Hepatocellular carcinoma (HCC) often arises in the setting of chronic inflammation with multiple inhibitory immune signals. V-domain Ig suppressor of T cell activation (VISTA) is identified as a novel negative checkpoint regulator. This study sought to determine the expression and prognostic value of VISTA in HCC and classify tumor microenvironments (TMEs) based on VISTA and CD8+ tumor-infiltrating lymphocytes (TILs). The expression of VISTA and CD8 proteins was assessed in 183 HCC tissue microarrays (TMAs) by immunohistochemistry (IHC). VISTA and CD8A mRNA extracted from 372 patients with HCC in The Cancer Genome Atlas (TCGA) database was included as a validation cohort. Associations between the VISTA, clinicopathological variables, and survival were analyzed. VISTA expression was detected in 29.5% HCC tissues, among which 16.4% tissues were positive for tumor cells (TCs), and 16.9% tissues were positive for immune cells (ICs). VISTA expression was significantly associated with tissues with a high pathological grading (p = 0.038), without liver cirrhosis (p = 0.011), and with a high density of CD8 + TILs (p < 0.001). Kaplan-Meier curves demonstrated that patients with VISTA-positive staining in TCs (p = 0.037), but not in ICs, (p = 0.779) showed significantly prolonged overall survival (OS) than those with VISTA-negative expression. Classification of HCC TME-based VISTA and CD8 + TILs showed 4 immune subtypes: VISTA+/CD8+ (16.9%), VISTA+/CD8- (12.6%), VISTA-/CD8+ (16.4%), and VISTA-/CD8+ (54.1%). The dual positive VISTA+/CD8+ subtype showed significantly prolonged OS than other subtypes (p = 0.023). VISTA protein expression in HCC showed cell specific and displayed different prognosis. VISTA expression was significantly associated with CD8 + TILs, Dual positive VISTA+/CD8+ showed favorable TME and better OS.

Background/purpose: Overt hepatic encephalopathy (HE) risk should be preoperatively predicted to identify patients suitable for curative transjugular intrahepatic portosystemic shunt (TIPS) instead of palliative treatments.Methods: A total of 185 patients who underwent TIPS procedure were randomised (130 in the training dataset and 55 in the validation dataset). Clinical factors and imaging characteristics were assessed. Three different models were established by logistic regression analyses based on clinical factors (Model^C), imaging characteristics (Model^I), and a combination of both (Model^CI). Their discrimination, calibration, and decision curves were compared, to identify the best model. Subgroup analysis was performed for the best model.Results: Model^CI, which contained two clinical factors and two imaging characteristics, was identified as the best model. The areas under the curve of Model^C, Model^I, and Model^CIwere 0.870, 0.963, and 0.978 for the training dataset and 0.831, 0.971, and 0.969 for the validation dataset. The combined model outperformed the clinical and imaging models in terms of calibration and decision curves. The performance of Model^CIwas not influenced by total bilirubin, Child–Pugh stages, model of end-stage liver disease score, or ammonia. The subgroup with a risk score ≥ 0.88 exhibited a higher proportion of overt HE (training dataset: 13.3% vs. 97.4%,p < 0.001; validation dataset: 0.0% vs. 87.5%,p < 0.001).Conclusion: Our combination model can successfully predict the risk of overt HE post-TIPS. For the low-risk subgroup, TIPS can be performed safely; however, for the high-risk subgroup, it should be considered more carefully.Graphic

Introduction: Second near-infrared photothermal therapy (NIR-II PTT) has become a promising strategy for treating cancer in terms of safety and potency. However, the application of NIR-II PTT was limited in the treatment of deep-buried solid tumors due to the low dose of NIR-II absorption nanomaterials and the inadequate laser energy in the deep tumor. Methods: Herein, the authors report the engineering of NIR-II absorbing polyaniline nanorods, termed [email protected] Nanorods, for in situ NIR-II PTT based on optical fibers transmission of laser power and transarterial infusion for the treatment of orthotopic hepatocellular carcinoma in the rabbit. [email protected] Nanorods were prepared via chemical oxidant polymerization of aniline under phosphotungstic acid, which exhibited effective NIR-II absorption for hyperthermia ablation cells. Results: [email protected] Nanorods were fast and efficiently deposited into primary orthotopic transplantation VX2 tumor in rabbits via transarterial infusion. Furthermore, an optical fiber was interventionally inserted into the primary VX2 tumor to transmit 1064nm laser energy for in situ NIR-II PTT, which could ablate primary tumor, inhibit distant tumor, and suppress peritoneal metastasis. Conclusion: This study provides new insights into the application of in situ NIR-II PTT based on optical fibers transmission of laser power and transarterial injection of NIR-II absorption nanomaterials to treat deep-buried tumors. Graphical Abstract:

Background: Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. High-mobility group box 1 (HMGB1), a highly conserved chromosome protein, is considered as a potential therapeutic target and novel biomarker because of its regulation in the proliferation and metastasis of HCC. Ozone has been shown to be beneficial in the treatment of cancer. The objective of this study was to explore the effects and molecular mechanism of ozonated water on the proliferation, migration, and invasion of BEL7402 HCC cells. Materials and Methods: We assessed cell proliferation using a CCK-8 assay kit and flow cytometry; we performed wound healing and transwell assays to evaluate the effects of ozonated water treatment on cell invasion and migration. We determined reactive oxygen species (ROS) values by flow cytometry and used ELISAs to detect cytokines HMGB1, IL-6, and TNF-α. In addition, we assessed mRNA and protein cytokine expressions using RT-qPCR and Western blot. Results: Ozonated water decreased the viability of the HCC cells; the IC50 of ozonated water at 24 h was approximately 1.5 μg/mL. Compared with control groups, ozone treated cells revealed reduced mobility on wound healing assays and decreased invasion in transwell assays. HMGB1, IL-6, and TNF-α cytokines were found at lower levels in ozone treated cells than in control cells. Ozonated water-induced ROS accumulation. Likewise, the expressions of phosphorylated nuclear factor Kappa B (NF-κB), p65, NF-κB, P-STAT3, IL-6, JAK2, Slug, Twist, vimentin, MMP-2, MMP-9, and HMGB1 were decreased in the treated cells. Conclusion: Our findings suggest that ozonated water inhibits the proliferation, invasion, and metastasis of HCC cells via regulation of the HMGB1/NF-κB/STAT3 signaling pathway.