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lnc-β-Catm elicits EZH2-dependent β-catenin stabilization and sustains liver CSC self-renewal

NATURE STRUCTURAL & MOLECULAR BIOLOGY 2016年第7期23卷 631-639页

作者： Zhu, Pingping Wang, Yanying Huang, Guanling Ye, Buqing Liu, Benyu Wu, Jiayi Du, Ying He, Lei Fan, Zusen Chinese Acad Sci Inst Biophys CAS Ctr Excellence Biomacromol Key Lab Infect & Immun CAS Beijing Peoples R China Univ Sci & Technol China Sch Life Sci Hefei Peoples R China Univ Chinese Acad Sci Beijing Peoples R China Peoples Liberat Army Gen Hosp Dept Hepatobiliary Surg Beijing Peoples R China

Liver cancer stem cells (CSCs) may contribute to the high rate of recurrence and heterogeneity of hepatocellular carcinoma (HCC);however, the molecular mechanisms underlying their self-renewal and differentiation remain largely unknown. Through analysis of transcriptome microarray data, we identified a long noncoding RNA (lncRNA) called lnc-beta-Catm, which is highly expressed in human HCC tumors and liver CSCs. We found that lnc-beta-Catm is required for self-renewal of liver CSCs and tumor propagation in mice. lnc-beta-Catm associates with beta-catenin and the methyltransferase EZH2, thereby promoting beta-catenin methylation. Methylation suppresses the ubiquitination of beta-catenin and promotes its stability, thus leading to activation of Wnt-beta-catenin signaling. Accordingly, the expression of lnc-beta-Catm, EZH2 and Wnt-beta-catenin targets is positively correlated with cancer severity and prognosis of people with HCC.

关键词： beta Catenin Prognosis Long Intergenic Non-Protein Coding RNA Ubiquitination Renewal Methylation Tumours human-centered computing Relapse

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Engaging adolescents in a computer-based weight management program: avatars and virtual coaches could help

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JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION 2016年第1期23卷 19-28页

作者： LeRouge, Cynthia Dickhut, Kathryn Lisetti, Christine Sangameswaran, Savitha Malasanos, Toree Univ Washington Dept Hlth Serv Sch Publ Hlth 1959 NE Pacific StBox 357660 Seattle WA 98195 USA St Louis Univ Coll Publ Hlth & Social Justice Dept Epidemiol St Louis MO 63103 USA Florida Int Univ Sch Comp & Informat Sci Miami FL 33199 USA Univ Michigan Sch Publ Hlth Dept Environm Hlth Sci Ann Arbor MI 48109 USA Health E LLC Gainesville FL USA

Objective This research focuses on the potential ability of animated avatars (a digital representation of the user) and virtual agents (a digital representation of a coach, buddy, or teacher) to deliver computer-based interventions for adolescents' chronic weight management. An exploration of the acceptance and desire of teens to interact with avatars and virtual agents for self-management and behavioral modification was undertaken. Materials and Methods The utilized approach was inspired by community-based participatory research. Data was collected from 2 phases: Phase 1) focus groups with teens, provider interviews, parent interviews;and Phase 2) mid-range prototype assessment by teens and providers. Results Data from all stakeholder groups expressed great interest in avatars and virtual agents assisting self-management efforts. Adolescents felt the avatars and virtual agents could: 1) reinforce guidance and support, 2) fit within their lifestyle, and 3) help set future goals, particularly after witnessing the effect of their current behavior(s) on the projected physical appearance (external and internal organs) of avatars. Teens wanted 2 virtual characters: a virtual agent to act as a coach or teacher and an avatar (extension of themselves) to serve as a "buddy" for empathic support and guidance and as a surrogate for rewards. Preferred modalities for use include both mobile devices to accommodate access and desktop to accommodate preferences for maximum screen real estate to support virtualization of functions that are more contemplative and complex (e.g., goal setting). Adolescents expressed a desire for limited co-user access, which they could regulate. Data revealed certain barriers and facilitators that could affect adoption and use. Discussion The current study extends the support of teens, parents, and providers for adding avatars or virtual agents to traditional computer-based interactions. Data supports the desire for a personal relationship with a virtu

关键词： avatars adolescent overweight and obesity consumer health informatics human-centered computing human centered design and evaluation methods participatory design virtual coaches chronic disease self-management weight management computer-based health interventions

