BACKGROUND:Keverprazan offers a new perspective for Helicobacter pylori eradication. This study compared 14-day keverprazan-amoxicillin therapy with esomeprazole-amoxicillin therapy to explore a superior treatment strategy. METHODS:This was a prospective, open-label, multicenter, randomized controlled trial in adult patients with treatment-naive H. pylori infection. Participants were randomly assigned to receive either 14-day of KA therapy (Keverprazan 20 mg b.i.d plus amoxicillin 1 g t.i.d) or 14-day of EA therapy (Esomeprazole 40 mg b.i.d plus amoxicillin 1 g t.i.d). The primary outcome was the H. pylori eradication rate. Secondary outcomes were the incidence of adverse events and patient adherence. RESULTS:A total of 264 patients were enrolled in the study. In the intention-to-treat (ITT) analysis, the eradication rates for the 14-day KA group and the 14-day EA group were 87.9% and 80.3%, respectively (p = 0.092); in the modified intention-to-treat (mITT) analysis, the eradication rates were 92.1% and 86.2%, respectively (p = 0.135); and in the per-protocol (PP) analysis, the eradication rates were 93.5% and 88.3%, respectively (p = 0.155). Non-inferiority was confirmed between the two groups (all p < 0.001). Adverse events and patient adherence were similar between the two groups. CONCLUSION:For treatment-naive H. pylori infection, the 14-day KA therapy is non-inferior to EA therapy. Given its good tolerability, pharmacogenomic independence, and potent acid suppression, KA is a rational first-line alternative to EA in the Chinese population.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet their efficacy in colorectal cancer (CRC) remains limited to a minority of patients with microsatellite instability-high (MSI-H) tumors, leaving the majority with microsatellite stable (MSS) disease unresponsive. The gut microbiota, a key regulator of host immunity, has emerged as a pivotal determinant of ICI response. This review delineates the dual role of the gut microbiome—encompassing specific bacterial strains, their metabolites, and bioactive components such as extracellular vesicles (EVs) and outer membrane vesicles (OMVs)—in either enhancing or impairing ICI efficacy through complex interactions with the host immune system. We further explore the emerging concept of gut microbiota circadian rhythms and their potential to inform personalized chrono-immunotherapy paradigms. Furthermore, we synthesize promising microbiota—targeting strategies as adjunctive approaches to overcome resistance and augment ICI efficacy in CRC. Finally, we present selected clinical evidence and outline future perspectives to expand the clinical benefit of immunotherapy in CRC patients.

This study aimed to investigate potential targets for the pathogenesis of atrial fibrillation to facilitate the development of effective treatments. Atrial fibroblasts were isolated and stimulated with 1 μM angiotensin-II (Ang-II) for 24 h. To increase interleukin 11 (IL-11) expression, overexpression plasmids were transfected into atrial fibroblasts. The role and the underlying mechanism of IL-11 in atrial fibrillation were examined by immunofluorescence, measurements of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP), and western blotting assays. Results demonstrated that IL-11 was upregulated in Ang-II-elicited atrial fibroblasts. Ang-II treatment increases alpha-smooth muscle actin (α-SMA), ROS and MMP levels, and p62 expression but decreases microtubule-associated protein light chain 3 II/I (LC3 II/I) and Beclin-1 expressions in atrial fibroblasts. These effects were further amplified by IL-11 overexpression. Mechanistically, the mammalian target of rapamycin (mTOR) pathway expression was enhanced in Ang-II-induced atrial fibroblasts, which was further elevated by IL-11 upregulation. IL-11 facilitates Ang II-induced differentiation of atrial fibroblasts into myofibroblasts by promoting oxidative stress, mitochondrial dysfunction, and autophagy inhibition through the mTOR pathway.

