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Tumor-associated autoantibodies are useful biomarkers in immunodiagnosis of α-fetoprotein-negative hepatocellular carcinoma

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World Journal of Gastroenterology 2017年第19期23卷 3496-3504页

作者： Ting Wang Mei Liu Su-Jun Zheng Dan-Dan Bian Jin-Yan Zhang Jia Yao Qing-Fen Zheng A-Meng Shi Wen-Han Li Lu Li Yu Chen Jin-Hai Wang Zhong-Ping Duan Lei Dong Department of Gastroenterology Second Affiliated Hospital of Xi’an Jiaotong University Beijing You’an Hospital Capital Medical University Department of Surgical Oncology First Affiliated Hospital of Xi’an Jiaotong University

AIM To determine the prevalence and diagnostic value of autoantibodies inα-fetoprotein(AFP)-negative hepatocellular carcinoma(HCC).METHODS Fifty-six serum samples from AFP-negative HCC cases,86 from AFP-positive HCC cases,168 from chronic liver disease cases,and 59 from normal human controls were included in this study.Autoantibodies to nucleophosmin(NPM)1,14-3-3zeta and mouse double minute 2 homolog(MDM2)proteins in AFP-negative HCC serum were evaluated by enzymelinked im munosorbent assay.Partially positive sera were further evaluated by western blotting.Immunohistochemistry was used to detect the expression of three tumor-associated antigens(TAAs)in AFP-negative HCC and normal control tissues.RESULTS The frequency of autoantibodies to the three TAAs in AFP-negative HCC sera was 21.4%,19.6%and 19.6%,which was significantly higher than in the chronic liver disease cases and normal human controls(P<0.01)as well as AFP-positive HCC cases.The sensitivity of the three autoantibodies for diagnosis of AFP-negative HCC ranged from 19.6%to 21.4%,and the specificity was approximately 95%.When the three autoantibodies were combined,the sensitivity reached 30.4%and the specificity reached 91.6%.CONCLUSION Autoantibodies to NPM1,14-3-3zeta and MDM2 may be useful biomarkers for immunodiagnosis of AFP-negative HCC.

关键词： α-fetoprotein Nucleophosmin 1 14-3-3zeta Mouse double minute 2 homolog Immunodiagnosis Autoantibody Hepatocellular carcinoma

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Expression of β-catenin Protein in Hepatocellular Carcinoma and Its Relationship with Alpha-fetoprotein

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2016年第6期36卷 846-851页

作者：任亚君黄涛余红璐张莉何前进熊枝繁彭桦 Division of Gastroenterology Liyuan HospitalTongji Medical CollegeHuazhong University of Science and Technology Division of Pediatrics Tianyou HospitalWuhan University of Science and Technology Department of General Surgery Center Hospital of Huanggang Department of Urology Liyuan HospitalTongji Medical CollegeHuazhong University of Science and Technology

This study aimed to investigate the expression of β-catenin in hepatocellular carcinoma（HCC） tissues and its relationship with α-fetoprotein（AFP） in HCC.Immunohistochemistry was used to determine the expression of β-catenin in normal liver tissues（n=10）,liver cirrhosis tissues（n=20）,and primary HCC tissues（n=60）.The relationship between β-catenin expression and clinical parameters of HCC was investigated.Real-time PCR and Western blotting were used to detect the m RNA and protein expression levels of β-catenin in the liver cancer cell line SMMC-7721 transfected with a plasmid encoding AFP,and also the m RNA and protein expression levels of β-catenin were measured in the liver cancer cell line Huh7 before and after the transfection with AFP sh RNA plasmids.The results showed that β-catenin was only expressed on the cell membrane in normal liver tissues.Its localization to the cytoplasm and nucleus of cells was observed in a small proportion of cirrhotic tissues or adjacent HCC tissues,and such ectopic expression of β-catenin was predominant in HCC tissues.The abnormal expression of β-catenin was correlated with serum AFP levels,cancer cell differentiation and vascular invasion（P〈0.05）.Additionally,the increased expression of AFP resulted in the upregulation of β-catenin m RNA and protein levels,while knockdown of AFP with AFP sh RNA led to significantly decreased β-catenin m RNA and protein levels（P〈0.05）.It was suggested that the abnormal expression of β-catenin is implicated in hepatic carcinogenesis and development.AFP can lead to increased expression of β-catenin,which may account for the poor prognosis of AFP-associated HCC patients.

