Cirrhosis is a form of end-stage liver disease characterized by extensive hepatic fibrosis and loss of liver parenchyma. It is most commonly the result of long-term alcohol abuse in the United States. Large animal models of cirrhosis, as well as of one of its common long-term sequelae, HCC, are needed to study novel and emerging therapeutic interventions. In the present study, liver fibrosis was induced in the Oncopig cancer model, a large animal HCC model, via intrahepatic, intra-arterial ethanol infusion. Liver sections from five fibrosis induced and five age-matched controls were harvested for RNA-seq (mRNA and lncRNA), small RNA-seq (miRNA), and reduced representation bisulfite sequencing (RRBS; DNA methylation). Single- and multi-omic analysis was performed to investigate the transcriptomic and epigenomic mechanisms associated with fibrosis deposition in this model. A total of 3,439 genes, 70 miRNAs, 452 lncRNAs, and 7,715 methylation regions were found to be differentially regulated through individual single-omic analysis. Pathway analysis indicated differentially expressed genes were associated with collagen synthesis and turnover, hepatic metabolic functions such as ethanol and lipid metabolism, and proliferative and anti-proliferative pathways including PI3K and BAX/BCL signaling pathways. Multi-omic latent variable analysis demonstrated significant concordance with the single-omic analysis. lncRNA's associated with UHRF1BP1L and S1PR1 genes were found to reliably discriminate the two arms of the study. These genes were previously implicated in human cancer development and vasculogenesis, respectively. These findings support the validity and translatability of this model as a useful preclinical tool in the study of alcoholic liver disease and its treatment.

Hepatocellular carcinoma (HCC), which accounts for about 90% of all primary liver cancer cases, is the fifth most common malignancy and the second leading cause of cancer-related mortality worldwide. This study aims to analyse the differential costs of HCC-related hospital admissions compared to the general population in Spain.

A retrospective multicenter study analyzed inpatient admissions from a Spanish national discharge database, covering 90% of hospitals between 2010 and 2022. HCC-related admissions were identified using ICD-9 and ICD-10 codes, while control admissions were selected from the general population in the same database without an HCC diagnosis. The direct hospitalization cost was included, covering medical examinations, procedures, medications, surgeries, personnel and equipment. Statistical methods, including nearest-neighbor matching, propensity score matching, and a generalized linear model, were used to estimate differential costs and to ensure comparability based on age, gender, and Charlson Comorbidity Index (CCI).

A total of 199,670 HCC-related hospital admissions and 200,000 control admissions were analyzed. Most HCC-related admissions involved male patients (78%) aged 66-85 years, with an average CCI of 5.18. HCC-related admissions incurred significantly higher costs, with an estimated differential cost of €1,303.68 using GLM, €1,804.25 via propensity score matching, and €1,767.77 using nearest-neighbor matching. Total costs per HCC admission ranged between €1,000 and €31,000.

HCC-related hospital admissions impose a significantly higher economic burden due to the complexity of care. Given the high mortality and resource utilization, advancements in early detection, treatment, and cost-effective interventions are needed to improve patient outcomes and reduce healthcare costs.

Several prognostic gene signatures have been proposed as predictors of the prognosis of hepatocellular carcinoma (HCC), yet none are implemented in the clinical setting. We aimed to validate two gene scores previously derived from European cohorts.

The patients who underwent liver resection for HCC at Copenhagen University Hospital, Rigshospitalet from 2014 to 2018 were included. RNA sequencing determined the expression of genes in the '5-gene score' (HN1, RAN, RAMP3, KRT19, TAF9B) and 'HepatoPredict' (CLU, DPT, SPRY2, CAPSN1). Univariable Cox regression assessed associations with overall and disease-free survival. These parameters were also analyzed in the The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) (n = 359) and National Institute of Health (NIH) (n = 178) cohorts.

Among 51 patients (88% male), 59% had no underlying liver disease and 25% had cirrhosis. No individual genes were significantly associated with overall survival in the Danish cohort. In the TCGA-LIHC cohort, CLU was linked to better overall survival, and in the NIH cohort, high expression of SPRY2 was associated with poorer overall survival. In the TCGA-LIHC cohort, HN1, RAN, and TAF9B were associated with poorer overall survival, while RAMP3 was linked to better overall survival. No genes were associated with disease-free survival.

Few individual genes significantly predicted survival in the larger cohorts, and none in the Danish cohort. However, the clinical implication of this needs further investigation.

Hepatocellular carcinoma (HCC), a severe consequence of hepatitis C virus infection, is significantly influenced by the virus's non-structural protein 3 (NS3). This study employed transcriptome sequencing to explore the role of NS3 in promoting HCC progression by comparing gene expression profiles between HCV-infected HCC tissues and healthy liver controls. Key genes regulated by NS3 were identified and validated with quantitative reverse transcription PCR (RT-qPCR) and western blot analyses. Functionality assays, including CCK-8, BrdU, and Transwell migration and invasion tests, were performed to evaluate the effects of NS3 on HCC cell proliferation, migration, and invasion. Further investigation through a dual-luciferase reporter and RNA pull-down assays revealed that NS3 specifically upregulates circ_0001175. This circular RNA interacts with and inhibits miR-130a-5p, diminishing its regulatory impact on P53 by modulating the MDM4 pathway, thereby promoting oncogenic characteristics. The findings highlight the NS3-induced circ_0001175/miR-130a-5p/MDM4/P53 pathway as a potential therapeutic target, offering promising directions for treatment strategies in HCV-related HCC.

Despite its established anti-diabetic activity, Metformin hydrochloride (MET) has been repurposed for the management of hepatocellular carcinoma (HCC). Owing to MET high aqueous solubility and poor oral permeability, a novel nanoplatform is sought to overcome the current challenges of traditional formulations. In this study, we developed MET-bridged nanocochleates (MET-CO) using a direct bridging method followed by optimization and assessment using various in-vitro and in-vivo pharmacokinetic methods. The optimized nanocochleates MET-CODCP 19, containing dicetyl phosphate (DCP), displayed uniform snail-shaped nano-rolls measuring 136.41 ± 2.11 nm with a PDI of 0.241 ± 0.005 and a highly negative ζ-potential of -61.93 ± 2.57 mV. With an impressive MET encochleation efficiency (> 75%), MET-CODCP 19 exhibited a controlled biphasic release profile, with minimal initial burst followed by prolonged release for 24 h. Importantly, they showed significant MET permeation in both in-vitro Caco-2 and ex-vivo intestinal models compared to non-DCP containing formula or MET solution. The in-vivo oral bioavailability study demonstrated pronounced improvements in the pharmacokinetic parameters with a 5.5 relative bioavailability compared to MET solution. Notably, a significant reduction in IC50 values in HepG2 cells after 24 h of treatment was observed. Furthermore, the optimized formulation showed a significant downregulation of anti-apoptotic and cancer stemness genes, with 12- and 2-fold lower expression compared to MET solution. These promising results highlight the efficacy of the novel MET-bridged nanocochleates as a stable nanoplatform for enhancing the oral bioavailability of MET and boosting its anticancer potential against HCC.

