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Salfi AB, Hussain M, Majeed MI, Nawaz H, Rashid N, Albekairi NA, Alshammari A, Yousaf A, Ullah MH, Fatima E, Mehmood S, Hakeem M, Amin I, Javed M. Surface-enhanced Raman spectroscopy for the characterization of filtrate portions of hepatitis B blood serum samples using 100 kDa ultra filtration devices. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 333:125883. [PMID: 39978181 DOI: 10.1016/j.saa.2025.125883] [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: 09/07/2024] [Revised: 12/30/2024] [Accepted: 02/08/2025] [Indexed: 02/22/2025]
Abstract
The blood serum of patients infected by the Hepatitis B virus contains high molecular weight fractions and low molecular weight fractions (LMWF) of biomarker proteins of the disease. The LMWF including the associated peptidome and metabolome, is recognized as a critical molecular population with high potential for research on disease-associated biomarkers. This fraction of biomarkers can be suppressed by HMWF, proteins such as albumin, and immunoglobulins hence difficult to be detected. The purpose of this study is to separate HMWF) and LMWF using 100 kDa centrifugal filtration devices resulting in two parts including residue (HMWF) and filtrate parts (LMWF) of blood serum followed by the analysis of the later part employing surface-enhanced Raman spectroscopy (SERS). This strategy can enhance this optical technique's capability to characterize the biochemical changes caused by the infection of HBV and the diagnosis of the disease. The silver nanoparticles (Ag-NPs) were employed as a SERS substrate to distinguish between filtrate parts of the blood serum of HBV patients and healthy individuals based on their specific SERS peaks. The SERS spectral features associated with the filtrate parts of HBV patients' blood serum are well differentiated from the healthy volunteers. Principle component analysis (PCA) was applied on the SERS spectral data sets of HBV patients and healthy individuals and found extremely beneficial for the classification of their SERS spectral groups. Moreover, partial least square regression analysis (PLSR) has shown excellent performance in the quantitative analysis of the viral load values of the HBV patients using their SERS spectral data sets.
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Affiliation(s)
- Abu Bakar Salfi
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan
| | - Munawar Hussain
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan
| | - Muhammad Irfan Majeed
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan.
| | - Haq Nawaz
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan.
| | - Nosheen Rashid
- Department of Chemistry, University of Education, Faisalabad Campus, Faisalabad 38000 Pakistan
| | - Norah A Albekairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2455, Riyadh 11451 Saudi Arabia
| | - Abdulrahman Alshammari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2455, Riyadh 11451 Saudi Arabia
| | - Arslan Yousaf
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan
| | - Muhammad Hafeez Ullah
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan
| | - Eman Fatima
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan
| | - Sana Mehmood
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan
| | - Munazza Hakeem
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan
| | - Imran Amin
- PCR Laboratory, PINUM Hospital, Faisalabad 38000 Pakistan
| | - Mahrosh Javed
- Nacionalinis Fizinių ir technologijos mokslų centras (NFTMC), Department of Environmental Research, Lithuania
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Qin A, Ho MC, Tsai CY, Liu CJ, Chen PJ. Sequential combination with ropeginterferon alfa-2b and anti-PD-1 treatment as adjuvant therapy in HBV-related HCC: a phase 1 dose escalation trial. Hepatol Int 2025:10.1007/s12072-025-10824-4. [PMID: 40186764 DOI: 10.1007/s12072-025-10824-4] [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: 09/20/2024] [Accepted: 03/12/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND/PURPOSE Post-operative recurrence is a major clinical challenge with hepatocellular carcinoma (HCC). While currently unapproved, anti-programmed cell death 1 (PD-1) and anti-vascular endothelial growth factor combination adjuvant therapy showed promise. We initiated a phase I trial using sequential treatment with ropeginterferon alfa-2b (ropeg), a novel interferon-based antiviral and antitumor agent, followed by anti-PD-1 therapeutic antibody nivolumab as an adjuvant therapy for hepatitis B virus (HBV)-related HCC. METHODS Patients who underwent surgical resection of HBV-related HCC with curative intent received sequential therapy with six doses of ropeg every two weeks at 450 μg, followed by three doses of nivolumab escalating from 0.3 to 0.75 mg/kg every two weeks. Safety, HBV surface antigen (HBsAg) loss or decrease, anti-HBV surface (HBs) antibodies, cancer recurrence, and survival were evaluated. RESULTS Fifteen eligible patients were enrolled. Most adverse events (AEs) were mild or moderate and no severe or serious AEs were observed. Alanine transaminase flares, including one grade 3 event as dose-limiting toxicity, were noted in five cases and the final recommended dose for anti-PD1 was determined at 0.75 mg/kg. Interestingly, all five cases had HBsAg clearance or reduction. All patients in the study were alive without cancer recurrence during a median follow-up of 1024 days with six patients surviving > 4 years and three for > 5 years. CONCLUSIONS This phase I trial supports the safety and clinical efficacy of sequential treatment with ropeg and nivolumab in post-resection HBV-related HCC. This regimen holds promise for further adjuvant therapy trials in HCC, both HBV-related and other types.
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Affiliation(s)
- Albert Qin
- Medical Research and Clinical Operations, PharmaEssentia Corporation, Taipei, Taiwan
| | - Ming-Chih Ho
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Department of Surgery, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan
| | - Chan-Yen Tsai
- Medical Research and Clinical Operations, PharmaEssentia Corporation, Taipei, Taiwan
| | - Chun-Jen Liu
- Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, No. 7, Chung Shan South Rd., Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, No. 7, Chung Shan South Rd., Taipei, Taiwan.
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
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Zhou X, Tang H, Luo G, Zou L, Liu H, Wen P, Yang R, Deng Z. Rapid and visual detection of hepatitis B virus using the ERA/Cas12f1_ge4.1-based lateral flow assay system. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2025; 17:1503-1510. [PMID: 39844718 DOI: 10.1039/d4ay02079k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
Hepatitis B virus (HBV) is a major pathogen posing significant challenges to global public health, making early diagnosis critical for preventing severe liver diseases. We previously developed a fluorescent biosensor named PAM-dependent dsDNA Target-activated Cas12f1 Trans Reporter (PDTCTR). However, its reliance on specialized fluorescence equipment and lack of visual readout limited its application in resource-limited settings. To address these limitations, we developed a lateral flow assay (LFA) that integrates enzymatic recombinase amplification (ERA) with the Cas12f1_ge4.1 system. This approach enables the specific amplification of the HBV target gene through ERA and leverages the precise cleavage activity of Cas12f1_ge4.1 for enhanced signal amplification. The entire detection process is completed within 50 minutes, with results readily interpretable through visual inspection. The assay achieves a minimum detection limit of 100 copies per μL and demonstrates high specificity, showing no cross-reactivity with related viruses. In a validation study involving 71 clinical samples, the system achieved a sensitivity of 94.23%, specificity of 100%, and a kappa value of 0.90 compared to quantitative PCR (qPCR), indicating high reliability. This method thus shows promise as an effective tool for early HBV diagnosis, particularly suited for rapid, on-site detection in resource-constrained environments, and holds broad potential for diverse applications.
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Affiliation(s)
- Xuan Zhou
- Department of Public Health Laboratory Sciences, College of Public Health, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
| | - Honghua Tang
- The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Gemiao Luo
- Department of Public Health Laboratory Sciences, College of Public Health, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
| | - Lintao Zou
- Department of Public Health Laboratory Sciences, College of Public Health, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
| | - Hangxi Liu
- Department of Public Health Laboratory Sciences, College of Public Health, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
| | - Piaoting Wen
- Department of Public Health Laboratory Sciences, College of Public Health, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
| | - Ruifu Yang
- State Key Laboratory of Pathogen and Biosecruity, Academy of Military Medical Sciences, Beijing, China
| | - Zhongliang Deng
- Department of Public Health Laboratory Sciences, College of Public Health, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
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Tu T, McQuaid TJ, Jacobson IM. HBV-Induced Carcinogenesis: Mechanisms, Correlation With Viral Suppression, and Implications for Treatment. Liver Int 2025; 45:e16202. [PMID: 39720865 DOI: 10.1111/liv.16202] [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: 02/05/2024] [Revised: 10/29/2024] [Accepted: 11/26/2024] [Indexed: 12/26/2024]
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is a common but underdiagnosed and undertreated health condition and is the leading cause of hepatocellular carcinoma (HCC) worldwide. HBV (rated a Grade 1 carcinogen by the International Agency for Research on Cancer) drives the transformation of hepatocytes in multiple ways by inducing viral DNA integrations, genetic dysregulation, chromosomal translocations, chronic inflammation, and oncogenic pathways facilitated by some HBV proteins. Importantly, these mechanisms are active throughout all phases of HBV infection. Nevertheless, most clinical guidelines for antiviral therapy recommend treatment based on a complex combination of HBV DNA levels, transaminasemia, liver histology, and demographic factors, rather than prompt treatment for all people with infection. AIMS To determine if current frameworks for antiviral treatment address the impacts of chronic HBV infection particularly preventing cancer development. MATERIALS AND METHODS We reviewed the recent data demonstrating pro-oncogenic factors acting throughout a chronic HBV infection can be inhibited by antiviral therapy. RESULTS We extensively reviewed Hepatitis B virology data and correlating clinical outcome data. From thi, we suggest that new findings support simplifying and expanding treatment initiation to reduce the incidence ofnew infections, progressive liver disease, and risk of hepatocellular carcinoma. We also consider lessons learned from other blood-borne pathogens, including the benefits of antiviral treatment in preventing transmission, reducing stigma, and reframing treatment as cancer prevention. CONCLUSION Incorporating these practice changes into treatment is likely to reduce the overall burden of chronic HBV infections and HCC. Through this, we may better achieve the World Health Organization's goal of eliminating viral hepatitis as a public health threat and minimise its impact on people's lives.
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Affiliation(s)
- Thomas Tu
- Storr Liver Centre, Westmead Clinical School, Centre for Infectious Diseases and Microbiology and Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales, Australia
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Wang Y, Guan X, Lv F, Rong Y, Meng X, Tong Y, Ma X, Zheng H, Chen C, Xie S, Zhang H, Dong F, Guo L, Lu R. HBx integration in diffuse large B-cell lymphoma inhibits Caspase-3-PARP related apoptosis. Tumour Virus Res 2024; 18:200290. [PMID: 39032828 PMCID: PMC11331954 DOI: 10.1016/j.tvr.2024.200290] [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: 01/11/2024] [Revised: 07/04/2024] [Accepted: 07/14/2024] [Indexed: 07/23/2024] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common pathological type of non-Hodgkin lymphoma, and is closely associated with hepatitis B virus (HBV) infection status and hepatitis B X (HBx) gene integration. This project investigated the cellular biological effects and molecular mechanisms responsible for lymphomagenesis and the progression of HBx integration in DLBCL. The data showed that clinical DLBCL cells demonstrated HBx integration, and the sequencing analysis of integrated sites validated HBx integration in the constructed HBx-transfected cells. Compared with control cells, HBx-transfected cells had a significantly reduced proportion of mitochondrial membrane potential, signals of chromosomal DNA breaks, and proportion of apoptotic cells. Further studies found that this decreased apoptosis level was associated with a significant reduction of cleaved Caspase-3 and downstream poly ADP-ribose polymerase (PARP) proteins, revealing the molecular mechanisms of HBx-associated apoptosis in DLBCL. Animal experiments also demonstrated that the protein expression of cleaved Caspase-3 and PARP was prominently reduced in HBx-transfected cells from subcutaneous tumors in mice. Furthermore, the HBx-integrated cells in clinical tissues had significantly lower cleaved PARP levels than the HBx-negative samples. Therefore, HBx integration inhibits cell apoptosis through the Caspase-3-PARP pathway in DLBCL indicating a potential biomarker and therapeutic target in HBV related DLBCL.
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Affiliation(s)
- Yanchun Wang
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaolin Guan
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fangfang Lv
- Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yi Rong
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xin Meng
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Ying Tong
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xiaolu Ma
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Hui Zheng
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Cuncun Chen
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Suhong Xie
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Heng Zhang
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Feng Dong
- Department of Outpatient Office, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Lin Guo
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Renquan Lu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Liu Y, Yang J, Wang Y, Zeng Q, Fan Y, Huang A, Fan H. The proteasome activator subunit PSME1 promotes HBV replication by inhibiting the degradation of HBV core protein. Genes Dis 2024; 11:101142. [PMID: 39281837 PMCID: PMC11400625 DOI: 10.1016/j.gendis.2023.101142] [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: 04/15/2023] [Revised: 08/27/2023] [Accepted: 09/10/2023] [Indexed: 09/18/2024] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a leading cause of liver cirrhosis and hepatocellular carcinoma, representing a global health problem for which a functional cure is difficult to achieve. The HBV core protein (HBc) is essential for multiple steps in the viral life cycle. It is the building block of the nucleocapsid in which viral DNA reverse transcription occurs, and its mediation role in viral-host cell interactions is critical to HBV infection persistence. However, systematic studies targeting HBc-interacting proteins remain lacking. Here, we combined HBc with the APEX2 to systematically identify HBc-related host proteins in living cells. Using functional screening, we confirmed that proteasome activator subunit 1 (PSME1) is a potent HBV-associated host factor. PSME1 expression was up-regulated upon HBV infection, and the protein level of HBc decreased after PSME1 knockdown. Mechanistically, the interaction between PSME1 and HBc inhibited the degradation of HBc by the 26S proteasome, thereby improving the stability of the HBc protein. Furthermore, PSME1 silencing inhibits HBV transcription in the HBV infection system. Our findings reveal an important mechanism by which PSME1 regulates HBc proteins and may facilitate the development of new antiviral therapies targeting PSME1 function.
