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Cen C, Liu X, He W, Tan X, Li G, Jintong N. Novel approaches in CRISPR/Cas12a-based sensing for HCC diagnosis - A review (2020-2025). J Pharm Biomed Anal 2025; 262:116878. [PMID: 40209498 DOI: 10.1016/j.jpba.2025.116878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 03/27/2025] [Accepted: 04/05/2025] [Indexed: 04/12/2025]
Abstract
Early diagnosis of hepatocellular carcinoma (HCC) is crucial for improving patient survival and treatment outcomes and the early detection of biomarkers for HCC is key to achieving this goal. However, conventional detection methods often lack sufficient specificity and sensitivity. In recent years, CRISPR/Cas12a-based biosensing has gained significant attention due to its ease of use and high sensitivity, demonstrating its potential to address the limitations of conventional detection methods. This paper primarily reviews the research progress of CRISPR/Cas12a-based biosensors for HCC detection, introducing their fluorescence, electrochemical, colorimetric, and other detection principles, as well as practical applications in detail. Additionally, the differences in sensitivity, specificity, and detection speed among different types of CRISPR/Cas12a biosensors are comparatively analyzed. Finally, the potential future directions for the development and application of CRISPR/Cas12a technology in clinical settings are explored.
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Affiliation(s)
- Cunhong Cen
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China
| | - Xiyu Liu
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China
| | - Wei He
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China
| | - Xiaohong Tan
- College of Chemistry, Guangdong University of Petrochemical Technology, Guandu Road, Maoming, Guangdong 525000, China
| | - Guiyin Li
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China; College of Chemistry, Guangdong University of Petrochemical Technology, Guandu Road, Maoming, Guangdong 525000, China.
| | - Na Jintong
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China.
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Klein J, Arce-Clachar AC, Bramlage K, Xanthakos S, Sheridan R, Mouzaki M. Elevated Alpha-Fetoprotein Levels in Children with Metabolic Dysfunction-Associated Liver Disease. Child Obes 2025. [PMID: 40205972 DOI: 10.1089/chi.2025.0010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) can progress to end-stage liver disease and hepatocellular carcinoma (HCC), albeit infrequently in childhood. Our objectives were to (1) investigate the prevalence of elevated alpha-fetoprotein (AFP) in children with advanced, MASLD-related, fibrosis (bridging fibrosis or cirrhosis) and (2) ascertain whether pediatric MASLD is associated with AFP elevations regardless of fibrosis severity. Methods: Retrospective cohort study of patients aged 6-18 years seen at a single center between 2000 and 2024. Demographics, anthropometrics, blood work, histological data, and relevant imaging studies were collected. Descriptive statistics were used. Results: Out of a cohort of 483 pediatric patients followed for MASLD with available AFP data, 161 had undergone liver biopsy, and of those, 22 had advanced fibrosis. Children with advanced fibrosis were predominantly male (82%) and non-Hispanic (55%), with a median age of 11 years (interquartile range [IQR] = 10-18) and severe obesity (median [IQR] body mass index z-score 2.56 [2.33-2.75]). No patients with advanced fibrosis had elevated AFP levels. Of the entire MASLD cohort, however, nine had elevated AFP levels. None were diagnosed with HCC or other tumors. Conclusions: In a pediatric cohort with MASLD, severe fibrosis was not associated with elevated AFP levels. AFP elevations were seen however in some patients with MASLD but were not associated with malignancies.
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Affiliation(s)
- Jamie Klein
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
| | - Ana Catalina Arce-Clachar
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati, Ohio, USA
| | - Kristin Bramlage
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati, Ohio, USA
| | - Stavra Xanthakos
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati, Ohio, USA
| | - Rachel Sheridan
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA
| | - Marialena Mouzaki
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati, Ohio, USA
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Huy DQ, Khai NX, Thinh TH, Linh BT, Minh NN, Thuy VTB. Application of Indirect ELISA and PCR Techniques for Detecting of Hepatocellular Carcinoma using Des-gamma Carboxyprothrombin, Alpha-fetoprotein, and Thioredoxin Biomarkers. Mol Biotechnol 2025:10.1007/s12033-025-01401-z. [PMID: 39998774 DOI: 10.1007/s12033-025-01401-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 02/03/2025] [Indexed: 02/27/2025]
Abstract
Hepatocellular carcinoma (HCC) is one of the five most common cancers and the second leading cause of cancer-related death worldwide. In this study, three monoclonal antibodies were developed for the early detection of HCC. The enzyme-linked immunosorbent assay (ELISA) method is used to detect antigens causing HCC. The final working dilutions of the coated antigen, monoclonal antibody, and enzyme-labeled secondary antibody were determined to be 1:5, 1:100, and 1:15,000, respectively. The optimal dilution of blocking buffer was 1.5% BSA phosphate buffer. The cutoff values were determined to be 0.1989, 0.2539, and 0.3059 for the Des-gamma carboxyprothrombin (DCP), Alpha-fetoprotein (AFP) and Thioredoxin (TXN) antigens, respectively. There is no cross-reaction between antigens and antibodies of different types. The coincidence rates between the indirect ELISA and commercial kits for detecting DCP, AFP, and TXN antigens were 95.24%, 95.24%, and 96.83%, respectively. In addition, a procedure to detect genes encoding TXN, DCP, and AFP via PCR has been developed. The results of the indirect ELISA and PCR methods are similar. In summary, we successfully constructed an indirect ELISA method to detect HCC-causing antigens via three monoclonal antibodies and designed primers to amplify HCC-causing gene fragments, which can be used for diagnosis and screening in clinical medicine.
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Affiliation(s)
- Duong Quang Huy
- 103 Military Hospital, Vietnam Military Medical University, Hanoi, Vietnam
| | - Nguyen Xuan Khai
- 103 Military Hospital, Vietnam Military Medical University, Hanoi, Vietnam
| | - Tran Hong Thinh
- Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam
| | - Bui Thuy Linh
- Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam
| | - Nghiem Ngoc Minh
- Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam
| | - Vo Thi Bich Thuy
- Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam.
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Zhu J, Pang K, Hu B, He R, Wang N, Jiang Z, Ji P, Zhao F. Custom microfluidic chip design enables cost-effective three-dimensional spatiotemporal transcriptomics with a wide field of view. Nat Genet 2024; 56:2259-2270. [PMID: 39256584 PMCID: PMC11525186 DOI: 10.1038/s41588-024-01906-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 08/13/2024] [Indexed: 09/12/2024]
Abstract
Spatial transcriptomic techniques offer unprecedented insights into the molecular organization of complex tissues. However, integrating cost-effectiveness, high throughput, a wide field of view and compatibility with three-dimensional (3D) volumes has been challenging. Here we introduce microfluidics-assisted grid chips for spatial transcriptome sequencing (MAGIC-seq), a new method that combines carbodiimide chemistry, spatial combinatorial indexing and innovative microfluidics design. This technique allows sensitive and reproducible profiling of diverse tissue types, achieving an eightfold increase in throughput, minimal cost and reduced batch effects. MAGIC-seq breaks conventional microfluidics limits by enhancing barcoding efficiency and enables analysis of whole postnatal mouse sections, providing comprehensive cellular structure elucidation at near single-cell resolution, uncovering transcriptional variations and dynamic trajectories of mouse organogenesis. Our 3D transcriptomic atlas of the developing mouse brain, consisting of 93 sections, reveals the molecular and cellular landscape, serving as a valuable resource for neuroscience and developmental biology. Overall, MAGIC-seq is a high-throughput, cost-effective, large field of view and versatile method for spatial transcriptomic studies.
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Affiliation(s)
- Junjie Zhu
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
| | - Kun Pang
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Beiyu Hu
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
| | - Ruiqiao He
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Ning Wang
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zewen Jiang
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Peifeng Ji
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China
| | - Fangqing Zhao
- Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- Key Laboratory of Systems Biology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
- University of Chinese Academy of Sciences, Beijing, China.
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Zhou Y, Tao L, Qiu J, Xu J, Yang X, Zhang Y, Tian X, Guan X, Cen X, Zhao Y. Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct Target Ther 2024; 9:132. [PMID: 38763973 PMCID: PMC11102923 DOI: 10.1038/s41392-024-01823-2] [Citation(s) in RCA: 128] [Impact Index Per Article: 128.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 05/21/2024] Open
Abstract
Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.
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Affiliation(s)
- Yue Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lei Tao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiahao Qiu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyu Yang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yu Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
- School of Medicine, Tibet University, Lhasa, 850000, China
| | - Xinyu Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinqi Guan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaobo Cen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yinglan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Lu Y, Lin B, Li M. The role of alpha-fetoprotein in the tumor microenvironment of hepatocellular carcinoma. Front Oncol 2024; 14:1363695. [PMID: 38660138 PMCID: PMC11039944 DOI: 10.3389/fonc.2024.1363695] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 03/28/2024] [Indexed: 04/26/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent malignant cancer worldwide, characterized by high morbidity and mortality rates. Alpha-fetoprotein (AFP) is a glycoprotein synthesized by the liver and yolk sac during fetal development. However, the serum levels of AFP exhibit a significant correlation with the onset and progression of HCC in adults. Extensive research has demonstrated that the tumor microenvironment (TME) plays a crucial role in the malignant transformation of HCC, and AFP is a key factor in the TME, promoting HCC development. The objective of this review was to analyze the existing knowledge regarding the role of AFP in the TME. Specifically, this review focused on the effect of AFP on various cells in the TME, tumor immune evasion, and clinical application of AFP in the diagnosis and treatment of HCC. These findings offer valuable insights into the clinical treatment of HCC.
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Affiliation(s)
- Yan Lu
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan, China
| | - Bo Lin
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan, China
| | - Mengsen Li
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan, China
- Department of Medical Oncology, Second Affiliated Hospital, Hainan Medical College, Haikou, Hainan, China
- Institution of Tumor, Hainan Medical College, Haikou, Hainan, China
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Song H, Wang J, Zhang H, Wu Y, Wang K, Wang X, Xu X. Combination of serum alpha-fetoprotein, PIVKA-Ⅱ and glypican-3 in diagnosis of hepatocellular carcinoma: a meta-analysis. Zhejiang Da Xue Xue Bao Yi Xue Ban 2024; 53:131-139. [PMID: 38310085 PMCID: PMC10945496 DOI: 10.3724/zdxbyxb-2023-0483] [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: 10/08/2023] [Accepted: 01/26/2024] [Indexed: 02/05/2024]
Abstract
OBJECTIVES To assess the value of serum alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-Ⅱ (PIVKA-Ⅱ) and glypican-3 (GPC-3) in the diagnosis of hepatocellular carcinoma (HCC). METHODS Studies of AFP, PIVKA-Ⅱ, GPC-3 or in combination for the diagnosis of HCC since 2002 were searched in PubMed, Web of Science and Embase databases. The literature was screened according to the inclusion and exclusion criteria, the quality of the included articles was evaluated by QUADAS checklist, and relevant data were extracted by Meta DiSc, Review Manager 5.4 and Stata 15.1. The diagnostic values of AFP, PIVKA-Ⅱ and GPC-3 alone or in combination for HCC were assessed with receiver operating characteristic (ROC) curve. RESULTS A total of 32 articles were included in the study. Meta-analysis showed that when a single marker was used to diagnose HCC, the area under the ROC curve (AUC) of PIVKA-Ⅱ was the highest (0.88, 95%CI: 0.85-0.91), followed by GPC-3 and AFP. The AUC of combination of serum markers was higher than that of a single marker, and the AUC of PIVKA-Ⅱ combined with GPC-3 was the highest (0.90, 95%CI: 0.87-0.92). When a single marker was used for diagnosis, the sensitivity of PIVKA-Ⅱ and GPC-3 were relatively high (0.75 and 0.76), while the specificity of PIVKA-Ⅱ (0.88) and AFP (0.87) were higher than that of GPC-3 (0.81). The sensitivity of the combination of serum markers was higher than that of a single marker, while the specificity was not significantly improved. When a single marker is used to diagnose HCC, the diagnostic odds ratio (DOR) of PIVKA-Ⅱ was the highest (22, 95%CI: 13-36), followed by GPC-3 and AFP. The DOR of the combination of two markers in the diagnosis of HCC was higher than that of a single marker, and the DOR of AFP combined with GPC-3 was the highest (25, 95%CI: 9-67). The DOR of the combination of the three markers was significantly reduced to 10 (95%CI: 7-45). CONCLUSIONS When a single marker is used, PIVKA-Ⅱ has a higher diagnostic value for HCC. The combination of two markers can significantly improve the diagnostic sensitivity, and AFP combined with PIVKA-Ⅱ is recommended for the diagnosis of HCC. The combination of all three markers failed to further improve the diagnostic value.
