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111.
SK Thompson WW Smith B Zhao SM Halbert TA Tomaszek DG Tew MA Levy CA Janson KJ DAlessio MS McQueney J Kurdyla CS Jones RL DesJarlais SS Abdel-Meguid DF Veber 《Canadian Metallurgical Quarterly》1998,41(21):3923-3927
Peptidomimetic cathepsin K inhibitors have been designed using binding models which were based on the X-ray crystal structure of an amino acid-based, active site-spanning inhibitor complexed with cathepsin K. These inhibitors, which contain a benzyloxybenzoyl group in place of a Cbz-leucine moiety, maintained good inhibitory potency relative to the amino acid-based inhibitor, and the binding models were found to be very predictive of relative inhibitor potency. The binding mode of one of the inhibitors was confirmed by X-ray crystallography, and the crystallographically determined structure is in close qualitative agreement with the initial binding model. These results strengthen the validity of a strategy involving iterative cycles of structure-based design, inhibitor synthesis and evaluation, and crystallographic structure determination for the discovery of peptidomimetic inhibitors. 相似文献
112.
A Seth I Ourmanov MJ Kuroda JE Schmitz MW Carroll LS Wyatt B Moss MA Forman VM Hirsch NL Letvin 《Canadian Metallurgical Quarterly》1998,95(17):10112-10116
The utility of modified vaccinia virus Ankara (MVA) as a vector for eliciting AIDS virus-specific cytotoxic T lymphocytes (CTL) was explored in the simian immunodeficiency virus (SIV)/rhesus monkey model. After two intramuscular immunizations with recombinant MVA-SIVSM gag pol, the monkeys developed a Gag epitope-specific CTL response readily detected in peripheral blood lymphocytes by using a functional killing assay. Moreover, those immunizations also elicited a population of CD8+ T lymphocytes in the peripheral blood that bound a specific major histocompatibility complex class I/peptide tetramer. These Gag epitope-specific CD8+ T lymphocytes also were demonstrated by using both functional and tetramer-binding assays in lymph nodes of the immunized monkeys. These observations suggest that MVA may prove a useful vector for an HIV-1 vaccine. They also suggest that tetramer staining may be a useful technology for monitoring CTL generation in vaccine trials in nonhuman primates and in humans. 相似文献
113.
C Prabhakar G Madhusudhan K Sahadev CM Reddy MR Sarma GO Reddy R Chakrabarti CS Rao TD Kumar R Rajagopalan 《Canadian Metallurgical Quarterly》1998,8(19):2725-2730
Novel compounds having a dual pharmacophore were synthesised and evaluated for their insulin sensitiser and anti-inflammatory properties in different animal models. 相似文献
114.
This is a case report of a 43-year-old woman who received a transplant for end-stage liver disease due to hereditary hemorrhagic telangiectasia and fibropolycystic liver disease. This is an uncommon association of two autosomal-dominant conditions with defined genetic and molecular defects. The liver showed extensive vascular malformations of arteries and veins as well as telangiectasia and fibrosis. In addition, there were cystically dilated ducts containing inspissated bile and extensive von Meyenburg complexes. This case raises interesting questions about the possible relationship of these genes and their gene products, both of which are related to cell-matrix interactions and are strongly associated with blood vessels, one of them being expressed on endothelial cells and the other being developmentally important in blood vessels. 相似文献
115.
