Bacteroides fragilis (B. fragilis) is a Gram-negative, obligate anaerobic, commensal bacterium residing in the human gut and holds therapeutic potential for ulcerative colitis (UC). Previous studies have indicated that capsular polysaccharide A (PSA) of B. fragilis is a crucial component for its effectiveness, possessing various biological activities such as anti-inflammatory, anti-tumor, and immune-modulating effects. We previously isolated and characterized the B. fragilis strain ZY-312 from the feces of a healthy breastfed infant, and extracted its PSA, named TP2. In this study, we explored the impact of TP2 on colonic inflammation and delved into its potential mechanisms. Initially, we used 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce colitis in rats and found that TP2 treatment significantly ameliorated TNBS-induced weight loss, increased clinical scores, extensive ulcers, and intestinal epithelial damage in UC rats. Further analysis revealed that TP2 effectively restored the intestinal barrier integrity in UC rats by regulating the expression of Muc-2, tight junction proteins (ZO-1, occludin, claudin-1, and claudin-2), as well as apoptosis-related proteins Bcl-2, BAX, and Cleaved-Caspase-3. Additionally, TP2 suppressed the expression of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL23, while promoting the secretion of anti-inflammatory cytokines IL-10 and IL-22, thereby inhibiting the occurrence of inflammation. TP2 also downregulated the phosphorylation levels of AKT and PI3K, effectively inhibiting the abnormal activation of the PI3K/AKT signaling pathway. More interestingly, 16S rRNA sequencing results showed that TP2 restored the ecological imbalance of the rat intestinal microbiota, with an increase in beneficial bacteria such as Lactobacillus and Limosilactobacillus observed in the treatment group. In conclusion, TP2 through the regulation of intestinal barrier-related cells and proteins, inhibition of apoptosis, modulation of inflammation-related cytokine levels, and control of abnormal activation of the PI3K/AKT signaling pathway, restores intestinal barrier integrity. Additionally, by reshaping the ecological imbalance of the gut microbiota, TP2 ultimately alleviates ulcerative colitis in rats.

Several studies have demonstrated that chronic hepatitis delta virus (HDV) infection is associated with a worsening of hepatitis B virus (HBV) infection and increased risk of hepatocellular carcinoma (HCC). However, there is limited data on the role of HDV in the oncogenesis of HCC. This study is aimed at assessing the potential mechanisms of HDV‐associated hepatocarcinogenesis, especially to screen and identify key genes and pathways possibly involved in the pathogenesis of HCC. We selected three microarray datasets: GSE55092 contains 39 cancer specimens and 81 paracancer specimens from 11 HBV‐associated HCC patients, GSE98383 contains 11 cancer specimens and 24 paracancer specimens from 5 HDV‐associated HCC patients, and 371 HCC patients with the RNA‐sequencing data combined with their clinical data from the Cancer Genome Atlas (TCGA). Afterwards, 948 differentially expressed genes (DEGs) closely related to HDV‐associated HCC were obtained using the R package and filtering with a Venn diagram. We then performed gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to determine the biological processes (BP), cellular component (CC), molecular function (MF), and KEGG signaling pathways most enriched for DEGs. Additionally, we performed Weighted Gene Coexpression Network Analysis (WGCNA) and protein‐to‐protein interaction (PPI) network construction with 948 DEGs, from which one module was identified by WGCNA and three modules were identified by the PPI network. Subsequently, we validated the expression of 52 hub genes from the PPI network with an independent set of HCC dataset stored in the Gene Expression Profiling Interactive Analysis (GEPIA) database. Finally, seven potential key genes were identified by intersecting with key modules from WGCNA, including 3 reported genes, namely, CDCA5, CENPH, and MCM7, and 4 novel genes, namely, CDC6, CDC45, CDCA8, and MCM4, which are associated with nucleoplasm, cell cycle, DNA replication, and mitotic cell cycle. The CDCA8 and stage of HCC were the independent factors associated with overall survival of HDV‐associated HCC. All the related findings of these genes can help gain a better understanding of the role of HDV in the underlying mechanism of HCC carcinogenesis.

Background and Aims: The predominantly progressive, indeterminate, and predominantly regressive (P-I-R) classification extends beyond staging and provides information on dynamic changes of liver fibrosis. However, the prognostic implication of P-I-R classification is not elucidated. Therefore, in the present research, we investigated the utility of P-I-R classification in predicting the on-treatment clinical outcomes. Approach and Results: In an extension study on a randomized controlled trial, we originally enrolled 1000 patients with chronic hepatitis B and biopsy-proven histological significant fibrosis, and treated them for more than 7 years with entecavir-based therapy. Among the 727 patients with a second biopsy at treatment week 72, we compared P-I-R classification and Ishak score changes in 646 patients with adequate liver sections for the histological evaluation. Progressive, indeterminate, and regressive cases were observed in 70%, 17%, and 13% of patients before treatments and 20%, 14%, and 64% after 72-week treatment, respectively, which could further differentiate the histological outcomes of patients with stable Ishak scores. The 7-year cumulative incidence of HCC was 1.5% for the regressive cases, 4.3% for the indeterminate cases, and 22.8% for the progressive cases (p<0.001). After adjusting for age, treatment regimen, platelet counts, cirrhosis, Ishak fibrosis score changes, and Laennec staging, the posttreatment progressive had a HR of 17.77 (vs. posttreatment regressive; 95% CI: 5.55–56.88) for the incidence of liver-related events (decompensation, HCC, and death/liver transplantation). Conclusions: The P-I-R classification can be a meaningful complement to the Ishak fibrosis score not only in evaluating the histological changes but also in predicting the clinical outcomes.

Aim: To evaluate the efficacy and safety of transarterial chemoembolization (TACE) plus regorafenib and PD-1 inhibitor (T-R-P) versus regorafenib plus PD-1 inhibitor (R-P) as the second-line treatment for unresectable hepatocellular carcinoma (uHCC). Methods: In this retrospective, single-center cohort study, 130 uHCC patients who received second-line therapy between February 2020 and July 2024 were enrolled. Among the 130 enrolled patients, 69 received T-R-P and 61 received R-P. Propensity score matching (PSM) and inverse probability treatment weighting (IPTW) were used to minimize confounding factors. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR). Multivariate Cox regression analysis was used to identify prognostic factors. Subgroup analyses were conducted to assess the treatment benefits in specific patient populations. Results: After PSM, the T-R-P regimen showed significantly improved OS (14.3 vs 8.1 months) and PFS (8.4 vs 4.3 months) compared to the R-P regimen (P < 0.001). According to mRECIST, ORR (56.5% vs 15.2%) and DCR (69.6% vs 37.0%) were also significantly higher with the T-R-P regimen. Multivariate Cox regression analysis identified the T-R-P regimen as an independent protective factor for both OS (hazard ratio [HR] = 0.33, P < 0.001) and PFS (HR = 0.39, P < 0.001). These consistent survival benefits in the T-R-P regimen were maintained in both the unmatched cohort and after IPTW. Subgroup analyses further confirmed the consistent survival benefits of the T-R-P regimen across the most predefined patient subgroups. No treatment-related deaths occurred during the study period. Conclusion: After PSM, the T-R-P regimen continued to demonstrate statistically significant and clinically meaningful improvements in both OS and PFS, coupled with a manageable safety profile, compared to the R-P regimen in patients with uHCC. These findings provide a rationale for considering the T-R-P regimen as a potential second-line treatment option.