GSTO1 aggravates EGFR-TKIs resistance and tumor metastasis via deglutathionylation of NPM1 in lung adenocarcinoma.

Despite significantly improved clinical outcomes in EGFR-mutant lung adenocarcinoma, all patients develop acquired resistance and malignancy on the treatment of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Understanding the resistance mechanisms is crucial to uncover novel therapeutic targets to improve the efficacy of EGFR-TKI treatment. Here, integrated analysis using RNA-Seq and shRNAs metabolic screening reveals glutathione S-transferase omega 1 (GSTO1) as one of the key metabolic enzymes that is required for EGFR-TKIs resistance in lung adenocarcinoma cells. Aberrant upregulation of GSTO1 confers EGFR-TKIs resistance and tumor metastasis in vitro and in vivo dependent on its active-site cysteine 32 (C32). Pharmacological inhibition or knockdown of GSTO1 restores sensitivity to EGFR-TKIs and synergistically enhances tumoricidal effects. Importantly, nucleophosmin 1 (NPM1) cysteine 104 is deglutathionylated by GSTO1 through its active C32 site, which leads to activation of the AKT/NF-κB signaling pathway. In addition, clinical data illustrates that GSTO1 level is positively correlated with NPM1 level, NF-κB-mediated transcriptions and progression of human lung adenocarcinoma. Overall, our study highlights a novel mechanism of GSTO1 mediating EGFR-TKIs resistance and malignant progression via protein deglutathionylation, and GSTO1/NPM1/AKT/NF-κB axis as a potential therapeutic vulnerability in lung adenocarcinoma.

Comparison of laparoscopic radiofrequency ablation with percutaneous radiofrequency ablation in the treatment of chronic hepatitis B-related hepatocellular carcinoma involving specific sites: A retrospective cohort study.

BACKGROUND: This study compared the effectiveness and safety of laparoscopic radiofrequency ablation (LRFA) and percutaneous radiofrequency ablation (PRFA) in the treatment of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) involving specific sites. METHODS: This retrospective cohort study included patients with HBV-related HCC involving specific sites treated with LRFA or PRFA between January 2012 and December 2020. The overall survival (OS), disease-free survival (DFS), and complications were compared between the LRFA and PRFA groups. The Cox proportional-hazards regression model was used to determine the factors affecting prognosis. RESULTS: This study included 109 patients: 69 in the LRFA group and 40 cases in the PRFA group. No significant differences were found in the 3-year OS rate between the two groups (73.7% vs. 70.0%, P = 0.514), but the LRFA group showed a higher 3-year DFS rate than the PRFA group (58.2% vs. 42.5%, P = 0.018). The RFA method was not associated with OS but was independently associated with DFS (LRPA vs. PRFA, HR = 2.078, P = 0.012). The common complications were ascites, pleural effusion, and fever in the two groups. The occurrence of complications in patients treated with LRFA or PRFA was similar (15.9% vs. 12.5%, P = 0.785). CONCLUSION: LRFA was associated with a better DFS in patients with HBV-related HCC involving specific sites. Thus, LRFA might have more advantages in treating liver cancer involving specific sites.

Comparison of RETREAT and CCFSS Scoring Systems for Risk Estimation of Hepatocellular Carcinoma Recurrence After Radical Resection.

