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ABSTRACTH. pylori infection is the strongest known risk factor for gastric carcinoma. The activation of the yes-associated protein 1 (YAP) and β-catenin pathways has been associated with multiple tumor types. In this study, we investigated the crosstalk between the YAP and β-catenin pathways in H. pylori-associated gastric tumorigenesis. Immunohistochemical analysis of YAP and β-catenin expression was performed in human gastric cancer tissues. The small molecules Super-TDU and KYA1797K, pharmacological inhibitors of YAP and β-catenin, respectively, were used to investigate the role of these signaling pathways in H. pylori-induced gastric carcinogenesis in murine models of infection. The common downstream targets of YAP and β-catenin signaling were evaluated by RNA sequencing (RNA-seq). Western blot, immunofluorescence, luciferase, RT-PCR, immunoprecipitation, cell counting kit-8 (CCK8), EdU and spheroid assays were used. H. pylori infection promoted YAP and β-catenin nuclear accumulation and transcriptional activity in gastric epithelial cells and transgenic insulin–gastrin (INS-GAS) mice, whereas silencing of both YAP and β-catenin synergistically inhibited H. pylori-induced cell proliferation and expansion. In addition, YAP was found to directly interact with β-catenin and knockdown of YAP suppressed H. pylori-induced nuclear translocation of β-catenin. Moreover, downstream genes caudal-type homeobox 2 (CDX2), leucine-rich repeat containing G protein-coupled receptor 5 (LGR5) and RuvB like AAA ATPase 1 (RUVBL1) were shared by both YAP and β-catenin signaling. Furthermore, treatment with the YAP inhibitor Super-TDU or β-catenin inhibitor KYA1797A significantly alleviated gastric inflammation and epithelial DNA damage in H. pylori-infected mice. Finally, the elevation of gastric YAP was positively correlated with β-catenin expression in human gastric cancer tissues. These findings indicate that YAP and β-catenin synergistically promote H. pylori-induced gastric carcinogenesis via their physical interaction and reveal that CDX2, LGR5 and RUVBL1 are the downstream genes shared by both the YAP and β-catenin signaling pathways, and potentially contribute to H. pylori pathogenesis.

Abstract Background Histone deacetylases (HDAC) contribute to oncogenic program, pointing to their inhibitors as a potential strategy against cancers. We, thus, studied the mechanism of HDAC inhibitor ITF2357 in resistance of mutant (mut)-KRAS non-small cell lung cancer (NSCLC) to pemetrexed (Pem). Methods We first determined the expression of NSCLC tumorigenesis-related HDAC2 and Rad51 in NSCLC tissues and cells. Next, we illustrated the effect of ITF2357 on the Pem resistance in wild type-KARS NSCLC cell line H1299, mut-KARS NSCLC cell line A549 and Pem-resistant mut-KARS cell line A549R in vitro and in xenografts of nude mice in vivo. Results Expression of HDAC2 and Rad51 was upregulated in NSCLC tissues and cells. Accordingly, it was revealed that ITF2357 downregulated HDAC2 expression to diminish the resistance of H1299, A549 and A549R cells to Pem. HDAC2 bound to miR-130a-3p to upregulate its target gene Rad51. The in vitro findings were reproduced in vivo, where ITF2357 inhibited the HDAC2/miR-130a-3p/Rad51 axis to reduce the resistance of mut-KRAS NSCLC to Pem. Conclusion Taken together, HDAC inhibitor ITF2357 restores miR-130a-3p expression by inhibiting HDAC2, thereby repressing Rad51 and ultimately diminishing resistance of mut-KRAS NSCLC to Pem. Our findings suggested HDAC inhibitor ITF2357 as a promising adjuvant strategy to enhance the sensitivity of mut-KRAS NSCLC to Pem.