关键词： β-catenin hepatocellular carcinoma α-fetoprotein

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A novel α-fetoprotein-MIP immunosensor based on AuNPs/PTh modified glass carbon electrode

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Chinese Chemical Letters 2019年第1期30卷 160-162页

作者： Yuxuan Lai Chuanxiang Zhang Yan Deng Gaojian Yang Song Li Congli Tang Nongyue He Hunan Key Laboratory of Biomedical Nanomaterials and Devices Hunan University of Technology College of Packing and Materials Engineering Hunan University of Technology State Key Laboratory of Bioelectronics Southeast University

A new α-fetoprotein-MIP(AFP-MIP) immunosensor based on glass carbon electrode(GCE) modified with polythionine(PTh) and gold nanoparticles(AuNPs) was successfully fabricated for sensitive detection ofα-fetoprotein(AFP). Through controlling electropolymerization, A "polydopamine(PDA)-AFP" complex was achieved applying AFP as template and dopamine(DA) as imprinted monomers. After elution, the specific cavities can adsorb the target molecules. Using differential pulse voltammetry(DPV) detection,the peak current decreased with the increase in concentration of AFP, and the linear response range of the AFP-MIP immunosensor was from 0.001 ng/mL to 800 ng/mL with the detection limit as low as0.8138 pg/mL. The MIP immunosensor could become a new promising method for the detection of AFP.Furthermore, this MIP sensor was demonstrated in testing AFP in human serum samples with satisfactory results.

关键词： Molecular imprinting polymer α-fetoprotein Electropolymerization Differential pulse voltammetry Immunosensor

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Value of α-fetoprotein in association with clinicopathological features of hepatocellular carcinoma

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World Journal of Gastroenterology 2013年第11期19卷 1811-1819页

作者： Chang Liu Guang-Qin Xiao Lu-Nan Yan Bo Li Li Jiang Tian-Fu Wen Wen-Tao Wang Ming-Qing Xu Jia-Yin Yang Department of Liver and Vascular Surgery West China HospitalSichuan University

AIM:To explore the relationship between α-fetoprotein(AFP) and various clinicopathological variables and different staging system of hepatocellular carcinoma(HCC) thoroughly.METHODS:A retrospective cohort study of consecutive patients diagnosed with HCC between January 2008 and December 2009 in West China Hospital was enrolled in our study.The association of serum AFP values with the HCC clinicopathological features was analysed by univariate and multivariate analysis,such as status of hepatitis B virus(HBV) infection,tumor size,tumor number,vascular invasion and degree of tumor differentiation.Also,patients were divided into four groups at the time of enrollment according to different cutoff values for serum value of AFP(≤ 20 μg/L,21-400 μg/L,401-800 μg/L,and ≥ 801 μg/L),to compare the positive rate of patient among four groups stratified by various clinicopathological variables.And the correlation of different kinds of tumor staging systems,such as TNM,Barcelona Clinic Liver Cancer(BCLC) staging classification and China staging,were compared with the serum concentration of AFP.RESULTS:A total of 2304 HCC patients were enrolled in this study totally;the mean serum level of AFP was 555.3 ± 546.6 μg/L.AFP levels were within the normal range(< 20 μg/L) in 27.4%(n = 631) of all the cases.81.4%(n = 1875) patients were infected with HBV,and those patients had much higher serum AFP level compared with non-HBV infection ones(573.9 ± 547.7 μg/L vs 398.4 ± 522.3 μg/L,P < 0.001).The AFP level in tumors ≥ 10 cm(808.4 ± 529.2 μg/L) was significantly higher(P < 0.001) than those with tumor size 5-10 cm(499.5 ± 536.4 μg/L) and with tumor size ≤ 5 cm(444.9 ± 514.2 μg/L).AFP levels increased significantly in patients with vascular invasion(694.1 ± 546.9 μg/L vs 502.1 ± 543.1 μg/L,P < 0.001).Patients with low tumor cell differentiation(559.2 ± 545.7 μg/L) had the significantly(P = 0.007) highest AFP level compared with high differentiation(207.3 ± 420.8 μg/L) and intermediate differentiation(527.9 ± 538.4 μg/L).In the multiple va

关键词： α-fetoprotein Hepatocellular carcinoma Tumor markers Clinical features Pathological features

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Prognostic roles of preoperative α-fetoprotein and des-γ-carboxy prothrombin in hepatocellular carcinoma patients

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World Journal of Gastroenterology 2015年第16期21卷 4933-4945页

作者： Makoto Meguro Toru Mizuguchi Toshihiko Nishidate Kenji Okita Masayuki Ishii Shigenori Ota Tomomi Ueki Emi Akizuki Koichi Hirata Department of Surgery Surgical Oncology and ScienceSapporo Medical University School of Medicine

