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Tacrolimus Enhances the Invasion Potential of Hepatocellular Carcinoma Cells and Promotes Lymphatic Metastasis in a Rat Model of Hepatocellular Carcinoma: Involvement of Vascular Endothelial Growth Factor-C

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TRANSPLANTATION PROCEEDINGS 2011年第7期43卷 2747-2754页

作者： Zhou, S. Tan, C. Dai, Z. Zhu, H. Xu, M. Zhou, Z. Wang, W. Zhao, Y. Fu, X. Zhou, J. Fan, J. Fudan Univ Liver Canc Inst Zhong Shan Hosp Shanghai 200032 Peoples R China Fudan Univ Shanghai Med Sch Shanghai 200032 Peoples R China Fudan Univ Chinese Minist Educ Inst Biomed Sci Key Lab Carcinogenesis & Canc Invas Shanghai 200032 Peoples R China Fudan Univ Huadong Hosp Dept Vasc Surg Shanghai 200032 Peoples R China

Purpose. The purpose of this study was to elucidate the effect of tacrolimus treatment on tumor growth and metastasis of hepatocellular carcinoma (HCC). Methods. The effect of tacrolimus was investigated on tumor growth and lymph node metastasis in a rat model of HCC. Angiogenesis and lymphangiogenesis were assessed by CD31 and vascular endothelial growth factor receptor 3 (VEGFR-3) immunostaining. Cell proliferation and invasion were monitored in vitro using the Cell Counting Kit-8 (CCK8) and Matrigel Invasion Chambers, respectively. Levels of vascular endothelial growth factor-C (VEGF-C) expression were measured using quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemisty and Western blots. Results. Tacrolimus had no effect on the proliferation of HCC in vitro or in vivo. Treatment with tacrolimus resulted in a dose-dependent increase in the invasive potential of HCC cells in vitro, in the density of peritumoral lymphatic vessels, and in the number and volume of metastatic lymph nodes in August Copenhagen Irish (ACT) rats. qRT-PCR, immunohistochemisty, and Western blot revealed that tacrolimus increased the levels of expression of VEGF-C in HCC. Conclusions. Tacrolimus enhanced the invasive potential of HCC cells, facilitating HCC lymphangiogenesis and promoting lymphatic metastasis in a rat model of HCC. This influence may be the result of an increase in VEGF-C expression by HCC cells. Targeting the VEGF-C/Fms-related tyrosine kinase 4 axis may be a novel treatment for HCC patients after liver transplantation.

关键词： Hepatocellular Cancer carcinoma cell Lymphangiogenesis rat model Vascular Endothelial Growth Factor Receptor-3 Vascular Endothelial Growth Factor C tumor growth Lymphatic Metastasis human-centered computing Tacrolimus

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Macrovascular Invasion Is Not an Absolute Contraindication for Living Donor Liver Transplantation

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LIVER TRANSPLANTATION 2017年第1期23卷 19-27页

作者： Lee, Kwang-Woong Suh, Suk-Won Choi, YoungRok Jeong, Jaehong Yi, Nam-Joon Kim, Hyeyoung Yoon, Kyung Chul Hong, Suk Kyun Kim, Hyo-Sin Lee, Kyung-Bun Suh, Kyung-Suk Seoul Natl Univ Coll Med Dept Surg 101 Daehak No Seoul 110744 South Korea Seoul Natl Univ Coll Med Dept Pathol Seoul South Korea

The indication of liver transplantation (LT) for the treatment of advanced hepatocellular carcinoma (HCC) is expanding. However, portal vein tumor thrombus (PVTT) has been still accepted as an absolute contraindication. We experienced an unexpectedly good prognosis in selected patients. Therefore, we tried to identify the prognostic factors after LT for HCC with major PVTT. Among 282 patients who underwent living donor liver transplantation (LDLT) for HCC from January 2009 to December 2013, 11 (3.9%) patients with major PVTT that was preoperatively diagnosed were investigated. The 1-, 3-, and 5-year recurrence-free survival rates were 63.6%, 45.5%, and 45.5%, respectively, and all recurrent cases showed intrahepatic and extrahepatic recurrence. The 1-, 3-, and 5-year overall survival rates were 72.7%, 63.6%, and 63.6%, respectively, and 2 patients with delayed recurrence survived approximately 5 years after LT. Main portal vein (PV) invasion (P < 0.01), high alpha-fetoprotein x protein induced by vitamin K absence/antagonist-II (AP) score (>= 20,000;P < 0.01), high standardized uptake value (SUV) ratio (tumor/background liver) in positron emission tomography (>= 2.1;P < 0.01), and a large original tumor (>= 7 cm;P=0.03) were significant risk factors for recurrence. In conclusion, if the PVTT has not expanded to the main PV and the AP score is not high, we can consider LDLT as a curative treatment option.

