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141.
Breslin MJ Duggan ME Halczenko W Fernandez-Metzler C Hunt CA Leu CT Merkle KM Naylor-Olsen AM Prueksaritanont T Stump G Wallace A Rodan SB Hutchinson JH 《Bioorganic & medicinal chemistry letters》2003,13(10):1809-1812
Two novel series of small-molecule RGD mimetics containing either a substituted pyridone or pyrazinone central constraint were prepared. Modification of the beta-alanine 3-substituent produced compounds that are potent and selective alpha(v)beta(3) antagonists and exhibit a range of physicochemical properties. 相似文献
142.
Hörig H Lee DS Conkright W Divito J Hasson H LaMare M Rivera A Park D Tine J Guito K Tsang KW Schlom J Kaufman HL 《Cancer immunology, immunotherapy : CII》2000,49(9):504-514
The generation of cytotoxic effector T cells requires delivery of two signals, one derived from a specific antigenic epitope
and one from a costimulatory molecule. A phase I clinical trial was conducted with a non-replicating canarypoxvirus (ALVAC)
constructed to express both human carcinoembryonic antigen (CEA) and the B7.1 costimulatory molecule. This was the first study
in cancer patients to determine if the delivery of costimulation with a tumor vaccine was feasible and improved immune responses.
Three cohorts of six patients, each with advanced CEA-expressing adenocarcinomas, were treated with increasing doses of an
ALVAC-CEA-B7.1 vaccine (4.5 × 106, 4.5 × 107, and 4.5 × 108 plaque-forming units, PFU). Patients were vaccinated by intramuscular injection every 4 weeks for 3 months and monitored
for side-effects, tumor growth and anti-CEA immune responses. ALVAC-CEA- B7.1 at doses up to 4.5 × 108 PFU was given without evidence of significant toxicity or autoimmune reactions. Three patients experienced clinically stable
disease that correlated with increasing CEA-specific precursor T cells, as shown by in vitro interferon-γ enzyme-linked immunoassay
spot tests (ELISPOT). These three patients underwent repeated vaccination resulting in augmented CEA-specific T cell responses.
This study represents the first use of costimulation to enhance antitumor vaccines in cancer patients. This approach resulted
in CEA-specific immunity associated with stable diseases in three patients. This study also demonstrated that CEA-specific
T cell responses could be sustained by repeated vaccinations. Although the number of patients was small, the addition of B7.1
to virus-based vaccines may improve immunological and stable diseases to vaccination against tumor-associated antigens with
tolerable toxicity.
Received: 6 May 2000 / Accepted: 13 July 2000 相似文献
143.
Taggart C Coakley RJ Greally P Canny G O'Neill SJ McElvaney NG 《American journal of physiology. Lung cellular and molecular physiology》2000,278(1):L33-L41
Cystic fibrosis (CF) is a lethal, hereditary disorder characterized by a neutrophil-dominated inflammation of the lung. We sought to determine whether neutrophils from individuals with CF release more neutrophil elastase (NE) than neutrophils from normal subjects. Our results showed that peripheral blood neutrophils (PBNs) from normal subjects and individuals with CF contained similar amounts of NE, but after preincubation with CF bronchoalveolar lavage (BAL) fluid, significantly more NE was released by CF PBNs, a release that was amplified further by incubation with opsonized Escherichia coli. To determine which components of CF BAL fluid stimulated this excessive NE release from CF PBNs, we repeated the experiments after neutralization or immunoprecipitation of tumor necrosis factor (TNF)-alpha and interleukin (IL)-8 in CF BAL fluid. We found that subsequent NE release from CF PBNs was reduced significantly when TNF-alpha and IL-8 were removed from CF BAL fluid. When TNF-alpha and IL-8 were used as activating stimuli, CF PBNs released significantly greater amounts of NE compared with PBNs from control subjects and individuals with bronchiectasis. These results indicate that CF PBNs respond abnormally to TNF-alpha and IL-8 in CF BAL fluid and react to opsonized bacteria by releasing more NE. This may help explain the increased NE burden seen in this condition. 相似文献
144.
