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Genes & Diseases 2023年第5期10卷 1739-1742页

作者： Ying Mei Qinglei Hang Hongqi Teng Fan Yao Mei-Kuang Chen mien-chie hung Yutong Sun Li Ma Department of Experimental Radiation Oncology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer CenterHoustonTX 77030USA The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences HoustonTX 77030USA Hubei Hongshan Laboratory College of Biomedicine and HealthCollege of Life Science and TechnologyHuazhong Agricultural UniversityWuhanHubei 430070China

Poly(ADP-ribose)polymerase inhibitors(PARPi)are used to treat ovarian cancer and triple-negative breast cancer(TNBC)with defective homologous recombination repair pathways.However,de novo and acquired PARPi resistance limits clinical benefits.1 The MRE11-RAD50-NBS1(MRN)complex mediates the sensing,processing,and signaling of DNA double-strand breaks(DSBs)and plays important roles in the efficacy of PARPi and radiation treatment,2 and yet the mechanisms for the regulation and degradation of the MRN complex are not well understood.ZRANB1,also known as Trabid,is a breast cancer-promoting deubiquitinase that preferentially cleaves K29-,K33-,and K63-linked ubiquitin chains,3 but its role in therapy resistance remains unknown.

关键词： ubiquitin resistance PARP

Sphingosine kinase 1 promotes tumor immune evasion by regulating the MTA3-PD-L1 axis

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Cellular & Molecular Immunology 2022年第10期19卷 1153-1167页

作者： Poyee Lau Guanxiong Zhang Shuang Zhao Long Liang Hailun Zhang Guowei Zhou mien-chie hung Xiang Chen Hong Liu Department of Dermatology Xiangya HospitalCentral South UniversityChangshaChina National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology ChangshaChina Hunan Key Laboratory of Skin Cancer and Psoriasis ChangshaChina Hunan Engineering Research Center of Skin Health and Disease ChangshaChina Medical Genetics&School of Life Sciences Central South UniversityChangshaHunan410078China Department of Research and Development Beijing GAP Biotechnology Co.LtdBeijing102600China Graduate Institute of Biomedical Sciences Research Center for Cancer Biology and Center for Molecular MedicineChina Medical UniversityTaichungTaiwanChina Department of Biotechnology Asia UniversityTaichungTaiwanChina Department of Molecular and Cellular Oncology the University of Texas MD Anderson Cancer CenterHoustonTXUSA Xiangya Clinical Research Center for Cancer Immunotherapy Central South UniversityChangshaChina

Immune checkpoint blockade(ICB)exhibits considerable benefits in malignancies,but its overall response rate is limited.Previous studies have shown that sphingosine kinases(SPHKs)are critical in the tumor microenvironment(TME),but their role in immunotherapy is unclear.We performed integrative analyses including bioinformatics analysis,functional study,and clinical validation to investigate the role of SPHK1 in tumor immunity.Functionally,we demonstrated that the inhibition of SPHK1 significantly suppressed tumor growth by promoting antitumor immunity in immunocompetent melanoma mouse models and tumor T-cell cocultures.A mechanistic analysis revealed that MTA3 functions as the downstream target of SPHK1 in transcriptionally regulating tumor PD-L1.Preclinically,we found that anti-PD-1 monoclonal antibody(mAb)treatment significantly rescued tumor SPHK1 overexpression or tumor MTA3 overexpression-mediated immune evasion.Significantly,we identified SPHK1 and MTA3 as biological markers for predicting the efficacy of anti-PD-1 mAb therapy in melanoma patients.Our findings revealed a novel role for SPHK1 in tumor evasion mediated by regulating the MTA3-PD-L1 axis,identified SPHK1 and MTA3 as predictors for assessing the efficacy of PD-1 mAb treatment,and provided a therapeutic possibility for the treatment of melanoma patients.

关键词： Sphingosine kinase Programmed cell death ligand 1 Programmed cell death protein 1 Melanoma Tumor microenvironment Immune checkpoint blockade

The role of T-cell immunoglobulin mucin-3 and its ligand galectin-9 in antitumor immunity and cancer immunotherapy

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Science China(Life Sciences) 2017年第10期60卷 1058-1064页

作者： Riyao Yang mien-chie hung Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Center for Molecular Medicine and Graduate Institute of Biomedical Sciences China Medical University Department of Biotechnology Asia University

Cancer treatment in the past few years has been transformed by a new kind of therapy that targets the immune system instead of the cancer itself to reinvigorate antitumor immunity with astonishing results. However, primary and acquired resistance to this type of treatment, namely immune checkpoint blockade(ICB), continue to counter treatment efficacy. In many cases, resistance has been attributed to defective or chronically enhanced interferon signaling and/or upregulation of alternative immune checkpoints,including T-cell immunoglobulin mucin-3(Tim-3) and its ligand galactin-9(Gal-9). In this article, we briefly describe the current knowledge of common checkpoint resistance mechanisms, focusing on the Tim-3/Gal-9 pathway as an alternative checkpoint that holds great promise as another target for ICB.

