胃肠外科领域文献阅读汇编

Patients with gastric cancer (GC) and peritoneal metastasis (PM) have poor prognoses due to drug resistance and metastatic relapse. The mechanism underlying PM recurrence remains unclear. This study investigates the mechanisms of ascitic neutrophil extracellular traps (NETs) in promoting GC immune escape and PM recurrence. Ascites from a patient with GC were analysed using flow cytometry, immunofluorescence and electron microscopy. In vitro and in vivo experiments demonstrated NETs promoted GC immune evasion. RNA sequencing and functional models identified the immune checkpoint molecule CEACAM1. Internalisation assay combined with inhibitors determined tumour cells internalised NETs via macropinocytosis. Immunofluorescence and western blot revealed that NETs upregulated CEACAM1 and programmed death-ligand 1 (PD-L1) by activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. The cotranscription factor interferon regulatory factor 1(IRF1) for CEACAM1 and PD-L1 were identified by dual-luciferase reporter assays and chromatin immunoprecipitation. Conditioned medium-culture systems identified CSF2 and CSF3 as NETs-inducing factors. Combination of DNase I and PD-L1 antibody was evaluated in humanised mice, organoid-T cell cocultures and ex-vivo ascites therapy models. We uncovered that macropinocytosis mediated uptake of NETs remodels an immunosuppressive microenvironment and promotes PM recurrence. Increased neutrophils and NETs in PM-relapsed ascites promote GC cell immune escape. Mechanistically, GC cells uptake NETs-DNA via macropinocytosis. Macropinocytic NETs-DNA activate the cGAS-STING-IRF1 pathway, upregulate immune-checkpoint molecules CEACAM1 and PD-L1, leading to immune escape. Moreover, clearing NETs-DNA combining with PD-L1 antibody achieves a synergistic inhibitory effect on PM. We highlight the importance of macropinocytosis mediated uptake of NETs in GC immune escape and PM recurrence, providing a potential combination therapeutic strategy for patients with PM.

Immune evasion driven by the tumor microenvironment is a major obstacle to effective immunotherapy in gastric cancer. To overcome this barrier, a detailed understanding of the mechanisms by which gastric cancer circumvents antitumor immunity is essential. In this study, we identified KDM5B as a pivotal epigenetic-metabolic orchestrator of immune evasion in gastric cancer. Clinically, KDM5B overexpression correlated with poor prognosis and diminished CD8+ T-cell infiltration. Mechanistically, KDM5B suppressed NLRP3-dependent pyroptosis via H3K4me3 demethylation and inhibited JAK1-STAT1/3-driven chemokine production. Crucially, a lactate-KDM5B feedforward loop facilitated immunosuppression, with KDM5B promoting lactate production and K868 lactylation enhancing KDM5B activity. Therapeutically, dual targeting of KDM5B and glycolysis overcame anti-PD-L1 resistance. Overall, these findings establish KDM5B as a central hub integrating epigenetic reprogramming, metabolic rewiring, and immunosuppression to drive progression and immune escape, positioning KDM5B as an actionable therapeutic target for reversing immunotherapy resistance in gastric cancer. KDM5B regulates an epigenetic-metabolic axis of immune evasion in gastric cancer that can be targeted to overcome anti-PD-L1 resistance, providing an effective combination immunotherapeutic strategy.

Extracellular vesicles (EVs) are promising liquid biopsy candidates for gastric cancer because they can capture tumor-, immune-, microbial-, and microenvironment-related signals. We argue that the main challenge is no longer simply to find more candidates but to advance EV biomarkers with demonstrated diagnostic, therapeutic-monitoring, or prognostic value toward clinical translation. In this opinion article, we highlight EVs from nonblood biofluids, non-tumor-derived EVs, and underexplored EV cargo types, particularly small noncoding RNA cargoes, as sources of biomarker potential. We further identify insufficient clinical evidence, technical bottlenecks, and incomplete quality-control and regulatory standards as key barriers to their clinical deployment.