AIM:To clarify the utility of using des-γ-carboxy prothrombin(DCP)andα-fetoprotein(AFP)levels to predict the prognosis of hepatocellular carcinoma(HCC)in patients with hepatitis B virus(HBV)and the hepatitis C virus(HCV)infections.METHODS:A total of 205 patients with HCC(105patients with HBV infection 100 patients with HCV infection)who underwent primary hepatectomy between January 2004 and May 2012 were enrolled retrospectively.Preoperative AFP and DCP levels were used to create interactive dot diagrams to predict recurrence within 2 years after hepatectomy,and cutoff levels were calculated.Patients in the HBV and HCV groups were classified into three groups:a group with low AFP and DCP levels(LL group),a group in which one of the two parameters was high and the other was low(HL group),and a group with high AFP and DCP levels(HH group).Liver function parameters,the postoperative recurrence-free survival rate,and postoperative overall survival were compared between groups.The survival curves were compared by logrank test using the Kaplan-Meier method.Multivariate analysis using a Cox forward stepwise logistic regression model was conducted for a prognosis.RESULTS:The preoperative AFP cutoff levels for recurrence within 2 years after hepatectomy in the HBV and HCV groups were 529.8 ng/m L and 60 m AU/m L,respectively;for preoperative DCP levels,the cutoff levels were 21.0 ng/m L in the HBV group and 67 m AU/m L in the HCV group.The HBV group was significantly different from the other groups in terms of vascular invasion,major hepatectomy,volume of intraoperative blood loss,and surgical duration.Significant differences were found between the LL group,the HL group,and the HH group in terms of both mean disease-free survival time(MDFST)and mean overall survival time(MOST):64.81±7.47 vs 36.63±7.62 vs 18.98±6.17mo(P=0.001)and 85.30±6.55 vs 59.44±7.87 vs46.57±11.20 mo(P=0.018).In contrast,the HCV group exhibited a significant difference in tumor size,vascular invasion,volume of intraoperative blood loss,and surgical dur

关键词： Hepatocellular carcinoma Hepatitis B Hepatitis C Des-γ-carboxy prothrombin α-fetoprotein

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Diagnostic value of glypican-3 in serum and liver for primary hepatocellular carcinoma

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World Journal of Gastroenterology 2010年第35期16卷 4410-4415页

作者： Hui Liu Li-Jie Zhang Peng Li Yun Zhai Yu-Fen Tan Ning Li Hui-Guo Ding Chun-Feng Qu Department of Pathology Beijing Youan Hospital Capital Medical University Beijing 100069 China Department of Hepatology and Gastroenterology China State Key Laboratory of Molecular Oncology Cancer Institute/Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100021China

AIM:To evaluate the diagnostic value of glypican-3(GPC3) in serum and liver for primary hepatocellular carcinoma(HCC).METHODS:Serum levels of GPC3 and α-fetoprotein(AFP) were measured in 75 patients with primary HCC and 32 patients with liver cirrhosis.Expression of GPC3 and AFP in 58 HCC and 12 cirrhotic specimens was detected with immunohistochemical staining.RESULTS:When the cut-off value of serum GPC3 was set at 300 ng/L,its sensitivity and specificity for HCC were 47.0% and 93.5%,respectively.Among the 14 patients with HCC at stage according to the Barcelona Clinic Liver Cancer staging system,the serum GPC3 level was higher than 300 ng/L in 50%(7/14) patients,the serum AFP level was not ≥ 400 μg/L in any patient.Combined serum AFP and GPC3 significantly increased the sensitivity to the diagnosis of HCC.The GPC3 expression was detected in cytoplasm of HCC cells but not in hepatocytes and bile ducts of benign tumors.Among the 58 HCC patients,the GPC3 was expressed in 100%(28/28) patients with their serum AFP level ≥ 400 μg/L,and in 90%(27/30) patients with their AFP level < 400 μg/L,respectively.The GPC3 was weakly or negatively expressed in all paracarcinomatous and cirrhotic tissue samples.AFP positive HCC cells were only found in 1 out of the 58 HCC patients.CONCLUSION:GPC3 protein is a sensitive and specific serum marker for diagnosis of early HCC.Its expression in liver tissues can be used to discriminate tumor cells from benign hepatic cells.