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Nested case-control study: hepatocellular carcinoma risk after hepatitis B surface antigen seroclearance

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ALIMENTARY PHARMACOLOGY & THERAPEUTICS 2016年第11期43卷 1197-1207页

作者： Gounder, P. P. Bulkow, L. R. Snowball, M. Negus, S. Spradling, P. R. Simons, B. C. McMahon, B. J. Ctr Dis Control & Prevent CDC Natl Ctr Emerging & Zoonot Infect Dis Div Preparedness & Emerging Infect Arctic Invest Program Anchorage AK USA Alaska Nat Tribal Hlth Consortium Liver Dis & Hepatitis Program Anchorage AK USA CDC Div Viral Hepatitis Natl Ctr HIV AIDS Viral Hepatitis STD & TB Prevent Atlanta GA USA

BackgroundHepatocellular carcinoma (HCC) risk after resolving chronic hepatitis B virus (HBV) infection is unclear. AimTo compare HCC risk between Alaska Native (AN) patients with and without hepatitis B surface antigen (HBsAg) seroclearance. MethodsWe selected persons with (case-patients) and without (control-patients) HBsAg seroclearance from a cohort of 1346 chronically HBV-infected AN patients followed during 19822013. We attempted to match two control-patients/case-patient on sex, HBV genotype, and age. Person-years of follow-up for case-patients began on the date of HBsAg resolution and for control-patients began on the date equivalent to the cohort entry date plus the years of HBsAg duration for their corresponding case-patient. We compared HCC risk using a Cox proportional hazards model. ResultsThe 238 case-patients (4 with HCC) and 435 control-patients (9 with HCC) were similar in age [P-value (P) = 0.30], sex (P = 0.53) and HBV genotype (P = 0.99). Case-patients had longer person-years of follow-up than control-patients (11.7 vs. 10.1 years;P = 0.04). The HCC rate/100 000 persons was similar between case- (132) and control-patients (178;P = 0.65). The adjusted hazard ratio comparing case- and control-patients was similar for HCC [0.7;95% confidence interval (CI): 0.2-2.4], increased for each 1-year increment for age (1.1;CI: 1.0-1.1;P < 0.01), and was greater if the initial HBeAg was positive (3.5;CI: 1.1-11.0;P = 0.03). ConclusionsHepatitis B surface antigen seroclearance was not associated with reduced HCC risk;the HCC risk estimates are limited by wide 95% confidence intervals. Persons meeting HCC surveillance indications prior to HBsAg seroclearance could benefit from continued surveillance after seroclearance.

关键词： Chronic Hepatitis B Hepatitis B virus human-centered computing Carcinoma

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ShRNA-mediated silencing of the Ndc80 gene suppress cell proliferation and affected hepatitis B virus-related hepatocellular carcinoma

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CLINICS AND RESEARCH IN HEPATOLOGY AND GASTROENTEROLOGY 2016年第3期40卷 297-303页

作者： Liu, Bo Yao, Zhicheng Hu, Kunpeng Huang, He Xu, Shilei Wang, Qinliang Yang, Yang Ren, Jie Sun Yat Sen Univ Affiliated Hosp 3 Dept Gen Surg Guangzhou 510530 Guangdong Peoples R China Sun Yat Sen Univ Affiliated Hosp 3 Dept Liver Transplantat Guangzhou 510530 Guangdong Peoples R China Sun Yat Sen Univ Affiliated Hosp 3 Dept Ultrasound Guangzhou 510530 Guangdong Peoples R China

Background: Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies in the world, and hepatitis B virus (HBV) has been well established to cause HCC. Ndc80 complex is a conserved mitotic regulator dedicated to ensuring faithful chromosome segregation and plays an important role in inducing tumor formation. However, its role in HCC caused by HBV infection remains unclear. Methods: Immunohistochemistry (IHC), Western blot (WB), and real-time qRT-PCR were used to measure the expression of Ndc80 in HBV-related HCC tissues. Ndc80-specific short hairpin RNA (shRNA) was used to knock-down Ndc80 expression in the hepatoma cell line HeG2 and HepG2.2.15, which is stable transcribed with HBV genome. Furthermore, the effect of Ndc80 on cellular proliferation and growth were examined, respectively. Results: The expression level of Ndc80 was remarkably up-regulated in HBV-related HCC tissues. Down-regulation of Ndc80 expression suppressed HBV replication. With cell counting and the MTS assay, cellular proliferation and growth of Ndc80 knocking-down cell line was shown to be effectively restrained. Conclusion: This study suggests that Ndc80 may play an important role in the process of HBV-related HCC, and that it may be a potential biological treatment target in the future. (C) 2015 Elsevier Masson SAS. All rights reserved.