Colorectal cancer (CRC) is a prevalent and lethal malignancy, with ubiquitination significantly influencing cellular processes involved in cancer progression. However, the contributions of ubiquitination-related genes in CRC remain unclear. This study conducted a detailed analysis of gene expression profiles associated with ubiquitination in CRC, evaluating 1006 genes across 46 pathways. By comparing CRC tissues to adjacent normal tissues, we identified differentially expressed genes and developed a ubiquitination-related pathway gene signature (URPGS) using LASSO regression analysis on genes with prognostic significance. The prognostic capability of the URPGS was validated in independent cohorts, and its associations with clinical characteristics, including post-chemotherapy survival outcomes, were examined. Machine learning techniques identified HSPA1A as a key gene relevant to CRC both in vitro and in vivo. Our analysis revealed 307 differentially expressed ubiquitination-related genes, with 24 significantly associated with patient prognosis. The developed 14-gene URPGS exhibited strong prognostic value, effectively stratifying patients into high-risk and low-risk groups for overall survival. The URPGS correlated with advanced clinical stages, lymph node metastasis, and recurrence, with higher scores linked to poorer post-chemotherapy survival outcomes. Knockdown of HSPA1A significantly inhibited CRC cell proliferation, migration, and invasion in vitro, as well as tumor growth and metastasis in vivo. This research establishes a novel URPGS that effectively predicts prognosis and chemotherapy outcomes in CRC, enhancing our understanding of ubiquitination's role and suggesting personalized treatment strategies.

Regulatory T cells (Tregs) can thrive in the harsh tumor microenvironment (TME) to dampen antitumor immunity. Chronic stresses within TME compromise canonical cap-dependent translation (CDT), which compromises effector T cell function but not Treg persistence. Death-associated protein 5 (DAP5/eIF4G2), a non-classical translational scaffold, has been reported to support human Treg differentiation in vitro, but its functions in thymic Treg development, peripheral Treg homeostasis, and tumor-infiltrating Treg (ti-Treg) fitness remain unclear. Here, it is shown that DAP5 expression positively correlates with ti-Treg frequencies in both colorectal cancer patients and murine subcutaneous tumors. Mice with homozygous Dap5 deletion in Tregs has intact thymic and peripheral Treg development but spontaneously developed typical scurfy symptoms. Haploinsufficiency of Dap5 in Tregs preserves peripheral immune homeostasis while suppressing tumor growth, with enhanced CD8+ T cell infiltration and effector function. Mechanistically, Dap5 mediates alternate mode of translation of transcripts encoding CD25 and MCL-1 in Tregs, thereby sustaining Treg lineage stability and survival in the stressful TME. Overall, Tregs rely on DAP5-driven alternate translation to maintain peripheral homeostasis and acquired fitness within the TME. Selective disruption of this pathway impairs ti-Tregs while sparing systemic tolerance, offering a potential therapeutic strategy to enhance anti-tumor immunity.

目的:探讨Bcl-2相关的永生基因 4(Bcl-2 associated athanogene 4,BAG4)在胃癌干细胞(gastric cancer stem cells,GC-SCs)自我更新能力中的调控作用.方法:采用成球培养法分离/富集GCSCs,并对其生物学特征进行鉴定.采用慢病毒干扰技术构建沉默BAG4表达的MGC803胃癌细胞系,以平板克隆形成和成球实验分别检测沉默BAG4对胃癌细胞克隆形成和成球能力的影响.结果:成球培养法成功分离/富集出球细胞(sphere cell,SC).与普通单层贴壁细胞相比,MGC803-SC高表达干性相关基因Sox2、Oct4和Bmi1,具有更强的克隆形成能力(198±17 vs.92±11,P＜0.001),诱导分化后干性标志物CD44表达下降,在体外具有更强的侵袭能力(185±18vs.84±11,P＜0.01).上述实验结果证实MGC803-SC具有GCSCs特性.BAG4在GCSCs中的表达水平明显高于普通贴壁胃癌细胞,沉默BAG4明显降低胃癌细胞的克隆形成和成球能力.结论:沉默BAG4基因能有效抑制GCSCs的自我更新能力,有望成为胃癌靶向治疗的新靶标.

