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BackgroundNonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in affluent countries. Recent studies have reported that circular RNAs (circRNAs) are important regulators of hepatic steatosis. However, the role and mechanism of circRNA in NAFLD are poorly understood.AimsThis study is to reveal the role and mechanism of circRNA in NAFLD.MethodsThrough NAFLD-related circRNA microarrays, we used real-time quantitative reverse transcription-polymerase chain reaction to screen circScd1 levels in control and test groups of mice fed a high-fat diet. RNA interference and over-expression plasmid vectors were used to manipulate the expression of circScd1, and the biological effects were evaluated by oil red staining, triglyceride detection, and western blot analysis.ResultsCircScd1 expression was significantly lower in NAFLD tissues than in control tissues. Moreover, over-expression of circScd1 significantly inhibited the formation of lipid droplets. Western blot analyses showed that the protein levels of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) were significantly increased. However, knockdown of circScd1 significantly promoted the degree of hepatocellular lipidosis and reduced the expression levels of JAK2 and STAT5.ConclusionsAberrant expression of circScd1 affects the extent of hepatocellular lipidosis in NAFLD and promotes fatty liver disease via the JAK2/STAT5 pathway.

Two large randomized clinical trials (RCTs) found that laparoscopic surgery failed to yield noninferior pathologic outcomes compared with open surgery for patients with rectal cancer. The results raised concerns regarding the effectiveness of the laparoscopic approach for patients with rectal cancer. To compare the long-term oncologic outcomes of laparoscopic and open surgery for patients with rectal cancer. PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were searched from database inception to August 13, 2021. Studies published in English were retrieved. The meta-analysis included RCTs that compared laparoscopic surgery with open surgery for patients with rectal cancer and reported the outcome of disease-free survival (DFS) or overall survival (OS). The following exclusion criteria were used: (1) non-RCTs, (2) studies without long-term survival outcomes of interest, and (3) studies that did not report Kaplan-Meier survival curves. This meta-analysis was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline for individual participant data development groups. Individual participant data on DFS and OS were extracted from the published Kaplan-Meier survival curves. One-stage and 2-stage meta-analyses were performed. Meta-analyses were conducted for DFS and OS. Hazard ratios (HRs) were used as effective measures. Of 8471 records screened, 10 articles with 12 RCTs and 3709 participants were selected. The reconstructed survival curves for the combined population showed that the 5-year estimated DFS rates were 72.2% (95% CI, 69.4%-74.8%) for the laparoscopic group and 70.1% (95% CI, 67.0%-73.0%) for the open surgery group, and the 5-year estimated OS rates were 76.2% (95% CI, 73.8%-78.5%) for the laparoscopic group and 72.7% (95% CI, 69.8%-75.3%) for open surgery group. In 1-stage meta-analyses, DFS had a nonsignificant HR of 0.92 (95% CI, 0.80-1.06; P = .26), which suggested that DFS in the laparoscopic and open surgery groups was comparable; however, OS was significantly better in the laparoscopic group (HR, 0.85; 95% CI, 0.74-0.97; P = .02). The results were confirmed by 2-stage meta-analyses and were validated by sensitivity analysis with large RCTs. A similar DFS but significantly better OS were found for patients who have undergone laparoscopic surgery compared with open surgery for rectal cancer. These findings address concerns regarding the effectiveness of laparoscopic surgery and support the routine use of laparoscopic surgery for patients with rectal cancer.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is characterized by chronic nonspecific intestinal inflammation. Despite considerable efforts, IBD remains a heavy burden on society and human health, with increasing morbidity. Posttranslational modification, especially histone acetylation, is a key process in controlling DNA transcriptional activity. Histone deacetylases (HDACs) play a vital role in the mechanism of IBD pathogenesis through histone and nonhistone protein deacetylation. Herein, we present a summary of different categories of HDACs as well as HDAC inhibitors (HDACis) and analyze the role of HDAC inhibition in alleviating IBD along with its mechanism, as well as clinical potential of HDACis in IBD treatment.

