胃肠外科领域文献阅读汇编

Gastric cancer (GC) ranks as the fifth most common cancer worldwide, however, accurate and non-invasive diagnostic modalities for GC remain limited. Cell-free DNA (cfDNA) fragmentomics has emerged as a promising tool for cancer cell detection. Here we develop a gastric cancer detection model, named GaFraD model. The GaFraD model uses four cfDNA fragmentomics features, including fragment size ratio (FSR), copy number variation (CNV), 9-bp end motif (Motif), and fragment size at transcription start sites (TF). This model achieves an area under the receiver-operating characteristic curve (AUC) of 0.970 (95% CI: 0.944 - 0.990), a sensitivity of 95.0% and a specificity of 80.9%. By combining the GaFraD model and conventional protein biomarkers CA19-9 and PG-I/PG-II, the CONFIRM model was generated. The CONFIRM model attained an AUC of 0.986 (95% CI: 0.966 - 1.000), a sensitivity of 95.0% and a specificity of 95.6% in detecting GC. Moreover, the CONFIRM model achieved remarkable performance (AUC = 0.983, sensitivity 95.6%, specificity 94.2%) in distinguishing patients with early-stage GC from controls. Our work showed the high discriminatory power in distinguishing GC patients from controls, indicating the clinical potential of using cfDNA fragmentomics combined with protein biomarkers for non-invasive GC detection. The results of the study provide a new avenue for early, accurate, and non-invasive clinical diagnosis of GC.

Cisplatin is widely employed in the treatment of gastric cancer (GC). However, the resistance mechanisms exhibited by GC cells often result in suboptimal clinical outcomes associated with cisplatin therapy. Autophagy, a self-degradative cellular process, plays a complex dual role in regulating tumor cell death and survival. In recent years, significant attention has been directed toward the relationship between autophagy and cisplatin resistance in GC, fostering the development of various autophagy-related drugs and potential targets aimed at enhancing the sensitivity of GC cells to cisplatin. Nevertheless, a comprehensive analysis of the correlations among relevant studies is still lacking. This review synthesizes recent research examining the impact of autophagy on cisplatin resistance in GC cells, with particular emphasis on existing drugs and potential therapeutic drugs/targets. It briefly explores the fundamental processes of autophagy and clarifies the relationship between autophagy mechanisms and GC. Furthermore, it summarizes the available drugs and potential candidates that can either enhance or inhibit autophagy, thereby improving GC cell sensitivity to cisplatin, alongside their underlying mechanisms. Additionally, it consolidates pertinent research findings to present a more thorough understanding of the intricate relationships between autophagy and cisplatin resistance in GC cells. We hope this review will encourage researchers to investigate novel mechanisms of cisplatin resistance in GC cells, discover new targeted therapies, and propose innovative strategies to tackle this challenge.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, largely due to aggressive tumor behavior, immune evasion, and limited responsiveness to immunotherapy. Circular RNAs (circRNAs) have emerged as important regulators of cancer progression; however, the roles of exosomal circRNAs in tumor-immune communication in GC remain poorly understood. Here, circRNA profiling of exosomes derived from GC tissues and matched adjacent normal tissues identified circFXR1 as an upregulated circRNA associated with poor survival and adverse clinicopathological features. Functional analyses using GC cell lines, patient-derived organoid, and multiple mouse models demonstrated that circFXR1 promotes tumor proliferation, migration, and growth both in vitro and in vivo. Mechanistically, circFXR1 interacts with miR-497-5p, thereby upregulating PD-L1 expression, which in turn impairs CD8+ T cell-mediated cytotoxicity. In parallel, circFXR1 activates tumor-intrinsic mTOR signaling in a miR-497-5p-dependent manner, further enhancing malignant phenotypes. Importantly, circFXR1 is enriched in tumor-derived exosomes and transferred to recipient tumor cells and CD8+ T cells, resulting in increased PD-L1 expression, impaired T cell effector function, and enhanced tumor progression. Clinically, circFXR1 expression was elevated in non-responders compared with responders to anti-PD-1 therapy. Consistently, in an NSG xenograft model with adoptive transfer of human CD8+ T cells, circFXR1 overexpression attenuated the therapeutic efficacy of anti-PD-1 treatment. Collectively, these findings identify exosomal circFXR1 as a regulator linking tumor-intrinsic signaling and CD8+ T cell-associated immune evasion in GC. CircFXR1 may be associated with anti-PD-1 treatment response in GC, although further validation in molecularly stratified, multi-center cohorts is required.

