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Jin C, Hu B, Liu H, Wang R, Jang J, Su M. Cystathionine gamma-lyase as an inflammatory factor and its link with immune inflammation in hepatitis B virus-related liver disease. Sci Rep 2025; 15:17777. [PMID: 40404804 PMCID: PMC12098708 DOI: 10.1038/s41598-025-98922-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 04/15/2025] [Indexed: 05/24/2025] Open
Abstract
We aimed to explore the effectiveness of CTH as a serum inflammation biomarker for HCC. Enzyme-linked immunosorbent assay was used to detect serum levels of CTH, interleukin-6 (IL-6), C-reactive protein (CRP), and IL-10. The Scheuer scoring system was used to assess the liver inflammation grading (significant liver inflammation: ≥ G2 grade). CTH levels in the HCC group were significantly elevated (P < 0.0001). Of 146 patients, 58.22% exhibited significant liver inflammation. CTH levels in patients with significant liver inflammation were significantly higher than those in patients with no or mild liver inflammation (< G 2) (p < 0.0001). The area under the Receiver Operating Characteristic (ROC) curve for CTH in predicting significant hepatitis was 0.77 (sensitivity, 81.2%; specificity,62.3%). There was a significant positive correlation (r = 0.50, p < 0.05) between serum CTH levels and histopathological parameter G. The area under the ROC curve for CTH in predicting hepatocellular carcinoma was 0.83 (sensitivity, 64.6%; specificity, 83.3%). CTH and AFP improved the diagnostic accuracy of HCC. CTH levels significantly decreased 6 months post-operation (p < 0.05). The recurrence of HCC caused significant increases in CTH levels. Thus, CTH can serve as a serum inflammation marker for HCC.
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Affiliation(s)
- Chao Jin
- Infectious Diseases Department, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road, Nanning, 530021, China
| | - Bobin Hu
- Infectious Diseases Department, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road, Nanning, 530021, China
| | - Hongyu Liu
- Infectious Diseases Department, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road, Nanning, 530021, China
| | - Rongming Wang
- Infectious Diseases Department, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road, Nanning, 530021, China
| | - Jianning Jang
- Infectious Diseases Department, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road, Nanning, 530021, China
| | - Minghua Su
- Infectious Diseases Department, The First Affiliated Hospital of Guangxi Medical University, Shuangyong Road, Nanning, 530021, China.
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Li K, Mathew B, Saldanha E, Ghosh P, Krainer AR, Dasarathy S, Huang H, Xiang X, Mishra L. New insights into biomarkers and risk stratification to predict hepatocellular cancer. Mol Med 2025; 31:152. [PMID: 40269686 PMCID: PMC12020275 DOI: 10.1186/s10020-025-01194-6] [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: 12/09/2024] [Accepted: 04/01/2025] [Indexed: 04/25/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the third major cause of cancer death worldwide, with more than a doubling of incidence over the past two decades in the United States. Yet, the survival rate remains less than 20%, often due to late diagnosis at advanced stages. Current HCC screening approaches are serum alpha-fetoprotein (AFP) testing and ultrasound (US) of cirrhotic patients. However, these remain suboptimal, particularly in the setting of underlying obesity and metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH), which are also rising in incidence. Therefore, there is an urgent need for novel biomarkers that can stratify risk and predict early diagnosis of HCC, which is curable. Advances in liver cancer biology, multi-omics technologies, artificial intelligence, and precision algorithms have facilitated the development of promising candidates, with several emerging from completed phase 2 and 3 clinical trials. This review highlights the performance of these novel biomarkers and algorithms from a mechanistic perspective and provides new insight into how pathological processes can be detected through blood-based biomarkers. Through human studies compiled with animal models and mechanistic insight in pathways such as the TGF-β pathway, the biological progression from chronic liver disease to cirrhosis and HCC can be delineated. This integrated approach with new biomarkers merit further validation to refine HCC screening and improve early detection and risk stratification.
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Affiliation(s)
- Katrina Li
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, NY, 11030, USA
| | - Brandon Mathew
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, NY, 11030, USA
| | - Ethan Saldanha
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, NY, 11030, USA
| | - Puja Ghosh
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, NY, 11030, USA
| | - Adrian R Krainer
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11724, USA
| | - Srinivasan Dasarathy
- Division of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, 44106, USA
| | - Hai Huang
- Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Donald and Barbara Zucker School of Medicine at Hofstra, Northwell Health, Manhasset, NY, 11030, USA
| | - Xiyan Xiang
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, NY, 11030, USA.
| | - Lopa Mishra
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, NY, 11030, USA.
- Department of Surgery, George Washington University, Washington, DC, 20037, USA.
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Wei C, Wang P, Zhang J, Jiang X, Xie Y, Li Y, Zhang W, Du Y, Zheng X, Fang X, Liu S, Cao L, Yao R, Jin X, Zhu D, Wu H, Wang Y, Li Z, Hu F. Combination of scavenger receptor-A with anti-cyclic citrullinated peptide antibody for the diagnosis of rheumatoid arthritis. Rheumatology (Oxford) 2025; 64:1513-1522. [PMID: 38781519 DOI: 10.1093/rheumatology/keae297] [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: 10/21/2023] [Revised: 03/27/2024] [Accepted: 04/24/2024] [Indexed: 05/25/2024] Open
Abstract
OBJECTIVES The routine biomarkers for RA, including anti-CCP, RF, IgM, ESR and CRP, have limited sensitivity and specificity. Scavenger receptor-A (SR-A) is a novel RA biomarker identified recently by our group, especially for seronegative RA. Here, we performed a large-scale, multicentre study to further assess the diagnostic value of SR-A in combination with other biomarkers for RA. METHODS The performance of SR-A in combination with other biomarkers for RA diagnosis was first revealed by a pilot study, and was further elucidated by a large-scale, multicentre study. A total of 1129 individuals from three cohorts were recruited in the study, including RA patients, healthy controls and patients with other common rheumatic diseases. Diagnostic properties were evaluated by the covariate-adjusted receiver operating characteristic curve, sensitivity, specificity and clinical association. RESULTS Large-scale multicentre analysis showed that SR-A and anti-CCP dual combination was the optimal method for RA diagnosis, increasing the sensitivity of anti-CCP by 13% (87% vs 74%) while maintaining a specificity of 90%. In early RA patients, SR-A and anti-CCP dual combination also showed promising diagnostic value, increasing the sensitivity of anti-CCP by 7% (79% vs 72%) while maintaining a specificity of 94%. Moreover, SR-A and anti-CCP dual combination was correlated with ESR, IgM and autoantibodies of RA patients, further revealing its clinical significance. CONCLUSION SR-A and anti-CCP dual combination could potentially improve early diagnosis of RA, thus improving the prognosis and reducing mortality.
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Affiliation(s)
- Chaonan Wei
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Ping Wang
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Jian Zhang
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Xiang Jiang
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yang Xie
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Yingni Li
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Wei Zhang
- Department of Rheumatology and Immunology, First Hospital Affiliated to Baotou Medical College & Inner Mongolia Key Laboratory of Autoimmunity, Baotou, China
| | - Yan Du
- Department of Rheumatology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xi Zheng
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Xiangyu Fang
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Shuyan Liu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Lulu Cao
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Ranran Yao
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
| | - Xu Jin
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Danxue Zhu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Huaxiang Wu
- Department of Rheumatology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yongfu Wang
- Department of Rheumatology and Immunology, First Hospital Affiliated to Baotou Medical College & Inner Mongolia Key Laboratory of Autoimmunity, Baotou, China
| | - Zhanguo Li
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Fanlei Hu
- Department of Rheumatology and Immunology, Peking University People's Hospital & Beijing Key Laboratory for Rheumatism Mechanism and Immune Diagnosis (BZ0135), Beijing, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
- Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
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Wu ST, Zhu L, Feng XL, Wang HY, Li F. Strategies for discovering novel hepatocellular carcinoma biomarkers. World J Hepatol 2025; 17:101201. [PMID: 40027561 PMCID: PMC11866143 DOI: 10.4254/wjh.v17.i2.101201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/13/2024] [Accepted: 12/23/2024] [Indexed: 02/20/2025] Open
Abstract
Liver cancer, particularly hepatocellular carcinoma (HCC), remains a significant global health challenge due to its high mortality rate and late-stage diagnosis. The discovery of reliable biomarkers is crucial for improving early detection and patient outcomes. This review provides a comprehensive overview of current and emerging biomarkers for HCC, including alpha-fetoprotein, des-gamma-carboxy prothrombin, glypican-3, Golgi protein 73, osteopontin, and microRNAs. Despite advancements, the diagnostic limitations of existing biomarkers underscore the urgent need for novel markers that can detect HCC in its early stages. The review emphasizes the importance of integrating multi-omics approaches, combining genomics, proteomics, and metabolomics, to develop more robust biomarker panels. Such integrative methods have the potential to capture the complex molecular landscape of HCC, offering insights into disease mechanisms and identifying targets for personalized therapies. The significance of large-scale validation studies, collaboration between research institutions and clinical settings, and consideration of regulatory pathways for clinical implementation is also discussed. In conclusion, while substantial progress has been made in biomarker discovery, continued research and innovation are essential to address the remaining challenges. The successful translation of these discoveries into clinical practice will require rigorous validation, standardization of protocols, and cross-disciplinary collaboration. By advancing the development and application of novel biomarkers, we can improve the early detection and management of HCC, ultimately enhancing patient survival and quality of life.
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Affiliation(s)
- Shi-Tao Wu
- Department of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing 401147, China
| | - Li Zhu
- Department of General Surgery, Chongqing General Hospital, Chongqing 401147, China
| | - Xiao-Ling Feng
- Department of General Surgery, Chongqing General Hospital, Chongqing 401147, China
| | - Hao-Yu Wang
- Department of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing 401147, China
| | - Fang Li
- Department of General Surgery, Chongqing General Hospital, Chongqing 401147, China.
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Khoshandam M, Sideris N, Ahmadieh-Yazdi A, Sheykhhasan M, Manoochehri H, Tanzadehpanah H, Mahaki H, Ghadam M, Lak S, Kalhor N, Rabiei M, Al-Musawi S, Dama P. The functional role of LncRNA HOXA-AS2 in multiple human cancers. Pathol Res Pract 2025; 266:155795. [PMID: 39756105 DOI: 10.1016/j.prp.2024.155795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 12/18/2024] [Accepted: 12/23/2024] [Indexed: 01/07/2025]
Abstract
Humans have more than 270,000 lncRNAs. Among these, lncRNA HOXA-AS2 is considered a transformative gene involved in various cellular processes, including cell proliferation, apoptosis, migration, and invasion. Thus, it can be regarded as a potential tumor marker for both diagnosis and prognosis. Aberrant expression of lncRNAs is associated with many cancers, including hepatocellular carcinoma (HCC), gallbladder carcinoma (GBC), acute promyelocytic leukemia (APL), lung cancer (LC), prostate cancer (PC), osteosarcoma (OS), colorectal cancer (CRC), cervical cancer (CC), and acute myeloid leukemia (AML). Targeting lncRNAs could be a promising strategy to complement or replace current cancer treatments. As a non-coding oncogene, lncRNA HOXA-AS2 is implicated in multiple cancers and could serve as a potential biomarker for various malignancies. The tumor size and disease stage of several cancers are correlated with HOXA-AS2 expression. Silencing HOXA-AS2 effectively suppresses tumor cell proliferation and promotes apoptosis, thereby inhibiting the progression of multiple cancer types. The regulatory mechanisms of HOXA-AS2 include inducing epithelial-mesenchymal transition (EMT), overexpressing B-cell lymphoma-2 (Bcl-2) and MYC proto-oncogene (c-Myc), gene silencing, activating AKT-MMP signaling pathways, EZH2 and LSD1, and functioning within a competing endogenous RNA (ceRNA) regulatory network by competitively binding miRNAs. This review surveys recent research on the structure, biological functions, abnormal expression, regulatory mechanisms, and diagnostic and therapeutic potential of HOXA-AS2 in various cancers.
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Affiliation(s)
- Mohadeseh Khoshandam
- Department of Reproductive Biology, Academic Center for Education, Culture and Research, Qom Branch, Qom, Iran
| | - Nikolaos Sideris
- Research Fellow School of Life Sciences, University of Sussex, Brighton, UK.
| | - Amirhossein Ahmadieh-Yazdi
- Stem Cell Biology Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mohsen Sheykhhasan
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran.
| | - Hamed Manoochehri
- The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Hamid Tanzadehpanah
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hanie Mahaki
- Vascular & Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mona Ghadam
- National Institute of genetic engineering and biotechnology (NIGEB), Tehran, Iran
| | - Shermin Lak
- National Institute of genetic engineering and biotechnology (NIGEB), Tehran, Iran
| | - Naser Kalhor
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research, Qom, Iran
| | | | | | - Paola Dama
- Research Fellow School of Life Sciences, University of Sussex, Brighton, UK.
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Shi T, Wei J. Targeting DKK1 to Remodel the Tumor Microenvironment and Enhance Immune Checkpoint Blockade Therapy. J Clin Oncol 2025; 43:350-353. [PMID: 39467221 DOI: 10.1200/jco-24-01619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 09/11/2024] [Accepted: 09/30/2024] [Indexed: 10/30/2024] Open
Affiliation(s)
- Tao Shi
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jia Wei
- Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
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Zhao J, Hu Z, Zheng X, Lin Y, Liu X, Zhang J, Peng J, Gao H. Blood biomarkers of hepatocellular carcinoma: a critical review. Front Cell Dev Biol 2024; 12:1489836. [PMID: 39650722 PMCID: PMC11621223 DOI: 10.3389/fcell.2024.1489836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 11/13/2024] [Indexed: 12/11/2024] Open
Abstract
Hepatocellular Carcinoma (HCC) is a malignant tumor with high morbidity and mortality worldwide, which represents a serious threat to human life, health and quality of life. Blood-based detection is essential for HCC screening, early diagnosis, prognosis evaluation, and surveillance. Current non-invasive detection strategy including serum alpha-fetoprotein (AFP), ultrasound, computerized tomography, and magnetic resonance imaging. The limited specificity of an AFP and the dependence on operator experience and diagnostic personnel for ultrasound have constrained their utility in early HCC diagnosis. In recent years, with the development of various detection technologies, there has been an increasing focus on exploring blood-based detection markers for HCC. The types of markers include protein markers, DNA mutation, DNA epigenetic modification, mRNA, miRNA, and so on. However, numerous methodological and biological factors limit the clinical sensitivity and generalization performance of these new biomarkers. In this review, we describe the state-of-the-art technologies for cfDNA analysis, and discuss outstanding biological and technical challenges that, if addressed, would substantially improve HCC diagnostics and patient care.
