Risk Factor For Hepatocellular Carcinoma Research Articles

From imaging to clinical outcome: dual-region CT radiomics predicting FOXM1 expression and prognosis in hepatocellular carcinoma.

Liver cancer, especially hepatocellular carcinoma (HCC), remains a significant global health challenge. Traditional prognostic indicators for HCC often fall short in providing comprehensive insights for individualized treatment. The integration of genomics and radiomics offers a promising avenue for enhancing the precision of HCC diagnosis and prognosis. From the Cancer Genome Atlas (TCGA) database, we categorized mRNA of HCC patients by Forkhead Box M1 (FOXM1) expression and performed univariate and multivariate studies to pinpoint autonomous HCC risk factors. We deployed subgroup, correlation, and interaction analyses to probe FOXM1's link with clinicopathological elements. The connection between FOXM1 and immune cells was evaluated using the CIBERSORTx database. The functions of FOXM1 were investigated through analyses of Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). After filtering through TCGA and the Cancer Imaging Archive (TCIA) database, we employed dual-region computed tomography (CT) radiomics technology to noninvasively predict the mRNA expression of FOXM1 in HCC tissues. Radiomic features were extracted from both tumoral and peritumoral regions, and a radiomics score (RS) was derived. The performance and robustness of the constructed models were evaluated using 10-fold cross-validation. A radiomics nomogram was developed by incorporating RS and clinical variables from the TCGA database. The models' discriminative abilities were assessed using metrics such as the area under the curve (AUC) of the receiver operating characteristic curves (ROC) and precision-recall (PR) curves. Our findings emphasized the overexpression of FOXM1 as a determinant of poor prognosis in HCC and illustrated its impact on immune cell infiltration. After selecting arterial phase CT, we chose 7 whole-tumor features and 3 features covering both the tumor and its surroundings to create WT and WP models for FOXM1 prediction. The WT model showed strong predictive capabilities for FOXM1 expression by PR curve. Conversely, the WP model did not demonstrate the good predictive ability. In our study, the radiomics score (RS) was derived from whole-tumor regions on CT images. The RS was significantly associated with FOXM1 expression, with an AUC of 0.918 in the training cohort and 0.837 in the validation cohort. Furthermore, the RS was correlated with oxidative stress genes and was integrated with clinical variables to develop a nomogram, which demonstrated good calibration and discrimination in predicting 12-, 36-, and 60-month survival probabilities. Additionally, bioinformatics analysis revealed FOXM1's potential role in shaping the immune microenvironment, with its expression linked to immune cell infiltration. This study highlights the potential of integrating FOXM1 expression and radiomics in understanding HCC's complexity. Our approach offers a new perspective in utilizing radiomics for non-invasive tumor characterization and suggests its potential in providing insights into molecular profiles. Further research is needed to validate these findings and explore their clinical implications in HCC management.

Liver fibrosis estimated using extracellular volume fraction obtained from dual-energy CT as a risk factor for hepatocellular carcinoma after sustained virologic response: A preliminary case–control study

PurposeTo assess hepatocellular carcinoma (HCC) risk after sustained virologic response (SVR) through clinical data analyses, including evaluation of liver fibrosis using the extracellular volume fraction (ECV) obtained from dual-energy computed tomography (DECT). MethodsNinety-two patients (52 men and 40 women; mean age, 69.9 years) with hepatitis C virus infection after SVR underwent DECT of the liver (3-minute equilibrium-phase images) between January 2020 and March 2022. The ECV was calculated by measuring iodine density; fibrous markers, including ECV, fibrosis-4 index, aspartate aminotransferase to platelet ratio index, and platelet count, were statistically analyzed (p < 0.05). The risk factors associated with HCC were analyzed using univariate and multivariate logistic regression analyses. ResultsThe ECV (26.1 ± 4.6 %) in patients with HCC (n,21) was significantly larger than the ECV (20.7 ± 3.3 %) in patients without HCC (n = 71) (p < 0.001). The cutoff value for the ECV was 24.3 %. The area under the operating characteristic curve of the ECV was 0.857, which was higher than that of the serum fibrosis markers. Older age, SVR achieved with interferon, alpha-fetoprotein level (>5 ng/mL), advanced fibrosis before treatment (>F3), and ECV were associated with HCC according to the univariate analysis. Multivariate analyses showed that ECV was the only factor independently associated with HCC (odds ratio 0.619, 95 % confidence interval 0.482–0.795, p < 0.001). ConclusionLiver fibrosis estimated using ECV can be a predictive marker in patients with HCC after SVR.