This review aims to provide a summary of treatment strategies for hypothalamic obesity (HO) and the latest data on pharmacologic interventions for HO. We summarize new consensus diagnostic criteria for acquired HO, non-pharmacologic interventions such as diet and physical activity, medications including the newly FDA approved setmelanotide, metabolic and bariatric surgery, and emerging treatment strategies that address the complex pathophysiology of HO. Hypothalamic obesity is caused by hypothalamic injury that impairs energy balance, metabolism, and satiety and leads to refractory obesity that is resistant to traditional diet and exercise interventions. Despite recent progress, effective long-term management of HO remains challenging, with few controlled trials, significant heterogeneity in patient response, and lack of long-term follow up data. A new medication targeting the melanocortin-4 receptor (MC4R) pathway was recently approved for treatment with additional newer drugs in development [1].

Obesity is a multifactorial, chronic, and relapsing non-communicable disease characterized by excessive adipose tissue accumulation and metabolic dysfunction. Increasing evidence indicates that biological sex influences not only the development and distribution of adipose tissue but also responses to obesity treatments, including metabolic-bariatric surgery. This narrative review synthesizes current evidence on sex-related differences in metabolic outcomes after bariatric surgery. Bariatric surgery induces substantial weight loss and marked improvement of obesity-related complications in both men and women along sex-specific differences in body composition changes, adipose tissue remodeling, adipokine secretion, inflammatory responses, and thermogenic adaptations. Estrogen signaling contributes to a more favorable adipose tissue phenotype through anti-inflammatory effects, enhanced adipokine profiles, preservation of lean mass, and stimulation of white adipose tissue beiging, a process by which an inducible form of thermogenic adipocytes within white adipose tissue (beige adipocytes) acquire thermogenic characteristics similar to brown adipose tissue. In women, menopausal status represents a key biological modifier of these responses. In contrast, androgen excess is associated with visceral fat accumulation and insulin resistance. Despite largely comparable rates of remission of major obesity-related complications between sexes, variances in adiposity, hormonal milieu, and postoperative metabolic outcomes suggest different underlying mechanisms. Although remission rates of obesity-related complications appear broadly comparable between sexes, the underlying metabolic and endocrine adaptations differ. Biological sex represents a determinant of post-bariatric metabolic remodeling. This review highlights the relevance of biological sex in obesity and its treatment, emphasizing the need for sex-stratified studies to elucidate underlying mechanisms and support the development of more precise, personalized strategies in obesity management.

The efficacy of postsurgical immunotherapy for gastric cancer (GC) remains controversial, and the effect of the number of dissected lymph nodes (DLNs) on the efficacy of immunotherapy remains unknown. We retrospectively reviewed 451 patients who received adjuvant or palliative therapies (including immunotherapy and chemotherapy) for GC at nationwide centers between 2020 and 2025 to investigate the influence of DLNs on postsurgical immunotherapy. Prognoses were assessed based on DLNs. In the adjuvant immunotherapy cohort (n = 139), the disease-free survival (DFS) was significantly lower in patients with DLNs >36 compared with those with DLNs ≤36 [hazard ratio (HR), 2.62; 95% confidence interval (CI), 1.39-4.95, P = 0.003)]. Moreover, patients with DLNs≤36 who received combined immunotherapy had a better DFS than patients who received only adjuvant chemotherapy (HR, 0.37; 95% CI, 0.17-0.78, P = 0.006). In the palliative immunotherapy cohort (n = 47), patients with DLNs>36 had significantly lower progression-free survival (PFS) (HR, 3.57; 95% CI, 1.61-7.94, P = 0.001) and DCR (6.67% vs 65.6%, P < 0.001) than those with DLNs≤36. Additionally, when matching with patients who received palliative immunotherapy without previous gastrectomy (DLNs = 0), the PFS decreased progressively in patients with DLNs = 0, DLNs>0 to ≤36, and DLNs>36 (median PFS, 16 vs. 11 vs. 3 months, P = 0.002). In conclusion, excessive lymph node dissection (DLNs≥36) compromised the efficacy of postsurgical adjuvant or palliative immunotherapy for GC.

