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Golizeh M, Melendez-Pena CE, Ward BJ, Saeed S, Santamaria C, Conway B, Cooper C, Klein MB, Ndao M. Proteomic fingerprinting in HIV/HCV co-infection reveals serum biomarkers for the diagnosis of fibrosis staging. PLoS One 2018; 13:e0195148. [PMID: 29608613 PMCID: PMC5880398 DOI: 10.1371/journal.pone.0195148] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 03/16/2018] [Indexed: 12/18/2022] Open
Abstract
Background Hepatic complications of hepatitis C virus (HCV), including fibrosis and cirrhosis are accelerated in human immunodeficiency virus (HIV)-infected individuals. Although, liver biopsy remains the gold standard for staging HCV-associated liver disease, this test can result in serious complications and is subject to sampling errors. These challenges have prompted a search for non-invasive methods for liver fibrosis staging. To this end, we compared serum proteome profiles at different stages of fibrosis in HIV/HCV co- and HCV mono-infected patients using surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS). Methods Sera from 83 HIV/HCV co- and 68 HCV mono-infected subjects in 4 stages of fibrosis were tested. Sera were fractionated, randomly applied to protein chip arrays (IMAC, CM10 and H50) and spectra were generated at low and high laser intensities. Results Sixteen biomarkers achieved a p value < 0.01 (ROC values > 0.75 or < 0.25) predictive of fibrosis status in co-infected individuals and 14 in mono infected subjects. Five of these candidate biomarkers contributed to both mono- and co-infected subjects. Candidate diagnostic algorithms were created to distinguish between non-fibrotic and fibrotic individuals using a panel of 4 biomarker peaks. Conclusion These data suggest that SELDI MS profiling can identify diagnostic serum biomarkers for fibrosis that are both common and distinct in HIV/HCV co-infected and HCV mono-infected individuals.
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Affiliation(s)
- Makan Golizeh
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | | | - Brian J. Ward
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
| | - Sahar Saeed
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Division of Infectious Diseases and Chronic Viral Illness Service, McGill University Health Centre, Montreal, Quebec, Canada
| | - Cynthia Santamaria
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Brian Conway
- Vancouver Infectious Diseases Center, Vancouver, British Columbia, Canada
| | - Curtis Cooper
- The Ottawa Hospital-General Campus, Ottawa, Ontario, Canada
| | - Marina B. Klein
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Division of Infectious Diseases and Chronic Viral Illness Service, McGill University Health Centre, Montreal, Quebec, Canada
| | - Momar Ndao
- Program in Infectious Diseases and Immunity in Global Health, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
- National Reference Centre for Parasitology, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- * E-mail:
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ITIH4: Effective Serum Marker, Early Warning and Diagnosis, Hepatocellular Carcinoma. Pathol Oncol Res 2017; 24:663-670. [DOI: 10.1007/s12253-017-0285-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 08/07/2017] [Indexed: 10/19/2022]
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3
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Li B, Li B, Guo T, Sun Z, Li X, Li X, Wang H, Chen W, Chen P, Qiao M, Xia L, Mao Y. Application Value of Mass Spectrometry in the Differentiation of Benign and Malignant Liver Tumors. Med Sci Monit 2017; 23:1636-1644. [PMID: 28376075 PMCID: PMC5388305 DOI: 10.12659/msm.901064] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Differentiation of malignant from benign liver tumors remains a challenging problem. In recent years, mass spectrometry (MS) technique has emerged as a promising strategy to diagnose a wide range of malignant tumors. The purpose of this study was to establish classification models to distinguish benign and malignant liver tumors and identify the liver cancer-specific peptides by mass spectrometry. Material/Methods In our study, serum samples from 43 patients with malignant liver tumors and 52 patients with benign liver tumors were treated with weak cation-exchange chromatography Magnetic Beads (MB-WCX) kits and analyzed by the Matrix-Assisted Laser Desorption Time of Flight Mass Spectrometry (MALDI-TOF-MS). Then we established genetic algorithm (GA), supervised neural networks (SNN), and quick classifier (QC) models to distinguish malignant from benign liver tumors. To confirm the clinical applicability of the established models, the blinded validation test was performed in 50 clinical serum samples. Discriminatory peaks associated with malignant liver tumors were subsequently identified by a qTOF Synapt G2-S system. Results A total of 27 discriminant peaks (p<0.05) in mass spectra of serum samples were found by ClinPro Tools software. Recognition capabilities of the established models were 100% (GA), 89.38% (SNN), and 80.84% (QC); cross-validation rates were 81.67% (GA), 81.11% (SNN), and 86.11% (QC). The accuracy rates of the blinded validation test were 78% (GA), 84% (SNN), and 84% (QC). From the 27 discriminatory peptide peaks analyzed, 3 peaks of m/z 2860.34, 2881.54, and 3155.67 were identified as a fragment of fibrinogen alpha chain, fibrinogen beta chain, and inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4), respectively. Conclusions Our results demonstrated that MS technique can be helpful in differentiation of benign and malignant liver tumors. Fibrinogen and ITIH4 might be used as biomarkers for the diagnosis of malignant liver tumors.
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Affiliation(s)
- Bo Li
- Center for Clinical Laboratory, 302 Hospital of PLA, Beijing, China (mainland)
| | - Boan Li
- Center for Clinical Laboratory, 302 Hospital of PLA, Beijing, China (mainland)
| | - Tongsheng Guo
- Center for Clinical Laboratory, 302 Hospital of PLA, Beijing, China (mainland)
| | - Zhiqiang Sun
- Center for Clinical Laboratory, 302 Hospital of PLA, Beijing, China (mainland)
| | - Xiaohan Li
- Center for Clinical Laboratory, 302 Hospital of PLA, Beijing, China (mainland).,Graduate Student Team, Medical University of PLA, Beijing, China (mainland)
| | - Xiaoxi Li
- Center for Clinical Laboratory, 302 Hospital of PLA, Beijing, China (mainland)
| | - Han Wang
- Center for Clinical Laboratory, 302 Hospital of PLA, Beijing, China (mainland)
| | - Weijiao Chen
- Center for Clinical Laboratory, 302 Hospital of PLA, Beijing, China (mainland)
| | - Peng Chen
- Center for Clinical Laboratory, 302 Hospital of PLA, Beijing, China (mainland)
| | - Mengran Qiao
- Center for Clinical Laboratory, 302 Hospital of PLA, Beijing, China (mainland)
| | - Lifang Xia
- Center for Clinical Laboratory, 302 Hospital of PLA, Beijing, China (mainland)
| | - Yuanli Mao
- Center for Clinical Laboratory, 302 Hospital of PLA, Beijing, China (mainland).,Graduate Student Team, Medical University of PLA, Beijing, China (mainland)
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Wu C, Liu L, Zhao P, Tang D, Yao D, Zhu L, Wang Z. Potential Serum Markers for Monitoring the Progression of Hepatitis B Virus-Associated Chronic Hepatic Lesions to Liver Cirrhosis. Gut Liver 2016; 9:665-71. [PMID: 25963079 PMCID: PMC4562785 DOI: 10.5009/gnl14212] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND/AIMS To screen for serum protein/peptide biomarkers of hepatitis B virus (HBV)-associated chronic hepatic lesions in an attempt to profile the progression of HBV-associated chronic hepatic lesions using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) techniques. METHODS Using SELDI-TOF MS, serum protein/peptide profiles on the CM10 ProteinChip arrays were obtained from a training group including 26 HBV-associated hepatocellular carcinoma patients with liver cirrhosis (LC), 30 HBV-associated LC patients, 85 patients at different stages of liver fibrosis, and 30 asymptomatic HBV carriers. The most valuable SELDI peak for predicting the progression to LC in HBV-infected patients was identified. RESULTS A SELDI peak of M/Z 5805 with value for predicting LC in HBV-infected patients was found and was identified as a peptide of the C-terminal fraction of the fibrinogen a-chain precursor, isoform 1. CONCLUSIONS The peptide of the C-terminal fraction of the fibrinogen α-chain precursor, isoform 1 with M/Z 5805, may be a serological biomarker for progression to LC in HBV-infected patients.
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Affiliation(s)
- Cheng Wu
- Department of Digestive Endoscopy, Division of Southern Building, Chinese PLA General Hospital, Beijing,China
| | - Lijie Liu
- The Third Department of Geratology, The 401 Hospital, PLA, Qingdao, China
| | - Peng Zhao
- Department of Health Management Specialist Center of Hangzhou Sanatorium of PLA, Hangzhou, China
| | - Dan Tang
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Dingkang Yao
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Liang Zhu
- Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Zhiqiang Wang
- Department of Digestive Endoscopy, Division of Southern Building, Chinese PLA General Hospital, Beijing,China
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Dai M, Chen X, Liu X, Peng Z, Meng J, Dai S. Diagnostic Value of the Combination of Golgi Protein 73 and Alpha-Fetoprotein in Hepatocellular Carcinoma: A Meta-Analysis. PLoS One 2015; 10:e0140067. [PMID: 26441340 PMCID: PMC4595485 DOI: 10.1371/journal.pone.0140067] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 09/20/2015] [Indexed: 12/11/2022] Open
Abstract
Conflicting results have been widely reported on the use of Golgi protein 73 (GP73) as a serum biomarker for diagnosing hepatocellular carcinoma (HCC). This study evaluated the accuracy of GP73, alpha-fetoprotein (AFP), and GP73 + AFP for diagnosing HCC. The meta-analysis was performed on 11 studies that were selected by means of a comprehensive systematic literature review. Summary diagnostic accuracy, meta-regression analysis for heterogeneity and publication bias, and other statistical analyses were performed using Meta-Disc (version 1.4) and Stata (version 12.0). Pooled sensitivity, specificity, and diagnostic odds ratio were 0.77 (95% CI: 0.75–0.79), 0.91 (95% CI: 0.90–0.92), and 12.49 (95% CI: 4.91–31.79) for GP73; 0.62 (95% CI: 0.60–0.64), 0.84 (95% CI: 0.83–0.85), and 11.61 (95% CI: 8.02–16.81) for AFP; and 0.87 (95% CI: 0.85–0.89), 0.85 (95% CI: 0.84–0.86), and 30.63 (95% CI: 18.10–51.84) for GP73 + AFP. The area under the curve values were 0.86, 0.84, and 0.91 for GP73, AFP, and GP73 + AFP, respectively. These results indicate that for HCC diagnosis, the accuracy of GP73 was higher than that of AFP, and that GP73 + AFP exhibited significantly higher diagnostic accuracy than did GP73 or AFP alone.