Comprehensive analysis and validation of SNX7 as a novel biomarker for the diagnosis, prognosis, and prediction of chemotherapy and immunotherapy response in hepatocellular carcinoma

BackgroundStudies have demonstrated that Sorting nexin 7 (SNX7) functions as an anti-apoptotic protein in liver tissue and plays a crucial role in the survival of hepatocytes during early embryonic development. However, its diagnostic and prognostic value as well as the predictive value of chemotherapy and immunotherapy have not been reported in hepatocellular carcinoma (HCC).MethodsSNX7 mRNA expression and its diagnostic efficacy were examined in GEO datasets, and the findings were further confirmed in TCGA, ICGC cohorts, and cell lines. The protein level of SNX7 was determined using CPTAC and HPA databases, and the results were validated through immunohistochemistry (IHC). Survival analyses were performed in TCGA and ICGC cohorts, and the results were subsequently validated via Kaplan–Meier Plotter. The response to chemotherapy and immunotherapy was predicted via GDSC dataset and TIDE algorithm, respectively. R packages were employed to explore the relationship between SNX7 expression and immune infiltration, m6A modification, as well as the functional enrichment of differentially expressed genes (DEGs).ResultsThe expression of SNX7 at both mRNA and protein levels was significantly upregulated in HCC tissues. SNX7 exhibited superior diagnostic efficacy compared to AFP alone for HCC detection, and combining it with AFP improved the diagnostic accuracy for HCC. High SNX7 was associated with unfavorable outcomes, including poor overall survival, disease-specific survival, progression-free survival, and advanced pathological stage, in patients with HCC, and SNX7 was identified as an independent risk factor for HCC. Moreover, elevated SNX7 expression was positively correlated with increased sensitivity to various chemotherapy drugs, including sorafenib, while it was associated with resistance to immunotherapy in HCC patients. Correlation analysis revealed a relationship between SNX7 and multiple m6A-related genes and various immune cells. Finally, enrichment analysis demonstrated strong associations of SNX7 with critical biological processes, such as cell cycle regulation, cellular senescence, cell adhesion, DNA replication, and mismatch repair pathway in HCC.ConclusionsOur study highlights the association of SNX7 with the immune microenvironment and its potential influence on HCC progression. SNX7 emerges as a promising novel biomarker for the diagnosis, prognosis, and prediction of response to chemotherapy and immunotherapy in patients with HCC.

Magnetic resonance imaging-based risk factors of hepatocellular carcinoma after direct-acting antiviral therapy: A multicenter observational study.

To determine risk factors associated with hepatocellular carcinoma (HCC) development following direct-acting antiviral (DAA) therapy. We enrolled patients with chronic hepatitisC who underwent direct-acting antiviral therapy and achieved sustained virologic response at 12weeks between 2012 and 2018. Subsequently, patients were followed up. The primary endpoint was the development of HCC or the date of the last follow up when the absence of HCC was confirmed. Uni- and multivariate Cox proportional hazards models were used to identify factors contributing to HCC development, including gadoxetic acid-enhanced magnetic resonance imaging findings. The cumulative incidence rates of HCC development were calculated using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. The final study cohort comprised 482 patients (median age 70.5years; 242 men). The median follow-up period was 36.8months. Among 482 patients, 96 developed HCC (19.9%). The 1-, 3-, and 5-year cumulative rates of HCC development were 4.9%, 18.6%, and 30.5%, respectively. Multivariate analysis revealed that age, male sex, history of HCC, and hepatobiliary phase hypointense nodules without arterial phase hyperenhancement were independent risk factors significantly associated with HCC development (p<0.001-0.04). The highest risk group included patients with both a history of HCC and the presence of hepatobiliary phase hypointense nodules without arterial phase hyperenhancement (the 1- and 3-year cumulative HCC development rates were 14.2% and 62.2%, respectively). History of HCC and presence of hepatobiliary phase hypointense nodules without arterial phase hyperenhancement were strong risk factors for HCC development following direct-acting antiviral therapy.