Background The occurrence of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) after using covered self-expandable metallic stents (CSEMS) and multiple plastic stents (MPS) in the therapy of benign biliary strictures (BBS) remains ambiguous, this analysis aimed to evaluate the outcomes.Methods A systematic search of electronic databases (PubMed, Web of Science and Cochrane Library) was conducted for randomised controlled trials (RCTs), and the included studies were published between 2008 and 2021. The primary outcome was PEP, while the secondary outcomes were stricture resolution, recurrence, overall adverse events, costs, and ERCP sessions. Pooled effect sizes were calculated with the random-effects model or fixed-effects model depending on the heterogeneity.Results Six RCTs contained 444 patients (221 with CSEMS, 223 with MPS) finally included in the meta-analysis. The present analysis shows that compared to MPS, PEP is more likely to occur in CSEMS (OR [odds ratio] = 3.34, 95% confidence intervals [CI]:1.44–7.77, p = .005). CSEMS needs fewer ERCP sessions (Mean Deviation [MD]: −1.56; 95%CI:−2.66, −0.46], p = .006). The difference in stricture resolution and recurrence was not significant between the two stent types (OR = 0.87, 95%CI: 0.49–1.56, p = .64; and OR = 2.3, 95%CI: 0.68–7.76, p = .18). The incidence of overall adverse events was comparable between CSEMS and the MPS group (OR = 1.49, 95% CI: 0.97–2.29, p = .07).Conclusions Compared with MPS, CSEMS caused a significantly higher incidence of PEP but fewer ERCP procedures, while the rate of stricture resolution, recurrence, and overall adverse events were comparable. Prevention methods of PEP should be further evaluated in BBS when undergoing CSEMS placement.Systematic Review Registration PROSPERO CRD42022314864. Key messagesCSEMS and MPS placement remain a mainstay for patients with BBS, and severe complications after stent placement have not been compared.The incidence of PEP was higher after deployment of CSEMS compared to MPS.Prevention methods of PEP should be evaluated in BBS when undergoing CSEMS placement.

Background and aimsBleeding is one of the common adverse events of endoscopic retrograde cholangiopancreatography (ERCP), which is mainly caused by endoscopic sphincterotomy (EST). At present, it remains unclear whether proton pump inhibitor (PPI) should be used to prevent post-EST bleeding. Therefore, we performed a randomized controlled trial to investigate whether PPI is effective in the prevention of post-EST delayed bleeding.MethodsConsecutive eligible patients were randomly assigned (1:1) to experimental group (PPI group) or control group (normal saline, NS group). The patients in PPI group received intravenous esomeprazole 40 mg and normal saline 100 mL every 12 h for 2 days after ERCP immediately, and followed by oral esomeprazole (Nexium) 20 mg once a day for 7 days. Correspondingly, patients in the control group received intravenous normal saline 100 mL and did not take PPIs or any acid-suppressing drugs during hospitalization and after discharge. All patients were followed up for 30 days after ERCP. The primary endpoint was the incidence and severity of post-EST delayed bleeding.ResultsBetween July 2020 and July 2022, 290 patients were randomly assigned to PPI group (n = 146) or NS group (n = 144). 5 patients from each group were excluded from the final analysis. There were 6 patients with post-EST delayed bleeding, with an incidence rate of 2.14%. The median time of delayed bleeding was 2.5 days after ERCP. 3 cases (2.12%, 3/141) occurred in the PPI group, with 1 case of mild and 2 cases of moderate bleeding. 3 cases (2.16%, 3/139) occurred in the NS group, with 2 cases of mild and 1 case of moderate bleeding. There was no significant difference in the incidence and the severity of post-EST delayed bleeding between the two groups (p = 1.000).ConclusionProphylactic use of PPI after EST does not reduce the incidence and severity of post-EST delayed bleeding in patients.Clinical Trial Registrationhttps://www.chictr.org.cn/searchproj.aspx, identifier ChiCTR2000034697.