In this research, we have crafted a high-throughput, cost-effective colorimetric immunoassay for aflatoxin B1 detection, utilizing custom-made polystyrene arrays and click chemistry-induced enzyme-free catalysis. We synthesized signal probes incorporating polydopamine, metal-organic framework (UiO-66-NH2), and aflatoxin B1 antigen. This probe, in conjunction with the immunoreaction occurring on the polystyrene array, modulates the Cu2+ concentration in solution, initiating click chemical reactions among short DNA sequences to form a G-quadruplex DNAzyme that catalyzes a chromogenic substrate. By capturing and analyzing the color variations through smartphone imagery, aflatoxin B1 concentrations can be accurately quantified. The linear range of aflatoxin B1 was 100 pg/mL to 50 ng/mL, with the limit of detection of 26.23 pg/mL. The average recoveries were 81.63 % - 112.21 % for peanut samples and 80.93 % - 113.95 % for maize samples. And the method was in good agreement with the HPLC method for peanut samples.

The year 2024 marks the 60th anniversary of the discovery of the Epstein-Barr virus (EBV), the first virus confirmed to cause human cancer. Viral infections significantly contribute to the global cancer burden, with seven known Group 1 oncogenic viruses, including hepatitis B virus (HBV), human papillomavirus (HPV), EBV, Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV), human T-cell leukemia virus type 1 (HTLV-1), and human immunodeficiency virus (HIV). These oncogenic viruses induce cellular transformation and cancer development by altering various biological processes within host cells, particularly under immunosuppression or co-carcinogenic exposures. These viruses are primarily associated with hepatocellular carcinoma, gastric cancer, cervical cancer, nasopharyngeal carcinoma, Kaposi sarcoma, lymphoma, and adult T-cell leukemia/lymphoma. Understanding the mechanisms of viral oncogenesis is crucial for identifying and characterizing the early biological processes of virus-related cancers, providing new targets and strategies for treatment or prevention. This review first outlines the global epidemiology of virus-related tumors, milestone events in research, and the process by which oncogenic viruses infect target cells. It then focuses on the molecular mechanisms by which these viruses induce tumors directly or indirectly, including the regulation of oncogenes or tumor suppressor genes, induction of genomic instability, disruption of regular life cycle of cells, immune suppression, chronic inflammation, and inducing angiogenesis. Finally, current therapeutic strategies for virus-related tumors and recent advances in preclinical and clinical research are discussed.

Methionine adenosyltransferases (MATs) catalyze the synthesis of S-adenosylmethionine (SAM), the universal methyl donor involved in methylation reactions, redox balance, and polyamine synthesis. In mammals, three MAT genes, MAT1A, MAT2A, and MAT2B, exhibit tissue-specific expression, with MAT1A predominating in healthy liver and MAT2A/MAT2B upregulated during liver injury and malignancy. A shift from MAT1A to MAT2A/MAT2B expression is a hallmark of hepatocellular carcinoma (HCC), contributing to decreased SAM levels and promoting tumorigenesis. Recent findings highlight the pivotal role of post-transcriptional regulation in controlling MAT gene expression. N6-methyladenosine (m6A) modification, the most prevalent internal mRNA modification, plays a dynamic role in determining the fate of MAT2A mRNA. m6A marks regulate MAT2A mRNA splicing and stability in response to stress and metabolic changes. Additionally, RNA-binding proteins (RBPs) such as ELAVL1 and hnRNPD bind to MAT mRNAs, modulating their stability and translation. Dysregulation of these RBPs in liver disease alters MAT expression profiles. Non-coding RNAs, including microRNAs such as miR-29, miR-21, and miR-485, and long non-coding RNAs such as LINC00662 and SNGH6, modulate MAT expression post-transcriptionally by targeting MAT transcripts directly or influencing RNA-binding proteins (RBPs) and m6A writers/readers. Together, these mechanisms form a complex and intricate post-transcriptional regulatory network that governs MAT activity in physiological and pathological states. This review examines emerging insights into MAT post-transcriptional regulation, focusing on its implications for liver cancer, and opens new avenues for developing therapies that target these regulatory mechanisms.

Progesterone and adipose Q receptor 5 (PAQR5), a membrane receptor characterized by seven transmembrane domains, has been indirectly implicated in pro-carcinogenic activities, though its specific role in hepatocellular carcinoma (HCC) remains to be defined.

This study aimed to elucidate the molecular mechanisms by which PAQR5 facilitates HCC progression and contributes to the immunosuppressive microenvironment through an integrative approach combining multi-omics analysis and experimental validation. Utilizing data from bulk, single-cell, and spatial transcriptomics cohorts, this study systematically assessed the expression patterns, immune landscape, and functional characteristics of PAQR5 across different levels of resolution in HCC.

PAQR5 expression was significantly upregulated in tumor tissues and correlated with poor clinical outcomes. Enrichment analysis revealed that PAQR5 activated the NF-κB signaling pathway in HCC. Single-cell transcriptomics identified PAQR5 as predominantly localized within malignant cell clusters, with significant association with NF-κB pathway activation. Spatial transcriptomics further corroborated the alignment of PAQR5 expression with tumor cell distribution. In vitro assays showed elevated PAQR5 levels in HCC cell lines, and silencing PAQR5 significantly suppressed cell proliferation, invasion, epithelial-mesenchymal transition (EMT), and prevented the formation of immunosuppressive microenvironment. In vivo studies demonstrated that targeting PAQR5 attenuated tumorigenic potential, disrupted the invasion-metastasis cascade and inhibited the tumor immune escape. Mechanistically, PAQR5 was found to activate NF-κB signaling by inducing ERK phosphorylation, thereby driving proliferation, invasion, EMT, and immune escape in HCC through the pathway.

Hepatocellular carcinoma (HCC) is among the most aggressive malignancies, marked by high recurrence rates and limited treatment efficacy, especially in HBV-associated HCC (HBV-HCC). This subtype exhibits pronounced metabolic reprogramming, with lipid synthesis playing a pivotal role in driving tumor aggressiveness and therapeutic resistance. However, the molecular mechanisms underlying this metabolic shift remain unclear. In our study, analysis of the LIHC-TCGA database and comparisons between HCC tissues and adjacent peri-tumoral tissues revealed that 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is significantly upregulated in HBV-HCC. Moreover, elevated PFKFB4 expression correlates with poorer prognosis and unfavorable overall survival among HBV-HCC patients. Functional assays demonstrated that PFKFB4 promotes HCC proliferation by enhancing glycolysis and de novo lipid synthesis. Notably, PFKFB4 not only increases glycolytic flux but also upregulates sterol regulatory element-binding protein 1 (SREBP1) expression via its enzymatic activity. Mechanistically, PFKFB4 suppresses phosphorylated AMP-activated protein kinase (p-AMPK) through enhanced aerobic glycolysis, which in turn stimulates the level of SREBP1. Collectively, these findings position PFKFB4 as a critical mediator of metabolic reprogramming in HBV-HCC and a promising therapeutic target.