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Affiliation(s)
- Yu Liu
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China
| | - Jiaxin Yang
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China
| | - Yanyan Wang
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China
| | - Qiqi Zeng
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China
| | - Yao Fan
- The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Ailong Huang
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China
| | - Hui Fan
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China
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Liu H, Zhang J, Rao Y, Jin S, Zhang C, Bai D. Intratumoral microbiota: an emerging force in diagnosing and treating hepatocellular carcinoma. Med Oncol 2024; 41:300. [PMID: 39453562 DOI: 10.1007/s12032-024-02545-9] [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: 09/12/2024] [Accepted: 10/17/2024] [Indexed: 10/26/2024]
Abstract
Hepatocellular carcinoma (HCC) ranks among the most prevalent types of cancer in the world and its incidence and mortality are increasing year by year, frequently diagnosed at an advanced stage. Traditional treatments such as surgery, chemotherapy, and radiotherapy have limited efficacy, so new diagnostic and treatment strategies are urgently needed. Recent research has discovered that intratumoral microbiota significantly influences the development, progression, and metastasis of HCC by modulating inflammation, immune responses, and cellular signaling pathways. Intratumoral microbiota contributes to the pathologic process of HCC by influencing the tumor microenvironment and altering the function of immune system. This article reviews the mechanism of intratumoral microbiota in HCC and anticipates the future possibilities of intratumoral microbiota-based therapeutic strategies for HCC management. This emerging field provides fresh insights into early diagnosis and personalized approaches for HCC while holding substantial clinical application potential to improve patient outcomes and tailor interventions to individual tumor profiles.
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Affiliation(s)
- Huanxiang Liu
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China
| | - Jiahao Zhang
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China
| | - Yuye Rao
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China
| | - Shengjie Jin
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital, Yangzhou, 225001, China
| | - Chi Zhang
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital, Yangzhou, 225001, China
| | - Dousheng Bai
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, 225001, China.
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital, Yangzhou, 225001, China.
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You HJ, Li Q, Ma LH, Wang X, Zhang HY, Wang YX, Bao ES, Zhong YJ, Kong DL, Liu XY, Kong FY, Zheng KY, Tang RX. Inhibition of GLUD1 mediated by LASP1 and SYVN1 contributes to hepatitis B virus X protein-induced hepatocarcinogenesis. J Mol Cell Biol 2024; 16:mjae014. [PMID: 38587834 PMCID: PMC11440430 DOI: 10.1093/jmcb/mjae014] [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: 04/27/2023] [Revised: 01/18/2024] [Accepted: 04/06/2024] [Indexed: 04/09/2024] Open
Abstract
Glutamate dehydrogenase 1 (GLUD1) is implicated in oncogenesis. However, little is known about the relationship between GLUD1 and hepatocellular carcinoma (HCC). In the present study, we demonstrated that the expression levels of GLUD1 significantly decreased in tumors, which was relevant to the poor prognosis of HCC. Functionally, GLUD1 silencing enhanced the growth and migration of HCC cells. Mechanistically, the upregulation of interleukin-32 through AKT activation contributes to GLUD1 silencing-facilitated hepatocarcinogenesis. The interaction between GLUD1 and AKT, as well as α-ketoglutarate regulated by GLUD1, can suppress AKT activation. In addition, LIM and SH3 protein 1 (LASP1) interacts with GLUD1 and induces GLUD1 degradation via the ubiquitin-proteasome pathway, which relies on the E3 ubiquitin ligase synoviolin (SYVN1), whose interaction with GLUD1 is enhanced by LASP1. In hepatitis B virus (HBV)-related HCC, the HBV X protein (HBX) can suppress GLUD1 with the participation of LASP1 and SYVN1. Collectively, our data suggest that GLUD1 silencing is significantly associated with HCC development, and LASP1 and SYVN1 mediate the inhibition of GLUD1 in HCC, especially in HBV-related tumors.
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Affiliation(s)
- Hong-Juan You
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
| | - Qi Li
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
- Laboratory Department, The People's Hospital of Funing, Yancheng 224400, China
| | - Li-Hong Ma
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
| | - Xing Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
| | - Huan-Yang Zhang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
| | - Yu-Xin Wang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
| | - En-Si Bao
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
| | - Yu-Jie Zhong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
| | - De-Long Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
| | - Xiang-Ye Liu
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
| | - Fan-Yun Kong
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
| | - Kui-Yang Zheng
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou 221004, China
| | - Ren-Xian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou 221004, China
- National Demonstration Center for Experimental Basic Medical Sciences Education, Xuzhou Medical University, Xuzhou 221004, China
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Vásquez Martínez IP, Pérez-Campos E, Pérez-Campos Mayoral L, Cruz Luis HI, Pina Canseco MDS, Zenteno E, Bazán Salinas IL, Martínez Cruz M, Pérez-Campos Mayoral E, Hernández-Huerta MT. O-GlcNAcylation: Crosstalk between Hemostasis, Inflammation, and Cancer. Int J Mol Sci 2024; 25:9896. [PMID: 39337387 PMCID: PMC11432004 DOI: 10.3390/ijms25189896] [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: 08/02/2024] [Revised: 09/03/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
O-linked β-N-acetylglucosamine (O-GlcNAc, O-GlcNAcylation) is a post-translational modification of serine/threonine residues of proteins. Alterations in O-GlcNAcylation have been implicated in several types of cancer, regulation of tumor progression, inflammation, and thrombosis through its interaction with signaling pathways. We aim to explore the relationship between O-GlcNAcylation and hemostasis, inflammation, and cancer, which could serve as potential prognostic tools or clinical predictions for cancer patients' healthcare and as an approach to combat cancer. We found that cancer is characterized by high glucose demand and consumption, a chronic inflammatory state, a state of hypercoagulability, and platelet hyperaggregability that favors thrombosis; the latter is a major cause of death in these patients. Furthermore, we review transcription factors and pathways associated with O-GlcNAcylation, thrombosis, inflammation, and cancer, such as the PI3K/Akt/c-Myc pathway, the nuclear factor kappa B pathway, and the PI3K/AKT/mTOR pathway. We also review infectious agents associated with cancer and chronic inflammation and potential inhibitors of cancer cell development. We conclude that it is necessary to approach both the diagnosis and treatment of cancer as a network in which multiple signaling pathways are integrated, and to search for a combination of potential drugs that regulate this signaling network.
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Affiliation(s)
- Itzel Patricia Vásquez Martínez
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - Eduardo Pérez-Campos
- National Institute of Technology of Mexico, Technological Institute of Oaxaca, Oaxaca 68033, Mexico; (E.P.-C.); (M.M.C.)
| | - Laura Pérez-Campos Mayoral
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - Holanda Isabel Cruz Luis
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - María del Socorro Pina Canseco
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - Edgar Zenteno
- Department of Biochemistry, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico;
| | - Irma Leticia Bazán Salinas
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - Margarito Martínez Cruz
- National Institute of Technology of Mexico, Technological Institute of Oaxaca, Oaxaca 68033, Mexico; (E.P.-C.); (M.M.C.)
| | - Eduardo Pérez-Campos Mayoral
- UNAM-UABJO Faculty of Medicine Research Center, Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68020, Mexico; (I.P.V.M.); (L.P.-C.M.); (H.I.C.L.); (M.d.S.P.C.); (I.L.B.S.); (E.P.-C.M.)
| | - María Teresa Hernández-Huerta
- National Council of Humanities, Sciences and Technologies (CONAHCYT), Faculty of Medicine and Surgery, Autonomous University “Benito Juarez” of Oaxaca, Oaxaca 68120, Mexico
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10
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Yu A, Yesilkanal A, Thakur A, Wang F, Yang Y, Phillips W, Wu X, Muir A, He X, Spitz F, Yang L. HYENA detects oncogenes activated by distal enhancers in cancer. Nucleic Acids Res 2024; 52:e77. [PMID: 39051548 PMCID: PMC11381332 DOI: 10.1093/nar/gkae646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 06/07/2024] [Accepted: 07/11/2024] [Indexed: 07/27/2024] Open
Abstract
Somatic structural variations (SVs) in cancer can shuffle DNA content in the genome, relocate regulatory elements, and alter genome organization. Enhancer hijacking occurs when SVs relocate distal enhancers to activate proto-oncogenes. However, most enhancer hijacking studies have only focused on protein-coding genes. Here, we develop a computational algorithm 'HYENA' to identify candidate oncogenes (both protein-coding and non-coding) activated by enhancer hijacking based on tumor whole-genome and transcriptome sequencing data. HYENA detects genes whose elevated expression is associated with somatic SVs by using a rank-based regression model. We systematically analyze 1146 tumors across 25 types of adult tumors and identify a total of 108 candidate oncogenes including many non-coding genes. A long non-coding RNA TOB1-AS1 is activated by various types of SVs in 10% of pancreatic cancers through altered 3-dimensional genome structure. We find that high expression of TOB1-AS1 can promote cell invasion and metastasis. Our study highlights the contribution of genetic alterations in non-coding regions to tumorigenesis and tumor progression.
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Affiliation(s)
- Anqi Yu
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA
| | - Ali E Yesilkanal
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA
| | - Ashish Thakur
- Department of Human Genetics, University of Chicago, Chicago, IL, USA
| | - Fan Wang
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA
| | - Yang Yang
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA
| | - William Phillips
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA
| | - Xiaoyang Wu
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA
- University of Chicago Comprehensive Cancer Center, Chicago, IL, USA
| | - Alexander Muir
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA
- University of Chicago Comprehensive Cancer Center, Chicago, IL, USA
| | - Xin He
- Department of Human Genetics, University of Chicago, Chicago, IL, USA
| | - Francois Spitz
- Department of Human Genetics, University of Chicago, Chicago, IL, USA
| | - Lixing Yang
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA
- Department of Human Genetics, University of Chicago, Chicago, IL, USA
- University of Chicago Comprehensive Cancer Center, Chicago, IL, USA
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11
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Wu M, Guan G, Yin H, Niu Q. A Review of the Bromodomain and Extraterminal Domain Epigenetic Reader Proteins: Function on Virus Infection and Cancer. Viruses 2024; 16:1096. [PMID: 39066258 PMCID: PMC11281655 DOI: 10.3390/v16071096] [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: 05/21/2024] [Revised: 06/28/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open
Abstract
The BET (bromodomain and extraterminal domain) family of proteins, particularly BRD4 (bromodomain-containing protein 4), plays a crucial role in transcription regulation and epigenetic mechanisms, impacting key cellular processes such as proliferation, differentiation, and the DNA damage response. BRD4, the most studied member of this family, binds to acetylated lysines on both histones and non-histone proteins, thereby regulating gene expression and influencing diverse cellular functions such as the cell cycle, tumorigenesis, and immune responses to viral infections. Given BRD4's involvement in these fundamental processes, it is implicated in various diseases, including cancer and inflammation, making it a promising target for therapeutic development. This review comprehensively explores the roles of the BET family in gene transcription, DNA damage response, and viral infection, discussing the potential of targeted small-molecule compounds and highlighting BET proteins as promising candidates for anticancer therapy.
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Affiliation(s)
- Mengli Wu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China; (M.W.); (G.G.); (H.Y.)
- African Swine Fever Regional Laboratory of China (Lanzhou), Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Guiquan Guan
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China; (M.W.); (G.G.); (H.Y.)
- African Swine Fever Regional Laboratory of China (Lanzhou), Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
| | - Hong Yin
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China; (M.W.); (G.G.); (H.Y.)
- African Swine Fever Regional Laboratory of China (Lanzhou), Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
- Jiangsu Co-Innovation Center for the Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou University, Yangzhou 225009, China
| | - Qingli Niu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou 730000, China; (M.W.); (G.G.); (H.Y.)
- African Swine Fever Regional Laboratory of China (Lanzhou), Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou 730046, China
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12
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Zhang S, Xiao X, Yi Y, Wang X, Zhu L, Shen Y, Lin D, Wu C. Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets. Signal Transduct Target Ther 2024; 9:149. [PMID: 38890350 PMCID: PMC11189549 DOI: 10.1038/s41392-024-01848-7] [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: 01/01/2024] [Revised: 04/23/2024] [Accepted: 04/27/2024] [Indexed: 06/20/2024] Open
Abstract
Tumorigenesis is a multistep process, with oncogenic mutations in a normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic mutations and clonal expansion in normal tissues, their transformation into cancer remains a rare event, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recently, researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution, independently of inducing mutations. Additionally, clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. In this review, we summarize the genetic, epigenetic, and external driver events, and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation.
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Affiliation(s)
- Shaosen Zhang
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Xinyi Xiao
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Yonglin Yi
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Xinyu Wang
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Lingxuan Zhu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Changping Laboratory, 100021, Beijing, China
| | - Yanrong Shen
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Dongxin Lin
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Changping Laboratory, 100021, Beijing, China.
