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γ-Catenin at Adherens Junctions: Mechanism and Biologic Implications in Hepatocellular Cancer after β-Catenin Knockdown

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NEOPLASIA 2013年第4期15卷 421-+页

作者： Wickline, Emily Diane Du, Yu Stolz, Donna B. Kahn, Michael Monga, Satdarshan P. S. Univ Pittsburgh Sch Med Dept Pathol Pittsburgh PA 15261 USA Univ Pittsburgh Sch Med Dept Cell Biol Pittsburgh PA 15261 USA Univ So Calif Ctr Mol Pathways & Drug Discovery Dept Mol Pharmacol & Toxicol Los Angeles CA USA Univ Pittsburgh Sch Med Dept Med Pittsburgh PA 15261 USA

beta-Catenin is important in liver homeostasis as a part of Wnt signaling and adherens junctions (AJs), while its aberrant activation is observed in hepatocellular carcinoma (HCC). We have reported hepatocyte-specific beta-catenin knockout (KO) mice to lack adhesive defects as gamma-catenin compensated at AJ. Because gamma-catenin is a desmosomal protein, we asked if its increase in KO might deregulate desmosomes. No changes in desmosomal proteins or ultrastructure other than increased plakophilin-3 were observed. To further elucidate the role and regulation of gamma-catenin, we contemplate an in vitro model and show gamma-catenin increase in HCC cells upon beta-catenin knockdown (KD). Here, gamma-catenin is unable to rescue beta-catenin/T cell factor (TCF) reporter activity;however, it sufficiently compensates at AJs as assessed by scratch wound assay, centrifugal assay for cell adhesion (CAFCA), and hanging drop assays. gamma-Catenin increase is observed only after beta-catenin protein decrease and not after blockade of its transactivation. gamma-Catenin increase is associated with enhanced serine/threonine phosphorylation and abrogated by protein kinase A (PKA) inhibition. In fact, several PKA-binding sites were detected in gamma-catenin by in silico analysis. Intriguingly gamma-catenin KD led to increased beta-catenin levels and transactivation. Thus, gamma-catenin compensates for beta-catenin loss at AJ without affecting desmosomes but is unable to fulfill functions in Wnt signaling. gamma-Catenin stabilization after gamma-catenin loss is brought about by PKA. Catenin-sensing mechanism may depend on absolute beta-catenin levels and not its activity. Anti-beta-catenin therapies for HCC affecting total beta-catenin may target aberrant Wnt signaling without negatively impacting intercellular adhesion, provided mechanisms leading to gamma-catenin stabilization are spared.

关键词： Hepatocellular Cancer Zonula Adherens beta Catenin Desmosomes Wnt Signaling Pathway PID Biologic Products gamma Catenin Protein Kinase A Genetic Trans-Activation human-centered computing

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Liver resection for hepatocellular carcinoma in patients without cirrhosis

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BRITISH JOURNAL OF SURGERY 2013年第1期100卷 130-137页

作者： Thelen, A. Benckert, C. Tautenhahn, H. -M. Hau, H. -M. Bartels, M. Linnemann, J. Bertolini, J. Moche, M. Wittekind, C. Jonas, S. Univ Leipzig Dept Visceral Transplantat Thorac & Vasc Surg D-04103 Leipzig Germany Univ Leipzig Dept Radiol D-04103 Leipzig Germany Univ Leipzig Dept Pathol D-04103 Leipzig Germany