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Affiliation(s)
- Hongliang Song
- The Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310053, China.
- Zhejiang Provincial Key Laboratory of Integrated Oncology and Intelligent Medicine, Hangzhou 310003, China.
| | - Jianguo Wang
- The Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310053, China
- Zhejiang Provincial Key Laboratory of Integrated Oncology and Intelligent Medicine, Hangzhou 310003, China
| | - Hui Zhang
- The Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310053, China
- Zhejiang Provincial Key Laboratory of Integrated Oncology and Intelligent Medicine, Hangzhou 310003, China
| | - Yongfeng Wu
- Zhejiang Provincial Key Laboratory of Integrated Oncology and Intelligent Medicine, Hangzhou 310003, China
| | - Kai Wang
- The Fourth Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou 310053, China.
- Zhejiang Provincial Key Laboratory of Integrated Oncology and Intelligent Medicine, Hangzhou 310003, China.
| | - Xiaobo Wang
- Zhejiang Provincial Key Laboratory of Integrated Oncology and Intelligent Medicine, Hangzhou 310003, China.
| | - Xiao Xu
- Zhejiang Provincial Key Laboratory of Integrated Oncology and Intelligent Medicine, Hangzhou 310003, China.
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Mansour A, Fytory M, Ahmed OM, Rahman FEZSA, El-Sherbiny IM. In-vitro and in-vivo assessment of pH-responsive core-shell nanocarrier system for sequential delivery of methotrexate and 5-fluorouracil for the treatment of breast cancer. Int J Pharm 2023; 648:123608. [PMID: 37972670 DOI: 10.1016/j.ijpharm.2023.123608] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 10/31/2023] [Accepted: 11/13/2023] [Indexed: 11/19/2023]
Abstract
Breast cancer (BC) is one of the leading fatal diseases affecting females worldwide. Despite the presence of tremendous chemotherapeutic agents, the resistance emergence directs the recent research towards synergistic drugs' combination along with encapsulation inside biocompatible smart nanocarriers. Methotrexate (MTX) and 5-fluorouracil (Fu) are effective against BC and have sequential synergistic activity. In this study, a core-shell nanocarrier composed of mesoporous silica nanoparticles (MSN) as the core and zeolitic imidazolate framework-8 nano metal organic frameworks (ZIF-8 NMOF) as the shell was developed and loaded with Fu and MTX, respectively. The developed nanostructure; Fu-MSN@MTX-NMOF was validated by several characterization techniques and conferred high drugs' entrapment efficiency (EE%). In-vitro assessment revealed a pH-responsive drug release pattern in the acidic pH where MTX was released followed by Fu. The cytotoxicity evaluation indicated enhanced anticancer effect of the Fu-MSN@MTX-NMOF relative to the free drugs in addition to time-dependent fortified cytotoxic effect due to the sequential drugs' release. The in-vivo anticancer efficiency was examined using Ehrlich ascites carcinoma (EAC) animal model where the anticancer effect of the developed Fu-MSN@MTX-NMOF was compared to the sequentially administrated free drugs. The results revealed enhanced anti-tumor effect while maintaining the normal functions of the vital organs as the heart, kidney and liver.
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Affiliation(s)
- Amira Mansour
- Nanomedicine Research Labs, Center for Materials Science (CMS), Zewail City of Science and Technology, 6(th) October City, 12578, Giza, Egypt
| | - Mostafa Fytory
- Nanomedicine Research Labs, Center for Materials Science (CMS), Zewail City of Science and Technology, 6(th) October City, 12578, Giza, Egypt; Material Science and Nanotechnology Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, 62511, Beni-suef, Egypt
| | - Osama M Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521, Egypt
| | | | - Ibrahim M El-Sherbiny
- Nanomedicine Research Labs, Center for Materials Science (CMS), Zewail City of Science and Technology, 6(th) October City, 12578, Giza, Egypt.
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Zhao C, Ma C, Zhang F, Lai W, Hong C, Qi Y. Preparation of oxidized acetylene black by high-temperature calcination for luminol efficient cathodic electrochemiluminescence. J Colloid Interface Sci 2023; 645:997-1004. [PMID: 37183158 DOI: 10.1016/j.jcis.2023.05.034] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/25/2023] [Accepted: 05/05/2023] [Indexed: 05/16/2023]
Abstract
The improvement of electrochemiluminescence (ECL) intensity in luminol, a classic electrochemiluminescent material, remains a controversial topic. In this study, synthesis of acetylene black oxide (ACETO) through simple air annealing was successful in introducing oxygen-containing groups and defects, which can act as active sites for the oxygen reduction reaction (ORR) and exhibit excellent catalytic activity. By introducing the two-electron (2e-) ORR into the cathode ECL system of luminol, integration of ACETO and luminol allows for in situ generation of dissolved oxygen into reactive oxygen species (ROS), thereby enhancing the ECL intensity of luminol. It is worth noting that iron-nitrogen-carbon (FeNC), as a secondary antibody (Ab2) label, can catalyze the decomposition of H2O2, the product of 2e- ORR, into ROS to achieve ECL amplification. Alpha-fetoprotein (AFP), an important tumor marker, was successfully detected with a detection limit of 0.01 pg/mL, indicating that this ECL signal amplification strategy has broad application prospects in biological analysis.
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Affiliation(s)
- Chulei Zhao
- School of Chemistry and Chemical Engineering/State Key Laboratory Incubation Base for Green Processing of Chemical Engineering, Shihezi University, Xinjiang Uygur Autonomous Region, PR China
| | - Chaoyun Ma
- School of Chemistry and Chemical Engineering/State Key Laboratory Incubation Base for Green Processing of Chemical Engineering, Shihezi University, Xinjiang Uygur Autonomous Region, PR China
| | - Fuping Zhang
- School of Chemistry and Chemical Engineering/State Key Laboratory Incubation Base for Green Processing of Chemical Engineering, Shihezi University, Xinjiang Uygur Autonomous Region, PR China
| | - Wenjing Lai
- School of Chemistry and Chemical Engineering/State Key Laboratory Incubation Base for Green Processing of Chemical Engineering, Shihezi University, Xinjiang Uygur Autonomous Region, PR China
| | - Chenglin Hong
- School of Chemistry and Chemical Engineering/State Key Laboratory Incubation Base for Green Processing of Chemical Engineering, Shihezi University, Xinjiang Uygur Autonomous Region, PR China.
| | - Yu Qi
- School of Chemistry and Chemical Engineering/State Key Laboratory Incubation Base for Green Processing of Chemical Engineering, Shihezi University, Xinjiang Uygur Autonomous Region, PR China.
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Pereira VM, Pinto PAF, Motta LCB, Almeida MF, de Andrade AFC, Pavaneli APP, Ambrósio CE. Initial Characterization of 3D Culture of Yolk Sac Tissue. Animals (Basel) 2023; 13:ani13091435. [PMID: 37174472 PMCID: PMC10177165 DOI: 10.3390/ani13091435] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 04/07/2023] [Accepted: 04/17/2023] [Indexed: 05/15/2023] Open
Abstract
The role of the yolk sac (YS) in miscarriage is not yet clear, largely due to ethical reasons that make in vivo studies difficult to conduct. However, 3D cultures could provide a solution to this problem by enabling cells to be arranged in a way that more closely mimics the structure of the YS as it exists in vivo. In this study, three domestic species (porcine, canine, and bovine) were chosen as models to standardize 3D culture techniques for the YS. Two techniques of 3D culture were chosen: the Matrigel® and Hanging-Drop techniques, and the 2D culture technique was used as a standardized method. The formed structures were initially characterized using scanning electron microscopy (SEM), immunohistochemistry (IHC), and quantitative real-time PCR (RT-qPCR). In general, the 3D culture samples showed better organization of the YS cells compared to 2D cultures. The formed structures from both 3D methods assemble the mesothelial layer of YS tissue. Regarding the IHC assay, all in vitro models were able to express zinc and cholesterol transport markers, although only 3D culture techniques were able to generate structures with different markers pattern, indicating a cell differentiation process when compared to 2D cultures. Regarding mRNA expression, the 3D models had a greater gene expression pattern on the Hemoglobin subunit zeta-like (HBZ) gene related to the YS tissue, although no significant expression was found in Alpha-fetoprotein (AFP), indicating a lack of endodermal differentiation in our 3D model. With the initial technique and characterization established, the next step is to maintain the cultures and characterize the diversity of cell populations, stemness, functions, and genetic stability of each 3D in vitro model.
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Affiliation(s)
- Vitória Mattos Pereira
- Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering (FZEA), University of São Paulo (USP), Pirassununga 13635-900, SP, Brazil
- School of Pharmacy, University of Wyoming, Laramie, WY 82072, USA
| | - Priscila Avelino Ferreira Pinto
- Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering (FZEA), University of São Paulo (USP), Pirassununga 13635-900, SP, Brazil
| | - Lina Castelo Branco Motta
- Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering (FZEA), University of São Paulo (USP), Pirassununga 13635-900, SP, Brazil
| | - Matheus F Almeida
- Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering (FZEA), University of São Paulo (USP), Pirassununga 13635-900, SP, Brazil
| | - André Furugen Cesar de Andrade
- Department of Animal Reproduction, School of Veterinary Medicine and Animal Science (FMVZ), University of São Paulo USP, Pirassununga 13635-900, SP, Brazil
| | - Ana Paula Pinoti Pavaneli
- Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering (FZEA), University of São Paulo (USP), Pirassununga 13635-900, SP, Brazil
| | - Carlos Eduardo Ambrósio
- Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering (FZEA), University of São Paulo (USP), Pirassununga 13635-900, SP, Brazil
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11
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Evmorfopoulos K, Vlachostergios PJ, Sountoulides P, Tzortzis V. Εmerging Biomarkers in the Diagnosis and Treatment of Testicular Tumors. Curr Cancer Drug Targets 2023; 23:858-867. [PMID: 36967458 DOI: 10.2174/1568009623666230324114236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 12/13/2022] [Accepted: 01/20/2023] [Indexed: 03/29/2023]
Abstract
Testicular germ cell tumors (TGCT) are the leading cause of cancer-related death in young males between the ages of 20-40. Surgical resection and cisplatin-based chemotherapy can achieve a cure for the majority of patients with TGCTs, with survival rates of up to 97% for patients diagnosed at an early stage. The use of serum biomarkers, such as AFP β-HCG, and LDH, plays a significant role in both diagnosis and evaluation of response to treatment, and despite their low sensitivity and specificity levels, they are an integral part of the current tumor staging system and daily practice. Molecular biomarkers, including micro-RNAs and gene-expression profiles, are currently being developed in TGCTs and could potentially hold a prominent place in the future diagnosis, treatment selection, surveillance, and prognostication of these tumors. This review discusses how current advances in our understanding of the underlying biology of TGCTs have helped biomarker discovery, with a focus on the recognition of key molecular alterations that could serve as potential indicators of disease onset, response to systemic or/and surgical therapies, and overall clinical course.
