Reinforced medication adherence improves Helicobacter pylori eradication rate in developing countries: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The eradication rate of Helicobacter pylori (H. pylori) remains variable for the same eradication regime even in the identical region, especially in developing countries. Herein, we conducted a systematic review to assess the effect of reinforced medication adherence on H. pylori eradication rate in developing countries. MATERIALS AND METHODS: A systematic review was conducted in literature databases to identify relevant randomized controlled trials (RCTs) from inception to March 2023. The core indicator was the changes in eradication rate after enhanced adherence. A meta-analysis was performed to estimate the pooled relative risk (RR) or weighted mean difference (WMD) with 95% confidence intervals (CI). RESULTS: Nineteen RCTs that included a total of 3286 patients were assessed. The measures to enhance compliance were mainly through face-to-face communication, phone calls, text messages, and social software. Compared with the control group, patients received reinforced measures showed a better medication adherence (89.6% vs. 71.4%, RR = 1.26 95% CI: 1.16-1.37), higher H. pylori eradication rate (intention-to-treat analysis: 80.2% vs. 65.9%, RR = 1.25, 95% CI: 1.12-1.31; per-protocol analysis: 86.8% vs. 74.8%, RR = 1.16, 95% CI: 1.09-1.23), higher symptom relief rates (81.8% vs. 65.1%, RR = 1.23, 95% CI: 1.09-1.38), higher degree of satisfaction (90.4% vs. 65.1%, RR = 1.26, 95% CI: 1.19-1.35), higher disease knowledge rates (SMD = 1.82, 95% CI: 0.77-2.86, p = 0.0007), and lower incidence of total adverse events (27.3% vs. 34.7%, RR = 0.72, 95% CI: 0.52-0.99). CONCLUSION: Based on available evidence, reinforced medication adherence as a nonnegligible measure improves H. pylori eradication rate in developing countries.

The assessment of the ASGE-grading system of ERCP: a large-sample retrospective study.

BACKGROUND AND AIMS: The American Society for Gastrointestinal Endoscopy (ASGE) has developed a complexity-grading system for endoscopic retrograde cholangiopancreatography (ERCP) to predict technical success and adverse events. This study aimed to assess the association between the degree of difficulty for ERCP and the rates of success and adverse event, in turn demonstrating the validity and practicality of this system. METHODS: ERCP procedures performed in the First Affiliated Hospital of Nanchang University from January 2011 to December 2020 were retrospectively reviewed. Procedural success and adverse events were recorded based on difficulty level according to the ASGE-grading system. RESULTS: A total of 20,652 ERCP procedures performed during the study period were analyzed, including 1908 procedures considered grade 1(9.2%), 10,170 procedures considered grade 2 (49.2%), 7764 procedures considered grade 3 (37.6%), 810 procedures considered grade 4 (3.9%). The overall success rate increased from 92.8% in 2011-2015 to 94.0% in 2016-2020, while the distribution of procedures and the incidence of complications showed little variation. The success rate revealed a significantly decreasing trend with increasing difficulty (ranging from 55.6 to 98.6%), mainly for biliary diseases. In addition, the difficulty scale was not associated with any differences in the rate of adverse event, except for the pancreatitis for grade 1 procedures, which had a low incidence. CONCLUSIONS: The ASGE-grading system can help predict the success rate of ERCP procedures but showed poor performance in predicting adverse events. Further exploration may be required to improve the grading system by adjusting or including certain clinical parameters, and to validate the system for extrapolation to other endoscopy units.

Hemodialysis and risk of acute pancreatitis: A systematic review and meta-analysis.