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Affiliation(s)
- Junsheng Zhao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zekai Hu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiaoping Zheng
- Hangzhou Tongchuang Medical Laboratory, Department of pathology, Hangzhou, China
| | - Yajie Lin
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiao Liu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Junjie Zhang
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan (Hangzhou) Hospital Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Jing Peng
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hainv Gao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan (Hangzhou) Hospital Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
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Sun H, Liu N, Lou J. Diagnostic value of serum STIP1 in HCC and AFP-negative HCC. Lab Med 2024; 55:700-707. [PMID: 38780206 PMCID: PMC11532616 DOI: 10.1093/labmed/lmae033] [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] [Indexed: 05/25/2024] Open
Abstract
OBJECTIVE This study aimed to investigate the diagnostic value of stress-induced phosphoprotein 1 (STIP1) in serum for hepatocellular carcinoma (HCC) and alpha-fetoprotein (AFP)-negative HCC (ANHC). METHODS In this study, serum samples were collected from 158 HCC patients and 63 non-HCC patients. Logistic regression analysis was performed to identify independent risk factors associated with HCC and ANHC. The diagnostic values of each index for HCC and ANHC were analyzed using receiver operating characteristic (ROC) curve analysis. RESULTS The STIP1, des-γ-carboxy prothrombin (DCP), and AFP levels were higher in the HCC groups than in the non-HCC groups (P < .05). Age, DCP, STIP1, and hepatitis B virus infection were independent predictors of HCC (P < .05). The diagnostic value of STIP1 for HCC was higher than that of DCP. Additionally, age, STIP1, and hepatitis B virus infection were independent predictors for ANHC patients. The ROC curve exhibited an area under the curve value of 0.919 for STIP1, with a diagnostic cutoff value of 68.5 U/mL. Moreover, 36 ANHC patients and 19 AFP-negative non-HCC patients were included to validate the diagnostic model. A total of 20 patients had STIP1 levels greater than 68.5 U/mL, resulting in diagnostic accuracy of 67.3%, sensitivity of 55.6%, and specificity of 89.5%. CONCLUSION STIP1 demonstrates excellent diagnostic value for HCC and ANHC.
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Affiliation(s)
- Haiqing Sun
- Department of Clinical Laboratory Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Ning Liu
- Department of Clinical Laboratory Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Jinli Lou
- Department of Clinical Laboratory Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
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Zhang ZS, Gao ZX, He JJ, Ma C, Tao HT, Zhu FY, Cheng YN, Xie CQ, Li JQ, Liu ZZ, Hou LL, Sun H, Xie SQ, Fang D. Andrographolide sensitizes glioma to temozolomide by inhibiting DKK1 expression. Br J Cancer 2024; 131:1387-1398. [PMID: 39266624 PMCID: PMC11473956 DOI: 10.1038/s41416-024-02842-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/17/2024] [Accepted: 08/28/2024] [Indexed: 09/14/2024] Open
Abstract
BACKGROUND Temozolomide (TMZ) is the first-line chemotherapeutic drug for gliomas treatment. However, the clinical efficacy of TMZ in glioma patients was very limited. Therefore, it is urgently needed to discover a novel approach to increase the sensitivity of glioma cells to TMZ. METHODS Western blot, immunohistochemical staining, and qRT-PCR assays were used to explore the mechanisms underlying TMZ promoting DKK1 expression and andrographolide (AND) inhibiting DKK1 expression. HPLC was used to detect the ability of andrographolide (AND) to penetrate the blood-brain barrier. MTT assay, bioluminescence images, magnetic resonance imaging (MRI) and H&E staining were employed to measure the proliferative activity of glioma cells and the growth of intracranial tumors. RESULTS TMZ can promote DKK1 expression in glioma cells and brain tumors of an orthotopic model of glioma. DKK1 could promote glioma cell proliferation and tumor growth in an orthotopic model of glioma. Mechanistically, TMZ increased EGFR expression and subsequently induced the activation of its downstream MEK-ERK and PI3K-Akt pathways, thereby promoting DKK1 expression in glioma cells. Andrographolide inhibited TMZ-induced DKK1 expression through inactivating MEK-ERK and PI3K-Akt pathways. Andrographolide can cross the blood-brain barrier, the combination of TMZ and andrographolide not only improved the anti-tumor effects of TMZ but also showed a survival benefit in an orthotopic model of glioma. CONCLUSION Andrographolide can enhance anti-tumor activity of TMZ against glioma by inhibiting DKK1 expression.
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Affiliation(s)
- Zhan-Sheng Zhang
- Department of Pharmacy, The First Afffliated Hospital of Henan University, N. Jinming Ave, Kaifeng, 475004, China
- Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China
| | - Zi-Xuan Gao
- Department of Pharmacy, The First Afffliated Hospital of Henan University, N. Jinming Ave, Kaifeng, 475004, China
- Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China
| | - Jin-Jin He
- Department of Pharmacy, The First Afffliated Hospital of Henan University, N. Jinming Ave, Kaifeng, 475004, China
| | - Can Ma
- Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China
| | - Hang-Tian Tao
- Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China
| | - Feng-Yi Zhu
- Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China
| | - Yu-Na Cheng
- Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China
| | - Cui-Qing Xie
- Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China
| | - Ji-Qin Li
- Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China
| | - Zhuang-Zhuang Liu
- Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China
| | - Li-Li Hou
- Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China
| | - Hua Sun
- Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China.
| | - Song-Qiang Xie
- Department of Pharmacy, The First Afffliated Hospital of Henan University, N. Jinming Ave, Kaifeng, 475004, China.
- Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China.
- Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, Kaifeng, 475004, China.
| | - Dong Fang
- Department of Pharmacy, The First Afffliated Hospital of Henan University, N. Jinming Ave, Kaifeng, 475004, China.
- Institute of Chemical Biology, School of Pharmacy, Henan University, N. Jinming Ave, Kaifeng, 475004, China.
- Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, Kaifeng, 475004, China.
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10
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Liu M, Wen Y. Point-of-care testing for early-stage liver cancer diagnosis and personalized medicine: Biomarkers, current technologies and perspectives. Heliyon 2024; 10:e38444. [PMID: 39397977 PMCID: PMC11470528 DOI: 10.1016/j.heliyon.2024.e38444] [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: 04/09/2024] [Revised: 09/21/2024] [Accepted: 09/24/2024] [Indexed: 10/15/2024] Open
Abstract
Liver cancer is a highly prevalent and lethal form of cancer worldwide. In the absence of early diagnosis, treatment options for this disease are severely restricted. Recent advancements in genomics and bioinformatics have facilitated the discovery of a multitude of novel biomarkers that accurately depict an individual's disease diagnosis, progression, and treatment response. Leveraging these breakthroughs, personalized medicine employs an individual's biomarker profile to enable early detection of liver cancer and inform decisions regarding treatment selection, dosage determination, and prognosis assessment. The current lack of readily applicable, timely, and economically viable tools for biomarker analysis has hindered the incorporation of personalized medicine into regular clinical procedures. Over the past decade, significant advancements have been achieved in the field of molecular point-of-care testing (POCT) and amplification techniques, leading to substantial improvements in the diagnosis of liver cancer and the implementation of precision medicine. Instrument-free PCR technology or plasma PCR technology can shorten the complex procedure of in vitro detection of nucleic acid-based biomarkers. Also, compared to traditional ELISA, various nanomaterials modified with monoclonal antibodies to target proteins for recognition, capture, and detection have improved the efficiency of protein-based biomarker detection. These advances have reduced the time and cost of clinical detection of early-stage hepatocellular carcinoma and improved the efficiency of timely diagnosis and survival of suspected patients while reducing unnecessary testing costs and procedures. This review aims to provide a comprehensive overview of the current and emerging biomarkers employed in the early detection of liver cancer, as well as the advancements in point-of-care molecular testing technology and platforms. The primary objective is to assess their potential in facilitating the implementation of personalized medicine. This review ultimately revealed that the diagnosis of early-stage hepatocellular carcinoma not only requires sensitive biomarkers, but its various modifications and changes during the progression of cirrhosis to early-stage hepatocellular carcinoma will be a greater focus of our attention in the future. The rapid development of POCT has facilitated the opportunity to readily detect liver cancer in the general population in the future, and the integration of multi-pathway multiplexing and intelligent algorithms has improved the sensitivity and accuracy of early liver cancer biomarker detection. It is expected that the integration of point-of-care technology will be instrumental in the widespread adoption of personalized medicine in the foreseeable future.
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Affiliation(s)
- Mengxiang Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China
| | - Yanrong Wen
- Department of Nuclear Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China
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11
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Chan YT, Zhang C, Wu J, Lu P, Xu L, Yuan H, Feng Y, Chen ZS, Wang N. Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma. Mol Cancer 2024; 23:189. [PMID: 39242496 PMCID: PMC11378508 DOI: 10.1186/s12943-024-02101-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 08/23/2024] [Indexed: 09/09/2024] Open
Abstract
Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.
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Affiliation(s)
- Yau-Tuen Chan
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Cheng Zhang
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Junyu Wu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Pengde Lu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Lin Xu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Hongchao Yuan
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Zhe-Sheng Chen
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY, 11439, USA.
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
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12
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Shao L, Yu H, Wang M, Chen L, Ji B, Wu T, Teng X, Su M, Han X, Shi W, Hu X, Wang Z, He H, Han G, Zhang Y, Wu Q. DKK1-SE recruits AP1 to activate the target gene DKK1 thereby promoting pancreatic cancer progression. Cell Death Dis 2024; 15:566. [PMID: 39107271 PMCID: PMC11303742 DOI: 10.1038/s41419-024-06915-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 07/15/2024] [Accepted: 07/16/2024] [Indexed: 08/09/2024]
Abstract
Super-enhancers are a class of DNA cis-regulatory elements that can regulate cell identity, cell fate, stem cell pluripotency, and even tumorigenesis. Increasing evidence shows that epigenetic modifications play an important role in the pathogenesis of various types of cancer. However, the current research is far from enough to reveal the complex mechanism behind it. This study found a super-enhancer enriched with abnormally active histone modifications in pancreatic ductal adenocarcinoma (PDAC), called DKK1-super-enhancer (DKK1-SE). The major active component of DKK1-SE is component enhancer e1. Mechanistically, AP1 induces chromatin remodeling in component enhancer e1 and activates the transcriptional activity of DKK1. Moreover, DKK1 was closely related to the malignant clinical features of PDAC. Deletion or knockdown of DKK1-SE significantly inhibited the proliferation, colony formation, motility, migration, and invasion of PDAC cells in vitro, and these phenomena were partly mitigated upon rescuing DKK1 expression. In vivo, DKK1-SE deficiency not only inhibited tumor proliferation but also reduced the complexity of the tumor microenvironment. This study identifies that DKK1-SE drives DKK1 expression by recruiting AP1 transcription factors, exerting oncogenic effects in PDAC, and enhancing the complexity of the tumor microenvironment.
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Affiliation(s)
- Lan Shao
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China
| | - Haoran Yu
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China
| | - Mengyun Wang
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China
| | - Lu Chen
- Department of Pathology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Boshu Ji
- Department of Pathology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tong Wu
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China
| | - Xiangqi Teng
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China
| | - Mu Su
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China
| | - Xiao Han
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China
| | - Weikai Shi
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China
| | - Xin Hu
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China
| | - Ziwen Wang
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China
| | - Hongjuan He
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China
| | - Guiping Han
- Department of Pathology, the Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yan Zhang
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China
| | - Qiong Wu
- School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, China.
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13
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Chu LY, Wu FC, Fang WK, Hong CQ, Huang LS, Zou HY, Peng YH, Chen H, Xie JJ, Xu YW. Secreted proteins encoded by super enhancer-driven genes could be promising biomarkers for early detection of esophageal squamous cell carcinoma. Biomed J 2024; 47:100662. [PMID: 37774793 PMCID: PMC11340493 DOI: 10.1016/j.bj.2023.100662] [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: 04/22/2023] [Revised: 08/25/2023] [Accepted: 09/22/2023] [Indexed: 10/01/2023] Open
Abstract
BACKGROUND Early detection of cancer remains an unmet need in clinical practice, and high diagnostic sensitivity and specificity biomarkers are urgently required. Here, we attempted to identify secreted proteins encoded by super-enhancer (SE)-driven genes as diagnostic biomarkers for esophageal squamous cell carcinoma (ESCC). METHODS We conducted an integrative analysis of multiple data sets including ChIP-seq data, secretome data, CCLE data and GEO data to screen secreted proteins encoded by SE-driven genes. Using ELISA, we further identified up-regulated secreted proteins through a small size of clinical samples and verified in a multi-centre validation stage (345 in test cohort and 231 in validation cohort). Receiver operating characteristic curves were used to calculate diagnostic accuracy. Artificial intelligence (AI) method named gradient boosting machine (GBM) were applied for model construction to enhance diagnostic accuracy. RESULTS Serum EFNA1 and MMP13 were identified, and showed significantly higher levels in ESCC patients compared to normal controls. An integrated Five-Biomarker Panel (iFBPanel) established by combining EFNA1, MMP13, carcino-embryonic antigen, Cyfra21-1 and squmaous cell carcinoma antigen had AUCs of 0.881 and 0.880 for ESCC in test and validation cohorts, respectively. Importantly, the iFBPanel also exhibited good performance in detecting early-stage ESCC patients (0.872 and 0.864). Furthermore, the iFBPanel was further empowered by AI technology which showed excellent diagnostic performance in early-stage ESCC (0.927 and 0.907). CONCLUSIONS Our study suggested that serum EFNA1 and MMP13 could potentially assist ESCC detection, and provided an easy-to-use detection model that might help the diagnosis of early-stage ESCC.