Research of &lt;i&gt;PNPLA3&lt;/i&gt; I148M Gene Polymorphism in Patients with Non-Alcoholic Fatty Liver Disease, with Liver Cirrhosis and with Hepatocellular Carcinoma

Aim: to determine the frequency of PNPLA3 rs738409 C&gt;G gene polymorphism, leading to p.I148M substitution, in patients with non-alcoholic fatty liver disease (NAFLD), and to reveal the association between polymorphism and probable NAFLD outcomes: liver cirrhosis (LC) and hepatocellular carcinoma (HCC).Materials and methods. The study was conducted according to the “case-control” design, three main groups were formed: a group with NAFLD (n = 46), a group with LC (n = 61), a group with HCC (n = 50), as well as a control group (n = 70), for all groups we performed genotyping of the rs738409 polymorphism of the PNPLA3 gene. The relationship between the occurrence of different genotype variants and the diagnosis of patients was evaluated, the odds ratio (OR) of progression of NAFLD and the reliability of intergroup differences were determined.Results. NAFLD patients with PNPLA3 I148M polymorphism have a significantly higher chance of developing LC and HCC. The odds ratio for the GG genotype was 7.94 (95 % Cl: 2.19–28.84; p = 0.030) for LC and 6.51 (95 % Cl: 1.15–4.08; p = 0.039) — for HCC with concomitant LC. The presence of the minor G allele also increases the likelhood of transition from NAFLD to LC (OR = 2.38; 95 % Cl: 1.41–4.02; p = 0.010) and HCC in the presence of cirrhosis (OR = 2.17; 95 % Cl: 1.15–4.08; p = 0.039). Differences in the frequency of PNPLA3 polymorphism between the NAFLD and HCC groups were not significant. Additional risk factors for HCC associated with NAFLD are overweight (OR = 5.14; 95 % Cl: 1.94–13.67; p &lt; 0.001), arterial hypertension (OR = 8.49; 95 % Cl: 3.05–23,62; p &lt; 0.001) and diabetes mellitus (OR = 8.57; 95 % Cl: 1.03–71.48; p = 0.032).Conclusion. The frequency of single nucleotide polymorphism PNPLA3 significantly differs in patients with NAFLD, cirrhosis and HCC compared with the control group of healthy volunteers. The PNPLA3 I148M polymorphism increases the incidence of NAFLD progression to cirrhosis and HCC, but only with concomitant cirrhosis.

Therapeutic blockade of ER stress and inflammation prevents NASH and progression to HCC.

The incidence of hepatocellular carcinoma (HCC) is rapidly rising largely because of increased obesity leading to nonalcoholic steatohepatitis (NASH), a known HCC risk factor. There are no approved treatments to treat NASH. Here, we first used single-nucleus RNA sequencing to characterize a mouse model that mimics human NASH-driven HCC, the MUP-uPA mouse fed a high-fat diet. Activation of endoplasmic reticulum (ER) stress and inflammation was observed in a subset of hepatocytes that was enriched in mice that progress to HCC. We next treated MUP-uPA mice with the ER stress inhibitor BGP-15 and soluble gp130Fc, a drug that blocks inflammation by preventing interleukin-6 trans-signaling. Both drugs have progressed to phase 2/3 human clinical trials for other indications. We show that this combined therapy reversed NASH and reduced NASH-driven HCC. Our data suggest that these drugs could provide a potential therapy for NASH progression to HCC.

Unmet Needs in the Post-Direct-Acting Antiviral Era: Hepatocarcinogenesis After Hepatitis C Virus Eradication.

Infection with chronic hepatitis C virus (HCV) is an important risk factor for hepatocellular carcinoma (HCC). Direct-acting antiviral therapy has transformed care for patients with HCV and reduces the risk of HCC. Despite HCV cure, a residual HCC risk remains in patients with advanced fibrosis and cirrhosis, with multiple mechanisms underlying subsequent hepatocarcinogenesis. Transcriptomic and proteomic signatures demonstrate the capacity for HCC risk stratification, and chemoprevention strategies are emerging. For now, pending more precise stratification, HCC surveillance of patients with cured HCV and advanced fibrosis or cirrhosis should continue.

