Gastric cancer (GC) is a globally prevalent malignancy with a particularly heavy burden in China. Helicobacter pylori ( H. pylori ) is a Group I carcinogen for GC, with a higher seroprevalence rate indicating a higher GC incidence. However, only approximately 3% of the individuals with H. pylori infection eventually develop GC, and about 2.6% still progress to GC even 10-20 years after the eradication of H. pylori . Thus, the pathogenic mechanism of H. pylori for GC must be elucidated, and high-risk individuals precisely identified. Furthermore, GC can occur even in individuals who have never been infected with H. pylori . As H. pylori infection rates decline, the proportion of H. pylori -negative GC cases is increasing annually, gaining significant research attention. In this review, potential pathogenic mechanisms of H. pylori infection are explored from the aspects of H. pylori virulence factors and host factors (genetic susceptibility and immune microenvironment). Possible risk factors for H. pylori -negative GC include infections by other microorganisms (e.g., bacteria, fungi, and viruses), autoimmune gastritis, bile reflux, genetic mutations, and environmental factors. We aim to review the potential mechanisms for GC with varying H. pylori infection statuses, identify the high-risk individuals, and pose questions that need to be addressed. In the future, as the prevalence of H. pylori infection gradually decreases, GC prevention and management must evolve to address host-specific factors and the growing challenge of H. pylori -negative GC by integrating multidisciplinary perspectives.
Stomach Neoplasms/genetics* ; Humans ; Helicobacter Infections/complications* ; Helicobacter pylori/pathogenicity* ; Risk Factors

OBJECTIVE: To explore the changes of CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) and programmed death-ligand 1 (PD-L1) expression in gastric mucosal epithelial cells after Helicobacter pylori infection and the regulation of CMTM6 on PD-L1, and to analyze the mRNA expression differences before and after CMTM6 gene knock-out in helicobacter pylori infected gastric epithelial cells by microarray analysis. METHODS: The standard Helicobacter pylori strain ATCC 26695 was co-cultured with human gastric epithelial cell GES-1 for 6, 24 and 48 hours, and the mRNA and protein levels of CMTM6 and PD-L1 were detected by real-time quantitative PCR and Western blot. Using CRISPR/Cas9 to construct CMTM6 gene knockout plasmid and knockout CMTM6 gene of GES-1 cells. Helicobacter pylori was co-cultured with CMTM6 gene knockout and wild type GES-1 cells for 48 hours to detect PD-L1 transcription and protein level changes, and CMTM6 gene knockout GES-1 cells were treated with the proteasome inhibitor MG-132 to detect the changes in PD-L1 protein levels. Agilent Human ceRNA Microarray 2019 was used to detect the differentially expressed genes in CMTM6 gene knockout and wild-type GES-1 cells co-cultured with Hp for 48 hours, and the signal pathway of differentially expressed genes enrichment was analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: The mRNA and protein levels of CMTM6 and PD-L1 in GES-1 cells were significantly up-regulated after Helicobacter pylori infection, and CMTM6 mRNA was most significantly up-regulated 48 hours after infection. After CMTM6 gene knockout, the CD274 gene transcription level of Helicobacter pylori infected GES-1 cells did not change significantly, but PD-L1 protein level was significantly down-regulated, and the PD-L1 level increased after the application of proteasome inhibitor MG-132. After CMTM6 gene knockout, 67 genes had more than two times of differential expression. The transcription levels of TMEM68, FERMT3, GPR142, ATP6V1FNB, NOV, UBE2S and other genes were significantly down-regulated. The transcription levels of PCDHGA6, CAMKMT, PDIA2, NTRK3, SPOCK1 and other genes were significantly up-regulated. After CMTM6 gene knockout, ubiquitin-conjugating enzyme E2S (UBE2S) gene expression was significantly down-regulated, which might affect protein ubiquitination degradation. After CMTM6 gene knockout, adrenoceptor alpha 1B (ADRA1B), cholinergic receptor muscarinic 1 (M1), CHRM1, platelet activating factor receptor (PTAFR) gene expression was significantly up-regulated. CONCLUSION Helicobacter pylori infection up-regulates the expression level of CMTM6 in gastric mucosa cells, and CMTM6 can stabilize PD-L1 and maintain the protein level of PD-L1. CMTM6 gene knockout may affect biological behaviors such as protein ubiquitination and cell surface receptor expression.
Humans ; MARVEL Domain-Containing Proteins/metabolism* ; Helicobacter pylori/physiology* ; B7-H1 Antigen/genetics* ; Helicobacter Infections/metabolism* ; Epithelial Cells/metabolism* ; Gastric Mucosa/metabolism* ; Chemokines/metabolism* ; Cell Line ; Gene Knockout Techniques ; Myelin Proteins