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Affiliation(s)
- Ling-Yu Chu
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou, China; Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Fang-Cai Wu
- Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shanto, China; Guangdong Esophageal Cancer Institute, Cancer Hospital of Shantou University Medical College, Shanto, China; Esophageal Cancer Prevention and Control Research Centre, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Wang-Kai Fang
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Chao-Qun Hong
- Department of Oncological Laboratory Research, Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Li-Sheng Huang
- Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shanto, China
| | - Hai-Ying Zou
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China
| | - Yu-Hui Peng
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou, China; Guangdong Esophageal Cancer Institute, Cancer Hospital of Shantou University Medical College, Shanto, China
| | - Hao Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Sun Yat-sen University Cancer Centre, Guangzhou, China.
| | - Jian-Jun Xie
- Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China.
| | - Yi-Wei Xu
- Department of Clinical Laboratory Medicine, Cancer Hospital of Shantou University Medical College, Shantou, China; Guangdong Esophageal Cancer Institute, Cancer Hospital of Shantou University Medical College, Shanto, China; Esophageal Cancer Prevention and Control Research Centre, Cancer Hospital of Shantou University Medical College, Shantou, China.
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14
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Wan F, Zhu Y, Wu F, Huang X, Chen Y, Zhou Y, Li H, Liang L, Qin L, Wang Q, He M. Retinol-binding protein 4 as a promising serum biomarker for the diagnosis and prognosis of hepatocellular Carcinoma. Transl Oncol 2024; 45:101979. [PMID: 38728873 PMCID: PMC11107351 DOI: 10.1016/j.tranon.2024.101979] [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: 02/08/2024] [Revised: 03/20/2024] [Accepted: 04/26/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND The prognosis of hepatocellular carcinoma (HCC) is universally poor. Early diagnosis plays a pivotal role in determining the outcome of HCC. METHODS We employed a comparative proteomics approach to identify potential biomarkers and validated the application of retinol-binding protein 4 (RBP4) as a biomarker for HCC. RBP4 protein expression was examined in liver tissues from 80 HCC patients through immunohistochemical analysis. Serum RBP4 concentrations were measured by ELISA in a cohort comprising 290 HCC patients, matched 202 chronic hepatitis B patients and 269 healthy controls. Survival data were collected from HCC patients. The diagnostic and prognostic values of RBP4 were evaluated using receiver operating curve (ROC) analysis. RESULTS The validation results demonstrated a significant reduction in RBP4 levels in both liver tissues and serum samples from HCC patients. ROC analysis of the diagnostic value of RBP4 revealed an AUC of 0.879 (95 % CI: 0.854∼0.903) for HCC. When combined with AFP, the AUC increased to 0.919, with a sensitivity of 87.9 % and specificity of 80 %. Survival analysis revealed significantly reduced overall survival time in individuals with low-expression of RBP4 compared to those with high-expression. The joint prognostic model exhibited an AUC of 0.926 (95 % CI: 0.888∼0.964), which was significantly higher than that of AFP alone (AUC=0.809; P <0.0001). CONCLUSIONS RBP4 shows a great potential as a biomarker with appreciable diagnostic value, complementing the AFP in HCC diagnosis. Additionally, it holds promise as a prognostic biomarker that, when integrated into a combined prognostic model, could greatly improve HCC prognosis efficiency.
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Affiliation(s)
- Fengjie Wan
- Guangxi Medical University School of Public Health, Nanning, Guangxi 530021, PR China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, Guangxi 530021, PR China
| | - Yujia Zhu
- Guigang Dermatosis Prevention and Treatment Hospital, Guigang, Guangxi 537100, PR China
| | - Feixiang Wu
- Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, PR China
| | - Xuejing Huang
- Animal Center of Guangxi Medical University, Nanning, Guangxi 530021, PR China
| | - Ying Chen
- Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA
| | - Yi Zhou
- Guangxi Medical University Life Sciences Institute, Nanning, Guangxi 530021, PR China
| | - Hongtao Li
- Guilin Medical University, Guilin, Guangxi 541001, PR China
| | - Lifang Liang
- Guangxi Medical University School of Public Health, Nanning, Guangxi 530021, PR China
| | - Lirong Qin
- The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, PR China
| | - Qi Wang
- Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, PR China.
| | - Min He
- Guangxi Medical University School of Public Health, Nanning, Guangxi 530021, PR China; Animal Center of Guangxi Medical University, Nanning, Guangxi 530021, PR China; Key Laboratory of High-Incidence-Tumor Prevention & Treatment, Guangxi Medical University, Ministry of Education, Nanning 530021, PR China.
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15
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Chen F, Che Z, Liu Y, Luo P, Xiao L, Song Y, Wang C, Dong Z, Li M, Tipoe GL, Yang M, Lv Y, Zhang H, Wang F, Xiao J. Invigorating human MSCs for transplantation therapy via Nrf2/DKK1 co-stimulation in an acute-on-chronic liver failure mouse model. Gastroenterol Rep (Oxf) 2024; 12:goae016. [PMID: 38529014 PMCID: PMC10963075 DOI: 10.1093/gastro/goae016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 11/27/2023] [Accepted: 02/21/2024] [Indexed: 03/27/2024] Open
Abstract
BACKGROUND Since boosting stem cell resilience in stressful environments is critical for the therapeutic efficacy of stem cell-based transplantations in liver disease, this study aimed to establish the efficacy of a transient plasmid-based preconditioning strategy for boosting the capability of mesenchymal stromal cells (MSCs) for anti-inflammation/antioxidant defenses and paracrine actions in recipient hepatocytes. METHODS Human adipose mesenchymal stem cells (hADMSCs) were subjected to transfer, either with or without the nuclear factor erythroid 2-related factor 2 (Nrf2)/Dickkopf1 (DKK1) genes, followed by exposure to TNF-α/H2O2. Mouse models were subjected to acute chronic liver failure (ACLF) and subsequently injected with either transfected or untransfected MSCs. These hADMSCs and ACLF mouse models were used to investigate the interaction between Nrf2/DKK1 and the hepatocyte receptor cytoskeleton-associated protein 4 (CKAP4). RESULTS Activation of Nrf2 and DKK1 enhanced the anti-stress capacity of MSCs in vitro. In a murine model of ACLF, transient co-overexpression of Nrf2 and DKK1 via plasmid transfection improved MSC resilience against inflammatory and oxidative assaults, boosted MSC transplantation efficacy, and promoted recipient liver regeneration due to a shift from the activation of the anti-regenerative IFN-γ/STAT1 pathway to the pro-regenerative IL-6/STAT3 pathway in the liver. Importantly, the therapeutic benefits of MSC transplantation were nullified when the receptor CKAP4, which interacts with DKK1, was specifically removed from recipient hepatocytes. However, the removal of the another receptor low-density lipoprotein receptor-related protein 6 (LRP6) had no impact on the effectiveness of MSC transplantation. Moreover, in long-term observations, no tumorigenicity was detected in mice following transplantation of transiently preconditioned MSCs. CONCLUSIONS Co-stimulation with Nrf2/DKK1 safely improved the efficacy of human MSC-based therapies in murine models of ACLF through CKAP4-dependent paracrine mechanisms.
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Affiliation(s)
- Feng Chen
- Division of Gastroenterology, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, P. R. China
- National Clinical Research Center for Infectious Diseases, Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, P. R. China
| | - Zhaodi Che
- Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, P. R. China
| | - Yingxia Liu
- National Clinical Research Center for Infectious Diseases, Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, P. R. China
| | - Pingping Luo
- Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, P. R. China
| | - Lu Xiao
- Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, P. R. China
| | - Yali Song
- Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, P. R. China
| | - Cunchuan Wang
- Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, P. R. China
| | - Zhiyong Dong
- Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, P. R. China
| | - Mianhuan Li
- National Clinical Research Center for Infectious Diseases, Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, P. R. China
| | - George L Tipoe
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, P. R. China
| | - Min Yang
- National Clinical Research Center for Infectious Diseases, Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, P. R. China
| | - Yi Lv
- Laboratory of Neuroendocrinology, Fujian Key Laboratory of Developmental and Neurobiology, School of Life Sciences, Fujian Normal University, Fuzhou, Fujian, P. R. China
| | - Hong Zhang
- Department of Surgery, The Sixth Affiliated Hospital of Jinan University, Jinan University, Dongguan, Guangdong, P. R. China
| | - Fei Wang
- Division of Gastroenterology, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, P. R. China
| | - Jia Xiao
- Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, P. R. China
- Department of Surgery, The Sixth Affiliated Hospital of Jinan University, Jinan University, Dongguan, Guangdong, P. R. China
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16
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Gajos-Michniewicz A, Czyz M. WNT/β-catenin signaling in hepatocellular carcinoma: The aberrant activation, pathogenic roles, and therapeutic opportunities. Genes Dis 2024; 11:727-746. [PMID: 37692481 PMCID: PMC10491942 DOI: 10.1016/j.gendis.2023.02.050] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 12/28/2022] [Accepted: 02/14/2023] [Indexed: 09/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a liver cancer, highly heterogeneous both at the histopathological and molecular levels. It arises from hepatocytes as the result of the accumulation of numerous genomic alterations in various signaling pathways, including canonical WNT/β-catenin, AKT/mTOR, MAPK pathways as well as signaling associated with telomere maintenance, p53/cell cycle regulation, epigenetic modifiers, and oxidative stress. The role of WNT/β-catenin signaling in liver homeostasis and regeneration is well established, whereas in development and progression of HCC is extensively studied. Herein, we review recent advances in our understanding of how WNT/β-catenin signaling facilitates the HCC development, acquisition of stemness features, metastasis, and resistance to treatment. We outline genetic and epigenetic alterations that lead to activated WNT/β-catenin signaling in HCC. We discuss the pivotal roles of CTNNB1 mutations, aberrantly expressed non-coding RNAs and complexity of crosstalk between WNT/β-catenin signaling and other signaling pathways as challenging or advantageous aspects of therapy development and molecular stratification of HCC patients for treatment.
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Affiliation(s)
- Anna Gajos-Michniewicz
- Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz 92-215, Poland
| | - Malgorzata Czyz
- Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz 92-215, Poland
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17
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Yang X, Yang C, Zhang S, Geng H, Zhu AX, Bernards R, Qin W, Fan J, Wang C, Gao Q. Precision treatment in advanced hepatocellular carcinoma. Cancer Cell 2024; 42:180-197. [PMID: 38350421 DOI: 10.1016/j.ccell.2024.01.007] [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: 09/15/2023] [Revised: 12/01/2023] [Accepted: 01/17/2024] [Indexed: 02/15/2024]
Abstract
The past decade has witnessed significant advances in the systemic treatment of advanced hepatocellular carcinoma (HCC). Nevertheless, the newly developed treatment strategies have not achieved universal success and HCC patients frequently exhibit therapeutic resistance to these therapies. Precision treatment represents a paradigm shift in cancer treatment in recent years. This approach utilizes the unique molecular characteristics of individual patient to personalize treatment modalities, aiming to maximize therapeutic efficacy while minimizing side effects. Although precision treatment has shown significant success in multiple cancer types, its application in HCC remains in its infancy. In this review, we discuss key aspects of precision treatment in HCC, including therapeutic biomarkers, molecular classifications, and the heterogeneity of the tumor microenvironment. We also propose future directions, ranging from revolutionizing current treatment methodologies to personalizing therapy through functional assays, which will accelerate the next phase of advancements in this area.
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Affiliation(s)
- Xupeng Yang
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Chen Yang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Immune Regulation in Cancer Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Shu Zhang
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Haigang Geng
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Andrew X Zhu
- I-Mab Biopharma, Shanghai, China; Jiahui International Cancer Center, Jiahui Health, Shanghai, China
| | - René Bernards
- Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Wenxin Qin
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Cun Wang
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
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18
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Seo SH, Cho KJ, Park HJ, Lee HW, Kim BK, Park JY, Kim DY, Ahn SH, Cheon JH, Yook JI, Kim MD, Joo DJ, Kim SU. Inhibition of Dickkopf-1 enhances the anti-tumor efficacy of sorafenib via inhibition of the PI3K/Akt and Wnt/β-catenin pathways in hepatocellular carcinoma. Cell Commun Signal 2023; 21:339. [PMID: 38012711 PMCID: PMC10680194 DOI: 10.1186/s12964-023-01355-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 10/14/2023] [Indexed: 11/29/2023] Open
Abstract
BACKGROUND Sorafenib improves the overall survival in patients with advanced hepatocellular carcinoma (HCC). Dickkopf-1 (DKK1) is commonly overexpressed in HCC. In this study, we investigated whether the inhibition of DKK1 enhances the anti-tumor efficacy of sorafenib in HCC. METHODS HCC cells were treated with sorafenib and WAY-262611, which is an inhibitor of DKK1. Transgenic mouse models were also developed using hydrodynamic tail vein injection. Mice were orally administered with sorafenib (32 mg/kg), WAY-262611 (16 mg/kg), or sorafenib + WAY-262611 for 10 days. Mechanisms of sorafenib and WAY-262611 were explored via western blotting, immunostaining, and RNA sequencing. RESULTS DKK1 was significantly overexpressed in patients with HCC than in the healthy controls and patients with liver diseases except HCC (all P < 0.05). Compared with sorafenib alone, sorafenib + WAY-262611 significantly inhibited the cell viability, invasion, migration, and colony formation by promoting apoptosis and altering the cell cycles in HCC cells (all P < 0.05). Moreover, sorafenib + WAY-262611 decreased the p110α, phospho-Akt (all P < 0.05), active β-catenin (all P < 0.05) and phospho-GSK-3β (Ser9) expression levels, while increasing the phospho-GSK-3β (Tyr216) expression levels compared with those in the sorafenib alone in vitro and in vivo. In addition, sorafenib + WAY-262611 inhibited tumor progression by regulating cell proliferation and apoptosis, significantly better than sorafenib alone in mouse models. CONCLUSIONS Our results indicate that DKK1 inhibition significantly enhances the anti-tumor efficacy of sorafenib by inhibiting the PI3K/Akt and Wnt/β-catenin pathways via regulation of GSK3β activity, suggesting a novel therapeutic strategy for HCC. Video Abstract.
