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Purpose: To provide a detailed pooled analysis of the diagnostic accuracy of microRNAs (miRNAs) in predicting the response to transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC). Methods: A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library, and Web of Science to identify studies assessing the diagnostic performance of miRNAs in predicting TACE response in HCC. Two independent reviewers performed quality assessment and data extraction using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the summary receiver operating characteristic (SROC) curve were calculated using a bivariate random-effects model. Subgroup analyses and meta-regression were performed to explore potential sources of heterogeneity, including sample size, response criteria, specimen source, response evaluation methods, TACE efficacy interval window, and geographical location. Results: Seven studies, comprising 320 HCC responders and 187 non-responders, were included in this meta-analysis. The miRNAs studied included miR-373, miR-210, miR-4492, miR-1271, miR-214, miR-133b, and miR-335. The pooled sensitivity of miRNAs in predicting recurrence after TACE was 0.79 [95% CI: 0.72-0.84], and the pooled specificity was 0.82 [95% CI: 0.74-0.88]. The DOR was 17 [95% CI: 9-33], and the pooled area under the SROC curve (AUC) was 0.85 [95% CI: 0.81-0.88], indicating excellent diagnostic accuracy. Subgroup analyses revealed significant differences in diagnostic performance based on response criteria and geographical location. Meta-regression did not identify any significant sources of interstudy heterogeneity. Conclusion: MiRNAs show promise as diagnostic tools for predicting TACE response in HCC patients. However, their clinical application requires further validation in larger cohorts. Future research should focus on standardizing RNA extraction methods, selecting consistent endogenous controls, and adopting uniform response evaluation criteria to improve reliability and reduce variability. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is the seventh most common cancer in the world and is a form of liver cancer that starts in the cells of the liver. The best way to increase the chances of survival for people at high risk for HCC is to detect it early through regular monitoring. For monitoring purposes, it is recommended to conduct ultrasound exams every 4 to 6 months, sometimes in combination with alpha-fetoprotein tests. Aim of the work: Assess the HCC surveillance and its ability to detect HCC patients early on and improve their management. Patients and methods: The study involved 300 patients of hepatocellular carcinoma (HCC) investigated at Menoufia University's Institute of National Liver in Egypt. Patients were evaluated using the Liver Cancer of Barcelona Clinic (BCLC) staging system. Furthermore, the patients were classified into three surveillance categories: no surveillance, routine surveillance, and sporadic surveillance. Results: A substantial difference statistically among the groups that received and did not receive surveillance with consideration for the stage of hepatocellular carcinoma (HCC) in particular was found. Patients who were observed usually got their diagnoses earlier. Those who were not under surveillance frequently had advanced cases of hepatocellular carcinoma upon diagnosis (HCC). Conclusion: High-risk patients were regularly investigated for having HCC is necessary for early disease detection, appropriate therapy, and improved survival. Consistent monitoring with AFP and ultrasound allows for early detection of HCC. [ABSTRACT FROM AUTHOR]

Background: Elevated levels of carbohydrate antigen 19-9 (CA19-9) levels are known to worsen outcomes in various tumors by influencing immune responses. However, the role of CA19-9 in immunotherapy for hepatocellular carcinoma (HCC) remains poorly understood. Methods: This study included 621 patients treated with anti-PD-1/PD-L1 treatment at the First Affiliated Hospital of Sun Yat-sen University from January 2017 to March 2023. During immunotherapy, CA19-9 levels were measured and classified as either elevated (≥35 U/mL) or normal (<35 U/mL) for clinical analysis. Results: Patients with elevated CA19-9 levels had significantly worse progression-free survival (PFS) and overall survival (OS). The 1-year and 2-year PFS rates were 53.3% and 29.1% in the normal CA19-9 group compared to 16.9% and 11.3% in the elevated group (p < 0.001). Similarly, the 1-year and 2-year OS rates were 90.5% and 75.5% in the normal group versus 64.0% and 36.5% in the elevated group (p < 0.001). Multivariate analysis confirmed CA19-9 was an independent prognostic factor for both PFS and OS. Bioinformatic analysis indicated that FUT3, a key gene in CA19-9 synthesis, correlated with increased macrophage infiltration. And increased M2 macrophage levels and reduced M1 macrophage levels were noted in HCC samples with elevated CA19-9 levels. Further in vivo experiments indicated blocking CA19-9 improved the efficacy of PD-1 treatment through inducing the M1-like polarization of macrophages. Conclusions: Our findings demonstrate that elevated CA19-9 levels during immunotherapy are associated with poor survival outcomes in HCC patients. These findings highlight the crucial role of CA19-9 in shaping the tumor immune environment, particularly through its effect on macrophage polarization, and suggest that targeting CA19-9 may improve immunotherapy outcomes. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the most prevalent causes of cancer-related morbidity and mortality worldwide. Late-stage detection and the complex molecular mechanisms driving tumor progression contribute significantly to its poor prognosis. Dysregulated R-loops, three-stranded nucleic acid structures associated with genome instability, play a key role in the malignant characteristics of various tumors. However, the detailed role and mechanism of R-loops in HCC progression remain elusive and require further exploration. This study aimed to construct an R-loop scoring signature centered on prognosis and lipid metabolism, thereby enhancing our understanding of HCC progression and identifying potential therapeutic targets. Methods: In this study, we utilized the single-cell RNA-sequencing (scRNA-seq) data from HCC patients (GSE149614 and CRA002308) to construct an R-loop scoring model based on the identified R-loop regulator genes (RLRGs) related to HBV infection through WGCNA analysis. We also explored the tumor microenvironment and intercellular communication related to R-loop score. Additionally, a prognostic risk model based on the fatty acid metabolism-associated RLRGs was constructed using data from the TCGA database, and its association with immune infiltration, mutations, and drug sensitivity was analyzed. In vitro and in vivo experiments were performed to investigate the role of RLRG CLTC in lipid metabolism and HCC progression. Results: Using scRNA-seq data from HCC, we established an R-loop scoring model based on identified RLRGs related to HBV infection. Moreover, the more suppressive tumor immune microenvironment and stronger intercellular communication were displayed in malignant cells with high R-loop scores. The cell trajectory and cellular metabolism analysis exhibited a significant association between lipid metabolism and RLRGs. Additionally, we constructed a prognostic risk model consisting of 8 RLRGs related to fatty acid metabolism, which effectively evaluated the prognostic value, status of tumor immune microenvironment, gene mutations, and chemotherapeutic drug sensitivity for HCC patients. Notably, validation experiments suggested that CLTC could regulate lipid metabolism through R-loop formation and facilitate tumor progression in HCC. Conclusion: Collectively, our study proposes an R-loop scoring model associated with tumor immune microenvironment, lipid metabolism and prognostic value. CLTC, an R-loop regulator, emerges as a promising prognostic biomarker and therapeutic target, offering new insights into potential treatment strategies for HCC patients. [ABSTRACT FROM AUTHOR]

Objectives: GPC3 has been recognized as a promising target for immunotherapy in hepatocellular carcinoma (HCC). However, the GPC3-targeted immunotherapies have shown limited therapeutic efficacy. The use of anti-PD-1/PD-L1 monoclonal antibodies in HCC treatment is considerably constrained. Furthermore, there is still a notable lack of understanding concerning the immune landscape in HCC, especially regarding varied GPC3 expression levels. Therefore, thorough exploration of the intricate tumor immune microenvironment at different GPC3 expression levels is essential for guiding and improving HCC treatment strategies. Methods: Sixty patients with HCC were enrolled in this study, receiving a first-line treatment that combined anti-angiogenesis targeted drugs and immunotherapy. Immunohistochemistry was used to assess the levels of GPC3 expression. Multiple immunohistochemical markers, such as CD8, PD-1, LAG3, TIGIT, TIM-3, CD103, Claudin18.2, PD-L1, CD4, Foxp3, CD68, CD163, GPC3, CD11C, CD14, CD66b, and HLA-DR, were used to characterize the immune microenvironment and spatial distribution of immune cells in HCC tumors with different levels of GPC3 expression. Cell expression levels and spatial distribution were determined by fluorescence staining and subsequent analysis of fluorescence intensity using the Panoramic Pathology Workstation (Pano ATLAS). This approach facilitated a detailed examination of cell characteristics and spatial information within the samples. Results: Based on the result of GPC3 immunohistochemical analysis, patients with strong positive GPC3 expression were classified as high GPC3 expression, while the others were classified as low GPC3 expression. Patients in the low GPC3 expression group had longer overall survival (OS) than in the high group (P = 0.003, HR = 2.9240). Further exploration of the immune microenvironment based on different GPC3 expression levels revealed that in high GPC3 expression group, the proportions of CD8+ T cells(P = 0.0435), TIM-3+ T cells(P = 0.0447), CD103+CD8+ tissue-resident T cells(P = 0.0410), CD11C+CD14−DC cells(P = 0.0497), CD11C+HLA-DR−DC cells(P = 0.0309), CD11C+CD14−HLA-DR−DC cells(P = 0.0233), and CD11C+CD14−CD66b−DC cells(P = 0.0474) were all higher compared to low expression group. At spatial distances of 10 μm, 20 μm, and 30 μm, the levels of CD8+ T cells were higher in the high expression group compared to the low expression group (high vs. low: P = 0.0281, P = 0.0236, P = 0.0220). Conclusions: Multiple immunohistochemistry is a powerful technique for exploring the intricate immune microenvironment of hepatocellular carcinoma, enabling the precise identification of diverse cell subsets and their spatial distribution within the tumor microenvironment. This methodology provides valuable insights into the complex interactions and spatial organization of immune cells in the context of hepatocellular carcinoma progression. Low GPC3 expression in HCC patients indicates potential benefits from combined targeted and immunotherapy. Different levels of GPC3 expression levels can predict the effectiveness of targeted combination immunotherapy in HCC patients. Additionally, different GPC3 expression patterns in HCC patients correspond to unique tumor immune microenvironments, which have implications for guiding HCC treatment approaches. [ABSTRACT FROM AUTHOR]

