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Hieromnimon M, Regan DP, Lokken RP, Schook LB, Gaba RC, Schachtschneider KM. Single and multi-omic characterization of a porcine model of ethanol-induced hepatic fibrosis. Epigenetics 2025; 20:2471127. [PMID: 40040391 PMCID: PMC11901410 DOI: 10.1080/15592294.2025.2471127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 02/10/2025] [Accepted: 02/18/2025] [Indexed: 03/06/2025] Open
Abstract
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.
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Affiliation(s)
- Mark Hieromnimon
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
| | - Daniel P. Regan
- Flint Animal Cancer Center, Colorado State University, Fort Collins, CO, USA
| | - R. Peter Lokken
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA
| | - Lawrence B. Schook
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Sus Clinicals Inc, Chicago, IL, USA
| | - Ron C. Gaba
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
| | - Kyle M. Schachtschneider
- Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA
- National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, Urbana, IL, USA
- Sus Clinicals Inc, Chicago, IL, USA
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA
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Darbà J, Ascanio M. Hepatocellular carcinoma: what are the differential costs compared to the general population? J Med Econ 2025; 28:471-478. [PMID: 40126406 DOI: 10.1080/13696998.2025.2484073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 03/25/2025]
Abstract
INTRODUCTION 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. METHODS 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). RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- Josep Darbà
- Department of Economics, Universitat de Barcelona, Barcelona, Spain
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Vrtělka O, Králová K, Fousková M, Setnička V. Comprehensive assessment of the role of spectral data pre-processing in spectroscopy-based liquid biopsy. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 339:126261. [PMID: 40273765 DOI: 10.1016/j.saa.2025.126261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 04/05/2025] [Accepted: 04/16/2025] [Indexed: 04/26/2025]
Abstract
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.
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Affiliation(s)
- Ondřej Vrtělka
- Department of Analytical Chemistry, Faculty of Chemical Engineering, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic.
| | - Kateřina Králová
- Department of Analytical Chemistry, Faculty of Chemical Engineering, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic
| | - Markéta Fousková
- Department of Analytical Chemistry, Faculty of Chemical Engineering, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic
| | - Vladimír Setnička
- Department of Analytical Chemistry, Faculty of Chemical Engineering, University of Chemistry and Technology, Prague, Technická 5, 166 28 Prague 6, Czech Republic.
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Schnabl SD, Klubien J, O'Rourke CJ, Bull Nordkild S, Kugler JM, Dam Nielsen S, Andersen JB, Pommergaard HC. Validation of Two Prognostic Gene Scores in Patients Undergoing Liver Resection for Hepatocellular Carcinoma. J Clin Exp Hepatol 2025; 15:102544. [PMID: 40248345 PMCID: PMC12002650 DOI: 10.1016/j.jceh.2025.102544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 03/04/2025] [Indexed: 04/19/2025] Open
Abstract
Background/Aims 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. Methods 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. Results 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. Conclusion 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.
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Affiliation(s)
- Stinna D. Schnabl
- Department of Surgery and Transplantation, Copenhagen University Hospital, Rigshospitalet, Denmark
- Hepatic Malignancy Surgical Research Unit (HEPSURU), Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Jeanett Klubien
- Department of Surgery and Transplantation, Copenhagen University Hospital, Rigshospitalet, Denmark
- Hepatic Malignancy Surgical Research Unit (HEPSURU), Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Colm J. O'Rourke
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Sophie Bull Nordkild
- Department of Surgery and Transplantation, Copenhagen University Hospital, Rigshospitalet, Denmark
- Hepatic Malignancy Surgical Research Unit (HEPSURU), Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Denmark
| | - Jan-Michael Kugler
- Institute for Molecular and Cellular Medicine, University of Copenhagen, Panum Institute, Copenhagen, Denmark
| | - Susanne Dam Nielsen
- Department of Surgery and Transplantation, Copenhagen University Hospital, Rigshospitalet, Denmark
- Viro-immunology Research Unit, Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Denmark
- Institute for Clinical Medicine, University of Copenhagen, Panum Institute, Copenhagen, Denmark
| | - Jesper B. Andersen
- Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Hans-Christian Pommergaard
- Department of Surgery and Transplantation, Copenhagen University Hospital, Rigshospitalet, Denmark
- Hepatic Malignancy Surgical Research Unit (HEPSURU), Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Denmark
- Institute for Clinical Medicine, University of Copenhagen, Panum Institute, Copenhagen, Denmark
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Liang Y, Luo J, Hu L, Zhang J. NS3 of hepatitis C virus drives hepatocellular carcinoma progression through a novel RNA-interference pathway. J Cell Commun Signal 2025; 19:e70013. [PMID: 40226576 PMCID: PMC11993122 DOI: 10.1002/ccs3.70013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 01/09/2025] [Accepted: 03/18/2025] [Indexed: 04/15/2025] Open
Abstract
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.
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Affiliation(s)
- Yajun Liang
- IV Ward of Pulmonary and Critical Care MedicineWuhan Pulmonary HospitalWuhanChina
| | - Jian Luo
- Department of GeriatricsTongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Liya Hu
- Department of GeriatricsTongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Jun Zhang
- Department of GeriatricsTongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
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Zhang ZJ, Wei BJ, Liu ZK, Xuan ZF, Zhou L, Zheng SS. Nomogram for prediction of hepatocellular carcinoma recurrence after liver resection. Hepatobiliary Pancreat Dis Int 2025; 24:269-276. [PMID: 39332935 DOI: 10.1016/j.hbpd.2024.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 09/02/2024] [Indexed: 09/29/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common malignancy with high mortality. Liver resection (LR) is a curative treatment for early-stage HCC, but the prognosis of HCC patients after LR is unsatisfactory because of tumor recurrence. Prognostic prediction models with great performance are urgently needed. The present study aimed to establish a novel prognostic nomogram to predict tumor recurrence in HCC patients after LR. METHODS We retrospectively analyzed 726 HCC patients who underwent LR between October 2011 and December 2016. Patients were randomly divided into the training cohort (n = 508) and the testing cohort (n = 218). The protein expression of 14 biomarkers in tumor tissues was assessed by immunohistochemistry. The nomogram predicting recurrence-free survival (RFS) was established by a multivariate Cox regression analysis model and was evaluated by calibration curves, Kaplan-Meier survival curves, time-dependent areas under the receiver operating characteristic (ROC) curves (AUCs), and decision curve analyses in both the training and testing cohorts. RESULTS Alpha-fetoprotein [hazard ratio (HR) = 1.013, P = 0.002], portal vein tumor thrombosis (HR = 1.833, P < 0.001), ascites (HR = 2.024, P = 0.014), tumor diameter (HR = 1.075, P < 0.001), E-cadherin (HR = 0.859, P = 0.011), EMA (HR = 1.196, P = 0.022), and PCNA (HR = 1.174, P = 0.031) immunohistochemistry scores were found to be independent factors for RFS. The 1-year and 3-year AUCs of the nomogram for RFS were 0.813 and 0.739, respectively. The patients were divided into the high-risk group and the low-risk group by median value which was generated from the nomogram, and Kaplan-Meier analysis revealed that the high-risk group had a shorter RFS than the low-risk group in both the training (P < 0.001) and testing cohorts (P < 0.001). CONCLUSIONS Our newly developed nomogram integrated clinicopathological data and key gene expression data, and was verified to have high accuracy in predicting the RFS of HCC patients after LR. This model could be used for early identification of patients at high-risk of postoperative recurrence.
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Affiliation(s)
- Zhi-Jun Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Ba-Jin Wei
- NHC Key Laboratory of Combined Multi-organ Transplantation, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Division of Breast Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Zhi-Kun Liu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou 310006, China
| | - Ze-Feng Xuan
- NHC Key Laboratory of Combined Multi-organ Transplantation, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Lin Zhou
- NHC Key Laboratory of Combined Multi-organ Transplantation, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shu-Sen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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Tefera J, Kuhn TN, Matuschewski NJ, Meister E, Nguyenová J, Kao T, Mutonga M, Bitar R, Kahl VH, Zhang X, Shewarega A, Chapiro J, Madoff DC. Portal and Hepatic Vein Embolization versus Portal Venous Embolization Alone in Cirrhotic and Noncirrhotic Swine: A Pilot Study. J Vasc Interv Radiol 2025; 36:1042-1050.e2. [PMID: 40043833 DOI: 10.1016/j.jvir.2025.02.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 02/11/2025] [Accepted: 02/21/2025] [Indexed: 04/17/2025] Open
Abstract
PURPOSE To evaluate the effectiveness of combined portal vein embolization (PVE) and hepatic vein embolization (HVE) compared with that of PVE alone in cirrhotic and noncirrhotic swine. MATERIALS AND METHODS Sixteen Yorkshire pigs were included in this study. In the cirrhotic group (n = 8) and noncirrhotic group (n = 8), subjects underwent embolization according to established protocols. Computed tomography (CT) scans were acquired before and at 2- and 4-week intervals following the embolization. Liver volumes were segmented in the portal venous phase. Student t test with a significance level at P < .05 was used. RESULTS Across all swine, the future liver remnant (FLR) was significantly larger after PVE + HVE than after PVE at 2 weeks (24.12% [95% CI, 15.36%-32.88%] vs 12.75% [95% CI, 7.43%-18.07%]; P = .021) and 4 weeks (23.23% [95% CI, 15.79%-33.47%] vs 15.08% [95% CI, 9.98%-20.87%]; P = .043) after embolization. In the cirrhotic group, the FLR increase was greater following PVE + HVE than after PVE at 2 weeks (20.85% [95% CI, 14.40%-27.30%] vs 8.66% [95% CI, 6.47%-10.86%]; P = .0089) and 4 weeks (19.27% [95% CI, 17.87%-20.67%] vs 13.33% [95% CI, 9.23%-13.33%]; P = .0003) after embolization. CONCLUSIONS PVE + HVE resulted in greater FLR hypertrophy than PVE alone, indicating that cirrhotic livers may benefit from the addition of HVE.