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Affiliation(s)
- Sang Hyun Seo
- Department of Internal Medicine, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Kyung Joo Cho
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Hye Jung Park
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Hye Won Lee
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
| | - Beom Kyung Kim
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
| | - Jun Yong Park
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
| | - Do Young Kim
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
| | - Sang Hoon Ahn
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Jong In Yook
- Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Korea
| | - Man-Deuk Kim
- Department of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Dong Jin Joo
- Department of Surgery, Yonsei University of College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Yonsei Liver Center, Severance Hospital, Seoul, Korea.
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea.
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Arvanitakis K, Papadakos SP, Lekakis V, Koufakis T, Lempesis IG, Papantoniou E, Kalopitas G, Georgakopoulou VE, Stergiou IE, Theocharis S, Germanidis G. Meeting at the Crossroad between Obesity and Hepatic Carcinogenesis: Unique Pathophysiological Pathways Raise Expectations for Innovative Therapeutic Approaches. Int J Mol Sci 2023; 24:14704. [PMID: 37834153 PMCID: PMC10572430 DOI: 10.3390/ijms241914704] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/21/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
The escalating global prevalence of obesity and its intricate association with the development of hepatocellular carcinoma (HCC) pose a substantial challenge to public health. Obesity, acknowledged as a pervasive epidemic, is linked to an array of chronic diseases, including HCC, catalyzing the need for a comprehensive understanding of its molecular underpinnings. Notably, HCC has emerged as a leading malignancy with rising incidence and mortality. The transition from viral etiologies to the prominence of metabolic dysfunction-associated fatty liver disease (MAFLD)-related HCC underscores the urgent need to explore the intricate molecular pathways linking obesity and hepatic carcinogenesis. This review delves into the interwoven landscape of molecular carcinogenesis in the context of obesity-driven HCC while also navigating using the current therapeutic strategies and future prospects for combating obesity-related HCC. We underscore the pivotal role of obesity as a risk factor and propose an integrated approach encompassing lifestyle interventions, pharmacotherapy, and the exploration of emerging targeted therapies. As the obesity-HCC nexus continues to challenge healthcare systems globally, a comprehensive understanding of the intricate molecular mechanisms and innovative therapeutic strategies is imperative to alleviate the rising burden of this dual menace.
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Affiliation(s)
- Konstantinos Arvanitakis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (K.A.); (E.P.); (G.K.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Stavros P. Papadakos
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.P.P.); (S.T.)
| | - Vasileios Lekakis
- Department of Gastroenterology, School of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece;
| | - Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Centre, First Department of Internal Medicine, Medical School, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece;
| | - Ioannis G. Lempesis
- Institute of Metabolism and Systems Research (IMSR), College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK;
| | - Eleni Papantoniou
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (K.A.); (E.P.); (G.K.)
| | - Georgios Kalopitas
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (K.A.); (E.P.); (G.K.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | | | - Ioanna E. Stergiou
- Pathophysiology Department, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Stamatios Theocharis
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.P.P.); (S.T.)
| | - Georgios Germanidis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (K.A.); (E.P.); (G.K.)
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
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20
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Lominadze Z, Shaik MR, Choi D, Zaffar D, Mishra L, Shetty K. Hepatocellular Carcinoma Genetic Classification. Cancer J 2023; 29:249-258. [PMID: 37796642 PMCID: PMC10686192 DOI: 10.1097/ppo.0000000000000682] [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] [Indexed: 10/07/2023]
Abstract
ABSTRACT Hepatocellular carcinoma (HCC) represents a significant global burden, with management complicated by its heterogeneity, varying presentation, and relative resistance to therapy. Recent advances in the understanding of the genetic, molecular, and immunological underpinnings of HCC have allowed a detailed classification of these tumors, with resultant implications for diagnosis, prognostication, and selection of appropriate treatments. Through the correlation of genomic features with histopathology and clinical outcomes, we are moving toward a comprehensive and unifying framework to guide our diagnostic and therapeutic approach to HCC.
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Affiliation(s)
- Zurabi Lominadze
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine
| | | | - Dabin Choi
- Department of Medicine, University of Maryland Medical Center
| | - Duha Zaffar
- Department of Medicine, University of Maryland Midtown Medical Center
| | - Lopa Mishra
- Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory; Divisions of Gastroenterology and Hepatology, Northwell Health
| | - Kirti Shetty
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine
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21
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Yu J, Park R, Kim R. Promising Novel Biomarkers for Hepatocellular Carcinoma: Diagnostic and Prognostic Insights. J Hepatocell Carcinoma 2023; 10:1105-1127. [PMID: 37483311 PMCID: PMC10362916 DOI: 10.2147/jhc.s341195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 07/07/2023] [Indexed: 07/25/2023] Open
Abstract
The systemic therapy landscape for hepatocellular carcinoma is rapidly evolving, as the recent approvals of checkpoint inhibitor-based regimens such as atezolizumab-bevacizumab and durvalumab-tremelimumab in advanced disease have led to an expanding therapeutic armamentarium. The development of biomarkers, however, has not kept up with the approvals of new agents. Nevertheless, biomarker research for hepatocellular carcinoma has recently been growing at a rapid pace. The most active areas of research are biomarkers for early detection and screening, accurate prognostication, and detection of minimal residual disease following curative intent therapies, and, perhaps most importantly, predictive markers to guide selection and sequencing of the individual agents, including tyrosine kinase inhibitors and immunotherapy. In this review, we briefly summarize the recent developments in systemic therapeutics for hepatocellular carcinoma, introduce the key completed and ongoing prospective and retrospective studies evaluating diagnostic, prognostic, and predictive biomarkers with high clinical relevance, highlight several potentially important areas of future research, and share our insights for each biomarker.
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Affiliation(s)
- James Yu
- Division of Hematology and Medical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Robin Park
- Division of Hematology and Medical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Richard Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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Xu FQ, Zhang Z, Hu A, Huang DS. Circulating biomarkers for diagnosis and management of hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2023; 31:404-411. [DOI: 10.11569/wcjd.v31.i10.404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/26/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, but the prognosis of HCC patients is poor due to the difficulty of early diagnosis and high recurrence rate. Therefore, it is particularly important to seek effective methods for early diagnosis and early recurrence monitoring after treatment. Circulating biomarkers play an important role in the diagnosis, progression monitoring, and prognosis evaluation of HCC. In recent years, with the discovery of a variety of new biomarkers, the development of biomarkers-related models, and the emergence of liquid biopsy technology, the diagnosis and treatment of HCC have been greatly improved. This article reviews the latest research advances of biomarkers in the diagnosis and treatment of HCC, aiming to provide new ideas for improving the prognosis of HCC patients.
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23
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Kim TW. Fisetin, an Anti-Inflammatory Agent, Overcomes Radioresistance by Activating the PERK-ATF4-CHOP Axis in Liver Cancer. Int J Mol Sci 2023; 24:ijms24109076. [PMID: 37240422 DOI: 10.3390/ijms24109076] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/16/2023] [Accepted: 05/20/2023] [Indexed: 05/28/2023] Open
Abstract
Fisetin, a well-known plant flavonol from the natural flavonoid group, is found in traditional medicines, plants, vegetables, and fruits. Fisetin also has anti-oxidant, anti-inflammatory, and anti-tumor effects. This study investigated the anti-inflammatory effects of fisetin in LPS-induced Raw264.7 cells and found that fisetin reduced the LPS-induced production of pro-inflammation markers, such as TNF-α, IL-1β, and IL-6, demonstrating the anti-inflammatory effects of fisetin. Furthermore, this study investigated the anti-cancer effects of fisetin and found that fisetin induced apoptotic cell death and ER stress through intracellular calcium (Ca2+) release, the PERK-ATF4-CHOP signaling pathway, and induction of GRP78 exosomes. However, the suppression of PERK and CHOP inhibited the fisetin-induced cell death and ER stress. Interestingly, fisetin induced apoptotic cell death and ER stress and inhibited the epithelial-mesenchymal transition phenomenon under radiation in radiation-resistant liver cancer cells. These findings indicate that the fisetin-induced ER stress can overcome radioresistance and induce cell death in liver cancer cells following radiation. Therefore, the anti-inflammatory agent fisetin, in combination with radiation, may be a powerful immunotherapy strategy to overcome resistance in an inflammatory tumor microenvironment.
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Affiliation(s)
- Tae Woo Kim
- Department of Biopharmaceutical Engineering, Dongguk University-WISE, 123 Dongdae-ro, Gyeongju 38066, Gyeongbuk, Republic of Korea
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24
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Mei Y, Li M, Wen J, Kong X, Li J. Single-cell characteristics and malignancy regulation of alpha-fetoprotein-producing gastric cancer. Cancer Med 2023; 12:12018-12033. [PMID: 37017469 PMCID: PMC10242870 DOI: 10.1002/cam4.5883] [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: 11/13/2022] [Revised: 03/13/2023] [Accepted: 03/17/2023] [Indexed: 04/06/2023] Open
Abstract
OBJECTIVE To characterize alpha-fetoprotein (AFP)-producing gastric cancer (AFPGC) at the single-cell level and to identify regulatory factors for AFP expression and malignancy. METHODS ScRNA-seq was performed on two tumors collected from patients with AFPGC. InferCNV and sub-clustering were applied to identify typical AFPGC cells, followed by AddModuleScore, pathway enrichment, Pseudo-time, and Scenic analyses. Data from a gastric cancer (GC) cohort were collected for conjoint analysis. The analytical results were verified by cell experiments and immunohistochemistry. RESULTS AFPGC cells are similar to hepatocytes in transcriptome and transcriptional regulation, with kinetic malignancy-related pathways, compared to the common malignant epithelium. In addition, compared to common GC cells, malignancy-related pathways, such as epithelial-mesenchymal transition (EMT) and angiogenesis, were upregulated in AFPGC. Mechanistically, Dickkopf-1 (DKK1) was found to be associated with AFP expression and malignant phenotype upon combining our scRNA-seq data with a public database, which was further verified by a series of in vitro experiments and immunohistochemistry. CONCLUSION We demonstrated the single-cell characteristics of AFPGC and that DKK1 facilitates AFP expression and malignancy.
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Affiliation(s)
- Yanxia Mei
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Zhejiang University Cancer CenterHangzhouZhejiangChina
| | - Ming Li
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Zhejiang University Cancer CenterHangzhouZhejiangChina
| | - Jihang Wen
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Zhejiang University Cancer CenterHangzhouZhejiangChina
| | - Xiangxing Kong
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Zhejiang University Cancer CenterHangzhouZhejiangChina
| | - Jun Li
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina
- Zhejiang University Cancer CenterHangzhouZhejiangChina
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25
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Shahini E, Pasculli G, Solimando AG, Tiribelli C, Cozzolongo R, Giannelli G. Updating the Clinical Application of Blood Biomarkers and Their Algorithms in the Diagnosis and Surveillance of Hepatocellular Carcinoma: A Critical Review. Int J Mol Sci 2023; 24:4286. [PMID: 36901717 PMCID: PMC10001986 DOI: 10.3390/ijms24054286] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/14/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
The most common primary liver cancer is hepatocellular carcinoma (HCC), and its mortality rate is increasing globally. The overall 5-year survival of patients with liver cancer is currently 10-20%. Moreover, because early diagnosis can significantly improve prognosis, which is highly correlated with tumor stage, early detection of HCC is critical. International guidelines advise using α-FP biomarker with/without ultrasonography for HCC surveillance in patients with advanced liver disease. However, traditional biomarkers are sub-optimal for risk stratification of HCC development in high-risk populations, early diagnosis, prognostication, and treatment response prediction. Since about 20% of HCCs do not produce α-FP due to its biological diversity, combining α-FP with novel biomarkers can enhance HCC detection sensitivity. There is a chance to offer promising cancer management methods in high-risk populations by utilizing HCC screening strategies derived from new tumor biomarkers and prognostic scores created by combining biomarkers with distinct clinical parameters. Despite numerous efforts to identify molecules as potential biomarkers, there is no single ideal marker in HCC. When combined with other clinical parameters, the detection of some biomarkers has higher sensitivity and specificity in comparison with a single biomarker. Therefore, newer biomarkers and models, such as the Lens culinaris agglutinin-reactive fraction of Alpha-fetoprotein (α-FP), α-FP-L3, Des-γ-carboxy-prothrombin (DCP or PIVKA-II), and the GALAD score, are being used more frequently in the diagnosis and prognosis of HCC. Notably, the GALAD algorithm was effective in HCC prevention, particularly for cirrhotic patients, regardless of the cause of their liver disease. Although the role of these biomarkers in surveillance is still being researched, they may provide a more practical alternative to traditional imaging-based surveillance. Finally, looking for new diagnostic/surveillance tools may help improve patients' survival. This review discusses the current roles of the most used biomarkers and prognostic scores that may aid in the clinical management of HCC patients.