Insulin resistance (IR) is the most common pathophysiological change in patients with type 2 diabetes mellitus (T2DM). Several recent studies have suggested that the gut microbiome and microbial metabolites are involved in the pathogenesis of IR. Bariatric surgery, as an effective treatment for T2DM, can markedly alleviate IR through mechanisms that have not been elucidated. In this review, we summarize the current evidence on the changes in the gut microbiome and microbial metabolites (including lipopolysaccharide, short-chain fatty acids, branched-chain amino acids, aromatic amino acids, bile acids, methylamines, and indole derivatives) after bariatric surgery. Additionally, we discuss the mechanisms that correlate the changes in microbial metabolites with the postoperative alleviation of IR. Furthermore, we discuss the prospect of bariatric surgery as a treatment for T2DM.

Gastric cancer (GC) is a highly aggressive malignancy with a poor prognosis. Transfer RNA-derived small RNAs (tsRNAs) are implicated in tumorigenesis, but their precise mechanistic roles in GC progression remain incompletely understood. We performed high-throughput sequencing in four paired GC/normal tissues to profile tsRNAs. The functional and mechanistic role of a candidate tsRNA was systematically investigated, alongside a suite of techniques including fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down, chromatin immunoprecipitation, and luciferase reporter assays. We identified a novel tsRNA, tRF-Ser, that was significantly downregulated in GC tissues and cell lines, and its expression was correlated with favorable survival. Functionally, tRF-Ser acted as a tumor suppressor by inhibiting epithelial-mesenchymal transition (EMT), inducing ferroptosis, and enhancing sensitivity to 5-fluorouracil chemotherapy. Mechanistically, tRF-Ser directly bound to the cellular nucleic acid-binding protein CNBP (a transcription factor), promoting its accumulation in the cytoplasm and preventing its binding to the HSPA8 promoter to downregulate HSPA8. Then, the tRF-Ser/CNBP/HSPA8 axis suppressed EMT by inhibiting β-catenin nuclear translocation and promoted ferroptosis by facilitating STUB1-mediated ubiquitination degradation of GPX4. Our study unveils that the tRF-Ser/CNBP/HSPA8 axis may constrain GC progression by regulating energy metabolism, which highlights the therapeutic potential of targeting this axis for GC treatment.

Objectives Colorectal cancer on the right side of the colon has been suggested to be harder to detect by colonoscopy. The aim of this study was to evaluate whether a second forward-view examination of the right side of the colon could increase the adenoma detection rate (ADR) and/or polyp detection rate (PDR). Methods This was a single-centre randomized controlled trial. Patients undergoing colonoscopy were recruited and randomly assigned to the second forward-view examination (SFE) group, in which the right side of the colon was examined twice or the traditional colonoscopy (TC) group in which the colonoscopy was performed in a standard manner. The primary outcome was the ADR of right colon. The overall PDR and ADR, PDR of the right colon, per-adenoma miss rate of the right colon, and advanced lesion detection rate were also recorded and compared. Results A total of 392 patients were included in the study (SFE group 197 vs. TC group 195). The ADR and PDR of the right colon in the SFE group were significantly higher than those in the TC group (ADR 10.7% vs. 5.1%; P  = 0.042); PDR 17.8% vs. 9.7%, P  = 0.021). No significant difference was found in overall PDR/ADR, or advanced lesion detection rate between the two groups. Conclusions This prospective controlled study revealed that a second forward-view examination could modestly increase the ADR and PDR of the right colon during unsedated colonoscopies. This simple, safe and time-effective technique might be recommended for routine unsedated colonoscopy. Trial registration: Clinical Trials.gov, NCT03619122. Registered on 7/8/2018.

To compare serum inflammatory cytokines between laparoscopic-assisted and open radical gastrectomy in the perioperative period, 80 cases of advanced gastric cancer were chosen for the study. They were divided into laparoscopy group (40 cases) and abdominal open surgery group (40 cases), performed laparoscopic-assisted radical gastrostomy and conventional open radical gastrectomy, respectively. Serum Heme oxygenase-1 (HO-1), TNF-α, IL-6 and CRP were measured by ELISA on preoperative day 1, post-operative day 1 and post-operative day3. Serum HO-1, TNF-α, IL-6 and CRP had no significant difference between the laparoscopy group and the open group on pre-operative day 1. Serum HO-1, IL-6 and CRP of the laparoscopy group were significantly lower than that of the open group on post-operative day 1 and day 3 except for Serum TNF-α which had no significant difference. Laparoscopic-assisted radical gastrectomy was minimally invasive compared with conventional open radical gastrectomy in advanced gastric cancer patients.