Several risk factors have been identified for the development of gastric adenocarcinoma (GAC), where the control group was usually a healthy population. However, it is unclear at what stage known risk factor exert their influence toward the progression to cancer. Based on the Wuwei Cohort, we enrolled 1,739 patients with chronic non-atrophic gastritis (no-CAG), 3,409 patients with chronic atrophic gastritis (CAG), 1,757 patients with intestinal metaplasia (IM), 2,239 patients with low-grade dysplasia (LGD), and 182 patients with high-grade dysplasia (HGD) or GAC to assess the risk factors between each two consecutive stages from no-CAG to GAC/HGD using adjusted logistic regression. We found that different groups of risk factors were associated with different stages. Age, occupation of farmer, low annual family income, Helicobacter pylori (H. pylori) infection, drinking, eating hot food, histories of gastritis and peptic ulcer were associated with the development of CAG. Age, illiteracy, H. pylori infection, smoking, eating hot food, eating quickly, and histories of gastritis and gallbladder diseases were associated with the progression to IM from CAG. Male, occupation of farmer and history of peptic ulcer were associated with the development of LGD from IM. Age, male and polyp history appeared to be risk factors associated with the development of GAC/HGD from LGD. In conclusion, it seems that most risk factors function more as a set of switches that initiated the GAC carcinogenesis. H. Pylori eradication and control of other risk factors should be conducted before IM to decrease the incidence of GAC.

Abstract Background Cancer cells often exhibit large‐scale genomic variations, such as circular extrachromosomal DNA (ecDNA) and structural variants (SVs), which have been highly correlated with the initiation and progression of cancer. Currently, no adequate method exists to unveil how these variations regulate gene expression in heterogeneous cancer cell populations at a single‐cell resolution. Methods Here, we developed a single‐cell multi‐omics sequencing method, scGTP‐seq, to analyse ecDNA and SVs using long‐read sequencing technologies. Results and Conclusions We demonstrated that our method can efficiently detect ecDNA and SVs and illustrated how these variations affect transcriptomic changes in various cell lines. Finally, we applied and validated this method in a clinical sample of hepatocellular carcinoma (HCC), demonstrating a feasible way to monitor the evolution of ecDNA and SVs during cancer progression.

Background: Gastrointestinal cancer poses a serious health threat owing to its high morbidity and mortality. Although immune checkpoint blockade (ICB) therapies have achieved meaningful success in most solid tumors, the improvement in survival in gastrointestinal cancers is modest, owing to sparse immune response and widespread resistance. Metabolic reprogramming, autophagy, and ferroptosis are key regulators of tumor progression. Methods: A literature review was conducted to investigate the role of the metabolic reprogramming, autophagy, and ferroptosis in immunotherapy resistance of gastrointestinal cancer. Results: Metabolic reprogramming, autophagy, and ferroptosis play pivotal roles in regulating the survival, differentiation, and function of immune cells within the tumor microenvironment. These processes redefine the nutrient allocation blueprint between cancer cells and immune cells, facilitating tumor immune evasion, which critically impacts the therapeutic efficacy of immunotherapy for gastrointestinal cancers. Additionally, there exists profound crosstalk among metabolic reprogramming, autophagy, and ferroptosis. These interactions are paramount in anti-tumor immunity, further promoting the formation of an immunosuppressive microenvironment and resistance to immunotherapy. Conclusions: Consequently, it is imperative to conduct comprehensive research on the roles of metabolic reprogramming, autophagy, and ferroptosis in the resistance of gastrointestinal tumor immunotherapy. This understanding will illuminate the clinical potential of targeting these pathways and their regulatory mechanisms to overcome immunotherapy resistance in gastrointestinal cancers.

PURPOSE:Noninvasive assessment of liver fibrosis holds significant clinical importance. We aimed to evaluate the clinical potential of using a continuous-time random-walk diffusion model (CTRW) for staging liver fibrosis. METHODS:This prospective study included 52 patients suspected of liver disease and scheduled for liver biopsy. All patients underwent multi-b value diffusion-weighted imaging (DWI) using a 1.5 T MR scanner to derive the anomalous diffusion coefficient (D) and temporal (α) and spatial (β) diffusion heterogeneity indexes sourced from the CTRW. The mono-exponential DWI-derived apparent diffusion coefficient (ADC), transient elastography-derived liver stiffness measurement (LSM), aspartate aminotransferase-to-platelet ratio index (APRI), and fibrosis-4 (FIB-4) index were calculated. We assessed and compared the correlations of these parameters with fibrosis stages and their efficacy in staging liver fibrosis. RESULTS:Significant correlations with fibrosis stages were found for APRI (r = 0.336), FIB-4 (r = 0.351), LSM (r = 0.523), D (r = -0.458), and ADC (r = -0.473). Significant differences were observed between APRI, LSM, D, and ADC of different fibrosis stages. The diagnostic performance of an index that combined D, α, β, ADC, and LSM was superior to that of ADC or LSM alone for fibrosis stage F ≥ 2 and better than the index that combined D, α, β for fibrosis stage F ≥ 4. CONCLUSIONS:Accurate liver fibrosis staging was achieved with a model that combined CTRW-derived parameters (D, α, and β), ADC, and LSM. The model could serve as a reliable tool for noninvasive fibrosis evaluation.