Elucidating Cuproptosis-Associated Genes in the Progression from Nash to HCC Using Bulk and Single-Cell RNA Sequencing Analyses and Experimental Validation.

Background and Objectives: Non-alcoholic steatohepatitis (NASH) is a significant risk factor for hepatocellular carcinoma (HCC) development. Timely treatment during the NASH stage is essential to minimize the possibility of disease progression to HCC. Cuproptosis is a newly identified form of cellular death that could impact the progression of various diseases and cancers. Materials and Methods: Transcriptome and single-cell sequencing datasets were utilized to investigate the role of cuproptosis-related genes (CRGs) in NASH progression to HCC. FDX1, LIPT1, and PDHP were identified as CRGs in NASH patients, and FDX1, DBT, GCSH, SLC31A1, and DLAT were identified as CRGs in patients with NASH progressing to HCC. FDX1 was found to play a significant role in both NASH patients and patients with NASH progressing to HCC. This study constructed cuproptosis-related clusters (CRCs) using the Nonnegative Matrix Factorization algorithm, and they were linked to fatty acid metabolism and the PPAR signaling pathway in both NASH CRCs and HCC CRCs. The Weighted Correlation Network Analysis algorithm identified CRP, CRC, TAT, CXCL10, and ACTA1 as highly relevant genes in NASH CRCs and HCC CRCs. The expression of FDX1 was validated in both mouse models and human NASH samples. Results: The investigation highlights FDX1 as a pivotal CRG in both NASH and NASH progression to HCC. The comprehensive characterization of CRGs sheds light on their potential biofunctional importance in the context of NASH and HCC. Our experimental results show that FDX1 expression was significantly increased in NASH patients. Conclusions: The present study identified key CRGs, revealing their potential impact on NASH and HCC. Meanwhile, targeting FDX1 may prevent the progression of NASH to HCC.

Transcription factor ETV4 promotes the development of hepatocellular carcinoma by driving hepatic TNF-α signaling.

Hepatic inflammation is the major risk factor of hepatocellular carcinoma (HCC). However, the underlying mechanism by which hepatic inflammation progresses to HCC is poorly understood. This study was designed to investigate the role of ETS translocation variant 4 (ETV4) in linking hepatic inflammation to HCC. Quantitative real-time PCR and immunoblotting were used to detect the expression of ETV4 in HCC tissues and cell lines. RNA sequencing and luciferase reporter assays were performed to identify the target genes of ETV4. Hepatocyte-specific ETV4-knockout (ETV4fl/fl, alb-cre ) and transgenic (ETV4Hep-TG ) mice and diethylnitrosamine-carbon tetrachloride (DEN-CCL4 ) treatment experiments were applied to investigate the function of ETV4 in vivo. The Cancer Genome Atlas (TCGA) database mining and pathological analysis were carried out to determine the correlation of ETV4 with tumor necrosis factor-alpha (TNF-α) and mitogen-activated protein kinase 11 (MAPK11). We revealed that ETV4 was highly expressed in HCC. High levels of ETV4 predicted a poor survival rate of HCC patients. Then we identified ETV4 as a transcription activator of TNF-α and MAPK11. ETV4 was positively correlated with TNF-α and MAPK11 in HCC patients. As expected, an increase in hepatic TNF-α secretion and macrophage accumulation were observed in the livers of ETV4Hep-TG mice. The protein levels of TNF-α, MAPK11, and CD68 were significantly higher in the livers of ETV4Hep-TG mice compared with wild type mice but lower in ETV4fl/fl, alb-cre mice compared with ETV4fl/fl mice as treated with DEN-CCL4 , indicating that ETV4 functioned as a driver of TNF-α/MAPK11 expression and macrophage accumulation during hepatic inflammation. Hepatocyte-specific knockout of ETV4 significantly prevented development of DEN-CCL4 -induced HCC, while transgenic expression of ETV4 promoted growth of HCC. ETV4 promoted hepatic inflammation and HCC by activating transcription of TNF-α and MAPK11. Both the ETV4/TNF-α and ETV4/MAPK11 axes represented two potential therapeutic targets for highly associated hepatic inflammation and HCC. ETV4+TNF-α were potential prognostic markers for HCC patients.