Background: Data on liver resection for hepatocellular carcinoma (HCC) without cirrhosis are sparse. The present study was conducted to evaluate the indications and results of liver resection for HCC with regard to safety and efficacy. Methods: Data for patients who had liver resection for HCC without cirrhosis between January 1996 and March 2011 were retrieved retrospectively using a prospective database containing information on all patients who underwent hepatectomy for HCC. Patient and tumour characteristics were analysed for influence on overall and disease-free survival to identify prognostic factors by univariable and multivariable analysis. Results: The 1-, 3- and 5-year overall survival rates after resection with curative intent for HCC without cirrhosis were 84, 66 and 50 per cent respectively. Disease-free survival rates were 69, 53 and 42 per cent respectively. The 90-day mortality rate was 4.5 per cent (5 of 110 patients). Surgical radicality and growth pattern of the tumour were independent prognostic factors for overall survival. Disease-free survival after resection with curative intent was independently affected by growth pattern and by the number and size of tumour nodules. Conclusion: Liver resection for HCC without cirrhosis carries a low perioperative risk and excellent long-term outcome if radical resection is achieved. Copyright (c) 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

关键词： Liver Cirrhosis Patients Hepatocellular Cancer Cirrhosis Growth patterns Hepatectomy Disease-Free Survival human-centered computing ectomy

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High Expression of Patched Homolog-1 Messenger RNA and Glioma-Associated Oncogene-1 Messenger RNA of Sonic Hedgehog Signaling Pathway Indicates a Risk of Postresection Recurrence of Hepatocellular Carcinoma

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ANNALS OF SURGICAL ONCOLOGY 2013年第2期20卷 464-473页

作者： Jeng, Kuo-Shyang Sheen, I-Shyan Jeng, Wen-Juei Lin, Chien-Chu Lin, Chien-Kuan Su, Jui-Chih Yu, Ming-Che Fang, Hsin-Yi Far Eastern Mem Hosp Dept Surg Taipei Taiwan Chang Gung Univ Linkou Med Ctr Chang Gung Mem Hosp Dept Hepatogastroenterol Tao Yuan Taiwan Far Eastern Mem Hosp Div Gastroenterol Taipei Taiwan Far Eastern Mem Hosp Dept Mediated Res Taipei Taiwan

Hepatocellular carcinoma (HCC) has a high recurrence rate after resection. Abnormal activation of the sonic hedgehog (SHH) signaling pathway contributing to the carcinogenesis of some organs had been reported. We hypothesize that activation of SHH pathway contributes to the recurrence of HCC after surgical resection. In a prospective study, from January 2006 to June 2010, a total of 50 consecutive patients with HCC after curative resection were enrolled. The ratio of the expression of messenger RNA (mRNA) of SHH, patched homolog-1 (PTCH-1) and glioma-associated oncogene-1 (GLI-1) between HCC tissues and the paired noncancerous liver tissues were measured. Both the clinicopathologic characteristics and these ratios were compared between those with recurrence and those without recurrence. They were also compared between those with and without survival. There was a statistically significant correlation among the ratios of PTCH-1 mRNA and serum AFP level (p = 0.045), tumor size (p = 0.001), vascular permeation (p = 0.043) and tumor, node, metastasis staging system (TNM) stage (p = 0.003). A borderline significant correlation was found among ratios of GLI-1 mRNA and tumor size (p = 0.062) and TNM stage (p = 0.051). There was no such significant correlation between SHH mRNA and any parameter. Both the ratios of PTCH-1 mRNA and GLI-1 mRNA significantly adversely affected recurrence (p = 0.003 and 0.005, respectively) and survival (p < 0.001 and < 0.001, respectively). Expression of PTCH-1 mRNA and GLI-1 mRNA in HCC tissues is a potential biomarker to predict postresection disease recurrence.

关键词： Hedgehog Signaling Pathway Messenger RNA Hepatocellular Cancer Relapse SHH gene human-centered computing Signal Pathways Repetition rate

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The importance of IL28B genotype in hepatitis C virus-associated liver transplantation

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LIVER INTERNATIONAL 2013年第2期33卷 169-171页

作者： Lange, Christian M. Klinikum JW Goethe Univ Frankfurt Frankfurt Germany

Infection with hepatitis C virus (HCV) is a major global health problem affecting approximately 3% of all individuals worldwide (1). Most patients develop a chronic infection resulting in various levels of hepatic inflammation, fibrosis and - after years - in cirrhosis in a significant proportion of patients (1). Because of the rising age of HCV-infected individuals in the Western world, a dramatic increase in cases of HCV-related cirrhosis and its complications, including hepa-tocellular carcinoma (HCC), is expected in the next decade (1). Obviously, this development may lead to a significantly rising number of patients requiring HCV-related liver transplantation caused by end-stage liver disease or HCC, which certainly represents an enormous task in allocating and fair distributing liver grafts in many countries.

