To identify the enhancer landscape marked by histone H3K27ac modifications in diffuse-type gastric cancer (DGC) tissues, and to elucidate the epigenetic remodeling mechanisms by which active enhancers regulate cachexia-related genes.

Gastric mucosal tissue samples were collected from Department of Gastroenterology of Army Medical Center of PLA during January 2022 to March 2023, including 10 normal gastric mucosa tissues (Normal group), 10 DGC tissues diagnosed with cachexia (DGC group), and 10 organoids derived from DGC tissues (Organoid group). Using H3K27ac chromatin targeting cleavage and tagmentation (CUT&Tag) technology, genomic modification regions were captured to screen specific active enhancers and their potential target genes in DGC tissues. CRISPR-dCas9 gene editing technology was used to intervene with the enhancers, and the expression of target genes was detected with Western blotting and qRT-PCR. Sixteen female SPF-grade BALB/c Nude mice (6~8 weeks old, weighing 18~21 g) were utilized to establish an orthotopic xenograft tumor model using the human diffuse-type gastric cancer cell line MKN45. Cachexia-related phenotypes were evaluated in 3 groups: normal group (n=4), silencing group (n=6), and control group (n=6).

Significant differential enhancer regions were identified between DGC and normal gastric mucosa tissues. DGC tissues exhibited a marked increase in enhancer abundance (P<0.05) and signal intensity when compared with the normal counterparts. Integrated analysis of transcriptome data revealed that some of these active enhancers up-regulated the expression of GDF15, a cachexia-associated target gene in DGC. Targeted silencing of the active enhancer of GDF15 using CRISPR/dCas9-KRAB plasmid technology resulted in a significant reduction in GDF15 expression at both mRNA levels (P<0.05) and protein. Results from orthotopic transplantation experiments of DGC demonstrated that silencing of active enhancers alleviated the cachexia phenotype in nude mice (P<0.05).

DGC exhibits enhancer remodeling, which regulates the expression of the cachexia-associated gene GDF15, and thereby contributes to the pathogenesis and progression of cancer cachexia.

To evaluate the therapeutic efficacies of neoadjuvant immunochemotherapy (NAIC) and neoadjuvant chemotherapy (NAC) for local advanced gastric adenocarcinoma and analyze the clinicopathological characteristics.

A retrospective cohort study was conducted on 243 patients with locally advanced gastric cancer admitted in Army Medical Center of PLA (Daping Hospital) and the First Affiliated Hospital of China Medical University from January 2017 to July 2023. After balancing the confounding factors by inclusion and exclusion criteria and propensity score matching (PSM), the tumor pathological regression (TRG) rate and safety of the 2 neoadjuvant treatment regimens were analyzed, and the clinical pathological characteristics were analyzed to find clinical pathological characteristics related to efficacy.

After using PSM to balance the baseline characteristics of the 2 groups of patients, 53 subjects in each group were included in the analysis. In terms of TRG, the pathological complete response (pCR) rate in the NAIC group (13 patients, 25%) was significantly higher than that in the NAC group (2 patients, 3.8%, P<0.05). Similar results were observed in terms of major pathological response (MPR), with 23 patients (43%) in the NAIC group achieving MPR, while 9 patients (17%) in the NAC group achieved MPR (P<0.05). In terms of safety, the incidence of treatment-related adverse events(TRAEs) of any grade in the NAIC group and the NAC group was comparable (96.2% and 96.2%, respectively). In an exploratory subgroup analysis of tumor pathological regression, the patients with clinicopathological features such as age <65 years, male, stage Ⅲ~ⅣA of American Joint Committee on Cancer (AJCC) staging, histological type of adenocarcinoma, high-moderate differentiated, intestinal-type gastric cancer, stage T3~4 of clinical T-staging, and stage N2~3 of clinical N-staging were more likely to benefit from NAIC.

NAIC results in a higher rate of pathological regression and a comparable incidence of adverse events when compared with chemotherapy alone for patients with local advanced gastric adenocarcinoma.