Two-sample Mendelian randomization analysis of the relationship between periodontitis and risk of upper gastrointestinal cancers.

PURPOSE: The aim of the present study is to explore the possible association between periodontitis and upper gastrointestinal (UGI) cancers, including esophageal and gastric cancers, utilizing the Mendelian randomization method. METHODS: In this research, we utilized the Mendelian randomization method to examine the causal association between periodontitis and UGI cancers. Genome-wide association studies data for periodontitis were obtained from the Gene-Lifestyle Interactions in Dental Endpoints consortium, while UGI cancers' data were accessed from FinnGen's Biobank. After rigorously screening instrumental variables for periodontitis, we analyzed them with UGI cancers primarily using the inverse variance weighted. Finally, to identify outliers, the results were subjected to a leave-one-out sensitivity analysis. RESULTS: Inverse variance weighted (fixed effect) results revealed that periodontitis is a risk factor for gastric cancer (OR = 1.7735, 95% CI: 1.1576 to 2.7170, P = 0.0085). As for esophageal cancer, no statistically significant correlation was observed. Furthermore, no outliers were detected in any of the results. CONCLUSION: Our two-sample Mendelian randomization study obviously demonstrates a significant positive association between periodontitis and gastric cancer, while no statistically significant correlation was found for esophageal cancer.

Association between inflammatory bowel disease and all-cause dementia: A two-sample Mendelian randomization study.

BACKGROUND: Numerous observational studies have documented a correlation between inflammatory bowel disease (IBD) and an increased risk of dementia. However, the causality of their associations remains elusive. AIM: To assess the causal relationship between IBD and the occurrence of all-cause dementia using the two-sample Mendelian randomization (MR) method. METHODS: Genetic variants extracted from the large genome-wide association study (GWAS) for IBD (the International IBD Genetics Consortium, n = 34652) were used to identify the causal link between IBD and dementia (FinnGen, n = 306102). The results of the study were validated via another IBD GWAS (United Kingdom Biobank, n = 463372). Moreover, MR egger intercept, MR pleiotropy residual sum and outlier, and Cochran's Q test were employed to evaluate pleiotropy and heterogeneity. Finally, multiple MR methods were performed to estimate the effects of genetically predicted IBD on dementia, with the inverse variance wei-ghted approach adopted as the primary analysis. RESULTS: The results of the pleiotropy and heterogeneity tests revealed an absence of significant pleiotropic effects or heterogeneity across all genetic variants in outcome GWAS. No evidence of a causal effect between IBD and the risk of dementia was identified in the inverse variance weighted [odds ratio (OR) = 0.980, 95%CI : 0.942-1.020, P value = 0.325], weighted median (OR = 0.964, 95%CI : 0.914-1.017, P value = 0.180), and MR-Egger (OR = 0.963, 95%CI : 0.867-1.070, P value = 0.492) approaches. Consistent results were observed in validation analyses. Reverse MR analysis also showed no effect of dementia on the development of IBD. Furthermore, MR analysis suggested that IBD and its subtypes did not causally affect all-cause dementia and its four subtypes, including dementia in Alzheimer's disease, vascular dementia, dementia in other diseases classified elsewhere, and unspecified dementia. CONCLUSION: Taken together, our MR study signaled that IBD and its subentities were not genetically associated with all-cause dementia or its subtypes. Further large prospective studies are warranted to elucidate the impact of intestinal inflammation on the development of dementia.

Efficacy of quadruple therapy with clarithromycin based on faecal molecular antimicrobial susceptibility tests as first-line treatment for Helicobacter pylori infection: a protocol of a single-centre, single-blind, randomised clinical trial in China.