Objective To analyze the clinical,pathological,and endoscopic features of differentiated early gastric cancer,and to study predictors to identify and screen high risk patients with early gastric cancer submucosal infiltration.Methods A total of 172 patients with differentiated early gastric cancer treated by surgical or endoscopic submucosal dissection in our hospital from January 2017 to December 2022 were included,which were divided into the mucosal layer group(144 patients)and submucosal layer group(28 patients)based on postoperative pathology.The clinical,pathological,and white-light endoscopy(WLE)and linked color imaging(LCI)features of the 2 groups were compared.The color difference between the lesion and the surrounding mucosa was evaluated by using the Commission International de L'Eclairage(CIE)L*a*b*system.Indicators with significant differences were included to multifactor logistic stepwise regression analysis(forward method)for the identification and screening of predictors.Results A history of alcohol consumption(P=0.037),a history of smoking(P=0.035),thickening of the gastric wall on enhanced CT(P=0.032),a lesion located in the upper 1/3(P＜0.001)or middle 1/3(P=0.009)part of the stomach,depressed macroscopic type(P＜0.001),marked margin elevation(P=0.003),presence of fold changes(P=0.006),color difference ≥12.3 under WLE(P=0.003)and≥18.2 under LCI(P=0.002)were associated with submucosal infiltration.Multivariate analysis showed that lesions located in the upper 2/3 portion of the stomach(OR=5.463,95％CI:2.562-11.648,P＜0.001),depressed macroscopic type(OR=5.992,95％CI:1.624-22.100,P=0.007),marked margin elevation(OR=4.338,95％CI:1.124-16.747,P=0.033),and color difference ≥18.2 under LCI(OR=4.675,95％CI:1.342-16.288,P=0.015)were independent risk factors for infiltration of submucosal layer of lesions.Conclusion Lesions with depressed macroscopic type,marked elevated margins,located in the upper 2/3 part of the stomach,and having a large color difference from the surrounding mucosa under LCI are high-risk lesions for submucosal infiltration and require more aggressive intervention.

Objective:To evaluate the long-term clinical efficacy of endoscopic submucosal dissection (ESD) in the treatment of early colorectal cancer and precancerous lesions, and to explore the risk factors of local recurrence after operation.Methods:From January 1, 2011 to December 31, 2022, the clinical and endoscopic follow-up data of 1 095 patients (1 186 lesions) who underwent ESD at Peking University Third Hospital and were pathologically diagnosed as early colorectal cancer or precancerous lesions after ESD were retrospectively analyzed. The long-term efficacy of ESD was evaluated, which included 5-year overall survival rate, disease-specific survival rate, local recurrence rate, and recurrence-free survival rate. The Kaplan-Meier method was used for survival analysis. Multivariate Cox proportional hazards regression models were performed to analyze local recurrence related clinical pathological factors.Results:After ESD, 1 067 patients were followed up, and the median follow-up period was 44.4 (20.3, 62.1) months. There were 734 patients having endoscopic follow-up (798 lesions, the follow-up rate was 67.0%). During the follow-up period, 26 patients died, and the 5-year overall survival rate and disease-specific survival rate were 96.0% and 100.0%, respectively. During the follow-up period, local recurrence was observed in 17 lesions, with a recurrence rate of 2.1%(17/798) and a median time of recurrence after ESD was 11.8 (4.9, 21.4) months. The 5-year cumulative recurrence rate was 3.4%, and the 5-year recurrence-free survival rate was 94.0%. The results of multivariate Cox regression analysis showed that lesions located in the rectum ( HR=2.64, 95% confidence interval (95% CI) 1.00 to 6.94, P=0.049), histologically incomplete resection ( HR = 4.40, 95% CI 1.62 to 11.94, P=0.004), and positive vertical margin ( HR=10.27, 95% CI 2.95 to 35.77, P<0.001) were independent risk factors for local recurrence after ESD in the treatment of colorectal mucosal lesions. Conclusions:Long-term efficacy of ESD in the treatment of colorectal mucosal lesions are favorable. Lesions located in the rectum, histologically incomplete resection, and positive vertical margin are independent risk factors for local recurrence after ESD in the treatment of colorectal mucosal lesions.