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Affiliation(s)
- Meiyu Dai
- Department of Clinical Laboratory, The Fourth Hospital Affiliated to Guangxi Medical University, Liuzhou City, Guangxi Province, China
| | - Xiaoli Chen
- Department of Clinical Laboratory, The Fourth Hospital Affiliated to Guangxi Medical University, Liuzhou City, Guangxi Province, China
| | - Xuexiang Liu
- Department of Clinical Laboratory, The Fourth Hospital Affiliated to Guangxi Medical University, Liuzhou City, Guangxi Province, China
| | - Zheng Peng
- Department of Clinical Laboratory, The Fourth Hospital Affiliated to Guangxi Medical University, Liuzhou City, Guangxi Province, China
| | - Jie Meng
- Department of Clinical Laboratory, The Fourth Hospital Affiliated to Guangxi Medical University, Liuzhou City, Guangxi Province, China
| | - Shengming Dai
- Department of Clinical Laboratory, The Fourth Hospital Affiliated to Guangxi Medical University, Liuzhou City, Guangxi Province, China
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Ji Q, Ma Z, Deng X. Volunteer study and serum protein profiling to understand inflammatory response induced by Satsuma mandarin. Food Res Int 2015; 75:367-373. [PMID: 28454968 DOI: 10.1016/j.foodres.2015.04.030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 04/12/2015] [Accepted: 04/17/2015] [Indexed: 11/27/2022]
Abstract
It has been observed that consumption of a certain amount of Satsuma, lychee, and longan often caused a symptom characterized by dry or sore throat, gum swelling and even mouth ulcer, which significantly impaired the life quality of a large population. We define the adverse reaction to Satsuma as Satsuma-induced syndrome (SIS). Volunteers were assigned to oral Satsuma challenge in an open manner. The results showed that SIS was characterized with symptoms affecting the throat, oral cavity, face, gastrointestinal system and eye either individually or in combination. A comparative proteomic study was performed to investigate the differences of serum proteins in the Post-SC (after Satsuma challenge) and Pre-SC (before Satsuma challenge) serum samples of 15 volunteers with severe SIS. Ten proteins were identified to be differentially expressed (P<0.05). Of these, levels of complement component C9 precursor were elevated significantly in the Post-SC serum samples and were further verified by enzyme-linked immunosorbent assay, indicating that the complement system may be activated and plays a significant role in inflammatory response. Meanwhile, serum samples were subjected to immobilized metal affinity capture (IMAC3) protein chip surfaces and tested by surface-enhanced laser desorption/ionization-time of flight-mass spectrometry. The data were analyzed by Ciphergen ProteinChip Software. A diagnostic model was constructed to discriminate the SIS from normal samples, using principal component analysis. A total of 50 detected biomarkers were found to be different with statistical significance (P<0.05). The multivariate logistic analysis demonstrates a complete distinction between the two groups. Our findings suggest that these assays may provide potential biomarkers for the diagnosis of SIS.
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Affiliation(s)
- Qun Ji
- College of Horticulture and Forestry Sciences, Key Laboratory of Horticultural Plant Biology, Huazhong Agricultural University, Ministry of Education, Wuhan 430070, China
| | - Zhaocheng Ma
- College of Horticulture and Forestry Sciences, Key Laboratory of Horticultural Plant Biology, Huazhong Agricultural University, Ministry of Education, Wuhan 430070, China.
| | - Xiuxin Deng
- College of Horticulture and Forestry Sciences, Key Laboratory of Horticultural Plant Biology, Huazhong Agricultural University, Ministry of Education, Wuhan 430070, China
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Wong RJ, Ahmed A, Gish RG. Elevated alpha-fetoprotein: differential diagnosis - hepatocellular carcinoma and other disorders. Clin Liver Dis 2015; 19:309-23. [PMID: 25921665 DOI: 10.1016/j.cld.2015.01.005] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The incidence of cirrhosis-related hepatocellular carcinoma (HCC) is rising. Curative surgical options are available; outcomes are acceptable with early diagnosis. Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) and des-gamma-carboxy prothrombin (DCP) are HCC risk markers. A high or increasing serum biomarker level can be predictive of the eventual development of HCC, large tumor size, advanced stage, extrahepatic metastases, portal vein thrombosis, and postoperative HCC recurrence. Based on FDA guidelines for HCC risk assessment, clinicians can consider using either the combination of AFP-L3 with DCP, or the combination of AFP-L3 with AFP and DCP.
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Affiliation(s)
- Robert J Wong
- Division of Gastroenterology and Hepatology, Alameda Health System-Highland Hospital, Highland Care Pavilion, 5th floor, 1411 East 31st Street, Oakland, CA 94602, USA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 750 Welch Road, Suite# 210, Palo Alto, CA 94304, USA; Liver Transplant Program, Stanford University Medical Center, 750 Welch Road, Suite# 210, Palo Alto, CA 94304, USA
| | - Robert G Gish
- Liver Transplant Program, Stanford University Medical Center, 750 Welch Road, Suite# 210, Palo Alto, CA 94304, USA; Hepatitis B Foundation, 3805 Old Easton Road, Doylestown, PA 18902, USA.
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8
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Xu Z, Liu L, Pan X, Wei K, Wei M, Liu L, Yang H, Liu Q. Serum Golgi protein 73 (GP73) is a diagnostic and prognostic marker of chronic HBV liver disease. Medicine (Baltimore) 2015; 94:e659. [PMID: 25816035 PMCID: PMC4554005 DOI: 10.1097/md.0000000000000659] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Revised: 02/21/2015] [Accepted: 02/24/2015] [Indexed: 12/17/2022] Open
Abstract
Alanine aminotransferase (ALT) is the most commonly used marker of liver injury, but normal ALT levels are seen in a proportion of chronic hepatitis B virus (HBV)-infected patients with severe liver injury. Golgi protein 73 (GP73) is a promising alternative marker of liver injury. This study assessed the relation between GP73 levels and liver disease severity, monitored the kinetic changes in GP73 levels in chronic HBV patients receiving entecavir (ETV) therapy, and investigated the potential diagnostic and prognostic values of serum GP73 as a new liver injury biomarker in chronic HBV infections. This study enrolled 1150 patients with chronic HBV infections, 200 of whom were retrospectively enrolled in this study after receiving 1 year of ETV treatment. GP73 expression in liver tissue was detected by immunohistochemistry. GP73 levels in single or serial serum samples were measured by enzyme-linked immunosorbent assay. Immunohistochemical analysis indicated that GP73 protein expression in the liver increased progressively with pathologic progression from nonexistent or mild hepatitis to severe hepatitis and cirrhosis during chronic HBV infection. Serum GP73 levels were positively correlated with the disease severity of chronic HBV infections (r = 0.58, P < 0.001). In patients with normal ALT levels, serum GP73 concentrations were significantly higher in patients with prominent hepatic inflammatory injury and fibrosis than in patients without hepatic inflammatory injury or fibrosis. Serum GP73 concentrations and GP73 protein expression were decreased in the liver tissues of patients whose ALT levels normalized after 1 year of ETV antiviral therapy. Changes in serum GP73 levels were closely associated with changes in liver injury severity, and, therefore, GP73 may be an effective new liver inflammatory injury biomarker, and could be useful for monitoring the prognosis of chronic HBV infectious patients with normal ALT levels.
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Affiliation(s)
- Zhengju Xu
- From the Clinical Liver Center (ZX, Liguan Liu, XP, HY, QL); Central Laboratory of Clinical Hepatology (KW, MW); and Department of Pathology (Lifei Liu), The 180th Hospital of the People's Liberation Army, Quanzhou, China
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Abstract
Liver cancer is the fifth most common cancer, but the second leading cause of cancer death, in the world, with more than 700,000 fatalities annually. The major etiology of liver cancer is infection with an hepatotropic virus such as hepatitis B virus or hepatitis C virus infection. While chronic viral infection remains the main cause of liver disease and risk of hepatocellular carcinoma (HCC), rates of nonviral-associated HCC are occurring at an alarmingly increasing rate. Like many cancers, survival rates are closely associated with time of detection. If HCC is caught early, survival rates can be as high as 50%. Regrettably, most cases of HCC are caught late where survival rates can be as low as 2-7%. Thus, there has been great interest in discovering serum biomarkers that could be used to identify those with HCC. To this end, many groups have examined the N-linked glycans to identify changes that occur with HCC. As the liver secretes the vast majority of proteins into the serum, this has often been a starting point for study. In serum, alterations in core fucosylation, outer-arm fucosylation, increased sialylation, and glycan branching have been observed in patients with HCC. Similar findings have been found directly in HCC tissue suggesting that these glycan changes may play a role in tumor formation and development.
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Affiliation(s)
- Anand Mehta
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA
| | - Harmin Herrera
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA
| | - Timothy Block
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA
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Yang J, Li J, Dai W, Wang F, Shen M, Chen K, Cheng P, Zhang Y, Wang C, Zhu R, Zhang H, Zheng Y, Wang J, Xia Y, Lu J, Zhou Y, Guo C. Golgi protein 73 as a biomarker for hepatocellular carcinoma: A diagnostic meta-analysis. Exp Ther Med 2015; 9:1413-1420. [PMID: 25780444 PMCID: PMC4353736 DOI: 10.3892/etm.2015.2231] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2014] [Accepted: 01/20/2015] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third leading cause of cancer-related mortality worldwide. Conflicting results have been reported regarding the use of serum Golgi protein 73 (GP73) as a promising serum marker for the diagnosis of HCC; therefore, the aim of the present study was to provide a systematic review of the diagnostic performance of GP73 for HCC. Following a systematic review of the relevant studies, a number of indices associated with the accuracy of the diagnostic performance of GP73, including the sensitivity and specificity, were pooled using Meta Disc 1.4 software. Data were presented as forest plots, and summary receiver operating characteristic (SROC) curve analysis was used to summarize the overall test performance. Eleven studies were included in this meta-analysis. The summary estimates for serum GP73 in diagnosing HCC were as follows: Sensitivity, 77% [95% confidence interval (CI), 75–79%]; specificity, 91% (95% CI, 90–92%); positive likelihood ratio, 4.34 (95% CI, 2.19–8.59); negative likelihood ratio, 0.30 (95% CI, 0.26–0.36) and diagnostic odds ratio, 15.78 (95% CI, 6.95–35.83). The area under the SROC curve was 0.8638, and the Q index was 0.7944. Significant heterogeneity was found. This meta-analysis indicates a moderate diagnostic value of GP73 in HCC; however, further studies with rigorous design, large sample size and multiregional cooperation are required.