PA Hollander SC Elbein IB Hirsch D Kelley J McGill T Taylor SR Weiss SE Crockett RA Kaplan J Comstock CP Lucas PA Lodewick W Canovatchel J Chung J Hauptman 《Canadian Metallurgical Quarterly》1998,21(8):1288-1294
OBJECTIVE: Obesity is an important risk factor for type 2 diabetes. Weight loss in patients with type 2 diabetes is associated with improved glycemic control and reduced cardiovascular disease risk factors, but weight loss is notably difficult to achieve and sustain with caloric restriction and exercise. The purpose of this study was to assess the impact of treatment with orlistat, a pancreatic lipase inhibitor, on weight loss, glycemic control, and serum lipid levels in obese patients with type 2 diabetes on sulfonylurea medications. RESEARCH DESIGN AND METHODS: In a multicenter 57-week randomized double-blind placebo-controlled study, 120 mg orlistat or placebo was administered orally three times a day with a mildly hypocaloric diet to 391 obese men and women with type 2 diabetes who were aged > 18 years, had a BMI of 28-40 kg/m2, and were clinically stable on oral sulfonylureas. Changes in body weight, glycemic control, lipid levels, and drug tolerability were measured. RESULTS: After 1 year of treatment, the orlistat group lost 6.2 +/- 0.45% (mean +/- SEM) of initial body weight vs. 4.3 +/- 0.49% in the placebo group (P < 0.001). Twice as many patients receiving orlistat (49 vs. 23%) lost > or = 5% of initial body weight (P < 0.001). Orlistat treatment plus diet compared with placebo plus diet was associated with significant improvement in glycemic control, as reflected in decreases in HbA1c (P < 0.001) and fasting plasma glucose (P < 0.001) and in dosage reductions of oral sulfonylurea medication (P < 0.01). Orlistat therapy also resulted in significantly greater improvements than placebo in several lipid parameters, namely, greater reductions in total cholesterol, (P < 0.001), LDL cholesterol (P < 0.001), triglycerides (P < 0.05), apolipoprotein B (P < 0.001), and the LDL-to-HDL cholesterol ratio (P < 0.001). Mild to moderate and transient gastrointestinal events were reported with orlistat therapy, although their association with study withdrawal was low. Fat-soluble vitamin levels generally remained within the reference range, and vitamin supplementation was required in only a few patients. CONCLUSIONS: Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinically meaningful weight loss and maintenance of weight loss, improved glycemic control, and improved lipid profile. 相似文献
116.
117.
CS Maas T Eriksson T McCalmont D Mabry D Cooke R Schindler 《Canadian Metallurgical Quarterly》1998,101(5):1307-1314
Soft-tissue augmentation using the synthetic nonfluid biomaterial expanded polytetrafluoroethylene (ePTFE) has been supported by number of recent reports citing the favorable characteristics of biocompatibility, soft and natural feel, ease of use, and permanent augmentation. Concern has been expressed about this application for ePTFE material because of the proximity of the implants to the skin surface and potential problems with infection and extrusion. We evaluated the behavior of a series of specific ePTFE implant designs using a long-term subcutaneous augmentation model. By using a porcine model, 466 implants of ePTFE in the form of strips, rolls, or tubes were placed using a percutaneous insertion device subcutaneously over the dorsum and face. The animals were divided into three study groups by length of implantation (3 weeks, control; 6 months, intermediate term; and 12 months, long-term) and en-bloc tissue specimens, including skin, implants, and underlying soft tissue, were harvested for gross and histologic examination. Implants were removed at the earliest sign of infection, exposure, or extrusion and the difficulty of removal was ascertained and recorded. These data reveal that ePTFE material elicits acceptable levels of tissue activity with low extrusion rates over the short and long term supporting its use for soft-tissue augmentation. The data show a clear difference, however, in the host response and behavior of the implants for this application based on shape or design. A statistically significant difference in the low, but measurable, extrusion rates was observed amongst these implant designs. ePTFE tubes showed greater stability and predictable augmentation over other implant designs for soft-tissue augmentation and seem to represent a substantial improvement for this application. 相似文献
118.