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Affiliation(s)
- Jonathan Tefera
- Department of Radiology and Biomedical Imaging, Section of Interventional Radiology, Yale School of Medicine, New Haven, Connecticut
| | - Tom N Kuhn
- Department of Neurology, Universitaetsmedizin Mannheim, Mannheim, Germany; Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
| | | | - Ellen Meister
- Department of Radiology, Charité-Universitaetsmedizin Berlin, Berlin, Germany
| | - Jana Nguyenová
- Department of Radiology, Charité-Universitaetsmedizin Berlin, Berlin, Germany
| | - Tabea Kao
- Department of Radiology, Charité-Universitaetsmedizin Berlin, Berlin, Germany
| | - Martin Mutonga
- Department of Radiology and Biomedical Imaging, Section of Interventional Radiology, Yale School of Medicine, New Haven, Connecticut
| | - Ryan Bitar
- Department of Radiology and Biomedical Imaging, Section of Interventional Radiology, Yale School of Medicine, New Haven, Connecticut
| | - Vinzent H Kahl
- Department of Radiology, Charité-Universitaetsmedizin Berlin, Berlin, Germany
| | - Xuchen Zhang
- Department of Pathology, Section of Gastrointestinal and Liver Pathology, Yale School of Medicine, New Haven, Connecticut
| | - Annabella Shewarega
- Department of Radiology and Biomedical Imaging, Section of Interventional Radiology, Yale School of Medicine, New Haven, Connecticut
| | - Julius Chapiro
- Department of Radiology and Biomedical Imaging, Section of Interventional Radiology, Yale School of Medicine, New Haven, Connecticut; Department of Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut; Department of Biomedical Engineering, School of Engineering and Applied Sciences, New Haven, Connecticut
| | - David C Madoff
- Department of Radiology and Biomedical Imaging, Section of Interventional Radiology, Yale School of Medicine, New Haven, Connecticut; Department of Medicine, Section of Medical Oncology, Yale School of Medicine, New Haven, Connecticut; Department of Surgery, Section of Surgical Oncology, Yale School of Medicine, New Haven, Connecticut.
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El-Melegy MG, El-Kamel AH, Mehanna RA, Gaballah A, Eltaher HM. Stable self-assembled oral metformin-bridged nanocochleates against hepatocellular carcinoma. Drug Deliv Transl Res 2025; 15:2064-2086. [PMID: 39537911 PMCID: PMC12037436 DOI: 10.1007/s13346-024-01724-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/30/2024] [Indexed: 11/16/2024]
Abstract
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.
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Affiliation(s)
- Mohamed G El-Melegy
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt
| | - Amal H El-Kamel
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt
| | - Radwa A Mehanna
- Medical Physiology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
- Center of Excellence for Research in Regenerative Medicine and Applications CERRMA, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Ahmed Gaballah
- Microbiology Department, Medical Research Institute, Alexandria University, Alexandria, 21561, Egypt
| | - Hoda M Eltaher
- Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
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Sayilan Ozgun G, Ozgun E, Karabas T, Suer Gokmen S, Eskiocak S. Piperine induces cellular stresses, apoptosis, and cytotoxicity via JNK signaling and has concentration-dependently additive or synergistic effects with sorafenib in hepatocellular carcinoma: an in-vitro study. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:7017-7025. [PMID: 39708099 DOI: 10.1007/s00210-024-03725-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 12/10/2024] [Indexed: 12/23/2024]
Abstract
We aimed to determine the effects of piperine on cell viability, cellular stresses, and apoptosis first, then the relationship of piperine's effects with the c-Jun N-terminal kinase (JNK) signaling pathway, and also the interaction of piperine with sorafenib in hepatocellular carcinoma. Hepatocellular carcinoma (HepG2 and Hep3B) and non-cancerous hepatocyte (AML12) cell lines were used. The cell viability was determined by using MTT assay. Cellular stresses, apoptosis, and JNK signaling markers were measured by Western blotting. Cells were pre-treated with SP600125 as a JNK inhibitor. The inhibitory concentration 50% (IC50) values and interaction of piperine with sorafenib were calculated by using CompuSyn software. IC50 values of piperine were 97 µM for HepG2, 58 µM for Hep3B, and 184 µM for AML12 with incubation for 48 h. Piperine caused a significant concentration-dependent increase in cellular stresses, apoptosis, and activated JNK signaling in hepatocellular carcinoma cells. Pre-treatment with a JNK inhibitor significantly reduced piperine-induced cellular stresses, apoptosis, and cytotoxicity. Piperine had concentration-dependent additive or synergistic effects when combined with sorafenib in both HepG2 and Hep3B cells. We found that piperine induces cellular stresses, apoptosis, and cytotoxicity via JNK signaling and has concentration-dependently additive or synergistic effects with sorafenib in hepatocellular carcinoma.
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Affiliation(s)
- Gulben Sayilan Ozgun
- Department of Medical Biochemistry, Trakya University School of Medicine, Edirne, 22030, Turkey.
| | - Eray Ozgun
- Department of Medical Biochemistry, Trakya University School of Medicine, Edirne, 22030, Turkey
| | - Tugce Karabas
- Department of Medical Biochemistry, Trakya University School of Medicine, Edirne, 22030, Turkey
| | - Selma Suer Gokmen
- Department of Medical Biochemistry, Trakya University School of Medicine, Edirne, 22030, Turkey
| | - Sevgi Eskiocak
- Department of Medical Biochemistry, Trakya University School of Medicine, Edirne, 22030, Turkey
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Dong X, Zhang M, Shu J, Li Y, Tan P, Peng T, Lu J, Zhang Y, Zhong X, Fang A. The quality of plant-based diets and liver cancer incidence and liver disease mortality in the UK Biobank. Clin Nutr ESPEN 2025; 67:541-548. [PMID: 40187730 DOI: 10.1016/j.clnesp.2025.03.166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 03/10/2025] [Accepted: 03/25/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND & AIMS Plant-based diets have been associated with a lower risk of various chronic diseases. However, their role in preventing liver cancer and liver-related death is currently unclear. We aimed to investigate the association between plant-based diets and the risk of liver cancer incidence and liver disease mortality in the UK Biobank. METHODS We included 85,810 males and 101,971 females from the UK Biobank in our analyses. Three plant-based diet indices, including an overall plant-based diet index (PDI), a healthful plant-based diet index (hPDI), and an unhealthful plant-based diet index (uPDI), were created based on 17 food groups using data from at least one 24-h dietary assessments. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HRs) and 95 % confidence intervals (CIs). RESULTS During follow-up, 109 males and 68 females developed liver cancer, and 190 males and 108 females died from liver diseases. Overall PDI scores were not associated with liver cancer incidence or liver disease mortality in either males or females. However, higher hPDI scores were linked to a lower risk of liver cancer incidence (HRQ5 vs. Q1: 0.47; 95%CI: 0.26, 0.85; P-trend = 0.005) and liver disease mortality (HRQ5 vs. Q1: 0.46; 95%CI: 0.27, 0.77; P-trend = 0.011) in males. Higher uPDI scores were associated with an increased incidence of liver cancer (HRQ5 vs. Q1: 1.90; 95%CI: 1.00, 3,63; P-trend = 0.038) and a higher risk of liver disease-related deaths (HRQ5 vs. Q1: 2.21; 95%CI: 1.37, 3.57; P-trend <0.001). However, no such associations between hPDI or uPDI and the risk of liver cancer or liver disease mortality were observed in females. CONCLUSIONS Our results suggest that higher adherence to plant-based diets, emphasizing healthful plant-based foods while restricting less healthful plant foods, may protect against liver cancer and liver disease-related deaths in males, but not in females.
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Affiliation(s)
- Xiaocong Dong
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Mingjie Zhang
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Jing Shu
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Yunshan Li
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Peishan Tan
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Tianyou Peng
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Jialin Lu
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China
| | - Yaojun Zhang
- Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiali Zhong
- Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, China.
| | - Aiping Fang
- Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, China; School of Public Health and Emergency Management, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
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11
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Ren L, Hong F, Wen J, Chen Y. High-throughput colorimetry immunoassay for aflatoxin B 1 detection using the synergistic regulation of click chemistry by polydopamine and metal-organic framework. Food Chem 2025; 475:143344. [PMID: 39946926 DOI: 10.1016/j.foodchem.2025.143344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 02/02/2025] [Accepted: 02/08/2025] [Indexed: 03/09/2025]
Abstract
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.
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Affiliation(s)
- Liangqiong Ren
- Dalian Jinshiwan Laboratory, Dalian 116034, Liaoning, China; College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Feng Hong
- Dalian Jinshiwan Laboratory, Dalian 116034, Liaoning, China; School of Food Science and Engineering, Ningxia University, Yinchuan 750021, China
| | - Junping Wen
- College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Yiping Chen
- Dalian Jinshiwan Laboratory, Dalian 116034, Liaoning, China; College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China; State Key Laboratory of Marine Food Processing and Safety Control, Dalian Polytechnic University, Dalian 116034, Liaoning, China.
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12
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Zhang Z, Wang J, Zhang Z, Gan Q, He Y, Chen D, Zhang Y, Zhao M. Systematic Exploration of Potential Toxicity Targets and Molecular Mechanisms of Emerging Short-Chain PFAS Substitutes: PFBA- and PFBS-Induced Hepatocellular Carcinoma Based on Toxicity Network Analysis, Machine Learning, and Biomimetic Calculations. J Appl Toxicol 2025. [PMID: 40448290 DOI: 10.1002/jat.4818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2025] [Revised: 05/09/2025] [Accepted: 05/16/2025] [Indexed: 06/02/2025]
Abstract
Perfluorobutanoic acid (PFBA) and perfluorobutanesulfonic acid (PFBS) are short-chain alternatives to traditional perfluoroalkyl and polyfluoroalkyl substances (PFASs). Long-term exposure to these pollutants is closely associated with hepatocellular carcinoma (HCC). However, the toxic targets and mechanisms underlying PFBA- and PFBS-induced HCC remain unclear. To address this knowledge gap, this study employed a multifaceted approach encompassing network toxicology, molecular docking, and molecular dynamic simulation. Thirty-six core targets associated with PFBA- and PFBS-induced HCC were identified, and 12 key genes were initially screened through network toxicity analysis. Subsequently, based on the TCGA and ICGC datasets, three classical algorithms were applied to screen key genes: PPARG, ESR1, and ALB. Further exploration of the HCC-related dataset from the GEO database identified six critical genes: PPARG, ESR1, CD36, ABCA1, ACACA, and ALB. Survival analysis and ROC analysis based on the TCGA dataset revealed and validated the strong association between the expression levels of key genes (PPARG, ESR1, and ACACA). Single-gene GSEA showed that these three key genes may induce HCC through multiple biological pathways via interfering with the normal growth and development of hepatocytes and promoting inflammation and cell proliferation. Ultimately, molecular dynamics demonstrated the strong binding affinities between PFBA, PFBS, and the three protein receptors, with the best stability and flexibility of the interaction between PFBS and PPARG. These findings provide insights into the theoretical foundation for applying network toxicology, molecular docking, and molecular dynamic simulations in environmental pollutant research.