BACKGROUND: Epidemiological evidence indicates that hemodialysis may be a risk factor for acute pancreatitis. This meta-analysis was conducted with the aim of summarizing all available data and examining the present evidence. AIM: To quantify the association between hemodialysis and the incidence of acute pancreatitis. METHODS: This meta-analysis included studies on the incidence of acute pancreatitis in patients with hemodialysis. We summarized the incidence of acute pancreatitis in hemodialysis patients, and compared the incidence of acute pancreatitis in hemodialysis patients with that in non-hemodialysis individuals. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: A total of 5 observational studies with 1059384 individuals were identified for the meta-analysis. Meta-analysis of these observational studies showed that the pooled prevalence of acute pancreatitis in hemodialysis patients was 1.1% (95% CI: 0.2%-2.3%). In addition, we found that hemodialysis was associated with an increased risk of acute pancreatitis (relative risk = 6.96; 95% CI 3.71-13.06). CONCLUSION: This meta-analysis confirmed that hemodialysis is associated with an increased risk of acute pancreatitis. More fundamental research should be carried out to elucidate the biological mechanisms.

Doxycycline and minocycline in Helicobacter pylori treatment: A systematic review and meta-analysis.

BACKGROUND AND AIMS: The decreasing Helicobacter pylori eradication rate and the increasing antibiotic resistance trend are of great concern. Therefore, new and effective therapies are needed for H. pylori infection. We conducted a systematic review and meta-analysis to assess the efficacy and safety of semisynthetic tetracycline regimens in H. pylori treatment. METHODS: PubMed, EMBASE, and the Cochrane library were searched. The outcome indicators were the eradication rate, risk ratio (RR, ie, the risk of the semisynthetic tetracycline regimen relative to the control), and 95% confidence interval (95% CI). Controls were patients undergoing any other treatment without semisynthetic tetracycline. RESULTS: Twenty-three studies with 5240 participants were included. The eradication rates of triple regimens with semisynthetic tetracyclines in most studies were less than 70% in both the intention-to-treat (ITT) and the per-protocol (PP) analyses. The pooled eradication rates of quadruple therapies with doxycycline and controls were 95% and 84% in the PP analyses, respectively. The pooled RR associated with efficacy in the quadruple therapy with doxycycline group compared with the control group was 1.12 (95% CI: 1.04-1.20) in the PP analysis. The pooled RR of side effects in the quadruple therapy with doxycycline group compared with the control group was 1.01 (95% CI: 0.65-1.55). CONCLUSION: Seven-day and ten-day quadruple therapy with doxycycline might be an optional first-line therapy. The safety of regimens containing semisynthetic tetracyclines was relatively satisfactory. However, the triple regimen is not recommended.

Prevalence of Helicobacter pylori babA, oipA, sabA, and homB genes in isolates from Chinese patients with different gastroduodenal diseases.

Disease outcome is associated with virulence factors of Helicobacter pylori (H. pylori), which are partially attributed to the outer membrane protein (OMP). This study aimed to investigate the correlation between the four OMP genes (babA, oipA, sabA, and homB) and gastroduodenal diseases. One hundred and seventy-seven H. pylori strains were isolated from Chinese patients with different gastroduodenal diseases (49 chronic gastritis, 19 gastric ulcer, 33 gastric cancer, and 76 duodenal ulcer), 94 of which contained pathological information (41 superficial gastritis, 24 intestinal hyperplasia, and 29 gastric adenocarcinoma). The full-length amplification of babA, oipA, sabA, and homB genes was acquired and sequenced. Then, the genetic polymorphism was analyzed to compare with the reference strains from the GenBank database. Functional status and cluster analysis were also performed to evaluate the impact of genetic polymorphism on disease outcome. The prevalence of babA, oipA, sabA, and homB genes were 91.5%, 100%, 94.0%, and 95.5%, respectively. The four OMP genes were characterized by genetic polymorphism and in the status of positive selection (Ka/Ks> 1). The proportion of strains with functional status on for oipA and sabA gene was 100% and 76.2%, respectively. The sequences of four OMP genes were mainly clustered together with the East Asian references. The four OMP genes were not different in patients with gastroduodenal diseases and pathologic changes (P > 0.05). H. pylori babA, oipA, sabA, and homB genes were common in the Chinese populations, but did not seem to be involved in the development of gastroduodenal diseases.