Background: Triggering receptor expressed on myeloid cells 2 (TREM2), a surface receptor predominantly expressed on myeloid cells, is a major hub gene in pathology-induced immune signaling. However, its function in hepatocellular carcinoma (HCC) remains controversial. This study aimed to evaluate the role of TREM2 in the tumor microenvironment in the context of HCC progression. Methods: HCC was experimentally induced in wild-type (WT) and Trem2-deficient (Trem2−/−) mice, and clinical sample analysis and in vitro studies on macrophages were conducted. HCC cells were treated with conditioned medium from WT or Trem2−/− macrophages, and their malignant phenotypes and underlying mechanisms were analyzed. Results: TREM2 deficiency reduced liver tumor burden in orthotopic and subcutaneous HCC models by altering CD8+ T cell infiltration. Trem2-deficient macrophages presented increased chemokine secretion. TGF-β1 was found to be positively correlated with TREM2 expression in HCC, and TGF-β blockade reversed TREM2 induction. On the other hand, TREM2+ macrophages were found to be associated with glycolysis and PKM2 expression in HCC cells; this association may be related to the secretion of IL-1β, which enhances the malignant phenotypes of HCC cells. Conclusions: These results reveal that TREM2+ macrophages play a driving role in HCC progression by suppressing CD8+ T cell infiltration and promoting tumor cell glycolysis, providing a new therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

The oncogenes yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are potent liver oncogenes. Because gene mutations cannot fully explain their nuclear enrichment, we aim to understand which mechanisms cause YAP/TAZ activation in liver cancer cells. The combination of proteomics and functional screening identified numerous apical cell polarity complex proteins interacting with YAP and TAZ. Co-immunoprecipitation (Co-IP) experiments confirmed that membrane protein palmitoylated 5 (MPP5; synonym: PALS1) physically interacts with YAP and TAZ. After removing different MPP5 protein domains, Co-IP analyses revealed that the PDZ domain plays a crucial role in YAP binding. The interaction between YAP and MPP5 in the cytoplasm of cancer cells was demonstrated by proximity ligation assays (PLAs). In human hepatocellular carcinoma (HCC) tissues, a reduction in apical MPP5 expression was observed, correlating with the nuclear accumulation of YAP and TAZ. Expression data analysis illustrated that MPP5 is inversely associated with YAP/TAZ target gene signatures in human HCCs. Low MPP5 levels define an HCC patient group with a poor clinical outcome. In summary, MPP5 facilitates the nuclear exclusion of YAP and TAZ in liver cancer. This qualifies MPP5 as a potential tumor-suppressor gene and explains how changes in cell polarity can foster tumorigenesis. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a heterogeneous tumor associated with several risk factors, with non-alcoholic fatty liver disease (NAFLD) emerging as an important cause of liver tumorigenesis. Due to the obesity epidemics, the occurrence of NAFLD has significantly increased with nearly 30% prevalence worldwide. HCC often arises in the background of chronic liver disease (CLD), such as nonalcoholic steatohepatitis (NASH) and cirrhosis. Gut microbiome (GM) alterations have been linked to NAFLD progression and HCC development, with several investigations reporting a crucial role for the gut–liver axis and microbial metabolites in promoting CLD. Moreover, the GM affects liver homeostasis, energy status, and the immune microenvironment, influencing the response to immunotherapy with interesting therapeutic implications. In this review, we summarize the main changes in the GM and derived metabolites (e.g., short-chain fatty acids and bile acids) occurring in HCC patients and influencing NAFLD progression, emphasizing their potential as early diagnostic biomarkers and prognostic tools. We discuss the weight loss effects of diet-based interventions and healthy lifestyles for the treatment of NAFLD patients, highlighting their impact on the restoration of the intestinal barrier and GM structure. We also describe encouraging preclinical findings on the modulation of GM to improve liver functions in CLD, boost the antitumor immune response (e.g., probiotic supplementations or anti-hypercholesterolemic drug treatment), and ultimately delay NAFLD progression to HCC. The development of safe and effective strategies that target the gut–liver axis holds promise for liver cancer prevention and treatment, especially if personalized options will be considered. [ABSTRACT FROM AUTHOR]

Background: Altered metabolism has become an important characteristic of cancer, and acyl-CoA dehydrogenase short-chain (ACADS), a regulator of lipid synthesis, is involved in carcinogenesis-associated metabolic pathways. DNA methylation is an important mechanism for silencing ACADS in various malignancies. However, the specific role of ACADS in hepatocellular carcinoma (HCC) pathogenesis remains poorly understood. Methods and results: Using RNA sequencing data from different tumours in The Cancer Genome Atlas database, we observed that ACADS was downregulated and hypermethylated in HCC. Three potential CpG island sites (cg01535453, cg08618068, and cg10174836) were identified in the ACADS promoter. Through in vivo and in vitro experiments, we confirmed that cg08618068 was methylated in HCC. We defined this site as ACADS methylation site-2 (ACADS MS-2). Methylation of ACADS MS-2 was associated with worse survival, and mutation of MS-2 increased ACADS mRNA levels in five HCC cell lines. Sustained overexpression of ACADS not only suppressed the proliferation, migration, and invasion of HCC cells but also promoted immunogenic cell death (ICD) via the upregulation of calreticulin. Subsequently, we established a specific nomogram based on ACADS methylation levels to evaluate the 3- and 5-year overall survival rates of patients with HCC who underwent surgical resection. Conclusions: Our work clarified that ACADS acts as a putative tumour suppressor in HCC and confirmed that a nomogram including ACADS methylation had good predictive performance in HCC. We also discovered a correlation between ACADS and ICD, suggesting that ACADS is an essential target for immunotherapy in HCC. [ABSTRACT FROM AUTHOR]

Background: The insulin-like growth factor 2 (IGF2) and H19 are overexpressed in hepatocellular carcinoma (HCC). IGF2-derived miR-483-5p is implicated in the development of cancers. Here, we investigated the involvement of miR-483-5p in IGF2 and H19 overexpression regulation and its role in HCC. Methods: Firstly, the effect of miR-483-5p on the expression of IGF2 and H19, and the binding of miR-483-5p to IGF2/H19 enhancer were evaluated in HCC cells. Next, miR-483-5p-mediated IGF2/H19 enhancer activation and its mechanism were investigated in HCC cells. Then, the mechanism by which active IGF2/H19 enhancer mediated by miR-483-5p activate IGF2/H19 promoters was studied in HCC cells. Finally, the effect of MED1 on the expression of IGF2/H19 as well as the malignant phenotype of HCC cells in vitro and in vivo mediated by miR-483-5p was evaluated. Results: Mir-483-5p up-regulated IGF2 P2 mRNA-P4 mRNA and H19 expression by binding to IGF2/H19 enhancer resulting in IGF2/H19 enhancer activation in HCC cells. Mechanistically, miR-483-5p increased recruitment of Ago1 and Ago2 at IGF2/H19 enhancer and then activated transcription of IGF2/H19 eRNA by RNA polymerase II and p300, which further induced chromatin loops formation between IGF2/H19 enhancer and IGF2/H19 promoters to activate IGF2/H19 promoters via IGF2/H19 eRNA-MED1-IGF2/H19 promoters complex in HCC cells. In this process, MED1 promoted chromatin loops formation as well as the malignant phenotype of HCC cells in vitro and in vivo mediated by miR-483-5p. Conclusions: miR-483-5p-mediated activating of IGF2/H19 enhancer up-regulates IGF2/H19 expression via DNA loops, thereby promoting the malignant progression of HCC. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular Carcinoma (HCC) and cholangiocellular adenocarcinoma (CCA) are the most common primary liver tumors representing a major global health burden. In early disease stages, tumor resection may provide long-term survival in selected patients. However, morbidity and mortality rates are still relatively high after extended liver surgery with perioperative bacterial infections representing major complications. In this study, we evaluate the impact of perioperative infection on the postoperative overall survival (OS) of patients undergoing resection of HCC or CCA. Material and methods: Two hundred two patients that received liver surgery for HCC (139) or CCA (63) at our tertiary referral center were included between 2008 and 2020. Infection prior or after surgery was assessed using patient documentation and correlated to patients´ survival rates and other clinical characteristics. Results: Patients with perioperative infection displayed a significantly impaired OS compared to patients without a documented infection (419 (95% CI: 262–576) days vs. 959 (95% CI: 637–1281) days; log rank X2(1) = 10.28; p < 0.001). Subgroup analysis revealed that this effect was only observed among HCC patients, while the outcome of CCA patients was independent of pre- or postoperative infections. Moreover, non-anatomical resection of liver tumors was beneficial in patients with HCC (1541 (95%CI: 1110–1972) vs. 749 (95%CI: 0–1528) days; log rank X2(1) = 5.387; p = 0.02) but not CCA. Conclusion: Perioperative infection is an important prognostic factor after surgery for HCC but not CCA. [ABSTRACT FROM AUTHOR]