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Affiliation(s)
- Zirui Zhang
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Jin Wang
- College of Computer Science, Chengdu University, Chengdu, Sichuan, China
| | - Zhongyi Zhang
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Qianrong Gan
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Yunliang He
- Institute of Traditional Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, Sichuan, China
| | - Donghui Chen
- Institute of Traditional Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, Sichuan, China
| | - Yong Zhang
- Institute of Traditional Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, Sichuan, China
| | - Mei Zhao
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
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13
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Mo PL, Lin M, Gao BW, Zhang SB, Chen JP. Knowledge structure analysis and network visualization of tumor-associated macrophages in hepatocellular carcinoma research: A bibliometric mapping. World J Clin Oncol 2025; 16:102747. [DOI: 10.5306/wjco.v16.i5.102747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 02/13/2025] [Accepted: 04/11/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) have demonstrated significant potential as a research and treatment approach for hepatocellular carcinoma (HCC). Nevertheless, a comprehensive quantitative analysis of TAMs in HCC remained insufficient. Therefore, the objective of this study was to employ bibliometric methods to investigate the development trends and research frontiers pertaining to this field.
AIM To determine the knowledge structure and current research hotspots by bibliometric analysis of scholarly papers pertaining to TAMs in HCC.
METHODS The present study employed the Web of Science Core Collection to identify all papers related to TAMs in HCC research. Utilizing the Analysis Platform of Bibliometrics, CiteSpace 6.2.R4, and Vosviewer 1.6.19, the study conducted a comprehensive analysis encompassing multiple dimensions such as publication quantity, countries of origin, affiliated institutions, publishing journals, contributing authors, co-references, author keywords, and emerging frontiers within this research domain.
RESULTS A thorough examination was undertaken on 818 papers within this particular field, published between January 1, 1985 to September 1, 2023, which has witnessed a substantial surge in scholarly contributions since 2012, with a notable outbreak in 2019. China was serving as the central hub in this field, with Fudan University leading in terms of publications and citations. Chinese scholars have taken the forefront in driving the research expansion within this field. Hepatology emerged as the most influential journal in this field. The study by Qian and Pollard in 2010 received the highest number of co-citations. It was observed that the citation bursts of references coincided with the outbreak of publications. Notably, “tumor microenvironment”, “immunotherapy”, “prognostic”, “inflammation”, and “polarization”, etc. emerged as frequently occurring keywords in this field. Of particular interest, “immune evasion”, “immune infiltration”, and “cancer genome atlas” were identified as emerging frontiers in recent research.
CONCLUSION The field of TAMs in HCC exhibited considerable potential, as evidenced by the promising prospects of immunotherapeutic interventions targeting TAMs for the amelioration of HCC. The emerging frontiers in this field primarily revolved around modulating the immunosuppressive characteristics of TAMs within a liver-specific immune environment, with a focus on how to counter immune evasion and reduce immune infiltration.
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Affiliation(s)
- Ping-Li Mo
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Ming Lin
- Department of Hepatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, Guangdong Province, China
| | - Bo-Wen Gao
- Department of Traditional Chinese Medicine, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
| | - Shang-Bin Zhang
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
| | - Jian-Ping Chen
- Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen 518033, Guangdong Province, China
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14
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Cicerone O, Mantovani S, Oliviero B, Basilico G, Corallo S, Quaretti P, Maestri M. Navigating the evidence for hepatocellular carcinoma treatment: Surgery vs radiofrequency ablation through sentiment and meta-analysis. World J Clin Oncol 2025; 16:105881. [DOI: 10.5306/wjco.v16.i5.105881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 03/13/2025] [Accepted: 04/08/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is among the most aggressive primary liver cancers, leading to significant global mortality. While early diagnosis improves prognosis, treatment decisions, particularly between surgical resection and radiofrequency ablation (RFA), remain controversial.
AIM To clarify this issue using sentiment analysis of medical literature alongside a meta-analysis of overall survival (OS).
METHODS We included studies comparing liver resection and RFA, excluding case reports, editorials, and studies without relevant outcomes. A systematic search in PubMed and Web of Science identified 197 studies. Abstracts underwent sentiment analysis using Python’s Natural Language Toolkit library, categorizing them as favoring resection, ablation, or neutral. We also performed a meta-analysis using a random-effects model on 11 studies reporting hazard ratios (HRs) for OS.
RESULTS Sentiment analysis revealed that 75.1% of abstracts were neutral, 14.2% favored resection, and 10.7% favored RFA. The meta-analysis showed a significant survival advantage for liver resection, with a pooled HR of 0.5924 (95% confidence interval: 0.540-0.649). Heterogeneity was moderate (I² = 39.98%). Despite the meta-analysis demonstrating clear survival benefits of liver resection, most abstracts maintained a neutral stance. This discrepancy highlights potential biases or hesitancy in drawing definitive conclusions.
CONCLUSION The study emphasizes the need for clinicians to prioritize robust statistical evidence over narrative impressions. Liver resection remains the preferred treatment for HCC in eligible patients.
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Affiliation(s)
- Ottavia Cicerone
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia 27100, Italy
| | - Stefania Mantovani
- Department of Infectious Diseases-Clinical Immunology, Fondazione IRCCS Policlinico San Matteo, Pavia 27100, Italy
| | - Barbara Oliviero
- Department of Infectious Diseases-Clinical Immunology, Fondazione IRCCS Policlinico San Matteo, Pavia 27100, Italy
| | - Giorgia Basilico
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia 27100, Italy
| | - Salvatore Corallo
- Department of Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia 27100, Italy
| | - Pietro Quaretti
- Department of Diagnostic Imaging-Interventional Radiology, Fondazione IRCCS Policlinico San Matteo, Pavia 27100, Italy
| | - Marcello Maestri
- Department of General Surgery I-Liver Service, Fondazione IRCCS Policlinico San Matteo, Pavia 27100, Italy
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15
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Yun B, Oh J, Ahn SH, Kim BK, Yoon JH. Association between early job loss and prognosis among hepatocellular carcinoma survivors. Occup Med (Lond) 2025:kqaf013. [PMID: 40408468 DOI: 10.1093/occmed/kqaf013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2025] Open
Abstract
BACKGROUND Early job loss after curative treatment for hepatocellular carcinoma (HCC) is associated with significant socioeconomic and health challenges, potentially worsening patient outcomes. AIMS To examine the impact of early job loss on all-cause mortality among HCC survivors following curative treatment. METHODS We conducted a retrospective cohort study using Korean National Health Insurance Service data on 4578 HCC survivors (aged 35-54) with economic activity treated between 2009 and 2015. Primary and secondary outcomes were all-cause mortality and HCC recurrence, respectively. Early job loss was defined as a shift from insurer to dependent status. Adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using multivariable Cox regression models, and subgroup analyses were performed. Causal mediation analysis assessed early HCC recurrence as a mediator between early job loss and all-cause mortality. RESULTS Among 4578 patients (median follow-up, 8.3 years), 1189 (26%) died including 989 (25%) in the job-maintained group and 200 (35%) in the early job loss group (P < .001). Early job loss was significantly associated with increased risk of all-cause mortality (adjusted HR 1.52 [95% CI 1.30-1.78]), but not with HCC recurrence (adjusted HR 1.07 [95% CI 0.91-1.25]). Subgroup analyses showed prominent association among middle-income level, non-liver cirrhosis, non-alcoholism, or surgical resection group. Early HCC recurrence plays a significant mediating role on the relationship between early job loss and all-cause mortality (mediated proportion 19%, 95% CI 5-31%). CONCLUSIONS Early job loss may increase risk of all-cause mortality among HCC survivors undergoing curative treatment.
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Affiliation(s)
- B Yun
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea 03722
- The Institute for Occupational Health, Yonsei University College of Medicine, Seoul, Republic of Korea 03722
| | - J Oh
- Department of Public Health, Graduate School, Yonsei University, Seoul, Republic of Korea 03722
| | - S H Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea 03722
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea 03722
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea 03722
| | - B K Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea 03722
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea 03722
- Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea 03722
| | - J-H Yoon
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea 03722
- The Institute for Occupational Health, Yonsei University College of Medicine, Seoul, Republic of Korea 03722
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Moris D, Martinino A, Schiltz S, Allen PJ, Barbas A, Sudan D, King L, Berg C, Kim C, Bashir M, Palta M, Morse MA, Lidsky ME. Advances in the treatment of hepatocellular carcinoma: An overview of the current and evolving therapeutic landscape for clinicians. CA Cancer J Clin 2025. [PMID: 40392748 DOI: 10.3322/caac.70018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 04/10/2025] [Accepted: 04/11/2025] [Indexed: 05/22/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the third leading cause of cancer-related death worldwide. Contemporary advances in systemic and locoregional therapies have led to changes in peer-reviewed guidelines regarding systemic therapy as well as the possibility of downstaging disease that may enable some patients with advanced disease to ultimately undergo partial hepatectomy or transplantation with curative intent. This review focuses on all modalities of therapy for HCC, guided by modern-day practice-changing randomized data where available. The surgical management of HCC, including resection and transplantation, both of which have evolving criteria for what is considered biologically resectable and transplantable, as well as locoregional therapy (i.e., therapeutic embolization, ablation, radiation, and hepatic arterial infusion), are discussed. Historical and modern-day practice-changing trials evaluating immunotherapy with targeted therapies for advanced disease, as well as adjuvant systemic therapy, are also summarized. In addition, this article examines the critical dimension of toxicities and patient-oriented considerations to ensure a comprehensive and balanced discourse on treatment implications.
