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 evaluate the clinical efficacy of Xiaoqinglong Decoction Granules in the treatment of chronic persistent cold syndrome of bronchial asthma; To explore its treatment mechanism.Methods:A randomized double-blind controlled study was performed. Totally 60 patients from the Respiratory Department of Guang'anmen Hospital, Chinese Academy of Traditional Chinese Medicine from January 2021 to January 2022 were selected as the observation subjects. They were divided into two groups using a random number table method, with 30 cases in each group. The control group was given conventional treatment plus placebo, and the experimental group was given conventional treatment plus Xiaoqinglong Decoction Granules. The treatment for both group lasted for 14d. TCM syndromes and clinical symptoms before and after treatment were scored. Asthma Control Test Questionnaire (ACT) was used to evaluate asthma control status, and the Asthma Quality of Life Questionnaire (Mini AQLQ) was used to evaluate the physiological and psychological effects of asthma on patients; FEV1 was detected using a German Jaeger lung function instrument FEV1/FVC. A exhaled nitric oxide (FeNO) detection instrument was used to observe the changes in FeNO at a flow rate of 50 ml/s, and non-targeted metabolomics analysis was performed using liquid chromatography-mass spectrometry (LC-MS); adverse reactions were observed during treatment and drug safety was evaluated.Results:Eventually 47 cases were included, 24 cases of test group and of 23 cases of control group. Xiaoqinglong Decoction Granules could reduce the TCM syndrome score of patients with chronic duration cold syndrome of asthma ( P<0.05). 2 weeks after treatment, follow up for 4 weeks experimental group clinical symptom score [3.00(1.00,4.00),3.00(0.00,4.00) vs. 3.5(3.00,5.00), Z=8.62], breathing symptom scores [1.00(0.00,1.00),1.00(0.00,1.00) vs. 1.00(0.75,2.00), Z=6.80], cough symptom score [0.50(0.00,1.00),1.00(0.00,1.00) vs. 1.00(0.00,1.25), Z=6.12] were lower than those in the experimental group before treatment in the same group ( P<0.01 or P<0.05). The ACT score of the experimental group at 4 weeks of follow-up was [22.50 (21.00, 24.00) vs. 9.00 (15.00, 21.50), Z=-4.87], Mini AQLQ score (78.5 ± 12.46 vs. 71.27 ± 9.70, t=-2.46) and the control group had an ACT score of [24.00 (19.00, 25.00) vs. 21.5 (8.00, 23.00) Z=-3.18] at 4 weeks of follow-up was higher than before treatment in the same group ( P<0.01 or P<0.05). The experimental group was followed up for 4 weeks with a FEV1 of [2.96 (2.27, 3.49) L vs. 2.60 (2.32, 3.49) L, Z=-3.72], FEV1/FVC [(80.83 ± 6.84)% vs. (77.46 ± 8.15)%, t=-2.32] and FeNO [24.00 (12.50, 31.00) ppb vs. 30.00 (17.00, 91.00) ppb, Z=-3.72] was higher than before treatment in the same group ( P<0.01 or P<0.05). Through LC-MS technique analysis, there were 75 kinds of different metabolites between the experimental group before and after treatment, and 295 kinds of different metabolites between the control group and the experimental group after treatment. Further intersection of differential metabolites showed that they were mainly concentrated in histidine metabolic pathway, phosphonate metabolic pathway and phosphate metabolic pathway. Related metabolites 2-aminoethyl phosphonate and thiomalonic acid were involved. Conclusions:Xiaoqinglong Decoction Granules can effectively improve the TCM syndrome and clinical symptoms of patients with chronic persistent cold syndrome of asthma, especially for wheezing, cough and chest tightness, which can improve the levels of FEV1 and FEV1/FVC in patients and effectively reduce FeNO. Through metabolomics studies, it is speculated that Xiaoqinglong Decoction Granules may play a role in the treatment of asthma by regulating histidine metabolism pathway through thiomalonic acid.

Recent studies have found that chondrocytes not only represent the cells targeted by rheumatoid ar-thritis(RA)but may also themselves induce the disease.This dual role indicates the significance of chondrocytes in the pathology of RA.This article summarizes the important roles played by chondrocytes in RA,providing a reference for the pathogenesis and treatment of RA.

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 study the osteoprotective effects and possible mechanism of total saponins of Chaenomeles speciosa on rheumatoid arthritis （RA） model mice， and to provide reference for further development of anti-RA drugs. METHODS Seventy male DBA/1 mice were randomly divided into normal group， model group， low-dose and high-dose groups of C. speciose total saponins （60， 240 mg/kg）， Tripterygium wilfordii polyglycoside tablets group （positive control， 30 mg/kg）， with 14 mice in each group. In addition to the normal group， the other groups of mice were induced by glucose-6-phosphate isomerase mixed polypeptide to prepare RA model. The body weight， rear toes thickness and arthritis scores of each group were recorded； the synovial inflammation， bone and cartilage destruction of ankle joint tissues were observed by hematoxylin-eosin staining， tartrate- resistant acid phosphatase staining and safranin O-fast green staining； the contents of interleukin-6 （IL-6） in serum and tumor necrosis factor α （TNF-α）， IL-4 and IL-10 in ankle joint tissues were detected by ELISA； the expression levels of receptor activator of nuclear factor-κB ligand （RANKL）， receptor activator of nuclear factor-κB （RANK）， osteoprotegerin （OPG）， tumor necrosis factor receptor-associated protein 6 （TRAF6） and nuclear factor of activated T cells 1 （NFATC1） protein in ankle joint tissues were detected by Western blot assay. RESULTS At the end of administration， compared with normal group， the body mass of mice in the model group was significantly reduced （P＜0.05）， and the arthritis score and the thickness of the left and right rear toes were significantly increased （P＜0.05）； the ankle joint tissues of mice in the model group showed significant synovial proliferation and inflammatory infiltration， the number of osteoclasts increased significantly and significant destruction of cartilage tissue. The content of IL-6 in serum， the content of TNF-α， the protein expression levels of RANKL， RANK， TRAF6 and NFATC1 in the ankle joint tissues were increased significantly （P＜0.05）， while the contents of IL- 4 and IL-10， the protein expression level of OPG in the ankle joint tissues were decreased significantly （P＜0.05）. Compared with model group， above pathomorphological changes and the content/level of indicators of mice in each administration group were significantly improved （P＜0.05）. CONCLUSIONS Total saponins of C. speciosa may exert osteoprotective effects on RA model mice， the mechanism of which may be associated with reducing the contents of IL-6 and TNF-α， increasing the contents of IL-4 and IL-10， inhibiting the activation of RANKL/RANK/OPG signal pathway， thus inhibiting the proliferation of osteoclasts and promoting the repair of cartilage and bone tissue.

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.

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.

In this paper, the domestic and international demand and development trend of clinical diagnostic radionuclides are analyzed, and the medium and high-energy cyclotrons, adequate and systematic facilities, and preparation techniques required for the production of medical radionuclides based on solid targets are introduced. This paper focuses on the research and development carried out by some important medical institutions and scientific research institutes in China over the years in the aspects of medium and high-energy cyclotrons, beam transmission lines, high-power irradiation target stations and new medical isotope production processes etc. It also looks forward to some new directions for the development of medical radionuclides in China during the 14th Five-Year Plan period.