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China.
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, 510060, China.
| | - Chen Wu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Changping Laboratory, 100021, Beijing, China.
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China.
- CAMS Oxford Institute, Chinese Academy of Medical Sciences, 100006, Beijing, China.
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13
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Kortei NK, Gillette VS, Wiafe-Kwagyan M, Ansah LO, Kyei-Baffour V, Odamtten GT. Fungal profile, levels of aflatoxin M1, exposure, and the risk characterization of local cheese ' wagashi' consumed in the Ho Municipality, Volta Region, Ghana. Toxicol Rep 2024; 12:186-199. [PMID: 38313814 PMCID: PMC10837644 DOI: 10.1016/j.toxrep.2024.01.009] [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: 10/17/2023] [Revised: 01/12/2024] [Accepted: 01/14/2024] [Indexed: 02/06/2024] Open
Abstract
Wagashi is a West African type cottage cheese locally prepared from cow milk. Wagashi like other milk products, is prone to microbial contamination, particularly by fungi. Many of these fungal species produce mycotoxins which are of serious public health concern. This work aimed to update the mycoflora profile and determine the concentrations of aflatoxin M1 and its health risk characterization due to the consumption of wagashi. Culturing the wagashi on mycological media (Oxytetracycline Glucose Yeast Extract OGYE, Dichloran Rose Bengal Chloramphenicol DRBC) caused a de-novo growth of the quiescent spores at 28-30 °C for 5-7 days. The analysis of AFM1 levels in the samples was done using High-Performance Liquid Chromatography connected to a Fluorescence detector (HPLC-FLD). The exposure and risk assessment to the AFMI levels were determined using deterministic models prescribed by the European Food Safety Authority (EFSA). The fungal counts ranged between 2.36-4.30 log10 CFU/g. In total, thirteen (13) fungal species from eight (8) genera were isolated from all wagashi samples. They are; Fusarium oxysporum, Aspergillus flavus, Aspergillus niger, Fusarium verticillioides, Penicillium digitatum, Trichoderma harzianum, Aspergillus terreus, Rhodotorula mucilaginosa, Rhizopus stolonifer, Aspergillus fumigatus, Yeast sp., Mucor racemosus and Fusarium oligosporum belonging to the genera Fusarium, Aspergillus, Penicillium, Trichoderma, Rhodotorula, Rhizopus, Yeast, and Mucor. The AFM1 observed in the wagashi samples' analysis was low, ranging from 0.00 (Not Detected) ± 0.00 - 0.06 ± 0.002 µg/Kg. Risk assessments of AFM1 using deterministic models produced outcomes that ranged between 5.92 × 10-3- 0.14 ng/kg bw/day, 1.42 -44.35, 0-0.0323 ng aflatoxins/kg bw/day, and 1.51 × 10-3 - 9.69 × 10-4 cases/100,000 person/yr for estimated daily intake (EDI), margin of exposure (MOE), average potency, and cancer risks, respectively, for the age categories investigated. Fungal counts were interpreted as medium to high. It was also established that the consumption of wagashi may pose adverse health effects on all age categories in the selected zones of the study since all calculated MOE values were less than 100,000.
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Affiliation(s)
- Nii Korley Kortei
- Department of Nutrition and Dietetics, School of Allied Health Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
- Department of Sports Nutrition, School of Sports and Exercise Medicine, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Valentina Sylvia Gillette
- Department of Nutrition and Dietetics, School of Allied Health Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Michael Wiafe-Kwagyan
- Department of Plant and Environmental Biology, College of Basic and Applied Sciences, University of Ghana, P. O. Box LG 55, Legon, Ghana
| | - Leslie Owusu Ansah
- Department of Food Laboratory, Food and Drugs Authority, P.O. Box CT 2783, Cantonments, Accra, Ghana
| | - Vincent Kyei-Baffour
- Food Chemistry and Nutrition Research Division, Council for Scientific and Industrial Research, Food Research Institute, P. O. Box M20, Accra, Ghana
| | - George Tawia Odamtten
- Department of Plant and Environmental Biology, College of Basic and Applied Sciences, University of Ghana, P. O. Box LG 55, Legon, Ghana
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14
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Yu A, Yesilkanal AE, Thakur A, Wang F, Yang Y, Phillips W, Wu X, Muir A, He X, Spitz F, Yang L. HYENA detects oncogenes activated by distal enhancers in cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.01.09.523321. [PMID: 38076958 PMCID: PMC10705271 DOI: 10.1101/2023.01.09.523321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2023]
Abstract
Somatic structural variations (SVs) in cancer can shuffle DNA content in the genome, relocate regulatory elements, and alter genome organization. Enhancer hijacking occurs when SVs relocate distal enhancers to activate proto-oncogenes. However, most enhancer hijacking studies have only focused on protein-coding genes. Here, we develop a computational algorithm "HYENA" to identify candidate oncogenes (both protein-coding and non-coding) activated by enhancer hijacking based on tumor whole-genome and transcriptome sequencing data. HYENA detects genes whose elevated expression is associated with somatic SVs by using a rank-based regression model. We systematically analyze 1,146 tumors across 25 types of adult tumors and identify a total of 108 candidate oncogenes including many non-coding genes. A long non-coding RNA TOB1-AS1 is activated by various types of SVs in 10% of pancreatic cancers through altered 3-dimensional genome structure. We find that high expression of TOB1-AS1 can promote cell invasion and metastasis. Our study highlights the contribution of genetic alterations in non-coding regions to tumorigenesis and tumor progression.
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Affiliation(s)
- Anqi Yu
- Ben May Department for Cancer Research, University of Chicago, Chicago IL, USA
| | - Ali E. Yesilkanal
- Ben May Department for Cancer Research, University of Chicago, Chicago IL, USA
| | - Ashish Thakur
- Department of Human Genetics, University of Chicago, Chicago IL, USA
| | - Fan Wang
- Ben May Department for Cancer Research, University of Chicago, Chicago IL, USA
| | - Yang Yang
- Ben May Department for Cancer Research, University of Chicago, Chicago IL, USA
| | - William Phillips
- Ben May Department for Cancer Research, University of Chicago, Chicago IL, USA
| | - Xiaoyang Wu
- Ben May Department for Cancer Research, University of Chicago, Chicago IL, USA
- University of Chicago Comprehensive Cancer Center, Chicago, IL, USA
| | - Alexander Muir
- Ben May Department for Cancer Research, University of Chicago, Chicago IL, USA
- University of Chicago Comprehensive Cancer Center, Chicago, IL, USA
| | - Xin He
- Department of Human Genetics, University of Chicago, Chicago IL, USA
| | - Francois Spitz
- Department of Human Genetics, University of Chicago, Chicago IL, USA
| | - Lixing Yang
- Ben May Department for Cancer Research, University of Chicago, Chicago IL, USA
- Department of Human Genetics, University of Chicago, Chicago IL, USA
- University of Chicago Comprehensive Cancer Center, Chicago, IL, USA
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15
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Zhang Y, Guo W, Zhan Z, Bai O. Carcinogenic mechanisms of virus-associated lymphoma. Front Immunol 2024; 15:1361009. [PMID: 38482011 PMCID: PMC10932979 DOI: 10.3389/fimmu.2024.1361009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Accepted: 02/12/2024] [Indexed: 04/17/2024] Open
Abstract
The development of lymphoma is a complex multistep process that integrates numerous experimental findings and clinical data that have not yet yielded a definitive explanation. Studies of oncogenic viruses can help to deepen insight into the pathogenesis of lymphoma, and identifying associations between lymphoma and viruses that are established and unidentified should lead to cellular and pharmacologically targeted antiviral strategies for treating malignant lymphoma. This review focuses on the pathogenesis of lymphomas associated with hepatitis B and C, Epstein-Barr, and human immunodeficiency viruses as well as Kaposi sarcoma-associated herpesvirus to clarify the current status of basic information and recent advances in the development of virus-associated lymphomas.
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Affiliation(s)
| | | | | | - Ou Bai
- Department of Hematology, The First Hospital of Jilin University, Changchun, Jilin, China
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16
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Pessino G, Scotti C, Maggi M, Immuno-Hub Consortium. Hepatocellular Carcinoma: Old and Emerging Therapeutic Targets. Cancers (Basel) 2024; 16:901. [PMID: 38473265 DOI: 10.3390/cancers16050901] [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: 01/31/2024] [Revised: 02/16/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024] Open
Abstract
Liver cancer, predominantly hepatocellular carcinoma (HCC), globally ranks sixth in incidence and third in cancer-related deaths. HCC risk factors include non-viral hepatitis, alcohol abuse, environmental exposures, and genetic factors. No specific genetic alterations are unequivocally linked to HCC tumorigenesis. Current standard therapies include surgical options, systemic chemotherapy, and kinase inhibitors, like sorafenib and regorafenib. Immunotherapy, targeting immune checkpoints, represents a promising avenue. FDA-approved checkpoint inhibitors, such as atezolizumab and pembrolizumab, show efficacy, and combination therapies enhance clinical responses. Despite this, the treatment of hepatocellular carcinoma (HCC) remains a challenge, as the complex tumor ecosystem and the immunosuppressive microenvironment associated with it hamper the efficacy of the available therapeutic approaches. This review explores current and advanced approaches to treat HCC, considering both known and new potential targets, especially derived from proteomic analysis, which is today considered as the most promising approach. Exploring novel strategies, this review discusses antibody drug conjugates (ADCs), chimeric antigen receptor T-cell therapy (CAR-T), and engineered antibodies. It then reports a systematic analysis of the main ligand/receptor pairs and molecular pathways reported to be overexpressed in tumor cells, highlighting their potential and limitations. Finally, it discusses TGFβ, one of the most promising targets of the HCC microenvironment.
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Affiliation(s)
- Greta Pessino
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Claudia Scotti
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Maristella Maggi
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Immuno-Hub Consortium
- Unit of Immunology and General Pathology, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
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17
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Varghese N, Majeed A, Nyalakonda S, Boortalary T, Halegoua-DeMarzio D, Hann HW. Review of Related Factors for Persistent Risk of Hepatitis B Virus-Associated Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:777. [PMID: 38398168 PMCID: PMC10887172 DOI: 10.3390/cancers16040777] [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: 12/24/2023] [Revised: 01/30/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Chronic hepatitis B virus (HBV) infection is the largest global cause of hepatocellular carcinoma (HCC). Current HBV treatment options include pegylated interferon-alpha and nucleos(t)ide analogues (NAs), which have been shown to be effective in reducing HBV DNA levels to become undetectable. However, the literature has shown that some patients have persistent risk of developing HCC. The mechanism in which this occurs has not been fully elucidated. However, it has been discovered that HBV's covalently closed circular DNA (cccDNA) integrates into the critical HCC driver genes in hepatocytes upon initial infection; additionally, these are not targets of current NA therapies. Some studies suggest that HBV undergoes compartmentalization in peripheral blood mononuclear cells that serve as a sanctuary for replication during antiviral therapy. The aim of this review is to expand on how patients with HBV may develop HCC despite years of HBV viral suppression and carry worse prognosis than treatment-naive HBV patients who develop HCC. Furthermore, HCC recurrence after initial surgical or locoregional treatment in this setting may cause carcinogenic cells to behave more aggressively during treatment. Curative novel therapies which target the life cycle of HBV, modulate host immune response, and inhibit HBV RNA translation are being investigated.
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Affiliation(s)
- Nevin Varghese
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Amry Majeed
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Suraj Nyalakonda
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
| | - Tina Boortalary
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Hie-Won Hann
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.V.); (A.M.); (S.N.); (T.B.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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18
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Liu Y, Kim ES, Guo H. Hepatitis B virus-related hepatocellular carcinoma exhibits distinct intratumoral microbiota and immune microenvironment signatures. J Med Virol 2024; 96:e29485. [PMID: 38377167 PMCID: PMC10916714 DOI: 10.1002/jmv.29485] [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: 01/12/2024] [Revised: 02/08/2024] [Accepted: 02/13/2024] [Indexed: 02/22/2024]
Abstract
Emerging evidence supports a high prevalence of cancer type-specific microbiota residing within tumor tissues. The intratumoral microbiome in hepatocellular carcinoma (HCC), especially in viral (hepatitis B virus [HBV]/hepatitis C virus [HCV]) HCC, has not been well characterized for their existence, composition, distribution, and biological functions. We report herein a finding of specific microbial signature in viral HCC as compared to non-HBV/non-HCV (NBNC) HCC. However, the significantly diverse tumor microbiome was only observed in HBV-related HCC, and Cutibacterium was identified as the representative taxa biomarker. Biological function of the unique tumor microbiota in modulating tumor microenvironment (TME) was characterized by using formalin-fixed paraffin-embedded (FFPE) tissue-based multiplex immunofluorescence histochemistry (mIFH) allowing simultaneous in situ detection of the liver cancer cells surrounded with high/low density of microbiota, and the infiltrating immune cells. In HBV_HCC, the intratumoral microbiota are positively associated with increased tumor-infiltrating CD8+ T lymphocytes, but not the CD56+ NK cells. Two subtypes of myeloid-derived suppressor cells (MDSCs): monocytic MDSCs and polymorphonuclear MDSCs, were also found to be positively correlated with the intratumoral microbiota in HBV_HCC, indicating an inhibitory role of these microbial species in antitumor immunity and the contribution to the liver TME in combination of chronic viral hepatitis during HCC development.