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Affiliation(s)
- Dimitrios Moris
- Division of Surgical Oncology, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Alessandro Martinino
- Division of Abdominal Transplantation, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Sarah Schiltz
- Patient Advocate Steering Committee, National Cancer Institute Hepatobiliary Task Force, Los Gatos, California, USA
- Blue Faery, Simi Valley, California, USA
- Cancer CAREpoint, Los Gatos, California, USA
| | - Peter J Allen
- Division of Surgical Oncology, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Andrew Barbas
- Division of Abdominal Transplantation, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Debra Sudan
- Division of Abdominal Transplantation, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Lindsay King
- Division of Gastroenterology and Hepatology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Carl Berg
- Division of Gastroenterology and Hepatology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Charles Kim
- Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA
| | - Mustafa Bashir
- Department of Radiology, Duke University Medical Center, Durham, North Carolina, USA
| | - Manisha Palta
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA
| | - Michael A Morse
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Michael E Lidsky
- Division of Surgical Oncology, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
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Дворяньчиков ЯВ, Деунежева СМ, Яцков ИА, Белоглазов ВА. [Overview of the prevalence and features of oncological diseases in type 2 diabetes and possible immunological mechanisms]. PROBLEMY ENDOKRINOLOGII 2025; 71:75-81. [PMID: 40411332 PMCID: PMC12117986 DOI: 10.14341/probl13452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 05/26/2025]
Abstract
Worldwide, the number of patients with diabetes has quadrupled over the past three decades. Every eleventh adult is currently diagnosed with diabetes mellitus, 90% of which are type 2 diabetes mellitus (DM2). Generally recognized complications of chronic hyperglycemia include micro- and macrovascular changes, damage to peripheral and/or autonomous nerve fibers. Scientists have also long discussed the relationship between an increase in the number of certain cancers and the presence of DM2. Based on the presence of common risk factors such as age, ethnicity, dietary habits and physical activity, many epidemiological and experimental studies are being conducted, which gradually contribute to understanding the relationship between these diseases. Taking into account the results of numerous studies, hyperglycemia, hyperinsulinemia and chronic inflammation, which are observed in DM 2, have a positive association with an increased risk of certain types of malignancies. In this article, the authors consider pathological changes in DM2 that potentiate the development of oncological diseases and epidemiological data reflecting the correlation between DM2 and the occurrence of malignant tumors.
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Affiliation(s)
| | - С. М. Деунежева
- Национальный медицинский исследовательский центр эндокринологии
| | - И. А. Яцков
- Крымский федеральный университет имени В.И. Вернадского
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18
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Wu W, Mao H, Song J, Yang F. Bibliometric analysis of hepatocellular carcinoma and tyrosine kinase inhibitors. Medicine (Baltimore) 2025; 104:e42015. [PMID: 40388796 PMCID: PMC12091622 DOI: 10.1097/md.0000000000042015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Accepted: 03/13/2025] [Indexed: 05/21/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common malignant tumor globally and in China, and its incidence and mortality rate are increasing year by year, and it faces many challenges and difficulties in treatment. Tyrosine kinase inhibitors (TKIs) have important roles in cell growth, proliferation, and differentiation, and have now become important drugs for cancer treatment. There are no bibliometric studies on liver cancer and TKIs to date. METHODS We retrieved 2848 records from the Web of Science™ Core Collection (WoSCC) database and analyzed them scientifically and metrically using CiteSpace and VOSviewer in terms of temporal and spatial distributions, author distributions, journal distributions, references, and keywords. RESULTS From January 1, 2004, to December 31, 2023, the WoSCC database documented 2848 publications related to tyrosinase inhibitors in HCC, comprising 2151 articles and 697 reviews. This literature involved 80 countries and regions, 3265 institutions, and 16,653 authors. Analysis shows a steady increase in publications annually since 2004, divided into 3 phases: 2004 to 2010 with fewer than 100 papers annually, suggesting minimal research attention; 2011 to 2019 with gradual growth, indicating increasing research interest; and a rapid surge post-2020, peaking in 2023, signaling heightened global interest in this field. CONCLUSION Our bibliometric analysis on TKIs and HCC spans years, countries, institutions, authors, disciplines, and journals. Since 2004, this field has gained attention, with current research focusing on inflammatory and immune mechanisms, associated diseases, cytokines, and TKIs' applications in liver cancer treatment, including combination therapies. These areas signify emerging research directions.
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Affiliation(s)
- Wurihan Wu
- Department of Neurology Department, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Hejun Mao
- Department of Hepatobiliary Surgery, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Jian Song
- Emergency Intensive Care Unit, Inner Mongolia Autonomous Region People’s Hospital, Hohhot, China
| | - Fan Yang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
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Abiru S, Kugiyama Y, Suehiro T, Motoyoshi Y, Saeki A, Nagaoka S, Yamasaki K, Komori A, Yatsuhashi H. Lactitol may improve the prognosis of hepatocellular carcinoma through the proliferation of Megasphaera as well as Bifidobacterium. Front Med (Lausanne) 2025; 12:1567849. [PMID: 40438352 PMCID: PMC12116508 DOI: 10.3389/fmed.2025.1567849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 04/28/2025] [Indexed: 06/01/2025] Open
Abstract
Background Increasing evidence suggests that gut microbiota and their metabolites can modulate antitumor immunity. However, sufficient evidence from human studies is lacking. We evaluated the association of lactitol and lactulose as prebiotics with the progression of hepatocellular carcinoma (HCC). Methods In Study 1, the effects of lactitol and lactulose on overall survival (OS) of patients with HCC with Child-Pugh scores of B or C were investigated in patients diagnosed at the Nagasaki Medical Center between 2003 and 2020. In Study 2, the effects of these substances on the gut microbiota of patients with cirrhosis were analyzed. Study 3 examined the effect of these substances on serum albumin levels in patients with cirrhosis. Results In Study 1, a total of 321 patients were evaluated, and 55 pairs of Lactitol and Non-Lactitol groups and 80 pairs of Lactulose and Non-Lactulose groups were created using one to one propensity score matching. The Lactitol group showed a significant improvement (p < 0.05) in OS compared to the Non-Lactitol group, but the Lactulose group did not show any significance compared to the Non-Lactulose group. In Study 2, the number of Bifidobacterium was higher in the Lactitol group and the Lactulose group than in the Control group, but the number of Megasphaera was significantly higher only in the Lactitol group. In addition, in a study of 10 cases in which the gut microbiota was examined before and after lactitol use, an increase in Bifidobacterium and Megasphaera was observed after lactitol use. Study 3 found that lactitol had no beneficial effect on serum albumin levels. Conclusion Lactitol may improve the prognosis of HCC through the proliferation of Megasphaera as well as Bifidobacterium.
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Affiliation(s)
- Seigo Abiru
- Department of Internal Medicine, NHO Saga Hospital, Saga, Japan
- Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, Japan
| | - Yuki Kugiyama
- Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, Japan
| | - Tomoyuki Suehiro
- Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, Japan
| | | | - Akira Saeki
- Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, Japan
| | - Shinya Nagaoka
- Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, Japan
| | - Kazumi Yamasaki
- Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, Japan
| | - Atsumasa Komori
- Clinical Research Center, NHO Nagasaki Medical Center, Nagasaki, Japan
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Ameri A, Gandomkar H, Ahmed HH, Kareem RA, Sameer HN, Yaseen A, Athab ZH, Adil M, Ghasemzadeh I. A review of the progress and challenges of developing dendritic-based vaccines against hepatitis B virus (HBV). Pathol Res Pract 2025; 271:156025. [PMID: 40382895 DOI: 10.1016/j.prp.2025.156025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Revised: 05/13/2025] [Accepted: 05/13/2025] [Indexed: 05/20/2025]
Abstract
Hepatitis B virus (HBV) infections that last a long time are a significant public health problem worldwide. About 254 million people around the world are chronically sick with HBV. Each year, 1.2 million new cases occur, and in 2022, 1.1 million people will die from the disease. So, it has been essential to work on finding ways to treat and avoid HBV. The process of therapeutic vaccination involves giving people a non-infectious form of a virus to start or improve immune reactions specific to HBV. This helps keep HBV infections under control. Dendritic cells (DCs) play a significant part in beginning the adaptive immune response, which could decide how well an HBV infection is treated. DC-based treatment has been looked into for people with chronic HBV (CHB) infection and has shown some sound effects. Vaccines for CHB that use DCs boost antiviral immunity by improving T cells and breaking the immune system's resistance against HBV. In these vaccines, DCs are loaded with HBV antigens (like HBsAg, HBcAg, or peptides) outside of the body and then put back into the patient to make the immune system work better. In conclusion, this DC treatment is a biological therapy method with a good chance of being used. This study examined the different DC-based medicines that can treat and prevent HBV. Finally, we've talked about clinical studies, the current problems, how to fix them, and the future of this vaccine for treating and preventing HBV.
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Affiliation(s)
- Ali Ameri
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Hossein Gandomkar
- Department of Surgical Oncology, Tehran University of Medical Medicine, Tehran, Iran
| | | | | | - Hayder Naji Sameer
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar 64001, Iraq
| | | | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | | | - Iman Ghasemzadeh
- Research Center Of Tropical and Infectious Diseases, Kerman University Of Medical Sciences, Kerman, Iran.