Recent advances in screening programs and the development of innovative therapeutic strategies have significantly improved the clinical outcomes of cancer patients. However, many patients still experience treatment failure, primarily due to inherent or acquired drug resistance mechanisms. This challenge underscores the urgent need for novel therapeutic targets for the effective treatment of malignancies, as well as cancer-specific biomarkers to enhance early diagnosis and guide interventions. Epigenetic mechanisms, including DNA methylation, have recently garnered growing interest as key regulators of gene expression under both physiological and pathological conditions. Although epigenetic dysregulations are reliable tumor hallmarks, DNA methylation is still not routinely integrated into clinical practice, highlighting the need for further research to translate preclinical findings from the bench to the bedside. On these bases, the present review aims to illustrate the state of the art regarding the role of DNA methylation in cancer, describing the technologies currently available for DNA methylation profiling. Furthermore, the latest evidence on the application of DNA methylation hotspots in cancer diagnosis and prognosis, as well as the impact of epidrugs in cancer care, is discussed to provide a comprehensive overview of the potential clinical relevance of DNA methylation in advancing personalized medicine.

To investigate the staining patterns of CD10 in hepatocellular carcinoma (HCC), focal nodular hyperplasia (FNH), and intrahepatic cholangiocarcinoma (ICC).

The expression pattern of CD10 was analyzed using immunohistochemistry in HCC cases. Focal nodular hyperplasia (FNH) and intrahepatic cholangiocarcinoma (ICC) cases were also examined. CD10 staining pattern in relationship with histologic subtypes and growth patterns of HCC was also analyzed.

CD10 expression was observed in 61% (64/105) of HCC cases, 100% (12/12) of FNH cases, and 31.6% (6/19) of ICC cases. Different expression patterns were noted, including cell membrane (13/64; 20.3%), luminal (9/64; 14.0%), cytoplasmic puncta (15/64; 23.4%), and canalicular (27/64; 42.3%) patterns of CD10 expression in HCC. Interestingly, CD10 membranous expression was found to be associated with steatosis changes. The observed pattern rates of CD10-positive ICC cases were 16.6% (1/6) for cell membrane, 50% (3/6) for cytoplasmic, and 33.3% (2/6) for luminal patterns; with 2 samples having a 1+ score (33.3%), 1 having a 2+ score (16.7%), and 3 having a 3+ score (50%).

Different CD10 expression patterns were observed in HCC, FNH, and ICC. A canalicular CD10 expression pattern does not distinguish between benign and malignant lesions in the HCC, but reduced CD10 expression or no canalicular pattern suggests that a tumor is more likely to be HCC. Contrary to previous understanding, we found that CD10 is also expressed in ICC cases.

One-third of patients with intermediate-stage hepatocellular carcinoma (HCC) can achieve imaging-based no evidence of disease (NED) during treatment after transarterial chemoembolization (TACE) and sequential therapies; however, its temporal dynamics, contributing factors and prognostic value remain unknown.

The longitudinal data of 1665 intermediate-stage HCC patients from Sun Yat-sen University Cancer Center were included as a derivation cohort; 414 patients from three external medical centers served as the validation cohort. Image-Only NED is defined as no evidence of disease based on imaging exams while having a serum level of alpha-fetoprotein (AFP) above the upper limit; Image-Bio NED pertains to an additional achievement of a normal level of AFP. A semi-Markov multistate model was adopted to identify the transitions between intermediate states, which included NED unreached, Image-Only NED, Image-Bio NED, recurrence after NED and death. A time-dependent Cox proportional hazards model for overall survival (OS) was utilised to evaluate the dynamic prognostic value of NED states.

The percentage of patients who reached Image NED and Image-Bio NED was 35.2% and 24.7% in the derivation cohort, and 37.4% and 31.4% in the validation cohort. The proportion of Image-Only NED and Image-Bio NED peaked by the end of the second year since initial treatment and declined gradually. Patients with Image-Only NED had a higher risk of recurrence compared to the Image-Bio NED subgroup (p < 0.05). With the subgroup of NED unreached as reference, the multivariate time-dependent Cox model showed Image-Only NED (HR 0.44; 95% CI 0.33-0.59) and Image-Bio NED (HR 0.26; 0.20-0.33) were significant intermediate states that predict distinct OS for patients with intermediate-stage HCC, which was further confirmed in the multi-centre validation cohort.

Our study highlights the clinical course of NED states and demonstrates its dynamic prognostic significance in patients with intermediate-stage HCC after TACE. The Image-Bio NED is recommended to serve as an important endpoint during the dynamic management of intermediate-stage HCC.

Diffusion-weighted imaging and the quantified apparent diffusion coefficient (ADC) correlate with cell density and histopathological features in tumors. Radiomics analysis may provide more insight into the underlying microstructure and may better correlate with histopathology. The present study used cross-sectional guided biopsy specimens to exploit the precise spatial localization of the performed biopsy to correlate radiomics features of the ADC map with immunohistochemical features in hepatocellular carcinoma (HCC).

A total of 51 patients (11 female patients, 21.6 %) were included in the present study. The mean age was 71.9 ± 9.9 years, ranging from 42 to 91 years. Prebioptic liver MRI with diffusion-weighted imaging was used to correlate the radiomics features of the ADC maps with the immunohistochemical features quantified in liver biopsy. Proliferation potential Ki 67, leukocyte count and tumor-stroma ratio were evaluated as histopathological parameters.

The following ADC texture features were correlated with the Ki 67 index _MinNorm (r = -0.307, p = 0.03), Vertl_RLNonUni (r = - 0.309, p = 0.03), 135dr_RLNonUni (r = -0.346, p = 0.01). The texture feature _MinNorm achieved the best diagnostic accuracy with an area under the curve of 0.76 (95 % CI 0.60-0.91, p < 0.01) to discriminate between low and high proliferative HCC. Multiple statistically significant correlations were found between ADC texture features and tumor-stroma-ratio, the highest for S(0,1)Contrast (r = 0.460, p = 0.001). No statistically significant correlations were found between the ADC texture features with the CD45+ leukocyte count and grading.

Radiomics features of the ADC maps can reflect the underlying histopathology in HCC patients including the proliferation potential and tumor-stroma ratio but not CD45 positive cells and tumor grading. The complex interactions between quantitative imaging and histopathology need to be further investigated in a validation cohort.