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Affiliation(s)
- Yuanjie Liu
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine
- Cancer Microbiome Facility, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine
| | - Elena S. Kim
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine
- Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine
| | - Haitao Guo
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine
- Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine
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19
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Noverati N, Jun JW, Yan V, Halegoua-DeMarzio D, Hann HW. Chronic Hepatitis B: A Summarized Anecdote of Complexities in Natural History, Treatment, and Complications. LIVERS 2023; 4:31-35. [DOI: 10.3390/livers4010003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/21/2025] Open
Abstract
Chronic hepatitis B is still a disease process that affects millions around the world. Serologies used to diagnose and follow the progression (or resolution) of the disease can be confusing for clinicians. Further, throughout years of treatment, there may be nuances in presentation that complicate management even further. In this short communication, we highlight six themes in response to treatment and outcomes, including complications. We have the unique perspective of following many patients over extended periods of time at our institution, which has brought these themes to life in order that they can be shared with other clinicians who may encounter similar situations.
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Affiliation(s)
- Nicholas Noverati
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Jay W. Jun
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Vivian Yan
- Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Hie-Won Hann
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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20
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Teixeira SC, Teixeira TL, Tavares PCB, Alves RN, da Silva AA, Borges BC, Martins FA, Dos Santos MA, de Castilhos P, E Silva Brígido RT, Notário AFO, Silveira ACA, da Silva CV. Subversion strategies of lysosomal killing by intracellular pathogens. Microbiol Res 2023; 277:127503. [PMID: 37748260 DOI: 10.1016/j.micres.2023.127503] [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: 07/16/2023] [Revised: 09/08/2023] [Accepted: 09/17/2023] [Indexed: 09/27/2023]
Abstract
Many pathogenic organisms need to reach either an intracellular compartment or the cytoplasm of a target cell for their survival, replication or immune system evasion. Intracellular pathogens frequently penetrate into the cell through the endocytic and phagocytic pathways (clathrin-mediated endocytosis, phagocytosis and macropinocytosis) that culminates in fusion with lysosomes. However, several mechanisms are triggered by pathogenic microorganisms - protozoan, bacteria, virus and fungus - to avoid destruction by lysosome fusion, such as rupture of the phagosome and thereby release into the cytoplasm, avoidance of autophagy, delaying in both phagolysosome biogenesis and phagosomal maturation and survival/replication inside the phagolysosome. Here we reviewed the main data dealing with phagosome maturation and evasion from lysosomal killing by different bacteria, protozoa, fungi and virus.
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Affiliation(s)
- Samuel Cota Teixeira
- Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil
| | - Thaise Lara Teixeira
- Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil
| | | | | | - Aline Alves da Silva
- Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil
| | - Bruna Cristina Borges
- Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil
| | - Flávia Alves Martins
- Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil
| | - Marlus Alves Dos Santos
- Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil
| | - Patrícia de Castilhos
- Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil
| | | | | | | | - Claudio Vieira da Silva
- Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil.
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21
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Saeed U, Piracha ZZ, Alrokayan S, Hussain T, Almajhdi FN, Waheed Y. Immunoinformatics and Evaluation of Peptide Vaccines Derived from Global Hepatitis B Viral HBx and HBc Proteins Critical for Covalently Closed Circular DNA Integrity. Microorganisms 2023; 11:2826. [PMID: 38137971 PMCID: PMC10745757 DOI: 10.3390/microorganisms11122826] [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: 10/18/2023] [Revised: 11/07/2023] [Accepted: 11/17/2023] [Indexed: 12/24/2023] Open
Abstract
The Hepatitis B virus (HBV) HBx and HBc proteins play a crucial role in associating with covalently closed circular DNA (cccDNA), the primary factor contributing to intrahepatic viral persistence and a major obstacle in achieving a cure for HBV. The cccDNA serves as a reservoir for viral persistence. Targeting the viral HBc and HBx proteins' interaction with cccDNA could potentially limit HBV replication. In this study, we present epitopes identified from global consensus sequences of HBx and HBc proteins that have the potential to serve as targets for the development of effective vaccine candidates. Furthermore, conserved residues identified through this analysis can be utilized in designing novel, site-specific anti-HBV agents capable of targeting all major genotypes of HBV. Our approach involved designing global consensus sequences for HBx and HBc proteins, enabling the analysis of variable regions and highly conserved motifs. These identified motifs and regions offer potent sites for the development of peptide vaccines, the design of site-specific RNA interference, and the creation of anti-HBV inhibitors. The epitopes derived from global consensus sequences of HBx and HBc proteins emerge as promising targets for the development of effective vaccine candidates. Additionally, the conserved residues identified provide valuable insights for the development of innovative, site-specific anti-HBV agents capable of targeting all major genotypes of HBV from A to J.
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Affiliation(s)
- Umar Saeed
- Clinical and Biomedical Research Center (CBRC) and Multidisciplinary Laboratory (MDL), Foundation University Islamabad, Islamabad 44000, Pakistan;
- Department of Microbiology, Ajou University School of Medicine, Suwon 443-749, Republic of Korea;
| | - Zahra Zahid Piracha
- Department of Microbiology, Ajou University School of Medicine, Suwon 443-749, Republic of Korea;
- International Center of Medical Sciences Research (ICMSR), Islamabad 44000, Pakistan
| | - Salman Alrokayan
- Research Chair for Biomedical Application of Nanomaterials, Biochemistry Department, College of Sciences, King Saud University, Riyadh 11362, Saudi Arabia;
| | - Tajamul Hussain
- Research Chair for Biomedical Application of Nanomaterials, Biochemistry Department, College of Sciences, King Saud University, Riyadh 11362, Saudi Arabia;
- Center of Excellence in Biotechnology Research, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11451, Saudi Arabia
| | - Fahad N. Almajhdi
- Botany and Microbiology Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia;
| | - Yasir Waheed
- Office of Research, Innovation, and Commercialization, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44000, Pakistan;
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Byblos 1401, Lebanon
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22
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Funato K, Miyake N, Sekiba K, Miyakawa Y, Seimiya T, Shibata C, Kishikawa T, Otsuka M. Cabozantinib inhibits HBV-RNA transcription by decreasing STAT3 binding to the enhancer region of cccDNA. Hepatol Commun 2023; 7:e0313. [PMID: 37938099 PMCID: PMC10635605 DOI: 10.1097/hc9.0000000000000313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/18/2023] [Indexed: 11/09/2023] Open
Abstract
BACKGROUND Precision medicine and customized therapeutics based on the features of each patient are important for maximizing therapeutic effects. Because most cases of HCC occur in the damaged liver through various etiologies, such as hepatitis virus infection, steatohepatitis, and autoimmune hepatitis, there should be a rationale for the choice of therapeutic options based on these etiologies. Although cabozantinib, an oral multikinase inhibitor, has demonstrated clinical effectiveness in advanced HCC, subgroup analyses showed a lower HR for death in HBV-related HCC. This study aimed to determine the therapeutic effects of cabozantinib in HBV-related HCC. METHODS Using HBV infection models and gene knockout cells, we determined the crucial signaling axis responsible for the effects of cabozantinib on HBV. A chromatin immunoprecipitation assay was performed to determine the interaction between the signaling molecules and HBV DNA. Agonists and inhibitors were used for confirmation. RESULTS Cabozantinib inhibited HBV replication through the HGF-mesenchymal-epithelial transition factor-signal transducer and activator of transcription 3 (MET-STAT3) signaling axis. The importance of STAT3 in viral replication has been confirmed using gene-edited STAT3 knockout cells. The chromatin immunoprecipitation assay revealed that the binding levels of phosphorylated STAT3 to enhancer region 1 of HBV covalently closed circular DNA were significantly increased by HGF stimulation. CONCLUSIONS Cabozantinib has favorable therapeutic effects on HBV-related HCC because it inhibits HCC not only directly but also indirectly by means of inhibitory effects on HBV.
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Affiliation(s)
- Kazuyoshi Funato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nozomi Miyake
- Department of Gastroenterology, Graduate School of Medicine, Okayama University, Okayama, Japan
| | - Kazuma Sekiba
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yu Miyakawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takahiro Seimiya
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Chikako Shibata
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Takahiro Kishikawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Gastroenterology, Graduate School of Medicine, Okayama University, Okayama, Japan
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23
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Wang Y, Deng B. Hepatocellular carcinoma: molecular mechanism, targeted therapy, and biomarkers. Cancer Metastasis Rev 2023; 42:629-652. [PMID: 36729264 DOI: 10.1007/s10555-023-10084-4] [Citation(s) in RCA: 83] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 01/16/2023] [Indexed: 02/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy and one of the leading causes of cancer-related death. The biological process of HCC is complex, with multiple factors leading to the broken of the balance of inactivation and activation of tumor suppressor genes and oncogenes, the abnormal activation of molecular signaling pathways, the differentiation of HCC cells, and the regulation of angiogenesis. Due to the insidious onset of HCC, at the time of first diagnosis, less than 30% of HCC patients are candidates for radical treatment. Systematic antitumor therapy is the hope for the treatment of patients with middle-advanced HCC. Despite the emergence of new systemic therapies, survival rates for advanced HCC patients remain low. The complex pathogenesis of HCC has inspired researchers to explore a variety of biomolecular targeted therapeutics targeting specific targets. Correct understanding of the molecular mechanism of HCC occurrence is key to seeking effective targeted therapy. Research on biomarkers for HCC treatment is also advancing. Here, we explore the molecular mechanism that are associated with HCC development, summarize targeted therapies for HCC, and discuss potential biomarkers that may drive therapies.
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Affiliation(s)
- Yu Wang
- Department of Infectious Diseases, The First Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China
| | - Baocheng Deng
- Department of Infectious Diseases, The First Hospital of China Medical University, 155 Nanjing North Street, Shenyang, 110001, Liaoning Province, China.
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24
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Coffin P, He A. Hepatocellular Carcinoma: Past and Present Challenges and Progress in Molecular Classification and Precision Oncology. Int J Mol Sci 2023; 24:13274. [PMID: 37686079 PMCID: PMC10487618 DOI: 10.3390/ijms241713274] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/23/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common solid tumor malignancies in the world and represents roughly 90% of all primary malignancies of the liver. The most common risk factors for HCC include hepatitis B virus, hepatitis C virus, alcohol, and increasingly, fatty liver. Most HCC is diagnosed at advanced stages, excluding the possibility of curative resection, which leaves systemic therapy as the only treatment option. However, given the extreme mutational diversity and heterogenous nature of HCC, efforts to develop new targeted systemic therapies were largely unsuccessful until recently. HCC pathogenesis is thought to be a multistage process driven by a wide array of nonmutually exclusive driver mutations accompanied by many passenger mutations, with the average tumor possessing approximately 40 genomic aberrations. Over the past two decades, several efforts to categorize HCC prognostically and therapeutically according to different molecular subclassifications with the intent to guide treatment and identify drug targets have emerged, though, no single consensus has been reached. Recent breakthroughs in drug development have greatly expanded treatment options, but the ideal of uniting each patient's unique HCC with a targeted systemic therapy remains elusive.
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Affiliation(s)
- Philip Coffin
- MedStar Georgetown University Hospital, Lombardi Cancer Center, 3800 Reservoir Rd NW, Washington, DC 20007, USA;
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25
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Ma S, Lv M, Chen X, Zang G, Tang Z, Zhang Y, Hu W. Avasimibe can cooperate with a DC-targeting and integration-deficient lentivector to induce stronger HBV specific T cytotoxic response by regulating cholesterol metabolism. Antiviral Res 2023; 216:105662. [PMID: 37393054 DOI: 10.1016/j.antiviral.2023.105662] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 06/25/2023] [Accepted: 06/29/2023] [Indexed: 07/03/2023]
Abstract
We have reported a lentivector which could effectively induce HBV-specific cytotoxic T lymphocytes (CTLs). Avasimibe is an inhibitor of acetyl-CoA acetyltransferase-1 (ACAT1), and has been shown to enhance T lymphocyte cytotoxicity on tumor cells. However, the role of avasimibe in lentivector-induced HBV-specific T cytotoxic response remains unknown. Based on previous study, we constructed an integration-deficient lentivector LVDC-ID-HBV (harboring HBcAg expression), and the in vitro experiments showed that the combination of avasimibe exhibited better efficacy in inducing HBV-specific CTL responses including cell proliferation, production of cytokines, as well as CTL killing activities. Mechanism experiments showed that increasing cell membrane cholesterol levels by MβCD-coated cholesterol or ACAT1 inhibition efficiently promoted TCR clustering, signaling transduction and immunological synapse formation, thereby mediating augmented CTL responses. Nevertheless, the depletion of plasma membrane cholesterol with MβCD led to obviously decreased CTL responses. The avasimibe-mediated strengthened immune effects were also determined in animal experiments and the results were in agreement with those from the in vitro research. In particular, the in vivo CTL killing activities were identified by the CFSE or BV-labeled splenocyte lysis assay. Moreover, the experiments in HBV transgenic mice showed that the LVDC-ID-HBV plus avasimibe group demonstrated the lowest serum HBsAg and HBV DNA levels, as well as the lowest expression of HBsAg and HBcAg in liver tissues. We concluded that the HBV-specific CTL immune responses could be potentiated by avasimibe through regulating plasma membrane cholesterol levels. Avasimibe may be a potential adjuvant for lentivector vaccine against HBV infection.