BACKGROUND A lack of research on the association of trefoil factors (TFFs) with gastric cancer (GC) and premalignant lesions (PMLs) in the general populations is an important obstacle to the application of TFFs for GC screening. We aimed to analyze the association of TFFs with GC and PMLs in a general population. METHODS We evaluated 3,986 adults residing in Wuwei, China. We collected baseline characteristics and GC risk factors, including TFFs, endoscopic diagnosis, and pathological information. Three logistic regression models were generated to analyze the association between TFFs and GC, as well as PMLs. Adjusted odds ratio (OR) and 95% confidence intervals (95% CI) were calculated to determine the strength of association. RESULTS Compared with pepsinogen (PG) and anti-Helicobacter pylori immunoglobulin G antibody (Hp-IgG), TFFs had significant association with GC and PMLs after adjusting for biomarkers and risk factors (P < 0.05). The ORs [95% CI] for TFF1 (1.67 [1.27-2.20]), TFF2 (2.66 [2.01-3.51]), and TFF3 (1.32 [1.00-1.74]) were larger than the ORs for PGI (0.79 [0.61-1.03]), PGI/II (1.00 [0.76-1.31]) and Hp-IgG (0.99 [0.73-1.35]) in the GC group. In intestinal metaplasia (IM) group, not only the TFF3 serum level was the highest, but also the OR (1.92 [1.64-2.25]) was the highest. CONCLUSIONS Trefoil factor were associated with risk of GC and PMLs. IMPACT Serum TFFs can improve the screening of high-risk populations for GC.

Background: The connection between B and T lymphocyte attenuator rs1982809 polymorphism and cancer risk has been investigated by several studies and yielded different results. Therefore, we adopted the meta-analysis method to assess the association of rs1982809 polymorphism with the susceptibility of cancers synthetically. Methods: Eligible publications were gathered by retrieving PubMed, Web of Science, Embase, Wan Fang, and China National Knowledge Infrastructure. We utilized odds ratio (OR) and 95% confidence intervals (95% CI) to assess correlation intensity and performed subgroup analyses, sensitivity analyses, and publication bias assessments. Results: Six researches that encompassed 3678 cases and 4866 controls were incorporated into our meta-analysis. The rs1982809 polymorphism was proved to be connected with cancer risk by the meta-analysis in the additive model (G vs A: OR = 1.11, 95% CI = 1.04-1.19, P-heterogeneity = .096). Subgroup analyses revealed that this SNP is regarded as a susceptible factor for cancers in the dominant, heterozygous, and additive model (AG + GG vs AA: OR = 1.46, 95% CI = 1.19-1.80, P-heterogeneity = .592; AG vs AA: OR = 1.47, 95% CI = 1.19-1.82, P-heterogeneity = .536; G vs A: OR = 1.32, 95% CI = 1.12-1.55, P-heterogeneity = .745) in Caucasians; And this SNP may increase the susceptibility to lung cancer (GG vs AG+AA: OR = 1.20, CI = 1.01-1.44, P-heterogeneity = .854; G vs A: OR = 1.17, CI = 1.02-1.33, P-heterogeneity = .232). Conclusion: The paper concludes that B and T lymphocyte attenuator rs1982809 polymorphism may contribute to cancers, especially in Caucasians, and it may associate with lung cancer.