Hepatocellular Carcinoma-Southeast Asia Updates.

Hepatocellular carcinoma (HCC) is one of the leading cancers worldwide. Classically, HCC develops in genetically susceptible individuals who are exposed to risk factors, especially in the presence of liver cirrhosis. Significant temporal and geographic variations exist for HCC and its etiologies. Over time, the burden of HCC has shifted from the low-moderate to the high sociodemographic index regions, reflecting the transition from viral to nonviral causes. Geographically, the hepatitis viruses predominate as the causes of HCC in Asia and Africa. Although there are genetic conditions that confer increased risk for HCC, these diagnoses are rarely recognized outside North America and Europe. In this review, we evaluate the epidemiologic trends and risk factors of HCC and discuss the prevention with surveillance and short management.

A Nomogram Prognostic Model for Advanced Hepatocellular Carcinoma Based on the Interaction Between CD8+T Cell Counts and Age.

CD8+T cells are essential components of the adaptive immune system and are crucial in the body's immune system. This study aimed to investigate how the prognosis of patients with advanced hepatocellular carcinoma (HCC) was affected by their CD8+ T cell counts and age and established an effective nomogram model to predict the overall survival (OS). A total of 427 patients with advanced HCC from Beijing Ditan Hospital, Capital Medical University, were enrolled in thisstudy and randomly divided into training and validation groups, with 300 and 127 individuals in each group, respectively. Coxregressionanalysis was used to screen for independent risk factors for advanced HCC, and the interactive relationship between CD8+T cells and patient age was examined to establish a nomogram prediction model. Cox multivariate regression and interaction analyses indicated that tumor number, tumor size, aspartate aminotransferase (AST), C-reactive protein (CRP), relationship of CD8+T cell counts and age were independent predictors of 6-month OS in patients with advanced HCC, and the nomogram model was established based on these factors. The area under the receiver operating characteristic curve (AUC) of the nomogram model for predicting the 3-month, 6-month, and 12-month OS rates were 0.821, 0.802, and 0.756, respectively. Moreover, in clinical practice, patients with true-positive survival benefit more than true-positive death, therefore, we selected 25% as the clinical decision threshold probability based on probability density functions (PDFs) and clinical utility curves (CUCs), which can distinguish approximately 92% of patients who died and 37% of patients who survived. The nomogram model based on CD8+T cell counts and age accurately assessed the prognosis of patients with advanced HCC and suggested that high CD8+T cell levels are beneficial to the survival of patients with advanced HCC.

Egyptian Society of Liver Cancer Recommendation Guidelines for the Management of Hepatocellular Carcinoma.

Globally, hepatocellular carcinoma (HCC) is the fourth most common cause of death from cancer. The prevalence of this pathology, which has been on the rise in the last 30 years, has been predicted to continue increasing. HCC is the most common cause of cancer-related morbidity and mortality in Egypt and is also the most common cancer in males. Chronic liver diseases, including chronic hepatitis C, which is a primary health concern in Egypt, are considered major risk factors for HCC. However, HCC surveillance is recommended for patients with chronic hepatitis B virus (HBV) and liver cirrhosis; those above 40 with HBV but without cirrhosis; individuals with hepatitis D co-infection or a family history of HCC; and Nonalcoholic fatty liver disease (NAFLD) patients exhibiting significant fibrosis or cirrhosis. Several international guidelines aid physicians in the management of HCC. However, the availability and cost of diagnostic modalities and treatment options vary from one country to another. Therefore, the current guidelines aim to standardize the management of HCC in Egypt. The recommendations presented in this report represent the current management strategy at HCC treatment centers in Egypt. Recommendations were developed by an expert panel consisting of hepatologists, oncologists, gastroenterologists, surgeons, pathologists, and radiologists working under the umbrella of the Egyptian Society of Liver Cancer. The recommendations, which are based on the currently available local diagnostic aids and treatments in the country, include recommendations for future prospects.