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Affiliation(s)
- Siyuan Ma
- Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Mengjiao Lv
- Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Xiaohua Chen
- Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Guoqing Zang
- Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Zhenghao Tang
- Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yi Zhang
- Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Weiwei Hu
- Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
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26
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Zhou Q, Li L, Sha F, Lei Y, Tian X, Chen L, Chen Y, Liu H, Guo Y. PTTG1 Reprograms Asparagine Metabolism to Promote Hepatocellular Carcinoma Progression. Cancer Res 2023; 83:2372-2386. [PMID: 37159932 DOI: 10.1158/0008-5472.can-22-3561] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 03/14/2023] [Accepted: 05/04/2023] [Indexed: 05/11/2023]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has a poor prognosis. Pituitary tumor transforming gene 1 (PTTG1) is highly expressed in HCC, suggesting it could play an important role in hepatocellular carcinogenesis. Here, we evaluated the impact of PTTG1 deficiency on HCC development using a diethylnitrosamine (DEN)-induced HCC mouse model and a hepatitis B virus (HBV) regulatory X protein (HBx)-induced spontaneous HCC mouse model. PTTG1 deficiency significantly suppressed DEN- and HBx-induced hepatocellular carcinogenesis. Mechanistically, PTTG1 promoted asparagine synthetase (ASNS) transcription by binding to its promoter, and asparagine (Asn) levels were correspondingly increased. The elevated levels of Asn subsequently activated the mTOR pathway to facilitate HCC progression. In addition, asparaginase treatment reversed the proliferation induced by PTTG1 overexpression. Furthermore, HBx promoted ASNS and Asn metabolism by upregulating PTTG1 expression. Overall, PTTG1 is involved in the reprogramming of Asn metabolism to promote HCC progression and may serve as a therapeutic and diagnostic target for HCC. SIGNIFICANCE PTTG1 is upregulated in hepatocellular carcinoma and increases asparagine production to stimulate mTOR activity and promote tumor progression.
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Affiliation(s)
- Qi Zhou
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Leijia Li
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Feifei Sha
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Yiming Lei
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Xuan Tian
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Lingjun Chen
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Yan Chen
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Huiling Liu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
| | - Yunwei Guo
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, Guangdong Province, China
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27
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Zou J, Li J, Zhong X, Tang D, Fan X, Chen R. Liver in infections: a single-cell and spatial transcriptomics perspective. J Biomed Sci 2023; 30:53. [PMID: 37430371 PMCID: PMC10332047 DOI: 10.1186/s12929-023-00945-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 06/27/2023] [Indexed: 07/12/2023] Open
Abstract
The liver is an immune organ that plays a vital role in the detection, capture, and clearance of pathogens and foreign antigens that invade the human body. During acute and chronic infections, the liver transforms from a tolerant to an active immune state. The defence mechanism of the liver mainly depends on a complicated network of intrahepatic and translocated immune cells and non-immune cells. Therefore, a comprehensive liver cell atlas in both healthy and diseased states is needed for new therapeutic target development and disease intervention improvement. With the development of high-throughput single-cell technology, we can now decipher heterogeneity, differentiation, and intercellular communication at the single-cell level in sophisticated organs and complicated diseases. In this concise review, we aimed to summarise the advancement of emerging high-throughput single-cell technologies and re-define our understanding of liver function towards infections, including hepatitis B virus, hepatitis C virus, Plasmodium, schistosomiasis, endotoxemia, and corona virus disease 2019 (COVID-19). We also unravel previously unknown pathogenic pathways and disease mechanisms for the development of new therapeutic targets. As high-throughput single-cell technologies mature, their integration into spatial transcriptomics, multiomics, and clinical data analysis will aid in patient stratification and in developing effective treatment plans for patients with or without liver injury due to infectious diseases.
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Affiliation(s)
- Ju Zou
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Jie Li
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Xiao Zhong
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Daolin Tang
- Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA
| | - Xuegong Fan
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Ruochan Chen
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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28
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Kwon H, Kim J, Song C, Sajjad MA, Ha J, Jung J, Park S, Shin HJ, Kim K. Peptidyl-prolyl cis/trans isomerase Pin1 interacts with hepatitis B virus core particle, but not with HBc protein, to promote HBV replication. Front Cell Infect Microbiol 2023; 13:1195063. [PMID: 37404723 PMCID: PMC10315659 DOI: 10.3389/fcimb.2023.1195063] [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: 03/28/2023] [Accepted: 06/01/2023] [Indexed: 07/06/2023] Open
Abstract
Here, we demonstrate that the peptidyl-prolyl cis/trans isomerase Pin1 interacts noncovalently with the hepatitis B virus (HBV) core particle through phosphorylated serine/threonine-proline (pS/TP) motifs in the carboxyl-terminal domain (CTD) but not with particle-defective, dimer-positive mutants of HBc. This suggests that neither dimers nor monomers of HBc are Pin1-binding partners. The 162TP, 164SP, and 172SP motifs within the HBc CTD are important for the Pin1/core particle interaction. Although Pin1 dissociated from core particle upon heat treatment, it was detected as an opened-up core particle, demonstrating that Pin1 binds both to the outside and the inside of the core particle. Although the amino-terminal domain S/TP motifs of HBc are not involved in the interaction, 49SP contributes to core particle stability, and 128TP might be involved in core particle assembly, as shown by the decreased core particle level of S49A mutant through repeated freeze and thaw and low-level assembly of the T128A mutant, respectively. Overexpression of Pin1 increased core particle stability through their interactions, HBV DNA synthesis, and virion secretion without concomitant increases in HBV RNA levels, indicating that Pin1 may be involved in core particle assembly and maturation, thereby promoting the later stages of the HBV life cycle. By contrast, parvulin inhibitors and PIN1 knockdown reduced HBV replication. Since more Pin1 proteins bound to immature core particles than to mature core particles, the interaction appears to depend on the stage of virus replication. Taken together, the data suggest that physical association between Pin1 and phosphorylated core particles may induce structural alterations through isomerization by Pin1, induce dephosphorylation by unidentified host phosphatases, and promote completion of virus life cycle.
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Affiliation(s)
- Hyeonjoong Kwon
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Jumi Kim
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Chanho Song
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Muhammad Azhar Sajjad
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Jiseon Ha
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Jaesung Jung
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Sun Park
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Ho-Joon Shin
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Kyongmin Kim
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
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29
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Liu S, Sun Q, Ren X. Novel strategies for cancer immunotherapy: counter-immunoediting therapy. J Hematol Oncol 2023; 16:38. [PMID: 37055849 PMCID: PMC10099030 DOI: 10.1186/s13045-023-01430-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/21/2023] [Indexed: 04/15/2023] Open
Abstract
The advent of immunotherapy has made an indelible mark on the field of cancer therapy, especially the application of immune checkpoint inhibitors in clinical practice. Although immunotherapy has proven its efficacy and safety in some tumors, many patients still have innate or acquired resistance to immunotherapy. The emergence of this phenomenon is closely related to the highly heterogeneous immune microenvironment formed by tumor cells after undergoing cancer immunoediting. The process of cancer immunoediting refers to the cooperative interaction between tumor cells and the immune system that involves three phases: elimination, equilibrium, and escape. During these phases, conflicting interactions between the immune system and tumor cells result in the formation of a complex immune microenvironment, which contributes to the acquisition of different levels of immunotherapy resistance in tumor cells. In this review, we summarize the characteristics of different phases of cancer immunoediting and the corresponding therapeutic tools, and we propose normalized therapeutic strategies based on immunophenotyping. The process of cancer immunoediting is retrograded through targeted interventions in different phases of cancer immunoediting, making immunotherapy in the context of precision therapy the most promising therapy to cure cancer.
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Affiliation(s)
- Shaochuan Liu
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, 300060, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China
- Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China
| | - Qian Sun
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China.
- Key Laboratory of Cancer Immunology and Biotherapy, 300060, Tianjin, China.
- Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, China.
- Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China.
- Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
| | - Xiubao Ren
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China.
- Key Laboratory of Cancer Immunology and Biotherapy, 300060, Tianjin, China.
- Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, China.
- Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China.
- Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
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Abstract
Significance: Liver disease is one of the biggest threats to public health, affecting as much as 5.5 million people worldwide. Mitochondrial dysfunction is associated with various acute and chronic liver diseases. Mitophagy, a selective form of autophagy for damaged/excessive mitochondria, plays a key role either in the pathogenesis or in maintaining hepatic homeostasis in response to various liver diseases. Recent Advances: Significant progress has been achieved to ascertain the causes of liver disease. The conserved pathways for mitochondrial degradation via mitophagy, the deregulation of mitophagy in liver diseases, and pharmacological or genetic maneuvers that alter the mitophagic flux for liver disease treatment have been widely studied but yet to be comprehensively reviewed. Critical Issues: Liver disease is considered a leading cause of mortality globally, causing the heavy burden of disability and the increased health care utilization that needs to be settled urgently. Mitophagy plays an important role in protecting liver from tissue damage to maintain hepatic homeostasis or in pathogenesis of liver disease. Elaborating mitophagy implicated in the pathogenesis of liver disease, as well as potential therapeutic regimens by targeting mitophagy is of great significance for the understanding and treatment of liver disease. Future Directions: This review comprehensively describes the distinct mitophagy signaling pathways and their interplay with various liver diseases. Given that mitophagy affects a wide array of physiological processes, a deeper understanding of how to modulate mitophagy could provide innovative avenues for precise therapy. Future studies based on pharmacologically or genetically targeting mitophagy-relevant factors will uncover the links between intact mitophagic responses and hepatic homeostasis in physiological and pathological settings. This will allow us to overcome obstacles of applying mitophagy as the therapeutic target in the clinic. Antioxid. Redox Signal. 38, 529-549.
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Affiliation(s)
- Chunling Wang
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Yijin Wang
- School of Medicine, Southern University of Science and Technology, Shenzhen, China
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31
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Xie C, Wang S, Zhang H, Zhu Y, Jiang P, Shi S, Si Y, Chen J. Lnc-AIFM2-1 promotes HBV immune escape by acting as a ceRNA for miR-330-3p to regulate CD244 expression. Front Immunol 2023; 14:1121795. [PMID: 36845111 PMCID: PMC9946971 DOI: 10.3389/fimmu.2023.1121795] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 01/13/2023] [Indexed: 02/11/2023] Open
Abstract
Chronic hepatitis B (CHB) virus infection is a major risk factor for cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) immune escape is regulated by the exhaustion of virus-specific CD8+ T cells, which is associated with abnormal expression of negative regulatory molecule CD244. However, the underlying mechanisms are unclear. To investigate the important roles of non-coding RNAs play in CD244 regulating HBV immune escape, we performed microarray analysis to determine the differential expression profiles of long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in patients with CHB and patients with spontaneous clearance of HBV. Competing endogenous RNA (ceRNA) was analyzed by bioinformatics methods and confirmed by the dual-luciferase reporter assay. Furthermore, gene silencing and overexpression experiments were used to further identify the roles of lncRNA and miRNA in HBV immune escape through CD244 regulation. The results showed that the expression of CD244 on the surface of CD8+ T cells was significantly increased in CHB patients and in the co-culture system of T cells and HBV-infected HepAD38 cells, which was accompanied by the reduction of miR-330-3p and the elevation of lnc-AIFM2-1. The down-regulated miR-330-3p induced the apoptosis of T cells by lifting the inhibition of CD244, which was reversed by miR-330-3p mimic or CD244-siRNA. Lnc-AIFM2-1 promotes the accumulation of CD244, which is mediated by decreased miR-330-3p, and then reduced the clearance ability of CD8+ T cells to HBV through regulated CD244 expression. And the injury in the ability of CD8+ T cells to clear HBV can be reversed by lnc-AIFM2-1-siRNA, miR-330-3p mimic, or CD244-siRNA. Collectively, our findings indicate that lnc-AIFM2-1 on CD244 by acting as a ceRNA of miR-330-3p contributes to HBV immune escape, which may provide novel insights into the roles of interaction networks among lncRNA, miRNA, and mRNA in HBV immune escape, highlighting potential applications of lnc-AIFM2-1 and CD244 for diagnosis and treatment in CHB.