INTRODUCTION: Helicobacter pylori is the most well-known risk factor for gastric cancer. Antibiotic resistance is the main reason for the failure of H. pylori eradication, and understanding the antibiotic resistance before treatment may be the main determinant of successful eradication of H. pylori. This study aims to evaluate the efficacy and safety of quadruple therapy based on faecal molecular antimicrobial susceptibility tests for the first-line eradication of H. pylori infection. METHODS AND ANALYSIS: This is a single-centre, single-blind, randomised controlled trial, enrolling 855 patients with H. pylori infection. Patients are randomised to three groups for a 14-day treatment: group A: amoxicillin- and clarithromycin-based bismuth-containing quadruple therapy (BQT) (rabeprazole 10 mg, amoxicillin 1 g, clarithromycin 500 mg and colloidal bismuth 200 mg two times per day); group B: clarithromycin medication history-based BQT (rabeprazole 10 mg, amoxicillin 1 g, furazolidone 100 mg (with clarithromycin medication history)/clarithromycin 500 mg (without clarithromycin medication history) and colloidal bismuth 200 mg two times per day); group C: antimicrobial susceptibility test-based BQT (rabeprazole 10 mg, amoxicillin 1 g, clarithromycin 500 mg (clarithromycin-sensitive)/furazolidone 100 mg (clarithromycin resistant) and colloidal bismuth 200 mg two times per day). The primary end point is the eradication rate. The secondary end points are the incidence of adverse events and compliance. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee of Second Affiliated Hospital, School of Medicine, Zhejiang University (Number 20230103). The results will be published in the appropriate peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05718609.

Quadruple therapy with vonoprazan 20 mg daily as a first-line treatment for Helicobacter pylori infection: A single-center, open-label, noninferiority, randomized controlled trial.

BACKGROUND: Although vonoprazan has been proven to be a highly potent drug for Helicobacter pylori eradication, there have been no randomized trials comparing the effectiveness of regimens containing vonoprazan 20 mg daily with alternative standard strategies. We aimed to assess the efficacy, tolerance, and cost-effectiveness of quadruple therapy with vonoprazan 20 mg daily as a first-line therapy for H. pylori eradication. MATERIALS AND METHODS: We conducted a single-center, open-label, noninferiority, randomized controlled study in Zhejiang, China. Treatment-naive H. pylori-positive participants (n = 234) were randomly assigned to three groups in a 1:1:1 ratio: vonoprazan 20 mg daily with amoxicillin 1000 mg, furazolidone 100 mg and colloidal bismuth 200 mg each given twice a day for 10 days (V10) or 14 days (V14), or esomeprazole 20 mg with amoxicillin 1000 mg, furazolidone 100 mg and colloidal bismuth 200 mg each given twice a day for 14 days (E14). The primary endpoint was the eradication rates in each group. The secondary endpoints were the incidence of adverse events (AEs) and compliance. RESULTS: The eradication rates in the V10, V14 and E14 groups were 96.2% (89.2-99.2%), 94.9% (87.4-98.6%), and 93.6% (85.7-97.9%) in the intention-to-treat analysis, and 98.6% (92.7-100.0%), 97.4% (90.8-99.7%), and 94.8% (87.2-98.6%) in the per-protocol analysis, respectively. Quadruple therapy with vonoprazan 20 mg daily was noninferior to the esomeprazole-based regimen (Farrington and Manning test: margin 10%, significance level 2.5%). The adverse event rates were 12.8% versus 3.8% versus 6.4% in the V10, V14, and E14 groups, respectively. All regimens were well tolerated without significant differences (p = 0.096). The cost-effectiveness ratio was 1.32, 1.88, and 3.06 for the V10, V14, and E14 groups in the intention-to-treat analysis, respectively. (NCT04907747). CONCLUSIONS: Vonoprazan (20 mg daily) was as effective as esomeprazole (20 mg twice a day) in quadruple therapies for the eradication of H. pylori, was more economical, and was well tolerated. In addition, the 10-day regimen of vonoprazan (20 mg daily) was comparable to the 14-day regimen.

MFAP2, upregulated by m1A methylation, promotes colorectal cancer invasiveness via CLK3.

