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Synergistic Effect of MiR-146a Mimic and Cetuximab on Hepatocellular Carcinoma Cells

BIOMED RESEARCH INTERNATIONAL 2014年第unknown期2014卷 384121-384121页

作者： Huang, Suning He, Rongquan Rong, Minhua Dang, Yiwu Chen, Gang Guangxi Med Univ Affiliated Hosp 1 Dept Radiotherapy Nanning 530021 Guangxi Zhuang Peoples R China Guangxi Med Univ Affiliated Hosp 1 Dept Med Oncol Nanning 530021 Guangxi Zhuang Peoples R China Guangxi Med Univ Affiliated Canc Hosp Res Dept Nanning 530021 Guangxi Zhuang Peoples R China Guangxi Med Univ Affiliated Hosp 1 Dept Pathol Nanning 530021 Guangxi Zhuang Peoples R China

Previously, we found that the expression of microRNA-146a (miR-146a) was downregulated in hepatocellular carcinoma (HCC) formalin-fixed paraffin-embedded (FFPE) tissues compared to the adjacent noncancerous hepatic tissues. In the current study, we have explored the in vitro effect of miR-146a on the malignant phenotypes of HCC cells. MiR-146a mimic could suppress cell growth and increase cellular apoptosis in HCC cell lines HepG2, HepB3, and SNU449, as assessed by spectrophotometry, fluorimetry, and fluorescence microscopy, respectively. Furthermore, western blot showed that miR-146a mimic downregulated EGFR, ERK1/2, and stat5 signalings. These effects were less potent compared to that of a siRNA targeting EGFR, a known target gene of miR-146a. Moreover, miR-146a mimic could enhance the cell growth inhibition and apoptosis induction impact of various EGFR targeting agents. The most potent combination was miR-146a mimic with cetuximab, presenting a synergistic effect. In conclusion, miR-146a plays a vital role in the cell growth and apoptosis of HCC cells and inducing miR-146a level might be a critical targeted molecular therapy strategy for HCC.

关键词： Erbitux Molecular Targeted Therapy Apoptosis Synergism growth inhibition Growth Retardation human-centered computing Fluorescence microscopy

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MicroRNAs in Nonalcoholic Fatty Liver Disease: Novel Biomarkers and Prognostic Tools during the Transition from Steatosis to Hepatocarcinoma

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BIOMED RESEARCH INTERNATIONAL 2014年第unknown期2014卷 741465-741465页

作者： Gori, Manuele Arciello, Mario Balsano, Clara Francesco Balsano Fdn Lab Mol Virol & Oncol I-00198 Rome Italy Univ Roma La Sapienza Dept Internal Med & Med Specialties I-00161 Rome Italy

Nonalcoholic fatty liver disease (NAFLD) is a metabolic-related disorder ranging from steatosis to steatohepatitis, which may progress to cirrhosis and hepatocellular carcinoma (HCC). The influence of NAFLD on HCC development has drawn attention in recent years. HCC is one of the most common malignant tumors and the third highest cause of cancer-related death. HCC is frequently diagnosed late in the disease course, and patient's prognosis is usually poor. Early diagnosis and identification of the correct stage of liver damage during NAFLD progression can contribute to more effective therapeutic interventions, improving patient outcomes. Therefore, scientists are always searching for new sensitive and reliable markers that could be analysed through minimally invasive tests. MicroRNAs are short noncoding RNAs that act as posttranscriptional regulators of gene expression. Several studies identified specific miRNA expression profiles associated to different histological features of NAFLD. Thus, miRNAs are receiving growing attention as useful noninvasive diagnostic markers to follow the progression of NAFLD and to identify novel therapeutic targets. This review focuses on the current knowledge of the miRNAs involved in NAFLD and related HCC development, highlighting their diagnostic and prognostic value for the screening of NAFLD patients.