Outer inflammatory protein of Helicobacter pylori impacts IL-8 expression, adherence, cell apoptosis and cell cycle of gastric cells independent of its copy number.

Outer inflammatory protein (OipA) is an important virulence factor of Helicobacter pylori (H. pylori), but the correlation between oipA copy number and its virulence remains unknown. The study was designed to investigate whether the duplicate oipA gene loci showed more virulent than one oipA gene in vitro. H. pylori strain CCS9803 (China Chongqing Strain 9803) that carries duplicate oipA loci was used to construct one or two oipA knockout mutant strain, which was further verified by qPCR and western blot. Gastric epithelial cells AGS and GES-1 were infected with wild-type (WT) or oipA mutants for 6 or 24 h. The expression levels of IL-8, bacterial adhesion, cell apoptosis and cell cycle were performed to analyze the function of oipA. The WT and oipA mutant strains induce significantly higher mRNA and protein levels of IL-8 than the uninfected group (P < 0.05), but only oipA2 mutants induced significantly decreased expression levels than the WT-infected group (P < 0.05). Adherence to gastric cells was significantly decreased by inactivated two oipA loci (P < 0.05). The WT strain caused a significant rising proportion of early apoptosis cell, which had dropped after duplicate oipA genes were both knockout (P < 0.05). WT and oipA1 mutants failed to affect cell cycle; however, the oipA2 mutants increased M phase and reduced S phase when compared to the uninfected group. In conclusion, our study demonstrated that oipA impacts IL-8 expression, adherence, cell apoptosis and cell cycle of gastric cells independent of its gene copy number.

The effect of antibiotic resistance on Helicobacter pylori eradication efficacy: A systematic review and meta-analysis.

BACKGROUND: The occurrence of antibiotic-resistant strains has been rapidly increasing due to the wide use of antibiotics. To evaluate the current effects of antibiotic resistance on Helicobacter pylori eradication efficacy, we conducted this systematic review and meta-analysis. METHODS: Literature searches were conducted in the following databases: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. Statistical analysis was performed using STATA version 12.0 (StataCorp LP, College Station, TX, USA). RESULTS: A total of 120 studies, including 28 707 patients, were assessed. Only first-line therapy was considered. The pooled RR of eradication rate in patients with Helicobacter pylori strains sensitive versus resistant to clarithromycin was 0.682 (95% CI: 0.636-0.731). The pooled RR of eradication rate in patients with Helicobacter pylori strains sensitive versus resistant to metronidazole was 0.843 (95% CI: 0.810-0.877). The pooled RR of eradication rate in patients with Helicobacter pylori strains sensitive versus resistant to levofloxacin was 0.794 (95% CI: 0.669-0.941). The pooled RR of eradication rate in patients with Helicobacter pylori strains sensitive versus resistant to dual clarithromycin and metronidazole was 0.674 (95% CI: 0.590-0.770). CONCLUSION: Antibiotic resistance causes a decrease in the eradication rate of H pylori today. Quadruple concomitant therapy may overcome the declining H pylori eradication rate caused by metronidazole-only resistance.

Correlation between antibiotic use in childhood and subsequent inflammatory bowel disease: a systematic review and meta-analysis.