Objective To explore factors influencing non-en bloc resection of endoscopic submucosal dissection(ESD)for colorectal neoplasms.Methods A retrospective analysis was conducted on clinical and pathological data of 1251 patients(1312 lesions)who underwent colorectal ESD from January 2011 to December 2022 and were pathologically confirmed as adenoma,serrated lesion,or early colorectal cancer.Clinical and pathological characteristics were compared between the en bloc resection group and the non-en bloc resection group.Univariate and multivariate logistic regression analyses were performed to identify factors influencing en bloc resection in ESD.Results The average size of the1312 lesions was(25.8±16.3)mm.Among the included lesions,there were728 adenomas(55.5%),193 serrated lesions(14.7%),and 391 early colorectal cancers(29.8%).ESD was completed in 1306 lesions and stopped due to perforation or technical difficulties in6 cases.The en bloc resection rate was89.5%(1174/1312),the complete resection rate was 73.8%(968/1312),and the curative resection rate was 70.6%(926/1312).Multivariate logistic regression analysis revealed that diameter of the lesions≥40 mm(OR =6.329,95%CI:4.278-9.384,P<0.001),negative lifting sign(OR =2.384,95%CI:1.424-3.903,P =0.005),scar location lesions(OR =2.997,95%CI:1.310-6.484,P = 0.023),protruded lesions(OR =8.458,95%CI:2.678-40.453,P =0.008),lateral spreading lesions(OR =5.898,95%CI:1.917-27.796,P =0.025),and hybrid ESD(OR =10.162,95%CI:5.705-19.692,P<0.001)were independent factors influencing en bloc resection of ESD for early colorectal cancer and precancerous lesions.Conclusions Diameter of the lesions≥40 mm,negative lifting sign,scar location lesions,protruded lesions,lateral spreading lesions,and hybrid ESD were significantly associated with non-en bloc resection of ESD for colorectal neoplasms.Strict evaluation should be conducted preoperatively to improve the efficacy of ESD.

Background:Cronkhite Canada syndrome(CCS)is a rare non hereditary disease of unknown etiology,there are still challenges in its diagnosis and treatment.Aims:To explore the clinical characteristics and treatment responses of CCS in Chinese population,and to improve the understanding of its diagnosis and treatment.Method:Retrospective analysis and summary of clinical data of CCS patients at Peking University Third Hospital from 2012 to 2022.Results:From the clinical data of a total of 9 cases,the patients'average age was 63.89 years,and the male to female ratio was 1.25.all patients presented with multiple gastrointestinal polyps,non-specific gastrointestinal symptoms and at least one ectodermal manifestation.Laboratory tests for fecal occult blood were positive,and iron deficiency anemia and hypoalbuminemia were common.Histological manifestations were hyperplastic polyps and adenomatous polyps,with commonly found eosinophil infiltration.Patients'conditions could be complicated with severe osteoporosis and fractures,intestinal bacterial overgrowth,asthma,membranous nephropathy,and nodular goiter.Most patients obtained positive currative effect with glucocorticoids therapy,but recurrence of the disease may occur during or after hormone reduction.Azathioprine treatment was attempted in one patient,but the effect was poor.Conclusions:The etiology and pathogenesis of CCS are unclear,and glucocorticoids therapy is still the main treatment method.However,there are still challenges for patients with glucocorticoids resistance and contraindications to glucocorticoids therapy.