Bcl2-associated athanogene 4 (BAG4) has been found to be aberrantly expressed in several types of human cancers. However, little is known about its expression, role, and clinical significance in gastric cancer (GC). In this study, we aimed to address these issues and to explore the underlying mechanisms. The expression level of BAG4, measured by immunohistochemistry, was significantly higher in GC tissues than in paired normal tissues. Elevated BAG4 expression was positively correlated with T stage, lymph node metastasis, and tumor size of GC and was associated with unfavorable outcomes of the patients. The overexpression of BAG4 promoted the in vitro invasion and in vivo metastasis of GC cells, and opposite results were observed after silencing of BAG4. Silencing of BAG4 significantly reduced the phosphorylation of PI3K, AKT, and p65, whereas overexpression of BAG4 markedly enhanced the phosphorylation of these molecules. At the same time, manipulating BAG4 expression resulted in the corresponding changes in p65 nuclear translocation and ZEB1 expression. Luciferase reporter and chromatin immunoprecipitation assays verified that p65 binds to the promoter of ZEB1 to upregulate its transcription. Our results demonstrate that BAG4 plays an oncogenic role in the invasion and metastasis of GC cells by activating the PI3K/AKT/NF-κB/ZEB1 axis to induce epithelial-mesenchymal transition.

Abstract Background: The lack of effective biomarkers for screening gastric cancer (GC) and premalignant lesions (PMLs) is a significant roadblock in the prevention and early intervention of GC. We aimed to identify noninvasive biomarkers to improve the screening of high-risk populations. Methods: We evaluated 25,000 adults residing in Wuwei. We collected baseline characteristics, GC risk indicators, including trefoil factors (TFF1–3), endoscopy diagnosis, and pathological information. We analyzed the data to determine the association of risk biomarkers with the progression of GC and the prediction capacities of these biomarkers using odds ratio (OR)-adjusted models and receiver operating characteristic (ROC) curve analyses. Results: TFF1 and TFF2 serum levels showed incremental changes from the PMLs to the GC group, with the highest serum TFF3 levels reported in the intestinal metaplasia group. TFF1 and TFF2 had significant predictive values in the PMLs and GC in the three OR-adjusted models but not in the non-atrophic gastritis group. Similar results were obtained after adjusting for all biomarkers and risk factors wherein the ORs (95 % confidence intervals) of TFF1 and TFF2 in the GC group were 2.71 (1.57–4.67) and 2.87 (1.75–4.71), respectively (P < 0.001). The combination of TFF1–3 showed the largest area under the curve across all four groups (chronic atrophic gastritis [0.74], intestinal metaplasia [0.79], low-grade intraepithelial neoplasia/dysplasia [0.79], and GC [0.84]), making it the best-fit ROC. Conclusions: TFF1, TFF2, and the combination of TFF1–3 can serve as sensitive, specific, and noninvasive biomarkers for detecting GC and PMLs, facilitating the early identification of these lesions.

Background: Gastric cancer is a common digestive tract tumor in our China, with high morbidity and mortality. Similar with other tumors, the occurrence of gastric cancer was also a complex pathophysiological process, regulated by a variety of oncogenes and tumor suppressor gene. Aims and Objectives: This study aims to investigate the expression of cyclin D1, CDC25B, and p27 in gastric carcinoma and to study their relationship with the occurrence and development of gastric cancer. Materials and Methods: SP immunohistochemical and Western blot analysis were used to detect the expression of cyclin D1, CDC25B, and p27 in 42 cases of gastric carcinoma, 42 cases of paracancer, and 42 cases of normal gastric tissue and then their relationship with clinical and pathological factors was analyzed. Results: (1) The expression of cyclin D1 increased gradually in normal gastric tissue, paracancer, and gastric carcinoma (P>0.05). The expression of CDC25B was higher in gastric carcinoma (P<0.05) while p27 was lower (P<0.05). (2) The result of Western blot shows that the expression of cyclin D1 and CDC25B was higher in gastric carcinoma than that in normal gastric tissue while p27 lower in gastric carcinoma (P<0.05), same with immunohistochemical. (3) The expressions of cyclin D1 and CDC25B had correlation with lymph nodes metastasis, and p27 had correlation with degrees of pathological differentiation, invasion depth, and lymph nodes metastasis. (4) There was a positive relationship between the expression of cyclin D1 and CDC25B in same sample (r=−0.392, P<0.05). Conclusion: Expression of cyclin D1, CDC25B, and p27 protein can be helpful in the prediction of the biological behavior and prognosis of gastric carcinoma.