Objective: RETREAT and CCFSS are two scoring systems specifically designed to predict postoperative recurrence in hepatocellular carcinoma (HCC). RETREAT and CCFSS are scoring systems designed to predict postoperative recurrence in hepatocellular carcinoma (HCC). This study aims to evaluate and compare the prognostic performance of two scoring systems, RETREAT and CCFSS, for predicting tumor recurrence after radical resection in patients with hepatocellular carcinoma (HCC). Methods: In this retrospective study, we analyzed the clinical data of 124 patients with HCC who underwent radical resection at our hospital between March 2017 and February 2020. The patients were categorized into a recurrence group (n = 41) and a non-recurrence group (n = 83) based on whether they experienced recurrence within 3 years of follow-up. Logistic regression analysis was conducted to compare the clinical characteristics between the two groups and identify factors associated with HCC recurrence. Additionally, we generated receiver operating characteristic (ROC) curves to evaluate the predictive value of the RETREAT and CCFSS scoring systems for predicting HCC recurrence after surgery. Results: Significant differences (P < .05) were found in the postoperative relapse-free survival time, HBsAg positivity, preoperative ALT≥ 40 U/L, preoperative Alb < 40 g/L, pericardial invasion, RETREAT score, and CCFSS score between the two groups. A multi-factor logistic regression analysis was performed between postoperative relapse in HCC patients and HBsAg positivity, preoperative ALT ≥ 40U/L, preoperative Alb<40g/L, pericardial invasion, RETREAT score, and CCFSS score grading as independent variables. The analysis revealed that HBsAg positivity (OR = 6.039, 95%CI: 2.994~12.182), preoperative ALT ≥ 40 U/L (OR = 3.738, 95%CI: 2.016-6.931), preoperative Alb< 40g/L (OR = 3.655, 95%CI: 2.083-6.415), envelope invasion (OR = 3.119, 95%CI: 1.922-5.061), RETREAT score (OR = 6.867, 95%CI: 3.204-14.719), and CCFSS score (OR = 3.228, 95%CI: 1.951-5.342) were significant factors influencing postoperative recurrence in HCC patients (P < .05). The RETREAT score had an area under the curve (AUC) of 0.853, with a sensitivity of 89.23% and a specificity of 93.87% (95%CI: 0.7567-0.950), while the AUC of the CCFSS score for predicting postoperative recurrence in HCC patients was 0.741, with a sensitivity of 78.57% and a specificity of 60.71% (95%CI: 0.609-0.873). Among the factors analyzed, including postoperative relapse-free survival time, HBsAg positivity, preoperative ALT≥ 40 U/L, preoperative Alb < 40 g/L, pericardial invasion, RETREAT score, and CCFSS score, statistically significant differences were observed between the recurrence and non-recurrence groups (P < .05). Conclusion: The RETREAT score demonstrates higher efficacy compared to the CCFSS score in predicting postoperative recurrence in hepatocellular carcinoma (HCC) patients and can serve as a valuable tool for the prognostic evaluation of HCC patients who undergo radical resection. The RETREAT score's superiority can be attributed to its higher area under the curve (AUC) and improved sensitivity and specificity, which allow for better discrimination between positive and negative cases. This enhanced accuracy enables clinicians to make more informed decisions towards post-surgical management and treatment strategies, ultimately improving patient outcomes. Thus, the RETREAT score serves as a vital tool for personalized and targeted care towards HCC patients undergoing radical resection.

A phosphoglycerate mutase 1 allosteric inhibitor overcomes drug resistance to EGFR-targeted therapy via disrupting IL-6/JAK2/STAT3 signaling pathway in lung adenocarcinoma.

Resistance to epidermal growth factor receptor (EGFR) inhibitors, from the first-generation erlotinib to the third generation osimertinib, is a clinical challenge in the treatment of patients with EGFR-mutant lung adenocarcinoma. Our previous work found that a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1), HKB99, restrains erlotinib resistance in lung adenocarcinoma cells. However, the role of HKB99 in osimertinib resistance and its underlying molecular mechanism remains to be elucidated. Herein, we found that IL-6/JAK2/STAT3 signaling pathway is aberrantly activated in both erlotinib and osimertinib resistant cells. Importantly, HKB99 significantly blocks the interaction of PGAM1 with JAK2 and STAT3 via the allosteric sites of PGAM1, which leads to inactivation of JAK2/STAT3 and thereby disrupts IL-6/JAK2/STAT3 signaling pathway. Consequently, HKB99 remarkably restores EGFR inhibitor sensitivity and exerts synergistic tumoricidal effect. Additionally, HKB99 alone or in combination with osimertinib down-regulated the level of p-STAT3 in xenograft tumor models. Collectively, this study identifies PGAM1 as a key regulator in IL-6/JAK2/STAT3 axis in the development of resistance to EGFR inhibitors, which could serve as a therapeutic target in lung adenocarcinoma with acquired resistance to EGFR inhibitors.

[Evaluation of hepatocellular function influenced by Chinese drug Dahuang Zhechong pill].

OBJECTIVE: To evaluate the influence of Chinese drug Dahuang Zhechong pill on the hepatocellular function. METHOD: Thirty-seven patients with hepatocirrhosis and twelve normal controls were performed the hepatobiliary scintgraphy with Tc-99m labeled ethylene hepatobiliary iminodiacetic acid (99 mTc-EHIDA), and the biochemical examination of hepatic function. There was 19 cases repeated the imaging after 6 months treated with chineses drug. By the three compartmental model configurations, the function parameters of hepatocellular extraction and excretion were calculated. RESULT: In the hepatocirrhosis groups, the hepatocellular uptake peak time and mean residence index were higher than those in normal controls (P < 0.01). Compared to normal controls, the uptake index, uptake speed index and descendent speed index were decreased markedly (P < 0.05). After treatment for 6 months with Chinese drug, the level of serum transaminase, globulin and bilirubin was lower than that before treatment. The uptake peak time and mean residence index decreased notably after treatment for 6 months (P < 0.01), and the uptake index increased, (P < 0.05). CONCLUSION: Chinese drug Dahuang Zhechong pill may improve the hepatocellular function and liver function status in patients with hepatocirrhosis.