Genomic profiling informs therapies and prognosis for patients with hepatocellular carcinoma in clinical practice.

Hepatocellular carcinoma (HCC) genomic research has discovered actionable genetic changes that might guide treatment decisions and clinical trials. Nonetheless, due to a lack of large-scale multicenter clinical validation, these putative targets have not been converted into patient survival advantages. So, it's crucial to ascertain whether genetic analysis is clinically feasible, useful, and whether it can be advantageous for patients. We sequenced tumour tissue and blood samples (as normal controls) from 111 Chinese HCC patients at Qingdao University Hospital using the 508-gene panel and the 688-gene panel, respectively. Approximately 95% of patients had gene variations related to targeted treatment, with 50% having clinically actionable mutations that offered significant information for targeted therapy. Immune cell infiltration was enhanced in individuals with TP53 mutations but decreased in patients with CTNNB1 and KMT2D mutations. More notably, we discovered that SPEN, EPPK1, and BRCA2 mutations were related to decreased median overall survival, although MUC16 mutations were not. Furthermore, we found mutant MUC16 as an independent protective factor for the prognosis of HCC patients after curative hepatectomy. In conclusion, this study connects genetic abnormalities to clinical practice and potentially identifies individuals with poor prognoses who may benefit from targeted treatment or immunotherapy.

M3 muscarinic acetylcholine receptors regulate epithelial-mesenchymal transition, perineural invasion, and migration/metastasis in cholangiocarcinoma through the AKT pathway.

BACKGROUND: Cholangiocarcinoma is a highly malignant tumor type that is not sensitive to radiotherapy or chemotherapy due to aggressive perineural invasion and metastasis. Unfortunately, the mechanisms underlying these processes and the signaling factors involved are largely unknown. In this study, we analyzed the role of M3 muscarinic acetylcholine receptors (M3-mAChR) in cell migration, perineural invasion, and metastasis during cholangiocarcinoma. METHODS: We assessed 60 human cholangiocarcinoma tissue samples and 30 normal biliary tissues. Immunohistochemical staining was used to detect M3-mAChR expression and the relationship between expression and clinical prognosis was evaluated. The biological functions of M3-mAChR in cholangiocarcinoma cell migration, perineural invasion, and epithelial-mesenchymal transition (EMT) were investigated using the human cholangiocarcinoma cell lines FRH0201 and RBE in conjunction with various techniques, including agonist/antagonist treatment, RNA interference, M3-mAChR overexpression, dorsal root ganglion co-culturing, immunohistochemistry, western blotting, etc. RESULTS: M3-mAChR were highly expressed in cholangiocarcinoma tissue and expression was closely related to differentiation and lymphatic metastasis, affecting patient survival. Treatment with the M3-mAChR agonist pilocarpine and M3-mAChR overexpression significantly promoted migration and perineural invasion, while the M3-mAChR antagonist atropine blocked these effects. Similarly, M3-mAChR knock-down also weakened cell migration and perineural invasion. The expression of phosphatase and tensin homolog, AKT, E-cadherin, vimentin, and Snail, which are components of the phosphatidylinositol 3-kinase/AKT signaling pathway and EMT, were altered by pilocarpine, and these effects were again blocked by atropine. Notably, AKT knock-down decreased M3-mAChR expression and reversed the downstream effects of this receptor. CONCLUSIONS: M3-mAChR are involved in tumor cell migration, perineural invasion, and EMT during cholangiocarcinoma, and these effects are modulated via the AKT signaling pathway.

Decreased expression of MUC1 induces apoptosis and inhibits migration in pancreatic cancer PANC-1 cells via regulation of Slug pathway.

MUC1, a membrane tethered mucin glycoprotein, is overexpressed in > 60% of human pancreatic cancers (PCs), and is associated with poor prognosis and enhanced metastasis. Here, we report the effect of silencing MUC1 expression on the growth, migration and invasive ability of pancreatic cancer cells, and explored its mechanisms. We observed that siRNA mediated suppression of the MUC1 expression significantly reduced invasive and migrative capability and induced apoptosis of the pancreatic cancer PANC-1 cells. We found that Slug was inhibited in the MUC1 siRNA transfected PANC-1 cells (MUC1 siRNA/PANC-1 cells). Expression of PUMA and E-cadherin was increased in the MUC1 siRNA/PANC-1 cells. PANC-1 cells overexpressing full long Slug gene (when transfected with Slug cDNA plasmid) significantly inhibited PUMA and E-cadherin expression in the MUC1 siRNA/PANC-1 cells. Silencing PUMA expression inhibited apoptosis in the MUC1 siRNA transfected PANC-1 cells (MUC1 siRNA/PANC-1 cells). Silencing E-cadherin expression restored the invasion and migration ability in the MUC1 siRNA/PANC-1 cells. We therefore concluded that silencing MUC1 expression inhibited migration and invasion, and induced apoptosis of PANC-1 cells via downregulation of Slug and upregulation of Slug dependent PUMA and E-cadherin expression. MUC1 could serve as a potential therapeutic target in pancreatic cancer.