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Affiliation(s)
- Konstantinos Evmorfopoulos
- Department of Urology, Faculty of Medicine, School of Health Sciences, University Hospital of Larissa, University of Thessaly, Larissa, 41100, Greece
| | - Panagiotis J Vlachostergios
- Department of Urology, Faculty of Medicine, School of Health Sciences, University Hospital of Larissa, University of Thessaly, Larissa, 41100, Greece
- Department of Medical Oncology, IASO Thessalias Hospital, Larissa, 41500, Greece
- Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Petros Sountoulides
- 1st Department of Urology, School of Medicine, "G Gennimatas" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, 54635, Greece
| | - Vassilios Tzortzis
- Department of Urology, Faculty of Medicine, School of Health Sciences, University Hospital of Larissa, University of Thessaly, Larissa, 41100, Greece
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12
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Hepatocellular Carcinoma, Alpha Fetoprotein, and Liver Allocation for Transplantation: Past, Present and Future. Curr Oncol 2022; 29:7537-7551. [PMID: 36290870 PMCID: PMC9600271 DOI: 10.3390/curroncol29100593] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 10/01/2022] [Accepted: 10/02/2022] [Indexed: 11/05/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading indications for liver transplantation and has been the treatment of choice due to the oncologic benefit for patients with advanced chronic liver disease (AdvCLD) and small tumors for the last 25 years. For HCC patients undergoing liver transplantation, alpha fetoprotein (AFP) has increasingly been applied as an independent predictor for overall survival, disease free recurrence, and waitlist drop out. In addition to static AFP, newer studies evaluating the AFP dynamic response to downstaging therapy show enhanced prognostication compared to static AFP alone. While AFP has been utilized to select HCC patients for transplant, despite years of allocation policy changes, the US allocation system continues to take a uniform approach to HCC patients, without discriminating between those with favorable or unfavorable tumor biology. We aim to review the history of liver allocation for HCC in the US, the utility of AFP in liver transplantation, the implications of weaving AFP as a biomarker into policy. Based on this review, we encourage the US transplant community to revisit its HCC organ allocation model, to incorporate more precise oncologic principles for patient selection, and to adopt AFP dynamics to better stratify waitlist dropout risk.
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13
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Li X, Cui K, Xiu M, Zhou C, Li L, Zhang J, Hao S, Zhang L, Ge S, Huang Y, Yu J. In situ growth of WO 3/BiVO 4 nanoflowers onto cellulose fibers to construct photoelectrochemical/colorimetric lab-on-paper devices for the ultrasensitive detection of AFP. J Mater Chem B 2022; 10:4031-4039. [PMID: 35506741 DOI: 10.1039/d2tb00297c] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
In this work, novel dual-mode lab-on-paper devices based on in situ grown WO3/BiVO4 heterojunctions onto cellulose fibers, as signal amplification probes, were successfully fabricated by the integration of photoelectrochemical (PEC)/colorimetric analysis technologies into a paper sensing platform for the ultrasensitive detection of alpha-fetoprotein (AFP). Specifically, to achieve an impressive PEC performance of the lab-on-paper device, the WO3/BiVO4 heterojunction was in situ grown onto the surface of cellulose fibers assisted with Au nanoparticle (Au NP) functionalization for enhancing the conductivity of the working zone of the device. With the target concentration increased, more immune conjugates could be captured by the proposed paper photoelectrode, which could lead to a quantitative decrease in the photocurrent intensity, eventually realizing the accurate PEC signal readout. To meet the requirement of end-user application, a colorimetric signal readout system was designed for the lab-on-paper device based on the color reaction of 3,3'5,5'-tetramethylbenzidine (TMB) oxidized by WO3/BiVO4 nanoflowers in the presence of H2O2. Noticeably, it is the first time that the WO3/BiVO4 heterojunction is in situ grown onto cellulose fibers, which enhances the sensitivity in view of both their PEC activity and catalytic ability. By controlling the conversion process of hydrophobicity and hydrophilicity on the lab-on-paper device combined with diverse origami methods, the dual-mode PEC/colorimetric signal output for the ultrasensitive AFP detection was realized. Under optimal conditions, the proposed dual-mode lab-on-paper device could enable the sensitive PEC/colorimetric diagnosis of AFP in the linear range of 0.09-100 ng mL-1 and 5-100 ng mL-1 with the limit of detection of 0.03 and 1.47 ng mL-1, respectively.
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Affiliation(s)
- Xu Li
- School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China.
| | - Kang Cui
- School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China.
| | - Mingzhen Xiu
- School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore.
| | - Chenxi Zhou
- School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China.
| | - Li Li
- School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China.
| | - Jing Zhang
- School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China.
| | - Shiji Hao
- School of Materials Science & Engineering, Dongguan University of Technology, Guangdong 523808, P. R. China
| | - Lina Zhang
- Shandong Provincial Key Laboratory of Preparation and Measurement of Building Materials, University of Jinan, Jinan, 250022, P. R. China
| | - Shenguang Ge
- School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China.
| | - Yizhong Huang
- School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore.
| | - Jinghua Yu
- School of Chemistry and Chemical Engineering, University of Jinan, Jinan 250022, P. R. China.
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14
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Ataikiru UO, Iacob ER, Miron I, Popoiu CM, Boia ES. A 10-year retrospective single-center study of alpha-fetoprotein and beta-human chorionic gonadotropin in Romanian children with (para)gonadal tumors and cysts. J Pediatr Endocrinol Metab 2022; 35:363-371. [PMID: 34968016 DOI: 10.1515/jpem-2021-0382] [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: 06/05/2021] [Accepted: 12/06/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Malignant tumor is a top-ranking cause of pediatric (>1-year) mortality in America and Europe. Among pediatric tumors, germ cell tumors (GCT) and gonadal tumors rank fourth (6%) by the Surveillance, Epidemiology, and End Results (SEER) program (seer.cancer.gov). Continuous research on tumor markers harnesses their full potential in tumor detection and management. We evaluated the effectiveness of beta-human chorionic gonadotropin (β-hCG) and Alpha-fetoprotein (AFP) in Romanian children with (para)gonadal tumors and cysts, determining their accuracy in detecting malignancy, tumor-type, stage, complications, prognosis, and treatment response. METHODS A 10-year retrospective study of AFP and β-hCG in 134 children with cysts and (para)gonadal tumors aged one month to 17 years was performed. RESULTS AFP/β-hCG was unelevated in patients with cysts and nonmalignant tumors. Forty-eight/86 patients (43 GCT and 5 non-GCT) with malignant tumors had elevated AFP/β-hCG, 3/48 patients had recurrences, and 25/48 had mixed-GCT (68% had elevated AFP + β-hCG). All 30 patients with Yolk sac tumors (YST) or their components had elevated AFP. Area under the curve, sensitivity and specificity for GCT were: AFP + β-hCG- 0.828, 67.2%, 100%; AFP- 0.813, 64.1%, 100%; and β-hCG- 0.664, 32.8%, 100%. Two patients whose AFP/β-hCG levels remained elevated died. Common mixed-GCT components were YST-80% and embryonal carcinoma-72%. Thirty of 34 metastasis cases were GCT, with 26/34 patients having elevated AFP/β-hCG. CONCLUSIONS AFP/β-hCG detects malignant GCT and can determine tumor-type. GCT patients with markedly elevated AFP + β-hCG had poor prognosis, especially if recurrence or metastasis was present. Recurrence is unrelated to elevated AFP/β-hCG. The tumor components and quantity present determine AFP/β-hCG values in mixed-GCT.
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Affiliation(s)
- Usiwoma O Ataikiru
- Department of Pediatric Surgery and Orthopedics, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
- Department of Pediatric Surgery and Orthopedics, "Louis Turcanu" Emergency Childrens Hospital, Timisoara, Romania
| | - Emil R Iacob
- Department of Pediatric Surgery and Orthopedics, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
- Department of Pediatric Surgery and Orthopedics, "Louis Turcanu" Emergency Childrens Hospital, Timisoara, Romania
| | - Ingrith Miron
- Department of Pediatric Hematology and Oncology, Saint Mary Clinical Emergency Hospital for Children, Iasi, Romania
| | - Calin M Popoiu
- Department of Pediatric Surgery and Orthopedics, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
- Department of Pediatric Surgery and Orthopedics, "Louis Turcanu" Emergency Childrens Hospital, Timisoara, Romania
| | - Eugen S Boia
- Department of Pediatric Surgery and Orthopedics, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
- Department of Pediatric Surgery and Orthopedics, "Louis Turcanu" Emergency Childrens Hospital, Timisoara, Romania
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15
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Almeida JI, Tenreiro MF, Martinez-Santamaria L, Guerrero-Aspizua S, Gisbert JP, Alves PM, Serra M, Baptista PM. Hallmarks of the human intestinal microbiome on liver maturation and function. J Hepatol 2022; 76:694-725. [PMID: 34715263 DOI: 10.1016/j.jhep.2021.10.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/05/2021] [Accepted: 10/17/2021] [Indexed: 12/18/2022]
Abstract
As one of the most metabolically complex systems in the body, the liver ensures multi-organ homeostasis and ultimately sustains life. Nevertheless, during early postnatal development, the liver is highly immature and takes about 2 years to acquire and develop almost all of its functions. Different events occurring at the environmental and cellular levels are thought to mediate hepatic maturation and function postnatally. The crosstalk between the liver, the gut and its microbiome has been well appreciated in the context of liver disease, but recent evidence suggests that the latter could also be critical for hepatic function under physiological conditions. The gut-liver crosstalk is thought to be mediated by a rich repertoire of microbial metabolites that can participate in a myriad of biological processes in hepatic sinusoids, from energy metabolism to tissue regeneration. Studies on germ-free animals have revealed the gut microbiome as a critical contributor in early hepatic programming, and this influence extends throughout life, mediating liver function and body homeostasis. In this seminar, we describe the microbial molecules that have a known effect on the liver and discuss how the gut microbiome and the liver evolve throughout life. We also provide insights on current and future strategies to target the gut microbiome in the context of hepatology research.