关键词： Level Trigger Medical Contraindication Risk Factors curative treatment Survival Rate Liver Transplantation human-centered computing Portal Vein Living Donors Relapse cell invasion

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Experiences inside the Ubiquitous Oulu Smart City

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COMPUTER 2011年第6期44卷 48-55页

作者： Gil-Castineira, Felipe Costa-Montenegro, Enrique Gonzalez-Castano, Francisco J. Lopez-Bravo, Cristina Ojala, Timo Bose, Raja Univ Vigo Dept Telemat Engn Informat Technol Grp Vigo Spain Univ Oulu MediaTeam Oulu Res Grp Comp Sci & Engn Lab Oulu Finland Nokia Res Ctr Palo Alto CA 94304 USA

The UrBan Interactions (UBI) research program, coordinated by the University of Oulu, has created a middleware layer on top of the panOULU wireless network and opened it up to ubiquitous-computing researchers, offerin... 详细信息

关键词： Cities and towns Computers Distributed applications human-centered computing Internet Local government Location-dependent and -sensitive mobile applications Middleware Pervasive computing Public networks Smart cities Ubiquitous computing Ubiquitous computing University of Oulu Urban areas Wireless sensor networks government middleware middleware layer panOULU wireless network public administration radio access networks ubiquitous Oulu smart city ubiquitous computing ubiquitous computing researchers urban interactions research program

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Correlation between enhancement pattern of hepatocellular carcinoma on real-time contrast-enhanced ultrasound and tumour cellular differentiation on histopathology

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BRITISH JOURNAL OF RADIOLOGY 2007年第953期80卷 321-330页

作者： Liu, G-J Xu, H-X Lu, M-D Xie, X-Y Xu, Z-F Zheng, Y-L Liang, J-Y Sun Yat Sen Univ Affiliated Hosp 1 Dept Hepatobiliary Surg Guangzhou 510080 Peoples R China Sun Yat Sen Univ Affiliated Hosp 1 Dept Med Ultrason Guangzhou Peoples R China

The objective of this study was to evaluate the correlation between the enhancement pattern of hepatocellular carcinoma (HCQ on contrast-enhancedultrasound (CEUS) and tumour cellular differentiation on histopathology. 189 HCC lesions in 189 patients were retrospectively evaluated with CEUS and histopathological examination. CEILIS was performed with SonoVue and contrast pulse sequencing. Histopathological diagnoses were made according to the Edmonson grading system. Significant differences were shown between the time that the HCC became hypoenhancing or remained echogenic in late phase and tumour cellular differentiation (p=0.006;p=0.036), but not with the time of commencement of hyperenhancing or commencement of isclenhancing in arterial phase and portal phase (p=0.164, p 0.1113;p-0.186, p-0.070). The timing of HCC becoming hypoenhancing on CEUS is correlated with tumour cellular differentiation;well differentiated turnours wash out more slowly than poorly differentiated ones.

关键词： Carcinoma Hepatocellular Liver Neoplasms 癌肝细胞肝肿瘤 Hepatocellular Cancer histopathology tumor differentiation Tumours Individualized Instruction contrast agent BR1 Liver Neoplasms human-centered computing Carcinoma

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Priority of Candidates With Hepatocellular Carcinoma Awaiting Liver Transplantation Can Be Reduced After Successful Bridge Therapy

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LIVER TRANSPLANTATION 2011年第11期17卷 1344-1354页

作者： Cucchetti, Alessandro Cescon, Matteo Bigonzi, Eleonora Piscaglia, Fabio Golfieri, Rita Ercolani, Giorgio Morelli, Maria Cristina Ravaioli, Matteo Pinna, Antonio Daniele Univ Bologna St Orsola Malpighi Hosp Dept Gen Surg Liver & Multiorgan Transplant Unit I-40138 Bologna Italy Univ Bologna St Orsola Malpighi Hosp Dept Internal Med & Gastroenterol I-40138 Bologna Italy Univ Bologna St Orsola Malpighi Hosp Radiol Unit I-40138 Bologna Italy