关键词： End Stage Liver Disease chronic infection Western World Liver Cirrhosis Cirrhosis Liver Transplantation human-centered computing Hepatitis C IFNL3 gene

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Metronomic Capecitabine in Advanced Hepatocellular Carcinoma Patients: A Phase II Study

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ONCOLOGIST 2013年第12期18卷 1256-1257页

作者： Brandi, Giovanni de Rosa, Francesco Agostini, Valentina di Girolamo, Stefania Andreone, Pietro Bolondi, Luigi Serra, Carla Sama, Claudia Golfieri, Rita Gramenzi, Annagiulia Cucchetti, Alessandro Pinna, Antonio Daniele Trevisani, Franco Biasco, Guido Univ Bologna Dept Expt Diagnost & Special Med St Orsola Malpighi Hosp I-40138 Bologna Italy Univ Bologna Dept Med & Surg Sci St Orsola Malpighi Hosp I-40138 Bologna Italy St Orsola Malpighi Hosp Dept Digest Dis & Internal Med Bologna Italy

Background. Anti-angiogenic treatment with targeted agents is effective in advanced hepatocellular carcinoma (HCC). This trial evaluated the safety and efficacy of metronomic capecitabine in patients with HCC. Methods. This single-institution phase II trial included 59 previously untreated patients with advanced HCC and 31 patients resistant to or intolerant of sorafenib. The treatment schedule was capecitabine 500 mg twice daily until progression of disease, unacceptable toxicity level, or withdrawal of informed consent. Progression-free survival (PFS) was chosen as the primary endpoint. Results. A total of 59 previously untreated and 31 previously treated patients with HCC were enrolled. The first cohortachieved a median PFS of 6.03 months and an overall survival (OS) of 14.47 months. Two patients achieved a complete response, 1 patient achieved partial response, and in 30 patients, stable disease was the best outcome. The second cohort achieved a median PFS of 3.27 months and a median OS of 9.77 months. No complete or partial responses were observed, but 10 patients had stable disease. An unscheduled comparison of the first cohort of patients with 3,027 untreated patients with HCC from the Italian Liver Cancer (***) database was performed. One-to-one matching according to demographic/etiologic/oncologic features was possible for 50 patients. The median OS for these 50 capecitabine-treated patients was 15.6 months, compared with a median OS of 8.0 months for the matched untreated patients (p = .043). Conclusion. Metronomic capecitabine is well tolerated by patients with advanced HCC and appears to have activity both in treatment-naive patients and in those previously treated with sorafenib.

关键词： osmium Stable Disease sorafenib Capecitabine human-centered computing Median Partial Remission Patients

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CF102 for the Treatment of Hepatocellular Carcinoma: A Phase I/II, Open-Label, Dose-Escalation Study

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ONCOLOGIST 2013年第1期18卷 25-26页

作者： Stemmer, Salomon M. Benjaminov, Ofer Medalia, Gal Ciuraru, Noab B. Silverman, Michael H. Bar-Yehuda, Sara Fishman, Sari Harpaz, Zivit Farbstein, Motti Cohen, Shira Patoka, Renana Singer, Barak Kerns, William D. Fishman, Pnina Tel Aviv Univ Sackler Sch Med Inst Oncol Dept Radiol OBDavidoff CtrRabin Med Ctr IL-69978 Tel Aviv Israel Can Fite BioPharma Ltd Petah Tiqwa Israel