Simple Summary: Tumor-associated macrophages (TAMs) represent a challenge in developing an effective and safe therapy for HCC. TAMs are considered to be one of the major mechanisms for HCC resistance to current therapies. TAMs, known as M1-like and M2-like macrophages, were discovered to be subdivided into four subsets (M2a, M2b, M2c, and M2d). Each subset has a hypothetical contribution as a TAM immunosuppressive cell. Several trials have studied removing or modulating the immune suppressive roles of TAMs in the HCC microenvironment. Identifying TAMs' behavior and subsets may be crucial for modulating the immune suppression in the HCC microenvironment. Hepatocellular carcinoma (HCC) is a major global health issue characterized by poor prognosis and complex tumor biology. One of the critical components of the HCC tumor microenvironment (TME) is tumor-associated macrophages (TAMs), which play a pivotal role in modulating tumor growth, immune evasion, and metastasis. Macrophages are divided into two major subtypes: pro-inflammatory M1 and anti-inflammatory M2, both of which may exist in TME with altered function and proportion. The anti-inflammatory M2 macrophages are further subdivided into four distinct immune suppressive subsets. TAMs are generally counted as M2-like macrophages with altered immune suppressive functions that exert a significant influence on both cancer progression and the ability of tumors to escape immune surveillance. Their involvement in modulating immune responses via different mechanisms at the local and systemic levels has made them a key target for therapeutic interventions seeking to enhance treatment outcomes. How TAMs' depletion influences immune responses in cancer is the primary interest in cancer immunotherapies. The purpose of this review is to delve into the recent progress made in TAM-targeting therapies. We will explore the current theories, benefits, and challenges associated with TAMs' depletion or inhibition. The manuscript concludes with future directions and potential implications for clinical practice. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is among the most aggressive and lethal human tumors. Many functional studies have demonstrated the role of non-coding RNAs (ncRNA), particularly microRNAs (miRNA), in the regulation of hepatocarcinogenesis driving pathways. MiR-125a-5p (miR-125a) has been consistently reported as an oncosuppressive miRNA, as demonstrated in vivo and in vitro. However, its HCC relevant targets and molecular mechanisms are still largely unknown. Here, a genome-wide perspective of the whole miR-125a targetome has been achieved. In particular, two different HCC cell lines were subjected to a miRNA boosting by mimic transfections, and consequently many genes were de-regulated, as observed by a transcriptomic approach. The merging of down-regulated genes with results from bioinformatic predictive tools yielded a number of candidate direct targets that were further experimentally validated by luciferase-based reporter assays. Different novel targets were found, in particular ARID3A, CCNJ, LIPA, NR6A1, and NUP210, oncogenes in various tumors and here also related to HCC through miR-125a regulation. The RNA interactions investigated in this work could pave the way to piece together the RNA regulatory networks governed by the miRNA impacting on hepatocarcinogenesis, and be exploited in the future for identifying novel biomarkers and therapeutic targets in HCC. [ABSTRACT FROM AUTHOR]

Background: The association between aspirin and hepatocellular carcinoma (HCC) has been reported to prevent carcinogenesis caused by hepatitis B or C virus infection. The objective of this study was to investigate the prognostic impact of aspirin in patients who underwent liver resection for HCC. Methods: Data for 1032 patients who underwent primary resection for HCC between 2000 and 2019 were reviewed. There were 87 patients (8.4%) who took aspirin (aspirin group) and 945 (91.6%) who did not (non-aspirin group). Short-term outcomes, recurrence-free survival (RFS), and overall survival (OS) were compared between two groups in the matched cohort using propensity-score matching. Results: The median patient follow-up was 42.6 months (95% confidence interval 3.12–136.8 months). There was no significant difference in short-term outcomes, including bleeding events. RFS and OS after liver resection in the aspirin group were significantly better than those in the non-aspirin group in the unmatched cohort [5-year RFS rate: 50.3% vs 31.4%, hazard ratio (HR) 0.55, P = 0.0002; 5-year OS rate: 82.9% vs 70.2%, HR 0.46, P = 0.002]. In the matched cohort, RFS and OS after liver resection in the aspirin group were also significantly better than those in the non-aspirin group (5-year RFS rate: 50.3% vs 32.0%, HR 0.60, P = 0.003; 5-year OS rate: 82.9% vs 74.6%, HR 0.56, P = 0.03). Conclusion: Use of aspirin was associated with better prognosis for patients who underwent primary resection for HCC. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor (ICI)-based immunotherapy has emerged as the most promising strategy for hepatocellular carcinoma (HCC) downstaging prior to liver transplantation (LT). However, further evidence is required to assess the feasibility and safety of pretransplant ICI exposure. We retrospective analyzed 159 HCC patients who underwent LT at our institution from June 2019 to December 2023, and 39 recipients (39/159, 24.5%) received pretransplant ICI therapy. The perioperative acute rejection rate and rejection-related mortality rate in the ICI group were 23.1% (9/39) and 12.8% (5/39), respectively, which were significantly higher than those in the non-ICI group, at 5% (6/120, P = 0.002) and 0% (0/120, P = 0.001). There was no significant difference in the 90-day post-transplant overall survival (OS) (P = 0.447) and recurrence-free survival (RFS) (P = 0.723) between these two groups. We found 37.1% (59/159) recipients were found to have microvascular invasion (MVI), no matter whether the HCC tumor is within Milan criteria or not. Notably, though MVI was identified as a risk factor for the LT recipients, pretransplant ICI exposure appeared to be a protective factor for HCC patients with MVI which benefits its overall survival. Besides, the RFS and OS in the ICI exposure recipients with MVI were comparable to the non-ICI exposure recipients without MVI. However, no synergistic anti-tumor effects were observed with pretransplant ICI immunotherapy when combined with locoregional of TACE, HAIC, RFA and systematic of lenvatinib or sorafenib downstaging treatments, nor with post-transplant adjuvant of systematic or FOLFOX chemotherapy. Further comprehensive studies are needed to balance the dual natural effects of immunotherapy by optimizing downstaging protocols and patient selection to reduce acute rejection and improve long-term survival. [ABSTRACT FROM AUTHOR]

Purpose The purpose of this article is to classify hepatocellular carcinoma (HCC) based on imaging and to evaluate the role of ultrasound-guided microwave ablation (MWA) in the management of type 2 exophytic HCC. Materials and Methods A retrospective study was performed at our institution after approval by the Institutional Review Board. The study was undertaken from January 2017 to May 2022. Based on the location, HCC was classified and categorized on cross-sectional imaging into four types. All MWA procedures were performed using ultrasound guidance. Patients were followed up every 3 months with cross-sectional imaging. Results During the study period, 225 lesions were reviewed. MWA was performed in 13 type 2 exophytic HCC patients. Segment 3 (38%) was the most common site when categorized as per Couinaud classification and segment 6 was the next common site. Technical success of complete ablation, evaluated by postprocedure contrast-enhanced computed tomography scan, was 100%. The median follow-up period was 24 months (range: 9–24 months). One patient presented with a residual lesion on the first follow-up at 30 days. Two other patients followed up to 9 months were free of HCC. Ten patients followed up at 1 year showed no recurrence, while 7 of them were followed up for 24 months, and 1 of whom showed multicentric recurrence which was treated by selective intra-arterial radiation therapy. Conclusion A classification system for exophytic lesions can allow for better patient selection, planning, and reporting of ablative outcomes. MWA has performed well when ablating these technically challenging lesions with a certain degree of planning. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a highly malignant cancer and lacks effective therapeutic targets. The role of LIM/homeobox protein Lhx3 (LHX3) has been extensively studied in various tumor tissues, where it has been identified as a promoter of tumorigenesis and malignancy. However, the specific functional role and potential mechanism of LHX3 in human HCCs are not clearly clarified. We found that LHX3 was overexpressed in HCC tissues compared to adjacent tissues. Moreover, it was observed that LHX3 promoted the epithelial-mesenchymal transition (EMT) of HCC cells, leading to increased proliferation, migration, and viability, and adhesion ability in vitro. Mechanistically, LHX3 facilitated TCF4 binding to β-catenin, forming a stable LHX3/TCF4/β-catenin complex that activated downstream target genes. Disruption of the β-catenin/TCF4 interaction by Toxoflavin prevented the EMT of HCC cells. Overall, these findings highlight the critical role of LHX3 in the EMT of HCC cells through the β-catenin/TCF4 axis, suggesting the LHX3/β-catenin/TCF4 axis as a potential therapeutic target for HCC treatment. [ABSTRACT FROM AUTHOR]

There is significant variation in HCC management across different centers with poor adherence to evidence-based clinical practice guidelines as assessed in prior studies. In Australia, quality indicators (QIs) have recently been proposed by a multidisciplinary group of experts to help provide a framework to assess and monitor the quality of HCC care. In this review, we discuss the many areas where real-world practice deviates from evidence-based medicine, the role that QI sets play in addressing this gap, and the similarities and differences between Australian QIs and other leading treatment guidelines and QI sets from around the world. We focus on the utility of QI sets to identify opportunities for targeted improvement in the real-world clinical environment. We conclude with a discussion about the formation of a national clinical quality registry as a long-term measure to facilitate continual improvements in patient care within and across sites in order to optimize patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Sorafenib is a first-line treatment for hepatocellular carcinoma (HCC); however, acquired resistance often results in a poor prognosis, indicating a need for more effective therapies. Sorafenib induces cell death through an iron-dependent mechanism known as ferroptosis, which is closely associated with the onset and progression of HCC. Methods: This study investigated the role of ACSL3 in sorafenib resistance and ferroptosis in HCC. The expression of ACSL3 was analyzed in HCC tissues and cell lines. Ferroptosis levels and cell viability were assessed in ACSL3-silenced HCC cells treated with sorafenib. The regulatory relationship between the transcription factor MEF2D and ACSL3 was evaluated using promoter binding assays and gene expression analysis. Results: ACSL3 was aberrantly expressed in HCC and promoted the progression of non-alcoholic fatty liver disease (NAFLD) to HCC. Elevated ACSL3 expression inhibited ferroptosis and enhanced resistance to sorafenib. The transcription factor MEF2D directly regulated the upregulation of ACSL3 expression. MEF2D bound to the promoter regions of ACSL3 to enhance its transcription and negatively regulate ferroptosis in HCC. Conclusion: This study demonstrated for the first time that MEF2D regulated ACSL3 expression and mediated sorafenib resistance by inhibiting ferroptosis in HCC, providing a potential therapeutic target for improving HCC outcomes. [ABSTRACT FROM AUTHOR]