Angiogenesis plays a crucial role in the development of HBV-related hepatocellular carcinoma (HCC). VEGFA is a key angiogenic factor, and while its transcriptional regulation by HBV has been extensively studied, its posttranscriptional regulation by HBV remains poorly understood. Building on our previous findings that delineated an RBM15/YTHDF2/IGF2BP3 regulatory axis in m6A-mediated RNA metabolism in HCC, this study further explores the posttranscriptional regulation of VEGFA by HBV. By MeRIP-qPCR and integrating MeRIP-seq data, we discovered that HBV enhances m6A methylation of VEGFA mRNA. Comprehensive cellular and molecular biology experiments demonstrated that HBV induces the upregulation of IGF2BP3, which serves as a key "reader" that recognizes and stabilizes VEGFA mRNA in an m6A methylation-dependent manner. This stabilization leads to elevated VEGFA expression, promoting enhanced cellular functions such as HUVEC migration and tube formation. Furthermore, in an HBV-associated HCC xenograft model, IGF2BP3 knockdown resulted in decreased VEGFA expression and inhibited tumor growth. This study expands our understanding of HBV-driven angiogenesis and identifies the IGF2BP3-VEGFA axis as a potential therapeutic target for antiangiogenic strategies in HBV-related HCC.

Systematic identification of patients with cirrhosis through electronic healthcare records (EHRs) using ICD-10 codes is essential for epidemiological research but is prone to discrepancies. We aim to validate and improve a recent consensus code set of nine ICD-10 codes to identify cirrhosis in a multi-ethnic Asian population.

We applied an initial broad algorithm of 25 ICD-10 codes related to cirrhosis and its complications to identify patients potentially with cirrhosis admitted to Singapore General Hospital in 2018 and confirmed true cirrhosis cases via manual EHR review. We evaluated the consensus code set's sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) in identifying cirrhosis cases. We examined alternative code sets to improve cirrhosis identification and validated them in another local hospital.

One thousand, seven hundred thirty-three patients potentially with cirrhosis were identified, with 937 (54.1%) confirmed. The median age at diagnosis was 71 years (IQR: 64-78), with 65.6% males, 75.2%/8.8%/9.3%/6.7% Chinese/Indians/Malays/Others, and 56.7% Child-Pugh A. The main etiologies were chronic hepatitis B (29.5%) and metabolic dysfunction-associated steatotic liver disease (25.5%). The consensus code set demonstrated sensitivity/specificity/PPV/NPV of 76.1%/82.0%/83.3%/74.5%, respectively. We identified a set of 10 ICD-10 codes (SingHealth Chronic Liver Disease Registry [SoLiDaRity]-10) with sensitivity/specificity/PPV/NPV of 76.5%/84.8%/85.6%/75.4%, respectively, demonstrating an improved specificity versus the consensus code set (p = 0.001). External validation in another local hospital with 578 patients potentially with cirrhosis demonstrated improved sensitivity of the SoLiDaRity-10 code set versus the consensus code set (p = 0.033) (sensitivity/specificity/PPV/NPV: 78.0%/93.6%/94.1%/76.4% vs. 76.2%/93.6%/94.0%/75.0%, respectively).

While the consensus code set performs well in identifying patients with cirrhosis in a multi-ethnic Asian population, we propose the improved SoLiDaRity-10 code set.

Hepatocellular carcinoma remains a life-threatening malignancy with limited therapeutic options following the failure of second-line treatments1,2. Oncolytic viruses selectively replicate in and lyse cancer cells, releasing neoantigens and stimulating systemic antitumour immunity3, offering a potential therapeutic option. Here we present the results of a multicentre phase 1 clinical trial evaluating VG161, an engineered oncolytic herpes simplex virus that expresses IL-12, IL-15, IL-15Rα and a PD-1-PD-L1-blocking fusion protein4, for safety and efficacy in patients with advanced liver cancer. VG161 was well tolerated, with no dose-limiting toxicities observed, and it demonstrated promising efficacy by reshaping the tumour immune microenvironment and re-sensitizing tumours that were previously resistant to systemic treatments. Notably, we also found that patients who had previously been sensitive to checkpoint inhibitor therapy showed enhanced efficacy with VG161 treatment. Furthermore, we developed an efficacy-prediction model based on differentially expressed genes, which successfully identified patients who were likely to benefit from VG161 and predicted prolonged overall survival. These findings position VG161 as a promising third-line therapeutic option for refractory hepatocellular carcinoma. This provides a new avenue for treatment and advances the field of oncolytic virus-based immunotherapies. ClinicalTrials.gov registration: NCT04806464 .

Pancreatic fat accumulation, that is, fatty pancreas (FP), has gained attention because it contributes to pancreatic carcinogenesis. However, the impact of FP on the survival of patients with pancreatic cancer has not yet been elucidated.

Overall, 87 consecutive patients who were pathologically diagnosed with pancreatic ductal adenocarcinoma and underwent potentially curative pancreatectomy were eligible for analysis. Histological pancreatic fat fraction (HPFF) was evaluated using hematoxylin & eosin-stained slides of tumor and non-tumor sections of the resected specimen, and quantified using imaging analysis software. The optimal HPFF value threshold for FP presence was determined using receiver operating characteristics curve analysis. The prognostic significance of FP was identified by a Cox proportional hazard model adjusted for the established prognostic covariates.

Fat accumulation within the invasive tumor front was scarce, with the median value for HPFF being 10.1% in the non-tumor portion (range: 2.2%-45.8%). Patients with FP (HPFF value ≥ 11.3%) in the non-tumor portion had significantly inferior overall survival (OS) and recurrence-free survival (RFS) than those without FP (HPFF value < 11.3%) (log-rank test: p = 0.012 and p = 0.00060, respectively). In the multivariate analyses, the presence of FP emerged as an independent inferior prognostic indicator (OS: hazard ratio [HR] 2.32, p = 0.0015; PFS: HR 2.33, p = 0.00080), together with lymph node metastases, presence of lymphatic involvement, and absence of adjuvant chemotherapy.

The present study indicates a possible prognostic role for pancreatic fat accumulation in patients with pancreatic adenocarcinoma.

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with transarterial chemoembolisation (TACE) being a primary treatment for intermediate-stage disease. However, post-procedural pain remains a significant challenge due to inconsistent management practices and a lack of standardised protocols. This scoping review synthesises current evidence on pain management strategies in HCC patients undergoing TACE, evaluates their effectiveness, identifies practice gaps, and proposes optimisation strategies. Methods: A comprehensive database search according to the methodological approach given by Arksey and O'Malley with the aid of the PRISMA-ScR guidelines across Cochrane Library, Web of Science, CINAHL, PubMed, and Scopus was performed. The terms associated with pain, TACE, and liver cancer were included in the search strategy. Two independent researchers systematically screened study titles, abstracts, and full texts and extracted key study characteristics and approaches to pain management. Results: Of 1515 identified studies, 29 met the inclusion criteria. Most (72.7%) focused on pharmacological interventions, with dexamethasone and lidocaine being the most frequently investigated agents. Non-pharmacological approaches, including psychological interventions, physical therapies, music therapy, health education, and comprehensive nursing, were also reported. Pain was primarily assessed using the visual analogue scale (VAS) and numeric rating scale (NRS). Conclusions: Pharmacological interventions, particularly dexamethasone and lidocaine, remain the cornerstone of pain management in TACE, yet consensus on their optimal use is lacking. Non-pharmacological strategies provide complementary benefits. standardised, evidence-based pain management protocols integrating both approaches are needed. Future large-scale, multicentre trials are essential to establish the most effective strategies for optimising patient outcomes.

