A Novel Rat Model to Simulate the Benign Esophageal Stricture Induced by Endoscopic Submucosal Dissection.

Objective: This study aimed to establish a rat model that simulates benign esophageal strictures induced by endoscopic submucosal dissection (ESD). Materials and Methods: Sixteen male Sprague-Dawley rats were randomly divided into mucosal resection (n = 8) and sham-operated groups (n = 8). The rats in the mucosal resection group underwent a 5-mm three-fourths mucosal resection by way of a 3-mm incision in the distal esophagus under direct visualization via laparotomy. Rats in the sham-operated group underwent a 3-mm incision of the muscularis propria layer in the distal esophagus via laparotomy without mucosal resection. Dysphagia score, weight gain, mucosal constriction rate, and histology were evaluated 2 weeks after surgery. Results: Technical success was achieved in all the animals. One rat in the mucosal resection group died of infection, and no other complications were observed. Weight gain (P < 0.001) and luminal diameter derived from the esophagograms (P < 0.001) were significantly lower in the mucosal resection group than those in the sham-operated group. Dysphagia score (P < 0.001) and mucosal constriction rate (P < 0.001) were significantly higher in the mucosal resection group than those in the sham-operated group. The inflammation grade (P = 0.002), damage to the muscularis propria (P < 0.001), number of nascent microvessels (P = 0.006), and degree of α-SMA positive deposition (P = 0.006) were significantly higher in the mucosal resection group. Conclusion: A rat model of benign esophageal stricture induced by ESD was successfully and safely established by mucosal resection.

The Role of GNMT and MMP12 Expression in Determining TACE Efficacy: Validation at Transcription and Protein Levels.

Purpose: Transarterial chemoembolization (TACE) represents a significant therapeutic modality for hepatocellular carcinoma (HCC). We aimed to develop a gene signature to accurately predict patient TACE response and explore the underlying mechanisms. Methods: Three independent datasets were utilized, including GSE104580, GSE14520 and external validation from the Cancer Hospital Chinese Academy of Medical Sciences. GSE104580 was randomly partitioned into a training set and a validation set, whereas GSE14520 was categorized into a resection group and a TACE group. Logistic regression was used to develop a TACE effectiveness model. Immunohistochemistry is utilized to confirm the protein expression trends of the signature genes. Immune infiltration and functional enrichment analyses were conducted to investigate the potential underlying mechanisms. Results: A 2-gene signature consisting of glycine N-methyltransferase (GNMT) and matrix metalloproteinase-12 (MMP12) was constructed, and based on this, all the patients were assigned TACE effectiveness scores and categorized into high effectiveness (HE) and low effectiveness (LE) groups. The HE group exhibited a better prognosis than the LE group in the various cohorts (p < 0.05). In the external validation set, immunohistochemistry confirmed the expression of the signature genes exhibiting an upregulated trend of GNMT in the HE group and MMP12 in the LE group, the LE group also exhibited a poorer prognosis [for overall survival (OS), HE group: 881 days vs LE group: 273 days (p < 0.05), and for progression-free survival (PFS), HE group: 458 days vs LE group: 136 days (p < 0.05)]. Multivariate analysis in all the datasets identified LE status as an independent risk factor for OS, disease-free survival (DFS) and PFS. The infiltration level of M0 macrophages and activated mast cells in the LE group was significantly higher than in the HE group. The hypoxia signaling pathway and glycolysis pathway were significantly enriched in the LE group. Conclusion: The loss of GNMT and the overexpression of MMP12 may be critical factors influencing TACE efficacy.

Autophagy is involved in Ficus carica fruit extract-induced anti-tumor effects on pancreatic cancer.