Receptor-coupled contraction of smooth muscle involves recruitment to the plasma membrane of downstream effector molecules PKCalpha and rhoA but the mechanism of this signal integration is unclear. Caveolins, the principal structural proteins of caveolar plasma membrane invaginations, have been implicated in the organization and regulation of many signal transducing molecules. Thus, using laser scanning confocal immunofluorescent microscopy, we tested the hypothesis that caveolin is involved in smooth muscle signaling by investigating caveolin isoform expression and localization, together with the effect of a peptide inhibitor of caveolin function, in intact differentiated smooth muscle cells. All three main caveolin isoforms were identified in uterine, stomach, and ileal smooth muscles and assumed a predominantly plasma membranous localization in myometrial cells. Cytoplasmic introduction of a peptide corresponding to the caveolin-1 scaffolding domain-an essential region for caveolin interaction with signaling molecules--significantly inhibited agonist-induced translocation of both PKCalpha and rhoA. Translocation was unimpaired by a scrambled peptide and was unaltered in sham-treated cells. The membranous localization of caveolins, and direct inhibition of receptor-coupled PKCalpha and rhoA translocation by the caveolin-1 scaffolding domain, supports the concept that caveolins can regulate the integration of extracellular contractile stimuli and downstream intracellular effectors in smooth muscle. 相似文献
145.
Direct somatic embryogenesis was induced in root tissues of the Cichorium hybrid `474' (C. intybus L. var. sativum×C. endivia L. var. latifolia). Addition of β-d-glucosyl Yariv reagent (βGlcY), a synthetic phenylglycoside that specifically binds arabinogalactan-proteins (AGPs), to the
culture medium blocked somatic embryogenesis in a concentration-dependent manner with complete inhibition of induction occurring
at 250 μM βGlcY. The AGP-unreactive α-d-galactosyl Yariv reagent had no biological activity in this system. Upon transfer of 250 μM βGlcY-treated roots to control
conditions, somatic embryogenesis was recovered with a time course similar to that of control roots. The βGlcY penetrated
roots and bound abundantly to developing somatic embryos, to the root epidermis and the stele. Immunofluorescence and immunogold
labelling using monoclonal antibodies (JIM13, JIM16 and LM2) revealed that AGPs were localised in the outer cell walls peripheral
cells of the globular embryo. A spatio-temporal expression of AGPs appeared to be associated with differentiation events in
the somatic embryo during the transition from the globular stage to the torpedo stage. To verify βGlcY specificity, molecules
that bound βGlcY were extracted from treated conditioned medium and identified as AGPs by using the same monoclonal antibodies.
In addition, AGPs were found to be abundantly present in the medium during embryogenic culture. All of these results establish
the implication of AGPs in embryo development, and their putative role in somatic embryogenesis is discussed.
Received: 26 August 1999 / Accepted: 28 January 2000 相似文献
146.
Heparins/heparan sulfates modulate the function of proteins and cell membranes in numerous biological systems including normal and disease processes in humans. Heparin has been used for many years as an anticoagulant, and anticoagulant heparin-mimetics were developed several decades ago by chemical sulfation of non-mammalian polysaccharides, e.g., an antithrombotic sulfated xylan. This pharmaceutical, which comprises a mixture of sulfated oligoxylans, also mimics most other biological actions of natural heparins in vitro, including inhibition of the human immunodeficiency virus, but the molecular basis for these actions has been unclear. Here, numerous Components of the sulfated oligoxylan mixture were isolated and when bioassayed in the case of anti-HIV-1 infectivity revealed that a structural specificity underlines the capacity of sulfated xylan to inhibit HIV-1, rather than a non-specific mechanism. Components were isolated by chromatographic fractionation through Bio-Gel P10 in 0.5M ammonium bicarbonate. This fractionation revealed an elution range associated with apparent molecular weights of 22 000 to <1500 relative to standard heparin and heparan sulfates and newly prepared sulfated oligosaccharide standards. Components were characterized by metachromatic absorption spectroscopy, ultracentrifugation, GlcA analysis, and potency against HIV-1 infectivity, both in the tetrazolium cytotoxicity assay and in syncytium-forming assays, in CD4-lymphocytes. Structural specificity was indicated by the differential potencies exhibited by the Components: Highest activity (cytotoxicity) was exhibited by Components in the chromatographic region 5500 in mass (50% effective (inhibitory) concentration=0.5–0.7 g ml–1 in the first fractionation series, and 0.1–0.5 g ml–1 in a second series). The potency declined sharply below 5400 in mass, but with an exception; a second structure exhibiting relatively high potency eluted among low-mass oligosaccharides which had an average size of a nonomer. Components displayed differential potencies also against the syncytium-forming infectivity of HIV-1. The high potency against syncytium-formation was retained by Components down to a minimum size of about 4500 in mass, smaller than the 5400 required above. One in ten of the 1,4-linked xyloses in the native xylan are substituted with a monomeric 1,2 DGlcA branch. We have speculated that pharmaceutical actions of sulfated xylan might be related to structures involving the -D linked substituents and this was examined using a space-filling model of a sulfated octaxylan and by analyses of Components for GlcA content. Understanding structure/function relations in the heparin-like actions of these agents would be of general significance for the careful examination of their potential clinical usefulness in many human processes modulated by heparins, including AIDS. 相似文献
147.
