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361.
362.
Philippe GAC Vanden Bergh Thomas Fett Laurent LM Zecchinon Anne VT Thomas Daniel JM Desmecht 《BMC veterinary research》2005,1(1):1-7
Background
Lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18, alphaLbeta2), the most abundant and widely expressed beta2-integrin, is required for many cellular adhesive interactions during the immune response. Many studies have shown that LFA-1 is centrally involved in the pathogenesis of several diseases caused by Repeats-in-toxin (RTX) -producing bacteria. 相似文献363.
364.
Coreceptor tropism can be influenced by amino acid substitutions in the gp41 transmembrane subunit of human immunodeficiency virus type 1 envelope protein 下载免费PDF全文
Huang W Toma J Fransen S Stawiski E Reeves JD Whitcomb JM Parkin N Petropoulos CJ 《Journal of virology》2008,82(11):5584-5593
Many studies have demonstrated that the third variable region (V3) of the human immunodeficiency virus type 1 (HIV-1) envelope protein (Env) is a major determinant of coreceptor tropism. Other regions in the surface gp120 subunit of Env can modulate coreceptor tropism in a manner that is not fully understood. In this study, we evaluated the effect of env determinants outside of V3 on coreceptor usage through the analysis of (i) patient-derived env clones that differ in coreceptor tropism, (ii) chimeric env sequences, and (iii) site-directed mutants. The introduction of distinct V3 sequences from CXCR4-using clones into an R5-tropic env backbone conferred the inefficient use of CXCR4 in some but not all cases. Conversely, in many cases, X4- and dual-tropic env backbones containing the V3 sequences of R5-tropic clones retained the ability to use CXCR4, suggesting that sequences outside of the V3 regions of these CXCR4-using clones were responsible for CXCR4 use. The determinants of CXCR4 use in a set of dual-tropic env sequences with V3 sequences identical to those of R5-tropic clones mapped to the gp41 transmembrane (TM) subunit. In one case, a single-amino-acid substitution in the fusion peptide of TM was able to confer CXCR4 use; however, TM substitutions associated with CXCR4 use varied among different env sequences. These results demonstrate that sequences in TM can modulate coreceptor specificity and that env sequences other than that of V3 may facilitate efficient CXCR4-mediated entry. We hypothesize that the latter plays an important role in the transition from CCR5 to CXCR4 coreceptor use. 相似文献
365.
Ruopp MD Perkins NJ Whitcomb BW Schisterman EF 《Biometrical journal. Biometrische Zeitschrift》2008,50(3):419-430
The receiver operating characteristic (ROC) curve is used to evaluate a biomarker's ability for classifying disease status. The Youden Index (J), the maximum potential effectiveness of a biomarker, is a common summary measure of the ROC curve. In biomarker development, levels may be unquantifiable below a limit of detection (LOD) and missing from the overall dataset. Disregarding these observations may negatively bias the ROC curve and thus J. Several correction methods have been suggested for mean estimation and testing; however, little has been written about the ROC curve or its summary measures. We adapt non-parametric (empirical) and semi-parametric (ROC-GLM [generalized linear model]) methods and propose parametric methods (maximum likelihood (ML)) to estimate J and the optimal cut-point (c *) for a biomarker affected by a LOD. We develop unbiased estimators of J and c * via ML for normally and gamma distributed biomarkers. Alpha level confidence intervals are proposed using delta and bootstrap methods for the ML, semi-parametric, and non-parametric approaches respectively. Simulation studies are conducted over a range of distributional scenarios and sample sizes evaluating estimators' bias, root-mean square error, and coverage probability; the average bias was less than one percent for ML and GLM methods across scenarios and decreases with increased sample size. An example using polychlorinated biphenyl levels to classify women with and without endometriosis illustrates the potential benefits of these methods. We address the limitations and usefulness of each method in order to give researchers guidance in constructing appropriate estimates of biomarkers' true discriminating capabilities. 相似文献
366.