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Affiliation(s)
- Joana I Almeida
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain; Instituto de Biologia Experimental e Tecnológica (iBET), Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), Oeiras, Portugal
| | - Miguel F Tenreiro
- Instituto de Biologia Experimental e Tecnológica (iBET), Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), Oeiras, Portugal
| | - Lucía Martinez-Santamaria
- Carlos III University of Madrid. Bioengineering and Aerospace Engineering, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, ISCIII), Madrid, Spain; Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain
| | - Sara Guerrero-Aspizua
- Carlos III University of Madrid. Bioengineering and Aerospace Engineering, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, ISCIII), Madrid, Spain
| | - Javier P Gisbert
- Gastroenterology Department. Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Paula M Alves
- Instituto de Biologia Experimental e Tecnológica (iBET), Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), Oeiras, Portugal
| | - Margarida Serra
- Instituto de Biologia Experimental e Tecnológica (iBET), Oeiras, Portugal; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), Oeiras, Portugal
| | - Pedro M Baptista
- Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain; Carlos III University of Madrid. Bioengineering and Aerospace Engineering, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain; Fundación ARAID, Zaragoza, Spain.
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16
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Turshudzhyan A, Wu GY. Persistently Rising Alpha-fetoprotein in the Diagnosis of Hepatocellular Carcinoma: A Review. J Clin Transl Hepatol 2022; 10:159-163. [PMID: 35233385 PMCID: PMC8845163 DOI: 10.14218/jcth.2021.00176] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 08/19/2021] [Accepted: 09/15/2021] [Indexed: 12/04/2022] Open
Abstract
Hepatocellular carcinoma (HCC), one of the most common malignant tumors worldwide, is known for its grim prognosis, with untreated life expectancy being only a matter of months after the diagnosis. The difficulty in making a diagnosis early is one of the main contributing factors to the poor prognosis. Alpha-fetoprotein (AFP) had long been used as a surveillance tool, but suboptimal specificity and sensitivity has prompted liver societies to abandon the recommendation for its universal use, even in combination with ultrasonography. Most studies have shown no obvious correlation between serum AFP level and HCC tumor size, stage, or survival post-diagnosis. However, some studies concluded that a gradual rise or persistent elevation in AFP were positive predictors for tumor development. Other studies reported a fall in AFP followed by a rise in patients with HCC as well as persistently rising AFP levels without development of HCC on follow up. Our calculation of the sensitivity and specificity of persistently rising AFP for HCC were both low, at 60% and 35.8%, respectively, indicating that the presence of persistently rising AFP per se did not offer diagnostic benefit. In addition, our calculated mean slopes of persistently rising AFP levels in HCC and non-HCC patients were numerically very different, but the difference was not statistically significant. We conclude that the published data do not support a role for rising AFP levels per se in the diagnosis of HCC.
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Affiliation(s)
- Alla Turshudzhyan
- Correspondence to: Alla Turshudzhyan, Department of Medicine, Division of Gastroenterology and Hepatology. University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06032, USA. ORCID: https://orcid.org/0000-0001-6867-7569. Tel: +1-860-679-6296, Fax: +1-860-679-6582, E-mail:
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17
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Mocan T, Kang DW, Molloy BJ, Jeon H, Spârchez ZA, Beyoğlu D, Idle JR. Plasma fetal bile acids 7α-hydroxy-3-oxochol-4-en-24-oic acid and 3-oxachola-4,6-dien-24-oic acid indicate severity of liver cirrhosis. Sci Rep 2021; 11:8298. [PMID: 33859329 PMCID: PMC8050265 DOI: 10.1038/s41598-021-87921-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 04/06/2021] [Indexed: 12/25/2022] Open
Abstract
Two 3-oxo-Δ4 fetal bile acids, 3-oxachola-4,6-dien-24-oic acid (1) and 7α-hydroxy-3-oxochol-4-en-24-oic acid (2), occur normally in the human fetus but remain elevated in neonates and children with severe cholestatic liver disease due to an autosomal recessive inborn error of metabolism affecting Δ4-3-oxo-steroid 5β-reductase (AKR1D1). Relatively little is known about 1 and 2 in adult patients with liver disease. The chemical synthesis of 1 and 2 is therefore described and their quantitation in plasma by ultrarapid chromatography-triple quadrupole mass spectrometry. Plasma concentrations of 1 and 2 were investigated in 25 adult patients with varying degrees of liver cirrhosis with and without hepatocellular carcinoma (HCC). Highly statistically significant correlations (P < 0.0001) were found between severity of liver cirrhosis, determined by the Child-Pugh and MELD scores, with plasma 1 and 2 concentrations, both alone and combined. The presence of HCC did not influence these correlations. Plasma cholic, chenodeoxycholic, deoxycholic, lithocholic or ursodeoxycholic acids, free and as their glycine or taurine conjugates, did not correlate with Child-Pugh or MELD score when corrected for multiple comparisons. These findings demonstrate that plasma levels of fetal bile acids 3-oxachola-4,6-dien-24-oic acid and 7α-hydroxy-3-oxochol-4-en-24-oic acid and likely deteriorating AKR1D1 activity indicate the severity of liver cirrhosis measured by the Child-Pugh and MELD scores.
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Affiliation(s)
- Tudor Mocan
- 3rd Medical Clinic, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Dong Wook Kang
- Department of Pharmaceutical Science and Technology, College of Health and Medical Science, Catholic University of Daegu, Gyeongsan-si, Gyeongsangbuk-do, 38430, Republic of Korea
| | | | - Hyeonho Jeon
- Department of Pharmaceutical Science and Technology, College of Health and Medical Science, Catholic University of Daegu, Gyeongsan-si, Gyeongsangbuk-do, 38430, Republic of Korea
| | - Zeno A Spârchez
- 3rd Medical Clinic, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Diren Beyoğlu
- Division of Systems Pharmacology and Pharmacogenomics, Samuel J. and Joan B. Williamson Institute, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, 11201, USA
| | - Jeffrey R Idle
- Division of Systems Pharmacology and Pharmacogenomics, Samuel J. and Joan B. Williamson Institute, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, 11201, USA.
- Department of BioMedical Research, University of Bern, 3008, Bern, Switzerland.
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18
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Song T, Wang L, Xin R, Zhang L, Tian Y. Evaluation of serum AFP and DCP levels in the diagnosis of early-stage HBV-related HCC under different backgrounds. J Int Med Res 2020; 48:300060520969087. [PMID: 33135527 PMCID: PMC7780580 DOI: 10.1177/0300060520969087] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 10/06/2020] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE This study compared the diagnostic performance of alpha-fetoprotein (AFP) and des-gamma-carboxyprothrombin (DCP) in early-stage hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) under different backgrounds. METHODS Patients were enrolled and divided in four groups: chronic HBV infection (CHB), liver cirrhosis (LC), early-stage CHB-HCC, and early-stage LC-HCC. Serum AFP and DCP levels were measured. Receiver-operating characteristic (ROC) curve and area under the curve (AUC) analyses were applied to compare the diagnostic performance of DCP and AFP for HCC. RESULTS In total, 200 patients were enrolled, including 48, 64, 33, and 55 patients with CHB, LC, CHB-HCC, and LC-HCC, respectively. ROC curve analysis revealed that the AUCs of AFP, DCP, and their combination in differentiating early-stage LC-HCC from LC were 0.776, 0.758, and 0.786, respectively. The values of these markers in discriminating early-stage CHB-HCC from CHB were 0.828, 0.731, and 0.862, respectively. CONCLUSIONS DCP was inferior to AFP in differentiating early-stage CHB-HCC from CHB. However, AFP and DCP displayed similar performance in distinguishing early-stage LC-HCC and LC.
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Affiliation(s)
- Ting Song
- Department of Hepatology, The Sixth People’s Hospital of Qingdao, Qingdao, Shandong, China
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Lili Wang
- Department of Hepatology, The Sixth People’s Hospital of Qingdao, Qingdao, Shandong, China
| | - Ruopei Xin
- Department of Hepatology, The Sixth People’s Hospital of Qingdao, Qingdao, Shandong, China
| | - Liping Zhang
- Department of Hepatology, The Sixth People’s Hospital of Qingdao, Qingdao, Shandong, China
| | - Yun Tian
- Department of Oncology, Shanghai Dermatology Hospital, Tongji University, Shanghai, China
- Tongji University Cancer Center, The Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
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19
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Ashokachakkaravarthy K, Pottakkat B. Mitotic quiescence in hepatic cancer stem cells: An incognito mode. Oncol Rev 2020; 14:452. [PMID: 32153726 PMCID: PMC7036709 DOI: 10.4081/oncol.2020.452] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 01/02/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma represents one of the most aggressive cancers with high recurrence rates. The high recurrence is a major problem in the management of this disease. Cancer stem cells (CSCs) are often regarded as the basis of cancer recurrence. The anti-proliferative therapy kills the proliferating cells but induces mitotic quiescence in CSCs which remain as residual dormant CSCs. Later on, withdrawal of treatment reactivates the residual CSCs from dormancy to produce new cancer cells. The proliferation of these newly formed cancer cells initiates new tumor formation in the liver leading to tumor recurrence. HCC cells evade the immune surveillance via modulating the key immune cells by alpha feto-protein (AFP) secreted from CSCs or hepatic progenitor cells. This AFP mediated immune evasion assists in establishing new tumors by cancer cells in the liver. In this review, we will summarise the CSC mechanisms of recurrence, mitotic quiescence, dormancy and reactivation of CSCs, metastasis and immune evasion of hepatocellular carcinoma.
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Affiliation(s)
- Kandasamy Ashokachakkaravarthy
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
| | - Biju Pottakkat
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India
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20
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Wang Q, Hu Y, Jiang N, Wang J, Yu M, Zhuang X. Preparation of Aptamer Responsive DNA Functionalized Hydrogels for the Sensitive Detection of α-Fetoprotein Using SERS Method. Bioconjug Chem 2020; 31:813-820. [PMID: 31977189 DOI: 10.1021/acs.bioconjchem.9b00874] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC), which is one of the three major cancers, has attracted growing attention due to its high mortality, health care cost, and circumscribed therapeutic methods. Hence, the development of a fast, accurate, and flexible method to detect α-fetoprotein (AFP), the specific marker of HCC, is significant for diagnosis and treatment of cancer. Here, we constructed a novel SERS biosensing platform combining the target-responsive DNA hydrogel for the sensitive detection of AFP. The linker strand in DNA hydrogel is an aptamer that can specifically recognize AFP and accurately control the release of immunoglobulin G (IgG) encapsulated in hydrogel. In the presence of AFP, the hydrogels were disentangled and the IgG was released. Thereafter, the released IgG was captured by SERS probes and biofunctional magnetic beads through formation of sandwich-like structures, resulting in the signal of Raman tags decreasing in the supernatant after magnetic separation. Due to the ultrahigh sensitivity of the SERS biosensor, the proposed method has a wide detection linear range (50 pg/mL to 0.5 μg/mL) and a detection limit down to 50 pg/mL. Moreover, the sequence of the linker strand in the DNA hydrogel can be specifically encoded into a new aptamer that responds to other cancer markers. This convenient and inexpensive detection method provides a new strategy for the detection of tumor markers.