Locoregional therapies (LRTs) play a considerable role in the management of hepatocellular carcinoma (HCC), especially for patients who are not suitable for radical resection or transplantation. In clinical practice, assessment of LRTs is mainly based on computed tomography and MR imaging, but functional and metabolic information is less accessible. This article reviews the use of various the standardized uptake value parameters based on PET and multiple radiotracers for managing HCC after treatment with different LRTs, as well as parts of preclinical research. It discusses the current use of PET in more detail, as well as its advantages, disadvantages, and prospects.

Chronic hepatitis B is a major worldwide public health concern. Entecavir, one nucleos(t)ide analogue antiviral therapy option, is recommended as the first-line drug for chronic hepatitis B in many clinical guidelines. However, none of the guideline recommendations are based on the findings of a systematic review with meta-analysis, where entecavir versus no treatment or placebo are compared directly.

To evaluate the benefits and harms of entecavir versus no treatment or placebo in children and adults with chronic hepatitis B, who are either hepatitis B e-antigen (HBeAg)-positive or HBeAg-negative.

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE Ovid, Embase Ovid, three other databases, online trial registries, and reference lists, and contacted authors. The latest search was on 19 July 2024.

We included randomised clinical trials comparing entecavir versus no treatment or placebo in children or adults, or both, with chronic hepatitis B, and irrespective of treatment history with other antiviral drugs and other viral co-infections. We allowed co-interventions when administered equally to all intervention groups.

The outcomes reported in this abstract and in the summary of findings table are all-cause mortality, health-related quality of life, and proportion of people with serious adverse events at the longest follow-up.

We used the Cochrane RoB 2 tool to assess risk of bias in the included trials.

We used a random-effects model to meta-analyse outcome results, where possible, and presented the results as a risk ratio (RR) with 95% confidence interval (CI). Where there was considerable heterogeneity, we performed a narrative analysis. We used a fixed-effect model for sensitivity analysis. We used GRADE to evaluate the certainty of evidence.

We included 22 randomised clinical trials (published from 2005 to 2022) with 2940 participants diagnosed with chronic hepatitis B. All trials had a parallel-group design. The experimental intervention was oral entecavir, with a follow-up duration of 5 weeks to 228 weeks. The comparator in 12 trials was no treatment, and in 10 trials was placebo. Fourteen trials equally administered co-interventions to the trial participants in the entecavir and no treatment and placebo groups. One trial included participants between 14 years and 55 years of age, one trial included only children, 19 trials included only adults, and one trial did not provide the age of participants.

Twenty trials contributed data to the quantitative analysis. Ten trials (1379 participants) reported all-cause mortality with a mean follow-up duration of 48.9 weeks (range 5 to 100 weeks). The result was not estimable because no deaths occurred in any of the entecavir and no treatment or placebo groups. None of the trials provided data on health-related quality of life. We are very uncertain about the effect of entecavir versus no treatment or placebo on the proportion of people with serious adverse events (RR 0.66, 95% CI 0.33 to 1.32; absolute risk difference 22 fewer per 1000 (from 44 fewer to 21 more); 15 trials, 1676 participants; very low-certainty evidence). The mean follow-up duration was 58.4 weeks (range 5 weeks to 228 weeks). We downgraded the certainty of evidence for these outcomes to very low, mainly because the overall risk of bias in most trials was with some concerns or high, and serious imprecision (no events or few events).

Given the issues of risk of bias and insufficient power of the included trials and the very low certainty of the available evidence, we could not determine the effect of entecavir versus no treatment or placebo on critical outcomes such as all-cause mortality and serious adverse events. There is a lack of data on health-related quality of life. Given the first-line recommendation and wide usage of entecavir in people with chronic hepatitis B, further evidence on clinically important outcomes, analysed in this review, is needed.

This Cochrane review had no dedicated funding.

Registration: Entecavir for children and adults with chronic hepatitis B, CD015536 via DOI 10.1002/14651858.CD015536.

Spectroscopic data often contain artifacts or noise related to the sample characteristics, instrumental variations, or experimental design flaws. Therefore, classifying the raw data is not recommended and might lead to biased results. Nevertheless, most issues may be addressed through appropriate data pre-processing. Effective pre-processing is particularly crucial in critical applications like liquid biopsy for disease detection, where even minor performance improvements may impact patient outcomes. Unfortunately, there is no consensus regarding optimal pre-processing, complicating cross-study comparisons. This study presents a comprehensive evaluation of various pre-processing methods and their combinations to assess their influence on classification results. The goal was to identify whether some pre-processing methods are associated with higher classification outcomes and find an optimal strategy for the given data. Data from Raman optical activity and infrared and Raman spectroscopy were processed, applying tens of thousands of possible pre-processing pipelines. The resulting data were classified using three algorithms to distinguish between subjects with liver cirrhosis and those who had developed hepatocellular carcinoma. Results highlighted that some specific pre-processing methods often ranked among the best classification results, such as the Rolling Ball for correcting the baseline of Raman spectra or the Doubly Reweighted Penalized Least Squares and Mixture model in the case of Raman optical activity. On the other hand, the selection of filtering and/or normalization approach usually did not have a significant impact. Nonetheless, the pre-processing of top-scoring pipelines also depended on the classifier utilized. The best pipelines yielded an AUROC of 0.775-0.823, varying with the evaluated spectroscopic data and classifier.

Hepatocellular carcinoma (HCC) is the primary form of liver cancer that poses a significant global health concern due to its increasing incidence rates and diverse etiology. Chronic infection induced by hepatitis B virus (HBV) is a prominent etiological factor influencing the development of HCC. Although recent advances in multi-omics approaches have facilitated extensive exploration of HCC molecular characteristics, translating the characteristics of subtypes into clinical applications has been challenging due to parameters like limited sample size and complex classifiers for early detection. In the present study, we performed transcriptomics profiling of HBV-infected HCC patient tissue data to gather comprehensive insights into the intricate molecular mechanisms underlying HBV-associated HCC, specifically, viral protein interactions that influence the expression of oncogenes. The 1059 differentially expressed genes (DEGs) identified across two GEO data sets revealed upregulation of cell cycle and mitosis-related genes, alongside downregulation of genes involved in fatty acid degradation and cytochrome P450 activity. CDK1 and CDC20 which are part of the top cluster and hub gene from interactome analysis were identified as potential markers for HBV-positive HCC through gene expression pattern and overall survival analysis. Additionally, 19 DEGs showing significance in HCC development were identified as interacting partners with HBV proteins. Among them, the interaction of HBsAg with ALB and SHBG and their downregulation correlates to the lower testosterone levels identified in HBV and HCC patients. Together, the study enhances the understanding of the heterogeneity and molecular pathogenesis of HBV-positive HCC.

