Notch3-specific inhibition using siRNA knockdown or GSI sensitizes paclitaxel-resistant ovarian cancer cells.

Notch signaling plays an important role in ovarian cancer chemoresistance, which is responsible for recurrence. Gamma-secretase inhibitor (GSI) is a broad-spectrum Notch inhibitor, but it has serious side effects. The efficacy of Notch3-specific inhibition in paclitaxel-resistant ovarian cancers was assessed in this study, which has not yet been evaluated relative to GSI. To analyze the effect of Notch3-specific inhibition on paclitaxel-resistant ovarian cancers, we compared cell viability, apoptosis, cell migration, angiogenesis, cell cycle, and spheroid formation after treatment with either Notch3 siRNA or GSI in paclitaxel-resistant SKpac cells and parental SKOV3 cells. Expression levels of survival, cell cycle, and apoptosis-related proteins were measured and compared between groups. Notch3 was significantly overexpressed in chemoresistant cancer tissues and cell lines relative to chemosensitive group. In paclitaxel-resistant cancer cells, Notch inhibition significantly reduced viability, migration, and angiogenesis and increased apoptosis, thereby boosting sensitivity to paclitaxel. Spheroid formation was also significantly reduced. Both Notch3 siRNA-treated cells and GSI-treated cells arrested in the G2/M phase of the cell cycle. Proteins of cell survival, cyclin D1 and cyclin D3 were reduced, whereas p21 and p27 were elevated. Both GSI and Notch3 siRNA treatment reduced expression of anti-apoptotic proteins (BCL-W, BCL2, and BCL-XL) and increased expression of pro-apoptotic proteins (Bad, Bak, Bim, Bid, and Bax). These results indicate that Notch3-specific inhibition sensitizes paclitaxel-resistant cancer cells to paclitaxel treatment, with an efficacy comparable to that of GSI. This approach would be likely to avoid the side effects of broad-spectrum GSI treatment. © 2015 Wiley Periodicals, Inc.

Robotic-Assisted Surgical Ablation of Atrial Fibrillation Combined With Mitral Valve Surgery.

BACKGROUND: Data on robotic-assisted surgical atrial fibrillation (AF) ablation in patients undergoing mitral valve (MV) operations are lacking. This study aimed to evaluate early and late outcomes after robotic-assisted ablation of AF combined with MV surgery. METHODS: Between 2007 and 2017, this study enrolled 94 patients (age: 53.9 ± 12.7 years; 67 men) undergoing AF ablation by using an argon-based flexible cryoablation system during robotic-assisted MV surgical procedures. Persistent (n = 34, 36.2%) or long-standing persistent (n = 38, 40.4%) AF was present in most patients. Primary valve procedures included isolated mitral repair in 58 patients, isolate mitral replacement in 2 patients, and combined mitral and tricuspid repair in 34 patients. RESULTS: Sixty patients (63.8%) received left-side-only AF ablation, whereas the others (n = 34, 36.2%) received biatrial ablation. The operation times for cardiopulmonary bypass and aortic cross-clamping were 222.7 ± 57.8 minutes and 134.1 ± 30.4 minutes, respectively. No early death was seen. Major early complications included neurologic injury in 2 patients (2.1%) and low cardiac output syndrome in 2 patients (2.1%). No patients required permanent pacemaker implantation. Early AF occurred in 14 patients (14.9%) during a postablation blanking period (90 days). During a median follow-up of 49.6 months (quartiles 1 to 3: 17.2 to 79.4 months, 95.7% complete), there were two late deaths (0.49% per patient-year) and one stroke (0.25% per patient-year). Five-year survival was greater than 96%, and results from largely electrocardiograms showed a low recurrence of AF (2.2% at 1 year, 6.7% at 5 years). CONCLUSIONS: Surgical AF ablation with the use of robotic-assistance in the setting of mitral valve surgery showed excellent safety and favorable long-term clinical outcomes.