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Affiliation(s)
- Qi Wang
- MOE & Guangdong Province Key Laboratory of Laser Life Science & Institute of Laser Life Science, Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, P R China
| | - Yongjun Hu
- MOE & Guangdong Province Key Laboratory of Laser Life Science & Institute of Laser Life Science, Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, P R China
| | - Ningjing Jiang
- MOE & Guangdong Province Key Laboratory of Laser Life Science & Institute of Laser Life Science, Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, P R China
| | - Junjie Wang
- MOE & Guangdong Province Key Laboratory of Laser Life Science & Institute of Laser Life Science, Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, P R China
| | - Meng Yu
- MOE & Guangdong Province Key Laboratory of Laser Life Science & Institute of Laser Life Science, Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, P R China
| | - Xiumei Zhuang
- MOE & Guangdong Province Key Laboratory of Laser Life Science & Institute of Laser Life Science, Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, P R China
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Linson EA, Hanauer SB. More Than a Tumor Marker…A Potential Role for Alpha-Feto Protein in Inflammatory Bowel Disease. Inflamm Bowel Dis 2019; 25:1271-1276. [PMID: 30624658 DOI: 10.1093/ibd/izy394] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 11/05/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Human alpha-fetoprotein (hAFP) is a glycoprotein derived from the gut entoderm and expressed sequentially by cells of the yolk sac, fetal liver, and gastrointestinal tract. By adulthood, serum levels of alpha-fetoprotein (AFP) are undetectable in healthy, nonpregnant adults. Despite the clinical utilities of AFP monitoring in pregnancy and malignancy, much remains to be determined regarding its potential physiological functions. METHODS We focused on literature related to AFP's immunoregulatory role and its ability to modulate disease activity both in animal models of autoimmune disorders and in human clinical studies. RESULTS Evidence suggests that AFP plays an important role in immunoregulation by inducing T-cell suppressor activity, downregulating dendritic-like cell antigen expression, and impairing the function of macrophages. Studies evaluating AFP and its effects in rodent models of autoimmune diseases have shown that AFP is associated with downregulation of inflammation. Observations in studies of pregnant patients with immune-mediated inflammatory diseases have also described potential correlations between AFP expression and disease activity during different stages of pregnancy and postpartum. CONCLUSIONS We propose further prospective evaluations of AFP expression during pregnancy in inflammatory bowel disease patients to further correlate with disease activity and consider the potential of AFP as a novel therapeutic agent.
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Affiliation(s)
| | - Stephen B Hanauer
- Northwestern University, Feinberg School of Medicine, Chicago Illinois
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22
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Rizzo A, Galgano M, Mutinati M, Sciorsci R. Alpha-fetoprotein in animal reproduction. Res Vet Sci 2019; 123:281-285. [DOI: 10.1016/j.rvsc.2019.01.028] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 01/24/2019] [Accepted: 01/27/2019] [Indexed: 11/27/2022]
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He Y, Lu H, Zhang L. Serum AFP levels in patients suffering from 47 different types of cancers and noncancer diseases. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2019; 162:199-212. [PMID: 30905450 DOI: 10.1016/bs.pmbts.2019.01.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Alpha-fetoprotein (AFP) is a glycoprotein and belongs to the gene family of serum albumins. The serum AFP levels were found to be elevated in the sera of liver cancer patients in 1964 and were subsequently developed and used as a liver cancer biomarker. However, elevated serum AFP levels have been observed in patients suffering from other cancer and noncancer diseases. Up to date, a systematic comparison of the serum AFP levels in different diseases has not been reported. In current study, 66,682 clinical lab test results of serum AFP levels from healthy individuals and patients with 47 different types of diseases during the past 5 years were retrieved and analyzed. Based on the mean (SD), median, and p (-Log10p) values, we found that patients suffering from liver, breast, esophagus, cervical, pancreatic, endometrial, gastric, lung, rectum cancers in addition to noncancer diseases cirrhosis, nephrotic syndrome, and gastritis had significantly (p<0.05) increased, whereas patients suffering from multiple myeloma, Wilms' tumor, and other 22 types of noncancer diseases had significantly decreased median serum AFP levels than that of healthy controls. Moreover, patients with liver cancer, cirrhosis, lymphoma, bone fracture, and Wilms' tumor had highest mean serum AFP levels and the biggest SD values. In summary, the increased serum AFP levels were most evident but not specific for liver cancer patients. The potential clinical use of the increased or decreased serum AFP levels for other types of cancer and noncancer diseases and the molecular mechanisms behind our current findings need to be investigated.
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Affiliation(s)
- Yanli He
- Systems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Haijun Lu
- Department of Radiology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lijuan Zhang
- Systems Biology and Medicine Center for Complex Diseases, Affiliated Hospital of Qingdao University, Qingdao, China.
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Wu M, Liu H, Liu Z, Liu C, Zhang A, Li N. Analysis of serum alpha-fetoprotein (AFP) and AFP-L3 levels by protein microarray. J Int Med Res 2018; 46:4297-4305. [PMID: 30111217 PMCID: PMC6166357 DOI: 10.1177/0300060518789304] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Objectives This study aimed to examine a simple, effective, time-saving, and low-cost
protein microarray method for detecting serum alpha-fetoprotein (AFP) and
AFP-L3 levels. Methods Serum samples from patients with hepatocellular carcinoma (HCC) (n = 33) and
control subjects (n = 39) were collected and evaluated for the presence of
AFP using a novel protein microarray. Glycoprotein (including AFP-L3) was
enriched from crude samples by a Hotgen Biotech glycosyl capture spin column
and then detected by protein microarray. An electrochemiluminescence
immunoassay (ECLIA) was used to validate the measured values. Results Neither AFP levels lower than 20 ng/mL in the HCC group nor AFP levels higher
than 20 ng/mL in the control group were found when tested by the ECLIA and
protein microarray. The kappa test showed good consistency in the diagnostic
performance of measuring serum AFP levels and the percentage of AFP-L3 in
total AFP by the ECLIA and protein microarray. Protein microarray had
advantages of smaller sample size required, low cost, and convenience
compared with the ECLIA. Conclusion The protein microarray assay that was developed in the present study shows
potential as an economic and convenient technique for detecting AFP and
AFP-L3 levels in serum samples from patients with HCC.
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Affiliation(s)
- Min Wu
- 1 Department of General Surgery, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Haidong Liu
- 1 Department of General Surgery, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Zhaobo Liu
- 1 Department of General Surgery, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Chao Liu
- 1 Department of General Surgery, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Aiying Zhang
- 2 Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Ning Li
- 1 Department of General Surgery, Beijing YouAn Hospital, Capital Medical University, Beijing, China.,2 Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
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Placenta Accreta Spectrum: A Review of Pathology, Molecular Biology, and Biomarkers. DISEASE MARKERS 2018; 2018:1507674. [PMID: 30057649 PMCID: PMC6051104 DOI: 10.1155/2018/1507674] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 06/10/2018] [Indexed: 12/14/2022]
Abstract
Background. Placenta accreta spectrum (PAS) is a condition of abnormal placental invasion encompassing placenta accreta, increta, and percreta and is a major cause of severe maternal morbidity and mortality. The diagnosis of a PAS is made on the basis of histopathologic examination and characterised by an absence of decidua and chorionic villi are seen to directly adjacent to myometrial fibres. The underlying molecular biology of PAS is a complex process that requires further research; for ease, we have divided these processes into angiogenesis, proliferation, and inflammation/invasion. A number of diagnostic serum biomarkers have been investigated in PAS, including human chorionic gonadotropin (HCG), pregnancy-associated plasma protein-A (PAPP-A), and alpha-fetoprotein (AFP). They have shown variable reliability and variability of measurement depending on gestational age at sampling. At present, a sensitive serum biomarker for invasive placentation remains elusive. In summary, there are a limited number of studies that have contributed to our understanding of the molecular biology of PAS, and additional biomarkers are needed to aid diagnosis and disease stratification.
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The fate of hepatocyte cell line derived from a liver injury model with long-term in vitro passage. Mol Cell Toxicol 2018. [DOI: 10.1007/s13273-018-0029-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
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Li L, Chen J, Xu W, Ding X, Wang X, Liang J. Clinical characteristics of hepatocellular carcinoma patients with normal serum alpha-fetoprotein level: A study of 112 consecutive cases. Asia Pac J Clin Oncol 2017; 14:e336-e340. [PMID: 29071776 DOI: 10.1111/ajco.12816] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 09/20/2017] [Indexed: 01/01/2023]
Abstract
BACKGROUND Serum alpha-fetoprotein (AFP) level is normal in 30-40% of hepatocellular carcinoma (HCC) patients, and knowledge on its characteristics and clinical outcome is limited. The purpose of this observational study was to determine the clinical presentation, biological behavior and outcome of HCC patients with normal AFP level. METHODS Data of 112 consecutive HCC patients with normal AFP level were analyzed retrospectively. Statistical analysis including survival and factors associated with serum AFP level were performed by Kaplan-Meier method and t-test, respectively. RESULTS Hepatitis B virus infection exited in 83.0% of all 112 HCC patients with normal AFP level. During a mean 52 ± 20 months (range 5-85 months) follow-up, the 1-, 2-, 3-year overall survival (OS) rate was 97.2%, 85.3% and 81.7%, respectively. The OS rates at 3 years stratified by stages at diagnosis were 100%, 96.2%, 85.7%, 11.1% and 0%, respectively for Barcelona Clinic Liver Cancer (BCLC) stage 0-D diseases. Significant difference in OS was observed among patients with BCLC stage 0-D diseases, P < 0.05. Using 8.78 ng/mL as the cut off value, serum AFP level elevated beyond normal figure during follow-up (AFP conversion) in 16 patients, which related with deterioration of liver function, quantitative changes of T helper cell subsets, rapid tumor progression and shorter survival. Patients with sustained normal AFP level had better survival than patients with AFP conversion, P < 0.05. There was significant difference between the time of diagnosis with HCC to serum AFP level elevation and the time of AFP elevation to death, P < 0.05. CONCLUSION Prognosis of HCC patients with normal AFP level was relatively optimal. Serum AFP level elevation during follow-up was significantly associated with clinical outcome in terms of OS.
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Affiliation(s)
- Li Li
- Department of Oncology, Peking University International Hospital, Beijing, China
| | - Jinglong Chen
- Department of Oncology, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Weiran Xu
- Department of Oncology, Peking University International Hospital, Beijing, China
| | - Xiaosheng Ding
- Department of Oncology, Peking University International Hospital, Beijing, China
| | - Xiangyi Wang
- Department of Oncology, Peking University International Hospital, Beijing, China
| | - Jun Liang
- Department of Oncology, Peking University International Hospital, Beijing, China
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Nakagawa H, Mizukoshi E, Kobayashi E, Tamai T, Hamana H, Ozawa T, Kishi H, Kitahara M, Yamashita T, Arai K, Terashima T, Iida N, Fushimi K, Muraguchi A, Kaneko S. Association Between High-Avidity T-Cell Receptors, Induced by α-Fetoprotein-Derived Peptides, and Anti-Tumor Effects in Patients With Hepatocellular Carcinoma. Gastroenterology 2017; 152:1395-1406.e10. [PMID: 28188748 DOI: 10.1053/j.gastro.2017.02.001] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 01/30/2017] [Accepted: 02/01/2017] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Levels of α-fetoprotein (AFP) are measured for surveillance and diagnosis of hepatocellular carcinoma (HCC). We performed a phase 1 trial to evaluate the safety and efficacy of AFP-derived peptides as an anti-tumor vaccine for patients with advanced HCC, and characterized induction of AFP-specific T-cell receptors (TCRs). METHODS We performed a prospective study of 15 patients with HCC seen at Kanazawa University Hospital in Japan from March 2010 through March 2012. Each patient was given a subcutaneous injection of 3 mg AFP-derived peptides (AFP357 and AFP403) in an emulsion with incomplete Freund's adjuvant every other week for at least 6 weeks. Patients were evaluated every 8 weeks by radiologic imaging; adverse events and toxicities were categorized and graded using the common terminology criteria for adverse events. Criteria for discontinuation included unacceptable toxicities and disease progression defined as progressive disease using the Response Evaluation Criteria In Solid Tumors criteria. Patients' immune responses were monitored using an interferon-gamma enzyme-linked immunospot assay. Peptide-specific TCRs were assessed using a rapid TCR cloning and evaluation system. The observation period was 730 days. A complete response was defined as the disappearance of all tumors; stable disease was defined as tumors whose total diameter remained between >70% and <120% of the baseline measurement, without new lesions. RESULTS We did not observe any serious adverse reactions to the peptides, which were well tolerated. Of the 15 patients who received at least 3 injections, 5 (33%) had an immune response to the peptides. One of the 15 patients had a complete response and disease stabilized in 8 patients. In 4 of the 15 patients, we detected AFP357-specific CD8 T cells; we cloned 14 different TCRs with different avidities for the peptide. A TCR with the highest avidity was observed in the patient who achieved a complete response for more than 2 years. CONCLUSIONS In a phase 1 trial, administration of AFP-derived peptides to 15 patients with HCC did not cause adverse events and produced T cells with receptors that reacted to the peptides; 1 patient had a complete response and tumor growth slowed in 8 patients. T cells from the patient with a complete response expressed a highly functional TCR induced by the peptide vaccines. UMIN-CTR no: UMIN000003514.