Liver cancer remains a significant public health issue in China, exhibiting high incidence, mortality, and burden. Understanding its temporal trends and projections is essential for designing targeted prevention and treatment strategies. This study analyzes long-term trends in liver cancer incidence, prevalence, mortality, and burden from 1990 to 2021, assessing age, period, and cohort effects, and projecting future trends. Data on liver cancer incidence, prevalence, mortality, disability-adjusted life years (DALYs), years lived with disability (YLDs), and years of life lost (YLLs) were analyzed from 1990 to 2021. Joinpoint regression analysis, age-period-cohort (APC) analysis, and BAPC modeling were applied to examine trends and project future trends. Decomposition analysis examined contributions of aging, epidemiological changes, and population growth. The study also compared China's liver cancer trends with global data. From 1990 to 2021, China experienced a decrease in age-standardized rates for liver cancer incidence, prevalence, mortality, and burden. Notably, Age-standardized incidence rates (ASIR) exhibited a decline after 2016, with a significant reduction in the male population. In 2021, there were 196,637 new cases of liver cancer in China, with a higher burden in males. ASIR were 14.34 per 100,000 for males and 4.89 per 100,000 for females. Mortality also followed a declining trend, with a notable decrease in age-standardized mortality rates. The age-standardized mortality rate (ASMR) for males was 12.4 per 100,000, significantly higher than for females (4.57 per 100,000) in 2021. Additionally, the age-standardized prevalence rate (ASPR) was 20.0 for males and 6.64 for females, with 265,539 total cases. The burden, measured by DALYs, YLDs, and YLLs, also showed a notable decline in age-standardized rates and significant gender disparities. Despite this, the absolute number of cases, deaths, and DALYs has continued to rise due to population growth and aging, with males bearing a significantly higher burden than females. The study also highlights the impact of aging, population growth, and epidemiological changes on liver cancer incidence and mortality in China. Projections for 2030 suggest a continued decrease in liver cancer incidence, especially among females, reflecting the effectiveness of public health interventions and medical advancements. However, gender disparities remain significant, and further efforts are needed to reduce the overall liver cancer burden, with an emphasis on early detection and prevention strategies.

Hepatocellular carcinoma stands as one of the foremost contributors to cancer-associated fatalities globally, and the limitations of traditional treatment methods have prompted researchers to explore new therapeutic options. Recently, cell therapy has emerged as a promising approach for HCC, showing significant potential in improving patient outcomes. This review article explores the use of cell therapy for HCC, covering different types, the mechanisms behind their effectiveness, recent advancements in clinical trials, and ongoing challenges. This article aims to provide insightful perspectives for future research and clinical applications in treating HCC by synthesizing current knowledge.

In most countries, males have ~2-3 times higher incidence of primary liver cancer than females. Sex hormones have been hypothesized to contribute to these differences, but the evidence remains unclear. Using data from the UK Biobank, which included ~200,000 males and ~180,000 postmenopausal females who provided blood samples at recruitment, we estimated hazard ratios (HR2) and 95% confidence intervals (CI) for a doubling in hormone concentration from multivariable adjusted Cox regression for circulating total testosterone, sex-hormone binding globulin (SHBG), and free testosterone concentrations and risk of primary liver cancer. After a median of 11.8 years of follow-up, 531 cases of primary liver cancer were observed, of which 366 occurred in males and 165 occurred in females. Total testosterone and SHBG were shown to be positively associated with liver cancer risk in both males and females (Total testosterone HR2: 3.42, 95% CI:2.42-4.84 and 1.29, 0.97-1.72, respectively; SHBG HR2: 5.44, 4.42-6.68 and 1.52, 1.09-2.12, respectively). However, free testosterone was inversely associated with primary liver cancer in males (HR2: 0.42, 0.32-0.55) and no association was observed in females. When analyses compared two main liver cancer subtypes, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), there was evidence of heterogeneity; associations for total testosterone and SHBG concentrations were only positively associated with HCC in both males (HR2: 3.56, 2.65-4.79 and 7.72, 6.12-9.73, respectively) and females (HR2: 1.65, 1.20-2.27 and 6.74, 3.93-11.5, respectively) but not with ICC. Further research understanding the mechanisms of how sex-steroids may influence liver cancer risk is needed.

Mitochondria are essential organelles for many aspects of cellular homeostasis. They play an indispensable role in the development and progression of diseases, particularly cancer which is a major cause of death worldwide. We analyzed the scientific research output on mitochondria and cancer via PubMed and Web of Science over the period 1990-2023.

Bibliometric analysis was performed by extracting data linking mitochondria to cancer pathogenesis over the period 1990-2023 from the PubMed database which has a precise and specific search engine. Only articles and reviews were considered. Since PubMed does not support analyses by countries or institutions, we utilized InCites, an analytical tool developed and marketed by Clarivate Analytics. We also used the VOSviewer software developed by the Centre for Science and Technology Studies (Bibliometric Department of Leiden University, Leiden, Netherlands), which enables us to graphically represent links between countries, authors or keywords in cluster form. Finally, we used iCite, a tool developed by the NIH (USA) to access a dashboard of bibliometrics for papers associated with a portfolio. This module can therefore be used to measure whether the research carried out is still basic, translational or clinical.

In total, 169,555 publications were identified in PubMed relating to 'mitochondria', of which 34,949 (20.61%) concerned 'mitochondria' and 'dysfunction' and 22,406 (13.21%) regarded 'mitochondria' and 'cancer'. Hence, not all mitochondrial dysfunctions may lead to cancer or enhance its progression. Qualitatively, the disciplines of journals were classified into 166 categories among which cancer specialty accounts for only 4.7% of publications. Quantitatively, our analysis showed that cancer/neoplasms in the liver (2569 articles) were placed in the first position. USA occupied the first position among countries contributing the highest number of publications (5695 articles), whereas Egypt came in the thirty-eight position with 84 publications (0.46%). Importantly, USA is the first-ranked country having both the top 1% and 10% impact indicators with 207 and 1459 articles, respectively. By crossing the query 'liver neoplasms' (155,678) with the query 'mitochondria' (169,555), we identified 1336 articles in PubMed over the study period. Among these publications, research areas were classified into 65 categories with the highest percentage of documents included in biochemistry and molecular biology (28.92%), followed by oncology (23.31%).

This study underscores the crucial yet underrepresented role of mitochondria in cancer research. Despite their significance in cancer pathogenesis, the proportion of related publications remains relatively low. Our findings highlight the need for further research to deepen our understanding of mitochondrial mechanisms in cancer, which could pave the way for new therapeutic strategies.

Studies have indicated that forgoing lung shunt fraction measurement in select patients undergoing Yttrium 90 (Y90) transarterial radioembolization (TARE) may be safe without sacrificing efficacy. This study evaluated the safety and efficacy of a streamlined treatment in patients with small hepatocellular carcinoma (HCC) receiving resin-based TARE.