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Affiliation(s)
- Jing Yang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Jingjing Li
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Weiqi Dai
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Fan Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Miao Shen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Kan Chen
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Ping Cheng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Yan Zhang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Chengfen Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Rong Zhu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Huawei Zhang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Yuanyuan Zheng
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Junshan Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Yujing Xia
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Jie Lu
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Yingqun Zhou
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Chuanyong Guo
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
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Xu Z, Pan X, Wei K, Ding H, Wei M, Yang H, Liu Q. Serum Golgi protein 73 levels and liver pathological grading in cases of chronic hepatitis B. Mol Med Rep 2014; 11:2644-52. [PMID: 25524053 PMCID: PMC4337480 DOI: 10.3892/mmr.2014.3114] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 11/25/2014] [Indexed: 12/20/2022] Open
Abstract
The present study was designed to assess the correlation between serum Golgi protein 73 (GP73) and liver pathological grading and staging in patients with chronic hepatitis B (CHB). Two hundred and fifty‑three patients with chronic hepatitis B virus (HBV) infections were enrolled in the present study. All patients received a serum GP73 test, and 91 CHB patients underwent liver biopsy. GP73 expression in liver tissue was assessed by immunohistochemical analysis. The results indicated that serum GP73 levels were positively correlated with disease progression in patients with chronic HBV infection (r=0.677). There was no significant difference in serum GP73 levels between hepatitis B e antigen‑positive and ‑negative patients (P>0.05). There were also no significant differences in serum GP73 levels among specimens with varying HBV DNA contents (P>0.05). Serum GP73 levels were positively correlated with increased liver pathological grading (r=0.737) and staging (r=0.692), and immunohistochemical analysis indicated that GP73 protein expression increased concurrently with liver pathological grading and staging. In conclusion, serum GP73 was found to be correlated with liver pathological grading and staging in patients with CHB, and may be an effective indicator for the evaluation of disease progression. However, serum GP73 levels were not associated with HBV replication.
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Affiliation(s)
- Zhengju Xu
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, Fujian 362000, P.R. China
| | - Xingnan Pan
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, Fujian 362000, P.R. China
| | - Kaipeng Wei
- Central Laboratory of Clinical Hepatology, The 180th Hospital of the People's Liberation Army, Quanzhou, Fujian 362000, P.R. China
| | - Hongbing Ding
- Liver Center Clinical Pathology, The 180th Hospital of the People's Liberation Army, Quanzhou, Fujian 362000, P.R. China
| | - Meijuan Wei
- Central Laboratory of Clinical Hepatology, The 180th Hospital of the People's Liberation Army, Quanzhou, Fujian 362000, P.R. China
| | - Huanwen Yang
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, Fujian 362000, P.R. China
| | - Qian Liu
- Clinical Liver Center, The 180th Hospital of the People's Liberation Army, Quanzhou, Fujian 362000, P.R. China
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Teng M, Pirrie S, Ward DG, Assi LK, Hughes RG, Stocken D, Johnson PJ. Diagnostic and mechanistic implications of serum free light chains, albumin and alpha-fetoprotein in hepatocellular carcinoma. Br J Cancer 2014; 110:2277-82. [PMID: 24603305 PMCID: PMC4007223 DOI: 10.1038/bjc.2014.121] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Revised: 01/15/2014] [Accepted: 02/11/2014] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Mass spectroscopy analysis suggested low serum albumin and high immunoglobulin free light chain (sFLC) levels may have diagnostic value in hepatocellular carcinoma (HCC). Our aims were to apply quantitative assays to confirm these observations, determine their diagnostic utility, and investigate the mechanisms involved. METHODS Albumin, sFLC, routine liver and renal function tests were measured in patients with chronic liver disease with (n=102) and without (n=113) HCC. The discriminant performance was compared with the current standard serological test alpha-fetoprotein (AFP) using receiver operating characteristic (ROC) and area under the curve (AUC) analyses. RESULTS sFLC and serum albumin were each confirmed to have discriminatory utility in HCC with AUC values of 0.7 and 0.8, respectively. sFLC were strongly correlated with gammaglobulin levels and both these were inversely related to serum albumin levels. The discriminatory utility of sFLC was retained after adjusting for renal and liver function. CONCLUSIONS Serum levels of sFLC and albumin were strongly associated with HCC as predicted by mass spectroscopy. Discrimination of HCC by AFP was improved by the addition of either albumin or sFLC. Larger prospective studies are required to determine how AFP, sFLC and albumin might be combined in a useful diagnostic approach for HCC.
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Affiliation(s)
- M Teng
- Cancer Research UK, Institute for Cancer Studies, School of Cancer Sciences, University of Birmingham, Vincent Drive, Edgbaston B15 2TT, UK
| | - S Pirrie
- Cancer Research UK, Institute for Cancer Studies, School of Cancer Sciences, University of Birmingham, Vincent Drive, Edgbaston B15 2TT, UK
| | - D G Ward
- Cancer Research UK, Institute for Cancer Studies, School of Cancer Sciences, University of Birmingham, Vincent Drive, Edgbaston B15 2TT, UK
| | - L K Assi
- The Binding Site Group Limited, 8 Calthorpe Road, Edgbaston B15 1QT, UK
| | - R G Hughes
- The Binding Site Group Limited, 8 Calthorpe Road, Edgbaston B15 1QT, UK
| | - D Stocken
- Cancer Research UK, Institute for Cancer Studies, School of Cancer Sciences, University of Birmingham, Vincent Drive, Edgbaston B15 2TT, UK
| | - P J Johnson
- Cancer Research UK, Institute for Cancer Studies, School of Cancer Sciences, University of Birmingham, Vincent Drive, Edgbaston B15 2TT, UK
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Proteins related to early changes in carcinogenesis of hepatic oval cells after treatment with methylnitronitrosoguanidine. ACTA ACUST UNITED AC 2013; 66:139-46. [PMID: 24360059 DOI: 10.1016/j.etp.2013.11.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Revised: 06/19/2013] [Accepted: 11/25/2013] [Indexed: 12/26/2022]
Abstract
Hepatic oval cells are considered as facultative progenitor/stem cells of liver and able to differentiate into either hepatocytes or biliary epithelial cells. The transformed oval cells by carcinogen possess potential to develop carcinomas in animal models. In order to better understand the molecular mechanism in carcinogenetic process, we used a proteomic approach to assess the early changes in protein expression of oval cells (OC3W3-15) initiated by methylnitronitrosoguanidine (MNNG). Meanwhile, we compared cell biologic characteristics of the MNNG treated OC3W3-15 cells and control oval cells by electron microscopy, flow cytometry, karyotype and soft agar assay. The mRNA levels of GGT and GSTP1 determined by real-time PCR were also detected in both cell lines. Our results showed that MNNG-treated OC3W3-15 cells exhibited characteristics of malignant transformation, including growth rate, chromosomal aberrations, abnormal DNA content, and the ability to form colonies. The cells expressed higher levels of the tumor marker AFP, GGT and GSTP1 mRNA than that of control cells. Significant changes of several proteins involved in the malignant transformation process, including cell cycle related proteins, proteins involved in organism development and cell differentiation, are found in OC3W3-15 cells. The proteins may provide early affection in malignant transformation of hepatic oval cells, and yield further insight into mechanism of carcinogenesis of hepatocellular carcinoma.
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Cao XL, Li H, Yu XL, Liang P, Dong BW, Fan J, Li M, Liu FY. Predicting early intrahepatic recurrence of hepatocellular carcinoma after microwave ablation using SELDI-TOF proteomic signature. PLoS One 2013; 8:e82448. [PMID: 24349287 PMCID: PMC3862627 DOI: 10.1371/journal.pone.0082448] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Accepted: 11/03/2013] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND/AIMS Despite great progress in the treatment of hepatocellular carcinoma (HCC) over the last-decade, intrahepatic recurrence is still the most frequent serious adverse event after all the treatments including microwave ablation. This study aimed to predict early recurrence of HCC after microwave ablation using serum proteomic signature. METHODS After curative microwave ablation of HCC, 86 patients were followed-up for 1 year. Serum samples were collected before microwave ablation. The mass spectra of proteins were generated using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). Serum samples from 50 patients were randomly selected as a training set and for biomarkers discovery and model development. The remaining serum samples were categorized for validation of the algorithm. RESULTS According to preablation serum protein profiling obtained from the 50 HCC samples in the training set, nine significant differentially-expressed proteins were detected in the serum samples between recurrent and non-recurrent patients. Decision classification tree combined with three candidate proteins with m/z values of 7787, 6858 and 6646 was produced using Biomarker Patterns Software with sensitivity of 85.7% and specificity of 88.9% in the training set. When the SELDI marker pattern was tested with the blinded testing set, it yielded a sensitivity of 80.0%, a specificity of 88.5% and a positive predictive value of 86.1%. CONCLUSIONS Differentially-expressed protein peaks in preablation serum screened by SELDI are associated with prognosis of HCC. The decision classification tree is a potential tool in predicting early intrahepatic recurrence in HCC patients after microwave ablation.
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Affiliation(s)
- Xiao-lin Cao
- Department of Interventional Ultrasound, General Hospital of People's Liberation Army, Beijing, China
- Department of Ultrasound, Southern Building Clinic Division, General Hospital of People's Liberation Army, Beijing, China
| | - Hua Li
- Department of Interventional Ultrasound, General Hospital of People's Liberation Army, Beijing, China
- Department of Ultrasound, the 306 Hospital of Chinese People's Liberation Army, Beijing, China
| | - Xiao-ling Yu
- Department of Interventional Ultrasound, General Hospital of People's Liberation Army, Beijing, China
- * E-mail: (XlY); (PL)
| | - Ping Liang
- Department of Interventional Ultrasound, General Hospital of People's Liberation Army, Beijing, China
- * E-mail: (XlY); (PL)
| | - Bao-wei Dong
- Department of Interventional Ultrasound, General Hospital of People's Liberation Army, Beijing, China
| | - Jin Fan
- Department of Interventional Ultrasound, General Hospital of People's Liberation Army, Beijing, China
| | - Meng Li
- Department of Interventional Ultrasound, General Hospital of People's Liberation Army, Beijing, China
| | - Fang-yi Liu
- Department of Interventional Ultrasound, General Hospital of People's Liberation Army, Beijing, China
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15
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Profiling serologic biomarkers in cirrhotic patients via high-throughput Fourier transform infrared spectroscopy: toward a new diagnostic tool of hepatocellular carcinoma. Transl Res 2013; 162:279-86. [PMID: 23920432 DOI: 10.1016/j.trsl.2013.07.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 07/09/2013] [Accepted: 07/11/2013] [Indexed: 12/14/2022]
Abstract
Identification of novel serum biomarkers of hepatocellular carcinoma (HCC) is needed for early-stage disease detection and to improve patients' survival. The aim of this study was to evaluate the potential of serum Fourier transform infrared (FTIR) spectroscopy for differentiating sera from cirrhotic patients with and without HCC. Serum samples were collected from 2 sets of patients: cirrhotic patients with HCC (n = 39) and without HCC (n = 40). The FTIR spectra (10 per sample) were acquired in the transmission mode, and data homogeneity was tested by cluster analysis to exclude outliers. After data preprocessing by extended multiplicative signal correction and principal component analysis, the Support Vector Machine (SVM) method was applied using a leave-one-out cross-validation algorithm to classify the spectra into 2 classes of cirrhotic patients with and without HCC. When SVM was applied to all spectra (n = 790), the sensitivity and the specificity for the diagnosis of HCC were, respectively, 82.02% and 82.5%. When applied to the subset of spectra excluding the outliers (n = 739), SVM classification led to a sensitivity and specificity of 87.18% and 85%, respectively. Using median spectra for each patient instead of all replicates, the sensitivity and specificity were 84.62% and 82.50%, respectively. The overall accuracy rate was 82%-86%. In conclusion, this study suggests that FTIR spectroscopy combined with advanced methods of pattern analysis shows potential for differentiating sera from cirrhotic patients with and without HCC.