关键词： Hepatocellular Cancer MicroRNAs Malignancy Disease Progression Steatohepatitis Fatty Change Liver Diseases human-centered computing Non-alcoholic Fatty Liver Disease

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Connectivism and leadership: harnessing a learning theory for the digital age to redefine leadership in the twenty-first century

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HELIYON 2020年第1期6卷 e03250-e03250页

作者： Corbett, Frederique Spinello, Elio Pepperdine Univ Grad Sch Educ & Psychol Los Angeles CA 90045 USA

This manuscript provides a literature review of connectivism. It presents evidence and thinking in which connectivism, a new learning theory which has typically been used for online learning, is applied to leadership, with a provocative discussion on the yet unexplored opportunities to use connectivism to redefine leadership in the twenty-first century. The paper aims to bridge the gap between the contributions of digital learning in education and the field of leadership theory and development. It seeks to apply the critical tenants of connectivism in education and learning to leadership theory and to stimulate a debate on new forms of leadership.

关键词： Connectivism Learning Education Learning theory Leadership Computer science human-centered computing Information systems Network (computer science)

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Public Attitudes to Digital Health Research Repositories: Cross-sectional International Survey

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JOURNAL OF MEDICAL INTERNET RESEARCH 2021年第10期23卷 e31294页

作者： Vilaza, Giovanna Nunes Coyle, David Bardram, Jakob Eyvind Tech Univ Denmark Dept Hlth Technol Orsteds Plads 345B DK-2800 Lyngby Denmark Univ Coll Dublin Sch Comp Sci Dublin Ireland

Background: Digital health research repositories propose sharing longitudinal streams of health records and personal sensing data between multiple projects and researchers. Motivated by the prospect of personalizing patient care (precision medicine), these initiatives demand broad public acceptance and large numbers of data contributors, both of which are challenging. Objective: This study investigates public attitudes toward possibly contributing to digital health research repositories to identify factors for their acceptance and to inform future developments. Methods: A cross-sectional online survey was conducted from March 2020 to December 2020. Because of the funded project scope and a multicenter collaboration, study recruitment targeted young adults in Denmark and Brazil, allowing an analysis of the differences between 2 very contrasting national contexts. Through closed-ended questions, the survey examined participants' willingness to share different data types, data access preferences, reasons for concern, and motivations to contribute. The survey also collected information about participants' demographics, level of interest in health topics, previous participation in health research, awareness of examples of existing research data repositories, and current attitudes about digital health research repositories. Data analysis consisted of descriptive frequency measures and statistical inferences (bivariate associations and logistic regressions). Results: The sample comprises 1017 respondents living in Brazil (1017/1600, 63.56%) and 583 in Denmark (583/1600, 36.44%). The demographics do not differ substantially between participants of these countries. The majority is aged between 18 and 27 years (933/1600, 58.31%), is highly educated (992/1600, 62.00%), uses smartphones (1562/1600, 97.63%), and is in good health (1407/1600, 87.94%). The analysis shows a vast majority were very motivated by helping future patients (1366/1600, 85.38%) and researchers (1253/1600,

关键词： digital medicine health informatics health data repositories personal sensing technology acceptance willingness to share data human-centered computing ethics

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Characterization of Basigin Isoforms and the Inhibitory Function of Basigin-3 in human Hepatocellular Carcinoma Proliferation and Invasion

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MOLECULAR AND CELLULAR BIOLOGY 2011年第13期31卷 2591-2604页

作者： Liao, Cheng-Gong Kong, Ling-Min Song, Fei Xing, Jin-Liang Wang, Long-Xin Sun, Zhi-Jian Tang, Hao Yao, Hui Zhang, Yang Wang, Li Wang, Yu Yang, Xiang-Min Li, Yu Chen, Zhi-Nan Fourth Mil Med Univ Cell Engn Res Ctr Xian 710032 Peoples R China Fourth Mil Med Univ Dept Cell Biol State Key Lab Canc Biol Xian 710032 Peoples R China Fourth Mil Med Univ Dept Histol & Embryol Xian 710032 Peoples R China Fourth Mil Med Univ Dept Oncol State Key Lab Canc Biol Xijing Hosp Xian 710032 Peoples R China Urumqi Gen Hosp Lanzhou Mil Command PLA Dept Oncol Urumqi 830000 Peoples R China