Tumour cells and tumour-associated stroma are key components of the tumour microenvironment, and their interaction impacts disease progression and treatment resistance in rectal cancer. This study introduces a computational approach to quantify tumour cell density (TCD) within epithelial and stromal regions and assess whether treatment response differs according to TCD status in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy (nCRT). The data of 414 ARISTOTLE trial (ISRCTN09351447) participants with available digitised pre-treatment biopsies were analysed in this study. We defined TCD as the proportion of tumour cells within the tumour and stroma tissues and quantified TCD using an AI framework applied to digitised haematoxylin and eosin-stained whole-slide images. The patients were stratified as TCD-high/TCD-low using a cut-off value of 0.5 (50% of tumour cells). The TCD status was combined with treatment arms [CRT (capecitabine + radiotherapy) and IrCRT (experimental capecitabine + irinotecan + radiotherapy)] to stratify the disease-free survival (DFS), overall survival (OS) and pathological complete response (pCR) rates. Among the patients analysed, 188 (45%) of 414 patients were classified as TCD-high and 226 (55%) as TCD-low. A significant treatment-TCD interaction was observed for both DFS (χ2 = 6.88, p = 0.009) and OS (χ2 = 10.61, p = 0.001). In the TCD-high subgroup, the use of IrCRT was associated with significantly longer DFS (HR = 0.57, 95% CI: 0.36-0.90, p = 0.014) and OS (HR = 0.50, 95% CI: 0.30-0.84, p = 0.008), along with a higher pCR rate (20 [23%] vs. 8 [11%], OR = 2.46, 95% CI: 1.01-5.98; p = 0.042 [p = 0.13 after adjustment for multiple testing]), compared to CRT. However, in the TCD-low subgroup, no significant difference in DFS was observed between treatment arms (HR = 1.29, 95% CI: 0.85-1.95, p = 0.22), while patients who received IrCRT exhibited a trend towards worse OS (HR = 1.55, 95% CI: 0.96-2.51, p = 0.07). No significant difference in pCR rates was observed (12 [14%] vs. 23 [22%], OR = 0.60, 95% CI: 0.28-1.29; p = 0.19). In this post-hoc, hypothesis-generating analysis of the ARISTOTLE trial, higher TCD was associated with differential outcomes after irinotecan-intensified neoadjuvant chemoradiotherapy compared with standard chemoradiotherapy. These findings support further evaluation of AI-derived TCD as a candidate predictive biomarker in independent retrospective and prospective cohorts. Cancer Research UK Radiation Research Network - Project Seed Funding (RRNPSF-Jan21/100001), Cancer Research UK ARISTOTLE sample collection grant (A18745), UK Research and Innovation Future Leadership Fellowship (No. MR/T040785/1) and the Radiation Research Unit at the Cancer Research UK City of London Centre Award (C7893/A2899).

Obesity is a major risk factor for colorectal cancer (CRC), yet the mechanisms linking obesity-associated gut dysbiosis to tumor progression remain unclear. Here, we show that a high-fat diet and fecal microbiota from patients with obesity-associated CRC deplete the GABA-producing commensal Bacteroides ovatus, resulting in reduced luminal GABA and accelerated tumorigenesis. Microbial GABA activates epithelial GABAB receptor signaling and induces TPI1 through the PI3K-HIF1α pathway. Increased TPI1-derived glyceraldehyde-3-phosphate inhibits PPP1CA, maintains YAP phosphorylation, restricts nuclear YAP activity, and suppresses pentose phosphate pathway flux, thereby limiting tumor growth. Consistently, obesity-associated CRC exhibits reduced fecal GABA, decreased TPI1 expression, and metabolic rewiring. A GABA-deficient B. ovatus mutant fails to restore GABA or suppress tumors despite normal colonization, whereas oral GABA supplementation or recolonization with wild-type B. ovatus markedly reduces tumor burden. These findings identify a microbiota-neurotransmitter-metabolism axis linking obesity to CRC and suggest microbiota-based GABA restoration as a potential preventive strategy.

Glucose Transporter 1 (GLUT1) is the quintessential facilitator of basal glucose uptake, indispensable for maintaining cellular energy homeostasis, particularly across the blood-brain barrier. Beyond physiological necessity, GLUT1 dysregulation drives a broad pathological spectrum. While genetic haploinsufficiency precipitates severe neurological energy crises like Glut1 deficiency syndrome (Glut1DS), oncogenic networks hyperactivate GLUT1 as the central executor of the Warburg effect to fuel malignant proliferation. Despite its immense therapeutic potential, severe on-target toxicity in normal tissues and adaptive metabolic plasticity remain critical roadblocks to systemic GLUT1 inhibition. This review comprehensively synthesizes GLUT1's multidimensional regulatory networks in health and disease, dissecting how its overexpression fundamentally remodels the tumor microenvironment (TME). We elucidate how GLUT1-driven "metabolic competition" fosters metabolic immune exclusion and drives therapeutic resistance. Furthermore, we map the paradigm shift from traditional systemic blockades to emerging precision interventions. Specifically, we highlight "Trojan horse" glycan-functionalized nanocarriers, targeted protein degradation technologies like PROTACs, and metabolically engineered CAR-T cells. By conceptualizing GLUT1 as the linchpin of the immunosuppressive ecosystem, this work provides a strategic roadmap for precision metabolic immuno-oncology, guiding the development of novel therapies that maximize durable efficacy while minimizing collateral physiological damage.