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Xiao J, Zhao Y, Varghese RS, Zhou B, Di Poto C, Zhang L, Tadesse MG, Ziada DH, Shetty K, Ressom HW. Evaluation of metabolite biomarkers for hepatocellular carcinoma through stratified analysis by gender, race, and alcoholic cirrhosis. Cancer Epidemiol Biomarkers Prev 2013; 23:64-72. [PMID: 24186894 DOI: 10.1158/1055-9965.epi-13-0327] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND The effects of hepatocellular carcinoma on liver metabolism and circulating metabolites have been subjected to continuing investigation. This study compares the levels of selected metabolites in sera of hepatocellular carcinoma cases versus patients with liver cirrhosis and evaluates the influence of gender, race, and alcoholic cirrhosis on the performance of the metabolites as candidate biomarkers for hepatocellular carcinoma. METHODS Targeted quantitation of 15 metabolites is performed by selected research monitoring in sera from 89 Egyptian subjects (40 hepatocellular carcinoma cases and 49 cirrhotic controls) and 110 U.S. subjects (56 hepatocellular carcinoma cases and 54 cirrhotic controls). Logistic regression models are used to evaluate the ability of these metabolites in distinguishing hepatocellular carcinoma cases from cirrhotic controls. The influences of gender, race, and alcoholic cirrhosis on the performance of the metabolites are analyzed by stratified logistic regression. RESULTS Two metabolites are selected on the basis of their significance to both cohorts. Although both metabolites discriminate hepatocellular carcinoma cases from cirrhotic controls in males and Caucasians, they are insignificant in females and African Americans. One metabolite is significant in patients with alcoholic cirrhosis and the other in nonalcoholic cirrhosis. CONCLUSIONS The study demonstrates the potential of two metabolites as candidate biomarkers for hepatocellular carcinoma by combining them with α-fetoprotein (AFP) and gender. Stratified statistical analyses reveal that gender, race, and alcoholic cirrhosis affect the relative levels of small molecules in serum. IMPACT The findings of this study contribute to a better understanding of the influence of gender, race, and alcoholic cirrhosis in investigating small molecules as biomarkers for hepatocellular carcinoma.
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Affiliation(s)
- Junfeng Xiao
- Authors' Affiliations: Department of Oncology, Lombardi Comprehensive Cancer Center and Georgetown University Medical Center; Department of Mathematics and Statistics, Georgetown University; MedStar Georgetown University Hospital and Georgetown University Medical Center, Washington, District of Columbia; and Department of Tropical Medicine and Infectious Diseases, Tanta Faculty of Medicine, Tanta University, Tanta, Egypt
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Tian L, Wang Y, Xu D, Gao Y, Wen X, Tian Y. The differential diagnostic model for serous peptidomics in HBV carriers established by MALDI-TOF-MS analysis. Clin Biochem 2013; 47:56-62. [PMID: 24183880 DOI: 10.1016/j.clinbiochem.2013.10.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 10/17/2013] [Accepted: 10/21/2013] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Hepatitis B virus (HBV) can result in asymptomatic carrier (AsC) state or chronic inflammation of liver, which depends on the host immunity. We therefore investigated the peptidomic profiling in the process of HBV infection. DESIGN AND METHODS In this study, serum from 116 HBV infected (AsC and chronic hepatitis), 60 HBV-immunized and 70 normal subjects was treated with MB-WCX (weak cation exchange based magnetic beads) kits and analyzed by the Clinprot/Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS) techniques. Purified serous proteins were subjected to FT-ICR-MS analysis, and Western blot further confirmed the results. RESULTS The specific model comprised of two peptides m/z 2882.89 and 4476.12 could distinguish HBV infected from healthy (HBV-immunized and normal) group and showed 95.5% of the sensitivity and 95.4% of the specificity by cross-validation analysis. 40/56 HBV infected and 43/50 healthy subjects could be correctly classified by the model. The area under the receiving operating curves (AUROC) of m/z 2882.89 and 4476.12, identified as subunits of fibrinogen beta chain (FBG) Bβ10-42 and nucleophosmin (NPM) respectively, were both up to 0.88 when discriminating AsC from the healthy group. The expression of Bβ10-42 and NPM decreased significantly in the plasma of HBV infected individuals by Western blot analysis. CONCLUSIONS There were specific serum peptide profilings for host responses to HBV infection, and m/z 2882.89 and 4476.12 could be valuable follow-up and prognostic tools for HBV infection.
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Affiliation(s)
- Liyuan Tian
- Clinical Laboratory Center, Hainan Branch of Chinese PLA General Hospital, Sanya, Hainan Province 572013, China; Department of Clinical Biochemistry, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing 100853, China
| | - Yu Wang
- Department of General Surgery, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing 100853, China
| | - Dabin Xu
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing 100853, China
| | - Yanhong Gao
- Department of Clinical Biochemistry, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing 100853, China
| | - Xinyu Wen
- Department of Clinical Biochemistry, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing 100853, China
| | - Yaping Tian
- Department of Clinical Biochemistry, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing 100853, China.
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GP73 is a potential marker for evaluating AIDS progression and antiretroviral therapy efficacy. Mol Biol Rep 2013; 40:6397-405. [PMID: 24068434 DOI: 10.1007/s11033-013-2754-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Accepted: 09/14/2013] [Indexed: 02/07/2023]
Abstract
Golgi protein-73 (GP73) is upregulated in cancers and viral infections; however, its role in human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) remains undetermined. GP73 was evaluated as a biomarker of HIV progression and AIDS treatment efficacy. Forty-eight HIV patients (≤ 350 CD4 + T cells/μL) undergoing highly active antiretroviral therapy (HAART group) and 18 HIV patients expected to undergo HAART within 9 months (>350 CD4 + T cells/μL) (control group) were enrolled in a prospective, single center, cohort study from May 2009 to Jun 2012. Blood aspartate aminotransferase, alanine aminotransferase (ALT), cholesterol, triglycerides, and total bilirubin were assessed at baseline, 2 weeks, and 1, 3, 6, 9, and 12 months (HAART group) or 3 month intervals (control group). Serum HIV RNA level (viral load) was determined by reverse-transcriptase polymerase chain reaction (RT-PCR), and serum and peripheral blood mononuclear cell (PBMC) GP73 concentration were determined by chemiluminescent immunoassay kit and western blot, respectively. Significant positive and negative correlations in baseline serum GP73 concentration and HIV viral load (r = 0.39, P < 0.001) and CD4 + T cell count (r = -0.501, P < 0.001) were observed, respectively. In receiver operator characteristic (ROC) analysis, area under the curve (AUC) was 0.79 (95 % CI 0.66-0.92). The sensitivity and specificity of GP73 for correct identification of patients with ≤350 CD4 + T cells/μL were 76.09 and 75.0 %, respectively, with an ROC-derived cut-off of 100.6 ng/mL. For HIV patients undergoing antiretroviral therapy, GP73 may be a potential biomarker treatment efficacy useful in AIDS management.
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Abstract
Tumor markers are gene products which signal the occurrence of tumors in different organs as well as their response to surgery and chemotherapy. The discovery of tumor markers occurred after the demonstration of tumor-specific transplantation antigens in chemically or virally induced tumors in syngenic rodents. The history of currently used tumor markers began in the 1940s, the first discovered being alpha-fetoprotein in 1956, followed by that of carcinoembryonic antigen in 1965. Since then the range of tumor markers has widened continously. Their chemical structure and genetics is now well known. Some may play part in tumor growth and development of metastases. The potential uses of tumor markers are general or high risk population screening, adjunct in diagnosis of cancer, preoperative indicator of tumor burden, indicator of therapeutic success, evidence of postoperative recurrences and use in tumor localization. However, there is no ideal tumor marker fulfilling all the criteria. Isotope-labeled anti-carcinoembryonic antigen antibodies and small molecular E-selectin inhibitors could play a role in the molecular radio- and chemotherapy of colon and pancreatic carcinomas.
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Affiliation(s)
- György Miklós Buzás
- Ferencvárosi Egészségügyi Szolgáltató KKNP Kft. Gasztroenterológia Budapest.
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Qian JY, Mou SH, Liu CB. SELDI-TOF MS combined with magnetic beads for detecting serum protein biomarkers and establishment of a boosting decision tree model for diagnosis of pancreatic cancer. Asian Pac J Cancer Prev 2013; 13:1911-5. [PMID: 22901146 DOI: 10.7314/apjcp.2012.13.5.1911] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
AIM New technologies for the early detection of pancreatic cancer (PC) are urgently needed. The aim of the present study was to screen for the potential protein biomarkers in serum using proteomic fingerprint technology. METHODS Magnetic beads combined with surface-enhanced laser desorption/ionization (SELDI) TOF MS were used to profile and compare the protein spectra of serum samples from 85 patients with pancreatic cancer, 50 patients with acute-on-chronic pancreatitis and 98 healthy blood donors. Proteomic patterns associated with pancreatic cancer were identified with Biomarker Patterns Software. RESULTS A total of 37 differential m/z peaks were identified that were related to PC (P<0.01). A tree model of biomarkers was constructed with the software based on the three biomarkers (7762 Da, 8560 Da, 11654 Da), this showing excellent separation between pancreatic cancer and non-cancer., with a sensitivity of 93.3% and a specificity of 95.6%. Blind test data showed a sensitivity of 88% and a specificity of 91.4%. CONCLUSIONS The results suggested that serum biomarkers for pancreatic cancer can be detected using SELDI-TOF-MS combined with magnetic beads. Application of combined biomarkers may provide a powerful and reliable diagnostic method for pancreatic cancer with a high sensitivity and specificity.
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Affiliation(s)
- Jing-Yi Qian
- Medical Services Section, Taizhou Municipal Hospital, Taizhou, Zhejiang, China
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Abdalla MA, Haj-Ahmad Y. Promising Urinary Protein Biomarkers for the Early Detection of Hepatocellular Carcinoma among High-Risk Hepatitis C Virus Egyptian Patients. J Cancer 2012; 3:390-403. [PMID: 23074380 PMCID: PMC3471080 DOI: 10.7150/jca.4280] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2012] [Accepted: 06/19/2012] [Indexed: 01/06/2023] Open
Abstract
Hepatocellular Carcinoma is a major healthcare problem, representing the third most common cause of cancer-related mortality worldwide. There are 130 million Hepatitis C virus infected patients worldwide who are at a high-risk for developing Hepatocellular Carcinoma. Due to the fact that reliable parameters and/or tools for the early detection of Hepatocellular Carcinoma among high-risk individuals are severely lacking, Hepatocellular Carcinoma patients are always diagnosed at a late stage where surgical solutions or effective treatment are not possible. Urine was collected from 106 Hepatitis C infected patients patients, 32 of whom had already developed Hepatocellular Carcinoma and 74 patients who were diagnosed as Hepatocellular Carcinoma -free at the time of initial sample collection. In addition to these patients, urine samples were also collected from 12 healthy control individuals. Total urinary proteins were isolated from the urine samples and LC-MS/MS was used to identify potential protein HCC biomarker candidates. This was followed by validating relative expression levels of proteins present in urine among all the patients using quantitative real time-PCR. This approach revealed that significant over-expression of three proteins: DJ-1, Chromatin Assembly Factor-1 (CAF-1) and Heat Shock Protein 60 (HSP60), was a characteristic event among Hepatocellular Carcinoma - post Hepatitis C virus infected patients. As a single-based Hepatocellular Carcinoma biomarker, CAF-1 over-expression identified Hepatocellular Carcinoma among Hepatitis C virus infected patients with a specificity of 90%, sensitivity of 66% and with an overall diagnostic accuracy of 78%. Moreover, the CAF-1/HSP60 tandem identified Hepatocellular Carcinoma among Hepatitis C virus infected patients with a specificity of 92%, sensitivity of 61% and with an overall diagnostic accuracy of 77%.