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Affiliation(s)
| | | | | | | | | | | | | | - Jie Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
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32
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PPIases Par14/Par17 Affect HBV Replication in Multiple Ways. Viruses 2023; 15:v15020457. [PMID: 36851672 PMCID: PMC9962505 DOI: 10.3390/v15020457] [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: 11/20/2022] [Revised: 01/14/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
Human parvulin 14 (Par14) and parvulin 17 (Par17) are peptidyl-prolyl cis/trans isomerases that upregulate hepatitis B virus (HBV) replication by binding to the conserved 133Arg-Pro134 (RP) motif of HBc and core particles, and 19RP20-28RP29 motifs of HBx. In the absence of HBx, Par14/Par17 have no effect on HBV replication. Interaction with Par14/Par17 enhances the stability of HBx, core particles, and HBc. Par14/Par17 binds outside and inside core particles and is involved in HBc dimer-dimer interaction to facilitate core particle assembly. Although HBc RP motif is important for HBV replication, R133 residue is solely important for its interaction with Par14/Par17. Interaction of Par14 and Par17 with HBx involves two substrate-binding residues, Glu46/Asp74 (E46/D74) and E71/D99, respectively, and promotes HBx translocation to the nucleus and mitochondria. In the presence of HBx, Par14/Par17 are efficiently recruited to cccDNA and promote transcriptional activation via specific DNA-binding residues Ser19/44 (S19/44). S19 and E46/D74 of Par14, and S44 and E71/D99 of Par17, are also involved in the recruitment of HBc onto cccDNA. Par14/Par17 upregulate HBV replication via various effects that are mediated in part through the HBx-Par14/Par17-cccDNA complex and triple HBc, Par14/Par17, and cccDNA interactions in the nucleus, as well as via core particle-Par14/Par17 interactions in the cytoplasm.
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33
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Modulation of mitochondria by viral proteins. Life Sci 2023; 313:121271. [PMID: 36526048 DOI: 10.1016/j.lfs.2022.121271] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/24/2022] [Accepted: 12/03/2022] [Indexed: 12/15/2022]
Abstract
Mitochondria are dynamic cellular organelles with diverse functions including energy production, calcium homeostasis, apoptosis, host innate immune signaling, and disease progression. Several viral proteins specifically target mitochondria to subvert host defense as mitochondria stand out as the most suitable target for the invading viruses. They have acquired the capability to control apoptosis, metabolic state, and evade immune responses in host cells, by targeting mitochondria. In this way, the viruses successfully allow the spread of viral progeny and thus the infection. Viruses employ their proteins to alter mitochondrial dynamics and their specific functions by a modulation of membrane potential, reactive oxygen species, calcium homeostasis, and mitochondrial bioenergetics to help them achieve a state of persistent infection. A better understanding of such viral proteins and their impact on mitochondrial forms and functions is the main focus of this review. We also attempt to emphasize the importance of exploring the role of mitochondria in the context of SARS-CoV2 pathogenesis and identify host-virus protein interactions.
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Zou G, Park JI. Wnt signaling in liver regeneration, disease, and cancer. Clin Mol Hepatol 2023; 29:33-50. [PMID: 35785913 PMCID: PMC9845677 DOI: 10.3350/cmh.2022.0058] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 06/30/2022] [Indexed: 02/02/2023] Open
Abstract
The liver exhibits the highest recovery rate from acute injuries. However, in chronic liver disease, the long-term loss of hepatocytes often leads to adverse consequences such as fibrosis, cirrhosis, and liver cancer. The Wnt signaling plays a pivotal role in both liver regeneration and tumorigenesis. Therefore, manipulating the Wnt signaling has become an attractive approach to treating liver disease, including cancer. Nonetheless, given the crucial roles of Wnt signaling in physiological processes, blocking Wnt signaling can also cause several adverse effects. Recent studies have identified cancer-specific regulators of Wnt signaling, which would overcome the limitation of Wnt signaling target approaches. In this review, we discussed the role of Wnt signaling in liver regeneration, precancerous lesion, and liver cancer. Furthermore, we summarized the basic and clinical approaches of Wnt signaling blockade and proposed the therapeutic prospects of cancer-specific Wnt signaling blockade for liver cancer treatment.
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Affiliation(s)
- Gengyi Zou
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Corresponding author : Gengyi Zou Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd Unit 1054, Houston, TX 77030, USA Tel: +1-713-792-3659, Fax: +1-713-794-5369, E-mail:
| | - Jae-Il Park
- Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences, Houston, TX, USA,Jae-Il Park Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Blvd. Unit 1052, Houston, TX 77030, USA Tel: +1-713-792-3659, Fax: +1-713-794-5369, E-mail:
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Hepatitis B Virus-Encoded HBsAg Contributes to Hepatocarcinogenesis by Inducing the Oncogenic Long Noncoding RNA LINC00665 through the NF-κB Pathway. Microbiol Spectr 2022; 10:e0273121. [PMID: 35993712 PMCID: PMC9603668 DOI: 10.1128/spectrum.02731-21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Clinical and in vivo studies have demonstrated a role for hepatitis B virus (HBV)-encoded HBsAg (hepatitis B surface antigen) in HBV-related hepatocellular carcinoma (HCC); however, the underlying mechanisms remain largely unknown. Here, we investigated the role of HBsAg in regulating long noncoding RNAs (lncRNAs) involved in HCC progression. Our analysis of microarray data sets identified LINC00665 as an HBsAg-regulated lncRNA. Furthermore, LINC00665 is upregulated in liver samples from HBV-infected patients as well as in HCC, specifically in HBV-related HCC liver samples. These findings were supported by our in vitro data demonstrating that HBsAg, as well as HBV, positively regulates LINC00665 in multiple HBV cell culture models. Next, we evaluated the oncogenic potential of LINC00665 by its overexpression and CRISPR interference (CRISPRi)-based knockdown in various cell-based assays. LINC00665 promoted cell proliferation, migration, and colony formation but inhibited cell apoptosis in vitro. We then identified the underlying mechanism of HBsAg-mediated regulation of LINC00665. We used immunofluorescence assays to show that HBsAg enhanced the nuclear translocation of NF-κB factors in HepG2 cells, confirming that HBsAg activates NF-κB. Inhibition of NF-κB signaling nullified HBsAg-mediated LINC00665 upregulation, suggesting that HBsAg acts through NF-κB to regulate LINC00665. Furthermore, the LINC00665 promoter contains NF-κB binding sites, and their disruption abrogated HBsAg-induced LINC00665 upregulation. Finally, HBsAg facilitated the enrichment of the NF-κB factors NF-κB1, RelA, and c-Rel in the LINC00665 promoter. Taken together, this work shows that HBsAg can drive hepatocarcinogenesis by upregulating oncogenic LINC000665 through the NF-κB pathway, thereby identifying a novel mechanism in HBV-related HCC. IMPORTANCE Hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma (HCC). Numerous reports indicate an oncogenic role for HBV-encoded HBsAg; however, the underlying mechanisms are not well understood. Here, we studied the role of HBsAg in regulating lncRNAs involved in hepatocarcinogenesis. We demonstrate that HBsAg, as well as HBV, positively regulates oncogenic lncRNA LINC00665. The clinical significance of this lncRNA is highlighted by our observation that LINC00665 is upregulated in liver samples during HBV infection and HBV-related HCC. Furthermore, we show LINC00665 can drive hepatocarcinogenesis by promoting cell proliferation, colony formation, and cell migration and inhibiting apoptosis. Taken together, this work identified LINC00665 as a novel gene through which HBsAg can drive hepatocarcinogenesis. Finally, we show that HBsAg enhances LINC00665 levels in hepatocytes by activating the NF-κB pathway, thereby identifying a novel mechanism by which HBV may contribute to HCC.
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36
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Imamura T, Okamura Y, Ohshima K, Uesaka K, Sugiura T, Ito T, Yamamoto Y, Ashida R, Ohgi K, Otsuka S, Ohnami S, Nagashima T, Hatakeyama K, Sugino T, Urakami K, Akiyama Y, Yamaguchi K. Overview and clinical significance of multiple mutations in individual genes in hepatocellular carcinoma. BMC Cancer 2022; 22:1046. [PMID: 36199046 PMCID: PMC9535898 DOI: 10.1186/s12885-022-10143-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 09/28/2022] [Indexed: 12/24/2022] Open
Abstract
Background Multiple mutation (MM) within a single gene has recently been reported as a mechanism involved in carcinogenesis. The present study investigated the clinical significance of MMs in hepatocellular carcinoma (HCC). Methods Two hundred twenty-three surgically resected HCCs were subjected to gene expression profiling and whole-exome sequencing. Results MMs in individual genes were detected in 178 samples (MM tumors: 79.8%). The remaining samples all carried a single mutation (SM tumors: 20.2%). Recurrence-free survival in the MM group was significantly worse in comparison to the SM group (P = 0.012). A Cox proportional hazard analysis revealed that MM tumor was an independent predictor for worse a prognosis (hazard ratio, 1.72; 95% confidence interval, 1.01–3.17; P = 0.045). MMs were frequently observed across in various genes, especially MUC16 (15% of samples had at least one mutation in the gene) and CTNNB1 (14%). Although the MUC16 mRNA expression of MUC16 wild-type and MUC16 SM tumors did not differ to a statistically significant extent, the expression in MUC16 MM tumors was significantly enhanced in comparison to MUC16 SM tumors (P < 0.001). In MUC16, MMs were associated with viral hepatitis, higher tumor marker levels and vascular invasion. The MUC16 MMs group showed significantly worse recurrence-free survival in comparison to the MUC16 SM group (P = 0.022), while no significant difference was observed between the MUC16 SM group and the MUC16 wild-type group (P = 0.324). Conclusions MM was a relatively common event that may occur selectively in specific oncogenes and is involved in aggressive malignant behavior. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-10143-z.
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Affiliation(s)
- Taisuke Imamura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Sunto-Nagaizumi, Shizuoka, 4118777, Japan
| | - Yukiyasu Okamura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Sunto-Nagaizumi, Shizuoka, 4118777, Japan. .,Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan.
| | - Keiichi Ohshima
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Katsuhiko Uesaka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Sunto-Nagaizumi, Shizuoka, 4118777, Japan
| | - Teiichi Sugiura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Sunto-Nagaizumi, Shizuoka, 4118777, Japan
| | - Takaaki Ito
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Sunto-Nagaizumi, Shizuoka, 4118777, Japan
| | - Yusuke Yamamoto
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Sunto-Nagaizumi, Shizuoka, 4118777, Japan
| | - Ryo Ashida
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Sunto-Nagaizumi, Shizuoka, 4118777, Japan
| | - Katsuhisa Ohgi
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Sunto-Nagaizumi, Shizuoka, 4118777, Japan
| | - Shimpei Otsuka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 1007 Shimonagakubo, Sunto-Nagaizumi, Shizuoka, 4118777, Japan
| | - Sumiko Ohnami
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Takeshi Nagashima
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.,SRL, Inc., Tokyo, Japan
| | - Keiichi Hatakeyama
- Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Takashi Sugino
- Division of Pathology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Kenichi Urakami
- Cancer Diagnostics Research Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Yasuto Akiyama
- Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan
| | - Ken Yamaguchi
- Shizuoka Cancer Center Hospital and Research Institute, Shizuoka, Japan
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Cao X, Chen H, Li Z, Li X, Yang X, Jin Q, Liang Y, Zhang J, Zhou M, Zhang N, Chen G, Du H, Zao X, Ye Y. Network pharmacology and in vitro experiments-based strategy to investigate the mechanisms of KangXianYiAi formula for hepatitis B virus-related hepatocellular carcinoma. Front Pharmacol 2022; 13:985084. [PMID: 36133813 PMCID: PMC9483169 DOI: 10.3389/fphar.2022.985084] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
The Chinese traditional medicine KangXianYiAi formula (KXYA) is used to treat hepatic disease in the clinic. Here we aim to confirm the therapeutic effects and explore the pharmacological mechanisms of KXYA on hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We first collected and analyzed clinical data of 40 chronic hepatitis B (CHB) patients with precancerous liver lesions under KXYA treatment. Then, the cell viability, migration, cell cycle, and apoptosis of HepAD38 cells with KXYA treatment were examined. Next, we performed network pharmacological analysis based on database mining to obtain the key target pathways and genes of KXYA treatment on HBV-related HCC. We finally analyzed the expression of the key genes between normal and HBV-related HCC tissues in databases and measured the mRNA expression of the key genes in HepAD38 cells after KXYA treatment. The KXYA treatment could reduce the liver nodule size of CHB patients, suppress the proliferation and migration capabilities, and promote apoptosis of HepAD38 cells. The key pathways of KXYA on HBV-related HCC were Cancer, Hepatitis B, Viral carcinogenesis, Focal adhesion, and PI3K-Akt signaling, and KXYA treatment could regulate the expression of the key genes including HNF4A, MAPK8, NR3C1, PTEN, EGFR, and HDAC1. The KXYA exhibited a curative effect via inhibiting proliferation, migration, and promoting apoptosis of HBV-related HCC and the pharmacological mechanism was related to the regulation of the expression of HNF4A, MAPK8, NR3C1, PTEN, EGFR, and HDAC1.