Abstract Helicobacter pylori (H. pylori) infection is a well-recognized contributing factor to gastritis, but the underlying mechanisms remain to be established. It is interesting to note that AQP5 was predicted to be highly expressed in intestinal metaplasia (IM) based on H. pylori infection-related microarray data, and the transcription factor ASCL1 was bioinformatically predicted to associate with AQP5. Therefore, the purpose of this study is to evaluate the mechanistic significance of ASCL1 and AQP5 in H. pylori infection of gastritis. Gastritis mouse models were established by H. pylori infection, followed by determination of AQP5 and ASCL1 in gastric mucosa. Besides, the effects of AQP5 on H. pylori-induced gastritis were explored using AQP5−/− mice. It was observed that H. pylori infection elevated expression of AQP5 and ASCL1 in gastric mucosa and gastric epithelial cells (GECs). H. pylori induced AQP5 expression by regulating ASCL1 and activated WNT/β-catenin signaling pathway in GECs. It was also found that AQP5 knockdown suppressed inflammatory response and apoptosis in H. pylori-infected mice. Moreover, H. pylori infection-elevated ASCL1 and AQP5 expression promoted apoptosis and inflammation in GECs. Taken together, the key findings of the present study demonstrate that H. pylori infection activated WNT/β-catenin signaling pathway by upregulating ASCL1/AQP5 to induce gastritis.

Background: Currently, the management of Helicobacter pylori (H. pylori) infection in elderly patients is controversial. We investigated whether high-dose dual therapy would serve as the first-line therapy in elderly patients.Methods: This was a single-center, randomized study of 150 elderly patients with H. pylori infection who were randomly assigned to 14-day therapy with pantoprazole 40 mg 3 times daily and either amoxicillin 1,000 mg 3 times daily or amoxicillin 1,000 mg twice daily, clarithromycin 500 mg twice daily and bismuth 220 mg twice daily. H. pylori eradication was evaluated by a 13C-urea breath test 4 weeks after the completion of treatment.Results: Successful eradication was achieved in 89.3% of the high-dose dual therapy (HT) group in the intention‐to‐treat (ITT) analysis, 91.7% in the modified intention-to-treat (mITT) analysis, and 93.0% for per‐protocol (PP) analysis which was similar to the bismuth-containing quadruple therapy (BQT) group (86.6%, 87.8%, and 90.3%, respectively). There were no significant difference between the HT group and the BQT group in the ITT analysis (p = 0.484), mITT analysis (p = 0.458), or PP analysis (p = 0.403). HT was associated with fewer side effects (10.6% of patients) than BQT (26.6%) (p = 0.026).Conclusion: In this trial, we found that 14-day HT had a similar eradication rate to BQT but fewer side effects, which may be better for elderly patients.

BackgroundColorectal cancer (CRC)is the third most common cancer in the world and the second leading cause of cancer-related deaths, and over the past two decades, many of these researchers have provided a substantial amount of important information on the role of gut microbes in the development and progression of CRC. A causal relationship between the presence of specific microorganisms and CRC development has also been validated. Although a large number of papers related to this area have been published, no bibliometric study has been conducted to review the current state of research in this area and to highlight the research trends and hotspots in this area. This study aims to analyze the current status and future research trends of gut microbiota and CRC through bibliometric analysis.MethodsPublications from 2001 to 2022 were retrieved from the Web of Science Core Collection database and screened according to inclusion criteria. VOSviewer and CiteSpace software were used to visualize the research trends in this field, including the analysis of title, country, institution, author, number of publications, year of publication, number of citations, journal, and H-index.ResultsA total of 863 studies were eventually identified, and the articles retrieved were cited an average of 44.85 times each. The number of publications on this topic has been increased steadily since 2011. China and the USA have made the largest contribution in the field. FRONTIERS IN MICROBIOLOGY is the top productive journal with 26 papers, and Gut journal has the highest average citation (167.23). Shanghai Jiao Tong University is the most contributive institution. Professor Yu J, Sung, Joseph J. Y and Fang JY are the most productive authors in this field. Keyword co-occurrence analysis showed that the terms of “Gut Microbiota”, “Colorectal Cancer”, “Inflammation”, “Probiotic” and “Fusobacterium Nucleatum” were the most frequent, which revealed the research hotpots and trends in this field.ConclusionsThere has been a growing number of publications over the past two decades according to the global trends. China and the USA still maintained the leading position in this field. However, collaboration between institutions needs to be strengthened. It’s commended to pay attention to the latest hotspots, such as “F. nucleatum” and “probiotics”. This bibliometric analysis evaluates the scope and trends of gut microbiota and CRC, providing a useful perspective on current research and future directions for studying the link between the gut microbiota and CRC.

