SNS-023 sensitizes hepatocellular carcinoma to sorafenib by inducing degradation of cancer drivers SIX1 and RPS16.

Hepatocellular carcinoma (HCC) remains challenging due to the lack of efficient therapy. Promoting degradation of certain cancer drivers has become an innovative therapy. The nuclear transcription factor sine oculis homeobox 1 (SIX1) is a key driver for the progression of HCC. Here, we explored the molecular mechanisms of ubiquitination of SIX1 and whether targeting SIX1 degradation might represent a potential strategy for HCC therapy. Through detecting the ubiquitination level of SIX1 in clinical HCC tissues and analyzing TCGA and GEPIA databases, we found that ubiquitin specific peptidase 1 (USP1), a deubiquitinating enzyme, contributed to the lower ubiquitination and high protein level of SIX1 in HCC tissues. In HepG2 and Hep3B cells, activation of EGFR-AKT signaling pathway promoted the expression of USP1 and the stability of its substrates, including SIX1 and ribosomal protein S16 (RPS16). In contrast, suppression of EGFR with gefitinib or knockdown of USP1 restrained EGF-elevated levels of SIX1 and RPS16. We further revealed that SNS-023 (formerly known as BMS-387032) induced degradation of SIX1 and RPS16, whereas this process was reversed by reactivation of EGFR-AKT pathway or overexpression of USP1. Consequently, inactivation of the EGFR-AKT-USP1 axis with SNS-032 led to cell cycle arrest, apoptosis, and suppression of cell proliferation and migration in HCC. Moreover, we showed that sorafenib combined with SNS-032 or gefitinib synergistically inhibited the growth of Hep3B xenografts in vivo. Overall, we identify that both SIX1 and RPS16 are crucial substrates for the EGFR-AKT-USP1 axis-driven growth of HCC, suggesting a potential anti-HCC strategy from a novel perspective.

Postoperative Adjuvant Hepatic Arterial Infusion Chemotherapy With FOLFOX in Hepatocellular Carcinoma With Microvascular Invasion: A Multicenter, Phase III, Randomized Study.

PURPOSE: To report the efficacy and safety of postoperative adjuvant hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and oxaliplatin (FOLFOX) in hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI). PATIENTS AND METHODS: In this randomized, open-label, multicenter trial, histologically confirmed HCC patients with MVI were randomly assigned (1:1) to receive adjuvant FOLFOX-HAIC (treatment group) or routine follow-up (control group). The primary end point was disease-free survival (DFS) by intention-to-treat (ITT) analysis while secondary end points were overall survival, recurrence rate, and safety. RESULTS: Between June 2016 and August 2021, a total of 315 patients (ITT population) at five centers were randomly assigned to the treatment group (n = 157) or the control group (n = 158). In the ITT population, the median DFS was 20.3 months (95% CI, 10.4 to 30.3) in the treatment group versus 10.0 months (95% CI, 6.8 to 13.2) in the control group (hazard ratio, 0.59; 95% CI, 0.43 to 0.81; P = .001). The overall survival rates at 1 year, 2 years, and 3 years were 93.8% (95% CI, 89.8 to 98.1), 86.4% (95% CI, 80.0 to 93.2), and 80.4% (95% CI, 71.9 to 89.9) for the treatment group and 92.0% (95% CI, 87.6 to 96.7), 86.0% (95% CI, 79.9 to 92.6), and 74.9% (95% CI, 65.5 to 85.7) for the control group (hazard ratio, 0.64; 95% CI, 0.36 to 1.14; P = .130), respectively. The recurrence rates were 40.1% (63/157) in the treatment group and 55.7% (88/158) in the control group. Majority of the adverse events were grade 0-1 (83.8%), with no treatment-related death in both groups. CONCLUSION: Postoperative adjuvant HAIC with FOLFOX significantly improved the DFS benefits with acceptable toxicities in HCC patients with MVI.

Laparoscopic Versus Open Colorectal Resection Within Fast Track Programs: An Update Meta-Analysis Based on Randomized Controlled Trials.

The objective of the study was to assess the safety and efficacy of laparoscopic colorectal surgery by comparing open operation within fast track (FT) programs. The Cochrane Library, PubMed, Embase and Chinese Biological Medicine Database were searched to identify all available randomized controlled trials (RCTs) comparing laparoscopic with open colorectal resection within FT programs. A total of seven RCTs were finally included, enrolling 714 patients with colorectal cancer: 373 patients underwent laparoscopic surgery and FT programs (laparoscopic/FT group) and 341 patients received open operation and FT programs (open/FT group). Postoperative hospital stay (weighted mean difference (WMD): 0.66; 95% CI: 0.27 - 1.04; P < 0.05), total hospital stay (WMD: 1.46; 95% CI: 0.40 - 2.51; P < 0.05) and overall complications (RR: 1.31; 95% CI: 1.12 - 1.54; P < 0.05) were significantly lower in laparoscopic/FT group than in open/FT group. However, no statistically significant differences on mortality (risk ratio (RR): 2.26; 95% CI: 0.62 - 8.22; P = 0.21), overall surgical complications (RR: 1.19; 95% CI: 0.94 - 1.51; P = 0.15) and readmission rates (RR: 1.33; 95% CI: 0.79 - 2.22; P = 0.28) were found between both groups. The laparoscopic colorectal surgery combined with FT programs shows high-level evidence on shortening postoperative and total hospital stay, reducing overall complications without compromising patients' safety.

The role of omega-3 fatty acids in acute pancreatitis: a meta-analysis of randomized controlled trials.

To determine whether treatment with omega-3 fatty acids (ω-3 FA) provides benefits to patients with acute pancreatitis (AP). The Cochrane Library, PubMed, Embase, Web of Science, and Chinese Biomedical Literature Database were searched. Data analysis was performed using Revman 5.2 software. A total of eight randomized controlled trials (RCTs) were included. Overall, ω-3 FA treatment resulted in a significantly reduced risk of mortality (RR 0.35; 95% CI 0.16 to 0.75, p < 0.05), infectious complications (RR 0.54; 95% CI 0.34 to 0.85, p < 0.05) and length of hospital stay (MD -6.50; 95% CI -9.54 to -3.46, p < 0.05), but not length of ICU stay (MD -1.98; 95% CI -6.92 to 2.96, p > 0.05). In subgroup analysis, only patients who received ω-3 FA parenterally had some statistically significant benefits in terms of mortality (risk ratio (RR) 0.37; 95% confidence interval (CI) 0.16 to 0.86, p < 0.05), infectious complications (RR 0.5; 95% CI 0.28 to 0.9, p < 0.05) and length of hospital stay (mean difference (MD) -8.13; 95% CI -10.39 to -5.87, p < 0.001). The administration of ω-3 FA may be beneficial for decreasing mortality, infectious complications, and length of hospital stay in AP, especially when used parenterally. Large and rigorously designed RCTs are required to elucidate the efficacy of parenteral or enteral ω-3 FA treatment in AP.