Rieke Alten Hermann Gram Leo A Joosten Bvanden Wim Berg Joachim Sieper Siegfrid Wassenberg Gerd Burmester Piet van Riel Maria Diaz-Lorente Gerardus JM Bruin Thasia G Woodworth Christiane Rordorf Yannik Batard Andrew M Wright Thomas Jung 《Arthritis research & therapy》2008,10(3):1-9
Introduction
IL-1β is a proinflammatory cytokine driving joint inflammation as well as systemic signs of inflammation, such as fever and acute phase protein production.Methods
ACZ885, a fully human monoclonal antibody that neutralizes the bioactivity of human IL-1β, was generated to study the potent and long-lasting neutralization of IL-1β in mechanistic animal models as well as in a proof-of-concept study in patients with rheumatoid arthritis (RA).Results
The mouse IL-1 receptor cross-reacts with human IL-1β, and it was demonstrated that ACZ885 can completely suppress IL-1β-mediated joint inflammation and cartilage destruction in mice. This observation prompted us to study the safety, tolerability and pharmacodynamic activity of ACZ885 in RA patients in a small proof-of-concept study – the first to be conducted in humans. Patients with active RA despite treatment with stable doses of methotrexate were enrolled in this dose escalation study. The first 32 patients were split into four cohorts of eight patients each (six were randomly assigned to active treatment and two to placebo). ACZ885 doses were 0.3, 1, 3 and 10 mg/kg, administered intravenously on days 1 and 15. To explore efficacy within 6 weeks of treatment, an additional 21 patients were randomly assigned to the 10 mg/kg cohort, resulting in a total of 20 patients dosed with 10 mg/kg and 15 patients treated with placebo. There was clinical improvement (American College of Rheumatology 20% improvement criteria) at week 6 in the 10 mg/kg treatment group; however, this did not reach statistical significance (P = 0.085). A statistically significant reduction in disease activity score was observed after 4 weeks in the 10 mg/kg group. Onset of action was rapid, because most responders exhibited improvement in their symptoms within the first 3 weeks. C-reactive protein levels decreased in patients treated with ACZ885 within 1 week. ACZ885 was well tolerated. Three patients receiving ACZ885 developed infectious episodes that required treatment. No anti-ACZ885 antibodies were detected during the study.Conclusion
ACZ885 administration to methotrexate-refractory patients resulted in clinical improvement in a subset of patients. Additional studies to characterize efficacy in RA and to determine the optimal dose regimen appear warranted.Trial Registration
ClinicalTrials.gov identifier NCT00619905. 相似文献367.
Background
The complex interactions between recurrent trypsin-mediated pancreatic injury, alcohol-associated pancreatic injury and SPINK1 polymorphisms in chronic pancreatitis (CP) are undefined. We hypothesize that CP occurs as a result of multiple pathological mechanisms (pathways) that are initiated by different metabolic or environmental factors (etiologies) and may be influenced differentially by downstream genetic risk factors. We tested this hypothesis by evaluating the differences in effect size of the high risk SPINK1 N34S haplotype on CP from multiple etiologies after combining clinical reports of SPINK1 N34S frequency using meta-analysis.Methods and Findings
The Pubmed and the Embase databases were reviewed. We studied 24 reports of SPINK1 N34S in CP (2,421 cases, 4,857 controls) using reported etiological factors as surrogates for pathways and multiple meta-analyses to determine the differential effects of SPINK1 N34S between alcoholic and non-alcoholic etiologies. Using estimates of between-study heterogeneity, we sub-classified our 24 studies into four specific clusters. We found that SPINK1 N34S is strongly associated with CP overall (OR 11.00; 95% CI: 7.59–15.93), but the effect of SPINK1 N34S in alcoholic CP (OR 4.98, 95% CI: 3.16–7.85) was significantly smaller than in idiopathic CP (OR 14.97, 95% C.I. = 9.09–24.67) or tropical CP (OR 19.15, 95% C.I. = 8.83–41.56). Studies analyzing familial CP showed very high heterogeneity suggestive of a complex etiology with an I2 = 80.95%.Conclusion
The small effect of SPINK1 N34S in alcoholic subjects suggests that CP is driven through a different pathway that is largely trypsin-independent. The results also suggest that large effect sizes of SPINK1 N34S in small candidate gene studies in CP may be related to a mixture of multiple etiologic pathways leading to the same clinical endpoint. 相似文献368.
369.
Grote T Siwak DR Fritsche HA Joy C Mills GB Simeone D Whitcomb DC Logsdon CD 《Proteomics》2008,8(15):3051-3060
The current study analyzed reverse phase protein arrays (RPPA) as a means to experimentally validate biomarkers in blood samples. One microliter samples of sera (n = 71), and plasma (n = 78) were serially diluted and printed on NC-coated slides. CA19-9 levels from RPPA results were compared with identical patient samples as measured by ELISA. There was a strong correlation between RPPA and ELISA (r = 0.87) as determined by scatter plots. Sample reproducibility of CA19-9 levels was excellent (interslide correlation r = 0.88; intraslide correlation r = 0.83). The ability of RPPA to accurately distinguish CA19-9 levels between cancer and noncancer samples were determined using receiver operating characteristic curves and compared with ELISA. The AUC for RPPA and ELISA was comparable (0.87 and 0.86, respectively). When the mean CA19-9 levels of normal samples was used as a cutoff for RPPA and compared with the standard clinical ELISA cutoff, comparable specificities (71% for both) were observed. Notably, RPPA samples normalized to albumin showed increased sensitivity compared to ELISA (90% vs. 75%). As RPPA is a high-throughput method that shows results comparable to that of ELISA, we propose that RPPA is a viable technique for rapid experimental screening and validation of candidate biomarkers in blood samples. 相似文献
370.
Marc Beyer Hongwei Wang Nina Peters Sandra Doths Cordula Koerner-Rettberg Peter JM Openshaw Jürgen Schwarze 《Respiratory research》2005,6(1):70