Objectives To evaluate the prevalence of Helicobacter pylori infection and risk factors and to serotype the strains in Wuwei, located in north-western China, which has a high incidence of gastric cancer. Methods Helicobacter pylori infection was analysed in 21 291 adults by C-14-urea breath test, and H. pylori antibody were detected in 9183 serum samples by latex immunoturbidimetric method. The correlation of H. pylori infection with demographic-economic, lifestyle factors and medical history among the participants was determined by questionnaire. The antibodies against H. pylori urease, VacA and CagA in serum were determined by dot immunobinding assay. Results The infection rate of H. pylori was 53.0%, and 90.1% of strains were type I strains. The H. pylori infection rate was higher among farmers (OR = 1.34, 95% CI: 1.19-1.50) and individuals who had a junior high school or higher education level (OR = 1.10, 95% CI: 1.06-1.15), and was lower in older individuals (OR = 0.86, 95% CI: 0.83-0.90), individuals with high income (OR = 0.93, 95% CI: 0.90-0.95), individuals with a habit of eating quickly (OR = 0.93, 95% CI: 0.87-0.99) and individuals who consumed more fruit and vegetables (OR = 0.90, 95% CI: 0.85-0.95). Individuals with history of cholecystitis/cholecystolithiasis, hypertension and asthma were negatively correlated with H. pylori infection (P < 0.05). Conclusion The prevalence of H. pylori infection is high in Wuwei. The major prevalent strain is type I strain. Age, education, occupation, household income, consumption of fruit and vegetables, and habit of eating quickly are independent risk factors for H. pylori infection, which is also associated with individuals with a history of extragastric diseases.

Abstract Background: Colorectal cancer (CRC) is the third most common cancer in the world, with 694,000 deaths each year. Despite improvements in treatment strategies in recent years, the overall survival rate of CRC is still very low and the survival rate is highly dependent on the stage at the time of diagnosis. Some biomarkers have shown great potential for early screening of CRC and some have been tested in systematic reviews (SRs). However, the quality of these SRs remains unclear and these SRs did not clarify which biomarker is the optimal diagnostic test. This overview will evaluate the methodological quality of available SRs and compare the diagnostic value of different biomarkers in order to find the best biomarker for diagnosing CRC. Methods: A comprehensive literature search for SRs published before February 2019 was conducted in the PubMed, Embase.com, Cochrane Library, and Web of Science without any language restrictions. We will use the assessment of multiple systematic reviews-2 instrument to assess the methodological quality of each SR. Bubble plots will be used to summarize the main characteristics and quality of SRs. Standard pairwise meta-analysis and adjusted indirect comparison will be conducted to compare the diagnostic value of different biomarkers. Results: The results of this overview will be submitted to a peer-reviewed journal for publication. Conclusion: The findings of this project will provide a general overview and evidence of the diagnostic value of biomarkers in detecting CRC. PROSPERO registration number: CRD42019125880.

Background: Colorectal cancer (CRC) is the third most common cancer in the world, with 694,000 deaths each year. Despite improvements in treatment strategies in recent years, the overall survival rate of CRC is still very low and the survival rate is highly dependent on the stage at the time of diagnosis. Some biomarkers have shown great potential for early screening of CRC and some have been tested in systematic reviews (SRs). However, the quality of these SRs remains unclear and these SRs did not clarify which biomarker is the optimal diagnostic test. This overview will evaluate the methodological quality of available SRs and compare the diagnostic value of different biomarkers in order to find the best biomarker for diagnosing CRC. Methods: A comprehensive literature search for SRs published before February 2019 was conducted in the PubMed, Embase.com, Cochrane Library, and Web of Science without any language restrictions. We will use the assessment of multiple systematic reviews-2 instrument to assess the methodological quality of each SR. Bubble plots will be used to summarize the main characteristics and quality of SRs. Standard pairwise meta-analysis and adjusted indirect comparison will be conducted to compare the diagnostic value of different biomarkers. Results: The results of this overview will be submitted to a peer-reviewed journal for publication. Conclusion: The findings of this project will provide a general overview and evidence of the diagnostic value of biomarkers in detecting CRC.