Background. The A(3) adenosine receptor (A(3)AR) is overexpressed in the tumor and in the peripheral blood mononuclear cells of patients with hepatocellular carcinoma (HCC). The orally active drug candidate CF102, an A(3)AR agonist, induces apoptosis of HCC cells via deregulation of the Wnt signaling pathway. In this open label phase I/II trial, the safety and clinical effects of CF102 were assessed in patients with advanced unresectable HCC. Methods. The primary objectives of this trial were to examine the safety and pharmacokinetic (PK) behavior of CF102 given orally (1, 5, and 25 mg BID) in 28-day cycles. Evaluation of anti-tumor effects and the utilization of A(3)AR as a biological predictive marker of response to CF102 were the secondary objectives. Results. Eighteen patients received CF102-six at each dose level. No serious drug-related adverse events or dose-limiting toxicities were observed. CF102 demonstrated good oral bioavailability and linear PK behavior. Median overall survival in the study population, 67% of whom had received prior sorafenib, was 7.8 months, and for Child Pugh B patients (28%) it was 8.1 months. Stable disease by RECIST was observed in four patients for at least 4 months. CF102 maintained liver function over a 6-month period. A correlation between receptor overexpression levels at baseline and patients' overall survival was found. One of the patients who presented with skin nodules that were biopsy-proven to be HCC metastases prior to the trial showed complete metastasis regression during three months of treatment with CF102. Conclusions. CF102 is safe and well-tolerated, showing favorable PK characteristics in Child Pugh A and B HCC patients, justifying further clinical development.

关键词： Hepatocellular Cancer Clinical Trials, Phase III as Topic Mouth Adenosine A3 Receptor human-centered computing Patients

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When Does Invasion Mean the War is Lost?

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ANNALS OF SURGICAL ONCOLOGY 2013年第12期20卷 3709-3711页

作者： Conrad, Claudius Vauthey, Jean-Nicolas Harvard Univ Sch Med Dept Surg Div Surg OncolMassachusetts Gen Hosp Boston MA 02115 USA Univ Texas MD Anderson Canc Ctr Dept Surg Oncol Div Surg Houston TX 77030 USA

The significance of macrovascular invasion (MVI) in hepatocellular carcinoma (HCC) is ill defined. Although the Barcelona Clinic Liver Cancer Classification System classifies disease associated with MVI as stage C and recommends that patients with MVI be offered palliative therapy with the oral multikinase inhibitor sorafenib, several centers have reported successful liver resection with good outcomes in patients with MVI. The paper by Roayaie et al. provides an excellent opportunity to revisit the significance of MVI in HCC. We congratulate the authors for their thorough evaluation of their results, critical discussion of their data, and comprehensive summary and analysis of the available relevant literature.

关键词： Warfare Invasions Terminal Care Cancer of Liver Hepatectomy human-centered computing cell invasion

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Ontology-Based Application Integration on the User Interface Level

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IT-INFORMATION TECHNOLOGY 2013年第4期55卷 165-168页

作者： Paulheim, Heiko Univ Mannheim Inst Informatik & Wirtschaftsinformatik B6 26 D-68159 Mannheim Germany

Application integration can be performed on three levels: the data source level, the business logic level, and the user interface level. Approaches of the latter kind include, e.g., portal and mashup solutions. Deeper integration offering rich interaction possibilities usually leads to strong dependencies between applications, and requires deep knowledge of those applications. To reduce such dependencies, ontologies have been proposed as an inter-lingua mediating between the applications. While there have been approaches for using ontologies for integration on the data source and business logic level, this dissertation is the first approach for ontology-based application integration on the user interface level. It discusses the development of suitable formal ontologies, the use of reasoning and rule-based event processing, as well as aspects such as performance and seamless cross-technological interaction.