关键词： Hepatitis B Virus-Related Hepatocellular Carcinoma Cell Proliferation Hepatitis B virus Ndc80 complex Chromosome Segregation human-centered computing

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Dynamic α-fetoprotein, platelets and AST-to-platelet ratio index predict hepatocellular carcinoma in chronic hepatitis C patients with sustained virological response after antiviral therapy

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JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY 2016年第7期71卷 1943-1947页

作者： Wu, Cheng-Kun Chang, Kuo-Chin Hung, Chao-Hung Tseng, Po-Lin Lu, Sheng-Nan Chen, Chien-Hung Wang, Jing-Houng Lee, Chuan-Mo Tsai, Ming-Chao Lin, Ming-Tsung Yen, Yi-Hao Hu, Tsung-Hui Kaohsiung Chang Gung Mem Hosp Dept Internal Med Div Hepatogastroenterol Kaohsiung Taiwan Chang Gung Univ Coll Med Kaohsiung Taiwan

Background: Hepatitis Cvirus (HCV)-infected patients who achieve viral eradication may still develop hepatocellular carcinoma (HCC). Little is known about the impact of dynamic change of serum markers on HCC development. Methods: We enrolled 1351 HCV-infected patients who achieved sustained virological response (SVR). Laboratory data were collected at least 1 year after IFN-based therapy and to the latest follow-up. Data on alpha-fetoprotein (AFP) were obtained >6 months prior to HCC development to exclude HCC-related AFP elevation. Results: HCC developed in 49 patients. Risk factors for HCC in SVR patients were old age, liver cirrhosis, higher pre- and post-treatment AFP and high post-treatment AST-to-platelet ratio index (APRI). Patients with pre-AFP >= 15 ng/mL -> post-AFP >= 15 ng/mL (at 1 year, 23.1%;5 years, 42.3%) and pre-AFP <15 ng/mL -> post-AFP >= 15 ng/mL (at 1 year, 25%;5 years, 50%) had the highest risk of HCC development, followed by pre-AFP >= 15 ng/mL -> post-AFP <15 ng/mL (at 1 year, 5.2%;5 years, 7.6%) and pre-AFP <15 ng/mL -> post-AFP ng/mL <15 ng/mL (at 1 year, 0.5%;5 years, 0.9%) (P < 0.001). The pattern was similar for platelets and APRI (P < 0.001). SVR patients with pre-APRI >= 0.7 -> post-APRI >= 0.7 had the highest risk of HCC development, followed by comparable risks among the other three groups. Conclusions: SVR patients with a persistently high AFP level (>= 15 ng/mL) and a high APRI (>= 0.7) before and after treatment had the highest incidence of HCC development. Patients with a reduction of AFP and APRI to the normal range after treatment had a markedly decreased risk of HCC. The risk was lowest for patients who kept persistently normal AFP and APRI before and after treatment.

关键词： antiviral therapy Chronic Hepatitis C Hepatocellular Cancer Serum Markers human-centered computing Hepatitis C Blood Platelets

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Grumpy & Pinocchio: Answering human-Agent Negotiation Questions through Realistic Agent Design 17

Grumpy & Pinocchio: Answering Human-Agent Negotiation Questi...

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International Conference on Autonomous Agents and Multiagent Systems

作者： Johnathan Mell Jonathan Gratch University of Southern California USC Institute for Creative Technologies

ISBN: (纸本)9781510855076

We present the Interactive Arbitration Guide Online (IAGO) platform, a tool for designing human-aware agents for use in negotiation. Current state-of-the-art research platforms are ideally suited for agent-agent interaction While helpful, these often fail to address the reality of human negotiation, which involves irrational actors, natural language, and deception To illustrate the strengths of the IAGO platform, the authors describe four agents which are designed to showcase the key design features of the system We go on to show how these agents might be used to answer core questions in human-centered computing, by reproducing classical human-human negotiation results in a 2×2 human-agent study. The study presents results largely in line with expectations of human-human negotiation outcomes, and helps to demonstrate the validity and usefulness of the IAGO platform.