Background: Programmed death-ligand 1 (PD-L1) expression is abundant not only in malignant cells but also in infiltrating cells within the tumor microenvironment (TME) of hepatocellular carcinoma (HCC). This study explored the association between PD-L1 expression in TME and outcomes in HCC patients treated with atezolizumab plus bevacizumab (AB), emphasizing the implications of PD-L1 expression in both malignant and tumor-infiltrating cells. Methods: This study included 72 patients with HCC who underwent percutaneous core needle liver biopsy before AB treatment between September 2020 and December 2023. PD-L1 expression on tumor tissues was assessed using the combined positive score (CPS) with cutoff values of 1 and 10, utilizing antibody clone 22C3 (Dako). Results: The distribution of PD-L1 CPS included 24 patients with CPS <1, 33 patients with CPS 1–10, and 15 patients with CPS ≥10. Significant differences in overall survival (OS) were observed across the three groups, with CPS ≥10 showing the highest survival rates (p = 0.010). Patients with CPS ≥10 had better OS than those with CPS <10 (median OS 14.8 vs. 8.3 months, P = 0.046), and CPS ≥1 had better OS than CPS <1 (P = 0.021). For progression-free survival (mPFS), the CPS ≥10 group had the highest median PFS of 11.0 months among the three groups (P = 0.044). Objective response rates (ORR) were higher in the PD-L1 CPS ≥10 group than in the 1-10 and <1 group (53.3%, 27.3%, and 16.7%, respectively; P =.047). Multivariate analysis identified that PD-L1 expression ≥10 and ≥1 were associated with favorable outcomes regarding OS (hazard ratio [HR] 0.283, P =.027 and HR 0.303, P =.006, respectively). Conclusions: Combined analysis of PD-L1 expression in malignant and tumor-infiltrating cells can be a promising biomarker for the prognosis of HCC patients treated with AB. [ABSTRACT FROM AUTHOR]

Purpose: This work investigated the effect of FBXO5 in hepatocellular carcinoma (HCC) and the mechanism of action of arbutin in its inhibition. Methods: FBXO5 mRNA and protein expressions in the tumor were assessed using TCGA, ICGC and HPA databases. Cox regression analysis and Kaplan–Meier survival curves were employed to assess the impact of FBXO5 on the survival outcomes of patients with HCC. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and Gene Set Variation Analysis (GSVA) were used to investigate the biological function associated with FBXO5-related genes. The role of FBXO5 as oncogene and the inhibitory mechanism of arbutin were confirmed through western blotting (WB), reverse transcription quantitative polymerase chain reaction (RT-qPCR), and in vitro experiments such as scratch wound-healing migration assay, plate clone formation assay, and transwell migration assay. Results: Patients with high FBXO5 expression showed shorted overall survival (OS), progression-free survival (PFS), disease-specific survival (DSS), and disease-free survival (DFS). FBXO5 was identified as an independent prognostic risk factor associated with the cell cycle. In vitro investigations indicated that FBXO5 facilitated HCC progression by modulating the cell cycle, while arbutin suppressed FBXO5 expression and regulated cell cycle dynamics. Conclusion: FBXO5 is a potential diagnostic and prognostic biomarker for HCC, and arbutin may exert anticancer effects through the suppression of FBXO5 expression. [ABSTRACT FROM AUTHOR]

Background: Human leukocyte antigen-G (HLA-G) is a cancer-associated immune checkpoint protein implicated in tumor-driven immune escape mechanisms. This study was undertaken to determine genetic variations at the 3'-UTR of the HLA-G gene that may alter its expression, identify risk alleles and genotypes for their association with hepatocellular carcinoma (HCC), and treatment responses in the Indian population. Objectives: Case-control genetic association study of HLA-G gene UTR polymorphisms with HCC and response to locoregional therapy (LRT). Methods: HCC cases (n = 100) and healthy controls (n = 110) were recruited for the genetic association study, of which 88 patients received LRT. Single nucleotide polymorphisms (SNPs) at the HLA-G 3'-UTR gene were genotyped by sequencing and PCR-RFLP. The genetic association of 14 SNPs with HCC and LRT responses was determined using population genetic approaches. Results: Three of the 14 SNPs (rs1707, rs1710, and rs1063320) were found to be genetically associated with HCC risk and treatment responses. These three UTR SNPs are important for miRNA binding. We did not observe significant association of the most studied SNP, rs371194629 (INDEL, +2960), with HCC or treatment response. Serum sHLA-G levels were found to be significantly (p = 0.027) higher in HCC patients as compared to healthy controls. Highly prevalent UTR haplotypes in Indian HCC patients were UTR-4, -1, and -7 whereas in healthy controls it was UTR-3, and 15 as determined by a linkage disequilibrium (LD) plot using 8 SNPs. Conclusion: HLA-G SNPs are genetically associated with HCC and treatment response. Haplotypes associated with high levels of HLA-G expression are more prevalent in HCC than in healthy controls. Core tip: Population genetic approaches were used to study HLA-G gene polymorphisms in the Indian population for its genetic association with HCC risk, treatment response and altered gene expression. Out of the 14 SNPs studied for HLA-G UTR, three were linked to HCC and response to locoregional therapy. Linkage disequilibrium and UTR haplotyping analysis show that the UTR-4 haplotype linked to high HLA-G levels, is more common in HCC patients, while the UTR-3 haplotype, linked to low HLA-G levels, is more common in healthy controls. This study is the first to look at the UTR types based on HLA-G gene polymorphisms of Indian HCC patients and their response to therapy. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent chronic liver condition globally, with its severe form, cirrhosis, leading to liver failure, hepatocellular carcinoma (HCC), and mortality. The causal relationships among them remain unclear. Methods: This study employed a two-sample Mendelian randomization (MR) approach to systematically investigate the causal relationships among inflammatory proteins, non-alcoholic steatohepatitis (NASH), and HCC. We utilized NASH data and HCC data from the FinnGen biobank, and genomic data for 91 circulating inflammatory factors from GWAS database. Bidirectional MR analyses were conducted using the Inverse-Variance Weighted method as the primary analysis, supplemented by MR-Egger and weighted median methods for sensitivity analyses. Additionally, we performed heterogeneity, pleiotropy, and MR-PRESSO tests to assess the robustness of our findings. Results: Forward MR analysis identified five inflammatory factors significantly associated with NASH risk: CCL25 (OR = 0.8703, p =.0159), S100A12 (OR = 0.7582, p =.0204), IL18 (OR = 0.7412, p =.0026), and LIFR (OR = 0.6804, p <.001) showed negative correlations, while CXCL11 (OR = 1.2625, p =.0354) demonstrated a positive correlation. Reverse analysis revealed that NASH significantly influenced the levels of 10 circulating inflammatory factors, including Beta-nerve growth factor (OR = 1.0286, p =.0245), CCL20 (OR = 1.0382, p =.0012), CD5 (OR = 1.0268, p =.0466), CUBD1 (OR = 1.0371, p =.0078), CSF1 (OR = 1.0231, p =.0458), IL-12β (OR = 1.0261, p =.0381), IL-22Rα1 (OR = 0.9722, p =.0311), CCL3 (OR = 1.0372, p =.0013), OPG (OR = 1.0436, p =.0103), and uPA (OR = 1.0320, p =.0054). Further analysis revealed that IL-1α levels were positively associated with HCC risk (OR = 1.5335, p =.0377), while SULT1A1 levels showed a negative correlation (OR = 0.7190, p =.0200). Pleiotropy analyses showed no significant heterogeneity or horizontal pleiotropy for most identified associations, except for OPG (heterogeneity p =.001, MR-PRESSO p <.001) and CUBD1 (MR-PRESSO p <.05) in the reverse analysis of NASH, which warrant cautious interpretation. Conclusion: This study unveils complex bidirectional causal relationships among inflammatory factors, NASH, and HCC. Intervention targeting IL-1α in patients with liver cirrhosis will significantly impact the progression of HCC. [ABSTRACT FROM AUTHOR]

M2-like tumor-associated macrophages (M2-TAM) played an essential part in hepatocellular carcinoma (HCC) progression. Long intergenic noncoding RNA 00161 (LINC00161), is a long non-coding RNA, that was related to HCC development. However, the relationship between LINC00161 and TAM remains indistinct. HCC cells were cocultured with an M2-like conditioned medium (M2-CM). cell counting kit-8 (CCK-8), plate cloning, cell scratch, and transwell assay evaluated cell biological activities of HCC cells. The interactions among molecules were analyzed by chromatin immunoprecipitation (CHIP), dual-luciferase reporter, and RNA immunoprecipitation (RIP). The methylation status of HECT domain and ankyrin repeat-containing, E3 ubiquitin protein ligase 1 (HACE1) was evaluated using methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP). The xenograft model was established in vivo using subcutaneous nude mice. Histological analyses were performed using hematoxylin–eosin (HE) staining. The expression of molecules was determined using immunohistochemistry (IHC), western blot and quantitative real-time PCR (qPCR). LINC00161 expression was promoted in HCC. LINC00161 knockdown significantly reduced HCC cell proliferation, migration, and invasion. Additionally, M2-TAM stimulated LINC00161 transcription and expression in HCC cells by secreting hepatocyte growth factor (HGF) to activate the Met/NFκB pathway. LINC00161 suppressed HACE1 expression, and knockdown of LINC00161 decreased the methylation on the HACE1 promoter. Meanwhile, a binding relationship between the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and HACE1 was observed. LINC00161 overexpression increased the binding of EZH2 on the HACE1 promoter region. Furthermore, LINC00161 knockdown suppressed tumor growth in vivo and induced HACE1 expression by inhibiting its methylation. LINC00161, induced by M2-TAM, played a pivotal role in contributing to HCC development by recruiting EZH2 to promote the methylation of HACE1. This underscores the significant involvement of LINC00161 in mediating the progression of HCC. [ABSTRACT FROM AUTHOR]