Background: Antibiotic use leads to a cascade of inflammatory reaction in the gastrointestinal tract due to its association with a temporary disruption of human microbiome.Objectives: To explore the undetermined correlation between antibiotic use in childhood and subsequent inflammatory bowel disease (IBD).Methods: PUBMED, EMBASE and Cochrane Central Register of Controlled Trials were searched to identify related articles. We extracted and pooled the (adjusted) odds ratio (OR) and (adjusted) risk ratio (RR).Results: This systematic review and meta-analysis included 11 studies. The pooled OR of all 11 studies was 1.5 (95% confidence interval (CI): 1.22-1.85). The pooled ORs of the subsequent Crohn's disease and ulcerative colitis after antibiotic use in childhood were 1.59 (95% CI: 1.06-2.4) and 1.22 (95% CI: 0.82-1.8). The sensitivity analysis showed no change. The meta-regression showed there was not statistical significance for the publication year, research area and research methods. Egger's test showed publication bias in the IBD studies (p = .006 < .05) but no publication bias for the CD (p = .275>.05) and UC studies (p = .537>.05).Conclusions: There was a positive association between antibiotic use in childhood and the subsequently risk of Crohn's disease in non-European countries in the west during 2010-2013. Children in the United States taking antibiotics will have a higher risk of subsequently IBD than Europe, Asia and Australia. Registration number: CRD42019147648 (PROSPERO).

Prophylactic antibiotics may be unnecessary in gastric endoscopic submucosal dissection due to the low incidence of bacteremia.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) was developed as a feasible and reliable treatment for gastrointestinal mucosal or submucosal lesions. Bacteremia may occur after ESD. Currently, the use of prophylactic antibiotics after gastric ESD is controversial. This study was designed to explore the value of prophylactic antibiotics in the treatment of gastric mucosal and submucosal lesions after ESD. METHODS: In this prospective study, in total, 103 patients who underwent gastric ESD were included, and the frequency of bacteremia and changes in inflammation-related indicators before and after the procedure were investigated. The patients did not receive prophylactic antibiotics. RESULTS: The body temperature (T), white blood cell count (WBC), and procalcitonin (PCT) and C-reactive protein (CRP) levels did not significantly differ between the perforation group (N = 40) and nonperforation group before gastric ESD (N = 63) (all P > 0.05). The T, WBC, and CRP levels (all P < 0.05) in the patients with perforation were significantly higher than those in the patients without perforation 24 h after gastric ESD. The incidence of bacteremia did not significantly differ between the two groups (all P > 0.05). In total, 6 of 309 blood cultures were cultured with bacteria. The total frequency of bacteremia in the perforation and nonperforation groups was 2.5% and 3.2%, respectively. No sepsis occurred in any patients. CONCLUSION: Regardless of whether perforation occurred after gastric ESD, the incidence of bacteremia was transient and low. Therefore, based on our single-center study in China, prophylactic antibiotics may not be necessary in patients with intraoperative perforation during gastric ESD. TRIAL REGISTRATION: A single-center prospective study at chictr.org.cn (ChiCTR1800019668).

Effectiveness and safety of furazolidone-containing quadruple regimens in patients with Helicobacter pylori infection in real-world practice.

BACKGROUND & AIMS: The eradication rate of Helicobacter pylori (H pylori) has decreased largely because of the antibiotic resistance. We aimed to evaluate the effectiveness and safety of furazolidone-containing quadruple regimens for H pylori eradication. METHODS: This was an observational study of furazolidone-containing quadruple regimens for H pylori infection in real-world settings. Data sets were collected from the medical records and telephone interviews of patients referred to a specialist clinic for suspected H pylori reinfection from January 1, 2015, to January 1, 2018, at the First Affiliated Hospital of Nanchang University. Main outcome measures were the eradication rate and adverse reactions during medication. RESULTS: Among 584 patients with H pylori infection that met the inclusion criteria, 561 (96.1%) were treated for the first time, 19 (3.3%) had one, and 4 (0.5%) had two or more prior to furazolidone-containing quadruple regimens. The eradication rates for 10-day and 14-day regimens were 93.7% (95% CI: 91.5%-95.9%) vs 98.2% (95% CI: 95.6%-99.3%), respectively (P = 0.098). Adverse drug reactions occurred in 8.2% (48/584) with abdominal discomfort being the most common symptom. Overall adverse events with 10-day regimens were lower than 14-day regimens (6.1% vs 17.4%, P < 0.001). Logistic regression analysis indicated that poor adherence (adjusted odds ratio [AOR] = 46.5, 95% CI: 9.7-222.4) was correlated with failed eradication. Adverse drug reactions during medication were related to smoking and tobacco status, alcohol intake history, regimens combined with tetracycline, and poor adherence (all P < 0.05). CONCLUSIONS: Furazolidone-containing quadruple regimens proved both safe and highly effective in a real-world setting.