P Bj?rses J Aaltonen A Vikman J Perheentupa G Ben-Zion G Chiumello N Dahl P Heideman JJ Hoorweg-Nijman L Mathivon PE Mullis M Pohl M Ritzen G Romeo MS Shapiro CS Smith J Solyom J Zlotogora L Peltonen 《Canadian Metallurgical Quarterly》1996,59(4):879-886
Autoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease (MIM 240300) characterized by hypoparathyroidism, primary adrenocortical failure, and chronic mucocutaneous candidiasis. The disease is highly prevalent in two isolated populations, the Finnish population and the Iranian Jewish one. Sporadic cases have been identified in many other countries, including almost all European countries. The APECED locus has previously been assigned to chromosome 21q22.3 by linkage analyses in 14 Finnish families. Locus heterogeneity is a highly relevant question in this disease affecting multiple tissues and with great phenotypic diversity. To solve this matter, we performed linkage and haplotype analyses on APECED families rising from different populations. Six microsatellite markers on the critical chromosomal region of 2.6 cM on 21q22.3 were analyzed. Pairwise linkage analyses revealed significant LOD scores for all these markers, maximum LOD score being 10.23. The obtained haplotype data and the geographic distribution of the great-grandparents of the Finnish APECED patients suggest the presence of one major, relatively old mutation responsible for approximately 90% of the Finnish cases. Similar evidence for one founder mutation was also found in analyses of Iranian Jewish APECED haplotypes. These haplotypes, however, differed totally from the Finnish ones. The linkage analyses in 21 non-Finnish APECED families originating from several European countries provided independent evidence for linkage to the same chromosomal region on 21q22.3 and revealed no evidence for locus heterogeneity. The haplotype analyses of APECED chromosomes suggest that in different populations APECED is due to a spectrum of mutations in a still unknown gene on chromosome 21. 相似文献
119.
We previously showed that vaccinia virus infection of BSC40 cells was blocked by soluble heparin, suggesting that cell surface heparan sulfate mediates vaccinia virus binding (C.-S. Chung, J.-C. Hsiao, Y. -S. Chang, and W. Chang, J. Virol. 72:1577-1585, 1998). In this study, we extended our previous work and demonstrated that soluble A27L protein bound to heparan sulfate on cells and interfered with vaccinia virus infection at a postbinding step. In addition, we investigated the structure of A27L protein that provides for its binding to heparan sulfate on cells. A mutant of A27L protein, named D-A27L, devoid of a cluster of 12 amino acids rich in basic residues, was constructed. In contrast to the soluble A27L protein, purified D-A27L protein was inactive in all of our assays, including binding to heparin in vitro, binding to heparan sulfate on cells, and the ability to block virus infection. These data demonstrated that the N-terminal region acts as a glycosaminoglycan (GAG)-binding domain critical for A27L protein binding to cells. Previously A27L protein was thought to be involved in fusion of virus-infected cells induced by acid treatment. When we investigated whether cell surface GAGs also participate in A27L-dependent fusion, our results indicated that soluble A27L protein blocked cell fusion, whereas D-A27L protein did not. Taken together, the results therefore demonstrated that A27L-mediated cell fusion is triggered by its interaction with cell surface GAGs through the N-terminal domain. 相似文献
120.
AR Young CS Potten O Nikaido PG Parsons J Boenders JM Ramsden CA Chadwick 《Canadian Metallurgical Quarterly》1998,111(6):936-940
Epidemiology shows a relationship between solar exposure and all types of skin cancer. Understanding the mechanisms of skin cancer requires knowledge of the photomolecular events that occur within the relevant epidermal cell types in vivo. Studies to date have focused on UVR-induced DNA lesions in keratinocytes, the majority epidermal cell population which gives rise to most skin cancers. Malignant melanoma, arising from melanocytes (5%-10% of epidermal cells), accounts for most skin cancer deaths. We report on new techniques to detect DNA photolesions in human epidermal melanocytes in situ. Previously nonexposed buttock skin of volunteers of skin types I/II was exposed to clinically relevant doses of narrow bandwidth UVB (300 nm) and UVA (320 nm, 340 nm, 360 nm) radiation. Biopsies were taken immediately afterwards and processed for routine histology. Microscope sections were prepared and double-stained with fluorescent-tagged monoclonal antibodies for thymine dimers and melanocytes. UVR dose-response curves for dimer levels within melanocyte nuclei were determined by image analysis and compared with dimer levels in adjacent basal cell keratinocytes. Our data show that UVB and UVA readily induce thymine dimers in melanocytes at levels that are comparable with those found in adjacent keratinocytes. This new technique will enable melanocyte specific studies, such as DNA repair kinetics, to be done in vivo. 相似文献