Aim: Gamma‐glutamyltransferase (GGT) is known as an oxidative stress marker, induced by alcohol consumption and metabolic disorders, and is reported as a predictor of hepatocellular carcinoma (HCC) development after hepatitis C virus (HCV) elimination. However, it is not clear whether GGT serves simply as a surrogate marker for overlapping metabolic diseases or reflects HCV‐specific carcinogenicity. We investigated the association between GGT and hepatocarcinogenesis after achieving a sustained viral response (SVR), accounting for drinking habits or diabetes, and examined predisposing factors associated with GGT levels after SVR. Methods: This is a prospective, multicenter, and observational study using the database of 1001 patients after HCV eradication with direct‐acting antiviral agents. The association of GGT at SVR with cumulative HCC development was examined in a multivariate analysis using Cox proportional hazard models after adjustment for covariates including alcohol and diabetes. The association between oxidative stress markers or genetic factors and GGT levels was analyzed. Results: High GGT levels at SVR were associated with HCC development (HR] 2.38, 95% CI 1.10–5.17). This association was also significant when restricted to patients without alcohol consumption or diabetes (HR 8.38, 95% CI 2.87–24.47). GGT levels were correlated with serum growth differentiation factor 15 levels, a marker of mitochondrial dysfunction. Single‐nucleotide polymorphisms of ZNF827 and GDF15 were associated with high GGT levels. Conclusions: High GGT levels at SVR were associated with HCC development after accounting for alcohol consumption and diabetes. GGT levels are influenced by genetic predisposition and may reflect mitochondrial dysfunction after HCV eradication. [ABSTRACT FROM AUTHOR]

Switched reluctance motors (SRMs) have gained prominence in various industrial applications due to their robustness and simplicity. One critical aspect of enhancing SRM efficiency is precise control, often necessitating complex sensor systems for accurate feedback. This research addresses this challenge by proposing a sensorless control system based on instantaneous direct torque control (IDTC) techniques. The study introduces a novel architecture integrating a DC power supply, (n + 1) diodes, and (n + 1) switches, forming a foundation for SRM control without the need for additional sensors. The core innovation lies in the implementation of a modified genetic algorithm optimized cascaded artificial neural network (MGAO-CANN) controller. This controller refines control signals through genetic algorithm optimization and neural network computations, optimizing the motor's performance. To enhance system stability and prevent rapid fluctuations, a hysteresis current controller (HCC) is employed, ensuring smooth operation. The research's focal point is the application of instantaneous direct torque control, enabling real-time and precise adjustments to motor torque. By eliminating the necessity for extra sensors, the proposed system not only reduces costs significantly but also enhances SRM efficiency and responsiveness. The validation of proposed research simulated using MATLAB/Simulink and the outcomes reveals that the developed approach promises a ground breaking advancements in the realm of motor control technology. [ABSTRACT FROM AUTHOR]

Background and Objectives: To report on the first results of safety, efficacy, and outcome of CT-navigated stereotactic percutaneous electrochemotherapy (SpECT) in patients with primary and secondary liver malignancies. Methods: This retrospective study included 23 consecutive lesions in 22 patients who underwent SpECT for primary and secondary malignant liver lesions with locally curative intention. The endpoints were primary technique efficacy (PTE), local tumor progression (LTP), time to progression (TTP), and occurrence of adverse events. Results: The mean maximum diameter of the treated lesions was 42 mm (range: 16 mm–72 mm). Eight lesions were hepatocellular carcinoma (34.8%), five lesions were colorectal liver metastases (21.7%), three lesions were cholangiocellular carcinoma (13.0%), and the other seven lesions were liver metastases from different primary cancers (30.4%). PTE was achieved for 22 lesions (95.7%). The mean follow-up time was 15 months (0–39 months). No LTP was observed. In six patients (27.3%), hepatic tumor progression was observed during follow-up with a mean TTP of 3.8 months (2–8 months). In 10 procedures (43.5%), minor complications (1 CIRSE Grade 2) and side effects occurred, but no major complications were observed. Conclusions: SpECT seems to be a safe and effective new local treatment modality for primary and secondary liver malignancies. [ABSTRACT FROM AUTHOR]

Centers for Medicare & Medicaid Services provides reimbursement through Hierarchical Condition Category (HCC) coding. Medical systems strive toward risk adjustment optimization, often implementing costly chart review processes. Previously, our organization implementing countermeasures through workflows was complex and performed in silos. Our goal was to put in place HCC-Risk Adjustment Factor (RAF) improvement tools to optimize HCC-RAF management in Population Health using rapid process improvement methods. In this quality improvement analysis (IRB#806198), we used Lean methodology to develop tools and implement streamlined processes for providers to manage, document, and code high-risk HCC conditions. Rather than applying costly countermeasures, Transformational Healthcare conducted a Rapid Process Improvement Workshop (RPIW), with workgroups implementing proposed changes, to improve processes. Each of these tools was embedded in standard work, for teams to use in practice. Tools included the development of RPIW-inspired work groups, a Provider Education website, tip sheets, clinical champions, trainings, audits, practice alerts, smart phrases, schedule view tools, severity scores, reports, dashboards, on-screen decision-support tools, coding expertise, and HCC standard work. Quantitatively, Year 1 showed enterprise HCC-RAF scores improved by 4.1%. We were able to develop tools for providers and team members to allow for more optimized pathways. Although quantitatively we realized an improvement in enterprise HCC-RAF score, our overall aim was to improve process flow and limit waste. Leveraging Lean improvement methods for the collective design of tools has supported culture change. In the end, we found that providers are indeed willing to adopt these newly built tools. These tools have optimized operations, allowing providers to work smarter, not harder. [ABSTRACT FROM AUTHOR]

Hypoxia plays an important role in the metastasis of hepatocellular carcinoma (HCC). Exosomes have been widely studied as mediators of communication between tumours and immune cells. However, the specific mechanism by which hypoxic HCC cell‐derived exosomes suppress antitumor immunity is unclear. Hypoxia scores were determined for The Cancer Genome‐Liver Hepatocellular Carcinoma (TCGA‐LIHC) dataset patients, and HCC patients in the hyperhypoxic group had a higher degree of M2 macrophage infiltration. Patients in the M2 high‐invasion group had a lower probability of survival than those in the low‐invasion group. In vivo and in vitro experiments demonstrated that exosomes secreted by hypoxic HCC cells promote M2 macrophage polarization. This polarization induces apoptosis in CD8+ T cells. Additionally, it encourages epithelial–mesenchymal transition (EMT), which increases HCC migration. Exosomal miRNA sequencing revealed that miR‐1290 was highly expressed in exosomes secreted by hypoxic HCC cells. Mechanistically, miR‐1290 in macrophages inhibited Akt2 while upregulating PD‐L1 to promote M2 polarization, induce apoptosis in CD8+ T cells, and enhance EMT in HCC. Animal studies found that the miR‐1290 antagomir in combination with the immune checkpoint inhibitor produced better antitumor effects than the monotherapies. In conclusion, the secretion of exosome‐derived miR‐1290 from HCC cells in a hypoxic environment supported immune escape by HCC cells by promoting M2 macrophage polarization to induce apoptosis in CD8+ T cells and enhance EMT that promoted HCC metastasis. Therefore, miR‐1290 is an important molecule in antitumor immunity in HCC, and inhibition of miR‐1290 could provide a novel immunotherapeutic approach for HCC treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Artemisia eriantha (Apennine Genepì) is a subendemic species native to the Central Apennines, valued locally for its use in traditional and ancient medicine due to its antibacterial, antifungal, anthelmintic, digestive, and antispasmodic properties. Many of these benefits are shared with other species within the Artemisia genus, which have also recently demonstrated anti-tumor properties. However, the potential cytotoxic and/or antitumor effects of A. eriantha have not yet been explored. The aim of this study was to evaluate the anti-proliferative, antitumor, and anti-metastatic properties of the plant using in vitro models of liver cancer cells. Treatment with an extract of A. eriantha inhibited the proliferation, survival, migration, and metastatic capabilities of liver cancer cell lines. A. eriantha extract appears to influence key factors associated with cancer cell proliferation and invasion, positioning it as a promising candidate for further research as an adjuvant in the prevention or treatment of liver cancer. Artemisia eriantha is a subendemic species of the Central Apennine, valued locally for its applications in ancient and traditional medicine for its antibacterial, antifungal, anthelmintic, digestive, and antispasmodic effects. Several of these properties are also found in other species within the same genus, including recent findings highlighting their anti-tumor actions. However, the presence of cytotoxic or anti-tumor activity has never been studied in A. eriantha. The aim of this study was thus to assess the potential anti-proliferative, pro-apoptotic, and antimetastatic effects of this plant using in vitro models of hepatocarcinoma cells (HepG2 and Huh7 cells). Treatment with A. eriantha extract (130 μg/mL) resulted in the reduced proliferation of HepG2 and Huh7 cells, driven by the dysregulation of proteins involved in the cell cycle (such as cyclin D1, cyclin E, and p27) and the activation of the p53-p21 pathway, leading to an increase in apoptotic activity. In addition, the treatment also lowered the healing capability after scratch wounds in Huh7 cells, which are characterized by a remarkable migratory capacity, suggesting that the A. eriantha extract may also be effective in controlling the migration and spread of metastatic cells. In conclusion, A. eriantha extract 130 μg/mL appears to interfere with key factors of HepG2 and Huh7 cell proliferation and invasion and emerges as a potential new adjuvant for the prevention and/or treatment of hepatocellular carcinoma. Additional research is necessary to establish if the effects observed are cell-specific and to elucidate the mechanisms of action and signaling pathways underlying its effectiveness. [ABSTRACT FROM AUTHOR]