Management of Helicobacter pylori infection by clinicians: A nationwide survey in a developing country.

BACKGROUND & AIMS: Developing countries are making efforts to improve health management. Practice deviating from the guideline means inefficient control. The study aims to investigate the management of Helicobacter pylori (H pylori) infection from a developing country perspective. METHODS: An authoritative survey was conducted in 14th (2014) and 17th (2017) Congress of Gastroenterology China, respectively. The Maastricht V/Florence consensus report was invoked as the evaluation criterion. RESULTS: A total of 4182 valid samples were included in this study. Most of the respondents (94%) updated knowledge by lectures. Respondents had a different awareness rate of H pylori-related diseases, ranging from 45% to 95%. Up to 40% of the respondents did not follow the recommendations for the diagnosis. Choice accuracy of eradication regimens and antibiotic combinations was <70%. About 20% of the respondents did not pay attention to the confirmation after the eradication. The situation had been improved in 2017 when compared with that in 2014 (all P < .05). Multivariate logistic regression analysis revealed that influencing factors including nongastroenterologists, bachelor degree and below, the primary professional title, hospital location, and a small proportion of H pylori infection in daily practice related to the deviation of consensus (all P < .05). CONCLUSIONS: Although the management of H pylori infection has been improved in a developing country, there is still a gap between the real-world practices and the consensus. Influencing factors should be taken into account in decision-making, and the corresponding population should be strengthened with precision training during the promotion of the guideline.

Emerging Trends in Intestinal Knowledge Structure Associated With Acute Pancreatitis From 1981 to 2021: A Bibliometric Analysis.

OBJECTIVES: Bibliometric analysis has not comprehensively summarized studies of acute pancreatitis (AP)-associated intestinal diseases. This work aimed to evaluate cooperative networks of authors, countries, and institutions and explore the field's developing trends and hot topics. METHODS: Original articles and reviews of AP-associated intestinal diseases were obtained from the Web of Science Core Collection on October 11, 2021. VOSviewer and CiteSpace software were used to perform co-occurrence analyses for authors, countries, and institutions and detect the highest citation burst. RESULTS: A total of 1634 articles on the intestine associated with AP were identified. The United States, the University of Auckland, and Roland Andersson are the most influential country, research institute, and scholar, respectively. The World Journal of Gastroenterology (73 articles) has the highest number of publications, and Gastroenterology was the most co-cited journal. The top 5 key words are "acute pancreatitis," "bacterial translocation," "management," "gut," and "inflammatory bowel disease." We find that several emergent key words like "gut microbiota," "pathway," "gut barrier," "risk," and "oxidative stress" experienced a continuous and rapid development as new research directions. CONCLUSIONS: This bibliometric study summarizes current important perspectives and offers comprehensive guidance on the AP-associated intestinal diseases, which may help researchers choose the most appropriate research directions.

Predicting Overall Survival in Patients with Nonmetastatic Gastric Signet Ring Cell Carcinoma: A Machine Learning Approach.