关键词： Hepatocellular carcinoma α-fetoprotein Glypican-3 Diagnosis

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Diagnostic value of cancer-testis antigen mRNA in peripheral blood from hepatocellular carcinoma patients

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World Journal of Gastroenterology 2010年第32期16卷 4072-4078页

作者： Li Zhao Dong-Cheng Mou Zeng-An Wu Ji-Run Peng Lei Huang Xi-Sheng Leng Department of Surgery Wangjing Hospital China Academy of Chinese Medical Sciences Beijing100102 China Center of Hepatobiliary Surgery Peking University People s Hospital Beijing 100044 China

AIM:To evaluate the diagnostic value of cancer-testis antigen(CTA) mRNA in peripheral blood samples from hepatocellular carcinoma(HCC) patients.METHODS:Peripheral blood samples were taken from 90 patients with HCC before operation.Expression of melanoma antigen-1(MAGE-1),synovial sarcoma X breakpoint-1(SSX-1),and cancer-testis-associated protein of 11 kDa(CTp11) mRNA in peripheral blood mononuclear cells(PBMC) was tested by nested reverse transcriptspolymerase chain reaction(RT-PCR).Serum α-fetoprotein(AFP) in these patients was also determined.RESULTS:The positive rate of MAGE-1,SSX-1 and CTp11 transcripts was 37.7%,34.4%,31.1% in PBMC samples,and 74.4%,73.3%,62.2% in their resected tumor samples,respectively.The positive rate for at least one of the transcripts of three CTA genes was 66.7% in PBMC samples and 91.1% in their resected tumor samples.MAGE-1,SSX-1 and/or CTp11 mRNA were not detected in the PBMC of those patients from whom the resected tumor samples were MAGE-1,SSX-1 and/or CTp11 mRNA negative,nor in the PBMC samples from 20 healthy donors and 10 cirrhotic patients.Among the 90 patients,the serum AFP in 44 patients met the general diagnostic standard(AFP > 400 μg/L) for HCC,and was negative(AFP ≤ 20 μg/L) or positive with a low concentration(20 μg/L < AFP ≤ 400 μg/L) in the other patients.The positive rate for at least one of the transcripts of three CTA genes in PBMC samples from the AFP negative or positive patients with a low concentration was 69.2% and 45.0%,respectively.Of the 90 patients,71(78.9%) were diagnosed as HCC by nested RT-PCR and serum AFP.Although the positive rate for at least one of the transcripts of three CTA genes in PBMC samples from 53 patients at TNM stage or was obviously higher than that in PBMC samples from 37 patients at stage or(77.9% vs 51.4%,P = 0.010),the CTA mRNA was detected in 41.7% and 56.0% of PBMC samples from HCC patients at stages andrespectively.CONCLUSION:Detecting MAGE-1,SSX-1 and CTp11 mRNA in PBMC improves the total diagnostic rate of HCC.

关键词： Hepatocellular carcinoma α-fetoprotein Cancer-testis antigen Diagnosis Nested reverse transcripts-polymerase chain reaction

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Primary hepatoid adenocarcinoma of the lung in Yungui Plateau,China:A case report

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World Journal of Clinical Cases 2019年第13期7卷 1711-1716页

作者： Yun-Fei Shi Jia-Gui Lu Qing-Mei Yang Jin Duan You-Ming Lei Wei Zhao Yin-Qiang Liu Department of Thoracic Surgery in the Elderly the First Affiliated Hospital of Kunming Medical University

BACKGROUND Hepatoid adenocarcinoma (HAC) occurs in extrahepatic organs such as the gastrointestinal tract, testes, ovaries, lungs, mediastinum and pancreas, and frequently produces α-fetoprotein (AFP). HAC of the lung (HAL) is rare, characterized by difficult treatment and poor prognosis. There are no reports of HAL in Yunnan-Guizhou Plateau, China. CASE SUMMARY A 60-year-old male patient was clinically diagnosed with HAL pT3NOM0, stage IIB. Chest computed tomography revealed a 7.5 cm × 7.2 cm soft tissue mass located in the right lung upper lobe and the adjacent superior mediastinum. Right upper lobectomy was performed. The diagnosis of HAL was confirmed by pathological examination, and the patient received paclitaxel and carboplatin as adjuvant chemotherapy after surgery. CONCLUSION Clinical manifestations, pathological features, imaging findings, auxiliary examination, and treatment planning of HAL are presented to help clinicians improve their diagnosis and treatment.