Hepatocellular Carcinoma Prediction and early Diagnosis of Hepatitis B and C viral infection using miR-122 and miR-223 in a sample of Iraqi patients.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. Therefore, it is critical for researchers to understand molecular biology in greater depth. In several diseases including cancer, abnormal miRNA expression has been linked to apoptosis, proliferation, differentiation, and metastasis. Many miRNAs have been studied in relation to cancer, including miR-122, miR-223, and others. Hepatitis B and C viruses are the most important global risk factors for HCC. This study is intended to test whether serum miRNAs serve as a potential biomarker for both HCC and viral infections HBV and C. The expression of miRNA in 64 serum samples was analyzed by RT-qPCR. Compared to healthy volunteers, HCC patients' sera expressed significantly lower levels of miR-122 and miR-223. Furthermore, we compared the expression of these miRNAs between early-diagnosed HCC patients and healthy controls. There was a significant difference between miR-122 expression in HCC sera and healthy volunteers' sera (0.000 and 0.253, respectively), with a P value of &lt;0.0001. Early diagnostic patients without treatment had completely deleted miR-122 expression levels, while those treated had slightly elevated levels. Clearly, miR-122 has been identified as a biomarker for early detection and follow-up of HCC treatment. HBV and HCV specimens expressed significantly lower levels of miRNA than normal samples with a P value of &lt;0.0001. It is recommended that these findings be further investigated for diagnostic purposes. Further, these miRNAs are highly specific for diagnosing HCC, HBV, and HCV, making them valuable therapeutic indicators.

Hepatocellular Carcinoma: Past and Present Challenges and Progress in Molecular Classification and Precision Oncology.

Hepatocellular carcinoma (HCC) is one of the most common solid tumor malignancies in the world and represents roughly 90% of all primary malignancies of the liver. The most common risk factors for HCC include hepatitis B virus, hepatitis C virus, alcohol, and increasingly, fatty liver. Most HCC is diagnosed at advanced stages, excluding the possibility of curative resection, which leaves systemic therapy as the only treatment option. However, given the extreme mutational diversity and heterogenous nature of HCC, efforts to develop new targeted systemic therapies were largely unsuccessful until recently. HCC pathogenesis is thought to be a multistage process driven by a wide array of nonmutually exclusive driver mutations accompanied by many passenger mutations, with the average tumor possessing approximately 40 genomic aberrations. Over the past two decades, several efforts to categorize HCC prognostically and therapeutically according to different molecular subclassifications with the intent to guide treatment and identify drug targets have emerged, though, no single consensus has been reached. Recent breakthroughs in drug development have greatly expanded treatment options, but the ideal of uniting each patient's unique HCC with a targeted systemic therapy remains elusive.

Exosomal MicroRNA and Protein Profiles of Hepatitis B Virus-Related Hepatocellular Carcinoma Cells.

Infection with hepatitis B virus (HBV) is a main risk factor for hepatocellular carcinoma (HCC). Extracellular vesicles, such as exosomes, play an important role in tumor development and metastasis, including regulation of HBV-related HCC. In this study, we have characterized exosome microRNA and proteins released in vitro from hepatitis B virus (HBV)-related HCC cell lines SNU-423 and SNU-182 and immortalized normal hepatocyte cell lines (THLE2 and THLE3) using microRNA sequencing and mass spectrometry. Bioinformatics, including functional enrichment and network analysis, combined with survival analysis using data related to HCC in The Cancer Genome Atlas (TCGA) database, were applied to examine the prognostic significance of the results. More than 40 microRNAs and 200 proteins were significantly dysregulated (p < 0.05) in the exosomes released from HCC cells in comparison with the normal liver cells. The functional analysis of the differentially expressed exosomal miRNAs (i.e., mir-483, mir-133a, mir-34a, mir-155, mir-183, mir-182), their predicted targets, and exosomal differentially expressed proteins (i.e., POSTN, STAM, EXOC8, SNX9, COL1A2, IDH1, FN1) showed correlation with pathways associated with HBV, virus activity and invasion, exosome formation and adhesion, and exogenous protein binding. The results from this study may help in our understanding of the role of HBV infection in the development of HCC and in the development of new targets for treatment or non-invasive predictive biomarkers of HCC.

