Cascade Amplification of Pyroptosis and Apoptosis for Cancer Therapy through a Black Phosphorous-Doped Thermosensitive Hydrogel.

Cell pyroptosis has a reciprocal relationship with various cancer treatment modalities such as chemotherapy. However, the tumor microenvironment, characterized by hypoxia, substantially restricts the development and application of tumor therapies that integrate cell pyroptosis. Therefore, the cascade amplification of oxidative stress by interfering with redox homeostasis in tumors may be a promising approach. In this study, black phosphorus (BP) nanosheets and a glutathione peroxidase 4 inhibitor (RSL3) were coloaded into a thermosensitive PDLLA-PEG-PDLLA (PLEL) hydrogel (RSL3/BP@PLEL). Owing to the photothermal property of BP nanosheets, the RSL3/BP@PLEL hydrogel may trigger the release of loaded drugs in a more controllable and on-demand manner. Investigation of the antitumor effect in a mouse liver tumor model demonstrated that local injection of the hydrogel formulation in combination with near infrared laser irradiation could efficiently suppress tumor growth by interfering with the redox balance in tumors. Mechanistic study indicated that the combined treatment of photothermal therapy and glutathione depletion based on this hydrogel efficiently induced cell pyroptosis through both caspase-1/GSDMD and caspase-3/GSDME pathways, thereby triggering the repolarization of tumor-associated macrophages from M2 to M1. Overall, we developed a biocompatible and biodegradable hydrogel formulation for application in combination cancer treatment, providing a new platform for enhancing the efficacy of cancer therapy by amplifying cell pyroptosis and apoptosis.

Comprehensive Analysis of RAPGEF2 for Predicting Prognosis and Immunotherapy Response in Patients with Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is the sixth most common tumor worldwide. Additionally, deletion of RAPGEF2 plays a critical role in CNV and related to tumor immune microenvironment, whereas the prognostic potential of RAPGEF2 in HCC patient needs to be explored. Methods: We looked for prognostic potential genes in HCC using a variety of R programs. Then, using the LASSO Cox regression, we thoroughly evaluated and integrated the RAPGEF2-related genes from TCGA database. Meanwhile, utilizing TCGA and ICGA databases, the link between RAPGEF2 and immunotherapy response in HCC was studied. In vivo, the effect of RAPGEF2 on tumor development and the capacity of natural killer (NK) cells to recruit were confirmed. To ascertain the connection between RAPGEF2-related genes and the prognosis of HCC, a prognostic model was created and validated. Result: We demonstrated RAPGEF2 has a differential expression, and patients with deletion of RAPGEF2 gene get shorter survival in HCC. Additionally, the tissues without RAPGEF2 have a weaker ability to recruit the NK cells and response to immunotherapy. After that, we scoured the database for eight RAPGEF2-related genes linked with a better prognosis in HCC patients. Additionally, silencing RAPGEF2 accelerated tumor development in the HCC mouse model and decreased CD56+ NK cell recruitment in HCC tissues. TCGA database was used to classify patients into low- and high-risk categories based on the expression of related genes. Patients in the low-risk group had a significantly greater overall survival than those in the high-risk group (P < 0.001). Meanwhile, the low-risk group demonstrated connections with the NK cell and immunotherapy response. Finally, the prognostic nomogram showed a high sensitivity and specificity for predicting the survival of HCC patients at 1, 2, and 3 years. Conclusion: The prognostic model based on RAPGEF2 and RAPGEF2-related genes showed an excellent predictive performance in terms of prognosis and immunotherapy response in HCC, therefore establishing a unique prognostic model for clinical assessment of HCC patients.

MORC2 promotes cell growth and metastasis in human cholangiocarcinoma and is negatively regulated by miR-186-5p.

