The objective of our study was to assess potential therapeutic efficacy of inhibitors of unfolded protein

response (UPR) in pancreatic cancers focusing on IRE1 alpha inhibitors. IRE1 alpha-mediated XBP-1 mRNA splicing encodes a transcription factor that enhances transcription of chaperone proteins in order to reverse S63845 concentration UPR. Proliferation assays using a panel of 14 pancreatic cancer cell lines showed a dose-and time-dependent growth inhibition by IRE1 alpha-specific inhibitors (STF-083010, 2-Hydroxy-1-naphthaldehyde, 3-Ethoxy-5,6-dibromosalicylaldehyde, toyocamycin). Growth inhibition was also noted using a clonogenic growth assay in soft agar, as well as a xenograft in vivo model of pancreatic cancer. Cell cycle analysis showed that these IRE1 alpha inhibitors caused growth arrest at either the G1 or G2/M phases BGJ398 inhibitor (SU8686, MiaPaCa2) and induced apoptosis (Panc0327, Panc0403). Western blot analysis showed cleavage of caspase 3 and PARP, and prominent induction of the apoptotic molecule BIM. In addition,

synergistic effects were found between either STF-083010, 2-Hydroxy-1-naphthaldehyde, 3-Ethoxy-5,6-dibromosalicylaldehyde, or toyocamycin and either gemcitabine or bortezomib. Our data suggest that use of an IRE1 alpha inhibitor is a novel therapeutic approach for treatment of pancreatic cancers.”
“Bicuspid aortic valve (BAV) is associated with ascending aortopathy predisposing to aneurysmal dilatation and dissection, even after successful aortic valve replacement (AVR). There is, however, scant evidence on which to make recommendations for prophylactic replacement of the ascending aorta at the time of AVR. The medical records of patients who underwent AVR for BAY without aortic replacement or repair from 1960 to 1995 were reviewed. Follow-up was by review of the medical record and postal questionnaire. Among 1,286 patients,

the mean age at operation was 58 +/- 14 years. During the follow-up interval (median 12 years, range 0 to 38), there were 13 documented aortic dissections (1%), 11 ascending aortic replacements (0.9%), and 127 documented cases of progressive aortic enlargement (9.9%). Fifteen-year freedom from aortic dissection, enlargement, or replacement was 89% (95% confidence interval [CI] 87% to 91%) and was lower in patients with documented aortic enlargement at the time of AVR (85%, 95% CI 81% to 89%) compared to those whose aortic PND-1186 concentration dimensions were normal (93%, 95% CI 90% to 96%) (p = 0.001). Multivariate predictors of aortic complications included interval (subsequent) AVR (hazard ratio [FIR] 3.5, 95% CI 2.3 to 5.4, p <0.001), concomitant coronary artery bypass grafting (HR 2.6, 95% CI 1.7 to 4.0, p <0.001), enlarged aorta (HR 1.8, 95% CI 1.3 to 2.6, p = 0.001), and history of tobacco abuse (RR 1.8,95% CI 1.2 to 2.6, p = 0.003). Aortic dilatation did not predict mortality. In conclusion, despite a true risk for aortic events after AVR for BAY, the occurrence of aortic dissection was low.