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摘要： BACKGROUND Patients with renal-cell carcinoma who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence. METHODS In a double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy, to receive either adjuvant pembrolizumab (at a dose of 200 mg) or placebo intravenously once every 3 weeks for up to 17 cycles (approximately 1 year). The primary end point was disease-free survival according to the investigator's assessment. Overall survival was a key secondary end point. Safety was a secondary end point. RESULTS A total of 496 patients were randomly assigned to receive pembrolizumab, and 498 to receive placebo. At the prespecified interim analysis, the median time from randomization to the data-cutoff date was 24.1 months. Pembrolizumab therapy was associated with significantly longer disease-free survival than placebo (disease-free survival at 24 months, 77.3% vs. 68.1%;hazard ratio for recurrence or death, 0.68;95% confidence interval [CI], 0.53 to 0.87;P = 0.002 [two-sided]). The estimated percentage of patients who remained alive at 24 months was 96.6% in the pembrolizumab group and 93.5% in the placebo group (hazard ratio for death, 0.54;95% CI, 0.30 to 0.96). Grade 3 or higher adverse events of any cause occurred in 32.4% of the patients who received pembrolizumab and in 17.7% of those who received placebo. No deaths related to pembrolizumab therapy occurred. CONCLUSIONS Pembrolizumab treatment led to a significant improvement in disease-free survival as compared with placebo after surgery among patients with kidney cancer who were at high risk for recurrence.

关键词： Acute myeloid leukaemia   Target identification  

摘要： Despite the fact that AML is the most common acute leukemia in adults, patient outcomes are poor necessitating the development of novel therapies. We identified that inhibition of Thioredoxin Reductase (TrxR) is a promising strategy for AML and report a highly potent and specific inhibitor of TrxR, S-250. Both pharmacologic and genetic inhibition of TrxR impairs the growth of human AML in mouse models. We found that TrxR inhibition leads to a rapid and marked impairment of metabolism in leukemic cells subsequently leading to cell death. TrxR was found to be a major and direct regulator of metabolism in AML cells through impacts on both glycolysis and the TCA cycle. Studies revealed that TrxR directly regulates GAPDH leading to a disruption of glycolysis and an increase in flux through the pentose phosphate pathway (PPP). The combined inhibition of TrxR and the PPP led to enhanced leukemia growth inhibition. Overall, TrxR abrogation, particularly with S-250, was identified as a promising strategy to disrupt AML metabolism.

摘要： Renal-cell carcinoma is a common cancer in both men and women around the world. Although nephrectomy remains the standard care for patients with locally advanced renal-cell carcinoma, recurrence occurs in up to 50 to 80% of patients, ultimately causing death from the disease. Adjuvant therapy, conceptually developed in the 1960s, is used to improve cure rates and prolong survival after surgical resection. The first studies of adjuvant therapy in renal-cell carcinoma began in the 1980s,1 and since that time, multiple trials have been conducted to test chemotherapy, immunotherapy, and targeted therapy regimens in patients after nephrectomy. Despite numerous worthy attempts, . . .

关键词： Wnt/beta-catenin signalling   beta-catenin destruction complex   adenomatous polyposis coli (APC)   axis inhibition protein (AXIN)   glycogen synthase kinase 3 (GSK3)   casein kinase 1 (CK1)   SCFβ-TrCP   biochemistry   ubiquitin   colorectal cancer  

摘要： The Wnt/beta-catenin pathway is a highly conserved, frequently mutated developmental and cancer pathway. Its output is defined mainly by beta-catenin's phosphorylation- and ubiquitylation-dependent proteasomal degradation, initiated by the multi-protein beta-catenin destruction complex. The precise mechanisms underlying destruction complex function have remained unknown, largely because of the lack of suitable in vitro systems. Here we describe the in vitro reconstitution of an active human beta-catenin destruction complex from purified components, recapitulating complex assembly, beta-catenin modification, and degradation. We reveal that AXIN1 polymerization and APC promote beta-catenin capture, phosphorylation, and ubiquitylation. APC facilitates beta-catenin's flux through the complex by limiting ubiquitylation processivity and directly interacts with the SCF beta-TrCP E3 ligase complex in a beta-TrCP-dependent manner. Oncogenic APC truncation variants, although part of the complex, are functionally impaired. Nonetheless, even the most severely truncated APC variant promotes beta-catenin recruitment. These findings exemplify the power of biochemical reconstitution to interrogate the molecular mechanisms of Wnt/beta-catenin signaling.

关键词： Pareto distribution   lifetime performance index   general progressive type II censoring   Bayesian estimation   MCMC  

摘要： In this paper, we study the statistical inference for the lifetime performance index of the Pareto distribution based on the general progressive type II censored data. Through data transformation, we derive the maximum likelihood estimator (MLE) of lifetime performance index and confidence interval. Further, the Bayesian estimator and the associated credible interval based on informative and non informative prior functions are also considered under the squared error loss function. Based on the non Bayesian and Bayesian estimators of lifetime performance indicators, the hypothesis testing process is constructed to evaluate the life performance of products. After the Monte Carlo simulation, we find that the Bayesian estimator is far better than MLE, and the Bayesian estimator based on informative prior has the best performance. The estimated mean squared errors for both MLE and Bayesian estimator are small, indicating that our considered method is effective to assess the lifetime performance of the products. Finally, a numerical example is analyzed for illustrative purposes.