BackgroundCholedocholithiasis complicated with cholecystolithiasis is a common disease. This study explores a novel strategy, called ERCP-based transcystic gallbladder-preserving cholecystolithotomy, for the simultaneous removal of common bile duct stones and gallbladder stones.MethodsFrom December 2018 to June 2021, all patients with cholecystolithiasis and common bile duct stones who met the criteria for gallbladder preservation in our hospital were included in the study and prospectively followed up.ResultsWe included 48 patients, including 20 patients with acute biliary pancreatitis. All patients successfully underwent ERCP to remove common bile duct stones. One patient had gallbladder perforation during gallbladder-preserving cholecystolithotomy. The guide wire successfully entered the gallbladder, and the transpapillary gallbladder metal-covered stent was successfully placed in 44 patients. The technical success rate was 91.67% (44/48). All stones were removed in 34 patients, for a clinical success rate of 77.27% (34/44). The total postoperative complication rate was 6.25% (3/48), with 2 cases of pancreatitis (4.17%) and 1 case of cholangitis (2.08%). Three patients were lost to follow-up. Among the 31 patients who were followed up for a mean of 27 months (6–40), 5 patients (16.13%) experienced gallstone recurrence. The recurrence rates at 12 months, 18 months, 24 months, 30 months and 36 months were 0%, 3.23%, 6.45%, 12.9%, and 16.13%, respectively.ConclusionFor patients with cholecystolithiasis and common bile duct stones, ERCP-based transcystic gallbladder-preserving cholecystolithotomy without gallbladder incision can preserve gallbladder structure, and this procedure is safe and feasible for the protection of gallbladder function.Clinical trial registration: The study was registered in the Chinese Clinical Trial Registry, and the registry number is ChiCTR1900028006.

BackgroundHelicobacter pylori infection is the strongest known risk factor for gastric cancer. The Hippo signaling pathway controls organ size and maintains tissue homeostasis by coordinately regulating cell growth and proliferation. Here, we demonstrate the interactive role of TAZ, the transcriptional coactivator of the Hippo pathway, and beta-catenin in promoting the pathogenesis of H. pylori infection.MethodsTAZ expression was evaluated in human gastric tissues and H. pylori-infected insulin–gastrin (INS-GAS) mice. Western blot, immunofluorescence, immunohistochemistry, and RT–PCR assays were performed. Coimmunoprecipitation was performed to examine the interaction between TAZ and β-catenin. TAZ and β-catenin were silenced using small interfering RNAs. HA-β-catenin and Flag-TAZ were constructed.ResultsIncreased TAZ was noted in human gastric cancer tissues compared to chronic gastritis tissues and in H. pylori-positive gastritis tissues compared to H. pylori-negative gastritis tissues. In addition, H. pylori infection induced TAZ expression and nuclear accumulation in the gastric tissue of INS-GAS mice and cultured gastric epithelial cells, which was dependent on the virulence factor CagA. Moreover, TAZ or β-catenin knockdown significantly suppressed H. pylori infection-induced cell growth, survival, and invasion. Furthermore, the interactive regulation of TAZ and β-catenin activation was revealed. Finally, β-catenin was required for H. pylori-induced TAZ activation.ConclusionThese findings suggest the existence of a positive feedback loop of activation between TAZ and β-catenin that could play an important role in CagA+ H. pylori infection-induced gastric carcinogenesis. TAZ inhibition represents a potential target for the prevention of H. pylori infection-associated gastric cancer.