Basigin, which has four isoforms, plays an important role in invasion of hepatocellular carcinoma (HCC). Detailed transcriptional regulation and functions of the basigin isoforms have not been reported except in the case of the predominant isoform basigin-2, which act as inducer of matrix metalloproteinases (MMPs). Here we determined that basigin-2, basigin-3, and basigin-4 were the most abundant transcript variants in human cell lines. GeneRacer PCR and luciferase reporter assays showed that basigin-3 and basigin-4 were initiated from an alternative promoter. Basigin-3 and basigin-4 were widely expressed in various normal human tissues at the mRNA level and were upregulated in HCC tissues compared to in normal tissues. Western blotting and confocal imaging showed that glycosylated basigin-3 and basigin-4 were expressed and localized to the plasma membrane. However, in cultured cell lines, only native basigin-3, and not basigin-4, was detected at protein level. Overexpression of basigin-3 inhibited HCC cell proliferation, MMP induction, and cell invasion in vitro and in vivo. Bimolecular fluorescence complementation assays and nuclear magnetic resonance (NMR) analysis indicated that basigin-3 interacted with basigin-2 to form hetero-oligomers. In conclusion, we systematically investigated the alternative splicing of basigin and found that basigin-3 could inhibit HCC proliferation and invasion, probably through interaction with basigin-2 as an endogenous inhibitor via hetero-oligomerization.

关键词： matrix metalloproteinase: MMP 141907-41-7 mRNA hetero-oligomer basigin-2: expression transcription regulation basigin-3: expression glycosylation basigin-4: expression cell proliferation cell invasion cell induction Cell Proliferation Matrix Metalloproteinases CD147 Antigens Glycosylation Protein Isoforms human-centered computing cell invasion Messenger RNA

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Mutation of Herpesvirus Saimiri ORF51 Glycoprotein Specifically Targets Infectivity to Hepatocellular Carcinoma Cell Lines

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JOURNAL OF BIOMEDICINE AND BIOTECHNOLOGY 2011年第unknown期2011卷 785158-785158页

作者： Turrell, Susan J. Whitehouse, Adrian Univ Leeds Inst Mol & Cellular Biol Fac Biol Sci Leeds LS2 9JT W Yorkshire England Univ Leeds Astbury Ctr Struct Mol Biol Leeds LS2 9JT W Yorkshire England

Herpesvirus saimiri (HVS) is a gamma herpesvirus with several properties that make it an amenable gene therapy vector;namely its large packaging capacity, its ability to persist as a nonintegrated episome, and its ability to infect numerous human cell types. We used RecA-mediated recombination to develop an HVS vector with a mutated virion protein. The heparan sulphate-binding region of HVS ORF51 was substituted for a peptide sequence which interacts with somatostatin receptors (SSTRs), overexpressed on hepatocellular carcinoma (HCC) cells. HVS mORF51 showed reduced infectivity in non-HCC human cell lines compared to wildtype virus. Strikingly, HVS mORF51 retained its ability to infect HCC cell lines efficiently. However, neutralisation assays suggest that HVS mORF51 has no enhanced binding to SSTRs. Therefore, mutation of the ORF51 glycoprotein has specifically targeted HVS to HCC cell lines by reducing the infectivity of other cell types;however, the mechanism for this targeting is unknown.

关键词： Saimiriine herpesvirus 2 Gene Transduction Agent peptide sequence Infectivity cell type Mutation Glycoproteins Herpesvirus 2, Saimiriine neutralization tests Hepatocellular Cancer Cell Line Pathogenicity human-centered computing

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Context-driven detection of distracted driving using images from in-car cameras

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INTERNET OF THINGS 2021年 14卷

作者： Dey, Arup Kanti Goel, Bharti Chellappan, Sriram Univ S Florida Dept Comp Sci & Engn 4202 E Fowler AveENG 030 Tampa FL 33620 USA