With a multitude of HCC mouse models available, choosing the one that most closely resembles human HCC can be challenging. This study addresses this gap by conducting a comprehensive transcriptomic similarity analysis of widely used HCC mouse models. In this study, RNA‐seq was performed on a model induced by double knockout of P53 and Pten via CRISPR/Cas9 in HBV‐transgenic mice. Additionally, RNA‐seq data from 2345 various other models induced by different methods were collected from GEO databases. The gene expression profiles, immune microenvironments, and metabolic pathways of these models were compared with those of human HCC. The analysis revealed distinct transcriptomic features among the different models. The HBV + P53&Pten KO model demonstrated the highest overall similarity to human HCC across various parameters. It shared a high degree of overlap in differentially expression genes (DEGs) between tumor and non‐tumor tissues with human HCC, exhibited a transcriptome profile and immune cell infiltration pattern closely resembling human HCC, and showed metabolic alterations similar to those in human HCC. Conversely the DEN + CCl4‐induced model showed the lowest similarity to human HCC in transcriptome profiles and DEGs and exhibited a distinct immune microenvironment with high NK cell infiltration, with minimal metabolic differences between tumor and non‐tumor tissues. This study highlights the importance of selecting appropriate HCC mouse models for research. The HBV + p53&Pten KO model emerged as the most promising due to its remarkable similarity to human HCC across various aspects. [ABSTRACT FROM AUTHOR]

Bleeding-related adverse events may occur due to anti-vascular endothelial growth factors. Here, we report two cases of variceal rupture during atezolizumab plus bevacizumab (ATZ/BV) treatment for unresectable hepatocellular carcinoma (u-HCC). Case 1 involved a man in his 60 s with alcoholic liver cirrhosis (LC) and u-HCC. Seventy-four days after ATZ/BV administration, the patient was admitted for hematemesis. Upper esophagogastroduodenoscopy (EGD) revealed worsening of the esophageal varices (EVs) to F2 grade with active bleeding. Endoscopic variceal ligation successfully achieved hemostasis. Case 2 involved a man in his 70 s with alcoholic LC and u-HCC. The patient was admitted with hematemesis 114 days after ATZ/BV administration. During EGD, the EVs deteriorated to F3 grade, although hemostasis had already been achieved. The evaluation was discontinued during the observation stage because of the worsening hepatic reserve. Neither patient had EVs warranting prophylactic treatment before ATZ/BV administration, showed a partial tumor response, or had portal vein tumor thrombus. Both patients demonstrated increased total diameters of the collateral veins and splenic volume compared to those before treatment. These findings suggest that ATZ/BV treatment may increase portal pressure. In conclusion, the administration of ATZ/BV to patients with LC and u-HCC necessitates careful management of EVs aggravation and rupture. [ABSTRACT FROM AUTHOR]

Krüppel‐like factor 7 is a transcriptional activator and acts as an oncogene in human cancers, including hepatocellular carcinoma (HCC). Tryptophan metabolism is important for HCC cell proliferation, metastasis, and invasion. It is unclear whether KLF7 could regulate Trp metabolism in HCC. In this study, we found that Trp metabolism was suppressed in HCC cells with KLF7 knockdown. The mRNA and protein levels of SLC1A5, SLC7A5, and TPH1, as well as the content of Trp and serotonin, were reduced after KLF7 knockdown, and were potentiated following KLF7 overexpression. Increasing the content of serotonin could restore the malignancy of tumour cells in vitro and tumour growth in vivo. Conversely, decreasing the content of serotonin suppressed HCC cell proliferation. The binding activity of KLF7 was on the promoter of SLC1A5, and KLF7 positively regulated the expression of SLC1A5. KLF7 contributed to the proliferation and migration of HCC cells by up‐regulation of SLC1A5. Collectively, KLF7 promotes the progression of HCC through regulating Trp metabolism. The newly identified axis of KLF7/ SLC1A5 in HCC could represent a potential target for HCC therapy. [ABSTRACT FROM AUTHOR]

Metastasis is responsible for approximately 90% of lethality from solid tumors. Metabolic abnormalities are one of the key characteristics of tumor cells, closely associated with tumorigenesis and progression. The de novo synthesis pathway of serine is a key metabolic bypass in glycolysis, which could provide material and energy basis for the rapid proliferation of tumor cells by mediating one-carbon metabolism. The transformation of metabolic patterns is particularly pronounced in HCC, often leading to a high dependence of HCC cells on glycolysis. However, up to now, the underlying relationship between serine metabolism and HCC metastasis remains largely unknown. Through a series of bioinformatics methods, we reported CCT6A, a serine related gene, was particularly associated with metastatic events of HCC. We furtherly demonstrated that CCT6A was highly expressed in HCC cells with high metastatic potential. Gain- and loss-of-function analyses showed that CCT6A could promote HCC cells migration and invasion. Mechanistically, CCT6A was found to be interacted with RPS3, and might potentiate the metastasis of HCC by affecting some metabolic processes. Totally, our results suggest that the metabolic reprogramming induced by interacting between CCT6A and RPS3 could advance HCC metastasis, making the CCT6A/RPS3 axis a promising target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Simple Summary: This review focuses on recent advancements in the surgical treatment of hepatocellular carcinoma (HCC), the most common type of primary liver cancer. Despite improvements in immunotherapy and surgery, HCC still has a poor outlook. This review discusses various surgical approaches and highlights new developments like 3D printing for surgical planning and minimally invasive techniques that reduce surgical trauma. The review covers recent progress in surgical methods, how patients are selected for surgery, and how they are cared for before and after the operation. Its goal is to update doctors and researchers on the changing role of surgery in treating HCC and to point out areas where more research could lead to better results for patients. Hepatocellular carcinoma (HCC) is the most common primary liver cancer, the incidence of which is rising globally. Despite recent advancements in immunotherapeutic and surgical treatment modalities, the prognosis for HCC remains poor. The surgical treatment strategy for HCC comprises a multimodal effort that ranges from ablative therapy and surgical resection to liver transplantation. Thanks to collective efforts from the surgical society, there have been rapid advances in resection strategies, such as 3D printing for surgical planning and minimally invasive techniques to minimize surgical trauma. This review examines recent advancements in surgical techniques, patient selection criteria, and perioperative management for HCC resection. The purpose of this review was to provide clinicians and researchers with an up-to-date perspective on the evolving role of surgical resection in HCC treatment, and to identify key areas for future investigation to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide. Affected patients have poor prognoses due to high rates of post-surgical recurrence and metastasis. Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) reportedly contributes to the development and progression of various human cancers. Thus far, there have been no comprehensive studies regarding the expression of BAMBI in HCC; similarly, no studies have investigated the prognostic significance of BAMBI and its associated mechanisms in HCC. In this study, we analyzed the expression profiles of BAMBI, along with its contributions to pathological findings, metastasis characteristics, and prognosis, in multiple human cancers. We found that upregulation of BAMBI was associated with poor prognosis in HCC. Next, we explored the associations of BAMBI with multiple cell signaling pathways, immune cells, and immune checkpoints in HCC. The results showed that BAMBI was associated with tumor proliferation, epithelial–mesenchymal transition (EMT) markers, glycolysis, fatty acid biosynthesis and degradation pathways, and immune checkpoint regulation in HCC. In vitro and in vivo experiments showed that BAMBI promoted polarization of M1 macrophages and is linked to the expression of key genes involved in glycolipid metabolism. Furthermore, protein–protein interaction analysis suggested that BAMBI plays multiple roles in HCC by regulating genes in the transforming growth factor (TGF)-β and Wnt signaling pathways. Our findings elucidated that BAMBI is a prognostic biomarker and is associated with macrophage polarization, glycolysis, and lipid metabolism in HCC. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) ranks among the most prevalent and lethal malignancies worldwide. Histone modifications (HMs) play a pivotal role in the initiation and progression of HCC. However, our understanding of HMs in HCC remains limited due to the disease's heterogeneity and the complexity of HMs. Methods: We integrated multi-omics data from multiple cohorts, including single-cell RNA sequencing, bulk RNA sequencing, and clinical information. Weighted gene co-expression network analysis (WGCNA) and consensus clustering were employed to identify histone-related genes. We developed a histone modification-related signature (HMRS) using 117 machine learning methods. Comprehensive analyses of molecular characteristics, immune landscape, and drug sensitivity associated with the HMRS were performed. Results: Through integrative analysis, we defined 110 histone-related genes and identified 45 HCC-HM-related genes (HCC-HMRgenes). The HMRS demonstrated robust prognostic value across multiple cohorts. Patients with high HMRS scores exhibited distinct genomic alterations, including higher tumor heterogeneity and TP53 mutations. The high-risk group showed enrichment in cell cycle, DNA repair, and metabolic pathways. Immune landscape analysis revealed significant differences in immune cell infiltration and pathway activities between high- and low-risk groups. Drug sensitivity prediction suggested potential therapeutic strategies for different risk groups. Conclusion: Our study provides a comprehensive understanding of HMs in HCC and establishes a robust prognostic signature. The HMRS not only stratifies patients into distinct risk groups but also offers insights into underlying molecular mechanisms, immune characteristics, and potential therapeutic strategies, paving the way for personalized medicine in HCC. [ABSTRACT FROM AUTHOR]