The allocation rules for patients with hepatocellular carcinoma (HCC) who are awaiting liver transplantation (LT) are a difficult issue and are continually evolving. To reduce tumor progression or down-stage advanced disease, most transplant centers have adopted the practice of treating HCC candidates with resection or locoregional therapies. This study was designed to assess the effectiveness of bridge therapy in preventing removal from the waiting list for death/sickness severity or tumor progression beyond the Milan criteria and in determining posttransplant outcomes. The removal rates for 315 adult patients with HCC who were listed for LT were analyzed and were correlated to responses to bridge therapy with a competing risk analysis. The 3-, 6-, and 12-month dropout rates were 3.5%, 6.5%, and 19.9%, respectively, and they were significantly affected by the Model for End-Stage Liver Disease score (P = 0.032), the tumor stage at diagnosis (P = 0.041), and the response to bridge therapy (P < 0.001). The stratification of candidates by the tumor stage and the response to bridge therapy showed that patients with T2 tumors who achieved only a partial response or no response to bridge therapy had the highest dropout rates, and they were followed by patients with successfully down-staged T3-T4a tumors (P = 0.037). Patients with T2 tumors who had a complete response and patients with T1 tumors had similar dropout rates (P = 0.964). The response to bridge therapy significantly affected both the recurrence rate of 176 transplant patients (P = 0.017) and the overall intention-to-treat survival rate (P = 0.001). In conclusion, the response to therapy is a potentially effective tool for prioritizing HCC patients for LT as well as select cases with different risks of tumor recurrence after transplantation. Liver Transpl 17:1344-1354, 2011. (C) 2011 AASLD.

关键词： Partial Remission Medicine Patients Neoplasm Staging precedence Tumours Tumor Progression human-centered computing Level Trigger Liver Transplantation Repetition rate

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In vitro regulation of hepatocellular carcinoma cell viability, apoptosis, invasion, and AEG-1 expression by LY294002

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CLINICS AND RESEARCH IN HEPATOLOGY AND GASTROENTEROLOGY 2014年第1期38卷 73-80页

作者： Ma, Jian Xie, Shu-Li Geng, Ya-Jun Jin, Shuo Wang, Guang-Yi Lv, Guo-Yue Jilin Univ Norman Bethune Hosp 1 Dept Hepatobillary & Pancreat Surg Changchun 130021 Peoples R China

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, and is characterized by advanced clinical stages at diagnosis and very poor prognosis. Subjects and methods: This study investigated the effects of PI3 K inhibitor, LY294002, on suppression of astrocyte elevated gene-1 (AEG-1) and regulation of HCC cell viability, apoptosis, and invasion in vitro. Cell lines derived from normal liver and HCC were treated with LY294002 and evaluated by RT-PCR, western blot, cell viability, migration, and invasion assays. Results: The data showed that AEG-1 mRNA and protein were overexpressed in HCC cells, compared to the normal liver cells. LY294002 treatment of HCC cells significantly reduced tumor cell viability, but promoted apoptosis. Tumor cell migration and invasion assays showed that LY294002 treatment also decreased the capacity of HCC cell migration and invasion. Molecularly, LY294002 treatment down-regulated AEG-1 expression, AKT and GSK3 beta phosphorylation, and expression of cyclinD1, CDK4, VEGF and Bcl(2), but up-regulated Bax and c-Myc expression. Conclusion: The data from this study demonstrated usefulness of LY294002 for effective control of HCC. Future studies should investigate the effects of LY294002 on HCC cells in vivo before initiating clinical trials in HCC patients. (C) 2013 Elsevier Masson SAS. All rights reserved.

关键词： cell viability clinical stages Cell Locomotion liver normal 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one human-centered computing Protein LYRIC Cell Migration cell invasion

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Multicenter validation of a score to predict prognosis after the development of HCC recurrence following liver transplantation

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HPB 2019年第6期21卷 731-738页

作者： Goldaracena, Nicolas Mehta, Neil Scalera, Irene Sposito, Carlo Atenafu, Eshetu G. Yao, Francis Y. Muiesan, Paolo Mazzaferro, Vincenzo Sapisochin, Gonzalo Univ Toronto Univ Hlth Network Dept Surg Div Gen SurgMultiorgan Transplant Toronto ON Canada Univ Calif San Francisco Div Med Dept Gastroenterol San Francisco CA 94143 USA Liver Univ Hosp Birmingham NHS Fdn Trust Birmingham W Midlands England Inst Nazl Tumori Dept Surg GI Surg & Liver Transplantat Milan Italy Univ Toronto Univ Hlth Network Biostat Dept Toronto ON Canada