The recurrence of colorectal polyps is caused by various factors and leads to the carcinogenesis of colorectal cancer, which ranks third in incidence and fourth in mortality among cancers worldwide. The potential risk factors for colorectal polyp recurrence have been demonstrated in multiple trials. However, an article that pools and summarizes the various results is needed. This review enumerates and analyzes some risk factors in terms of patient characteristics, procedural operations, polyp characteristics, and dietary aspects to propose some effective prophylactic measures. This review aimed to provide a reference for clinical application and guide patients to prevent colorectal polyp recurrence in a more effective manner.

Helicobacter pylori (H. pylori) infection is the greatest known risk factor for gastric cancer (GC). Long non-coding RNAs (lncRNAs) are implicated in multiple biological processes. However, their contribution in H. pylori-associated GC remains largely unknown. We performed transcriptome sequencing to investigate differential lncRNA and mRNA expression profiles in gastric AGS cells infected with the H. pylori strain 7.13 or 43504. We identified significantly differentially expressed (SDE) mRNAs and lncRNAs following H. pylori infection. A co-expression network of lncRNAs and mRNAs was constructed via WGCNA analysis. Moreover, several of the most significantly upregulated genes were selected for further validation by qRT-PCR analysis in H. pylori-infected gastric cells and transgenic INS-GAS mice. We finally evaluated these genes in human GC tissues. A total of 158442 genes were identified between uninfected and infected cells. Of these, 298 mRNAs and 73 lncRNAs were consistently differentially expressed following infection with the H. pylori 7.13 and 43504 strains, respectively. The expression levels of most upregulated mRNAs (DDIT4, NDRG1, CHAC1, IL32, RELB, CTH, and SLC7A1) and lncRNAs (lncRNA36068, lncRNA51663, lncRNA49853, lncRNA49852, and FLJ46906) were validated by qRT-PCR analysis. We found that H. pylori infection significantly induced the transcript levels of the coding genes RELB and SLC7A11 in in vitro and in vivo assays, which was supported by their high expression levels in GC tissues. In addition, lncRNA51663 and FLJ46906 were remarkably increased in H. pylori-infected cells and consistently overexpressed in human GC tissues compared to adjacent normal tissues. Our study identified mRNA and lncRNA expression profiles related to H. pylori infection. These results may provide important insights regarding lncRNAs in H. pylori-induced gastric carcinogenesis.

Background: Endoscopic resection has been increasingly adopted for neoplasms in the major duodenal papilla. Previous studies have reached varying conclusions on whether prophylactic pancreatic stent (PS) placement is an effective measure against post-procedure complications. We aimed to investigate whether PS could reduce the incidence of post-procedure complications. Methods: The PubMed, Cochrane Library , and EMBASE databases were systematically searched from the inception dates to 25 December 2018 to identify all randomized controlled trials (RCTs) and retrospective cohort studies (RCSs) comparing prophylactic PS and no PS against post-procedure complications. The main outcomes measurements were post-procedure pancreatitis, bleeding, perforation and late papillary stenosis. Results: 23 RCSs (1001 subjects) and 2 RCTs met the inclusion criteria. Meta-analysis of the RCSs showed that prophylactic PS decreased the odds of post-procedure pancreatitis (OR, 0.71; 95% CI, 0.36–1.40; p = 0.325) as well as late papillary stenosis (OR, 0.35; 95% CI, 0.07–1.75; p = 0.200; I 2 =0%) and increased the odds of bleeding (OR, 1.32; 95% CI, 0.50–3.46; p = 0.572; I 2 = 0%) and perforation (OR, 2.25; 95% CI, 0.33–15.50; p = 0.412; I 2 = 0%) but not significantly. Sensitivity analysis illustrated prophylactic PS significantly decreased the risk of post-procedure pancreatitis (OR, 0.44; 95% CI, 0.24–0.80; p = 0.007). Conclusions: PS placement was prophylactic against post-procedure complications although not significantly. Sensitivity analysis suggests the significant effect of prophylactic PS against post-procedure pancreatitis. More RCTs are required to validate the statistical significance of our results and potentially relevant characteristics improving the prophylactic efficacy of stents.