Remodeling of the liver fibrosis microenvironment based on nilotinib-loaded multicatalytic nanozymes with boosted antifibrogenic activity

Liver fibrosis is a reversible pathological process caused by chronic liver damage and a major risk factor for hepatocellular carcinoma (HCC). Hepatic stellate cell (HSC) activation is considered the main target for liver fibrosis therapy. However, the efficiency of this strategy is limited due to the complex microenvironment of liver fibrosis, including excessive extracellular matrix (ECM) deposition and hypoxia-induced imbalanced ECM metabolism. Herein, nilotinib (NIL)-loaded hyaluronic acid (HA)-coated Ag@Pt nanotriangular nanozymes (APNH NTs) were developed to inhibit HSCs activation and remodel the microenvironment of liver fibrosis. APNH NTs efficiently eliminated intrahepatic reactive oxygen species (ROS) due to their inherent superoxide dismutase (SOD) and catalase (CAT) activities, thereby downregulating the expression of NADPH oxidase-4 (NOX-4) and inhibiting HSCs activation. Simultaneously, the oxygen produced by the APNH NTs further alleviated the hypoxic microenvironment. Importantly, the released NIL promoted collagen depletion by suppressing the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), thus synergistically remodeling the microenvironment of liver fibrosis. Notably, an in vivo study in CCl4-induced mice revealed that APNH NTs exhibited significant antifibrogenic effects without obvious long-term toxicity. Taken together, the data from this work suggest that treatment with the synthesized APNH NTs provides an enlightening strategy for remodeling the microenvironment of liver fibrosis with boosted antifibrogenic activity.

MiR-9-5p expression is associated with vascular invasion and prognosis in hepatocellular carcinoma, and in vitro verification.

Hepatocellular carcinoma (HCC) is a common liver malignancy. Early vascular invasion (VI) has been associated with poor prognosis in HCC patients. MicroRNAs (miRNAs) play a significant role in the emergence and development of many tumor types. Differential expression analysis of miRNAs related to VI was performed based on data from the TCGA database, and survival-associated miRNAs identified. We identified miR-9-5p as a survival-related miRNA and verified its expression in 61 clinical samples using quantitative real-time PCR. We further performed functional enrichment analysis, protein-protein interaction analysis, univariate and multivariate analysis of the survival-related miRNAs, and cell function assays. In this study, we identified miR-9-5p that could predict VI and prognosis in HCC patients. Cellular experiments demonstrated that downregulation of miR‑9‑5p inhibits migration, invasion, and angiogenesis of HCC cells. Further, we explored and verified the possible mechanism through which miR-9-5p is involved in HCC progression. Univariate and multivariate analysis revealed that miR-9-5p was an independent risk factor for HCC. Finally, the nomogram based on miR-9-5p showed a good predictive value of HCC survival. MiR-9-5p is associated with VI in HCC, and higher expression of miR-9-5p indicates poor prognosis in HCC.

Diagnostic performance of US LI-RADS in hepatocellular carcinoma surveillance

BackgroundLiver cirrhosis and chronic infection with hepatitis B virus are major risk factors for hepatocellular carcinoma (HCC). Guidelines recommend ultrasound (US) surveillance for population at risk of HCC. The US Liver Imaging Reporting and Data System (LI-RADS) aims at standardization of interpretation, reporting, and management recommendations for US surveillance examinations. The aim of this study is to assess the diagnostic accuracy of US LI-RADS in early HCC detection in patients at risk.ResultsThis retrospective study included patients with surveillance US between January 2018 and January 2020 who had a contrast-enhanced CT or MRI of the liver within 1 month from the date of US examination. Visualization scores and US categories were assigned according to the US LI-RADS lexicon. A total of 264 participants were eligible for the study. HCC was diagnosed in 33 participants. The US-3 category had a 39.4% sensitivity and 93.5% specificity for HCC detection. The US-2 category had a 45.4% sensitivity and 87% specificity for HCC detection. The visualization score C showed the highest number of HCC (19/33) and had the highest false-negative rate (76%, 13 of 17).ConclusionsBoth US-2 and US-3 categories showed high specificity and low sensitivity for HCC detection in the setting of surveillance of patients at high risk. Visualization score C had the highest risk for HCC and the highest rate of false-negative results. Intense surveillance by contrast-enhanced CT or MRI might be beneficial for patients with limited visualization scores B and C.