The thermic and kinetic effects of a low dose of morphine sulphate (5mg/kg) were monitored using a remote biotelemetric procedure. Drug and control (saline) injections were administered at two times of day, during the high and low phases of the circadian temperature/activity cycle respectively. Standard measures of the responses revealed that the effect of a dose of morphine differs significantly according to the phase of the circadian rhythm in which it is administered. In contrast to previous studies employing standard stress-inducing rectal probing techniques of temperature measurement, the direction and time-course of thermic and kinetic responses were uncorrelated. The implications for research on physiological and behavioral drug effects and for theories of drug tolerance/dependence are considered. 相似文献
148.
Historical records demonstrate that the most numerous, per capita, ocean-going-vessel strikes recorded among large-whale species accrue to the North Atlantic right whale ( Eubalaena glacialis ). As vessel speed restrictions are being considered to reduce the likelihood and severity of vessel collisions with right whales, we present an analysis of the published historical records of vessels striking large whales. We examine the influence of vessel speed in contributing to either a lethal injury (defined as killed or severely injured) or a nonlethal injury (defined as minor or no apparent injury) to a large whale when struck. A logistic regression model fitted to the observations, and consistent with a bootstrap model, demonstrates that the greatest rate of change in the probability of a lethal injury ( P lethal ) to a large whale occurs between vessel speeds of 8.6 and 15 knots where P lethal increases from 0.21 to 0.79. The probability of a lethal injury drops below 0.5 at 11.8 knots. Above 15 knots, P lethal asymptotically approaches 1. The uncertainties in the logistic regression estimates are relatively large at relatively low speeds ( e.g. , at 8 knots the probability is 0.17 with a 95% CI of 0.03–0.6). The results we provide can be used to assess the utility of vessel speed limits that are being considered to reduce the lethality of vessels striking the critically endangered North Atlantic right whale and other large whales that are frequent victims of vessel strikes. 相似文献
149.
Sanjiv M. Baxi Ruth M. Greenblatt Peter Bacchetti Chengshi Jin Audrey L. French Marla J. Keller Michael H. Augenbraun Stephen J. Gange Chenglong Liu Wendy J. Mack Monica Gandhi Women’s Interagency HIV Study 《PloS one》2015,10(6)
Effective antiretroviral (ARV) therapy depends on adequate drug exposure, yet methods to assess ARV exposure are limited. Concentrations of ARV in hair are the product of steady-state pharmacokinetics factors and longitudinal adherence. We investigated nevirapine (NVP) concentrations in hair as a predictor of treatment response in women receiving ARVs. In participants of the Women’s Interagency HIV Study, who reported NVP use for >1 month from 2003–2008, NVP concentrations in hair were measured via liquid-chromatography-tandem mass-spectrometry. The outcome was virologic suppression (plasma HIV RNA below assay threshold) at the time of hair sampling and the primary predictor was nevirapine concentration categorized into quartiles. We controlled for age, race/ethnicity, pre-treatment HIV RNA, CD4 cell count, and self-reported adherence over the 6-month visit interval (categorized ≤ 74%, 75%–94% or ≥ 95%). We also assessed the relation of NVP concentration with changes in hepatic transaminase levels via multivariate random intercept logistic regression and linear regression analyses. 271 women contributed 1089 person-visits to the analysis (median 3 of semi-annual visits). Viral suppression was least frequent in concentration quartile 1 (86/178 (48.3%)) and increased in higher quartiles (to 158/204 (77.5%) for quartile 4). The odds of viral suppression in the highest concentration quartile were 9.17 times (95% CI 3.2–26, P < 0.0001) those in the lowest. African-American race was associated with lower rates of virologic suppression independent of NVP hair concentration. NVP concentration was not significantly associated with patterns of serum transaminases. Concentration of NVP in hair was a strong independent predictor of virologic suppression in women taking NVP, stronger than self-reported adherence, but did not appear to be strongly predictive of hepatotoxicity. 相似文献
150.
Integrating Phosphoproteome and Transcriptome Reveals New Determinants of Macrophage Multinucleation