Microrchidia family CW-type zinc finger 2 (MORC2) is a ubiquitously expressed protein that contributes to chromatin remodeling, DNA repair, and lipogenesis. However, its role in cholangiocarcinoma (CCA) remains largely unknown. The aim of this study was to investigate the expression profile of MORC2 and its potential functions in CCA progression. The results showed that MORC2 was upregulated in human CCA specimens and cell lines. MORC2 expression was significantly associated with serum CA19-9 levels (P = 0.009), TNM stage (P = 0.003) and lymph node invasion (P = 0.004). Furthermore, high MORC2 expression was associated with poor 5-year survival (P = 0.016). Functional experiments revealed that MORC2 knockdown could suppress CCA cell proliferation, migration, and invasion both in vivo and in vitro. Mechanically, we found that MORC2 promoted CCA cell metastasis through the EMT process and enhanced proliferation via the Akt signaling pathway. Moreover, MORC2 was negatively regulated by miR-186-5p. MiR-186-5p could influence CCA cell proliferation, migration and metastasis by regulating MORC2. Taken together, the findings of this study demonstrated the oncogenic role of MORC2 in CCA tumorigenesis and metastasis, and clarified an underlying regulatory mechanism mediating MORC2 upregulation, which may provide a novel therapeutic target in CCA treatment.

Safety and Efficacy of Laparoscopic Radiofrequency Ablation for Hepatic Hemangiomas: A Multicenter Retrospective Study.

INTRODUCTION: Radiofrequency ablation (RFA) is an effective and minimally invasive technique for the management of hepatic hemangiomas (HHs). This study aims to assess the safety and efficacy of laparoscopic RFA for HHs. MATERIAL AND METHODS: Forty-four patients with 50 hepatic hemangiomas (5-10 cm in diameter) undergoing laparoscopic RFA from January 2012 to May 2015 at three tertiary hospitals in China were retrospectively analyzed. RESULTS: Thirty-three patients with subcapsular hemangiomas were treated with a laparoscopic approach, and 11 patients with lesions in the liver parenchyma were treated with a combined laparoscopy and an ultrasound-guided percutaneous approach. No conversion to open surgery or two-step surgery occurred during the study period. Patients with small hemangiomas (< 7 cm) required a significantly shorter operating time (71.1 ± 20.18 min vs. 106 ± 23.55 min, p = 0.000) and fewer punctures compared with patients with large hemangiomas (> 7 cm) (4.61 ± 1.09 vs. 6.73 ±1.01, P < 0.05). According to the Dindo-Clavien classification, 15 patients experienced 34 Grade 1 complications, and two had complications of Grade 3a. All complications were resolved by conservative treatment. Forty-three (86.0%) HHs in 38 patients were completely ablated after RFA, and 7 (14.0%) HHs in 6 patients were incompletely ablated. All patients were followed up for 6-24 months (mean 15 ± 6 months). CONCLUSION: The data showed that laparoscopic RFA is an effective treatment for small (< 10 cm) HHs. While the incidence of postoperative complications remains high, the majority of complications are minor. Patients undergoing laparoscopic RFA for HHs, even for the small ones, should be carefully selected.

Appropriate Patient Selection Is Essential for the Success of Primary Closure After Laparoscopic Common Bile Duct Exploration.

BACKGROUND: Laparoscopic common bile duct exploration (LCBDE) is being increasingly used for management of common bile duct (CBD) stones. Primary CBD closure has been reported to have better short-term outcomes compared to T-tube placement. However, primary CBD closure cannot be performed in all patients. AIM: This study aims to evaluate the short- and long-term outcomes of LCBDE with primary CBD closure in appropriately selected patients and compare them with T-tube drainage. METHODS: Retrospective analysis of patients undergoing LCBDE in our department from June 2011 to October 2014 was performed. Primary closure was performed in 52 patients (group A), and a T-tube was placed in 33 patients (group B). Patient demographics, intraoperative findings, postoperative stay, complications, and long-term follow-up data were recorded and compared. RESULTS: The mean operating time was much longer in group A compared to group B (113.92 vs. 95.92 min, p = 0.032). The overall complication rate (9.6 vs. 6.3%, p = 0.701) and hospital stay (4 vs. 5.11 days, p = 0.088) were similar in both groups. No patient required conversion to the open procedure. Bile leakage was more frequent in group A (5.78 vs. 0%, p = 0.279), but this was not statistically significant. All three patients with bile leakage were treated successfully by conservative measures and gradual drain withdrawal. On long-term follow-up, recurrent stones were detected in two patients in group A. No patient was found to develop CBD stricture. CONCLUSION: LCBDE and primary CBD closure has excellent short- and long-term outcomes when performed in appropriately selected patients.

Harmonic Scalpel versus Monopolar Electrocauterization in Cholecystectomy.