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Affiliation(s)
- Hidetoshi Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan; Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
| | - Eiji Kobayashi
- Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Toshikatsu Tamai
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan; Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Hiroshi Hamana
- Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Tatsuhiko Ozawa
- Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Hiroyuki Kishi
- Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Masaaki Kitahara
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takeshi Terashima
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Noriho Iida
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kazumi Fushimi
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Atsushi Muraguchi
- Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
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Nguyen K, Jimenez M, Moghadam N, Wu C, Farid A, Grotts J, Elashoff D, Choi G, Durazo FA, El-Kabany MM, Han SHB, Saab S. Decrease of Alpha-fetoprotein in Patients with Cirrhosis Treated with Direct-acting Antivirals. J Clin Transl Hepatol 2017; 5:43-49. [PMID: 28507926 PMCID: PMC5411356 DOI: 10.14218/jcth.2016.00057] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 01/26/2017] [Accepted: 02/01/2017] [Indexed: 12/11/2022] Open
Abstract
Background and Aims: The lack of specificity has limited the role of serum alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) screening among patients with cirrhosis related to hepatitis C virus (HCV) infection. We sought to examine whether AFP may decrease after achieving a sustained virological response (SVR) in patients with HCV-related cirrhosis. Methods: We performed a retrospective study of patients with HCV-related cirrhosis who were cured with direct-acting antiviral (DAA) therapy at the University of California, Los Angeles. Laboratory values, including serum AFP, were measured before and after completing the DAA treatment. Results: Fifty-six patients met the inclusion criteria, with median (interquartile range [IQR]) age of 67 (58-69) years and with 51.8% being male. All patients received DAA therapy without interferon. AFP decreased from median (IQR) 7.2 (4.2-13.4) ng/mL before DAAs to 4.2 (2.7-6.3) ng/mL at the end of treatment and 4.2 (2.9-6.8) ng/mL at 12 weeks after treatment (p < 0.001). Model for end-stage liver disease (MELD), fibrosis-4 (FIB4), and aspartate transaminase (AST) to platelet ratio index (APRI) scores at baseline were not significantly associated with AFP reduction. On multivariate analysis, platelet count, AST and total bilirubin at baseline were significantly correlated to AFP reduction (p = 0.04, 0.009 and 0.04, respectively). The higher the baseline AFP, the greater the reduction in AFP. There was no statistically significant correlation between baseline AFP and MELD, FIB4 or APRI scores. Conclusion: There was a significant decrease in AFP in patients with cirrhosis who achieved a SVR with DAAs. Given a reduction in AFP after DAA treatment, AFP should be further studied as a screening modality for HCC in patients with cirrhosis.
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Affiliation(s)
- Kelvin Nguyen
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Melissa Jimenez
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Nima Moghadam
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Crystal Wu
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Alex Farid
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Jonathan Grotts
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
| | - David Elashoff
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
- Departments of Biostatistics, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Gina Choi
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Francisco A. Durazo
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Mohamed M. El-Kabany
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Steven-Huy B. Han
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Sammy Saab
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
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Viggiani V, Palombi S, Gennarini G, D'Ettorre G, De Vito C, Angeloni A, Frati L, Anastasi E. Protein induced by vitamin K absence or antagonist-II (PIVKA-II) specifically increased in Italian hepatocellular carcinoma patients. Scand J Gastroenterol 2016; 51:1257-62. [PMID: 27227515 DOI: 10.1080/00365521.2016.1183705] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE As a marker for Hepatocellular Carcinoma (HCC), Protein Induced by Vitamin K Absence II (PIVKA-II) seems to be superior to alpha fetoprotein (AFP). To better characterize the role of PIVKA-II, both AFP and PIVKA-II have been measured in Italian patients with diagnosis of HCC compared with patients affected by non-oncological liver pathologies. MATERIALS AND METHODS Sixty serum samples from patients with HCC, 60 samples from patients with benign liver disease and 60 samples obtained from healthy blood donors were included in the study. PIVKA-II and AFP were measured by LUMIPULSE(®) G1200 (Fujirebio-Europe, Belgium). We considered as PIVKA-II cutoff 70 mAU/ml (mean +3SD) of the values observed in healthy subjects. RESULTS The evaluation of PIVKA-II showed a positivity of 70% in patients with HCC and 5% in patients with benign diseases (p < 0.0001) whereas high levels of AFP were observed in 55% of HCC patients and in 47% of patients with benign diseases. The combined Receiver Operating Characteristic (ROC) analysis of the two analytes revealed a higher sensitivity (75%) compared to those observed for the individual biomarkers. In conclusion, we demonstrate that as a marker for HCC, PIVKA-II is more specific for HCC and less prone to elevation during chronic liver diseases. CONCLUSIONS The combination of the two biomarkers, evaluated by the ROC analysis, improved the specificity compared to a single marker. These data suggest that the combined analysis of the two markers could be a useful tool in clinical practice.
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Affiliation(s)
- Valentina Viggiani
- a Department of Molecular Medicine , "Sapienza" University of Rome , Roma , Italy
| | - Sara Palombi
- a Department of Molecular Medicine , "Sapienza" University of Rome , Roma , Italy
| | - Giuseppina Gennarini
- a Department of Molecular Medicine , "Sapienza" University of Rome , Roma , Italy
| | - Gabriella D'Ettorre
- b Department of Public Health and Infectious Diseases , ''Sapienza'' University of Rome , Roma , Italy
| | - Corrado De Vito
- b Department of Public Health and Infectious Diseases , ''Sapienza'' University of Rome , Roma , Italy
| | - Antonio Angeloni
- a Department of Molecular Medicine , "Sapienza" University of Rome , Roma , Italy
| | - Luigi Frati
- a Department of Molecular Medicine , "Sapienza" University of Rome , Roma , Italy
| | - Emanuela Anastasi
- a Department of Molecular Medicine , "Sapienza" University of Rome , Roma , Italy
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Sun J, Hu T, Chen C, Zhao D, Yang F, Yang X. Fluorescence Immunoassay System via Enzyme-Enabled in Situ Synthesis of Fluorescent Silicon Nanoparticles. Anal Chem 2016; 88:9789-9795. [DOI: 10.1021/acs.analchem.6b02847] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Jian Sun
- State
Key Laboratory of Electroanalytical Chemistry, Changchun Institute
of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China
| | - Tao Hu
- State
Key Laboratory of Electroanalytical Chemistry, Changchun Institute
of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China
- Department
of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Chuanxia Chen
- State
Key Laboratory of Electroanalytical Chemistry, Changchun Institute
of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Dan Zhao
- State
Key Laboratory of Electroanalytical Chemistry, Changchun Institute
of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Fan Yang
- State
Key Laboratory of Electroanalytical Chemistry, Changchun Institute
of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China
| | - Xiurong Yang
- State
Key Laboratory of Electroanalytical Chemistry, Changchun Institute
of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China
- Department
of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
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Charrière B, Maulat C, Suc B, Muscari F. Contribution of alpha-fetoprotein in liver transplantation for hepatocellular carcinoma. World J Hepatol 2016; 8:881-890. [PMID: 27478538 PMCID: PMC4958698 DOI: 10.4254/wjh.v8.i21.881] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 05/30/2016] [Accepted: 06/29/2016] [Indexed: 02/06/2023] Open
Abstract
Alpha-fetoprotein (AFP) is the main tumor biomarker available for the management of hepatocellular carcinoma (HCC). Although it is neither a good screening test nor an accurate diagnostic tool for HCC, it seems to be a possible prognostic marker. However, its contribution in liver transplantation for HCC has not been fully determined, although its use to predict recurrence after liver transplantation has been underlined by international societies. In an era of organ shortages, it could also have a key role in the selection of patients eligible for liver transplantation. Yet unanswered questions remain. First, the cut-off value of serum AFP above which liver transplantation should not be performed is still a subject of debate. We show that a concentration of 1000 ng/mL could be an exclusion criterion, whereas values of < 15 ng/mL indicate patients with an excellent prognosis whatever the size and number of tumors. Monitoring the dynamics of AFP could also prove useful. However, evidence is lacking regarding the values that should be used. Today, the real input of AFP seems to be its integration into new criteria to select patients eligible for a liver transplantation. These recent tools have associated AFP values with morphological criteria, thus refining pre-existing criteria, such as Milan, University of California, San Francisco, or “up-to-seven”. We provide a review of the different criteria submitted within the past years. Finally, AFP can be used to monitor recurrence after transplantation, although there is little evidence to support this claim. Future challenges will be to draft new international guidelines to implement the use of AFP as a selection tool, and to determine a clear cut-off value above which liver transplantation should not be performed.
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The human fetoembryonic defense system hypothesis: Twenty years on. Mol Aspects Med 2016; 51:71-88. [PMID: 27349751 DOI: 10.1016/j.mam.2016.06.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 06/13/2016] [Accepted: 06/21/2016] [Indexed: 11/21/2022]
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An SL, Xiao T, Wang LM, Rong WQ, Wu F, Feng L, Liu FQ, Tian F, Wu JX. Prognostic Significance of Preoperative Serum Alpha- fetoprotein in Hepatocellular Carcinoma and Correlation with Clinicopathological Factors: a Single-center Experience from China. Asian Pac J Cancer Prev 2016; 16:4421-7. [PMID: 26028108 DOI: 10.7314/apjcp.2015.16.10.4421] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVES To investigate the prognosis significance of preoperative serum alpha-fetoprotein (AFP) and the correlation with clinicopathological factors of hepatocellular carcinoma (HCC) patients who underwent hepatectomy. MATERIALS AND METHODS Clinicopathological data of retrospective analysis were collected for 251 HCC patients undergoing hepatectomy in this study. According to preoperative AFP level, patients were categorized into AFP-negative (0-20 ng/mL) and AFP-positive (>20 ng/mL) groups for Kaplan-Meier analysis and Cox proportional hazard regression modeling. RESULTS The results demonstrated that increased AFP was associated with longer prothrombin time (PTs), liver capsule invasion, low grade differentiation, and late Barcelona Clinic Liver Center (BCLC) stage. Moreover, the female patients had a greater prevalence of increased preoperative AFP than male patients [284.8 (3.975-3167.5) vs (3.653-140.65); Z-2.895, p=0.004]. The 1-, 3-, and 5-year recurrence-free survival (RFS) rates were 78.1, 57.5, and 40.6 % in the AFP-negative group and 61.8, 37.7, and 31.4 %, respectively, in the AFP-positive group (log-rank test 8.312, p=0.004). The 1-, 3-, and 5-year overall survival (OS) rates were 94.4, 83.8, and 62.3% in the AFP-negative group and 87.2, 60.0, and 36.7%, respectively, in the AFP-positive group. The difference was statistically significant (log-rank test, 16.884, p=0.000). Cox proportional-hazards model identified preoperative AFP to be an independent prognostic predictor of overall survival. CONCLUSIONS Preoperative serum AFP is an independent predictor of prognosis among HCC patients following surgical resection. Female patients have a higher preoperative AFP than their male counterparts.