Background: The response of hepatocellular carcinoma (HCC) to transarterial chemoembolization (TACE) treatment and its underlying mechanisms remain elusive. This study investigates the role of enzymes involved in fatty acid activation, specifically Acyl-CoA synthetase long chain 4 (ACSL4), in HCC patients treated with postoperative adjuvant TACE (PA-TACE) and in nutrient-deprived HCC cells. Methods: We examined the expression of ACSL4 and its family members in HCC clinical samples and cell lines. The clinical significance of ACSL4, particularly regarding the prognosis of patients treated with PA-TACE, was assessed using two independent HCC cohorts. We further explored the role of ACSL4 in glucose starvation-induced cell death in HCC cells and xenograft mouse models. Results: Among the family members, ACSL4 is the most up-regulated enzyme, associated with poor survival in HCC patients, particularly in post-recurrent TACE-treated patients in a Singapore cohort. ACSL4 is essential for HCC cell survival in response to glucose starvation, rather than to hypoxia or to the combination of hypoxia with doxorubicin or cisplatin. ACSL4-mediated arachidonic acid (AA) metabolism supports mitochondrial β-oxidation and energy production. CCAAT/enhancer binding protein α (CEBPA) transcriptionally regulates ACSL4 by binding 3 motifs (-623 to -613, -1197 to -1187 and -1745 to -1735) of ACSL4 upstream promoter region, enhancing its pro-survival effects. Furthermore, canagliflozin (Cana), a clinical-approved drug for type 2 diabetes, mimics glucose starvation and inhibits the growth of ACSL4-low xenograft tumors. Moreover, high ACSL4 or CEBPA expressions correlate with increased recurrence susceptibility after PA-TACE in the China-Guangxi HCC cohort. Conclusions: The CEBPA-ACSL4 pathway is critical in protecting HCC cells from glucose starvation-induced cell death, suggesting that ACSL4 and CEBPA could serve as valuable prognostic indicators and potential therapeutic targets in the context of PA-TACE treatment for HCC. TACE is the first-line treatment for intermediate-stage HCC patients with unresectable tumor and a common postoperative adjuvant (PA) treatment. The present study found that HCC patients with the presence of CEBPA-ACSL4 expression in tumor are more resistant to TACE, susceptible for PA-TACE relapse and poorer survival. Mechanically, ACSL4 is essential for fatty acid activation particularly conversion of arachidonic acid (AA) into AA-CoA, which promotes lipid anabolism in nutrition-replete condition and lipid catabolism in glucose-deplete condition. As a result, ACSL4-high HCC cells, in response to glucose restriction (rather than hypoxia and chemotherapeutic drugs), can donor mitochondrial energy production through β-oxidation and protect HCC cells from mitochondrial membrane impairment and cell death in vitro and in vivo. In addition, CEBPA transcriptionally activates ACSL4 , and knockout of CEBPA aborted ACSL4-mediated lipid metabolism.Highlights: 1. Elevated CEBPA-ACSL4 levels in tumors links to adverse prognosis in HCC patients treated with PA-TACE. 2. ACSL4 shields HCC cells from TACE-triggered glucose starvation via AA-involved β-oxidation. 3. CEBPA up-regulates ACSL4 transcriptionally and protects HCC cells from cell death. [ABSTRACT FROM AUTHOR]

We have previously found that the DAPK-DDX20 signaling axis exerts an anti-cancer activity in hepatocellular carcinoma (HCC) by inhibiting the GTPase activity of CDC42, thereby reducing the invasive and migratory capabilities of cancer cells without affecting cell proliferation. DDX20 serves as an intermediate protein regulated by DAPK in the control of CDC42. Specifically, DAPK enhances DDX20 protein levels by suppressing DDX20 degradation. However, the mechanism underlying DAPK regulation of DDX20 remains unclear. In the current study, we discovered that DDX20 is degraded through the ubiquitin–proteasome pathway and identified TRIM25 as the E3 ubiquitin ligase of DDX20. TRIM25 mediates the proteasomal degradation of DDX20 by binding to, and ubiquitinating the 1-244 amino acid region of DDX20. Moreover, DAPK interacts with this 1-244 segment of DDX20, inhibiting its ubiquitination and enhancing its stability, despite the lack of direct physical interaction between DAPK and the 1-244 region of DDX20. Remarkably, DAPK, TRIM25, and DDX20 form a ternary protein complex in cells, and knockdown of TRIM25 leads to a reduction in the cellular levels of the binary DAPK-DDX20 complex, suggesting that TRIM25 acts as an important intermediate protein linking DAPK and DDX20. TRIM25 functions as an oncogene in liver cancer, as shRNA-mediated silencing of TRIM25 inhibits cell migration and invasion. Therefore, these novel findings of the interaction among these three proteins not only enhances our knowledge of the downstream molecular network of DAPK and its possible role in the development of HCC, but also provides potential druggable targets for the future development of novel anticancer drug therapeutics. [ABSTRACT FROM AUTHOR]

Objective: Mac-2 binding protein glycosylation isomer (M2BPGi) is produced in the extracellular matrix and serves as an indicator of hepatic stellate cell activation. Assessing M2BPGi levels could aid in predicting hepatocellular carcinoma (HCC) in individuals with hepatitis C virus (HCV). The objective of this study was to evaluate the usefulness of M2BPGi as a biomarker for HCC in HCV patients and its association with disease severity and progression. Methods: This study included patients who were cured of chronic hepatitis C virus. The patients were divided into three subgroups: HCV without cirrhosis, HCV with cirrhosis, and HCV with HCC. These subgroups were then compared to a subgroup of healthy volunteers. In addition to routine laboratory investigations, M2BPGi levels were measured in all the enrolled subjects. Results: The level of serum M2BPGi was significantly greater in the HCV with cirrhosis and HCC groups than in the control group (P < 0.001). Additionally, it was significantly greater in multifocal HCC than in those with unifocal HCC (P < 0.001), and it was directly proportional to the size of the focal lesion of HCC (P = 0.001). The cutoff for serum M2BPGi in diagnosing HCC was ≥ 0.869 (C.O.I), with an AUC of 0.762, a sensitivity of 78.6%, and a specificity of 61.9% (P = 0.004). Furthermore, the cutoff for predicting multifocality was > 0.93 (C.O.I), with an AUC of 0.73, sensitivity of 66.7%, and specificity of 63.8% (P = 0.03). Although the AFP level was still superior in predicting cirrhosis and HCC, the M2BPGi level was better at predicting the size and diagnostic value of HCC when the AFP level was normal. The cutoff for M2BPGi in this case was 0.903(C.O.I), with a sensitivity of 80%, specificity of 75%, and an accuracy of 76.25%. M2BPGi was independently associated with the CRP level (β = 0.484, P = 0.001) and the size of the HCC focal lesion (β = 1.422, P = 0.001). Conclusion: M2BPGi can be used as an effective marker to assess the biological behavior and aggressiveness of HCC. Further studies are warranted on a large scale of patients to confirm our findings. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death world-wide. Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is a novel imaging modality used in prostate cancer that appears to demonstrate uptake in HCC. The aim of this systematic review and meta-analysis was to determine the sensitivity and specificity of PSMA PET for HCC. On systematic review, 68Ga-PSMA-11 demonstrated a high sensitivity on per-patient analysis for HCC, 89.9% (95% CI 78.5–95.5), and on a per-lesion analysis, this increased to 94.5% (95% CI 82.9–98.4). Specificity, however, was poorly reported, with insufficient data for analysis. The meta-analysis of studies with sufficient data demonstrated a sensitivity of 97.1% (95% CI 87.8–99.4) and specificity of 42.2% (95% CI 0.3–99.4) on per-lesion level for HCC. Specificity has been poorly reported, and diagnostic accuracy remains unclear. Further prospective studies are required to define the true specificity of PSMA PET for HCC. Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is widely used in prostate cancer. Recent studies indicate hepatocellular carcinoma (HCC) demonstrates PSMA PET uptake. The diagnostic accuracy of PSMA PET for HCC is not known. We conducted a systematic review and meta-analysis of studies assessing 68Ga-PSMA-11 in HCC. Nine studies were included, with 196 patients and a total of 491 HCC lesions. Per-patient analysis yielded a pooled sensitivity of 89.8% (95% CI 78.5–95.5). Specificity was poorly reported, with insufficient data. When per-lesion level analysis was performed on seven studies, the pooled sensitivity was 94.5% (95% CI 82.9–98.4), and specificity was again poorly reported with insufficient data. Among the three studies with adequate data for full per-lesion meta-analysis, 115 lesions in 41 patients demonstrated sensitivity of 97.1% (95% CI 87.8–99.4), while specificity was 42.2% (95% CI 0.3–99.4). Two studies provided sufficient data for meta-analysis on a per-patient level (n = 50 patients), demonstrating a sensitivity of 92.5% (95% CI 64.0–98.9) and specificity of 72.4% (95% CI 1.3–99.8). PSMA PET demonstrates a high sensitivity for HCC and shows promise as an imaging modality for diagnosis and staging of HCC. However, the existing literature does not provide enough data to confidently evaluate its specificity and, therefore, accuracy. Further prospective studies are necessary, with a focus on the accurate reporting of benign lesions and inclusion of patients with an intermediate probability of HCC. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a high-incidence, poor-prognosis malignancy worldwide, requiring new strategies for treatment. Ubiquitination, especially ubiquitination through E3 ubiquitin ligases, plays an indispensable role in the development and progression of HCC. E3 ubiquitin ligases are crucial enzymes in ubiquitination, controlling the degradation of specific substrate proteins and influencing various cellular functions, such as tumor cell proliferation, apoptosis, migration, and immune evasion. In this review, we systematically summarize the mechanisms of E3 ubiquitin ligases in HCC, with a focus on the significance of RING, HECT, and RBR types in HCC progression. The review also looks at the potential for targeting E3 ligases to modulate the tumor microenvironment (TME) and increase immunotherapy efficacy. Future studies will optimize HCC treatment by formulating specific inhibitors or approaches that will be based on gene therapy targeting E3 ligases in order to overcome resistance issues with present treatments and create optimism in the journey of treatment for HCC patients. [ABSTRACT FROM AUTHOR]

