). The average annual incidence of ALS and PDC was calculated for each 5-year period from 1940 to 1999, utilizing registration records of all ALS and PDC cases on Guam during that period. The results of this study confirmed that the incidence of ALS declined steadily during the past 40 years. The incidence of PDC also declined until the late 1980s but, unlike ALS, showed a slight increase from 1980 to 1999. The rapid decrease in incidence is not likely to be due to genetic factors. Instead, it is most likely to be the results of radical socioeconomic, ethnographic, and ecologic changes brought about by the rapid westernization of Guam. C1 Univ Calif San Diego, Sch Med, Dept Neurosci, La Jolla, CA 92093 USA. SUNY Binghamton, Dept Anthropol & Biol Sci, Binghamton, NY USA. NIH, Cent Nervous Syst Studies Lab, Bethesda, MD 20892 USA. Univ Guam, Mangilao, GU USA. Athi Media, San Diego, CA USA. RP Plato, CC (reprint author), Univ Calif San Diego, Sch Med, Dept Neurosci, 9500 Gilman Dr, La Jolla, CA 92093 USA. FU NIA NIH HHS [AG 14382] NR 40 TC 89 Z9 95 U1 4 U2 19 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 JAN 15 PY 2003 VL 157 IS 2 BP 149 EP 157 DI 10.1093/aje/kwf175 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 634UG UT WOS:000180359300008 PM 12522022 ER PT J AU Hanover, JA Yu, S Lubas, WB Shin, SH Ragano-Caracciola, M Kochran, J Love, DC AF Hanover, JA Yu, S Lubas, WB Shin, SH Ragano-Caracciola, M Kochran, J Love, DC TI Mitochondrial and nucleocytoplasmic isoforms of O-linked GlcNAc transferase encoded by a single mammalian gene SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article ID ESTROGEN-RECEPTOR-BETA; N-ACETYLGLUCOSAMINE; NUCLEAR-PORE; TETRATRICOPEPTIDE REPEATS; GLYCOSYLATION/O-PHOSPHORYLATION; PROTEIN INTERACTIONS; C-MYC; DOMAIN; P62; EXPRESSION AB O-Linked N-acetylglucosamine (GlcNAc) transferase (OGT) mediates a novel hexosamine-dependent signal transduction pathway. Yet, little is known about the regulation of ogt gene expression in mammals. We report the sequence and characterization of the mouse ogt locus and provide a comparison with the human and rat ogt genes. The mammalian ogt genes are similar in structure and exhibit similar to80% sequence identity. The mouse and human ogt genes contain two potential promoters producing four major transcripts. By analyzing 56 human cDNA clones and other existing expressed sequence tags, we found that at least three protein products differing at their amino terminus result from alternative splicing. We used OGT-specific antisera to demonstrate the presence of these isoforms in HeLa cells. The longest form is a nucleocytoplasmic OGT (ncOGT) with 12 tetratricopeptide repeats (TPRs); a shorter form of OGT encodes a mitochondrially sequestered enzyme with 9 TPRs and an N-terminal mitochondrion-targeting sequence (mOGT). An even shorter form of OGT (sOGT) contains only 2 TPRs. The genomic organization of OGT appears to be highly conserved throughout metazoan evolution. These results provide the basis for a more detailed analysis of the significance and regulation of the nucleocytoplasmic and mitochondrial isoforms of OGT in mammals. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Hanover, JA (reprint author), NIDDK, Lab Cell Biochem & Biol, NIH, Bldg 8,Room 402,8 Ctr Dr,MSC 0850, Bethesda, MD 20892 USA. NR 36 TC 102 Z9 107 U1 5 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 15 PY 2003 VL 409 IS 2 BP 287 EP 297 AR PII S0003-9861(02)00578-7 DI 10.1016/S0003-9861(02)00578-7 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 633ZC UT WOS:000180314100005 PM 12504895 ER PT J AU Breunis, MN Kupka, RW Nolen, WA Suppes, T Denicoff, KD Leverich, GS Post, RM Drexhage, HA AF Breunis, MN Kupka, RW Nolen, WA Suppes, T Denicoff, KD Leverich, GS Post, RM Drexhage, HA TI High numbers of circulating activated T cells and raised levels of serum IL-2 receptor in bipolar disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE bipolar disorder; T cells; B cells; NK cells; sIL-2R ID SOLUBLE INTERLEUKIN-2 RECEPTOR; NECROSIS-FACTOR-ALPHA; ACUTE-PHASE PROTEINS; MAJOR DEPRESSION; SCHIZOPHRENIC-PATIENTS; LYMPHOCYTE SUBSETS; PERIPHERAL-BLOOD; TRANSFERRIN RECEPTOR; CYTOTOXIC ACTIVITY; CELLULAR-IMMUNITY AB Background: Previously, we found an increased prevalence of thyroid autoantibodies in patients with bipolar disorder. In the present study, we investigated other signs of immune activation in bipolar patients, in particular an activation of the T cell system. Methods: Fluorescence activated cell scanning (FACS) analysis was performed on lymphocytes of 64 outpatients with DSM-IV bipolar disorder using the T cell marker CD3 in combination with the activation markers MHC-class II, CD25, CD69 or CD71. In 34 patients, these assays were repeated after an interval of 2 years. In addition, T cell activation was determined by measuring serum soluble IL-2 receptor (sIL-2R) in 172 bipolar outpatients. Outcomes were compared with a healthy control group. Results: Significantly higher numbers of circulating activated T cells and raised sIL-2R levels were found in euthymic, manic, and depressed bipolar patients when compared with health v controls. In general, these abnormalities were stable over time. Manic patients showed significantly higher levels of sIL-2R in comparison with depressed patients. Conclusions: The T cell system was found to be activated in both symptomatic and euthymic patients with bipolar disorder. The pathophysiological significance of these findings remains to be explored. (C) 2003 Society of Biological Psychiatry. C1 Erasmus Univ, Dept Immunol, NL-3000 DR Rotterdam, Netherlands. Altrecht Inst Mental Htlh Care, Utrecht, Netherlands. Univ Utrecht, Med Ctr, Utrecht, Netherlands. Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. RP Erasmus Univ, Erasme Univ Hosp, Dept Immunol, Lab Ee 838, POB 1738, NL-3000 DR Rotterdam, Netherlands. RI Nolen, Willem/E-9006-2014 NR 52 TC 70 Z9 73 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 EI 1873-2402 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 15 PY 2003 VL 53 IS 2 BP 157 EP 165 DI 10.1016/S0006-3223(02)01452-X PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 637NM UT WOS:000180518900008 PM 12547472 ER PT J AU Frye, MA Pazzaglia, PJ George, MS Luckenbaugh, DA Vanderham, E Davis, CL Rubinow, DR Post, RM AF Frye, MA Pazzaglia, PJ George, MS Luckenbaugh, DA Vanderham, E Davis, CL Rubinow, DR Post, RM TI Low CSF somatostatin associated with response to nimodipine in patents with affective illness SO BIOLOGICAL PSYCHIATRY LA English DT Article DE nimodipine; somatostatin; cerebrospinal fluid; affective illness ID CEREBROSPINAL-FLUID SOMATOSTATIN; MULTIPLE-SCLEROSIS; DISORDER; DISEASE; TRIAL AB Background: In patients with depression, treatment with nimodipine has been shown to increase cerebrospinal fluid (CSF) somatostatin (SRIF) and ameliorate baseline global cerebral hypometabolism. This study was conducted to assess whether a low baseline level of CSF SRIF was associated with response to nimodipine treatment. Methods: Twenty-one depressed patients underwent lumbar puncture for analysis of CSF somatostatin-like immunoreactivity (SRIF-LI) during a medication-free period and after at least 6 weeks of nimodipine monotherapy. Twenty-five healthy control subjects were utilized as a comparison group. Clinical improvement was assessed using the Clinical Global Impression Scale for Bipolar Illness. Results: As predicted, baseline CSF SRIF-LI was significantly lower in eventual nimodipine responders (33.1 +/- 2.8 pg/mol) compared to eventual nonresponders [41.9 +/- 2.6 pg/mL; t(19) = 1.98, p =.03, one-tailed]. Conclusions: Low baseline CSF somatostatin in depression may be associated with response to nimodipine, which in turn may be related to the ability of nimodipine to increase CSF somatostatin. (C) 2003 Society of Biological Psychiatry. C1 NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. NIMH, Behav Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Inst Neuropsychiat, Los Angeles, CA 90024 USA. Univ Texas, Hlth Sci Ctr, Houston, TX USA. Med Univ S Carolina, Charleston, SC 29425 USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, NIH, 10 Ctr Dr,MSC 1272,Bldg 10,Room 3S239, Bethesda, MD 20892 USA. NR 30 TC 9 Z9 9 U1 0 U2 0 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 JAN 15 PY 2003 VL 53 IS 2 BP 180 EP 183 DI 10.1016/S0006-3223(02)01343-4 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 637NM UT WOS:000180518900011 PM 12547475 ER PT J AU Marcucci, G Byrd, JC Dai, GW Klisovic, MI Kourlas, PJ Young, DC Cataland, SR Fisher, DB Lucas, D Chan, KK Porcu, P Lin, ZP Farag, SF Frankel, SR Zvviebel, JA Kraut, EH Balcerzak, SP Bloomfield, CD Grever, MR Caligiuri, MA AF Marcucci, G Byrd, JC Dai, GW Klisovic, MI Kourlas, PJ Young, DC Cataland, SR Fisher, DB Lucas, D Chan, KK Porcu, P Lin, ZP Farag, SF Frankel, SR Zvviebel, JA Kraut, EH Balcerzak, SP Bloomfield, CD Grever, MR Caligiuri, MA TI Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; COLONY-STIMULATING FACTOR; NON-HODGKINS-LYMPHOMA; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; G-CSF; CYTOSINE-ARABINOSIDE; FLAG FLUDARABINE; HEMATOLOGIC MALIGNANCIES; IN-VITRO AB Overexpression of BcI-2 is a potential mechanism for chemoresistance in acute leukemia and has been associated with unfavorable clinical outcome. We hypothesized that down-regulation of BcI-2 would restore chemosensitivity in leukemic cells. To test this hypothesis, we performed a phase 1 study of G3139 (Genasense, Genta, Berkeley Heights, NJ), an 18-mer phosphorothioate BcI-2 antisense, with fludarabine (FL), cytarabine (ARA-C), and granulocyte colony-stimulating factor (G-CSF) (FLAG) salvage chemotherapy in patients with refractory or relapsed acute leukemia. Twenty patients with refractory or relapsed acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) were enrolled. G3139 was delivered by continuous infusion on days 1 to 10. FLAG chemotherapy was administered on days 5 to 10. Common side effects of this combination included fever, nausea, emesis, electrolyte imbalance, and fluid retention that were not dose limiting. Plasma pharmacokinetics of G3139 demonstrated steady-state concentration (Css) within 24 hours. Of the 20 patients, 9 (45%) had disease response, 6 (5 AML, 1 ALL) with complete remission (CR) and 3 (2 AML and 1 ALL) with no evidence of disease but failure to recover normal neutrophil and/or platelet counts or to remain in remission for at least 30 days (incomplete remission). Bcl-2 mRNA levels were down-regulated in 9 of the 12 (75%) evaluable patients. This study demonstrates that G3139 can be administered safely with FLAG chemotherapy and down-regulate its target, Bcl-2. The encouraging clinical and laboratory results justify the current plans for a phase 3 study in previously untreated high-risk AML (ie, age at least 60 years). (C) 2003 by The American Society of Hematology. C1 Ohio State Univ, Ctr Comprehens Canc, Div Hematol & Oncol, Dept Med, Columbus, OH 43210 USA. Genta, Berkeley Hts, NJ USA. NCI, Bethesda, MD 20892 USA. RP Marcucci, G (reprint author), Ohio State Univ, Ctr Comprehens Canc, Div Hematol & Oncol, Dept Med, 433 A Starling Loving Hall,320 W 10th Ave, Columbus, OH 43210 USA. RI Lucas, David/E-3555-2011 FU NCI NIH HHS [R21-CA094552, K08-CA90469, P30-CA16058, U01-CA76576] NR 34 TC 153 Z9 175 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2003 VL 101 IS 2 BP 425 EP 432 DI 10.1182/blood-2002-06-1899 PG 8 WC Hematology SC Hematology GA 635EG UT WOS:000180384800009 PM 12393493 ER PT J AU Wojda, U Leigh, KR Njoroge, JM Jackson, KA Natarajan, B Stitely, M Miller, JL AF Wojda, U Leigh, KR Njoroge, JM Jackson, KA Natarajan, B Stitely, M Miller, JL TI Fetal hemoglobin modulation during human erythropoiesis: stem cell factor has "late" effects related to the expression pattern of CD117 SO BLOOD LA English DT Article ID ERYTHROID PROGENITOR CELLS; BURST-FORMING UNITS; C-KIT; PHARMACOLOGICAL INDUCTION; DISEASE; LIGAND; REACTIVATION; THALASSEMIA; BUTYRATE; CULTURE AB A cytokine-screening assay of cultured peripheral blood cells obtained using immune rosetting and separation of progenitors was developed to identify determinants of fetal hemoglobin (HbF) modulation during adult erythropoiesis. Among the 12 erythroid growth-promoting cytokines tested, stem cell factor (SCF) at a concentration of 50 ng/mL resulted in the most significant increase in cell proliferation and HbF content. The average HbF/hemoglobin A (HbA) ratio was 30.9% +/- 18.7% in cultures containing SCF compared with 4.1% +/- 2.2% in those grown with erythropoietin (EPO) alone (P = 8.5E-8). To further investigate the hemoglobin-modulating effects of SCF, we examined the surface expression pattern of the SCF receptor, CD117, among maturing erythroblasts. CD117 expression increased during the first week of culture and peaked on culture days 7 to 9. After culture day 9, the level of CD117 declined to lower levels. The rise in CD117 expression to high levels mirrored that of the transferrin receptor (CD71), and the subsequent reduction in CD117 was inversely related to increases in expression of glycophorin A. SCF-related increases in the HbF/HbA ratio correlated with the expression pattern of CD117. SCF added during days 7 to 14 resulted in a more pancellular distribution of HbF on day 14 compared with the heterocellular distribution present in cultures supplemented with SCF on days 0 to 7. A significant SCF-mediated increase in HbF was also measured using progenitors derived from cord blood. These results suggest that the HbF response to SCF is greatest at the late progenitor stage as a function of surface CD117 expression. (C) 2003 by The American Society of Hematology. C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDKD, Biol Chem Lab, NIH, Bldg 10,Rm 9B17, Bethesda, MD 20892 USA. RI Wojda, Urszula/M-6079-2015 OI Wojda, Urszula/0000-0002-4525-2004 NR 33 TC 28 Z9 30 U1 2 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2003 VL 101 IS 2 BP 492 EP 497 DI 10.1182/blood-2002-03-0756 PG 6 WC Hematology SC Hematology GA 635EG UT WOS:000180384800020 PM 12393703 ER PT J AU Cao, ZH Flanders, KC Bertolette, D Lyakh, LA Wurthner, JU Parks, WT Letterio, JJ Ruscetti, FW Roberts, AB AF Cao, ZH Flanders, KC Bertolette, D Lyakh, LA Wurthner, JU Parks, WT Letterio, JJ Ruscetti, FW Roberts, AB TI Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-beta and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells SO BLOOD LA English DT Article ID GROWTH-FACTOR-BETA; ACUTE PROMYELOCYTIC LEUKEMIA; PROTEIN PHOSPHATASE 2A; P70 S6 KINASE; SIGNALING PATHWAYS; CROSS-TALK; DEPENDENT DEGRADATION; CATALYTIC SUBUNIT; UBIQUITIN LIGASE; RECEPTOR AB We have investigated the role of Smad family proteins, known to be important cytoplasmic mediators of signals from the transforming growth factor-beta (TGF-beta) receptor serine/threonine kinases, in TGF-beta-dependent differentiation of hematopoietic cells, using as a model the human promyelocytic leukemia cell line, HIL-60. TGF-beta-dependent differentiation of these cells to monocytes, but not retinoic acid-dependent differentiation to granulocytes, was accompanied by rapid phosphorylation and nuclear translocation of Smad2 and Smad3. Vitamin D-3 also induced phosphorylation of Smad2/3 and monocytic differentiation; however the effects were indirect, dependent on its ability to induce expression of TGF-beta1. Simultaneous treatment of these cells with TGF-beta1 and all-trans-retinoic acid (ATRA), which leads to almost equal numbers of granulocytes and monocytes, significantly reduced the level of phospho-Smad2/3 and its nuclear accumulation, compared with that in cells treated with TGF-beta1 alone. TGF-beta1 and ATRA activate P42/44 mitogen-activated protein (MAP) kinase with nearly identical kinetics, ruling out its involvement in these effects on Smad phosphorylation. Addition of the inhibitor-of-protein serine/threonine phosphatases, okadaic acid, blocks the ATRA-mediated reduction in TGF-beta-induced phospho-Smad2 and shifts the differentiation toward monocytic end points. In HL-60R mutant cells, which harbor a defective retinoic acid receptor-alpha (RAR-alpha), ATRA is unable to reduce levels of TGF-beta-induced phospho-Smad2/3, coincident with its inability to differentiate these cells along granulocytic pathways. Together, these data suggest a new level of cross-talk between ATRA and TGF-beta, whereby a putative RAR-alpha-dependent phosphatase activity limits the levels of phospho-Smad2/3 induced by TGF-beta, ultimately reducing the levels of nuclear Smad complexes mediating the TGF-beta-dependent differentiation of the cells to monocytic end points. (C) 2003 by The American Society of Hematology. C1 NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. NCI, Basic Res Lab, Frederick, MD 21701 USA. RP Roberts, AB (reprint author), NCI, Lab Cell Regulat & Carcinogenesis, Bldg 41,Rm C629,41 Lib Dr,MSC 5055, Bethesda, MD 20892 USA. NR 53 TC 43 Z9 46 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JAN 15 PY 2003 VL 101 IS 2 BP 498 EP 507 DI 10.1182/blood-2002-05-1549 PG 10 WC Hematology SC Hematology GA 635EG UT WOS:000180384800021 PM 12393416 ER PT J AU Weerasinghe, GR Seemann, R Rapoport, SI Bosetti, F AF Weerasinghe, GR Seemann, R Rapoport, SI Bosetti, F TI Lithium chloride, administered chronically to rats, does not affect the fractional phosphorylation of brain cytosolic phospholipase A(2), while reducing its net protein level SO BRAIN RESEARCH BULLETIN LA English DT Article DE arachidonic acid; bipolar disorder; mood stabilizer; chronic; lithium; rat; cPLA(2); immunoprecipitation; brain; phosphorylation ID KINASE-C; SIGNAL-TRANSDUCTION; EXPRESSION AB Lithium, used to treat bipolar disorder, has been reported to decrease rat brain mRNA and protein levels of cytosolic phospholipase A(2) (cPLA(2)), an enzyme that selectively hydrolyzes arachidonic acid from the stereospecifically numbered (sn)-2 position of membrane phospholipids, and to decrease PLA(2) activity. cPLA(2) can be activated by being phosphorylated at its Ser-228, Ser-505, and Ser-727 sites. In this study, we show that the percent phosphorylated cPLA(2) protein in rat brain is unaffected by lithium. Male Fischer-344 rats were fed lithium chloride for 6 weeks, so as to produce a therapeutically equivalent brain lithium concentration; control rats were fed lithium-free chow under parallel conditions. cPLA(2) was immunoprecipitated from brain homogenate and phosphorylated cPLA(2) protein was quantified using an anti-phosphoserine antibody, and compared to net cPLA(2) protein. The mean ratio of phosphorylated/total cPLA(2) was not changed significantly in the lithium-treated compared to the control group. Thus, decreased brain PLA(2) enzyme activity caused by chronic lithium is likely a consequence only of lithium's downregulation of cPLA(2) transcription. Published by Elsevier Science Inc. C1 NIA, NIH, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. RP Bosetti, F (reprint author), NIA, NIH, Brain Physiol & Metab Sect, 9000 Rockville Pike,Bldg 10,Rm 6N202, Bethesda, MD 20892 USA. NR 27 TC 7 Z9 7 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD JAN 15 PY 2003 VL 59 IS 4 BP 303 EP 306 AR PII S0361-9230(02)00913-9 DI 10.1016/S0361-9230(02)00913-9 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 630MD UT WOS:000180110800008 PM 12464403 ER PT J AU Haddad, R Colevas, AD Tishler, R Busse, P Goguen, L Sullivan, C Norris, CM Lake-Willcutt, B Case, MA Costello, R Posner, M AF Haddad, R Colevas, AD Tishler, R Busse, P Goguen, L Sullivan, C Norris, CM Lake-Willcutt, B Case, MA Costello, R Posner, M TI Docetaxel, cisplatin, and 5-fluorouracil-based induction chemotherapy in patients with locally advanced squamous cell carcinoma of the head and neck - The Dana Farber Cancer Institute experience SO CANCER LA English DT Article DE head and neck carcinoma; induction chemotherapy; docetaxel; cisplatin; 5-fluorouracil; hyperfractionated radiotherapy ID PHASE-III TRIAL; RADIATION-THERAPY; RANDOMIZED TRIAL; FLUOROURACIL; LEUCOVORIN AB BACKGROUND. The authors conducted a series of four Phase I-II trials of high-dose and intermediate-dose docetaxel, cisplatin, and 5-fluorouracil (TPF)-based induction chemotherapy for patients with advanced squamous cell carcinoma of the head and neck (SCCHN). The chemotherapy regimens and response rates for each trial were published previously. In the current analysis, the authors report the data on long-term survival, patterns of failure, and morbidity among the patients who were treated at their institution. METHODS. A total of 101 patients with Previously untreated, locally advanced, curable SCCHN were entered onto the studies. Overall, 68 patients (67%) had N2-N3 disease, and 86 patients (85%) had Stage IV disease. Patients were treated with combinations of TPF with or without leucovorin. Cycles were repeated every 21-28 days for a total of 3 cycles followed by hyperfractionated radiotherapy. RESULTS. After a median follow-up of 49 months, 65 patients (64%) remain alive with no evidence of disease (NED), and 3 patients remain alive with disease, for an overall survival rate of 67% (68 patients). Twenty-six patients had locoregional recurrences (LRR), and 5 patients had both LRR and distant metastasis (DM). Only five patients had DM as the sole site of failure. Four patients underwent salvage surgery at the primary site and remain alive with NED. Excluding 17 patients with nasopharyngeal carcinoma, of 84 patients, 55 patients remain alive with NED (65%). Notably, 43 of 84 patients (51%) had oropharyngeal primary tumors, and 30 of those patients remain alive with NED (70%). Significant morbidity was low, with two treatment-related deaths. All but two of the surviving patients are able to swallow and had their feeding tubes removed. CONCLUSIONS. These data suggest that docetaxel adds incrementally to the efficacy of cisplatin and fluorouracil. Local-regional failures continue to be the major impediment to cure in these patients. Given the increase in local-regional dose intensity with chemoradiation, sequential treatment plans that integrate induction chemotherapy and chemoradiotherapy seem to be the logical next step. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. NCI, CTEP, Invest Drug Branch, Rockville, MD USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Otolaryngol, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, Boston, MA 02215 USA. Dana Farber Canc Inst, Head & Neck Oncol Program, Boston, MA 02115 USA. RP Haddad, R (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, SW430G,44 Binney St, Boston, MA 02115 USA. NR 20 TC 67 Z9 67 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JAN 15 PY 2003 VL 97 IS 2 BP 412 EP 418 DI 10.1002/cncr.11063 PG 7 WC Oncology SC Oncology GA 635LW UT WOS:000180401600009 PM 12518365 ER PT J AU Alter, BP AF Alter, BP TI Cancer in Fanconi anemia, 1927-2001 SO CANCER LA English DT Review DE Fanconi anemia; cancer; leukemia; myelodysplastic syndrome; malignancy; aplastic anemia; liver tumor; bone marrow transplant ID BONE-MARROW TRANSPLANTATION; SQUAMOUS-CELL CARCINOMA; ACUTE LYMPHOBLASTIC-LEUKEMIA; SEVERE APLASTIC-ANEMIA; ACUTE NONLYMPHOBLASTIC LEUKEMIA; 1ST HEMATOLOGIC MANIFESTATION; ACUTE NONLYMPHOCYTIC LEUKEMIA; ANABOLIC STEROID-THERAPY; ESTREN-DAMESHEK VARIANT; SOLID MALIGNANT-TUMORS AB BACKGROUND. Fanconi anemia (FA) is an autosomal recessive disease associated with an abnormal response to DNA damage. Although FA is well known for the association of aplastic anemia and characteristic birth defects, leukemia and solid tumors also occur at a high rate in this group of patients. A review of all reported cases is informative with regard to the specific types of cancer, the ages at which they occur, and the cumulative probability of their development. METHODS. Medline and bibliographies of publications were searched for articles containing "Fanconi's anemia" or "aplastic anemia" and all cases of FA from 1927 through 2001 were included in the database. Cancer cases were identified within these reports. Descriptive statistical analyses were performed using Stata7 software. RESULTS. One thousand three hundred cases of FA were identified. Nine percent had leukemia (primarily acute myeloid leukemia), 7% had myelodysplastic syndrome, 5% had solid tumors, and 3% had liver tumors. Patients with cancer were older than the cancer-free patients at the time of diagnosis of FA. The median age for cancer (including leukemia) was 16, compared with 68 in the general population. The most frequent solid tumors were aerodigestive and gynecological carcinomas. In approximately 25% of patients with cancer, the malignancy preceded the diagnosis of FA. CONCLUSIONS. If the competing risks of aplastic anemia and leukemia could be removed, the estimated cumulative probability of development of a solid tumor in FA patients is 76% by the age of 45 years. Carcinogenic pathways and cancer prevention, surveillance, and treatment can be studied to advantage in this genetic model of human cancer. C1 NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Alter, BP (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS Room 7020, Bethesda, MD 20892 USA. NR 221 TC 231 Z9 236 U1 1 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JAN 15 PY 2003 VL 97 IS 2 BP 425 EP 440 DI 10.1002/cncr.11046 PG 16 WC Oncology SC Oncology GA 635LW UT WOS:000180401600011 PM 12518367 ER PT J AU Yuan, BZ Durkin, ME Popescu, NC AF Yuan, BZ Durkin, ME Popescu, NC TI Promoter hypermethylation of DLC-1, a candidate tumor suppressor gene, in several common human cancers SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID CPG-ISLAND METHYLATION; PROLIFERATION; PATTERNS; RHOGAP; RAS AB Aberrant methylation of CpG islands within the promoter regions Of tumor Suppressor or cancer-related genes is a common mechanism leading to the silencing of gene expression. To determine whether aberrant methylation is a contributing factor to transcriptional inactivation of DLC-1 (deleted in liver cancer- 1), a candidate tumor suppressor gene, we examined its methylation status in twelve hepatocellular carcinoma, breast, colon, and prostate tumor cell lines with low or undetectable expression of DLC-1. By Southern blot analysis of DNA digested with the methylation sensitive enzyme HpaII, we found a different degree of promoter hypermethylation in all cell lines with aberrant DLC-1 expression. The hypermethylation status was reversed by the addition of 5-aza-2'-deoxycytidine, a demethylating agent, in one human hepatocellular carcinoma line. These observations suggest that hypermethylation is responsible for abrogating the function of the DLC-1 gene in a subset of liver, breast, colon, and prostate cancers. (C) 2003 Elsevier Science Inc. All rights reserved. C1 NCI, Ctr Canc Res, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NIOSH, Div Toxicol, Hlth Effects Lab, Morgantown, WV 26505 USA. NIOSH, Mol Biol Branch, Morgantown, WV 26505 USA. RP Popescu, NC (reprint author), NCI, Ctr Canc Res, Expt Carcinogenesis Lab, NIH, Bldg 37, Room 3C05, Bethesda, MD 20892 USA. NR 25 TC 91 Z9 99 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD JAN 15 PY 2003 VL 140 IS 2 BP 113 EP 117 AR PII S0165-4608(02)00674-X DI 10.1016/S0165-4608(02)00674-X PG 5 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 641TH UT WOS:000180762100004 PM 12645648 ER PT J AU Kobayashi, H Kawamoto, S Star, RA Waldmann, TA Tagaya, Y Brechbiel, MW AF Kobayashi, H Kawamoto, S Star, RA Waldmann, TA Tagaya, Y Brechbiel, MW TI Micro-magnetic resonance lymphangiography in mice using a novel dendrimer-based magnetic resonance imaging contrast agent SO CANCER RESEARCH LA English DT Article ID IRON-OXIDE PARTICLES; MR-LYMPHOGRAPHY; POLYAMIDOAMINE DENDRIMER; PHARMACOKINETIC PROPERTIES; MONOCLONAL-ANTIBODY; TRANSGENIC MICE; LYMPH-NODES; CORE; ANGIOGRAPHY; LYMPHOSCINTIGRAPHY AB Major advances in cancer biology and immunology have been gained using mouse models. However, very few methods are currently available to visualize the deep lymphatic system. A new micro-magnetic resonance lymphangiography (MRL) method in mice, which uses dendrimer-based magnetic resonance imaging contrast agents, was developed. Micro-MRL imaging clearly visualized most of the mouse lymphatic system, including both lymphatics and lymph nodes. This method could detect and distinguish among dilation of lymphatic vessels in a lymphangitis model, proliferative or neoplastic lymph node swellings in a lymphoproliferative model, and inflammatory lymph node swellings in an infection/inflammation model. Changes in the lymphoid system of transgenic mice overexpressing interleukin-15 could be visualized. Abnormal enlarged lymph nodes identified by micro-MRL were selectively removed and analyzed to demonstrate their cell type, receptor expression, and clonality in individual mice. We conclude that the enhanced resolution of this noninvasive micro-MRL can detect and classify lymphatic and lymph node abnormalities in mice, which should have wide applicability to the study of immunology and cancer in both experimental animals and clinical medicine. C1 NCI, Metab Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Radiol, Sch Med, Baltimore, MD 21287 USA. RP Kobayashi, H (reprint author), NCI, Metab Branch, Canc Res Ctr, NIH, Bldg 10,Room 4N109,10 Ctr Dr, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov NR 37 TC 91 Z9 95 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2003 VL 63 IS 2 BP 271 EP 276 PG 6 WC Oncology SC Oncology GA 640PQ UT WOS:000180697500001 PM 12543772 ER PT J AU Zavras, AI Pitiphat, W Wu, TX Cartsos, V Lam, A Douglass, CW Diehl, SR AF Zavras, AI Pitiphat, W Wu, TX Cartsos, V Lam, A Douglass, CW Diehl, SR TI Insulin-like growth factor II receptor gene-167 genotype increases the risk of oral squamous cell carcinoma in humans SO CANCER RESEARCH LA English DT Article ID CATHEPSIN-D; HEAD; NECK; HETEROZYGOSITY; RETINOIDS; CANCER; LOCUS AB Our purpose was to evaluate inherited short tandem repeat polymorphisms of the insulin-like growth factor II receptor gene (IGF2R) in oral cancer risk. The 197 individuals that consented to participate in a hospital-based, case-control study were interviewed with a structured questionnaire and provided blood and saliva. DNA was extracted for genotyping using a PCR-based method. Odds ratios were calculated using multivariate logistic regression. Subjects carrying the heterozygous 167-bp IGF2R genotype had a 2.7-fold higher risk of oral cancer compared with subjects with other genotypes (odds ratio = 2.7, 95% confidence interval: 1.16-6.48), controlling for major confounders. Our results suggest that genetic variation of IGF2R may influence significantly the risk of oral cancer. C1 Harvard Univ, Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, Boston, MA 02115 USA. Khon Kaen Univ, Dept Community Dent, Fac Dent, Khon Kaen 40002, Thailand. Natl Inst Dent & Craniofacial Res, Craniofacial Epidemiol & Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, Ctr Pharmacogenom & Complex Dis Res, Newark, NJ 07101 USA. RP Zavras, AI (reprint author), Harvard Univ, Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, 188 Longwood Ave, Boston, MA 02115 USA. FU NIDCR NIH HHS [K23DE0420]; NIMHD NIH HHS [MD-538024, MD-726655, MD-626829] NR 19 TC 19 Z9 21 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2003 VL 63 IS 2 BP 296 EP 297 PG 2 WC Oncology SC Oncology GA 640PQ UT WOS:000180697500006 PM 12543777 ER PT J AU Protopopov, A Kashuba, V Zabarovska, VI Muravenko, OV Lerman, MI Klein, G Zabarovsky, ER AF Protopopov, A Kashuba, V Zabarovska, VI Muravenko, OV Lerman, MI Klein, G Zabarovsky, ER TI An integrated physical and gene map of the 3.5-Mb chromosome 3p21.3 (AP20) region implicated in major human epithelial malignancies SO CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; NOTI LINKING CLONES; IN-SITU HYBRIDIZATION; CANCER CELL-LINE; LUNG-CANCER; HOMOZYGOUS DELETION; HUMAN-CHROMOSOME-3; IDENTIFICATION; CONSTRUCTION; PROTEIN AB To facilitate the identification of tumor suppressor genes in the chromosome 3p21.3-p22 AP20 subregion, we constructed a 3.5-Mb physical and gene map of this segment (between markers D3S4285 and D3S3873) that spans the distance from 124.4cR(3000) to 133.5 cR(3000) of the GB4 genetic map. We used NotI-linking and -jumping clones, sequence-tagged site PCR marker analysis, and multicolor and fiber fluorescence in situ hybridization to confirm the sequence order and map orientation. An integrated clone contig composed of 5 yeast artificial chromosome, 15 bacterial artificial chromosome, 5 PI artificial chromosome, and 8 NotI-linking clones provided the physical base of the map. We unequivocally established the order of 28 sequence-tagged sites and 35 genes in the region. Gaps between published bacterial artificial chromosome contigs were determined and covered by our own sequence data. Furthermore, three new genes were isolated, namely the human homologue to the rat Golgi peripheral membrane protein p65, GOLPH5 (GORASP1), the gene for stress-inducible protein, ST12, and the AP20-region gene 1, APRG1. The tumor suppressor gene candidate APRG1 was positioned close to the border of the homozygous deletion in a small cell lung cancer cell line ACC-LC5. Expression analysis with a tissue-specific panel of cDNA revealed seven distinct tissue-specific splice variants (A-G) of the message (size range, 1.0-1.8 kb). Although the gene was expressed at a low level in all tested tissues, comparatively higher expression was detected in pancreas (splice forms B and D), kidney (A) and placenta (B and C). The APRG1 gene encoded a predicted protein of 170 amino acids (isoform B), which had an NH2-terminal part conserved among members of the eukaryotic translation factor 6 gene family. A Prosite pattern corresponding to the cell attachment sequence Arg-Gly-Asp was also found. The presence of this domain raised the intriguing possibility that APRG1B may be directly involved in membrane interactions and cell adhesion. We showed that the AP20 region was duplicated during mammalian evolution and homologous gene clusters were present in human chromosome 2 and syntenic mouse regions on chromosomes 1, 2, and 9. Interestingly, the HYA22 gene (human ortholog of the yeast YA22 gene) was located at the borders of both breakpoints, evolutionarily conserved gene cluster and homozygous deletions detected in lung, kidney and other cancers. NotI digestion revealed that the AP20 region was frequently and extensively methylated in renal carcinoma cell lines and tumor biopsies. C1 Karolinska Inst, Ctr Microbiol & Tumor Biol, S-17177 Stockholm, Sweden. Karolinska Inst, Ctr Genom & Bioinformat, S-17177 Stockholm, Sweden. Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. Ukrainian Acad Sci, Inst Mol Biol & Genet, UA-252627 Kiev, Ukraine. Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow 117984, Russia. NCI, Canc Causing Genes Sect, Immunobiol Lab, Frederick, MD 21702 USA. RP Protopopov, A (reprint author), Karolinska Inst, Ctr Microbiol & Tumor Biol, Box 280, S-17177 Stockholm, Sweden. RI Zabarovsky, Eugene/A-6645-2010 NR 40 TC 42 Z9 52 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JAN 15 PY 2003 VL 63 IS 2 BP 404 EP 412 PG 9 WC Oncology SC Oncology GA 640PQ UT WOS:000180697500024 PM 12543795 ER PT J AU Olsen, DS Savner, EM Mathew, A Zhang, F Krishnamoorthy, T Phan, L Hinnebusch, AG AF Olsen, DS Savner, EM Mathew, A Zhang, F Krishnamoorthy, T Phan, L Hinnebusch, AG TI Domains of eIF1A that mediate binding to eIF2, eIF3 and eIF5B and promote ternary complex recruitment in vivo SO EMBO JOURNAL LA English DT Article DE eIF1A; eIF2; eIF3; GCN4; ribosomes; translation ID TRANSLATION INITIATION; SACCHAROMYCES-CEREVISIAE; YEAST; PROTEIN; RNA; GENE; GCN4; IF2; MODULATION; EIF2-ALPHA AB Translation initiation factor 1A (eIF1A) is predicted to bind in the decoding site of the 40S ribosome and has been implicated in recruitment of the eIF2-GTP-Met-tRNA(i)(Met) ternary complex (TC) and ribosomal scanning. We show that the unstructured C-terminus of eIF1A interacts with the C-terminus of eIF5B, a factor that stimulates 40S-60S subunit joining, and removal of this domain of eIF1A diminishes translation initiation in vivo. These findings support the idea that eIF1A-eIF5B association is instrumental in releasing eIF1A from the ribosome after subunit joining. A larger C-terminal truncation that removes a 310 helix in eIF1A deregulates GCN4 translation in a manner suppressed by overexpressing TC, implicating eIF1A in TC binding to 40S ribosomes in vivo. The unstructured N-terminus of eIF1A interacts with eIF2 and eIF3 and is required at low temperatures for a step following TC recruitment. We propose a modular organization for eIF1A wherein a core ribosome-binding domain is flanked by flexible segments that mediate interactions with other factors involved in recruitment of TC and release of eIF1A at subunit joining. C1 NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. NR 36 TC 84 Z9 90 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JAN 15 PY 2003 VL 22 IS 2 BP 193 EP 204 DI 10.1093/emboj/cdg030 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 638KJ UT WOS:000180569900003 PM 12514125 ER PT J AU Yang, YA Morin, PJ Han, WF Chen, TH Bornman, DM Gabrielson, EW Pizer, ES AF Yang, YA Morin, PJ Han, WF Chen, TH Bornman, DM Gabrielson, EW Pizer, ES TI Regulation of fatty acid synthase expression in breast cancer by sterol regulatory, element binding protein-1c SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE fatty acid synthase; EGF; MAP kinase; PI 3-kinase; SREBP-1c; breast cancer; real-time RT-PCR ID TRANSGENIC MICE; GENE-EXPRESSION; TRANSCRIPTION FACTOR; ADIPOSE-TISSUE; CULTURED-CELLS; CHOLESTEROL; PATHWAY; INSULIN; METABOLISM; ENZYMES AB Activation of fatty acid synthase (FAS) expression and fatty acid synthesis is a common event in human breast cancer. Sterol regulatory element binding proteins (SREBPs) are a family of transcription factors that regulate genes involved in lipid metabolism, including FAS. SREBP-1c expression is induced in liver and adipose tissue by insulin and by fasting/refeeding and is critical for nutritional regulation of lipogenic gene expression. In contrast, upregulation of fatty acid metabolism during in vitro transformation of human mammary epithelial cells and in breast cancer cells was driven by increased MAP kinase and PI 3-kinase signaling, which increased SREBP-1 levels. SREBP-1a was more abundant than SREBP-1c in many proliferative tissues and cultured cells and was thus a candidate to regulate lipogenesis for support of membrane synthesis during cell growth. We now show that SREBP-Ic and FAS mRNA were both increased by H-ras transformation of MCF-10a breast epithelial cells and were both reduced by exposure of MCF-7 breast cancer cells to the MAP kinase inhibitor, PD98059, or the PI 3-kinase inhibitor, wortmannin, while SREBP-1a and SREBP-2 showed less variation. Similarly, the mRNA levels for FAS and SREBP-1c in a panel of primary human breast cancer samples showed much greater increases than did those for SREBP-1a and SREBP-2 and were significantly correlated with each other, suggesting coordinate regulation of SREBP-1c and FAS in clinical breast cancer. We conclude that regulation of FAS expression in breast cancer is achieved through modulation of SREBP-1c, similar to the regulation in liver and adipose tissue, although the upstream regulation of liopgenesis differs in these tissues. (C) 2003 Elsevier Science (USA). All rights reserved. C1 Johns Hopkins Bayview Med Ctr, Dept Pathol, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21224 USA. NIA, Gerontol Res Ctr, Biol Chem Lab, Baltimore, MD 21224 USA. RP Pizer, ES (reprint author), Johns Hopkins Bayview Med Ctr, Dept Pathol, AA154C,4940 Eastern Ave, Baltimore, MD 21224 USA. FU NCI NIH HHS [R29CA75219] NR 37 TC 96 Z9 102 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD JAN 15 PY 2003 VL 282 IS 2 BP 132 EP 137 AR PII S0014-4827(02)00023-X DI 10.1016/S0014-4827(02)00023-X PG 6 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 633ZR UT WOS:000180315700008 PM 12531699 ER PT J AU Samuni, AM Barenholz, Y AF Samuni, AM Barenholz, Y TI Site-activity relationship of nitroxide radical's antioxidative effect SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE free radicals; lipid bilayer; liposomes; partition coefficient; antioxidant ID LIPID-PEROXIDATION; FLUORESCENCE POLARIZATION; DAMAGE; BILAYERS; LIPOSOMES; 4-HEPTADECYL-7-HYDROXYCOUMARIN; PROTECTION; PARAMETERS; PROBE AB A relatively new strategy in preventing oxidative damage employs cyclic nitroxides. These stable radicals have been widely used as biophysical probes, spin labels, and are currently tested as contrast agents for nuclear magnetic resonance imaging. Nitroxides were found to protect cells, organs, and whole animals against diverse oxidative insults. The present study concentrated on comparing the antioxidative activity of nitroxides against oxidative damage, initiated either in the lipid or aqueous phase, to egg phosphatidylcholine acyl chains (13.4% polyunsaturated fatty acids) in small unilamellar vesicles. We determined the lipophilicity and liposome-membrane/aqueous-medium partition coefficient for several nitroxides and compared their specific protective effects. The aim was to study the relation between nitroxides' concentration, location in the lipid bilayer, and their protection against oxidative damage. Both 6-membered- and 5-membered-ring nitroxides were studied for: (i) partitioning between the lipid bilayer and the aqueous phase (nitroxides were quantified using EPR spectroscopy); (ii) the intrabilayer distribution, using three different fluorescent probes of known location of their fluorophors in the lipid bilayer; and (iii) the specific antioxidative effect (protection per concentration) against radicals formed in a liposomal dispersion. The radicals were generated using the thermolabile, radical-generating compounds 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) in the aqueous phase, and 2,2'-azobis (2,4-dimethyl-valeronitrile) (AMVN) in the lipid phase. The results show that nitroxides react, in a concentration-dependent manner, with deleterious species at their formation sites, both in the aqueous and the lipid phase, and that their specific protective effects for the lipophilic target, the lipid bilayer, are similar for both the lipophilic and the hydrophilic nitroxides. (C) 2003 Elsevier Science Inc. C1 Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Biochem, Lab Membrane & Liposome Res, Jerusalem, Israel. RP Samuni, AM (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, NIH, 10 Rm B3B69, Bethesda, MD 20892 USA. NR 35 TC 23 Z9 24 U1 0 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JAN 15 PY 2003 VL 34 IS 2 BP 177 EP 185 AR PII S0891-5849(02)01238-8 DI 10.1016/S0891-5849(02)01238-8 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 633RJ UT WOS:000180296000003 PM 12521599 ER PT J AU Felix, K Rockwood, LD Pretsch, W Bornkamm, GW Janz, S AF Felix, K Rockwood, LD Pretsch, W Bornkamm, GW Janz, S TI Redox imbalance and mutagenesis in spleens of mice harboring a hypomorphic allele of Gpdx(a) encoding glucose 6-phosphate dehydrogenase SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE glucose 6-phoshpate dehydrogenase deficiency; endogenous oxidative stress; in vivo mutagenesis; pUR288; spleen; free radicals ID OXIDATIVE STRESS; GLUCOSE-6-PHOSPHATE-DEHYDROGENASE G6PD; HYDROGEN-PEROXIDE; NITRIC-OXIDE; GROWTH; CELLS; GLUTATHIONE; METABOLISM; MUTATIONS; CATALASE AB Mice harboring the activity-attenuated Gpdx(a-m2Neu) allele and also harboring a chromosomally integrated lacZ reporter gene to study mutagenesis (pUR288) were used to demonstrate that moderate glucose 6-phosphate dehydrogenase (G6PD) deficiency causes elevated mutagenesis and endogenous oxidative stress in the spleen. G6PD-deficient spleens with a residual enzyme activity of 22% exhibited a dramatic shift in the mutational pattern of lacZ (4.6-fold increase in the prevalence of recombination mutations of lacZ) together with a 1.8-fold increase in mutant frequencies in lacZ. A concomitant 3-fold reduction in catalase activity (dependent upon NADPH) indicated that the in vivo supply of G6PD-generated NADPH was insufficient. An additional 3-fold increase in oxidized glutathione suggested that redox control was disturbed in G6PD-deficient spleens. These findings indicate that G6PD is required for limiting oxidative mutagenesis in the mouse spleen. Gpdx(a-m2Neu) is the first hypomorphic allele of a mouse housekeeping gene associated with elevated somatic mutagenesis in vivo. (C) 2003 Elsevier Science Inc. C1 NCI, Ctr Canc Res, Genet Lab, NIH, Bethesda, MD 20892 USA. GSF Res Ctr, Inst Human Genet, Neuherberg, Germany. GSF, Inst Clin Mol Biol & Tumor Genet, Munich, Germany. RP Janz, S (reprint author), NCI, Ctr Canc Res, Genet Lab, NIH, 37 Convent Dr,Bldg 37,Rm 2B10, Bethesda, MD 20892 USA. NR 30 TC 7 Z9 7 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JAN 15 PY 2003 VL 34 IS 2 BP 226 EP 232 AR PII S0891-5849(02)02143-1 DI 10.1016/S0891-5849(02)01243-1 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 633RJ UT WOS:000180296000008 PM 12521604 ER PT J AU Cao, L Li, WM Kim, S Brodie, SG Deng, CX AF Cao, L Li, WM Kim, S Brodie, SG Deng, CX TI Senescence aging, and malignant transformation mediated by p53 in mice lacking the Brcal full-length isoform SO GENES & DEVELOPMENT LA English DT Article DE p53; p21; senescence; aging; tumorigenesis ID BREAST-CANCER SUSCEPTIBILITY; OXIDATIVE DNA-DAMAGE; HUMAN FIBROBLASTS; CELLULAR SENESCENCE; GENETIC INSTABILITY; TUMOR-FORMATION; CELLS; IMMORTALIZATION; MUTATION; CYCLE AB Senescence may function as a two-edged sword that brings unexpected consequences to organisms. Here we provide evidence to support this theory by showing that the absence of the Brca1 full-length isoform causes senescence in mutant embryos and cultured cells as well as aging and tumorigenesis in adult mice. Haploid loss of p53 overcame embryonic senescence but failed to prevent the adult mutant mice from prematurely aging, which included decreased life span, reduced body fat deposition, osteoporosis, skin atrophy, and decreased wound healing. We further demonstrate that mutant cells that escaped senescence had undergone clonal selection for faster proliferation and extensive genetic/molecular alterations, including overexpression of cyclin D1 and cyclin A and loss of p53. These observations provide the first in vivo evidence that links cell senescence to aging due to impaired function of Brcal at the expense of tumorigenesis. C1 NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 62 TC 168 Z9 176 U1 1 U2 3 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JAN 15 PY 2003 VL 17 IS 2 BP 201 EP 213 DI 10.1101/gad.1050003 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 637DP UT WOS:000180496600005 PM 12533509 ER PT J AU Habas, R Dawid, IB He, X AF Habas, R Dawid, IB He, X TI Coactivation of Rac and Rho by Wnt/Frizzled signaling is required for vertebrate gastrulation SO GENES & DEVELOPMENT LA English DT Article DE Wnt; Frizzled; Rac; Rho; gastrulation; vertebrates ID PLANAR CELL POLARITY; CONVERGENT EXTENSION MOVEMENTS; XENOPUS-LAEVIS; ACTIN CYTOSKELETON; HUMAN NEUTROPHILS; MAMMARY ONCOGENE; MAMMALIAN-CELLS; TISSUE POLARITY; DROSOPHILA EYE; WNT AB Wnt/Frizzled (Fz) signaling controls cell polarity/movements during vertebrate gastrulation via incompletely defined mechanisms. We demonstrated previously that Wnt/Fz activation of Rho, a GTPase and regulator of cytoskeletal architecture, is essential for vertebrate gastrulation. Here we report that in mammalian cells and Xenopus embryos, Wnt/Fz signaling coactivates Rho and Rac, another GTPase and distinct regulator of cytoskeletal architecture. Wnt/Fz activation of Rac is independent of Rho and mediates Wnt/Fz activation of Jun N-terminal kinase (JNK). Dishevelled (Dvl), a cytoplasmic protein downstream of Fz, forms a Wnt-induced complex with Rac independent of the Wnt-induced Dv1-Rho complex. Depletion or inhibition of Rac function perturbs Xenopus gastrulation without affecting Wnt/Fz activation of the Rho or beta-catenin pathway. We propose that parallel activation of Rac and Rho pathways by Wnt/Fz signaling is required for cell polarity and movements during vertebrate gastrulation. C1 Harvard Univ, Sch Med, Dept Neurol, Childrens Hosp,Div Neurosci, Boston, MA 02115 USA. NICHHD, Genet Mol Lab, Bethesda, MD 20892 USA. RP He, X (reprint author), Harvard Univ, Sch Med, Dept Neurol, Childrens Hosp,Div Neurosci, Boston, MA 02115 USA. FU NINDS NIH HHS [NS07473, T32 NS007473] NR 70 TC 368 Z9 372 U1 2 U2 10 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JAN 15 PY 2003 VL 17 IS 2 BP 295 EP 309 DI 10.1101/gad.1022203 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 637DP UT WOS:000180496600012 PM 12533515 ER PT J AU Jencks, SF Huff, ED Cuerdon, T AF Jencks, SF Huff, ED Cuerdon, T TI Change in the quality of care delivered to Medicare beneficiaries, 1998-1999 to 2000-2001 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID PROSPECTIVE PAYMENT SYSTEM; IMPLEMENTATION AB Context Despite widespread concern regarding the quality and safety of healthcare, and a Medicare Quality Improvement Organization (QIO) program intended to improve that care in the United States, there is only limited information on whether quality is improving. Objective To track national and state-level changes in performance on 22 quality indicators for care of Medicare beneficiaries. Design, Patients, and Setting National observational cross-sectional studies of national and state-level fee-for-service data for Medicare beneficiaries during 19981999 (baseline) and 2000-2001 (follow-up). Main Outcome Measures Twenty-two QIO quality indicators abstracted from statewide random samples of medical records for inpatient fee-for-service care and from Medicare beneficiary, surveys or Medicare claims for outpatient care. Absolute improvement is defined as the change in performance from baseline to follow-up (measured in percentage points for all indicators except those measured in minutes); relative improvement is defined as the absolute improvement divided by the difference between the baseline performance and perfect performance (100%). Results The median state's performance improved from baseline to follow-up on 20 of the 22 indicators. In the median state, the percentage of patients receiving appropriate care on the median indicator increased from 69.5% to 73.4%, a 12.8% relative improvement. The average relative improvement was 19.9% for outpatient indicators combined and 11.9% for inpatient indicators combined (P<.001). For all but one indicator, absolute improvement was greater in states in which performance was low at baseline than those in which it was high at baseline (median r=-0.43; range: 0.12 to -0.93). When states were ranked on each indicator, the state's average rank was highly stable over time (r=0.93 for 1998-1999 vs 2000-2001). Conclusions Care for Medicare fee-for-service plan beneficiaries improved substantially between 1998-1999 and 2000-2001, but a much larger opportunity remains for further improvement. Relative rankings among states changed little. The improved care is consistent with QIO activities over this period, but these cross-sectional data do not provide conclusive information about the degree to which the improvement can be attributed to the QIOs' quality improvement efforts. C1 Ctr Medicare Serv, Off Clin Stand & Qual, Baltimore, MD 21244 USA. Ctr Medicaid Serv, Off Clin Stand & Qual, Baltimore, MD 21244 USA. Ctr Medicare Serv, Div Clin Stand & Qual, Boston, MA USA. Ctr Medicaid Serv, Div Clin Stand & Qual, Boston, MA USA. NIMH, Hlth & Behav Sci Res Branch, Bethesda, MD 20892 USA. RP Jencks, SF (reprint author), Ctr Medicare Serv, Off Clin Stand & Qual, 7500 Secur Blvd,Mail Stop S3-02-01, Baltimore, MD 21244 USA. NR 15 TC 361 Z9 362 U1 0 U2 10 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 JAN 15 PY 2003 VL 289 IS 3 BP 305 EP 312 DI 10.1001/jama.289.3.305 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 634MV UT WOS:000180345100025 PM 12525231 ER PT J AU Marti-Verdeaux, S Pombo, I Iannascoli, B Roa, M Varin-Blank, N Rivera, J Blank, U AF Marti-Verdeaux, S Pombo, I Iannascoli, B Roa, M Varin-Blank, N Rivera, J Blank, U TI Evidence of a role for Munc18-2 and microtubules in mast cell granule exocytosis SO JOURNAL OF CELL SCIENCE LA English DT Article DE mast cell; exocytosis; cytoskeleton; Munc18 ID STIMULATED GLUT4 TRANSLOCATION; BASOPHILIC LEUKEMIA-CELLS; MEMBRANE-FUSION; NEUROTRANSMITTER RELEASE; REGULATED EXOCYTOSIS; EPITHELIAL-CELLS; T-CELLS; ACTIN; SECRETION; PROTEINS AB Compound exocytosis of inflammatory mediators from mast cells requires SNARE and a series of accessory proteins. However, the molecular steps that regulate secretory granule movement and membrane fusion as well as the role of the cytoskeleton are still poorly understood. Here, we report on our investigation of the role of syntaxin-binding Munc18 isoforms and the microtubule network in this process. We found that mast cells express Munc18-2, which interacts with target SNAREs syntaxin 2 or 3, as well as Munc18-3, which interacts with syntaxin 4. Munc18-2 was localised to secretory granules, whereas Munc18-3 was found on the plasma membrane. Increased expression of Munc18-2 and derived peptides containing an interfering effector loop inhibited IgE-triggered exocytosis, while increased expression of Munc18-3 showed no effect. Munc18-2 localisation on granules is polarised; however, upon stimulation Munc18-2 redistributed into forming lamellipodia and persisted on granules that were aligned along microtubules, but was excluded from F-actin ruffles. Disruption of the microtubule network with nocodazole provoked Munc18-2 redistribution and affected mediator release. These findings suggest a role for Munc18-2 and the microtubule network in the regulation of secretory granule dynamics in mast cells. C1 Inst Pasteur, Unite Immunoallergie, F-75724 Paris, France. Hop Cochin, ICGM, INSERM, U363, F-75674 Paris, France. NIAMSD, Mol Inflammat Sect, NIH, Bethesda, MD 20892 USA. RP Blank, U (reprint author), Inst Pasteur, Unite Immunoallergie, 28 Rue Dr Roux, F-75724 Paris, France. RI Wan, Daniel/F-4689-2010 NR 65 TC 85 Z9 85 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JAN 15 PY 2003 VL 116 IS 2 BP 325 EP 334 DI 10.1242/jcs.00216 PG 10 WC Cell Biology SC Cell Biology GA 640FG UT WOS:000180677200012 PM 12482918 ER PT J AU Smorenburg, CH Sparreboom, A Bontenbal, M Stoter, G Nooter, K Verweij, J AF Smorenburg, CH Sparreboom, A Bontenbal, M Stoter, G Nooter, K Verweij, J TI Randomized cross-over evaluation of body-surface area-based dosing versus flat-fixed dosing of paclitaxel SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CREMOPHOR EL; HUMAN PLASMA; UNBOUND PACLITAXEL; DOSE CALCULATION; PHARMACOKINETICS; RECOMMENDATIONS; NORMALIZATION; METABOLISM; INFUSION; TOXICITY AB Purpose: Despite dose calculation using body-surface area (BSA), pharmacokinetics of most anticancer drugs show wide interindividual variability. In this study, we evaluated the role of BSA in paclitaxel disposition. Patients and Methods: Paclitaxel pharmacakinetics were prospectively studied in 12 patients that were treated in a randomixed cross-over design with paclitaxel (3-hour infusion at a 3-week interval) at 175 mg/m(2) in cycle 1 (A) and a flat-fixed dose of 300 mg in cycle 2 (B), or vice versa. Blood samples were collected up to 24 hours after dosing and analyzed for total and unbound paclitaxel. Results: The area under the curves (AUC) of unbound paclitaxel were similar in both dosing groups, with mean values +/- SD (A v B) of 1.34 +/- 0.158 versus 1.30 +/- 0.329 muM-h, indicating that BSA-based dosing reduced the coefficient of variation by 53.3%. Unbound and total paclitaxel clearance was also significantly related to various body-size measures, including BSA (R greater than or equal to 0.617; P less than or equal to .033), weight (R greater than or equal to 0.62 1; P greater than or equal to .031), and lean-body mass (r greater than or equal to 0.630; P less than or equal to 028). We hypothesize that this is caused by the association of paclitaxel in the circulation with Cremophor EL, the distribution of which is linked to total blood volume, and thus to BSA. Conclusion: This study indicates that paclitaxel disposition is significantly related to BSA. This provides a pharmacokinetic rationale for BSA-based dosing of this drug. (C) 2003 by American Society of Clinical Oncology. C1 Erasmus MC Daniel den Hoed Canc Ctr, Dept Med Oncol, Rotterdam, Netherlands. RP Sparreboom, A (reprint author), NCI, Med Oncol Clin Res Unit, 9000 Rockville Pike,Bldg 10,Rm 5A01, Bethesda, MD 20892 USA. RI Sparreboom, Alex/B-3247-2008 NR 32 TC 43 Z9 44 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JAN 15 PY 2003 VL 21 IS 2 BP 197 EP 202 DI 10.1200/JCO.2003.01.058 PG 6 WC Oncology SC Oncology GA 685UG UT WOS:000183281200005 PM 12525510 ER PT J AU Thomas, JP Arzoomanian, RZ Alberti, D Marnocha, R Lee, F Friedl, A Tutsch, K Dresen, A Geiger, P Pluda, J Fogler, W Schiller, JH Wilding, G AF Thomas, JP Arzoomanian, RZ Alberti, D Marnocha, R Lee, F Friedl, A Tutsch, K Dresen, A Geiger, P Pluda, J Fogler, W Schiller, JH Wilding, G TI Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ANGIOGENESIS INHIBITOR ENDOSTATIN; ENDOTHELIAL-CELL APOPTOSIS; GROWTH-FACTOR; ANTIANGIOGENIC ACTIVITY; CANCER-THERAPY; ZINC-BINDING; MOUSE MODEL; ANGIOSTATIN; VITRO; GENERATION AB Purpose: Endostatin is the first endogenous angiogenesis inhibitor to enter clinical trials. Laboratory investigations with endostatin have indicated broad antitumor activity coupled with remarkably low toxicity. A phase I trial of recombinant human endostatin was designed to evaluate toxicity and explore biologic effectiveness in patients with refractory solid tumors. Patients and Methods: Endostatin was administered as a 1-hour intravenous infusion given daily for a 28-day cycle. A starting dose of 30 mg/m(2) was explored with subsequent dose escalations of 60, 100, 150, 225, and 300 mg/m(2). Assessment of serum pharmacokinetics was performed on all 21 patients. Western blot assay and mass spectroscopy were employed to evaluate endostatin metabolism. Circulating levels of endogenous proangiogenic growth factors were examined. Tumor and tumor blood supply were imaged by dynamic computed tomography (CT), magnetic resonance imaging, ultrasound, and positron emission tomography. Results: Endostatin given on this schedule was essentially free of significant drug-related toxicity. Two transient episodes of grade 1 rash were observed. No clinical responses were observed. Endostatin pharmacokinetics were linear with dose, and serum concentrations were achieved that are associated with antitumor activity in preclinical models. No aggregate effect on circulating proangiogenic growth factors were seen, although several patients exhibited persistent declines in vascular endothelial growth factor levels while enrolled in the study. A few patients demonstrated changes in their dynamic CT scans suggestive of a decline in microvessel density, although overall, no consistent effect of endostatin on tumor vasculature was seen. Conclusion: Endostatin given daily as a 1-hour intravenous infusion was well tolerated without dose-limiting toxicity at doses up to 300 mg/m(2). (C) 2003 by American Society of Clinical Oncology. C1 Univ Wisconsin, Ctr Comprehens Canc, Sch Med, Madison, WI 53792 USA. Univ Wisconsin, Sch Med, Dept Med, Sect Med Oncol, Madison, WI 53792 USA. NCI, Bethesda, MD 20892 USA. EntreMed, Rockville, MD USA. RP Wilding, G (reprint author), Univ Wisconsin, Ctr Comprehens Canc, Sch Med, 600 Highland Ave K6-5 CSC, Madison, WI 53792 USA. FU NCI NIH HHS [U01 CA62491, U01 CA062491]; NCRR NIH HHS [M01RR03186] NR 60 TC 174 Z9 196 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 JAN 15 PY 2003 VL 21 IS 2 BP 223 EP 231 DI 10.1200/JCO.2003.12.120 PG 9 WC Oncology SC Oncology GA 685UG UT WOS:000183281200008 PM 12525513 ER PT J AU Panasci, L Stinson, SF Melnychuk, D Sandor, V Miller, WH Batist, G Patenaude, F Bangash, N Panarello, L Alaoui-Jamali, M Sausville, E AF Panasci, L Stinson, SF Melnychuk, D Sandor, V Miller, WH Batist, G Patenaude, F Bangash, N Panarello, L Alaoui-Jamali, M Sausville, E TI SarCNU, a nitrosourea analog on a day 1, 5, and 9 oral schedule: A phase I and pharmacokinetic study in patients with advanced solid tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CELL-LINES SK-MG-1; (2-CHLOROETHYL)-3-SARCOSINAMIDE-1-NITROSOUREA; CYTOTOXICITY; PLASMA; 1-(2-CHLOROETHYL)-3-SARCOSINAMIDE-1-NITROSOUREA; 2-CHLOROETHYL-3-SARCOSINAMIDE-1-NITROSOUREA; TRANSPORT; CARRIER; SKI-1; ASSAY AB Purpose: 2-Chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) is a novel chloroethylnitrosourea that demonstrates selective cytotoxicity in athymic mice bearing human glioma. SarCNU demonstrates selective cytotoxicity in vitro against human glioma at least in part because of the selective SarCNU uptake by the extraneuronal monoamine transporter. The purpose of this phase I study was to determine the maximum-tolerated dose (MTD), the toxicity profile, the pharmacokinetics profile, and recommended phase 11 dose. Patients and Methods: Forty-three eligible patients with advanced solid tumors were enrolled. SarCNU was administered orally on days 1,5, and 9 every 28 days. The dose ranged from 30 to 1,075 mg/m(2). Pharmacokinetic evaluation was done on the first cycle (one dose was given intravenously on day 1 or 5 of the first cycle to determine bioavailability). Results: Delayed myelosuppression (thrombocytopenia and neutropenia occurring 4 to 6 weeks after administration) was the dose-limiting toxicity (DLT). Anemic occurred but was mild. Nonhematologic toxicity was generally mild, but one patient died with pulmonary toxicity that was probably secondary to SarCNU. There were no partial or complete responses, but eight patients had stable disease for 19 to 46 weeks. The oral bioavailability of SarCNU was 80% +/- 37%. The terminal phase half-life was similar after intravenous (58.4 +/- 23.5 minutes) or oral (64.0 +/- 34.8 minutes) administration. The total plasma clearance was 20.4 +/- 8.8 L/h/m(2), and the apparent volume of distribution was 29.9 +/- 17.6 L/m(2). The area under the plasma concentration-time profile increased proportionally with the dose, and the pharmacokinetics seemed to be independent of the route of administration and the number of doses. Conclusion: SarCNU was well tolerated and the MTD was 1,075 mg/m(2). The recommended starting dose for phase II trials is 860 mg/m(2) orally on days 1, 5, and 9 every 6 weeks. (C) 2003 by American Society of Clinical Oncology. C1 Jewish Gen Hosp, McGill Ctr Translat Res Canc, Montreal, PQ H3T 1E2, Canada. NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. RP Panasci, L (reprint author), Jewish Gen Hosp, McGill Ctr Translat Res Canc, 3755 Cote Ste Catherine Rd, Montreal, PQ H3T 1E2, Canada. FU NCI NIH HHS [R01-CA-78205] NR 18 TC 7 Z9 7 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 JAN 15 PY 2003 VL 21 IS 2 BP 232 EP 240 DI 10.1200/JCO.2003.03.047 PG 9 WC Oncology SC Oncology GA 685UG UT WOS:000183281200009 PM 12525514 ER PT J AU Allegra, CJ Paik, S Colangelo, LH Parr, AL Kirsch, I Kim, G Klein, P Johnston, PG Wolmark, N Wieand, HS AF Allegra, CJ Paik, S Colangelo, LH Parr, AL Kirsch, I Kim, G Klein, P Johnston, PG Wolmark, N Wieand, HS TI Prognostic value of thymidylate synthase, Ki-67, and p53 in patients with Dukes' B and C colon cancer: A national cancer institute-national surgical adjuvant breast and bowel project collaborative study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 37th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 12-15, 2001 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Clin Oncol ID FLUOROURACIL-BASED CHEMOTHERAPY; ANTICANCER DRUG SCREEN; COLORECTAL-CANCER; NUCLEAR OVEREXPRESSION; PROTEIN EXPRESSION; THERAPEUTIC AGENTS; RECTAL-CARCINOMA; CELL-LINES; DNA-PLOIDY; KI-RAS AB Purpose: To define the value of thymidylate synthase (TS), Ki-67, and p53 as prognostic markers in patients with stage 11 and III colon carcinoma. Patients and Methods: We retrospectively analyzed the prognostic value of TS, Ki-67, and p53 in 706 patients with Dukes' B (291 patients) or Dukes' C (415 patients) colon carcinoma who were treated with either surgery alone (275 patients) or surgery plus fluorouracil (FU)-leucovorin chemotherapy (431 patients) in National Surgical Adjuvant Breast and Bowel Project (NSABP) protocols C01 -C04. All three markers were assayed using immunohistochemical techniques. Results: Using 5 years of follow-up data, our retrospective analysis demonstrated an association between TS intensity (relapse-free survival [RFS]: risk ratio [RR] = 1.46, P = .01; overall survival [OS]: RR = 1.54, P = .002), Ki-67 (RFS: RR = 0.76, P = .05; OS: RR = 0.62, P = .001), and p53 (RFS: RR = 1.49, P = .01; OS: RR = 1.21, P = .18) for RFS and OS. High TS intensity levels and positive p53 staining were associated with a worse outcome. Tumors containing a high percentage of Ki-67-positive cells enjoyed an improved outcome compared with those patients whose tumors contained relatively few positive cells. An interaction with treatment was not identified for any of the markers. Conclusion: This retrospective investigation demonstrated that TS, Ki-67, and p53 staining each had significant prognostic value for patients with Dukes' B and C colon carcinoma. However, none of the markers could be used to clearly discern groups of individuals who would be predicted to derive greater or lesser benefit from the use of adjuvant chemotherapy. (C) 2003 by American Society of Clinical Oncology. C1 NCI, Med Branch, NIH, Bethesda, MD USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Belfast City Hosp, Dept Oncol, Belfast BT9 7AD, Antrim, North Ireland. RP Allegra, CJ (reprint author), 31 Ctr Dr,MSC 2440,Bldg 31,Rm 3A-44, Bethesda, MD 20892 USA. FU NCI NIH HHS [U10CA69651, U10CA69974, U10CA12027, U10CA37377] NR 50 TC 199 Z9 203 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 JAN 15 PY 2003 VL 21 IS 2 BP 241 EP 250 DI 10.1200/JCO.2003.05.044 PG 10 WC Oncology SC Oncology GA 685UG UT WOS:000183281200010 PM 12525515 ER PT J AU Lumsden, JM Williams, JA Hodes, RJ AF Lumsden, JM Williams, JA Hodes, RJ TI Differential requirements for expression of CD80/86 and CD40 on B cells for T-dependent antibody responses in vivo SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GERMINAL CENTER FORMATION; HUMORAL IMMUNE-RESPONSE; CD40-CD40 LIGAND; CO-STIMULATION; CD86 B7-2; MICE; ACTIVATION; CD4(+); LYMPHOCYTES; DEFICIENT AB The CD80/86-CD28 and CD40-CD40 ligand costimulatory pathways are essential for Th cell-dependent B cell responses that generate high-affinity, class-switched Ab in vivo. Disruption of either costimulatory pathway results in defective in vivo humoral immune responses, but it remains unclear to what extent this is due to deficient activation of Th cells and/or of B cells. To address this issue, we generated mixed chimeras in which CD80/86- or CD40-deficient bone marrow-derived cells coexist with wild-type (WT) cells, thereby providing the functional T cell help and accessory cell functions required for fully competent B cell responses. We were then able to assess the requirement for CD80/86 or CD40 expression on B cells producing class-switched Ig in response to a T-dependent Ag. In CD80/86 WT plus CD80/86 double-knockout mixed chimeras, both WT- and CD80/86-deficient B cells produced IgG1 and IgE responses, indicating that direct signaling by CD80/86 is not essential for efficient B cell activation. In marked contrast, only WT IgG1 and IgE responses were detected in the chimeras containing CD40-deficient cells, demonstrating that CD40 expression on B cells is essential for class switching by those B cells. Thus, while disrupting either the CD80/86-CD28 or the CD40-CD40 ligand costimulatory pathway abrogates T-dependent B cell immune responses, the two pathways are non-redundant and mediated by distinct mechanisms. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NIA, NIH, Bethesda, MD 20892 USA. RP Lumsden, JM (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B10,MSC 1360,10 Ctr Dr, Bethesda, MD 20892 USA. EM lumsdenj@mail.nih.gov NR 35 TC 32 Z9 34 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2003 VL 170 IS 2 BP 781 EP 787 PG 7 WC Immunology SC Immunology GA 633QQ UT WOS:000180294300016 PM 12517941 ER PT J AU Raval, A Weissman, JD Howcroft, TK Singer, DS AF Raval, A Weissman, JD Howcroft, TK Singer, DS TI The GTP-binding domain of class II transactivator regulates its nuclear export SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BARE LYMPHOCYTE SYNDROME; MHC CLASS-I; SELF-ASSOCIATION; SUBCELLULAR-LOCALIZATION; CYTOPLASMIC RETENTION; INTERFERON-GAMMA; CIITA INTERACTS; GENE; PROTEIN; RICH AB The transcriptional coactivator class II transactivator (CIITA), although predominantly localized in the nucleus, is also present in the cytoplasm. The subcellular distribution of CIITA is actively regulated by the opposing actions of nuclear export and import. In this study, we show that nuclear export is negatively regulated by the GTP-binding domain (GBD; aa 421-561) of CIITA: mutation or deletion of the GBD markedly increased export of CIITA from the nucleus. Remarkably, a CIITA GBD mutant binds CRM1/exportin significantly better than does wild-type CIITA, leading to the conclusion that GTP is a negative regulator of CIITA nuclear export. We also report that, in addition to the previously characterized N- and C-terminal nuclear localization signal elements, there is an additional N-terminal nuclear localization activity, present between aa 209 and 222, which overlaps the proline/serine/threonine-rich domain of CIITA. Thus, fine-tuning of the nucleocytoplasmic distribution of coactivator proteins involved in transcription is an active and dynamic process that defines a novel mechanism for controlling gene regulation. C1 NCI, Expt Immunol Branch, NCI, Bethesda, MD 20892 USA. RP Singer, DS (reprint author), NCI, Expt Immunol Branch, NCI, Bldg 10,Rm 4B-36, Bethesda, MD 20892 USA. NR 43 TC 27 Z9 29 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JAN 15 PY 2003 VL 170 IS 2 BP 922 EP 930 PG 9 WC Immunology SC Immunology GA 633QQ UT WOS:000180294300033 PM 12517958 ER PT J AU Viscidi, RP Ahdieh-Grant, L Clayman, B Fox, K Massad, LS Cu-Uvin, S Shah, KV Anastos, KM Squires, KE Duerr, A Jamieson, DJ Burk, RD Klein, RS Minkoff, H Palefsky, J Strickler, H Schuman, P Piessens, E Miotti, P AF Viscidi, RP Ahdieh-Grant, L Clayman, B Fox, K Massad, LS Cu-Uvin, S Shah, KV Anastos, KM Squires, KE Duerr, A Jamieson, DJ Burk, RD Klein, RS Minkoff, H Palefsky, J Strickler, H Schuman, P Piessens, E Miotti, P TI Serum immunoglobulin G response to human papillomavirus type 16 virus-like particles in human immunodeficiency virus (HIV) - Positive and risk-matched HIV-negative women SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 19th International Papillomavirus Conference CY SEP 01-07, 2001 CL FLORIANOPLIS, BRAZIL ID CERVICAL INTRAEPITHELIAL NEOPLASIA; MAJOR CAPSID PROTEIN; HPV DNA; SEROPOSITIVE WOMEN; SEXUAL-BEHAVIOR; CYTOLOGIC ABNORMALITIES; PAPANICOLAOU SMEARS; ANTIBODIES; INFECTION; PREVALENCE AB Baseline serum samples from 2815 human immunodeficiency virus (HIV)-positive and 963 HIV-negative women enrolled in 2 cohort studies were tested for immunoglobulin G antibodies to human papillomavirus type 16 (HPV-16) capsids. HPV-16 seropositivity was associated with lifetime number of sex partners (P<.001) among both HIV-positive and HIV-negative women. Approximately 50%-60% of HPV-16 DNA-positive women were HPV-16 positive. HPV-16 seropositivity was associated with HIV infection; however, after adjustment for baseline cervical HPV infection and disease, the association disappeared. Thus, the high seroprevalence of HPV-16 among HIV-positive women may be explained by a high prevalence of HPV of all types. Approximately 50% of HIV-positive women had serological evidence of prior HPV-16 infection, but only &SIM;5% had an HPV-16 cervical infection at baseline. Despite the higher prevalence of HPV infection in this group, most HIV-positive women are able to control HPV-16 replication at the cervix, and reactivation, if it occurs, is not very common. C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. NIAID, Div AIDS, Bethesda, MD 20892 USA. Cook Cty Hosp, Chicago, IL 60612 USA. Rush Med Coll, Chicago, IL 60612 USA. Brown Univ, Miriam Hosp, Providence, RI USA. Montefiore Med Ctr, Bronx, NY 10467 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Maimonides Hosp, Brooklyn, NY 11219 USA. Univ So Calif, Sch Med, Los Angeles, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Wayne State Univ, Sch Med, Detroit, MI USA. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. RP Viscidi, RP (reprint author), Johns Hopkins Univ Hosp, Blalock Rm 1105,600 N Wolfe St, Baltimore, MD 21287 USA. FU NCRR NIH HHS [M01-RR00079, M01-RR00083]; NIAID NIH HHS [U01-AI-31834, U01-AI-34994, AI-42058, U01-AI-35004, U01-AI-42590, AI-34989]; NICHD NIH HHS [U01-HD-32632]; ODCDC CDC HHS [U64/CCU506831, U64/CCU106795, U64/CCU306802, U64/CCU206798]; PHS HHS [U01-A1-34993] NR 49 TC 46 Z9 48 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 15 PY 2003 VL 187 IS 2 BP 194 EP 205 DI 10.1086/346052 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 632MF UT WOS:000180226500004 PM 12552444 ER PT J AU Valdez, H Mitsuyasu, R Landay, A Sevin, AD Chan, ES Spritzler, J Kalams, SA Pollard, RB Fahey, J Fox, L Namkung, A Estep, S Moss, R Sahner, D Lederman, MM AF Valdez, H Mitsuyasu, R Landay, A Sevin, AD Chan, ES Spritzler, J Kalams, SA Pollard, RB Fahey, J Fox, L Namkung, A Estep, S Moss, R Sahner, D Lederman, MM TI Interleukin-2 increases CD4(+) lymphocyte numbers but does not enhance responses to immunization: Results of A5046s SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 14th International AIDS Conference CY JUL 07-12, 2002 CL BARCELONA, SPAIN ID IMMUNODEFICIENCY-VIRUS INFECTION; ANTIRETROVIRAL THERAPY; HIV-1 INFECTION; VACCINATION; RECALL AB To ascertain whether CD4(+) lymphocyte increases induced by interleukin (IL)-2 enhanced in vivo immune responses, 38 human immunodeficiency virus (HIV)-infected patients who had received highly active antiretroviral therapy (HAART) or HAART and IL-2 for at least 60 weeks were immunized with tetanus toxoid, inactivated glycoprotein 120-depleted HIV-1, and hepatitis A and B vaccines. Despite dramatic increases in CD4(+) lymphocyte counts, IL-2 did not enhance immunization responses. C1 Univ Hosp Cleveland, AIDS Clin Trials Unit, Div Infect Dis, Cleveland, OH 44106 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Immune Response Corp, Carlsbad, CA USA. Chiron Corp, Emeryville, CA 94608 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Massachusetts Gen Hosp, Charlestown, MA USA. Univ Texas, Galveston, TX 77555 USA. NIH, Div AIDS, Bethesda, MD 20892 USA. AIDS Clin Trials Grp Operat Ctr, Silver Spring, MD USA. RP Valdez, H (reprint author), Univ Hosp Cleveland, AIDS Clin Trials Unit, Div Infect Dis, 2061 Cornell Rd,Rm 401B, Cleveland, OH 44106 USA. FU NCRR NIH HHS [RR00080]; NIAID NIH HHS [AI-50501-01, AI-25879, AI-38855, AI-38858, AI-36219] NR 15 TC 40 Z9 40 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JAN 15 PY 2003 VL 187 IS 2 BP 320 EP 325 DI 10.1086/346056 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 632MF UT WOS:000180226500019 PM 12552459 ER PT J AU Vogel, C Mossner, R Gerlach, M Heinemann, T Murphy, DL Riederer, P Lesch, KP Sommer, C AF Vogel, C Mossner, R Gerlach, M Heinemann, T Murphy, DL Riederer, P Lesch, KP Sommer, C TI Absence of thermal hyperalgesia in serotonin transporter-deficient mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE serotonin; serotonin transporter-deficient mice; hyperalgesia; allodynia; neuropathy; chronic constriction injury ID RAT SCIATIC-NERVE; PAINFUL PERIPHERAL NEUROPATHY; SPINAL-CORD; REUPTAKE INHIBITOR; INTRATHECAL SEROTONIN; DIABETIC-NEUROPATHY; 5-HT2A RECEPTORS; MODEL; MONONEUROPATHY; AMITRIPTYLINE AB Antidepressants in the treatment of neuropathic pain are thought to partially exert their effect by inhibition of serotonin (5-HT) reuptake and thus activation of central antinociceptive pathways. Mice deficient for the 5-HT transporter (5-HTT-/- mice) are regarded as a model of lifelong treatment with a serotonin reuptake inhibitor. Here we investigated 5-HTT-/- mice and compared their pain-related behavior after a unilateral chronic constrictive sciatic nerve injury (CCI) with that of wild-type littermates. Wild-type mice reproducibly developed ipsilateral thermal hyperalgesia and mechanical allodynia after CCI. 5-HTT-/- mice did not develop thermal hyperalgesia, but showed bilateral mechanical allodynia after the nerve injury. 5-HT levels as measured with HPLC increased after CCI in the injured nerve in both genotypes and decreased in the lumbar spinal cord in wild-type mice. 5-HTT-/- mice had significantly lower 5-HT concentrations than wild-type mice in all tissues investigated. Thus, in 5-HTT-/- mice, reduced 5-HT levels in the injured peripheral nerves correlate with diminished behavioral signs of thermal hyperalgesia, a pain-related symptom caused by peripheral sensitization. In contrast, bilateral mechanical allodynia, a centrally mediated phenomenon, was associated with decreased spinal 5-HT concentrations in 5-HTT-/- mice and may possibly be caused by a lack of spinal inhibition. C1 Univ Wurzburg, Neurol Klin, Dept Neurol, D-97080 Wurzburg, Germany. Univ Wurzburg, Dept Psychiat & Psychotherapy, D-97080 Wurzburg, Germany. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Univ Wurzburg, Neurol Klin, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany. EM sommer@mail.uni-wuerzburg.de RI Lesch, Klaus-Peter/J-4906-2013; Sommer, Claudia/A-9820-2010 OI Lesch, Klaus-Peter/0000-0001-8348-153X; Sommer, Claudia/0000-0002-7064-5002 NR 49 TC 69 Z9 70 U1 0 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JAN 15 PY 2003 VL 23 IS 2 BP 708 EP 715 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 637QC UT WOS:000180523000037 PM 12533631 ER PT J AU Moaddel, R Wainer, IW AF Moaddel, R Wainer, IW TI Immobilized nicotinic receptor stationary phases: going with the flow in high-throughput screening and pharmacological studies SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Review DE nicotinic agonists; nicotinic antagonists; non-competitive inhibitors; affinity chromatography; immobilized receptors ID LIQUID-CHROMATOGRAPHIC DETERMINATION; ACETYLCHOLINE-RECEPTORS; INHIBITION; AFFINITIES; SUBTYPES; BINDING; TARGETS AB The nicotinic acetylcholine receptor (nAChR) subtypes alpha3beta4-nAChR and alpha4beta2-nAChR have been immobilized and the resulting stationary phases used to determine binding affinities. The alpha3beta4-nAUR column was coupled to a C-18 column and a mixture of 18 compounds was sorted into ligands and non-ligands for the alpha3beta4-nAUR. The results demonstrate that the nAChR stationary phases can be used for on-line high-throughput screening (HTS). Published by Elsevier Science B.V. 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. NR 22 TC 30 Z9 34 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD JAN 15 PY 2003 VL 30 IS 6 BP 1715 EP 1724 AR PII S0731-7085(02)00513-7 DI 10.1016/S0731-7085(02)00513-7 PG 10 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 637AC UT WOS:000180488600006 PM 12485712 ER PT J AU Lei, SB McBain, CJ AF Lei, SB McBain, CJ TI GABA(B) receptor modulation of excitatory and inhibitory synaptic transmission onto rat CA3 hippocampal interneurons SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID LONG-TERM POTENTIATION; GAMMA-AMINOBUTYRIC-ACID; PAIRED-PULSE FACILITATION; G-PROTEIN INHIBITION; PRESYNAPTIC INHIBITION; CALCIUM CHANNELS; CA2+ CHANNELS; POSTSYNAPTIC RESPONSES; MEDIATED INHIBITION; GLUTAMATE RECEPTORS AB Hippocampal stratum radiatum inhibitory interneurons receive glutamatergic excitatory innervation via the recurrent collateral fibers of CA3 pyramidal neurons and GABAergic inhibition from other interneurons. We examined both presynaptic- and postsynaptic-GABA(B) receptor-mediated responses at both synapse types. Postsynaptic GABA(B) receptor-mediated responses were absent in recordings from young (P16-18) but present in recordings from older animals (greater than or equal toP30) suggesting developmental regulation. In young animals, the GABA(B) receptor agonist, baclofen, inhibited the amplitude of evoked EPSCs and IPSCs, an effect blocked by prior application of the selective antagonist CGP55845. Baclofen enhanced the paired-pulse ratio and coefficient of variation of evoked EPSCs and IPSCs, consistent with a presynaptic mechanism of regulation. In addition, baclofen reduced the frequency of miniature IPSCs but not mEPSCs. However, baclofen reduced the frequency of KCl-induced mEPSCs; an effect blocked by Cd2+, implicating presynaptic voltage-gated Ca2+ channels as a target for baclofen modulation. In contrast, although Cd2+ prevented the KCl-induced increase in mIPSC frequency, it failed to block baclofen's reduction of mIPSC frequency. Whereas N- and P/Q-types of Ca2+ channels contributed equally to GABAB receptor-mediated inhibition of EPSCs, more P/Q-type Ca2+ channels were involved in GABA(B) receptor-mediated inhibition of IPSCs. Finally, baclofen blocked the frequency-dependent depression of EPSCs and IPSCs, but was less effective at blocking frequency-dependent facilitation of EPSCs. Our results demonstrate that presynaptic GABA(B) receptors are expressed on the terminals of both excitatory and inhibitory synapses onto CA3 interneurons and that their activation modulates essential components of the release process underlying transmission at these two synapse types. C1 NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. RP McBain, CJ (reprint author), NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. NR 62 TC 76 Z9 78 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JAN 15 PY 2003 VL 546 IS 2 BP 439 EP 453 DI 10.1113/jphysiol.2002.034017 PG 15 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 690UW UT WOS:000183569700011 PM 12527730 ER PT J AU Dorgan, JF Hunsberger, SA McMahon, RP Kwiterovich, PO Lauer, RM Van Horn, L Lasser, NL Stevens, VJ Friedman, LA Yanovski, JA Greenhut, SF Chandler, DW Franklin, FA Barton, BA Buckman, DW Snetselaar, LG Patterson, BH Schatzkin, A Taylor, PR AF Dorgan, JF Hunsberger, SA McMahon, RP Kwiterovich, PO Lauer, RM Van Horn, L Lasser, NL Stevens, VJ Friedman, LA Yanovski, JA Greenhut, SF Chandler, DW Franklin, FA Barton, BA Buckman, DW Snetselaar, LG Patterson, BH Schatzkin, A Taylor, PR TI Diet and sex hormones in girls: Findings from a randomized controlled clinical trial SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BREAST-CANCER RISK; POSTMENOPAUSAL WOMEN; CHILDREN DISC; FEMALE PUBERTY; MAMMARY-GLANDS; TEENAGE GIRLS; SERUM; GROWTH; PROGESTERONE; INTERVENTION AB Background: Results of several studies have suggested that diet during adolescence may influence the risk of breast cancer in adulthood. We evaluated whether an intervention to lower fat intake among adolescent girls altered their serum concentrations of sex hormones that, in adults, are related to breast cancer development. Methods: We conducted an ancillary hormone study among 286 of the 301 girls who participated between 1988 and 1997 in the Dietary Intervention Study in Children, in which healthy, prepubertal, 8- to 10-year-olds with elevated low-density lipoprotein cholesterol were randomly assigned to usual care or to a behavioral intervention that promoted a low-fat diet. Median time on the intervention was 7 years. Blood samples collected before randomization and at the year 1, year 3, year 5, and last visits were assayed to determine the girls' serum levels of sex hormones. All P values are two-sided. Results: At the year 5 visit, girls in the intervention group had 29.8% (95% confidence interval [CI] = 5.4% to 47.9%; P = .02) lower estradiol, 30.2% (95% CI = 7.0% to 47.7%; P = .02) lower non-sex hormone binding globulin-bound estradiol, 20.7% (95% CI 4.7% to 34.0%; P = .02) lower estrone, and 28.7% (95% CI 5.1% to 46.5%; P = .02) lower estrone sulfate levels during the follicular phase of the menstrual cycle and 27.2% (95% CI = 5.7% to 53.1%; P = .01) higher testosterone levels during the luteal phase of the menstrual cycle than did girls in the usual care group. At the last visit, the luteal phase progesterone level was 52.9% (95% CI = 20.0% to 72.3%) lower for girls in the intervention group than for girls in the usual care group (P = .007). Conclusion: Modest reductions in fat intake during puberty are associated with changes in sex hormone concentrations that are consistent with alterations in the function of the hypothalamic-pituitary-ovarian axis. Whether these changes influence breast cancer risk is currently unknown. C1 Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. NCI, Div Canc Treatment & Diagnosis, Bethesda, MD 20892 USA. NCI, Off Canc Genomics, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21205 USA. Univ Iowa, Iowa City, IA USA. Northwestern Univ, Sch Med, Chicago, IL 60611 USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Maryland Med Res Inst, Baltimore, MD USA. Natl Inst Child Hlth & Human Dev, Bethesda, MD USA. Esoterix Endocrinol Inc, Calabasas Hills, CA USA. Childrens Hosp Alabama, Birmingham, AL USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Dorgan, JF (reprint author), Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA. RI McMahon, Robert/C-5462-2009; OI Barton, Bruce/0000-0001-7878-8895 FU NHLBI NIH HHS [U01-HL37948, U01-HL37947, U01-HL37954, U01-HL37962, U01-HL37966, U01-HL37975, U01-HL38110] NR 53 TC 55 Z9 56 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JAN 15 PY 2003 VL 95 IS 2 BP 132 EP 141 PG 10 WC Oncology SC Oncology GA 634QA UT WOS:000180350800010 PM 12529346 ER PT J AU Zhang, JZ Dyer, KD Rosenberg, HF AF Zhang, JZ Dyer, KD Rosenberg, HF TI Human RNase 7: a new cationic ribonuclease of the RNase A superfamily SO NUCLEIC ACIDS RESEARCH LA English DT Article ID EOSINOPHIL-DERIVED NEUROTOXIN; RESPIRATORY SYNCYTIAL VIRUS; GENE FAMILY; MOLECULAR-CLONING; RANA-CATESBEIANA; PROTEIN; EVOLUTION; SELECTION; BULLFROG AB Here we report on the expression and function of RNase 7, one of the final RNase A superfamily ribonucleases identified in the human genome sequence. The human RNase 7 gene is expressed in various somatic tissues including the liver, kidney, skeletal muscle and heart. Recombinant RNase 7 is ribonucleolytically active against yeast tRNA, as expected from the presence of eight conserved cysteines and the catalytic histidine-lysine-histidine triad which are signature motifs of this superfamily. The protein is atypically cationic with an isoelectric point (pI) of 10.5. Expression of recombinant RNase 7 in Escherichia coli completely inhibits the growth of the host bacteria, similar to what has been observed for the cationic RNase, eosinophil cationic protein (ECP/RNase 3, pI 11.4). An in vitro assay demonstrates dose-dependent cytotoxicity of RNase 7 against bacteria E.coli, Pseudomonas aeruginosa and Staphylococcus aureus. While RNase 7 and ECP/RNase 3 are both cationic and share this particular aspect of functional similarity, their protein sequence identity is only 40%. Of particular interest, ECP/RNase 3's cationicity is based on an (over)abundance of arginine residues, whereas RNase 7 includes an excess of lysine. This difference, in conjunction with the independent origins and different expression patterns, suggests that RNase 7 and ECP/RNase 3 may have been recruited to target different pathogens in vivo, if their physiological functions are indeed host defenses. C1 Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Zhang, JZ (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, 3003 Nat Sci Bldg,830 N Univ Ave, Ann Arbor, MI 48109 USA. NR 28 TC 64 Z9 70 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN 15 PY 2003 VL 31 IS 2 BP 602 EP 607 DI 10.1093/nar/gkg157 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 647FE UT WOS:000181081500010 PM 12527768 ER PT J AU Li, W Ma, BY Shapiro, BA AF Li, W Ma, BY Shapiro, BA TI Binding interactions between the core central domain of 16S rRNA and the ribosomal protein S15 determined by molecular dynamics simulations SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CONTINUUM SOLVENT; CONFORMATIONAL-CHANGES; FORCE-FIELD; RNA; SUBUNIT; SITE; STABILITY; MODEL; DNA; RECOGNITION AB The goal of the current study is to utilize molecular dynamic (MD) simulations to investigate the dynamic behavior of 16S rRNA in the presence and absence of S15 and to identify the binding interactions between these two molecules. The simulations show that: (i) 16S rRNA remains in a highly folded structure when it is bound to S15; (ii) in the absence of S15, 16S rRNA significantly alters its conformation and transiently forms conformations that are similar to the bound structure that make it available for binding with S15; (iii) the unbound rRNA spends the majority of its time in extended conformations. The formation of the extended conformations is a result of the molecule reaching a lower electrostatic energy and the formation of the highly folded, crystal-like conformation is a result of achieving a lower solvation energy. In addition, our MD simulations show that 16S rRNA and S15 bind across the major groove of helix 22 (H22) via electrostatic interactions. The negatively charged phosphate groups of G658, U740, G741 and G742 bind to the positively charged S15 residues Lys7, Arg34 and Arg37. The current study provides a dynamic view of the binding of 16S rRNA with S15. C1 NCI, Lab Expt & Computat Biol, NCI Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Shapiro, BA (reprint author), NCI, Lab Expt & Computat Biol, NCI Ctr Canc Res, NIH, Bldg 469,Room 150, Frederick, MD 21702 USA. RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X NR 38 TC 18 Z9 20 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN 15 PY 2003 VL 31 IS 2 BP 629 EP 638 DI 10.1093/nar/gkg149 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 647FE UT WOS:000181081500013 PM 12527771 ER PT J AU Panchenko, AR AF Panchenko, AR TI Finding weak similarities between proteins by sequence profile comparison SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HIDDEN MARKOV-MODELS; DATABASE SEARCHES; PSI-BLAST; ALIGNMENT; PREDICTIONS; INFORMATION; STATISTICS; PROGRAMS; ACCURACY; HOMOLOGS AB To improve the recognition of weak similarities between proteins a method of aligning two sequence profiles is proposed. It is shown that exploring the sequence space in the vicinity of the sequence with unknown properties significantly improves the performance of sequence alignment methods. Consistent with the previous observations the recognition sensitivity and alignment accuracy obtained by a profile-profile alignment method can be as much as 30% higher compared to the sequence-profile alignment method. It is demonstrated that the choice of score function and the diversity of the test profile are very important factors for achieving the maximum performance of the method, whereas the optimum range of these parameters depends on the level of similarity to be recognized. C1 NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Panchenko, AR (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A,Room 8N805,8600 Rockville Pike, Bethesda, MD 20894 USA. NR 44 TC 45 Z9 46 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JAN 15 PY 2003 VL 31 IS 2 BP 683 EP 689 DI 10.1093/nar/gkg154 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 647FE UT WOS:000181081500019 PM 12527777 ER PT J AU Kafadar, K Prorok, PC AF Kafadar, K Prorok, PC TI Alternative definitions of comparable case groups and estimates of lead time and benefit time in randomized cancer screening trials SO STATISTICS IN MEDICINE LA English DT Article DE cancer screening; sojourn time; length bias; bivariate gamma distribution; logrank test; survival function; catch up time; confidence interval coverage probability ID DEATH RATES; NEOPLASMS; GROWTH AB Randomized screening trials provide the optimal meam of assessing the benefit of screening for cancer and other chronic diseases. Unlike therapy trials. however, where strict eligibility criteria assure the comparability of cases of disease in the arms of the trial, the cancer cases identified during follow-up are a subset of all randomized participants. Furthermore, those cases detected by screening tend to arise from length biased sampling which also can bias estimates of the screening benefit and of average lead time. To reduce or eliminate this bias, we propose several methods for defining comparable groups of cases from the trial arms. We examine, via simulation. these methods with respect to their effects on (i) point and interval estimates of average lead time aid average benefit time and (ii) the logrank test statistic for a mortality effect of screening. The most successful new method for defining comparable case groups uses an estimate of the mean sojourn time (mean preclinical duration), and results in nearly unbiased estimates of average lead time and average benefit time as well as an unbiased logrank test statistic. Published in 2003 by John Wiley Sons, Ltd. C1 Univ Colorado, Dept Math, Denver, CO 80217 USA. NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20982 USA. RP Kafadar, K (reprint author), Univ Colorado, Dept Math, Campus Box 170,POB 173364, Denver, CO 80217 USA. NR 22 TC 6 Z9 6 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD JAN 15 PY 2003 VL 22 IS 1 BP 83 EP 111 DI 10.1002/sim.1331 PG 29 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 630JD UT WOS:000180103000007 PM 12486753 ER PT J AU Li, YL Urrutia, M Smith-Gill, SJ Mariuzza, RA AF Li, YL Urrutia, M Smith-Gill, SJ Mariuzza, RA TI Dissection of binding interactions in the complex between the anti-lysozyme antibody HyHEL-63 and its antigen SO BIOCHEMISTRY LA English DT Article ID T-CELL-RECEPTOR; ALANINE-SCANNING MUTAGENESIS; PROTEIN-PROTEIN INTERACTIONS; DOUBLE MUTANT CYCLES; ESCHERICHIA-COLI; MUTATIONAL ANALYSIS; HOT-SPOTS; CRYSTAL-STRUCTURE; LYSOZYME COMPLEX; SALT BRIDGES AB Alanine-scanning mutagenesis, X-ray crystallography, and double mutant cycles were used to characterize the interface between the anti-hen egg white lysozyme (HEL) antibody HyHEL-63 and HEL. Eleven HEL residues in contact with HyHEL-63 in the crystal structure of the antigen-antibody complex, and 10 HyHEL-63 residues in contact with HEL, were individually truncated to alanine in order to determine their relative contributions to complex stabilization. The residues of HEL (Tyr20, Lys96, and Lys97) most important for binding HyHEL-63 (DeltaG(mutant) - DeltaG(wild type) > 3.0 kcal/mol) form a contiguous patch at the center of the surface contacted by the antibody. Hot spot residues of the antibody (DeltaDeltaG > 2.0 kcal/mol) are organized in two clusters that juxtapose hot spot residues of HEL, resulting in energetic complementarity across the interface. All energetically critical residues are centrally located, shielded from solvent by peripheral residues that contribute significantly less to the binding free energy. Although HEL hot spot residues Lys96 and Lys97 make similar interactions with antibody in the HyHEL-63/HEL complex, alanine substitution of Lys96 results in a nearly 100-fold greater reduction in affinity than the corresponding mutation in Lys97. To understand the basis for this marked difference, we determined the crystal structures of the HyHEL-63/HEL Lys96Ala and HyHEL-63/HEL Lys97Ala complexes to 1.80 and 1.85 A resolution, respectively. Whereas conformational changes in the proteins and differences in the solvent networks at the mutation sites appear too small to explain the observed affinity difference, superposition of free HEL in different crystal forms onto bound HEL in the wild type and mutant HyHEL-63/HEL complexes reveals that the side-chain conformation of Lys96 is very similar in the various structures, but that the Lys97 side chain displays considerable flexibility. Accordingly, a greater entropic penalty may be associated with quenching the mobility of the Lys97 than the Lys96 side chain upon complex formation, reducing binding. To further dissect the energetics of specific interactions in the HyHEL-63/HEL interface, double mutant cycles were constructed to measure the coupling of 13 amino acid pairs, 11 of which are in direct contact in the crystal structure. A large coupling energy, 3.0 kcal/mol, was found between HEL residue Lys97 and HyHEL-63 residue V(H)Asp32, which form a buried salt bridge surrounded by polar residues of the antigen. Thus, in contrast to protein folding where buried salt bridges are generally destabilizing, salt bridges in protein-protein interfaces, whose residual composition is more hydrophilic than that of protein interiors, may contribute significantly to complex stabilization. C1 Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, WM Keck Lab Struct Biol, Rockville, MD 20850 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Mariuzza, RA (reprint author), Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, WM Keck Lab Struct Biol, 9600 Gudelsky Dr, Rockville, MD 20850 USA. EM mariuzza@carb.nist.gov FU NIGMS NIH HHS [GM5280] NR 60 TC 46 Z9 46 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JAN 14 PY 2003 VL 42 IS 1 BP 11 EP 22 DI 10.1021/bi020589+ PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 634DG UT WOS:000180324300003 PM 12515535 ER PT J AU Bhargava, R Levin, IW AF Bhargava, R Levin, IW TI Noninvasive imaging of molecular dynamics in heterogeneous materials SO MACROMOLECULES LA English DT Article ID DISPERSED LIQUID-CRYSTALS; SCANNING OPTICAL MICROSCOPY; REORIENTATION DYNAMICS; FT-IR; SPECTROSCOPY; TRANSITION; SYSTEMS; MATRIX AB The macroscopic properties of microscopically heterogeneous materials are often determined by specific molecular changes within constitutive microdomains. In particular, the electrooptical properties of a class of composites termed polymer-dispersed liquid crystals (PDLCs) are established by the orientation dynamics of the component liquid crystals (LCs) and the dissolved species dictated by applied electric fields. We demonstrate the accessibility of spatially resolved molecular dynamics in the millisecond time regime by developing a time-resolved Fourier transform infrared (FTIR) spectroscopic imaging technique. Applying this approach to PDLCs, we determine the molecular reorientation dynamics to be a strong function of spatial position. The liquid crystal and polymer segmental dynamics correlate through dipole-dipole interactions, demonstrating that chemical factors other than surface anchoring interactions contribute significantly to the electrooptical characteristics of polymer-LC composites. The morphologically specific dynamics and molecular interactions are determined noninvasively and without addition of foreign materials or molecular labeling. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Levin, IW (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. OI Bhargava, Rohit/0000-0001-7360-994X NR 34 TC 14 Z9 14 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0024-9297 J9 MACROMOLECULES JI Macromolecules PD JAN 14 PY 2003 VL 36 IS 1 BP 92 EP 96 DI 10.1021/ma021336r PG 5 WC Polymer Science SC Polymer Science GA 634WK UT WOS:000180364900016 ER PT J AU Lamar, M Resnick, SM Zonderman, AB AF Lamar, M Resnick, SM Zonderman, AB TI Longitudinal changes in verbal memory in older adults - Distinguishing the effects of age from repeat testing SO NEUROLOGY LA English DT Article ID LEARNING TEST; DISEASE AB Objective: To characterize the relationship between age-related memory change and repeat testing using serial administrations of the California Verbal Learning Test (CVLT) in 385 nondemented Baltimore Longitudinal Study of Aging participants aged 55 and older with two or more memory assessments. Methods: The authors investigated longitudinal change and the effects of age, sex, education, and repeat testing on new learning and recall by analyzing measures of learning and interference, short- and long-delay free and cued recall, and recognition hits in separate mixed-effects regressions. Results: The authors found cross-sectional effects of age (p less than or equal to 0.001) and sex (p less than or equal to 0.05) on learning and interference, regardless of baseline performance. Younger adults outperformed older adults, and women outperformed men. Longitudinal age changes were documented across total learning and long-delay free and cued recall regardless of baseline scores (p less than or equal to 0.05). In addition, controlling for baseline scores enhanced the sensitivity for detection of longitudinal age changes on Trial 5, short-delay cued recall and recognition hits (p :5 0.05). The influence of repeated administrations changed with advancing baseline age for total learning and short- and long-delay recall such that younger baseline age was associated with improvement over time whereas older baseline age was associated with decline over time. Conclusion: Longitudinal declines in CVLT performance exist in normal aging and are influenced by baseline age. Furthermore, failure to account for the influence of repeat testing with aging may decrease sensitivity to detect pathologic decline. C1 NIA, Gerontol Res Ctr, LPC, Baltimore, MD 21224 USA. RP Lamar, M (reprint author), NIA, Gerontol Res Ctr, LPC, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Zonderman, Alan B/0000-0002-6523-4778 NR 20 TC 52 Z9 53 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 14 PY 2003 VL 60 IS 1 BP 82 EP 86 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 633ZU UT WOS:000180316000017 PM 12525723 ER PT J AU Gaillard, WD Balsamo, LM Ibrahim, Z Sachs, BC Xu, B AF Gaillard, WD Balsamo, LM Ibrahim, Z Sachs, BC Xu, B TI fMRI identifies regional specialization of neural networks for reading in young children SO NEUROLOGY LA English DT Article ID FUNCTIONAL MRI; LANGUAGE DOMINANCE; RIGHT-HEMISPHERE; INDIVIDUAL VARIABILITY; CORTICAL LOCALIZATION; ACTIVATION PATTERNS; WADA TEST; BRAIN; ANATOMY; COMPREHENSION AB Background: fMRI allows mapping of neural networks underlying cognitive networks during development, but few studies have systematically examined children 7 and younger, in whom language networks may be more diffusely organized than in adults. Objective: To identify neural networks during early reading consolidation in young children. Methods: The authors studied 16 normal, right-handed, native English-speaking children with a mean age of 7.2 years (range 5.8 to 7.9) with fMRI reading paradigms adjusted for reading level. Data were acquired with the echoplanar imaging BOLD technique at 1.5 T. Group data were analyzed with statistical parametric mapping (SPM-99); individual data sets were analyzed with a region of interest approach from individual study t maps (t = 4). The number of activated pixels in brain regions was determined and an asymmetry index (AI) ([L-R]/[L+Rl) calculated for each region. Results: In group analysis the authors found prominent activation in left inferior temporal occipital junction and left fusiform gyrus (Brodmann area [BAJ 37), middle temporal gyrus (BA 21, 22),,middle frontal gyrus (BA 44, 45), and the supplementary motor area. Activation was strongly lateralized in middle frontal gyrus and Wernicke areas (Al 0.54, 0.62). Fourteen subjects had left-sided language lateralization, one was bilateral, and one had poor activation. Conclusions: The neural networks that process reading are strongly lateralized and regionally specific by age 6 to 7 years. Neural networks in early readers are similar to those in adults. C1 Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. NINDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. RP Gaillard, WD (reprint author), Childrens Natl Med Ctr, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA. FU NICHD NIH HHS [P30HD40677]; NINDS NIH HHS [KO8-NS1663] NR 41 TC 75 Z9 81 U1 6 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JAN 14 PY 2003 VL 60 IS 1 BP 94 EP 100 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 633ZU UT WOS:000180316000019 PM 12525725 ER PT J AU Vineis, P Miligi, L Crosignani, P Davico, L Fontana, A Masala, G Nanni, O Ramazzotti, V Rodella, S Stagnaro, E Tumino, R Vigano, C Vindigni, C Costantini, AS AF Vineis, P Miligi, L Crosignani, P Davico, L Fontana, A Masala, G Nanni, O Ramazzotti, V Rodella, S Stagnaro, E Tumino, R Vigano, C Vindigni, C Costantini, AS TI Delayed infection, late tonsillectomy or adenoidectomy and adult leukaemia: a case-control study SO BRITISH JOURNAL OF CANCER LA English DT Article ID ASSOCIATION AB In a population-based case-control study among adults in Italy, of 261 lymphoid and 313 myeloid leukaemias and 17 18 controls, a later age at adenoidectomy and tonsillectomy (after age 10 years) increased consider-ably the risk of lymphocytic (but not myeloid) leukaemia (odds ratio 4.2, 95% confidence interval 1.1 - 16.2). We propose that late infection is a proliferative stimulus for B-cells. (C) 2003 Cancer Research UK. C1 Osped San Giovanni Battista, Serv Epidemiol Tumori, I-10123 Turin, Italy. Univ Turin, I-10123 Turin, Italy. Ctr Studio & Prevenz Oncol, I-50131 Florence, Italy. Natl Canc Inst, I-20133 Milan, Italy. Local Hlth Unit, Novara, Italy. Ist Oncol Romagnolo, Forli, Italy. Canc Registry, Latina, Italy. Local Hlth Unit, Verona, Italy. Natl Canc Inst, Genoa, Italy. Canc Registry, Ragusa, Italy. Univ Siena, Dept Pathol, I-53100 Siena, Italy. RP Vineis, P (reprint author), Osped San Giovanni Battista, Serv Epidemiol Tumori, Via Santena 7, I-10123 Turin, Italy. OI NANNI, ORIANA/0000-0001-7338-2896; Masala, Giovanna/0000-0002-5758-9069 NR 9 TC 10 Z9 10 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JAN 13 PY 2003 VL 88 IS 1 BP 47 EP 49 DI 10.1038/sj.bjc.6600689 PG 3 WC Oncology SC Oncology GA 647EF UT WOS:000181078900009 PM 12556958 ER PT J AU Althuis, MD Brogan, DR Coates, RJ Daling, JR Gammon, MD Malone, KE Schoenberg, JB Brinton, LA AF Althuis, MD Brogan, DR Coates, RJ Daling, JR Gammon, MD Malone, KE Schoenberg, JB Brinton, LA TI Hormonal content and potency of oral contraceptives and breast cancer risk among young women SO BRITISH JOURNAL OF CANCER LA English DT Article DE breast cancer; oestrogen; formulation; oral contraceptives; progestin ID UNITED-STATES; PROLIFERATION; PROGESTINS; RECALL; TRENDS; AGE AB Recent use of oral contraceptive pills is associated with a modest risk of breast cancer among very young women. In this US population-based case-control study, we evaluated whether the excess risk associated with recent oral contraceptive use is ubiquitous for all pill types or attributable to specific oral contraceptive preparations. Hormonal content and potency of combination oral contraceptives used for the longest duration within 5 years of inter-view for breast cancer cases aged 20-44 years (N = 1640) were compared with age-matched community controls (N = 1492). Women who recently used oral contraceptives containing more than 35 mug of ethinyl oestradiol per pill were at higher risk of breast cancer than users of lower dose preparations when compared to never users (respective relative risks of 1.99 and 1.27, P-trend <0.01). This relationship was more marked among women <35 years of age, where risks associated with high- and low-dose ethinyl oestradiol use were 3.62 and 1.91 (P-trend <0.01), respectively. We also found significant trends of increasing breast cancer risk for pills with higher progestin and oestrogen potencies (P-trend <0.05), which were most pronounced among women aged <35 years of age (P-trend <0.01). Risk was similar across recently used progestin types. Our findings suggest that newer low-potency/low oestrogen dose oral contraceptives may impart a lower risk of breast cancer than that associated with earlier high-potency/high-dose preparations. (C) 2003 Cancer Research UK. C1 NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Rollins Sch Publ Hlth, Atlanta, GA USA. Ctr Dis Control & Prevent, Atlanta, GA USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ N Carolina, Chapel Hill, NC 27515 USA. New Jersey State Dept Hlth & Senior Serv, Trenton, NJ USA. RP Althuis, MD (reprint author), NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Rm 7084,EPS MSC 7234, Rockville, MD 20852 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 39 TC 45 Z9 47 U1 2 U2 12 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 JAN 13 PY 2003 VL 88 IS 1 BP 50 EP 57 DI 10.1038/sj.bjc.6600691 PG 8 WC Oncology SC Oncology GA 647EF UT WOS:000181078900010 PM 12556959 ER PT J AU Zheng, T Holford, TR Zahm, SH Owens, PH Boyle, P Zhang, Y Zhang, B Wise, JP Stephenson, LP Ali-Osman, F AF Zheng, T Holford, TR Zahm, SH Owens, PH Boyle, P Zhang, Y Zhang, B Wise, JP Stephenson, LP Ali-Osman, F TI Glutathione S-transferase MI and TI genetic polymorphisms, alcohol consumption and breast cancer risk SO BRITISH JOURNAL OF CANCER LA English DT Article DE alcohol drinking; breast cancers; case-control; GST genotypes ID SUSCEPTIBILITY; GSTM1; GSTT1; LOCUS; M1; MUTAGENESIS; THETA; ASSOCIATION; GENOTYPES; DAMAGE AB Alcohol consumption has been inconsistently associated with breast cancer risk. Recent studies suggest that genetic polymorphisms of glutathione S-transferases (GSTs) may modify this relation. To determine if breast cancer risk is associated with GSTM1 and GSTT1 genetic polymorphisms, and to evaluate the effect modification between GST genotypes and alcohol consumption in the risk of breast cancer, we conducted a case-control study in the state of Connecticut in the period 1998 and 2001. Cases were histologically confirmed, incident breast cancer patients in New Haven County, CT. Controls were randomly selected from women histologically confirmed to be without breast cancer. The study results show that, while GSTM1 genotypes were not associated with breast cancer risk, GSTT1-null genotype was associated with a significant 90% increased risk for postmenopausal women (OR= 1.9, 95% CI 1.2 - 3.0). Analysis by GST genotypes and alcohol consumption shows that GSTM1A ever-drinking women had a 2.5-fold (OR = 2.5, 95% CI 1.1 - 5.5) increased risk of breast cancer compared to the GSTM1A never-drinkers, and the risk increases with duration and daily amount of alcohol consumption. Postmenopausal women with GSTT1-null genotype, who consumed a lifetime of >250 kg of spirit-equivalents, had an almost seven-fold increased risk (OR = 6.8, 95% CI 1.4 - 33.9), and drinking commencing at younger ages appears to carry a higher risk. An OR of 8.2 (95% Cl 1.2 - 57.4) was observed for those with GSTM1A, and GSTT1-null genotypes who had consumed a lifetime of > 250 kg of spirit-equivalents. In conclusion, alcohol consumption may increase breast cancer risk among those who carry susceptible GST genotypes. (C) 2003 Cancer Research UK. C1 Yale Univ, Sch Med, Coll 60, Dept Epidemiol & Publ Hlth, New Haven, CT USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. European Inst Oncol, Dept Epidemiol & Biostat, I-20141 Milan, Italy. McGill Univ, Dept Epidemiol & Biostat, Montreal, PQ H3A 1A2, Canada. Univ Texas, MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA. RP Zheng, T (reprint author), 129 Church St,Suite 700, New Haven, CT 06510 USA. RI Boyle, Peter/A-4380-2014; Zahm, Shelia/B-5025-2015 OI Boyle, Peter/0000-0001-6251-0610; FU NCI NIH HHS [CA-81810, U01 CA081810] NR 26 TC 29 Z9 30 U1 0 U2 1 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 JAN 13 PY 2003 VL 88 IS 1 BP 58 EP 62 DI 10.1038/sj.bjc.6600708 PG 5 WC Oncology SC Oncology GA 647EF UT WOS:000181078900011 PM 12556960 ER PT J AU Schernhammer, ES Leitzmann, MF Michaud, DS Speizer, FE Giovannucci, E Colditz, GA Fuchs, CS AF Schernhammer, ES Leitzmann, MF Michaud, DS Speizer, FE Giovannucci, E Colditz, GA Fuchs, CS TI Cholecystectomy and the risk for developing colorectal cancer and distal colorectal adenomas SO BRITISH JOURNAL OF CANCER LA English DT Article DE colon cancer; colon adenomas; gallstones; cholecystectomy; risk factors ID COLON CANCER; METAANALYSIS; COHORT; CARCINOMA; WOMEN; FAT AB Earlier work describes a modest association between cholecystectomy and the risk of colorectal cancer. We conducted a prospective study of 85 184 women, 36-61 year's old, who had no history of cancer to evaluate whether known risk factor's for colorectal cancer, including dietary history, that have not been controlled for in previous analyses can help explain the observed association. During 16 years of follow-up, 877 cases of colorectal cancer were documented and 1452 women who underwent endoscopy during the follow-up time were diagnosed with distal adenomas. After adjustment for age and other known or suspected risk factors, we found a significant, positive association between cholecystectomy and the risk of colorectal cancer (multivariate relative risk RR 1.21, 95% Cl 1.01-1.46). The risk was highest for cancers of the proximal colon (RR 1.34, 95% Cl 0.97-1.88) and the rectum (RR 1.58, 95% Cl 1.05-2.36). However, we did not observe a significant association between cholecystectomy and distal colorectal adenomas. In this large prospective cohort study, a history of cholecystectomy appears to increase modestly the risk of colorectal cancer, even after adjustment for other colorectal cancer risk factors. (C) 2003 Cancer Research UK. C1 Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. KFJ Spital, Ludwig Boltzmann Inst Appl Canc Res, Vienna, Austria. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. NCI, Nutr Epidemiol Branch, Rockville, MD USA. Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. Harvard Ctr Canc Prevent, Boston, MA USA. Dana Faber Harvard Canc Ctr, Program Epidemiol, Boston, MA USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Schernhammer, ES (reprint author), Brigham & Womens Hosp, Dept Med, Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. RI Michaud, Dominique/I-5231-2014; Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NCI NIH HHS [R01 CA086102, CA 40356, CA 55075, CA 86102, CA/ES62984, CA87969, P01 CA055075, P01 CA087969, R01 CA040356] NR 23 TC 33 Z9 45 U1 0 U2 3 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 JAN 13 PY 2003 VL 88 IS 1 BP 79 EP 83 DI 10.1038/sj.bjc.6600661 PG 5 WC Oncology SC Oncology GA 647EF UT WOS:000181078900014 PM 12556963 ER PT J AU Carrasco, E Blum, M Weickert, CS Casper, D AF Carrasco, E Blum, M Weickert, CS Casper, D TI Epidermal growth factor receptor expression is related to post-mitotic events in cerebellar development: regulation by thyroid hormone SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Article DE thyroid hormone; epidermal growth factor receptor; transforming growth factor-alpha; cerebellum; development ID DEVELOPING RAT CEREBELLUM; HUMAN NERVOUS-SYSTEM; ALPHA MESSENGER-RNA; GENE-EXPRESSION; POSTNATAL-DEVELOPMENT; MOLECULAR LAYER; EGF RECEPTOR; TGF-ALPHA; PERINATAL HYPOTHYROIDISM; EMBRYONIC MESENCEPHALON AB It has been established that thyroid hormone and neurotrophic factors both orchestrate developmental events in the brain. However, it is not clear how these two influences are related. In this study, we investigated the effects of thyroid hormone on cerebellar development and the coincident expression of transforming growth factor-alpha (TGF-alpha), a ligand in the epidermal growth factor (EGF) family, and the epidermal growth factor receptor (EGFR). Profiles of thyroid hormone expression were measured in postnatal animals and were found to peak at postnatal day 15 (P15). These levels dropped below detectable levels when mice were made hypothyroid with propylthiouracil (PTU). TGF-alpha and EGFR expression, as determined by RNAse protection assay, was maximal at P6 in normal animals, but remained low in hypothyroid animals, suggesting that thyroid hormone was responsible for their induction. In situ hybridization and immunohistochemical analysis of EGFR expression revealed that this receptor was present on granule cells within the inner zone of the external granule cell layer (EGL), suggesting that EGFR-ligands were not inducing granule cell proliferation. The persistence of EGFR expression on migrating granule cells and subsequent down-regulation of expression in the internal granule cell layer (IGL) implicates a role for EGFR-ligands in differentiation and/or migration. In hypothyroid animals, we observed a delayed progression of granule cell migration, consistent with the persistence of EGFR labeling in the EGL, and in the 'pile-up' of labeled cells at the interface between the molecular layer and the Purkinje cell layer. Taken together, these results implicate thyroid hormone in the coordinated expression of TGF-alpha and EGFR, which are positioned to play a role in post-mitotic developmental events in the cerebellum. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Montefiore Med Ctr, Dept Neurol Surg, Neurosurg Lab, Bronx, NY 10467 USA. CUNY Hunter Coll, Subprogram Biopsychol, New York, NY 10021 USA. Univ Texas, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX 78284 USA. NIMH, Clin Brain Disorders Branch, IRP, NIH, Bethesda, MD USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Montefiore Med Ctr, Dept Neurol Surg, Neurosurg Lab, Moses Bldg 3rd Floor,111 E 210th St, Bronx, NY 10467 USA. EM casper@aecom.yu.edu RI Shannon Weickert, Cynthia/G-3171-2011 NR 80 TC 13 Z9 13 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-3806 J9 DEV BRAIN RES JI Dev. Brain Res. PD JAN 13 PY 2003 VL 140 IS 1 BP 1 EP 13 AR PII S0165-3806(02)00539-4 DI 10.1016/S0165-3806(02)00539-4 PG 13 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 640KV UT WOS:000180688800001 ER PT J AU Kirmani, BF Jacobowitz, DM Namboodiri, MAA AF Kirmani, BF Jacobowitz, DM Namboodiri, MAA TI Developmental increase of aspartoacylase in oligodendrocytes parallels CNS myelination SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Article DE Canavan disease; N-acetylaspartate; oligodendroglia; in situ hybridization; acetate deficiency hypothesis; acetate supplementation therapy ID ACETYL-L-ASPARTATE; N-ACETYLASPARTATE; CANAVAN-DISEASE; NERVOUS-SYSTEM; RAT-BRAIN; LIPID-SYNTHESIS; GENE-TRANSFER; BOVINE BRAIN; EXPRESSION; CELLS AB Canavan disease, an autosomal-recessive neurogenetic disorder, is caused by mutations in aspartoacylase, an enzyme that deacetylates N-acetylaspartate to generate free acetate in the brain. Earlier studies have shown that aspartoacylase is primarily restricted to myelin synthesizing cells (oligodendroglia) in the CNS. These findings have led us to investigate the developmental expression of aspartoacylase gene in the rat brain in an attempt to shed more light on the role of this enzyme in myelination. In situ hybridization using a 35S riboprobe based on murine aspartoacylase cDNA was used in this study. The probe hybridized mostly to the white matter tracts with different densities depending on the age of the animal and region of the brain examined. Little or no hybridization signals were detected in the 1-day-old rats, whereas the signal was clearly detectable in most of the white matter regions of the CNS in the 11-day-old rats. The signal density markedly increased at postnatal day 17, the peak of myelination. Thereafter, the hybridization signals decreased somewhat but still could be observed in the adult animals. Thus, the developmental expression pattern of aspartoacylase gene in the postnatal brain closely parallels myelination in the CNS. In the CNS, the hybridization signal of ASPA appeared to be restricted primarily to oligodendrocytes, the primary myelin synthesizing cell type in the CNS. However, the signal was not detectable in rat sciatic nerve (Schwann cells) of the peripheral nervous system. These findings indicate that the role of N-acetylaspartate in myelin synthesis is restricted to the CNS. Furthermore, they provide additional support for the acetate deficiency hypothesis of Canavan disease and also make a stronger case for acetate supplementation as an immediate and inexpensive therapy for Canavan disease. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Namboodiri, MAA (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bldg C,Room 2166,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. NR 27 TC 18 Z9 19 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-3806 J9 DEV BRAIN RES JI Dev. Brain Res. PD JAN 13 PY 2003 VL 140 IS 1 BP 105 EP 115 AR PII S0165-3806(02)00592-8 DI 10.1016/S0165-3806(02)00592-8 PG 11 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 640KV UT WOS:000180688800010 ER PT J AU Maher, B Russo, E Cohen, H AF Maher, B Russo, E Cohen, H TI Judging DNA SO SCIENTIST LA English DT Editorial Material C1 The Scientist, Philadelphia, PA 19104 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Rockefeller Univ, New York, NY 10021 USA. Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA. Univ Calif Santa Barbara, Santa Barbara, CA 93106 USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Manchester, Manchester M13 9PL, Lancs, England. RP Maher, B (reprint author), The Scientist, 3535 Market St,Suite 200, Philadelphia, PA 19104 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU SCIENTIST INC PI PHILADELPHIA PA 3535 MARKET ST, SUITE 200, PHILADELPHIA, PA 19104-3385 USA SN 0890-3670 J9 SCIENTIST JI Scientist PD JAN 13 PY 2003 VL 17 IS 1 BP 27 EP 29 PG 3 WC Information Science & Library Science; Multidisciplinary Sciences SC Information Science & Library Science; Science & Technology - Other Topics GA 634DA UT WOS:000180323700023 ER PT J AU Comin, MJ Rodriguez, JB Russ, P Marquez, VE AF Comin, MJ Rodriguez, JB Russ, P Marquez, VE TI Synthesis of conformationally locked carbocyclic nucleosides built on an oxabicyclo[3.1.0]hexane system SO TETRAHEDRON LA English DT Article DE carbocyclic nucleosides; conformationally locked nucleosides; 6-oxobicyclo[3.1.0]hexane; 2 '-deoxyneplanocin C; antiviral activity; EBV ID ADENOSINE RECEPTOR AGONISTS; BIOLOGICAL-ACTIVITY; NEPLANOCIN-C; (CYTOSINE C5)-METHYLTRANSFERASE; BICYCLO<3.1.0>HEXANE TEMPLATE; REVERSE-TRANSCRIPTASE; ANALOGS; OLIGONUCLEOTIDES; DEAMINASE AB The rigid 6-oxobicyclo[3.1.0]hexane scaffold, characteristic of the natural antibiotic neplanocin C (3), was used to build prototypes of conformationally locked deoxynucleosides in the North hemisphere of the pseudorotational cycle. The purine analogues 6 and 7 are conformationally equivalent to carbocyclic nucleosides built with the bicyclo[3.1.0]hexane template. The pyrimidine nucleosides were unstable and underwent a facile intramolecular epoxide ring-opening reaction leading to heterocycle 22. Only the deoxyguanosine analogue 7 showed antiviral activity against EBV. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Organ, RA-1428 Buenos Aires, DF, Argentina. NCI, Med Chem Lab, Canc Res Ctr, Frederick, MD 21702 USA. RP Rodriguez, JB (reprint author), Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Organ, Pabellon 2,Ciudad Univ, RA-1428 Buenos Aires, DF, Argentina. EM marquezv@dc37a.nci.nih.gov OI Rodriguez, Juan Bautista/0000-0002-5180-096X NR 38 TC 15 Z9 15 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD JAN 13 PY 2003 VL 59 IS 3 BP 295 EP 301 AR PII S0040-4020(02)01528-4 DI 10.1016/S0040-4020(02)01528-4 PG 7 WC Chemistry, Organic SC Chemistry GA 636JH UT WOS:000180450900003 ER PT J AU Bischoff, FZ Hahn, S Johnson, KL Simpson, JL Bianchi, DW Lewis, DE Weber, WD Klinger, K Elias, S Jackson, LG Evans, MI Holzgreve, W de la Cruz, F AF Bischoff, FZ Hahn, S Johnson, KL Simpson, JL Bianchi, DW Lewis, DE Weber, WD Klinger, K Elias, S Jackson, LG Evans, MI Holzgreve, W de la Cruz, F TI Intact fetal cells in maternal plasma: are they really there? SO LANCET LA English DT Article ID PRENATAL DETECTION; DOWNS-SYNDROME AB Rare fetal cells can be recovered from maternal blood, which suggests that non-invasive prenatal diagnosis is possible. However, recovery and analysis of fetal cells from blood is complex, and sensitivity is low because of the rarity of these cells in the maternal circulation. An alternative strategy, which suggested that intact fetal cells can be found in maternal plasma by use of simple enrichment methods, has been reported. We aimed to replicate this technique. However, five independent laboratories were unable to identify any intact male cells from the plasma of 38 women known to be carrying male fetuses. Although apoptotic intact fetal cells could contribute to the detection of fetal DNA in maternal plasma, we believe that recovery of these cells is difficult and not clinically practical. C1 Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Univ Basel, Dept Obstet & Gynecol, CH-4003 Basel, Switzerland. Tufts Univ, Sch Med, Dept Pediat Obstet & Gynecol, Div Genet, Boston, MA 02111 USA. Genzyme Genet, Framingham, MA USA. Univ Illinois, Dept Obstet & Gynecol, Chicago, IL 60612 USA. Med Coll Penn & Hahnemann Univ, Dept Obstet & Gynecol, Philadelphia, PA USA. NICHHD, Mental Retardat Res Branch, Bethesda, MD 20892 USA. RP Bischoff, FZ (reprint author), Baylor Coll Med, Dept Obstet & Gynecol, 6550 Fannin St,Suite 885, Houston, TX 77030 USA. FU NICHD NIH HHS [N01-HD-4-3203, N01-HD-4-3201, N01-HD-4-3202, N01-HD-4-3204] NR 5 TC 24 Z9 28 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 JAN 11 PY 2003 VL 361 IS 9352 BP 139 EP 140 DI 10.1016/S0140-6736(03)12191-5 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 635YP UT WOS:000180428000015 PM 12531583 ER PT J AU Wang, Q Song, CC Li, CCH AF Wang, Q Song, CC Li, CCH TI Hexamerization of p97-VCP is promoted by ATP binding to the D1 domain and required for ATPase and biological activities SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE p97-VCP; ATPase; hexamerization; ATP-binding; ubiquitin-proteasome degradation ID VALOSIN-CONTAINING PROTEIN; SENSITIVE FUSION PROTEIN; ESCHERICHIA-COLI; AAA; DEGRADATION; PROTEASOME; HYDROLYSIS; HSP104; ASSAY; ROLES AB The 97-kDa valosin-containing protein (p97-VCP or VCP), a hexameric AAA ATPase, plays an important role in diverse cell activities, including ubiquitin-proteasome mediated protein degradation. In this report, we studied dissociation-reassembly kinetics to analyze the structure-function relationship in VCP. Urea-dissociated VCP can reassemble by itself, but addition of ATP, ADP, or ATP-gammaS accelerates the reassembly. Mutation in the ATP-binding site of D1, but not D2, domain abolishes the ATP acceleration effect and further delays the reassembly. Using hybrid hexamers of the wild type and ATP-binding site mutant, we show that hexameric structure and proper communication among the subunits are required for the ATPase activity and ubiquitin-proteasome mediated degradation. Thus, ATP-binding site in D1 plays a major role in VCP hexamerization, of which proper inter-subunit interaction is essential for the activities. Published by Elsevier Science (USA). C1 NCI, SAIC Frederick, Basic Res Program, Ft Detrick, MD 21702 USA. NCI, Basic Res Lab, Ft Detrick, MD 21702 USA. RP Li, CCH (reprint author), NCI, SAIC Frederick, Basic Res Program, Ft Detrick, MD 21702 USA. FU NCI NIH HHS [N01CO56000] NR 26 TC 78 Z9 78 U1 2 U2 4 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 JAN 10 PY 2003 VL 300 IS 2 BP 253 EP 260 AR PII S0006-291X(02)02840-1 DI 10.1016/S0006-291X(02)02840-1 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 639BD UT WOS:000180607000002 PM 12504076 ER PT J AU Okafor, CC Saunders, L Li, XP Ito, T Dixon, M Stepenek, A Hajjar, RJ Wood, JR Doye, AA Gwathmey, JK AF Okafor, CC Saunders, L Li, XP Ito, T Dixon, M Stepenek, A Hajjar, RJ Wood, JR Doye, AA Gwathmey, JK TI Myofibrillar responsiveness to cAMP, PKA, and caffeine in an animal model of heart failure SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE calcium; cardiomyopathy; contractile function; troponin T; thin myofilament; heart failure; ventricular function ID HUMAN VENTRICULAR MYOCARDIUM; HUMAN DILATED CARDIOMYOPATHY; HYPERTROPHIED FERRET HEARTS; ADULT CARDIAC MYOCYTES; INTRACELLULAR CALCIUM; SARCOPLASMIC-RETICULUM; TENSION DEVELOPMENT; PRESSURE-OVERLOAD; ISOMETRIC TENSION; DPI 201-106 AB We investigated whether an alteration of myofilament calcium responsiveness and contractile activation may in part contribute to heart failure. A control group of Broad Breasted White turkey poults was given regular feed without additive, whereas the experimental group was given the control ration with 700 ppm of furazolidone at 1 week of age for 3 weeks (DCM). At 4 weeks of age, left ventricular trabeculae carneae were isolated from hearts and calcium-force relationships studied. No differences in calcium-activation between fibers from control or failing hearts were noted under standard experimental conditions. Also failing hearts demonstrated no significant shift in the population of troponin T isoforms but we did observe a significant 4-fold decrease in TnT content in failing hearts compared to non-failing hearts. Addition of caffeine, however, resulted in a greater leftward shift on the calcium axis in fibers from failing hearts. At pCa 6, caffeine increased force by 26 +/- 2.1% in control fibers and 44.5 +/- 8.7% in myopathic fibers. Cyclic AMP resulted in a greater rightward shift on the calcium axis in failing myocardium. In control muscles, the frequency of minimum stiffness (f(min)) was higher than in muscles from failing hearts. cAMP and caffeine both shifted f(min) to higher frequencies in control fibers whereas in fibers from failing hearts both caused a greater shift. These results lead us to conclude that heart failure exerts differential effects on cAMP and caffeine responsiveness. Our data suggest that changes tit the level of the thin myofilaments may alter myofilament calcium responsiveness and contribute to the contractile dysfunction seen in heart failure. (C) 2002 Elsevier Science (USA). All rights reserved. C1 Boston Univ, Med Ctr, Boston, MA 02118 USA. NIAMSD, NIH, Bethesda, MD 20892 USA. Smith Coll, Dept Biol, Northampton, MA 01063 USA. Gwathmey Inc, Cambridge, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Arizona, Tucson, AZ 85721 USA. RP Boston Univ, Med Ctr, 715 Albany St, Boston, MA 02118 USA. EM gwathmey@earthlink.net FU NHLBI NIH HHS [HL 49574] NR 47 TC 2 Z9 3 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 EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 10 PY 2003 VL 300 IS 2 BP 592 EP 599 DI 10.1016/S0006-291X(02)02885-1 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 639BD UT WOS:000180607000050 PM 12504124 ER PT J AU Lohr, M Kibler, KV Zachary, I Jeang, KT Selwood, DL AF Lohr, M Kibler, KV Zachary, I Jeang, KT Selwood, DL TI Small HIV-1-Tat peptides inhibit HIV replication in cultured T-cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE human immunodeficiency virus; Tat protein; chemokine receptor; cyclic peptide ID STRUCTURAL-CHARACTERIZATION; TAT PROTEIN; ENDOTHELIAL-CELLS; CYSTEINE-RICH; ANGIOGENESIS; ACTIVATION; RECEPTOR; DOMAIN; CXCR4 AB Full-length soluble HIV-1 Tat protein has been shown to bind the CXCR4 receptor. Occupancy of CXCR4 by Tat inhibits infection of cells by T-tropic HIV-1. To understand if fragments of the Tat protein may have similar anti-HIV activity, we synthesized Tat peptides and tested their activity in tissue culture. Here, we report a sequence-specific contribution of Tat residues 31-35 to anti-HIV-1 activity. (C) 2002 Elsevier Science (USA). All rights reserved. C1 UCL, Wolfson Inst Biomed Res, London WC1E 6BT, England. NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. UCL, Dept Med, BHF Labs, London WC1E 6JJ, England. RP Selwood, DL (reprint author), UCL, Wolfson Inst Biomed Res, Cruciform Bldg,Gower St, London WC1E 6BT, England. EM d.selwood@ucl.ac.uk RI Selwood, David/C-1571-2008; Jeang, Kuan-Teh/A-2424-2008 NR 17 TC 11 Z9 11 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 10 PY 2003 VL 300 IS 2 BP 609 EP 613 DI 10.1016/S0006-291X(02)02903-0 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 639BD UT WOS:000180607000052 PM 12504126 ER PT J AU d'Uscio, LV Milstien, S Richardson, D Smith, L Katusic, ZS AF d'Uscio, LV Milstien, S Richardson, D Smith, L Katusic, ZS TI Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity SO CIRCULATION RESEARCH LA English DT Article DE tetrahydrobiopterin; nitric oxide synthase; nitric oxide; antioxidants; superoxide anion ID VEIN ENDOTHELIAL-CELLS; SOLUBLE GUANYLYL CYCLASE; CORONARY-ARTERY DISEASE; CHOLESTEROL-FED RABBITS; APOE-DEFICIENT MICE; ASCORBIC-ACID; L-ARGININE; ATHEROSCLEROTIC VESSELS; REDUCES ATHEROSCLEROSIS; DEPENDENT VASODILATION AB In cultured endothelial cells, the antioxidant, L-ascorbic acid (vitamin C), increases nitric oxide synthase (NOS) enzyme activity via chemical stabilization of tetrahydrobiopterin. Our objective was to determine the effect of vitamin C on NOS function and tetrahydrobiopterin metabolism in vivo. Twenty-six to twenty-eight weeks of diet supplementation with vitamin C (1%/kg chow) significantly increased circulating levels of vitamin C in wild-type (C57BL/6J) and apolipoprotein E (apoE)-deficient mice. Measurements of NOS enzymatic activity in aortas of apoE-deficient mice indicated a significant increase in total NOS activity. However, this increase was mainly due to high activity of inducible NOS, whereas eNOS activity was reduced. Significantly higher tetrahydrobiopterin levels were detected in aortas of apoE-deficient mice. Long-term treatment with vitamin C restored endothelial NOS activity in aortas of apoE-deficient mice, but did not affect activity of inducible NOS. In addition, 7,8-dihydrobiopterin levels, an oxidized form of tetrahydrobiopterin, were decreased and vascular endothelial function of aortas was significantly improved in apoE-deficient mice. Interestingly, vitamin C also increased tetrahydrobiopterin and NOS activity in aortas of C57BL/6J mice. In contrast, long-term treatment with vitamin E (2000 U/kg chow) did not affect vascular NOS activity or metabolism of tetrahydrobiopterin. In vivo, beneficial effect of vitamin C on vascular endothelial function appears to be mediated in part by protection of tetrahydrobiopterin and restoration of eNOS enzymatic activity. C1 Mayo Clin & Mayo Fdn, Dept Anesthesiol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Mol Pharmacol & Expt Therapeut, Rochester, MN 55905 USA. NIMH, NIH, Bethesda, MD 20892 USA. RP Katusic, ZS (reprint author), Mayo Clin & Mayo Fdn, Dept Anesthesiol, 200 1St St SW, Rochester, MN 55905 USA. FU NHLBI NIH HHS [HL-53524, HL-58080, HL-66958] NR 60 TC 165 Z9 171 U1 1 U2 4 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 JAN 10 PY 2003 VL 92 IS 1 BP 88 EP 95 DI 10.1161/01.RES.0000049166.33035.62 PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 634XF UT WOS:000180367200016 PM 12522125 ER PT J AU Okura, T Varga, EV Hosohata, Y Navratilova, E Cowell, SM Rice, K Nagase, H Hruby, VJ Roeske, WR Yamamura, HI AF Okura, T Varga, EV Hosohata, Y Navratilova, E Cowell, SM Rice, K Nagase, H Hruby, VJ Roeske, WR Yamamura, HI TI Agonist-specific down-regulation of the human delta-opioid receptor SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE delta-opioid receptor; human; down-regulation; agonist-directed trafficking; phosphorylation; pertussis toxin ID PROTEIN-KINASE ACTIVATION; SIGNAL-TRANSDUCTION; BETA-ARRESTIN; PHOSPHORYLATION; INTERNALIZATION; TRAFFICKING; ENDOCYTOSIS; DYNAMIN; CELLS; BRAIN AB Down-regulation of the delta-opioid receptor contributes to the development of tolerance to delta-opioid receptor agonists. The involvement of the carboxy terminus of the mouse delta-opioid receptor in peptide agonist-mediated down-regulation has been established. In the present study, we examined the down-regulation of the truncated human delta-opioid receptor by structurally distinct delta-opioid receptor agonists. Chinese hamster ovary (CHO) cells, expressing the full-length or truncated epitope-tagged human delta-opioid receptors were incubated with various delta-opioid receptor agonists (100 nM, 24 h), and membrane receptor levels were determined by [H-3]naltrindole saturation binding. Each delta-opioid receptor agonist tested down-regulated the full-length receptor. Truncation of the carboxy terminus abolished down-regulation by all 8-opioid receptor agonists, except SNC80 ((+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]N,N-diethylbenzamide). In addition, truncation of the C-terminus completely attenuated [D-Pen(2)-D-Pen(5)]enkephalin (DPDPE), but not SNC80-mediated [P-32] incorporation into the protein immunoreactive with an anti-epitope-tagged antibody. These findings suggest that SNC80-mediated phosphorylation and down-regulation of the human delta-opioid receptor involves other receptor domains in addition to the carboxy terminus. Pertussis toxin treatment did not block SNC80-mediated down-regulation of the truncated Et-hDOR, indicating that the down-regulation is independent of G(i/o) protein activation and subsequent downstream signaling. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Arizona, Hlth Sci Ctr, Dept Pharmacol, Coll Med, Tucson, AZ 85724 USA. Univ Arizona, Hlth Sci Ctr, Sarver Heart Ctr, Tucson, AZ 85724 USA. Univ Arizona, Hlth Sci Ctr, Dept Chem, Tucson, AZ 85724 USA. NIDDKD, Med Chem Lab, NIH, Bethesda, MD USA. Toray Industries Ltd, Kamakura, Kanagawa, Japan. Univ Arizona, Hlth Sci Ctr, Dept Biochem, Tucson, AZ 85724 USA. Univ Arizona, Hlth Sci Ctr, Dept Med, Tucson, AZ 85724 USA. Univ Arizona, Hlth Sci Ctr, Dept Psychiat, Tucson, AZ 85724 USA. RP Yamamura, HI (reprint author), Univ Arizona, Hlth Sci Ctr, Dept Pharmacol, Coll Med, Tucson, AZ 85724 USA. NR 33 TC 17 Z9 20 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JAN 10 PY 2003 VL 459 IS 1 BP 9 EP 16 AR PII S0014-2999(02)02823-6 DI 10.1016/S0014-2999(02)02823-6 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 633VB UT WOS:000180303900002 PM 12505529 ER PT J AU Mohan, AK Hauptmann, M Freedman, DM Ron, E Matanoski, GM Lubin, JH Alexander, BH Boice, JD Doody, MM Linet, MS AF Mohan, AK Hauptmann, M Freedman, DM Ron, E Matanoski, GM Lubin, JH Alexander, BH Boice, JD Doody, MM Linet, MS TI Cancer and other causes of mortality among radiologic technologists in the United States SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cancer mortality; occupational radiation exposure; radiologic technologists ID ATOMIC-BOMB SURVIVORS; BREAST-CANCER; TUBERCULOSIS PATIENTS; BRITISH RADIOLOGISTS; IONIZING-RADIATION; MASSACHUSETTS; FLUOROSCOPY; COHORT; RATES; DEATH AB Data are limited on the role of chronic exposure to low-dose ionizing radiation in the etiology of cancer. In a nationwide cohort of 146,022 U.S. radiologic technologists (73% female), we evaluated mortality risks in relation to work characteristics. Standardized mortality ratios (SMRs) were computed to compare mortality in the total cohort vs. the general population of the United States. Mortality risks were low for all causes (SMR = 0.76) and for all cancers (SMR = 0.82) among the radiologic technologists. We also calculated relative risks (RR) for the 90,305 technologists who responded to a baseline mailed questionnaire, using Poisson regression models, adjusted for known risk factors. Risks were higher for all cancers (RR = 1.28, 95% confidence interval [CI] = 0.93-1.69) and breast cancer (RR = 2.92, 95% CI = 1.22-7.00) among radiologic technologists first employed prior to 1940 compared to those first employed in 1960 or later, and risks declined with more recent calendar year of first employment (p-trend = 0.04 and 0.002, respectively), irrespective of employment duration. Risk for the combined category of acute lymphocytic, acute myeloid and chronic myeloid leukemias was increased among those first employed prior to 1950 (RR = 1.64, 95% CI = 0.42-6.31) compared to those first employed in 1950 or later. Risks rose for breast cancer (p-trend = 0.018) and for acute lymphocytic, acute myeloid and chronic myeloid leukemias (p-trend = 0.05) with increasing duration of employment as a radiologic technologist prior to 1950. The elevated mortality risks for breast cancer and for the combined group of acute lymphocytic, acute myeloid and chronic myeloid leukemias are consistent with a radiation etiology given greater occupational exposures to ionizing radiation prior to 1950 than in more recent times. (C) 2002 Wiley-Liss, Inc. C1 Johns Hopkins Bloomberg, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21287 USA. Univ Minnesota, Div Environm & Occupat Hlth, Minneapolis, MN USA. Int Epidemiol Inst, Rockville, MD USA. Vanderbilt Univ, Ctr Med, Dept Med, Nashville, TN 37232 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Mohan, AK (reprint author), NCI, Biostat Branch, 6120 Execut Blvd,EPS 8050, Bethesda, MD 20892 USA. FU NCI NIH HHS [N02-CP-81005, N01-CP-51016, N02-CP-81121] NR 35 TC 45 Z9 46 U1 2 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JAN 10 PY 2003 VL 103 IS 2 BP 259 EP 267 DI 10.1002/ijc.10811 PG 9 WC Oncology SC Oncology GA 625BJ UT WOS:000179796800021 PM 12455042 ER PT J AU Andoh, T Chiueh, CC Chock, PB AF Andoh, T Chiueh, CC Chock, PB TI Cyclic GMP-dependent protein kinase regulates the expression of thioredoxin and thioredoxin peroxidase-1 during hormesis in response to oxidative stress-induced apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NECROSIS-FACTOR-ALPHA; NITRIC-OXIDE; CELL-DEATH; TRANSCRIPTION FACTORS; SUPEROXIDE-DISMUTASE; HYDROGEN-PEROXIDE; PC12 CELLS; BCL-2; INHIBITION; REDUCTASE AB Human neuroblastoma cells, SH-SY5Y, contain relatively low levels of thioredoxin (Trx); thus, they serve favorably as a model for studying oxidative stress-induced apoptosis (Andoh, T., Chock, P. B., and Chiueh, C. C. (2001) J. BioL Chem. 277, 9655-9660). When these neurotrophic cells were subjected to nonlethal 2-h serum deprivation, their neuronal nitric oxide synthase and Trx were up-regulated, and the cells became more tolerant of oxidative stress, indicating that NO may protect cells from serum deprivation-induced apoptosis. Here, the mechanism by which NO exerts its protective effects was investigated. Our results reveal that in SH-SY5Y cells, NO inhibits apoptosis through its ability to activate guanylate cyclase, which in turn activates the cGMP-dependent protein kinase (PKG). The activated PKG is required to protect cells from lipid peroxidation and apoptosis, to inhibit caspase-9 and caspase-3 activation, and to elevate the levels of Trx peroxidase-1 and Trx, which subsequently induces the expression of Bcl-2. Furthermore, active PKG promotes the elevation of c-Jun, phosphorylated MAPK/ERK1/2, and c-Myc, consistent with the notion that PKG enhances the expression of Trx through its c-Myc-, AP-1-, and PEA3-binding motifs. Elevation of Trx and Trx peroxidase-1 and Mn(II)-superoxide dismutase would reduce H2O2 and O-2(.-), respectively. Thus, the cytoprotective effect of NO in SH-SY5Y cells appears to proceed via the PKG-mediated pathway, and S-nitrosylation of caspases plays a minimal role. C1 NHLBI, LB, NIH, Bethesda, MD 20892 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD USA. RP Chock, PB (reprint author), NHLBI, LB, NIH, Bldg 50,Rm 2134,50 S Dr,MSC-8012, Bethesda, MD 20892 USA. NR 45 TC 64 Z9 66 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 10 PY 2003 VL 278 IS 2 BP 885 EP 890 DI 10.1074/jbc.M209914200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 634CF UT WOS:000180321900026 PM 12414792 ER PT J AU Popkov, M Mage, RG Alexander, CB Thundivalappil, S Barbas, CF Rader, C AF Popkov, M Mage, RG Alexander, CB Thundivalappil, S Barbas, CF Rader, C TI Rabbit immune repertoires as sources for therapeutic monoclonal antibodies: The impact of kappa allotype-correlated variation in cysteine content on antibody libraries selected by phage display SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE rabbit monoclonal antibodies; antibody engineering; antibody library; phage display; immunoglobulin kappa light chain ID SPLENIC GERMINAL-CENTERS; V-H GENES; LIGHT-CHAINS; GENERATION; HYPERMUTATION; EXPRESSION; CONVERSION; DIVERSIFICATION; MECHANISMS; DIVERSITY AB The rabbit immune repertoire has long been a rich source of diagnostic polyclonal antibodies. Now it also holds great promise as a source of therapeutic monoclonal antibodies. On the basis of phage display technology, we recently reported the first humanization of a rabbit monoclonal antibody. The allotypic diversity of rabbit immunoglobulins prompted us to compare different rabbit immune repertoires for the generation and humanization of monoclonal antibodies that bind with strong affinity to antigens involved in tumor angiogenesis. In particular, we evaluated the diversity of unselected and selected chimeric rabbit/human Fab libraries that were derived from different kappa light chain allotypes. Most rabbit light chains have an extra disulfide bridge that links the variable and constant domains in addition to the two intrachain disulfide bridges shared with mouse and human kappa light chains. Here we evaluate the impact of this increased disulfide bridge complexity on the generation and selection of chimeric rabbit/human Fab libraries. We demonstrate that rabbits with mutant bas and wild-type parental b9 allotypes are excellent sources for therapeutic monoclonal antibodies. Featured among the selected clones with b9 allotype is a rabbit/human Fab that binds with a dissociation constant of 1 nM to both human and mouse Tie-2, which will facilitate its evaluation in mouse models of human cancer. Examination of 228 new rabbit antibody sequences allowed for a comprehensive comparison of the LCDR3 and HCDR3 length diversity in rabbits. This study revealed that rabbits exhibit an HCDR3 length distribution more closely related to human antibodies than mouse antibodies. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. RP Rader, C (reprint author), NIAID, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA 94966]; NIAID NIH HHS [AI 37470] NR 37 TC 59 Z9 60 U1 1 U2 14 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 JAN 10 PY 2003 VL 325 IS 2 BP 325 EP 335 DI 10.1016/S0022-2836(02)01232-9 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 637MB UT WOS:000180514700007 PM 12488098 ER PT J AU Weaver, RP Malling, HV AF Weaver, RP Malling, HV TI The in vivo but not the in vitro am3 revertant frequencies increase linearly with increased ethylnitrosourea doses in spleen of mice transgenic for phiX174 am3, cs70 using the single burst assay SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE PhiX174 transgenic mice; ethylnitrosourea dose response; spleen; single burst assays; in vivo and in vitro mutations; O-2 ET-dT lesions; base substitution ID ETHYL-N-NITROSOUREA; SHUTTLE VECTOR; MOLECULAR ANALYSIS; HPRT LOCUS; DNA-DAMAGE; IN-VITRO; MUTATIONS; MUTAGENESIS; PHI-X174; REPAIR AB The am3 revertant frequencies (RF) in spleens from male mice transgenic for phiX174 am3, cs70 were analyzed 14 weeks after ethylnitrosourea (ENU) treatment, both by the single burst assay (SBA) [1] and the mixed burst assay (MBA). The mean in vivo (burst size >30/assay plate) revertant frequency (MRF) for the vehicle control was 2.6 x 10(-7). The ENU induced in vivo RF were linear over the dose range 0-150 mg/kg, (r(2) = 0.999). The concomitant in (burst size less than or equal to30/assay plate) was independent of dose (r(2) = 0.216). The only viable revertants are base pair substitutions of the center base pair in the am3 nonsense (TAG) codon in the phiX174 lysis E gene. Sequenced revertants chosen randomly from in vitro plates and in vivo untreated control plates were A --> G transitions. Sequence analysis of in vivo revertants from ENU treated animals revealed revertants that were 17% A --> G transitions and 83% A --> T transversions, the latter being consistent with the reported A:T base pair alterations induced by ENU. No A --> C transitions were seen. This suggests the occurrence of an ENU-induced O-2 ET-dT lesion leading to a dT base mismatch. The observations in this report both confirm and validate the use of the SBA for distinguishing between in vivo mutations that are fixed in the animal and in vitro mutations that arise from other sources. The ability of the SBA to distinguish the in vivo from the in vitro origin of mutations has increased the specificity, sensitivity and utility of the phiX transgenic system. (C) 2002 Elsevier Science B.V. All rights reserved. C1 NIEHS, Mammalian Mutagenesis Grp, Toxicol Lab, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Malling, HV (reprint author), NIEHS, Mammalian Mutagenesis Grp, Toxicol Lab, Environm Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. NR 40 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD JAN 10 PY 2003 VL 534 IS 1-2 BP 1 EP 13 AR PII S1383-5718(02)00242-5 DI 10.1016/S1383-5718(02)00242-5 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 638ZH UT WOS:000180602800001 PM 12504750 ER PT J AU Levin-Zaidman, S Englander, J Shimoni, E Sharma, AK Minton, KW Minsky, A AF Levin-Zaidman, S Englander, J Shimoni, E Sharma, AK Minton, KW Minsky, A TI Ringlike structure of the Deinococcus radiodurans genome: A key to radioresistance? SO SCIENCE LA English DT Article ID IONIZING-RADIATION; CELL-DIVISION; DNA; RESISTANT; REPAIR; RECOMBINATION; FRAGMENTS; MODEL AB The bacterium Deinococcus radiodurans survives ionizing irradiation and other DNA-damaging assaults at doses that are lethal to all other organisms. How D. radiodurans accurately reconstructs its genome from hundreds of radiation-generated fragments in the absence of an intact template is unknown. Here we show that the D. radiodurans genome assumes an unusual toroidal morphology that may contribute to its radioresistance. We propose that, because of restricted diffusion within the tightly packed and laterally ordered DNA toroids, radiation-generated free DNA ends are held together, which may facilitate template-independent yet error-free joining of DNA breaks. C1 Weizmann Inst Sci, Dept Organ Chem, IL-76100 Rehovot, Israel. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. RP Minsky, A (reprint author), Weizmann Inst Sci, Dept Organ Chem, IL-76100 Rehovot, Israel. NR 22 TC 158 Z9 179 U1 3 U2 18 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 JAN 10 PY 2003 VL 299 IS 5604 BP 254 EP 256 DI 10.1126/science.1077865 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 633LD UT WOS:000180284000040 PM 12522252 ER PT J AU Seibert, E Chin, AS Pfleiderer, W Hawkins, ME Laws, WR Osman, R Ross, JBA AF Seibert, E Chin, AS Pfleiderer, W Hawkins, ME Laws, WR Osman, R Ross, JBA TI pH-dependent spectroscopy and electronic structure of the guanine analogue 6,8-dimethylisoxanthopterin SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID PTERIDINE NUCLEOSIDE ANALOGS; FLUORESCENCE PROPERTIES; DNA; OLIGONUCLEOTIDES; 2-AMINOPURINE; CONTINUUM; BINDING AB Fluorescent nucleic acid analogues are valuable tools for studying DNA dynamics, protein-DNA interactions and nucleotide-dependent enzyme activities. The recent development of guanine analogues based on the isoxanthopterin structure offers new opportunities to investigate these dynamics, interactions, and activities. Our combined experimental/theoretical investigation of one such analogue, 6,8-dimethylisoxanthopterin (6,8DMI), has shown that absorbance and fluorescence emission spectra of 6,8DMI shift to lower energies as the pH is increased, yielding pK(a) values of 8.3 and 8.5, respectively. We show that these pH-dependent spectral changes result from protonation/deprotonation of the nitrogen at position 3 of 6,8DMI on the basis of pH-dependent iodide ion quenching of 6,8DMI fluorescence and pH-independent absorption and fluorescence properties of 3,6,8-trimethylisoxanthopterin. Quantum mechanical calculations on the neutral and deprotonated forms of 6,8DMI confirm the observed spectral changes. C1 CUNY Mt Sinai Sch Med, Dept Pharmacol, New York, NY 10029 USA. CUNY Mt Sinai Sch Med, Dept Biol Chem, New York, NY 10029 USA. CUNY Mt Sinai Sch Med, Dept Physiol, New York, NY 10029 USA. CUNY Mt Sinai Sch Med, Dept Biophys, New York, NY 10029 USA. Univ Konstanz, Fac Chem, Constance, Germany. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Univ Montana, Dept Chem, Missoula, MT 59812 USA. RP Osman, R (reprint author), CUNY Mt Sinai Sch Med, Dept Pharmacol, 1 Gustave L Levy Pl, New York, NY 10029 USA. NR 30 TC 12 Z9 12 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD JAN 9 PY 2003 VL 107 IS 1 BP 178 EP 185 DI 10.1021/jp026907j PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 632ZL UT WOS:000180254700023 ER PT J AU Pessoa, L Desimone, R AF Pessoa, L Desimone, R TI From humble neural beginnings comes knowledge of numbers SO NEURON LA English DT Editorial Material AB Following a recent report that monkey prefrontal cortex contains cells that represent number concepts, Neider and Miller investigated the scale used to code numbers. In this issue of Neuron, they report that prefrontal cells use the same scale (Weber's Law) used by sensory neurons to code stimulus intensity, suggesting how abstract cognitive operations may arise from simpler building blocks that humans share with other animals. C1 Natl Inst Mental Hlth, Dept Hlth & Human Serv, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Natl Inst Mental Hlth, Dept Hlth & Human Serv, Lab Neuropsychol, NIH, Bethesda, MD 20892 USA. RP Pessoa, L (reprint author), Natl Inst Mental Hlth, Dept Hlth & Human Serv, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. NR 12 TC 1 Z9 1 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JAN 9 PY 2003 VL 37 IS 1 BP 4 EP 6 DI 10.1016/S0896-6273(02)01179-0 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 646UV UT WOS:000181054700003 PM 12526766 ER PT J AU Cookson, MR AF Cookson, MR TI Pathways to parkinsonism SO NEURON LA English DT Review ID ALPHA-SYNUCLEIN; PROTEIN; DISEASE; DJ-1; PROMOTES AB A novel gene for Parkinson's disease (PD), DJ-1, has been identified that encodes a multifunctional product with several known protein-protein interactions and effects on gene expression. Here, I outline how it is possible to construct hypotheses that place DJ-1 in different relationships to the other known PD genes, (x-synuclein and parkin. The identification of multiple genetic causes will provide further impetus to describe the pathway leading to PD. C1 Natl Inst Aging, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), Natl Inst Aging, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. NR 26 TC 72 Z9 82 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JAN 9 PY 2003 VL 37 IS 1 BP 7 EP 10 DI 10.1016/S0896-6273(02)01166-2 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 646UV UT WOS:000181054700004 PM 12526767 ER PT J AU Wartenburger, I Heekeren, HR Abutalebi, J Cappa, SF Villringer, A Perani, D AF Wartenburger, I Heekeren, HR Abutalebi, J Cappa, SF Villringer, A Perani, D TI Early setting of grammatical processing in the bilingual brain SO NEURON LA English DT Article ID 2ND LANGUAGE; 2ND-LANGUAGE ACQUISITION; SENTENCE COMPREHENSION; CRITICAL PERIOD; MATURATIONAL CONSTRAINTS; CHILDREN; SYNTAX; FMRI; AGE; PROFICIENCY AB The existence of a "critical period" for language acquisition is controversial. Bilingual subjects with variable age of acquisition (AOA) and proficiency level (PL) constitute a suitable model to study this issue. We used functional magnetic resonance imaging to investigate the effects of AOA and PL on neural correlates of grammatical and semantic judgments in Italian-German bilinguals who learned the second language at different ages and had different proficiency levels. While the pattern of brain activity for semantic judgment was largely dependent on PL, AOA mainly affected the cortical representation of grammatical processes. These findings support the view that both AOA and PL affect the neural substrates of second language processing, with a differential effect on grammar and semantics. C1 Humboldt Univ, Charite, Dept Neurol, D-10117 Berlin, Germany. Natl Inst Mental Hlth, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Univ Vita Salute San Raffaele, Inst Neurosci & Bioimaging, CNR, I-20132 Milan, Italy. RP Wartenburger, I (reprint author), Humboldt Univ, Charite, Dept Neurol, Schumannstr 20-21, D-10117 Berlin, Germany. RI Heekeren, Hauke/B-7739-2008; Wartenburger, Isabell/A-2820-2013; OI Heekeren, Hauke/0000-0001-7912-6826; Abutalebi, Jubin/0000-0003-3016-9184; Wartenburger, Isabell/0000-0001-5116-4441 NR 46 TC 213 Z9 229 U1 7 U2 51 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JAN 9 PY 2003 VL 37 IS 1 BP 159 EP 170 DI 10.1016/S0896-6273(02)01150-9 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 646UV UT WOS:000181054700018 PM 12526781 ER PT J AU Silverstein, RA Richardson, W Levin, H Allshire, R Ekwall, K AF Silverstein, RA Richardson, W Levin, H Allshire, R Ekwall, K TI A new role for the transcriptional corepressor SIN3; Regulation of centromeres SO CURRENT BIOLOGY LA English DT Article ID HISTONE DEACETYLASE GENE; FISSION YEAST; SCHIZOSACCHAROMYCES-POMBE; CHROMO DOMAIN AB Centromeres play a vital role in maintaining the genomic stability of eukaryotes by coordinating the equal distribution of chromosomes to daughter cells during mitosis and meiosis. Fission yeast (S. pombe) centromeres consist of a 4-9 kb central core region and 30-100 kb of flanking inner (imr/B) and outer (otr/K) repeats [1-3]. These sequences direct a laminar kinetochore structure similar to that of human centromeres [4, 5]. Centromeric heterochromatin is generally underacetylated [6, 7]. We have previously shown that inhibition of histone deacetylases (HDACs) caused hyperacetylation of centromeres and defective chromosome segregation [8]. SIN3 is a HDAC corepressor that has the ability to mediate HDAC targeting in the repression of promoters. In this study, we have characterized S. pombe sin three corepressors (Pst1p and Pst2p) to investigate whether SIN3-HDAC is required in the regulation of centromeres. We show that only pst1-1 and not pst2Delta cells displayed anaphase defects and thiabendazole sensitivity. pst1-1 cells showed reduced centromeric silencing, increased histone acetylation in centromeric chromatin, and defective centromeric sister chromatid cohesion. The HDAC Clr6p and Pst1p coimmunoprecipitated, and Pst1p colocalized with centromeres, particularly in binucleate cells. These data are consistent with a model in which Pst1 pClr6p temporally associate with centromeres to carry out the initial deacetylation necessary for subsequent steps in heterochromatin formation. C1 Univ Coll Sodertorn, Karolinska Inst, Dept Biosci Novum, Dept Nat Sci, S-14189 Huddinge, Sweden. NICHNH, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. Western Gen Hosp, Human Genet Unit, Med Res Council, Edinburgh EH4 2XU, Midlothian, Scotland. RP Ekwall, K (reprint author), Univ Coll Sodertorn, Karolinska Inst, Dept Biosci Novum, Dept Nat Sci, S-14189 Huddinge, Sweden. EM karl.ekwall@cbt.ki.se NR 22 TC 25 Z9 26 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JAN 8 PY 2003 VL 13 IS 1 BP 68 EP 72 AR PII S0960-9822(02)01401-X DI 10.1016/S0960-9822(02)01401-X PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 644KC UT WOS:000180915600025 PM 12526748 ER PT J AU Neaton, JD Domanski, M Stamler, J AF Neaton, JD Domanski, M Stamler, J CA MRFIT Res Grp TI Pulse pressure and risk of cardiovascular disease - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. NHLBI, Clin Trials Grp, Bethesda, MD 20892 USA. Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL USA. RP Neaton, JD (reprint author), Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JAN 8 PY 2003 VL 289 IS 2 BP 175 EP 175 DI 10.1001/jama.289.2.175-a PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 632ME UT WOS:000180226400021 ER PT J AU Morens, DM AF Morens, DM TI Influenza-related mortality considerations for practice and public health SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID VACCINATION; ADULTS; VACCINES; OLDER C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, NIH, 6700-B Rockledge Dr,Room 3149, Bethesda, MD 20892 USA. NR 18 TC 31 Z9 32 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 JAN 8 PY 2003 VL 289 IS 2 BP 227 EP 229 DI 10.1001/jama.289.2.227 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 632ME UT WOS:000180226400035 PM 12517235 ER PT J AU Moeri, O Sternberg, LDL Rodicio, LP Walsh, PJ AF Moeri, O Sternberg, LDL Rodicio, LP Walsh, PJ TI Direct effects of ambient ammonia on the nitrogen isotope ratios of fish tissues SO JOURNAL OF EXPERIMENTAL MARINE BIOLOGY AND ECOLOGY LA English DT Article DE ammonia; ammonotele; damselfish; nitrogen isotope ratios; toadfish; trophic level; ureotele ID STABLE ISOTOPES AB We tested the assumption that the nitrogen isotope ratios of fish are solely determined by their diet by exposing two species of fish having contrasting nitrogen metabolic profiles to N-15 ammonia. Beaugregory damselfish (Stegastes leucostictus) representing ammonotelic species and toadfish (Opsanus beta) representing ureotelic species were exposed to N-15 ammonia for a period of 4 weeks, after which muscle and liver tissues were analyzed for N-15 abundance and compared to their respective control group. Both species showed significant N-15 enrichment when exposed to N-15 ammonia, with the ammonotelic fish showing a greater enrichment compared to the urcotelic fish. We propose that the toadfish showed less enrichment in its muscle tissue because its active omithine-urea cycle (O-UC) rapidly sequesters ammonia away from the circulatory system and into liver tissue, thereby preventing any substantial exchange between ammonia and muscle tissue. We propose that no such sequestering occurs in the ammonotelic damselfish because they lack a functional O-UC. These results have important implications for studies using nitrogen isotope ratios to delineate trophic structure in aquatic ecosystems. (C) 2003 Elsevier Science B.V. All rights reserved. C1 Univ Miami, Dept Biol, Coral Gables, FL 33124 USA. Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, Div Marine Biol & Fisheries, NIEHS Marine & Freshwater Biomed Sci Ctr, Miami, FL 33149 USA. RP Sternberg, LDL (reprint author), Univ Miami, Dept Biol, Coral Gables, FL 33124 USA. NR 13 TC 8 Z9 8 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-0981 J9 J EXP MAR BIOL ECOL JI J. Exp. Mar. Biol. Ecol. PD JAN 8 PY 2003 VL 282 IS 1-2 BP 61 EP 66 AR PII S0022-0981(02)00446-X DI 10.1016/S0022-0981(02)00446-X PG 6 WC Ecology; Marine & Freshwater Biology SC Environmental Sciences & Ecology; Marine & Freshwater Biology GA 635UM UT WOS:000180417900004 ER PT J AU Haider, AW Larson, MG Franklin, SS Levy, D AF Haider, AW Larson, MG Franklin, SS Levy, D TI Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID LEFT-VENTRICULAR HYPERTROPHY; MYOCARDIAL-INFARCTION; AORTIC COMPLIANCE; CARDIOVASCULAR MORTALITY; ARTERIAL DISTENSIBILITY; SUBENDOCARDIAL ISCHEMIA; ESSENTIAL-HYPERTENSION; DISEASE; DOGS; DYSFUNCTION AB Background: Although hypertension is a principal precursor of congestive heart failure (CHF), the separate relations of systolic, diastolic, and pulse pressure with risk for heart failure have not been fully elucidated. Objective: To examine the value of blood pressure predictors of heart failure. Design: Community-based inception cohort study. Setting: Framingham, Massachusetts. Patients: 2040 free-living Framingham Heart Study participants (mean age, 61 years [range, 50 to 79 years]). Measurements: The association of baseline systolic, diastolic, and pulse pressure with risk for incident CHF was examined in 894 men and 1146 women. Framingham Heart Study participants free of CHF at the baseline examination (performed from 1968 to 1973) were monitored for up to 24 years (mean, 17.4 years) for new-onset heart failure. Cox proportional hazards models were used to adjust for age, sex, smoking, left ventricular hypertrophy, body mass index, diabetes mellitus, high-density lipoprotein cholesterol level, and heart rate; hazard ratios and 95% Cis for blood pressure variables were estimated. Results: CHF developed in 234 participants (11.8%) during the follow-up period. All three blood pressure components were related to the risk for CHF, but the relation was strongest for systolic and pulse pressure. A 1-SD (20 mm Hg) increment in systolic pressure conferred a 56% increased risk for CHF (hazard ratio, 1.56 [95% Cl, 1.37 to 1.77]); similarly, a 1-SD (16 mm Hg) increment in pulse pressure conferred a 55% increased risk for CHF (hazard ratio, 1.55 [Cl, 1.37 to 1.75]). These associations were unrelated to age, duration of follow-up, and initiation of treatment for hypertension during follow-up; they were also observed in patients with systolic hypertension (systolic blood pressure greater than or equal to 140 mm Hg) at the baseline examination (hazard ratio, 1.41 [Cl, 1.18 to 1.69] for pulse pressure and 1.42 [Cl, 1.14 to 1.76] for systolic pressure). Conclusions: Although each component of blood pressure was associated with risk for CHF, pulse and systolic pressure conferred greater risk than diastolic pressure. Increased pulse pressure may help identify hypertensive patients at high risk for overt CHF who are candidates for aggressive blood pressure control. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Univ Calif Irvine, Irvine, CA 92717 USA. Vet Adm Med Ctr, W Roxbury, MA USA. MCP Hahnemann Univ Hosp, Philadelphia, PA USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. FU NHLBI NIH HHS [N01-HC-38038] NR 45 TC 236 Z9 252 U1 1 U2 9 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JAN 7 PY 2003 VL 138 IS 1 BP 10 EP 16 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 645TV UT WOS:000180996200002 PM 12513039 ER PT J AU Gail, M AF Gail, M TI Weighing the risks and benefits of tamoxifen - Response SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Letter ID BREAST-CANCER C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Gail, M (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU CANADIAN MEDICAL ASSOCIATION PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD JAN 7 PY 2003 VL 168 IS 1 BP 13 EP 13 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 634NF UT WOS:000180346400008 ER PT J AU Shlipak, MG Fried, LF Crump, C Bleyer, AJ Manolio, TA Tracy, RP Furberg, CD Psaty, BM AF Shlipak, MG Fried, LF Crump, C Bleyer, AJ Manolio, TA Tracy, RP Furberg, CD Psaty, BM TI Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency SO CIRCULATION LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Heart-Associations-Epidemiology-Council CY APR 24, 2002 CL HONOLULU, HAWAII SP Amer Heart Assoc Epidemiol Council DE inflammation; coagulation; kidney; coronary disease ID C-REACTIVE PROTEIN; CORONARY HEART-DISEASE; CARDIOVASCULAR-DISEASE; HEMODIALYSIS-PATIENTS; CREATININE CLEARANCE; SERUM CREATININE; FACTOR-VII; D-DIMER; FIBRINOGEN; RISK AB Background-Renal insufficiency has been associated with cardiovascular disease events and mortality in several prospective studies, but the mechanisms for the elevated risk are not clear. Little is known about the association of renal insufficiency with inflammatory and procoagulant markers, which are potential mediators for the cardiovascular risk of kidney disease. Methods and Results-The cross-sectional association of renal insufficiency with 8 inflammatory and procoagulant factors was evaluated using baseline data from the Cardiovascular Health Study, a population-based cohort study of 5888 subjects aged greater than or equal to65 years. C-reactive protein. fibrinogen, factor VIII, and factor VIIIc levels were treasured in nearly all participants; interleukin-6, intercellular adhesion molecule-1, plasmin-antiplasmin complex, and D-dither levels were measured in nearly half of participants. Renal insufficiency was defined as a serum creatinine level greater than or equal to1.3 mg/dL in women and greater than or equal to1.5 mg/dL in men. Multivariate linear regression was used to compare adjusted mean levels of each biomarker in persons with and without renal insufficiency after adjustment for other baseline characteristics. Renal insufficiency was present in 617 (11%) of Cardiovascular Health Study participants. After adjustment for baseline differences, levels of C-reactive protein, fibrinogen, interleukin-6, factor VIII, factor VIIIc, plasmin-antiplasmin complex, and D-dieter were significantly greater among persons with renal insufficiency (P<0.001). In participants with clinical, subclinical, and no cardiovascular disease at baseline, the positive associations of renal insufficiency with these inflammatory and procoagulant markers were similar. Conclusion-Renal insufficiency was independently associated with elevations in inflammatory and procoagulant biomarkers. These pathways may be important mediators leading to the increased cardiovascular risk of persons with kidney disease. C1 Vet Affairs Med Ctr, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. Univ Pittsburgh, Sch Med, Renal Electrolyte Div, Pittsburgh, PA 15260 USA. VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. Wake Forest Univ, Bowman Gray Sch Med, Nephrol Sect, Winston Salem, NC USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. Univ Vermont, Coll Med, Dept Biochem, Burlington, VT 05405 USA. RP Shlipak, MG (reprint author), Vet Affairs Med Ctr, 111A1,4150 Clement St, San Francisco, CA 94121 USA. FU NHLBI NIH HHS [R03 HL68099-01] NR 30 TC 441 Z9 463 U1 1 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 JAN 7 PY 2003 VL 107 IS 1 BP 87 EP 92 DI 10.1161/01.CIR.0000042700.48769.59 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 634WZ UT WOS:000180366600030 PM 12515748 ER PT J AU Lakatta, EG Levy, D AF Lakatta, EG Levy, D TI Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises Part I: Aging arteries: A "set up" for vascular disease SO CIRCULATION LA English DT Article DE aging; cardiovascular disease; epidemiology; remodeling; risk factors ID CROSS-LINK BREAKER; ISOLATED SYSTOLIC HYPERTENSION; CONVERTING ENZYME-INHIBITION; DIASTOLIC BLOOD-PRESSURE; CORONARY HEART-DISEASE; PULSE PRESSURE; HEALTHY-MEN; AGE; OLDER; RISK C1 NIA, Intramural Res Program, Ctr Gerontol Res, Cardiovasc Sci Lab,NIH, Baltimore, MD 21224 USA. NHLBI, Framingham Heart Dis Epidemiol Study, NIH, Framingham, MA USA. RP Lakatta, EG (reprint author), NIA, Intramural Res Program, Ctr Gerontol Res, Cardiovasc Sci Lab,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 46 TC 884 Z9 952 U1 2 U2 27 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 7 PY 2003 VL 107 IS 1 BP 139 EP 146 DI 10.1161/01.CIR.0000048892.83521.58 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 634WZ UT WOS:000180366600038 PM 12515756 ER PT J AU Hodges, M Bailey, JJ Church, TR AF Hodges, M Bailey, JJ Church, TR TI B-type natriuretic peptide predicts sudden death in patients with chronic heart failure SO CIRCULATION LA English DT Letter C1 Minneapolis Heart Inst Fdn, Minneapolis, MN USA. NIH, Bethesda, MD 20892 USA. Univ Minnesota, Minneapolis, MN USA. RP Hodges, M (reprint author), Minneapolis Heart Inst Fdn, Minneapolis, MN USA. NR 2 TC 5 Z9 5 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JAN 7 PY 2003 VL 107 IS 1 BP E13 EP E13 DI 10.1161/01.CIR.0000046777.74753.F8 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 634WZ UT WOS:000180366600013 PM 12515766 ER PT J AU Hofseth, LJ Saito, S Hussain, SP Espey, MG Miranda, KM Araki, Y Jhappan, C Higashimoto, Y He, PJ Linke, SP Quezado, MM Zurer, I Rotter, V Wink, DA Appella, E Harris, CC AF Hofseth, LJ Saito, S Hussain, SP Espey, MG Miranda, KM Araki, Y Jhappan, C Higashimoto, Y He, PJ Linke, SP Quezado, MM Zurer, I Rotter, V Wink, DA Appella, E Harris, CC TI Nitric oxide-induced cellular stress and p53 activation in chronic inflammation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE posttranslational modification; phosphorylation ID ULCERATIVE-COLITIS; DNA-DAMAGE; CYCLE ARREST; P53-DEPENDENT APOPTOSIS; SYNTHASE ACTIVITY; CROHNS-DISEASE; MUTATION LOAD; CANCER; EXPRESSION; PROTEIN AB Free radical-induced cellular stress contributes to cancer during chronic inflammation. Here, we investigated mechanisms of p53 activation by the free radical, NO. NO from donor drugs induced both ataxia-telangiectasia mutated (ATM)- and ataxia-telangiectasia mutated and Rad3-related-dependent p53 posttranslational modifications, leading to an increase in p53 transcriptional targets and a G(2)/M cell cycle checkpoint. Such modifications were also identified in cells cocultured with NO-releasing macrophages. In noncancerous colon tissues from patients with ulcerative colitis (a cancer-prone chronic inflammatory disease), inducible NO synthase protein levels were positively correlated with p53 serine 15 phosphorylation levels. Immunostaining of HDM-2 and p21(WAF1) was consistent with transcriptionally active p53. Our study highlights a pivotal role of NO in the induction of cellular stress and the activation of a p53 response pathway during chronic inflammation. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. RI Miranda, Katrina/B-7823-2009 NR 47 TC 231 Z9 241 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 7 PY 2003 VL 100 IS 1 BP 143 EP 148 DI 10.1073/pnas.0237083100 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 633WG UT WOS:000180307100027 PM 12518062 ER PT J AU Marth, G Schuler, G Yeh, R Davenport, R Agarwala, R Church, D Wheelan, S Baker, J Ward, M Kholodov, M Phan, L Czabarka, E Murvai, J Cutler, D Wooding, S Rogers, A Chakravarti, A Harpending, HC Kwok, PY Sherry, ST AF Marth, G Schuler, G Yeh, R Davenport, R Agarwala, R Church, D Wheelan, S Baker, J Ward, M Kholodov, M Phan, L Czabarka, E Murvai, J Cutler, D Wooding, S Rogers, A Chakravarti, A Harpending, HC Kwok, PY Sherry, ST TI Sequence variations in the public human genome data reflect a bottlenecked population history SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; LINKAGE DISEQUILIBRIUM; GENETIC-VARIATION; SNP MAP; RECOMBINATION; REGIONS AB Single-nucleotide polymorphisms (SNPs) constitute the great majority of variations in the human genome, and as heritable variable landmarks they are useful markers for disease mapping and resolving population structure. Redundant coverage in overlaps of large-insert genomic clones, sequenced as part of the Human Genome Project, comprises a quarter of the genome, and it is representative in terms of base compositional and functional sequence features. We mined these regions to produce 500,000 high-confidence SNP candidates as a uniform resource for describing nucleotide diversity and its regional variation within the genome. Distributions of marker density observed at different overlap length scales under a model of recombination and population size change show that the history of the population represented by the public genome sequence is one of collapse followed by a recent phase of mild size recovery. The inferred times of collapse and recovery are Upper Paleolithic, in agreement with archaeological evidence of the initial modern human colonization of Europe. C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Washington Univ, Sch Med, Dept Genet, St Louis, MO 63130 USA. Washington Univ, Sch Med, Div Internal Med, St Louis, MO 63130 USA. Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. Univ Utah, Dept Anthropol, Salt Lake City, UT 84112 USA. Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. RP Sherry, ST (reprint author), NIH, Natl Ctr Biotechnol Informat, Bldg 10, Bethesda, MD 20894 USA. EM sherry@ncbi.nlm.nih.gov RI Kwok, Pui-Yan/F-7725-2014 OI Kwok, Pui-Yan/0000-0002-5087-3059 FU NHGRI NIH HHS [HG01720, R01 HG001720] NR 34 TC 66 Z9 67 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JAN 7 PY 2003 VL 100 IS 1 BP 376 EP 381 DI 10.1073/pnas.222673099 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 633WG UT WOS:000180307100067 PM 12502794 ER PT J AU Vacchio, MS Hodes, RJ AF Vacchio, MS Hodes, RJ TI CD28 costimulation is required for in vivo induction of peripheral tolerance in CD8 T cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE pregnancy; clonal deletion; clonal anergy; B7 costimulatory molecules; cytotoxic T lymphocytes ID ANERGY IN-VIVO; B7 COSTIMULATION; CTLA-4; ACTIVATION; RECEPTOR; ANTIGEN; DIFFERENTIATION; GENERATION; PATHWAY; MECHANISMS AB Whereas ligation of CD28 is known to provide a critical costimulatory signal for activation of CD4 T cells, the requirement for CD28 as a costimulatory signal during activation of CD8 cells is less well defined. Even less is known about the involvement of CD28 signals during peripheral tolerance induction in CD8 T cells. In this study, comparison of T cell responses from CD28-deficient and CD28 wild-type H-Y-specific T cell receptor transgenic mice reveals that CD8 cells can proliferate, secrete cytokines, and generate cytotoxic T lymphocytes efficiently in the absence of CD28 costimulation in vitro. Surprisingly, using pregnancy as a model to study the H-Y-specific response of maternal T cells in the presence or absence of CD28 costimulation in vivo, it was found that peripheral tolerance does not occur in CD28KO pregnants in contrast to the partial clonal deletion and hyporesponsiveness of remaining T cells observed in CD28WT pregnants. These data demonstrate for the first time that CD28 is critical for tolerance induction of CD8 T cells, contrasting markedly with CD28 independence of in vitro activation, and suggest that the role of CD28/B7 interactions in peripheral tolerance of CD8 T cells may differ significantly from that of CD4 T cells. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NIA, NIH, Bethesda, MD 20892 USA. RP Vacchio, MS (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Rm 4B10,10 Ctr Dr, Bethesda, MD 20892 USA. NR 36 TC 24 Z9 24 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 JAN 6 PY 2003 VL 197 IS 1 BP 19 EP 26 DI 10.1084/jem.20021429 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 635QJ UT WOS:000180410100003 PM 12515810 ER PT J AU Watzl, C Long, EO AF Watzl, C Long, EO TI Natural killer cell inhibitory receptors block actin cytoskeleton-dependent recruitment of 2B4 (CD244) to lipid rafts SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE natural killer cell; raft; tyrosine phosphorylation; inhibitory receptor; activation ID LINKED LYMPHOPROLIFERATIVE DISEASE; HUMAN NK CELLS; CUTTING EDGE; SIGNAL-TRANSDUCTION; SURFACE-MOLECULE; T-CELLS; TYROSINE PHOSPHORYLATION; CYTOTOXIC LYMPHOCYTES; SPATIAL-ORGANIZATION; INFECTED CELLS AB A dynamic balance of positive and negative signals regulates target cell lysis by natural killer (NK) cells upon engagement of a variety of different activation receptors and of inhibitory receptors that recruit the tyrosine phosphatase SHP-1. However, the step at which activation signals are blocked by SHP-1 is not known. We have been using activation receptor 2134 (CD244) to study the influence of inhibitory receptors on NK cell activation. Engagement of inhibitory receptors by HLA class I on target cells blocks phosphorylation of 2134, placing the inhibitory step at the level, or upstream of 2134 phosphorylation. Here we show that phosphorylated 2134, after engagement with either antibodies or target cells that express the 2134 ligand, is found exclusively in a detergent-resistant membrane fraction that contains lipid rafts. Integrity of lipid rafts was essential for phosphorylation and activating function of 2134. Coengagement of inhibitory receptors blocked 2134 phosphorylation and 2134 association with detergent-resistant membranes, indicating that inhibitory receptors function upstream of raft-dependent signals. Recruitment of 2134 into detergent-resistant membrane fractions and 2134 phosphorylation were dependent on actin polymerization. Blocking actin cytoskeleton-dependent raft recruitment of different receptors may be a general mechanism by which inhibitory receptors control NK cell activation. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. Univ Heidelberg, Inst Immunol, D-69120 Heidelberg, Germany. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. RI Watzl, Carsten/B-4911-2013; Long, Eric/G-5475-2011 OI Watzl, Carsten/0000-0001-5195-0995; Long, Eric/0000-0002-7793-3728 NR 49 TC 92 Z9 93 U1 1 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 JAN 6 PY 2003 VL 197 IS 1 BP 77 EP 85 DI 10.1084/jem.20020427 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 635QJ UT WOS:000180410100008 PM 12515815 ER PT J AU Xu, Y Grem, JL AF Xu, Y Grem, JL TI Liquid chromatography-mass spectrometry method for the analysis of the anti-cancer agent capecitabine and its nucleoside metabolites in human plasma SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE capecitabine; 5-deoxy-5-fluorocytidine; 5-deoxy-5-fluorouridine ID ORAL FLUOROPYRIMIDINE CARBAMATE; FLUOROURACIL PLUS LEUCOVORIN; METASTATIC COLORECTAL-CANCER; BREAST-CANCER; PHASE-III; 5-FLUOROURACIL; PHARMACOKINETICS; TUMORS AB A reversed-phase high-performance liquid chromatography method with electrospray ionization and mass spectral detection is described for the determination of capecitabine, 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine in human plasma with 5-chloro-2'-deoxyuridine as the internal standard. An on-line sample clean-up procedure allows dilution of the plasma sample with the initial mobile phase. The linear dynamic range is 0.0500-10.0 mug/ml for capecitabine, and 0.0500-25.0 mug/ml for the metabolites, 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine, respectively. This method has been used to analyze plasma samples from patients receiving capecitabine in combination. with oxaliplatin. Published by Elsevier Science B.V. C1 NCI, Gastrointestinal Malignancies Sect, Canc Therapeut Branch, Ctr Canc Res, Bethesda, MD 20889 USA. RP Grem, JL (reprint author), NCI Navy Med Oncol, Natl Naval Med Ctr, 8901 Wisconsin Ave,Bldg 8,Room 5101, Bethesda, MD 20889 USA. NR 10 TC 34 Z9 35 U1 0 U2 8 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 JAN 5 PY 2003 VL 783 IS 1 BP 273 EP 285 AR PII S1570-0232(02)00674-8 DI 10.1016/S1570-0232(02)00674-8 PG 13 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 631KJ UT WOS:000180166700030 PM 12450548 ER PT J AU Chen, WS Bennink, JR Yewdell, JW AF Chen, WS Bennink, JR Yewdell, JW TI Systematic search fails to detect immunogenic MHC class-I-restricted determinants encoded by influenza A virus noncoding sequences SO VIROLOGY LA English DT Article ID NEWLY SYNTHESIZED PROTEINS; READING FRAME; CTL EPITOPES; PEPTIDES; TRANSLATION; ANTIGEN; VIVO; RECOGNITION; DEGRADATION; MECHANISM AB It has been demonstrated in a number of systems that CD8(+) T cells (TCD8+) can be induced by peptides encoded in alternative reading frames (ARFs) that do not appear to code for bona fide proteins. The biological relevance of ARF peptides remains to be firmly established, however. With this as a goal, we systematically searched for ARF determinants recognized by mouse TCD8+ induced by influenza A virus infection. Of 35 candidate ARF peptides that matched H-2 D-b, K-b, or K-d binding motifs, we found that 13 bind to their respective class I molecules at or above the minimal affinity associated with immunogenicity established by past studies. Nine of these peptides were able to induce TCD8+ capable of recognizing peptide-coated target cells. Of these, only alone determinant is antigenic and immunogenic in the context of influenza A virus infections. Ironically, this peptide is derived from a reading frame that encodes a previously unknown influenza virus protein. These findings suggest that alternative reading frames are not a significant source of antigenic peptides in influenza virus infections and raise doubts regarding the general biological significance of ARF determinants. (C) 2002 Elsevier science (USA). C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bennink, JR (reprint author), NIAID, Viral Dis Lab, NIH, Room 211,Bldg 4,4 Ctr Dr,MSC 0440, Bethesda, MD 20892 USA. RI yewdell, jyewdell@nih.gov/A-1702-2012; Chen, Weisan/E-7828-2012 NR 22 TC 8 Z9 8 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JAN 5 PY 2003 VL 305 IS 1 BP 50 EP 54 DI 10.1006/viro.2002.1744 PG 5 WC Virology SC Virology GA 632FX UT WOS:000180214200006 PM 12504540 ER PT J AU Nacsa, J Stanton, J Kunstman, KJ Tsai, WP Watkins, DI Wolinsky, SM Franchini, G AF Nacsa, J Stanton, J Kunstman, KJ Tsai, WP Watkins, DI Wolinsky, SM Franchini, G TI Emergence of cytotoxic T lymphocyte escape mutants following antiretroviral treatment suspension in rhesus macaques infected with SIVmac251 SO VIROLOGY LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; STRUCTURED TREATMENT INTERRUPTIONS; ANTIVIRAL IMMUNE-RESPONSES; MHC CLASS-I; TYPE-1 INFECTION; PERIPHERAL-BLOOD; IL-2 PRODUCTION; VIREMIA CONTROL; DECAY KINETICS; HIV-INFECTION AB Structured treatment interruption (STI) of antiretroviral drugs has been proposed as an alternative approach for managing patients infected with HIV-1. While STI is thought to spare drug-related side effects and enhance the HIV-1-specific immune response, the long-lasting clinical benefit of this approach remains uncertain, particularly in patients with long-standing HIV-1 infection. Here, we investigated the basis of unabated virological replication following different STI regimens in rhesus macaques that expressed the MHC class I Mamu-A*01 molecule treated during acute and long-standing infection with SIVmac251. An amino acid change at the anchor residue within the immunodominant Mamu-A*01-restricted Gag(181-189) CM9 epitope (T --> A) in one of six macaques with acute SIVmac251 infection and in three of four macaques with long-standing SIVmac251 infection (T --> A; T --> S; S --> C) was found in the majority of plasma virus. These amino acid changes have been shown to severely decrease binding of the corresponding peptides to the Mamu-A*01 molecule and, in the case of the T --> A change, escape from CTL. In one macaque with long-standing SIVmac251 infection, a mutation emerged that conferred resistance to one of the antiretroviral drugs (PMPA) as well. These results provide insights into the mechanism underlying the limited capacity of repeated interruption of antiretroviral therapy as an approach to restrain viral replication. In addition, these data also suggest that interruption of therapy may be less effective in chronic infection because of preexisting immune escape and that immune escape is a risk of interruption of therapy. (C) 2002 Elsevier Science (USA). C1 NCI, Basic Res Labs, Bethesda, MD 20892 USA. Northwestern Univ, Sch Med, Div Infect Dis, Chicago, IL 60611 USA. Univ Wisconsin, Wisconsin Reg Primate Res Ctr, Madison, WI 53715 USA. RP Franchini, G (reprint author), NCI, Basic Res Labs, 41-D804, Bethesda, MD 20892 USA. RI Wolinsky, Steven/B-2893-2012; OI Wolinsky, Steven/0000-0002-9625-6697 NR 46 TC 14 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 0042-6822 J9 VIROLOGY JI Virology PD JAN 5 PY 2003 VL 305 IS 1 BP 210 EP 218 DI 10.1006/viro.2002.1753 PG 9 WC Virology SC Virology GA 632FX UT WOS:000180214200020 PM 12504554 ER PT J AU Zheng, CY Wang, JH Baum, BJ AF Zheng, CY Wang, JH Baum, BJ TI Integration efficiency of a hybrid adenoretroviral vector SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE hybrid vector; adenovirus; retrovirus; integration; non-homologous recombination ID RETROVIRAL DNA INTEGRATION; CELL LINE; ADENOVIRUS; GENE; PROTEIN; REPAIR AB The frequency with which the hybrid vector AdLTR-luc mediates genomic integration [Nat. Biotech. 18 (2000) 176-180] is unknown. To address this, we constructed AdLTR-red, using the AdLTR-luc backbone and the enhanced red fluorescence protein cDNA. Kinetic studies showed that AdLTR-red and a conventional adenoviral vector, AdCMV-red, entered and transduced epithelial cells comparably. AdLTR-red integration frequency in vitro, i.e., the percentage of red clones after 10-12 doubling times from limiting dilutions, was 8.0% (36/450: at 67 particles/cell). With AdCMV-red. 0/549 clones were integration-positive. Seven days after AdLTR-luc or AdCMV-Iuc (10(11) particles) femoral vein administration to adult rats splenocytes were prepared, stimulated with concanavalin A, and examined by FISH. AdLTR-luc integration occurred in 5-11% of mitotic rat splenocytes, while no unequivocal integration was found with AdCMV-luc. These data provide the first quantitative evidence of the frequency for genomic integration with this hybrid vector. Published by Elsevier Science (USA). C1 Natl Inst Dent & Craniofaicla Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), Natl Inst Dent & Craniofaicla Res, Gene Therapy & Therapeut Branch, NIH, Bldg 10,Room 1N113,MSC 1190, Bethesda, MD 20892 USA. NR 19 TC 9 Z9 10 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JAN 3 PY 2003 VL 300 IS 1 BP 115 EP 120 AR PII S0006-291X(02)02801-2 DI 10.1016/S0006-291X(02)02801-2 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 634CV UT WOS:000180323200019 PM 12480529 ER PT J AU Axelrod, J AF Axelrod, J TI Journey of a late blooming biochemical neuroscientist SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NEUROTRANSMITTER TRANSPORTERS; NEURONS; RHYTHM C1 NIH, Bethesda, MD 20892 USA. RP Axelrod, J (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 61 TC 11 Z9 11 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JAN 3 PY 2003 VL 278 IS 1 BP 1 EP 13 DI 10.1074/jbc.X200004200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 632ZX UT WOS:000180255700001 PM 12414788 ER PT J AU Ren, H Honse, Y Karp, BJ Lipsky, RH Peoples, RW AF Ren, H Honse, Y Karp, BJ Lipsky, RH Peoples, RW TI A site in the fourth membrane-associated domain of the N-methyl-D-aspartate receptor regulates desensitization and ion channel gating SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GLYCINE-BINDING-SITE; GAMMA-AMINOBUTYRIC-ACID; NMDA RECEPTOR; GLUTAMATE-RECEPTOR; MOLECULAR DETERMINANTS; PYRAMIDAL CELLS; SINGLE-CHANNEL; TIME COURSE; ADULT-RAT; SUBUNIT AB The N-methyl-D-aspartate (NMDA) receptor has four membrane-associated domains, three of which are membrane-spanning (M1, M3, and M4) and one of which is a re-entrant pore loop (M2). The M2-M3 domains have been demonstrated to influence the function of the ion channel, but a similar role for the M4 domain has not been reported. We have identified a methionine residue (Met(823)) in the M4 domain of the NR2A subunit that regulates desensitization and ion channel gating. A tryptophan substitution at this site did not alter the EC50 for glycine or the peak NMDA EC50 but decreased the steady-state NMDA EC50 and markedly increased apparent desensitization, mean open time, and peak current density. Results of rapid solution exchange experiments revealed that changes in microscopic desensitization rates and closing rates could account for the changes in macroscopic desensitization, steady-state NMDA EC50, and current density. Other amino acid substitutions at this site could increase or decrease the rate of desensitization and mean open time of the ion channel. Both mean open time and desensitization were dependent primarily upon the hydrophobic character of the amino acid at the position. These results demonstrate an important role for hydrophobic interactions at Met(823) in regulation of NMDA receptor function. C1 NIAAA, Unit Cellular Neuropharmacol, LMCN, Bethesda, MD 20892 USA. RP Peoples, RW (reprint author), NIAAA, Unit Cellular Neuropharmacol, LMCN, Pk 2 Bldg,Rm 150,12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. OI Lipsky, Robert/0000-0001-7753-1473 NR 52 TC 39 Z9 41 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 JAN 3 PY 2003 VL 278 IS 1 BP 276 EP 283 DI 10.1074/jbc.M209486200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 632ZX UT WOS:000180255700037 PM 12414797 ER PT J AU Yu, ST Matsusue, K Kashireddy, P Cao, WQ Yeldandi, V Yeldandi, AV Rao, MS Gonzalez, FJ Reddy, JK AF Yu, ST Matsusue, K Kashireddy, P Cao, WQ Yeldandi, V Yeldandi, AV Rao, MS Gonzalez, FJ Reddy, JK TI Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma 1 (PPAR gamma 1) overexpression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PPAR-ALPHA; BETA-OXIDATION; TRANSCRIPTIONAL REGULATION; ADIPOSE DIFFERENTIATION; C/EBP-ALPHA; TARGET GENE; PROTEIN; ACID; TISSUE; INDUCTION AB Peroxisome proliferator activated-receptor (PPAR) isoforms, alpha and gamma, function as important coregulators of energy (lipid) homeostasis. PPARalpha regulates fatty acid oxidation primarily in liver and to a lesser extent in adipose tissue, whereas PPARgamma serves as a key regulator of adipocyte differentiation and lipid storage. Of the two PPARgamma isoforms, PPARgamma1 and PPARgamma2 generated by alternative splicing, PPARgamma1 isoform is expressed in liver and other tissues, whereas PPARgamma2 isoform is expressed exclusively in adipose tissue where it regulates adipogenesis and lipogenesis. Since the function of PPARgamma1 in liver is not clear, we have, in this study, investigated the biological impact of overexpression of PPARgamma1 in mouse liver. Adenovirus-PPARgamma1 injected into the tail vein induced hepatic steatosis in PPARalpha(-/-) mice. Northern blotting and gene expression profiling results showed that adipocyte-specific genes and lipogenesis-related genes are highly induced in PPARalpha(-/-) livers with PPARgamma1 overexpression. These include adipsin, adiponectin, aP2, caveolin-1, fasting-induced adipose factor, fat-specific gene 27 (FSP27), CD36, Delta(9) desaturase, and malic enzyme among others, implying adipogenic transformation of hepatocytes. Of interest is that hepatic steatosis per se, induced either by feeding a diet deficient in choline or developing in fasted PPARalpha(-/-) mice, failed to induce the expression of these PPARgamma-regulated adipogenesis-related genes in steatotic liver. These results suggest that a high level of PPARgamma1 in mouse liver is sufficient for the induction of adipogenic transformation of hepatocytes with adipose tissue-specific gene expression and lipid accumulation. We conclude that excess PPARgamma activity can lead to the development of a novel type of adipogenic hepatic steatosis. C1 Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Reddy, JK (reprint author), Northwestern Univ, Dept Pathol, Feinberg Sch Med, 303 E Chicago Ave, Chicago, IL 60611 USA. FU NCI NIH HHS [CA84472]; NIGMS NIH HHS [GM23750] NR 61 TC 356 Z9 374 U1 3 U2 18 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 JAN 3 PY 2003 VL 278 IS 1 BP 498 EP 505 DI 10.1074/jbc.M210062200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 632ZX UT WOS:000180255700066 PM 12401792 ER PT J AU Richard, JP Melikov, K Vives, E Ramos, C Verbeure, B Gait, MJ Chernomordik, LV Lebleu, B AF Richard, JP Melikov, K Vives, E Ramos, C Verbeure, B Gait, MJ Chernomordik, LV Lebleu, B TI Cell-penetrating peptides - A reevaluation of the mechanism of cellular uptake SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIV-1 TAT PROTEIN; HUMAN IMMUNODEFICIENCY VIRUS; IN-VIVO; ANTENNAPEDIA HOMEODOMAIN; BASIC DOMAIN; 3RD HELIX; DELIVERY; TRANSDUCTION; OLIGONUCLEOTIDES; INTERNALIZATION AB Cellular uptake of a family of cationic cell-penetrating peptides (examples include Tat peptides and penetratin) have been ascribed in the literature to a mechanism that does not involve endocytosis. In this work we reevaluate the mechanisms of cellular uptake of Tat 48-60 and (Arg)(9). We demonstrate here that cell fixation, even in mild conditions, leads to the artifactual uptake of these peptides. Moreover, we show that flow cytometry analysis cannot be used validly to evaluate cellular uptake unless a step of trypsin digestion of the cell membrane-adsorbed peptide is included in the protocol. Fluorescence microscopy on live unfixed cells shows characteristic endosomal distribution of peptides. Flow cytometry analysis indicates that the kinetics of uptake are similar to the kinetics of endocytosis. Peptide uptake is inhibited by incubation at low temperature and cellular ATP pool depletion. Similar data were obtained for Tat-conjugated peptide nucleic acids. These data are consistent with the involvement of endocytosis in the cellular internalization of cell-penetrating peptides and their conjugates to peptide nucleic acids. C1 NICHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. Univ Montpellier 2, CNRS, Unite Mixte Rech 5124, Montpellier, France. MRC, Mol Biol Lab, Cambridge CB2 2QH, England. RP Melikov, K (reprint author), NICHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, 10 Ctr Dr,Bldg 10,Rm 10D05, Bethesda, MD 20892 USA. EM melikovk@mail.nih.gov RI Melikov, Kamran/A-6604-2009 NR 36 TC 1105 Z9 1130 U1 31 U2 261 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 JAN 3 PY 2003 VL 278 IS 1 BP 585 EP 590 DI 10.1074/jbc.M209548200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 632ZX UT WOS:000180255700076 PM 12411431 ER PT J AU Hong, MK Harbron, EJ O'Connor, DB Guo, JH Barbara, PF Levin, JG Musier-Forsyth, K AF Hong, MK Harbron, EJ O'Connor, DB Guo, JH Barbara, PF Levin, JG Musier-Forsyth, K TI Nucleic acid conformational changes essential for HIV-1 nucleocapsid protein-mediated inhibition of self-priming in minus-strand transfer SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE FRET; chaperone activity; nucleocapsid protein; self-priming; TAR ID IMMUNODEFICIENCY-VIRUS TYPE-1; STRONG-STOP DNA; RESONANCE ENERGY-TRANSFER; ZINC-FINGER STRUCTURES; REVERSE TRANSCRIPTION; IN-VITRO; POSTTRANSLATIONAL MODIFICATIONS; SHORT OLIGONUCLEOTIDES; ANNEALING ACTIVITIES; CHAPERONE ACTIVITY AB Reverse transcription of the HIV-1 genome is a complex multi-Step process. HIV-1 nucleocapsid protein (NC) is a nucleic acid chaperone protein that has been shown to greatly facilitate the nucleic acid rearrangements that precede the minus-strand transfer step in reverse transcription. NC destabilizes the highly structured transactivation response region (TAR) present in the R region of the RNA genome, as well as a complementary hairpin structure ("TAR DNA") at the 3'-end of the newly synthesized minus-strand strong-stop DNA ((-) SSDNA). Melting of the latter structure inhibits a self-priming (SP) reaction that competes with the strand transfer reaction. In an in vitro minus-strand transfer system consisting of a (-) SSDNA mimic and a TAR-containing acceptor RNA molecule, we find that when both nucleic acids are present, NC facilitates formation of the transfer product and the SP reaction is greatly reduced. In contrast, in the absence of the acceptor RNA, NC has only a small inhibitory effect on the SP reaction. To further investigate NC-mediated inhibition of SP, we developed a FRET-based assay that allows us to directly monitor conformational changes in the TAR DNA structure upon NC binding. Although the majority (similar to71%) of the TAR DNA molecules assume a folded hairpin conformation in the absence of NC, two minor "semifolded" and "unfolded" populations are also observed. Upon NC binding to the TAR DNA alone, we observe a modest shift in the population towards the less-folded states. In the presence of the RNA acceptor molecule, NC binding to TAR DNA results in a shift of the majority of molecules to the unfolded state. These measurements help to explain why acceptor RNA is required for significant inhibition of the SP reaction by NC, and support the hypothesis that NC-mediated annealing of nucleic acids is a concerted process wherein the unwinding step occurs in synchrony with hybridization. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA. Univ Texas, Dept Chem & Biochem, Austin, TX 78712 USA. NICHD, NIH, Bethesda, MD 20892 USA. RP Musier-Forsyth, K (reprint author), Univ Minnesota, Dept Chem, 207 Pleasant St SE, Minneapolis, MN 55455 USA. FU NIAID NIH HHS [AI 65056, AI 10463]; NIGMS NIH HHS [T32 GM 08277] NR 52 TC 60 Z9 63 U1 2 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 3 PY 2003 VL 325 IS 1 BP 1 EP 10 DI 10.1016/S0022-2836(02)01177-4 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 641HN UT WOS:000180739500001 PM 12473448 ER PT J AU Barrientos, LG Louis, JM Ratner, DM Seeberger, PH Gronenborn, AM AF Barrientos, LG Louis, JM Ratner, DM Seeberger, PH Gronenborn, AM TI Solution structure of a circular-permuted variant of the potent HIV-inactivating protein cyanovirin-N: Structural basis for protein stability and oligosaccharide interaction SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE cyanovirin-N; circular permuted CV-N; high-mannose sugars; protein-carbohydrate interaction; gp120 ID GP120; BINDING; NMR; PROGRAM; GLYCOPROTEINS; SYSTEM; PHASE; CD4 AB The high-resolution solution structure of a monomeric circular permuted (cp) variant of the potent HIV-inactivating protein cyanovirin-N (CV-N) was determined by NMR. Comparison with the wild-type (wt) structure revealed that the observed loss in stability of cpCV-N compared to the wt protein is due to less favorable packing of several residues at the pseudo twofold axis that are responsible for holding the two halves of the molecule together. In particular, the N and C-terminal amino acid residues exhibit conformational flexibility, resulting in fewer and less favorable contacts between them. The important hydrophobic and hydrogen-bonding network between residues W49, D89, H90, Y100 and E101 that was observed in wt CV-N is no longer present. For instance, Y100 and E101 are flexible and the tryptophan side-chain is in a different conformation compared to the wt protein. The stability loss amounts to similar to 2 kcal/mol and the mobility of the protein is evident by fast amide proton exchange throughout the chain. Mutation of the single proline residue to glycine (P52G) did not substantially affect the stability of the protein, in contrast to the finding for wtCV-N. The binding of high-mannose type oligosaccharides to cpCV-N was also investigated. Similar to wtCV-N, two carbohydrate-binding sites were identified on the protein and the Man alpha1 --> 2Man linked moieties on the sugar were delineated as binding epitopes. Unlike in wtCV-N, the binding sites on cpCV-N are structurally similar and exhibit comparable binding affinities for the respective sugars. On the basis of the studies presented here and previous results on high-mannose binding to wtCV-N, we discuss a model for the interaction between gp120 and CV-N. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. MIT, Dept Chem, Cambridge, MA 02139 USA. RP Gronenborn, AM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,room 130, Bethesda, MD 20892 USA. OI Gronenborn, Angela M/0000-0001-9072-3525 NR 32 TC 26 Z9 27 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JAN 3 PY 2003 VL 325 IS 1 BP 211 EP 223 DI 10.1016/S0022-2836(02)01205-6 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 641HN UT WOS:000180739500016 PM 12473463 ER PT J AU Bisley, JW Goldberg, ME AF Bisley, JW Goldberg, ME TI Neuronal activity in the lateral intraparietal area and spatial attention SO SCIENCE LA English DT Article ID POSTERIOR PARIETAL CORTEX; SELECTIVE VISUAL-ATTENTION; MOTOR INTENTION ACTIVITY; SACCADIC EYE-MOVEMENTS; SUPERIOR COLLICULUS; MONKEY; MACAQUES; ENHANCEMENT; RESPONSES; PLAN AB Although the parietal cortex has been implicated in the neural processes underlying visual attention, the nature of its contribution is not well understood. We tracked attention in the monkey and correlated the activity of neurons in the lateral intraparietal area (LIP) with the monkey's attentional performance. The ensemble activity in LIP across the entire visual field describes the spatial and temporal dynamics of a monkey's attention. Activity subtending a single location in the visual. field describes the attentional priority at that area but does not predict that the monkey will actually attend to or make an eye movement to that location. C1 New York State Psychiat Inst & Hosp, Ctr Neurobiol & Behav, Mahoney Keck Ctr Mind & Brain, Unit 87, New York, NY 10032 USA. NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. Georgetown Univ, Sch Med, Dept Neurol, Washington, DC 20007 USA. Columbia Univ Coll Phys & Surg, Ctr Neurobiol & Behav, Keck Ctr Cognit & Plast,Dept Neurol, Mahoney Ctr Mind & Brain, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Ctr Neurobiol & Behav, Keck Ctr Cognit & Plast,Dept Psychiat, Mahoney Ctr Mind & Brain, New York, NY 10032 USA. RP Bisley, JW (reprint author), New York State Psychiat Inst & Hosp, Ctr Neurobiol & Behav, Mahoney Keck Ctr Mind & Brain, Unit 87, Room 5-06,1051 Riverside Dr, New York, NY 10032 USA. OI Bisley, James/0000-0002-2841-0306 NR 43 TC 487 Z9 492 U1 6 U2 29 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 JAN 3 PY 2003 VL 299 IS 5603 BP 81 EP 86 DI 10.1126/science.1077395 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 631JZ UT WOS:000180165800036 PM 12511644 ER PT J AU Shen, XT Xiao, H Ranallo, R Wu, WH Wu, C AF Shen, XT Xiao, H Ranallo, R Wu, WH Wu, C TI Modulation of ATP-dependent chromatin-remodeling complexes by inositol polyphosphates SO SCIENCE LA English DT Article ID MESSENGER-RNA EXPORT; SACCHAROMYCES-CEREVISIAE; TRANSCRIPTION; PHOSPHATES; EXPRESSION; BINDING; KINASE; CELLS; GENES; NURF AB Eukaryotes use adenosine triphosphate (ATP)-dependent chromatin-remodeling complexes to regulate gene expression. Here, we show that inositol polyphosphates can modulate the activities of several chromatin-remodeling complexes in vitro. Inositol hexakisphosphate (IP6) inhibits nucleosome mobilization by NURF, ISW2, and INO80 complexes. In contrast, nucleosome mobilization by the yeast SWI/SNF complex is stimulated by inositol tetrakisphosphate (IP4) and inositol pentakisphosphate (IP5). We demonstrate that mutations in genes encoding inositol polyphosphate kinases that produce IP4, IP5, and IP6 impair transcription in vivo. These results provide a link between inositol polyphosphates, chromatin remodeling, and gene expression. C1 NCI, Ctr Canc Res, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wu, C (reprint author), NCI, Ctr Canc Res, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 29 TC 229 Z9 232 U1 1 U2 8 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 JAN 3 PY 2003 VL 299 IS 5603 BP 112 EP 114 DI 10.1126/science.1078068 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 631JZ UT WOS:000180165800046 PM 12434013 ER PT J AU Webb, TR Lvovskiy, D Kim, SA Ji, XD Melman, N Linden, J Jacobson, KA AF Webb, TR Lvovskiy, D Kim, SA Ji, XD Melman, N Linden, J Jacobson, KA TI Quinazolines as adenosine receptor antagonists: SAR and selectivity for A(2B) receptors SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID LIGANDS; DERIVATIVES; ASTHMA AB We have recently reported the discovery of numerous new compounds that are selective inhibitors of all of the subtypes of the adenosine receptor family via a pharmacophore database searching and screening strategy. During the course of this work we made the unexpected discovery of a potent A(2B) receptor antagonist, 4-methyl-7-methoxyquinazolyl-2-(2'-amino-4'-imidazolinone) (38, CMB 6446), which showed selectivity for this receptor and functioned as an antagonist, with a binding K-i value of H 2 nM. We explored the effects of both substituent- and ring-structural variations on the receptor affinity in this series of derivatives, which were found to be mostly non-selective adenosine receptor ligands with K-i values in the micromolar range. Since no enhancement of A(2B) receptor affinity of 38 was achieved, the previously reported pharmacophore-based searching strategy yielded the most potent and selective structurally-related hit in the database originally searched. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Chembridge Corp, San Diego, CA 92127 USA. NIDDK, Lab Bioorgan Chem, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. Univ Virginia, Charlottesville, VA USA. RP Webb, TR (reprint author), Chembridge Corp, 16981 Via Tazon,Suite G, San Diego, CA 92127 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20] NR 19 TC 31 Z9 33 U1 1 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 JAN 2 PY 2003 VL 11 IS 1 BP 77 EP 85 AR PII S0968-0896(02)00323-1 DI 10.1016/S0968-0896(02)00323-1 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 626WX UT WOS:000179897800009 PM 12467710 ER PT J AU Sun, GY AF Sun, GY TI Assigning the major isomers of fullerene C-88 by theoretical C-13 NMR spectra SO CHEMICAL PHYSICS LETTERS LA English DT Article ID DENSITY-FUNCTIONAL THEORY; IPR ISOMERS; IDENTIFICATION; C-60; C-72 AB The IPR isomers of fullerene C-88 have been studied using density functional theory. Structures of all C88 isomers with non-zero HOMO-LUMO gaps were optimized at the B3LYP/STO-3G level. Those isomers having energies lower than 25 kcal/mol were subjected to geometry optimization using the 6-31G basis set. Isomer 17 has the lowest energy, followed by 7 and 33. All three isomers have large HOMO-LUMO gaps. C-13 NMR chemical shifts were obtained employing the GIAO method. The comparison between predicted and measured NMR spectra strongly supports the observed C-88-1(C-s) as isomer 17, and isomers C-88-2(C-2) and C-88-3(C-2) as 7 and 33, respectively. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Georgetown Univ, Dept Chem, Washington, DC 20057 USA. RP Sun, GY (reprint author), NCI, Med Chem Lab, NIH, 376 Boyles St, Frederick, MD 21702 USA. NR 22 TC 31 Z9 31 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-2614 J9 CHEM PHYS LETT JI Chem. Phys. Lett. PD JAN 2 PY 2003 VL 367 IS 1-2 BP 26 EP 33 AR PII S0009-2614(02)01664-0 DI 10.1016/S0009-2614(02)01664-0 PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 633GB UT WOS:000180273300004 ER PT J AU Horton, JK Joyce-Gray, DF Pachkowski, BF Swenberg, JA Wilson, SH AF Horton, JK Joyce-Gray, DF Pachkowski, BF Swenberg, JA Wilson, SH TI Hypersensitivity of DNA polymerase beta null mouse fibroblasts reflects accumulation of cytotoxic repair intermediates from site-specific alkyl DNA lesions SO DNA REPAIR LA English DT Article DE DNA polymerase beta; base excision repair; cell cycle; DNA alkylation; monofunctional alkylating agent; 5-hydroxymethyl-2 '-deoxyuridine ID BASE-EXCISION-REPAIR; HAMSTER OVARY CELLS; COLON-CANCER CELLS; METHYL METHANESULFONATE; ESCHERICHIA-COLI; CYCLE CHECKPOINTS; DAMAGING AGENTS; KNOCKOUT MICE; CHK2 KINASE; IN-VIVO AB Monofunctional alkylating agents react with DNA by S(N)1 or S(N)2 mechanisms resulting in formation of a wide spectrum of cytotoxic base adducts. DNA polymerase p (beta-pol) is required for efficient base excision repair of N-alkyl adducts, and we make use of the hypersensitivity of beta-pol null mouse fibroblasts to investigate such alkylating agents with a view towards understanding the DNA lesions responsible for the cellular phenotype. The inability of O-6-benzylguanine to sensitize wild-type or beta-pol null cells to S(N)1-type methylating agents indicates that the observed hypersensitivity is not due to differential repair of cytotoxic O-alkyl adducts. Using a 3-methyladenine-specific agent and an inhibitor of such methylation, we find that inefficient repair of 3-methyladenine is not the reason for the hypersensitivity of beta-pol null cells to methylating agents, and further that 3-methyladenine is not the adduct primarily responsible for methyl methanesulfonate (MMS)- and methyl nitrosourea-induced cytotoxicity in wild-type cells. Relating the expected spectrum of DNA adducts and the relative sensitivity of cells to monofunctional alkylating agents, we propose that the hypersensitivity of beta-pol null cells reflects accumulation of cytotoxic repair intermediates, such as the 5'-deoxyribose phosphate group, following removal of 7-alkylguanine from DNA. In support of this conclusion, beta-pol null cells are also hypersensitive to the thymidine analog 5-hydroxymethyl-2'-deoxyuridine (hmdUrd). This agent is incorporated into cellular DNA and elicits cytotoxicity only when removed by glycosylase-initiated base excision repair. Consistent with the hypothesis that there is a common repair intermediate resulting in cytotoxicity following treatment with both types of agents, both MMS and hmdUrd-initiated cell death are preceded by a similar rapid concentration-dependent suppression of DNA synthesis and a later cell cycle arrest in G(0)/G(1) and G(2)M phases. Published by Elsevier Science B.V. C1 NIEHS, Lab Struct Biol, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. RP Wilson, SH (reprint author), NIEHS, Lab Struct Biol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 65 TC 68 Z9 69 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 JAN 2 PY 2003 VL 2 IS 1 BP 27 EP 48 AR PII S1568-7864(02)00184-2 DI 10.1016/S1568-7864(02)00184-2 PG 22 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 634BD UT WOS:000180319400003 PM 12509266 ER PT J AU Mattera, R Arighi, CN Lodge, R Zerial, M Bonifacino, JS AF Mattera, R Arighi, CN Lodge, R Zerial, M Bonifacino, JS TI Divalent interaction of the GGAs with the Rabaptin-5-Rabex-5 complex SO EMBO JOURNAL LA English DT Article DE clathrin; endosomes; GGA; Rabaptin-5; Rabex-5 ID ENDOCYTIC MEMBRANE-FUSION; ADAPTER-LIKE PROTEIN; EAR HOMOLOGY DOMAIN; SMALL GTPASE RAB5; GAMMA-ADAPTIN; TRANS-GOLGI; VHS DOMAINS; BINDING; CLATHRIN; EFFECTOR AB Cargo transfer from trans-Golgi network (TGN)-derived transport carriers to endosomes involves a still undefined set of tethering/fusion events. Here we analyze a molecular interaction that may play a role in this process. We demonstrate that the GGAs, a family of Arf-dependent clathrin adaptors involved in selection of TGN cargo, interact with the Rabaptin-5-Rabex-5 complex, a Rab4/Rab5 effector regulating endosome fusion. These interactions are bipartite: GGA-GAE domains recognize an FGPLV sequence (residues 439-443) in a predicted random coil of Rabaptin-5 (a sequence also recognized by the gamma1-and gamma2-adaptin ears), while GGA-GAT domains bind to the C-terminal coiled-coils of Rabaptin-5. The GGA-Rabaptin-5 interaction decreases binding of clathrin to the GGA-hinge domain, and expression of green fluorescent protein (GFP)-Rabaptin-5 shifts the localization of endogenous GGA1 and associated cargo to enlarged early endosomes. These observations thus identify a binding sequence for GAE/gamma-adaptin ear domains and reveal a functional link between proteins regulating TGN cargo export and endosomal tethering/fusion events. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Max Planck Inst Mol Cell Biol & Genet, D-01307 Dresden, Germany. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. OI Bonifacino, Juan S./0000-0002-5673-6370 NR 40 TC 106 Z9 114 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JAN 2 PY 2003 VL 22 IS 1 BP 78 EP 88 DI 10.1093/emboj/cdg015 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 636BR UT WOS:000180435100008 PM 12505986 ER PT J AU Gatongi, PM Njoroge, JM Scott, ME Ranjan, S Gathuma, JM Munyua, WK Cheruiyot, H Prichard, RK AF Gatongi, PM Njoroge, JM Scott, ME Ranjan, S Gathuma, JM Munyua, WK Cheruiyot, H Prichard, RK TI Susceptibility to IVM in a field strain of Haemonchus contortus subjected to four treatments in a closed sheep-goat flock in Kenya SO VETERINARY PARASITOLOGY LA English DT Article DE Haemonchus contortus; IVM; susceptibility; resistance; sheep; goats; larval migration inhibition; faecal egg count reduction; total worm count ID MULTIPLE ANTHELMINTIC RESISTANCE; THIABENDAZOLE; MANAGEMENT; IVERMECTIN; FARM AB Susceptibility to IVM (IVM) of "strain A" Haemonchus contortus which had been exposed to IVM four times over a 2-year period was compared to IVM susceptibility of "strain C" H. contortus which had no prior field exposure to IVM, by in vivo and in vitro methods. In vivo, the percentage reduction in faecal egg counts (FEC) and the total worm counts (TWC) were compared between control animals (lambs and kids) and animals treated with low dose IVM (20 mug/kg). In vitro susceptibility to IVM was evaluated by larval migration inhibition (LMI) after the two strains of H. contortus were exposed to different concentrations of IVM. The dose response, measured as the proportion of larvae inhibited from migrating, was used to estimate LD50. Although differences in response to IVM in the in vivo determinations were not significant, "strain A" H. contortus had a significantly higher LD50 than "strain C" in the LMI assay. Coincident with the conduct of the in vivo experiment, it was observed that "strain A" H. contortus established and survived better than "strain C" in the control lambs. (C) 2002 Elsevier Science B.V. All rights reserved. C1 McGill Univ, Inst Parasitol, Ste Anne De Bellevue, PQ H9X 3V9, Canada. Kenya Agr Res Inst, Nairobi, Kenya. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. Ft Dodge Anim Hlth, Princeton, NJ 08543 USA. Univ Nairobi, Fac Med Vet, Kabete, Kenya. RP Prichard, RK (reprint author), McGill Univ, Inst Parasitol, Macdonald Campus 21-111 Lakeshore Rd, Ste Anne De Bellevue, PQ H9X 3V9, Canada. RI Scott, Marilyn/L-5347-2015 NR 17 TC 10 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4017 J9 VET PARASITOL JI Vet. Parasitol. PD JAN 2 PY 2003 VL 110 IS 3-4 BP 235 EP 240 AR PII S0304-4017(02)00318-7 DI 10.1016/S0304-4017(02)00318-7 PG 6 WC Parasitology; Veterinary Sciences SC Parasitology; Veterinary Sciences GA 634EY UT WOS:000180328100008 PM 12482652 ER PT B AU Rausch, TL Wirick, BA Stanhope, SJ Sheehan, FR AF Rausch, TL Wirick, BA Stanhope, SJ Sheehan, FR GP ASME TI A method for mechanically loading joints during dynamic magnetic resonance imaging SO 2003 ADVANCES IN BIOENGINEERING LA English DT Proceedings Paper CT ASME International Mechanical Engineering Congress CY NOV 15-21, 2003 CL Washington, DC SP ASME, Fluid Power Syst & Technol Div, ASME, Micro Elect Mech Syst Div, ASME, Fluids Engn Div, ASME, Bioengn Div, ASME, Appl Mech Div, ASME, Elect & Photon Packaging Div, ASME, Mfg Engn Div, ASME, Adv Energy Syst Div, ASME, Aerosp Div AB In order to take advantage of the opportunities that dynamic Magnetic Resonance Imaging (d-MRI) offers to the study of in vivo joint mechanics, d-MRI compatible devices capable of producing joint loads replicating dynamic physiological activities are needed (Sheehan et al., 1999). The purpose of this research effort was to design, model and test a device for the expressed purpose of using d-MRI to study precise ankle joint dynamics during loaded pseudo-functional movements. The device adjusts to subject specific anthropometric measurements, allowing for the device's axis of rotation to approximate the ankle's transverse axis. By combining imaging data and the model of the device, the magnitude, direction and point of application of the force applied to the foot were calculated throughout the motion cycle, with an average error of .7 Nm. This allows for comparisons between the externally applied load and internal ankle joint kinematics to be made, which are essential determinants for in vivo estimates of forces within tendon and ligament. The next phase of this work will be to combine this device with fast-Phase Contrast MRI (fast-pc), a previously developed d-MRI technique for the quantification of 3D musculoskeletal motion, in order to create a complete tool for the noninvasive in vivo measurement of joint kinematics during a loaded dynamic functional task in both healthy and impaired ankles. C1 NIH, Phys Disabil Branch, Bethesda, MD 20892 USA. RP Rausch, TL (reprint author), NIH, Phys Disabil Branch, Bldg 10, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC MECHANICAL ENGINEERS PI NEW YORK PA THREE PARK AVENUE, NEW YORK, NY 10016-5990 USA BN 0-7918-3710-6 PY 2003 BP 229 EP 230 PG 2 WC Biophysics; Engineering, Biomedical; Mechanics; Medicine, Research & Experimental SC Biophysics; Engineering; Mechanics; Research & Experimental Medicine GA BAL07 UT WOS:000222660500102 ER PT B AU Rebmann, AJ Boden, BP Sheehan, FT AF Rebmann, AJ Boden, BP Sheehan, FT GP ASME TI Patellar maltracking: No longer just a 2D problem SO 2003 ADVANCES IN BIOENGINEERING LA English DT Proceedings Paper CT ASME International Mechanical Engineering Congress CY NOV 15-21, 2003 CL Washington, DC SP ASME, Fluid Power Syst & Technol Div, ASME, Micro Elect Mech Syst Div, ASME, Fluids Engn Div, ASME, Bioengn Div, ASME, Appl Mech Div, ASME, Elect & Photon Packaging Div, ASME, Mfg Engn Div, ASME, Adv Energy Syst Div, ASME, Aerosp Div ID TRACKING AB In order to correctly diagnose and treat pathological knee joint mechanics we must be able to non-invasively quantify the 3D in vivo kinematics of this joint. Unfortunately, the majority of clinical diagnoses, for this joint, are based upon static 2D imaging. This is due to the fact that currently there is a scarcity of noninvasive measurement techniques that acquire 3D in vivo data dynamically. Thus, in vivo patellofemoral (PF) kinematic measurements typically compress a 3D time-dependent joint attitude to a static 2D representation. The purpose of this study was to investigate if patellar maltracking is limited to two dimensions, as assumed clinically, or if it is a complete six-degree of freedom problem. To do this, we quantified the 3D patellofemoral and tibiofemoral (TF) kinematics in both healthy individuals and those with suspected patellofemoral maltracking using fast-phase contrast magnetic resonance imaging, a technique developed in our previous work. Our data suggest that variations in kinematics were not confined to the standard axial plane measures (e.g. patellar tilt, patellar subluxation), but variations are exhibited in all six degrees of freedom. Therefore, future clinical diagnoses and interventions along with future research will be most effective if the measures used are broadened to include all six-degrees of freedom. C1 NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Rebmann, AJ (reprint author), NIH, Dept Diagnost Radiol, Bldg 10, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MECHANICAL ENGINEERS PI NEW YORK PA THREE PARK AVENUE, NEW YORK, NY 10016-5990 USA BN 0-7918-3710-6 PY 2003 BP 239 EP 240 PG 2 WC Biophysics; Engineering, Biomedical; Mechanics; Medicine, Research & Experimental SC Biophysics; Engineering; Mechanics; Research & Experimental Medicine GA BAL07 UT WOS:000222660500107 ER PT S AU Mao, S Rosenfeld, A Kanungo, T AF Mao, S Rosenfeld, A Kanungo, T GP IEEE IEEE TI Stochastic attributed K-D tree modeling of technical paper title pages SO 2003 INTERNATIONAL CONFERENCE ON IMAGE PROCESSING, VOL 1, PROCEEDINGS SE IEEE International Conference on Image Processing (ICIP) LA English DT Proceedings Paper CT IEEE International Conference on Image Processing CY SEP 14-17, 2003 CL BARCELONA, SPAIN SP IEEE Signal Proc Soc AB Structural information about a document is essential for structured query processing, indexing, and retrieval. A document page can be partitioned into a hierarchy of homogeneous regions such as columns, paragraphs, etc.; these regions are called physical components, and define the physical layout of the page. In this paper we develop a class of models for the physical layouts of technical paper title pages. We model physical layout using hidden semi-Markov models for directional projections of page regions, and a stochastic attributed K-d tree grammar model for the 2D hierarchical structure. of these regions. We use the models to generate sets of synthetic title page images of three distinctive styles, which we use in controlled experiments on page structure analysis. C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Mao, S (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 5 TC 3 Z9 3 U1 0 U2 0 PU IEEE PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017 USA SN 1522-4880 BN 0-7803-7750-8 J9 IEEE IMAGE PROC PY 2003 BP 533 EP 536 PG 4 WC Imaging Science & Photographic Technology SC Imaging Science & Photographic Technology GA BX96E UT WOS:000187010000134 ER PT B AU Le, DX Thoma, GR AF Le, DX Thoma, GR BE Callaos, N Chien, BC Dong, J Li, W TI Automated document labeling for web-based Online medical journals SO 7TH WORLD MULTICONFERENCE ON SYSTEMICS, CYBERNETICS AND INFORMATICS, VOL II, PROCEEDINGS: COMPUTER SCIENCE AND ENGINEERING LA English DT Proceedings Paper CT 7th World Multiconference on Systemics, Cybernetics and Informatics CY JUL 27-30, 2003 CL ORLANDO, FL SP Int Inst Informat & System DE W3C document object model; automated document labeling; MEDLINE (R); database; National Library of Medicine AB An increasing number of publishers are using the Internet and the World Wide Web to provide their subscribers with access to online journals. New techniques are needed to capture, classify, analyze, extract, modify, and reformat Web-based document information for computer storage, access, and processing. An R&D division of the National Library of Medicine (NLM) is developing an automated system, temporarily code-named WebMARS for Web-based Medical Article Records System, to download, analyze and extract bibliographic information from Web-based journal articles to produce citation records for its MEDLINE(R) database. This paper describes one component of this system: assigning meaningful labels to text zones containing article title, author names, affiliation, and abstract. This labeling technique is based on features derived from the World Wide Web Consortium Document Object Model (W3C DOM) and an analysis of the page layout for each journal, a DOM-based document node location and content analysis, string pattern matching, and a depth-first node traversal algorithm. Experiments carried out on a variety of Web-based medical journals have proved the feasibility of this automated document labeling approach. Preliminary evaluation results on a small set of Web-based medical journal articles show that the system is capable of labeling text zones at an accuracy of over 95%. C1 Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. RP Le, DX (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU INT INST INFORMATICS & SYSTEMICS PI ORLANDO PA 14269 LORD BARCLAY DR, ORLANDO, FL 32837 USA BN 980-6560-01-9 PY 2003 BP 411 EP 415 PG 5 WC Computer Science, Artificial Intelligence; Computer Science, Theory & Methods SC Computer Science GA BY46S UT WOS:000189328700075 ER PT B AU Kim, J Le, DX Thoma, GR AF Kim, J Le, DX Thoma, GR BE Callaos, N Margenstern, M Zhang, J Castillo, O Doberkat, EE TI Automated labeling algorithms for biomedical document images SO 7TH WORLD MULTICONFERENCE ON SYSTEMICS, CYBERNETICS AND INFORMATICS, VOL V, PROCEEDINGS: COMPUTER SCIENCE AND ENGINEERING: I LA English DT Proceedings Paper CT 7th World Multiconference on Systemics, Cybernetics and Informatics CY JUL 27-30, 2003 CL ORLANDO, FL SP Int Inst Informat & System DE labeling module; zoning module; rule-based algorithm; OCR; MARS AB The National Library of Medicine (NLM) has developed an automated system, named Medical Article Records System (MARS), to process bibliographic data (title, authors, affiliation, abstract, etc.) in biomedical journal articles for its MEDLINE(R) database. This paper describes a labeling module in the MARS, which automatically extract the bibliographic data in biomedical journal articles. The labeling module is composed of two sub modules: General label type module (GLTM) and Arbitrary label type module (ALTM). Six label types, which are commonly used in the journals, are collected from several thousand journals. Journals are classified as general label types if label types of the journals belong to one of the six label types. Otherwise, journals are classified as arbitrary label types. The GLTM processes journals that belong to general label types and the ALTM processes journals that belong to arbitrary label types. Rule-based algorithms are used for both modules and the rules are derived from analysis of several journal articles and features extracted from the optical character recognition (OCR) results. There are 126 rules derived for the GLTM and 49 rules for the ALTM. Experiments conducted with several medical journal articles show relatively accurate labeling results. C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Kim, J (reprint author), Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 7 TC 0 Z9 1 U1 0 U2 0 PU INT INST INFORMATICS & SYSTEMICS PI ORLANDO PA 14269 LORD BARCLAY DR, ORLANDO, FL 32837 USA BN 980-6560-01-9 PY 2003 BP 352 EP 357 PG 6 WC Computer Science, Artificial Intelligence; Computer Science, Software Engineering; Computer Science, Theory & Methods; Telecommunications SC Computer Science; Telecommunications GA BY46V UT WOS:000189330600068 ER PT B AU Mao, S Kim, J Le, DX Thoma, GR AF Mao, S Kim, J Le, DX Thoma, GR BE Callaos, N Loutfi, M Feng, X Klima, J Komiyama, M TI Generating robust features for style-independent Labeling of bibliographic fields in medical journal articles SO 7TH WORLD MULTICONFERENCE ON SYSTEMICS, CYBERNETICS AND INFORMATICS, VOL VIII, PROCEEDINGS LA English DT Proceedings Paper CT 7th World Multiconference on Systemics, Cybernetics and Informatics CY JUL 27-30, 2003 CL ORLANDO, FL SP Int Inst Informat & System DE MARS; MEDLINE; style-independent labeling; rule-based algorithm; string matching AB Bibliographical data such as title, author, affiliation, and abstract are crucial for indexing biomedical journal articles. The Medical Article Records System (MARS) has been developed at the National Library of Medicine (NLM) to automate bibliographical data extraction for MEDLINE(R), the NLM's premier database of citations to the biomedical literature. The automatic extraction of bibliographic data involves the process of assigning logical labels (title, author, affiliation, and abstract) to homogeneous regions or zones on page images. While an OCR- and rule-based labeling module (called ZoneCzar) in MARS can reliably label medical journals with regular layout styles, it cannot accurately label the journals with arbitrary or unusual layout styles, and new rules have to be manually created for these journals. Furthermore, the OCR zoning errors, particularly merging errors, can greatly affect the labeling accuracy of ZoneCzar. In this paper, we describe an algorithm for automatic generation of robust features that are used by the labeling algorithm to perform style-independent labeling. C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Mao, S (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU INT INST INFORMATICS & SYSTEMICS PI ORLANDO PA 14269 LORD BARCLAY DR, ORLANDO, FL 32837 USA BN 980-6560-01-9 PY 2003 BP 53 EP 56 PG 4 WC Computer Science, Artificial Intelligence; Computer Science, Cybernetics; Computer Science, Interdisciplinary Applications; Engineering, Electrical & Electronic SC Computer Science; Engineering GA BY46Y UT WOS:000189331600011 ER PT B AU Warzel, DB Covitz, PA AF Warzel, DB Covitz, PA BE Callaos, N Lesso, W Schewe, KD Atlam, E TI Metadata management and information modeling SO 7TH WORLD MULTICONFERENCE ON SYSTEMICS, CYBERNETICS AND INFORMATICS, VOL XII, PROCEEDINGS: INFORMATION SYSTEMS, TECHNOLOGIES AND APPLICATIONS: II LA English DT Proceedings Paper CT 7th World Multiconference on Systemics, Cybernetics and Informatics CY JUL 27-30, 2003 CL ORLANDO, FL SP Int Inst Informat & System DE metadata management; common data elements; cancer data standards AB The National Cancer Institute (NCI) conducts and funds basic scientific and clinical cancer research in a complex environment of independent but interrelated activities that cross multiple scientific and academic domains. Each independent activity requires collection of accurate, timely, well defined data serving a particular scientific purpose, while interoperability necessitates that data be unambiguous, semantically meaningful and consistent. The demand for sharing cancer research resources and findings and performing metadata collection and analysis comes from national and international biomedical scientists in academia, researchers, clinicians, industry and government agencies. Intelligible, reusable, interoperable data is required. The NCI is meeting this challenge by supporting a broad effort to standardize the data elements used in cancer research, data collection and reporting instruments. These common data elements (CDEs) are developed and deployed in a robust metadata management system. C1 NCI, Ctr Bioinformat, Rockville, MD 20852 USA. RP Warzel, DB (reprint author), NCI, Ctr Bioinformat, MSC 8335, Rockville, MD 20852 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU INT INST INFORMATICS & SYSTEMICS PI ORLANDO PA 14269 LORD BARCLAY DR, ORLANDO, FL 32837 USA BN 980-6560-01-9 PY 2003 BP 480 EP 483 PG 4 WC Computer Science, Information Systems SC Computer Science GA BY50U UT WOS:000189395000087 ER PT J AU Wlodawer, A Li, M Gustchina, A Oyama, H Dunn, BM Oda, K AF Wlodawer, A Li, M Gustchina, A Oyama, H Dunn, BM Oda, K TI Structural and enzymatic properties of the sedolisin family of serine-carboxyl peptidases SO ACTA BIOCHIMICA POLONICA LA English DT Review DE protein structure; enzyme families; enzymatic machanism; active site; sequence conservation ID NEURONAL CEROID-LIPOFUSCINOSIS; SUBSTRATE-SPECIFICITY; SUBSITE PREFERENCES; CRYSTAL-STRUCTURE; PROTEIN-STRUCTURE; TRANSITION-STATE; BINDING-PROTEIN; KUMAMOLYSIN; SUBTILISIN; IDENTIFICATION AB Sedolisins (serine-carboxyl peptidases) are proteolytic enzymes whose fold resembles that of subtilisin; however, they are considerably larger, with the mature catalytic domains containing approximately 375 amino acids. The defining features of these enzymes are a unique catalytic triad, Ser-Glu-Asp, as well as the presence of an aspartic acid residue in the oxyanion hole. High-resolution crystal structures have now been solved for sedolisin from Pseudomonas sp. 101, as well as for kumamolisin from a thermophilic bacterium, Bacillus novo sp. MN-32. The availability of these crystal structures enabled us to model the structure of mammalian CLN2, an enzyme which, when mutated in humans, leads to a fatal neurodegenerative disease. This review compares the structural and enzymatic properties of this newly defined MEROPS family of peptidases, S53, and introduces their new nomenclature. C1 Natl Canc Inst, Prot Structure Sect, Macromol Crystallog Lab, Ft Detrick, MD 21702 USA. Natl Canc Inst, SAIC Frederick Inc, Basic Res Program, Ft Detrick, MD 21702 USA. Kyoto Inst Technol, Dept Appl Biol, Fac Text Sci, Sakyo Ku, Kyoto 6068585, Japan. Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. RP Wlodawer, A (reprint author), Natl Canc Inst, Prot Structure Sect, Macromol Crystallog Lab, Ft Detrick, MD 21702 USA. FU NIAID NIH HHS [AI39211]; NIDDK NIH HHS [DK18865]; PHS HHS [N01-C0-12400] NR 41 TC 64 Z9 65 U1 0 U2 1 PU ACTA BIOCHIMICA POLONICA PI WARSAW PA PASTEURA 3, 02-093 WARSAW, POLAND SN 0001-527X J9 ACTA BIOCHIM POL JI Acta Biochim. Pol. PY 2003 VL 50 IS 1 BP 81 EP 102 PG 22 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 662VZ UT WOS:000181970800009 PM 12673349 ER PT J AU Copeland, WC Ponamarev, MV Nguyen, D Kunkel, TA Longley, MJ AF Copeland, WC Ponamarev, MV Nguyen, D Kunkel, TA Longley, MJ TI Mutations in DNA polymerase gamma cause error prone DNA synthesis in human mitochondrial disorders SO ACTA BIOCHIMICA POLONICA LA English DT Article; Proceedings Paper CT 32nd Annual Meeting of the European-Environmental-Mutagen-Society CY SEP, 2002 CL WARSAW, POLAND SP European Enviro Mutagen Soc DE mitochondria; DNA polymerase; DNA replication; DNA repair; aging ID PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; I KLENOW FRAGMENT; TRANSFER-RNA SYNTHETASES; P55 ACCESSORY SUBUNIT; BASE EXCISION-REPAIR; OXIDATIVE DAMAGE; CATALYTIC SUBUNIT; ESCHERICHIA-COLI; XENOPUS-LAEVIS; SACCHAROMYCES-CEREVISIAE AB This paper summarizes recent advances in understanding the links between the cell's ability to maintain integrity of its mitochondrial genome and mitochondrial genetic diseases. Human mitochondrial DNA is replicated by the two-subunit DNA polymerase gamma (pol gamma). We investigated the fidelity of DNA replication by pol gamma with and without exonucleolytic proofreading and its p55 accessory subunit. Pol gamma has high base substitution fidelity due to efficient base selection and exonucleolytic proofreading, but low frameshift fidelity when copying homopolymeric sequences longer than four nucleotides. Progressive external ophthalmoplegia (PEO) is a rare disease characterized by the accumulation of large deletions in mitochondrial DNA. Recently, several mutations in the polymerase and exonuclease domains of the human pol gamma have been shown to be associated with PEO. We are analyzing the effect of these mutations on the human pol gamma enzyme. In particular, three autosomal dominant mutations alter amino acids located within polymerase motif B of pol gamma. These residues are highly conserved among family A DNA polymerases, which include T7 DNA polymerase and E. coli pol I. These PEO mutations have been generated in pol gamma to analyze their effects on overall polymerase function as well as the effects on the fidelity of DNA synthesis. One mutation in particular, Y955C, was found in several families throughout Europe, including one Belgian family and five unrelated Italian families. The Y955C mutant pol gamma retains a wild-type catalytic rate but suffers a 45-fold decrease in apparent binding affinity for the incoming dNTP. The Y955C derivative is also much less accurate than is wild-type pol gamma, with error rates for certain mismatches elevated by 10- to 100-fold. The error prone DNA synthesis observed for the Y955C pol gamma is consistent with the accumulation of mtDNA mutations in patients with PEO. The effects of other pol gamma mutations associated with PEO are discussed. C1 NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 76 TC 36 Z9 36 U1 0 U2 5 PU ACTA BIOCHIMICA POLONICA PI WARSAW PA PASTEURA 3, 02-093 WARSAW, POLAND SN 0001-527X J9 ACTA BIOCHIM POL JI Acta Biochim. Pol. PY 2003 VL 50 IS 1 BP 155 EP 167 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 662VZ UT WOS:000181970800016 PM 12673356 ER PT J AU Baker, T Dauter, Z AF Baker, T Dauter, Z TI Changing of the guard SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Editorial Material C1 Univ Auckland, Sch Biol Sci, Auckland 1, New Zealand. Brookhaven Natl Lab, Natl Canc Inst, Dept Biol, Upton, NY 11973 USA. RP Baker, T (reprint author), Univ Auckland, Sch Biol Sci, Auckland 1, New Zealand. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JAN PY 2003 VL 59 BP 1 EP 1 DI 10.1107/S090744490202245X PN 1 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 627UW UT WOS:000179955400001 PM 12499532 ER PT J AU Uson, I Schmidt, B von Bulow, R Grimme, S von Figura, K Dauter, M Rajashankar, KR Dauter, Z Sheldrick, GM AF Uson, I Schmidt, B von Bulow, R Grimme, S von Figura, K Dauter, M Rajashankar, KR Dauter, Z Sheldrick, GM TI Locating the anomalous scatterer substructures in halide and sulfur phasing SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID CRYSTAL-STRUCTURE; SIGNAL; CRYSTALLOGRAPHY; DIFFRACTION; RESOLUTION; PROGRAM; ATOM AB Improved data quality now makes it feasible to exploit the weak anomalous signal derived only from the sulfurs inherent to the protein or in particular from halide ions incorporated by soaking. The latter technique requires the location of a high number of partially occupied halide sites. This number appears to be roughly proportional to the exposed protein surface. This paper explores the application of dual-space ab initio methods as implemented in the program SHELXD to the location of substructures of sulfur in SAD experiments, bromide in SAD and MAD experiments and iodide using SAD and SIRAS to determine the anomalous-atom substructure. Sets of atoms consistent with the Patterson function were generated as a starting point for the dual-space recycling procedure in SHELXD. The substructure is then expanded to the full structure by maximum-likelihood phasing with SHARP and density modification with the program DM. Success in the location of the substructures and subsequent phasing depends critically on the quality of the data and on the extent of the anomalous signal. This varies with each crystal and soak, but for the same crystal the significance of the anomalous signal was found to be highly sensitive to the redundancy of the intensity measurements, which in some cases made all the difference. This is illustrated by the determination of the previously unknown structure of repeat 11 of the human mannose-6-phosphate/insulin-like growth factor II receptor (Man6P/IGFII-receptor), with 310 amino acids in the asymmetric unit, which was phased by soaking the crystals in a cryoprotectant solution containing halide anions. C1 Univ Gottingen, Inst Anorgan Chem, Lehrstuhl Strukturchem, D-37077 Gottingen, Germany. Univ Gottingen, Zentrum Biochem & Mol Zellbiol, Abt Biochem 2, D-37073 Gottingen, Germany. Brookhaven Natl Lab, Natl Canc Inst, Synchrotron Radiat Res Sect, Upton, NY 11973 USA. RP Uson, I (reprint author), Univ Gottingen, Inst Anorgan Chem, Lehrstuhl Strukturchem, Tammannstr 4, D-37077 Gottingen, Germany. EM uson@shelx.uni-ac.gwdg.de NR 32 TC 38 Z9 40 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JAN PY 2003 VL 59 BP 57 EP 66 DI 10.1107/S090744490201884X PN 1 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 627UW UT WOS:000179955400009 PM 12499540 ER PT J AU Lubkowski, J Dauter, M Aghaiypour, K Wlodawer, A Dauter, Z AF Lubkowski, J Dauter, M Aghaiypour, K Wlodawer, A Dauter, Z TI Atomic resolution structure of Erwinia chrysanthemi L-asparaginase SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID 7A GLUTAMINASE-ASPARAGINASE; CRYSTAL-STRUCTURE; PROTEIN-STRUCTURE; REFINEMENT; PROGRAM; MUTANT AB An X-ray structure of L-asparaginase from Erwinia chrysanthemi (ErA) has been refined at 1 Angstrom resolution to an R factor of below 0.1, using data collected on a synchrotron source. With four molecules of the enzyme consisting of 327 amino acids each, this crystal contains one of the largest asymmetric units of a protein refined to date at atomic resolution. Previously, structures of ErA and of related enzymes from other bacterial sources have been refined at resolutions not exceeding 1.7 Angstrom; thus, the present structure represents a very significant improvement in the quality of the available models of these proteins and should provide a good basis for future studies of the conformational variability of proteins, identification of subtle conformational features and corroboration of the stereochemical libraries, amongst other things. L-Asparaginases, which are enzymes that catalyze the hydrolysis of L-asparagine to aspartic acid, have been used for over 30 y as therapeutic agents in the treatment of acute childhood lymphoblastic leukemia, although the details of the enzymatic reaction and substrate specificity have not yet been completely elucidated. This atomic resolution structure is a step in that direction. C1 NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. NCI, SAIC Frederick, Intramural Res Support Program, Frederick, MD 21702 USA. RP Lubkowski, J (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 37 TC 34 Z9 37 U1 0 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JAN PY 2003 VL 59 BP 84 EP 92 DI 10.1107/S0907444902019443 PN 1 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 627UW UT WOS:000179955400013 PM 12499544 ER PT J AU Asojo, OA Cater, S Hoover, DM Boulegue, C Lu, WY Lubkowski, J AF Asojo, OA Cater, S Hoover, DM Boulegue, C Lu, WY Lubkowski, J TI Crystallization and preliminary X-ray studies of thymus and activation-regulated chemokine (TARC) SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID CC-CHEMOKINE; CRYSTAL-STRUCTURE; RESOLUTION; CELLS; MICE AB Thymus and activation-regulated chemokine (TARC) is a CC chemokine that is most highly expressed in the thymus. TARC interacts primarily with the CCR4 receptor and to a lesser extent with the CCR8 receptor. Three different crystal forms of synthetically prepared TARC were grown in triclinic, hexagonal and tetragonal systems. The X-ray data for the triclinic crystals (unit-cell parameters a = 56.46, b = 76.48, c = 88.37 Angstrom, alpha = 85.8, beta = 72.8, gamma = 70.0degrees) extend to 1.85 Angstrom on a conventional radiation source. The hexagonal crystals diffracted to 2.2 Angstrom at a synchrotron-radiation source and belong to either space group P6(1)22 or P6(5)22, with unit-cell parameters a = 61.8, c = 315. Angstrom. The tetragonal crystals diffracted to about 5 Angstrom at a synchrotron-radiation source and had approximate unit-cell parameters a = b = 47.7, c = 58.2 Angstrom. C1 NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. Univ Maryland Biotechnol Inst, Inst Human Virol, Baltimore, MD 21201 USA. RP Lubkowski, J (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RI Boulegue, Cyril/A-4092-2009; Lu, Wuyuan/B-2268-2010; OI Asojo, Oluwatoyin/0000-0002-4043-2700 NR 20 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JAN PY 2003 VL 59 BP 163 EP 165 DI 10.1107/S0907444902018863 PN 1 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 627UW UT WOS:000179955400027 PM 12499558 ER PT J AU Lipardi, C Wei, Q Paterson, BM AF Lipardi, C Wei, Q Paterson, BM TI RNA silencing in Drosophila SO ACTA HISTOCHEMICA ET CYTOCHEMICA LA English DT Article DE RNAi; RdRp; siRNAs; 3 '-hydroxyl; RNA ligase ID DOUBLE-STRANDED-RNA; MESSENGER-RNA; HUMAN DICER; GENE; INTERFERENCE; RIBONUCLEASE; ELEGANS; DSRNAS; CELLS; ATP AB RNA silencing is a highly conserved mechanism found in both the plant and animal kingdoms that is thought to protect the genome from disruption by transposons and viral integration events. Double stranded RNAs (dsRNA) produced by transposons or replicating virus result in the production of short 21-25 nucleotide double stranded RNA molecules containing a hydroxyl group on a two base-pair 3' overhang and a 5' phosphate residue. These siRNAs are the hallmark of RNA silencing, also known as post transcriptional gene silencing (PTGS) in plants, quelling in Neurospora, and RNA interference in C. elegans, Drosophila, and Dictyostelium. Remarkably these siRNAs direct the degradation of the complementary target RNA through a complicated mechanism that is just now being understood. From our studies on RNA interference in Drosophila we propose a model in which the siRNAs interact through complementarity with the target RNA and are extended by a cellular RNA-dependent RNA polymerase (RdRP) to form a critical length of dsRNA that is subsequently degraded by RNase III-related enzymes. Here, we discuss this model and the data produced in Drosophila to support it and, in turn, this model is compared to the proposed scheme for RNA silencing in mammalian systems. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Paterson, BM (reprint author), NCI, Biochem Lab, NIH, Bldg 37,Room 6118,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 28 TC 2 Z9 2 U1 1 U2 5 PU JAPAN SOC HISTOCHEMISTRY & CYTOCHEMISTRY PI KYOTO PA C/O NAKANISHI PRINTING CO LTD, SHIMODACHIURI-OGAWA, KAMIGYO-KU, KYOTO, 602-8048, JAPAN SN 0044-5991 EI 1347-5800 J9 ACTA HISTOCHEM CYTOC JI Acta Histochem. Cytochem. PY 2003 VL 36 IS 2 BP 123 EP 134 PG 12 WC Cell Biology SC Cell Biology GA 672XC UT WOS:000182547500005 ER PT J AU Liberski, PP Sikorska, B Bratosiewicz-Wasik, J Walis, A Brown, P Brown, D AF Liberski, PP Sikorska, B Bratosiewicz-Wasik, J Walis, A Brown, P Brown, D TI Exuberant cellular reaction of the optic nerves in experimental Creutzfeldt-Jakob disease SO ACTA NEUROBIOLOGIAE EXPERIMENTALIS LA English DT Article DE prions; Creutzfeldt-Jakob disease; macrophages ID TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; STRAUSSLER-SCHEINKER-DISEASE; PRION PROTEIN-FRAGMENT; NECROSIS-FACTOR-ALPHA; EXPERIMENTAL SCRAPIE; RETINAL DEGENERATION; ULTRASTRUCTURAL PATHOLOGY; PANENCEPHALOPATHIC TYPE; INTRAOCULAR INOCULATION; ELECTRON-MICROSCOPY AB We report here on the exuberant glial reaction in the optic nerves affected by prion diseases. Optic nerves from CJD- and GSS-, and scrapie-infected mice and hamsters showed severe pathology. These lesions were qualitatively indistinguishable from each other but were more intense in the Fujisaki model than in the hamsters inoculated with Echigo-1. Exuberant cellular reaction comprised of macrophages containing numerous mitochondria, abundant rough endoplasmic reticulum, and secondary lysosomes filled with digested myelin debris, electron-dense material and occasionally, entire myelin-bound vacuoles were readily observed in both models. Macrophages actively digesting myelin fragments and containing lyre-like bodies and paracrystalline inclusions were frequently noted. Some macrophages extended long filopodia, to form labyrinth-like structures, and within a few macrophages, concentric arrays of cisterns and channels sequestrated part of the cytoplasm. An analogous network of narrow cisterns was seen to surround whole segments of the myelinated fibers. C1 Med Univ Lodz, Chair Oncol, Dept Mol Pathol & Neuropathol, Lodz, Poland. Med Univ Silesia, Dept Virol Diagnost, Chair Mol Biol Biochem & Biopharm, Katowice, Poland. NINDS, Cent Nervous Syst Studies Lab, NIH, Bethesda, MD 20892 USA. Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England. RP Liberski, PP (reprint author), Med Univ Lodz, Chair Oncol, Dept Mol Pathol & Neuropathol, Lodz, Poland. RI Brown, David /A-4083-2008 NR 85 TC 2 Z9 2 U1 0 U2 0 PU NENCKI INST EXPERIMENTAL BIOLOGY PI WARSAW PA UL PASTEURA 3, 02-093 WARSAW, POLAND SN 0065-1400 J9 ACTA NEUROBIOL EXP JI Acta Neurobiol. Exp. PY 2003 VL 63 IS 4 BP 309 EP 318 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 752VP UT WOS:000187197100002 PM 15053254 ER PT J AU Saif, MW Quinn, MG Thomas, RR Ernst, A Grem, JL AF Saif, MW Quinn, MG Thomas, RR Ernst, A Grem, JL TI Cardiac toxicity associated with capecitabine therapy SO ACTA ONCOLOGICA LA English DT Editorial Material ID FLUOROURACIL PLUS LEUCOVORIN; METASTATIC COLORECTAL-CANCER; HIGH-DOSE 5-FLUOROURACIL; ORAL CAPECITABINE; SYMPTOMATIC CARDIOTOXICITY; FOLINIC ACID; PHASE-III; INFUSION; DOXIFLURIDINE; CARCINOMA C1 NCI, Canc Therapeut Branch, Ctr Canc Res, Natl Naval Med Ctr, Bethesda, MD 20889 USA. RP Grem, JL (reprint author), NCI, Canc Therapeut Branch, Ctr Canc Res, Natl Naval Med Ctr, Bldg 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. NR 23 TC 9 Z9 9 U1 0 U2 0 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0284-186X J9 ACTA ONCOL JI Acta Oncol. PY 2003 VL 42 IS 4 BP 342 EP 344 DI 10.1080/02841860310011861 PG 3 WC Oncology SC Oncology GA 700ZZ UT WOS:000184142200012 PM 12899507 ER PT J AU Merikangas, KR Lieb, R Wittchen, HU Avenevoli, S AF Merikangas, KR Lieb, R Wittchen, HU Avenevoli, S TI Family and high-risk studies of social anxiety disorder SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Article; Proceedings Paper CT Global Research on Anxiety and Depression Consensus Conference (GRAD) CY OCT 02-04, 2001 CL MARTHAS VINEYARD, MA DE anxiety; anxiety disorders; epidemiologic studies; epidemiology; genetics; phobic disorders; social anxiety ID EARLY DEVELOPMENTAL-STAGES; PARENTAL REARING BEHAVIOR; FEAR-POTENTIATED STARTLE; DIRECT-INTERVIEW FAMILY; PANIC DISORDER; DIAGNOSTIC INTERVIEW; PSYCHIATRIC-DISORDERS; MAJOR DEPRESSION; GENETIC-ANALYSIS; HISTORY METHOD AB Objective: To present data on the role of familial factors in the etiology of social anxiety disorder. Method: Findings presented from a family/high-risk study (the Yale Family Study) and a prospective community study of youth (the Munich Early Developmental Stages of Psychopathology (EDSP) Study). Results: The Yale Family Study demonstrated a substantial degree of familial aggregation of social anxiety disorder and specificity with respect to other anxiety subtypes among adult relatives. The Yale high-risk component and the EDSP Study confirm the association between parental and offspring social anxiety, but did not yield consistent evidence for an association between familial environmental factors and social anxiety. Conclusion: Future studies are needed to examine mechanisms for the specificity of social anxiety disorder aggregation, to identify vulnerability factors for its development and to pinpoint environmental conditions that may enhance or suppress expression of underlying vulnerability. C1 NIMH, Mood & Axiety Disorders Program, NIH, US Dept HHS, Bethesda, MD 20892 USA. Yale Univ, Sch Med, New Haven, CT USA. Max Planck Inst Psychiat, D-80804 Munich, Germany. RP Merikangas, KR (reprint author), NIMH, Mood & Axiety Disorders Program, NIH, US Dept HHS, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. EM Kathleen.Merikangas@nih.gov RI Wittchen, Hans-Ulrich/A-8507-2014 NR 77 TC 25 Z9 25 U1 5 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0001-690X J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PY 2003 VL 108 SU 417 BP 28 EP 37 DI 10.1034/j.1600-0447.108.s417.5.x PG 10 WC Psychiatry SC Psychiatry GA 717WR UT WOS:000185114200004 ER PT J AU Charney, DS AF Charney, DS TI Neuroanatomical circuits modulating fear and anxiety behaviors SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Article; Proceedings Paper CT Global Research on Anxiety and Depression Consensus Conference (GRAD) CY OCT 02-04, 2001 CL MARTHAS VINEYARD, MASSACHUSETTS DE anxiety; fear; neuroanatomical circuits; neurobiology ID POSTTRAUMATIC-STRESS-DISORDER; CORTICOTROPIN-RELEASING HORMONE; MEDIAL PREFRONTAL CORTEX; POSITRON-EMISSION-TOMOGRAPHY; CHILDHOOD SEXUAL-ABUSE; LONG-TERM POTENTIATION; CEREBRAL-BLOOD-FLOW; OBSESSIVE-COMPULSIVE DISORDER; 24-HOUR URINARY CORTISOL; H-3 IMIPRAMINE BINDING AB Objective: Our understanding of the neurobiology of anxiety disorders, although not complete, has advanced significantly with the development and application of genetic, neuroimaging and neurochemical approaches. Method: The neuroanatomical basis of anxiety disorders is reviewed with particular focus on the amygdala and the temporal and prefrontal cortex. The functional anatomical correlates of anxiety disorders such as panic disorder, specific phobias and post-traumatic stress disorder are also discussed. Results: Functional neuroimaging studies in patients with anxiety disorders have shown neurophysiological abnormalities during symptom provocation tests, implicating the limbic, paralimbic and sensory association regions. The involvement of neurotransmitters such as serotonin and norepinephrine in depressive disorders is well established. Antidepressants that affect these neurotransmitter systems have also been shown to be useful in the treatment and management of patients with anxiety disorders. The role of serotonin and norepinephrine in the pathophysiology of anxiety disorders is reviewed. In addition, the involvement of the stress hormone corticotropin-releasing hormone, the peptide cholecystokinin and the amino acid transmitter gamma-amino butyric acid in anxiety disorders is reviewed. Conclusion: The inconsistency in the results of biologic investigations of anxiety disorders highlights the importance of addressing the neurobiologic heterogeneity inherent within criteria-based, psychiatric diagnoses. Understanding of this heterogeneity will be facilitated by the continued development and application of genetic, neuroimaging and neurochemical approaches that can re. ne anxiety disorder phenotypes and elucidate the genotypes associated with these disorders. Application of these experimental approaches will also facilitate research aimed at clarifying the mechanisms of anti-anxiety therapies. C1 NIMH, Bethesda, MD 20892 USA. RP Charney, DS (reprint author), NIMH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 180 TC 20 Z9 24 U1 8 U2 15 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-690X J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PY 2003 VL 108 SU 417 BP 38 EP 50 DI 10.1034/j.1600-0447.108.s417.3.x PG 13 WC Psychiatry SC Psychiatry GA 717WR UT WOS:000185114200005 ER PT J AU Muneshige, H Toda, K Kimura, H Asou, T AF Muneshige, H Toda, K Kimura, H Asou, T TI Does a viral infection cause complex regional pain syndrome? SO ACUPUNCTURE & ELECTRO-THERAPEUTICS RESEARCH LA English DT Article DE complex regional pain syndrome (CRPS); herpes simplex virus (HSV); antibody titer; enzyme immunoassay (EIA); enzyme-linked fluorescent immunoassay (ELFA); etiology ID REFLEX SYMPATHETIC DYSTROPHY; HERPES-SIMPLEX-VIRUS; QI-GONG ENERGY; INTRACTABLE PAIN; SPECIAL EMPHASIS; MEDICAL PROBLEMS; BELLS-PALSY; DRUG UPTAKE; ACUPUNCTURE; LOCALIZATION AB In 1990 Omura, Y. reported that Herpes Simplex. Virus Type I as the major cause of chronic intractable pain and its effective treatment using mixture of EPA & DHA with Selective Drug Uptake Enhancement Method. Subsequently among the other causes of pain, he included Chlamydia Trachomatis, Borrelia Burgdorferi, Mycobacterium, Tuberculosis, human Herpes Virus type 6, and Circulatory Disturbances. In order to test possible involvement of viral infection in Complex Regional Pain Syndrome (CRPS), a disease which usually occurs in the extremities, we did a study of 17 patients with CRPS. They were examined for Herpes Simplex Virus (HSV) and Varicella Zoster Virus (VZV) by measuring IgG and IgM antibody titers, and 14 of these patients were also examined for Cytomegalo-Virus (CMV). As a control group 100 healthy Japanese employees at SRL, Inc. were also studied. In CRPS group, HSV IgG was positive in 12 of the 17 patients with an average antibody titer of 90.0 EIA value. VZV IgG was positive in all 17 patients with an average antibody titer of 26.8 EIA value. CMV IgG was positive in all 14 patients with an average antibody titer of 66.6 UA/ml. In control group, HSV IgG was positive in 54 subjects with an average antibody titer of 42.3 EIA value. VZV IgG was positive in 97 subjects with an average antibody titer of 26.2 EIA value. CMV IgG was positive in 82 subjects. There were no significant differences of positive rate of IgG antibody for the three viruses between patient and control groups. Although the difference was not significant, the average antibody titers of HSV in CRPS group were more than twice of those in healthy group. Antibody titers were almost equal in both groups for VZV. Possibly, some people in the control group who had latent virus, were also asymptomatic. In 2000, Takasaki, I. et al. in a separate animal study, inoculated with HSV Type-I the shin of the mouse causing allodynia and hyperalgesia (which are some of the characteristic findings seen in CRPS in humans). Also, VZV, which causes shingles which is sometimes followed by Post-Herpetic Neuralgia (PHN), is in the same family of HSV As PHN resembles CRPS in symptoms, it is possible that HSV contributes to CRPS. Therefore, virus infection theory is an attractive hypothesis that accounts for many enigmas of CRPS. C1 Hiroshima Univ Hosp, Dept Rehabil, Minami Ku, Hiroshima 7348551, Japan. RP Muneshige, H (reprint author), NIDCR, NIH, PNMB, Bldg 10-1N-118,10 Ctr Dr, Bethesda, MD 20892 USA. NR 30 TC 5 Z9 6 U1 1 U2 3 PU COGNIZANT COMMUNICATION CORP PI ELMSFORD PA 3 HARTSDALE ROAD, ELMSFORD, NY 10523-3701 USA SN 0360-1293 J9 ACUPUNCTURE ELECTRO JI Acupunct. Electro-Ther. Res. PY 2003 VL 28 IS 3-4 BP 183 EP 192 PG 10 WC Integrative & Complementary Medicine; Neurosciences SC Integrative & Complementary Medicine; Neurosciences & Neurology GA 772RD UT WOS:000188854300005 PM 14998056 ER PT J AU Ohlsson, R Kanduri, C Whitehead, J Pfeifer, S Lobanenkov, V Feinberg, AP AF Ohlsson, R Kanduri, C Whitehead, J Pfeifer, S Lobanenkov, V Feinberg, AP TI Epigenetic variability and the evolution of human cancer SO ADVANCES IN CANCER RESEARCH, VOL 88 SE ADVANCES IN CANCER RESEARCH LA English DT Review ID GROWTH-FACTOR-II; RANDOM MONOALLELIC EXPRESSION; CPG ISLAND METHYLATION; DNA METHYLATION; GENE-EXPRESSION; HISTONE H3; H19 GENE; WILMS TUMORIGENESIS; MOUSE DEVELOPMENT; IMPRINTED IGF2 C1 Uppsala Univ, Evolut Biol Ctr, Dept Dev & Genet, S-75236 Uppsala, Sweden. NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Inst Genet Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Inst Genet Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Inst Genet Med, Dept Oncol, Baltimore, MD 21205 USA. RP Ohlsson, R (reprint author), Uppsala Univ, Evolut Biol Ctr, Dept Dev & Genet, S-75236 Uppsala, Sweden. RI Whitehead, Joanne/A-8597-2008; OI Whitehead, Joanne/0000-0002-9602-2081; Lobanenkov, Victor/0000-0001-6665-3635 FU NCI NIH HHS [R37 CA054358, R37 CA054358-13] NR 101 TC 23 Z9 24 U1 3 U2 5 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-230X J9 ADV CANCER RES JI Adv.Cancer Res. PY 2003 VL 88 BP 145 EP 168 DI 10.1016/S0065-230X(03)88306-9 PG 24 WC Oncology SC Oncology GA BW53A UT WOS:000182317600005 PM 12665055 ER PT J AU Franchini, G Nicot, C Johnson, JM AF Franchini, G Nicot, C Johnson, JM TI Seizing of T cells by human T-Cell leukemia/lymphoma virus type 1 SO ADVANCES IN CANCER RESEARCH, VOL 89 SE ADVANCES IN CANCER RESEARCH LA English DT Review ID NF-KAPPA-B; HTLV-I TAX; TROPICAL SPASTIC PARAPARESIS; ELEMENT-BINDING-PROTEIN; BLOOD MONONUCLEAR-CELLS; LONG TERMINAL REPEAT; LEUKEMIA-LYMPHOMA VIRUS; TRANSCRIPTIONAL ACTIVATOR TAX; RECEPTOR GENE-EXPRESSION; TUMOR-SUPPRESSOR PROTEIN C1 NCI, Basic Res Labs, Bethesda, MD 20892 USA. RP Franchini, G (reprint author), NCI, Basic Res Labs, Bethesda, MD 20892 USA. NR 433 TC 59 Z9 62 U1 2 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-230X J9 ADV CANCER RES JI Adv.Cancer Res. PY 2003 VL 89 BP 69 EP 132 DI 10.1016/S0065-230X(03)01003-0 PG 64 WC Oncology SC Oncology GA BX81J UT WOS:000186503300003 PM 14587871 ER PT S AU Bonvini, E DeBell, KE Veri, MC Graham, L Stoica, B Laborda, J Aman, MJ DiBaldassarre, A Miscia, S Rellahan, BL AF Bonvini, E DeBell, KE Veri, MC Graham, L Stoica, B Laborda, J Aman, MJ DiBaldassarre, A Miscia, S Rellahan, BL BE Weber, G TI On the mechanism coupling phospholipase C gamma 1 to the B- and T-cell antigen receptors SO ADVANCES IN ENZYME REGULATION, VOL 43 SE Advances in Enzyme Regulation LA English DT Review CT 43rd International Symposium on Regulation of Enzyme Activity and Synthesis in Normal and Neoplastic Tissues CY SEP 23-24, 2002 CL INDIANA UNIV SCH MED, INDIANAPOLIS, IN HO INDIANA UNIV SCH MED ID PROTEIN-TYROSINE KINASE; EPIDERMAL GROWTH-FACTOR; FACTOR-INDUCED ACTIVATION; HOMOLOGY 3 DOMAIN; C-GAMMA; SIGNAL-TRANSDUCTION; SH2 DOMAINS; PLASMA-MEMBRANE; EGF RECEPTOR; BINDING-SITE C1 US FDA, Ctr Biol Evaluat & Res, Div Monoclonal Antibodies, Immunobiol Lab, Bethesda, MD 20892 USA. USA, Med Res Inst Infect Dis, Dept Biochem & Cell Biol, Frederick, MD 21702 USA. Univ G dAnnunzio, Dipartimeno Biomorfologia, I-66100 Chieti, Italy. RP US FDA, Ctr Biol Evaluat & Res, Div Monoclonal Antibodies, Immunobiol Lab, HFM-564,NIH Campus,Bldg 29B,Rm 3NN10,8800 Rockvil, Bethesda, MD 20892 USA. EM bonvini@mail.nih.gov RI STOICA, BOGDAN/H-9782-2013; Laborda, Jorge/L-5726-2014 OI STOICA, BOGDAN/0000-0002-2501-6434; Laborda, Jorge/0000-0002-9210-838X NR 105 TC 11 Z9 11 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI KIDLINGTON PA THE BOULEVARD, LANGFORD LANE,, KIDLINGTON OX5 1GB, OXFORD, ENGLAND SN 0065-2571 BN 0-08-044294-3 J9 ADV ENZYME REGUL JI Adv. Enzym. Regul. PY 2003 VL 43 BP 245 EP 269 DI 10.1016/S0065-2571(02)00033-X PG 25 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA BX22L UT WOS:000184694600018 PM 12791395 ER PT J AU Morse, HC McCarty, T Qi, CF Torrey, TA Naghashfar, Z Chattopadhyay, SK Fredrickson, TN Hartley, JW AF Morse, HC McCarty, T Qi, CF Torrey, TA Naghashfar, Z Chattopadhyay, SK Fredrickson, TN Hartley, JW TI B lymphoid neoplasms of mice: Characteristics of naturally occurring and engineered diseases and relationships to human disorders SO ADVANCES IN IMMUNOLOGY, VOL 81 SE ADVANCES IN IMMUNOLOGY LA English DT Review ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ZINC-FINGER PROTEIN; CELL LYMPHOMA; MULTIPLE-MYELOMA; TRANSGENIC MICE; DEFICIENT MICE; MARGINAL ZONE; PLASMA-CELLS; HEMATOPOIETIC NEOPLASMS; BETHESDA PROPOSALS C1 NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. RP Morse, HC (reprint author), NIAID, Immunopathol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. OI Morse, Herbert/0000-0002-9331-3705 NR 96 TC 13 Z9 15 U1 3 U2 3 PU ELSEVIER ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-2776 J9 ADV IMMUNOL JI Adv.Immunol. PY 2003 VL 81 BP 97 EP 121 DI 10.1016/S0065-2776(03)81003-9 PG 25 WC Immunology SC Immunology GA BEL40 UT WOS:000237769700003 PM 14711054 ER PT B AU Hallett, M AF Hallett, M BE Sorkoker, N Ring, H TI Human brain plasticity and recovery from stroke SO ADVANCES IN PHYSICAL AND REHABILITATION MEDICINE LA English DT Proceedings Paper CT 2nd World Congress of the International-Society-of-Physical-and-Rehabilitation-Medicine (ISPRM) CY MAY 18-23, 2003 CL Prague, CZECH REPUBLIC SP Int Soc Phys & Rehabilitat Med ID MOTOR CORTEX; NERVE-STIMULATION; D-AMPHETAMINE; DOUBLE-BLIND; HAND; MOVEMENT; THERAPY; ARM; MODULATION; INJURY AB After stroke, many patients improve spontaneously, at least to some extent, and after the acute period the principal mechanism appears to be brain plasticity. The task for rehabilitation is to improve on spontaneous recovery, and this might well be accomplished by manipulating plasticity. Body parts compete for representation in brain, and use of a body part enhances its representation. Hence, physical therapy should help, as has been demonstrated. by constraint-induced movement therapy. Other techniques use the same principle such as neuromuscular electrical stimulation, robot-enhanced training and virtual reality training. Bilateral, symmetical arm movement training helps, possibly by enhancement of function of the undamaged hemisphere. Sensory stimulation enhances plasticity and can be delivered in a number of ways, from passive movement to cutaneous stimulation. Reduction of inhibition enhances plasticity, and this can be used in rehabilitation using deafferentation. Pharmacological agents can enhance plasticity by several mechanisms. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. NR 32 TC 1 Z9 1 U1 0 U2 0 PU MEDIMOND S R L PI 40128 BOLOGNA PA VIA MASERATI 5, 40128 BOLOGNA, 00000, ITALY BN 88-323-3122-5 PY 2003 BP 1 EP 8 PG 8 WC Clinical Neurology; Orthopedics; Rehabilitation SC Neurosciences & Neurology; Orthopedics; Rehabilitation GA BX05W UT WOS:000184146600002 ER PT J AU Kimmel, PL Patel, SS AF Kimmel, PL Patel, SS TI Psychosocial issues in women with renal disease SO ADVANCES IN RENAL REPLACEMENT THERAPY LA English DT Article DE women; kidney diseases; psychosocial issues ID URBAN HEMODIALYSIS-PATIENTS; LONG-TERM DIALYSIS; QUALITY-OF-LIFE; MARITAL RELATIONSHIPS; KIDNEY-DISEASE; SOCIAL SUPPORT; TRANSPLANTATION; DEPRESSION; GENDER; SURVIVAL AB In this article, we review data on the epidemiology and outcomes of women in the US End-Stage Renal Disease (ESRD) Program. The complexity of the psychosocial milieu of patients is described, and levels of analysis are delineated. The relationships between age, marital status and satisfaction, and perception of quality of life and depressive affect level and diagnosis of depression, and medical outcomes have not been determined in large studies of women with renal disease. We present data from our cross-sectional and longitudinal studies of psychosocial outcomes in a population comprised primarily of black patients with ESRD and review some differences between relationships of parameters in the groups of men and women in the study. Women are more likely to be kidney donors rather than recipients in national programs. Women with ESRD treated with hemodialysis appear to be more immunologically responsive to the psychosocial milieu than men. These differences in access to and utilization of health care and relationships between perceptions and immunochemical mediators may have important ramifications for outcomes in women with chronic renal disease. (C) 2003 by the National Kidney Foundation, Inc. C1 NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. George Washington Univ, Med Ctr, Dept Med, Div Renal Dis & Hypertens, Washington, DC 20037 USA. RP Kimmel, PL (reprint author), NIDDKD, Div Kidney Urol & Hematol Dis, NIH, 6707 Democracy Blvd, Bethesda, MD 20892 USA. NR 66 TC 7 Z9 8 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 1073-4449 J9 ADV RENAL REPLACE TH JI Adv. Renal Replace. Ther. PD JAN PY 2003 VL 10 IS 1 BP 61 EP 70 DI 10.1053/jarr.2003.50000 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 672HW UT WOS:000182516000008 PM 12616464 ER PT S AU Piletz, JE May, PJ Wang, G Zhu, H AF Piletz, JE May, PJ Wang, G Zhu, H BE Piletz, JE Regunathan, S Ernsberger, P TI Agmatine crosses the blood-brain barrier SO AGMATINE AND IMIDAZOLINES: THEIR NOVEL RECEPTORS AND ENZYMES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 4th International Symposium on Agmatine and Imidazoline Systems CY APR 09-11, 2003 CL San Diego, CA SP Amer Radiolabeled Chem Inc, Amer Soc Pharmacol & Expt Therapeut, Aventis Pharmaceut, Solvay Pharmaceut DE agmatine; arginine; blood-brain barrier; monkey; cerebrospinal fluid ID IMIDAZOLINE RECEPTORS; RATS; NEUROTRANSMITTER; DEPRESSION; ARGININE; INJURY; CELLS AB The question of whether agmatine crosses the blood-brain barrier has not been directly addressed, even though peripheral injection of this compound has produced behavioral responses in drug withdrawal, antidepressant, and anti-anxiety paradigms. Two models were used in this investigation. In the first, mice were injected intraperitoneally (i.p.) with agmatine (10, 50, or 300 mg/kg body weight) or arginine (600 mg/kg). After I or 3 hours, the animals were killed under gas anesthesia by perfusing their brains with ice-cold saline, and whole-brain agmatine was measured by HPLC. In parallel studies, a rhesus monkey was injected under gas anesthesia either intravenously (i.v.) with agmatine (30 mg/kg) or arginine (150 mg/kg), or intracerebroventricularly (i.c.v.) with agmatine (0.3 mg/kg i.c.v.). At varying times thereafter, cisterna magna cerebrospinal fluid (CSF) and blood plasma were collected and analyzed for agmatine levels. A rise in mouse brain agmatine was apparent after doses of 50 and 300 mg/kg i.p. Monkey CSF agmatine peaked in parallel with plasma agmatine 15 minutes following intravenous (i.v.) agmatine injection and at one sixth the level of the plasma peak. Monkey CSF agmatine peaked 43 minutes after i.v. arginine injection. The ventricular injection of agmatine resulted in a threefold sustained rise in blood plasma agmatine for at least 24 hours after injection. Therefore, agmatine and its precursor, arginine, cross the blood-brain barrier. CSF agmatine may be newly synthesized from peripherally injected arginine. C1 Univ Mississippi, Med Ctr, Dept Psychiat, Jackson, MS 39216 USA. Jackson State Univ, Jackson, MS USA. NIMH, Unit Mol Neurotherapeut, NIH, Bethesda, MD 20892 USA. RP Zhu, H (reprint author), Univ Mississippi, Med Ctr, Dept Psychiat, 2500 N State St, Jackson, MS 39216 USA. EM HZhu@psychiatry.umsmed.edu RI Ernsberger, Paul/O-2702-2014 OI Ernsberger, Paul/0000-0003-2372-2500 FU NIMH NIH HHS [MH57601] NR 21 TC 40 Z9 40 U1 2 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-498-6 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2003 VL 1009 BP 64 EP 74 DI 10.1196/annals.1304.007 PG 11 WC Biochemistry & Molecular Biology; Multidisciplinary Sciences; Neurosciences; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Science & Technology - Other Topics; Neurosciences & Neurology; Pharmacology & Pharmacy GA BY70T UT WOS:000189443800007 PM 15028571 ER PT J AU Ardell, S Jacobson, S Albertini, RJ Sullivan, L Allegretta, M AF Ardell, S Jacobson, S Albertini, RJ Sullivan, L Allegretta, M TI Reporter gene mutant T-cells in HTLV-1-infected individuals are clonally expanded in vivo and express autoreactive TCRs. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. NIH, Bethesda, MD 20892 USA. BioMosaics, Burlington, VT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P41 BP S41 EP S41 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000117 ER PT J AU Baker, G Cranston, B Hanchard, B Maloney, E AF Baker, G Cranston, B Hanchard, B Maloney, E TI Maternal HTLV-I status is not associated with adverse pregnancy outcomes or early childhood mortality in Jamaica. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD 21218 USA. Univ W Indies, Kingston 7, Jamaica. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P26 BP S36 EP S36 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000102 ER PT J AU Chung, H Derse, D Bangham, CR AF Chung, H Derse, D Bangham, CR TI Activation of interleukin-13 expression in HTLV-1 infected T-cells in vivo and in vitro. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Adv Biosci Labs Inc, Kensington, MD USA. NCI, Basic Res Lab, Frederick, MD 21701 USA. Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Immunol, London, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P83 BP S53 EP S53 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000159 ER PT J AU Derse, D Hill, SA Mitchell, M Heidecker, G AF Derse, D Hill, SA Mitchell, M Heidecker, G TI Composition of mature HTLV-1 reverse transcriptase and analysis of reverse transcriptase inhibitors in a cell culture assay system. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NIH, Basic Res Lab, Frederick, MD USA. NIH, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O71 BP S27 EP S27 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000072 ER PT J AU Fukumoto, R Nicot, C Tsai, W Franchini, G AF Fukumoto, R Nicot, C Tsai, W Franchini, G TI Uncoupling of proximal and distal TCR signaling pathways by the HTLV-1 p121 protein. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NCI, AMRVS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P161 BP S75 EP S75 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000237 ER PT J AU Grant, C Mostoller, K Harhaj, E Yamano, Y Jacobson, S Wigdahl, B AF Grant, C Mostoller, K Harhaj, E Yamano, Y Jacobson, S Wigdahl, B TI HTLV-I infection of hematopoietic progenitor cells: Impact on differentiation of CD34-derived dendritic cells and cells of the monocyte/macrophage lineage. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Penn State Univ, Dept Microbiol & Immunol, Hershey, PA USA. NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O67 BP S26 EP S26 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000068 ER PT J AU Hague, BF Zhao, TM Kindt, TJ AF Hague, BF Zhao, TM Kindt, TJ TI Binding of HTLV-1 virions to target T-cells occurs by a calcium dependent process and is inhibited by certain type 2 adenosine receptor antagonists. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O72 BP S27 EP S27 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000073 ER PT J AU Hamano, A Koiwa, T Futagami, Y Arakawa, M Ishida, T Lobanenkov, VV Mochizuki, M Watanabe, T AF Hamano, A Koiwa, T Futagami, Y Arakawa, M Ishida, T Lobanenkov, VV Mochizuki, M Watanabe, T TI Involvement of nuclear receptors in the suppression of unmethylated HTLV-1 LTR promoter activity. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Univ Tokyo, Inst Med Sci, Dept Canc Res, Div Pathol, Tokyo, Japan. Tokyo Med & Dent Univ, Dept Ophthalmol, Tokyo, Japan. NIAID, Immunopathol Lab, Sect Mol Pathol, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P110 BP S60 EP S61 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000186 ER PT J AU Heidecker, G Lloyd, PA Fox, K Hill, S Derse, DD AF Heidecker, G Lloyd, PA Fox, K Hill, S Derse, DD TI Late assembly domain mutants are arrested early in HTLV-1 release. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NIH, Frederick, MD USA. SAIC Frederick, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O74 BP S28 EP S28 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000075 ER PT J AU Hisada, M Yao, K Maloney, EM Yamano, Y Wilks, RJ Rios, M Jacobson, S AF Hisada, M Yao, K Maloney, EM Yamano, Y Wilks, RJ Rios, M Jacobson, S TI HTLV-I/II western blot seroindeterminates represent exposure to prototype HTLV-I. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. NINDS, Neuroimmunol Branch, Bethesda, MD 20892 USA. Univ W Indies, Kingston 7, Jamaica. US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P51 BP S44 EP S44 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000127 ER PT J AU Hisada, M LaGrenade, L Manns, A Maloney, EM Dotrang, M Sawada, T Li, H Jack, N Morgan, O Hanchard, B Bartholomew, CF Wilks, RJ AF Hisada, M LaGrenade, L Manns, A Maloney, EM Dotrang, M Sawada, T Li, H Jack, N Morgan, O Hanchard, B Bartholomew, CF Wilks, RJ TI Evaluation of viral markers in families with HTLV-I-associated diseases in the Caribbean. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. US FDA, Rockville, MD 20857 USA. Dept Clin Practice, Kensington, MD USA. Comp Sci Corp, Rockville, MD USA. Eisai & Co Ltd, Diagnost Dept, Tsukuba, Ibaraki, Japan. Univ W Indies, Port Of Spain, Trinid & Tobago. Univ W Indies, Kingston 7, Jamaica. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P23 BP S35 EP S35 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000099 ER PT J AU Hisada, M Stuver, SO Li, H Sawada, T Okayama, A Mueller, NE AF Hisada, M Stuver, SO Li, H Sawada, T Okayama, A Mueller, NE TI Age- and sex-matched comparison of viral markers among HTLV-I carriers in Japan and Jamaica. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Natl Canc Inst, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. Eisai & Co Ltd, Diagnost Dept, Tsukuba, Ibaraki, Japan. Miyazaki Med Coll, Dept Internal Med 2, Kiyotake, Miyazaki, Japan. Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O1 BP S7 EP S7 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000002 ER PT J AU Iha, H AF Iha, H TI Functional dissection of NEMO/IKKgamma segregates cytokine-induced versus Tax-mediated NF-kB activation. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O44 BP S19 EP S19 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000045 ER PT J AU Jeang, KT Majone, F AF Jeang, KT Majone, F TI Role of HTLV-I Tax, Ku and DNA PKcs in structural chromosomal instability. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NIH, Bethesda, MD 20892 USA. Univ Padua, I-35100 Padua, Italy. RI Jeang, Kuan-Teh/A-2424-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O51 BP S21 EP S21 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000052 ER PT J AU Johnson, JM Fullen, J Nicot, C Franchini, G AF Johnson, JM Fullen, J Nicot, C Franchini, G TI SH3-binding domains are dispensable for interaction of HTLV-1 p121 with the free chain of MHC I-Hc. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NCI, AMRVS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P159 BP S74 EP S74 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000235 ER PT J AU Jones, KS Tomaru, U Yamano, Y Sadowski, C Dambach, M Jacobson, S Ruscetti, FW AF Jones, KS Tomaru, U Yamano, Y Sadowski, C Dambach, M Jacobson, S Ruscetti, FW TI Components of the cellular membrane involved in HTLV-I Env-mediated entry. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 SAIC Frederick, Frederick, MD USA. NIH, Frederick, MD USA. NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O75 BP S28 EP S28 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000076 ER PT J AU Kazanji, M Sundaram, R Merien, F Heraud, JM Jacobson, S Kaumaya, PT AF Kazanji, M Sundaram, R Merien, F Heraud, JM Jacobson, S Kaumaya, PT TI The immunogenicity of a chimeric peptide vaccine construct composed of a B-cell epitope (gp46) combined with CTL epitopes derived from the Tax protein in squirrel monkeys (Saimiri sciureus). SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Inst Pasteur, Cayenne, French Guiana. Ohio State Univ, Columbus, OH 43210 USA. NIH, Bethesda, MD 20892 USA. Ohio State Univ, Dept Microbiol, Columbus, OH 43210 USA. RI HERAUD, Jean-Michel/O-1464-2013 OI HERAUD, Jean-Michel/0000-0003-1107-0859 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P40 BP S40 EP S41 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000116 ER PT J AU Li, H Hisada, M Yamano, Y Maloney, E Yao, K Hanchard, B Morgan, O Jacobson, S AF Li, H Hisada, M Yamano, Y Maloney, E Yao, K Hanchard, B Morgan, O Jacobson, S TI HTLV-I proviral load is strongly correlated with the HTLV-I disease status but not with the presence or absence of HLA-A*02 in Jamaica. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. NINDS, Neuroimmunol Branch, Viral Immunol Sect, Bethesda, MD 20892 USA. Univ W Indies, Kingston 7, Jamaica. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P9 BP S31 EP S31 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000085 ER PT J AU Lu, H Pise-Masison, CA Linton, R Radonovich, M Brady, JN AF Lu, H Pise-Masison, CA Linton, R Radonovich, M Brady, JN TI Nucleosomal histone acetylation and deacetylation regulates Tax-transactivation of the HTLV-I LTR. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NCI, CCR, BRL, VTB,NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O46 BP S20 EP S20 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000047 ER PT J AU Maloney, E Nagai, M Sawada, T Hisada, M Hanchard, B Jacobson, S AF Maloney, E Nagai, M Sawada, T Hisada, M Hanchard, B Jacobson, S TI Low levels of vitamin A are associated with high levels of HTLV-I proviral load in HTLV-I infected Jamaican children. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. Kagoshima Univ, Dept Internal Med, Kagoshima 890, Japan. Eisai & Co Ltd, Tsukuba Res Labs, Tsukuba, Ibaraki 30026, Japan. Univ W Indies, Dept Pathol, Kingston 7, Jamaica. NINDS, Lab Neuroimmunol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O61 BP S24 EP S24 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000062 ER PT J AU Meertens, L Shanmugam, V Gessain, A Beer, BE Tooze, Z Heneine, W Switzer, WM AF Meertens, L Shanmugam, V Gessain, A Beer, BE Tooze, Z Heneine, W Switzer, WM TI A novel, divergent simian T-cell lymphotropic virus type 3 in a wild-caught red-capped mangabey (Cercocebus torquatus) from Nigeria. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Inst Pasteur, Paris, France. Ctr Dis Control & Prevent, Atlanta, GA USA. NIAID, Rockville, MD USA. Cercopan, Calabar, Nigeria. RI Meertens, Laurent/E-8043-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P6 BP S30 EP S30 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000082 ER PT J AU Meertens, L Pise-Masison, CA Quere, N Brady, JN Gessain, A Mahieux, R AF Meertens, L Pise-Masison, CA Quere, N Brady, JN Gessain, A Mahieux, R TI HTLV-2-Tax mediated repression of p53 is independent of the CREB/ATF activation and does not involve p300 squelching. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Inst Pasteur, EEMI, Paris, France. NCI, NIH, Bethesda, MD 20892 USA. RI Meertens, Laurent/E-8043-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O30 BP S15 EP S15 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000031 ER PT J AU Mora, CA Yao, K Yamano, Y Jacobson, S AF Mora, CA Yao, K Yamano, Y Jacobson, S TI Elevated gliadin IgA antibodies in patients with HAM/TSP without other serological markers typical of celiac disease. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P75 BP S51 EP S51 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000151 ER PT J AU Mora, CA Yamano, Y Leist, TP Akhyani, N Brennan, M Soldan, S Yao, K Ohayon, J McFarland, H Jacobson, S AF Mora, CA Yamano, Y Leist, TP Akhyani, N Brennan, M Soldan, S Yao, K Ohayon, J McFarland, H Jacobson, S TI Evaluation of the viral load and immune response in HTLV-I-associated myelopathy patients treated with recombinant human interferon beta-1A. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O25 BP S14 EP S14 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000026 ER PT J AU Nasr, R Rosenwald, A El-Sabban, ME Hermine, O Bex, F Staudt, L de The, H Bazarbachi, A AF Nasr, R Rosenwald, A El-Sabban, ME Hermine, O Bex, F Staudt, L de The, H Bazarbachi, A TI Arsenic/interferon specifically reverses two distinct gene networks critical for the survival of HTLV-I infected leukemic cells. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Amer Univ Beirut, Dept Internal Med, Beirut, Lebanon. NCI, Bethesda, MD 20892 USA. Amer Univ Beirut, Dept Human Morphol, Beirut, Lebanon. Grp Hosp Necker, Paris, France. Free Univ Brussels, B-1050 Brussels, Belgium. CNRS UPR 9051, Paris, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P79 BP S52 EP S52 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000155 ER PT J AU Nicot, C Dundr, M Johnson, JM Fukumoto, R Misteli, T Franchini, G AF Nicot, C Dundr, M Johnson, JM Fukumoto, R Misteli, T Franchini, G TI HTLV-I p30II retains the Tax/Rex mRNA in the nucleus and suppresses replication of both HTLV-1 and-2. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NCI, AMRVS, Bethesda, MD 20892 USA. NCI, LRBGE, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O47 BP S20 EP S20 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000048 ER PT J AU Pecon-Slattery, J Lee, T DeVita, D O'Brien, SJ Murphy, EL AF Pecon-Slattery, J Lee, T DeVita, D O'Brien, SJ Murphy, EL TI Correlations between proviral HTLV-2 genetic diversity and patient susceptibility to pneumonia. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NIH, Frederick, MD USA. Blood Ctr Pacific, San Francisco, CA USA. Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. NCI, Lab Genome Divers, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P24 BP S36 EP S36 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000100 ER PT J AU Pise-Masison, CA Jeong, S Radonovich, M Brady, JN AF Pise-Masison, CA Jeong, S Radonovich, M Brady, JN TI The rela subunit of NF-kB is necessary for inhibition of p53 function by the HTLV-1 Tax protein. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NCI, Basic Res Lab, CCR, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O49 BP S21 EP S21 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000050 ER PT J AU Puccioni-Sohler, M Papaiz-Alvarenga, R de Souza, PM de Franca, SC Cercilier, H Carellos, S Yamano, Y Jacobson, S AF Puccioni-Sohler, M Papaiz-Alvarenga, R de Souza, PM de Franca, SC Cercilier, H Carellos, S Yamano, Y Jacobson, S TI Parkinsonism in the course of HTLV-I associated myelopathy. A case report. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Univ Rio de Janeiro, Neurolife Lab, Dept Specialized Med Neurol, Rio De Janeiro, Brazil. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P68 BP S49 EP S49 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000144 ER PT J AU Puccioni-Sohler, M Yamano, Y Papaiz-Alvarenga, R Goncalves, RR Carvalho, S Rios, M Jacobson, S AF Puccioni-Sohler, M Yamano, Y Papaiz-Alvarenga, R Goncalves, RR Carvalho, S Rios, M Jacobson, S TI HTLV-I proviral load in PBMC and CSF can differentiate HAM/TSP from patients with other neurological disorders infected with HTLV-I. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD USA. US FDA, Rockville, MD 20857 USA. HEMORIO, Rio De Janeiro, Brazil. Univ Fed Rio de Janeiro, Neurolife Lab, Rio De Janeiro, Brazil. Univ Rio de Janeiro, Rio De Janeiro, Brazil. NIH, Rockville, MD USA. NIH, Rio De Janeiro, Brazil. Univ Fed Rio de Janeiro, BR-21941 Rio De Janeiro, Brazil. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P67 BP S48 EP S48 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000143 ER PT J AU Ruckes, T Henning, G Waldele, K Forster, R Morris, J Schneider, G Jacobson, S Grassmann, R AF Ruckes, T Henning, G Waldele, K Forster, R Morris, J Schneider, G Jacobson, S Grassmann, R TI The capacity to invade lymphoid organs of HTLV-1-infected lymphocytes is augmented by viral tax protein via transactivation of the chemokine receptor CCR-7. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Artus GmbH, Hamburg, Germany. Hannover Med Sch, Hannover, Germany. Univ Erlangen Nurnberg, Inst Klin & Mol Virol, D-8520 Erlangen, Germany. NIH, Toledo, OH USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O16 BP S11 EP S11 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000017 ER PT J AU Samms-Vaughan, ME Maloney, E Palmer, P Hanchard, B AF Samms-Vaughan, ME Maloney, E Palmer, P Hanchard, B TI Does HTLV1 infection affect childhood mental development? SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Univ W Indies, Dept Med Sci, Kingston 7, Jamaica. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O22 BP S13 EP S13 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000023 ER PT J AU Semmes, J Haoudi, A Cazeres, L Ward, M Maloney, E Hisada, M Jacobson, S AF Semmes, J Haoudi, A Cazeres, L Ward, M Maloney, E Hisada, M Jacobson, S TI Serum protein profiling and identification of biomarker proteins of HTLV-I associated neurologic and hematologic disease. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Eastern Virginia Med Sch, Dept Microbiol & Mol Cell Biol, Norfolk, VA 23501 USA. NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. NIH, Dept Viral Immunobiol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O21 BP S13 EP S13 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000022 ER PT J AU Sharma, S Grandvaux, N Mamane, Y Azimi, N Lin, R Hiscott, J AF Sharma, S Grandvaux, N Mamane, Y Azimi, N Lin, R Hiscott, J TI Dysregulation of NF-kB and IRF signaling in HTLV-I leukemogenesis. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 McGill Univ, Dept Microbiol & Immunol, Montreal, PQ H3A 2T5, Canada. McGill Univ, Dept Med, Montreal, PQ H3A 2T5, Canada. NCI, Bethesda, MD 20892 USA. RI Lin, Rongtuan/A-1442-2008 OI Lin, Rongtuan/0000-0002-2238-3503 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P163 BP S75 EP S76 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000239 ER PT J AU Sibon, D Gabet, AS Mortreux, F Nicolini, F Rufer, N Gout, O Gessain, A Jacobson, S Wattel, E AF Sibon, D Gabet, AS Mortreux, F Nicolini, F Rufer, N Gout, O Gessain, A Jacobson, S Wattel, E TI Different effects of HTLV-I infection on cell cycle and growth kinetics between CD4+ and CD8+ T cells cloned from patients with TSP/HAM SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Ctr Leon Berard, Unite Oncogenese Virale, F-69373 Lyon, France. Univ Hosp Geneva, Unite Immunol Transplantat, Geneva, Switzerland. Fdn Rotschild, Paris, France. Inst Pasteur, Paris, France. NIH, HNQ2242, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P145 BP S70 EP S71 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000221 ER PT J AU Sibon, D Gabet, AS Mortreux, F Gessain, A Gout, O Jacobson, S Wattel, E AF Sibon, D Gabet, AS Mortreux, F Gessain, A Gout, O Jacobson, S Wattel, E TI Differences in cell-associated HTLV-1 expansion between CD4+ and CD8+ T cells in vivo SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Ctr Leon Berard, Unite Oncogenese Virale, F-69373 Lyon, France. Inst Pasteur, Paris, France. Fdn Rotschild, Paris, France. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P147 BP S71 EP S71 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000223 ER PT J AU Sundaram, R Walker, CM Lemonnier, FA Jacobson, S Rawale, SV Kaumaya, PT AF Sundaram, R Walker, CM Lemonnier, FA Jacobson, S Rawale, SV Kaumaya, PT TI A multiepitope tax peptide induces protective CTL responses against HTLV-1 recombinant vaccinia virus challenge in HLA-A*0201 transgenic mice. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 Ohio State Univ, Dept Microbiol, Columbus, OH 43210 USA. Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA. Inst Pasteur, Paris, France. NIH, Bethesda, MD 20892 USA. Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O10 BP S9 EP S10 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000011 ER PT J AU Tomaru, U Yamano, Y Nagai, M Maric, D Kaumaya, PT Biddison, W Jacobson, S AF Tomaru, U Yamano, Y Nagai, M Maric, D Kaumaya, PT Biddison, W Jacobson, S TI Detection of HTLV-I-specific T cells and novel CD8+ T cell epitopes by acquisition of peptide/HLA-GFP complexes. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NINDS, NIB, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. Kagoshima Univ, Fac Med, Dept Internal Med 3, Kagoshima 890, Japan. NIH, Neurophysiol Lab, Bethesda, MD 20892 USA. Ohio State Univ, Dept Mol & Cellular Biochem, Columbus, OH 43210 USA. NINDS, NIB, Mol Immunol Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P54 BP S44 EP S45 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000130 ER PT J AU Tomaru, U Yamano, Y Nagai, M Jacobson, S AF Tomaru, U Yamano, Y Nagai, M Jacobson, S TI Transference of peptide/HLA complexes among HTLV-I-specific T cells; A new concept of antigen spread in HTLV-I-associated disease. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NINDS, NIB, Virol Immunol Sect, NIH, Bethesda, MD 20892 USA. Kagoshima Univ, Fac Med, Dept Internal Med 3, Kagoshima 890, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA O7 BP S8 EP S9 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000008 ER PT J AU VanVeldhuisen, PC Sawada, T Hanchard, B Wilks, RJ Hisada, M AF VanVeldhuisen, PC Sawada, T Hanchard, B Wilks, RJ Hisada, M TI Longitudinal changes of HTLV-I viral markers in asymptomatic carriers in Jamaica. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 George Washington Univ, Rockville, MD USA. EMMES Corp, Rockville, MD USA. Eisai & Co Ltd, Diagnost Dept, Tsukuba, Ibaraki, Japan. Univ W Indies, Kingston 7, Jamaica. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P1 BP S29 EP S29 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000077 ER PT J AU Yamano, Y Tomaru, U Nagai, M Jacobson, S AF Yamano, Y Tomaru, U Nagai, M Jacobson, S TI T cell differentiation phenotype and cytolytic function of CMV and HTLV-I-specific CD8+ T cells in HAM/TSP patients: Evidence for insufficient control of persistent HTLV-I infection. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NINDS, NIB, NIH, Bethesda, MD 20892 USA. Kagoshima Univ, Dept Internal Med 3, Kagoshima 890, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P42 BP S41 EP S41 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000118 ER PT J AU Yamano, Y Cohen, CJ Tomaru, U Reiter, Y Jacobson, S AF Yamano, Y Cohen, CJ Tomaru, U Reiter, Y Jacobson, S TI Detection of HTLV-I Tax11-19 peptide/HLA-A*201 complexes are overexpressed in HAM/TSP patients. SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Meeting Abstract CT 11th International Conference on Human Retrovirology: HTLV and Related Viruses CY JUN 09-12, 2003 CL SAN FRANCISCO, CALIFORNIA C1 NINDS, NIB, NIH, Bethesda, MD 20892 USA. Technion Israel Inst Technol, Haifa, Israel. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PY 2003 VL 19 SU S MA P32 BP S38 EP S38 PG 1 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 685TU UT WOS:000183280000108 ER PT J AU Dawson, DA AF Dawson, DA TI Methodological issues in measuring alcohol use SO ALCOHOL RESEARCH & HEALTH LA English DT Article DE alcohol quantity-frequency methods; survey; interview; study design; reliability (research methods); validity (research methods) ID LIFETIME DRINKING HISTORY; CONSUMPTION; RELIABILITY; QUESTIONS; QUANTITY; PATTERNS AB Various methodological issues influence the measurement of alcohol consumption in surveys. One factor is the reference period for which questions are asked-that is, whether respondents are asked for an exact recall of their intake during a short, recent period or for a summary of their drinking behavior over a longer period, such as the past year. Longer recall periods provide sufficient time to link consumption data with concurrently collected data on the prevalence of alcohol-related outcomes. Another factor influencing survey results is the approach used to measure alcohol consumption. Two commonly used measures are the usual quantity/frequency (QF) and graduated frequency (GF) approaches, both of which allow researchers to estimate the volume of alcohol intake. Other issues that researchers conducting surveys should consider include the use of beverage-specific versus overall questions, open-ended versus categorical responses, and measurement of standard versus actual drink sizes. Finally, features of the overall survey design-such as the mode of interview (i.e., in person versus by telephone), the use of computerized survey instruments, and measures to ensure confidentiality-influence the reliability and validity of the data. C1 NIAAA, Bethesda, MD USA. RP Dawson, DA (reprint author), NIAAA, Bethesda, MD USA. NR 27 TC 159 Z9 160 U1 2 U2 19 PU NATL INST ALCOHOL ABUSE ALCOHOLISM PI ROCKVILLE PA 6000 EXECUTIVE BLVD, ROCKVILLE, MD 20892-7003 USA SN 0090-838X J9 ALCOHOL RES HEALTH JI Alcohol Res. Health PY 2003 VL 27 IS 1 BP 18 EP 29 PG 12 WC Substance Abuse SC Substance Abuse GA 853BE UT WOS:000223800300002 PM 15301397 ER PT J AU Yoon, YH Stinson, FS Yi, HY Dufour, MC AF Yoon, YH Stinson, FS Yi, HY Dufour, MC TI Accidental alcohol poisoning mortality in the United States, 1996-1998 SO ALCOHOL RESEARCH & HEALTH LA English DT Article DE AOD (alcohol and other drug) poisoning; accident mortality; AODR (alcohol and other drug related) mortality; prevalence; etiology; gender differences; age differences; racial differences; educational level achieved; risk analysis; statistical data; United States ID EXPOSURE SURVEILLANCE SYSTEM; SEEKING COCAINE ABUSERS; HEROIN-RELATED DEATHS; AMERICAN ASSOCIATION; CERTIFICATES; WITHDRAWAL; ETIOLOGY AB This study examines the prevalence and patterns of mortality resulting from unintentional poisoning by alcohol (ICD-9 code E860) in the United States. Relevant data for the most recently available years (1996 through 1998) were derived from the Multiple Cause of Death public-use computer data files compiled by the National Center for Health Statistics (NCHS). Data on deaths ascribed to alcohol poisoning as either the underlying cause or as 1 of up to 20 contributing causes were selected and analyzed. The annual average number of deaths for which alcohol poisoning was listed as an underlying cause was 317, with an age-adjusted death rate of 0. 11 per 100,000 population. An average of 1,076 additional deaths included alcohol poisoning as a contributing cause, bringing the total number of deaths with any mention of alcohol poisoning to 1,393 per year (0.49 per 100,000 population). Males accounted for more than 80 percent of these deaths. The rate was lower among married than unmarried people (i.e., never married, divorced, or widowed) and was inversely related to education. Among males, the alcohol poisoning death rate was higher for Hispanics and non-Hispanic Blacks than non-Hispanic Whites. Among females, raciallethnic differences were small, but Black women had higher alcohol poisoning death rates than White or Hispanic women. Alcohol poisoning deaths tended to be most prevalent among people ages 35 to 54; only 2 percent of alcohol poisoning decedents were younger than age 21. Among deaths with a contributing cause of alcohol poisoning, almost 90 percent had an underlying cause related to some type of poisoning from other drugs. C1 NIAA, CRS Inc, Alcohol Epidemiol Data Syst, Arlington, VA USA. NIAAA, Div Intramural Clin & Biol Res, Lab Epidemiol & Biometry, Bethesda, MD USA. RP Yoon, YH (reprint author), NIAA, CRS Inc, Alcohol Epidemiol Data Syst, Arlington, VA USA. NR 38 TC 12 Z9 12 U1 1 U2 1 PU NATL INST ALCOHOL ABUSE ALCOHOLISM PI ROCKVILLE PA 6000 EXECUTIVE BLVD, ROCKVILLE, MD 20892-7003 USA SN 0090-838X J9 ALCOHOL RES HEALTH JI Alcohol Res. Health PY 2003 VL 27 IS 1 BP 110 EP 118 PG 9 WC Substance Abuse SC Substance Abuse GA 853BE UT WOS:000223800300010 PM 15301405 ER PT J AU Hommer, DW AF Hommer, DW TI Male and female sensitivity to alcohol-induced brain damage SO ALCOHOL RESEARCH & HEALTH LA English DT Article DE AODR (alcohol and other drug related) structural brain damage; AOD sensitivity; gender differences; AODR biological markers; cerebrospinal fluid; hippocarnpus; corpus callosum; cerebral cortex; brain imaging ID SEXUAL-DIFFERENTIATION; CORPUS-CALLOSUM; WHITE-MATTER; WOMEN; VOLUME; GENDER; SIZE; MEN; MRI; DISEASE AB Women are more vulnerable than men to many of the medical consequences of alcohol use. Although research has shown that male alcoholics generally have smaller brain volumes than nonalcoholic males, the few studies that have compared brain structure in alcoholic men and women have had mixed results. To adequately compare brain damage between alcoholic women and men, it is necessary to control for age and to have separate control groups of nonalcoholic men and women. Although the majority of studies suggest that women are more vulnerable to alcohol-induced brain damage than men, the evidence remains inconclusive. C1 NIAAA, Sect Brain Electrophysiol & Imaging, Clin Studies Lab, Div Intramural Clin & Biol Res, Bethesda, MD USA. RP Hommer, DW (reprint author), NIAAA, Sect Brain Electrophysiol & Imaging, Clin Studies Lab, Div Intramural Clin & Biol Res, Bethesda, MD USA. NR 26 TC 58 Z9 61 U1 2 U2 13 PU NATL INST ALCOHOL ABUSE ALCOHOLISM PI ROCKVILLE PA 6000 EXECUTIVE BLVD, ROCKVILLE, MD 20892-7003 USA SN 0090-838X J9 ALCOHOL RES HEALTH JI Alcohol Res. Health PY 2003 VL 27 IS 2 BP 181 EP 185 PG 5 WC Substance Abuse SC Substance Abuse GA 853BG UT WOS:000223800500008 PM 15303629 ER PT J AU Riley, EP Guerri, C Calhoun, F Charness, ME Foroud, TM Li, TK Mattson, SN May, PA Warren, KR AF Riley, EP Guerri, C Calhoun, F Charness, ME Foroud, TM Li, TK Mattson, SN May, PA Warren, KR TI Prenatal alcohol exposure: Advancing knowledge through international collaborations SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE FAS; international studies; review ID CELL-CELL ADHESION; ETHANOL EXPOSURE; GENETIC PREDISPOSITION; POTENTIAL MECHANISM; SEROTONIN NEURONS; END-POINTS; RAT-BRAIN; FETAL; INHIBITION; ALLELE AB Fetal alcohol syndrome (FAS) is a major public health issue that is evident on an international scale. The current article summarizes a meeting that was held in Valencia, Spain, in September 2001, that reviewed ongoing international collaborations and the prospects for new collaborative research. The attendees represented nine different countries and many different specialties. Following overviews of existing international collaborations in South Africa, Russia, and Chile, a number of topics for future work were discussed. Issues related to the diagnosis of FAS, its prevalence and how measures might be enhanced and standardized were presented, as obtaining consistency across populations is of prime importance. Another session discussed the current state of basic research and how collaborations in this area might be initiated. The neurobehavioral profile of FAS and how work in this area could be advanced and interpreted in light of findings with different populations generated considerable discussion. There was a review of brain imaging data in FAS and how this might be utilized in assisting the diagnosis of FAS and alcohol-related neurodevelopmental disorder (ARND). A presentation on the utilization of international collaborations in defining the role of genetics in the etiology of FAS was included. Finally, issues related to the prevention of FAS and how these issues might be modified based upon different populations were presented. International collaborations provide a wealth of resources for the study of FAS, and it was hoped that this meeting might better enhance the work ongoing in this area, and provide opportunities for future work. C1 San Diego State Univ, Ctr Behav Teratol, San Diego, CA 92120 USA. Inst Invest Citological Caja Ahorros Valencia, Valencia, Spain. NIAAA, Bethesda, MD USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Indiana Univ, Sch Med, Indianapolis, IN 46204 USA. Univ New Mexico, Albuquerque, NM 87131 USA. RP Riley, EP (reprint author), San Diego State Univ, Ctr Behav Teratol, 6363 Alvarado Court 209, San Diego, CA 92120 USA. RI Riley, Edward/E-6369-2013; Guerri, Consuelo/B-5181-2014; Mattson, Sarah/G-5344-2011; OI Riley, Edward/0000-0001-8747-891X; Mattson, Sarah/0000-0001-8499-9605; Charness, Michael/0000-0002-3301-8966 NR 49 TC 27 Z9 30 U1 0 U2 8 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 JAN PY 2003 VL 27 IS 1 BP 118 EP 135 DI 10.1097/01.ALC.0000047351.03586.A3 PG 18 WC Substance Abuse SC Substance Abuse GA 640VZ UT WOS:000180709800019 PM 12544016 ER PT B AU Kirshenbaum, AS Akin, C Metcalfe, DD AF Kirshenbaum, AS Akin, C Metcalfe, DD BE Bienenstock, J Ring, J Togias, AG TI Spontaneous development of human mast cell lines SO ALLERGY FRONTIERS AND FUTURES LA English DT Proceedings Paper CT 27th Symposium of the Collegium-Internationale-Allergologicum CY NOV, 2002 CL Southampton, BERMUDA SP Collegium Int Allergologicum DE mast cell; SCF; Fc epsilon RI; Fc gamma RI ID HMC-1; BASOPHILS; RECEPTOR; EXPRESS AB Stem cell factor dependent human mast cell lines have been established from bone marrow aspirates obtained from a patient with mast cell sarcoma/leukemia. These cells have the ultrastructural features of human mast cells and are tryptase and chymase positive. These cells release beta-hexosaminidase following FcepsilonRI or FcgammaRI aggregation, differentiating them from human mast cell lines that are surface FcepsilonRI negative. The availability of these cell lines should facilitate research on human mast cell biology. C1 NIAID, NIH, Lab Allerg Dis, Bethesda, MD 20892 USA. RP Kirshenbaum, AS (reprint author), NIAID, NIH, Lab Allerg Dis, Bldg 10,Room 11C205,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU HOGREFE & HUBER PUBLISHERS PI TORONTO PA 12 BRUCE PARK AVE, TORONTO, ON M4P 2S3, CANADA BN 0-88937-279-9 PY 2003 BP 120 EP 122 PG 3 WC Allergy SC Allergy GA BAS25 UT WOS:000223347200032 ER PT B AU Rivera, J Furumoto, Y Gonzalez-Espinosa, C Kovarova, M Odom, S Parravicini, V AF Rivera, J Furumoto, Y Gonzalez-Espinosa, C Kovarova, M Odom, S Parravicini, V BE Bienenstock, J Ring, J Togias, AG TI Functional coupling of Fc epsilon RI employs two proximal Src family kinases - A new paradigm in mast cell activation SO ALLERGY FRONTIERS AND FUTURES LA English DT Proceedings Paper CT 27th Symposium of the Collegium-Internationale-Allergologicum CY NOV, 2002 CL Southampton, BERMUDA SP Collegium Int Allergologicum DE Fc epsilon RI; Lyn; Fyn; IgE; mast cell; degranulation ID ALLERGIC RESPONSE; TYROSINE KINASES; RECEPTOR; IGE; AGGREGATION; LYN; DEGRANULATION; ASSOCIATION; ADHESION AB Background: The initial steps in immunoglobulin E (IgE)-dependent mast cell activation were shown to require the Src family kinase, Lyn, the signal amplifying kinase, Syk, and the adapter molecule, LAT. However, new evidence, provided by studies on mast cells derived from genetically modified mice, suggests that other early molecular events are required for mast cell responses. Methods: In vitro studies on bone marrow derived cultured mast cells (BMMC) from genetically altered mice and in vivo anaphylaxis studies on these mice are the principal source of data. Results: Antigen-aggregation of IgE-occupied FcepsilonRI was found to elicit the activation of a second Src family kinase, Fyn, whose activity was essential for the phosphorylation of the adapter molecule Gab2 and the activation of phosphatidylinositol 3-OH kinase (PI3K). Lyn kinase, which is required for FcepsilonRI phosphorylation (activation), negatively regulated the phosphorylation of Gab2. In vitro and in vivo experiments on Lyn- and Fyn-deficient mast cells or mice, respectively, showed that Lyn was dispensable for mast cell degranulation whereas Fyn was required. Inhibitors of PI3K were found to inhibit degranulation in wild-type and Lyn-null mast cells demonstrating the importance of PI3K activation to mast cell function. Lyn and Fyn were found to synergize in mast cell degranulation. Lyn was required for normal mast cell calcium responses whereas Fyn contributed to protein kinase C (PKC) activation. Conclusion: The identification of the Fyn/Gab2 pathway provides a new model for IgE-dependent mast cell activation with possible therapeutic implications in allergic disease. C1 NIAMSD, NIH, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. RP Rivera, J (reprint author), NIAMSD, NIH, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, Bldg 10,Room 9N228, Bethesda, MD 20892 USA. NR 17 TC 0 Z9 0 U1 0 U2 2 PU HOGREFE & HUBER PUBLISHERS PI TORONTO PA 12 BRUCE PARK AVE, TORONTO, ON M4P 2S3, CANADA BN 0-88937-279-9 PY 2003 BP 152 EP 156 PG 5 WC Allergy SC Allergy GA BAS25 UT WOS:000223347200041 ER PT J AU Etzel, RA Crain, EF Gitterman, BA Oberg, C Scheidt, P Landrigan, PJ AF Etzel, RA Crain, EF Gitterman, BA Oberg, C Scheidt, P Landrigan, PJ TI Pediatric environmental health competencies for specialists SO AMBULATORY PEDIATRICS LA English DT Article DE competency; competency-based education; pediatric environmental health ID TRENDS; LEAD AB Background.-Because environmental health problems are complex and require specialty training, the Ambulatory Pediatric Association initiated a 3-year postgraduate fellowship in Pediatric Environmental Health. Objective.-To develop competencies for the specialty of Pediatric Environmental Health and appropriate measures (performance indicators) for the achievement of these competencies. Methods.-The President of the Ambulatory Pediatric Association appointed a 6-member Fellowship Oversight Committee to guide the development of the Fellowship Program and to draft competencies for fellows in Pediatric Environmental Health. The Committee developed a list of proposed competencies for graduates of Pediatric Environmental Health fellowships. These were skills identified as very important for a specialist to have for minimal competency in the practice of pediatric environmental health. Results.-Twenty-seven Pediatric Environmental Health competencies are proposed. The competencies are presented from 3 separate perspectives: academic, individual patient care, and community advocacy. Each competency has a list of suggested performance indicators. Conclusion.-These competencies are intended to assist in structuring the training experience, achieving consensus with respect to expectations of fellows and faculty, providing opportunities for fellows to assess their own needs or gaps in training, and identifying the expertise of fellowship graduates to potential employers. C1 George Washington Univ, Sch Publ Hlth, Washington, DC USA. George Washington Univ, Hlth Serv, Washington, DC USA. Albert Einstein Coll Med, Jacobi Med Ctr, Dept Pediat, Bronx, NY USA. Childrens Natl Med Ctr, Washington, DC USA. Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. Natl Inst Child Hlth & Human Dev, Bethesda, MD USA. Natl Inst Hlth, Bethesda, MD USA. Mt Sinai Sch Med, New York, NY USA. RP Etzel, RA (reprint author), 4320 Diplomacy Dr, Anchorage, AK 99508 USA. NR 23 TC 12 Z9 12 U1 0 U2 0 PU ALLIANCE COMMUNICATIONS GROUP DIVISION ALLEN PRESS PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 1530-1567 J9 AMBUL PEDIATR JI Ambul. Pediatr. PD JAN-FEB PY 2003 VL 3 IS 1 BP 60 EP 63 DI 10.1367/1539-4409(2003)003<0060:PEHCFS>2.0.CO;2 PG 4 WC Pediatrics SC Pediatrics GA 638QK UT WOS:000180581600014 PM 12540257 ER PT J AU Goldstein, DS Holmes, C Frank, SM Naqibuddin, M Dendi, R Snader, S Calkins, H AF Goldstein, DS Holmes, C Frank, SM Naqibuddin, M Dendi, R Snader, S Calkins, H TI Sympathoadrenal imbalance before neurocardiogenic syncope SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID VASOVAGAL SYNCOPE; VASODEPRESSOR SYNCOPE; PLASMA NOREPINEPHRINE; CENTRAL HYPOVOLEMIA; TILT; EPINEPHRINE; RESPONSES; STRESS; HUMANS; CATECHOLAMINE AB Neurocardiogenic syncope is the most common cause of acute loss of consciousness in adults. The present study attempted to identify neuroendocrine and hemodynamic changes before syncope that could therefore play a pathophysiologic role. Twenty-five patients referred for chronic orthostatic intolerance had plasma catecholamines measured serially; 21 patients during tilt-table testing (evoking syncope in 13) and 4 others with spontaneous syncope while supine. Forearm blood flow was measured by impedance plethysmography. All 12 patients with blood sampled before tilt-induced syncope had progressive, marked increases in plasma epinephrine levels (mean 11 times baseline, p <0.0001) before syncope. Simultaneously obtained norepinephrine levels increased to a much smaller extent than did epinephrine levels ("sympothoadrenal imbalance"). In the same patients, forearm vascular resistance decreased by 21% before syncope. Proportionate changes in forearm vascular resistance before syncope correlated negatively with those in the epinephrine:norepinephrine ratio (r = -0.75, p = 0.005). Patients without syncope had forearm vasoconstriction and no sympothoadrenal imbalance during tilt. Patients with syncope while supine also had sympathoadrenal imbalance before loss of consciousness. Sympathoadrenal imbalance precedes tilt-evoked and spontaneous neurocardiogenic syncope and correlates with concurrent skeletal muscle vasodilation. Sympathoadrenal imbalance may contribute to hemodynamic derangements precipitating neurocardiogenic syncope. (C) 2003 by Excerpta Medica, Inc. C1 NINDS, Clin Neurol Sect, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ Hosp, Dept Anesthesiol & Crit Care Med, Johns Hopkins Med Inst, Baltimore, MD 21287 USA. Johns Hopkins Univ Hosp, Div Cardiol, Baltimore, MD 21287 USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurol Sect, Clin Neurocardiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. NR 26 TC 32 Z9 34 U1 2 U2 2 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JAN 1 PY 2003 VL 91 IS 1 BP 53 EP 58 AR PII S0002-9149(02)02997-1 DI 10.1016/S0002-9149(02)02997-1 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 632AP UT WOS:000180201000010 PM 12505571 ER PT J AU DiGiovanna, JJ Robinson-Bostom, L AF DiGiovanna, JJ Robinson-Bostom, L TI Ichthyosis - Etiology, diagnosis, and management SO AMERICAN JOURNAL OF CLINICAL DERMATOLOGY LA English DT Review ID SJOGREN-LARSSON-SYNDROME; X-LINKED ICHTHYOSIS; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; AUTOSOMAL RECESSIVE ICHTHYOSIS; SYSTEMIC LUPUS-ERYTHEMATOSUS; ALDEHYDE DEHYDROGENASE GENE; EPIDERMOLYTIC HYPERKERATOSIS; LAMELLAR ICHTHYOSIS; KAPOSIS-SARCOMA; CONGENITAL ICHTHYOSES AB The ichthyoses are a heterogeneous group of disorders with both inherited and acquired forms. Clinical presentation, pattern of inheritance, and laboratory evaluation may establish a precise diagnosis, which can assist in prognosis and genetic counseling. Congenital autosomal recessive ichthyosis (CARI) usually presents at birth, often as a collodion baby. CARI can progress into any one of a spectrum of disorders. Lamellar ichthyosis is characterized by dark, plate (armor)-like scale. This disease is often caused by mutations in the gene encoding the enzyme transglutaminase 1. Congenital ichthyosiform erythroderma is another phenotype within CARI, marked by generalized redness and fine white scale. Epidermolytic hyperkeratosis is an autosomal dominant disorder characterized by hyperkeratosis and blistering, and at least six clinical phenotypes have been described. It may be due to mutations in the gene encoding the intermediate filament proteins keratin 1 and 10. C1 Brown Med Sch, Dept Dermatol, Div Dermatopharmacol, Providence, RI 02903 USA. Rhode Isl Hosp, Dept Pathol, Providence, RI 02902 USA. NCI, Basic Res Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP DiGiovanna, JJ (reprint author), Brown Med Sch, Dept Dermatol, Div Dermatopharmacol, 593 Eddy St,JBS-1, Providence, RI 02903 USA. NR 99 TC 68 Z9 82 U1 0 U2 3 PU ADIS INTERNATIONAL LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 10, NEW ZEALAND SN 1175-0561 J9 AM J CLIN DERMATOL JI Am. J. Clin. Dermatol. PY 2003 VL 4 IS 2 BP 81 EP 95 DI 10.2165/00128071-200304020-00002 PG 15 WC Dermatology SC Dermatology GA 729XW UT WOS:000185801200002 PM 12553849 ER PT J AU England, LJ Kendrick, JS Gargiullo, PM AF England, LJ Kendrick, JS Gargiullo, PM TI Re: "Measures of maternal tobacco exposure and infant birth weight at term" - Reply SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID FETAL GROWTH; PREGNANCY; SMOKING C1 NICHHD, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA 30341 USA. Ctr Dis Control & Prevent, Canc Surveillance Branch, Atlanta, GA 30341 USA. RP England, LJ (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. NR 10 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 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JAN 1 PY 2003 VL 157 IS 1 BP 87 EP 88 DI 10.1093/aje/kwf169 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 632KZ UT WOS:000180223600014 ER PT J AU Chen, Q Reis, SE Kammerer, CM McNamara, DM Holubkov, R Sharaf, BL Sopko, G Pauly, DF Merz, CNB Kamboh, MI AF Chen, Q Reis, SE Kammerer, CM McNamara, DM Holubkov, R Sharaf, BL Sopko, G Pauly, DF Merz, CNB Kamboh, MI CA WISE Study Grp TI Association between the severity of angiographic coronary artery disease and paraoxonase gene polymorphisms in the National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) study SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; SERUM PARAOXONASE; OXIDATIVE MODIFICATION; GLN-ARG192 POLYMORPHISM; CARDIOVASCULAR-DISEASE; INCREASED RISK; PON1; ATHEROSCLEROSIS; PROTECTION; ATHEROGENESIS AB (PON), a high-density lipoprotein-associated enzyme, is believed to protect against low-density lipoprotein oxidation and thus affects the risk of coronary artery disease (CAD). Three polymorphisms in the PON1 (Leu55Met and Gln192Arg) and PON2 (Ser311Cys) genes have been shown to be associated with the risk of CAD in several European or European-derived populations. In the present study, we examined the associations between these three markers and the severity of CAD as determined by the number of diseased coronary artery vessels in 711 subjects (589 whites and 122 blacks) from the Women's Ischemia Syndrome Evaluation (WISE) study. WISE is a National Heart, Lung, and Blood Institute-sponsored multicenter study designed to address issues related to ischemic-heart-disease recognition and diagnosis in women. Subjects were classified as having normal/minimal CAD (<20% stenosis), mild CAD (20%-49% stenosis), and significant CAD (&GE;50% stenosis). The women who had &GE;50% stenosis were further classified into groups with one-, two-, or three-vessel disease if any of the three coronary arteries had diameter stenosis &GE;50%. No significant association was found between the PON polymorphisms and stenosis severity in either white or black women. However, among white women, when data were stratified by the number of diseased vessels, the frequency of the PON1 codon 192 Arg/Arg genotype was significantly higher in the group with three-vessel disease than in the other groups (those with one- vessel and two- vessel disease) combined (17.02% vs. 4.58%; P = .0066). Similarly, the frequency of the PON2 codon 311 Cys/Cys genotype was significantly higher in the group with three-vessel disease than in the other groups combined (15.22% vs. 4.61%; P = .018). The adjusted odds ratios for the development of three-vessel disease were 2.80 (95% confidence interval 1.06-7.37; P = .038 ) for PON1 codon 192 Arg/Arg and 3.68 (95% confidence interval 1.26-10.68; for PON2 codon 311 Cys/Cys. Our data indicate that the severity of CAD, in terms of the number of diseased vessels, may be affected by common genetic variation in the PON gene cluster, on chromosome 7. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Math, Cardiovasc Inst, Pittsburgh, PA 15260 USA. Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT 84112 USA. Rhode Isl Hosp, Div Cardiol, Providence, RI USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. Univ Florida, Div Cardiol, Gainesville, FL USA. Cedars Sinai Med Ctr, Div Cardiol, Los Angeles, CA 90048 USA. RP Kamboh, MI (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, 130 De Soto St, Pittsburgh, PA 15261 USA. RI Reis, Steven/J-3957-2014; OI Kamboh, M. Ilyas/0000-0002-3453-1438 FU NHLBI NIH HHS [R01 HL64924-01, U01 HL064829, N01HV68162, N01-HV68163, R01 HL054900, HL54900, N01 HV068161, N01 HV068164, N01-HV68164, N01HV68163, R01 HL64829-01, U01 HL064924, R01 HL64914-01, N01-HV68162] NR 57 TC 80 Z9 88 U1 1 U2 1 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 JAN PY 2003 VL 72 IS 1 BP 13 EP 22 DI 10.1086/345312 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 631VE UT WOS:000180186800002 PM 12454802 ER PT J AU Bulik, CM Devlin, B Bacanu, SA Thornton, L Klump, KL Fichter, MM Halmi, KA Kaplan, AS Strober, M Woodside, DB Bergen, AW Ganjei, JK Crow, S Mitchell, J Rotondo, A Mauri, M Cassano, G Keel, P Berrettini, WH Kaye, WH AF Bulik, CM Devlin, B Bacanu, SA Thornton, L Klump, KL Fichter, MM Halmi, KA Kaplan, AS Strober, M Woodside, DB Bergen, AW Ganjei, JK Crow, S Mitchell, J Rotondo, A Mauri, M Cassano, G Keel, P Berrettini, WH Kaye, WH TI Significant linkage on chromosome 10p in families with bulimia nervosa SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DIABETES SUSCEPTIBILITY GENES; TRANSMISSION RATIO DISTORTION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; 10-YEAR FOLLOW-UP; BODY-MASS INDEX; ANOREXIA-NERVOSA; GENOME SCAN; EATING DISORDERS; 72 FAMILIES; SCHIZOPHRENIA AB Bulimia nervosa (BN) is strongly familial, and additive genetic effects appear to contribute substantially to the observed familiality. In turn, behavioral components of BN, such as self-induced vomiting, are reliably measured and heritable. To identify regions of the genome harboring genetic variants conferring susceptibility to BN, we conducted a linkage analysis of multiplex families with eating disorders that were identified through a proband with BN. Linkage analysis of the entire sample of 308 families yielded a double peak, with the highest nonparametric multipoint maximum LOD score (MLS), of 2.92, on chromosome 10. Given the high heritability of self-induced vomiting and the reliability with which it can be measured, we performed linkage analysis in a subset (n = 133) of families in which at least two affected relatives reported a symptom pattern that included self-induced vomiting. The highest MLS (3.39) observed was on chromosome 10, between markers D10S1430 and D10S1423. These results provide evidence of the presence of a susceptibility locus for BN on chromosome 10p. Using simulations, we demonstrate that both of these scores, 2.92 and 3.39, meet the widely accepted criterion for genomewide significance. Another region on 14q meets the criterion for genomewide suggestive linkage, with MLSs of 1.97 (full sample) and 1.75 (subset) at 62 centimorgans from p-ter. C1 Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA 23298 USA. Univ Pittsburgh, Dept Psychiat, Med Ctr, Pittsburgh, PA 15213 USA. Michigan State Univ, Dept Psychol, E Lansing, MI 48824 USA. Univ Munich, Roseneck Hosp Behav Med, Prien Am Chiemsee, Germany. Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, White Plains, NY USA. Toronto Gen Hosp, Univ Hlth Network, Program Eating Disorders, Toronto, ON, Canada. Toronto Gen Hosp, Univ Hlth Network, Dept Psychiat, Toronto, ON, Canada. Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. NCI, Core Genotyping Facil, Ctr Adv Technol, Gaithersburg, MD USA. Biognosis US, Gaithersburg, MD USA. Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. Neuropsychiat Res Unit, Fargo, ND USA. Univ Pisa, Dept Psychiat Neurobiol Pharmacol & Biotechnol, Pisa, Italy. Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. Univ Penn, Ctr Neurobiol & Behav, Philadelphia, PA 19104 USA. RP Bulik, CM (reprint author), Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Dept Psychiat, Richmond, VA 23298 USA. OI Bergen, Andrew/0000-0002-1237-7644 FU NIMH NIH HHS [MH57881, R01 MH057881, K01-MH01553, R37 MH057881] NR 59 TC 68 Z9 69 U1 3 U2 7 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 JAN PY 2003 VL 72 IS 1 BP 200 EP 207 DI 10.1086/345801 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 631VE UT WOS:000180186800021 PM 12476400 ER PT J AU Nowaczyk, MJM McCaughey, D Whelan, DT Porter, FD AF Nowaczyk, MJM McCaughey, D Whelan, DT Porter, FD TI Reply to correspondence from Martinez-Frias et al. - "Incidence of Smith-Lemli-Opitz syndrome in Ontario, Canada" SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Letter C1 McMaster Univ, Hamilton Reg Lab, Program Med, Dept Pathol, Hamilton, ON, Canada. McMaster Univ, Hamilton Reg Lab, Program Med, Dept Mol Med, Hamilton, ON, Canada. NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Nowaczyk, MJM (reprint author), Rm 3N16,MUMC Campus,1200 Main St W, Hamilton, ON, Canada. NR 1 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JAN 1 PY 2003 VL 116A IS 1 BP 102 EP 102 DI 10.1002/ajmg.a.10092 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 670GC UT WOS:000182398300021 ER PT J AU Potash, JB Chiu, YF MacKinnon, DF Miller, EB Simpson, SG McMahon, FJ McInnis, MG DePaulo, JR AF Potash, JB Chiu, YF MacKinnon, DF Miller, EB Simpson, SG McMahon, FJ McInnis, MG DePaulo, JR TI Familial aggregation of psychotic symptoms in a replication set of 69 bipolar disorder pedigrees SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE genetics; subtype; heterogeneity; psychosis; family study; bipolar disorder; schizophrenia ID SCHIZOAFFECTIVE DISORDER; DIAGNOSTIC INTERVIEW; ROSCOMMON FAMILY; SCHIZOPHRENIA; RELATIVES; DEPRESSION; UNIPOLAR; FEATURES; ILLNESS; HETEROGENEITY AB We found evidence previously of familial aggregation of psychotic symptoms in 65 bipolar disorder pedigrees. This finding, together with prior evidence from clinical, family, neurobiological, and linkage studies, suggested that psychotic bipolar disorder may delineate a valid subtype. We sought to replicate this finding in 69 new bipolar disorder pedigrees. The presence of psychotic symptoms, defined as hallucinations or delusions, during an affective episode was compared in families of 46 psychotic and 23 non-psychotic bipolar I probands ascertained at Johns Hopkins for the NIMH Bipolar Disorder Genetics Initiative. There were 198 first-degree relatives with major affective disorder including 90 with bipolar I disorder. Significantly more psychotic proband families than non-psychotic proband families (76% vs. 48%) contained at least one affected relative with psychotic symptoms. Psychotic symptoms occurred in 35% of relatives of psychotic probands and in 22% of relatives of non-psychotic probands (P = 0.10). Both psychotic affective disorder generally and psychotic bipolar I disorder clustered significantly in families. These results are consistent with our prior report although the magnitude of the predictive effect of a psychotic proband is less in the replication families. Our findings provide modest support for the validity of psychotic bipolar disorder as a subtype of bipolar disorder. This clinically defined subtype may prove more homogeneous than the disorder as a whole at the level of genetic etiology and of neuropathology/pathophysiology. Families with this subtype should be used to search for susceptibility genes common to bipolar disorder and schizophrenia, and for biological markers that may be shared with schizophrenia. Published 2003 Wiley-Liss, Inc.dagger C1 Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC USA. Univ Colorado, Sch Med, Dept Psychiat, Denver, CO 80262 USA. NIMH, Mood & Anxiety Disorders Res Program, NIH, Bethesda, MD 20892 USA. RP Potash, JB (reprint author), Johns Hopkins Univ Hosp, 600 N Wolfe St,Meyer 3-181, Baltimore, MD 21287 USA. RI McMahon, Francis/A-7290-2009; McInnis, Melvin/F-6963-2012; Chiu, Yen-Feng /E-3847-2010; OI McInnis, Melvin/0000-0002-0375-6247; McMahon, Francis/0000-0002-9469-305X FU NIMH NIH HHS [K08 MH-02026, U10 MH-46274] NR 38 TC 48 Z9 49 U1 2 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JAN 1 PY 2003 VL 116B IS 1 BP 90 EP 97 DI 10.1002/ajmg.b.10761 PG 8 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 670GU UT WOS:000182399800017 PM 12497621 ER PT J AU Baird, DD Dunson, DB Hill, MC Cousins, D Schectman, JM AF Baird, DD Dunson, DB Hill, MC Cousins, D Schectman, JM TI High cumulative incidence of uterine leiomyoma in black and white women: Ultrasound evidence SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE uterine leiomyoma; uterine fibroid tumors; ultrasonography ID UNITED-STATES; HYSTERECTOMY; AGE; UTERUS; MANAGEMENT; DIAGNOSIS; SYMPTOMS; SAMPLE; SIZE AB OBJECTIVE: Uterine leiomyoma, or fibroid tumors, are the leading indication for hysterectomy in the United States, but the proportion of women in whom fibroid tumors develop is not known. This study screened for fibroid tumors, independently of clinical symptoms, to estimate the age-specific proportion of black and white women in whom fibroid tumors develop. STUDY DESIGN: Randomly selected members of an urban health plan who were 35 to 49 years old participated (n = 1364 women). Medical records and self-report were used to assess fibroid status for those women who were no longer menstruating (most of whom had had hysterectomies). Premenopausal women were screened by,ultrasonography. We estimated the age-specific cumulative incidence of fibroid tumors for black and white women. RESULTS: Thirty-five percent of premenopausal women had a previous diagnosis of fibroid tumors. Fifty-one percent of the premenopausal women who had no previous diagnosis had ultrasound evidence of fibroid tumors. The estimated cumulative incidence of tumors by age 50 was >80% for black women and nearly 70% for white women. The difference between the age-specific cumulative incidence curves for black and white women was highly significant (odds ratio, 2.9; 95% CI, 2.5-3.4; P < .001). CONCLUSION: The results of this study suggest that most black and white women in the United States develop uterine fibroid tumors before menopause and that uterine fibroid tumors develop in black women at earlier ages than in white women. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. George Washington Univ, Med Ctr, Dept Radiol, Washington, DC 20037 USA. George Washington Univ, Med Ctr, Dept Hlth Care Sci, Washington, DC 20037 USA. RP Baird, DD (reprint author), NIEHS, Epidemiol Branch, 111 TW Alexander Dr,Bldg 101,Rm 308,South Campus, Res Triangle Pk, NC 27709 USA. OI Baird, Donna/0000-0002-5544-2653 NR 30 TC 447 Z9 459 U1 1 U2 18 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 JAN PY 2003 VL 188 IS 1 BP 100 EP 107 DI 10.1067/mob.2003.99 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 640FD UT WOS:000180676900018 PM 12548202 ER PT J AU Tran-Thanh, D Provencher, D Koushik, A Duarte-Franco, E Kessous, A Drouin, P Wheeler, CM Dubuc-Lissoir, J Gauthier, P Allaire, G Vauclair, R DiPaolo, JA Gravitt, P Franco, E Coutlee, F AF Tran-Thanh, D Provencher, D Koushik, A Duarte-Franco, E Kessous, A Drouin, P Wheeler, CM Dubuc-Lissoir, J Gauthier, P Allaire, G Vauclair, R DiPaolo, JA Gravitt, P Franco, E Coutlee, F TI Herpes simplex virus type II is not a cofactor to human papillomavirus in cancer of the uterine cervix SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE herpes simplex virus-2; human papillomavirus; cervical cancer; Chlamydia trachomatis ID POLYMERASE CHAIN-REACTION; HUMAN GENITAL TUMORS; INTRAEPITHELIAL NEOPLASIA; CHLAMYDIA-TRACHOMATIS; TRANSFORMING FRAGMENT; N-FRAGMENT; INFECTION; RISK; KERATINOCYTES; ASSOCIATION AB OBJECTIVE: Cells that were cotransfected with herpes simplex virus-16 and the herpes simplex virus type 2 Xho-2 DNA induce tumors in nude mice. In a cross-sectional study, we investigated the role of herpes simplex virus type 2 as a cofactor to human papillomavirus in cervical cancer. STUDY DESIGN: Cervical cells that were obtained with an endocervical Cytobrush brush. (Medscand) from 439 women (50 women with cancer lesions, 65 women with high-grade squamous intraepithelial lesions, 80 women with low-grade squamous intraepithelial lesions, 244 healthy subjects) and DNA that was extracted from 150 cervical cancer biopsy specimens were analyzed with polymerase chain reaction for herpes simplex virus type 2 Xho-2 and Bgl IIC transforming DNA sequences. RESULTS: All 439 cervical samples and 150 cervical cancer biopsy specimens tested negative for herpes simplex virus type 2 Xho-2 and Bgl IIC DNA by polymerase chain reaction. Overall, none of 200 samples (0%) from women with invasive cervical cancer contained herpes simplex virus type 2 Xho-2 or Bgl IIC DNA (95% CI, 0.0-1.8). CONCLUSION: Although herpes simplex virus type 2 BglIIN transforms epithelial cells in vitro, it was not detected in cervical cancer specimens. C1 Univ Montreal, Ctr Hosp, Dept Microbiol Infectiol, Montreal, PQ, Canada. Univ Montreal, Ctr Hosp, Dept Obstet Gynecol, Montreal, PQ, Canada. Univ Montreal, Ctr Hosp, Dept Pathol, Montreal, PQ, Canada. McGill Univ, Div Canc Epidemiol, Montreal, PQ, Canada. Univ New Mexico, Sch Med, Dept Mol Genet & Microbiol, Epidemiol & Canc Control Program, Albuquerque, NM 87131 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Coutlee, F (reprint author), Univ Montreal, Ctr Hosp, Hop Notre Dame, Dept Microbiol & Infectiol, 1560 Sherbrooke Est, Montreal, PQ H2L 4M1, Canada. OI Koushik, Anita/0000-0001-5304-7660; Franco, Eduardo/0000-0002-4409-8084 NR 31 TC 25 Z9 28 U1 0 U2 3 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 JAN PY 2003 VL 188 IS 1 BP 129 EP 134 DI 10.1067/mob.2003.66 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 640FD UT WOS:000180676900022 PM 12548206 ER PT J AU Rouse, DJ Hirtz, DG Thom, E AF Rouse, DJ Hirtz, DG Thom, E TI Association between use of antenatal magnesium sulfate in preterm labor and adverse health outcomes in infants SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Letter ID TOTAL PEDIATRIC MORTALITY C1 Univ Alabama, OHB 457, Birmingham, AL 35249 USA. NINDS, Rockville, MD USA. George Washington Univ, Ctr Biostat, Washington, DC USA. RP Rouse, DJ (reprint author), Univ Alabama, OHB 457, 619 St S, Birmingham, AL 35249 USA. NR 4 TC 3 Z9 3 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD JAN PY 2003 VL 188 IS 1 BP 295 EP 295 DI 10.1067/mob.2003.130 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 640FD UT WOS:000180676900051 PM 12548234 ER PT J AU Cleveland, A Westergaard, GC Hoos, B Chavanne, TJ Shoaf, SE Snoy, PJ Suomi, SJ Higley, JD AF Cleveland, A Westergaard, GC Hoos, B Chavanne, TJ Shoaf, SE Snoy, PJ Suomi, SJ Higley, JD TI Serotonergic influences on life history outcomes in free-ranging male primates SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract C1 LABS Virginia Inc, Div Res & Dev, Yemassee, SC USA. NIAAA, Clin Studies Lab, NIH, Bethesda, MD USA. US FDA, Div Vet Serv, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. NICHHD, Lab Comparat Ethol, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PY 2003 SU 36 BP 77 EP 77 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 657MB UT WOS:000181670000088 ER PT J AU Czarnecki, JM Friedlaender, JS Mgone, CS Koki, G Stoner, GL AF Czarnecki, JM Friedlaender, JS Mgone, CS Koki, G Stoner, GL TI Virus genotypes in Papua New Guinea. SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract C1 Temple Univ, Philadelphia, PA 19122 USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PY 2003 SU 36 BP 82 EP 83 PG 2 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 657MB UT WOS:000181670000109 ER PT J AU Gonder, MK Norman, JE Furano, AV AF Gonder, MK Norman, JE Furano, AV TI LINE-1 evolutionary dynamics among apes. SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract C1 NIDDK, Sect Gen Struct & Funct, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Biol, College Pk, MD 20742 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PY 2003 SU 36 BP 102 EP 102 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 657MB UT WOS:000181670000184 ER PT J AU Hill, CA Reeves, RH Epstein, CJ Valeri, C Lindsay, ES Baxter, LA Cole, TM Richtsmeier, JT AF Hill, CA Reeves, RH Epstein, CJ Valeri, C Lindsay, ES Baxter, LA Cole, TM Richtsmeier, JT TI Developmental instability and skeletal phenotypes in Down syndrome. SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract C1 Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NHGRI, Bethesda, MD 20892 USA. Univ Missouri, Sch Med, Kansas City, MO 64108 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PY 2003 SU 36 BP 114 EP 114 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 657MB UT WOS:000181670000231 ER PT J AU Mulligan, CJ Osier, MV Sambuughin, N Kittles, RA Goldman, D Long, JC AF Mulligan, CJ Osier, MV Sambuughin, N Kittles, RA Goldman, D Long, JC TI Allelic variation at alcohol metabolism genes and alcohol dependence in an American Indian population. SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Meeting Abstract C1 Univ Florida, Dept Anthropol, Gainesville, FL 32611 USA. Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. St Josephs Hosp, Barrow Neurol Inst, Phoenix, AZ 85013 USA. Med Ctr, Phoenix, AZ USA. Howard Univ, Washington, DC 20059 USA. NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PY 2003 SU 36 BP 156 EP 156 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 657MB UT WOS:000181670000393 ER PT J AU Cintas, HL Siegel, KL Furst, GP Gerber, LH AF Cintas, HL Siegel, KL Furst, GP Gerber, LH TI Brief assessment of motor function - Reliability and concurrent validity of the Gross Motor Scale SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article; Proceedings Paper CT Annaul Meeting of the American-Academy-of-Cerebral-Palsy-and-Developmental-Medicine CY SEP 21, 2000 CL TORONTO, CANADA SP American Acad Cerebral palsy Dev Med DE rehabilitation; disabled children; osteogenesis imperfecta; walking ID CHILDREN AB Objective: The Brief Assessment of Motor Function (BAMF) is a series of 10-point ordinal scales developed for rapid description of gross motor, fine motor, and oral motor performance. We examined interrater and intrarater reliability and concurrent validity of the BAMF Gross Motor Scale. Design: This validation study included 48 children (age, 5 mo to 17 yr) with a wide range of gross motor capability. Ten children with varied diagnoses participated in the reliability study. For concurrent validity, the BAMF performance of 38 children with osteogenesis imperfecta was compared with scores on the Peabody Developmental Motor Scales, laboratory gait analysis, and manual muscle testing. Results: Reliability values for intraclass correlations were 0.996 (interrater) and 1.00 (intrarater). Significant relationships were identified between the BAMF and gait speed (r=0.68, P<0.0001), stride length (r=0.71, P<0.0001), duration of double-limb support (r=-0.40, P<0.03), number of weak muscles (r=-0.74, P<0.0001), and the Peabody Developmental Motor Scales (r=0.95, P<0.0001). Number of weak muscles was the strongest predictor of BAMF score (R-2=0.5080, F=24.77, P<0.0001). Conclusions: The BAMF demonstrates good reliability for children with a range of diagnoses and acceptable concurrent validity with gross motor development, muscle strength, and formal gait assessment in children with osteogenesis imperfecta. C1 NIH, Warren G Magnuson Clin Ctr, Dept Rehabil Med, Bethesda, MD 20892 USA. RP Cintas, HL (reprint author), NIH, Phys Therapy Rehabil Med Dept, Bldg 10,Room 6 S 235, Bethesda, MD 20892 USA. RI Siegel, Karen Lohmann/B-5898-2008; OI Siegel, Karen Lohmann/0000-0002-0788-6612 NR 32 TC 17 Z9 21 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD JAN PY 2003 VL 82 IS 1 BP 33 EP 41 DI 10.1097/01.PHM.0000043767.35490.42 PG 9 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 632AA UT WOS:000180199700006 PM 12510183 ER PT J AU Steenbergen, C Afshari, CA Petranka, JG Collins, J Martin, K Bennett, L Haugen, A Bushel, P Murphy, E AF Steenbergen, C Afshari, CA Petranka, JG Collins, J Martin, K Bennett, L Haugen, A Bushel, P Murphy, E TI Alterations in apoptotic signaling in human idiopathic cardiomyopathic hearts in failure SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE TNF-alpha; GADD45 beta; BAD; gene profiling ID TUMOR-NECROSIS-FACTOR; FAILING HUMAN HEART; PROTEIN-KINASE; FACTOR-ALPHA; GENE-EXPRESSION; CELL-SURVIVAL; MAP KINASE; KAPPA-B; PHOSPHORYLATION; BAD AB Dilated cardiomyopathy, a disease of unknown etiology and pathogenesis, is associated with heart failure and compensatory hypertrophy. Although cell and animal models suggest a role for altered gene expression in the transition to heart failure, there is a paucity of data derived from the study of human heart tissue. In this study, we used DNA microarray profiling to investigate changes in the expression of genes involved in apoptosis that occur in human idiopathic dilated cardiomyopathic hearts that had progressed to heart failure. We observed altered gene expression consistent with a proapoptotic shift in the TNF-alpha signaling pathway. Specifically, we found decreased expression of TNF-alpha- and NF-kappaB-induced antiapoptotic genes such as growth arrest and DNA damage-inducible (GADD)45beta, Flice inhibitory protein (FLIP), and TNF-induced protein 3 (A20). Consistent with a role for apoptosis in heart failure, we also observed a significant decrease in phosphorylation of BAD at Ser-112. This study identifies several pathways that are altered in human heart failure and provides new targets for therapy. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. NIEHS, Microarray Ctr, NIH, Res Triangle Pk, NC 27709 USA. RP Murphy, E (reprint author), NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. FU NHLBI NIH HHS [R01 HL039752, R01-HL-39752] NR 29 TC 46 Z9 49 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 JAN PY 2003 VL 284 IS 1 BP H268 EP H276 DI 10.1152/ajpheart.00707.2002 PG 9 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 626DW UT WOS:000179857900032 PM 12388275 ER PT J AU Brooks, HL Ageloff, S Kwon, TH Brandt, W Terris, JM Seth, A Michea, L Nielsen, S Fenton, R Knepper, MA AF Brooks, HL Ageloff, S Kwon, TH Brandt, W Terris, JM Seth, A Michea, L Nielsen, S Fenton, R Knepper, MA TI cDNA array identification of genes regulated in rat renal medulla in response to vasopressin infusion SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE aldosterone; kidney; sodium; epithelia ID COLLECTING DUCT; UREA TRANSPORTER; AQUAPORIN-2 TRAFFICKING; INDUCED ANTIDIURESIS; MEDIATED REGULATION; SODIUM-TRANSPORT; PLASMA-MEMBRANE; IN-VIVO; KIDNEY; PROTEIN AB With the aim of identifying possible gene targets for direct or indirect regulation by vasopressin in the renal medulla, we have carried out cDNA array experiments in inner medullas of Brattleboro rats infused with the V(2) receptor-selective vasopressin analog desamino-Cys1,D-Arg8 vasopressin (dDAVP) for 72 h. Of the 1,176 genes on the array, 137 transcripts were increased by 2-fold or more, and 10 transcripts were decreased to 0.5-fold or less. Quantitative, real-time RT-PCR measurements confirmed increases seen for six selected transcripts (Wilms' tumor protein, beta-arrestin 2, neurofibromin, casein kinase IIbeta, aquaporin-3, and aquaporin-4). To correlate changes in mRNA expression with changes in protein expression, we carried out quantitative immunoblotting for 28 of the proteins whose cDNAs were on the array. For several targets including aquaporin-2, transcript abundance and protein abundance changes did not correlate. However, for most genes examined, changes in mRNA abundances were associated with concomitant protein abundance changes. Targets with demonstrated increases in both protein and mRNA abundances included neurofibromin, casein kinase IIbeta, the beta-subunit of the epithelial Na channel (beta-ENaC), 11beta-hydroxysteroid dehydrogenase type 2, and c-Fos. Additional cDNA arrays revealed that several transcripts that were increased in abundance after 72 h of dDAVP were also increased after 4 h, including casein kinase IIbeta, beta-ENaC, aquaporin-3, UT-A, and syntaxin 2. These studies have identified several transcripts whose abundances are regulated in the inner medulla in response to infusion of dDAVP and that could play roles in the regulation of salt and water excretion. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Aarhus Univ, Inst Anat, Dept Cell Biol, DK-8000 Aarhus C, Denmark. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Rm 6N260,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. EM knep@helix.nih.gov FU Intramural NIH HHS [Z99 HL999999, Z01 HL001285-21]; NHLBI NIH HHS [Z01-HL-01282-KE] NR 58 TC 59 Z9 62 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JAN PY 2003 VL 284 IS 1 BP F218 EP F228 DI 10.1152/ajprenal.00054.2002 PG 11 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 623NK UT WOS:000179709600024 PM 12388413 ER PT J AU Li, CL Wang, WD Kwon, TH Knepper, MA Nielsen, S Frokiaer, J AF Li, CL Wang, WD Kwon, TH Knepper, MA Nielsen, S Frokiaer, J TI Altered expression of major renal Na transporters in rats with unilateral ureteral obstruction SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE thick ascending limb of Henle's loop; collecting duct; proximal tubule; distal convoluted tubule; obstructive nephropathy; sodium excretion ID THICK ASCENDING LIMB; K-CL COTRANSPORTER; HENLES LOOP; CHLORIDE TRANSPORT; NEPHRON SEGMENTS; POSTOBSTRUCTIVE DIURESIS; CONCENTRATING DEFECT; PROXIMAL TUBULE; COLLECTING DUCT; VASOPRESSIN AB It has been demonstrated previously that ureteral obstruction was associated with downregulation of renal AQP2 expression and an impaired urinary concentrating capacity (Li C, Wang W, Kwon TH, Isikay L, Wen JG, Marples D, Djurhuus JC, Stockwell A, Knepper MA, Nielsen S, and Frokiaer J. Am J Physiol Renal Physiol 281: F163-F171, 2001). In the present study, changes in the expression of major renal Na transporters were examined in a rat model with 24 h of unilateral ureteral obstruction (UUO) to clarify the molecular mechanisms of the marked natriuresis seen after release of UUO. Urine collection for 2 h after release of UUO revealed a significant reduction in urinary osmolality, solute-free water reabsorption, and a marked natriuresis (0.29 +/- 0.03 vs. 0.17 +/- 0.03 mumol/min, P < 0.05). Consistent with this, immunoblotting revealed significant reductions in the abundance of major renal Na transporters: type 3 Na(+)/H(+) exchanger (NHE3; 24 +/- 4% of sham-operated control levels), type 2 Na-P(i) cotransporter (NaPi-2; 21 +/- 4%), Na-K-ATPase (37 +/- 4%), type 1 bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1; 15 +/- 3%), and thiazide-sensitive Na-Cl cotransporter (TSC; 15 4%). Immunocytochemistry confirmed the downregulation of NHE3, BSC-1, and TSC in response to obstruction. In nonobstructed contralateral kidneys, a significant reduction in the abundance of inner medullary Na-K-ATPase and cortical NaPi-2 was found. This may contribute to the compensatory increase in urinary production (23 +/- 2 vs. 13 +/- 1 mu l.min(-1).kg(-1)) and increased fractional excretion of urinary Na (0.62 +/- 0.03 vs. 0.44 +/- 0.03%, P < 0.05). In conclusion, downregulation of major renal Na transporters in rats with UUO may contribute to the impairment in urinary concentrating capacity and natriuresis after release of obstruction, and reduced levels of Na-K-ATPase and NaPi-2 in the contralateral nonobstructed kidney may contribute to the compensatory increase in water and Na excretion from that kidney during UUO and after release of obstruction. C1 Univ Aarhus, Aarhus Univ Hosp Skejby, Dept Clin Physiol, DK-8200 Aarhus N, Denmark. Univ Aarhus, Aarhus Univ Hosp Skejby, Inst Expt Clin Res, DK-8200 Aarhus N, Denmark. Aarhus Univ, Inst Anat, Dept Cell Biol, DK-8000 Aarhus C, Denmark. Aarhus Univ, Water & Salt Res Ctr, DK-8000 Aarhus C, Denmark. Dongguk Univ, Sch Med, Dept Physiol, Kyungju 780714, South Korea. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Frokiaer, J (reprint author), Aarhus Univ, Hosp Skejby, Inst Expt Clin Res, DK-8200 Aarhus, Denmark. EM JF@IEKF.AU.DK FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 50 TC 40 Z9 41 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 JAN PY 2003 VL 284 IS 1 BP F155 EP F166 DI 10.1152/ajprenal.00272.2002 PG 12 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 623NK UT WOS:000179709600017 PM 12388400 ER PT J AU Na, KY Oh, YK Han, JS Joo, KW Lee, JS Earm, JH Knepper, MA Kim, GH AF Na, KY Oh, YK Han, JS Joo, KW Lee, JS Earm, JH Knepper, MA Kim, GH TI Upregulation of Na+ transporter abundances in response to chronic thiazide or loop diuretic treatment in rats SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE collecting duct; epithelial sodium channel; distal convoluted tubule; thiazide-sensitive sodium-chloride cotransporter ID DISTAL CONVOLUTED TUBULE; COLLECTING DUCT; MEDIATED REGULATION; ALTERED EXPRESSION; CL COTRANSPORTER; K-ATPASE; CHANNEL; ALDOSTERONE; ENAC; KIDNEY AB Furosemide and hydrochlorothiazide (HCTZ) exert their diuretic actions by binding to apical Na+ transporters, viz., the Na+-K+-2Cl(-) cotransporter in the thick ascending limb and the Na+-Cl- cotransporter in the distal convoluted tubule, respectively. We carried out semiquantitative immunoblotting and immunohistochemistry of rat kidneys to investigate whether chronic administration of furosemide or HCTZ is associated with compensatory changes in the abundance of Na+ transporters downstream from the primary site of action. Osmotic minipumps were implanted into Sprague-Dawley rats to deliver furosemide (12 mg/day) or HCTZ (3.75 mg/day) for 7 days. To prevent volume depletion, all animals were offered tap water and a solution containing 0.8% NaCl and 0.1% KCl as drinking fluid. The diuretic/natriuretic response was quantified in response to both agents by using quantitative urine collections. Semiquantitative immunoblotting revealed that the abundances of thick ascending limb Na+-K+-2C1(-) cotransporter and all three subunits of the epithelial Na+ channel (ENaC) were increased by furosemide infusion. HCTZ infusion increased the abundances of thiazide-sensitive Na+-Cl- cotransporter and beta-ENaC in the cortex and beta- and gamma-ENaC in the outer medulla. Consistent with these results, beta-ENaC immunohistochemistry showed a remarkable increase in immunoreactivity in the principal cells of collecting ducts with either diuretic treatment. These increases in the abundance of Na+ transporters in response to chronic diuretic treatment may account for the generation of diuretic tolerance associated with long-term diuretic use. C1 Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul Natl Univ Hosp,Clin Res Inst, Seoul 110744, South Korea. Eulji Med Coll, Dept Internal Med, Seoul 110744, South Korea. Hallym Univ, Hangang Sacred Heart Hosp, Dept Internal Med, Seoul 110744, South Korea. Chungbuk Natl Univ, Dept Internal Med, Seoul 361711, South Korea. NIH, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. RP Han, JS (reprint author), Seoul Natl Univ, Coll Med, Dept Internal Med, 28 Yongun Dong, Seoul 110744, South Korea. EM jshan@snu.ac.kr RI Oh, Yun Kyu/J-5542-2012; Han, Jin-Suk/J-5711-2012; Na, Ki Young/J-5456-2012; Joo, Kwon Wook/J-5675-2012 FU Intramural NIH HHS [Z99 HL999999, Z01 HL001285-21] NR 42 TC 53 Z9 53 U1 0 U2 4 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 JAN PY 2003 VL 284 IS 1 BP F133 EP F143 DI 10.1152/ajprenal.00227.2002 PG 11 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 623NK UT WOS:000179709600015 PM 12388392 ER PT J AU Wall, SM Hassell, KA Royaux, IE Green, ED Chang, JY Shipley, GL Verlander, JW AF Wall, SM Hassell, KA Royaux, IE Green, ED Chang, JY Shipley, GL Verlander, JW TI Localization of pendrin in mouse kidney SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE intercalated cell; distal convoluted tubule; cortical collecting duct; connecting tubule; anion exchange ID CORTICAL COLLECTING DUCT; INTERCALATED CELL SUBTYPES; APICAL ANION-EXCHANGER; RAT-KIDNEY; SYNDROME GENE; H+-ATPASE; BICARBONATE SECRETION; METABOLIC-ACIDOSIS; BAND-3; TRANSPORT AB Pendrin is an anion exchanger expressed in type B intercalated cells of the cortical collecting duct (CCD). Whether pendrin localizes to other nephron segments with intercalated cells is unknown. Moreover, whether pendrin is expressed in proximal tubule is debated. Thus the distribution of pendrin mRNA and protein expression in mouse kidney was investigated by using light and electron microscopic immunohistochemistry and quantitative real-time PCR. We observed that pendrin mRNA is expressed mainly in cortex. Within cortex, pendrin mRNA is at least fivefold higher in CCD and the connecting tubule (CNT) than in the other segments. Pendrin protein was observed in a subset of cells within the distal convoluted tubule as well as in type B and in non-A-non-B intercalated cells of the CNT and CCD. In type B intercalated cells, pendrin immunoreactivity was highest in apical cytoplasmic vesicles with little immunolabel along the apical plasma membrane. In non-A-non-B intercalated cells, intense pendrin immunoreactivity was detected along the apical plasma membrane. These differences in the subcellular distribution of pendrin immunolabel were confirmed by morphometric analysis. In conclusion, pendrin is expressed in the mouse distal convoluted tubule, CCD, and CNT along the apical plasma membrane of non-A-non-B intercalated cells and in subapical cytoplasmic vesicles of type B intercalated cells. C1 Univ Texas, Sch Med, Dept Med, Houston, TX 77030 USA. Univ Texas, Sch Med, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Univ Florida, Coll Med, Dept Med, Gainesville, FL 32610 USA. RP Wall, SM (reprint author), Emory Univ, Sch Med, Div Renal, WMRB, Rm 338,1639 Pierce Dr NE, Atlanta, GA 30322 USA. RI Verlander, Jill/I-5991-2015 FU NIDDK NIH HHS [DK-52935] NR 35 TC 102 Z9 102 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JAN PY 2003 VL 284 IS 1 BP F229 EP F241 DI 10.1152/ajprenal.00147.2002 PG 13 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 623NK UT WOS:000179709600025 PM 12388426 ER PT J AU Denny, CH Serdula, MK Holtzman, D Nelson, DE AF Denny, CH Serdula, MK Holtzman, D Nelson, DE TI Physician advice about smoking and drinking - are US adults being informed? SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID UNITED-STATES; ALCOHOL; HEALTH; RISK; INTERVENTIONS; PREVENTION; STRATEGIES; PREDICTORS; BEHAVIOR; SERVICES AB Background: Population-based estimates for the prevalence of smokers receiving advice from a health professional to quit smoking and the prevalence of binge drinkers being talked to about alcohol use are lacking for U.S. adults. This information is useful for clinicians and public health professionals. Methods: Data are from the Behavioral Risk Factor Surveillance System, a continuous random-digit-dial telephone survey of U.S. adults. In 1997, 10 states collected data on these health interventions for tobacco and alcohol use. The prevalence of professional advice to quit smoking and about alcohol use was calculated and examined by demographic characteristics. The number of at-risk adults who had a routine checkup in the last year and had not received these interventions was also estimated. Results: By self-report, 70% of smokers were advised to quit, and 23% of binge drinkers were talked to about their alcohol use. Using multivariate logistic regression analyses, we found among smokers that women and older persons were more likely to receive advice; among binge drinkers, health intervention was more likely to occur for men and non-Hispanic blacks. Across the 10 states, approximately 2 million smokers and 2 million binge drinkers with a routine checkup in the past 12 months were not advised to quit smoking or talked to about their alcohol use. Conclusions: Many opportunities to intervene with smokers and binge drinkers are lost. Efforts to increase physician education and to identify and reduce other barriers may help. C1 Ctr Dis Control & Prevent, Div Adult & Community Hlth, Atlanta, GA 30341 USA. Ctr Dis Control & Prevent, Div Nutr & Phys Act, Atlanta, GA USA. NCI, NIH, Bethesda, MD 20892 USA. RP Denny, CH (reprint author), Ctr Dis Control & Prevent, Div Adult & Community Hlth, 4770 Buford Highway NE,MS K-66, Atlanta, GA 30341 USA. NR 40 TC 66 Z9 67 U1 4 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD JAN PY 2003 VL 24 IS 1 BP 71 EP 74 AR PII S0749-3797(02)00568-8 DI 10.1016/S0749-3797(02)00568-8 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 634EA UT WOS:000180326000010 PM 12554026 ER PT J AU Ernst, M Grant, SJ London, ED Contoreggi, CS Kimes, AS Spurgeon, L AF Ernst, M Grant, SJ London, ED Contoreggi, CS Kimes, AS Spurgeon, L TI Decision making in adolescents with behavior disorders and adults with substance abuse SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID DEFICIT-HYPERACTIVITY DISORDER; CARD SORTING TEST; VENTROMEDIAL PREFRONTAL CORTEX; FUTURE CONSEQUENCES; RESPONSE COST; ATTENTION; CHILDREN; PERFORMANCE; ADHD; REWARD AB Objective: The study assessed the validity of the Gambling Task as a test of decision-making ability in adolescents and examined whether adolescents with behavior disorders, who are at risk for substance abuse, have deficits in decision making similar to those exhibited by adults with substance abuse. Method: Performance on the Gambling Task in two testing sessions separated by 1 week was assessed in 64 12-14-year-old adolescents (31 healthy, 33 with externalizing behavior disorders) and 52 adults (22 healthy, 30 with substance abuse). Results: The healthy adolescents and the healthy adults had similar performance on the Gambling Task. Adolescents with behavior disorders performed more poorly than healthy adolescents, but only in the second testing session. In adults, overall Gambling Task performance did not differ between the healthy and substance abuse groups at either testing session, indicating no difference in learning of decision-making strategies between groups. However, adults with substance abuse performed more poorly than healthy adults during an early stage of the task, when participants presumably begin to understand the rewards and penalties involved in the task but a re not yet sure of the actual risk of incurring penalities. Conclusions: The Gambling Task can be used with adolescents. Testing with the Gambling Task revealed a deficit in decision making in adolescents with behavior disorders, who are at risk for substance abuse. This deficit may represent a vulnerability factor-for the development of substance abuse. C1 NIDA, Baltimore, MD 21224 USA. NIMH, Mood & Anxiety Disorders Program, Rockville, MD 20857 USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Biobehav Sci, Los Angeles, CA USA. Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA USA. RP Ernst, M (reprint author), NIMH, MAP, NIH, 15K North Dr,Room 118,MSC 2670, Bethesda, MD 20892 USA. NR 55 TC 159 Z9 164 U1 5 U2 19 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JAN PY 2003 VL 160 IS 1 BP 33 EP 40 DI 10.1176/appi.ajp.160.1.33 PG 8 WC Psychiatry SC Psychiatry GA 631YG UT WOS:000180195400008 PM 12505799 ER PT J AU Raedler, TJ Knable, MB Jones, DW Urbina, RA Gorey, JG Lee, KS Egan, MF Coppola, R Weinberger, DR AF Raedler, TJ Knable, MB Jones, DW Urbina, RA Gorey, JG Lee, KS Egan, MF Coppola, R Weinberger, DR TI In vivo determination of muscarinic acetylcholine receptor availability in schizophrenia SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; STRIATAL DOPAMINE RELEASE; CHOLINERGIC RECEPTORS; IN-VIVO; NEGATIVE SYMPTOMS; D2 DOPAMINE; NEUROTRANSMITTER RECEPTORS; COMPUTERIZED-TOMOGRAPHY; CHRONIC FLUPHENAZINE; CAUDATE-PUTAMEN AB Objective: Postmortem studies have implicated the central muscarinic acetylcholine system in schizophrenia. However, central muscarinic receptor availability has not previously been studied in vivo. Using [1-123]iodoquinuclidinyl benzilate ([I-123]IQNB) single photon emission computed tomography (SPECT), the authors sought to compare the muscarinic receptor availability in vivo in unmedicated patients with schizophrenia and normal subjects. Method: Twelve medication-free patients with schizophrenia underwent an [I-123]IQNB SPECT scan during approximate-equilibrium conditions. A group of,10 age- and gender-matched normal comparison subjects were given the same kind of scan under similar conditions. Regions of interest were analyzed in the cortex, basal ganglia, thalamus, and pons. Binding data were analyzed as nCi/ml tissue per mCi injected dose. Results: Muscarinic receptor availability was significantly less in patients with schizophrenia than in normal subjects in all regions of interest except the pons. Reductions ranged from -33% in the caudate to -20% in the occipital cortex. Positive symptoms of schizophrenia correlated negatively with muscarinic receptor availability in the striatum and the frontal cortex. Conclusions: These results indicate a reduction in muscarinic acetylcholine receptor availability in vivo in unmedicated patients with schizophrenia, confirming results from postmortem studies and adding further evidence that the muscarinic system is involved in the pathophysiology of schizophrenia. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Programs, NIH, Bethesda, MD 20892 USA. Univ Hamburg, Dept Psychiat, Hamburg, Germany. Stanley Res Fdn, Bethesda, MD USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Programs, NIH, 10 Ctr Dr,4S-235,MSC 1379, Bethesda, MD 20892 USA. NR 63 TC 126 Z9 128 U1 2 U2 2 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JAN PY 2003 VL 160 IS 1 BP 118 EP 127 DI 10.1176/appi.ajp.160.1.118 PG 10 WC Psychiatry SC Psychiatry GA 631YG UT WOS:000180195400019 PM 12505810 ER PT J AU Keller, A Castellanos, FX Vaituzis, AC Jeffries, NO Giedd, JN Rapoport, JL AF Keller, A Castellanos, FX Vaituzis, AC Jeffries, NO Giedd, JN Rapoport, JL TI Progressive loss of cerebellar volume in childhood-onset schizophrenia SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID COGNITIVE DYSMETRIA; BRAIN ABNORMALITIES; 4TH VENTRICLE; VERMIS; MRI; MORPHOLOGY; ADOLESCENCE; CIRCUITS; ATROPHY; DYSFUNCTION AB Objective: Childhood-onset schizophrenia is a severe and unremitting form of the disorder. Prospective brain magnetic resonance imaging (MRI) studies have found progressive loss of total cerebral volume during adolescence, primarily attributable to accelerated loss of cortical gray matter. Because there is evidence of cerebellar involvement in schizophrenia, the authors examined cerebellar volume and its relation to cortical gray matter development during adolescence in patients with childhood-onset schizophrenia and healthy comparison subjects. Method: Total cerebellar volume was algorithmically calculated for 108 anatomical brain MRI scans from 50 patients (20 of whom were female) and 101 scans from 50 age- and gender-matched healthy volunteers (20 of whom were female). The age range of the patients and comparison subjects was 8 to 24. Midsagittal vermal area and posterior-inferior vermal lobe volume were measured by hand. Prospective rescans were obtained at approximately 2-year intervals. Cross-sectional and longitudinal data were combined in mixed model regressions to compare developmental changes for the groups. Results: In contrast to healthy volunteers, patients with schizophrenia showed a progressive loss of cerebellar volume during adolescence. Cerebellar and cerebral volume decreases were significantly correlated in childhood-onset schizophrenia. Conclusions: Childhood-onset schizophrenia is associated with significant progressive loss of cerebellar volume during adolescence, consistent with previously reported decreases in total cerebral and cortical gray matter. At least in these patients with severe early-onset schizophrenia, the loss appears secondary to a generalized process. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Rapoport, JL (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Rm 3N 202, Bethesda, MD 20892 USA. RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 NR 59 TC 67 Z9 70 U1 2 U2 3 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JAN PY 2003 VL 160 IS 1 BP 128 EP 133 DI 10.1176/appi.ajp.160.1.128 PG 6 WC Psychiatry SC Psychiatry GA 631YG UT WOS:000180195400020 PM 12505811 ER PT J AU Birn, AE Brown, TM Fee, E Lear, WJ AF Birn, AE Brown, TM Fee, E Lear, WJ TI Struggles for national health reform in the United States SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article AB Highlights in a century of popular efforts to achieve a national system of health care in the United States. C1 New Sch Univ, Robert J Milano Grad Sch, Grad Sch Management & Urban Policy, New York, NY 10011 USA. Univ Rochester, Dept Hist, Rochester, NY USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY USA. NIH, Natl Lib Med, Hist Med Div, Bethesda, MD 20892 USA. Inst Social Med & Community Hlth, Philadelphia, PA USA. RP Birn, AE (reprint author), New Sch Univ, Robert J Milano Grad Sch, Grad Sch Management & Urban Policy, 72 5th Ave,Room 503, New York, NY 10011 USA. NR 20 TC 8 Z9 8 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD JAN PY 2003 VL 93 IS 1 BP 86 EP 91 DI 10.2105/AJPH.93.1.86 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 632MR UT WOS:000180227500023 PM 12511391 ER PT J AU Garayoa, M Man, YG Martinez, A Cuttitta, F Mulshine, JL AF Garayoa, M Man, YG Martinez, A Cuttitta, F Mulshine, JL TI Downregulation of hnRNP A2/B1 expression in tumor cells under prolonged hypoxia SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article ID INDUCIBLE FACTOR-I; HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN-A2/B1; MESSENGER-RNA STABILITY; LUNG-CANCER DETECTION; TRANSCRIPTION; PROTEIN; BINDING; OVEREXPRESSION; MECHANISM; THERAPY AB Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 has been previously shown to be overexpressed in breast and lung tumors. Because hypoxia is a feature inherent in solid tumors, the regulation of hnRNP A2/B1 expression and subcellular localization under hypoxic conditions was studied on human lung and breast carcinoma cell lines. We found that sustained hypoxic treatment downregulated hnRNP A2/B1 expression in MCF7 and H157 cell lines. Northern blot analysis showed that this decay: (i) was observed as a marked diminution of transcript levels after 24-48 h of exposure to low oxygen tension; (ii) is not mediated by the transcription factor, hypoxia inducible factor-1; and (iii) is partially dependent on a higher hnRNP A2/B1 messenger RNA turnover under hypoxic than normoxic conditions. Immunocytochemical staining also showed a significant diminution of hnRNP A2/B1 staining in these cell lines after 24-48 h of hypoxia, together with a predominant loss of cytoplasmic staining. Further investigations are warranted to evaluate the relevance of modulation of hnRNP A2/B1 in hypoxic environments relative to its previously reported utility as a marker of early lung carcinogenesis. C1 NCI, Intervent Sect, Cell & Canc Biol Branch, CCR,NIH, Bethesda, MD 20892 USA. Univ Navarra, Dept Histol & Pathol, Carcinogenesis Unit, E-31080 Pamplona, Spain. Armed Forces Inst Pathol, Dept Gynecol & Breast Pathol, Washington, DC 20306 USA. RP Mulshine, JL (reprint author), NCI, Intervent Sect, Cell & Canc Biol Branch, CCR,NIH, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Martinez, Alfredo/A-3077-2013 OI Martinez, Alfredo/0000-0003-4882-4044 NR 37 TC 18 Z9 20 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD JAN PY 2003 VL 28 IS 1 BP 80 EP 85 DI 10.1165/rcmb.4880 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 630VU UT WOS:000180131500011 PM 12495935 ER PT B AU Burkhart, JG Bidwell, JR Fort, DJ Sheffield, SR AF Burkhart, JG Bidwell, JR Fort, DJ Sheffield, SR BE Linder, G Krest, SK Sparling, DW TI Chemical stressors SO AMPHIBIAN DECLINE: AN INTEGRATED ANALYSIS OF MULTIPLE STRESSOR EFFECTS LA English DT Proceedings Paper CT Workshop on Global Decline of Amphibian Populations CY AUG 18-23, 2001 CL Racine, WI ID FROG RANA-CLAMITANS; COAL COMBUSTION WASTE; BUFO-TERRESTRIS; PREDATOR AVOIDANCE; AQUATIC ORGANISMS; SOUTHERN TOADS; XENOPUS-LAEVIS; ACUTE TOXICITY; PHOTOCATALYTIC DEGRADATION; ENVIRONMENTAL CONTAMINANTS C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Burkhart, JG (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 94 TC 5 Z9 9 U1 0 U2 2 PU SETAC PRESS PI PENSACOLA PA 1010 N 12TH AVE, PENSACOLA, FL 32501 USA BN 1-880611-55-4 PY 2003 BP 111 EP 128 PG 18 WC Ecology; Zoology SC Environmental Sciences & Ecology; Zoology GA BY75H UT WOS:000189454800005 ER PT S AU Rogawski, MA Gryder, D Castaneda, D Yonekawa, W Banks, MK Li, H AF Rogawski, MA Gryder, D Castaneda, D Yonekawa, W Banks, MK Li, H BE ShinnickGallagher, P Pitkanen, A Shekhar, A Cahill, L TI GluR5 kainate receptors, seizures, and the amygdala SO AMYGDALA IN BRAIN FUNCTION: BACIC AND CLINICAL APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on the Amygdala in Brain Function CY JUN 24-26, 2002 CL GALVESTON, TEXAS SP Univ Texas Med Branch, NY Acad Sci, NIH, RW Johnson Pharmaceut Inst, NIA, Natl Inst Neurol Dis & Stroke DE amygdala; GluR5 kainate receptor; AMPA receptor; epilepsy; ATPA; LY293558; topiramate; synaptic transmission; synaptic plasticity ID EXCITATORY SYNAPTIC TRANSMISSION; RAT BASOLATERAL AMYGDALA; TEMPORAL-LOBE EPILEPSY; LONG-TERM POTENTIATION; MOSSY FIBER SYNAPSES; KAINIC ACID; HIPPOCAMPAL-NEURONS; EPILEPTIFORM ACTIVITY; SLICE CULTURES; PLASTICITY AB The amygdala is a critical brain region for limbic seizure activity, but the mechanisms underlying its epileptic susceptibility are obscure. Several lines of evidence implicate GluR5 (GLU(K5)) kainate receptors, a type of ionotropic glutamate receptor, in the amygdala's vulnerability to seizures and epileptogenesis. GluR5 mRNA is abundant in temporal lobe structures including the amygdala. Brain slice recordings indicate that GluR5 kainate receptors mediate a portion of the synaptic excitation of neurons in the rat basolateral amygdala. Whole-cell voltage-clamp studies demonstrate that GluR5 kainate receptor-mediated synaptic currents are inwardly rectifying and are likely to be calcium permeable. Prolonged activation of basolateral amygdala GluR5 kainate receptors results in enduring synaptic facilitation through a calcium-dependent process. The selective GluR5 kainate receptor agonist ATPA induces spontaneous epileptiform bursting that is sensitive to the GluR5 kainate receptor antagonist LY293558. Intra-amygdala infusion of ATPA in the rat induces limbic status epilepticus; in some animals, recurrent spontaneous seizures occur for months after the ATPA treatment. Together, these observations indicate that GluR5 kainate receptors have a unique role in triggering epileptiform activity in the amygdala and could participate in long-term plasticity mechanisms that underlie some forms of epileptogenesis. Accordingly, GluR5 kainate receptors represent a potential target for antiepileptic and antiepileptogenic drug treatments. Most antiepileptic drugs do not act through effects on glutamate receptors. However, topiramate at low concentrations causes slow inhibition of GluR5 kainate receptor-mediated synaptic currents in the basolateral amygdala, indicating that it may protect against seizures, at least in part, through suppression of GluR5 kainate receptor responses. C1 NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Psychiat, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Neurosci Program, Bethesda, MD 20814 USA. RP Rogawski, MA (reprint author), NINDS, Epilepsy Res Sect, NIH, Bldg 49,Room 5A75,49 Convent Dr MSC 4475, Bethesda, MD 20892 USA. RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 NR 62 TC 39 Z9 41 U1 0 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-404-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2003 VL 985 BP 150 EP 162 PG 13 WC Multidisciplinary Sciences; Neurosciences; Psychiatry SC Science & Technology - Other Topics; Neurosciences & Neurology; Psychiatry GA BW71H UT WOS:000182918800013 PM 12724156 ER PT S AU Drevets, WC AF Drevets, WC BE ShinnickGallagher, P Pitkanen, A Shekhar, A Cahill, L TI Neuroimaging abnormalities in the amygdala in mood disorders SO AMYGDALA IN BRAIN FUNCTION: BACIC AND CLINICAL APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on the Amygdala in Brain Function CY JUN 24-26, 2002 CL GALVESTON, TEXAS SP Univ Texas Med Branch, NY Acad Sci, NIH, RW Johnson Pharmaceut Inst, NIA, Natl Inst Neurol Dis & Stroke DE amygdala; neuroimaging; mood disorders ID MEDIAL PREFRONTAL CORTEX; CEREBRAL BLOOD-FLOW; POSITRON EMISSION TOMOGRAPHY; MAJOR DEPRESSIVE DISORDER; GLIAL-CELL DENSITY; BIPOLAR DISORDER; ANTIDEPRESSANT TREATMENTS; BASOLATERAL AMYGDALA; UNIPOLAR DEPRESSION; GLUCOSE-METABOLISM AB Neuroimaging technology has been applied to investigate the pathophysiology of mood disorders in studies aimed at characterizing the anatomical correlates of depressive symptoms, the neurophysiological effects of antidepressant treatments, and the trait-like abnormalities that persist despite symptom remission. These studies have identified cerebral blood flow and metabolic differences between depressives and controls in the amygdala and anatomically related areas of the prefrontal cortex, striatum, and thalamus. Taken together with converging evidence from neuroendocrine, lesion analysis, and postmortem studies of clinically depressed subjects, these data suggest that emotional/stress-response systems that include the amygdala are pathologically activated in major depression and that this activity is associated with dysfunction of the prefrontal cortex and monoamine neurotransmitter systems that normally modulate such responses. C1 NIMH, Mood & Anxiety Disorders Program, MIB, NIH, Bethesda, MD 20892 USA. RP Drevets, WC (reprint author), NIMH, Mood & Anxiety Disorders Program, MIB, NIH, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. NR 145 TC 287 Z9 298 U1 6 U2 15 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-404-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2003 VL 985 BP 420 EP 444 PG 25 WC Multidisciplinary Sciences; Neurosciences; Psychiatry SC Science & Technology - Other Topics; Neurosciences & Neurology; Psychiatry GA BW71H UT WOS:000182918800032 PM 12724175 ER PT S AU Hommer, DW Knutson, B Fong, GW Bennett, S Adams, CM Varner, JL AF Hommer, DW Knutson, B Fong, GW Bennett, S Adams, CM Varner, JL BE ShinnickGallagher, P Pitkanen, A Shekhar, A Cahill, L TI Amygdalar recruitment during anticipation of monetary rewards - An event-related fMRI study SO AMYGDALA IN BRAIN FUNCTION: BACIC AND CLINICAL APPROACHES SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on the Amygdala in Brain Function CY JUN 24-26, 2002 CL GALVESTON, TEXAS SP Univ Texas Med Branch, NY Acad Sci, NIH, RW Johnson Pharmaceut Inst, NIA, Natl Inst Neurol Dis & Stroke DE amygdala; fMRI; behavior; reward assessment C1 NIAAA, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. RP Hommer, DW (reprint author), NIAAA, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. OI Knutson, Brian/0000-0002-7669-426X NR 4 TC 36 Z9 36 U1 0 U2 6 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-404-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2003 VL 985 BP 476 EP 478 PG 3 WC Multidisciplinary Sciences; Neurosciences; Psychiatry SC Science & Technology - Other Topics; Neurosciences & Neurology; Psychiatry GA BW71H UT WOS:000182918800037 PM 12724180 ER PT J AU Blegen, H Will, JS Ghadimi, BM Nash, HP Zetterberg, A Auer, G Ried, T AF Blegen, H Will, JS Ghadimi, BM Nash, HP Zetterberg, A Auer, G Ried, T TI DNA amplifications and aneuploidy, high proliferative activity and impaired cell cycle control characterize breast carcinomas with poor prognosis SO ANALYTICAL CELLULAR PATHOLOGY LA English DT Article DE breast cancer; survival; CGH; cell cycle ID COMPARATIVE GENOMIC HYBRIDIZATION; POSTOPERATIVE RADIOTHERAPY; CANCER PATIENTS; OVARIAN-TUMORS; INHIBITOR P27; SURVIVAL; P53; HETEROZYGOSITY; EXPRESSION; INSTABILITY AB In order to explore whether specific cytogenetic abnormalities can be used to stratify tumors with a distinctly different clinical course, we performed comparative genomic hybridization (CGH) of tumors from patients who were diagnosed with metastatic disease after an interval of less than 2 years or who remained free from distant metastases for more than 10 years. All patients presented with distant metastases after mastectomy indicating that none of the patients in this study was cured and free of remaining tumor cells. Tumors in the group of short-term survivors showed a higher average number of chromosomal copy alterations compared to the long-term survivors. Of note, the number of sub-chromosomal high-level copy number increases (amplifications) was significantly increased in the group of short-term survivors. In both short- and long-term survivors recurrent chromosomal gains were mapped to chromosomes 1q, 4q, 8q, and 5p. Copy number changes that were more frequent in the group of short-term survivors included gains of chromosome 3q, 9p, 11p and 11q and loss of 17p. Our results indicate that low- and high grade malignant breast adenocarcinomas are characterized by a specific pattern of chromosomal copy number changes. Furthermore, immunohistochemical evaluation of the expression levels of Ki-67, p27(KIP1), p21(WAF1), p53, cyclin A and cyclin E revealed a correlation between increased proliferative activity and poor outcome. C1 NCI, Dept Genet, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, SE-17176 Stockholm, Sweden. RP Ried, T (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, Bldg 50,Rm 1306,50 South Dr, Bethesda, MD 20892 USA. NR 42 TC 22 Z9 23 U1 0 U2 0 PU IOS PRESS PI AMSTERDAM PA NIEUWE HEMWEG 6B, 1013 BG AMSTERDAM, NETHERLANDS SN 0921-8912 J9 ANAL CELL PATHOL JI Anal. Cell. Pathol. PY 2003 VL 25 IS 3 BP 103 EP 114 PG 12 WC Oncology; Cell Biology; Pathology SC Oncology; Cell Biology; Pathology GA 701FJ UT WOS:000184157300001 PM 12775914 ER PT J AU Adams, EW Ueberfeld, J Ratner, DM O'Keefe, BR Walt, DR Seeberger, PH AF Adams, EW Ueberfeld, J Ratner, DM O'Keefe, BR Walt, DR Seeberger, PH TI Encoded fiber-optic microsphere arrays for probing protein-carbohydrate interactions SO ANGEWANDTE CHEMIE-INTERNATIONAL EDITION LA English DT Article DE biosensors; carbohydrates; proteins ID ENVELOPE GLYCOPROTEIN GP120; CYANOVIRIN-N; MICROARRAYS; GLYCOSYLATION; BINDING C1 Tufts Univ, Dept Chem, Max Tishler Lab Organ Chem, Medford, MA 02155 USA. NCI, Mol Targets Dev Program, NCI Ctr Canc Res, Ft Detrick, MD 21702 USA. MIT, Dept Chem, Cambridge, MA 02139 USA. RP Walt, DR (reprint author), Tufts Univ, Dept Chem, Max Tishler Lab Organ Chem, Medford, MA 02155 USA. EM david.walt@tufts.edu; seeberg@mit.edu FU NIDCR NIH HHS [U01 DE14950-01] NR 21 TC 39 Z9 40 U1 0 U2 8 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1433-7851 J9 ANGEW CHEM INT EDIT JI Angew. Chem.-Int. Edit. PY 2003 VL 42 IS 43 BP 5317 EP 5320 DI 10.1002/anie.200351286 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 744DL UT WOS:000186612600009 PM 14613164 ER PT J AU Cragg, GM Newman, DJ AF Cragg, GM Newman, DJ TI Plants as a source of anti-cancer and anti-HIV agents SO ANNALS OF APPLIED BIOLOGY LA English DT Article DE AIDS; cancer; drugs; HIV; plant products ID INHIBITORY NATURAL-PRODUCTS; NATIONAL-CANCER-INSTITUTE; CYCLIN-DEPENDENT KINASES; SAMOAN MEDICINAL-PLANT; DRUG DISCOVERY; ANCISTROCLADUS-KORUPENSIS; PROSTRATIN; APOPTOSIS; MOLECULE; PHORBOL AB Plant-derived compounds have played an important role in the development of several clinically useful anti-cancer agents. These include vinblastine, vincristine, the camptothecin derivatives, topotecan and irinotecan, etoposide, and paclitaxel (Taxol(R)). Several promising new agents are in clinical development based on selective activity against cancer-related molecular targets, including flavopiridol and Combretastatin A4 phosphate. Recently, plants have yielded several agents showing anti-AIDS activity, and one of these, (+)-calanolide A, is in clinical development. C1 NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis, Ft Detrick, MD 21702 USA. RP Cragg, GM (reprint author), NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diagnosis, POB B, Ft Detrick, MD 21702 USA. NR 35 TC 39 Z9 41 U1 1 U2 12 PU ASSOC APPLIED BIOLOGISTS PI WARWICK PA C/O HORTICULTURE RESEARCH INT WELLSBOURNE, WARWICK CV35 9EF, ENGLAND SN 0003-4746 J9 ANN APPL BIOL JI Ann. Appl. Biol. PY 2003 VL 143 IS 2 BP 127 EP 133 DI 10.1111/j.1744-7348.2003.tb00278.x PG 7 WC Agriculture, Multidisciplinary SC Agriculture GA 728FB UT WOS:000185705100002 ER PT J AU Lyon, GR Shaywitz, SE Shaywitz, BA AF Lyon, GR Shaywitz, SE Shaywitz, BA TI A definition of dyslexia SO ANNALS OF DYSLEXIA LA English DT Article ID WORD FORM AREA; DEVELOPMENTAL DYSLEXIA; READING-DISABILITY; CEREBRAL MECHANISMS; COGNITIVE PROFILES; PHONOLOGICAL-CORE; CHILDREN; BRAIN; PERSISTENCE; ADULTS AB This paper elaborates on the components of a working definition of developmental dyslexia. It follows the general format of a paper by Lyon published in Annals of Dyslexia in 1995, which elaborated on a working definition proposed in 1994 (Lyon, 1995). The current definition agreed on by the work group updates and expands on the working definition from 1994. C1 NICHHD, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, New Haven, CT 06520 USA. RP Lyon, GR (reprint author), NICHHD, Child Dev & Behav Branch, NIH, 6100 Execut Blvd, Rockville, MD 20850 USA. NR 66 TC 478 Z9 510 U1 16 U2 127 PU INT DYSLEXIA ASSOC PI BALTIMORE PA CHESTER BUILDING, STE 382, 8600 LA SALLE RD, BALTIMORE, MD 21286-2044 USA SN 0736-9387 J9 ANN DYSLEXIA JI Ann. Dyslexia PY 2003 VL 53 BP 1 EP 14 DI 10.1007/s11881-003-0001-9 PG 14 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA 751YD UT WOS:000187117300001 ER PT J AU Blair, A Petralia, SA Stewart, PA AF Blair, A Petralia, SA Stewart, PA TI Extended mortality follow-up of a Cohort of dry cleaners SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE dry cleaners; organic solvents; occupational exposures; cancer risks; mortality ID PRIMARY LIVER-CANCER; OCCUPATIONAL-CANCER; ORGANIC-SOLVENTS; UNITED-STATES; WOMEN; TRICHLOROETHYLENE; PERCHLOROETHYLENE; HYDROCARBONS; EXPOSURE; DEATH AB Purpose: The mortality follow-up of a cohort of dry cleaners was extended evaluate cancers risks associated with organic solvents. Methods: The underlying and contributing causes of death among 5,369 members of a dry cleaning union in St. Louis were determined through December 31, 1993. The mortality experience of the cohort was compared to that of the US population adjusted for age at entry, year of death, race and gender. Results: The total mortality was about as expected (SMR = 1.0, N = 2351, 95% CI = 1.0-1.1). Excesses were observed for emphysema (SMR = 1.7, N = 21, 95% CI = 1.05-2.5), Hodgkin's disease (SMR = 2.0, N = 5, 95% CI = 0.6-4.6) and cancers of esophagus (SMR = 2.2, N = 26, 95% CI = 1.5-3.3), larynx (SMR = 1.7, N = 6, 95% CI = 0.6-3.7) lung (SMR = 1.4, N = 1250, 95% CI = 1.1-1.6), and cervix (SMR = 1.6 N = 27, 95% CI = 1.0-2.3). These excesses occurred among men and women and blacks and whites. Bladder cancer was elevated among white men and women and kidney cancer among black men and women, but not significantly so. None of these causes death showed strong relationships with duration or estimated level of exposure to dry cleaning solvents, although relative risks for cancers of the larynx, lung and kidney were larger among subjects estimated to have higher levels of exposure and risks from bladder cancer and chronic nephritis were greater among persons who entered the union after 1960. Conclusion: The excesses observed are unlikely to be due to chance because most occurred in earlier as well as the recent follow-up. The specific factors contributing to excesses, however, are not clear. Socioeconomic, lifestyle, and occupational exposure are all possibilities. Lack of information on socioeconomic and lifestyle factors hampers evaluation. (C) 2002 Elsevier Science Inc. All rights reserved. C1 NCI, Div Canc Epidemiol & Genet, Occupat Epidemiol Branch, Bethesda, MD 20892 USA. Pfizer Pharmaceut Inc, New York, NY USA. RP Blair, A (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat Epidemiol Branch, EPS Room 8118, Bethesda, MD 20892 USA. NR 27 TC 43 Z9 45 U1 0 U2 6 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 JAN PY 2003 VL 13 IS 1 BP 50 EP 56 AR PII S1047-2797(02)00250-8 DI 10.1016/S1047-2797(02)00250-8 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 631BT UT WOS:000180147700007 PM 12547485 ER PT J AU Honkakoski, P Sueyoshi, T Negishi, M AF Honkakoski, P Sueyoshi, T Negishi, M TI Drug-activated nuclear receptors CAR and PXR SO ANNALS OF MEDICINE LA English DT Review DE CAR; cytochrome P450; drug metabolism; induction; intestine; liver; nuclear receptor; PXR; RXR ID PREGNANE-X-RECEPTOR; CONSTITUTIVE-ANDROSTANE RECEPTOR; RESPONSIVE ENHANCER MODULE; PRIMARY HUMAN HEPATOCYTES; HUMAN CYP2B6 GENE; XENOBIOTIC RECEPTOR; TRANSCRIPTIONAL REGULATION; GLUCOCORTICOID RECEPTOR; SIGNALING PATHWAY; CYP3A4 INDUCTION AB The metabolism and elimination of drugs is mainly mediated by cytochrome P450 (CYP) enzymes, aided by conjugative enzymes and transport proteins. An integral aspect of this elimination process is the induction of drug metabolism through activation of gene expression of metabolic and transport proteins. There is compelling evidence that induction is regulated by drug-activated nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR). This review outlines the basic properties of CAR and PXR, their ligands and target genes, and the mechanisms of the induction process. The implications of nuclear receptor-mediated induction for drug research are also discussed. C1 NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. Univ Kuopio, Dept Pharmaceut, FIN-70211 Kuopio, Finland. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. OI Honkakoski, Paavo/0000-0002-4332-3577 NR 87 TC 119 Z9 124 U1 0 U2 9 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 0785-3890 J9 ANN MED JI Ann. Med. PY 2003 VL 35 IS 3 BP 172 EP 182 DI 10.1080/07853890310008224 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 686ZC UT WOS:000183350500004 PM 12822739 ER PT J AU Gropman, A AF Gropman, A TI Vigabatrin and newer interventions in succinic semialdehyde dehydrogenase deficiency SO ANNALS OF NEUROLOGY LA English DT Article; Proceedings Paper CT 1st International Symposium on Pediatric Neurotransmitter Diseases CY MAY 18-19, 2002 CL WASHINGTON, D.C. ID GAMMA-HYDROXYBUTYRIC ACID; 4-HYDROXYBUTYRIC ACIDURIA; MICE DEFICIENT; INBORN ERROR; PRENATAL-DIAGNOSIS; CLINICAL PHENOTYPE; GABA-METABOLISM; THERAPY; SEIZURES; PATIENT AB Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare disorder characterized by an inborn error of the catabolism of the inhibitory neurotransmitter GABA. Because of the deficiency of SSADH, the final enzyme of the GABA degradation pathway, the substrate, succinic semialdehyde, is shunted towards production of 4-hydroxybutyric acid (gamma-hydroxybutyric acid). Elevations of gamma-hydroxybutyric acid can be detected in the physiologic fluids of patients with SSADH deficiency, and forms the mainstay of diagnosis. The clinical features of SSADH deficiency include nonspecific neurologic manifestations such as mental retardation/developmental delay, absent speech, hypotonia, nonprogressive ataxia, features of autism or pervasive developmental delay, developmental language delay (dyspraxia, receptive, and expressive delays), and occasionally, seizures. Although the metabolic pathway has been established, it is not known whether insufficient GABA and/or excess gamma-hydroxybutyric acid contribute to the disease phenotype. Pharmacological therapy in patients with this disorder has been limited to vigabatrin, an anticonvulsant that blocks GABA transaminase. This review will discuss therapeutic options in SSADH deficiency, on the basis of patient experience, and preliminary work using a murine model. Finally, a discussion of adjunctive therapies will be included. C1 NIH, Neurogenet Branch, Sect Neuronal Migrat, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Neurogenet Clin, Washington, DC 20010 USA. RP Gropman, A (reprint author), NIH, Neurogenet Branch, Sect Neuronal Migrat, Bldg 10,10 Ctr Dr,Rm 3B04, Bethesda, MD 20892 USA. NR 35 TC 31 Z9 33 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PY 2003 VL 54 SU 6 BP S66 EP S72 DI 10.1002/ana.10626 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 706AQ UT WOS:000184429800010 PM 12891656 ER PT J AU Isacson, O Bjorklund, LM Schumacher, JM AF Isacson, O Bjorklund, LM Schumacher, JM TI Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson's disease by stem cells SO ANNALS OF NEUROLOGY LA English DT Review ID FETAL VENTRAL MESENCEPHALON; INTRASTRIATAL NIGRAL GRAFTS; SUBSTANTIA-NIGRA; TYROSINE-HYDROXYLASE; RAT MODEL; IN-VIVO; NEUROTROPHIC FACTOR; IMMUNOREACTIVE NEURONS; INTRACEREBRAL DIALYSIS; EXCITOTOXIC LESIONS AB New therapeutic nonpharmacological methodology in Parkinson's disease (PD) involves cell and synaptic renewal or replacement to restore function of neuronal systems, including the dopaminergic (DA) system. Using fetal DA cell therapy in PD patients and laboratory models, it has been demonstrated that functional motor deficits associated with parkinsonism can be reduced. Similar results have been observed in animal models with stem cell-derived DA neurons. Evidence obtained from transplanted PD patients further shows that the underlying disease process does not destroy transplanted fetal DA cells, although degeneration of the host nigrostriatal system continues. The optimal DA cell regeneration system would reconstitute a normal neuronal network capable of restoring feedback-controlled release of DA in the nigrostriatal system. The success of cell therapy for PD is limited by access to preparation and development of highly specialized dopaminergic neurons found in the A9 and A10 region of the substantia nigra pars compacta as well as the technical and surgical steps associated with the transplantation procedure. Recent laboratory work has focused on using stem cells as a starting point for deriving the optimal DA cells to restore the nigrostriatal system. Ultimately, understanding the cell biological principles necessary for generating functional DA neurons can provide many new avenues for better treatment of patients with PD. C1 Harvard Univ, McLean Hosp, Sch Med, Neurogenerat Labs, Belmont, MA 02478 USA. Harvard Univ, McLean Hosp, Sch Med, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. Univ Miami, Dept Neurosurg, Miami, FL 33152 USA. RP Isacson, O (reprint author), Harvard Univ, McLean Hosp, Sch Med, Neurogenerat Labs, 115 Mill St, Belmont, MA 02478 USA. FU NINDS NIH HHS [R01-NS-41263, P50 NS39793, R01-NS-30064] NR 108 TC 66 Z9 71 U1 2 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PY 2003 VL 53 SU 3 BP S135 EP S146 DI 10.1002/ana.10482 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 661XM UT WOS:000181915200024 PM 12666105 ER PT J AU van-Wendel-de-Joode, B Brouwer, DH Vermeulen, R Van Hemmen, JJ Heederik, D Kromhout, H AF van-Wendel-de-Joode, B Brouwer, DH Vermeulen, R Van Hemmen, JJ Heederik, D Kromhout, H TI DREAM: A method for semi-quantitative dermal exposure assessment SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE dermal exposure; semi-quantitative methods; measurement strategy; exposure assessment ID RUBBER MANUFACTURING-INDUSTRY; OCCUPATIONAL EXPOSURE; POTENTIAL EXPOSURE; PROTECTIVE GLOVES; SOIL ADHERENCE; SKIN; CONTAMINATION; MODEL AB This paper describes a new method (DREAM) for structured, semi-quantitative dermal exposure assessment for chemical or biological agents that can be used in occupational hygiene or epidemiology. It is anticipated that DREAM could serve as an initial assessment of dermal exposure, amongst others, resulting in a ranking of tasks and subsequently jobs. DREAM consists of an inventory and evaluation part. Two examples of dermal exposure of workers of a car-construction company show that DREAM characterizes tasks and gives insight into exposure mechanisms, forming a basis for systematic exposure reduction. DREAM supplies estimates for exposure levels on the outside clothing layer as well as on skin, and provides insight into the distribution of dermal exposure over the body. Together with the ranking of tasks and people, this provides information for measurement strategies and helps to determine who, where and what to measure. In addition to dermal exposure assessment, the systematic description of dermal exposure pathways helps to prioritize and determine most adequate measurement strategies and methods. DREAM could be a promising approach for structured, semi-quantitative, dermal exposure assessment. C1 Univ Utrecht, Inst Risk Assessment Sci, Environm & Occupat Hlth Div, NL-3508 TD Utrecht, Netherlands. TNO Chem, Dept Chem Exposure Assessment, NL-3700 AJ Zeist, Netherlands. NCI, Div Canc Epidemiol & Genet, Occupat Epidemiol Branch, Bethesda, MD USA. RP Kromhout, H (reprint author), Univ Utrecht, Inst Risk Assessment Sci, Environm & Occupat Hlth Div, POB 80176, NL-3508 TD Utrecht, Netherlands. RI Kromhout, Hans/A-9159-2008; Vermeulen, Roel/F-8037-2011; Brouwer, Derk/A-1594-2016 OI Vermeulen, Roel/0000-0003-4082-8163; NR 42 TC 26 Z9 26 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD JAN PY 2003 VL 47 IS 1 BP 71 EP 87 DI 10.1093/annhyg/meg012 PG 17 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA 639PG UT WOS:000180638000008 PM 12505908 ER PT J AU Leonard, GD Zujewski, JA AF Leonard, GD Zujewski, JA TI Docetaxel-related skin, nail, and vascular toxicity SO ANNALS OF PHARMACOTHERAPY LA English DT Article C1 NCI, Med Oncol Clin Res Unit, Breast Canc Clin Res Sect, Bethesda, MD 20892 USA. RP Leonard, GD (reprint author), NCI, Med Oncol Clin Res Unit, Breast Canc Clin Res Sect, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD JAN PY 2003 VL 37 IS 1 BP 148 EP 148 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 632PE UT WOS:000180231200028 PM 12564432 ER PT J AU Alexander, R Libutti, SK Pingpank, JF Bartlett, DL Helsabeck, C Kranda, K Beresnev, T AF Alexander, R Libutti, SK Pingpank, JF Bartlett, DL Helsabeck, C Kranda, K Beresnev, T TI Hyperthermic isolated hepatic perfusion (IHP) using melphalan for patients with ocular melanoma (OM) metastatic to liver SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 56th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 05-09, 2003 CL LOS ANGELES, CALIFORNIA SP Soc Surg Oncol C1 NCI, Surg Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JAN PY 2003 VL 10 IS 1 SU S MA 34 BP S18 EP S18 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 706AK UT WOS:000184429300035 ER PT J AU Finkelstein, SE Theoret, MR Overwijk, WO Antony, PA Spiess, PJ Surman, DR Palmer, DC Rosenberg, SA Restifo, NP AF Finkelstein, SE Theoret, MR Overwijk, WO Antony, PA Spiess, PJ Surman, DR Palmer, DC Rosenberg, SA Restifo, NP TI How to destroy large established subcutaneous B16 melanoma: Implications for the design of immunotherapy trials in humans SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 56th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 05-09, 2003 CL LOS ANGELES, CALIFORNIA SP Soc Surg Oncol C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JAN PY 2003 VL 10 IS 1 SU S MA 63 BP S27 EP S27 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 706AK UT WOS:000184429300064 ER PT J AU Kesmodel, SB Canter, RJ Mick, R Karakousis, G Whitman, E Tyler, DS Ross, MI Alexander, HR Fraker, DL AF Kesmodel, SB Canter, RJ Mick, R Karakousis, G Whitman, E Tyler, DS Ross, MI Alexander, HR Fraker, DL TI Effect of intra-operative perfusate pH on tumor response following isolated limb perfusion SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 56th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 05-09, 2003 CL LOS ANGELES, CALIFORNIA SP Soc Surg Oncol C1 Univ Penn, Philadelphia, PA 19104 USA. Melanoma Ctr St Louis, St Louis, MO USA. Duke Univ, Durham, NC USA. MD Anderson, Houston, TX USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JAN PY 2003 VL 10 IS 1 SU S MA P123 BP S77 EP S77 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 706AK UT WOS:000184429300220 ER PT J AU Rodriguez, LM Glebov, O Soballe, P Denobile, J Cliatt, J Nakahara, K Allaire, J Hawk, E Kirsch, I AF Rodriguez, LM Glebov, O Soballe, P Denobile, J Cliatt, J Nakahara, K Allaire, J Hawk, E Kirsch, I TI Characterization of gene expression in colonic aberrant crypt foci SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 56th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 05-09, 2003 CL LOS ANGELES, CALIFORNIA SP Soc Surg Oncol C1 NCI, Genet Branch, Bethesda, MD 20892 USA. Natl Naval Med Res Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD JAN PY 2003 VL 10 IS 1 SU S MA 1 BP S8 EP S8 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 706AK UT WOS:000184429300002 ER PT J AU Jacobson, KA Tchilibon, S Joshi, BV Gao, ZG AF Jacobson, KA Tchilibon, S Joshi, BV Gao, ZG TI A(3) adenosine receptors SO ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 38 SE ANNUAL REPORTS IN MEDICINAL CHEMISTRY LA English DT Review ID IN-VIVO; INTRAOCULAR-PRESSURE; BIOLOGICAL-ACTIVITY; HIGHLY POTENT; A-3 RECEPTOR; MAST-CELL; DERIVATIVES; AGONISTS; LIGANDS; ANTAGONISTS C1 NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20] NR 59 TC 8 Z9 8 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-7743 J9 ANNU REP MED CHEM PY 2003 VL 38 BP 121 EP 130 DI 10.1016/S0065-7743(03)38014-5 PG 10 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA BX55L UT WOS:000185669300013 PM 26640305 ER PT J AU Pierce, SK AF Pierce, SK TI Lipid rafts in immune cell signaling SO ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 38 SE ANNUAL REPORTS IN MEDICINAL CHEMISTRY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; POLYUNSATURATED FATTY-ACIDS; PROTEIN-TYROSINE KINASE; INSOLUBLE MEMBRANE DOMAINS; GPI-ANCHORED PROTEINS; SRC-FAMILY KINASES; IMMATURE B-CELLS; ANTIGEN RECEPTOR; PLASMA-MEMBRANE; T-LYMPHOCYTES C1 NIAID, DHHS, NIH, Rockville, MD 20852 USA. RP Pierce, SK (reprint author), NIAID, DHHS, NIH, Twinbrook 2,12441 Parklawn Dr,Room 200B,MSC 8180, Rockville, MD 20852 USA. NR 72 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0065-7743 J9 ANNU REP MED CHEM PY 2003 VL 38 BP 275 EP 283 DI 10.1016/S0065-7743(03)38028-5 PG 9 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA BX55L UT WOS:000185669300027 ER PT J AU Chernomordik, LV Kozlov, MM AF Chernomordik, LV Kozlov, MM TI Protein-lipid interplay in fusion and fission of biological membranes SO ANNUAL REVIEW OF BIOCHEMISTRY LA English DT Review DE hemagglutinin; hemifusion; stalk; fusion pore; membrane curvature ID INFLUENZA-VIRUS HEMAGGLUTININ; CLATHRIN-MEDIATED ENDOCYTOSIS; COATED-VESICLE FORMATION; SEMLIKI-FOREST-VIRUS; BORNE ENCEPHALITIS-VIRUS; CELL-CELL FUSION; ENVELOPE GLYCOPROTEIN; LOW-PH; CONFORMATIONAL-CHANGE; MOLECULAR-MECHANISM AB Disparate biological processes involve fusion of two membranes into one and fission of one membrane into two. To formulate the possible job description for the proteins that mediate remodeling of biological membranes, we analyze the energy price of disruption and bending of membrane lipid bilayers at the different stages of bilayer fusion. The phenomenology and the pathways of the well-characterized reactions of biological remodeling, such as fusion mediated by influenza hemagglutinin, are compared with those studied for protein-free bilayers. We briefly consider some proteins involved in fusion and fission, and the dependence of remodeling on the lipid composition of the membranes. The specific hypothetical mechanisms by which the proteins can lower the energy price of the bilayer rearrangement are discussed in light of the experimental data and the requirements imposed by the elastic properties of the bilayer. C1 NICHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. RP Chernomordik, LV (reprint author), NICHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. RI Wunder, Stephanie/B-5066-2012; Zdilla, Michael/B-4145-2011 NR 187 TC 412 Z9 417 U1 7 U2 61 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4154 J9 ANNU REV BIOCHEM JI Annu. Rev. Biochem. PY 2003 VL 72 BP 175 EP 207 DI 10.1146/annurev.biochem.72.121801.161504 PG 33 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 717MB UT WOS:000185092500008 PM 14527322 ER PT J AU Bonifacino, JS Traub, LM AF Bonifacino, JS Traub, LM TI Signals for sorting of transmembrane proteins to endosomes and lysosomes SO ANNUAL REVIEW OF BIOCHEMISTRY LA English DT Review DE endocytosis; plasma membrane; trans-Golgi network; receptor downregulation; multivesicular bodies; vacuole; phosphoinositides ID MANNOSE 6-PHOSPHATE RECEPTOR; GROWTH-FACTOR RECEPTOR; TRANS-GOLGI NETWORK; FACTOR-II RECEPTOR; DI-LEUCINE MOTIF; CLATHRIN-MEDIATED ENDOCYTOSIS; EPITHELIAL SODIUM-CHANNEL; LOW-DENSITY-LIPOPROTEIN; CASEIN KINASE-II; PLASMA-MEMBRANE PROTEINS AB Sorting of transmembrane proteins to endosomes and lysosomes is mediated by signals present within the cytosolic domains of the proteins. Most signals consist of short, linear sequences of amino acid residues. Some signals are referred to as tyrosine-based sorting signals and conform to the NPXY or YXXO consensus motifs. Other signals known as dileucine-based signals fit [DE]XXYL[LI] or DXXLL consensus motifs. All of these signals are recognized by components of protein coats peripherally associated with the cytosolic face of membranes. YXXO and [DE]XXXL[LI] signals are recognized with characteristic fine specificity by the adaptor protein (AP) complexes AP-1, AP-2, AP-3, and AP-4, whereas DXXLL signals are recognized by another family of adaptors known as GGAs. Several proteins, including clathrin, AP-2, and Dab2, have been proposed to function as recognition proteins for NPXY signals. YXXO and DXXLL signals bind in an extended conformation to the mu2 subunit of AP-2 and the VHS domain of the GGAs, respectively. Phosphorylation events regulate signal recognition. In addition to peptide motifs, ubiquitination of cytosolic lysine residues also serves as a signal for sorting at various stages of the endosomal-lysosomal system. Conjugated ubiquitin is recognized by UIM, UBA, or UBC domains present within many components of the internalization and lysosomal targeting machinery. This complex array of signals and recognition proteins ensures the dynamic but accurate distribution of transmembrane proteins to different compartments of the endosomal-lysosomal system. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Dept Cell Biol & Physiol, Pittsburgh, PA 15261 USA. RP Bonifacino, JS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. OI Bonifacino, Juan S./0000-0002-5673-6370 NR 276 TC 1291 Z9 1320 U1 14 U2 117 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4154 J9 ANNU REV BIOCHEM JI Annu. Rev. Biochem. PY 2003 VL 72 BP 395 EP 447 DI 10.1146/annurev.biochem.72.121801.161800 PG 53 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 717MB UT WOS:000185092500014 PM 12651740 ER PT J AU Radaev, S Sun, PD AF Radaev, S Sun, PD TI Structure and function of natural killer cell surface receptors SO ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE LA English DT Review DE KIR; KIR/HLA complex; allotype specificity; CD94; NKG2D/ULBP complex ID MHC CLASS-I; COMPLEX CLASS-I; ACTIVATING IMMUNORECEPTOR NKG2D; HLA-C MOLECULES; CRYSTAL-STRUCTURE; INHIBITORY RECEPTOR; T-CELLS; NK CELLS; IMMUNOGLOBULIN-SUPERFAMILY; MURINE NKG2D AB Since mid-1990, with cloning and identification of several families of natural killer (NK) receptors, research on NK cells began to receive appreciable attention. Determination of structures of NK cell surface receptors and their ligand complexes led to a fast growth in our understanding of the activation and ligand recognition by these receptors as well as their function in innate immunity. Functionally, NK cell surface receptors are divided into two groups, the inhibitory and the activating receptors. Structurally, they belong to either the immunoglobulin (Ig)-like receptor superfamily or the C-type lectin-like receptor (CTLR) superfamily. Their ligands are either members of class I major histocompatibility complexes (MHC) or homologs of class I MHC molecules. The inhibitory form of NK receptors provides the protective immunity through recognizing class I MHC molecules with self-peptides on healthy host cells. The activating, or the noninhibitory, NK receptors mediate the killing of tumor or virally infected cells through their specific ligand recognition. The structures of activating and inhibitory NK cell surface receptors and their complexes with the ligands determined to date, including killer immunoglobulin-like receptors (KIRs) and their complexes with HLA molecules, CD94, Ly49A, and its complex with H-2D(d), and NKG2D receptors and their complexes with class I MHC homologs, are reviewed here. C1 NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Radaev, S (reprint author), NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. NR 80 TC 44 Z9 46 U1 0 U2 5 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1056-8700 J9 ANNU REV BIOPH BIOM JI Annu. Rev. Biophys. Biomolec. Struct. PY 2003 VL 32 BP 93 EP 114 DI 10.1146/annurev.biophys.32.110601.142347 PG 22 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 717MD UT WOS:000185092700006 PM 12471063 ER PT J AU Morrison, DK Davis, RJ AF Morrison, DK Davis, RJ TI Regulation of map kinase signaling modules by scaffold proteins in mammals SO ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY LA English DT Review DE ERK; JNK; p38 MAP kinase; SAPK; signal transduction ID DUAL-SPECIFICITY PHOSPHATASE; AMYLOID PRECURSOR PROTEIN; FACTOR HOMOLOGOUS FACTORS; KSR-1 GENE ENCODES; KAPPA-B ACTIVATION; BETA-ARRESTIN; INTERACTING PROTEIN-1; MEK KINASE; TRANSDUCTION PATHWAY; JNK ACTIVATION AB The mitogen-activated protein kinase (MAPK) group of serine/threonine protein kinases mediates the response of cells to many extracellular stimuli such as cytokines and growth factors. These protein kinases include the extracellular signal-regulated protein kinases (ERK) and two stress-activated protein kinases (SAPK), the c-Jun N-terminal kinases (INK), and the p38 MAPK. The enzymes are evolutionarily conserved and are activated by a common mechanism that involves a protein kinase cascade. Scaffold proteins have been proposed to interact with MAPK pathway components to create a functional signaling module and to control the specificity of signal transduction. Here we critically evaluate the evidence that supports a physiologically relevant role of MAPK scaffold proteins in mammals. C1 NCI, Regulat Cell Growth Lab, Frederick, MD 21702 USA. Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Worcester, MA 01605 USA. Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. RP Morrison, DK (reprint author), NCI, Regulat Cell Growth Lab, POB B, Frederick, MD 21702 USA. NR 114 TC 526 Z9 548 U1 1 U2 30 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1081-0706 J9 ANNU REV CELL DEV BI JI Annu. Rev. Cell Dev. Biol. PY 2003 VL 19 BP 91 EP 118 DI 10.1146/annurev.cellbio.19.111401.091942 PG 30 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 749LP UT WOS:000186922500006 PM 14570565 ER PT J AU Gottesman, S AF Gottesman, S TI Proteolysis in bacterial regulatory circuits SO ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY LA English DT Review DE Clp; Lon; FtsH; Hsl; chaperone ID ATP-DEPENDENT PROTEASE; BACTERIOPHAGE-LAMBDA REPRESSOR; CLPX-RECOGNITION SIGNALS; ESCHERICHIA-COLI K-12; HEAT-SHOCK PROTEIN; CELL-CYCLE CONTROL; BACILLUS-SUBTILIS; LON PROTEASE; TRANSCRIPTION FACTOR; CRYSTAL-STRUCTURE AB Proteolysis by cytoplasmic, energy-dependent proteases plays a critical role in many regulatory circuits, keeping basal levels of regulatory proteins low and rapidly removing proteins when they are no longer needed. In bacteria, four families of energy-dependent proteases carry out degradation. In all of them, substrates are first recognized and bound by ATPase domains and then unfolded and translocated to a sequestered proteolytic chamber. Substrate selection depends not on ubiquitin but on intrinsic recognition signals within the proteins and, in some cases, on adaptor or effector proteins that participate in delivering the substrate to the protease. For some, the activity of these adaptors can be regulated, which results in regulated proteolysis. Recognition motifs for proteolysis are frequently found at the N and C termini of substrates. Proteolytic switches appear to be critical for cell cycle development in Caulobacter crescentus, for proper sporulation in Bacillus subtilis, and for the transition in and out of stationary phase in Escherichia coli. In eukaryotes, the same proteases are found in organelles, where they also play important roles. C1 NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. NR 141 TC 282 Z9 287 U1 3 U2 28 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1081-0706 J9 ANNU REV CELL DEV BI JI Annu. Rev. Cell Dev. Biol. PY 2003 VL 19 BP 565 EP 587 DI 10.1146/annurev.cellbio.19.110701.153228 PG 25 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 749LP UT WOS:000186922500023 PM 14570582 ER PT J AU Ribeiro, JMC Francischetti, IMB AF Ribeiro, JMC Francischetti, IMB TI Role of arthropod saliva in blood feeding: Sialome and post-sialome perspectives SO ANNUAL REVIEW OF ENTOMOLOGY LA English DT Review DE hemostasis; inflammation; nociception; mast cells; salivary glands ID FLY LUTZOMYIA-LONGIPALPIS; MOSQUITO ANOPHELES-ALBIMANUS; YELLOW-FEVER MOSQUITO; NECROSIS-FACTOR-ALPHA; AEDES-AEGYPTI; NITRIC-OXIDE; INFLAMMATORY HYPERALGESIA; IXODES-SCAPULARIS; CIMEX-LECTULARIUS; DERMACENTOR-ANDERSONI AB This review addresses the problems insects and ticks face to feed on blood and the solutions these invertebrates engender to overcome these obstacles, including a sophisticated salivary cocktail of potent pharmacologic compounds. Recent advances in transcriptome and proteome research allow an unprecedented insight into the complexity of these compounds, indicating that their molecular diversity as well as the diversity of their targets is still larger than previously thought. C1 NIAID, Med Entomol Sect, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Ribeiro, JMC (reprint author), NIAID, Med Entomol Sect, Lab Malaria & Vector Res, NIH, 4 Ctr Dr, Bethesda, MD 20892 USA. OI Ribeiro, Jose/0000-0002-9107-0818 NR 108 TC 402 Z9 422 U1 4 U2 33 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4170 J9 ANNU REV ENTOMOL JI Annu. Rev. Entomol. PY 2003 VL 48 BP 73 EP 88 DI 10.1146/annurev.ento.48.060402.102812 PG 16 WC Entomology SC Entomology GA 640VT UT WOS:000180709200005 PM 12194906 ER PT J AU Rattray, AJ Strathern, JN AF Rattray, AJ Strathern, JN TI Error-prone DNA polymerases: When making a mistake is the only way to get ahead SO ANNUAL REVIEW OF GENETICS LA English DT Review DE translesion polymerase; somatic hypermutation; untargeted mutagenesis; nonhomologous end joining; polymerase recruitment ID BASE EXCISION-REPAIR; XERODERMA-PIGMENTOSUM VARIANT; STRAND-BREAK-REPAIR; TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE; RADIATION-SENSITIVE STRAINS; STATIONARY-PHASE MUTATION; ESCHERICHIA-COLI-CELLS; THYMINE-THYMINE DIMER; YEAST REV1 PROTEIN; V GENE CONVERSION AB Cells have high-fidelity polymerases whose task is to accurately replicate the genome, and low-fidelity polymerases with specialized functions. Although some of these low-fidelity polymerases are exceptional in their ability to replicate damaged DNA and restore the undamaged sequence, they are error prone on undamaged DNA. In fact, these error-prone polymerases are sometimes used in circumstances where the capacity to make errors has a selective advantage. The mutagenic potential of the error-prone polymerases requires that their expression, activity, and access to undamaged DNA templates be regulated. Here we review these specialized polymerases with an emphasis on their biological roles. C1 NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP Rattray, AJ (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RI Rattray, Alison/A-4847-2008 NR 217 TC 113 Z9 119 U1 1 U2 9 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4197 J9 ANNU REV GENET JI Annu. Rev. Genet. PY 2003 VL 37 BP 31 EP 66 DI 10.1146/annurev.genet.37.04.2203.132748 PG 36 WC Genetics & Heredity SC Genetics & Heredity GA 760CD UT WOS:000187792500003 PM 14616055 ER PT J AU Friedman, TB Griffith, AJ AF Friedman, TB Griffith, AJ TI Human nonsyndromic sensorineural deafness SO ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS LA English DT Review DE myosin; cadherin; channel; connexin; claudin ID AUTOSOMAL-RECESSIVE DEAFNESS; SYNDROMIC HEARING-LOSS; COCHLEAR HAIR-CELLS; LINKED MIXED DEAFNESS; RENAL TUBULAR-ACIDOSIS; NUCLEAR MODIFIER GENE; PENDRED-SYNDROME GENE; MYOSIN-VIIA GENE; SYNDROME TYPE 1D; HETEROZYGOUS MISSENSE MUTATION AB Given the unique biological requirements of sound transduction and the selective advantage conferred upon a species capable of sensitive sound detection, it is not surprising that up to 1% of the approximately 30,000 or more human genes are necessary for hearing. There are hundreds of monogenic disorders for which hearing loss is one manifestation of a syndrome or the only disorder and therefore is nonsyndromic. Herein we review the supporting evidence for identifying over 30 genes for dominantly and recessively inherited, nonsyndronlic, sensorineural deafness. The state of knowledge concerning their biological roles is discussed in the context of the controversies within an evolving understanding of the intricate molecular machinery of the inner car. C1 NIDOCD, Mol Genet Lab, NIH, Rockville, MD 20850 USA. NIDOCD, Neurotol Branch, Hearing Sect, NIH, Rockville, MD 20850 USA. RP Friedman, TB (reprint author), NIDOCD, Mol Genet Lab, NIH, Rockville, MD 20850 USA. EM friedman@nidcd.nih.gov; griffita@nidcd.nih.gov NR 337 TC 128 Z9 134 U1 0 U2 4 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 1527-8204 J9 ANNU REV GENOM HUM G JI Annu. Rev. Genomics Hum. Genet. PY 2003 VL 4 BP 341 EP 402 DI 10.1146/annurev.genom.4.070802.110347 PG 62 WC Genetics & Heredity SC Genetics & Heredity GA 836UG UT WOS:000222580700012 PM 14527306 ER PT J AU Waldmann, TA AF Waldmann, TA TI The meandering 45-year odyssey of a clinical immunologist SO ANNUAL REVIEW OF IMMUNOLOGY LA English DT Review DE interleukin-2 (IL-2); interleukin-15 (IL-15); monoclonal antibody; suppressor T cell; immunoglobulin metabolism ID T-CELL LEUKEMIA; INTERLEUKIN-2 RECEPTOR; MONOCLONAL-ANTIBODY; ALPHA-FETOPROTEIN; IL-2 RECEPTOR; GROWTH-FACTOR; KILLER-CELLS; GENE-THERAPY; BETA-CHAIN; TAC AB My work on basic and clinical immunology has focused on the regulation of the human immune response and how its dysregulation can lead to immunodeficiency, autoimmune, and malignant disorders. The early focus in our laboratory was on pathogenic mechanisms underlying hypogammaglobulinemia. Our demonstration of active suppression by human suppressor T cells changed thinking about the pathogenesis of certain immunodeficiency disorders. Recently we have focused on the cytokines interleukin-2 (IL-2) and IL-15, which have competitive functions in adaptive immune responses. IL-2 is necessary to destroy self-reactive lymphocytes and thus favors peripheral tolerance to self-antigens, whereas IL-15 favors the persistence of lymphocytes involved in the memory and effector responses to invading pathogens but risks the development of inflammatory autoimmune diseases. Our murine anti-Tac monoclonal antibody exploits these differences, as does a humanized form (daclizumab) now approved for the prevention of renal allograft rejection. New forms of therapy directed at IL-2 and IL-15 receptors may be effective against certain neoplastic diseases and autoimmune disorders and in the prevention of allograft rejection. C1 NCI, Canc Res Ctr, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NCI, Canc Res Ctr, Metab Branch, NIH, 10 Ctr Dr,MSC 1374,Bldg 10,Room 4N1165, Bethesda, MD 20892 USA. NR 53 TC 9 Z9 10 U1 0 U2 0 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0732-0582 J9 ANNU REV IMMUNOL JI Annu. Rev. Immunol. PY 2003 VL 21 BP 1 EP 27 DI 10.1146/annrev.immunol.21.120601.140933 PG 27 WC Immunology SC Immunology GA 672MB UT WOS:000182523500001 PM 12359737 ER PT J AU Douek, DC Picker, LJ Koup, RA AF Douek, DC Picker, LJ Koup, RA TI T cell dynamics in HIV-1 infection SO ANNUAL REVIEW OF IMMUNOLOGY LA English DT Review DE T cells; activation; lymphopenia ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; BONE-MARROW TRANSPLANTATION; FOLLICULAR DENDRITIC CELLS; RECENT THYMIC EMIGRANTS; HOMEOSTASIS-DRIVEN PROLIFERATION; SYNCYTIUM-INDUCING PHENOTYPE; LONG-TERM NONPROGRESSORS; MEMORY-LIKE PHENOTYPE; HUMAN LYMPHOID-TISSUE AB In the absence of antiretroviral treatment, HIV-1 establishes a chronic, progressive infection of the human immune system that invariably, over the course of years, leads to its destruction and fatal immunodeficiency. Paradoxically, while viral replication is extensive throughout the course of infection, deterioration of conventional measures of immunity is slow, including the characteristic loss of CD4(+) T cells that is thought to play a key role in the development of immunodeficiency. This conundrum suggests that CD4(+) T cell-directed viral cytopathicity alone cannot explain the course of disease. Indeed, recent advances now indicate that HIV-1 pathogenesis is likely to result from a complex interplay between the virus and the immune system, particularly the mechanisms responsible for T cell homeostasis and regeneration. We review these data and present a model of HIV-1 pathogenesis in which the protracted loss of CD4(+) T cells results from early viral destruction of selected memory T cell populations, followed by a combination of profound increases in overall memory T cell turnover, damage to the thymus and other lymphoid tissues, and physiological limitations in peripheral CD4(+) T cell renewal. C1 NIAID, Human Immunol Sect, NIH, Bethesda, MD 20892 USA. NIAID, Vaccine Res Ctr, Immunol Lab, NIH, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Vaccine Gene Therapy Inst, Beaverton, OR 97006 USA. RP Douek, DC (reprint author), NIAID, Human Immunol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 337 TC 361 Z9 378 U1 2 U2 21 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0732-0582 J9 ANNU REV IMMUNOL JI Annu. Rev. Immunol. PY 2003 VL 21 BP 265 EP 304 DI 10.1146/annurev.immunol.21.120601.14053 PG 44 WC Immunology SC Immunology GA 672MB UT WOS:000182523500009 PM 12524385 ER PT J AU Schwartz, RH AF Schwartz, RH TI T cell anergy SO ANNUAL REVIEW OF IMMUNOLOGY LA English DT Review DE clonal anergy; adaptive tolerance; regulatory T cells; CD28/CTLA-4; IL-2/IL-2R ID PROTEIN-TYROSINE KINASES; CLONAL ANERGY; IN-VIVO; CYCLE PROGRESSION; TOLERANCE INDUCTION; TRANSGENIC MICE; DENDRITIC CELLS; IL-2 GENE; PERIPHERAL TOLERANCE; ANTIGEN PRESENTATION AB T cell anergy is a tolerance mechanism in which the lymphocyte is intrinsically functionally inactivated following an antigen encounter, but remains alive for an extended period of time in a hyporesponsive state. Models of T cell anergy affecting both CD4(+) and CD8(+) cells fall into two broad categories. One, clonal anergy, is principally a growth arrest state, whereas the other, adaptive tolerance or in vivo anergy, represents a more generalized inhibition of proliferation and effector functions. The former arises from incomplete T cell activation, is mostly observed in previously activated T cells, is maintained by a block in the Ras/MAP kinase pathway, can be reversed by IL-2 or anti-OX40 signaling, and usually does not result in the inhibition of effector functions. The latter is most often initiated in naive T cells in vivo by stimulation in an environment deficient in costimulation or high in coinhibition. Adaptive tolerance can be induced in the thymus or in the periphery. The cells proliferate and differentiate to varying, degrees and then downregulate both functions in the face of persistent antigen. The state involves an early block in tyrosine kinase activation, which predominantly inhibits calcium mobilization, and an independent mechanism that blocks signaling through the IL-2 receptor. Adaptive tolerance reverses in the absence of antigen. Aspects of both of the anergic states are found in regulatory T cells, possibly preventing them from dominating initial immune responses to foreign antigens and shutting down such responses prematurely. C1 NIH, Cellular & Mol Immunol Lab, Bethesda, MD 20892 USA. RP Schwartz, RH (reprint author), NIH, Cellular & Mol Immunol Lab, Bldg 10, Bethesda, MD 20892 USA. NR 121 TC 773 Z9 803 U1 5 U2 40 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0732-0582 J9 ANNU REV IMMUNOL JI Annu. Rev. Immunol. PY 2003 VL 21 BP 305 EP 334 DI 10.1146/annurev.immunol.21.120601.141110 PG 30 WC Immunology SC Immunology GA 672MB UT WOS:000182523500010 PM 12471050 ER PT J AU Wynn, TA AF Wynn, TA TI IL-13 effector functions SO ANNUAL REVIEW OF IMMUNOLOGY LA English DT Review DE IL-4; parasite; cancer; asthma; fibrosis ID INDUCED AIRWAY HYPERRESPONSIVENESS; SMOOTH-MUSCLE CELLS; INTESTINAL NEMATODE INFECTION; SCHISTOSOMA-MANSONI EGGS; RECEPTOR ALPHA-2 CHAIN; REED-STERNBERG CELLS; GASTROINTESTINAL HELMINTH INFECTION; PULMONARY GRANULOMA-FORMATION; LEISHMANIA-MAJOR INFECTION; TYPE-2 CYTOKINE RESPONSES AB IL-13 was first recognized for its effects on B cells and monocytes, where it upregulated class II expression, promoted IgE class switching and inhibited inflammatory cytokine production. It was also thought to be functionally redundant with IL-4. However, studies conducted with knockout mice, neutralizing antibodies, and novel antagonists demonstrate that IL-13 possesses several unique effector functions that distinguish it from IL-4. Resistance to most gastrointestinal nematodes is mediated by type-2 cytokine responses, in which IL-13 plays a dominant role. By regulating cell-mediated immunity, IL-13 modulates resistance to intracellular organisms including Leishmania major, Leishmania mexicana, and Listeria monocytogenes. In the lung, IL-13 is the central mediator of allergic asthma, where it regulates eosinophilic inflammation, mucus secretion, and airway hyperresponsiveness. Manipulation of IL-13 effector function may also prove useful in the treatment of some cancers like B-cell chronic lymphocytic leukemia and Hodgkin's disease, where IL-13 modulates apoptosis or tumor cell growth. IL-13 can also inhibit tumor immunosurveillance. As such, inhibitors of IL-13 might be effective as cancer immunotherapeutics by boosting type-1-associated anti-tumor defenses. Finally, IL-13 was revealed as a potent mediator of tissue fibrosis in both schistosomiasis and asthma, which indicates that it is a key regulator of the extracellular matrix. The mechanisms that regulate IL-13 production and/or function have also been investigated, and IL-4, IL-12, IL-18, IFN-gamma, IL-10, TGF-beta, TNF-alpha, and the IL-4/IL-13 receptor complex play important roles. This review highlights the effector functions of IL-13 and describes multiple pathways for modulating its activity in vivo. C1 NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Wynn, TA (reprint author), NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Wynn, Thomas/C-2797-2011 NR 187 TC 516 Z9 558 U1 6 U2 46 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0732-0582 J9 ANNU REV IMMUNOL JI Annu. Rev. Immunol. PY 2003 VL 21 BP 425 EP 456 DI 10.1146/annurev.immunol.21.120601.141142 PG 32 WC Immunology SC Immunology GA 672MB UT WOS:000182523500013 PM 12615888 ER PT J AU Dykstra, M Cherukuri, A Sohn, HW Tzeng, SJ Pierce, SK AF Dykstra, M Cherukuri, A Sohn, HW Tzeng, SJ Pierce, SK TI Location is everything: Lipid rafts and immune cell signaling SO ANNUAL REVIEW OF IMMUNOLOGY LA English DT Review DE B cells; T cells; mast cells; antigen receptors; coreceptors ID FC-EPSILON-RI; HUMAN-IMMUNODEFICIENCY-VIRUS; POLYUNSATURATED FATTY-ACIDS; PROTEIN-TYROSINE KINASE; DETERGENT-RESISTANT MEMBRANES; IMMUNOGLOBULIN-E RECEPTOR; GPI-ANCHORED PROTEINS; SRC-FAMILY KINASES; IMMATURE B-CELLS; TCR-ZETA-CHAIN AB The cells of both the adaptive and innate immune systems express a dizzying array of receptors that transduce and integrate an enormous amount of information about the environment that allows the cells to mount effective immune responses. Over the past several years, significant advances have been made in elucidating the molecular details of signal cascades initiated by the engagement of immune cell receptors by their ligands. Recent evidence indicates that immune receptors and components of their signaling cascades are spatially organized and that this spatial organization plays a central role in the initiation and regulation of signaling. A key organizing element for signaling receptors appears to be cholesterol- and sphingolipid-rich plasma membrane microdomains termed lipid rafts. Research into the molecular basis of the spatial segregation and organization of signaling receptors provided by rafts is adding fundamentally to our understanding of the initiation and prolongation of signals in the immune system. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Dykstra, M (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. OI Tzeng, Shiang-Jong/0000-0003-1633-020X NR 149 TC 357 Z9 367 U1 0 U2 14 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0732-0582 J9 ANNU REV IMMUNOL JI Annu. Rev. Immunol. PY 2003 VL 21 BP 457 EP 481 DI 10.1146/annurev.immunol.21.120601.141021 PG 25 WC Immunology SC Immunology GA 672MB UT WOS:000182523500014 PM 12615889 ER PT J AU Hursting, SD Lavigne, JA Berrigan, D Perkins, SN Barrett, JC AF Hursting, SD Lavigne, JA Berrigan, D Perkins, SN Barrett, JC TI Calorie restriction, aging, and cancer prevention: Mechanisms of action and a applicability to humans SO ANNUAL REVIEW OF MEDICINE-SELECTED TOPICS IN THE CLINICAL SCIENCES LA English DT Review DE carcinogenesis; insulin-like growth factor-1; apoptosis; reactive oxygen species ID GROWTH-FACTOR-I; RADIATION-INDUCED TUMORS; GENE-EXPRESSION PROFILE; BONE-MINERAL DENSITY; BREAST-CANCER; LIFE-SPAN; DIETARY RESTRICTION; CAENORHABDITIS-ELEGANS; BINDING PROTEIN-3; STRESS RESISTANCE AB Calorie restriction (CR) is the most effective and reproducible intervention for increasing lifespan in a variety of animal species, including mammals. CR is also the most potent, broadly acting cancer-prevention regimen in experimental car-cinogensis models. Translation of the knowledge gained from CR research to human chronic disease prevention and the promotion of healthy aging is critical, especially because obesity, which is an important risk factor for several chronic diseases, including many cancers, is alarmingly increasing in the Western world. This review synthesizes the key biological mechanisms underlying many of the beneficial effects of CR, with a particular focus on the insulin-like growth,factor-1 pathway. We also describe some of the opportunities now available for investigations, including gene expression profiling studies, the development of pharmacological mimetics of CR, and the integration of CR regimens with targeted, mechanism-based interventions. These approaches will facilitate the translation of CR research into strategies for effective human chronic disease prevention. C1 NCI, Ctr Canc Res, Lab Biosyst & Canc, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD 20892 USA. RP Hursting, SD (reprint author), NCI, Ctr Canc Res, Lab Biosyst & Canc, Bethesda, MD 20892 USA. NR 122 TC 355 Z9 367 U1 3 U2 35 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4219 J9 ANNU REV MED JI Annu. Rev. Med. PY 2003 VL 54 BP 131 EP 152 DI 10.1146/annurev.med.54.101601.15216 PG 22 WC Medicine, General & Internal SC General & Internal Medicine GA 670WV UT WOS:000182433600008 PM 12525670 ER PT J AU Goldbach-Mansky, R Lipsky, PE AF Goldbach-Mansky, R Lipsky, PE TI New concepts in treatment of rheumatoid arthritis SO ANNUAL REVIEW OF MEDICINE-SELECTED TOPICS IN THE CLINICAL SCIENCES LA English DT Review DE combination therapy; anti-cytokine therapy; early aggressive treatment; DMARDs; prognosis; outcome ID PLACEBO-CONTROLLED TRIAL; CONTROLLED CLINICAL-TRIAL; PROSPECTIVE FOLLOW-UP; INTERLEUKIN-1 RECEPTOR ANTAGONIST; LOW-DOSE METHOTREXATE; DOUBLE-BLIND; COMBINATION THERAPY; RADIOGRAPHIC DAMAGE; PROGNOSTIC FACTORS; INFLAMMATORY POLYARTHRITIS AB Recent advances have made rheumatoid arthritis (RA) amenable to treatment. Clinical studies in patients with early and established RA have broadened understanding of its pathogenesis and have fundamentally changed the therapeutic approach to this disease. Quantum leaps in therapy-including the use of early, aggressive therapy, combination therapy, and the introduction of anti-cytokine agents-have improved patients' quality of life, eased clinical symptoms, retarded the progression of joint destruction, and delayed disability. We review clinical evidence supporting these therapeutic approaches. Diagnostic and therapeutic challenges are highlighted, and a decision tree to guide treatment in patients with early or established RA is provided. C1 NIAMSD, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Goldbach-Mansky, R (reprint author), NIAMSD, Off Clin Director, NIH, Bethesda, MD 20892 USA. NR 103 TC 36 Z9 37 U1 0 U2 2 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4219 J9 ANNU REV MED JI Annu. Rev. Med. PY 2003 VL 54 BP 197 EP 216 DI 10.1146/annurev.med.54.101601.152342 PG 20 WC Medicine, General & Internal SC General & Internal Medicine GA 670WV UT WOS:000182433600012 PM 12359827 ER PT J AU Zbar, B Klausner, R Linehan, WM AF Zbar, B Klausner, R Linehan, WM TI Studying cancer families to identify kidney cancer genes SO ANNUAL REVIEW OF MEDICINE-SELECTED TOPICS IN THE CLINICAL SCIENCES LA English DT Review DE von Hippel-Lindau disease (VHL); MET proto-oncogene; hereditary papillary renal carcinoma (HPRC; Birt-Hogg-Dube syndrome (BHD); multiple cutaneous leiomyoma (MCL); famarate hydratase (FH) ID TUMOR-SUPPRESSOR GENE; RENAL-CELL CARCINOMA; HIPPEL-LINDAU-DISEASE; HOGG-DUBE-SYNDROME; HUMAN-CHROMOSOME 3P21.3; MET PROTOONCOGENE; CLEAR-CELL; VHL GENE; SPONTANEOUS PNEUMOTHORAX; GERMLINE MUTATIONS AB We studied families with multiple members affected with renal cancer to delineate clinically distinct forms of inherited renal cancer, and to identify and characterize the genes responsible for these disorders. Today, cancer geneticists recognize seven clinically distinct, inherited forms of epithelial renal cancer; genes responsible for five inherited predispositions have been found. Positional cloning efforts for one kidney cancer gene are nearing completion. These discoveries will provide diagnostic tests for these diseases, a foundation for studies of the relationship between genotype and phenotype, and a basis for studies of the pathophysiology of the diverse types of epithelial renal cancer. C1 NCI, Immunobiol Lab, Canc Res Ctr, Frederick, MD 21702 USA. NCI, Ctr Canc Res, Urol Oncol Branch, Bethesda, MD 20894 USA. RP Zbar, B (reprint author), NCI, Immunobiol Lab, Canc Res Ctr, Frederick, MD 21702 USA. NR 64 TC 34 Z9 38 U1 0 U2 0 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4219 J9 ANNU REV MED JI Annu. Rev. Med. PY 2003 VL 54 BP 217 EP 233 DI 10.1146/annurev.med.54.101601.152514 PG 19 WC Medicine, General & Internal SC General & Internal Medicine GA 670WV UT WOS:000182433600013 PM 12525673 ER PT J AU Carrington, M O'Brien, SJ AF Carrington, M O'Brien, SJ TI The influence of HLA genotype on AIDS SO ANNUAL REVIEW OF MEDICINE-SELECTED TOPICS IN THE CLINICAL SCIENCES LA English DT Review DE HIV; AIDS immunity; genetic epidemiology ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-LYMPHOCYTE RESPONSES; CLASS-I MOLECULES; HIV TYPE-1 INFECTION; HEPATITIS-C VIRUS; REVERSE-TRANSCRIPTASE; NUCLEOTIDE SUBSTITUTION; LINKAGE DISEQUILIBRIUM; OVERDOMINANT SELECTION; DISEASE PROGRESSION AB Genetic resistance to infectious diseases is likely to involve a complex array of immune-response and other genes with variants that impose subtle but significant consequences on gene expression or protein function. We have gained considerable insight into the genetic determinants of HIV-1 disease, and the HLA class I genes appear to be highly influential in this regard. Numerous reports have identified a role for HLA genotype in AIDS outcomes, implicating many HLA alleles in various aspects of HIV disease. Here we review the HLA associations with progression to AIDS that have been consistently affirmed and discuss the underlying mechanisms behind some of these associations based on functional studies of immune cell recognition. C1 NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Carrington, M (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. NR 97 TC 489 Z9 522 U1 2 U2 34 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4219 J9 ANNU REV MED JI Annu. Rev. Med. PY 2003 VL 54 BP 535 EP 551 DI 10.1146/annurev.med.54.101601.152346 PG 19 WC Medicine, General & Internal SC General & Internal Medicine GA 670WV UT WOS:000182433600031 PM 12525683 ER PT J AU Schofield, MJ Hsieh, P AF Schofield, MJ Hsieh, P TI DNA mismatch repair: Molecular mechanisms and biological function SO ANNUAL REVIEW OF MICROBIOLOGY LA English DT Review DE recombination; mutagenesis; MutS; MutL; cancer ID CELL NUCLEAR ANTIGEN; NUCLEOTIDE-EXCISION-REPAIR; SACCHAROMYCES-CEREVISIAE MSH2; MEIOTIC CROSSING-OVER; DOUBLE-STRAND BREAKS; STATIONARY-PHASE MUTATION; ESCHERICHIA-COLI MUTS; IN-VIVO; HETERODUPLEX DNA; SLIDING CLAMP AB DNA mismatch repair (MMR) guards the integrity of the genome in virtually all cells. It contributes about 1000-fold to the overall fidelity of replication and targets mispaired bases that arise through replication errors, during homologous recombination, and as a result of DNA damage. Cells deficient in MMR have a mutator phenotype in which the rate of spontaneous mutation is greatly elevated, and they frequently exhibit microsatellite instability at mono- and dinucleotide repeats. The importance of MMR in mutation avoidance is highlighted by the finding that defects in MMR predispose individuals to hereditary nonpolyposis colorectal cancer. In addition to its role in postreplication repair, the MMR machinery serves to police homologous recombination events and acts as a barrier to genetic exchange between species. C1 NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Schofield, MJ (reprint author), NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. NR 177 TC 325 Z9 339 U1 5 U2 59 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4227 J9 ANNU REV MICROBIOL JI Annu. Rev. Microbiol. PY 2003 VL 57 BP 579 EP 608 DI 10.1146/annurev.micro.57.030502.090847 PG 32 WC Microbiology SC Microbiology GA 742AU UT WOS:000186493700025 PM 14527292 ER PT J AU Caughey, B Lansbury, PT AF Caughey, B Lansbury, PT TI Protofibrils, pores, fibrils, and neurodegeneration: Separating the responsible protein aggregates from the innocent bystanders SO ANNUAL REVIEW OF NEUROSCIENCE LA English DT Review DE Alzheimer's; Parkinson's; scrapie; prion; amyloid ID AMYOTROPHIC-LATERAL-SCLEROSIS; AMYLOID-BETA-PROTEIN; RESISTANT PRION PROTEIN; CUZN-SUPEROXIDE-DISMUTASE; INTERMOLECULAR DISULFIDE BONDS; ALPHA-SYNUCLEIN MUTATIONS; ATOMIC-FORCE MICROSCOPY; SCRAPIE-ASSOCIATED FORM; CENTRAL-NERVOUS-SYSTEM; BODY-LIKE INCLUSIONS AB Many neurodegenerative diseases, including Alzheimer's and Parkinson's and the transmissible spongiform encephalopathies (prion diseases), are characterized at autopsy by neuronal loss and protein aggregates that are typically fibrillar. A convergence of evidence strongly suggests that protein aggregation is neurotoxic and not a product of cell death. However, the identity of the neurotoxic aggregate and the mechanism by which it disables and eventually kills a neuron are unknown. Both biophysical studies aimed at elucidating the precise mechanism of in vitro aggregation and animal modeling studies support the emerging notion that an ordered prefibrillar oligomer, or protofibril, may be responsible for cell death and that the fibrillar form that is typically observed at autopsy may actually be neuroprotective. A subpopulation of protofibrils may function as pathogenic amyloid pores. An analogous mechanism may explain the neurotoxicity of the prion protein; recent data demonstrates that the disease-associated, infectious form of the prion protein differs from the neurotoxic species. This review focuses on recent experimental studies aimed at identification and characterization of the neurotoxic protein aggregates. C1 NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Neurol Dis, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Dept Neurol, Cambridge, MA 02139 USA. RP Caughey, B (reprint author), NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM bcaughey@niaid.nih.gov; plansbury@rics.bwh.harvard.edu NR 199 TC 1059 Z9 1089 U1 12 U2 149 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0147-006X J9 ANNU REV NEUROSCI JI Annu. Rev. Neurosci. PY 2003 VL 26 BP 267 EP 298 DI 10.1146/annurev.neuro.26.010302.081142 PG 36 WC Neurosciences SC Neurosciences & Neurology GA 717MJ UT WOS:000185093200011 PM 12704221 ER PT J AU Bonini, NM Fortini, ME AF Bonini, NM Fortini, ME TI Human neurodegenerative disease modeling using Drosophila SO ANNUAL REVIEW OF NEUROSCIENCE LA English DT Review DE polyglutamine; tau; presenilin; Alzheimer's disease; Parkinson's disease ID AMYLOID PRECURSOR PROTEIN; GAMMA-SECRETASE ACTIVITY; INHIBITS HUNTINGTIN AGGREGATION; GLYCOGEN-SYNTHASE KINASE-3; CREB-BINDING PROTEIN; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; CAENORHABDITIS-ELEGANS; ALPHA-SYNUCLEIN; EXPANDED POLYGLUTAMINE AB A number of approaches have been taken to recreate and to study the role of genes associated with human neurodegenerative diseases in the model organism Drosophila. These studies encompass the polyglutamine diseases, Parkinson's disease, Alzheimer's disease, and tau-associated pathologies. The findings highlight Drosophila as an important model system in which to study the fundamental pathways influenced by these genes and have led to new insights into aspects of pathogenesis and modifier mechanisms. C1 Univ Penn, Howard Hughes Med Inst, Dept Biol, Philadelphia, PA 19104 USA. NCI, Div Basic Sci, Ft Detrick, MD 21702 USA. RP Bonini, NM (reprint author), Univ Penn, Howard Hughes Med Inst, Dept Biol, 415 S Univ Ave, Philadelphia, PA 19104 USA. EM nbonini@sas.upenn.edu; fortini@ncifcrf.gov NR 178 TC 95 Z9 100 U1 4 U2 19 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0147-006X J9 ANNU REV NEUROSCI JI Annu. Rev. Neurosci. PY 2003 VL 26 BP 627 EP 656 DI 10.1146/annurev.neuro.26.041002.131425 PG 34 WC Neurosciences SC Neurosciences & Neurology GA 717MJ UT WOS:000185093200022 PM 12704223 ER PT J AU Sausville, EA Elsayed, Y Monga, M Kim, G AF Sausville, EA Elsayed, Y Monga, M Kim, G TI Signal transduction-directed cancer treatments SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY LA English DT Review DE protein kinase; ansamycin; farnesyltransferase; phospholipid; monoclonal antibody ID GROWTH-FACTOR-RECEPTOR; FARNESYL-PROTEIN TRANSFERASE; TYROSINE KINASE INHIBITOR; PHASE-I TRIAL; METASTATIC BREAST-CANCER; CELL-CYCLE ARREST; PRECLINICAL ANTITUMOR-ACTIVITY; CHRONIC MYELOID-LEUKEMIA; GENE-PRODUCT P185; CARCINOMA-CELLS AB The pathogenic mechanisms giving rise to cancer frequently involve altered signal transduction pathways. Therefore therapeutic agents that directly address signal transduction molecules are being explored as cancer treatments. Inhibitors of protein tyrosine and threonine kinases including STI-571, ZD-1839, OSI-774, and flavopiridol are ATP-site antagonists that have completed initial phase I and phase II evaluations. Herceptin and C225 are monoclonal antibodies also directed against signaling targets. Numerous other kinase antagonists are in clinical evaluation, including UCN-01 andPD184352. Alternative strategies to downmodulate kinase-driven signaling include 17-allyl-amino-17-demethoxygeldanamycin and rapamycin derivatives, and phospholipase-directed signaling may be modulated by alkylphospholipids. Farnesyltransferase inhibitors were originally developed as inhibitors of ras-driven signals but may have activity by affecting other or additional targets. Signal transduction will remain a fertile basis for suggesting cancer treatments of the future, the evaluation of which should include monitoring effects of the drugs on their intended target signaling molecules in preclinical and early clinical studies. C1 NCI, Dev Therapeut Program, Rockville, MD 20852 USA. RP Sausville, EA (reprint author), NCI, Dev Therapeut Program, Rockville, MD 20852 USA. NR 182 TC 66 Z9 67 U1 0 U2 3 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0362-1642 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2003 VL 43 BP 199 EP 231 DI 10.1146/annurev.pharmtox.43.100901.135813 PG 33 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 653KP UT WOS:000181434600009 PM 12195027 ER PT J AU Wenthold, RJ Prybylowski, K Standley, S Sans, N Petralia, RS AF Wenthold, RJ Prybylowski, K Standley, S Sans, N Petralia, RS TI Trafficking of NMDA receptors SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY LA English DT Review DE PDZ proteins; synapse; postsynaptic density; glutamate receptor; subunit assembly ID D-ASPARTATE RECEPTOR; DEPENDENT PROTEIN-KINASE; RAT CORTICAL-NEURONS; MEDIATED TYROSINE PHOSPHORYLATION; HIPPOCAMPAL SYNAPTIC PLASTICITY; CELL-SURFACE EXPRESSION; ER RETENTION SIGNAL; C-TERMINAL DOMAIN; NR1 SUBUNIT; MICE LACKING AB The NNMA receptor (NMDAR) plays a central role in the function of excitatory synapses. Recent studies have provided interesting insights into several aspects of the trafficking of this receptor in neurons. The NMDAR is not a static resident of the synapse. Rather, the number and composition of synaptic NMDARs can be modulated by several factors. The interaction of PDZ proteins, generally thought to occur at the synapse, appears to occur early in the secretory pathway; this interaction may play a role in the assembly of the receptor complex and its exit from the endoplasmic reticulum. This review addresses recent advances in our understanding of NMDAR trafficking and its synaptic delivery and maintenance. C1 NIDCD, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Wenthold, RJ (reprint author), NIDCD, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NR 138 TC 250 Z9 261 U1 1 U2 5 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0362-1642 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2003 VL 43 BP 335 EP 358 DI 10.1146/annurev.pharmtox.43.100901.135803 PG 28 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 653KP UT WOS:000181434600014 PM 12540744 ER PT J AU Kinsel, JE Straus, SE AF Kinsel, JE Straus, SE TI Complementary and alternative therapeutics: Rigorous research is needed to support claims SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY LA English DT Review DE CAM; drug development; dietary supplements; natural products ID ST-JOHNS-WORT; NATIONAL SURVEY; UNITED-STATES; MEDICINE; THERAPIES; EXTRACT; TRENDS AB The establishment of the National Center for Complementary and Alternative Medicine (NCCAM) in 1998 as a part of the National Institutes of Health was catalyzed by the increasing interest and use of complementary and alternative medicine (CAM) modalities by the public. This article presents an overview of CAM, summarizes similarities and differences between the regulatory requirements for drugs and CAM/botanical products, identifies several challenges and opportunities for conducting research to demonstrate the safety and efficacy of CAM therapeutics, and highlights the role of NCCAM in supporting and stimulating research in this area. C1 Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Kinsel, JE (reprint author), Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. NR 29 TC 26 Z9 27 U1 5 U2 6 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0362-1642 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2003 VL 43 BP 463 EP 484 DI 10.1146/annurev.pharmtox.43.100901.135757 PG 24 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 653KP UT WOS:000181434600019 PM 12540748 ER PT J AU Keefer, LK AF Keefer, LK TI Progress toward clinical application of the nitric oxide-releasing diazeniumdiolates SO ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY LA English DT Review DE restenosis; thromboresistance; vasospasm; impotence; respiratory distress ID PULMONARY-HYPERTENSION; SUBARACHNOID HEMORRHAGE; CEREBRAL VASOSPASM; LUNG INJURY; IN-VIVO; DONOR; OXYGENATION; REVERSAL; PREVENTION; POLYMERS AB Diazeniumdiolates, compounds of structure (RRNN)-R-1-N-2(O)=NOR3, which have also been called NONOates, have proven useful for treating an increasing diversity of medical disorders in relevant animal models. Here, I review the chemical features that make them such excellent starting points for designing materials capable of targeting reliable and controllable fluxes of bioactive NO for in vitro and in vivo applications. This is followed by a consideration of recent proof-of-concept studies that underscore what I believe to be the substantial clinical promise of such materials. Examples covered include progress toward inhibiting restenosis after angioplasty, preparing thromboresistant medical devices, reversing vasospasm, and relieving pulmonary hypertension. Together with a very recent report describing the beneficial effects of diazeniumdiolate therapy in a patient with acute respiratory distress syndrome, the results of the animal experiments support the prediction that a broad selection of problems in clinical medicine can be solved by judiciously mining the enormous variety of possible (RRNN)-R-1-N-2(O)=NOR3 structures. C1 NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Keefer, LK (reprint author), NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 39 TC 125 Z9 127 U1 1 U2 10 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0362-1642 J9 ANNU REV PHARMACOL JI Annu. Rev. Pharmacol. Toxicol. PY 2003 VL 43 BP 585 EP 607 DI 10.1146/annurev.pharmtox.43.100901.135831 PG 25 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 653KP UT WOS:000181434600023 PM 12415121 ER PT J AU Drobny, GP Long, JR Karlsson, T Shaw, W Popham, J Oyler, N Bower, P Stringer, J Gregory, D Mehta, M Stayton, PS AF Drobny, GP Long, JR Karlsson, T Shaw, W Popham, J Oyler, N Bower, P Stringer, J Gregory, D Mehta, M Stayton, PS TI Structural studies of biomaterials using double-quantum solid-state NMR spectroscopy SO ANNUAL REVIEW OF PHYSICAL CHEMISTRY LA English DT Review DE dipolar recoupling NMR; biocompatibility; biomineralization ID NUCLEAR-MAGNETIC-RESONANCE; HUMAN SALIVARY STATHERIN; CALCIUM-PHOSPHATE PRECIPITATION; RESIDUE CARBONYL CARBONS; ANGLE-SPINNING NMR; ROTATING SOLIDS; CHEMICAL-SHIFT; PULSE SEQUENCE; POLYMERIC BIOMATERIALS; PEPTIDE CONFORMATION AB Proteins directly control the nucleation and growth of biominerals, but the details of molecular recognition at the protein-biomineral interface remain poorly understood. The elucidation of recognition mechanisms at this interface may provide design principles for advanced materials development in medical and ceramic composites technologies. Here, we describe both the theory and practice of double-quantum solid-state NMR (ssNMR) structure-determination techniques, as they are used to determine the secondary structures of surface-adsorbed peptides and proteins. In particular, we have used ssNMR dipolar techniques to provide the first high-resolution structural and dynamic characterization of a hydrated biomineralization protein, salivary statherin, adsorbed to its biologically relevant hydroxyapatite (HAP) surface. Here, we also review NMR data on peptides designed to adsorb from aqueous solutions onto highly porous hydrophobic surfaces with specific helical secondary structures. The adsorption or covalent attachment of biological macromolecules onto polymer materials to improve their biocompatibility has been pursued using a variety of approaches, but key to understanding their efficacy is the verification of the structure and dynamics of the immobilized biomolecules using double-quantum ssNMR spectroscopy. C1 Univ Washington, Dept Chem, Seattle, WA 98195 USA. Univ Washington, Dept Bioengn, Seattle, WA 98195 USA. Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32611 USA. Pacific NW Lab, Richland, WA 99352 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Varian Associates Inc, Ft Collins, CO 80525 USA. Quantum Magnet Inc, San Diego, CA 92121 USA. Oberlin Coll, Dept Chem, Oberlin, OH 44074 USA. RP Drobny, GP (reprint author), Univ Washington, Dept Chem, Seattle, WA 98195 USA. EM drobny@chem.washington.edu; stayton@u.washington.edu OI mehta, minesh/0000-0002-4812-5713 FU NIDCR NIH HHS [DE 12554] NR 82 TC 50 Z9 51 U1 4 U2 32 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-426X J9 ANNU REV PHYS CHEM JI Annu. Rev. Phys. Chem. PY 2003 VL 54 BP 531 EP 571 DI 10.1146/annurev.physchem.54.011002.103903 PG 43 WC Chemistry, Physical SC Chemistry GA 717MQ UT WOS:000185093900019 PM 12709513 ER PT J AU Schnermann, J Levine, DZ AF Schnermann, J Levine, DZ TI Paracrine factors in tubuloglomerular feedback: Adenosine, ATP, and nitric oxide SO ANNUAL REVIEW OF PHYSIOLOGY LA English DT Review DE purinoceptors; 5 '-nucleotidase; cyclic AMP; superoxide; diabetes mellitus ID EXPERIMENTAL DIABETES-MELLITUS; MACULA DENSA CELLS; RENAL INTERSTITIAL ADENOSINE; RABBIT AFFERENT ARTERIOLES; GLOMERULAR-FILTRATION RATE; BETA-GAMMA-SUBUNITS; PHOSPHOLIPASE-C; ANGIOTENSIN-II; A(1) RECEPTOR; OXIDATIVE STRESS AB The tubuloglomerular feedback response, the change in afferent arteriolar tone caused by a change in NaCl concentration at the macula densa, is likely initiated by the generation of a vasoactive mediator within the confines of the juxtaglomerular apparatus. Substantial progress has been made in identifying the nature of this mediator and the factors that modulate its effect on vascular tone. In support of earlier studies using P1 purinergic antagonists, the application of the knockout technique has shown that adenosine 1 receptors are absolutely required for eliciting TGF responses. The background level of angiotensin II appears to be an important cofactor determining the efficiency of A1AR-induced vasoconstriction, probably through a synergistic interaction at the level of the G protein-dependent transduction mechanism. The source of the adenosine is still unclear, but it is conceivable that adenosine is generated extracellularly from released ATP through a cascade of ecto-nucleotidases. There is also evidence that ATP may activate P2 receptors in pre-glomerular vessels, which may contribute to autoregulation of renal vascular resistance. Nitric oxide (NO), generated by the neuronal isoform of nitric oxide synthase in macula densa cells, reduces the constrictor effect of adenosine, but the regulation of NO release and its exact role in states of TGF-induced hyperfiltration are still unclear. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Ottawa, Ottawa, ON K1H 8M5, Canada. Ottawa Hlth Res Inst, Kidney Res Ctr, Div Nephrol, Ottawa, ON K1H 8M5, Canada. RP Schnermann, J (reprint author), NIDDKD, NIH, Bethesda, MD 20892 USA. NR 161 TC 107 Z9 112 U1 0 U2 2 PU ANNUAL REVIEWS PI PALO ALTO PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA SN 0066-4278 J9 ANNU REV PHYSIOL JI Annu. Rev. Physiol. PY 2003 VL 65 BP 501 EP 529 DI 10.1146/annurev.physiol.65.050102.085738 PG 29 WC Physiology SC Physiology GA 672MD UT WOS:000182523700022 PM 12208992 ER PT J AU Marth, G Schuler, G Yeh, R Davenport, R Agarwala, R Church, D Wheelan, S Baker, J Ward, M Kholdov, M Phan, L Harpending, H Chakravarti, A Kwok, P Sherry, S AF Marth, G Schuler, G Yeh, R Davenport, R Agarwala, R Church, D Wheelan, S Baker, J Ward, M Kholdov, M Phan, L Harpending, H Chakravarti, A Kwok, P Sherry, S TI The structure of single-nucleotide variation in overlapping regions of human genome sequence. SO ANTHROPOLOGICAL SCIENCE LA English DT Meeting Abstract C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. EM sherry@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU ANTHROPOLOGICAL SOC NIPPON PI TOKYO PA C/O GALILEO INC, URBAN-OHTSUKA BLDG, 3RD FL, 3-21-10 KITA-OHTSUKA, TOSHIMA-KU, TOKYO, 170-0004, JAPAN SN 0918-7960 EI 1348-8570 J9 ANTHROPOL SCI JI Anthropol. Sci. PD JAN PY 2003 VL 111 IS 1 BP 63 EP 63 PG 1 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 647LD UT WOS:000181093500059 ER PT J AU Ratnasinghe, DL Yao, SX Forman, M Oiao, YL Andersen, MR Giffen, CA Erozan, Y Tockman, MS Taylor, PR AF Ratnasinghe, DL Yao, SX Forman, M Oiao, YL Andersen, MR Giffen, CA Erozan, Y Tockman, MS Taylor, PR TI Gene-environment interactions between the codon 194 polymorphism of XRCC1 and antioxidants influence lung cancer risk SO ANTICANCER RESEARCH LA English DT Article DE lung cancer; XRCC1; polymorohisms; antioxidants ID DNA-REPAIR PROFICIENCY; TIN MINERS; BREAST-CANCER; DAMAGE; SENSITIVITY; FREQUENCY; PROTEINS; EXPOSURE; YUNNAN; COHORT AB X-ray repair cross complementing group 1 (XRCC1) is a DNA repair gene whose polymorphisms appear to influence the risk of lung cancer. We explored the influence of antioxidants on the association between the codon 194 arganine to tryptophan substitution polymorphism of XRCC1 and lung cancer risk. In a case-control study nested within a cohort of tin miners the cases were those diagnosed with lung cancer over 6 years of follow-up (n = 108). Two controls, matched on age and sex, were selected for each case by incidence density sampling. Individuals with the variant Arg194Trp allele seemed to be at lower risk for lung cancer (odds ratio (OR): 0.7, 95% confidence interval (95%CL): 0.4-1.2). Furthermore, high serum alpha-tocopherol (OR: 0.4, 95%CL: 0.2-0.9) and retinol (OR: 0.4, 95%CL: 0.2-0.9) levels were associated with significantly reduced risk of lung cancer among individuals with the Arg194Trp variant allele, but not among individuals with the wild-type genotype. In addition, the Arg194Trp variant reduced the risk of lung cancer associated with increased serum carotenoids compared to those with the homozygous wild-type allele. Our results show that Arg194Trp XRCC1 variant modifies the association between serum antioxidants and lung cancer risk. C1 US FDA, Natl Ctr Toxicol Res, Ctr Struct Genom, Jefferson, AR 72079 USA. NCI, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Yunnan Tin Corp, Gejiu, Yunnan Prov, Peoples R China. Appl Biosyst Inc, Foster City, CA USA. Chinese Acad Med Sci, Inst Canc, Beijing 100037, Peoples R China. Informat Management Serv Inc, Silver Spring, MD USA. Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD USA. H Lee Moffit Canc Ctr & Res Inst, Tampa, FL USA. RP Ratnasinghe, DL (reprint author), US FDA, Natl Ctr Toxicol Res, Ctr Struct Genom, 3900 NCTR Dr, Jefferson, AR 72079 USA. RI Qiao, You-Lin/B-4139-2012 OI Qiao, You-Lin/0000-0001-6380-0871 NR 24 TC 25 Z9 26 U1 0 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD JAN-FEB PY 2003 VL 23 IS 1B BP 627 EP 632 PG 6 WC Oncology SC Oncology GA 657LR UT WOS:000181669100020 PM 12680158 ER PT J AU Bray, M AF Bray, M TI Defense against filoviruses used as biological weapons SO ANTIVIRAL RESEARCH LA English DT Article DE filovirus; ebola virus; marburg virus; biological warfare; bioterrorism; biodefense ID EBOLA-VIRUS INFECTION; HEMORRHAGIC-FEVER; NONHUMAN-PRIMATES; RHESUS-MONKEYS; MARBURG VIRUS; PASSIVE TRANSFER; MOUSE MODEL; MICE; THERAPY; PROPHYLAXIS AB The filoviruses, Marburg and Ebola, are classified as Category A biowarfare agents by the Centers for Disease Control. Most known human infections with these viruses have been fatal, and no vaccines or effective therapies are currently available. Filoviruses are highly infectious by the airborne route in the laboratory, but investigations of African outbreaks have shown that person-to-person spread requires direct contact with virus-containing material. In consequence, filovirus epidemics can be halted by isolating patients and instituting standard infection control and barrier nursing procedures. The filovirus disease syndrome resembles that caused by other hemorrhagic fever viruses, necessitating studies in a biocontainment laboratory to confirm the diagnosis. Some progress has been made in developing vaccines and antiviral drugs, but efforts are hindered by the limited number of maximum containment laboratories. Terrorists might have great difficulty acquiring a filovirus for use as a weapon, but my attempt to do so because of the agents' ability to inspire fear. Accurate information is the best tool to prevent panic in the event of an attack. Published by Elsevier Science B.V. C1 NIAID, Biodef Clin Res Branch, OCR,OD, NIH, Bethesda, MD 20892 USA. RP Bray, M (reprint author), NIAID, Biodef Clin Res Branch, OCR,OD, NIH, 6700A Rockledge Dr,Room 5132, Bethesda, MD 20892 USA. EM mbray@niaid.nih.gov NR 64 TC 62 Z9 62 U1 2 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD JAN PY 2003 VL 57 IS 1-2 SI SI BP 53 EP 60 AR PII S0166-3542(02)00200-0 DI 10.1016/S0166-3542(02)00200-0 PG 8 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 658DF UT WOS:000181705800008 PM 12615303 ER PT J AU Brodie, C Blumberg, PM AF Brodie, C Blumberg, PM TI Regulation of cell apoptosis by protein kinase c delta SO APOPTOSIS LA English DT Review DE apoptosis; c-Abl; caspases; nucleus; phosphorylation; protein kinase C delta; translocation mitochondria ID ETOPOSIDE-INDUCED APOPTOSIS; ABL TYROSINE KINASE; GLAND ACINAR-CELLS; PKC-DELTA; GROWTH-FACTOR; DNA-DAMAGE; IONIZING-RADIATION; PHORBOL ESTER; PHOSPHOLIPID SCRAMBLASE; PROTEOLYTIC ACTIVATION AB The isoforms of the PKC family are activated in response to mitogenic stimuli, to inflammatory stimuli, and to stress and play important roles in a variety of cellular functions including apoptosis. PKCdelta a member of the novel PKC subfamily, is actively involved in cell apoptosis in a stimulus and tissue specific manner; it both regulates the expression and function of apoptotic related proteins and is itself a target for caspases. Activation of PKCdelta by various apoptotic stimuli results in the translocation of PKCdelta to distinct cellular compartments such as mitochondria, golgi and nucleus, and the differential translocation contributes to its different effects. In addition, phosphorylation of PKCdelta on distinct tyrosine residues and its association with specific apoptotic related proteins such as c-AbI, DNA-PK, p73 and lamin B are pivotal to its function in cell apoptosis. Recent findings on these aspects of the PKCdelta cascades are the major focus of this review. C1 Bar Ilan Univ, Fac Life Sci, Gonda Goldschmied Med Diag Res Ctr, IL-52900 Ramat Gan, Israel. NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. RP Brodie, C (reprint author), Bar Ilan Univ, Fac Life Sci, Gonda Goldschmied Med Diag Res Ctr, IL-52900 Ramat Gan, Israel. NR 105 TC 319 Z9 336 U1 1 U2 17 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1360-8185 J9 APOPTOSIS JI Apoptosis PD JAN PY 2003 VL 8 IS 1 BP 19 EP 27 DI 10.1023/A:1021640817208 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 626NW UT WOS:000179880200003 PM 12510148 ER PT S AU Lahiri, DK Chen, D Ge, YW Farlow, M Kotwal, G Kanthasamy, A Ingram, DK Greig, NH AF Lahiri, DK Chen, D Ge, YW Farlow, M Kotwal, G Kanthasamy, A Ingram, DK Greig, NH BE Diederich, M TI Does nitric oxide synthase contribute to the pathogenesis of Alzheimer's disease? Effects of beta-amyloid deposition on NOS in transgenic mouse brain with AD pathology SO APOPTOSIS: FROM SIGNALING PATHWAYS TO THERAPEUTIC TOOLS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT 5th International Conference on Apoptosis from Signalling Pathways to Therapeutic Tools CY JAN 29-FEB 01, 2003 CL LUXEMBOURG, LUXEMBOURG DE aging; beta-protein; dementia; neurodegeneration; nitric oxide; free radicals; oxidative stress; ROS ID PRESENILIN-1; TARGETS; MICE AB Oxidative stress is a risk factor for Alzheimer's disease (AD) whose major hallmark includes brain depositions of the amyloid beta peptide (A) derived from the beta-amyloid precursor protein (APP). Our aim was to determine whether or not excessive Abeta deposition would alter nitric oxide synthase (NOS) activity, and thereby affect NOS-mediated superoxide formation. We compared NOS activity in brain extracts between Tg mice (expressing APP Swedish double mutation plus presenilin [PS-1] and nontransgenic [nTg] mice. Five brain regions, including cerebral cortex, hippocampus, cerebellum, and striatum from both nTg and Tg mice showed a detectable level of neuronal (n) NOS activity. Cerebellar extracts from both nTg and Tg mice displayed the highest level of nNOS activity, which was fourfold higher than cortical extracts. Although there was an increase in nNOS activity in Tg brain extracts, this did not attain statistical significance. A similar result was obtained for inducible NOS levels. Our results suggest that excess levels of Abeta failed to both trigger NOS activity and change NOS levels. C1 Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN 46202 USA. Univ Louisville, Louisville, KY 40202 USA. Iowa State Univ, Ames, IA 50011 USA. NIA, GRC, NIH, Baltimore, MD 21224 USA. RP Lahiri, DK (reprint author), Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, PR 313,791 Union Dr, Indianapolis, IN 46202 USA. EM dlahiri@iupui.edu NR 7 TC 15 Z9 15 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-474-9 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 2003 VL 1010 BP 639 EP 642 DI 10.1196/annals.1299.117 PG 4 WC Cell Biology; Medicine, Research & Experimental; Multidisciplinary Sciences SC Cell Biology; Research & Experimental Medicine; Science & Technology - Other Topics GA BY71U UT WOS:000189446300118 PM 15033804 ER PT J AU Gonzalez, FJ Kimura, S AF Gonzalez, FJ Kimura, S TI Study of P450 function using gene knockout and transgenic mice SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Review ID PHENACETIN O-DEETHYLASE; 4-AMINOBIPHENYL-DNA ADDUCTS; CYTOCHROME-P450 2E1; TARGETED DISRUPTION; EPOXIDE HYDROLASE; CYP2E1 EXPRESSION; AROMATIC-AMINES; N-OXIDATION; NULL MICE; METABOLISM AB The xenobiotic-metabolizing P450s have been extensively studied for their ability to metabolize endogenous and exogenous chemicals. The latter include drugs and dietary and environmentally derived toxicants and carcinogens. These enzymes also metabolize endogenous steroids and fatty acids. P450s are thought to be required for efficient removal of most xenobiotics from the body and to be responsible for the hazardous effects of toxicants and carcinogens based on their ability to convert chemicals to electrophilic metabolites that can cause cellular damage and gene mutations. P450 catalytic activities have been extensively studied in vitro and in cell culture, yielding considerable information on their mechanisms of catalysis, substrate specificities, and metabolic products. Targeted gene disruption has been used to determine the roles of P450s in intact animals and their contributions to the mechanisms of toxicity and carcinogenesis. The P450s chosen for study, CYP1A1, CYP1B1, CYP1A2, and CYP2E1, are conserved in mammals and are known to metabolize most toxicants and chemical carcinogens. Mice lacking expression of these enzymes do not differ from wild-type mice, indicating that these P450s are not required for development and physiological homeostasis. However, the P450 null mice have altered responses to the toxic and carcinogenic effects of chemicals as compared with wild-type mice. These studies establish that P450s mediate the adverse effects of drugs and dietary, environmental, and industrial chemicals and serve to validate molecular epidemiology studies that seek to determine links between P450 polymorphisms and susceptibility to chemically associated diseases. More recently, P450 humanized mice have been produced. (C) 2002 Elsevier Science (USA). All rights reserved. C1 NCI, Lab Metab, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Bldg 37,Room 3E-24, Bethesda, MD 20892 USA. NR 48 TC 67 Z9 70 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 1 PY 2003 VL 409 IS 1 BP 153 EP 158 AR PII S0003-9861(02)00364-8 DI 10.1016/S0003-9861(02)00364-8 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 625PW UT WOS:000179825700019 PM 12464254 ER PT J AU Yamamoto, Y Kawamoto, T Negishi, M AF Yamamoto, Y Kawamoto, T Negishi, M TI The role of the nuclear receptor CAR as a coordinate regulator of hepatic gene expression in defense against chemical toxicity SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article ID CYP2B GENE; ENHANCER MODULE; MOUSE-LIVER; BILE-ACID; INDUCTION; CHOLESTEROL; METABOLISM; TRANSLOCATION; HEPATOCYTES; ACTIVATION AB The nuclear receptor CAR (constitutive active receptor) mediates the induction of transcription of cytochrome P450 (CYP) genes by phenobarbital (PB) and PB-type inducers. A recent study using CAR-null mice has shown that CAR regulates not only the CYP genes but also other genes encoding various drug/steroid-metabolizing enzymes. In addition to coordinating these enzymes, CAR plays other roles in hepatic gene expression: CAR represses various genes including carnitine palmitoyltransferase 1a and phosphoenolpyruvate carboxykinase 1 in response to PB, and the receptor regulates the constitutive expression of genes such as squalene epoxidase. On the other hand, induction of certain genes such as amino levulinate synthase 1 by PB is not regulated by CAR. Here we describe diverse roles of CAR in hepatic gene expression with a particular focus on endogenous substances such as cholesterol, bilirubin, and steroid hormones. Published by Elsevier Science (USA). C1 NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Kawamoto, Takeshi/D-7938-2015 OI Kawamoto, Takeshi/0000-0003-3337-1775 NR 38 TC 58 Z9 60 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 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD JAN 1 PY 2003 VL 409 IS 1 BP 207 EP 211 AR PII S0003-9861(02)00456-3 DI 10.1016/S0003-9861(02)00456-3 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 625PW UT WOS:000179825700025 PM 12464260 ER PT J AU Selemon, LD Mrzljak, J Kleinman, JE Herman, MM Goldman-Rakic, PS AF Selemon, LD Mrzljak, J Kleinman, JE Herman, MM Goldman-Rakic, PS TI Regional specificity in the neuropathologic substrates of schizophrenia - A morphometric analysis of Broca's area 44 and area 9. SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 29th Annual Meeting of the Society-for-Neuroscience CY OCT 23-28, 1999 CL MIAMI BEACH, FL SP Soc Neurosci ID DORSOLATERAL PREFRONTAL CORTEX; GRAY-MATTER VOLUME; FIRST-EPISODE SCHIZOPHRENIA; CORTICAL PYRAMIDAL NEURONS; DENDRITIC SPINE DENSITY; WORKING-MEMORY; PHYSIOLOGICAL DYSFUNCTION; PATHOLOGY; ACTIVATION; DEFICITS AB Background: Numerous recent studies of postmortem schizophrenic brains have reported the presence of structural abnormalities in the dorsolateral prefrontal cortex (dlPFC) that are consistent with a reduction of neuropil. Ventrolateral prefrontal areas have been studied less extensively, and therefore it is not clear whether these cortices exhibit pathologic abnormalities of the same type and magnitude. Because thought disturbances in schizophrenic patients involve language processing, we have performed a morphometric analysis of Broca's area in the ventral frontal lobe. Methods: Neuronal and glial density and somal size were assessed via stereologic cell counting in postmortem samples of Broca's area 44 in 9 schizophrenic patients and 14 normal controls. Cell density was reexamined in dorsolateral prefrontal Area 9 as an internal control. Results: We did not detect abnormalities in overall or laminar neuronal density, glial density, cortical thickness, or somal size in area 44 of schizophrenic patients. In contrast, neuronal density in area 9 exhibited a 12% increase in the schizophrenic cohort, replicating previous findings. In addition, there was a significant effect of disease on laminar neuronal density in area 9, with neuronal density tending to be higher (7%-29%) in all layers. Conclusions: The absence of significant cytoarchitectonic abnormalities in Broca's area in the same brains in which the dlPFC exhibited an increase in neuronal density suggests that the neuropil deficit is a regionally specific pathologic finding in schizophrenia and indicates that the dlPFC is a particularly vulnerable target of the disease process. C1 Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06510 USA. NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Selemon, LD (reprint author), Yale Univ, Sch Med, Dept Neurobiol, 333 Cedar St,Room C-303 SHM, New Haven, CT 06510 USA. EM ldselemon@aol.com FU NIMH NIH HHS [R01 MH59329] NR 53 TC 112 Z9 117 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD JAN PY 2003 VL 60 IS 1 BP 69 EP 77 PG 9 WC Psychiatry SC Psychiatry GA 633MJ UT WOS:000180286800009 PM 12511174 ER PT J AU Murata, T Sugatani, T Shimizu, K Manganiello, VC Tagawa, T AF Murata, T Sugatani, T Shimizu, K Manganiello, VC Tagawa, T TI Effect of the phosphodiesterase 4 inhibitor, rolipram, on retinoic acid-increased alkaline phosphatase activity in the mouse fibroblastic C3H1OT1/2 cell line SO ARCHIVES OF ORAL BIOLOGY LA English DT Article DE phosphodiesterase 4 (PDE 4); retinoic acid; C3H1OT1/2 cell line ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; PROTEIN-KINASE-A; PARATHYROID-HORMONE; RXR-ALPHA; EXPRESSION; VARIANTS; PDE11A; GENE; BONE; RAT AB We have evaluated effects of a phosphodiesterase (PDE) 4 inhibitor on retinoic acid-increased alkaline phosphatase activity in the mouse fibroblastic C3H10T1/2 clone 8 (10T1/2) cell tine. 10T1/2 cells were cultured in minimum essential medium (MEM) and 10% fetal bovine serum with or without 1 muM retinoic acid and/or the PDE 4 inhibitor, rolipram, and harvested at specific intervals before measurement of alkaline phosphatase activity, cAMP production in response to parathyroid hormone, osteocalcin synthesis and expression, and phosphodiesterase activity. Retinoic acid-increased alkaline phosphatase activity, and slightly enhanced cAMP production in response to parathyroid hormone. However, it did not affect osteocalcin synthesis and expression. In the presence of retinoic acid, PDE 4 activity was not changed. A PDE 4 inhibitor, rolipram, and cAMP analog, 8-bromo-cAMP dramatically increased retinoic acid's ability to induce alkaline phosphatase activity. This is the first report that PDE 4 may be involved in regulation of retinoic acid-increased alkaline phosphatase activity. (C) 2003 Elsevier Science Ltd. All rights reserved. C1 Mie Univ, Dept Oral & Maxillofacial Surg, Fac Med, Tsu, Mie 5148507, Japan. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Murata, T (reprint author), Mie Univ, Dept Oral & Maxillofacial Surg, Fac Med, 2-174 Edobashi, Tsu, Mie 5148507, Japan. NR 22 TC 1 Z9 2 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0003-9969 J9 ARCH ORAL BIOL JI Arch. Oral Biol. PD JAN PY 2003 VL 48 IS 1 BP 63 EP 67 DI 10.1016/S0003-9969(02)00166-8 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 675GR UT WOS:000182686000008 PM 12615143 ER PT J AU Grether, JK Nelson, KB Walsh, E Willoughby, RE Redline, RW AF Grether, JK Nelson, KB Walsh, E Willoughby, RE Redline, RW TI Intrauterine exposure to infection and risk of cerebral palsy in very preterm infants SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID LOW-BIRTH-WEIGHT; 32 WEEKS GESTATION; INTRAVENTRICULAR HEMORRHAGE; PERIVENTRICULAR LEUKOMALACIA; MATERNAL INFECTION; MAGNESIUM-SULFATE; BRAIN-DAMAGE; CHORIOAMNIONITIS; ANTECEDENTS; BORN AB Objective: To evaluate exposure to intrauterine infection as an independent risk factor for spastic cerebral palsy (CP) among very prematurely born infants. Study Design: Retrospective case-control study Methods: Singleton children with gestational ages less than 32 weeks and birth weights less than 1999 g who survived to age 2 years and were born from 1988 to 1994 in a level 2 or 3 hospital in California were included in the study. Cases were children with congenital spastic CP (n = 170). Controls were children randomly sampled within 250-g birth weight intervals (n = 270). Gestational age was controlled through multiple logistic models. Major analyses were controlled for preeclampsia and short time between admission and delivery. Results: Neither clinical nor histologic indicators of intrauterine infection were associated with total spastic CP or spastic diplegia in these infants. Although not predicted by prior hypothesis, we observed an approximate doubling of risk for infants of infected mothers among children born to white women, whereas no association was noted among children born to women of other races/ ethnicities. White controls had lower frequency of all measured infection indicators compared with white cases and cases and controls of other races/ethnicities. Conclusion: Exposure to intrauterine infection was not an independent risk factor for CP in very premature infants when gestational age and other confounders were tightly controlled. C1 Calif Dept Hlth Serv, Environm Hlth Invest Branch, Oakland, CA 94612 USA. Calif Dept Hlth Serv, Calif Birth Defects Monitoring Program, Oakland, CA 94612 USA. NINCDS, NIH, Bethesda, MD 20892 USA. Alta Bates Summit Med Ctr, Berkeley, CA USA. Johns Hopkins Univ, Dept Pediat, Div Infect Dis, Baltimore, MD 21218 USA. Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. RP Grether, JK (reprint author), Calif Dept Hlth Serv, Environm Hlth Invest Branch, 1515 Clay St,17th Floor, Oakland, CA 94612 USA. FU NINDS NIH HHS [NS35573-01] NR 48 TC 60 Z9 62 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD JAN PY 2003 VL 157 IS 1 BP 26 EP 32 PG 7 WC Pediatrics SC Pediatrics GA 632NP UT WOS:000180229600003 PM 12517191 ER PT J AU Brenner, RA Simons-Morton, BG Bhaskar, B Revenis, M Das, A Clemens, JD AF Brenner, RA Simons-Morton, BG Bhaskar, B Revenis, M Das, A Clemens, JD TI Infant-parent bed sharing in an inner-city population SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID PRONE SLEEP POSITION; DEATH-SYNDROME; CONSUMER PRODUCT; SAFEST PLACE; NEW-ZEALAND; CHILDREN; PREVALENCE; RISK; PREDICTORS; LOCATION AB Background: In the United States, infant-parent bed sharing is a controversial and poorly understood practice. Proponents site potential advantages such as increases in bonding and facilitation of breastfeeding, whereas opponents site potential increases in risks of suffocation and sudden infant death syndrome, particularly among mothers who smoke. Few studies have examined normative practices in low-income populations. Objectives: To describe sleep practices in a cohort of infants born to predominantly low-income, inner-city mothers, to examine stability in-sleep practices during the first 7 to 12 months of life, and to identify factors associated with bed sharing. Design and Setting: Prospective birth cohort study in the District of Columbia, with recruitment taking place between August 1995 and September 1996 and follow-up from November 1995 to September 1997. Participants: Maternal-infant pairs were systematically selected from 3 hospitals. We interviewed 394 mothers shortly after delivery and at 3 to 7 months post partum. Of these, 369 were interviewed again at 7 to 12 months post partum. Main Outcome Measure: Usual bed sharing. Results: At age 3 to 7 months (mean age, 129 days), 201 infants (51%) usually slept alone and 191 (48%) usually slept in a bed with a parent or other adult. Similarly, at age 7 to 12 months (mean age, 262 days), 190 infants (51%) usually slept alone and 175 (47%) usually slept in a bed with a parent or other adult. Of the infants who slept with a parent or other adult at age 3 to 7 months 75% continued to do so at age 7 to 12 months. Similarly, of infants who usually slept alone at age 3 to 7 months, only 22% were reported to be usual bed sharers at age 7 to 12 months. In multivariate analyses, factors associated with bed sharing at both follow-up interviews included single marital status of the mother (first interview: odds ratio [OR] = 1.90; 95% confidence interval [ CI 1, 1.11-3.27; second interview: OR= 1.81; 95% CI, 1.02-3.25) and I or more moves since the birth of the infant (first interview: OR= 1.82; 95% CI, 1.10-3.01; second interview: OR= 1.73; 950% CI, 1.05-2.86). Breastfeeding and household crowding were not significantly associated with bed sharing. Conclusions: Bed sharing was common in this inner-city population, and sleep practices were relatively stable during the first 7 to 12 months of life. These findings underscore the need for additional research clarifying, the benefits and risks of bed sharing. C1 NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. Res Triangle Inst, Rockville, MD USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Int Vaccine Inst, Seoul, South Korea. RP Brenner, RA (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B03, Bethesda, MD 20892 USA. OI Simons-Morton, Bruce/0000-0003-1099-6617 FU NICHD NIH HHS [U18-HD30445, U18-HD30447, U18-HD30450, U18-HD30454, U18-HD30458, U18-HD31206, U18-HD31919] NR 42 TC 44 Z9 46 U1 1 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD JAN PY 2003 VL 157 IS 1 BP 33 EP 39 PG 7 WC Pediatrics SC Pediatrics GA 632NP UT WOS:000180229600004 PM 12517192 ER PT J AU Willinger, M Ko, CW Hoffman, HJ Kessler, RC Corwin, MJ AF Willinger, M Ko, CW Hoffman, HJ Kessler, RC Corwin, MJ TI Trends in infant bed sharing in the United States, 1993-2000 - The National Infant Sleep Position study SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID DEATH-SYNDROME; RISK; ENVIRONMENT; PREVENTION; SIDS AB Background: Bed sharing with parents has been described as both beneficial to infant well-being and as a potentially lethal situation. Objective: To examine trends in bed sharing between infants and caregivers, and the factors that influence this behavior. Design: Annual nationally representative telephone surveys conducted between 1993 and 2000. Setting: The 48 contiguous United States. Participants: Nighttime caregivers of infants born within 7 months prior to interview between 1993 and 2000. Approximately 1000 interviews were conducted each year for a total sample of 8453 nighttime caregivers. Main Outcome Measures: Where and with whom the infant usually slept at night in the preceding 2 weeks. Results: Forty-five percent of infants spent at least some time at night on an adult bed in the last 2 weeks. Between 1993 and 2000, the proportion of infants usually sharing an adult bed at night increased from 5.5% to 12.8%. More than 90% of infants who "usually" slept on an adult bed shared it with their parents. In a multivariate analysis, factors associated with increased probability of routine bed sharing included: maternal age less than 18 years (odds ratio [OR]= 2.26; 95% confidence interval [CI], 1.22-4.21), maternal race or ethnicity reported as black (OR=4.04; 95% Cl, 3.04-5.36) or as Asian or "other" (OR= 2.72; 95% Cl, 1.74-4.22), household income less than $20 000 (OR= 1.49; 95% Cl, 1.15 = 1.92), living in the Southern states compared with living in the Midwest (OR, 1.59; 95% CI = 1.23, 2.06), and infant age less than 8 weeks (OR= 1.60; 95% Cl, 1.10-2.33). Living in the Mid-Atlantic compared with the Midwest (OR= 0.63; 95% Cl, 0.44-0.90), and being born with low birthweight and preterm (OR = 0.32; 95% Cl, 0.14-0.74) were associated with decreased probability of routine bed sharing. Conclusions: Bed sharing as a routine practice is growing in the United States. Given that this practice seems to be widespread and strongly influenced by cultural factors, more studies of the consequences of bed sharing are needed to inform health care providers and parents on the risks and benefits. C1 NICHHD, Pregnancy & Peronatol Branch, Ctr Res Mother & Children, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, Epidemiol & Biostat Program, NIH, Bethesda, MD USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Boston Univ, Sch Med, Dept Pediat, Boston Med Ctr, Boston, MA 02215 USA. RP Willinger, M (reprint author), NICHHD, Pregnancy & Peronatol Branch, Ctr Res Mother & Children, NIH, 6100 Execut Blvd,Room 4B03,MSC 7510, Bethesda, MD 20892 USA. FU NICHD NIH HHS [HD-2-9067] NR 31 TC 98 Z9 101 U1 1 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD JAN PY 2003 VL 157 IS 1 BP 43 EP 49 PG 7 WC Pediatrics SC Pediatrics GA 632NP UT WOS:000180229600005 PM 12517193 ER PT J AU Koshkaryev, A Barshtein, G Nyska, A Ezov, N Levin-Harrus, T Shabat, S Nyska, M Redlich, M Tsipis, F Yedgar, S AF Koshkaryev, A Barshtein, G Nyska, A Ezov, N Levin-Harrus, T Shabat, S Nyska, M Redlich, M Tsipis, F Yedgar, S TI 2-Butoxyethanol enhances the adherence of red blood cells SO ARCHIVES OF TOXICOLOGY LA English DT Article DE rat; 2-butoxyethanol; hemolysis; thrombosis; red blood cell ID MONOBUTYL ETHER 2-BUTOXYETHANOL; COMPUTERIZED IMAGE-ANALYSIS; BETA-THALASSEMIA MAJOR; FEMALE F344 RATS; BUTOXYACETIC ACID; HEMOLYTIC-ANEMIA; ERYTHROCYTES; AGGREGATION; THROMBOSIS; INFARCTION AB We recently presented a unique, chemically-induced rat model of hemolytic anemia and disseminated thrombosis. In this 2-butoxyethanol (BE)-induced model the organs developing infarction are comparable to those seen in human diseases, characterized by hemolysis and thrombosis (e.g., thalassemia, sickle-cell disease, paroxysmal nocturnal hemoglobinuria, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome). Red blood cells (RBCs) have special flow properties, namely, self-aggregability, deformability, and potential adherence to endothelial cells (ECs) of the blood vessel wall, which are essential for adequate blood flow and tissue perfusion; their alteration facilitates circulatory disorders. To examine the possible contribution of alterations in RBC flow properties to the observed thrombosis in the present investigation we determined the BE-induced changes in adherence, aggregability, and deformability of RBCs from male and female Fischer F344 rats exposed to two, three, or four daily doses of BE at 250 mg BE/kg body weight. Control animals were treated with the vehicle alone. Blood was taken on days 2, 3, 4, and 29. The administration of BE did not affect the RBCs aggregability but markedly enhanced their adherence to extracellular matrix; such enhancement was correlated with adherence to cultured ECs. RBC/EC interaction has been shown to be a potent catalyst of vascular occlusion in hemolytic hemoglobinopathies; thus the enhanced RBC adherence to EC is a likely mechanism by which thrombosis and organ infarct are induced in BE-treated rats. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Biochem, IL-91010 Jerusalem, Israel. Harlan Biotech Israel Ltd, IL-76326 Rehobot, Israel. Sapir Med Ctr, Dept Orthoped Surg, Kefar Sava, Israel. Hebrew Univ Jerusalem, Hadassah Med Sch, Fac Med Dent, Dept Orthodont, IL-91010 Jerusalem, Israel. RP Nyska, A (reprint author), NIEHS, Lab Expt Pathol, POB 12233, Res Triangle Pk, NC 27709 USA. RI Koshkaryev, Alexander /J-3619-2012 NR 33 TC 16 Z9 17 U1 4 U2 5 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-5761 J9 ARCH TOXICOL JI Arch. Toxicol. PY 2003 VL 77 IS 8 BP 465 EP 469 DI 10.1007/s00204-003-0471-x PG 5 WC Toxicology SC Toxicology GA 715DG UT WOS:000184954800007 PM 12756519 ER PT J AU Kobayashi, SD DeLeo, FR AF Kobayashi, SD DeLeo, FR TI Apoptosis in human polymorphonuclear leukocytes: Searching for a genetic roadmap SO ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS LA English DT Review DE neutrophil; apoptosis; gene transcription; inflammation ID PROGRAMMED CELL-DEATH; HUMAN PERIPHERAL-BLOOD; HUMAN NEUTROPHIL APOPTOSIS; NECROSIS-FACTOR-ALPHA; PROTEIN-SYNTHESIS; HEMATOPOIETIC-CELLS; AGING NEUTROPHILS; III SECRETION; MESSENGER-RNA; EXPRESSION AB Polymorphonuclear leukocytes (PMNs or neutrophils) are essential components of the innate immune system in humans and function primarily to eliminate invading microorganisms. Neutrophil influx to sites of infection is desirable because it also initiates an inflammatory response. Paradoxically, PMNs are also intimately associated with inflammatory disease. As part of normal neutrophil turnover in humans and to limit inflammatory potential, PMNs undergo programmed cell death, or apoptosis. Several host factors, including cytokines and growth factors, are capable of extending neutrophil survival and, thus, capacity to fight infection. On the other hand, phagocytosis of bacterial pathogens generally accelerates PMN apoptosis. Due in part to the extensive complexity of programmed cell death, relatively little is known about the signaling pathways that govern these processes in PMNs. Recently, microarray strategies have been employed to gain an understanding of these processes in activated PMNs, and new evidence indicates that gene transcription is important in the regulation of neutrophil apoptosis and, thus, inflammation. A series of provocative discoveries led to the hypothesis that neutrophil programmed cell death is the result of an apoptosis-differentiation program, a final stage of transcriptionally regulated PMN maturation or hematopoietic differentiation. Further characterization of the apoptosis-differentiation program and associated biochemical pathways in mature PMNs will likely yield important insights into the resolution of inflammation and infection. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP DeLeo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. OI DeLeo, Frank/0000-0003-3150-2516 NR 61 TC 3 Z9 3 U1 0 U2 0 PU INST IMMUNOLOGY & EXPERIMENTAL THERAPY PI WROCLAW PA POLISH ACADEMY OF SCIENCES CZERSKA 12, 53-114 WROCLAW, POLAND SN 0004-069X J9 ARCH IMMUNOL THER EX JI Arch. Immunol. Ther. Exp. PY 2003 VL 51 IS 1 BP 1 EP 8 PG 8 WC Immunology SC Immunology GA 650KB UT WOS:000181261500001 PM 12691299 ER PT J AU Mocellin, S Rossi, CR Marincola, FM AF Mocellin, S Rossi, CR Marincola, FM TI Quantitative real-time PCR in cancer research SO ARCHIVUM IMMUNOLOGIAE ET THERAPIAE EXPERIMENTALIS LA English DT Review DE quantitative PCR; cancer research ID POLYMERASE-CHAIN-REACTION; MINIMAL RESIDUAL DISEASE; CHRONIC MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; GENE-EXPRESSION ANALYSIS; REACTION RT-PCR; LASER-ASSISTED MICRODISSECTION; BLOOD MONONUCLEAR-CELLS; CYTOKINE MESSENGER-RNA; OCCULT TUMOR-CELLS AB In the era of the Human Genome Project, quantitation of gene expression by tumor/host cells is of paramount importance to investigate gene patterns responsible for cancer development, progression and response/resistance to treatment. Quantitative real-time PCR (qrt-PCR) technology has recently reached a level of sensitivity, accuracy and practical ease that support its use as a routine bioinstrumentation for gene level measurement. Several applications have been already implemented in the field of cancer research, and others are being validated, showing that this molecular biology tool can provide both researchers and clinicians with precious information concerning the behaviour of tumors. The knowledge of the biochemical principles underlying this biotechnology can be of great value to correctly interpret qrt-PCR data. C1 NIH, Immunogenet Lab, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Univ Padua, Dept Oncol & Surg Sci, Surg Branch, I-35100 Padua, Italy. RP Marincola, FM (reprint author), NIH, Immunogenet Lab, Dept Transfus Med, Ctr Clin, 10 Ctr Dr,Bldg 10,Room 1C711, Bethesda, MD 20892 USA. RI Rossi, Carlo Riccardo/A-7685-2010 OI Rossi, Carlo Riccardo/0000-0001-7875-5655 NR 121 TC 9 Z9 11 U1 2 U2 11 PU INST IMMUNOLOGY & EXPERIMENTAL THERAPY PI WROCLAW PA POLISH ACADEMY OF SCIENCES CZERSKA 12, 53-114 WROCLAW, POLAND SN 0004-069X J9 ARCH IMMUNOL THER EX JI Arch. Immunol. Ther. Exp. PY 2003 VL 51 IS 5 BP 301 EP 313 PG 13 WC Immunology SC Immunology GA 737PV UT WOS:000186241700005 PM 14626430 ER PT B AU Trouba, K Nyska, A Styblo, M Dunson, D Lomnitski, L Grossman, S Moser, G Suttie, A Patterson, R Walton, F Germolec, D AF Trouba, K Nyska, A Styblo, M Dunson, D Lomnitski, L Grossman, S Moser, G Suttie, A Patterson, R Walton, F Germolec, D BE Chappell, WR Abernathy, CO Calderon, RL Thomas, DJ TI Effect of antioxidants on the papilloma response and liver glutathione modulation mediated by arsenic in Tg.AC transgenic mice SO ARSENIC EXPOSURE AND HEALTH EFFECTS V LA English DT Proceedings Paper CT 5th International Conference on Arsenic Exposure and Health Effects CY JUL 14-18, 2002 CL San Diego, CA SP Soc Environm Geochem & Hlth DE antioxidants; papilloma; Tg.AC; glutathione; NAO; vitamin E ID V-HA-RAS; WATER-SOLUBLE ANTIOXIDANT; INDUCED OXIDATIVE STRESS; MOUSE SKIN; VITAMIN-E; MULTISTAGE CARCINOGENESIS; SODIUM ARSENITE; GROWTH-FACTORS; INORGANIC ARSENICALS; HUMAN KERATINOCYTES AB Epidemiological studies indicate that inorganic arsenicals produce various skin lesions as well as skin, lung, bladder, liver, prostate, and renal cancer. Our laboratory previously demonstrated that low-dose 12-O-tetradecanoylphorbol-13-acetate (TPA) increased the number of skin papillomas in Tg.AC transgenic mice that received sodium arsenite in drinking water, an effect dependent on proinflammatory cytokines. Because proinflammatory cytokine expression can be modulated by free radicals and oxidative stress, we hypothesized that oxidative stress contributes to TPA-promoted papilloma development in Tg.AC mice exposed to sodium arsenite. To evaluate the contribution of oxidative stress to arsenic skin carcinogenesis, two free-radical scavengers were tested for their ability to suppress papilloma responses (e.g. induction, latency, and multiplicity) modulated by arsenite in Tg.AC mice. Data indicate that arsenite increased papilloma responses in TPA-promoted Tg.AC mice as compared to control animals (no arsenite). The antioxidant vitamin E or a water-soluble natural antioxidant fraction from spinach had no inhibitory effect on TPA-promoted papilloma responses following arsenite exposure. Although not conclusively defined by our studies, oxidative stress generated by arsenic may contribute to skin carcinogenesis; however, it is not likely to be the sole or primary mechanism that enhances papilloma responses following arsenite exposure and TPA promotion. C1 NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Trouba, K (reprint author), NIEHS, Mol Toxicol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. NR 63 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS BN 0-444-51441-4 PY 2003 BP 283 EP 293 DI 10.1016/B978-044451441-7/50022-1 PG 11 WC Biochemistry & Molecular Biology; Engineering, Environmental; Public, Environmental & Occupational Health; Toxicology SC Biochemistry & Molecular Biology; Engineering; Public, Environmental & Occupational Health; Toxicology GA BY53D UT WOS:000189401600021 ER PT B AU Liu, J Chen, H Kadiiska, M Xie, Y Waalkes, MP AF Liu, J Chen, H Kadiiska, M Xie, Y Waalkes, MP BE Chappell, WR Abernathy, CO Calderon, RL Thomas, DJ TI Application of filter arrays to the study of arsenic toxicity and carcinogenesis SO ARSENIC EXPOSURE AND HEALTH EFFECTS V LA English DT Proceedings Paper CT 5th International Conference on Arsenic Exposure and Health Effects CY JUL 14-18, 2002 CL San Diego, CA SP Soc Environm Geochem & Hlth DE cDNA microarray; arsenic; acute and chronic toxicity; carcinogenesis ID INDUCED MALIGNANT-TRANSFORMATION; GENE-EXPRESSION; ASSOCIATION; OVEREXPRESSION; TOLERANCE; MICE AB Arsenic is a known human carcinogen. Acute arsenic exposure produces toxicity to multiple organs, while chronic exposure to arsenic causes tumors of the skin, lung, bladder, liver, and kidney. Since alterations in gene expression following arsenic exposure that are linked to toxic effects are incompletely understood, microarray technology was utilized to analyze gene expression changes associated with arsenic toxicity and carcinogenesis. Total RNA was extracted from cells transformed by chronic arsenic exposure, from mouse livers of acute and chronic arsenic exposure, and from liver tumors induced by transplacental arsenic exposure. RNA was then converted to cDNA probes using reverse transcriptase and cDNA synthesis primers. The P-32-labeled cDNA probes were hybridized to array membranes on which hundreds of known cDNA fragments are fixed The hybridization intensity was quantified using AtlasImage software, and the selected gene expression was further confirmed by RT-PCR or Western blot analysis. Induction of oxidative stress-related genes, such as heme oxygenase-1 and heat-shock proteins, is associated with acute arsenic exposure, while the activation of oncogenes, such as c-myc, H-ras, c-met. and Wilm's tumor protein, is associated with chronic arsenic exposure and/or arsenic transformation. Dysregulation of cell cycles, such as overexpression of estrogen receptor-alpha, cyclin D1, proliferative cell nuclear antigen (PCNA), and downregulation of p27 is observed following chronic exposure to arsenic. Overexpression of a-fetoprotein and downregulation of syndecan-1 were mainly seen in arsenic-induced tumors. Thus, microarray is a useful tool to profile genetic events associated with arsenic toxicity and carcinogenesis. C1 NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. RP Liu, J (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. NR 16 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS BN 0-444-51441-4 PY 2003 BP 295 EP 303 DI 10.1016/B978-044451441-7/50023-3 PG 9 WC Biochemistry & Molecular Biology; Engineering, Environmental; Public, Environmental & Occupational Health; Toxicology SC Biochemistry & Molecular Biology; Engineering; Public, Environmental & Occupational Health; Toxicology GA BY53D UT WOS:000189401600022 ER PT J AU Tuan, RS Boland, G Tuli, R AF Tuan, RS Boland, G Tuli, R TI Adult mesenchymal stem cells and cell-based tissue engineering SO ARTHRITIS RESEARCH & THERAPY LA English DT Review DE cell differentiation; cell signaling; mesenchymal stem cells; stem cells; tissue engineering ID MARROW STROMAL CELLS; HUMAN-BONE-MARROW; HUMAN TRABECULAR BONE; ARTICULAR-CARTILAGE DEFECTS; BETA SIGNAL-TRANSDUCTION; FIBROBLAST-GROWTH-FACTOR; HUMAN ADIPOSE-TISSUE; IN-VITRO; GENE-EXPRESSION; OSTEOGENIC DIFFERENTIATION AB The identification of multipotential mesenchymal stem cells (MSCs) derived from adult human tissues, including bone marrow stroma and a number of connective tissues, has provided exciting prospects for cell-based tissue engineering and regeneration. This review focuses on the biology of MSCs, including their differentiation potentials in vitro and in vivo, and the application of MSCs in tissue engineering. Our current understanding of MSCs lags behind that of other stem cell types, such as hematopoietic stem cells. Future research should aim to define the cellular and molecular fingerprints of MSCs and elucidate their endogenous role(s) in normal and abnormal tissue functions. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bldg 50,Room 1503,MSC 8022, Bethesda, MD 20892 USA. EM Tuanr@mail.nih.gov NR 150 TC 430 Z9 466 U1 12 U2 57 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 IS 1 BP 32 EP 45 DI 10.1186/ar614 PG 14 WC Rheumatology SC Rheumatology GA 660BG UT WOS:000181813600007 PM 12716446 ER PT J AU Langford, CA AF Langford, CA TI Wegener's granulomatosis: current and upcoming therapies SO ARTHRITIS RESEARCH & THERAPY LA English DT Review DE granulomatosis; treatment; vasculitis; Wegener ID ANCA-ASSOCIATED VASCULITIS; LOW-DOSE METHOTREXATE; TNF-ALPHA BLOCKADE; SYSTEMIC VASCULITIS; INTRAVENOUS IMMUNOGLOBULIN; PULSE CYCLOPHOSPHAMIDE; TRIMETHOPRIM-SULFAMETHOXAZOLE; STAPHYLOCOCCUS-AUREUS; RENAL INVOLVEMENT; DISEASE-ACTIVITY AB Wegener's granulomatosis is a complex multisystem disease that can be associated with morbidity and mortality. The introduction of cyclophosphamide and glucocorticoids brought about the potential for long-term survival and provided the opportunity and impetus to explore treatment options that can reduce the toxicity of therapy and lessen the likelihood of relapse. With the growth of knowledge regarding disease pathophysiology and the increasing ability to selectively target the immune system, the potential options for therapeutic investigation have continued to expand. Careful study of new agents through rigorously designed trials is essential to answering questions of safety and efficacy in Wegener's granulomatosis. C1 NIAID, Immunol Dis Sect, Immunoregulat Lab, MHS,NIH, Bethesda, MD 20892 USA. RP Langford, CA (reprint author), NIAID, Immunol Dis Sect, Immunoregulat Lab, MHS,NIH, Bldg 10,Room 11B-13, Bethesda, MD 20892 USA. EM clangford@niaid.nih.gov NR 56 TC 18 Z9 22 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 IS 4 BP 180 EP 191 DI 10.1186/ar771 PG 12 WC Rheumatology SC Rheumatology GA 688JU UT WOS:000183431600013 PM 12823849 ER PT J AU Tuli, R Li, WJ Tuan, RS AF Tuli, R Li, WJ Tuan, RS TI Current state of cartilage tissue engineering SO ARTHRITIS RESEARCH & THERAPY LA English DT Article DE biomaterials; cartilage; mesenchymal progenitor cells; tissue engineering ID MESENCHYMAL STEM-CELLS; ARTICULAR CHONDROCYTES; TRABECULAR BONE; ALGINATE; REPAIR; GENERATION; SCAFFOLD; DEFECTS; POLYMER; MARROW AB Damage to cartilage is of great clinical consequence given the tissue's limited intrinsic potential for healing. Current treatments for cartilage repair are less than satisfactory, and rarely restore full function or return the tissue to its native normal state. The rapidly emerging field of tissue engineering holds great promise for the generation of functional cartilage tissue substitutes. The general approach involves a biocompatible, structurally and mechanically sound scaffold, with an appropriate cell source, which is loaded with bioactive molecules that promote cellular differentiation and/or maturation. This review highlights aspects of current progress in cartilage tissue engineering. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, US Dept HHS, NIH, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, US Dept HHS, NIH, Bldg 50,Room 1503,50 South Dr,MSC 8022, Bethesda, MD 20892 USA. EM Tuanr@mail.nih.gov RI Li, Wan-Ju/A-7002-2008 NR 23 TC 103 Z9 108 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 IS 5 BP 235 EP 238 DI 10.1186/ar991 PG 4 WC Rheumatology SC Rheumatology GA 711FW UT WOS:000184729800006 PM 12932283 ER PT J AU Eskandari, F Webster, JI Sternberg, EM AF Eskandari, F Webster, JI Sternberg, EM TI Neural immune pathways and their connection to inflammatory diseases SO ARTHRITIS RESEARCH & THERAPY LA English DT Review DE cytokine; hypothalamic-pituitary-adrenal axis; immune; inflammatory; neural; rheumatoid arthritis ID PITUITARY-ADRENAL AXIS; CORTICOTROPIN-RELEASING HORMONE; TUMOR-NECROSIS-FACTOR; GLUCOCORTICOID-RECEPTOR-BETA; ADJUVANT-INDUCED ARTHRITIS; COLLAGEN-INDUCED ARTHRITIS; DIAGNOSED RHEUMATOID-ARTHRITIS; CHRONIC-FATIGUE-SYNDROME; VASOACTIVE-INTESTINAL-PEPTIDE; SYSTEMIC-LUPUS-ERYTHEMATOSUS AB Inflammation and inflammatory responses are modulated by a bidirectional communication between the neuroendocrine and immune system. Many lines of research have established the numerous routes by which the immune system and the central nervous system (CNS) communicate. The CNS signals the immune system through hormonal pathways, including the hypothalamic - pituitary - adrenal axis and the hormones of the neuroendocrine stress response, and through neuronal pathways, including the autonomic nervous system. The hypothalamic - pituitary - gonadal axis and sex hormones also have an important immunoregulatory role. The immune system signals the CNS through immune mediators and cytokines that can cross the blood - brain barrier, or signal indirectly through the vagus nerve or second messengers. Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. This review discusses neuroimmune interactions and evidence for the role of such neural immune regulation of inflammation, rather than a discussion of the individual inflammatory mediators, in rheumatoid arthritis. C1 NIMH, Integrat Neurol Immune Program, Sect Neuroendocrine Immunol & Behav, NIH,DHHS, Bethesda, MD 20892 USA. RP Sternberg, EM (reprint author), NIMH, Integrat Neurol Immune Program, Sect Neuroendocrine Immunol & Behav, NIH,DHHS, 36 Convent Dr,Room 1A23, Bethesda, MD 20892 USA. EM ems@codon.nih.gov RI Webster Marketon, Jeanette/H-5613-2011 OI Webster Marketon, Jeanette/0000-0002-3627-1094 NR 276 TC 117 Z9 126 U1 4 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 IS 6 BP 251 EP 265 DI 10.1186/ar1002 PG 15 WC Rheumatology SC Rheumatology GA 736BT UT WOS:000186151000001 PM 14680500 ER PT J AU Fairhurst, AM Connolly, JE Hintz, KA Goulding, NJ Rassias, AJ Yeager, MP Rigby, W Wallace, PK AF Fairhurst, AM Connolly, JE Hintz, KA Goulding, NJ Rassias, AJ Yeager, MP Rigby, W Wallace, PK TI Regulation and localization of endogenous human tristetraprolin SO ARTHRITIS RESEARCH & THERAPY LA English DT Article DE endotoxic shock; inflammation; lipopolysaccharide; tristetraprolin ID TUMOR-NECROSIS-FACTOR; ZINC-FINGER PROTEINS; RHEUMATOID-ARTHRITIS; FACTOR-ALPHA; MESSENGER-RNA; TNF-ALPHA; MONOCLONAL-ANTIBODIES; INTRAVENOUS ENDOTOXIN; TRANSCRIPTION FACTOR; DEFICIENCY SYNDROME AB Tumor necrosis factor (TNF) has been implicated in the development and pathogenicity of infectious diseases and autoimmune disorders, such as septic shock and arthritis. The zinc-finger protein tristetraprolin (TTP) has been identified as a major regulator of TNF biosynthesis. To define its intracellular location and examine its regulation of TNF, a quantitive intracellular staining assay specific for TTP was developed. We establish for the first time that in peripheral blood leukocytes, expression of endogenous TTP is confined to the cytoplasm. Baseline expression of TTP was higher in monocytes than in lymphocytes or neutrophils. After in vitro incubation with lipopolysaccharide (LPS), leukocyte TTP levels increased rapidly, peaking after approximately 2 hours. Monocytes showed the greatest response to LPS stimulation and lymphocytes the least. TTP levels were also studied in leukocytes isolated from healthy volunteers infused with a bolus dose of LPS. TTP expression and initial upregulation in response to LPS infusion were consistent with the in vitro data. Neutrophil TTP levels responded first, reaching an initial peak within 1 hour, monocyte levels peaked next at 2 hours, followed by lymphocytes at 4 hours. This response paralleled plasma TNF levels, which peaked 2 hours after infusion and were no longer detectable after 12 hours. A second rise in intracellular TTP levels, which did not parallel plasma TNF levels, was observed in all leukocyte populations, starting 12 hours after infusion. These data establish the cytoplasmic location of TTP, supporting a major role for this protein in regulating TNF production, and suggest that TTP levels are not regulated solely by TNF. C1 Univ London, William Harvey Res Inst, London, England. Dartmouth Coll Sch Med, Dept Microbiol & Immunol, Lebanon, NH USA. Dartmouth Coll Sch Med, Dept Physiol, Lebanon, NH USA. Dartmouth Coll Sch Med, Dept Anesthesiol, Lebanon, NH USA. Dartmouth Coll Sch Med, Dept Med, Lebanon, NH USA. RP Fairhurst, AM (reprint author), NIAMS, NIH, Bldg 10 6D52 6000 Rockville Pike, Bethesda, MD 20892 USA. EM fairhursta@mail.nih.gov RI Connolly, John/B-8099-2014; OI Fairhurst, Anna-Marie/0000-0002-8950-6192 FU NCI NIH HHS [P30 CA023108]; NCRR NIH HHS [P20 RR16437, P20 RR016437]; NIAID NIH HHS [T32 AI007363]; NIAMS NIH HHS [T32 AR007576] NR 50 TC 16 Z9 17 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 IS 4 BP R214 EP R225 DI 10.1186/ar778 PG 12 WC Rheumatology SC Rheumatology GA 688JU UT WOS:000183431600006 PM 12823857 ER PT J AU Newkirk, MM Goldbach-Mansky, R Lee, J Hoxworth, J McCoy, A Yarboro, C Klippel, J El-Gabalawy, HS AF Newkirk, MM Goldbach-Mansky, R Lee, J Hoxworth, J McCoy, A Yarboro, C Klippel, J El-Gabalawy, HS TI Advanced glycation end-product (AGE)-damaged IgG and IgM autoantibodies to IgG-AGE in patients with early synovitis SO ARTHRITIS RESEARCH & THERAPY LA English DT Article DE nonenzymatic glycation; rheumatoid arthritis; rheumatoid factor ID EARLY RHEUMATOID-ARTHRITIS; DISEASE-ACTIVITY; CROSS-LINKS; PENTOSIDINE; SERUM; PROGRESSION; FLUID; CLASSIFICATION; ASSOCIATION; CRITERIA AB Advanced glycation end-product (AGE)-damaged IgG occurs as a result of hyperglycemia and/or oxidative stress. Autoantibodies to IgG-AGE were previously demonstrated in patients with severe, longstanding rheumatoid arthritis (RA). We investigated whether IgG-AGE and anti-IgG-AGE antibodies were present early in the course of RA and other inflammatory arthropathies. We prospectively followed a cohort of 238 patients with inflammatory arthritis of duration less than 1 year. Patients were evaluated clinically and serologically, and radiographs were obtained at initial and 1-year visits. Sera were assayed for IgG-AGE and anti-IgG-AGE antibodies by enzyme-linked immunosorbent assay (ELISA). Rheumatoid factor (RF) was determined by nephelometry and ELISA. Of all patients, 29% had RF-positive RA, 15% had RF-negative RA, 18% had spondyloarthropathy, and 38% had undifferentiated arthritis. IgG-AGE was present in 19% of patients, and was similar in amount and frequency in all groups. Patients with elevated IgG-AGE levels had significantly higher levels of the inflammatory markers C-reactive protein and erythrocyte sedimentation rate, but there was no correlation with blood glucose levels. Overall, 27% of the patients had IgM anti-IgG-AGE antibodies. These antibodies were highly significantly associated with RFs (P< 0.0001) and with swollen joint count ( P< 0.01). In early onset arthritis, IgG damaged by AGE was detected in all patient groups. The ability to make IgM anti-IgG-AGE antibodies, however, was restricted to a subset of RF-positive RA patients with more active disease. The persistence of the anti-IgG-AGE response was more specific to RA, and was transient in the patients with spondyloarthropathy and with undifferentiated arthritis who were initially found to be positive for anti-IgG-AGE antibodies. C1 McGill Univ, Ctr Hlth, Montreal, PQ, Canada. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Newkirk, MM (reprint author), Montreal Gen Hosp, 1650 Cedar Ave, Montreal, PQ H3G 1A4, Canada. EM Marianna.Newkirk@mcgill.ca NR 25 TC 34 Z9 36 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 IS 2 BP R82 EP R90 DI 10.1186/ar622 PG 9 WC Rheumatology SC Rheumatology GA 660BM UT WOS:000181814100009 PM 12718751 ER PT J AU Dorner, T Jacobi, A Odendahl, M Burmester, GR Radbruch, A Valet, G Lipsky, PE AF Dorner, T Jacobi, A Odendahl, M Burmester, GR Radbruch, A Valet, G Lipsky, PE TI Analysis of B-cell subpopulations in systemic lupus erythematosus SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract CT 3rd World Congress of the Global-Arthritis-Research-Network (GARN) CY SEP 14-17, 2003 CL Miyakazi, JAPAN C1 Charite Univ Hosp, Dept Rheumat & Clin Immunol, Berlin, Germany. Deutsch Rheumaforschungszentrum, Berlin, Germany. Max Planck Inst Biochem, D-8000 Munich, Germany. NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 SU 3 MA 27 BP S9 EP S9 DI 10.1186/ar828 PG 1 WC Rheumatology SC Rheumatology GA 801SX UT WOS:000220116700029 ER PT J AU El-Gabalawy, H Wilkins, J Dasuri, K Duggan, D AF El-Gabalawy, H Wilkins, J Dasuri, K Duggan, D TI Changes in the synovial cell proteome induced by hypoxia SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract CT 3rd World Congress of the Global-Arthritis-Research-Network (GARN) CY SEP 14-17, 2003 CL Miyakazi, JAPAN C1 Univ Manitoba, Arthrit Ctr, Winnipeg, MB, Canada. NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 SU 3 MA 124 BP S39 EP S39 DI 10.1186/ar925 PG 1 WC Rheumatology SC Rheumatology GA 801SX UT WOS:000220116700126 ER PT J AU Ettinger, R Sims, GP Tackey, E Yarboro, C Illei, G Lipsky, PE AF Ettinger, R Sims, GP Tackey, E Yarboro, C Illei, G Lipsky, PE TI Expanded circulating transitional B cells in a patient with systemic lupus erythematosus SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract CT 3rd World Congress of the Global-Arthritis-Research-Network (GARN) CY SEP 14-17, 2003 CL Miyakazi, JAPAN C1 NIH, Autoimmun Branch, Bethesda, MD 20892 USA. NIH, Off Clin Director, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 SU 3 MA 158 BP S49 EP S50 DI 10.1186/ar959 PG 2 WC Rheumatology SC Rheumatology GA 801SX UT WOS:000220116700160 ER PT J AU Grammer, A Fischer, R Slota, R Longo, N Sohn, H Yarboro, C Illei, G Pierce, S Lipsky, P AF Grammer, A Fischer, R Slota, R Longo, N Sohn, H Yarboro, C Illei, G Pierce, S Lipsky, P TI Circulating anergic B cells in the periphery of active systemic lupus erythematosus patients: functional and phenotypic characterization SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract CT 3rd World Congress of the Global-Arthritis-Research-Network (GARN) CY SEP 14-17, 2003 CL Miyakazi, JAPAN C1 NIAMS, Cell Biol Grp B, Autoimmun Branch, NIH, Bethesda, MD USA. NIAMS, Repertoire Anal Grp, Autoimmun Branch, NIH, Bethesda, MD USA. NIAMS, Off Clin Director, NIH, Bethesda, MD USA. NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 SU 3 MA 96 BP S30 EP S30 DI 10.1186/ar897 PG 1 WC Rheumatology SC Rheumatology GA 801SX UT WOS:000220116700098 ER PT J AU Grammer, AC Lipsky, PE AF Grammer, AC Lipsky, PE TI B cell abnormalities in systemic lupus erythematosus SO ARTHRITIS RESEARCH & THERAPY LA English DT Review DE B cells; germinal centers; immunoglobulin-secreting cells; plasma cells; systemic lupus erythematosus ID IMMUNOGLOBULIN-SECRETING CELLS; ANTI-CD40 LIGAND ANTIBODY; GERMINAL-CENTERS; AUTOIMMUNE-DISEASE; CD40 LIGAND; LYMPHOCYTE STIMULATOR; PLASMA-CELLS; PERIPHERAL-BLOOD; DENDRITIC CELLS; TRANSGENIC MICE AB Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease characterized by the differentiation of short- and long-lived immunoglobulin secreting plasma cells that secrete pathogenic autoantibodies. Ectopic germinal centers and plasma cells secreting autoantibodies have been observed in lupus nephritis kidneys. Candidate genetic susceptibility loci for SLE include genes that affect differentiation and survival of plasma cells, such as those that influence activation, proliferation, cytokine and chemokine secretion/responsiveness, and apoptosis of the T and B cells that are involved in humoral immunity generated in germinal centers, as well as genes that are involved in presentation and clearance of apoptotic material and autoantigens by antigen presenting cells and other phagocytes. Emerging data have demonstrated that B lymphocytes are active participants in humoral immune responses that lead to T-dependent and T-independent differentiation of immunoglobulin-secreting plasma cells by homotypic CD154-CD40 interactions as well as continued stimulation by B cell activating factor through B cell maturation antigen, B cell activating factor receptor and transmembrane activater. C1 NIAMSD, Autoimmun Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Grammer, AC (reprint author), NIAMSD, Autoimmun Branch, Intramural Res Program, NIH, 9000 Rockville Pike,Bldg 10,Rm 6D47A, Bethesda, MD 20892 USA. EM grammera@mail.nih.gov NR 54 TC 70 Z9 74 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 SU 4 BP S22 EP S27 DI 10.1186/ar1009 PG 6 WC Rheumatology SC Rheumatology GA 776HD UT WOS:000189109800005 PM 15180894 ER PT J AU Lee, J Lipsky, PE AF Lee, J Lipsky, PE TI The systemic lupus erythematosus V lambda J lambda repertoire harbors characteristics of the natural antibody repertoire SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract CT 3rd World Congress of the Global-Arthritis-Research-Network (GARN) CY SEP 14-17, 2003 CL Miyakazi, JAPAN C1 Ewha Womans Univ, Coll Med, Dept Internal Med, Seoul, South Korea. NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 SU 3 MA 150 BP S47 EP S47 DI 10.1186/ar951 PG 1 WC Rheumatology SC Rheumatology GA 801SX UT WOS:000220116700152 ER PT J AU Longo, NS Fischer, R Daruwalla, J Grammer, AC Lipsky, PE AF Longo, NS Fischer, R Daruwalla, J Grammer, AC Lipsky, PE TI Repertoire analysis of anergic B cells from patients with systemic lupus erythematosus SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract CT 3rd World Congress of the Global-Arthritis-Research-Network (GARN) CY SEP 14-17, 2003 CL Miyakazi, JAPAN C1 NIAMS, Autoimmun Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 SU 3 MA 86 BP S27 EP S27 DI 10.1186/ar887 PG 1 WC Rheumatology SC Rheumatology GA 801SX UT WOS:000220116700088 ER PT J AU Samelson, L AF Samelson, L TI Characterization of signaling complexes at the T-cell antigen receptor SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract CT 3rd World Congress of the Global-Arthritis-Research-Network (GARN) CY SEP 14-17, 2003 CL Miyakazi, JAPAN C1 NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 SU 3 MA 14 BP S5 EP S5 DI 10.1186/ar815 PG 1 WC Rheumatology SC Rheumatology GA 801SX UT WOS:000220116700016 ER PT J AU Scheinecker, C McHugh, R Shevach, E Germain, R AF Scheinecker, C McHugh, R Shevach, E Germain, R TI Dendritic cells present a tissue-specific autoantigen under steady state and autoimmune conditions in the draining lymph node SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract CT 3rd World Congress of the Global-Arthritis-Research-Network (GARN) CY SEP 14-17, 2003 CL Miyakazi, JAPAN C1 Univ Vienna, Dept Rheumatol, A-1010 Vienna, Austria. NIAID, Cellular Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 SU 3 MA 103 BP S32 EP S33 DI 10.1186/ar904 PG 2 WC Rheumatology SC Rheumatology GA 801SX UT WOS:000220116700105 ER PT J AU Schulze-Koops, H Lipsky, PE Kalden, JR Skapenko, A AF Schulze-Koops, H Lipsky, PE Kalden, JR Skapenko, A TI T-cell regulation in the pathogenesis of autoimmune diseases SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract CT 3rd World Congress of the Global-Arthritis-Research-Network (GARN) CY SEP 14-17, 2003 CL Miyakazi, JAPAN C1 Univ Erlangen Nuremberg, Nikolaus Fiebiger Ctr Mol Med, Clin Res Grp 3, Erlangen, Germany. NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 SU 3 MA 117 BP S37 EP S37 DI 10.1186/ar918 PG 1 WC Rheumatology SC Rheumatology GA 801SX UT WOS:000220116700119 ER PT J AU Skapenko, A Niedobitek, GU Kalden, JR Lipsky, PE Schulze-Koops, H AF Skapenko, A Niedobitek, GU Kalden, JR Lipsky, PE Schulze-Koops, H TI The Th2 cytokines IL-4 and IL-10 are internal controllers of human Th1-biased immunity in vivo SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract CT 3rd World Congress of the Global-Arthritis-Research-Network (GARN) CY SEP 14-17, 2003 CL Miyakazi, JAPAN C1 Univ Erlangen Nurnberg, Nikolaus Fiebiger Ctr Mol Med, Clin Res Grp 3, Erlangen, Germany. Univ Erlangen Nurnberg, Dept Pathol, Erlangen, Germany. NIAMS, NIH, Bethesda, MD USA. NR 0 TC 3 Z9 3 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PY 2003 VL 5 SU 3 MA 88 BP S28 EP S28 DI 10.1186/ar889 PG 1 WC Rheumatology SC Rheumatology GA 801SX UT WOS:000220116700090 ER PT J AU Schlom, J Sabzevari, H Grosenbach, DW Hodge, JW AF Schlom, J Sabzevari, H Grosenbach, DW Hodge, JW TI A triad of costimulatory molecules synergize to amplify T-cell activation in both vector-based and vector-infected dendritic cell vaccines SO ARTIFICIAL CELLS BLOOD SUBSTITUTES AND IMMOBILIZATION BIOTECHNOLOGY LA English DT Article DE vaccines; cancer vaccine; cancer; costimulation; T cells ID TUMOR-IMMUNITY; ANTIGEN GENE; ANTITUMOR IMMUNITY; MATURATION; ICAM-1; LFA-3; VIRUS; B7; LYMPHOCYTES; INDUCTION AB The activation of a T cell has been shown to require two signals via molecules present on professional antigen presenting cells: signal 1, via a peptide/MHC complex, and signal 2, via a costimulatory molecule. Here, the role of three costimulatory molecules in the activation of T cells was examined. Poxvirus (vaccinia and avipox) vectors were employed because of their ability to efficiently express multiple genes. Murine cells provided with signal I and infected with either recombinant vaccinia or avipox vectors containing a TRIad of COstimulatory Molecules (B7-1/ICAM-1/LFA-3, designated TRICOM) induced the activation of T cells to a far greater extent than cells infected with vectors expressing any one or two costimulatory molecules. Despite this T-cell "hyperstimulation" using TRICOM vectors, no evidence of apoptosis above that seen using the B7-1 vector was observed. Results employing the TRICOM vectors were most dramatic under conditions of either low levels of first signal or low stimulator cell to T-cell ratios. Experiments employing a four-gene construct also showed that TRICOM recombinants could enhance antigen-specific T-cell responses in vivo. These studies thus demonstrate the ability of vectors to introduce three costimulatory molecules into cells, thereby activating both CD4(+) and CD8(+) T-cell populations to levels greater than those achieved with the use of only one or two costimulatory molecules. This new threshold of T-cell activation has broad implications in vaccine design and development. Dendritic cells infected with TRICOM vectors were found to greatly enhance naive T-cell activation, and peptide-specific T-cell stimulation. In vivo, peptide-pulsed DCs infected with TRICOM vectors induced cytotoxic T lymphocyte activity markedly and significantly greater than peptide-pulsed DCs. C1 NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Rm 8B09, Bethesda, MD 20892 USA. RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 NR 30 TC 5 Z9 5 U1 0 U2 0 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 1073-1199 J9 ARTIF CELL BLOOD SUB JI Artif. Cells Blood Substit. Immobil. Biotechnol. PY 2003 VL 31 IS 2 BP 193 EP 228 DI 10.1081/BIO-120020178 PG 36 WC Biotechnology & Applied Microbiology; Engineering, Biomedical; Materials Science, Biomaterials SC Biotechnology & Applied Microbiology; Engineering; Materials Science GA 676QK UT WOS:000182763300016 PM 12751840 ER PT S AU Nuss, C Chang, HF Moore, D Fonger, GC AF Nuss, C Chang, HF Moore, D Fonger, GC BE Bryans, JB TI Automated indexing of the hazardous substances data bank SO ASIST 2003: PROCEEDINGS OF THE 66TH ASIST ANNUAL MEETING, VOL 40, 2003: HUMANIZING INFORMATION TECHNOLOGY: FROM IDEAS TO BITS AND BACK SE PROCEEDINGS OF THE ASIST ANNUAL MEETING LA English DT Article; Proceedings Paper CT 66th Annual Meeting of the American-Society-for-Information-Science-and-Technology CY OCT 19-22, 2003 CL Long Beach, CA SP Amer Soc Informat Sci & Technol AB The Hazardous Substances Data Bank (HSDB), a factual data file produced and maintained by the Specialized Information Services (SIS) Division of the National Library of Medicine (NLM), contains over 4600 records on potentially hazardous chemicals. To improve information retrieval from HSDB, SIS has undertaken the development of an automated indexing protocol in collaboration with NLM's Indexing Initiative group. The Indexing Initiative investigates methods whereby automated indexing may partially or completely substitute for human indexing. Three main methodologies are applied: the MetaMap Indexing method, which maps text to concepts in the Unified Medical Language System (UMLS) Metathesaurus; the Trigram Phrase Matching method, which uses character trigrams to match text to Metathesaurus concepts; and a variant of the PubMed Related Citations method to find MeSH terms related to input text. The UMLS concepts generated by the first two methods are mapped to MeSH main headings through the Restrict-to-MeSH algorithm. The resulting MeSH terms are then clustered into a ranked list of recommended indexing terms. The purpose of the poster is to present our experience in applying these automated indexing methodologies to a large data file with highly structured records, a variety of text and data formats, and complex technical and biomedical terminology. C1 Natl Lib Med, Specialized Informat Serv Div, NIH, Dept HHS, Bethesda, MD 20892 USA. RP Natl Lib Med, Specialized Informat Serv Div, NIH, Dept HHS, 6707 Democracy Blvd,Suite 510, Bethesda, MD 20892 USA. EM tehip@teh.nlm.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU INFORMATION TODAY INC PI MEDFORD PA 143 OLD MARLTON PIKE, MEDFORD, NJ 08055 USA SN 0044-7870 BN 1-57387-197-4 J9 P ASIST ANNU PY 2003 VL 40 BP 537 EP 539 DI 10.1002/meet.14504001112 PG 3 WC Computer Science, Information Systems; Information Science & Library Science SC Computer Science; Information Science & Library Science GA BBZ20 UT WOS:000228354100112 ER PT J AU Jacques, PF Bostom, AG Selhub, J Rich, S Ellison, RC Eckfeldt, JH Gravel, RA Rozen, R AF Jacques, PF Bostom, AG Selhub, J Rich, S Ellison, RC Eckfeldt, JH Gravel, RA Rozen, R TI Effects of polymorphisms of methionine synthase and methionine synthase reductase on total plasma homocysteine in the NHLBI Family Heart Study SO ATHEROSCLEROSIS LA English DT Article DE homocysteine; methionine synthase; methionine synthase reductase; B vitamins; epidemiologic study ID CORONARY-ARTERY DISEASE; VASCULAR-DISEASE; METHYLENETETRAHYDROFOLATE REDUCTASE; RISK FACTOR; D919G POLYMORPHISM; COMMON MUTATION; INCREASES RISK; CDNA CLONING; GENE; FOLATE AB The metabolism of homocysteine requires contributions of several enzymes and vitamin cofactors. Earlier studies identified a common polymorphism of methylenetetrahydrofolate reductase that was associated with mild hyperhomocysteinemia. Common variants of two other enzymes involved in homocysteine metabolism, methionine synthase and methionine synthase reductase, have also been identified. Methionine synthase catalyzes the remethylation of homocysteine to form methionine and methionine synthase reductase is required for the reductive activation of the cobalamin-dependent methionine synthase. The methionine synthase gene (MTR) mutation is an A to G substitution, 2756A --> G, which converts an aspartate to a glycine codon. The methionine synthase reductase gene (MTRR) mutation is an A to G substitution, 66A --> G, that converts an isoleucine to a methionine residue. To determine if these polymorphisms were associated with mild hyperhomocysteinemia, we investigated subjects from two of the NHLBI Family Heart Study field centers, Framingham and Utah. Total plasma homocysteine concentrations were determined after an overnight fast and after a 4-h methionine load test. MTR and MTRR genotype data were available for 677 and 562 subjects, respectively. The geometric mean fasting homocysteine was unrelated to the MTR or MTRR genotype categories (AA, AG, GG). After a methionine load, a weak positive association was observed between change in homocysteine after a methionine load and the number of mutant MTR alleles (P-trend = 0.04), but this association was not statistically significant according to the overall F-statistic (P = 0.12). There was no significant interaction between MTR and MTRR genotype or between these genotypes and any of the vitamins with respect to homocysteine concentrations. This study provides no evidence that these common MTR and MTRR mutations are associated with alterations in plasma homocysteine. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Tufts Univ, Human Nutr Res Ctr Aging, Jean Mayer USDA, Boston, MA 02111 USA. Mem Hosp Rhode Isl, Div Gen Internal Med, Providence, RI USA. NHLBI, Family Heart Study Field Ctr, Framingham, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Univ Minnesota, Dept Lab Med & Pathol, NHLBI, Family Heart Study Cent Lab, Minneapolis, MN 55455 USA. Univ Calgary, Dept Kinesiol, Calgary, AB, Canada. Univ Calgary, Dept Cell Biol & Anat, Calgary, AB, Canada. McGill Univ, Montreal Childrens Hosp, Dept Human Genet, Montreal, PQ H3H 1P3, Canada. McGill Univ, Montreal Childrens Hosp, Dept Pediat, Montreal, PQ H3H 1P3, Canada. McGill Univ, Montreal Childrens Hosp, Dept Biol, Montreal, PQ H3H 1P3, Canada. RP Jacques, PF (reprint author), Tufts Univ, Human Nutr Res Ctr Aging, Jean Mayer USDA, 711 Wasington St, Boston, MA 02111 USA. FU NHLBI NIH HHS [HL58955-01, N01-HC-25106]; PHS HHS [53-3K06-01] NR 29 TC 66 Z9 73 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD JAN PY 2003 VL 166 IS 1 BP 49 EP 55 AR PII S0021-9150(02)00204-6 DI 10.1016/S0021-9150(02)00204-6 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 639BM UT WOS:000180607800006 PM 12482550 ER PT J AU Chen, H Matsuoka, Y Chen, Q Cox, NJ Murphy, BR Subbarao, K AF Chen, H Matsuoka, Y Chen, Q Cox, NJ Murphy, BR Subbarao, K TI Generation and characterization of an H9N2 cold-adapted reassortant as a vaccine candidate SO AVIAN DISEASES LA English DT Article; Proceedings Paper CT 5th International Symposium on Avian Influenza CY APR 14-17, 2002 CL ATHENS, GEORGIA DE influenza H9N2; live attenuated vaccines ID INFLUENZA-A VIRUSES; SOUTHEASTERN CHINA; HONG-KONG; POULTRY; HUMANS AB H9N2 subtype avian influenza viruses have been identified in avian species worldwide, and infections in pigs were confirmed in Hong Kong in 1998. Subsequently, H9N2 viruses were isolated from two children in Hong Kong in 1999, and five human infections were reported from China, raising the possibility that H9N2 viruses pose a potential pandemic threat for humans. These events prompted us to develop a vaccine candidate to protect humans against this subtype of influenza A viruses. Reassortant H1N1 and H3N2 human influenza A viruses with the six internal gene segments of A/Ann Arbor/6/60 (H2N2)(AA) cold-adapted (ca) virus have been tested extensively in humans and have proved to be attenuated and safe as live virus vaccines. Using classical genetic reassortment, we generated a reassortant that contains the hemagglutinin and neuraminidase genes from A/chicken/Hong Kong/G9/97 (H9N2) and six internal gene segments from the AAca virus. The G9/AAca reassortant virus exhibits the ca phenotype and the temperature-sensitive phenotypes of the AAca virus and was attenuated in mice. The reassortant virus was immunogenic and protected mice from wild-type H9N2 virus challenge. The G9/AAca virus bears the in vitro and in vivo phenotypes specified by the AAca virus and will be evaluated as a potential vaccine candidate in humans. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Influenza Branch, Div Viral & Rickettsial Dis, Natl Ctr Infect Dis, Atlanta, GA 30333 USA. RP Chen, H (reprint author), NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NR 16 TC 5 Z9 7 U1 0 U2 0 PU AMER ASSOC AVIAN PATHOLOGISTS PI KENNETT SQ PA UNIV PENN, NEW BOLTON CENTER, KENNETT SQ, PA 19348-1692 USA SN 0005-2086 J9 AVIAN DIS JI Avian Dis. PY 2003 VL 47 SU S BP 1127 EP 1130 DI 10.1637/0005-2086-47.s3.1127 PG 4 WC Veterinary Sciences SC Veterinary Sciences GA 724YN UT WOS:000185516000066 PM 14575127 ER PT J AU Winterer, G Mahlberg, R Smolka, MN Samochowiec, J Ziller, M Rommelspacher, HP Herrmann, WM Schmidt, LG Sander, T AF Winterer, G Mahlberg, R Smolka, MN Samochowiec, J Ziller, M Rommelspacher, HP Herrmann, WM Schmidt, LG Sander, T TI Association analysis of exonic variants of the GABA(B)-receptor gene and alpha electroencephalogram voltage in normal subjects and alcohol-dependent patients SO BEHAVIOR GENETICS LA English DT Article DE alpha EEG; association analysis; GABA(B) receptor gene polymorphism; intermediate phenotype ID IDIOPATHIC GENERALIZED EPILEPSY; TO-NOISE RATIO; GABA(B) RECEPTORS; THALAMIC NEURONS; ABSENCE SEIZURES; EEG; SCHIZOPHRENIA; MECHANISMS; LOCUS; POLYMORPHISMS AB Based on pharmacologic evidence, it has been suggested that GABA(B) receptors may play a crucial role in the generation of alpha-electroencephalogram (EEG) oscillations. We tested whether three exonic variants of the gene encoding the human GABA(B) receptor (GABA(B)R1) modify scalp-recorded alpha-EEG voltage. One hundred twenty-eight patients suffering from alcoholism and 114 normal subjects were investigated. Alcohol-dependent patients were included because evidence exists that the frequently observed alpha low voltage in these subjects is at least partly a trait variable. Logistic regression analyses revealed no associations between alpha-EEG voltage and polymorphic variations in exon 1a1 or exon 11. A significant interaction was observed for an exon 7 substitution polymorphism and diagnosis (P = 0.009). Post hoc analyses showed an association between EEG phenotype and exon 7 genotype in normal subjects only. It is concluded that this particular association may only be observable under physiologic conditions and that alpha low voltage in alcohol-dependent subjects is under the control of either different genes or that it is related to the disease process. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Free Univ Berlin, Benjamin Franklin Univ Hosp, Dept Psychiat, D-1000 Berlin, Germany. Heidelberg Univ, Cent Inst Mental Hlth, D-6900 Heidelberg, Germany. Pomerenian Acad Med, Dept Psychiat, Szczecin, Poland. Humboldt Univ, Univ Hosp Charite, Dept Neurol, Berlin, Germany. RP NIMH, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,Room 4S235,MSC 1379, Bethesda, MD 20892 USA. EM wintereg@intra.nimh.nih.gov RI Smolka, Michael/B-4865-2011; Samochowiec, Jerzy/G-8175-2014 OI Smolka, Michael/0000-0001-5398-5569; Samochowiec, Jerzy/0000-0003-1438-583X NR 58 TC 24 Z9 25 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 EI 1573-3297 J9 BEHAV GENET JI Behav. Genet. PD JAN PY 2003 VL 33 IS 1 BP 7 EP 15 DI 10.1023/A:1021043315012 PG 9 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 614QR UT WOS:000179201400002 PM 12645817 ER PT J AU Bock, BC Carmona-Barros, RE Esler, JL Tilkemeier, PL AF Bock, BC Carmona-Barros, RE Esler, JL Tilkemeier, PL TI Program participation and physical activity maintenance after cardiac rehabilitation SO BEHAVIOR MODIFICATION LA English DT Article ID AMERICAN-HEART-ASSOCIATION; MYOCARDIAL-INFARCTION; EXERCISE; WOMEN; CARE; MEN; PROFESSIONALS; INTERVENTION; STATEMENT; REDUCTION AB This study examined exercise maintenance among patients after completing cardiac rehabilitation. Subjects were men and women who had completed a Phase II Cardiac Rehabilitation Program approximately 12 months previously. Subjects were classified according to whether they had (a) never participated in a Phase III program (G-I) (N = 37), (b) enrolled and completed a Phase III program (G-II) (N = 30), or (c) were currently enrolled in a Phase III maintenance program (G-III) (N=33). Subjects were significantly more likely to be participating in regular exercise if they had participated in a Phase III program (p < .05). Individuals in G-II and G-III engaged in more minutes of physical activity per week and were more likely to meet recommended levels of physical activity compared to G-I subjects. G-I individuals who had longer Phase II programs were more likely to maintain their exercise habits following graduation (p < .05). Results suggest that Phase III maintenance programs and longer Phase II participation improved exercise maintenance following rehabilitation. C1 Brown Med Sch, Ctr Behav Med, Providence, RI USA. Brown Med Sch, Ctr Prevent Med, Providence, RI USA. NHLBI, NIH, Bethesda, MD USA. RP Bock, BC (reprint author), Brown Med Sch, Ctr Behav Med, Providence, RI USA. NR 38 TC 42 Z9 45 U1 0 U2 12 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-4455 J9 BEHAV MODIF JI Behav. Modificat. PD JAN PY 2003 VL 27 IS 1 BP 37 EP 53 DI 10.1177/0145445502238692 PG 17 WC Psychology, Clinical SC Psychology GA 625LQ UT WOS:000179818300003 PM 12587259 ER PT J AU Rutledge, T Reis, SE Olson, M Owens, J Kelsey, SF Pepine, CJ Reichek, N Rogers, WJ Bairey-Merz, CN Sopko, G Cornell, CE Matthews, KA AF Rutledge, T Reis, SE Olson, M Owens, J Kelsey, SF Pepine, CJ Reichek, N Rogers, WJ Bairey-Merz, CN Sopko, G Cornell, CE Matthews, KA TI Socioeconomic status variables predict cardiovascular disease risk factors and prospective mortality risk among women with chest pain - The WISE study SO BEHAVIOR MODIFICATION LA English DT Article ID CORONARY HEART-DISEASE; UNITED-STATES; HEALTH; SUSCEPTIBILITY; EXPLANATIONS; ASSOCIATION; POPULATION; CHALLENGE; GRADIENT; PATHWAYS AB This study examined the relationship between socioeconomic status (SES), coronary artery disease (CAD) risk factors, and all-cause mortality in a cohort of women with chest pain. A total of 743 women (mean age = 59.6 years) with chest pain who were referred for coronary angiography completed a diagnostic protocol including CAD risk factor assessment, ischemic testing, psychosocial testing, and queries of SES. Patients were followed for about 2 years to track subsequent all-cause mortality. Results indicated that low SES was associated with CAD risk factors, including higher BMI and waist-hip ratios, cigarette smoking, lower reported activity levels, and a greater probability of hypertension. Low income also predicted all-cause mortality (RR = 2.7, 95% CI 1.4, 5.2), including after adjusting for proposed psychosocial and behavioral variables (RR = 5.9, 95% CI 1.2-29.7). Future research will require a thorough a priori focus on potential mechanisms to better understand SES effects on health. C1 NHLBI, Bethesda, MD 20892 USA. Univ Alabama, Birmingham, AL USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. RP Rutledge, T (reprint author), VA San Diego Healthcare Syst, Psychol Serv 116B, Med Ctr, 3350 La Jolla Village Dr, San Diego, CA 92161 USA. RI Reis, Steven/J-3957-2014 FU NCRR NIH HHS [M01-RR00425]; NHLBI NIH HHS [N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164] NR 27 TC 22 Z9 22 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-4455 J9 BEHAV MODIF JI Behav. Modificat. PD JAN PY 2003 VL 27 IS 1 BP 54 EP 67 DI 10.1177/0145445502238693 PG 14 WC Psychology, Clinical SC Psychology GA 625LQ UT WOS:000179818300004 PM 12587260 ER PT J AU Murali, J Koteeswari, D Rifkind, JM Jayakumar, R AF Murali, J Koteeswari, D Rifkind, JM Jayakumar, R TI Amyloid insulin interaction with erythrocytes SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Article DE insulin amyloid; erythrocyte membrane; amyloid binding; flow cytometry; dissociation constant ID HEMOGLOBIN BINDING; BETA-PROTEIN; MEMBRANE; AGGREGATION; FIBRILS; PLASMA; FLUORESCENCE; LIPOPROTEIN; RESISTANCE; RECEPTORS AB Erythrocyte membrane interactions with insulin fibrils (amyloid) have been investigated using centrifugation, fluorescence spectroscopy, light scattering, and flow cytometric techniques. The results indicate that insulin fibrils are having moderate affinity to erythrocyte membrane. However, analysis of the apparent dissociation constants of human erythrocyte membranes (leaky and resealed vesicles) with amyloid insulin reveal that the insulin binding is drastically reduced on attaining the fibrillar state compared with native insulin. To understand the role of insulin receptors on erythrocytes binding to amyloid, we have studied the interaction of biotinylated forms of denatured and amyloidic insulin with erythrocytes. FITC-streptavidin was used as a counter staining in flow cytometry measurements. We found that insulin fibrils bind 10 times more with erythrocyte membranes than with amylin and denatured insulin. C1 Cent Leather Res Inst, Bioorgan & Neurochem Lab, Madras 600020, Tamil Nadu, India. NIA, Sect Mol Dynam, Baltimore, MD 21224 USA. RP Cent Leather Res Inst, Bioorgan & Neurochem Lab, Madras 600020, Tamil Nadu, India. EM karkuvi77@hotmail.com NR 59 TC 6 Z9 6 U1 1 U2 3 PU CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS PI OTTAWA PA 65 AURIGA DR, SUITE 203, OTTAWA, ON K2E 7W6, CANADA SN 0829-8211 EI 1208-6002 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD JAN PY 2003 VL 81 IS 1 BP 51 EP 59 DI 10.1139/O03-009 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 649LV UT WOS:000181210800007 PM 12683636 ER PT J AU Campbell, JL Cohen-Fix, O AF Campbell, JL Cohen-Fix, O TI Chromosome cohesion: ring around the sisters? SO BIOFUTUR LA French DT Article ID CHROMATID COHESION; DNA-REPLICATION; SMC PROTEINS; COMPLEX; IDENTIFICATION; CONDENSATION; SEPARATION; BINDING; SITES; MCD1P C1 NIDDK, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Campbell, JL (reprint author), NIDDK, Mol & Cellular Biol Lab, NIH, 8 Ctr Dr, Bethesda, MD 20892 USA. NR 20 TC 0 Z9 0 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 0294-3506 J9 BIOFUTUR JI Biofutur PD JAN PY 2003 IS 229 BP 28 EP 31 PG 4 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 660FF UT WOS:000181822600004 ER PT J AU He, F Yang, XP Srivastava, DK Wilson, SH AF He, F Yang, XP Srivastava, DK Wilson, SH TI DNA polymerase beta gene expression: The promoter activator CREB-1 is upregulated in Chinese hamster ovary cells by DNA alkylating agent-induced stress SO BIOLOGICAL CHEMISTRY LA English DT Article DE base excision repair; mammalian DNA repair; promoter-binding protein; transcription factor ID CAMP-RESPONSE-ELEMENT; BASE-EXCISION-REPAIR; TRANSCRIPTION FACTOR; BINDING-PROTEIN; INDUCED CYTOTOXICITY; N-METHYL-N'-NITRO-N-NITROSOGUANIDINE; PURIFICATION; ATF/CREB; LYASE; SITE AB The DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) upregulates the level of the base excision DNA repair enzyme DNA polymerase beta (beta-pol) in several mammalian cell types. Previous studies suggested that beta-pol expression is upregulated via a transcriptional mechanism that requires: the specific (c) under bar AMP (r) under bar esponse (e) under bar lement (CRE) in the beta-pol core promoter; a phosphorylated form of CREbinding protein-1 (CREB-1); and cellular protein kinase A activity. A large family of CREbinding proteins, i.e., the ATF/CREB factors, has been identified in various cell types. This study further examines the role of CREbinding proteins in regulating beta-pol expression through study of Chinese hamster ovary (CHO) cells. In CHO cell nuclear extract, CREB-1 and ATF-1 are the predominant CREbinding protein family members recognizing the CRE in the beta-pol core promoter. The concentration of CREB-1 increases strongly in CHO cells after exposure to MNNG. In contrast, the level of ATF-1 does not change after MNNG treatment. Recombinant expression of CREB-1 in CHO cells is sufficient to increase expression of the endogenous beta-pol gene, even in the absence of MNNG exposure. These results indicate that beta-pol gene expression in CHO cells can be upregulated by CREB-1 and that the activation of beta-pol gene expression in response to DNA alkylating agent exposure involves a strong increase in the level of CREB-1. C1 Univ Texas, Med Branch, Sealy Ctr Mol Sci, Galveston, TX 77555 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), Univ Texas, Med Branch, Sealy Ctr Mol Sci, Galveston, TX 77555 USA. FU NIEHS NIH HHS [ES06492] NR 27 TC 11 Z9 12 U1 1 U2 1 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 1431-6730 J9 BIOL CHEM JI Biol. Chem. PD JAN PY 2003 VL 384 IS 1 BP 19 EP 23 DI 10.1515/BC.2003.003 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 639NB UT WOS:000180634700003 PM 12674496 ER PT J AU Mullegger, J Rustom, A Kreil, G Gerdes, HH Lepperdinger, G AF Mullegger, J Rustom, A Kreil, G Gerdes, HH Lepperdinger, G TI 'Piggy-back' transport of Xenopus hyaluronan synthase (XHAS1) via the secretory pathway to the plasma membrane SO BIOLOGICAL CHEMISTRY LA English DT Article DE extracellular matrix; glycosaminoglycan; hyaluronan; hyaluronan synthase; secretory pathway ID STREPTOCOCCUS-PYOGENES; DG42 GENE; CELLS; PROTEIN; GOLGI; MOUSE; IDENTIFICATION; EMBRYOGENESIS; GRANULES; DYNAMICS AB Hyaluronan is the sole glycosaminoglycan whose biosynthesis takes place directly at the plasma membrane. The mechanism by which hyaluronan synthase (HAS) becomes inserted there, as well as the question of how the enzyme discriminates between particular membrane species in polarized cells, are largely unknown. In vitro translation of HAS suggested that the nascent protein becomes stabilized in the presence of microsomal membranes, but would not insert spontaneously into membranes after being translated in the absence of those. We therefore monitored the membrane attachment of enzymatically active fusion proteins consisting of Xenopus HAS1 and green fluorescent protein shortly after de novo synthesis in Vero cells. Our data strongly suggest that HAS proteins are directly translated on the ER membrane without exhibiting an Nterminal signal sequence. From there the inactive protein is transferred to the plasma membrane via the secretory pathway. For unknown reasons, HAS inserted into membranes other than the plasma membrane remains inactive. C1 Austrian Acad Sci, Inst Mol Biol, A-5020 Salzburg, Austria. Univ Heidelberg, Dept Neurobiol, D-69120 Heidelberg, Germany. NICHD LMG, NIH, Bethesda, MD 20892 USA. RP Lepperdinger, G (reprint author), Austrian Acad Sci, Inst Mol Biol, Billrothstr 11, A-5020 Salzburg, Austria. NR 27 TC 14 Z9 14 U1 2 U2 4 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 1431-6730 J9 BIOL CHEM JI Biol. Chem. PD JAN PY 2003 VL 384 IS 1 BP 175 EP 182 DI 10.1515/BC.2003.019 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 639NB UT WOS:000180634700019 PM 12674512 ER PT J AU Charney, DS Innis, RB Nestler, EJ AF Charney, DS Innis, RB Nestler, EJ TI New initiatives in Biological Psychiatry SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material C1 NIMH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. RP Charney, DS (reprint author), NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JAN 1 PY 2003 VL 53 IS 1 BP 1 EP 2 AR PII S0006-3223(02)01858-9 DI 10.1016/S0006-3223(02)01858-9 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 637ME UT WOS:000180515000001 ER PT B AU Kimber, WI Piao, YL Tanaka, TS Yoshikawa, T Hamatani, T Carter, MG Ko, MSH AF Kimber, WI Piao, YL Tanaka, TS Yoshikawa, T Hamatani, T Carter, MG Ko, MSH GP OECD TI Systematic analysis of mouse preimplantation development SO BIOLOGICAL RESOURCE MANAGEMENT IN AGRICULTURE: MAMMALIAN EMBRYO GENOMICS LA English DT Proceedings Paper CT 1st International Meeting on Biological Resource Management in Agriculture CY JUL 20, 2002 CL Quebec City, CANADA ID EQUALIZED CDNA LIBRARY; INITIAL ANNOTATION; CELL-ADHESION; CLONE SET; EMBRYOS; VERIFICATION; CONSTRUCTION; CADHERIN; DESIGN AB Many important and complex events occur during the preimplantation period of mouse development as the embryo transitions from a single totipotent cell to the differentiated structure of the blastocyst. Using an embryogenomics approach, we aim to identify and study genes with key roles in these processes. Our study utilizes the unique resource of the NIA mouse cDNA clone set, which contains many novel, full-length cDNAs representing all mouse preimplantation stages. This clone set provides the basis for microarray experiments enabling us to study global gene expression and assemble gene expression profiles. In addition, we are using EST frequency in individual libraries to identify genes with restricted expression profiles, implying a role at specific stages of preimplantation development. This work is complemented with functional assays including gene "knock-down" experiments using antisense oligo technology. These studies lay the foundation for a systematic evaluation of the role of large numbers of genes in preimplantation development. C1 NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. NR 23 TC 0 Z9 0 U1 0 U2 0 PU ORGANIZATION ECONOMIC COOPERATION & DEVELOPMENT PI PARIS PA 2, RUE ANDRE PASCAL, CEDEX 16, 75775 PARIS, FRANCE BN 92-64-10426-7 PY 2003 BP 37 EP 46 PG 10 WC Agriculture, Dairy & Animal Science; Biochemistry & Molecular Biology; Reproductive Biology SC Agriculture; Biochemistry & Molecular Biology; Reproductive Biology GA BAE40 UT WOS:000221809100004 ER PT J AU Bellino, FL Wise, PM AF Bellino, FL Wise, PM TI Nonhuman Primate Models of Menopause Workshop SO BIOLOGY OF REPRODUCTION LA English DT Review DE aging; neuroendocrinology; ovary; pituitary hormones; steroid hormones ID FEMALE RHESUS-MONKEYS; ESTROGEN REPLACEMENT THERAPY; POSTMENOPAUSAL CYNOMOLGUS MONKEYS; ATHEROSCLEROTIC CORONARY-ARTERIES; DORSOLATERAL PREFRONTAL CORTEX; CEREBRAL BLOOD-FLOW; REPRODUCTIVE SENESCENCE; GENE-EXPRESSION; OVARIAN HORMONES; MACACA-FASCICULARIS AB The Nonhuman Primate Models of Menopause Workshop was held on the National Institutes of Health campus in January 2001. The purpose of this workshop, sponsored by the National Institute on Aging, was to review what is known about the female reproductive aging process in various species of monkeys (particularly rhesus, baboons, cynomolgus, and chimpanzees), including hormone profiles during the menopausal transition, occurrence of hot flashes, extent of age-related and menopause-associated changes in hormone levels on metabolism, bone loss, and impaired cardiovascular and cognitive function. Many aspects of the female reproductive aging process appear to be concordant between humans and these monkey species, but several important features may be species-specific. Those features that appear to parallel human menopause and aging include general similarity of hormone profiles across the menopausal transition, progression to cycle termination through irregular cycles, declining fertility with age, age-related gains in weight and percentage body fat content (with tendencies toward insulin resistance and glucose intolerance), increased low-density lipoprotein cholesterol and decreased high-density lipoprotein cholesterol, declines in serum dehydroepiandrosterone, similarities in temperature-regulation systems, protective responses to estrogen replacement following ovariectomy in terms of bone metabolism, lipid profiles, and cognitive changes. Important differences include relatively short postmenopausal life span, timing in menopause-related changes in hormone secretion, and seasonal menstrual cycles. In addition, the question of whether ovariectomy in young adults is an appropriate model for the consequences of natural or surgical menopause in middle-aged and older adults is unresolved, and the numbers of older female animals available for research on menopause are very limited. The use of animal models is seen by workshop participants to be crucial for a mechanistic understanding of the human menopausal process and its connections to postmenopausal health problems; however, extensive in-depth and broad-based research is required to determine if nonhuman primates are appropriate models of human menopause. C1 NIA, Biol Aging Program, Bethesda, MD 20892 USA. Univ Calif Davis, Div Biol Sci, Davis, CA 95616 USA. RP Bellino, FL (reprint author), NIA, Biol Aging Program, 7201 Wisconsin Ave,Suite 2C231,Gateway Bldg, Bethesda, MD 20892 USA. NR 87 TC 95 Z9 96 U1 0 U2 3 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD JAN PY 2003 VL 68 IS 1 BP 10 EP 18 DI 10.1095/biolreprod.102.005215 PG 9 WC Reproductive Biology SC Reproductive Biology GA 630MJ UT WOS:000180111500002 PM 12493689 ER PT J AU Daston, G Mahesh, VB Cruz, YP Tolivar, A AF Daston, G Mahesh, VB Cruz, YP Tolivar, A TI Trainee and minority affairs forum. Career devlopment and networking: An open discussion with professionals from a variety of scientific careers. SO BIOLOGY OF REPRODUCTION LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-the-Study-of-Reproduction CY JUL 19-22, 2003 CL CINCINNATI, OHIO SP Soc Study Reproduct C1 Procter & Gamble Co, Cincinnati, OH USA. Med Coll Georgia, Augusta, GA 30912 USA. Oberlin Coll Sci Ctr, Oberlin, OH USA. NIGMS, MARC, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PY 2003 VL 68 SU 1 MA TMF1 BP 88 EP 88 PG 1 WC Reproductive Biology SC Reproductive Biology GA 695FX UT WOS:000183821400011 ER PT J AU Davis, BJ AF Davis, BJ TI Cellular and molecular targets in chemically mediated ovarian dysfunction. SO BIOLOGY OF REPRODUCTION LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-the-Study-of-Reproduction CY JUL 19-22, 2003 CL CINCINNATI, OHIO SP Soc Study Reproduct C1 NIEHS, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PY 2003 VL 68 SU 1 MA MS9 BP 92 EP 92 PG 1 WC Reproductive Biology SC Reproductive Biology GA 695FX UT WOS:000183821400020 ER PT J AU Foster, PMD Barlow, NJ Turner, KJ AF Foster, PMD Barlow, NJ Turner, KJ TI Disruption of reproductive development by environmental antiandrogens. SO BIOLOGY OF REPRODUCTION LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-the-Study-of-Reproduction CY JUL 19-22, 2003 CL CINCINNATI, OHIO SP Soc Study Reproduct C1 Natl Inst Enviromn Hlth Sci, Res Triangle Pk, NC USA. Aventis Pharmaceut, Bridgewater, NJ USA. Merck Res Labs, W Point, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PY 2003 VL 68 SU 1 MA MS32 BP 103 EP 103 PG 1 WC Reproductive Biology SC Reproductive Biology GA 695FX UT WOS:000183821400043 ER PT J AU Hewitt, SC Deroo, BJ Hansen, KJ Collins, J Grissom, S Afshari, C Korach, KS AF Hewitt, SC Deroo, BJ Hansen, KJ Collins, J Grissom, S Afshari, C Korach, KS TI Microarray analysis indicates biphasic biological responses of the mouse uterus to acute estradiol are recapitulated in genomic responses. SO BIOLOGY OF REPRODUCTION LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-the-Study-of-Reproduction CY JUL 19-22, 2003 CL CINCINNATI, OHIO SP Soc Study Reproduct C1 NIEHS, Microarray Grp, Res Triangle Pk, NC USA. Amgen Inc, Thousand Oaks, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PY 2003 VL 68 SU 1 MA 11 BP 116 EP 116 PG 1 WC Reproductive Biology SC Reproductive Biology GA 695FX UT WOS:000183821400067 ER PT J AU Deroo, BJ Hewitt, SC Korach, KS AF Deroo, BJ Hewitt, SC Korach, KS TI Estrogen treatment reduces expression of thioredoxin interacting protein in the mouse uterus. SO BIOLOGY OF REPRODUCTION LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-the-Study-of-Reproduction CY JUL 19-22, 2003 CL CINCINNATI, OHIO SP Soc Study Reproduct C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PY 2003 VL 68 SU 1 MA 15 BP 118 EP 118 PG 1 WC Reproductive Biology SC Reproductive Biology GA 695FX UT WOS:000183821400071 ER PT J AU Vesterlund, LEC Jetten, AM AF Vesterlund, LEC Jetten, AM TI Novel putative ligands regulating the transcriptional activity of the retinoid-related testis-associated receptor (RTR). SO BIOLOGY OF REPRODUCTION LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-the-Study-of-Reproduction CY JUL 19-22, 2003 CL CINCINNATI, OHIO SP Soc Study Reproduct C1 NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PY 2003 VL 68 SU 1 MA 193 BP 191 EP 191 PG 1 WC Reproductive Biology SC Reproductive Biology GA 695FX UT WOS:000183821400248 ER PT J AU Christenson, LK Wood, JR Sterneck, E AF Christenson, LK Wood, JR Sterneck, E TI Thecal hypertrophy and enhanced CYP17 expression in the CCAAT/enhancer-binding protein beta knockout mouse ovary implicate this granulosa cell transcription factor in the regulation of theca cells. SO BIOLOGY OF REPRODUCTION LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-the-Study-of-Reproduction CY JUL 19-22, 2003 CL CINCINNATI, OHIO SP Soc Study Reproduct C1 Univ Penn, Philadelphia, PA 19104 USA. NCI, Frederick, MD 21701 USA. RI Christenson, Lane/G-6435-2013 NR 0 TC 0 Z9 0 U1 1 U2 1 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PY 2003 VL 68 SU 1 MA 248 BP 214 EP 214 PG 1 WC Reproductive Biology SC Reproductive Biology GA 695FX UT WOS:000183821400303 ER PT J AU Dixit, VD Easterling, TJ Taub, DD AF Dixit, VD Easterling, TJ Taub, DD TI Gonadotropin releasing hormone (GnRH) stimulates the proinflammatory cytokine expression and promotes the directional migration of human T lymphocytes. SO BIOLOGY OF REPRODUCTION LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-the-Study-of-Reproduction CY JUL 19-22, 2003 CL CINCINNATI, OHIO SP Soc Study Reproduct C1 NIA, Immunol Lab, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PY 2003 VL 68 SU 1 MA 267 BP 222 EP 222 PG 1 WC Reproductive Biology SC Reproductive Biology GA 695FX UT WOS:000183821400322 ER PT J AU Rodriguez, CI Cheng, JG Liu, L Stewart, CL AF Rodriguez, CI Cheng, JG Liu, L Stewart, CL TI Coch, a gene regulated by LIF, is expressed during development and at the time of embryo implantation SO BIOLOGY OF REPRODUCTION LA English DT Meeting Abstract CT 36th Annual Meeting of the Society-for-the-Study-of-Reproduction CY JUL 19-22, 2003 CL CINCINNATI, OHIO SP Soc Study Reproduct C1 Natl Canc Inst, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PY 2003 VL 68 SU 1 MA 396 BP 275 EP 275 PG 1 WC Reproductive Biology SC Reproductive Biology GA 695FX UT WOS:000183821400450 ER EF