Gastroenterology Report最新文献

Background: The tumor microenvironment (TME) plays an important role in regulating gastric cancer (GC) progression. The infiltration of M0 macrophages into the TME negatively affects the prognosis of patients with various tumors.

Methods: The data were obtained from the TCGA and GEO databases and our hospital (107 patients). The expression of IQGAP3 was knocked down in AGS and NCI-N87 GC cells. Cell proliferation, migration, and invasion assays were performed. RNA sequencing was performed on GC cells with different IQGAP3 expression. AGS and THP-1 cells were mixed to create a co-cultured subcutaneous tumor model in nude mice. Tumor growth in the mice was observed by using luciferin fluorescence and the tumor tissues were subjected to immunohistochemistry.

Results: The expression of IQGAP3 was increased in GC tissues (P < 0.001) and was associated with infiltration of M0 macrophages and a poor prognosis for GC patients (P < 0.01). Knockdown of IQGAP3 resulted in decreased expression of CXCL13 (P < 0.001) and less phosphorylation of pSTAT3 and pERK1/2 (P < 0.001). The expression of CXCL13 was decreased after the pSTAT3 and pERK1/2 phosphorylation inhibitors were added. In the co-culture experiment, the M0/THP-1 ratio decreased significantly in the low-IQGAP3-expression group (P < 0.001). However, adding recombinant human CXCL13 proteins to the low IQGAP3 expression group increased the M0/THP-1 ratio. In vivo, tumor growth and M0 macrophage infiltration were both suppressed in the group with low IQGAP3 expression.

Conclusion: IQGAP3 is a potential pro-carcinogenic factor in GC. IQGAP3 promotes the expression and secretion of CXCL13 via the ERK1/2 and STAT3 pathways, thereby causing M0 macrophages to infiltrate the TME.

Background: Chimeric antigen receptor (CAR) T-cell therapy has shown notable advancements in the treatment of solid tumors. Nevertheless, its effectiveness is limited to a small group of patients, highlighting the need for predictive biomarkers. This study aimed to investigate biomarkers associated with the efficacy of CAR-T therapy in hepatocellular carcinoma (HCC).

Methods: We prospectively collected plasma samples from 17 patients with HCC before and after they underwent CAR-glypican-3 (GPC3) T-cell therapy as part of three clinical trials. Plasma proteomic profiling was conducted by using liquid chromatography-mass spectrometry. We examined sequential plasma samples to evaluate the impact of CAR T-cell therapy on the systemic plasma proteome. Additionally, we compared the pretreatment plasma protein profiles between groups with and without clinical benefit (CB) to identify proteins linked to treatment efficacy. The Cox proportional hazard model was used to evaluate the relationship between plasma protein levels and survival outcomes.

Results: Among 5337 plasma proteins, 225 exhibited significant changes following CAR-GPC3 T-cell therapy. The CB group showed an increased expression in proteins related to the type I interferon signaling pathway, T-cell proliferation and activation, tumor necrosis factor production, and antigen processing and presentation. In addition, plasma proteins were significantly associated with survival outcomes, whereas no significant association was observed between clinical variables and prognosis.

Conclusions: Plasma proteomics not only captured CAR-GPC3-driven plasma microenvironment remodeling but also identified baseline proteins predictive of CB and survival, which were superior to clinical variables, thus constituting a candidate biomarker panel for HCC patient selection and response monitoring.

Background: Irritable bowel syndrome (IBS) is a condition with undetermined pathophysiology. Dysregulation of the gut-brain axis has been implicated in its development. This study aimed to investigate the association between gut microbial dysbiosis and brain N-methyl-D-aspartate receptor (NMDAR) hyperfunction in a mouse model of post-infectious IBS (PI-IBS) with visceral hypersensitivity.

Methods: Four-week-old mice were divided into four groups: control mice, PI-IBS mice, PI-IBS mice co-housing with normal mice, and PI-IBS mice administrated with a cocktail of antibiotics. The PI-IBS mouse model was established by using Trichinella spiralis infection. Visceral sensitivity was measured by using the abdominal withdrawal reflex in response to colorectal distension. c-FOS and NMDAR expression in the insula, hippocampus, and hypothalamus were evaluated by using immunostaining and Western blot, respectively. Additionally, NMDAR-mediated evoked excitatory postsynaptic currents (eEPSCs) in these brain regions were recorded by using patch clamp techniques.