Although there have been remarkable advances in the treatment of hepatocellular carcinoma (HCC), the prognosis remains poor in those with advanced stage and more effective therapeutic options are urgently needed. Lenvatinib (Len), a multiple receptor tyrosine kinase inhibitor, is an emerging molecular targeted agent for HCC, whose immunomodulatory activities have been investigated. However, Len utilization is limited because of its low metabolic stability, poor bioavailability and dose-dependent toxicity, rendering its direct use insufficient for immune modulation. Stimuli-responsive nanoparticles, which are drug-targeted delivery platforms for on-demand drug release, facilitate deeper and uniform tumour penetration, providing alternative solutions to overcome current limitations. Ultrasound (US) exhibits superior tissue penetration abilities and can produce reactive oxygen species (ROS) at the tumour site to treat deeper tumours. In addition, US serves as an excellent and selective drug delivery mediator for tumour treatment. Herein, we designed US-triggered lenvatinib nanoparticles (Len-RNPs) for selective drug delivery that utilize US-triggered ROS to induce in situ oxidation reactions, resulting in nanoparticle disintegration. Len-RNPs mitigate the toxicity of Len and effectively trigger robust systemic anti-tumour immune responses in a H22 tumour model, resulting in a tumour suppression rate of 95.7%, with 60% of mice being cured. Our study elucidates a novel and precise strategy of combining Len and US therapy for enhanced HCC immunotherapy. [ABSTRACT FROM AUTHOR]

Objective: Long non-coding RNAs (lncRNAs) LINC02466 is an lncRNA newly linked to the adverse outcomes in primary liver cancer patients, and its crucial involvement in the disease's escalation. Decoding the specific role of LINC02466 in HCC progression is of great significance to provide a potential therapeutic target for HCC. Methods: RT-qPCR and Western Blot techniques was used to analyze the expression levels of LINC02466 in both malignant and surrounding healthy liver tissues. CCK8 assays and colony formation experiments indicates the LINC02466's effect on the proliferation rates of liver cancer cells. Flow cytometry was pivotal in revealing its significant influence on the cell cycle of these cells. Kaplan–Meier survival analysis with log-rank tests were employed. Results: The suppression of LINC02466 markedly reduces the stemness attributes of liver cancer cells, indicating a potential therapeutic target. LINC02466 overexpression significantly increased tumor growth rates and final volumes. Further research indicated that LINC02466 significantly influences liver cancer progression through regulating the mTOR signaling pathway. Conclusion: LINC02466 regulating cell proliferation, the cell cycle, and stemness characteristics via the mTOR pathway, suggesting LINC02466 as a potential therapeutic target for primary liver cancer. [ABSTRACT FROM AUTHOR]

Background: Cancer-associated fibroblasts (CAFs) play a pivotal role in shaping the microenvironment of hepatocellular carcinoma (HCC). However, the mechanisms through which CAFs influence the progression of HCC remain incompletely understood. Methods: Single-cell RNA sequencing datasets (GSE158723 and GSE112271) were retrieved from the Gene Expression Omnibus (GEO) database at the National Center for Biotechnology Information (NCBI) and analyzed using R software. Our analysis suggested that CAFs may promote liver cancer cell development, possibly through the interaction of pleiotrophin (PTN) and syndecan-2 (SDC2). Clinical samples from HCC patients were collected and processed into frozen sections and single-cell suspensions for Masson staining, immunofluorescence staining, and flow cytometry. Additionally, Huh7 liver cancer cells and LO2 normal liver cells were cultured and subjected to immunofluorescence assays using cell slides. Results: The proportion of CAFs in cancerous tissues was higher than in adjacent non-cancerous tissues, and pleiotrophin (PTN) expression was elevated in cancer tissues compared to adjacent tissues. These findings aligned with the results of the single-cell RNA sequencing (scRNA-seq) analysis. Furthermore, SDC2 expression was significantly upregulated in Huh7 liver cancer cells compared to LO2 normal liver cells. Discussion: This study suggests that CAFs may contribute to HCC progression via the PTN/SDC2 signaling pathway. Our findings provide deeper insights into the interactions between CAFs and HCC cells within the tumor microenvironment (TME). [ABSTRACT FROM AUTHOR]

Purpose: To create and evaluate prediction models of local tumor recurrence after successful conventional transcatheter arterial chemoembolization (c-TACE) via radiomics analysis of lipiodol deposition using cone-beam computed tomography (CBCT) images obtained at the completion of TACE. Materials and Methods: A total of 103 hepatocellular carcinoma nodules in 71 patients, who achieved a complete response (CR) based on the modified Response Evaluation Criteria in Solid Tumors 1 month after TACE, were categorized into two groups: prolonged CR and recurrence groups. Three types of areas were segmented on CBCT: whole segment (WS), tumor segment (TS), and peritumor segment (PS). From each segment, 105 radiomic features were extracted. The nodules were randomly divided into training and test datasets at a ratio of 7:3. Following feature reduction for each segment, three models (clinical, radiomics, and clinical–radiomics models) were developed to predict recurrence based on logistic regression. Results: The clinical–radiomics model of WS showed the best performance, with the area under the curve values of 0.853 (95% confidence interval: 0.765–0.941) in training and 0.752 (0.580–0.924) in test dataset. In the analysis of radiomic feature importance of all models, among all radiomic features, glcm_MaximumProbability, shape_MeshVolume and shape_MajorAxisLength had negative coefficients. In contrast, shape_SurfaceVolumeRatio, shape_Elongation, glszm_SizeZoneNonUniformityNormalized, and gldm_GrayLevelNonUniformity had positive coefficients. Conclusion: In this study, a machine-learning model based on cone-beam CT images obtained at the completion of c-TACE was able to predict local tumor recurrence after successful c-TACE. Nonuniform lipiodol deposition and irregular shapes may increase the likelihood of recurrence. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study investigates the role and mechanisms of ADAM9 as a biomarker and potential therapeutic target in HCC. Utilizing RNA-sequencing data and clinicopathological characteristics from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we conducted survival and meta-analyses, functional enrichment, and immune infiltration studies. Additionally, we evaluated the effects of ADAM9 silencing on HCC cell proliferation, migration, and invasion through in vitro experiments. Our results demonstrate that high ADAM9 expression is associated with poor prognosis and increased immune infiltration in HCC patients. Furthermore, ADAM9 knockdown significantly inhibited tumor cell proliferation and migration. These findings indicate that ADAM9 is a promising prognostic biomarker and potential therapeutic target in HCC. In conclusion, ADAM9 could offer avenues for developing strategies to inhibit tumor progression and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Ferroptosis, a recently elucidated style of regulated cell death, has emerged as a significant area of investigation in cancer biology. Natural active compounds that have anti-cancer effects are promising candidates for cancer prevention. Iberverin, a natural compound derived from Brassica oleracea var. capitata, has been shown to exert anti-tumor activities in some cancers. However, its role in hepatocellular carcinoma (HCC) cells and the molecular mechanisms are still poorly understood. In this study, we proved that iberverin can induce intracellular reactive oxygen species (ROS) generation to inhibit cell proliferation and initiate ferroptotic cell death in HCC cells, which can be eradicated by the ferroptosis inhibitor ferrostatin-1 (Fer-1) or deferoxamine mesylate (DFO) and ROS scavenger (GSH or NAC). Mechanistically, iberverin treatment can simultaneously downregulate SLC7A11 mRNA level and degrade GPX4 through the ubiquitination pathway, leading to lipid peroxidation and ferroptotic cell death in HCC cells. Significantly, a low dose of iberverin can remarkably increase the sensitivity of HCC cells to ferroptosis induced by canonical ferroptosis inducers RSL3 and imidazole ketone erastin (IKE). This study uncovers a critical function of iberverin in preventing HCC through ferroptosis and provides a promising strategy for HCC treatment either via iberverin alone or in combination with canonical ferroptosis inducers in the future. [ABSTRACT FROM AUTHOR]

Background: Recent genome-wide association studies (GWASs) in liver diseases have generated some polygenic risk scores (PRSs), but their predictive effectiveness on hepatocellular carcinoma (HCC) risk assessment remains unclear. Methods: Here, we constructed a novel combined polygenic risk score and evaluated its increment to the well-established risk model. We used 15 HCC-associated genetic loci from two PRSs and FinnGen GWAS data to calculate a PRS-combined score and to fit the related PRS model in the UK Biobank cohort (N = 436,162). The PRS-combined score was further assessed for risk stratification for HCC integrating with the recommended clinical risk scores. Results: The PRS-combined model achieved a better AUC (0.657) than that of PRS-HFC (0.637) and PRS-cirrhosis (0.645). The top 20% of the PRS-combined distribution had a 3.25 increased risk of HCC vs. the middle decile (45–55%). At the population level, the addition of PRS-combined to the CLivD score significantly increased the C-statistic (from 0.716 to 0.746) and provided a remarkable improvement in reclassification (NRI = 0.088) at the 10-year risk threshold of 0.2%. In clinic, additional assessment of PRS-combined would reclassify 34,647 intermediate-risk participants as high genetic risk, corresponding to an increase of 63.92% (62/97) of the HCC events classified at high risk using the Fibrosis-4 alone. Conclusions: The PRS may enhance HCC risk prediction effectiveness in the general population and refine risk stratification of the conventional clinical indicator. [ABSTRACT FROM AUTHOR]