Development and application of hepatocellular carcinoma risk prediction model based on clinical characteristics and liver related indexes.

Hepatocellular carcinoma (HCC) is difficult to diagnose with poor therapeutic effect, high recurrence rate and has a low survival rate. The survival of patients with HCC is closely related to the stage of diagnosis. At present, no specific serological indicator or method to predict HCC, early diagnosis of HCC remains a challenge, especially in China, where the situation is more severe. To identify risk factors associated with HCC and establish a risk prediction model based on clinical characteristics and liver-related indicators. The clinical data of patients in the Affiliated Hospital of North Sichuan Medical College from 2016 to 2020 were collected, using a retrospective study method. The results of needle biopsy or surgical pathology were used as the grouping criteria for the experimental group and the control group in this study. Based on the time of admission, the cases were divided into training cohort (n = 1739) and validation cohort (n = 467). Using HCC as a dependent variable, the research indicators were incorporated into logistic univariate and multivariate analysis. An HCC risk prediction model, which was called NSMC-HCC model, was then established in training cohort and verified in validation cohort. Logistic univariate analysis showed that, gender, age, alpha-fetoprotein, and protein induced by vitamin K absence or antagonist-II, gamma-glutamyl transferase, aspartate aminotransferase and hepatitis B surface antigen were risk factors for HCC, alanine aminotransferase, total bilirubin and total bile acid were protective factors for HCC. When the cut-off value of the NSMC-HCC model joint prediction was 0.22, the area under receiver operating characteristic curve (AUC) of NSMC-HCC model in HCC diagnosis was 0.960, with sensitivity 94.40% and specificity 95.35% in training cohort, and AUC was 0.966, with sensitivity 90.00% and specificity 94.20% in validation cohort. In early-stage HCC diagnosis, the AUC of NSMC-HCC model was 0.946, with sensitivity 85.93% and specificity 93.62% in training cohort, and AUC was 0.947, with sensitivity 89.10% and specificity 98.49% in validation cohort. The newly NSMC-HCC model was an effective risk prediction model in HCC and early-stage HCC diagnosis.

Near infrared-emitting multimodal nanosystem for in vitro magnetic hyperthermia of hepatocellular carcinoma and dual imaging of in vivo liver fibrosis

Prolonged usage of traditional nanomaterials in the biological field has posed several short- and long-term toxicity issues. Over the past few years, smart nanomaterials (SNs) with controlled physical, chemical, and biological features have been synthesized in an effort to allay these challenges. The current study seeks to develop theranostic SNs based on iron oxide to enable simultaneous magnetic hyperthermia and magnetic resonance imaging (MRI), for chronic liver damage like liver fibrosis which is a major risk factor for hepatocellular carcinoma. To accomplish this, superparamagnetic iron oxide nanoparticles (SPIONs) were prepared, coated with a biocompatible and naturally occurring polysaccharide, alginate. The resultant material, ASPIONs were evaluated in terms of physicochemical, magnetic and biological properties. A hydrodynamic diameter of 40 nm and a transverse proton relaxation rate of 117.84 mM−1 s−1 pronounces the use of ASPIONs as an efficient MRI contrast agent. In the presence of alternating current of 300 A, ASPIONs could elevate the temperature to 45 °C or more, with the possibility of hyperthermia based therapeutic approach. Magnetic therapeutic and imaging potential of ASPIONs were further evaluated respectively in vitro and in vivo in HepG2 carcinoma cells and animal models of liver fibrosis, respectively. Finally, to introduce dual imaging capability along with magnetic properties, ASPIONs were conjugated with near infrared (NIR) dye Atto 700 and evaluated its optical imaging efficiency in animal model of liver fibrosis. Histological analysis further confirmed the liver targeting efficacy of the developed SNs for Magnetic theranostics and optical imaging as well as proved its short-term safety, in vivo.