BACKGROUND: Distant metastasis is the main cause of mortality in colorectal cancer (CRC) patients. N1-methyladenosine (m1A) is a type of epitranscriptome modification. While its regulatory effect on mRNA and its role in CRC metastasis remain unclear. METHODS: The m1A methylation profile of mRNAs in CRC was revealed by m1A methylated RNA immunoprecipitation sequencing. The expression of MFAP2 in tumor tissues was measured by immunohistochemistry and then correlated with the clinical characteristics and prognosis of CRC patients. The role of MFAP2 in the invasiveness of CRC cells was evaluated by transwell assays and peritoneal metastatic model in nude mice. The downstream targets of MFAP2 was screened by mass spectrometry analysis. Then the role of MFAP2-CLK3 signaling axis was verified by cotransfecting MFAP2 siRNA and CLK3 plasmid in CRC cells. RESULTS: Microfibril associated protein 2 (MFAP2) mRNA was overexpressed and m1A-hypermethylated in CRC. High expression of MFAP2 was closely related to lymph node metastasis and distant metastasis, leading to poor prognosis in patients with CRC. In vivo and in vitro studies showed that silencing of MFAP2 inhibited the migration, invasion and metastasis of CRC cells. CDC Like Kinase 3 (CLK3) was a potential downstream target of MFAP2. Further studies showed that MFAP2 depletion might induce autophagic degradation of CLK3, and the role of MFAP2 in the invasiveness of CRC cells was dependent on CLK3. CONCLUSIONS: Our results uncover a newly identified MFAP2-CLK3 signaling axis, which is a potential therapeutic target for CRC metastasis.

Effectiveness and safety of a newly designed self-assembling gel in the treatment of endoscopic submucosal dissection-induced gastric ulcer: A multicenter randomized controlled trial.

Objectives: To evaluate the effectiveness and safety of a newly designed self-assembling gel in treating ESD-induced gastric ulcers in patients. Methods: This open-label, multicenter, randomized controlled trial enrolled patients who underwent ESD between September 2020 and May 2021. Patients were randomized (1:1) to receive the gel (applied to cover the entire ulcer bed under endoscopic guidance immediately after ESD; gel group) or not (control group). The primary outcome was the ulcer healing rate at 28 days. And the secondary outcomes were the delayed bleeding, changes in the ulcer stage, and adverse events. Results: Finally, 125 patients (mean age, 63.7 years; 70 [56.0%] males) were enrolled. The ulcer healing rate was higher in the gel group than in the control group at 28 days (96.9 ± 4.1% vs. 94.7 ± 5.0%; p = 0.001). The ulcer reduction rate at 28 days differed significantly (p < 0.001) between ulcers with majority gel coverage (99.8%), ulcers with minority gel coverage (96.2%), and ulcers with no gel coverage (98.0%). Delayed bleeding was found in 1/63 gel-treated patients (1.6%) versus 5/62 controls (8.1%). A1-stage ulcers were found in 16/63 patients in the gel group versus 44/62 patients in the control group (25.4% vs. 71.0%, p < 0.001) at 3-5 days. Conclusion: The newly developed self-assembling gel was safe and effective in accelerating gastric ulcer healing in patients after ESD. Clinical Trial Registration: UMIN Clinical Trials Registry System (registration number, ChiCTR2100052935).

Aberrant lipid metabolism in cancer cells and tumor microenvironment: the player rather than bystander in cancer progression and metastasis.

As the primary cause of cancer-induced fatality and morbidity, cancer metastasis has been a hard nut to crack. Existing studies indicate that lipid metabolism reprogramming occurring in cancer cells and surrounding cells in TME also endows the aggressive and spreading properties with malignant cells. In this review we describe the lipid metabolic reprogramming of cancer cells at different steps along the metastatic process, we also summarize the altered lipid metabolism of non-cancer cells in TME during tumor metastasis. Additionally, we reveal both intrinsic and extrinsic factors which influence the cellular lipid metabolism reprogramming.

The diagnosis of intramural esophageal squamous cell carcinoma without mucosal invasion using endoscopic ultrasound-guided fine needle aspiration biopsy: A case report.