Results: Visceral hypersensitivity was observed in PI-IBS mice compared with control mice. Increased c-FOS expressions were observed in the insula and hippocampus of PI-IBS mice. Although no changes in the NMDAR subtypes expression were observed, enhanced NMDAR-mediated eEPSCs were detected in the insula and hippocampus of PI-IBS mice compared with control mice. Co-housing and antibiotics treatment effectively reduced NMDAR-mediated eEPSCs and alleviated visceral hypersensitivity.

Conclusion: Gut microbiota dysbiosis may serve as an initiating factor for NMDAR hyperfunction in PI-IBS with visceral hypersensitivity.

Background: Gastric cancer predominantly occurs in middle-aged and elderly individuals, whereas cases arising in individuals before the age of 45 years are defined as early-onset gastric cancer (EOGC). The biological and clinical characteristics of EOGC remain insufficiently understood. This study aimed to investigate the sex-specific clinicopathological and molecular features of EOGC.

Methods: We retrospectively analysed a large cohort of 4,903 gastric cancer patients, including 410 EOGC patients, to compare survival outcomes and clinicopathological features between EOGC patients and late-onset gastric cancer (LOGC) patients and between male and female EOGC patients. Additionally, transcriptome and genome sequencing data from a public Korean EOGC cohort were analysed to identify sex-specific molecular alterations, which were further validated in a Chinese EOGC cohort by using immunohistochemistry.

Results: Overall survival was significantly shorter in the LOGC group than in the EOGC group. In contrast, EOGC patients were characterized by a greater proportion of females, later T and N stages, more tumours located in the middle third of the stomach, a higher prevalence of diffuse and signet ring cell types, poorer differentiation, smaller tumour size, and lower HER2- and Ki67-positive rates. Among patients with EOGC, females accounted for the majority but had worse outcomes; these female EOGC patients were diagnosed earlier, presented with high proportions of lymph node metastasis and advanced stage, and a higher incidence of differentiated diffuse-type tumours than male EOGC patients. Molecular analyses further revealed female-specific HOXB8 expression upregulation, increased CDH1 mutation numbers, and distinct immune infiltration patterns, which were validated in a Chinese cohort.

Conclusion: EOGC displays pronounced sex-specific clinicopathological and molecular features. These findings highlight the need for sex-based considerations in understanding EOGC biology and tailoring clinical management strategies.

Background: There is no consensus on the adjuvant treatment regimen for patients with colorectal cancer liver metastasis (CRLM) who have achieved successful conversion after surgery. This study aimed to compare the efficacy and safety of chemotherapy alone (CA) versus chemotherapy plus targeted therapy (CT) as adjuvant therapy for CRLM patients.

Methods: Initially unresectable CRLM patients who were converted to hepatectomy with no evidence of disease between June 2013 and June 2020 were retrospectively analysed. The baseline characteristics were balanced between the CA and CT cohorts by using 1:2 propensity score matching (PSM). After PSM, disease-free survival (DFS) and overall survival (OS) were evaluated. A comprehensive subgroup analysis compared the efficacy between the cohorts, with DFS and OS assessed by using a stratified log-rank test and summarized by using Kaplan-Meier and Cox proportional hazards methods.

Results: After PSM, 66 CA and 132 CT patients were included. DFS and OS were similar between the CA and CT cohorts (median DFS: 8.5 vs 10.8 months; median OS: 51.7 vs 56.5 months; both P > 0.050). In the CT cohort, subgroup analysis indicated a favorable trend of DFS for patients with KRAS/NRAS/BRAF mutations and receiving up to four cycles of conversion therapy (P_interaction, 0.005 and 0.013, respectively). In the KRAS/NRAS/BRAF-mutated cohort, CT significantly improved median DFS compared with CA (11.3 vs 7.4 months; hazard ratio, 0.42; 95% confidence interval, 0.26-0.69; P < 0.001).

Conclusion: CT, as adjuvant therapy, effectively reduced intrahepatic and extrahepatic recurrence in initially unresectable CRLM patients. The patients with KRAS/NRAS/BRAF mutations or undergoing up to four cycles of conversion therapy benefited more from CT than from CA.