Potential role of mesenchymal stem cells in alleviating intestinal ischemia/reperfusion impairment.

BACKGROUND: Transplantation of bone marrow mesenchymal stem cells (MSCs) provides a promising therapeutic efficiency for a variety of disorders caused by ischemia or reperfusion impairment. We have previously demonstrated the efficacy of MSCs in mitigating intestinal ischemia/reperfusion (I/R) injuries in rats, but the mechanism by which MSCs engraft ameliorates I/R injuries has largely been unknown. The present study aimed at investigating probable mechanisms by which MSCs exert their function. METHODS: Male donor derived rat MSCs were implanted into intestine of female recipient rat by direct submucosal injection after superior mesenteric artery clamping and unclamping. The homed MSCs were detected by Y chromosome in situ hybridization probe, and the tumor necrosis factor-α (TNF-α) content in intestinal mucosa was determined by ELISA. Expression of proliferative cell nuclear antigen (PCNA) in bowel mucosa was assayed by real-time PCR and intestinal mucosa expression of phosphorylation extracellular signal-regulated kinase (pERK1/2) and nuclear factor-κB (NF-κB) were evaluated by western blot. RESULTS: Four and seven days after MSCs transplantation, the TNF-α content of bowel mucosa in MSCs group was significantly lower than that in saline group. The PCNA in bowel mucosa showed higher expression in MSCs treated group than the saline group, both at 4 and 7 days after cell transplantation. The expression of intestinal mucosal pERK1/2 in MSCs treated group was markedly higher than that in saline group, and the expression of NF-κB in MSCs treated group was noticeably decreased than that in saline group at 4 and 7 days post MSCs transplantation. CONCLUSION: The present investigation provides novel evidence that MSCs have the potential to reduce intestinal I/R injuries probably due to their ability to accelerate cell proliferation and decrease the inflammatory response within intestinal mucosa after ischemia and reperfusion.

[Effect of intensive insulin therapy on the clinical results of postoperative patients with gastric cancer].

OBJECTIVE: To investigate the influence of intensive insulin therapy on the results of postoperative patients with gastric cancer. METHODS: Forty-six patients with gastric cancer underwent radical operation were randomly divided into two groups: intensive group (n=23, to control blood glucose at 4.4 to 6.1 mmol/L) and conventional group (n=23, to control blood glucose at 10.0 to 11.1 mmol/L). Fasting blood glucose( FBG), fasting insulin (FINS), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and C reaction protein (CRP) in 46 patients were detected dynamically during perioperative period. Insulin resistance index (HOMA-IR) were calculated using Homeostasis Model Assessment (HOMA) to evaluate insulin sensitivity. Postoperative complications and other clinical data were recorded. RESULTS: No hypoglycemia occurred in the two groups. Compared with conventional group, morbidity and postoperative duration of fever, antibiotic use and the length of hospital stay in intensive group were significantly reduced (P < 0.05). On the day 1 and 3 after surgery, HOMA-IR and serum levels of TNF-alpha, IL-6 and CRP in patients of intensive group were significantly lower than those in conventional group (P < 0.05). CONCLUSIONS: Intensive insulin therapy could counteract the state of high-inflammation and then improve the outcome of postoperative patients.

[Effects of intensive insulin therapy on insulin resistance and serum proteins after radical gastrectomy].

OBJECTIVE: To investigate the effects of intensive insulin therapy on insulin resistance(IR) and serum proteins after radical gastrectomy. METHODS: Twenty-two gastric cancer patients were randomly divided into the control (n=11) and intensive insulin therapy group (n=11), and underwent distal radical subtotal gastrectomy under epidural anesthesia. Fasting blood glucose (FBG), fasting insulin (FINS) and serum proteins were assayed preoperatively and at day 1, 3, 7 postoperatively. Insulin resistance index was calculated using homeostasis model assessment (HOMA). The length of hospital stay and postoperative complications were recorded respectively. RESULTS: (1)The levels of FBG, FINS, lnHOMA-IR (P<0.01,P<0.05) and the incidence of insulin resistance were remarkably decreased by intensive insulin therapy after the surgical procedure.(2)The levels of serum transferrin (TRF), prealbumin (PRE) and retinal binding protein (RBP) in the intensive insulin therapy group were significantly improved as compared to control group after operation(P<0.05). (3) The duration of fever, antibiotic use, passage of gas by anus, length of hospital stay and the occurrence of postoperative complications were also significantly lower than those in control group(P<0.01,P<0.05). CONCLUSION: Compared to routine therapy, the intensive insulin therapy has more beneficial effects on the patients undergone distal radical subtotal gastrectomy in decreasing the insulin resistance, improving the status of nutrition and preventing postoperative complications.