Background and Aims: Accurate prediction is essential for the survival of patients with nonmetastatic gastric signet ring cell carcinoma (GSRC) and medical decision-making. Current models rely on prespecified variables, limiting their performance and not being suitable for individual patients. Our study is aimed at developing a more precise model for predicting 1-, 3-, and 5-year overall survival (OS) in patients with nonmetastatic GSRC based on a machine learning approach. Methods: We selected 2127 GSRC patients diagnosed from 2004 to 2014 from the Surveillance, Epidemiology, and End Results (SEER) database and then randomly partitioned them into a training and validation cohort. We compared the performance of several machine learning-based models and finally chose the eXtreme gradient boosting (XGBoost) model as the optimal method to predict the OS in patients with nonmetastatic GSRC. The model was assessed using the receiver operating characteristic curve (ROC). Results: In the training cohort, for predicting OS rates at 1-, 3-, and 5-year, the AUCs of the XGBoost model were 0.842, 0.831, and 0.838, respectively, while in the testing cohort, the AUCs of 1-, 3-, and 5-year OS rates were 0.749, 0.823, and 0.829, respectively. Besides, the XGBoost model also performed better when compared with the American Joint Committee on Cancer (AJCC) stage. The performance for this model was stably maintained when stratified by age and ethnicity. Conclusion: The XGBoost-based model accurately predicts the 1-, 3-, and 5-year OS in patients with nonmetastatic GSRC. Machine learning is a promising way to predict the survival outcomes of tumor patients.

Identification and Validation of Immune Cells and Hub Genes in Gastric Cancer Microenvironment.

Gastric cancer (GC) is the most common malignant tumor in the digestive system, traditional radiotherapy and chemotherapy are not effective for some patients. The research progress of immunotherapy seems to provide a new way for treatment. However, it is still urgent to predict immunotherapy biomarkers and determine novel therapeutic targets. In this study, the gene expression profiles and clinical data of 407 stomach adenocarcinoma (STAD) patients were downloaded from The Cancer Genome Atlas (TCGA) portal, and the abundance ratio of immune cells in each sample was obtained via the "Cell Type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT)" algorithm. Five immune cells were obtained as a result of abundance comparison, and 295 immune-related genes were obtained through differential gene analysis. Enrichment, protein interaction, and module analysis were performed on these genes. We identified five immune cells associated with infiltration and 20 hub genes, of which five genes were correlated with overall survival. Finally, we used Real-time PCR (RT-PCR) to detect the expression differences of the five hub genes in 18 pairs of GC and adjacent tissues. This research not only provides cellular and gene targets for immunotherapy of GC but also provides new ideas for researchers to explore immunotherapy for various tumors.

Efficacy and safety of indocyanine green tracer-guided lymph node dissection in minimally invasive radical gastrectomy for gastric cancer: A systematic review and meta-analysis.

Background: The implementation of indocyanine green (ICG) tracer-guided lymph node dissection is still in the preliminary stages of laparoscopic surgery, and its safety and efficacy for gastric cancer remain unclear. Methods: A systematic review was conducted in PubMed, Embase, Web of Science, the Cochrane Library, and Scopus to identify relevant subjects from inception to June 2022. The core indicators were the total number of harvested lymph nodes and the safety of the laparoscopic gastrectomy with ICG. A meta-analysis was performed to estimate the pooled weighted mean difference (WMD) and 95% confidence interval (CI). Results: Thirteen studies and 2,027 participants were included (642 for the ICG-group and 1,385 for the non-ICG group). The mean number of lymph nodes dissected in the ICG group was significantly greater than that in the non-ICG group (WMD = 6.24, 95% CI: 4.26 to 8.22, P <0.001). However, there was no significant difference in the mean number of positive lymph nodes dissected between the ICG and the non-ICG groups (WMD = 0.18, 95% CI: -0.70 to 1.07, P = 0.879). Additionally, ICG gastrectomy did not increase the risk in terms of the operative time, estimated blood loss, and postoperative complications. Conclusion: ICG tracer with favorable safety increases the number of harvested lymph nodes but not the number of positive lymph nodes in laparoscopic gastrectomy. More high-quality, large-sample-size randomized controlled trials are still needed to enhance this evidence.

Increased IGFBP7 Expression Correlates with Poor Prognosis and Immune Infiltration in Gastric Cancer.