Helicobacter pylori (Hp) infection is one of the main causes of gastric cancer. The virulence factors of Hp, cytotoxin⁃associated gene A (CagA) and vacuolating cytotoxin A (VacA), are closely related to the pathogenicity of Hp in European and American countries. However, the positivity rate of CagA is as high as 90% in East Asian countries, indicating that the above⁃mentioned virulence factors could not fully explain the differences in pathogenicity of Hp, and other pathogenic factors might be speculated. In our previous studies, thioredoxin⁃1 (Trx1) was found to be a virulence factor of highly pathogenic Hp, and a series of studies were conducted on Hp Trx1 in cytology, zoology and human histology. This article reviewed the progress in research on Hp Trx1.

Helicobacter pylori (Hp) is a Gram-negative bacterium selectively colonized in gastric mucosa, and is one of the main factors inducing chronic gastritis and even gastric cancer. Recent studies have shown that Hp infection induces various stress responses, including oxidative stress, nitrosative stress and endoplasmic reticulum stress. Hp can stimulate neutrophils, macrophages and gastric epithelial cells to express reactive oxygen species and reactive nitrogen species, resulting in excessive accumulation of reactive oxygen species and reactive nitrogen species, aggravating inflammation and damage to gastric mucosa. Such long-term inflammation and oxidative stress may increase the risk of cancer. In addition, Hp induced endoplasmic reticulum stress plays an important role in the early stages of precancerous lesion formation. This article reviewed the research progress of role of stress response induced by Hp infection in gastric mucosal diseases.

Gastric cancer is a malignant tumor with worldwide high incidence and threatening the human health severely. It is a disease induced by multiple factors. Exosomes play an important role in the pathogenesis and development of many malignant tumors including gastric cancer. Exosomes can transport specific contents to regulate local and distant cell communications, and are able to promote or inhibit the development of gastric cancer through regulating the growth and proliferation of tumor cells, relevant immune function and angiogenesis of tumors. This article reviewed the effects of exosomes and their contents on the pathogenesis and development of gastric cancer.

Objective:To preliminarily understand the living habits, medication taking and treatment status including the therapeutic regimen, compliance and short-term efficacy of patients with chronic atrophic gastritis and erosion in Beijing area.Methods:From April to September in 2019 at Peking Union Medical College Hospital, Peking University Third Hospital and Peking University Shougang Hospital, the outpatients with chronic atrophic gastritis and erosion diagnosed with endoscopy within two weeks before visiting were prospectively included in this non-interventional observation study. Chi square test was used for statistical analysis.Results:A total of 277 patients with chronic atrophic gastritis and erosion had complete follow-up data, of which male patients accounted for 49.8% (138/277). The common initial symptoms of patients with chronic atrophic gastritis and erosion included acid reflux, abdominal distension, epigastric pain and postprandial distension, which accounted for 60.3% (167/277), 59.6% (165/277) , 58.8% (163/277) and 52.3% (145/277), respectively. For treatment, 36.8% (102/277) of the patients only received lifestyle instruction without medication. Among the patients with medication treatment, the short-term efficacy of gastric mucosal protectants+ proton pump inhibitor+ gastro-kinetic agent for abnominal distension, postprandial distention, acid reflux and nausea was highest as compared with other therapeutic regimen, and the differences were statistically significant ( χ2=25.18, 19.49, 13.75, 8.84, all P<0.05). Conclusions:Chronic gastritis with erosion may be caused by a combination of multiple factors, and the symptoms of which lack specific. If necessary, gastroscopy may help the diagnosis. Individualized treatment strategies based on the symptoms of patients is needed for treatment.