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Affiliation(s)
- Moemen Ak Abdalla
- Centre for Biotechnology, Brock University, St. Catharines, ON, L2S 3A1, Canada
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Gao H, Zheng Z, Yue Z, Liu F, Zhou L, Zhao X. Evaluation of serum diagnosis of pancreatic cancer by using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Int J Mol Med 2012; 30:1061-8. [PMID: 22941199 DOI: 10.3892/ijmm.2012.1113] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Accepted: 06/15/2012] [Indexed: 11/06/2022] Open
Abstract
Proteomic methods have been widely used in disease marker discovery research. The aim of this study was to discover potential biomarkers for pancreatic cancer (PCa) using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Crude serum samples from 132 patients with PCa and 67 healthy controls (HCs) were analyzed in duplicate using SELDI. Support vector machine (SVM) analysis of the spectra was used to generate a predictive algorithm based on proteins that were maximally differentially expressed between patients with PCa and the HCs in the training cohort. This algorithm was tested using leave-one-out cross-validation in the test cohort. From the 4 significant peaks in the training cohort, a classifier for separating patients with PCa from HCs was developed. The classifier was challenged with all samples achieving 96.67% sensitivity and 100% specificity in the training cohort and 93.1% sensitivity and 78.57% specificity in the test cohort. Additionally, the classifier correctly classified 12/12 stage Ia and 13/16 stage IIa PCa cases. The combination of the SELDI panel and CA19-9 was superior to CA19-9 alone in distinguishing individuals with PCa from the healthy subject group. These results suggest that high-throughput proteomic profiling has the capacity to provide new biomarkers for the early detection and diagnosis of PCa.
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Affiliation(s)
- Hongjun Gao
- Clinical Laboratory of Coal General Hospital, Beijing, PR China
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Evaluation of proteomics-identified CCL18 and CXCL1 as circulating tumor markers for differential diagnosis between ovarian carcinomas and benign pelvic masses. Int J Biol Markers 2012; 26:262-73. [PMID: 21928244 DOI: 10.5301/jbm.2011.8616] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/15/2011] [Indexed: 11/20/2022]
Abstract
A lack of sensitive and specific tumor markers for early diagnosis and treatment is a major cause for the high mortality rate of ovarian cancer. The purpose of this study was to identify potential proteomics-based biomarkers useful for the differential diagnosis between ovarian cancer and benign pelvic masses. Serum samples from 41 patients with ovarian cancer, 32 patients with benign pelvic masses, and 41 healthy female blood donors were examined, and proteomic profiling of the samples was assessed by surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectroscopy (MS). A confirmatory study was also conducted with serum specimens from 58 patients with ovarian carcinoma, 37 patients with benign pelvic masses, and 48 healthy women. A classification tree was established using Biomarker Pattern Software. Six differentially expressed proteins (APP, CA 125, CCL18, CXCL1, IL-8, and ITIH4) were separated by high-performance liquid chromatography and identified by matrix-assisted laser desorption/ionization (MALDI)-MS/MS and database searches. Two of the proteins overexpressed in ovarian cancer patients, chemokine CC2 motif ligand 18 (CCL18) and chemokine CXC motif ligand 1 (CXCL1), were automatically selected in a multivariate predictive model. These two protein biomarkers were then validated and evaluated by enzyme-linked immunosorbent assay (ELISA) in 535 serum specimens (130 ovarian cancer, 64 benign ovarian masses, 36 lung cancer, 60 gastric cancer, 55 nasopharyngeal carcinoma, 48 hepatocellular carcinoma, and 142 healthy women). The combined use of CCL18 and CXCL1 as biomarkers for ovarian cancer had a sensitivity of 92% and a specificity of 97%. The multivariate ELISA analysis of the two putative markers in combination with CA 125 resulted in a sensitivity of 99% for healthy women and 94% for benign pelvic masses, and a specificity of 92% for both groups; these values were significantly higher than those obtained with CA 125 alone (p and lt;0.05). We conclude that serum CCL18 and CXCL1 are potentially useful as novel circulating tumor markers for the differential diagnosis between ovarian cancer and benign ovarian masses.
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Henkel C, Schwamborn K, Zimmermann HW, Tacke F, Kühnen E, Odenthal M, Groseclose MR, Caprioli RM, Weiskirchen R. From proteomic multimarker profiling to interesting proteins: thymosin-β(4) and kininogen-1 as new potential biomarkers for inflammatory hepatic lesions. J Cell Mol Med 2012; 15:2176-88. [PMID: 21496200 PMCID: PMC4394227 DOI: 10.1111/j.1582-4934.2010.01204.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Despite tremendous efforts in disclosing the pathophysiological and epidemiological factors associated with liver fibrogenesis, non-invasive diagnostic measures to estimate the clinical outcome and progression of liver fibrogenesis are presently limited. Therefore, there is a mandatory need for methodologies allowing the reasonable and reliable assessment of the severity and/or progression of hepatic fibrogenesis. We here performed proteomic serum profiling by matrix-assisted laser desorption ionization time-of-flight mass spectrometry in 179 samples of patients chronically infected with hepatitis C virus and 195 control sera. Multidimensional analysis of spectra allowed the definition of algorithms capable to distinguish class-specific protein expression profiles in serum samples. Overall about 100 peaks could be detected per single spectrum. Different algorithms including protein peaks in the range of 2000 and 10,000 Da were generated after pre-fractionation on a weak cation exchange surface. A specificity of 93% with a sensitivity of 86% as mean of the test set results was found, respectively. The nature of three of these protein peaks that belonged to kininogen-1 and thymosin-β4 was further analysed by tandem mass spectrometry (MS)/MS. We further found that kininogen-1 mRNA was significantly down-regulated in cirrhotic livers. We have identified kininogen-1 and thymosin-β4 as potential new biomarkers for human chronic hepatitis C and conclude that serum profiling is a reliable technique to identify hepatitis-associated expression patterns. Based on the high throughput capability, the identified differential protein panel may serve as a diagnostic marker and warrants further validation in larger cohorts.
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Affiliation(s)
- Corinna Henkel
- Institute of Pathology, RWTH University Hospital Aachen, Aachen, Germany
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Ndao M. Biomarker discovery in serum/plasma using surface enhanced laser desorption ionization time of flight (SELDI-TOF) mass spectrometry. Methods Mol Biol 2012; 818:67-79. [PMID: 22083816 DOI: 10.1007/978-1-61779-418-6_5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Proteins and peptides that undergo variations in concentration or state as a result of a biological process or disease may be used as biomarkers for the diagnosis or prognosis of diseases and/or for the monitoring of therapy. Serum/plasma is one of the most easily obtained patient specimens and contains thousands of proteins produced and secreted from cells and tissues. While serum/plasma is a valuable specimen for protein biomarker research, especially in the area of infectious diseases, the dynamic range of the proteome presents a technical challenge. Serum/plasma is dominated by high abundance proteins, such as albumin, immunoglobulins, haptogloblulin, which constitute almost 90% of the total serum/plasma protein by weight and make the detection of the low abundance proteins difficult. Therefore, effective fractionation and separation methods are essential to detect potential biomarker proteins present in small quantities for mass spectrometry.The current tests for blood-borne protozoan diseases are inadequate by monitoring treatment efficacy or for prognosis and also lack sensitivity and specificity. To overcome these limitations, we began a program to develop novel assays for infectious diseases using mass spectrometric data directly as well as "next generation" assays that exploit the richness of the MS data converted to standard platforms. Here we focus on high-throughput fractionation and proteomic analysis using Surface Enhanced Laser Desorption Ionization Time of Flight (SELDI-TOF) mass spectrometry platform. Separation and enrichment is achieved using stepwise anion exchange fractionation prior to analysis on multiple ProteinChip array chemistries. We have used this approach successfully to identify proteins/peptides or protein "profiles" (biomarkers) in subjects chronically infected with blood-borne protozoan parasites (i.e. Chagas disease, babesia, toxoplasma, malaria), fascioliosis, and cysticercosis.
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Affiliation(s)
- Momar Ndao
- National Reference Centre for Parasitology, Research Institute of the McGill University Health Centre, Montreal General Hospital, Montreal, QC, Canada.
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Mass spectrometry-based plasma peptide profiling of acute exacerbation in HBeAg-positive chronic hepatitis B. Clin Chim Acta 2011; 412:2174-82. [PMID: 21867694 DOI: 10.1016/j.cca.2011.08.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2010] [Revised: 07/30/2011] [Accepted: 08/01/2011] [Indexed: 01/16/2023]
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Zhu P, Bowden P, Zhang D, Marshall JG. Mass spectrometry of peptides and proteins from human blood. MASS SPECTROMETRY REVIEWS 2011; 30:685-732. [PMID: 24737629 DOI: 10.1002/mas.20291] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2008] [Revised: 12/09/2009] [Accepted: 01/19/2010] [Indexed: 06/03/2023]
Abstract
It is difficult to convey the accelerating rate and growing importance of mass spectrometry applications to human blood proteins and peptides. Mass spectrometry can rapidly detect and identify the ionizable peptides from the proteins in a simple mixture and reveal many of their post-translational modifications. However, blood is a complex mixture that may contain many proteins first expressed in cells and tissues. The complete analysis of blood proteins is a daunting task that will rely on a wide range of disciplines from physics, chemistry, biochemistry, genetics, electromagnetic instrumentation, mathematics and computation. Therefore the comprehensive discovery and analysis of blood proteins will rank among the great technical challenges and require the cumulative sum of many of mankind's scientific achievements together. A variety of methods have been used to fractionate, analyze and identify proteins from blood, each yielding a small piece of the whole and throwing the great size of the task into sharp relief. The approaches attempted to date clearly indicate that enumerating the proteins and peptides of blood can be accomplished. There is no doubt that the mass spectrometry of blood will be crucial to the discovery and analysis of proteins, enzyme activities, and post-translational processes that underlay the mechanisms of disease. At present both discovery and quantification of proteins from blood are commonly reaching sensitivities of ∼1 ng/mL.