关键词： ACM CSS Software and its engineering Integration frameworks ACM CSS computing methodologies Ontology engineering, ACM CSS Theory of computation Semantics and reasoning, ACM CSS human-centered computing User interface programming

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Can tobacco use promote HCV-induced miR-122 hijacking and hepatocarcinogenesis?

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MEDICAL HYPOTHESES 2013年第2期80卷 131-133页

作者： Zhao, Lijun Li, Farong Taylor, Ethan Will Shaanxi Normal Univ Coll Life Sci Xian 710062 Peoples R China Univ N Carolina Dept Nanosci Joint Sch Nanosci & Nanoengn Greensboro NC 27401 USA

Chronic hepatitis C virus (HCV) infection is a well-recognized risk factor for hepatocellular carcinoma (HCC). As a co-risk factor, the role of tobacco use in HCV-driven carcinogenesis and relevant underlying mechanisms remain largely unclear. The latest discoveries about HCV replication have shown that HCV RNA hijacks cellular miRNA-122 by forming an Ago2-HCV-miR-122 complex that stabilizes the HCV genome and enhances HCV replication. Our previous work has demonstrated that aqueous tobacco smoke extract (TSE) is a potent activator of HIV replication via TSE-mediated viral protection from oxidative stress and activation of a set of genes that can promote viral replication. Since HCV is, like HIV, an enveloped virus that should be equally susceptible to lipid peroxidation, and since one of the TSE-upregulated genes, the DDX3 helicase, is known to facilitate HCV replication, we hypothesize that (1) tobacco use can similarly enhance HCV viability and replication, and promote HCC progression by up-regulation of DDX3, and (2) by competing for binding with miR-122 as a competing endogenous RNA (ceRNA), HCV replication can liberate miR-122's direct target, oncogenic gene cyclin G1 (CCNG1);furthermore, simultaneous tobacco use can synergistically enhance this competing effect via HCV upregulation. Our hypotheses may lay a foundation for better understanding of carcinogenesis in HCV-driven HCC and the potential role of tobacco as a cofactor. Disrupting the HCV ceRNA effect may provide a new strategy for designing anti HCV/HCC drugs. (c) 2012 Elsevier Ltd. All rights reserved.

关键词： Tobacco Use Hepatocarcinogenesis Tobacco Products Hijacking DDX3X gene human-centered computing Carcinogenesis

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Hepatocellular Carcinoma and Hepatitis B Virus: Family Matters

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CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2013年第12期11卷 1646-1647页

作者： McMahon, Brian J. Alaska Native Tribal Hlth Consortium Alaska Native Med Ctr Liver Dis & Hepatitis Program Anchorage AK USA

In much of the world, hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, especially in men. In sub-Saharan Africa, most of eastern and southeast Asia, and the Pacific Islands, chronic hepatitis B virus (HBV) is the primary etiology for HCC, where the prevalence of chronic HBV infection ranges from 2% to more than 10% of the population. Several demographic, viral, and environmental factors have been found to increase the risk of HCC in HBV infection, Which can help to identify those persons who should be targeted for regular surveillance to detect this tumor early, at a more treatable stage. More than 30 years ago, several case-control studies found family history of HCC to be a risk factor in relatives who were infected with HBV, but the magnitude of the risk previously was unknown. In this issue of Clinical Gastroenterology and Hep-atology is an important article that takes advantage of a large population-based cohort study conducted in Taiwan, the REVEAL study, to better define and quantify the risk of family history of HCC. Briefly, the investigators screened more than 22,000 residents of 7 townships in Taiwan for HBV seromarkers and found almost 4000 to be positive for hepatitis B surface antigen (HBsAg). They then followed up those persons positive for HBsAg prospectively for 16 years and have written multiple publications regarding risk factors associated with HCC and cirrhosis that were found in this cohort.

关键词： Hepatocellular Cancer Genealogical Tree Risk Factors Hepatitis B virus Pacific Islands Persons Southeast Asia human-centered computing Hepatitis B Surface Antigens

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