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Affiliation(s)
- Song-Lin An
- Department of Abdominal Surgical Oncology, State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China E-mail :
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Butterfield LH. Lessons learned from cancer vaccine trials and target antigen choice. Cancer Immunol Immunother 2016; 65:805-12. [PMID: 26842127 DOI: 10.1007/s00262-016-1801-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 01/21/2016] [Indexed: 01/15/2023]
Abstract
A wide variety of tumor antigens have been targeted in cancer immunotherapy studies. Traditionally, the focus has been on commonly overexpressed antigens shared across many patients and/or tumor types. As the field has progressed, the identity of human tumor rejection antigens has broadened. Immunologic monitoring of clinical trials has slowly elucidated candidate biomarkers of immune response and clinical response, and conversely, of immune dysfunction and suppression. We have utilized MART-1/Melan-A in our melanoma studies and observed a high frequency of immune responses and several significant clinical responses in patients vaccinated with this melanosomal protein. Alpha-fetoprotein is a shared, overexpressed tumor antigen and secreted glycoprotein that we have tested in hepatocellular cancer vaccines. Our recent studies have identified immunosuppressive and immune-skewing activities of this antigen. The choice of target antigen and its form can have unexpected effects.
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Affiliation(s)
- Lisa H Butterfield
- University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. .,Departments of Medicine, Surgery and Immunology, Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA, 15213, USA.
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Xu R, Jiang Y, Xia L, Zhang T, Xu L, Zhang S, Liu D, Song H. A sensitive photoelectrochemical biosensor for AFP detection based on ZnO inverse opal electrodes with signal amplification of CdS-QDs. Biosens Bioelectron 2015; 74:411-7. [DOI: 10.1016/j.bios.2015.06.037] [Citation(s) in RCA: 96] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Revised: 06/15/2015] [Accepted: 06/17/2015] [Indexed: 10/23/2022]
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Fahrner R, Dondorf F, Ardelt M, Dittmar Y, Settmacher U, Rauchfuß F. Liver transplantation for hepatocellular carcinoma - factors influencing outcome and disease-free survival. World J Gastroenterol 2015; 21:12071-12082. [PMID: 26576092 PMCID: PMC4641125 DOI: 10.3748/wjg.v21.i42.12071] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 08/04/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma is one of the leading causes of cancer-related death worldwide. Liver transplantation can be a curative treatment in selected patients. However, there are several factors that influence disease-free survival after transplantation. This review addresses the pre-, intra- and postoperative factors that influence the risk of tumor recurrence after liver transplantation.
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Sensitive electrochemical immunosensor for α-fetoprotein based on graphene/SnO 2 /Au nanocomposite. Biosens Bioelectron 2015; 71:82-87. [DOI: 10.1016/j.bios.2015.04.012] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 03/19/2015] [Accepted: 04/05/2015] [Indexed: 01/25/2023]
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Pardee AD, Yano H, Weinstein AM, Ponce AAK, Ethridge AD, Normolle DP, Vujanovic L, Mizejewski GJ, Watkins SC, Butterfield LH. Route of antigen delivery impacts the immunostimulatory activity of dendritic cell-based vaccines for hepatocellular carcinoma. J Immunother Cancer 2015. [PMID: 26199728 PMCID: PMC4509479 DOI: 10.1186/s40425-015-0077-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background Dendritic cells (DC) are uniquely equipped to capture, process, and present antigens from their environment. The context in which an antigen is acquired by DC helps to dictate the subsequent immune response. Cancer vaccination promotes antitumor immunity by directing an immune response to antigens expressed by tumors. We have tested the tumor-associated antigen alpha-fetoprotein (AFP) as an immunotherapy target. The majority of hepatocellular carcinomas (HCC) upregulate and secrete this oncofetal antigen. Methods To develop cancer vaccines for HCC capable of promoting potent tumor-specific T cell responses, we tested adenovirally-encoded synthetic AFP, with or without its signal sequence, as well as protein forms of AFP and compared intracellular routing and subsequent antigen-specific CD8+ and CD4+ T cell responses. Results Surprisingly, the secreted form of antigen was superior for both CD4+ and CD8+ T cell activation. We also examined the mechanism through which AFP protein is endocytosed and trafficked in human DC. We identify the mannose receptor (MR/CD206) as the primary uptake pathway for both normal cord blood-derived AFP (nAFP) and tumor-derived AFP (tAFP) proteins. While in healthy donors, nAFP and tAFP were cross-presented to CD8+ T cells similarly and CD4+ T cell responses were dependent upon MR-mediated uptake. In HCC patient cells, tAFP was more immunogenic, and CD4+ T cell responses were not MR-dependent. Conclusions Secreted, cytoplasmically retained, and endocytosed forms of AFP utilize unique uptake and processing pathways, resulting in different immunologic responses from the induced antigen-specific CD4+ and CD8+ T cells and between healthy donors and HCC patients. Collectively, these data elucidate pathways of spontaneous and induced anti-tumor immunity in HCC patients to this secreted antigen. Electronic supplementary material The online version of this article (doi:10.1186/s40425-015-0077-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | - Hiroshi Yano
- Departments of Medicine, Pittsburgh, PA 15261 USA
| | | | | | | | | | - Lazar Vujanovic
- Departments of Medicine, Pittsburgh, PA 15261 USA ; Departments of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA
| | - Gerald J Mizejewski
- Non-paid Advisor at the Wadsworth Center, New York State Department of Health, Albany, NY 12201 USA
| | - Simon C Watkins
- Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA 15261 USA
| | - Lisa H Butterfield
- Departments of Medicine, Pittsburgh, PA 15261 USA ; Departments of Surgery, Pittsburgh, PA 15261 USA ; Departments of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA ; University of Pittsburgh Cancer Institute, Hillman Cancer Center 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213 USA
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Zhu M, Lin B, Zhou P, Li M. Molecular Analysis of AFP and HSA Interactions with PTEN Protein. BIOMED RESEARCH INTERNATIONAL 2015; 2015:256916. [PMID: 26078940 PMCID: PMC4452835 DOI: 10.1155/2015/256916] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 05/01/2015] [Accepted: 05/02/2015] [Indexed: 12/13/2022]
Abstract
Human cytoplasmic alpha-fetoprotein (AFP) has been classified as a member of the albuminoid gene family. The protein sequence of AFP has significant homology to that of human serum albumin (HSA), but its biological characteristics are vastly different from HSA. The AFP functions as a regulator in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway, but HSA plays a key role as a transport protein. To probe their molecular mechanisms, we have applied colocalization, coimmunoprecipitation (co-IP), and molecular docking approaches to analyze the differences between AFP and HSA. The data from colocalization and co-IP displayed a strong interaction between AFP and PTEN (phosphatase and tensin homolog), demonstrating that AFP did bind to PTEN, but HSA did not. The molecular docking study further showed that the AFP domains I and III could contact with PTEN. In silicon substitutions of AFP binding site residues at position 490M/K and 105L/R corresponding to residues K490 and R105 in HSA resulted in steric clashes with PTEN residues R150 and K46, respectively. These steric clashes may explain the reason why HSA cannot bind to PTEN. Ultimately, the experimental results and the molecular modeling data from the interactions of AFP and HSA with PTEN will help us to identify targets for designing drugs and vaccines against human hepatocellular carcinoma.
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Affiliation(s)
- Mingyue Zhu
- College of Agriculture, Hainan University, Haikou, Hainan 570228, China
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, China
| | - Bo Lin
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, China
| | - Peng Zhou
- College of Agriculture, Hainan University, Haikou, Hainan 570228, China
| | - Mengsen Li
- College of Agriculture, Hainan University, Haikou, Hainan 570228, China
- Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou, Hainan 571199, China
- Key Laboratory of Molecular Biology, Hainan Medical College, Haikou, Hainan 571199, China
- Institution of Tumor, Hainan Medical College, Haikou, Hainan 570102, China
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Carmichael J, Krantz D, Liu HP, Janik D, Hallahan T. Incorporation of dried blood alpha fetoprotein into traditional first trimester Down syndrome screening service. Prenat Diagn 2015; 35:703-8. [PMID: 25846256 PMCID: PMC4690508 DOI: 10.1002/pd.4596] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 03/21/2015] [Accepted: 03/26/2015] [Indexed: 02/05/2023]
Abstract
Abstract What’s already known about this topic? What does this study add?
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Blank S, Wang Q, Fiel MI, Luan W, Kim KW, Kadri H, Mandeli J, Hiotis SP. Assessing prognostic significance of preoperative alpha-fetoprotein in hepatitis B-associated hepatocellular carcinoma: normal is not the new normal. Ann Surg Oncol 2014; 21:986-94. [PMID: 24232510 DOI: 10.1245/s10434-013-3357-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatitis B (HBV)-associated hepatocellular carcinoma (HCC) is often associated with alpha-fetoprotein (AFP) production. Although serum AFP has been demonstrated to be a prognostic factor for patient survival, optimal cutoff levels remain unclear. METHODS Patients with HBV-associated HCC treated by primary liver resection were prospectively followed at a single institution between 1995 and 2008. AFP level was categorized into quintiles for Kaplan–Meier analysis and multivariable Cox proportional hazards regression models. RESULTS Best 5-year survival after surgery was observed for patients with AFP in the first quintile (1.4-4.1 ng/mL), with progressively worse outcomes for patients in each increasing quintile. AFP was associated with overall survival (HR = 1.61; 95 % CI 1.30-1.98), disease-free survival (HR = 1.26; 95 % CI 1.10-1.44), and 2-year recurrence (HR = 1.30; 95 % CI 1.07-1.57) in multivariate analysis. Noncirrhotic patients (Ishak 1-5) with AFP in quintile 1 had 94 % 5-year survival, compared with 0 % survival for patients with AFP in quintile 5 (2,332.7-327,560.0 ng/mL) and Ishak stage 6 cirrhosis. CONCLUSIONS Preoperative serum AFP is an independent predictor of prognosis among HBV-HCC patients following surgical resection. Categorizing AFP into quintiles creates the opportunity to observe differences in outcomes even at low serum levels within the normal range. Additionally, combining AFP quintiles and fibrosis staging provides a predictive model of prognosis for HCC. Thus, even small differences in AFP within the normal range may impact prognosis and disease progression for HBV-HCC.