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Affiliation(s)
- Xu Cao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hening Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Zhiguo Li
- Beijing Fengtai Hospital of Integrated Traditional and Western Medicine, Beijing, China
| | - Xiaoke Li
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Xianzhao Yang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Qiushuo Jin
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yijun Liang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jiaxin Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Meiyue Zhou
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Ningyi Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Guang Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Guang Chen, ; Hongbo Du, ; Xiaobin Zao, ; Yong’an Ye,
| | - Hongbo Du
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Guang Chen, ; Hongbo Du, ; Xiaobin Zao, ; Yong’an Ye,
| | - Xiaobin Zao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Guang Chen, ; Hongbo Du, ; Xiaobin Zao, ; Yong’an Ye,
| | - Yong’an Ye
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Guang Chen, ; Hongbo Du, ; Xiaobin Zao, ; Yong’an Ye,
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Chung KM, Chen YT, Hong CC, Chang IC, Lin SY, Liang LY, Chen YR, Yeh CT, Huang SF. CA10 is associated with HBV-related hepatocarcinogenesis. Biochem Biophys Rep 2022; 31:101303. [PMID: 35800619 PMCID: PMC9254355 DOI: 10.1016/j.bbrep.2022.101303] [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: 04/25/2022] [Revised: 06/22/2022] [Accepted: 06/24/2022] [Indexed: 11/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the main threat for the patients infected with hepatitis B virus (HBV), but the oncogenic mechanism of HBV-related HCC is still controversial. Previously, we have found that several HBV surface gene (HBS) non-sense mutations are oncogenic. Among these mutations, sW182* was found to have the most potent oncogenicity. In this study, we found that Carbonic Anhydrase X (CA10) level was specifically increased in sW182* mutant-expressing cells. CA10 overexpression was also associated with HBS nonsense mutation in HBV-related HCC tumor tissues. Transformation and tumorigenesis assays revealed that CA10 had significant oncogenic activity. In addition, CA10 overexpression resulted in dysregulation of apoptosis-related proteins, including Mcl-1, Bcl-2, Bcl-xL and Bad. While searching for the regulatory mechanism of CA10, miR-27b was found to downregulate CA10 expression by regulating its mRNA degradation and its expression was decreased in sW182* mutant cells. Moreover, CA10 overexpression was associated with down-regulation of miR-27b in human HBV-related HCC tumor tissues with sW182* mutation. Therefore, induction of the expression of CA10 through repression of miR-27b by sW182* might be one mechanism involved in HBS mutation-related hepatocarcinogenesis.
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Affiliation(s)
- Kuei-Min Chung
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan
- Liver Research Unit, Linko Chang Gung Memorial Hospital, Chang-Gung University, Taoyuan, Taiwan
| | - Ya-Ting Chen
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan
| | - Chih-Chen Hong
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan
- Liver Research Unit, Linko Chang Gung Memorial Hospital, Chang-Gung University, Taoyuan, Taiwan
| | - Il-Chi Chang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan
| | - Si-Ying Lin
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan
| | - Li-Yu Liang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan
| | - Yi-Rong Chen
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan
| | - Chau-Ting Yeh
- Liver Research Unit, Linko Chang Gung Memorial Hospital, Chang-Gung University, Taoyuan, Taiwan
| | - Shiu-Feng Huang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan
- Department of Anatomic Pathology, Linko Chang Gung Memorial Hospital, Chang-Gung University, Taoyuan, Taiwan
- Department of Anatomical Pathology, Chung-Shan Medical University Hospital, Taichung, Taiwan
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Kortei NK, Annan T, Boakye AA, Essuman EK, Tettey CO, Kyei-Baffour V. Aflatoxin M 1 exposure in a fermented millet-based milk beverage 'brukina' and its cancer risk characterization in Greater Accra, Ghana. Sci Rep 2022; 12:12562. [PMID: 35869134 PMCID: PMC9307601 DOI: 10.1038/s41598-022-15157-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 06/20/2022] [Indexed: 12/02/2022] Open
Abstract
Brukina is a millet based fermented milk product which is consumed as a beverage in Ghana. It is however prone to aflatoxin M1 (AFM1) contamination, which is a serious health challenge for low and middle-income countries in subtropical regions. This study aimed at evaluating AFM1 levels and cancer risks associated with brukina (n = 150) sampled from different locations of the Greater Accra Region of Ghana. AFM1 were measured with High-Performance Liquid Chromatography (HPLC) connected to a Fluorescence Detector (FLD).Cancer risk assessments were also conducted using models prescribed by the Joint FAO/WHO Expert Committee on Additives (JECFA). Out of the 150 samples analyzed for AFM1, 80/150 (53%) tested positive between the range 0.00 ± 0.001-3.14 ± 0.77 µg/kg. Cancer risk assessments of AFM1 produced outcomes which ranged between 0.64 and 1.88 ng/kg bw/day, 0.31-9.40, 0.0323, and 1.94 × 10-3-0.06 for cases/100,000 person/yr for Estimated Daily Intake (EDI), Hazard Index (H.I), Average Potency, and Cancer Risks respectively for all age categories investigated. It was concluded that the consumption of brukina posed adverse health effects on the majority of the age categories in the different locations of Greater Accra Region since the calculated H.Is were greater than one (> 1). Therefore, contamination of brukina with AFM1 should be considered a high priority in public health and Ghana's cancer risk management actions.
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Affiliation(s)
- Nii Korley Kortei
- Department of Nutrition and Dietetics, School of Allied Health Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana.
| | - Theophilus Annan
- Food Microbiology Division, Council for Scientific and Industrial Research- Food Research Institute, P. O. Box M20, Accra, Ghana
| | - Adjoa Agyemang Boakye
- Department of Biomedical Sciences, School of Basic and Biomedical Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Edward Ken Essuman
- Department of Nutrition and Dietetics, School of Allied Health Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Clement Okraku Tettey
- Department of Biomedical Sciences, School of Basic and Biomedical Sciences, University of Health and Allied Sciences, PMB 31, Ho, Ghana
| | - Vincent Kyei-Baffour
- Food Chemistry and Nutrition Research Division, Council for Scientific and Industrial Research-Food Research Institute, P. O. Box M20, Accra, Ghana
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Che L, Du ZB, Wang WH, Wu JS, Han T, Chen YY, Han PY, Lei Z, Chen XX, He Y, Xu L, Lin X, Lin ZN, Lin YC. Intracellular antibody targeting HBx suppresses invasion and metastasis in hepatitis B virus-related hepatocarcinogenesis via protein phosphatase 2A-B56γ-mediated dephosphorylation of protein kinase B. Cell Prolif 2022; 55:e13304. [PMID: 35811356 PMCID: PMC9628248 DOI: 10.1111/cpr.13304] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 06/15/2022] [Accepted: 06/22/2022] [Indexed: 12/24/2022] Open
Abstract
Objectives Hepatitis B virus X (HBx) is closely associated with HBV‐related hepatocarcinogenesis via the inactivation of tumour suppressors. Protein phosphatase 2A (PP2A) regulatory subunit B56 gamma (B56γ), as a tumour suppressor, plays a critical role in regulating cellular phosphorylation signals via dephosphorylation of signalling proteins. However, the underlying mechanism that B56γ involved in regulating HBx‐associated hepatocarcinogenesis phenotypes and mediating anti‐HBx antibody‐mediated tumour suppression remains unknown. Materials and Methods We used bioinformatics analysis, paired HCC patient specimens, HBx transgenic (HBx‐Tg) mice, xenograft nude mice, HBV stable replication in the HepG2.2.15 cells, and anti‐HBx antibody intervention to systematically evaluate the biological function of protein kinase B (AKT) dephosphorylation through B56γ in HBx‐associated hepatocarcinogenesis. Results Bioinformatics analysis revealed that AKT, matrix metalloproteinase 2 (MMP2), and MMP9 were markedly upregulated, while cell migration and viral carcinogenesis pathways were activated in HBV‐infected liver tissues and HBV‐associated HCC tissues. Our results demonstrated that HBx‐expression promotes AKT phosphorylation (p‐AKTThr308/Ser473), mediating the migration and invasion phenotypes in vivo and in vitro. Importantly, in clinical samples, HBx and B56γ were downregulated in HBV‐associated HCC tumour tissues compared with peritumor tissues. Moreover, intervention with site‐directed mutagenesis (AKTT308A, AKTS473A) of p‐AKTThr308/Ser473 mimics dephosphorylation, genetics‐based B56γ overexpression, and intracellular anti‐HBx antibody inhibited cell growth, migration, and invasion in HBx‐expressing HCC cells. Conclusions Our results demonstrated that B56γ inhibited HBV/HBx‐dependent hepatocarcinogenesis by regulating the dephosphorylation of p‐AKTThr308/Ser473 in HCC cells. The intracellular anti‐HBx antibody and the activator of B56γ may provide a multipattern chemopreventive strategy against HBV‐related HCC.
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Affiliation(s)
- Lin Che
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Ze-Bang Du
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Wei-Hua Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Jia-Shen Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Tun Han
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Yuan-Yuan Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.,China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Pei-Yu Han
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China.,Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Zhao Lei
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Xiao-Xuan Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Yun He
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Ling Xu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Xu Lin
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Zhong-Ning Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Yu-Chun Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
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Yoon H, Jang KL. Hepatitis B virus X protein and hepatitis C virus core protein cooperate to repress E-cadherin expression via DNA methylation. Heliyon 2022; 8:e09881. [PMID: 35832344 PMCID: PMC9272347 DOI: 10.1016/j.heliyon.2022.e09881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 10/12/2021] [Accepted: 06/30/2022] [Indexed: 11/27/2022] Open
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Lee CK, Chan SL, Chon HJ. Could We Predict the Response of Immune Checkpoint Inhibitor Treatment in Hepatocellular Carcinoma? Cancers (Basel) 2022; 14:3213. [PMID: 35804984 PMCID: PMC9264773 DOI: 10.3390/cancers14133213] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/27/2022] [Accepted: 06/27/2022] [Indexed: 12/12/2022] Open
Abstract
The use of anti-programmed cell-death protein (ligand)-1 (PD-[L]1) is an important strategy for treating hepatocellular carcinoma (HCC). However, the treatment only benefits 10-20% of patients when used as a monotherapy. Therefore, the selection of patients for anti-PD-1/PD-L1 treatment is crucial for both patients and clinicians. This review aimed to explore the existing literature on tissue or circulating markers for the identification of responders or non-responders to anti-PD-1/PD-L1 in HCC. For the clinically available markers, both etiological factors (viral versus non-viral) and disease extent (intra-hepatic vs. extrahepatic) impact the responses to anti-PD-1/PD-L1, warranting further studies. Preliminary data suggested that inflammatory indices (e.g., neutrophil-lymphocyte ratio) may be associated with clinical outcomes of HCC during the anti-PD-1/PD-L1 treatment. Finally, although PD-L1 expression in tumor tissues is a predictive marker for multiple cancer types, its clinical application is less clear in HCC due to the lack of a clear-cut association with responders to anti-PD-1/PD-L1 treatment. Although all translational markers are not routinely measured in HCC, recent data suggest their potential roles in selecting patients for anti-PD-1/PD-L1 treatment. Such markers, including the immune classification of HCC, selected signaling pathways, tumor-infiltrating lymphocytes, and auto-antibodies, were discussed in this review.
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Affiliation(s)
- Choong-kun Lee
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea;
| | - Stephen L. Chan
- State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Sir YK Pao Centre for Cancer, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
| | - Hong Jae Chon
- Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13496, Korea
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Dietary Exposure to Aflatoxins in Some Randomly Selected Foods and Cancer Risk Estimations of Cereals Consumed on a Ghanaian Market. J FOOD QUALITY 2022. [DOI: 10.1155/2022/5770836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Aflatoxins have gained so much reputation among all mycotoxins due to their notoriety in causing countless adverse health effects on humans as well as animals. It continues to be a major concern in food safety globally. In this study, total and constitutive aflatoxins levels as well as the carcinogenic risks posed by 110 food and feed samples (55 cereals, 20 nuts and oils, 18 animal feed, and 18 fruits and vegetables) collected from the Ho Central market in the Volta region, Ghana, were assessed. Using high-performance liquid chromatography connected to a fluorescent detector (HPLC-FLD), levels of total aflatoxins (AFtotal) and aflatoxins constituents, namely, AFB1, AFB2, AFG1, and AFG2, were analyzed. By using the model prescribed by Joint FAO/WHO Expert Committee on Food Additives (JECFA), the risks posed by the food and feed samples were determined. The degrees of toxicity were in the ranges of 0.78–234.73 μg/kg, 0.47–21.6 μg/kg, 1.01–13.75 μg/kg, and 0.66–5.51 μg/kg, respectively, for AFB1, AFB2, AFG1, and AFG2. Out of the samples analyzed for AFtotal, about 51 (46.4%) exceeded the limits of GSA and were in the range 10.63 ± 1.20–236.28 ± 4.2 μg/kg. While for EFSA, 71 (64.54%) exceeded and ranged between 4.72 ± 0.28 and 236.28 ± 4.2 μg/kg. Furthermore, estimated daily intake (EDI) of 27.10–283.70 ng/kg·bw/day, margin of exposure (MOE) of 1.409–14.76, average potency of 0–0.00396 ng aflatoxins/kg·bw/day, and cancer risks with a range of 0.107–1.122 cases/100,000 person/yr were observed. Taken together, it could be concluded that consuming cereals pose adverse effects on human health regardless of the age of the consumer.
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DNA Repair Factor Poly(ADP-Ribose) Polymerase 1 Is a Proviral Factor in Hepatitis B Virus Covalently Closed Circular DNA Formation. J Virol 2022; 96:e0058522. [DOI: 10.1128/jvi.00585-22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
The biogenesis and eradication of HBV cccDNA have been a research priority in recent years. In this study, we identified the DNA repair factor PARP1 as a host factor required for the HBV
de novo
cccDNA formation.