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Affiliation(s)
- Endrit Shahini
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
| | - Giuseppe Pasculli
- National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
| | - Antonio Giovanni Solimando
- Guido Baccelli Unit of Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area-(DiMePRe-J), University of Bari “A. Moro”, 70121 Bari, Italy
| | | | - Raffaele Cozzolongo
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
| | - Gianluigi Giannelli
- Scientific Director, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
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Abd-Elsalam S, Alegaily HS, Soliman MY, Gad AM, Abou-Omar EAM, Saleh M, Abdellatif RS, Fouad A, Azzam OM, Abo-Amer YEE. The Value of Thioredoxin Level and its Gene Polymorphism in the
Diagnosis of Post- HCV Hepatocellular Carcinoma. CURRENT CANCER THERAPY REVIEWS 2023; 19:67-73. [DOI: 10.2174/1573394718666220829122410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 04/16/2022] [Accepted: 06/29/2022] [Indexed: 11/22/2022]
Abstract
Background:
Hepatocellular carcinoma (HCC) is one of the most common malignancies
and a leading cause of cancer-related death worldwide. Indeed, we need a novel tumor marker other
than AFP for early detection and to improve the outcome. Serum thioredoxin is a promising protein
involved in the pathogenesis of many malignancies. The study aims to evaluate serum thioredoxin
and its gene polymorphism in HCC in cirrhotic patients due to HCV infection.
Patients and Methods:
350 patients with HCC, 350 patients with chronic liver diseases, and 300
healthy controls were enrolled in our study. Serum thioredoxin level was measured by ELISA, and
molecular study of thioredoxin domain-containing 5 (TXNDC5) gene polymorphism (rs1225943)
polymorphism using real-time polymerase chain reaction by Taqman allele discrimination was done
for all subjects.
Results:
Our study revealed a significant increase in serum thioredoxin levels in patients with HCC
compared to chronic liver diseases and healthy controls. Using the Receiver operating characteristic
(ROC) curve at the area under the curve (AUC) 0.917 and a cut-off value of > 14.6 U/ml, our overall
sensitivity and specificity for the HCC group over the other groups were 86 % and 92.15%, respectively
with 92.2% positive predictive value and 54.9% negative predictive value. The molecular
study of TXNDC5 gene polymorphism (rs1225943) polymorphism revealed no significant difference
between the studied groups.
Conclusion:
Serum thioredoxin may be used as a promising tumor marker for HCC. Future research
is needed to assess its use as a single or combined with other markers in the diagnosis and follow-up
of the patients after interventions.
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Affiliation(s)
| | - Hatem Samir Alegaily
- Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Benha University, Benha,
Egypt
| | - Moataz Yousry Soliman
- Hepatology, Gastroenterology and Infectious Diseases, Mahala Hepatology Teaching Hospital, Mahalla, Gharbia,
Egypt
| | - Ahmed Mehrez Gad
- Hepatobiliary and GIT Surgical Department, Mahalla Liver Teaching Hospital Egypt
| | | | - Mohamed Saleh
- Internal Medicine
Department, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Raghda Samir Abdellatif
- Clinical Pathology
Department, National Hepatolgy and Tropical Medicine Research Institute, Cairo, Egypt
| | - Amina Fouad
- Clinical Pathology
Department, National Hepatolgy and Tropical Medicine Research Institute, Cairo, Egypt
| | - Omar Mahmoud Azzam
- Internal Medicine Department,
Ahmed Maher Teaching Hospital, Cairo, Egypt
| | - Yousry Esam-Eldin Abo-Amer
- Hepatology, Gastroenterology and Infectious Diseases, Mahala Hepatology Teaching Hospital, Mahalla, Gharbia,
Egypt
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27
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Zhao Y, Yang D, Yan Y, Zhang X, Yang N, Guo Y, Yu C. Secular Trends of Liver Cancer Mortality and Years of Life Lost in Wuhan, China 2010-2019. Curr Oncol 2023; 30:938-948. [PMID: 36661720 PMCID: PMC9858443 DOI: 10.3390/curroncol30010071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/02/2023] [Accepted: 01/05/2023] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Liver cancer has caused a heavy burden worldwide. This study aimed to estimate the trends in the mortality and years of life lost (YLL) due to liver cancer and decompose the total deaths into three contributors: population growth, population aging, and mortality change. METHODS Our study used data from the cause-of-death surveillance system in Wuhan. The mortality and YLL rates were standardized according to the sixth national population census in China. This study calculated the estimated annual percentage change (EAPC) to estimate the trends in the age-standardized mortality rate (ASMR) and age-standardized YLL rate (ASYR). Meanwhile, a decomposition analysis was used to explore the effect of population growth, population aging, and age-specific mortality change on the change in liver cancer deaths. RESULTS The ASMR of liver cancer declined at an annual rate of 4.6% from 30.87 per 100,000 people in 2010 to 20.29 per 100,000 people in 2019, while the ASYR was at an annual rate of 5.6% from 969.35 per 100,000 people in 2010 to 581.82 per 100,000 people in 2019. Similar downward trends were seen in men and women. The decomposition analysis found that total deaths number changed by -12.42% from 2010 to 2019, of which population growth and population aging caused the total death numbers to increase by 9.75% and 21.15%, while the age-specific mortality change caused the total death numbers to decrease by 43.32%. CONCLUSION Although the ASMR of liver cancer has declined in recent years in Wuhan, it still causes a heavy burden with the increasing population and rapid population aging and remains an essential public health issue. The government should take measures to reduce the burden of liver cancer, especially among men.
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Affiliation(s)
- Yuanyuan Zhao
- Wuhan Center for Disease Control and Prevention, Wuhan 430024, China
| | - Donghui Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan 430072, China
| | - Yaqiong Yan
- Wuhan Center for Disease Control and Prevention, Wuhan 430024, China
| | - Xiaoxia Zhang
- Wuhan Center for Disease Control and Prevention, Wuhan 430024, China
| | - Niannian Yang
- Wuhan Center for Disease Control and Prevention, Wuhan 430024, China
| | - Yan Guo
- Wuhan Center for Disease Control and Prevention, Wuhan 430024, China
| | - Chuanhua Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan 430072, China
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Parikh ND, Tayob N, Singal AG. Blood-based biomarkers for hepatocellular carcinoma screening: Approaching the end of the ultrasound era? J Hepatol 2023; 78:207-216. [PMID: 36089157 PMCID: PMC10229257 DOI: 10.1016/j.jhep.2022.08.036] [Citation(s) in RCA: 84] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 08/23/2022] [Accepted: 08/29/2022] [Indexed: 02/01/2023]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, in part because of inadequate early detection strategies. Current recommendations for screening consist of semi-annual abdominal ultrasound with or without serum alpha-fetoprotein in patients with cirrhosis and in demographic subgroups with chronic hepatitis B infection. However, this screening strategy has several deficiencies, including suboptimal early-stage sensitivity, false positives with subsequent harms, inter-operator variability in ultrasound performance, and poor adherence. A blood-based biomarker with sufficient performance characteristics for early-stage disease could overcome several of these barriers to improving early-stage detection. However, prior to use of a biomarker for screening in clinical practice, a multistep validation is required in order to understand test performance characteristics. These steps include case-control validation, followed by validation in prospective cohorts of at-risk patients. Until recently, we lacked adequate longitudinal validation cohorts for early HCC detection; however, several validation cohorts are maturing, including the Hepatocellular Carcinoma Early Detection Study and the Texas Hepatocellular Carcinoma Consortium, which will allow for rigorous validation of candidate biomarkers. While there are several promising biomarkers awaiting validation, in order to supplant abdominal ultrasound, a candidate biomarker must show adequate test performance and overcome practical hurdles to ensure adoption in clinical practice. The promise of blood-based biomarkers is significant, especially given the limitations of ultrasound-based screening; however, they require adequate validation and several logistical obstacles must be overcome prior to clinical implementation.
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Affiliation(s)
- Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
| | - Nabihah Tayob
- Department of Biostatistics, Dana Farber Cancer Center, Boston, MA, USA
| | - Amit G Singal
- Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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Luo Y, Hong CQ, Huang BL, Ding TY, Chu LY, Zhang B, Qu QQ, Li XH, Liu CT, Peng YH, Guo HP, Xu YW. Serum insulin-like growth factor binding protein-3 as a potential biomarker for diagnosis and prognosis of oesophageal squamous cell carcinoma. Ann Med 2022; 54:2153-2166. [PMID: 35930383 PMCID: PMC9359171 DOI: 10.1080/07853890.2022.2104921] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 07/14/2022] [Accepted: 07/18/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Insulin-like growth factor binding protein-3 (IGFBP3) has been reported to be related to the risk of some cancers. Here we focussed on serum IGFBP3 as a possible biomarker of diagnosis and prognosis for oesophageal squamous carcinoma (ESCC). METHODS Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum IGFBP3 level in the training cohort including 136 ESCC patients and 119 normal controls and the validation cohort with 55 ESCC patients and 42 normal controls. The receiver operating characteristics curve (ROC) was used to assess the diagnosis value. Cox proportional hazards model was applied to select factors for survival nomogram construction. RESULTS Serum IGFBP3 levels were significantly lower in early-stage ESCC or ESCC patients than those in normal controls (p < .05). The specificity and sensitivity of serum IGFBP3 for the diagnosis of ESCC were 95.80% and 50.00%, respectively, with the area under the ROC curve (AUC) of 0.788 in the training cohort. Similar results were observed in the validation cohort (88.10%, 38.18%, and 0.710). Importantly, serum IGFBP3 could also differentiate early-stage ESCC from controls (95.80%, 52.54%, 0.777 and 88.10%, 36.36%, 0.695 in training and validation cohorts, respectively). Furthermore, Cox multivariate analysis revealed that serum IGFBP3 was an independent prognostic risk factor (HR = 2.599, p = .002). Lower serum IGFBP3 level was correlated with reduced overall survival (p < .05). Nomogram based on serum IGFBP3, TNM stage, and tumour size improved the prognostic prediction of ESCC with a concordance index of 0.715. CONCLUSION We demonstrated that serum IGFBP3 was a potential biomarker of diagnosis and prognosis for ESCC. Meanwhile, the nomogram might help predict the prognosis of ESCC. Key MessageSerum IGFBP3 showed early diagnostic value in oesophageal squamous cell carcinoma with independent cohort validation. Moreover, serum IGFBP3 was identified as an independent prognostic risk factor, which was used to construct a nomogram with improved prognosis ability in oesophageal squamous cell carcinoma.
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Affiliation(s)
- Yun Luo
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou, China
| | - Chao-Qun Hong
- Department of Oncological Laboratory Research, the Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Bin-Liang Huang
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou, China
- Guangdong Esophageal Cancer Institute, Guangzhou, China
| | - Tian-Yan Ding
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou, China
| | - Ling-Yu Chu
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou, China
| | - Biao Zhang
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou, China
| | - Qi-Qi Qu
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou, China
| | - Xin-Hao Li
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou, China
| | - Can-Tong Liu
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou, China
- Guangdong Esophageal Cancer Institute, Guangzhou, China
| | - Yu-Hui Peng
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou, China
- Guangdong Esophageal Cancer Institute, Guangzhou, China
| | - Hai-Peng Guo
- Department of Head and Neck Surgery, the Cancer Hospital of Shantou University Medical College, Shantou, China
| | - Yi-Wei Xu
- Department of Clinical Laboratory Medicine, the Cancer Hospital of Shantou University Medical College, Shantou, China
- Precision Medicine Research Center, Shantou University Medical College, Shantou, China
- Guangdong Esophageal Cancer Institute, Guangzhou, China
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Kim EJ, Ganga A, Lee JY, Zawadzki RS, Adriance W, Wang R, Cholankeril G, Somasundar PS. Disparities in hepatocellular carcinoma survival by Medicaid-status: A national population-based risk analysis. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2022; 49:794-801. [PMID: 36503726 DOI: 10.1016/j.ejso.2022.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/14/2022] [Accepted: 12/04/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Previous studies have demonstrated disparities in survival surrounding hepatocellular carcinoma (HCC) across a variety of socio-demographic factors; however, the relationship between Medicaid-status and HCC survival is poorly understood. METHODS We constructed 5-year, disease-specific survival curves using the Kaplan-Meier method and performed an adjusted survival analysis using multivariate Cox-proportional hazard regression. RESULTS We analyzed 17,059 non-elderly patients (12,194 non-Medicaid, 4875 Medicaid) diagnosed between 2006 and 2013 and found that Medicaid status was not associated with higher risk of diseases-specific death compared to other insurance types (p = .232, aHR 1.02, 95% CI: 0.983-1.07) after for controlling for a variety of co-variates (ie. marital status, urbanicity, etc.). We found no difference in the risk of death between patients enrolled in Medicaid for more than three years versus those enrolled for less than three years. In all models, rurality and unmarried status were also associated with an increased risk of death (aHR 1.11, 95% CI: 1.03-1.18, p = .002 and aHR 1.18, 95% CI: 1.13-1.23, p < .001, respectively). DISCUSSION Those enrolled in Medicaid prior to HCC diagnosis may not be associated with a higher risk of disease-specific death compared to non-Medicaid enrolled patients.
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Affiliation(s)
- Eric J Kim
- Roger Williams Medical Center, Department of Surgical Oncology, Providence, RI, USA
| | - Arjun Ganga
- Roger Williams Medical Center, Department of Surgical Oncology, Providence, RI, USA
| | - James Y Lee
- Division of Pediatric Cardiac Surgery, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Roy S Zawadzki
- University of California, Department of Statistics, Irvine, CA, USA
| | - William Adriance
- Brown University, Department of Computer Science, Providence, RI, USA
| | - Rachel Wang
- Brown University, Department of Computer Science, Providence, RI, USA
| | | | - Ponnandai S Somasundar
- Roger Williams Medical Center, Department of Surgical Oncology, Providence, RI, USA; Boston University School of Medicine, Department of Surgery, Boston, MA, USA.