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Pardee AD, Shi J, Butterfield LH. Tumor-derived α-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells. THE JOURNAL OF IMMUNOLOGY 2014; 193:5723-32. [PMID: 25355916 DOI: 10.4049/jimmunol.1400725] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Several tumor-derived factors have been implicated in dendritic cell (DC) dysfunction in cancer patients. α-fetoprotein (AFP) is an oncofetal Ag that is highly expressed in abnormalities of prenatal development and several epithelial cancers, including hepatocellular carcinoma (HCC). In HCC patients exhibiting high levels of serum AFP, we observed a lower ratio of myeloid/plasmacytoid circulating DCs compared with patients with low serum AFP levels and healthy donors. To test the effect of AFP on DC differentiation in vitro, peripheral blood monocytes from healthy donors were cultured in the presence of cord blood-derived normal AFP (nAFP) or HCC tumor-derived AFP (tAFP), and DC phenotype and function were assessed. Although the nAFP and tAFP isoforms only differ at one carbohydrate group, low (physiological) levels of tAFP, but not nAFP, significantly inhibited DC differentiation. tAFP-conditioned DCs expressed diminished levels of DC maturation markers, retained a monocyte-like morphology, exhibited limited production of inflammatory mediators, and failed to induce robust T cell proliferative responses. Mechanistic studies revealed that the suppressive activity of tAFP is dependent on the presence of low molecular mass (LMM) species that copurify with tAFP and function equivalently to the LMM fractions of both tumor and nontumor cell lysates. These data reveal the unique ability of tAFP to serve as a chaperone protein for LMM molecules, both endogenous and ubiquitous in nature, which function cooperatively to impair DC differentiation and function. Therefore, novel therapeutic approaches that antagonize the regulatory properties of tAFP will be critical to enhance immunity and improve clinical outcomes.
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Affiliation(s)
- Angela D Pardee
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | - Jian Shi
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | - Lisa H Butterfield
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213
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Schumacher A, Costa SD, Zenclussen AC. Endocrine factors modulating immune responses in pregnancy. Front Immunol 2014; 5:196. [PMID: 24847324 PMCID: PMC4021116 DOI: 10.3389/fimmu.2014.00196] [Citation(s) in RCA: 157] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 04/22/2014] [Indexed: 12/16/2022] Open
Abstract
How the semi-allogeneic fetus is tolerated by the maternal immune system remains a fascinating phenomenon. Despite extensive research activity in this field, the mechanisms underlying fetal tolerance are still not well understood. However, there are growing evidences that immune–immune interactions as well as immune–endocrine interactions build up a complex network of immune regulation that ensures fetal survival within the maternal uterus. In the present review, we aim to summarize emerging research data from our and other laboratories on immune modulating properties of pregnancy hormones with a special focus on progesterone, estradiol, and human chorionic gonadotropin. These pregnancy hormones are critically involved in the successful establishment, maintenance, and termination of pregnancy. They suppress detrimental maternal alloresponses while promoting tolerance pathways. This includes the reduction of the antigen-presenting capacity of dendritic cells (DCs), monocytes, and macrophages as well as the blockage of natural killer cells, T and B cells. Pregnancy hormones also support the proliferation of pregnancy supporting uterine killer cells, retain tolerogenic DCs, and efficiently induce regulatory T (Treg) cells. Furthermore, they are involved in the recruitment of mast cells and Treg cells into the fetal–maternal interface contributing to a local accumulation of pregnancy-protective cells. These findings highlight the importance of endocrine factors for the tolerance induction during pregnancy and encourage further research in the field.
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Affiliation(s)
- Anne Schumacher
- Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University , Magdeburg , Germany
| | - Serban-Dan Costa
- University Women's Clinic, Otto-von-Guericke University , Magdeburg , Germany
| | - Ana Claudia Zenclussen
- Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University , Magdeburg , Germany
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LABSCH SABRINA, LIU LI, BAUER NATHALIE, ZHANG YIYAO, ALEKSANDROWICZ EWA, GLADKICH JURY, SCHÖNSIEGEL FRANK, HERR INGRID. Sulforaphane and TRAIL induce a synergistic elimination of advanced prostate cancer stem-like cells. Int J Oncol 2014; 44:1470-80. [PMID: 24626333 PMCID: PMC4027950 DOI: 10.3892/ijo.2014.2335] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Accepted: 01/03/2014] [Indexed: 01/31/2023] Open
Abstract
Advanced androgen-independent prostate cancer (AIPC) is an aggressive malignancy with a poor prognosis. Apoptosis-resistant cancer stem cells (CSCs) have been identified in AIPC and are not eliminated by current therapeutics. Novel therapeutic options, which are currently being evaluated in patient studies, include TRAIL and the broccoli-derived isothiocyanate sulforaphane. Although neither agent targets normal cells, TRAIL induces apoptosis in most cancer cells, and sulforaphane eliminates CSCs. In this study, the established AIPC cell lines DU145 and PC3, with enriched CSC features, and primary patient-derived prostate CSCs were treated with sulforaphane and recombinant soluble TRAIL. We examined the effects of these drugs on NF-κB activity, self-renewal and differentiation potential, and stem cell signaling via spheroid- and colony-forming assays, FACS and western blot analyses, immunohistochemistry, and an antibody protein array in vitro and after xenotransplantation. We largely found a stronger effect of sulforaphane on CSC properties compared to TRAIL, though the agents acted synergistically when applied in combination. This was associated with the inhibition of TRAIL-induced NF-κB binding; CXCR4, Jagged1, Notch 1, SOX 2, and Nanog expression; ALDH1 activity inhibition; and the elimination of differentiation and self-renewal potential. In vivo, tumor engraftment and tumor growth were strongly inhibited, without the induction of liver necrosis or other obvious side effects. These findings suggest that sulforaphane shifts the balance from TRAIL-induced survival signals to apoptosis and thus explains the observed synergistic effect. A nutritional strategy for high sulforaphane intake may target the cancer-specific activity of TRAIL in CSCs.
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Affiliation(s)
- SABRINA LABSCH
- Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg,
Germany
| | - LI LIU
- Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg,
Germany
| | - NATHALIE BAUER
- Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg,
Germany
| | - YIYAO ZHANG
- Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg,
Germany
| | - EWA ALEKSANDROWICZ
- Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg,
Germany
| | - JURY GLADKICH
- Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg,
Germany
| | - FRANK SCHÖNSIEGEL
- Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg,
Germany
| | - INGRID HERR
- Experimental Surgery, General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg,
Germany
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Abstract
Mammalian alpha-fetoprotein (AFP) as a fetal specific alpha-globulin has long been used as a serum fetal defect/tumor marker for diagnosis and prediction of liver diseases. In the last decade, clinical and basic research data indicated that AFP acts not only as a biomarker but also as an intracellular signal molecule to play multifarious role in the development of hepatocellular carcinoma.
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Tumour markers and kidney function: a systematic review. BIOMED RESEARCH INTERNATIONAL 2014; 2014:647541. [PMID: 24689048 PMCID: PMC3933284 DOI: 10.1155/2014/647541] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Revised: 12/02/2013] [Accepted: 12/06/2013] [Indexed: 01/18/2023]
Abstract
Tumour markers represent useful tools in diagnosis and clinical management of patients with cancer, because they are easy to use, minimally invasive, and easily measured in either blood or urine. Unfortunately, such an ideal marker, as yet, does not exist. Different pathological states may increase the level of a tumour marker in the absence of any neoplasia. Alternatively, low levels of tumour markers could be also found in the presence of neoplasias. We aimed at reviewing studies currently available in the literature examining the association between tumour markers and different renal impairment conditions. Each tumour marker was found to be differently influenced by these criteria; additionally we revealed in many cases a lack of available published data.
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Uveitis and gender: the course of uveitis in pregnancy. J Ophthalmol 2014; 2014:401915. [PMID: 24683491 PMCID: PMC3941965 DOI: 10.1155/2014/401915] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 12/09/2013] [Indexed: 12/26/2022] Open
Abstract
The hormonal and immunological changes in pregnancy have a key role in maintaining maternal tolerance of the semiallogeneic foetus. These pregnancy-associated changes may also influence the course of maternal autoimmune diseases. Noninfectious uveitis tends to improve during pregnancy. Specifically, uveitis activity tends to ameliorate from the second trimester onwards, with the third trimester being associated with the lowest disease activity. The mechanism behind this phenomenon is likely to be multifactorial and complex. Possible mechanisms include Th1/Th2 immunomodulation, regulatory T-cell phenotype plasticity, and immunosuppressive cytokines. This clearly has management implications for patients with chronic sight threatening disease requiring systemic treatment, as most medications are not recommended during pregnancy due to lack of safety data or proven teratogenicity. Given that uveitis activity is expected to decrease in pregnancy, systemic immunosuppressants could be tapered during pregnancy in these patients, with flare-ups being managed with local corticosteroids till delivery. In the postpartum period, as uveitis activity is expected to rebound, patients should be reviewed closely and systemic medications recommenced, depending on uveitis activity and the patient's breastfeeding status. This review highlights the current understanding of the course of uveitis in pregnancy and its management to help guide clinicians in managing their uveitis patients during this special time in life.
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Quantum-dot-based homogeneous time-resolved fluoroimmunoassay of alpha-fetoprotein. Anal Chim Acta 2012; 741:100-5. [DOI: 10.1016/j.aca.2012.06.042] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Revised: 06/18/2012] [Accepted: 06/20/2012] [Indexed: 11/24/2022]
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Xieraili M, Yasen M, Mogushi K, Obulhasim G, Mayinuer A, Aihara A, Tanaka S, Mizushima H, Tanaka H, Arii S. Villin 1 is a predictive factor for the recurrence of high serum alpha-fetoprotein-associated hepatocellular carcinoma after hepatectomy. Cancer Sci 2012; 103:1493-1501. [PMID: 22530999 PMCID: PMC7659241 DOI: 10.1111/j.1349-7006.2012.02315.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2012] [Revised: 03/12/2012] [Accepted: 04/14/2012] [Indexed: 12/27/2022] Open
Abstract
The prognostic assessment of patients with hepatocellular carcinoma (HCC) after resection is an important clinical issue. The present study investigated those genes associated with high serum alpha-fetoprotein (AFP), and their clinical significance, including prognosis and recurrence after hepatectomy. Based on gene expression analysis of 110 training HCC cases, 20 genes whose mRNA expression levels were significantly upregulated and 50 genes that were downregulated correlated with high serum AFP-associated HCC patients. Gene expression profiles of Villin1 (Vil1) were obtained in high serum AFP-associated HCC tumor tissues. In the present analysis, only VIL1 was significantly correlated with the recurrence of HCC. The results were validated independently using Taqman gene expression assays and immunostaining analysis. Results showed that the upregulation of VIL1 mRNA was also correlated with high serum PIVKAII, vascular invasion (P < 0.05), poor differentiation, an advanced cancer stage (P < 0.01) and recurrence-free survival (P = 0.017). The upregulation of VIL1 mRNA was observed more frequently in the early recurrence patients as compared to the late recurrence patients. Cox regression univariate and multivariate analyses indicated that high serum AFP levels (overall survival, HR 1.675, P = 0.002; FRS, HR 1.359, P = 0.039) and Vil1 protein expression (overall survival, HR 0.253, P = 0.009; FRS, HR 0.401, P = 0.041) were independent, unfavorable prognostic factors for overall and recurrence-free survival of patients. We demonstrated that the VIL1 gene is a potential candidate molecular marker for high serum AFP-associated HCC and a predictive candidate for the postoperative recurrence and poorer prognosis of HCC.
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Affiliation(s)
- Maimaiti Xieraili
- Departments of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Tokyo, Japan
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