Selecting effective chemotherapy after immunotherapy remains a major clinical challenge in advanced gastric cancer because patient responses are highly heterogeneous. A major obstacle is the lack of personalized preclinical models that faithfully recapitulate the immune-activated tumor microenvironment (TME) following immunotherapy and enable evaluation of subsequent chemotherapy responses while preserving immune-tumor interactions. Here, we developed an immune-activated co-culture model comprising patient-derived gastric cancer organoids and autologous peripheral blood mononuclear cells (PBMCs). Immune activation was achieved using anti-PD-1-loaded gold nanocages (aPD-1@Au NCs), which integrate near-infrared-triggered photothermal tumor ablation with sustained anti-PD-1-mediated immune modulation. The resulting model recapitulates key features of the post-immunotherapy TME, including enhanced immune-cell infiltration, increased tumor-cell apoptosis, and CD8+ T-cell activation. We then applied this model to evaluate five clinically relevant chemotherapeutic agents, including oxaliplatin, irinotecan, fluorouracil, doxorubicin, and docetaxel, for personalized chemotherapy screening after immunotherapy. Compared with monoculture organoids or non-activated co-cultures, the immune-activated model revealed drug-specific differences in tumor-killing efficacy, immune-mediated chemosensitization, and PBMC toxicity. Among the tested agents, oxaliplatin showed the strongest immune-mediated chemosensitization, whereas docetaxel achieved favorable tumor cell killing with relatively low immunotoxicity. These findings demonstrate that chemotherapy responses after immune activation are highly drug-specific, underscoring the importance of personalized chemotherapy selection following immunotherapy. As a proof-of-concept study, this work establishes an immune-activated patient-derived gastric cancer organoid-PBMC co-culture model that partially recapitulates the post-immunotherapy TME. This model provides a promising framework for developing personalized chemotherapy screening strategies after immunotherapy. STATEMENT OF SIGNIFICANCE: Selecting effective chemotherapy after immunotherapy remains a major challenge in advanced gastric cancer because of substantial interpatient heterogeneity. Progress in personalized treatment is limited by the lack of preclinical models that faithfully recapitulate the post-immunotherapy tumor microenvironment (TME). Here, we developed an immune-activated co-culture model integrating patient-derived gastric cancer organoids with autologous peripheral blood mononuclear cells (PBMCs). Immune activation was achieved using anti-PD-1-loaded gold nanocages (aPD-1@Au NCs), which combine near-infrared-triggered photothermal tumor ablation with sustained aPD-1-mediated immune modulation. This platform preserves patient-specific tumor characteristics while capturing key immune-tumor interactions following immunotherapy. Using this model, we evaluated five clinically relevant chemotherapeutic agents and identified distinct drug-specific differences in tumor-killing efficacy, immune-mediated chemosensitization, and immunotoxicity. As a proof-of-concept study, this work establishes a promising framework for personalized chemotherapy screening after immunotherapy and supports the development of precision treatment strategies for gastric cancer.

Alcohol-related hepatitis (AH) is a complex disease associated with numerous unmet needs, particularly in diagnosis and treatment. The epidemiology of AH has evolved in recent years, reflecting changes in alcohol consumption during the COVID-19 pandemic and the increasing incidence of AH following bariatric surgery. Advances have also been made in the non-invasive diagnosis of AH, helping to reduce the need for liver biopsy, as well as in the management of infection. Several novel therapeutic strategies have been evaluated, including faecal microbiota transplantation, IL-1 receptor antagonists, oxysterols, and reduced exposure to corticosteroids or antibiotics. Although the results of these trials have been relatively disappointing, they have helped identify promising directions for future research. In patients with the most severe form of AH, particularly those who do not respond to corticosteroids, several studies have suggested that the indications for early liver transplantation could be expanded. Overall, developments over recent years have generated increased optimism regarding the management of patients with severe AH.