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Dickkopf-Related Protein 1 as Response Marker for Transarterial Chemoembolization of Hepatocellular Carcinomas. Cancers (Basel) 2022; 14:cancers14194807. [PMID: 36230730 PMCID: PMC9563450 DOI: 10.3390/cancers14194807] [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: 08/19/2022] [Revised: 09/23/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Background and Aims: In the treatment of hepatocellular carcinoma (HCC), response prediction to transarterial chemoembolization (TACE) based on serum biomarkers is not established. We have studied the association of circulating Dickkopf-related protein 1 (DKK-1) with baseline characteristics and response to TACE in European HCC patients. Methods: Patients with HCC treated with TACE from 2010 to 2018 at a tertiary referral hospital were retrospectively enrolled. Levels of DKK-1 were measured in serum samples collected before TACE. Response was assessed according to mRECIST criteria at week 12 after TACE. Results: Ninety-seven patients were enrolled, including seventy-nine responders and eighteen refractory. Before TACE, median DKK-1 serum levels were 922 [range, 199−4514] pg/mL. DKK-1 levels were lower in patients with liver cirrhosis (p = 0.002) and showed a strong correlation with total radiologic tumor size (r = 0.593; p < 0.001) and with Barcelona Clinic Liver Cancer stages (p = 0.032). Median DKK-1 levels were significantly higher in refractory patients as compared to responders (1471 pg/mL [range, 546−2492 pg/mL] versus 837 pg/mL [range, 199−4515 pg/mL]; p < 0.001), and DKK-1 could better identify responders than AFP (AUC = 0.798 vs. AUC = 0.679; p < 0.001). A DKK-1 cutoff of ≤1150 pg/mL was defined to identify responders to TACE with a sensitivity of 78% and specificity of 77%. DKK-1 levels were suitable to determine response to TACE in patients with low AFP serum levels (AFP levels < 20 ng/mL; AUC = 0.843; 95% CI [0.721−0.965]; p = 0.003). Conclusion: DKK-1 levels in serum are strongly associated tumor size and with response to TACE in European HCC patients, including those patients with low AFP levels.
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Mulherkar TH, Gómez DJ, Sandel G, Jain P. Co-Infection and Cancer: Host–Pathogen Interaction between Dendritic Cells and HIV-1, HTLV-1, and Other Oncogenic Viruses. Viruses 2022; 14:v14092037. [PMID: 36146843 PMCID: PMC9503663 DOI: 10.3390/v14092037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/08/2022] [Accepted: 09/12/2022] [Indexed: 11/16/2022] Open
Abstract
Dendritic cells (DCs) function as a link between innate and adaptive immune responses. Retroviruses HIV-1 and HTLV-1 modulate DCs to their advantage and utilize them to propagate infection. Coinfection of HTLV-1 and HIV-1 has implications for cancer malignancies. Both viruses initially infect DCs and propagate the infection to CD4+ T cells through cell-to-cell transmission using mechanisms including the formation of virologic synapses, viral biofilms, and conduits. These retroviruses are both neurotrophic with neurovirulence determinants. The neuropathogenesis of HIV-1 and HTLV-1 results in neurodegenerative diseases such as HIV-associated neurocognitive disorders (HAND) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Infected DCs are known to traffic to the brain (CNS) and periphery (PNS, lymphatics) to induce neurodegeneration in HAND and HAM/TSP patients. Elevated levels of neuroinflammation have been correlated with cognitive decline and impairment of motor control performance. Current vaccinations and therapeutics for HIV-1 and HTLV-1 are assessed and can be applied to patients with HIV-1-associated cancers and adult T cell leukemia/lymphoma (ATL). These diseases caused by co-infections can result in both neurodegeneration and cancer. There are associations with cancer malignancies and HIV-1 and HTLV-1 as well as other human oncogenic viruses (EBV, HBV, HCV, HDV, and HPV). This review contains current knowledge on DC sensing of HIV-1 and HTLV-1 including DC-SIGN, Tat, Tax, and current viral therapies. An overview of DC interaction with oncogenic viruses including EBV, Hepatitis viruses, and HPV is also provided. Vaccines and therapeutics targeting host–pathogen interactions can provide a solution to co-infections, neurodegeneration, and cancer.
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Affiliation(s)
- Tania H. Mulherkar
- Department of Microbiology and Immunology, Drexel University, College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA
| | - Daniel Joseph Gómez
- Department of Microbiology and Immunology, Drexel University, College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA
- Department of Biological Sciences, California State University, 25800 Carlos Bee Blvd, Hayward, CA 94542, USA
| | - Grace Sandel
- Department of Microbiology and Immunology, Drexel University, College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA
| | - Pooja Jain
- Department of Microbiology and Immunology, Drexel University, College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA
- Correspondence:
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Oikawa T, Yamada K, Tsubota A, Saeki C, Tago N, Nakagawa C, Ueda K, Kamioka H, Taniai T, Haruki K, Nakano M, Torisu Y, Ikegami T, Yoshida K, Saruta M. Protein Kinase C Delta Is a Novel Biomarker for Hepatocellular Carcinoma. GASTRO HEP ADVANCES 2022; 2:83-95. [PMID: 39130149 PMCID: PMC11308090 DOI: 10.1016/j.gastha.2022.07.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 07/25/2022] [Indexed: 08/13/2024]
Abstract
Backgrounds and Aims Hepatocellular carcinoma (HCC) is the most common cancer with a poor prognosis. Identification of an alternative biomarker that can detect early-stage and conventional tumor marker-negative HCC is urgently needed. We found that protein kinase C delta (PKCδ) is specifically secreted from HCC cell lines into extracellular space and contributes to tumor development and that its serum levels were elevated in HCC patients. This study aimed to assess the practical usefulness of serum PKCδ for detecting HCC in chronic liver disease (CLD) patients. Methods Serum PKCδ levels in 313 CLD patients with and without HCC (n = 187 and 126, respectively) were measured using a sandwich enzyme-linked immunosorbent assay. The diagnostic performance of PKCδ for HCC was evaluated using the receiver operating characteristic curve analysis and was compared with that of conventional markers, α-fetoprotein (AFP), and des-γ-carboxy prothrombin (DCP). Results Serum PKCδ levels in HCC patients were significantly higher than those in CLD patients without HCC. PKCδ distinguished HCC patients from CLD patients without HCC, with high sensitivity and specificity. Subgroup analyses revealed that the diagnostic performance of PKCδ for HCC was comparable to that of AFP and DCP, and that approximately 40% of AFP/DCP double-negative HCC patients were positive for PKCδ. PKCδ yielded better diagnostic performance for detecting solitary small-sized (ie, very early stage) HCC than AFP and DCP. There was no significant correlation between serum PKCδ and AFP/DCP levels. Conclusion Serum PKCδ is a novel HCC biomarker, which is independent of and complementary to conventional markers. Specifically, PKCδ may be useful for detecting very early-stage or AFP/DCP double-negative HCC.
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Affiliation(s)
- Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kohji Yamada
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
| | - Akihito Tsubota
- Core Research Facilities, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan
| | - Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Naoko Tago
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
| | - Chika Nakagawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kaoru Ueda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Hiroshi Kamioka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
| | - Tomohiko Taniai
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Koichiro Haruki
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Masanori Nakano
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Yuichi Torisu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Toru Ikegami
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Kiyotsugu Yoshida
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
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Chen YQ, Zheng L, Zhou J, Wang P, Wang L, Zhang Y, Man ZS, Chen YH, Gu F, Niu GP. Evaluation of plasma LC3B+extracellular vesicles as a potential novel diagnostic marker for hepatocellular carcinoma. Int Immunopharmacol 2022; 108:108760. [DOI: 10.1016/j.intimp.2022.108760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/31/2022] [Accepted: 04/03/2022] [Indexed: 11/05/2022]
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Combined Efficacy of CXCL5, STC2, and CHI3L1 in the Diagnosis of Colorectal Cancer. JOURNAL OF ONCOLOGY 2022; 2022:7271514. [PMID: 35646113 PMCID: PMC9142324 DOI: 10.1155/2022/7271514] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 04/25/2022] [Indexed: 12/23/2022]
Abstract
Objective To improve the diagnostic capacity of serum biomarkers for colorectal cancer (CRC), we introduced three novel indicators, namely, the C-X-C motif chemokine ligand 5 (CXCL5), stanniocalcin 2 (STC2), and chitinase 3 like 1 (CHI3L1) and assessed their performances in the detection of CRC. Methods A total of 887 serum samples (153 health, 342 polyps, and 392 CRCs) were collected. Concentrations of CXCL5, STC2, and CHI3L1 were measured by the ELISA. CEA and CA199 were determined by electrochemiluminescence. Binary logistic regression was used to build the combination model. ROC analysis was used to evaluate the performance of biomarkers alone or in combination. Results Model_2 that based on CXCL5, STC2, and CHI3L1 was the best approach in discriminating CRC from non-CRC controls (AUC, 0.943 (0.922–0.960); sensitivity, 0.848; specificity, 0.917; and accuracy, 0.887 in the training cohort and 0.959 (95% CI 0.927–0.980), 0.878, 0.917, and 0.900 in the testing cohort, respectively). In the detection of early CRC, Model_2 revealed AUC, sensitivity, specificity, and accuracy of 0.925 (0.897–0.947), 0.793, 0.917, and 0.886 in the training cohort and those of 0.926 (0.979–0.959), 0.786, 0.931, and 0.898 in the testing cohort. Furthermore, Model_2 exhibited an excellent diagnostic performance in CEA-negative cases (0.938 (0.913–0.957), 0.826, 0.917, and 0.888 in the training cohort and 0.961 (0.925–0.983), 0.887, 0.931, and 0.918 in the testing cohort). As used alone, STC2 achieved the capacities that is second only to that of Model_2 (0.866 (0.837–0.892), 0.859, 0.842, and 0.853 in the training cohort and 0.887 (0.842–0.923), 0.922, 0.799, and 0.853 in the testing cohort). STC2 alone also yielded acceptable results for early CRC detection (0.815 (0.776–0.849), 0.767, 0.849, and 0.829 in the training cohort and 0.870 (0.812–0.914), 0.952, 0.799, and 0.833 in the testing cohort). Moreover, STC2 maintained diagnostic accuracy for CRC patients with negative CEA (0.874 (0.842–0.901), 0.862, 0.849, and 0.853 in the training cohort and 0.898 (0.848–0.936), 0.930, 0.801, and 0.842 in the testing cohort). In comparison, the performances of the CEA and CA199 based Model_1 were far from satisfactory, especially in early cases (0.767 (0.726–0.805), 0.491, 0.863, and 0.771 in the training cohort and 0.817 (0.754–0.870), 0.476, 0.889, and 0.796 in the testing cohort). Conclusions STC2 was a promising serum biomarker for CRC diagnosis either used alone or in combination with CXCL5 and CHI3L1.
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Identification of CCL20 and LCN2 as Efficient Serological Tools for Detection of Hepatocellular Carcinoma. DISEASE MARKERS 2022; 2022:7758735. [PMID: 35308139 PMCID: PMC8930252 DOI: 10.1155/2022/7758735] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 02/26/2022] [Indexed: 11/18/2022]
Abstract
Objectives To discover a more powerful diagnostic tool for the detection of hepatocellular carcinoma (HCC). Methods 16 extracellularly located candidates were selected by analyzing the expression array datasets in GEO. 10 of them were validated in clinical samples by ELISA. Differences of each variable were compared by one-way ANOVA or Kruskal-Wallis test. CCL20 and LCN2 were determined in all samples (HCC, 167; liver cirrhosis, 106; and healthy control, 106) and finally chosen for the construction of the combination model by binary logistic regression. The models were first built using a comprehensive control, including both liver cirrhosis (LC) and healthy donors. Then, the models were rebuilt by using the LC group alone as a control. ROC analysis was performed to compare the diagnostic efficiency of each indicator. Results Levels of CCL20 and LCN2 in HCC sera were significantly higher than those in all controls. Using the comprehensive control, ROC curves showed that the optimum diagnostic cutoff of the CCL20 and LCN2 combination was 0.443 (area under curve (AUC) of 0.927 (95% CI 0.896-0.951), sensitivity of 0.808, specificity of 0.892, and accuracy of 0.859). For detection of HCC from LC control, the optimum diagnostic cutoff was 0.590 (AUC of 0.919 (95% CI 0.880-0.948), sensitivity of 0.814, specificity of 0.868, and accuracy of 0.834). Furthermore, the model maintained diagnostic accuracy for patients with HCC in the early stage, with the sensitivity and specificity of 0.75 and 0.77 from LC control, yet the AFP only reached 0.5 and 0.67, respectively. Conclusion A combination model composed of CCL20 and LCN2 may serve as a more efficient tool for distinguishing HCC from nonmalignant liver diseases.