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Affiliation(s)
- Peihong Zhu
- Department of Chemistry and Biology, Ryerson University, 350 Victoria Street, Toronto, Ontario, Canada M5B 2K3
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Sun Y, Yang H, Mao Y, Xu H, Zhang J, Li G, Lu X, Sang X, Zhao H, Zhong S, Huang J, Zhang H. Increased Golgi protein 73 expression in hepatocellular carcinoma tissue correlates with tumor aggression but not survival. J Gastroenterol Hepatol 2011; 26:1207-12. [PMID: 21443671 DOI: 10.1111/j.1440-1746.2011.06733.x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Serum Golgi protein 73 (sGP73) is a novel and promising biomarker for hepatocellular carcinoma (HCC). However, there are few reports on the pattern of GP73 expression in HCC and the relationship of this expression to clinicopathologic features of patients. This study aimed to investigate the expression of GP73 and it correlation with clinical parameters. METHODS We examined GP73 expression in HCC and adjacent paracarcinomatous liver (PCL) tissue in 36 HCC patients, and took 14 normal liver (NL) samples from hepatic hemangioma patients. Western blot analysis and quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) were used for analyses. RESULTS GP73 expression in HCC was significantly higher than in the corresponding PCL and NL samples at both protein and mRNA levels (P < 0.001). The elevated level of GP73 protein was strongly associated with tumor size, vein invasion, and tumor differentiation, suggesting augmented tumor invasion and metastasis. However, there was no association between GP73 expression and patient survival. CONCLUSION Significant overexpression of GP73 at both protein and mRNA levels along with overexpression of GP73 protein is associated with aggressive behavior of HCC, but not overall patient survival. Further research is needed to determine the potential of GP73 as a therapeutic target.
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Affiliation(s)
- Yongliang Sun
- Department of Liver Surgery, Peking Union Medical College (PUMC) Hospital, Beijing, China
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Gonzalez SA, Keeffe EB. Diagnosis of hepatocellular carcinoma: role of tumor markers and liver biopsy. Clin Liver Dis 2011; 15:297-306, vii-x. [PMID: 21689614 DOI: 10.1016/j.cld.2011.03.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Early diagnosis of hepatocellular carcinoma (HCC) has a significant impact on survival by implementation of effective treatment strategies, including hepatic resection, locoregional ablative therapy, and liver transplantation. The use of serum tumor markers and biopsy are particularly important for diagnosis of small hepatic lesions with atypical features on imaging studies. α-Fetoprotein remains the most frequently used tumor marker for the diagnosis of HCC. The development of novel serum biomarkers for HCC, identification of molecular markers for tissue immunohistochemistry, and emergence of new diagnostic techniques such as proteomic profiling may improve the early detection rate of HCC in the future.
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Affiliation(s)
- Stevan A Gonzalez
- Division of General and Transplant Hepatology, Baylor Regional Transplant Institute, Baylor All Saints Medical Center at Fort Worth, Baylor University Medical Center at Dallas, 1250 8th Avenue, Suite 515, Fort Worth, TX 76104, USA
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31
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Hsu PS, Wang YS, Huang SC, Lin YH, Chang CC, Tsang YW, Jiang JS, Kao SJ, Uen WC, Chi KH. Improving Detection Accuracy of Lung Cancer Serum Proteomic Profiling via Two-Stage Training Process. Proteome Sci 2011; 9:20. [PMID: 21496334 PMCID: PMC3102603 DOI: 10.1186/1477-5956-9-20] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2010] [Accepted: 04/17/2011] [Indexed: 01/17/2023] Open
Abstract
Background Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS) is a frequently used technique for cancer biomarker research. The specificity of biomarkers detected by SELDI can be influenced by concomitant inflammation. This study aimed to increase detection accuracy using a two-stage analysis process. Methods Sera from 118 lung cancer patients, 72 healthy individuals, and 31 patients with inflammatory disease were randomly divided into training and testing groups by 3:2 ratio. In the training group, the traditional method of using SELDI profile analysis to directly distinguish lung cancer patients from sera was used. The two-stage analysis of distinguishing the healthy people and non-healthy patients (1st-stage) and then differentiating cancer patients from inflammatory disease patients (2nd-stage) to minimize the influence of inflammation was validated in the test group. Results In the test group, the one-stage method had 87.2% sensitivity, 37.5% specificity, and 64.4% accuracy. The two-stage method had lower sensitivity (> 70.1%) but statistically higher specificity (80%) and accuracy (74.7%). The predominantly expressed protein peak at 11480 Da was the primary splitter regardless of one- or two-stage analysis. This peak was suspected to be SAA (Serum Amyloid A) due to the similar m/z countered around this area. This hypothesis was further tested using an SAA ELISA assay. Conclusions Inflammatory disease can severely interfere with the detection accuracy of SELDI profiles for lung cancer. Using a two-stage training process will improve the specificity and accuracy of detecting lung cancer.
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Affiliation(s)
- Pei-Sung Hsu
- Division of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
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Ning QY, Wu JZ, Li GJ, Zang N, Hu DF, Wu JL, Chen MW, Wan PQ. Screening of differentially expressed low-abundance proteins among serum samples from patients with different HBV-related hepatic diseases by SELDI-TOF-MS. Shijie Huaren Xiaohua Zazhi 2011; 19:143-150. [DOI: 10.11569/wcjd.v19.i2.143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To screen differentially expressed low-abundance proteins among serum samples from patients with different HBV-related hepatic diseases and to evaluate their possible value in the diagnosis of these diseases.
METHODS: The surface-enhanced laser desorption or ionization time-of-flight mass spectroscopy (SELDI-TOF-MS) was used to screen differentially expressed proteins among serum samples, in which high-abundance proteins had been removed with acetonitrile, collected from patients with asymptomatic chronic hepatitis B (ASC), chronic hepatitis B (CHB), liver cirrhosis (LC), hepatocellular carcinoma (HCC), and normal controls. Diagnostic models for each disease were then established with differentially expressed proteins. Protein databases were searched to predict the possible structure and function of differentially expressed proteins.
RESULTS: Compared with the normal control group, 63 differentially expressed protein peaks were detected in the ASC group, of which 29 were up-regulated and 34 down-regulated (P < 0.05); 57 in the CHB group, of which 29 up-regulated and 34 down-regulated; 68 in the LC group, of which 33 up-regulated and 35 down-regulated; and 74 in the HCC group, of which 28 up-regulated and 46 down-regulated. A peak with a m/z of 15 889.8 corresponded to a protein whose expression was up-regulated gradually in an order of healthy controls, ASC, CHB and LC patients, and its expression level in the HCC group was lower than those in the CHB group and LC group. The expression of a protein with a m/z of 11 742.2 was higher in the LC group and HCC group than in other groups, and its expression was gradually increased in an order of healthy controls, CHB, and LC patients, or in another order of healthy controls, CHB, and HCC patients. The sensitivity and specificity using the protein peak at 11 742.2 for diagnosis of LC were 90% and 86.67% and for HCC were 93.33% and 83.33%, respectively.
CONCLUSION: Ten protein peaks with m/z values of 8 709.7, 13 759.8, 14 004.0, 15 361.89, 16 072.3, 2 746.8, 3 449.1, 3 941.06, 4 098.3, and 9 445.5 correspond to proteins that might be involved in HBV infection. The protein peak with a m/z of 15 889.8 might be used as a biomarker for early diagnosis of HBV-related liver cirrhosis, while that with a m/z of 11 742.2 might be an important biomarker for the development of HBV-related liver cirrhosis or HCC.
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Liu Z, Ma Y, Yang J, Qin H. Upregulated and Downregulated Proteins in Hepatocellular Carcinoma: A Systematic Review of Proteomic Profiling Studies. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2011; 15:61-71. [PMID: 20726783 DOI: 10.1089/omi.2010.0061] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Zhihua Liu
- Evidence-Based Medicine Group, Department of Surgery, the Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Yanlei Ma
- Evidence-Based Medicine Group, Department of Surgery, the Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Jianjun Yang
- Evidence-Based Medicine Group, Department of Surgery, the Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, People's Republic of China
| | - Huanlong Qin
- Evidence-Based Medicine Group, Department of Surgery, the Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, People's Republic of China
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Ndao M, Rainczuk A, Rioux MC, Spithill TW, Ward BJ. Is SELDI-TOF a valid tool for diagnostic biomarkers? Trends Parasitol 2010; 26:561-7. [PMID: 20708969 DOI: 10.1016/j.pt.2010.07.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2010] [Revised: 07/15/2010] [Accepted: 07/19/2010] [Indexed: 01/25/2023]
Abstract
The genome revolution is providing fresh insights into host and parasite genomes, and new tools are becoming available for examining host-parasite interactions at the proteome level. Technologies such as surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry (MS) can be applied to discover biomarkers (alterations in both host and parasite proteomes) associated with parasitic diseases. Such biomarkers can represent host proteins, fragments of host proteins or parasite proteins that appear in body fluids or tissues following infection. Individual biomarkers or biomarker patterns not only have diagnostic utility (e.g. in active disease, prognosis, tests of cure) but can also provide unique insights into the mechanisms underlying host responses and pathogenesis.
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Affiliation(s)
- Momar Ndao
- National Reference Centre for Parasitology, Research Institute of the McGill University Health Centre, Montreal General Hospital, Montreal, Quebec, Canada.
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35
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Du J, Yang S, Lin X, Bu L, Nan Y, Huo S, Shang W. Use of anchorchip-time-of-flight spectrometry technology to screen tumor biomarker proteins in serum for small cell lung cancer. Diagn Pathol 2010; 5:60. [PMID: 20854674 PMCID: PMC2955651 DOI: 10.1186/1746-1596-5-60] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2010] [Accepted: 09/20/2010] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The purpose of this study is to discover potential biomarkers in serum for the detection of small cell lung cancer (SCLC). METHODS 74 serum samples including 30 from SCLC patients and 44 from healthy controls were analyzed using ClinProt system combined with matrix-assisted laser desorption/ionization time-of-flight masss spectrometry (MALDI-TOF-MS). ClinProt software and genetic algorithm analysis selected a panel of serum markers that most efficiently predicted which patients had SCLC. RESULTS The diagnostic pattern combined with 5 potential biomarkers could differentiate SCLC patients from healthy persons, with a sensitivity of 90%, specificity of 97.73%. Remarkably, 88.89% of stage I/II patients were accurately assigned to SCLC. CONCLUSIONS Anchorchip-time-of-flight spectrometry technology will provide a highly accurate approach for discovering new biomarkers for the detection of SCLC.