Myocardial ischemia-reperfusion (I/R) injury presents a significant clinical challenge characterized by a complex pathological mechanism. The role of protein ubiquitination in I/R injury has not been systematically investigated. Global ubiquitinome profiling was conducted to identify the potential key players in myocardial I/R injury. The ubiquitination levels of proteins in mouse hearts subjected to either sham surgery or I/R injury were analyzed using ubiquitinome. A combined analysis of ubiquitinome, single-cell RNA sequencing (RNA-seq), and proteomics data was employed to predict potential E3 ubiquitin ligases associated with myocardial I/R injury. Global heterozygous 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase degradation 1 (Hrd1) knockout, endothelial cell (EC)-specific Hrd1 deficiency (Hrd1f/f; Cdh5Cre), and EC-specific Hrd1 overexpression (AAV-EC-Hrd1) mice were used to assess the role of Hrd1 in myocardial I/R injury. Mass spectrometry and immunoprecipitation were used to elucidate the interaction between Hrd1 and aldehyde dehydrogenase 2 (ALDH2). Additionally, we assessed ubiquitination and vasomotor reactivity to clarify the mechanisms by which Hrd1 regulates ALDH2 activity and EC dysfunction during I/R injury. Ubiquitinome analysis revealed that protein ubiquitination exacerbates endothelial dysfunction after myocardial I/R injury. Integrative analysis of the ubiquitinome, proteomics, and single-cell RNA-seq revealed a significant upregulation of the E3 ubiquitin-protein ligase Hrd1 in CD45+ ECs. In both humans and mice, the level of endothelial Hrd1 protein was found to increase in response to I/R in vivo. Genetic ablation of Hrd1 significantly alleviated myocardial infarction, endothelial dysfunction, and infiltration of inflammatory cells after I/R injury. Mechanistically, Hrd1 promoted the K33-linked polyubiquitination of ALDH2 and then inhibited the formation of its active tetramers, which reduced the apoptosis of CD45+ ECs and exacerbated endothelial dysfunction through the NO/cGMP/PKG (nitric oxide-cyclic guanosine monophosphate-protein kinase G) signaling pathway. Furthermore, our findings demonstrated that pharmacological inhibition of Hrd1 robustly ameliorated myocardial I/R injury and endothelial dysfunction. Our findings demonstrated a previously unidentified crucial role of cardiac EC Hrd1 in myocardial I/R injury. Hrd1 may serve as a therapeutic target for preventing myocardial I/R injury.

Interleukin-1β (IL-1β) has long been characterized as a foundational mediator of innate immunity, yet this designation captures only a fraction of its biological significance. A growing body of evidence now positions IL-1β as a molecular arbiter of tissue restoration - a context-sensitive instructor that orchestrates the dynamic interplay between inflammatory signaling, stem cell fate, and niche remodeling that collectively determines whether an injured tissue regenerates or degenerates. Far beyond its canonical role in host defense, IL-1β functions as a critical regulator of cell state plasticity, driving the transition of lineage-committed progenitors into highly plastic, transitional identities that are indispensable for effective wound repair. Yet the very mechanisms that render IL-1β essential for regeneration also render it capable of profound pathological consequence when its activity is sustained, amplified, or spatiotemporally dysregulated. This review explores the spatiotemporal logic governing IL-1β-mediated plasticity, with particular emphasis on the respiratory epithelium as a primary and instructive model of inflammatory reprogramming and niche remodeling. We examine how the signaling thresholds, cellular contexts, and temporal dynamics of IL-1β activity collectively determine regenerative outcomes - and how the failure to terminate this program pathologically stabilizes transitional progenitor states, predisposing tissues to fibrosis, functional exhaustion, and malignant transformation. By integrating evidence spanning transcriptional, epigenetic, and metabolic rewiring, we propose a unified conceptual framework for understanding IL-1β as a master coordinator of the regenerative ecosystem - one whose precise modulation represents a compelling therapeutic target for resetting pathological cell states toward functional recovery in chronic inflammatory diseases.