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He Q, Fan B, Du P, Jin Y. Construction and Validation of Two Hepatocellular Carcinoma-Progression Prognostic Scores Based on Gene Set Variation Analysis. Front Cell Dev Biol 2022; 10:806989. [PMID: 35356272 PMCID: PMC8959467 DOI: 10.3389/fcell.2022.806989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 02/01/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Liver hepatocellular carcinoma (LIHC) remains a global health challenge with a low early diagnosis rate and high mortality. Therefore, finding new biomarkers for diagnosis and prognosis is still one of the current research priorities. Methods: Based on the variation of gene expression patterns in different stages, the LIHC-development genes (LDGs) were identified by differential expression analysis. Then, prognosis-related LDGs were screened out to construct the LIHC-unfavorable gene set (LUGs) and LIHC-favorable gene set (LFGs). Gene set variation analysis (GSVA) was conducted to build prognostic scoring models based on the LUGs and LFGs. ROC curve analysis and univariate and multivariate Cox regression analysis were carried out to verify the diagnostic and prognostic utility of the two GSVA scores in two independent datasets. Additionally, the key LCGs were identified by the intersection analysis of the PPI network and univariate Cox regression and further evaluated their performance in expression level and prognosis prediction. Single-sample GSEA (ssGSEA) was performed to understand the correlation between the two GSVA enrichment scores and immune activity. Result: With the development of LIHC, 83 LDGs were gradually upregulated and 247 LDGs were gradually downregulated. Combining with LIHC survival analysis, 31 LUGs and 32 LFGs were identified and used to establish the LIHC-unfavorable GSVA score (LUG score) and LIHC-favorable GSVA score (LFG score). ROC curve analysis and univariate/multivariate Cox regression analysis suggested the LUG score and LFG score could be great indicators for the early diagnosis and prognosis prediction. Four genes (ESR1, EHHADH, CYP3A4, and ACADL) were considered as the key LCGs and closely related to good prognosis. The frequency of TP53 mutation and copy number variation (CNV) were high in some LCGs. Low-LFG score patients have active metabolic activity and a more robust immune response. The high-LFG score patients characterized immune activation with the higher infiltration abundance of type I T helper cells, DC, eosinophils, and neutrophils, while the high-LUG score patients characterized immunosuppression with the higher infiltration abundance of type II T helper cells, TRegs, and iDC. The high- and low-LFG score groups differed significantly in immunotherapy response scores, immune checkpoints expression, and IC50 values of common drugs. Conclusion: Overall, the LIHC-progression characteristic genes can be great diagnostic and prognostic signatures and the two GSVA score systems may become promising indices for guiding the tumor treatment of LIHC patients.
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Wu Z, Cheng H, Liu J, Zhang S, Zhang M, Liu F, Li Y, Huang Q, Jiang Y, Chen S, Lv L, Li D, Zeng JZ. The Oncogenic and Diagnostic Potential of Stanniocalcin 2 in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2022; 9:141-155. [PMID: 35300206 PMCID: PMC8922464 DOI: 10.2147/jhc.s351882] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/26/2022] [Indexed: 02/05/2023] Open
Abstract
PURPOSE Early detection and prognostic prediction of hepatocellular carcinoma (HCC) remain a great challenge. In this study, we explored the role and diagnostic significance of stanniocalcin 2 (STC2), recently identified as a secretory protein, in HCC. METHODS STC2 mRNA and protein in HCC tissues were examined by qRT-PCR and immunohistochemistry. The regulatory role of HCC growth by STC2 was evaluated in vitro and in vivo. Serum STC2 levels were determined in HCC patients and compared to those with liver cirrhosis (LC) and normal controls (NC). The difference and significance of STC2 levels between groups were analyzed by Mann-Whitney U-test. The diagnostic value of serum STC2 in detecting early HCC was assayed with receiver operating characteristics (ROC). The association of STC2 with overall survival (OS) was determined with Kaplan-Meier method. RESULTS STC2 was elevated in about 77.1% HCC patients and correlated with advanced tumor progression. Overexpression or knockdown of STC2 stimulated or suppressed HCC colony formation and xenograft tumor growth. AKT activation played a critical role in tumor-promoting effect of STC2. The median level of serum STC2 in HCC patients (n = 98, 2086.6 ng/L) was 2.6-fold and 4.2-fold that in LC patients (n = 42, 801.9 ng/L) and NC (n = 26, 496.9 ng/L), respectively. A cut-off value 1493 ng/L for STC2 could distinguish early HCC from LC with a sensitivity of 76.9% and a specificity of 76.2%, both of which were superior to AFP at 20 μg/L (sensitivity 69.2%, specificity 52.4%). STC2 was positive in 77.8% (14/18) AFP-negative patients. High STC2 level was correlated with poor overall and disease specific survival. CONCLUSION STC2 is upregulated in both tumor and serum of HCC patients, and its overexpression promotes HCC via AKT pathway. STC2 possesses a diagnostic significance and may serve as an auxiliary biomarker of AFP for detecting early HCC.
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Affiliation(s)
- Zhixian Wu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, People’s Republic of China
- Department of Hepatobiliary Disease, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China
| | - Hongwei Cheng
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, People’s Republic of China
| | - Jie Liu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, People’s Republic of China
| | - Shuaishuai Zhang
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, People’s Republic of China
| | - Minda Zhang
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, People’s Republic of China
| | - Fangzhou Liu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, People’s Republic of China
| | - Yinghui Li
- Department of Hepatobiliary Disease, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China
| | - Qian Huang
- Department of Hepatobiliary Disease, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China
| | - Yi Jiang
- Department of Hepatobiliary Surgery, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China
| | - Shaohua Chen
- Department of Hepatobiliary Surgery, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China
| | - Lizhi Lv
- Department of Hepatobiliary Surgery, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China
| | - Dongliang Li
- Department of Hepatobiliary Disease, Dongfang Hospital, Xiamen University, Fuzhou, People’s Republic of China
| | - Jin-Zhang Zeng
- Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, People’s Republic of China
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Suda T, Yamashita T, Sunagozaka H, Okada H, Nio K, Sakai Y, Yamashita T, Mizukoshi E, Honda M, Kaneko S. Dickkopf-1 Promotes Angiogenesis and is a Biomarker for Hepatic Stem Cell-like Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms23052801. [PMID: 35269944 PMCID: PMC8911428 DOI: 10.3390/ijms23052801] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/26/2022] [Accepted: 02/27/2022] [Indexed: 12/24/2022] Open
Abstract
Cancer stemness evinces interest owing to the resulting malignancy and poor prognosis. We previously demonstrated that hepatic stem cell-like hepatocellular carcinoma (HpSC-HCC) is associated with high vascular invasion and poor prognosis. Dickkopf-1 (DKK-1), a Wnt signaling regulator, is highly expressed in HpSC-HCC. Here, we assessed the diagnostic and prognostic potential of serum DKK-1. Its levels were significantly higher in 391 patients with HCC compared with 205 patients with chronic liver disease. Receiver operating characteristic curve analysis revealed the optimal cutoff value of DKK-1 to diagnose HCC and predict the 3-year survival as 262.2 and 365.9 pg/mL, respectively. HCC patients with high-serum DKK-1 levels showed poor prognosis. We evaluated the effects of anti-DKK-1 antibody treatment on tumor growth in vivo and of recombinant DKK-1 on cell proliferation, invasion, and angiogenesis in vitro. DKK-1 knockdown decreased cancer cell proliferation, migration, and invasion. DKK-1 supplementation promoted angiogenesis in vitro; this effect was abolished by an anti-DKK-1 antibody. Co-injection of the anti-DKK-1 antibody with Huh7 cells inhibited their growth in NOD/SCID mice. Thus, DKK-1 promotes proliferation, migration, and invasion of HCC cells and activates angiogenesis in vascular endothelial cells. DKK-1 is a prognostic biomarker for HCC and a functional molecule for targeted therapy.
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40
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Chen F, Wang J, Wu Y, Gao Q, Zhang S. Potential Biomarkers for Liver Cancer Diagnosis Based on Multi-Omics Strategy. Front Oncol 2022; 12:822449. [PMID: 35186756 PMCID: PMC8851237 DOI: 10.3389/fonc.2022.822449] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/17/2022] [Indexed: 12/11/2022] Open
Abstract
Liver cancer is the fourth leading cause of cancer-related death worldwide. Hepatocellular carcinoma (HCC) accounts for about 85%-90% of all primary liver malignancies. However, only 20-30% of HCC patients are eligible for curative therapy mainly due to the lack of early-detection strategies, highlighting the significance of reliable and accurate biomarkers. The integration of multi-omics became an important tool for biomarker screening and unique alterations in tumor-associated genes, transcripts, proteins, post-translational modifications and metabolites have been observed. We here summarized the novel biomarkers for HCC diagnosis based on multi-omics technology as well as the clinical significance of these potential biomarkers in the early detection of HCC.
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Affiliation(s)
- Fanghua Chen
- Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Junming Wang
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Yingcheng Wu
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Qiang Gao
- Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Shu Zhang
- Center for Tumor Diagnosis & Therapy, Jinshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
- *Correspondence: Shu Zhang,
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41
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El-Nakeep S. Molecular and genetic markers in hepatocellular carcinoma: In silico analysis to clinical validation (current limitations and future promises). World J Gastrointest Pathophysiol 2022; 13:1-14. [PMID: 35116176 PMCID: PMC8788164 DOI: 10.4291/wjgp.v13.i1.1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/15/2021] [Accepted: 12/22/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second cause of cancer-related mortality. The diagnosis of HCC depends mainly on -fetoprotein, which is limited in its diagnostic and screening capabilities. There is an urgent need for a biomarker that detects early HCC to give the patients a chance for curative treatment. New targets of therapy could enhance survival and create future alternative curative methods. In silico analysis provides both; discovery of biomarkers, and understanding of the molecular pathways, to pave the way for treatment development. This review discusses the role of in silico analysis in the discovery of biomarkers, molecular pathways, and the role the author has contributed to this area of research. It also discusses future aspirations and current limitations. A literature review was conducted on the topic using various databases (PubMed, Science Direct, and Wiley Online Library), searching in various reviews, and editorials on the topic, with overviewing the author's own published and unpublished work. This review discussed the steps of the validation process from in silico analysis to in vivo validation, to incorporation into clinical practice guidelines. In addition, reviewing the recent lines of research of bioinformatic studies related to HCC. In conclusion, the genetic, molecular and epigenetic markers discoveries are hot areas for HCC research. Bioinformatics will enhance our ability to accomplish this understanding in the near future. We face certain limitations that we need to overcome.
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Affiliation(s)
- Sarah El-Nakeep
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo 11591, Egypt
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42
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Hanif H, Ali MJ, Susheela AT, Khan IW, Luna-Cuadros MA, Khan MM, Lau DTY. Update on the applications and limitations of alpha-fetoprotein for hepatocellular carcinoma. World J Gastroenterol 2022; 28:216-229. [PMID: 35110946 PMCID: PMC8776528 DOI: 10.3748/wjg.v28.i2.216] [Citation(s) in RCA: 125] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/26/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Alpha-fetoprotein (AFP) is an oncofetal glycoprotein that has been used as a tumor marker for hepatocellular carcinoma (HCC) in combination with ultrasound and other imaging modalities. Its utility is limited because of both low sensitivity and specificity, and discrepancies among the different methods of measurements. Moreover, its accuracy varies according to patient characteristics and the AFP cut-off values used. Combination of AFP with novel biomarkers such as AFP-L3, Golgi specific membrane protein (GP73) and des-gamma-carboxyprothrombin significantly improved its accuracy in detecting HCC. Increased AFP level could also signify severity of hepatic destruction and subsequent regeneration and is commonly observed in patients with acute and chronic liver conditions and cirrhosis. Hereditary and other non-hepatic disorders can also cause AFP elevation.
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Affiliation(s)
- Hira Hanif
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Mukarram Jamat Ali
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Ammu T Susheela
- Internal Medicine, Loyola MacNeal Hospital, Berwyn, PA 60402, United States
| | - Iman Waheed Khan
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Maria Alejandra Luna-Cuadros
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Muzammil Muhammad Khan
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Daryl Tan-Yeung Lau
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
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43
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He K, Xing S, Shen Y, Jin C. A flexible optical gas pressure sensor as the signal readout for point-of-care immunoassay. Analyst 2022; 147:5428-5436. [DOI: 10.1039/d2an01305c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Inspired by the concept of pneumatic micro/nanoscale surface morphing, an optical flexible gas pressure immunosensor constructed with an optical Ag/PDMS BGPS and a SiO2/Pt immunocomplex induced gas-generated reaction element for the sensitive detection of AFP was proposed.
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Affiliation(s)
- Kai He
- State Key Laboratory of Optoelectronic Materials and Technologies, Sun Yat-sen University, Guangzhou, 510275, China
- Guangzhou Key Laboratory of Flexible Electronic Materials and Wearable Devices, Sun Yat-sen University, Guangzhou, 510275, China
- School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, China
| | - Shan Xing
- State Key Laboratory of Optoelectronic Materials and Technologies, Sun Yat-sen University, Guangzhou, 510275, China
- Department of Clinical Laboratory, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou 510275, China
| | - Yang Shen
- State Key Laboratory of Optoelectronic Materials and Technologies, Sun Yat-sen University, Guangzhou, 510275, China
- Guangzhou Key Laboratory of Flexible Electronic Materials and Wearable Devices, Sun Yat-sen University, Guangzhou, 510275, China
- School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, China
| | - Chongjun Jin
- State Key Laboratory of Optoelectronic Materials and Technologies, Sun Yat-sen University, Guangzhou, 510275, China
- Guangzhou Key Laboratory of Flexible Electronic Materials and Wearable Devices, Sun Yat-sen University, Guangzhou, 510275, China
- School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, China
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44
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Xu B, Sun HC. Camrelizumab: an investigational agent for hepatocellular carcinoma. Expert Opin Investig Drugs 2021; 31:337-346. [PMID: 34937475 DOI: 10.1080/13543784.2022.2022121] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Although many approaches have been used to treat hepatocellular carcinoma (HCC), the clinical benefits were limited, particularly for advanced HCC. However, recent treatments with PD-1/PD-L1 inhibitor monotherapy and its combination with other therapies, have demonstrated remarkable results. Camrelizumab, a selective, humanized, high-affinity IgG4 PD-1 monoclonal antibody, has been approved as a second-line treatment in patients with advanced HCC by NMPA in China. AREAS COVERED This paper introduces anti-PD-1/PD-L1 immunotherapies for advanced HCC and progresses to discuss the pharmacology, safety, and efficacy of camrelizumab in the treatment of advanced HCC. It also considers future research directions for camrelizumab in this setting. EXPERT OPINION The PD-1 binding epitope of camrelizumab is different from other PD-1 inhibitors. The IC50 and EC50 of camrelizumab for inhibiting the binding of PD-1 and PD-L1 is similar to pembrolizumab, is significantly lower than other PD-1 inhibitors, and has a higher affinity for PD-1 site. Camrelizumab exhibits a promising antitumor activity and an acceptable safety profile similar to other PD-1 inhibitors in advanced HCC. Apatinib (a VEGFR-2 tyrosine kinase inhibitor) can reduce the incidence of camrelizumab-specific reactive cutaneous capillary endothelial proliferation (RCCEP).