Patients who received single-session Y90 TARE between September 2023 and May 2024 were retrospectively evaluated. Treatment response was evaluated at the 3-month follow-up using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Adverse events (AEs) ≥ Grade 3 were recorded post-procedurally at 3 months. The time from the interventional radiology clinic visit to the procedure date was compared to patients receiving the conventional TARE treatment.

Ten consecutive patients were treated with 12 treatments. Each treatment targeted an isolated lesion with median size of 2.5 cm (IQR: 2.1, 2.9). Two patients received two treatments (one for treatment of a separate lesion and the other for the initial incomplete targeting of the tumor). The median delivered tumor dose was 377.7 Gy (IQR: 246.5, 570.1). No patients developed ≥ Grade 3 AEs post-TARE. Complete response was achieved in 11/12 patients (92%). The conventional cohort consisted of 60 patients, all OPTN T2 treated with radiation segmentectomy with glass microspheres. Patients undergoing SSMT had a median time from clinic visit to treatment of 26.5 days (IQR: 15.3, 39) vs. 61 days (IQR: 48, 88.8) in the conventional TARE group (p < 0.001).

Streamlined single-session resin-based Y90-TARE in patients with OPTN T2 stage HCC is feasible, efficacious, safe, and associated with reduced time to treatment.

As a novel genetic biomarker, the potential role of SH3D21 in hepatocellular carcinoma remains unclear. Here, we decipher the expression and function of SH3D21 in human hepatocellular carcinoma. The expression level and clinical significance of SH3D21 in hepatocellular carcinoma patients, the relationship between SH3D21 and the features of tumor microenvironment (TME) and role of SH3D21 in promoting hepatocellular carcinoma progression were analyzed based on the bulk samples obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. Single-cell sequencing samples from Gene Expression Omnibus (GEO) database were employed to verify the prediction mechanism. Additionally, different biological effects of SH3D21 on hepatocellular carcinoma cells were investigated by qRT-PCR, CCK-8 assay, colony forming assay and Western blot analysis. Bioinformatics analysis and in vitro experiments revealed that the expression level of SH3D21 was up-regulated in hepatocellular carcinoma and correlated with the poor prognosis in hepatocellular carcinoma patients. SH3D21 effectively promoted the proliferation, invasion, and migration as well as the formation of immunosuppressive microenvironment of hepatocellular carcinoma. In addition, SH3D21 can activate the PI3K/AKT/mTOR signaling pathway. SH3D21 stimulates the progression of hepatocellular carcinoma by activating the PI3K/AKT/mTOR signaling pathway, and SH3D21 can serve as a prognostic biomarker and therapeutic target for hepatocellular carcinoma.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease influenced by genetic, lifestyle, and environmental factors. While MASLD is more prevalent in men, women are at increased risk after menopause, highlighting the critical pathogenetic role of sex hormones. The complex interplay between estrogen deficiency, visceral fat accumulation, metabolic syndrome (MetS), and inflammation accelerates disease progression, increases cardiovascular (CV) risk, and triggers a cycle of worsening adiposity, metabolic dysfunction, and psychological problems, including eating disorders. Weight loss in postmenopausal women can significantly improve both metabolic and psychological outcomes, helping to prevent MASLD and related conditions. This review examines the prevalence of MASLD, its comorbidities (type 2 diabetes T2D, CV, mental disorders), pathogenetic mechanisms, and pharmacological treatment with GLP-1 receptor agonists (GLP1-RAs), with a focus on postmenopausal women. Given the use of GLP1-RAs in the treatment of obesity and T2D in MASLD patients, and the increase in MetS and MASLD after menopause, this review analyzes the potential of a stable GLP-1-estrogen conjugate as a therapeutic approach in this subgroup. By combining the synergistic effects of both hormones, this dual agonist has been shown to increase food intake and food reward suppression, resulting in greater weight loss and improved insulin sensitivity, glucose, and lipid metabolism. Therefore, we hypothesize that this pharmacotherapy may provide more targeted therapeutic benefits than either hormone alone by protecting the liver, β-cells, and overall metabolic health. As these effects are only supported by preclinical data, this review highlights the critical need for future research to evaluate and confirm the mechanisms and efficacy in clinical settings, particularly in postmenopausal women.

Fibrolamellar carcinoma (FLC) is a unique primary carcinoma of the liver that is characterized by distinct morphologic findings and a recurrent DNAJB1::PRKACA gene fusion. It typically presents in young individuals without underlying liver dysfunction. FLC is difficult to diagnose when based only on morphology, and misdiagnosis is common. Frequent differential diagnoses include conventional hepatocellular carcinoma and intrahepatic cholangiocarcinoma, both of which can show similar morphologic and immunohistochemical features. If based only on molecular analysis, other differential diagnoses have recently emerged, as the DNAJB1::PRKACA fusion has now been reported in cases of intraductal oncocytic papillary neoplasm and intraductal papillary mucinous neoplasm. In this article, we review our diagnostic approach to FLC, which relies on both morphologic and immunohistochemical features, as well as molecular analysis.

Liver cancer is a major global health burden, with alcohol use being a well-established risk factor. This study aims to analyze the global, regional, and national incidence, prevalence, mortality, and disability-adjusted life years (DALYs) attributable to liver cancer due to alcohol use from 1990 to 2021.

Data on liver cancer due to alcohol use were collected from the 2021 Global Burden of Disease (GBD) study. The changing trend of liver cancer among alcohol users was described using the linear regression model. In addition, we employed a hierarchical cluster analysis to study the evolving patterns across diverse GBD regions and conducted a frontier analysis to explore the nexus between the burden and sociodemographic progress.

In 2021, alcohol-related liver cancer globally accounted for 99 544 incidence cases, 132 033 prevalence cases, 92 228 death cases, and 2 316 027 DALYs cases. Males and middle-aged adults emerged as high-risk populations, while regions with a higher sociodemographic index (SDI) were identified as high-risk areas. From 1990 to 2021, both the number of cases and age-standardized rates (ASRs) increased. Our frontier analysis revealed unattained health gains between 1990 and 2021, highlighting disparities in disease burden among countries with varying SDI levels. This analysis further demonstrated an inverse correlation between SDI and alcohol-related liver cancer ASRs, with the ASRs stabilizing once the SDI exceeded 0.40.

Alcohol use is a significant contributor to the global burden of liver cancer. Comprehensive policies and interventions targeting alcohol use are needed to reduce the burden of alcohol-related liver cancer.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Radiofrequency ablation (RFA) can be utilized in elderly patients and those with cirrhosis with reduced functional liver reserve as it is less invasive. The arfa RFA system is the first system to offer a linear mode. However, the differences in performance between the linear and existing (nonlinear) modes remain unknown.

This retrospective observational study compared the performance of the linear (linear group) and nonlinear RFA modes (nonlinear group) in HCC.