Background: HCC recurrence after LT impacts negatively on survival. A recent study detected late recurrence (>= 12 months), alpha-fetoprotein (AFP) < 100 ng/mL at recurrence and being amenable for curative-intent treatments as good prognostic factors. With these variables a prognostic score was proposed. The objective of this study was to validate the prognostic score for hepatocellular carcinoma (HCC) recurrence following liver transplantation (LT). Methods: Data from the University of California, San Francisco, the University Hospital of Birmingham and Instituto Nazionale dei Tumori, Milan including patients with HCC recurrence after LT were analyzed. The previous reported score was applied to this cohort. Results: From June 2002-December 2014, 1328 patients had a confirmed HCC in their explanted liver. The study group comprised 130 patients (9.8%) diagnosed with HCC recurrence after LT. Overall median survival after HCC recurrence was 12.4 (95% CI 10.2-16.3) months. Application of the previously reported score showed a significantly superior survival for the good prognosis group compared to moderate and poor prognosis groups (p < 0.0001). Conclusion: The score continues to identify a group of patients who would benefit from aggressive treatment and experience significant improved survival following recurrent HCC after LT.

关键词： Level Trigger Prognosis Prognostic Factors Liver Transplantation human-centered computing Relapse

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Pre-liver transplant biopsy in hepatocellular carcinoma: a potential criterion for exclusion from transplantation?

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HPB 2013年第6期15卷 418-427页

作者： Young, Richard S. Aldiwani, Mohammed Hakeem, Abdul R. Nair, Amit Guthrie, Ashley Wyatt, Judy Treanor, Darren Morris-Stiff, Gareth Jones, Rebecca L. Prasad, K. Rajendra St James Univ Hosp Dept Transplant & Hepaticopancreaticobiliary Surg Leeds LS9 7TF W Yorkshire England St James Univ Hosp Dept Radiol Leeds LS9 7TF W Yorkshire England St James Univ Hosp Dept Histol Leeds LS9 7TF W Yorkshire England St James Univ Hosp Dept Hepatol Leeds LS9 7TF W Yorkshire England

Background In cirrhotic patients with hepatocellular carcinoma (HCC), poor differentiation in pre-liver transplantation (LT) biopsy of the largest tumour is used as a criterion for exclusion from LT in some centres. The potential role of pre-LT biopsy at one centre was explored. Methods A prospective database of patients undergoing orthotopic LT for radiologically diagnosed HCC at St James's University Hospital, Leeds during 20062011 was analysed. Results A total of 60 predominantly male (85.0%) patients with viral hepatitis were identified. There were discrepancies between radiological and histopathological findings with respect to the number of tumours identified (in 27 patients, 45.0%) and their size (in 63 tumours, 64.3%). In four (6.7%) patients, the largest lesion, which would theoretically have been targeted for biopsy, was not the largest in the explant. Nine (31.0%) patients with multifocal HCC had tumours of differing grades. In two (6.9%) patients, the largest tumour was well differentiated, but smaller tumours in the explant were poorly differentiated. In one patient, the largest lesion was benign and smaller invasive tumours were confirmed histologically. Conclusions The need to optimize selection for LT in HCC remains. In the present series, the largest tumour was not always representative of overall tumour burden or biological aggression and its potential use to exclude patients from LT is questionable.

关键词： Level Trigger Biopsy Explants Number of tumors Cancer Tumours Tumor Burden human-centered computing Patients Viral Hepatitis

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human homolog of NOTUM, overexpressed in hepatocellular carcinoma, is regulated transcriptionally by β-catenin/TCF

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CANCER SCIENCE 2008年第6期99卷 1139-1146页

作者： Torisu, Yuichi Watanabe, Akira Nonaka, Aya Midorikawa, Yutaka Makuuchi, Masatoshi Shimamura, Takahiro Sugimura, Haruhiko Niida, Atsushi Akiyama, Tetsu Iwanari, Hiroko Kodama, Tatsuhiko Zeniya, Mikio Aburatani, Hiroyuki Univ Tokyo Adv Sci & Technol Res Ctr Genome Sci Div Meguro Ku Tokyo 1538904 Japan Univ Tokyo Adv Sci & Technol Res Ctr Lab Syst Biol & Med Meguro Ku Tokyo 1538904 Japan Univ Tokyo Dept Surg Hepatobiliary Pancreat Surg Div Bunkyo Ku Tokyo 1138655 Japan Univ Tokyo Inst Mol & Cellular Biosci Lab Mol & Genet Informat Bunkyo Ku Tokyo 1130032 Japan Jikei Univ Sch Med Dept Internal Med Div Gastroenterol & HepatolMinato Ku Tokyo 1058471 Japan Teikyo Univ Sch Med Mizonokuchi Hosp Takatsu Ku Kanagawa 2138507 Japan Hamamatsu Univ Sch Med Dept Pathol 1 Higashi Ku Shizuoka 4313192 Japan Perseus Proteom Meguro Ku Tokyo 1530041 Japan