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Affiliation(s)
- Bin Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hui-Chuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
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Xu J, Hong J, Wang Y, Zhou L, Xu B, Si Y, He Y, Chen Y. Prognostic Influence of Spontaneous Tumor Rupture in Patients With Hepatocellular Carcinoma After Hepatectomy: A Meta-Analysis of Observational Studies. Front Surg 2021; 8:769233. [PMID: 34869566 PMCID: PMC8635041 DOI: 10.3389/fsurg.2021.769233] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 10/26/2021] [Indexed: 01/10/2023] Open
Abstract
Objective: This study aims to comprehensively analyze the influence of spontaneous tumor rupture on the prognosis of hepatocellular carcinoma patients following hepatic resection. Methods: We systematically searched four online electronic databases, including PubMed, Embase, Web of Science, and Cochrane Library, for eligible studies published from inception to March 2021. The main endpoints were overall survival (OS) and disease-free survival (DFS). Results: This meta-analysis included 21 observational articles with 57,241 cases. The results revealed that spontaneous tumor rupture was associated with worse OS (hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.33–2.05) and DFS (HR, 1.42; 95% CI, 1.12–1.80) in resectable hepatocellular carcinoma patients. This phenomenon was observed in most subgroups, which were classified by recorded survival time, age, country, alpha-fetoprotein (AFP) concentration, liver cirrhosis, and microvascular invasion. However, in subgroups of macrovascular invasion positive, spontaneous tumor rupture was not a risk factor for OS (HR, 1.55; 95% CI, 0.99–2.42) and DFS (HR, 1.23; 95% CI, 0.91–1.65) in hepatocellular carcinoma patients after hepatectomy. For macrovascular invasion negative, compared with non-ruptured hepatocellular carcinoma patients, ruptured hepatocellular carcinoma patients exhibited worse prognosis for OS (HR, 1.55; 95% CI, 0.99–2.42) and DFS (HR, 1.23; 95% CI, 0.91–1.65) following hepatectomy. Conclusions: Spontaneous tumor rupture was a prognostic risk factor for hepatocellular carcinoma patients after hepatic resection. However, in macrovascular invasion patients, spontaneous tumor rupture was not a prognostic risk factor.
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Affiliation(s)
- Jiaxuan Xu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jiaze Hong
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yiran Wang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Lingling Zhou
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Binbin Xu
- Department of Nutrition, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, China
| | - Yuexiu Si
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yujing He
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yizhou Chen
- Emergency Medical Center, Ningbo Yinzhou No. 2 Hospital, Ningbo, China
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46
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47
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Wang Y, Qiao L, Yang J, Li X, Duan Y, Liu J, Chen S, Li H, Liu D, Fang T, Ma J, Li X, Ye F, Wan J, Wei J, Xu Q, Guo E, Jin P, Wu M, Zhang L, Xia Y, Wu Y, Shao J, Feng Y, Zhang Q, Yang Z, Chen G, Zhang Q, Li X, Wang S, Hu J, Wang X, Tan MP, Takabe K, Kong B, Yang Q, Ma D, Gao Q. Serum semaphorin 4C as a diagnostic biomarker in breast cancer: A multicenter retrospective study. Cancer Commun (Lond) 2021; 41:1373-1386. [PMID: 34738326 PMCID: PMC8696225 DOI: 10.1002/cac2.12233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 09/28/2021] [Accepted: 10/05/2021] [Indexed: 12/15/2022] Open
Abstract
Background To date, there is no approved blood‐based biomarker for breast cancer detection. Herein, we aimed to assess semaphorin 4C (SEMA4C), a pivotal protein involved in breast cancer progression, as a serum diagnostic biomarker. Methods We included 6,213 consecutive inpatients from Tongji Hospital, Qilu Hospital, and Hubei Cancer Hospital. Training cohort and two validation cohorts were introduced for diagnostic exploration and validation. A pan‐cancer cohort was used to independently explore the diagnostic potential of SEMA4C among solid tumors. Breast cancer patients who underwent mass excision prior to modified radical mastectomy were also analyzed. We hypothesized that increased pre‐treatment serum SEMA4C levels, measured using optimized in‐house enzyme‐linked immunosorbent assay kits, could detect breast cancer. The endpoints were diagnostic performance, including area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Post‐surgery pathological diagnosis was the reference standard and breast cancer staging followed the TNM classification. There was no restriction on disease stage for eligibilities. Results We included 2667 inpatients with breast lesions, 2378 patients with other solid tumors, and 1168 healthy participants. Specifically, 118 patients with breast cancer were diagnosed with stage 0 (5.71%), 620 with stage I (30.00%), 966 with stage II (46.73%), 217 with stage III (10.50%), and 8 with stage IV (0.39%). Patients with breast cancer had significantly higher serum SEMA4C levels than benign breast tumor patients and normal controls (P < 0.001). Elevated serum SEMA4C levels had AUC of 0.920 (95% confidence interval [CI]: 0.900–0.941) and 0.932 (95%CI: 0.911–0.953) for breast cancer detection in the two validation cohorts. The AUCs for detecting early‐stage breast cancer (n = 366) and ductal carcinoma in situ (n = 85) were 0.931 (95%CI: 0.916–0.946) and 0.879 (95%CI: 0.832–0.925), respectively. Serum SEMA4C levels significantly decreased after surgery, and the reduction was more striking after modified radical mastectomy, compared with mass excision (P < 0.001). The positive rate of enhanced serum SEMA4C levels was 84.77% for breast cancer and below 20.75% for the other 14 solid tumors. Conclusions Serum SEMA4C demonstrated promising potential as a candidate biomarker for breast cancer diagnosis. However, validation in prospective settings and by other study groups is warranted.
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Affiliation(s)
- Ya Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Long Qiao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450000, P. R. China
| | - Jie Yang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Xiong Li
- Department of Gynecology and Obstetrics, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430014, P. R. China
| | - Yaqi Duan
- Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Jiahao Liu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Shaoqi Chen
- Department of Obstetrics and Gynecology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, P. R. China
| | - Huayi Li
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Dan Liu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Tian Fang
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Jingjing Ma
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Xiaoting Li
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Fei Ye
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Junxiang Wan
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, 90001, USA
| | - Juncheng Wei
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Qin Xu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Ensong Guo
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Ping Jin
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Mingfu Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Lin Zhang
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Yun Xia
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Yaqun Wu
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Jun Shao
- Department of Breast Surgery, Hubei Cancer Hospital, Wuhan, Hubei, 430079, P. R. China
| | - Yaojun Feng
- Department of Breast Surgery, Hubei Cancer Hospital, Wuhan, Hubei, 430079, P. R. China
| | - Qing Zhang
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, P. R. China
| | - Zongyuan Yang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Gang Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Qinghua Zhang
- Department of Gynecology and Obstetrics, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430014, P. R. China
| | - Xingrui Li
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Junbo Hu
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Xiaoyun Wang
- Yidu Cloud (Beijing) Technology Co., Beijing, 100000, P. R. China
| | - Mona P Tan
- MammoCare, The Breast Clinic & Surgery, Singapore, 329563, Singapore
| | - Kazuaki Takabe
- Department of Surgery and the Massey Cancer Centre, Virginia Commonwealth University School of Medicine, Richmond, Virginia, 23298, USA
| | - Beihua Kong
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, P. R. China
| | - Qifeng Yang
- Department of Breast Surgery, Qilu Hospital of Shandong University, No.107, Jinan Culture Road, Jinan, Shandong, 250012, P. R. China
| | - Ding Ma
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
| | - Qinglei Gao
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P. R. China
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48
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Adeniji N, Dhanasekaran R. Current and Emerging Tools for Hepatocellular Carcinoma Surveillance. Hepatol Commun 2021; 5:1972-1986. [PMID: 34533885 PMCID: PMC8631096 DOI: 10.1002/hep4.1823] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 08/04/2021] [Accepted: 08/30/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related mortality worldwide. Early detection of HCC enables patients to avail curative therapies that can improve patient survival. Current international guidelines advocate for the enrollment of patients at high risk for HCC, like those with cirrhosis, in surveillance programs that perform ultrasound every 6 months. In recent years, many studies have further characterized the utility of established screening strategies and have introduced new promising tools for HCC surveillance. In this review, we provide an overview of the most promising new imaging modalities and biomarkers for the detection of HCC. We discuss the role of imaging tools like ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) in the early detection of HCC, and describe recent innovations which can potentially enhance their applicability, including contrast enhanced ultrasound, low‐dose CT scans, and abbreviated MRI. Next, we outline the data supporting the use of three circulating biomarkers (i.e., alpha‐fetoprotein [AFP], AFP lens culinaris agglutinin‐reactive fraction, and des‐gamma‐carboxy prothrombin) in HCC surveillance, and expand on multiple emerging liquid biopsy biomarkers, including methylated cell‐free DNA (cfDNA), cfDNA mutations, extracellular vesicles, and circulating tumor cells. These promising new imaging modalities and biomarkers have the potential to improve early detection, and thus improve survival, in patients with HCC.
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Affiliation(s)
- Nia Adeniji
- Stanford School of Medicine, Stanford, CA, USA
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49
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Cao X, Cao Z, Ou C, Zhang L, Chen Y, Li Y, Zhu B, Shu H. Combination of serum paraoxonase/arylesterase 1 and antithrombin-III is a promising non-invasion biomarker for discrimination of AFP-negative HCC versus liver cirrhosis patients. Clin Res Hepatol Gastroenterol 2021; 45:101583. [PMID: 33756265 DOI: 10.1016/j.clinre.2020.11.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 11/10/2020] [Accepted: 11/13/2020] [Indexed: 02/04/2023]
Abstract
OBJECTIVE α-fetoprotein is often used in the diagnosis of hepatocellular carcinoma (HCC). However, there are currently less efficient and highly specific biomarkers to distinguish AFP-negative HCC from liver cirrhosis (LC) patients. PATIENTS AND METHODS We retrospectively analyzed the data of patients who were treated in our hospitals. iTRAQ coupled with mass spectrometry was used to identify candidate serum proteins in a discovery set (n = 36) including AFP-negative HCC and LC patients. After Western blot detection, potential serum biomarkers were confirmed using ELISA in a validation set (n = 90). The diagnostic performance of the selected proteins was assessed using receiver operating characteristic (ROC). RESULTS PON1 and ATIII were selected as target proteins and were significantly higher in LC than those in AFP-negative HCC patients as validated by Western blot and ELISA, which was consistent with the result of iTRAQ. The AUC was 0.848 as PON1 and ATIII were combined (sensitivity: 80.0%; specificity: 73.3%), and performed much better than that of a single biomarker. CONCLUSION These findings suggest that PON1 and ATIII have the potential to serve as effective biomarkers for distinguishing AFP-negative HCC from cirrhosis.
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Affiliation(s)
- Xinyi Cao
- Department of Clinical Laboratory, Cancer Hospital of Guangxi Medical University, Nanning 530021, Guangxi, PR China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China
| | - Zhao Cao
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, PR China
| | - Chao Ou
- Department of Clinical Laboratory, Cancer Hospital of Guangxi Medical University, Nanning 530021, Guangxi, PR China
| | - Lei Zhang
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China
| | - Yanhua Chen
- Department of Clinical Laboratory, Cancer Hospital of Guangxi Medical University, Nanning 530021, Guangxi, PR China
| | - Yanqiu Li
- Department of Clinical Laboratory, Cancer Hospital of Guangxi Medical University, Nanning 530021, Guangxi, PR China
| | - Bo Zhu
- Department of Clinical Laboratory, Cancer Hospital of Guangxi Medical University, Nanning 530021, Guangxi, PR China.
| | - Hong Shu
- Department of Clinical Laboratory, Cancer Hospital of Guangxi Medical University, Nanning 530021, Guangxi, PR China; Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai 200032, PR China.
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50
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Wang Y, Liu J, Li J, Li H, Li X, Qiao L, Yang J, Fang T, Chen S, Ma J, Wan J, Li X, Zhang L, Xia Y, Wu Y, Xu T, Shao J, Feng Y, Kamel IR, Yang Q, Li Z, Gao Q. Serum semaphorin4C as an auxiliary diagnostic biomarker for breast cancer. Clin Transl Med 2021; 11:e480. [PMID: 34459126 PMCID: PMC8351518 DOI: 10.1002/ctm2.480] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/10/2021] [Accepted: 06/15/2021] [Indexed: 11/24/2022] Open
Affiliation(s)
- Ya Wang
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiahao Liu
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiali Li
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huayi Li
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiong Li
- Department of Gynecology and Obstetrics, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Long Qiao
- Department of Gynecology and Obstetrics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
| | - Jie Yang
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tian Fang
- Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaoqi Chen
- Department of Obstetrics and Gynecology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingjing Ma
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junxiang Wan
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, California, USA
| | - Xingrui Li
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lin Zhang
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yun Xia
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaqun Wu
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Xu
- Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Shao
- Department of Breast Surgery, Hubei Cancer Hospital, Wuhan, China
| | - Yaojun Feng
- Department of Breast Surgery, Hubei Cancer Hospital, Wuhan, China
| | - Ihab R Kamel
- Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
| | - Qifeng Yang
- Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Ji'nan, China
| | - Zhen Li
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qinglei Gao
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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