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61.
Kristina I. Rother Lisa M. Spain Robert A. Wesley Benigno J. Digon III Alain Baron Kim Chen Patric Nelson H.-Michael Dosch Jerry P. Palmer Barbara Brooks-Worrell Michael Ring David M. Harlan 《Diabetes care》2009,32(12):2251-2257
OBJECTIVE
In patients with long-standing type 1 diabetes, we investigated whether improved β-cell function can be achieved by combining intensive insulin therapy with agents that may 1) promote β-cell growth and/or limit β-cell apoptosis and 2) weaken the anti–β-cell autoimmunity.RESEARCH DESIGN AND METHODS
For this study, 20 individuals (mean age 39.5 ± 11.1 years) with long-standing type 1 diabetes (21.3 ± 10.7 years) were enrolled in this prospective open-label crossover trial. After achieving optimal blood glucose control, 16 subjects were randomized to exenatide with or without daclizumab. Endogenous insulin production was determined by repeatedly measuring serum C-peptide.RESULTS
In 85% of individuals with long-standing type 1 diabetes who were screened for participation in this trial, C-peptide levels ≥0.05 ng/ml (0.02 nmol/l) were found. Residual β-cells responded to physiological (mixed-meal) and pharmacological (arginine) stimuli. During exenatide treatment, patients lost 4.1 ± 2.9 kg body wt and insulin requirements declined significantly (total daily dose on exenatide 0.48 ± 0.11 vs. 0.55 ± 0.13 units · kg−1 · day−1 without exenatide; P = 0.0062). No signs of further activation of the underlying autoimmune disease were observed. Exenatide delayed gastric emptying, suppressed endogenous incretin levels, but did not increase C-peptide secretion.CONCLUSIONS
In long-standing type 1 diabetes, which remains an active autoimmune disease even decades after its onset, surviving β-cells secrete insulin in a physiologically regulated manner. However, the combination of intensified insulin therapy, exenatide, and daclizumab did not induce improved function of these remaining β-cells.In the past 2 decades, several lines of research dominated the field of type 1 diabetes: trials to alter the immunological response against β-cells and attempts to develop and replace β-cells. The latter, represented by islet transplantation in the clinical arena, has led to the realization that lasting insulin independence could not be achieved (1), but progress was made by gaining insight into β-cell development (2–4) and immunomodulation. Experimental therapies such as administration of the monoclonal antibody anti-CD3 and the β-cell antigen GAD65 slowed β-cell destruction when administered soon after disease onset (5,6). Currently, however, no therapy is available that results in a complete halt or reversal of β-cell failure.We initiated this trial in patients with well-controlled long-standing type 1 diabetes who had evidence of endogenous insulin production documented by measurable C-peptide concentrations ≥0.3 ng/ml (0.1 nmol/l). The study participants received exenatide, a glucagon-like peptide (GLP)-1 agonist, to stimulate β-cell recovery and possibly regeneration (7,8); 50% of patients also received daclizumab to diminish the underlying autoimmunity and to curb a potential autoimmune reactivation. β-Cell function was repeatedly assessed by measuring basal and stimulated C-peptide concentrations (9). We speculated that the difference between greater β-cell mass and improved function could be determined by observing the duration of any treatment effect; i.e., if the intervention resulted in increased β-cell mass, improved pancreatic insulin production would be expected to persist beyond the exenatide treatment. Daclizumab was chosen as a mild immunosuppressive agent because of its safety profile and its demonstrated efficacy in other T-cell–mediated autoimmune conditions such as uveitis and multiple sclerosis (10,11). 相似文献62.
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64.
P. Benigno 《Naunyn-Schmiedeberg's archives of pharmacology》1942,199(2-5):265-273
Ohne Zusammenfassung 相似文献
65.
B B Benigno L C Ford W D Lawrence W J Ledger F W Ling S G McNeeley 《Surgery, gynecology & obstetrics》1986,162(1):1-7
Data are presented from a randomized, double-blind multicenter trial (six study sites, involving 346 patients) in which piperacillin was compared with cefoxitin as a prophylactic agent for patients undergoing cesarean section. One hundred and sixty-nine patients received piperacillin and 177 received cefoxitin; in each instance, the total dosage was 6 grams. Strict criteria were used to evaluate safety and efficacy. The courses of all of the patients were evaluable for safety and 183 courses were evaluable for efficacy (136 efficacy-evaluable courses were from patients treated with piperacillin and 147, from those treated with cefoxitin). Postoperative infection was prevented in 89 per cent of the patients treated with piperacillin and in 93 per cent of the those treated with cefoxitin. The difference was not statistically significant. The data from each of the individual study sites, as well as the pooled data, indicated that the short term perioperative administration of piperacillin in patients undergoing a cesarean section was as safe and effective as cefoxitin with regard to prophylactic response, duration of hospitalization and the usage of other systemic antibiotics. 相似文献
66.
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Walter Henriques da Costa Aline Fusco Fares Stephania M. Bezerra Mariana A Morini Ligia Alencar de Toledo Benigno Diego Abreu Clavijo Lucas Fornazieri Maurício Murce Rocha Isabela Werneck da Cunha Stenio de Cassio Zequi 《Urologic oncology》2019,37(1):78-85
Purpose
To evaluate the prognostic impact of the protein expression of both PBRM1 and BAP1 in metastatic tissue of patients with metastatic clear cell renal cell carcinoma (ccRCC).Patients and methods
In all 124 consecutive cases of metastatic ccRCC, who underwent metastasectomy or biopsy of metastatic tumor tissue between 2007 and 2016 were selected from the medical records of our institution. Additionally, 38 paired cases with tissue from the primary tumor involving radical or partial nephrectomy for ccRCC were also selected. All cases were reviewed for uniform reclassification and the most representative tumor areas were selected for the construction of a tissue microarray.Results
PBRM1 nuclear staining of the 124-immunostained metastases of ccRCC specimens showed that 98 (79.0%) had negative expression and 26 (21.0%) positive expression of PBRM1. Regarding BAP1 expression, we observed that 77 (62.1%) specimens were negative and 47 (37.9%) showed positive nuclear staining. When we compared the expression of both markers on primary tumor and tumor metastasis, we found disagreement in half of the cases. Five-year overall survival rates in patients with positive expression and negative expression of BAP1 were 53.2% and 35.1%, respectively (P?=?0.004). Five-year progression-free survival rates in patients with positive expression and negative expression of BAP1 were 14.9% and 3.9%, respectively (P?=?0.003). Conversely, PBRM1 expression did not significantly influence either overall survival or progression-free survival rates. In multivariate analysis, negative expression of BAP1 tumors also presented higher risks of death (hazard ratio (HR)?=?1.913, P?=?0.041) and disease progression (HR?=?1.656, P?=?0.021).Conclusion
The use of prognostic biomarkers identified in the primary tumor tissue might be not reliable in the metastatic disease scenario. Patients with metastatic ccRCC that present loss of BAP1 expression in metastatic tissue demonstrated poor survival rates and represent a relevant risk group for tumor recurrence and death. 相似文献69.
70.