Data of 425 patients with one to three HCC tumors measuring ≤ 3 cm who underwent RFA were analyzed. Recurrence (local and distant), survival, and complication rates between the linear and nonlinear groups were determined.

The intrahepatic distant recurrence rate was lower in the linear group than in the nonlinear group (p < 0.05). Multivariate analysis showed that the high platelet count, low AFP-L3 levels, initial case, and linear mode were independent factors associated with a low intrahepatic distant recurrence rate following RFA. Liver disease-related survival, HCC survival, overall survival of the initial HCC, local recurrence, and complication rates were comparable between the linear and nonlinear groups.

The linear mode of the RFA protocol results in a lower intrahepatic distant recurrence rate compared with the nonlinear protocol.

Observational studies have reported conflicting associations between periodontitis (PD) and hepatocellular carcinoma (HCC). To overcome these limitations, we performed a two-sample Mendelian randomization (MR) analysis to investigate the potential association between PD and HCC.

We used summary data from genome-wide association studies (GWASs) of European ancestry, integrating data from chronic/acute periodontitis (CP/AP) samples (n1 = 34,615; n2 = 277,036; n3 = 410,811) and HCC samples (n1 = 456,348; n2 = 475,638). The inverse variance-weighted (IVW) approach represents our primary analysis method, supplemented by MR-Egger regression, weighted median, weighted-mode, and simple-mode methods. Pleiotropy and heterogeneity tests were also performed.

IVW analysis suggested that PD had no effect on HCC (Group 1: odds ratio [OR] = 0.912, 95% confidence interval [CI] = 0.690-1.204, P = .514; Group 2: OR = 1.038, 95% CI = 0.895-1.203, P = .623; Group 3: OR = 0.966, 95% CI = 0.851-1.096, P = .591; Group 4: OR = 1.103, 95% CI = 0.576-2.113, P = .768; Group 5: OR = 1.257, 95% CI = 0.511-1.037, P = .540; Group 6: OR = 0.728, 95% CI = 0.511-1.037, P = .079). Four complementary analyses further support this conclusion. Both the IVW and MR-Egger results indicate that the instrumental variables in each group did not exhibit significant pleiotropy. MR-Egger regression analysis showed no evidence of pleiotropic effects.

Our MR analysis suggests that PD does not significantly impact the risk of developing HCC. These results provide a new perspective on the relationship between these 2 conditions.

This MR study suggests no significant genetic causal relationship between PD and HCC, providing a new perspective. It indicates that clinicians may not need to over-intervene in periodontal disease to prevent liver cancer, thereby avoiding unnecessary psychological burden on patients.

Hepatocyte-specific deficiency of the phosphatase and tensin homolog (PTEN) triggers steatosis and the development of hepatic tumors. The hepatoprotective effect of PTEN may partly depend on its ability to block insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) signaling. This study aimed to evaluate the individual/combined contributions of IR and IGF1R to hepatic metabolism and tumorigenesis induced by PTEN deficiency.

Mouse models with hepatocyte-specific deletions of Insr, Igf1r, or both, in addition to Pten, were used to investigate the distinct/combined roles of IR and IGF1R. Analyses focused on the impact of these deletions on hepatic steatosis and metabolism, whole-body adiposity, and liver tumor incidence.

IR and IGF1R signaling contribute to steatosis induced by Pten ablation through distinct mechanisms. Hepatic IGF1R regulates hepatic glucose output and glycogen storage (2.1-fold increase in hepatic glycogen in PTEN-IGF1RKO mice [n = 10], compared with PTENKO mice [n = 7], p <0.0001). In contrast, hepatic IR exerts a stringent regulation on whole-body adiposity (4-fold increase in white adipose tissue volume in PTEN-IRKO mice [n = 5], compared with PTENKO mice [n = 6], p = 0.0004). Interestingly, triple knockout (Insr, Igf1r, and Pten) in hepatocytes of young adult mice is largely asymptomatic, indicating that PTEN deficiency exerts a major overriding control on the effects of Insr and Igf1r deletion. Furthermore, the combined loss of IR and IGF1R signaling in PTEN-deficient livers restrains liver carcinogenesis, but both receptors have individually distinct effects on the malignancy of liver cancers, with IR deficiency reducing overall cancer incidence and IGF1R deficiency promoting malignancy.

These findings increase our understanding of the intricate interplay between PTEN, IR, and IGF1R signaling and provide valuable insights into potential therapeutic interventions in hepatic disorders and hepatocellular carcinoma.

This study underscores the pivotal roles of phosphatase and tensin homolog (PTEN), insulin receptor (IR), and IGF-1 receptor (IGF1R) in controlling liver metabolism, systemic adiposity, and liver cancer progression. Our findings on the distinct and combined effects of these receptors in PTEN-deficient mice offer key insights into the mechanisms driving metabolic dysfunction-associated steatotic liver disease and related hepatocarcinogenesis. In addition, this research reveals the potential of IR and IGF1R as biomarkers in liver cancer development, presenting new opportunities for therapeutic targeting and disease monitoring.

Despite increasing incidence of hepatocellular carcinoma (HCC) in vulnerable populations, accurate early detection tools are lacking. We aimed to investigate the associations between prediagnostic plasma metabolites and incident HCC in a diverse population. In a prospective, nested case-control study within the Southern Community Cohort Study, we conducted prediagnostic LC/MS metabolomic profiling in 150 incident HCC cases (median time to diagnosis, 7.9 years) and 100 controls with cirrhosis. Logistic regression assessed metabolite associations with HCC risk. Metabolite set enrichment analysis identified enriched pathways, and a random forest classifier was used for risk classification models. Candidate metabolites were validated in the UK Biobank (N = 12 incident HCC cases and 24 cirrhosis controls). In logistic regression analysis, seven metabolites were associated with incident HCC (MeffP < 0.0004), including N-acetylmethionine (OR = 0.46; 95% confidence interval, 0.31-0.66). Multiple pathways were enriched in HCC, including histidine and CoA metabolism (FDR P < 0.001). The random forest classifier identified 10 metabolites for inclusion in HCC risk classification models, which improved HCC risk classification compared with clinical covariates alone (AUC = 0.66 for covariates vs. 0.88 for 10 metabolites plus covariates; P < 0.0001). Findings were consistent in the UK Biobank (AUC = 0.72 for covariates vs. 0.88 for four analogous metabolites plus covariates; P = 0.04), assessed via nuclear magnetic resonance spectroscopy. Prediagnostic metabolites, primarily amino acid and sphingolipid derivatives, are associated with HCC risk and improve HCC risk classification beyond clinical covariates. These metabolite profiles, detectable years before diagnosis, could serve as early biomarkers for HCC detection and risk stratification if validated in larger studies. Prevention Relevance: Our findings support the need for larger prospective studies examining the role of prediagnostic plasma metabolomics for the preventive management of HCC in diverse patients across multiple etiologies of liver disease. This approach could improve HCC care by identifying metabolic changes years before diagnosis, potentially enhancing screening and early detection practices.