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Affiliation(s)
- Jie Du
- Department of Respiratory Medicine, Second Affiliated Hospital of Medical School, Xi'an Jiaotong University, N-710000 Xi'an, China
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36
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Li SQ, Chen Q. Advances in understanding the relationship between GP73 and hepatic diseases. Shijie Huaren Xiaohua Zazhi 2010; 18:2117-2120. [DOI: 10.11569/wcjd.v18.i20.2117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Golgi protein-73 (GP73), a recently discovered Golgi glycoprotein localized on the membrane of the Golgi complex, is expressed in many types of human epithelial cells. In normal human liver, GP73 is highly expressed in biliary epithelial cells, but barely detectable in hepatocytes. However, GP73 expression has been found to be strongly up-regulated in hepatocytes and elevated in the serum in patients with liver diseases, especially those with hepatocellular carcinoma (HCC). Thus, GP73 is a candidate serum marker for the early detection of HCC.
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Fang M, Zhao YP, Zhou FG, Lu LG, Qi P, Wang H, Zhou K, Sun SH, Chen CY, Gao CF. N-glycan based models improve diagnostic efficacies in hepatitis B virus-related hepatocellular carcinoma. Int J Cancer 2010; 127:148-59. [PMID: 19904744 DOI: 10.1002/ijc.25030] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The early diagnosis of hepatocellular carcinoma (HCC) is of great clinical desirable due to lack of specific and sensitive markers. Alterations in the sugar chains of glycoprotein synthesized by the liver contribute to the molecular basis of abnormalities in carcinogenesis. This study aims to construct and assess the diagnostic value of N-glycan based diagnostic model in HCC identification and follow-up. A total of 393 subjects including HBV-related HCC, liver fibrosis and healthy controls were recruited. Follow-up was carried out before and after surgical treatment in HCC. N-glycome of serum glycoprotein was profiled by DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis (DSA-FACE). Multiparameters diagnostic models were constructed based on N-glycan markers. The result found that 2 N-glycan structure abundances (NG1A2F, Peak 4; NA3Fb, Peak 9) were useful as N-glycan markers. The diagnostic efficacy of the log ratio [log(p9/4)] was similar to that of AFP in differentiating HCC from fibrosis. The accuracy and sensitivity of the diagnostic model combining AFP and N-glycan markers (Cscore B) were increased 7-10% compared with that of AFP. Log(p9/4) was more efficient in monitoring the progression of HCC with regarding to vascular invasion at improved specificity (16%) and accuracy (8%) compared with that of AFP. The N-glycan markers were found to be changed significantly after surgical resection in HCC follow-up. We conclude that the branching alpha (1,3)-fucosylated triantennary glycan and a biantennary glycan are promising as N-glycan markers. The diagnostic models based on the N-glycan markers and AFP improve the efficacy in HCC diagnosis and progression monitoring.
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Affiliation(s)
- Meng Fang
- Department of Laboratory Medicine, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China
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Lee NPY, Cheung ST, Poon RTP, Fan ST, Luk JM. Genomic and proteomic biomarkers for diagnosis and prognosis of hepatocellular carcinoma. Biomark Med 2010; 1:273-84. [PMID: 20477402 DOI: 10.2217/17520363.1.2.273] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Hepatocellular carcinoma is one of the most deadly liver malignancies found worldwide, with hepatitis virus infection being the prominent risk factor for this lesion. Patients with hepatocellular carcinoma are usually first diagnosed when in the advanced stage; thus, long-term clinical outcomes are poor and patients have limited treatment options. Currently, surveillance of hepatocellular carcinoma relies upon serological testing of alpha-fetoprotein levels and hepatic ultrasonography, which have low sensitivity and specificity, and are sometimes operator-dependent, respectively. Therefore, discovery of new biomarkers for early and accurate detection of hepatocellular carcinoma would be of great clinical value. Genomic and proteomic approaches are two major laboratory platforms for the identification of candidate hepatocellular carcinoma biomarkers based on profiling and validating with tumor and nontumor clinical samples. Frequently, these diagnostic markers have been found in association with genetic aberrations, protein-level alterations, post-translational modifications and immune functions. With the discovery of these biomarkers, earlier detection of hepatocellular carcinoma in high-risk subjects (e.g., cirrhosis and hepatitis carriers) becomes possible, which will enable clinicians to offer patients better clinical management and more effective treatment modalities.
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Affiliation(s)
- Nikki P Y Lee
- The University of Hong Kong, Department of Surgery and Center for Cancer Research, Queen Mary Hospital, Pokfulam, Hong Kong, PR China
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Ndao M, Spithill TW, Caffrey R, Li H, Podust VN, Perichon R, Santamaria C, Ache A, Duncan M, Powell MR, Ward BJ. Identification of novel diagnostic serum biomarkers for Chagas' disease in asymptomatic subjects by mass spectrometric profiling. J Clin Microbiol 2010; 48:1139-49. [PMID: 20071547 PMCID: PMC2849606 DOI: 10.1128/jcm.02207-09] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2009] [Revised: 12/26/2009] [Accepted: 01/07/2010] [Indexed: 01/10/2023] Open
Abstract
More than 10 million people are thought to be infected with Trypanosoma cruzi, primarily in the Americas. The clinical manifestations of Chagas' disease (CD) are variable, but most subjects remain asymptomatic for decades. Only 15 to 30% eventually develop terminal complications. All current diagnostic tests have limitations. New approaches are needed for blood bank screening as well as for improved diagnosis and prognosis. Sera from subjects with asymptomatic CD (n = 131) were compared to those from uninfected controls (n = 164) and subjects with other parasitic diseases (n = 140), using protein array mass spectrometry. To identify biomarkers associated with CD, sera were fractionated by anion-exchange chromatography and bound to two commercial ProteinChip array chemistries: WCX2 and IMAC3. Multiple candidate biomarkers were found in CD sera (3 to 75.4 kDa). Algorithms employing 3 to 5 of these biomarkers achieved up to 100% sensitivity and 98% specificity for CD. The biomarkers most useful for diagnosis were identified and validated. These included MIP1 alpha, C3a anaphylatoxin, and unusually truncated forms of fibronectin, apolipoprotein A1 (ApoA1), and C3. An antipeptide antiserum against the 28.9-kDa C terminus of the fibronectin fragment achieved good specificity (90%) for CD in a Western blot format. We identified full-length ApoA1 (28.1 kDa), the major structural and functional protein component of high-density lipoprotein (HDL), as an important negative biomarker for CD, and relatively little full-length ApoA1 was detected in CD sera. This work provides proof of principle that both platform-dependent (i.e., mass spectrometry-based) and platform-independent (i.e., Western blot) tests can be generated using high-throughput mass profiling.
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Affiliation(s)
- Momar Ndao
- National Reference Centre for Parasitology, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
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Kanmura S, Uto H, Sato Y, Kumagai K, Sasaki F, Moriuchi A, Oketani M, Ido A, Nagata K, Hayashi K, Stuver SO, Tsubouchi H. The complement component C3a fragment is a potential biomarker for hepatitis C virus-related hepatocellular carcinoma. J Gastroenterol 2010; 45:459-67. [PMID: 20012107 DOI: 10.1007/s00535-009-0160-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2009] [Accepted: 10/28/2009] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) has a high mortality rate, and early detection of HCC improves patient survival. However, the molecular diagnostic markers for early HCC have not been fully elucidated. The aim of this study was to identify novel diagnostic markers for HCC. METHODS Serum protein profiles of 45 hepatitis C virus infection (HCV)-related HCC patients (HCV-HCC) were compared to 42 HCV-related chronic liver disease patients without HCC (HCV-CLD) and 21 healthy volunteers using the ProteinChip SELDI system. One of the identified proteins was evaluated as a diagnostic marker for HCC in patients with HCV. RESULTS Five protein peaks (4067, 4470, 7564, 7929, and 8130 m/z) had p-values less than 1 x 10(-7) and were significantly increased in the sera of HCV-HCC patients compared to HCV-CLD patients and healthy volunteers. Among these proteins, an 8130 m/z peak was the most differentially expressed and identified as the complement component 3a (C3a) fragment. For HCV-HCC and HCV-CLD, the relative intensity of this C3a fragment had the best area under the ROC curve [0.70], followed by des-gamma-carboxy prothrombin (DCP) [0.68], lectin-bound alpha fetoprotein (AFP-L3) [0.58] and AFP [0.53] for HCC. A combined analysis of the C3a fragment, AFP and DCP led to a 98% positive identification rate. In addition, the measurable C3a fragment in some HCC patients was not only significantly higher in the year of HCC onset compared to the pre-onset year, but also decreased after treatment. CONCLUSIONS The 8130 m/z C3a fragment is a potential marker for the early detection of HCV-related HCC.
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Affiliation(s)
- Shuji Kanmura
- Digestive Disease and Life-style Related Disease Health Research, Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan
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Chen L, Ho DWY, Lee NPY, Sun S, Lam B, Wong KF, Yi X, Lau GK, Ng EWY, Poon TCW, Lai PBS, Cai Z, Peng J, Leng X, Poon RTP, Luk JM. Enhanced detection of early hepatocellular carcinoma by serum SELDI-TOF proteomic signature combined with alpha-fetoprotein marker. Ann Surg Oncol 2010; 17:2518-25. [PMID: 20354800 PMCID: PMC2924503 DOI: 10.1245/s10434-010-1038-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2009] [Indexed: 01/10/2023]
Abstract
Background Biomarkers for accurate diagnosis of early hepatocellular carcinoma (HCC) are limited in number and clinical validation. We applied SELDI-TOF-MS ProteinChip technology to identify serum profile for distinguishing HCC and liver cirrhosis (LC) and to compare the accuracy of SELDI-TOF-MS profile and alpha-fetoprotein (AFP) level in HCC diagnosis. Patients and Methods Serum samples were obtained from 120 HCC and 120 LC patients for biomarker discovery and validation studies. ProteinChip technology was employed for generating SELDI-TOF proteomic features and analyzing serum proteins/peptides. Results A diagnostic model was established by CART algorithm, which is based on 5 proteomic peaks with m/z values at 3324, 3994, 4665, 4795, and 5152. In the training set, the CART algorithm could differentiate HCC from LC subjects with a sensitivity and specificity of 98% and 95%, respectively. The results were assessed in blind validation using separate cohorts of 60 HCC and 60 LC patients, with an accuracy of 83% for HCC and 92% for LC patients. The diagnostic odd ratio (DOR) indicated that SELDI-TOF proteomic signature could achieve better diagnostic performance than serum AFP level at a cutoff of 20 ng/mL (AFP20) (92.72 vs 9.11), particularly superior for early-stage HCC (87% vs 54%). Importantly, a combined use of both tests could enhance the detection of HCC (sensitivity, 95%; specificity, 98%; DOR, 931). Conclusion Serum SELDI-TOF proteomic signature, alone or in combination with AFP marker, promises to be a good tool for early diagnosis and/screening of HCC in at-risk population with liver cirrhosis.