BACKGROUND AND OBJECTIVES: Laparoscopic cholecystectomy (LC) using surgical electrocautery is considered to be the gold standard procedure for the treatment of uncomplicated cholecystitis and cholelithiasis. The objective of the current study was to evaluate the effectiveness and safety of the Harmonic scalpel, an advanced laparoscopic technique associated with less thermal damage in LC, when compared to electrocautery. METHODS: From October 2010 through June 2013, a total of 198 patients were randomly allocated to LC with a Harmonic scalpel (experimental group, 117 patients) or conventional monopolar electrocautery (control group, 81 patients). The main outcome measures were operative time, blood loss, conversion to laparotomy, postoperative hospital stay, post-LC pain, and cost effectiveness. RESULTS: The 2 groups were comparable with respect to baseline patient characteristics. When compared to conventional monopolar electrocautery, there were no significant reductions in the operative time, bleeding, frequency of conversion to laparotomy, and duration of postoperative recovery with the Harmonic scalpel (P > .05 for all). CONCLUSIONS: Laparoscopic cholecystectomy using conventional monopolar electrocautery is as effective and safe as that with the Harmonic scalpel, for treating uncomplicated cholecystitis and cholelithiasis.

Laparoscopic gastrectomy for remnant gastric cancer: Risk factors associated with conversion and a systematic analysis of literature.

BACKGROUND: In traditional opinion, history of abdominal surgery was the relative contraindication for Laparoscopic gastrectomy (LG) with high rate of conversion to Open gastrectomy (OG).Use of LG for treatment of remnant gastric cancer (RGC) has been documented in some case studies and controlled clinical trials. However, whether LG is superior, equal or inferior to OG in these patients is not clear. METHODS: English language articles published between January 2005 and January 2016 were searched in MEDLINE, Embase and the Cochrane Database of Systematic Reviews. Main outcome measures were: conversion of LG to OG, operative time, intraoperative blood loss, tumor size, positive proximal resection margin, lymph node dissection, disease stage, post-operative resumption of oral intake, postoperative hospital stay, complications, mortality and follow-up findings. Published clinical data which was in the situation of conversion to OG was collected, and the factors associated with conversion to open surgery were examined. RESULTS: Five non-randomized controlled trials and seven LG case studies were included in the systematic review. Meta-analysis of the data could not be performed due to high variation and heterogeneity in study design, study population, LG technique, and outcome measures among the included studies. Systematic analysis of the included studies showed that LG was associated with significantly shorter mean operative time, early resumption of oral intake, and shorter hospital stay, as compared to that with OG. No significant difference in complications was observed between the two groups. CONCLUSION: LG in the hands of experienced surgeons is relative feasibility and safety for RGC. Previous surgical anastomosis, previous open surgery and surgical experience were associated with conversion to OG. However, these findings should be validated with robust prospective comparative studies.

Antiproliferative effects of cinobufacini on human hepatocellular carcinoma HepG2 cells detected by atomic force microscopy.

AIM: To investigate the antiproliferative activity of cinobufacini on human hepatocellular carcinoma HepG2 cells and the possible mechanism of its action. METHODS: HepG2 cells were treated with different concentrations of cinobufacini. Cell viability was measured by methylthiazolyl tetrazolium (MTT) assay. Cell cycle distribution was analyzed by flow cytometry (FCM). Cytoskeletal and nuclear alterations were observed by fluorescein isothiocyanate-phalloidin and DAPI staining under a laser scanning confocal microscope. Changes in morphology and ultrastructure of cells were detected by atomic force microscopy (AFM) at the nanoscale level. RESULTS: MTT assay indicated that cinobufacini significantly inhibited the viability of HepG2 cells in a dose-dependent manner. With the concentration of cinobufacini increasing from 0 to 0.10 mg/mL, the cell viability decreased from 74.9% ± 2.7% to 49.41% ± 2.2% and 39.24% ± 2.1% (P < 0.05). FCM analysis demonstrated cell cycle arrest at S phase induced by cinobufacini. The immunofluorescence studies of cytoskeletal and nuclear morphology showed that after cinobufacini treatment, the regular reorganization of actin filaments in HepG2 cells become chaotic, while the nuclei were not damaged seriously. Additionally, high-resolution AFM imaging revealed that cell morphology and ultrastructure changed a lot after treatment with cinobufacini. It appeared as significant shrinkage and deep pores in the cell membrane, with larger particles and a rougher cell surface. CONCLUSION: Cinobufacini inhibits the viability of HepG2 cells via cytoskeletal destruction and cell membrane toxicity.