Tumor cells promote metabolic dysregulation of immune cells by controlling the metabolic landscape of the tumor microenvironment. It is unclear whether tumors restrict specific nutrients to drive rapid growth and immune evasion in addition to the overconsumption of nutrients to support anabolism. We identified that up-regulation of solute carrier family 7 member 1 (SLC7A1) increased arginine utilization and promoted tumor growth, whereas down-regulation of SLC7A2 decreased lysine catabolism to support immune evasion. Repression of lysine catabolism in tumor cells reduced glutaconic acid (GC), a medium-chain acyl-CoA dehydrogenase-dependent lysine catabolite that has immunostimulatory effects on antitumor CD8 T cells. GC modified pyruvate kinase M2 (PKM2) through posttranslational glutaconylation at key lysine residues Lys336 (K336) and K337. This modification reinforced PKM2 dimers, transcriptionally driving metabolic reprogramming and reinvigorating antitumor CD8 T cells. Our study highlights an amino acid trade-off that dynamically optimizes the metabolic preferences of tumors to promote proliferation and immune evasion.

KRASG12D mutation drives oncogenic progression and creates an immunosuppressive microenvironment in cancers like pancreatic ductal adenocarcinoma and colorectal cancer. We investigate the immunomodulatory mechanisms of the KRASG12D inhibition and its synergy with natural killer (NK) cell therapies. We demonstrate that KRASG12D inhibition with MRTX1133 remodels the immune landscape by reducing myeloid-derived suppressor cell (MDSC) accumulation and facilitating infiltration and activation of NK and CD8+ T cells. Crucially, MRTX1133 reverses systemic immunosuppression, restoring the fitness of adoptively transferred NK cells. Mechanistically, KRASG12D inhibition impairs IFNGR1 palmitoylation and subsequent lysosomal degradation. MRTX1133 stabilizes IFNGR1 by reducing palmitoyltransferase expression and the palmitate pool. This stabilization increases IFN-γ/IFNGR signaling and up-regulates NK cell-activating ligands ICAM1 and ULBP1, thereby sensitizing cancer cells to NK cells. Consequently, combining MRTX1133 with IL-15 or adoptive NK cell therapy yields synergistic antitumor responses and prolonged survival. Our findings provide mechanistic rationale for combining KRASG12D inhibitors with NK cell-based immunotherapies to improve outcomes for patients with KRASG12D-mutant cancers.

The asymmetric collapse of cavitation bubbles near a rigid boundary generates high-speed microjets, which, when confined by a perforated boundary, possess the potential to drive directional fluid transport. However, existing studies have long treated this pumping effect as a subordinate phenomenon within cavitation bubble dynamics, and no independent theoretical framework or performance evaluation system has been established for engineering applications. This paper formally defines the"Cavitation-Bubble Pump (CBP)"as an independent fluid transport technology. We systematically investigate the asymmetric collapse morphology, microjet characteristics, and near-orifice flow field of single bubbles under the constraints of orifice diameter Φ (2-19 mm) and dimensionless distance γ (0-2.0). The transient response of the liquid column and the buildup of macroscopic head under continuous bubble excitation are analyzed, and the evolution of steady-state headHs, time-averaged flow rateQt, and energy conversion efficiency with Φ and γ is quantitatively evaluated. The results show that orifice size is one of the main determinants of macroscopic pumping performance: the steady-state head decreases monotonically with increasing orifice diameter, whereas the flow rate first increases and then decreases, leading to an optimal operating condition and a critical dead-head state. The standoff distance also plays a key role, with the experimentally identified optimum agreeing well with the geometric tangency condition. Cross-scale analysis indicates that the microjet is the primary source of momentum injection, while shock waves provide an auxiliary contribution. Experiments using variable cross-section channels further reveal that the pumping head is determined by the orifice diameter at the injection boundary rather than by the tube diameter, enabling an impedance-matching design strategy that decouples the driving and transport sections. Based on time-averaged impulse balance and forced liquid-column oscillation dynamics, a theoretical model is developed to describe the H-Q characteristics and liquid-column motion. The results provide a theoretical foundation and design basis for the development of novel fluid transport devices.