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21
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Xiao Q, Liu Y, Li T, Wang C, He S, Zhai L, Yang Z, Zhang X, Wu Y, Liu Y. Viral oncogenesis in cancer: from mechanisms to therapeutics. Signal Transduct Target Ther 2025; 10:151. [PMID: 40350456 PMCID: PMC12066790 DOI: 10.1038/s41392-025-02197-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 01/22/2025] [Accepted: 03/03/2025] [Indexed: 05/14/2025] Open
Abstract
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.
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Affiliation(s)
- Qing Xiao
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Yi Liu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Tingting Li
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Chaoyu Wang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Sanxiu He
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Liuyue Zhai
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Zailin Yang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Xiaomei Zhang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yongzhong Wu
- Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yao Liu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China.
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22
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Passerini S, Messina S, Moens U, Pietropaolo V. Merkel Cell Polyomavirus (MCPyV) and Its Possible Role in Head and Neck Cancers. Biomedicines 2025; 13:1180. [PMID: 40427007 PMCID: PMC12109148 DOI: 10.3390/biomedicines13051180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 05/08/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
Despite significant progress in its prevention, diagnosis, and treatment, head and neck cancer (HNC) remains a major global health issue due to its multifactorial pathogenesis. Indeed, HNCs have been found to be associated with different environmental and lifestyle factors, as well as with infection with oncogenic viruses. To date, seven viruses are recognized for their tumorigenic properties and have been proposed as implicated in HNC development, including Merkel Cell Polyomavirus (MCPyV). MCPyV is well recognized as the major etiological agent of Merkel cell carcinoma (MCC), a rare but rapidly metastasizing skin neoplasm. Specifically, in almost 80% of MCC cases, viral genome integration occurs, and a truncated form of Large T Antigen (tLT) is expressed. Although MCC is a rare cancer, MCPyV is a ubiquitous virus, widely distributed among the human population. Therefore, a plausible role of the virus has been proposed, even for other tumors. The current review provides an overview of the available data describing the presence of MCPyV in non-MCC tumors, such as HNCs, with the aim of elucidating the potential contribution of MCPyV to oral cancer. Understanding the role of viral infections in the etiology of cancer opens up the opportunity for developing preventive measures and targeted therapies that effectively address HNC progression while reducing treatment-related side effects.
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Affiliation(s)
- Sara Passerini
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, 00185 Rome, Italy;
| | - Sara Messina
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, 00185 Rome, Italy;
| | - Ugo Moens
- Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, UiT-The Arctic University of Norway, 9037 Tromsø, Norway;
| | - Valeria Pietropaolo
- Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, 00185 Rome, Italy;
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23
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Tellai AD, Haghnejad V, Antoine J, Khemiri Merouani B, Bronowicki JP, Dreumont N. The complex post-transcriptional regulation of genes coding for methionine adenosyl transferase: New insights for liver cancer. Biochimie 2025:S0300-9084(25)00082-3. [PMID: 40348354 DOI: 10.1016/j.biochi.2025.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
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.
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Affiliation(s)
| | - Vincent Haghnejad
- Université de Lorraine, Inserm, NGERE, F-54000, Nancy, France; Université de Lorraine, CHRU-Nancy, Department of Hepatology and Gastroenterology, F-54000, France
| | - Justine Antoine
- Université de Lorraine, Inserm, NGERE, F-54000, Nancy, France
| | | | - Jean-Pierre Bronowicki
- Université de Lorraine, Inserm, NGERE, F-54000, Nancy, France; Université de Lorraine, CHRU-Nancy, Department of Hepatology and Gastroenterology, F-54000, France
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24
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Yang R, Wang H, Wu C, Shi Y, Li H, Bao X, Yang Y, Han S, Yang X, Tao J, Sun H, Wu S, Sun L. PAQR5 drives the malignant progression and shapes the immunosuppressive microenvironment of hepatocellular carcinoma by activating the NF-κB signaling. Biomark Res 2025; 13:70. [PMID: 40336138 PMCID: PMC12060467 DOI: 10.1186/s40364-025-00785-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 04/26/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND 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. METHODS 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. RESULTS 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.
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Affiliation(s)
- Ruida Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
- Department of Thoracic Surgery, National Clinical Research Center for Cancer/Cancer Hospital, National Cancer Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huanhuan Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Cong Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Yu Shi
- Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Hanqi Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Xinyue Bao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Yuqian Yang
- Department of Medical Oncology, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, 711018, Shaanxi, People's Republic of China
| | - Shaoshan Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Xue Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Jie Tao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Hao Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
| | - Shaobo Wu
- Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.
| | - Liankang Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
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25
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Zhou S, Liu Y, Zhang N, Sun L, Ji C, Cui T, Chu Q, Zhang S, Wang J, Liu L. Glycolytic enzyme PFKFB4 governs lipolysis by promoting de novo lipogenesis to drive the progression of hepatocellular carcinoma. Cancer Lett 2025; 626:217774. [PMID: 40339954 DOI: 10.1016/j.canlet.2025.217774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 04/21/2025] [Accepted: 05/05/2025] [Indexed: 05/10/2025]
Abstract
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.
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Affiliation(s)
- Shuo Zhou
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China; Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Yao Liu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China; Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Ning Zhang
- Department of General Surgery, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China
| | - Linmao Sun
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China; Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Changyong Ji
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China; Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Tianming Cui
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China; Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Qi Chu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China; Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China
| | - Shugeng Zhang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China; Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China; Department of Organ Transplantation Center, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
| | - Jiabei Wang
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China; Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China; Department of Organ Transplantation Center, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
| | - Lianxin Liu
- Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China; Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China; Department of Organ Transplantation Center, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
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Lavoro A, Ricci D, Gattuso G, Longo F, Spoto G, Vitale ACV, Giuliana MC, Falzone L, Libra M, Candido S. Recent advances on gene-related DNA methylation in cancer diagnosis, prognosis, and treatment: a clinical perspective. Clin Epigenetics 2025; 17:76. [PMID: 40325471 PMCID: PMC12054201 DOI: 10.1186/s13148-025-01884-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 04/13/2025] [Indexed: 05/07/2025] Open
Abstract
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.
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Affiliation(s)
- Alessandro Lavoro
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy
| | - Daria Ricci
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy
| | - Giuseppe Gattuso
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy
| | - Federica Longo
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy
| | - Graziana Spoto
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy
| | | | - Maria Chiara Giuliana
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy
| | - Luca Falzone
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy.
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123, Catania, Italy
| | - Saverio Candido
- Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy
- Research Center for Prevention, Diagnosis and Treatment of Cancer, University of Catania, 95123, Catania, Italy
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27
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Capinha F, Carvalhana S, Cortez-Pinto H. Role of Alcohol in Steatotic Liver Disease: Impact on Patients with Cardiometabolic Risk Factors. Dig Dis Sci 2025; 70:1746-1756. [PMID: 40025309 DOI: 10.1007/s10620-025-08912-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 02/03/2025] [Indexed: 03/04/2025]
Abstract
The new definition of steatotic liver disease (SLD), as a broader concept, was a step forward in the increasing recognition of the substantial overlap between alcohol and cardiometabolic risk factors (CMRFs), in a continuum way. The spectrum of pathophysiological aspects, ranging from liver steatosis to fibrosis, has similarities in MASLD and ALD. Also, there is now considerable evidence that the association of metabolic dysfunction with increased alcohol consumption impacts on the risk of severe liver disease and prognosis. The new MetALD class, as recently proposed, shows clear differences in prognosis when comparing with MASLD and ALD groups. However, there is room for improvement, such as considering the role of previous alcohol intake, fluctuations of consumption over time, including binge drinking, refinement of alcohol assessment, and better understanding of the role of biomarkers. In summary, SLD is no doubt a significant improvement, but the new classification needs to be dynamic and adapting to patients needing frequent reassessment. Furthermore, it brings opportunities for research on the interaction between alcohol consumption and CMRFs.
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Affiliation(s)
- Francisco Capinha
- Serviço de Gastrenterologia e Hepatologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035, Lisbon, Portugal
| | - Sofia Carvalhana
- Serviço de Gastrenterologia e Hepatologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035, Lisbon, Portugal
| | - Helena Cortez-Pinto
- Serviço de Gastrenterologia e Hepatologia, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-035, Lisbon, Portugal.
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28
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Liu X, Ma Q, Jia Z, Zhou Y, Zou C, Xiao Y, Chen Y, Ma C, Song L, Yang J, Wang C, Xu H, Chen H, Shi J, Yue J, Sun Y, Hu D, Petersen RB, Li Y, Peng A, Huang K, Zheng L. ISG15 Enhances the Activity of γ-Glutamate Cysteine Ligase to Suppress Apoptosis in High Fat Diet-Promoted Hepatocellular Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2416401. [PMID: 40126377 PMCID: PMC12097128 DOI: 10.1002/advs.202416401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 03/07/2025] [Indexed: 03/25/2025]
Abstract
Obesity is a leading risk factor for development of hepatocellular carcinoma (HCC). High-fat intake produces cytotoxic effects in liver cells, such as excessive reactive oxygen species (ROS) accumulation and apoptosis. How HCC cells regulate ROS level and escape the cytotoxic effects of high fat diet (HFD) stress remains unclear. Herein, this work reports a critical anti-ROS/apoptotic role of the ubiquitin-like protein interferon stimulated gene 15 (ISG15) in HFD-promoted HCC. In mouse models and clinical HCC samples, upregulation of ISG15 is associated with hepatic steatosis. Notably, upregulated ISG15 elevates cellular glutathione levels, which subsequently reduces ROS accumulation and confers resistance to apoptosis in HCC cells. In diethylnitrosamine-induced HCC mouse model, HFD-feeding promotes HCC progression in wildtype mice, while tumor growth is significantly suppressed accompanied by apoptosis of HCC cells in Isg15-KO mice. Mechanistically, ISG15 promotes the activity of γ-glutamate cysteine ligase (γ-GCL), a rate-limiting heterodimeric holoenzyme of glutathione synthesis consisting of glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate-cysteine ligase modifier subunit (GCLM). Independent of ISGylation, ISG15 forms an ISG15/GCLM/GCLC complex that promotes GCLM-GCLC interaction, increases glutathione generation and inhibits HFD-induced apoptosis in HCC cells. Together, an anti-apoptotic ISG15-γ-GCL-glutothione axis is suggested in HFD-promoted HCC.