Distracted driving on roads has been a perennial problem. There is increasing consensus now among various stakeholders that this practice will not be eliminated with mere warnings from subject matter experts. Instead, these warnings must also be augmented with appropriate technological assistance to facilitate safer driving. There has been an urgent interest in the community to devise newer technologies for detecting when drivers are distracted on roads. In this paper, we design a computer vision techniques that process image data recorded from inside of cars to automatically infer when subjects are driving distracted. However, our innovation lies in adding context to the predictions. We do so, by first detecting and localizing a number of objects in cars that contribute to distracted driving (e.g., hands, smartphones, radio etc.) from images. Then, we process the relative locations of these objects using machine learning algorithms within an image to make predictions on distracted driving. We believe that our proposed context-driven approach is unique. We expect it to better facilitate correction of distracted driving, when real-time feedback to subjects come with appropriate contextual interpretation of the specific aspects that contributed to distracted driving. Performance evaluations of our techniques reveal a) mAP score of 63.90 for an IoU of 0.5 in object localization;and b) an overall accuracy of 94% in detecting instances of distracted driving based on object localization. Processing time incurred by our technique is around 200ms only. As such, we believe that our system is accurate, fast, practical and context-aware also. (C) 2021 Elsevier B.V. All rights reserved.

关键词： Distracted driving Object detection Deep learning AI Convolutional neural networks human-centered computing

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Brain hierarchy score: Which deep neural networks are hierarchically brain-like?

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ISCIENCE 2021年第9期24卷 103013页

作者： Nonaka, Soma Majima, Kei Aoki, Shuntaro C. Kamitani, Yukiyasu Kyoto Univ Fac Integrated Human Studies Kyoto 6068501 Japan Kyoto Univ Grad Sch Informat Kyoto 6068501 Japan Seika ATR Computat Neurosci Labs Kyoto 6190288 Japan

Achievement of human-level image recognition by deep neural networks (DNNs) has spurred interest in whether and how DNNs are brain-like. Both DNNs and the visual cortex perform hierarchical processing, and correspondence has been shown between hierarchical visual areas and DNN layers in representing visual features. Here, we propose the brain hierarchy (BH) score as a metric to quantify the degree of hierarchical correspondence based on neural decoding and encoding analyses where DNN unit activations and human brain activity are predicted from each other. We find that BH scores for 29 pre-trained DNNs with various architectures are negatively correlated with image recognition performance, thus indicating that recently developed high-performance DNNs are not necessarily brain-like. Experimental manipulations of DNN models suggest that single-path sequential feedforward architecture with broad spatial integration is critical to brain-like hierarchy. Our method may provide new ways to design DNNs in light of their representational homology to the brain.

关键词： Neuroscience Neural networks human-centered computing

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Challenging the principle of utility as a barrier for wider use of liver transplantation for hepatocellular cancer

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ANNALS OF SURGICAL ONCOLOGY 2017年第11期24卷 3188-3195页

作者： Grat, Michal Stypulkowski, Jan Patkowski, Waldemar Wronka, Karolina M. Bik, Emil Krasnodebski, Maciej Masior, Lukasz Lewandowski, Zbigniew Wasilewicz, Michal Grat, Karolina Krawczyk, Marek Zieniewicz, Krzysztof Med Univ Warsaw Dept Gen Transplant & Liver Surg Warsaw Poland Med Univ Warsaw Dept Epidemiol Warsaw Poland Med Univ Warsaw Dept Gen Transplant & Liver Surg Hepatol & Internal Med Unit Warsaw Poland Med Univ Warsaw Dept Clin Radiol 2 Warsaw Poland