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Affiliation(s)
- Lei Chen
- Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
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Proteomic approaches in the search for biomarkers of liver fibrosis. Trends Mol Med 2010; 16:171-83. [PMID: 20304704 DOI: 10.1016/j.molmed.2010.01.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2009] [Revised: 01/14/2010] [Accepted: 01/27/2010] [Indexed: 02/07/2023]
Abstract
Chronic liver diseases (CLDs) can cause progressive hepatic fibrosis culminating in cirrhosis. Fibrosis staging requires liver biopsy, which is invasive, expensive and frequently poorly tolerated by patients. Serum-based panels of fibrosis biomarkers have been developed as alternatives to biopsy. Recent advances in high-throughput proteomic methods have the potential to optimise combinations of biomarkers for the diagnosis of liver fibrosis. Here, we review the key recent developments in the field of proteomics and their application to this important clinical question. We critically discuss the challenges and priorities for future research that are of critical importance to clinical hepatology.
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Han T, Liu H, Yu ZL, Li J, Wang L, Xiao SX, Li Y, Yu ML. Serum peptide profiles during progression of chronic hepatitis B virus infection to liver failure. J Viral Hepat 2010; 17 Suppl 1:18-23. [PMID: 20586930 DOI: 10.1111/j.1365-2893.2010.01267.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Chronic hepatitis B virus (HBV)-infected patients with liver failure have a poor prognosis, and no satisfactory biomarkers are available for diagnosis before the end-stage. We explored serum peptide profiling for diagnosis and prediction of progression to liver failure in HBV-infected patients. Serum samples (164) from healthy subjects (n = 20), or subjects with chronic hepatitis B without cirrhosis and liver failure [chronic hepatitis B subjects without cirrhosis and liver failure (CHB); n = 33], with compensated liver cirrhosis (compensated liver cirrhosis (LC); n = 35), with acute-on-chronic liver failure [acute-on-chronic liver failure (ACLF); n = 38] or with chronic liver failure [chronic liver failure (CLF), n = 38] were applied to ClinProt magnetic beads, and bound peptides/proteins were analyzed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Our classification diagnostic models of liver disease were generated based on the Genetic Algorithm (GA) and Quick Classifier Algorithm (QC). Differentially expressed peptides were found among all test groups, with patterns of difference that readily distinguished between healthy and various HBV-associated liver disease samples. The model generated seven characteristic peptide peaks at 4053 m/z, 3506 m/z, 4963 m/z, 9289 m/z, 2628 m/z, 3193 m/z and 6432 m/z, giving overall predictive capability of 54.27%. Two-way comparisons of LC, ACLF or CLF vs CHB had predictive capabilities of 79.8%, 91.41% and 97.99%, respectively. Comparisons of ACLF or CLF vs LC were predictive at 87.72% and 82.18%, respectively and ACLF vs CLF was predictive at 75.05%. These classification diagnostic models generated by different peptide peaks were further validated in blinded tests with 67-100% accuracy. Serum peptide patterns vary during progression of chronic HBV infection to liver failure and may be used to distinguish different stages of the disease.
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Affiliation(s)
- T Han
- Department of Hepatology, Tianjin Institute of Hepatobiliary Disease, Tianjin Key Laboratory of Artificial Cells, Tianjin Third Central Hospital, Tianjin Medical University, Tianjin, China.
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Dancygier H. Malignant Tumors. CLINICAL HEPATOLOGY 2010:1305-1350. [DOI: 10.1007/978-3-642-04519-6_48] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Levin Y, Jaros JAJ, Schwarz E, Bahn S. Multidimensional protein fractionation of blood proteins coupled to data-independent nanoLC-MS/MS analysis. J Proteomics 2009; 73:689-95. [PMID: 19896566 DOI: 10.1016/j.jprot.2009.10.013] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2009] [Revised: 09/29/2009] [Accepted: 10/30/2009] [Indexed: 11/19/2022]
Abstract
In order to exploit human blood as a source of protein disease biomarkers, robust analytical methods are needed to overcome the inherent molecular complexity of this bio-fluid. We present the coupling of label-free SAX chromatography and IMAC to a data-independent nanoLC-MS/MS (nanoLC-MS(E)) platform for analysis of blood plasma and serum proteins. The methods were evaluated using protein standards added at different concentrations to two groups of samples. The results demonstrate that both techniques enable accurate protein quantitation using low sample volumes and a minimal number of fractions. Combining both methods, 883 unique proteins were identified, of which 423 proteins showed high reproducibility. The two approaches resulted in identification of unique molecular signatures with an overlap of approximately 30%, thus providing complimentary information on sub-proteomes. These methods are potentially useful for systems biology, biomarker discovery, and investigation of phosphoproteins in blood.
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Affiliation(s)
- Yishai Levin
- Cambridge Centre for Neuropsychiatric Research, Institute of Biotechnology, Department of Chemical Engineering and Biotechnology, University of Cambridge, Tennis Court Road, CB 2 1QT Cambridge, United Kingdom
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Gast MCW, van Gils CH, Wessels LFA, Harris N, Bonfrer JMG, Rutgers EJT, Schellens JHM, Beijnen JH. Influence of sample storage duration on serum protein profiles assessed by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF MS). Clin Chem Lab Med 2009; 47:694-705. [PMID: 19416081 DOI: 10.1515/cclm.2009.151] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND Issues have been raised concerning the robustness and validity of alleged serum markers discovered by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF MS). Pre-analytical variables have been shown to exert a profound effect on protein profiles, irrespective of true biological variation. However, little is known about the possible effects of sample storage duration on protein profiles. We, therefore, aimed to investigate the effects of extended storage duration on the serum protein profile. METHODS Archival sera from 140 breast cancer patients, stored at -30 degrees C for 1-11 years, were profiled by SELDI-TOF MS using immobilised metal affinity capture (IMAC) arrays, a condition applied in the majority of breast cancer biomarker discovery studies. RESULTS Fourteen peak clusters, structurally identified as C3a des-arginine anaphylatoxin and multiple fragments of albumin and fibrinogen, were found to be significantly associated with sample storage duration by five distinct patterns. These proteins have been described previously as potential cancer markers, rendering them specific to both disease and sample handling issues. CONCLUSIONS To prevent experimental variation being interpreted erroneously as disease associated variation, assessment of potential confounding pre-analytical parameters is a pre-requisite in biomarker discovery and validation studies. In addition, with respect to the different (non-)linear patterns observed in the current study, simply performing linear corrections to account for sample storage duration will not necessarily suffice.
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Affiliation(s)
- Marie-Christine W Gast
- Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands.
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Findeisen P, Neumaier M. Mass spectrometry based proteomics profiling as diagnostic tool in oncology: current status and future perspective. Clin Chem Lab Med 2009; 47:666-84. [PMID: 19445650 DOI: 10.1515/cclm.2009.159] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Proteomics analysis has been heralded as a novel tool for identifying new and specific biomarkers that may improve diagnosis and monitoring of various disease states. Recent years have brought a number of proteomics profiling technologies. Although proteomics profiling has resulted in the detection of disease-associated differences and modification of proteins, current proteomics technologies display certain limitations that are hampering the introduction of these new technologies into clinical laboratory diagnostics and routine applications. In this review, we summarize current advances in mass spectrometry based biomarker discovery. The promises and challenges of this new technology are discussed with particular emphasis on diagnostic perspectives of mass-spectrometry based proteomics profiling for malignant diseases.
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Affiliation(s)
- Peter Findeisen
- Institute for Clinical Chemistry, Medical Faculty Mannheim of the University of Heidelberg, Heidelberg, Germany.
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Cheng L, Zhou L, Tao L, Zhang M, Cui J, Liu Y. Preliminary study of proteomic shift from normal to premalignant laryngeal lesions and to laryngeal squamous cell carcinoma. Acta Otolaryngol 2009; 129:774-8. [PMID: 18821292 DOI: 10.1080/00016480802412797] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
CONCLUSIONS The malignant shift was discovered to begin even in the premalignant stage in the comparison of premalignant laryngeal lesions (PMLLs) with laryngeal squamous cell carcinoma (LSCC) and healthy controls. The differential expression of proteins among normal, PMLL, and cancer cells might provide the prediction for the changes from normal to PMLL and to malignant disease. OBJECTIVES To study the serum proteomic shift from normal control to PMLL and progression to LSCC. MATERIALS AND METHODS A total of 211 serum samples from patients with LSCC (n = 89 at stage I-II) or PMLL (n = 57), or normal controls (n = 65) were obtained with informed consent. Serum protein profiles on weak cationic exchange (WCX2) were performed by surface-enhanced laser desorption/ionization mass spectrometry (SELDI-TOF MS) and then analyzed by Biomarker Wizard software. RESULTS Peak intensities of serum from PMLLs were compared to normal controls and serum from patients with LSCC. Mean intensity differed significantly only for one peak (4532 Da, p = 0.032) between LSCC and precancerous diseases, while 13 peaks differed significantly between precancerous diseases and normal controls. Eighteen biomarkers were selected to separate stage I- II LSCC patients and healthy controls.
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Varghese RS, Goldman L, An Y, Loffredo CA, Abdel-Hamid M, Kyselova Z, Mechref Y, Novotny M, Drake SK, Goldman R, Ressom HW. Integrated peptide and glycan biomarker discovery using MALDI-TOF mass spectrometry. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2009; 2008:3791-4. [PMID: 19163537 DOI: 10.1109/iembs.2008.4650034] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Quantitative comparison of peptides and glycans in serum is conducted using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) to identify biomarkers. A peak selection algorithm is developed to identify a panel of integrated peptide and glycan peaks to distinguish hepatocellular carcinoma (HCC) cases from high-risk population of patients with chronic liver disease (CLD). Candidate peptide and glycan markers selected frequently in multiple runs of the algorithm are presented. The performance of these markers is evaluated in terms of their ability to distinguish HCC cases from patients with CLD in a blinded validation set.
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Affiliation(s)
- Rency S Varghese
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
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Simpson KL, Whetton AD, Dive C. Quantitative mass spectrometry-based techniques for clinical use: biomarker identification and quantification. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877:1240-9. [PMID: 19058768 PMCID: PMC7185464 DOI: 10.1016/j.jchromb.2008.11.023] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2008] [Accepted: 11/13/2008] [Indexed: 01/03/2023]
Abstract
The potential for development of personalised medicine through the characterisation of novel biomarkers is an exciting prospect for improved patient care. Recent advances in mass spectrometric (MS) techniques, liquid phase analyte separation and bioinformatic tools for high throughput now mean that this goal may soon become a reality. However, there are challenges to be overcome for the identification and validation of robust biomarkers. Bio-fluids such as plasma and serum are a rich source of protein, many of which may reflect disease status, and due to the ease of sampling and handling, novel blood borne biomarkers are very much sought after. MS-based methods for high throughput protein identification and quantification are now available such that the issues arising from the huge dynamic range of proteins present in plasma may be overcome, allowing deep mining of the blood proteome to reveal novel biomarker signatures for clinical use. In addition, the development of sensitive MS-based methods for biomarker validation may bypass the bottleneck created by the need for generation and usage of reliable antibodies prior to large scale screening. In this review, we discuss the MS-based methods that are available for clinical proteomic analysis and highlight the progress made and future challenges faced in this cutting edge area of research.
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Affiliation(s)
- Kathryn L Simpson
- Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester, M20 4BX, United Kingdom.
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