The Drosophila Notum gene, which is regulated by the Wingless pathway, encodes a secreted hydrolase that modifies heparan sulfate proteoglycans. In comparative analysis of the gene expression profiles in primary human hepatocellular carcinomas (HCC) and normal organs, we observed that the human ortholog of Drosophila Notum was overexpressed markedly in a subset of HCC, but expressed rarely in adult normal tissues. Immunoblotting confirmed the overexpression of NOTUM protein in 12 of 40 primary HCC cases (30%). High levels of NOTUM protein were significantly associated with intracellular (nuclear or cytoplasmic) accumulation of beta-catenin protein: all 10 HCC with high intracellular beta-catenin also had high NOTUM expression, whereas only 2 of 30 cases (6.7%) without intracellular beta-catenin had high NOTUM expression (P < 0.00001). NOTUM expression in HepG2 cells was downregulated significantly by induction of a dominant-negative mutant of TCF4, a beta-catenin partner. In vivo binding of the beta-catenin/TCF complex to the NOTUM promoter was demonstrated by chromatin immunoprecipitation in HepG2 and SW480 cells, where canonical Wnt signaling is activated constitutively. These findings provide evidence that NOTUM is a novel target of beta-catenin/TCF4 and is upregulated in Wnt/beta-catenin signaling-activated HCC.

关键词： Adult Aged Animals Antibodies Monoclonal Carcinoma Hepatocellular 成年人老年人动物抗体单克隆癌肝细胞基因表达调控肿瘤免疫法 beta Catenin Carcinoma Wnt Signaling Pathway PID Hepatocellular Cancer Heparan Sulfate Proteoglycans Dominant-Negative Mutation human-centered computing Monoclonal Antibodies Adults Cytoplasmic accumulation Chromatin Immunoprecipitation

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Prediction of Recurrence after Curative Resection of Hepatocellular Carcinoma using Liver Stiffness Measurement (FibroScan^A®)

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ANNALS OF SURGICAL ONCOLOGY 2012年第13期19卷 4278-4286页

作者： Jung, Kyu Sik Kim, Seung Up Choi, Gi Hong Park, Jun Yong Park, Young Nyun Kim, Do Young Ahn, Sang Hoon Chon, Chae Yoon Kim, Kyung Sik Choi, Eun Hee Choi, Jin Sub Han, Kwang-Hyub Yonsei Univ Coll Med Dept Internal Med Seoul South Korea Yonsei Univ Coll Med Inst Gastroenterol Seoul South Korea Yonsei Univ Coll Med Dept Surg Seoul South Korea Yonsei Univ Coll Med Dept Pathol Seoul South Korea Yonsei Univ Coll Med Dept Biostat Seoul South Korea Yonsei Univ Coll Med Liver Canc Special Clin Seoul South Korea Liver Cirrhosis Clin Res Ctr Seoul South Korea Brain Korea 21 Project Med Sci Seoul South Korea

The purpose of this study was to investigate whether preoperative liver stiffness measurement (LSM) can predict recurrence after curative resection of hepatocellular carcinoma (HCC). LSM using FibroScan(A (R)) can assess the severity of liver fibrosis, which is significantly associated with recurrence after curative resection of HCC. Between February 2006 and March 2009, 133 patients who underwent preoperative LSM and curative resection for HCC were enrolled in this prospective study. LSM values were analyzed for association with recurrence, together with other clinical variables. The mean age of the patients (117 men and 16 women) was 57 years. During the follow-up period (median, 25.0 (range, 3.0-54.6) months), HCC recurred in 62 (46.6 %) patients. In multivariate analysis, together with satellite nodule and Edmonson-Steiner grade III-IV, LSM was selected as an independent predictor of recurrence (P < 0.05;hazard ratio, 1.034;95 % confidence interval, 1.007-1.061). When the study population was stratified into two groups using the optimal cutoff value (13.4 kPa) that maximized the sum of sensitivity (64.7 %) and specificity (76.1 %) from time-dependent receiver operating characteristic curves (area under the receiver operating characteristic curve = 0.676), patients with LSM values > 13.4 kPa were at a significantly greater risk for recurrence with a hazard ratio of 1.925 (P = 0.01;95 % confidence interval, 1.17-3.168) compared with those with LSM values a parts per thousand currency sign13.4 kPa. Our data suggest that LSM can be a useful predictor of recurrence after curative resection of HCC.

关键词： Hepatocellular Cancer ectomy Liver Fibrosis Linux Security Module hazard ratio human-centered computing Relapse

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