Although transplant benefit appears superior for patients with advanced hepatocellular cancer (HCC), liver transplantation remains limited to selected low-risk HCC patients to keep their outcomes similar to heterogeneous group of non-HCC patients. The purpose of this study was to assess the rationale for current policy of restricting access to liver transplantation to minority of HCC patients based on utility principle. This retrospective cohort study comprised 1246 liver transplant recipients, including 206 HCC and 1040 non-HCC patients. Patient survival was the primary outcome measure. Patients with HCC and benign diseases were divided into low-, moderate-, and high-risk subgroups basing on independent risk factors for disease-free survival and model for end-stage liver disease (MELD) score (< 30, 30-40, > 40), respectively. MELD (p < 0.001) and presence of HCC (p = 0.008) were independent risk factors for early and late mortality, respectively. Total tumor volume (p = 0.008) and alpha-fetoprotein (p = 0.013) were independent predictors of recurrence and mortality used for division of HCC patients into low-, moderate-, and high-risk subgroups, with disease-free survival rates of 74.9% (5 years), 51.7% (5 years), and 8.0% (3 years), respectively (p < 0.001). There were no differences in 5-year overall survival between low-risk HCC (74.9%) and non-HCC (81.9%) patients (p = 0.210), moderate-risk HCC (63.3%) and non-HCC (68.0%) patients (p = 0.372), and high-risk HCC (55.0%) and non-HCC (56.0%) patients (p = 0.559). The principle of utility is unequally applied for restriction of access to liver transplantation for HCC patients. The results provide rationale for discussion on reinitiation of liver transplantation for advanced HCCs.

关键词： Hepatocellular Cancer Risk Factors Liver Transplantation Disease-Free Survival human-centered computing patient history of liver transplantation Patients

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Nuclear β-Catenin Induces an Early Liver Progenitor Phenotype in Hepatocellular Carcinoma and Promotes Tumor Recurrence

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AMERICAN JOURNAL OF PATHOLOGY 2010年第1期176卷 472-481页

作者： Zulehner, Gudrun Mikula, Mario Schneller, Doris van Zijl, Franziska Huber, Heidemarie Sieghart, Wolfgang Grasl-Kraupp, Bettina Waldhoer, Thomas Peck-Radosavljevic, Markus Beug, Hartmut Mikulits, Wolfgang Med Univ Vienna Div Inst Canc Res Dept Internal Med 1 A-1090 Vienna Austria Med Univ Vienna Div Gastroenterol & Hepatol Dept Internal Med 3 A-1090 Vienna Austria Med Univ Vienna Ctr Publ Hlth Dept Epidemiol A-1090 Vienna Austria Res Inst Mol Pathol A-1030 Vienna Austria

Transforming growth factor-beta cooperates with oncogenic Ras to activate nuclear beta-catenin during the epithelial to mesenchymal transition of hepatocytes, a process relevant in the progression of hepatocellular carcinoma (HCC). In this study we investigated the role of beta-catenin in the differentiation of murine, oncogene-targeted hepatocytes and in 133 human HCC patients scheduled for orthotopic liver transplantation. Transforming growth factor-beta caused dissociation of plasma membrane E-cadherin/beta-catenin complexes and accumulation of nuclear beta-catenin in Ras-transformed, but otherwise normal hepatocytes in p19(ARF)-/- mice. Both processes were inhibited by Smad7-mediated disruption of transforming growth factor-beta signaling. Overexpression of constitutively active beta-catenin resulted in high levels of CK19 and M2-PK, whereas ablation of beta-catenin by axin overexpression caused strong expression of CK8 and CK18. Therefore, nuclear beta-catenin resulted in dedifferentiation of neoplastic hepatocytes to immature progenitor cells, whereas loss of nuclear beta-catenin led to a differentiated HCC phenotype. Poorly differentiated human HCC showed cytoplasmic redistribution or even loss of E-cadherin, suggesting epithelial to mesenchymal transition. Analysis of 133 HCC patient samples revealed that 58.6% of human HCC exhibited strong nuclear beta-catenin accumulation, which correlated with clinical features such as vascular invasion and recurrence of disease after orthotopic liver transplantation. These data suggest that activation of beta-catenin signaling causes dedifferentiation to malignant, immature hepatocyte progenitors and facilitates recurrence of human HCC after orthotopic liver transplantation. (Am J Pathol 2010, 176:472-481;DOI: 10.2353/ajpath.2010.090300)

关键词： Stem Cells beta Catenin Recurrent Neoplasm Hepatocellular Cancer Epithelial-Mesenchymal Transition Relapse KRT8 gene human-centered computing Hepatocytes Liver Transplantation Anaplasia

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