Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous LCZ696 supplier treatment and then randomly assigned (1: 1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment.
The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov, number NCT00678392.
Findings A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6.7 months with axitinib compared to 4.7 months with sorafenib MX69 purchase (hazard ratio 0.665; 95% CI 0.544-0.812; one-sided p<0.0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm.
Interpretation Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced
renal cell carcinoma.”
“Manganese is a common environmental and occupational pollutant. Excessive intake of manganese
can cause toxicity known as manganism. Recently it has been demonstrated that unusual expression of cell cycle proteins and aberrant cell cycle Nutlin-3a chemical structure progression in the central nervous system are involved in the pathogenesis of neurodegenerative diseases. The present studies were initiated to investigate whether p21 are induced after manganese exposure and its potential effects in vitro, with particular attention being given to understand the underlying regulatory mechanism of p21 induction by manganese in this process. We found that manganese induced DAergic cells injury and upregulation of p21 levels in nigrostriatal regions. Treatment of the PC12 cells with manganese resulted in a time- and concentration-dependent loss of cell viability. Analysis of cell cycle profile indicated that manganese blocked cell cycle progression by arresting the cell cycle at G2/M phase. Moreover, manganese treatment resulted in an increase in the mRNA and protein levels of p21, but did not have the same effect on other related factors. Silencing p21 by RNA interference showed a marked reversal of both G2/M arrest and the decrease in cell viability induced by manganese. Manganese did not stabilize the p21 protein and mRNA, and caused a marked increase in p21 mRNA levels together with an increase in its promoter activity, indicating a transcriptional mechanism. Overall, the in vivo and in vitro data suggest that exposure to manganese can increase p21 levels.