关键词： Experimentation human Factors Virtual humans human-Agent Competition Negotiation IAGO negotiations avatars human factors experimentation Agents human-centered computing Platform

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Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma

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LABORATORY INVESTIGATION 2016年第2期96卷 197-205页

作者： Tang, Xiaowei Wang, Yun Fan, Zhining Ji, Guozhong Wang, Min Lin, Jie Huang, Shu Meltzer, Stephen J. Nanjing Med Univ Affiliated Hosp 2 Med Ctr Digest Dis 121 Jiangjiayuan Rd Nanjing 210011 Jiangsu Peoples R China Southern Med Univ Nanfang Hosp Dept Gastroenterol Guangzhou Guangdong Peoples R China Johns Hopkins Univ Sch Med Dept Med Div Gastroenterol 1503 E Jefferson StRoom 112 Baltimore MD 21231 USA Johns Hopkins Univ Sch Med Dept Oncol Div Gastroenterol 1503 E Jefferson StRoom 112 Baltimore MD 21231 USA Sidney Kimmel Comprehens Canc Ctr 1503 E Jefferson StRoom 112 Baltimore MD 21231 USA

Klotho, an anti-aging gene, has recently been shown to contribute to human hepatic tumorigenesis. In addition, it is known that Wnt signaling is antagonized by the protein klotho. Because augmented Wnt signaling has an important role in tumorigenesis of human hepatocellular carcinoma (HCC), we studied the relationship of klotho expression and activity to the Wnt pathway in this malignancy. Immunohistochemical analysis performed on tissue arrays revealed that klotho expression levels were significantly lower in HCC than in adjacent noncancerous tissues, while klotho staining was inversely correlated with clinical stage and histologic grade. Patients with klotho-expressing tumors had longer survival periods than did those with klotho-negative tumors. Overexpression of klotho as well as treatment with soluble klotho protein reduced hepatoma cell growth in vitro and in vivo, whereas klotho silencing enhanced cellular proliferation. Moreover, forced expression of klotho inhibited Wnt/beta-catenin signaling, as confirmed by reduced expression of beta-catenin, inhibition of translocation of beta-catenin from the cytoplasm to the nucleus, and reduced expression of c-myc and cyclin D1, two known target genes of the Wnt/beta-catenin pathway. In contrast, activation of the Wnt/beta-catenin pathway was enhanced when klotho was silenced by inhibitory RNAs. Furthermore, serum levels of soluble klotho in patients with malignant tumors were studied, and results suggested a significant increase in these levels in HCC patients. These data suggest that klotho acts as a tumor suppressor and an inhibitor of the Wnt/beta-catenin pathway in HCC, and moreover, that soluble klotho is a potential serum biomarker for HCC.

关键词： Wnt Signaling Pathway PID Tumor Suppressor Genes human-centered computing Modulators KL gene

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Accuracy of microRNAs for the diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis

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CLINICS AND RESEARCH IN HEPATOLOGY AND GASTROENTEROLOGY 2016年第4期40卷 405-417页

作者： He, Song Hu, Xiao-Wu Wang, Dong Han, Ling-Fei Zhang, De-Chun Wei, Cheng Maanshan Municipal Hosp Grp Maanshan Ctr Clin Lab 45 Hubei Rd Maanshan 243000 Peoples R China Chongqing Med Univ Mol Med & Tumor Res Ctr Chongqing 400016 Peoples R China

Due to the high morbidity, mortality and late detection of hepatocellular carcinoma (HCC), it becomes a major public health challenge. MicroRNAs (miRNAs) have been reported to be aberrantly expressed in patients with HCC and thus may serve as potential diagnostic biomarkers. The aim of this study was to systematically assess the diagnostic accuracy of miRNAs as biomarkers for diagnosing HCC through a meta-analysis. Our results indicated that serum miRNAs had a relatively high diagnostic value for HCC diagnosis;the combination of serum 0:fetoprotein (AFP) and miRNAs displayed a better diagnostic accuracy than using AFP or miRNAs alone;the combination of multiple miRNAs assay in serum had the highest diagnostic accuracy in HCC diagnosis based on the published data. In conclusion, our meta-analysis suggests that miRNAs, especially serum miRNAs, had a relatively high diagnostic value for HCC diagnosis, which can discriminate HCC from healthy subjects and those with chronic hepatitis and cirrhosis easily, and may serve as a novel, less-invasive screening tool. (C) 2016 Elsevier Masson SAS. All rights reserved.