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Affiliation(s)
- Xinran Liu
- School of PharmacyTongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science & TechnologyWuhan430030China
| | - Qiujin Ma
- School of PharmacyTongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science & TechnologyWuhan430030China
| | - Zhao Jia
- School of PharmacyTongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science & TechnologyWuhan430030China
| | - Yihao Zhou
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, TaiKang Center for Life and Medical Sciences; Frontier Science Center for Immunology and Metabolism, College of Life SciencesWuhan UniversityWuhan430072China
| | - Churong Zou
- School of PharmacyTongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science & TechnologyWuhan430030China
| | - Yushuo Xiao
- School of PharmacyTongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science & TechnologyWuhan430030China
| | - Yuchen Chen
- School of PharmacyTongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science & TechnologyWuhan430030China
| | - Chuyao Ma
- School of PharmacyTongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science & TechnologyWuhan430030China
| | - Liangliang Song
- School of PharmacyTongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science & TechnologyWuhan430030China
| | - Jing Yang
- School of PharmacyTongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science & TechnologyWuhan430030China
| | - Chen Wang
- School of PharmacyTongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science & TechnologyWuhan430030China
| | - Huidie Xu
- School of PharmacyTongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science & TechnologyWuhan430030China
| | - Hong Chen
- School of PharmacyTongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science & TechnologyWuhan430030China
| | - Jiajian Shi
- School of PharmacyTongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science & TechnologyWuhan430030China
| | - Junqiu Yue
- Department of PathologyHubei Cancer HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430079China
| | - Yu Sun
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, TaiKang Center for Life and Medical Sciences; Frontier Science Center for Immunology and Metabolism, College of Life SciencesWuhan UniversityWuhan430072China
| | - Desheng Hu
- Department of Integrated Traditional Chinese and Western MedicineUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
- China‐Russia Medical Research Center for Stress ImmunologyUnion HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430000China
| | - Robert B Petersen
- Foundational SciencesCentral Michigan University College of MedicineMt. PleasantMI48859USA
| | - Yangkai Li
- Department of Thoracic SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China
| | - Anlin Peng
- Department of PharmacyThe Third Hospital of WuhanTongren Hospital of Wuhan UniversityWuhan430070China
| | - Kun Huang
- School of PharmacyTongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesHuazhong University of Science & TechnologyWuhan430030China
| | - Ling Zheng
- State Key Laboratory of Metabolism and Regulation in Complex Organisms, TaiKang Center for Life and Medical Sciences; Frontier Science Center for Immunology and Metabolism, College of Life SciencesWuhan UniversityWuhan430072China
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Wen C, Huang C, Chen S, Liu X, Yin W, Tao L. Membranous Staining of CD10 Is Related to Steatosis Changes in Hepatocellular Carcinoma: An Investigation of CD10 Stainning in Hepatocellular Carcinoma, Focal Nodular Hyperplasia, and Intrahepatic Cholangiocarcinoma. Appl Immunohistochem Mol Morphol 2025; 33:180-185. [PMID: 39948747 DOI: 10.1097/pai.0000000000001249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 01/03/2025] [Indexed: 05/07/2025]
Abstract
AIMS To investigate the staining patterns of CD10 in hepatocellular carcinoma (HCC), focal nodular hyperplasia (FNH), and intrahepatic cholangiocarcinoma (ICC). METHODS 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. RESULTS 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%). CONCLUSIONS 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.
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Affiliation(s)
- Caiyan Wen
- Department of Pathology, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, Shenzhen University School of Medicine
| | - Chuqiang Huang
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, Guangdong
| | - Shouguo Chen
- Department of Gastroenterology, Funing County People's Hospital, Jiangsu, China
| | - Xia Liu
- Department of Pathology, Shenzhen Second People's Hospital, Shenzhen University 1st Affiliated Hospital, Shenzhen University School of Medicine
| | - Weihua Yin
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, Guangdong
| | - Lili Tao
- Department of Pathology, Peking University Shenzhen Hospital, Shenzhen, Guangdong
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Meyer HJ, Leonhardi J, Potratz J, Jechorek D, Schramm KI, Borggrefe J, Surov A. Association between radiomics of diffusion-weighted imaging and histopathology in hepatocellular carcinoma. A preliminary investigation. Magn Reson Imaging 2025; 118:110356. [PMID: 39938670 DOI: 10.1016/j.mri.2025.110356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 02/06/2025] [Accepted: 02/08/2025] [Indexed: 02/14/2025]
Abstract
OBJECTIVE 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). MATERIALS AND METHODS 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. RESULTS 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. CONCLUSION 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.
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Affiliation(s)
- Hans-Jonas Meyer
- Department of Diagnostic and Interventional Radiology, University Hospital Leipzig, Leipzig, Germany.
| | - Jakob Leonhardi
- Department of Diagnostic and Interventional Radiology, University Hospital Leipzig, Leipzig, Germany
| | - Johann Potratz
- Department of Pathology, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Dörthe Jechorek
- Department of Pathology, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Kai Ina Schramm
- Department of Radiology and Nuclear Medicine, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Jan Borggrefe
- Institute for Radiology, Neuroradiology and Nuclear Medicine, Johannes Wesling University, Ruhr University Bochum, Minden, Germany
| | - Alexey Surov
- Institute for Radiology, Neuroradiology and Nuclear Medicine, Johannes Wesling University, Ruhr University Bochum, Minden, Germany
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Shen L, Jiang Y, Wu Y, Li C, Zeng Q, Lin L, Wang Y, Chen S, Cao F, Nuerhashi G, Zhang S, Zhou Z, An C, Du Z, Fan W. The Value of no Evidence of Disease (NED) in Intermediate-Stage Hepatocellular Carcinoma After TACE: A Real-World Study. Liver Int 2025; 45:e70101. [PMID: 40231897 DOI: 10.1111/liv.70101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 03/22/2025] [Accepted: 04/07/2025] [Indexed: 04/16/2025]
Abstract
BACKGROUND AND AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- Lujun Shen
- Department of Minimally Invasive Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yiquan Jiang
- Department of Minimally Invasive Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yueqian Wu
- Department of Medical Statistics, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Chen Li
- Department of Minimally Invasive Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Qi Zeng
- Department of Traditional Chinese Medicine Oncology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Letao Lin
- Department of Minimally Invasive Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yujia Wang
- Department of Minimally Invasive Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Shuanggang Chen
- Department of Minimally Invasive Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Fei Cao
- Department of Minimally Invasive Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Gulijiayina Nuerhashi
- Department of Minimally Invasive Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Sen Zhang
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei, China
| | - Zhongguo Zhou
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Chao An
- Department of Minimally Invasive Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Zhicheng Du
- Department of Medical Statistics, School of Public Health, Sun Yat-Sen University, Guangzhou, China
| | - Weijun Fan
- Department of Minimally Invasive Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, China
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Xu X, Zhang Y, Wu S, Wu Y, Lin X, Chen K, Lin X. Hepatitis B Virus Promotes Angiogenesis in Hepatocellular Carcinoma by Increasing m6A Modification of VEGFA mRNA via IGF2BP3. J Med Virol 2025; 97:e70356. [PMID: 40260505 DOI: 10.1002/jmv.70356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 03/28/2025] [Accepted: 04/04/2025] [Indexed: 04/23/2025]
Abstract
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.
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MESH Headings
- Humans
- Carcinoma, Hepatocellular/virology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- RNA-Binding Proteins/metabolism
- RNA-Binding Proteins/genetics
- Liver Neoplasms/virology
- Liver Neoplasms/pathology
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Animals
- Neovascularization, Pathologic/virology
- Neovascularization, Pathologic/genetics
- RNA, Messenger/metabolism
- RNA, Messenger/genetics
- Hepatitis B virus/pathogenicity
- Hepatitis B virus/physiology
- Mice
- Methylation
- Cell Line, Tumor
- Human Umbilical Vein Endothelial Cells
- Mice, Nude
- Hepatitis B/virology
- Hepatitis B/complications
- Angiogenesis
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Affiliation(s)
- Xiaoxin Xu
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
| | - Yi Zhang
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
| | - Shuxiang Wu
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Yuecheng Wu
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
| | - Xinjian Lin
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
| | - Kunqi Chen
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
| | - Xu Lin
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
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Chang JP, Lin H, Loi P, Ng JP, De Roza M, Kumar R, Tan H, Ho CK, Teo W, Chung AHH, Raj P. Validation of ICD-10 Consensus Code Set for Cirrhosis Detection Using Electronic Health Records in an Asian Population. JGH Open 2025; 9:e70156. [PMID: 40330254 PMCID: PMC12053512 DOI: 10.1002/jgh3.70156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 04/01/2025] [Indexed: 05/08/2025]
Abstract
Background 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. Methods 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. Results 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). Conclusions 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.
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Affiliation(s)
- Jason Pik‐Eu Chang
- Department of Gastroenterology and HepatologySingapore General HospitalSingaporeSingapore
- Duke‐NUS Medical SchoolSingaporeSingapore
| | - Hong‐Yi Lin
- Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Pooi‐Ling Loi
- Department of Gastroenterology and HepatologySingapore General HospitalSingaporeSingapore
| | - Jeanette Pei‐Xuan Ng
- Department of Gastroenterology and HepatologySingapore General HospitalSingaporeSingapore
| | - Marianne De Roza
- Duke‐NUS Medical SchoolSingaporeSingapore
- Department of Gastroenterology and HepatologySengkang General HospitalSingaporeSingapore
| | - Rahul Kumar
- Duke‐NUS Medical SchoolSingaporeSingapore
- Department of Gastroenterology and HepatologyChangi General HospitalSingaporeSingapore
| | - Hiang‐Keat Tan
- Department of Gastroenterology and HepatologySingapore General HospitalSingaporeSingapore
- Duke‐NUS Medical SchoolSingaporeSingapore
| | - Chanda Kendra Ho
- Department of Gastroenterology and HepatologySingapore General HospitalSingaporeSingapore
- Duke‐NUS Medical SchoolSingaporeSingapore
- SingHealth Duke‐NUS Transplant CentreSingaporeSingapore
| | - Wei‐Quan Teo
- SingHealth Duke‐NUS Transplant CentreSingaporeSingapore
| | | | - Prema Raj
- Duke‐NUS Medical SchoolSingaporeSingapore
- SingHealth Duke‐NUS Transplant CentreSingaporeSingapore
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Fukuda Y, Koga C, Minami S, Ishikawa S, Gakuhara A, Fukuda S, Haraguchi N, Hida J, Wakasa T, Kimura Y. Pancreatic Fat Accumulation Impacts Postoperative Survival in Patients With Pancreatic Ductal Adenocarcinoma. World J Surg 2025; 49:1327-1335. [PMID: 40181477 PMCID: PMC12058435 DOI: 10.1002/wjs.12576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 03/08/2025] [Accepted: 03/22/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSION The present study indicates a possible prognostic role for pancreatic fat accumulation in patients with pancreatic adenocarcinoma.