Metabolic syndrome describes a set of risk factors that can eventually lead to the occurrence of cardiovascular and cerebrovascular disease. Metabolic syndrome has emerged as a significant global health issue, associated with various metabolic diseases, including obesity, diabetes, hypertension, dyslipidemia, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease, and other metabolic disorders. Here, we summarize the intricate mechanisms including insulin resistance, chronic low-grade inflammation, oxidative stress, and epigenetic modifications, and how they contribute to the disease progression of metabolic syndrome. The gut-adipose tissue axis in the progression of metabolic syndrome is emphasized here, mainly involving adipocyte-derived extracellular vesicles and adipokines, as well as specific gut microbiota and their secreted factors, such as lipopolysaccharide, short-chain fatty acids, endocannabinoids, bile acids, aryl hydrocarbon receptor ligands, and tryptophan derivatives. Furthermore, the contemporary management for metabolic syndrome mainly includes some established pharmacological treatments such as GLP-1 receptor agonists, SGLT2 inhibitors, and RAAS inhibitors, as well as promising emerging therapies targeting the gut-adipose tissue axis such as lifestyle modifications, prebiotics, probiotics, synbiotic supplements, FMT, bariatric surgery, CB1R antagonists, and novel pharmacological agents. These strategies may pave the way for the development of effective treatments for metabolic diseases in future research.

The efficacy of chimeric antigen receptor T (CAR-T) cell therapy in solid tumors is limited by the scarcity of stable antigen targets. To enhance CAR-T cell immunotherapy for solid tumors, we developed an integrated system that simultaneously introduces a surface antigen target for CAR-T cells and remodels the immunosuppressive tumor immune microenvironment (TIME) using an oncolytic adenovirus (OVs). This system leverages B cell membrane-derived CD19 as an artificial antigen target on tumor cells and enables in situ production of an αCD3e-αEpCAM bispecific T cell engager (BiTEs), which further strengthens the binding and cytotoxicity of CD19 CAR-T cells to cancer cells. The "double strike" therapeutic potential of Epv@CMP, both alone and in combination with CD19 CAR-T cells, was evaluated in colorectal cancer (CRC) and gastric cancer (GC) models. We have designed a lentiviral delivery system (Epv@CMP) that combines the homologous tumor cell membrane with the B cell membrane. The lentivirus has been genetically modified to express the dual-specificity antibody (αCD3e-αEpCAM) in tumor cells (Epv), aiming to enhance the accumulation of the virus in tumors and the efficacy of immunotherapy. Epv@CMP demonstrated efficient tumor-specific delivery and robust viral replication in vivo, leading to tumor regression and immune activation. Successful CD19 target anchor was also confirmed. The combination of Epv@CMP with CD19 CAR-T cells potently eliminated tumors in mouse models. Collectively, Epv@CMP represents a novel synergistic strategy that integrates oncolytic virotherapy with CAR-T cell immunotherapy to achieve potent tumor eradication and immune activation.

Observational studies have long suggested an association between gut microbiota dysbiosis and gastric cancer, yet the causal relevance and underlying biological pathways remain poorly defined. Here, we applied a comprehensive Mendelian randomization (MR) framework to gut microbiota and gastric cancer GWAS summary statistics to identify 14 microbial taxa significantly associated with gastric cancer risk. Sensitivity analyses, including tests for horizontal pleiotropy, heterogeneity, and genetic co-localization, revealed no strong evidence of shared causal variants (H4 < 2%); however, convergent results across five complementary MR models support overall causal inference. Mediation analysis further identified a partial pathway from the taxon ebi-a-GCST90027718 to gastric cancer via the metabolite met-c-926 (sdLDL), accounting for 4.31% of the total effect. Preliminary 16S rRNA sequencing in a pilot cohort (n = 5 per group) revealed divergent shifts in Ruminococcus subgroups without disrupting overall community stability, though these observations require replication. Collectively, this study establishes a genetically anchored evidence chain linking host genetics, gut microbiota, and gastric cancer pathogenesis, providing insights for microbiota-targeted prevention strategies.

Gastric cancer remains a major global health burden, with high mortality driven by late-stage diagnoses that limit treatment options and reduce survival. Current diagnostic methods such as endoscopy and biopsy are invasive, resource-intensive, and impractical for large-scale early detection. This study aimed to develop and validate an ensemble machine learning model integrating four cell-free DNA (cfDNA) fragmentomic feature classes derived from 5 × whole genome sequencing (WGS) data to non-invasively differentiate malignant gastric cancer from benign gastric lesions in high-risk or symptomatic patients. A total of 681 plasma samples were prospectively collected, comprising 329 from patients with gastric cancer or high-grade intraepithelial neoplasia (HGIN) and 352 from individuals with benign gastric conditions. The dataset was divided into a training cohort (n = 333) and a temporally independent validation cohort (n = 348). An external validation cohort of 305 participants was also included. The ensemble model achieved an AUROC of 0.920 in cross-validation testing on the training cohort, 0.912 in the independent validation cohort, and 0.896 (95% CI 0.860-0.932) in the external cohort. At a pre-specified prediction threshold of 0.402, the model demonstrated 93.3% sensitivity and 71.9% specificity in the validation cohort, yielding a PPV of 71.3% and an NPV of 93.5%. In the external cohort, sensitivity and specificity were 91.7% and 69.1%, respectively (PPV 75.7%, NPV 88.8%). Model scores correlated with clinical stage, tumor grade, and histopathological subtype. Approximately 71% of non-cancer patients could have been spared unnecessary endoscopy. The cfDNA fragmentomics-based ensemble model enables accurate, non-invasive differentiation between gastric cancer and benign gastric lesions in high-risk or symptomatic patients. This approach demonstrates strong potential as a pre-endoscopy triage tool, supporting earlier detection and more efficient use of diagnostic resources.