RATIONALE: Intramural esophageal squamous cell carcinoma (ESCC) without mucosal invasion is extremely rare. Endoscopic mucosal biopsy results are often negative, making diagnosis difficult. In these cases, endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy is a useful diagnostic method. PATIENT CONCERNS: A 78-year-old female was admitted to hospital due to dysphagia, and gastroscopy showed a concentric narrowing of the esophageal lumen with a smooth and undamaged esophageal mucosa. DIAGNOSES: Endoscopic ultrasound (EUS) revealed that the esophageal mucosa was thickened with a low echo, and the layers of the esophageal wall could not be clearly distinguished. Cytologic and pathologic diagnoses were obtained through EUS-FNA, which suggested ESCC. INTERVENTIONS: According to the pathologic diagnosis obtained by EUS-FNA, surgery or radiotherapy were recommended for this patient. Eventually, this patient elected to seek treatment at another medical institution. OUTCOMES: This type of disease cannot be diagnosed according to gastroscopic biopsy alone, and the diagnosis was eventually confirmed through EUS-FNA. LESSONS: When an imaging examination suggests a possible malignant lesion of the oesophagus, EUS-FNA may be considered if the surface mucosa contains no endoscopic damage. EUS-FNA has high diagnostic value with high sensitivity, minimal invasiveness, and high safety.

MT1­MMP promotes the proliferation and invasion of gastric carcinoma cells via regulating vimentin and E­cadherin.

The present study aimed to explore the possible effects of membrane­type 1 matrix metalloproteinase (MT1­MMP) on gastric carcinoma cells proliferation and invasion. Immunohistochemistry analysis was conducted to measure MT1­MMP expression level in 15 patients with gastric carcinoma. Subsequently, recombinant short hairpin RNA (shRNA) vectors targeting MT1­MMP were constructed to silence the expression of MT1­MMP in gastric carcinoma cells. Then, the inhibitive efficiency was verified via reverse transcription quantitative polymerase chain reaction (RT­qPCR) and western blot analysis. The effects of MT1­MMP silencing on cell proliferation and invasion were detected through Cell Counting Kit­8 test and Transwell assays. The expression levels of vimentin and epithelial cadherin (E­cadherin) were detected by RT­qPCR. The immunohistochemistry analysis results revealed that MT1­MMP expression in gastric carcinoma tissues was markedly overexpressed compared with non­cancerous adjacent tissues. The MT1­MMP expression level in cancer­derived cell line AGS cells was also significantly increased compared with that in non­cancer­derived GES­1 cells. In addition, the MT1­MMP expression level in AGS cells was significantly decreased via shRNA transfection. Cell proliferation and invasion were markedly inhibited following knockdown of MT1­MMP level in AGS cells. These inhibitory effects were associated with the decreased expression of vimentin and increased expression of E­cadherin. MT1­MMP was overexpressed in gastric carcinoma cells, and silencing of MT1­MMP inhibited the proliferation and invasion of cells via regulating the expression of vimentin and E­cadherin.

Expression and Transcriptional Regulation of Human ATP6V1A Gene in Gastric Cancers.

Recent studies demonstrate that the invasion and metastasis of gastric cancer (GC) is closely associated with a multi-subunit vacuolar H+-ATPase (V-ATPase). Here we investigated the expression and role of the human ATP6V1A gene that encodes the catalytic subunit A of V-ATPase in GC. We found that ATP6V1A expression level is significantly elevated in GCs compared to normals, but GC patients with higher expression levels of ATP6V1A have a better prognosis. Genomic analysis revealed that APT6V1A copy number is gained in a small fraction of GC patients and lost in a minimum number. Moreover, the ATP6V1A copy number was positively correlated with its mRNA level. To explore additional mechanisms by which ATP6V1A overexpressed in GCs, we investigated the relationship between transcription factor YY1 and ATP6V1A, and found that mRNA expression of YY1 had significant correlation with that of ATP6V1A. To validate that YY1 transcriptionally regulates ATP6V1A, we discovered that the ATP6V1A core promoter region contains three YY1 binding sites. Moreover, RNAi-mediated knockdown of YY1 in GC cells significantly decreased ATP6V1A mRNA and protein expression, while YY1 overexpression increased ATP6V1A expression level. In conclusion, YY1 may play an important regulatory role in ATP6V1A expression with potential mechanistic and clinical implications in GC.