关键词： Hepatic adenocarcinoma Lung cancer Immunohistochemistry α-fetoprotein Case report

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Clinical relevance of increased serum preneoplastic antigen in hepatitis C-related hepatocellular carcinoma

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World Journal of Gastroenterology 2020年第13期26卷 1463-1473页

作者： Satoyoshi Yamashita Akira Kato Toshitaka Akatsuka Takashi Sawada Tomohide Asai Noriyuki Koyama Kiwamu Okita Department of Gastroenterology and Hepatology Japan Community Health Care Organization Shimonoseki Medical CenterShimonosekiYamaguchi 7500061Japan Department of Physiology Faculty of MedicineSaitama Medical UniversityIruma-gunSaitama 3500495Japan Research and Development Division Sekisui Medical Company LimitedRyugasakiIbaraki 3010852Japan Clinical Research Department Eidia Company LimitedChiyoda-kuTokyo 1010032Japan Eisai Company Limited Shinjuku-kuTokyo 1600812Japan Department of Internal Medicine Shunan Memorial HospitalKudamatsuYamaguchi 7440033Japan

BACKGROUND The prognosis of hepatocellular carcinoma(HCC)patients remains poor despite advances in treatment modalities and diagnosis.It is important to identify useful markers for the early detection of HCC in patients.Preneoplastic antigen(PNA),originally reported in a rat carcinogenesis model,is increased in the tissues and serum of HCC patients.AIM To determine the diagnostic value of PNA for discriminating HCC and to characterize PNA-positive HCC.METHODS Patients with hepatitis C virus(HCV)-related hepatic disorders were prospectively enrolled in this study,which included patients with hepatitis,with cirrhosis,and with HCC.A novel enzyme-linked immunosorbent assay was developed to measure serum PNA concentrations in patients.RESULTS Serum PNA concentrations were measured in 89 controls and 141 patients with HCV infections(50 hepatitis,44 cirrhosis,and 47 HCC).Compared with control and non-HCC patients,PNA was increased in HCC.On receiver operating characteristic curve analysis,the sensitivity of PNA was similar to the HCC markers des-γ-carboxy-prothrombin(DCP)andα-fetoprotein(AFP),but the specificity of PNA was lower.There was no correlation between PNA and AFP and a significant but weak correlation between PNA and DCP in HCC patients.Importantly,the correlations with biochemical markers were completely different for PNA,AFP,and DCP;glutamyl transpeptidase was highly correlated with PNA,but not with AFP or DCP,and was significantly higher in PNA-high patients than in PNA-low patients with HCV-related HCC.CONCLUSION PNA may have the potential to diagnose a novel type of HCC in which glutamyl transpeptidase is positively expressed but AFP or DCP is weakly or negatively expressed.

关键词： Serum preneoplastic antigen Hepatitis C virus Hepatocellular carcinoma Des-γ-carboxy-prothrombin α-fetoprotein Sensitivity Specificity

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Hepatocellular carcinoma in developing countries:Prevention,diagnosis and treatment

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World Journal of Hepatology 2012年第3期4卷 99-104页

作者： Michael C Kew Department of Medicine University of Cape Town and Groote Schuur HospitalCape Town Department of Medicine University of the Witwatersrand

Hepatocellular carcinoma(HCC)occurs commonly and with increasing frequency in developing countries,where it also carries an especially grave prognosis.The major risk factor for HCC in these regions is chronic hepatitis B virus(HBV)infection,although dietary exposure to aflatoxin B1 also plays an important etio-logical role.Prevention of HCC in developing regions is unlikely in the foreseeable future.Although an effec-tive vaccine against HBV is available,the percentage of babies born in developing countries that receive the full course of immunization remains low.Moreover,the usually long interval between infection with HBV and the development of HCC means that 30 to 50 years will elapse before the full effect of the vaccine will be realized.Practical measures to prevent aflatoxin B1 ex-posure are not in place.Serumα-fetoprotein levels are a useful pointer to the diagnosis of HCC in low-income countries,but definitive diagnosis is hampered both by the lack of the sophisticated imaging equipment now available in developed countries and by obstacles to obtaining histological proof.In the majority of patients in low-income regions,the tumor is inoperable by the time the patient presents.Hepatic resection is seldom possible in sub-Saharan Africa,although the tumor is successfully resected in a larger number of patients in China.Liver transplantation for HCC is rarely performed in either region.Sophisticated new radiotherapy tech-niques are not available in developing countries.The beneficial effects of the multikinase inhibitor,sorafenib,are encouraging,although financial considerations may restrict its use in low-income countries.

关键词： Hepatitis B virus infection Aflatoxin B1 α-fetoprotein Hepatic resection Hepatic transplantation Sorafenib

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