Background: Insulin-like growth factor binding protein-7 (IGFBP7) contributes to multiple biological processes in various tumors. However, the role of IGFBP7 in gastric cancer (GC) is still undetermined. The study aims to explore the role of IGFBP7 in GC via an integrated bioinformatics analysis. Methods: IGFBP7 expression levels in GC and its normal gastric tissues were analyzed using multiple databases, including the Tumor Immune Estimation Resource (TIMER), Oncomine, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, as well as by our clinical gastric specimens. The methylation analysis was conducted with MEXPRESS, UALCAN and Xena online tools. The survival analysis was conducted using the Kaplan-Meier Plotter and Gene Expression Profiling Interactive Analysis (GEPIA) databases. Coexpressed genes of IGFBP7 were selected with the cBioPortal tool and enrichment analysis was conducted with the clusterProfiler package in R software. Gene set enrichment analysis (GSEA) was performed to explore the IGFBP7-related biological processes involved in GC. Correlations between IGFBP7 and immune cell infiltrates were analyzed using the TIMER database. Results: IGFBP7 expression was significantly upregulated in GC and correlated with stage, grade, tumor status and Helicobacter pylori infection. High IGFBP7 expression and low IGFBP7 methylation levels were significantly associated with short survival of patients with GC. Univariate and multivariate analyses revealed that IGFBP7 was an independent risk factor for GC. The coexpressed genes LHFPL6, SEPTIN4, HSPB2, LAYN and GGT5 predicted unfavorable outcomes of GC. Enrichment analysis showed that the coexpressed genes were involved in extracellular matrix (ECM)-related processes. GSEA indicated that IGFBP7 was positively related to ECM and inflammation-related pathways. TIMER analysis indicated that the mRNA level of IGFBP7 was strongly correlated with genes related to various infiltrating immune cells in GC, especially with gene markers of tumor associated macrophages (TAMs). Conclusions: Increased IGFBP7 expression correlates with poor prognosis and immune cell infiltration in GC, which might be a potential biomarker for the diagnosis of GC.

Weighted correlation network analysis identifies FN1, COL1A1 and SERPINE1 associated with the progression and prognosis of gastric cancer.

BACKGROUND: Gastric cancer (GC) is one of the most deadliest tumours worldwide, and its prognosis remains poor. OBJECTIVE: This study aims to identify and validate hub genes associated with the progression and prognosis of GC by constructing a weighted correlation network. METHODS: The gene co-expression network was constructed by the WGCNA package based on GC samples and clinical data from the TCGA database. The module of interest that was highly related to clinical traits, including stage, grade and overall survival (OS), was identified. GO and KEGG pathway enrichment analyses were performed using the clusterprofiler package in R. Cytoscape software was used to identify the 10 hub genes. Differential expression and survival analyses were performed on GEPIA web resources and verified by four GEO datasets and our clinical gastric specimens. The receiver operating characteristic (ROC) curves of hub genes were plotted using the pROC package in R. The potential pathogenic mechanisms of hub genes were analysed using gene set enrichment analysis (GSEA) software. RESULTS: A total of ten modules were detected, and the magenta module was identified as highly related to OS, stage and grade. Enrichment analysis of magenta module indicated that ECM-receptor interaction, focal adhesion, PI3K-Akt pathway, proteoglycans in cancer were significantly enriched. The PPI network identified ten hub genes, namely COL1A1, COL1A2, FN1, POSTN, THBS2, COL11A1, SPP1, MMP13, COMP, and SERPINE1. Three hub genes (FN1, COL1A1 and SERPINE1) were finally identified to be associated with carcinogenicity and poor prognosis of GC, and all were independent risk factors for GC. The area under the curve (AUC) values of FN1, COL1A1 and SERPINE1 for the prediction of GC were 0.702, 0.917 and 0.812, respectively. GSEA showed that three hub genes share 15 common upregulated biological pathways, including hypoxia, epithelial mesenchymal transition, angiogenesis, and apoptosis. CONCLUSION: We identified FN1, COL1A1 and SERPINE1 as being associated with the progression and poor prognosis of GC.