Human aldo-keto reductase family 1 member C3 (AKR1C3) is an important molecule that participates in multiple physiological metabolic processes. However, its expression, biological functions and clinical significance in gastric carcinogenesis are unclear. We collected data from several public data portals and clinical samples and systematically analyzed the clinical significance of tissue and plasma AKR1C3 expression. Then, we filtered prognostic risk factors and established novel prognosis-related nomogram models for predicting overall survival time and postoperative recurrence risk. The application value of the nomogram models was further assessed using clinical samples. Moreover, we explored the potential biological functions of AKR1C3 in gastric carcinogenesis and metastasis through multiomics functional analysis and immune infiltration analysis. AKR1C3 levels were reduced in cancer tissue but increased significantly in the plasma of GC patients; AKR1C3 expression in either sample type was closely associated with multiple clinicopathological characteristics. By combining clinicopathological factors and AKR1C3 levels, two novel nomogram models were developed to predict overall survival time and postoperative recurrence risk. Multiomics functional analysis revealed that when its expression is dysregulated, AKR1C3 can widely participate in gene expression regulation through multiple regulatory modes at the gene, RNA and protein levels and exert various crucial biological effects in carcinogenesis and metastasis. Moreover, AKR1C3 expression was correlated with the infiltration of several immune cell types, and AKR1C3 was predicted to interact with several clinical drugs. : Dysregulated AKR1C3 expression is related to gastric carcinogenesis and immunotherapy response and is a promising biomarker and effective biotherapy target in GC.

Immunotherapy confers little to no benefit in the treatment of microsatellite stable (MSS) metastatic colorectal cancer (mCRC). Mechanistic insights suggested that epidermal growth factor receptor (EGFR) antibody plus irinotecan might augment the tumor immune response in mCRC. Therefore, we conducted a proof-of-concept, single-arm, phase 2 study (ChiCTR identifier: ChiCTR2000035642) of a combination treatment regimen including tislelizumab (anti-PD-1), cetuximab (anti-EGFR) and irinotecan in 33 patients with MSS and RAS wild-type (WT) mCRC who were previously treated with ≥2 lines of therapy. The primary endpoint was met, with a confirmed objective response rate of 33%. As secondary endpoints, the disease control rate was 79%, and the median progression-free survival and overall survival were 7.3 and 17.4 months respectively. Among the 33 patients, 32 (97.0%) had treatment-related adverse events (AEs). Three (9.1%) reported grade ≥ 3 AEs, including rash ( n  = 1), neutropenia ( n  = 2). The post-hoc evaluation of dynamic circulating tumor DNA using next generation sequencing and the analysis of peripheral immune proteomics landscape using Olink revealed that lower variant allele frequency (VAF) at baseline, greater reduction in VAF on treatment, and a hot peripheral macroenvironment were associated with the treatment response independently. Our study showed the antitumor activity of tislelizumab, cetuximab, and irinotecan combination with a tolerable safety profile in previously treated MSS and RAS WT mCRC. Monotherapy with immune checkpoint inhibitors has shown limited clinical activity in patients with microsatellite stable (MSS) colorectal cancer (CRC). Here the authors report the results of a clinical trial of tislelizumab (anti-PD1) in combination with cetuximab (anti-EGFR) and irinotecan in patients with refractory MSS and RAS wild-type metastatic CRC.

In recent years, immunotherapy, particularly PD-1 antibodies, have significantly enhanced the outcome of gastric cancer patients. Despite these advances, some patients do not respond well to treatment, highlighting the need to understand resistance mechanisms and develop predictive markers of treatment effectiveness. This study retrospectively analyzed data from 106 patients with stage IV gastric cancer who were treated with first-line immunotherapy in combination with chemotherapy. By comparing plasma cytokine levels between patients resistant and sensitive to PD-1 antibody therapy, the researchers identified elevated IL-4 expression in the resistant patients. Mechanical investigations revealed that IL-4 induces metabolic changes in macrophages that activate the PI3K/AKT/mTOR pathway. This alteration promotes ATP production, enhances glycolysis, increases lactic acid production, and upregulates FcγRIIB expression in macrophages. Ultimately, these changes lead to CD8+ T cell dysfunction and resistance to PD-1 antibody therapy in gastric cancer. These findings highlight the role of IL-4-induced macrophage polarization and metabolic reprogramming in immune resistance and verify IL-4 as potential targets for improving treatment outcomes in gastric cancer patients.