Combination of HDAC inhibitor TSA and silibinin induces cell cycle arrest and apoptosis by targeting survivin and cyclinB1/Cdk1 in pancreatic cancer cells.

Histone deacetylases (HDAC) are involved in diverse biological processes and therefore emerge as potential targets for pancreatic cancer. Silibinin, an active component of silymarin, is known to inhibit growth of pancreatic cancer in vivo and in vitro. Herein, we examined the cytotoxic effects of TSA in combination with silibinin and investigated the possible mechanism in two pancreatic cancer cell lines (Panc1 and Capan2). Our study found that combination treatment of HDAC inhibitor and silibinin exerted additive growth inhibitory effect on pancreatic cancer cell. Annexin V-FITC/PI staining and flow cytometry analysis demonstrated that combination therapy induced G2/M cell cycle arrest and apoptosis in Panc1and Capan2 cells. The induction of apoptosis was further confirmed by evaluating the activation of caspases. Moreover, treatment with TSA and silibinin resulted in a profound reduction in the expression of cyclinA2, cyclinB1/Cdk1 and survivin. Taken together, our study might indicate that the novel combination of HDAC inhibitor and silibinin could offer therapeutic potential against pancreatic cancer.

A retrospective study on endoscopic missing diagnosis of colorectal polyp and its related factors.

BACKGROUND/AIMS: To investigate missing diagnosis of the polyp by colonoscopy, and to reveal the endoscopic, pathological features of missed polyps and related factors inducing missing diagnosis. MATERIALS AND METHODS: We reviewed the data of the patients who received colonoscopy twice within 180 days. The missing rate of the colorectal polyps ware calculated and the endoscopic and pathological features of the missed polyps were summarized. Possible related factors inducing the missing diagnosis were analyzed. RESULTS: The missing rate of colorectal polyps in this study was 27.7%, with as high as 11.5% missing rate of advanced polyps. Most missed polyps were those of <5 mm in diameter (55.2%) or flat ones (75.9%). Most of missed polyps are located in the rectum (21.8%), sigmoid (41.4%) and transverse colon (17.2%). No significant correlation was observed between the missing rate and colonoscopic manners (p>0.05), neither between the missing rate and operators (p>0.05). But number of basal polyps was proved to be significantly correlative with number of missed polyps (r=0.694, p<0.001). CONCLUSION: Polyps of <5 mm in diameter or flat polyps are more likely to be missed in the endoscopy. Most of missed polyps are located in rectum, sigmoid and transverse colon. More basal polyps usually accompany with more polyps missed.

The accumulating appreciation of endoscopic submucosal dissection in the treatment of gastrointestinal neoplasms: preliminary experience in local eastern China.

BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD), an emerging technique originated from Japan, has been introduced into China in recent years. The aim of this study was to evaluate the efficacy and safety of ESD in the treatment of gastrointestinal (GI) neoplasms. METHODOLOGY: Early GI neoplasms (n=41) in 40 patients from local Eastern China were treated with ESD at Zhejiang Provincial People's Hospital and followed-up from January 2009 to December 2011. Postoperative pathology, complications and therapeutic outcomes were retrospectively analyzed. RESULTS: Mean size of the resected lesions was 2.2±0.81cm (1.2-6.0cm) and mean operation time was 77±28 minutes (20-150 minutes). The rates for successful resection, en bloc resection and complications were 90.2% (37/41), 83.8% (31/37) and 9.8% (4/41), respectively. The postoperative pathology showed 4 cases of early esophageal cancer, 6 of early gastric cancer or high-grade intraepithelial neoplastic changes, 5 of rectal laterally spreading tumor, 5 of esophageal or gastric leiomyoma, 2 of gastric heterotopic pancreas, and 18 of esophageal and gastric flat lesions with low-grade intraepithelial neoplastic changes. Tumor residue or recurrence was not been detected in all 40 patients during follow-up. CONCLUSIONS: According to our experience in local Eastern China, ESD is a feasible technique for the treatment of GI neoplasms. Even though it has promising resection rate and acceptable complication rate, the indication of ESD should be selected strictly and the operators need to be well-trained.