Advanced gastric cancer (GC) poses a significant threat to public health, leading to substantial consumption of healthcare resources due to its aggressive nature and poor prognosis. Hairy and enhancer of split 6 (Hes6), a member of the mammalian homologs of Drosophila's hairy and enhancer of split (HES) family, functions as a transcriptional cofactor owing to its unique structural features. Previous studies have indicated that Hes6 expression is elevated in several malignant tumors, contributing to the enhanced proliferation and invasion of tumor cells. However, the precise role and underlying mechanisms of Hes6 in gastric cancer initiation and progression remain poorly understood. In this study, we demonstrate that Hes6 expression is significantly up-regulated in gastric cancer tissues, with elevated levels of Hes6 correlating with poor prognosis in certain patient cohorts. Functionally, Hes6 mediates gastric cancer cells to obtain stronger proliferation, migration, and invasion abilities by activating the PI3K/AKT signaling pathway, thereby accelerating tumor progression. Moreover, Hes6 interacts with the Twist1 protein, stabilizing it and facilitating the epithelial-mesenchymal transition (EMT). Collectively, these findings offer valuable insights into the regulatory mechanisms underlying gastric cancer progression, highlighting the potential of transcriptional cofactors, such as Hes6, in PI3K/AKT signaling as promising targets for therapeutic intervention in gastric cancer.

Abdominal wall repair remains challenging as conventional hernia meshes frequently fail to simultaneously provide robust mechanical support, effective anti-adhesion, and rapid tissue regeneration. To address these limitations, an asymmetric bacterial cellulose/collagen (BC/COL) membrane is developed via "biological suturing" and "in situ pore formation" strategies. By spraying collagen Pickering emulsion onto the growing BC network during Komagataeibacter xylinus fermentation, a BC-interwoven collagen layer is produced. Subsequent fermentation without further emulsion addition produces an upper layer consisting solely of BC. This in situ fermentation process integrates the collagen and "sutures" the two layers, which we aptly term "biological suturing". Upon final freeze-drying, it yields a robust bilayer structure consisting of a porous layer (BC/COL-COL) and a dense layer (BC/COL-BC). This asymmetric design enables spatial functionalization: BC/COL-BC provides robust mechanical support and effective anti-adhesion, while BC/COL-COL facilitates cell infiltration and tissue regeneration. The scaffold exhibits high tensile strength (27.4 MPa) and good biocompatibility. In vitro tests confirm high cell attachment on the BC/COL-COL side and minimal adhesion on the BC/COL-BC side, demonstrating distinct bifunctional roles. In vivo experiments indicate that the BC/COL scaffold promotes tissue regeneration more effectively than polypropylene (PP) meshes. This composite presents a promising candidate for advanced clinical hernia repair.

Tuft cells are rare, chemosensory epithelial cells present in various tissues, including the respiratory and gastrointestinal tracts. Recent studies have revealed their significant role in cancer biology, particularly through the expression of the transcription factor POU2F3, which serves as a master regulator of tuft cell lineage. In several cancer types, including small cell lung cancer, gastric cancer, and breast cancer, POU2F3 expression defines a distinct molecular subtype termed "tuft cell-like" tumors. These tumors exhibit unique transcriptional programs and altered tumor-immune interactions, contributing to their distinct therapeutic sensitivities. In this review, we first analyze the expression patterns of POU2F3 across cancer types using the TCGA datasets, revealing differential expression profiles and supporting the classification of tuft cell-like subtypes. We further explore cancer-type-specific signaling pathways regulating tuft cell differentiation and function, such as IL-25, acetylcholine, and taste receptor-related pathways. Finally, we propose that tuft cell-like signatures may serve as promising biomarkers for diagnosis, prognosis, and treatment stratification. Understanding the tuft cell-like-POU2F3 axis could open new avenues for targeted therapies in lineage-defined cancers.