Deubiquitinase USP39 and E3 ligase TRIM26 balance the level of ZEB1 ubiquitination and thereby determine the progression of hepatocellular carcinoma.

Emerging evidence suggests that USP39 plays an important role in the development of hepatocellular carcinoma (HCC). However, the molecular mechanism by which USP39 promotes HCC progression has not been well defined, especially regarding its putative ubiquitination function. Zinc-finger E-box-binding homeobox 1 (ZEB1) is a crucial inducer of epithelial-to-mesenchymal transition (EMT) to promote tumor proliferation and metastasis, but the regulatory mechanism of ZEB1 stability in HCC remains enigmatic. Here, we reveal that USP39 is highly expressed in human HCC tissues and correlated with poor prognosis. Moreover, USP39 depletion inhibits HCC cell proliferation and metastasis by promoting ZEB1 degradation. Intriguingly, deubiquitinase USP39 has a direct interaction with the E3 ligase TRIM26 identified by co-immunoprecipitation assays and immunofluorescence staining assays. We further demonstrate that TRIM26 is lowly expressed in human HCC tissues and inhibits HCC cell proliferation and migration. TRIM26 promotes the degradation of ZEB1 protein by ubiquitination in HCC. Deubiquitinase USP39 and E3 ligase TRIM26 function in an antagonistic pattern, but not a competitive pattern, and play key roles in controlling ZEB1 stability to determine the HCC progression. In summary, our data reveal a previously unknown mechanism that USP39 and TRIM26 balance the level of ZEB1 ubiquitination and thereby determine HCC cell proliferation and migration. This novel mechanism may provide new approaches to target treatment for inhibiting HCC development by restoring TRIM26 or suppressing USP39 expression in HCC cases with high ZEB1 protein levels.

Single immunoglobulin and Toll­interleukin­1 receptor domain containing molecule protects against severe acute pancreatitis in vitro by negatively regulating the Toll­like receptor­4 signaling pathway: A clinical and experimental study.

Single immunoglobulin and Toll­interleukin­1 receptor domain­containing molecule (SIGIRR) is a specific inhibitor of IL­1R and Toll­like receptor (TLR) signaling and considered a potential target for the treatment of inflammatory diseases. Pathogenic mechanisms associated with the TLR4 signaling pathway have a critical role in the development of severe acute pancreatitis (SAP). The aim of the present study was to determine the role of SIGIRR in the regulation of TLR4 signaling during the progression of SAP. Pancreatitis­associated ascitic fluid (PAAF) was collected from patients with SAP. Murine RAW264.7 macrophages were transfected with a SIGIRR overexpression plasmid and co­cultured with the PAAF from the donors in order to evaluate the effect of SIGIRR in vitro. The mRNA expression of TLR4, SIGIRR and other key downstream signaling molecules was quantified using semi­quantitative PCR with agarose gel electrophoresis. Furthermore, the levels of pro­inflammatory cytokines in the culture supernatant were detected using ELISA. In contrast to SIGIRR, the mRNA expression levels of TLR4, myeloid differentiation factor 88 (MyD88), IL­1R­associated kinase­1 (IRAK­1) and TNF receptor­associated factor­6 (TRAF­6) were significantly increased in RAW264.7 cells following treatment with PAAF. Furthermore, TLR4, MyD88, IRAK­1 and TRAF­6 mRNA levels were significantly downregulated following SIGIRR overexpression and PAAF treatment in RAW264.7 cells. The levels of IL­2, IL­12, IL­17 and IFN­Î³ in the culture supernatant were also significantly decreased, while IL­10 levels were increased. Overall, SIGIRR negatively regulated the TLR4 signaling pathway to protect against the development of SAP in an in vitro model. Therefore, SIGIRR may represent a promising therapeutic target for SAP.