Helicobacter pylori (H. pylori) is a main risk factor for gastric cancer (GC). Epithelial-mesenchymal transition (EMT) is involved in the development and progression of H. pylori-associated GC. However, the exact molecular mechanism of this process remains unclear. The AKT/GSK3β signaling pathway has been demonstrated to promote EMT in several types of cancer. The present study investigated whether H. pylori infection induced EMT, and promoted the development and metastasis of cancer in the normal gastric mucosa, and whether this process was dependent on AKT activation. The expression levels of the EMT-associated proteins, including E-cadherin and N-cadherin, were determined in 165 gastric mucosal samples of different disease stages by immunohistochemical analysis. The expression levels of E-cadherin, N-cadherin, AKT, phosphorylated (p-) AKT (Ser473), GSK3β and p-GSK3β (Ser9) were further determined in H. pylori-infected Mongolian gerbil gastric tissues and cells co-cultured with H. pylori by immunohistochemical analysis and western blotting. The results indicated that the expression levels of the epithelial marker E-cadherin were decreased, whereas the expression levels of the mesenchymal marker N-cadherin were increased during gastric carcinogenesis. Their expression levels were associated with H. pylori infection. Furthermore, H. pylori infection resulted in downregulation of E-cadherin expression and upregulation of N-cadherin expression in Mongolian gerbils and GES-1 cells. In addition, an investigation of the associated mechanism of action revealed that p-AKT (Ser473) and p-GSK3β (Ser9) were activated in GES-1 cells following co-culture with H. pylori. Furthermore, following pretreatment of the cells with the AKT inhibitor VIII, the expression levels of E-cadherin, N-cadherin, p-AKT and p-GSK3β did not show significant differences between GES-1 cells that were co-cultured with or without H. pylori. The levels of p-AKT and p-GSK3β were increased in H. pylori-infected Mongolian gerbils. In conclusion, the present study demonstrated that H. pylori infection activated AKT and resulted in the phosphorylation and inactivation of GSK3β, which in turn promoted early stage EMT. These effects were AKT-dependent. This mechanism may serve as a prerequisite for GC development. [ABSTRACT FROM AUTHOR]

Objectives: We evaluate the efficacy of concomitant therapy for Helicobacter pylori infection and the associated factors that influence it in China, where it has not previously been investigated.Methods: In this prospective study, 374 consecutive patients with H. pylori infection were randomly assigned to 10 day regimens of concomitant therapy with different proton pump inhibitors: esomeprazole (20 mg)/omeprazole (20 mg), amoxicillin (1000 mg), clarithromycin (500 mg) and metronidazole (400 mg). All drugs were administered twice daily. A [(13)C]urea breath test was performed at least 4 weeks after the completion of treatment. Gene polymorphisms and antimicrobial susceptibility were determined.Results: A total of 374 patients with active, uncomplicated duodenal ulcer disease were enrolled in the study (187 cases in each group). The overall eradication rate resulting from concomitant therapy was 90.7% (PP) and 86.1% (ITT) and the eradication rate was significantly higher in the group that received an esomeprazole-based regimen compared with the group that received an omeprazole-based regimen [95.4% versus 86.0%, respectively, P = 0.003 (PP) and 89.8% versus 82.4%, P = 0.036 (ITT), respectively]. Moreover, the omeprazole-based regimen was an independent risk factor for treatment failure (P = 0.039), as were CYP2C19 extensive metabolizer (P = 0.005), clarithromycin (P = 0.000) and metronidazole resistance (P = 0.000). In addition, CYP2C19 polymorphisms and antibiotic resistance had a synergistic effect on eradication rates. The majority of side effects were mild and none was serious.Conclusions: The 10 day concomitant therapy yielded an eradication rate of nearly 90%. Antibiotic resistance, CYP2C19 polymorphisms and their interactions were closely associated with regimen efficacy. [ABSTRACT FROM AUTHOR]