Pancreatic cancer (PaCa), a common and highly lethal malignant cancer, is often insensitive to radio- and/or chemotherapy. Therefore, effective treatment regiments are still lacking. Herein, we found that an extract of Ficus carica fruit (EFCF) exerted anti-tumor effects on PaCa cells. EFCF induced cell viability inhibition and apoptotic cell death in two PaCa cell lines in a dose- and time dependent manner. EFCF effectively suppressed the migration, metastasis, invasion, and colony formation of PaCa cells. Mechanistically, EFCF stimulated an increase in intracellular ROS to promote cell death and senescence. EFCF treatment also triggered autophagy, and autophagy inhibition enhanced EFCF-induced cell death. We found that EFCF decreased mitochondrial membrane potential and promoted lipid peroxidation. Moreover, intragastric administration of EFCF effectively suppressed xenograft PaCa growth inhibition by activating cell death. EFCF had no apparent toxicity to normal pancreatic epithelial cells. Together, these findings suggest that EFCF may be a potential treatment for PaCa.

The potential roles of p53 signaling reactivation in pancreatic cancer therapy.

Globally, pancreatic cancer (PC) is a common and highly malignant gastrointestinal tumor that is characterized by an insidious onset and ready metastasis and recurrence. Over recent decades, the incidence of PC has been increasing on an annual basis; however, the pathogenesis of this condition remains enigmatic. PC is not sensitive to radio- or chemotherapy, and except for early surgical resection, there is no curative treatment regime; consequently, the prognosis for patients with PC is extremely poor. Transcription factor p53 is known to play key roles in many important biological processes in vertebrates, including normal cell growth, differentiation, cell cycle progression, senescence, apoptosis, metabolism, and DNA damage repair. However, there is a significant paucity of basic and clinical studies to describe how p53 gene mutations or protein dysfunction facilitate the occurrence, progression, invasion, and resistance to therapy, of malignancies, including PC. Herein, we describe the involvement of p53 signaling reactivation in PC treatment as well as its underlying molecular mechanisms, thereby providing useful insights for targeting p53-related signal pathways in PC therapy.

Predictors for the risk of permanent pacemaker implantation after transcatheter aortic valve replacement: A systematic review and meta-analysis.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a less invasive treatment than surgery for severe aortic stenosis. However, its use is restricted by the fact that many patients eventually require permanent pacemaker implantation (PPMI). This meta-analysis was performed to identify predictors of post-TAVR PPMI. METHODS: The PubMed, Embase, Web of Science, and Cochrane Library databases were systematically searched. Relevant studies that met the inclusion criteria were included in the pooling analysis after quality assessment. RESULTS: After pooling 67 studies on post-TAVR PPMI risk in 97,294 patients, balloon-expandable valve use was negatively correlated with PPMI risk compared with self-expandable valve (SEV) use (odds ratio [OR]: 0.44, 95% confidence interval [CI]: 0.37-0.53). Meta-regression analysis revealed that history of coronary artery bypass grafting and higher Society of Thoracic Surgeons (STS) risk score increased the risk of PPMI with SEV utilization. Patients with pre-existing cardiac conduction abnormalities in 28 pooled studies also had a higher risk of PPMI (OR: 2.33, 95% CI: 1.90-2.86). Right bundle branch block (OR: 5.2, 95% CI: 4.37-6.18) and first-degree atrioventricular block (OR: 1.97, 95% CI: 1.38-2.79) also increased PPMI risk. Although the trans-femoral approach was positively correlated with PPMI risk, the trans-apical pathway showed no statistical difference to the trans-femoral pathway. The approach did not increase PPMI risk in patients with STS scores >8. Patient-prosthesis mismatch did not influence post-TAVR PPMI risk (OR: 0.88, 95% CI: 0.67-1.16). We also analyzed implantation depth and found no difference between patients with PPMI after TAVR and those without. CONCLUSIONS: SEV selection, pre-existing cardiac conduction abnormality, and trans-femoral pathway selection are positively correlated with PPMI after TAVR. Pre-existing left bundle branch block, patient-prosthesis mismatch, and implantation depth did not affect the risk of PPMI after TAVR.