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Affiliation(s)
- Yasunari Fukuda
- Department of Gastroenterological SurgeryKindai University Nara HospitalNaraJapan
| | - Chikato Koga
- Department of Gastroenterological SurgeryKindai University Nara HospitalNaraJapan
| | - Soichiro Minami
- Department of Gastroenterological SurgeryKindai University Nara HospitalNaraJapan
| | - Satoshi Ishikawa
- Department of Gastroenterological SurgeryKindai University Nara HospitalNaraJapan
| | - Atsushi Gakuhara
- Department of Gastroenterological SurgeryKindai University Nara HospitalNaraJapan
| | - Shuichi Fukuda
- Department of Gastroenterological SurgeryKindai University Nara HospitalNaraJapan
| | - Naotsugu Haraguchi
- Department of Gastroenterological SurgeryKindai University Nara HospitalNaraJapan
| | - Jinichi Hida
- Department of Gastroenterological SurgeryKindai University Nara HospitalNaraJapan
| | - Tomoko Wakasa
- Department of PathologyKindai University Nara HospitalNaraJapan
| | - Yutaka Kimura
- Department of Gastroenterological SurgeryKindai University Nara HospitalNaraJapan
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Shen Y, Bai X, Zhang Q, Liang X, Jin X, Zhao Z, Song W, Tan Q, Zhao R, Jia W, Gu S, Shi G, Zheng Z, Wei G, Wang Y, Fang T, Li Y, Wang Z, Yang Z, Guo S, Lin D, Wei F, Wang L, Sun X, Qin A, Xie L, Qiu Y, Bao W, Rahimian S, Singh M, Murad Y, Shang J, Chu M, Huang M, Ding J, Chen W, Ye Y, Chen Y, Li X, Liang T. Oncolytic virus VG161 in refractory hepatocellular carcinoma. Nature 2025; 641:503-511. [PMID: 40108464 DOI: 10.1038/s41586-025-08717-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 01/30/2025] [Indexed: 03/22/2025]
Abstract
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 .
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Affiliation(s)
- Yinan Shen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Xingmei Liang
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinyan Jin
- Department of Ultrasound Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zeda Zhao
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Wei Song
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Qian Tan
- Shanghai Virogin Biotech, Shanghai, China
| | | | - William Jia
- Shanghai Virogin Biotech, Shanghai, China
- Virogin Biotech Canada, Richmond, British Columbia, Canada
- CNBG-Virogin Biotech (Shanghai), Shanghai, China
| | - Shanzhi Gu
- Department of Interventional Radiology, Hunan Cancer Hospital, Changsha, China
| | - Guoming Shi
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | | | - Guyue Wei
- Department of Ultrasound Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Youlei Wang
- Key Laboratory for Drug Evaluation and Clinical Research of Zhejiang Province, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tian Fang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuwei Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Zijun Wang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Zifan Yang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Sida Guo
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Danni Lin
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Fang Wei
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Lei Wang
- Department of Radiotherapy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoli Sun
- Department of Radiotherapy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Aijun Qin
- Shanghai Virogin Biotech, Shanghai, China
| | - Longshen Xie
- CNBG-Virogin Biotech (Shanghai), Shanghai, China
| | - Yeting Qiu
- Shanghai Virogin Biotech, Shanghai, China
| | | | - Shah Rahimian
- Virogin Biotech Canada, Richmond, British Columbia, Canada
| | - Manu Singh
- Virogin Biotech Canada, Richmond, British Columbia, Canada
| | - Yanal Murad
- Virogin Biotech Canada, Richmond, British Columbia, Canada
| | | | - Min Chu
- Shanghai Virogin Biotech, Shanghai, China
| | | | - Jun Ding
- Shanghai Virogin Biotech, Shanghai, China
- Virogin Biotech Canada, Richmond, British Columbia, Canada
| | - Wei Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yufu Ye
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yiwen Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Xiang Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.
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Zhang WZ, Chin KY, Zakaria R, Hassan NH. Strategies for Pain Management in Hepatocellular Carcinoma Patients Undergoing Transarterial Chemoembolisation: A Scoping Review of Current Evidence. Healthcare (Basel) 2025; 13:994. [PMID: 40361772 PMCID: PMC12071419 DOI: 10.3390/healthcare13090994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 04/08/2025] [Accepted: 04/08/2025] [Indexed: 05/15/2025] Open
Abstract
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.
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Affiliation(s)
- Wei-Zheng Zhang
- Department of Nursing, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (W.-Z.Z.); (R.Z.)
| | - Kok-Yong Chin
- Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia;
| | - Roshaya Zakaria
- Department of Nursing, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (W.-Z.Z.); (R.Z.)
| | - Nor Haty Hassan
- Department of Nursing, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia; (W.-Z.Z.); (R.Z.)
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He Y, Rogasch JMM, Savic LJ. PET Imaging and Key Radiotracers for Evaluating Response to Locoregional Therapy in Hepatocellular Carcinoma. PET Clin 2025:S1556-8598(25)00024-0. [PMID: 40287367 DOI: 10.1016/j.cpet.2025.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2025]
Abstract
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.
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Affiliation(s)
- Yubei He
- Department of Radiology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany; Experimental and Clinical Research Center, A Joint Cooperation of Max Delbrück Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Berlin 13125, Germany
| | - Julian M M Rogasch
- Department of Nuclear Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin 10117, Germany
| | - Lynn Jeanette Savic
- Department of Radiology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany; Experimental and Clinical Research Center, A Joint Cooperation of Max Delbrück Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, Berlin 13125, Germany; Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin 10117, Germany.
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38
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Wu J, Xie S, Ma Y, He X, Dong X, Shi Q, Wang Q, Li M, Yao N, Yao L. Entecavir for children and adults with chronic hepatitis B. Cochrane Database Syst Rev 2025; 4:CD015536. [PMID: 40260837 PMCID: PMC12012880 DOI: 10.1002/14651858.cd015536.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
RATIONALE 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. OBJECTIVES 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. SEARCH METHODS 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. ELIGIBILITY CRITERIA 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. OUTCOMES 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. RISK OF BIAS We used the Cochrane RoB 2 tool to assess risk of bias in the included trials. SYNTHESIS METHODS 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. INCLUDED STUDIES 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. SYNTHESIS OF RESULTS 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). AUTHORS' CONCLUSIONS 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. FUNDING This Cochrane review had no dedicated funding. REGISTRATION Registration: Entecavir for children and adults with chronic hepatitis B, CD015536 via DOI 10.1002/14651858.CD015536.
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Affiliation(s)
- Jing Wu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Shitong Xie
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
| | - Yanfang Ma
- Chinese EQUATOR Centre, Hong Kong Baptist University, Hong Kong, China
| | - Xiaoning He
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Xinyue Dong
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Qianling Shi
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Evidence-based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Qi Wang
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
| | - Meixuan Li
- Evidence-based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Naijuan Yao
- The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Liang Yao
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
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Ananthakrishnan AI, Mahin A, Prasad TSK, Abhinand CS. Transcriptome Profiling and Viral-Human Interactome Insights Into HBV-Driven Oncogenic Alterations in Hepatocellular Carcinoma. Microbiol Immunol 2025. [PMID: 40243270 DOI: 10.1111/1348-0421.13219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Revised: 03/21/2025] [Accepted: 03/27/2025] [Indexed: 04/18/2025]
Abstract
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.
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Affiliation(s)
- Anilkumar I Ananthakrishnan
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India
| | - Althaf Mahin
- Centre for Integrative Omics Data Science (CIODS), Yenepoya (Deemed to be University), Mangalore, India
| | | | - Chandran S Abhinand
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India
- Department of Virus Genomics, Bioinformatics, and Statistics, Institute of Advanced Virology, Thiruvananthapuram, India
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Zhan Z, Chen B, Huang R, Lin W, Lan S, Yao X, Huang S, Lin W, Xu S, Zhou S, Yu J, Wang X, Lin X, Guo Z. Long-term trends and future projections of liver cancer burden in China from 1990 to 2030. Sci Rep 2025; 15:13120. [PMID: 40240432 PMCID: PMC12003824 DOI: 10.1038/s41598-025-96615-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 03/31/2025] [Indexed: 04/18/2025] Open
Abstract
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.
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Affiliation(s)
- Zhouwei Zhan
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Fuzhou, 350014, Fujian, China
| | - Bijuan Chen
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian, China
| | - Rui Huang
- Digestive Endoscopy Center, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian, China
| | - Wei Lin
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian, China
| | - Shuangting Lan
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian, China
| | - Xintong Yao
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian, China
| | - Shuqi Huang
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian, China
| | - Wenlong Lin
- Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian, China
| | - Shaohua Xu
- Department of Hepatobiliary and Pancreatic Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian, China
| | - Sijing Zhou
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Fuzhou, 350014, Fujian, China
| | - Jiami Yu
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Fuzhou, 350014, Fujian, China
| | - Xiaojie Wang
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Fuzhou, 350014, Fujian, China
| | - Xiaoyan Lin
- Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China.
- Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, 350001, Fujian, China.
| | - Zengqing Guo
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, No. 420 Fuma Road, Fuzhou, 350014, Fujian, China.
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Zhang T, Ren C, Yang Z, Zhang N, Tang H. Exploration of the role of immune cells and cell therapy in hepatocellular carcinoma. Front Immunol 2025; 16:1569150. [PMID: 40308592 PMCID: PMC12040661 DOI: 10.3389/fimmu.2025.1569150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 03/27/2025] [Indexed: 05/02/2025] Open
Abstract
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.
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Affiliation(s)
- Tao Zhang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Cong Ren
- The Second Clinical College, Chongqing Medical University, Chongqing, China
| | - Zhanyu Yang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Ning Zhang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Haowen Tang
- Faculty of Hepato-Pancreato-Biliary Surgery, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
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Watling CZ, Kelly RK, Watts EL, Graubard BI, Petrick JL, Matthews CE, McGlynn KA. Total testosterone, sex hormone-binding globulin, and free testosterone concentrations and risk of primary liver cancer: A prospective analysis of 200,000 men and 180,000 postmenopausal women. Int J Cancer 2025; 156:1518-1528. [PMID: 39499225 PMCID: PMC11826138 DOI: 10.1002/ijc.35244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/07/2024] [Accepted: 10/17/2024] [Indexed: 11/07/2024]
Abstract
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.
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Affiliation(s)
- Cody Z. Watling
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMarylandUSA
| | - Rebecca K. Kelly
- The George Institute for Global HealthUniversity of New South WalesSydneyNew South WalesAustralia
- School of Medicine, College of Health and MedicineUniversity of TasmaniaHobartTasmaniaAustralia
| | - Eleanor L. Watts
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMarylandUSA
| | - Barry I. Graubard
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMarylandUSA
| | | | - Charles E. Matthews
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMarylandUSA
| | - Katherine A. McGlynn
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMarylandUSA
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El Wakil A, Devos P, Abdelmegeed H, Kamel A. Mitochondria in cancer: a comprehensive review, bibliometric analysis, and future perspectives. Discov Oncol 2025; 16:517. [PMID: 40214834 PMCID: PMC11992316 DOI: 10.1007/s12672-025-02139-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 03/13/2025] [Indexed: 04/14/2025] Open
Abstract
INTRODUCTION 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. METHODS 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. RESULTS 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%). CONCLUSIONS 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.
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Affiliation(s)
- Abeer El Wakil
- Department of Biological and Geological Sciences, Faculty of Education, Alexandria University, Alexandria, 21526, Egypt.
| | - Patrick Devos
- Université Lille, Lillometrics, 59000, Lille, France
- CHU Lille, Direction de la Recherche et de l'Innovation, 59000, Lille, France
| | - Heba Abdelmegeed
- Department of Chemistry of Natural Compounds, National Research Centre, Giza, Egypt
| | - Alaa Kamel
- Department of Zoology, Faulty of Science, Alexandria University, Alexandria, Egypt
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Mohnasky M, Gad S, Fanous M, Du Pisanie JL, Ivanovic M, Mauro DM, Yu H, Villalobos A, Moon AM, Sanoff HK, Jia J, Kokabi N. Initial Experience with Single-Session Resin-Based Transarterial Radioembolization Mapping and Treatment of Small Hepatocellular Carcinomas. Cancers (Basel) 2025; 17:1265. [PMID: 40282441 PMCID: PMC12026212 DOI: 10.3390/cancers17081265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 03/26/2025] [Accepted: 03/28/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND/OBJECTIVES 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.
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Affiliation(s)
- Michael Mohnasky
- School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (S.G.); (M.F.)
| | - Sandra Gad
- School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (S.G.); (M.F.)
- School of Medicine, Saint George’s University, West Indies P.O. Box 7, Grenada
| | - Marco Fanous
- School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (S.G.); (M.F.)
| | - Johannes L. Du Pisanie
- Department of Radiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (J.L.D.P.); (M.I.); (D.M.M.); (H.Y.); (N.K.)
| | - Marija Ivanovic
- Department of Radiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (J.L.D.P.); (M.I.); (D.M.M.); (H.Y.); (N.K.)
| | - David M. Mauro
- Department of Radiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (J.L.D.P.); (M.I.); (D.M.M.); (H.Y.); (N.K.)
| | - Hyeon Yu
- Department of Radiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (J.L.D.P.); (M.I.); (D.M.M.); (H.Y.); (N.K.)
| | - Alex Villalobos
- Department of Radiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (J.L.D.P.); (M.I.); (D.M.M.); (H.Y.); (N.K.)
| | - Andrew M. Moon
- Department of Gastroenterology and Hepatology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Hanna K. Sanoff
- Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (H.K.S.); (J.J.)
| | - Jingquan Jia
- Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (H.K.S.); (J.J.)
| | - Nima Kokabi
- Department of Radiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (J.L.D.P.); (M.I.); (D.M.M.); (H.Y.); (N.K.)
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Tong W, Qin N, Lu T, Liu L, Liu R, Chen J, Luo N. Integrating bulk and single-cell RNA sequencing reveals SH3D21 promotes hepatocellular carcinoma progression by activating the PI3K/AKT/mTOR pathway. PLoS One 2025; 20:e0302766. [PMID: 40179068 PMCID: PMC11967960 DOI: 10.1371/journal.pone.0302766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 02/16/2025] [Indexed: 04/05/2025] Open
Abstract
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.
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Affiliation(s)
- Wangxia Tong
- Department of Hepatology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Na Qin
- The Graduate School of Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Tao Lu
- Department of hepatobiliary surgery, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Li Liu
- Department of Hepatology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Rong Liu
- Department of Hepatology, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Jibing Chen
- Centre for Translational Medical Research in Integrative Chinese and Western Medicine, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi, China
| | - Ning Luo
- Department of Neurology, RuiKang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi, China
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Milani I, Chinucci M, Leonetti F, Capoccia D. MASLD: Prevalence, Mechanisms, and Sex-Based Therapies in Postmenopausal Women. Biomedicines 2025; 13:855. [PMID: 40299427 PMCID: PMC12024897 DOI: 10.3390/biomedicines13040855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Revised: 03/27/2025] [Accepted: 03/31/2025] [Indexed: 04/30/2025] Open
Abstract
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.
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Affiliation(s)
- Ilaria Milani
- Department of Medico-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine, University of Rome La Sapienza, 04100 Latina, Italy; (M.C.); (F.L.); (D.C.)
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Einarsson H, Graham RP. How Do I Diagnose Fibrolamellar Carcinoma? Mod Pathol 2025; 38:100711. [PMID: 39814265 DOI: 10.1016/j.modpat.2025.100711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 01/07/2025] [Indexed: 01/18/2025]
Abstract
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.
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Affiliation(s)
- Haukur Einarsson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Rondell P Graham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
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Wang Q, Jia W, Liu J, Zhao Q, Yang Z. Global, regional, and national burden of liver cancer due to alcohol use, 1990-2021: results from the Global Burden of Disease study 2021. Eur J Gastroenterol Hepatol 2025; 37:466-476. [PMID: 39621868 DOI: 10.1097/meg.0000000000002899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSION 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.
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Affiliation(s)
- Qihong Wang
- Department of Digestive Endoscopy, General Hospital of Northern Theater Command, Shenyang, Liaoning Province, China
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Liu Y, Peng F, Wang S, Xing J. Correspondence to editorial on "Aberrant fragmentomic features of circulating cell-free mitochondrial DNA enable early detection and prognosis prediction of hepatocellular carcinoma". Clin Mol Hepatol 2025; 31:e166-e168. [PMID: 39761959 PMCID: PMC12016617 DOI: 10.3350/cmh.2024.1185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 01/01/2025] [Indexed: 04/18/2025] Open
Affiliation(s)
- Yang Liu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
- Department of Clinical Diagnosis, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
| | - Fan Peng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Siyuan Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Jinliang Xing
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
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Takaya H, Namisaki T, Komeda Y, Kinoshita H, Nishimura N, Tsuji Y, Sato S, Nishimura N, Saito K, Aizawa S, Morioka C, Noguchi R, Yoshida M, Kaji K, Yoshiji H. Low Intrahepatic Distant Recurrence Rate Following RFA Using Linear Mode in Patients With Hepatocellular Carcinoma. JGH Open 2025; 9:e70145. [PMID: 40171402 PMCID: PMC11959191 DOI: 10.1002/jgh3.70145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/28/2025] [Accepted: 03/17/2025] [Indexed: 04/03/2025]
Abstract
BACKGROUND 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. AIM This retrospective observational study compared the performance of the linear (linear group) and nonlinear RFA modes (nonlinear group) in HCC. METHODS 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. RESULTS 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. CONCLUSION The linear mode of the RFA protocol results in a lower intrahepatic distant recurrence rate compared with the nonlinear protocol.
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Affiliation(s)
- Hiroaki Takaya
- Department of GastroenterologyNara Prefecture Seiwa Medical CenterNaraJapan
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | | | - Yusuke Komeda
- Department of GastroenterologyNara Prefecture Seiwa Medical CenterNaraJapan
| | - Hiroki Kinoshita
- Department of GastroenterologyNara Prefecture Seiwa Medical CenterNaraJapan
| | - Naoki Nishimura
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | - Yuki Tsuji
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | - Shinya Sato
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | | | - Ko Saito
- Department of GastroenterologyNara Prefecture Seiwa Medical CenterNaraJapan
| | - Shigeyuki Aizawa
- Department of GastroenterologyNara Prefecture Seiwa Medical CenterNaraJapan
| | - Chie Morioka
- Department of GastroenterologyNara Prefecture Seiwa Medical CenterNaraJapan
| | - Ryuichi Noguchi
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | - Motoyuki Yoshida
- Department of GastroenterologyNara Prefecture Seiwa Medical CenterNaraJapan
| | - Kosuke Kaji
- Department of GastroenterologyNara Medical UniversityNaraJapan
| | - Hitoshi Yoshiji
- Department of GastroenterologyNara Medical UniversityNaraJapan
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