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Aflatoxin M1 Contamination of Ghanaian Traditional Soft Cottage Cheese (Wagashie) and Health Risks Associated with Its Consumption. J FOOD QUALITY 2022. [DOI: 10.1155/2022/7595545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Wagashie is an unripened traditional cheese consumed in West Africa including Ghana. Being a milk product, it is unfortunately susceptible to aflatoxin M1 (AFM1) contamination, which is indeed a grave health challenge globally. This study evaluated AFM1 levels and health risk characterization associated with wagashie (n = 182) sampled from different locations in Ghana. AFM1 was measured with high-performance liquid chromatography with a fluorescence detector (HPLC-FLD). Risk assessments were also conducted using models prescribed by the Joint FAO/WHO Expert Committee on Food Additives (JECFA). Out of the 182 samples analyzed for AFM1, 93/182 (51.1%) tested positive between the range 0.00 ± 0.00–3.60 ± 0.99 µg/kg. Risk assessments of AFM1 using deterministic models produced outcomes that ranged between 0.11 and 3.60 ng/kg bw/day, 0.09–1.54, 0–0.0323 ng aflatoxins/kg bw/day, and 3.5 x 10−3 −0.06 cases/100,000 person/yr for estimated daily intake (EDI), margin of exposure (MOE), average potency, and cancer risks, respectively, for the age categories investigated. It was established that the consumption of wagashie posed adverse health effects on all age categories in the selected regions of the study because all calculated MOE values were less than 100,000. Therefore, contamination of wagashie with AFM1 should be a serious public health concern and as such considered a high precedence for Ghana’s risk management actions.
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Tsai MK, Sytwu HK, Hsieh TY, Chien WC, Lai CH, Chen HC. Association Between Depression or Anxiety and the Risk of Hepatitis B Flares: A Nationwide Population-Based Cohort Study. J Inflamm Res 2022; 15:2983-2993. [PMID: 35615105 PMCID: PMC9126231 DOI: 10.2147/jir.s355314] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 04/30/2022] [Indexed: 12/02/2022] Open
Abstract
Purpose Depression and anxiety have been reported to increase the risk of infectious diseases and reactivation of latent infection. We conducted a nationwide population-based retrospective cohort study to determine the relationship between hepatitis B flares and depression or anxiety, utilizing outpatient and inpatient data from the Taiwan National Health Insurance Research database collected from 2000 to 2015. Patients and Methods A total of 12,992 patients with chronic hepatitis B and newly diagnosed anxiety/depression, without advanced liver disease, were propensity score-matched for age, sex, and comorbidities in a 1:4 ratio to 51,968 controls with chronic hepatitis B without depression/anxiety or advanced liver disease. Both groups were followed-up until December 31, 2015. Cox proportional hazards regression was used to determine the risk factors for hepatitis B flares. The Log rank test and Kaplan-Meier analysis were performed to assess differences in the cumulative incidence of hepatitis B flares according to anxiety/depression status. Results The incidence of hepatitis B flares was higher in the depression/anxiety cohort than in the control cohort (log-rank; p < 0.001). Patients with depression/anxiety had a significantly higher incidence rate of hepatitis B flares than those without depression/anxiety (3017 per 105 person-years versus 2042 per 105 person-years, p = 0.003). After adjusting for age and comorbidities, anxiety/depression was independently associated with an increased risk of hepatitis B flares (hazard ratio, 1.173; 95% confidence interval, 1.033-1.277; p = 0.003). Conclusion This analysis suggests that in patients with chronic hepatitis B without advanced liver disease, those with concomitant depression or anxiety may be at higher risk of hepatitis B flares.
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Affiliation(s)
- Meng-Ko Tsai
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Taichung Armed Forces General Hospital, Taichung, Taiwan
- Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Institute of Medical Sciences, National Defense Medical Center, Taipei, 114, Taiwan
| | - Huey-Kang Sytwu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Taiwan
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan
| | - Tsai-Yuan Hsieh
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Wu-Chien Chien
- School of Public Health, National Defense Medical Center, Taipei, Taiwan
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chao-Hung Lai
- Division of Cardiology, Department of Internal Medicine, Taichung Armed Forces General Hospital, Taichung, Taiwan
| | - Hsiang-Cheng Chen
- Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
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Ren W, Wang X, Yang M, Wan H, Li X, Ye X, Meng B, Li W, Yu J, Lei M, Xie F, Jiang W, Kimby E, Huang H, Liu D, Li ZM, Wu K, Zhang H, Pan-Hammarström Q. Distinct clinical and genetic features of hepatitis B virus-associated follicular lymphoma in Chinese patients. Blood Adv 2022; 6:2731-2744. [PMID: 35030632 PMCID: PMC9092402 DOI: 10.1182/bloodadvances.2021006410] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 12/19/2021] [Indexed: 12/15/2022] Open
Abstract
Hepatitis B virus (HBV) infection has been associated with an increased risk for B-cell lymphomas. We previously showed that 20% of diffuse large B-cell lymphoma (DLBCL) patients from China, an endemic area of HBV infection, have chronic HBV infection (surface antigen-positive, HBsAg+) and are characterized by distinct clinical and genetic features. Here, we showed that 24% of follicular lymphoma (FL) Chinese patients are HBsAg+. Compared with the HBsAg- FL patients, HBsAg+ patients are younger, have a higher histological grade at diagnosis, and have a higher incidence of disease progression within 24 months. Moreover, by sequencing the genomes of 109 FL tumors, we observed enhanced mutagenesis and distinct genetic profile in HBsAg+ FLs, with a unique set of preferentially mutated genes (TNFAIP3, FAS, HIST1H1C, KLF2, TP53, PIM1, TMSB4X, DUSP2, TAGAP, LYN, and SETD2) but lack of the hallmark of HBsAg- FLs (ie, IGH/BCL2 translocations and CREBBP mutations). Transcriptomic analyses further showed that HBsAg+ FLs displayed gene-expression signatures resembling the activated B-cell-like subtype of diffuse large B-cell lymphoma, involving IRF4-targeted genes and NF-κB/MYD88 signaling pathways. Finally, we identified an increased infiltration of CD8+ memory T cells, CD4+ Th1 cells, and M1 macrophages and higher T-cell exhaustion gene signature in HBsAg+ FL samples. Taken together, we present new genetic/epigenetic evidence that links chronic HBV infection to B-cell lymphomagenesis, and HBV-associated FL is likely to have a distinct cell-of-origin and represent as a separate subtype of FL. Targetable genetic/epigenetic alterations identified in tumors and their associated tumor microenvironment may provide potential novel therapeutic approaches for this subgroup of patients.
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Affiliation(s)
- Weicheng Ren
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Xianhuo Wang
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Mingyu Yang
- BGI-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen, China
| | - Hui Wan
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Xiaobo Li
- BGI-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen, China
| | - Xiaofei Ye
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
| | - Bing Meng
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Wei Li
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Jingwei Yu
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Mengyue Lei
- BGI-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen, China
| | - Fanfan Xie
- BGI-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen, China
| | - Wenqi Jiang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Eva Kimby
- Unit of Hematology, Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden; and
| | - Huiqiang Huang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Dongbing Liu
- BGI-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen, China
| | - Zhi-Ming Li
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Kui Wu
- BGI-Shenzhen, Shenzhen, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, Shenzhen, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Huilai Zhang
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Qiang Pan-Hammarström
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
- Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
- BGI-Shenzhen, Shenzhen, China
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Sun Y, Teng Y, Wang L, Zhang Z, Chen C, Wang Y, Zhang X, Xiang P, Song X, Lu J, Li N, Gao L, Liang X, Xia Y, Wu Z, Ma C. LINC01431 Promotes Histone H4R3 Methylation to Impede HBV Covalently Closed Circular DNA Transcription by Stabilizing PRMT1. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2103135. [PMID: 35398991 PMCID: PMC9165498 DOI: 10.1002/advs.202103135] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 03/11/2022] [Indexed: 06/14/2023]
Abstract
Covalently closed circular DNA (cccDNA) is the transcriptional template of hepatitis B virus (HBV), which interacts with both host and viral proteins to form minichromosome in the nucleus and is resistant to antiviral agents. Identification of host factors involved in cccDNA transcriptional regulation is expected to prove a new venue for HBV therapy. Recent evidence suggests the involvement of long noncoding RNAs (lncRNAs) in mediating the interaction of host factors with various viruses, however, lncRNAs that HBV targets and represses cccDNA transcription have not been fully elucidated. Here, the authors identified LINC01431 as a novel host restriction factor for HBV transcription. Mechanically, LINC01431 competitively bound with type I protein arginine methyltransferase (PRMT1) to block the HBx-mediated PRMT1 ubiquitination and degradation. Consequently, LINC01431 increased the occupancy of PRMT1 on cccDNA, leading to enhanced H4R3me2a modification and reduced acetylation of cccDNA-bound histones, thereby repressing cccDNA transcription. In turn, to facilitate viral replication, HBV transcriptionally repressed LINC01431 expression by HBx-mediated repression of transcription factor Zinc fingers and homeoboxes 2 (ZHX2). Collectively, the study demonstrates LINC01431 as a novel epigenetic regulator of cccDNA minichromosome and highlights a feedback loop of HBx-LINC01431-PRMT1 in HBV replication, which provides potential therapeutic targets for HBV treatment.
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Affiliation(s)
- Yang Sun
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Yan Teng
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and ImmunologyInstitute of Medical VirologySchool of Basic Medical SciencesWuhan UniversityWuhanHubei430072China
| | - Liyuan Wang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Zhaoying Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - ChaoJia Chen
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Yingchun Wang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Xiaodong Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Peng Xiang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Xiaojia Song
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Jinghui Lu
- Department of Hepatobiliary SurgeryQilu Hospital of Shandong University, JinanShandong250012China
| | - Nailin Li
- Karolinska InstituteDepartment of Medicine‐SolnaClinical Pharmacology GroupStockholm17176Sweden
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Yuchen Xia
- State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and ImmunologyInstitute of Medical VirologySchool of Basic Medical SciencesWuhan UniversityWuhanHubei430072China
| | - Zhuanchang Wu
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
| | - Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of Education and Department of ImmunologySchool of Basic Medical SciencesCheeloo Medical CollegeShandong UniversityJinanShandong250012China
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Noverati N, Bashir-Hamidu R, Halegoua-DeMarzio D, Hann HW. Hepatitis B Virus-Associated Hepatocellular Carcinoma and Chronic Stress. Int J Mol Sci 2022; 23:3917. [PMID: 35409275 PMCID: PMC8999024 DOI: 10.3390/ijms23073917] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 01/27/2023] Open
Abstract
The Hepatitis B virus is one of the most significant hepatocarcinogens globally. The carcinogenic mechanisms of this virus are complex, and may include interactions with the host's immune system. Certain factors, such as stress on the body, can also potentiate these mechanisms. Stress, although adaptive in an acute form, is deleterious to health when chronic and can both suppress and activate the host's defense system. In hepatocellular carcinoma, this can lead to tumor initiation and progression. Those that are more prone to stress, or exposed to situations that incite stress, may be at higher risk of developing cancer. Racial disparities, for example, are a source of chronic psychosocial stress in America and predispose minorities to poorer outcomes. As it remains perplexing why some individuals with chronic hepatitis B develop feared complications while others do not, it is important to recognize as many risk factors as possible, including those often overlooked such as chronic stress.
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Affiliation(s)
- Nicholas Noverati
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.N.); (R.B.-H.); (D.H.-D.)
| | - Rukaiya Bashir-Hamidu
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.N.); (R.B.-H.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.N.); (R.B.-H.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
| | - Hie-Won Hann
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA; (N.N.); (R.B.-H.); (D.H.-D.)
- Division of Gastroenterology and Hepatology, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
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Spradling PR, Xing J, Zhong Y, Rupp LB, Moorman AC, Lu M, Teshale EH, Schmidt MA, Daida YG, Boscarino JA, Gordon SC. Incidence of malignancies among patients with chronic hepatitis B in US health care organizations, 2006-2018. J Infect Dis 2022; 226:896-900. [PMID: 35039863 DOI: 10.1093/infdis/jiac011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 01/13/2022] [Indexed: 12/09/2022] Open
Abstract
Hepatitis B virus (HBV) infection causes hepatocellular carcinoma but its association with other cancers is not well established. We compared age-adjusted incidence of primary cancers among 5,773 HBV-infected persons with US cancer registries during 2006-2018. Compared with the US population, substantially higher incidence among HBV-infected persons was observed for hepatocellular carcinoma (Standardized rate ratio [SRR] 30.79), gastric (SRR 7.95), neuroendocrine (SRR 5.88), cholangiocarcinoma (SRR 4.62), and ovarian (SRR 3.72) cancers, and non-Hodgkin lymphoma (SRR 2.52). Clinicians should be aware of a heightened potential for certain non-hepatic malignancies among hepatitis B patients, as earlier diagnosis favors improved survival.
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Affiliation(s)
- Philip R Spradling
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Jian Xing
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Y Zhong
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | | | - Anne C Moorman
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Mei Lu
- Henry Ford Health System, Detroit, MI, USA
| | - Eyasu H Teshale
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Mark A Schmidt
- The Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA
| | - Yihe G Daida
- The Center for Integrated Health Care Research, Kaiser Permanente Hawaii, Honolulu, HI, USA
| | - Joseph A Boscarino
- Department of Population Health Sciences, Geisinger Clinic, Danville, PA, USA
| | - Stuart C Gordon
- Henry Ford Health System, Detroit, MI, USA.,Wayne State University School of Medicine, Detroit, MI, USA
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