关键词： Diagnosis Hepatocellular Cancer MicroRNAs diagnosis quality/standard Biological Markers Serum Meta-Analysis human-centered computing Chronic Hepatitis

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Chronic hepatitis C virus infection and pathogenesis of hepatocellular carcinoma

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CURRENT OPINION IN VIROLOGY 2016年 20卷 99-105页

作者： Bandiera, Simonetta Bian, C. Billie Hoshida, Yujin Baumert, Thomas F. Zeisel, Mirjam B. INSERM Inst Rech Malad Virales & Hepat U1110 Strasbourg France Univ Strasbourg Strasbourg France Icahn Sch Med Mt Sinai Div Liver Dis Dept Med Liver Canc ProgramTisch Canc Inst New York NY 10029 USA Nouvel Hop Civil Pole Hepatodigestif Inst Hosp Univ Strasbourg France

Hepatitis C virus (HCV) infection is one of the major causes of advanced liver disease and hepatocellular carcinoma (HCC) worldwide. While the knowledge about the molecular virology of HCV infection has markedly advanced, the molecular mechanisms of disease progression leading to fibrosis, cirrhosis and HCC are still unclear. Accumulating experimental and clinical studies indicate that HCV may drive hepatocarcinogenesis directly via its proteins or transcripts, and/or indirectly through induction of chronic liver inflammation. Despite the possibility to eradicate HCV infection through direct-acting antiviral treatment, the risk of HCC persists although specific biomarkers to estimate this risk are still missing. Thus, a better understanding of HCV-induced HCC and more physiological liver disease models are required to prevent cancer development.

关键词： Chronic Hepatitis C Hepatocellular Cancer Liver Diseases Infection Hepatitis C virus transcript human-centered computing Clinical Study Disease Progression pathogenesis

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Outcomes of Patients With Poorly Differentiated Hepatocellular Carcinoma After Liver Transplantation

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TRANSPLANTATION PROCEEDINGS 2016年第5期48卷 1713-1716页

作者： Krasnodebski, M. Grat, M. Masior, L. Wronka, K. M. Grat, K. Stypulkowski, J. Bik, E. Patkowski, W. Krawczyk, M. Med Univ Warsaw Dept Gen Transplant & Liver Surg 1A Banacha St PL-02097 Warsaw Poland

Background. Liver transplantation (LT) outcomes for patients with poorly differentiated (G3) hepatocellular carcinoma (HCC) are unsatisfactory. The aim of this study was to evaluate outcomes in patients with poorly differentiated HCC undergoing LT. Patients and Methods. There were 192 HCC patients after LT in the Department of General, Transplant and Liver Surgery, Medical University of Warsaw, between January 2001 and April 2014. The study group comprised 24 patients with poorly differentiated tumors. Results. Disease-free survival (DFS) for all patients was 49.5% at 5 years. The 5-year DFS for patients who met the Milan criteria (n = 9, 88.9%) was significantly better compared to those who did not (n = 15, 28.0%, P = .025). Multivariable analysis revealed that only the largest tumor diameter (P = .014) and alpha-fetoprotein (AFP) concentration (P = .001) were independent risk factors for DFS. The optimal cut-off AFP and tumor size that could distinguish patients with the highest risk were >= 500 ng/mL and >= 3.5 cm, respectively. DFS for patients with AFP <500 ng/mL and tumor size <3.5 cm was 100% after 2.8 years, and for those with >= 500 ng/mL or tumor size >= 3.5 cm was 46.9% after 5 years. However, the DFS for patients with AFP >= 500 ng/mL and tumor size >3.5 cm was only 12.5% after 4.7 years (P = .002). Conclusions. Outcomes of patients with poorly differentiated HCC treated with LT can be characterized with acceptable survival when applying criteria based on tumor size <3.5 cm and AFP <500 ng/mL.

关键词： Patients Hepatocellular Cancer differentiated batholith human-centered computing Level Trigger Liver Transplantation

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