关键词：肿瘤免疫免疫球蛋白免疫治疗 T细胞配体

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Activation of phagocytosis by immune checkpoint blockade

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Frontiers of Medicine 2018年第4期12卷 473-480页

作者： Chia-Wei Li Yun-Ju Lai Jennifer L. Hsu mien-chie hung Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Houston TX 77030 USA Department of Neurology McGovern Medical School The University of Texas Health Science Center at Houston Houston TX 77030 USA

Inhibition of macrophage-mediated phagocytosis has emerged as an essential mechanism for tumor immune evasion. One mechanism inhibiting the innate response is the presence of the macrophage inhibitory molecule, signal regulatory protein-a （SIRPa）, on tumor-associated macrophages （TAMs） and its cognate ligand cluster of differentiation 47 （CD47） on tumor cells in the tumor microenvironment. On the basis of a recently discovered programmed death protein 1 （PD-1） in TAMs, we discuss the potential inhibitory receptors that possess new functions beyond T cell exhaustion in this review. As more and more immune receptors are found to be expressed on TAMs, the corresponding therapies may also stimulate macrophages for phagocytosis and thereby provide extra anti-tumor benefits in cancer therapy. Therefore, identification of biomarkers and combinatorial therapeutic strategies, have the potential to improve the efficacy and safety profiles of current immunotherapies.

关键词： CD47 PD-1 PD-L1 immunotherapy TAM phagocytosis macrophage

A Novel mRNA Signature Related to Immunity to Predict Survival and Immunotherapy Response in Hepatocellular Carcinoma

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Journal of Clinical and Translational Hepatology 2022年第5期10卷 925-938页

作者： Chenhao Zhou Jialei Weng Yuan Gao Chunxiao Liu Xiaoqiang Zhu Qiang Zhou Chia-Wei Li Jialei Sun Manar Atyah Yong Yi Qinghai Ye Yi Shi Qiongzhu Dong Yingbin Liu mien-chie hung Ning Ren Department of Liver Surgery Liver Cancer InstituteZhongshan Hospitaland Key Laboratory of Carcinogenesis and Cancer Invasion(Ministry of Education)Fudan UniversityShanghaiChina Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer CenterHoustonTXUSA Department of Biliary-Pancreatic Surgery Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina School of Biomedical Sciences Li Ka Shing Faculty of MedicineThe University of Hong KongPok Fu LamHong Kong SARChina Biomedical Research Center Zhongshan HospitalFudan UniversityShanghaiChina Institute of Fudan Minhang Academic Health System and Key Laboratory of Whole-period Monitoring and Precise Intervention of Digestive Cancer(SMHC)Minhang Hospital&AHSFudan UniversityShanghaiChina Institutes of Biomedical Sciences Fudan UniversityShanghaiChina Graduate Institute of Biomedical Sciences and Center for Molecular Medicine China Medical UniversityTaichung

Background and Aims:Hepatocellular carcinoma(HCC)is the most common primary liver cancer and the incidence and mortality rates are increasing.Given the limited treatments of HCC and promising application of immunotherapy for cancer,we aimed to identify an immune-related prognostic signature that can predict overall survival(OS)rates and immunotherapy response in HCC.Methods:The initial signature development was conducted using a training dataset from the Cancer Genome Atlas followed by independent internal and external validations from that resource and the Gene Expression Omnibus.A signature based nomogram was generated using multivariate Cox regression analysis.The associations of signature score with tumor immune phenotype and response to immunotherapy were analyzed using single-sample gene set enrichment analysis and tumor immune dysfunction and exclusion algorithm.A cohort from Zhongshan Hospital was employed to verify the pre dictive robustness of the signature regarding prognostic risk and immunotherapy response.Results:The prognostic signature,IGS_(HCC),consisting of 22 immune-related genes,had independent prognostic ability,with training and validation cohorts.Also,IGS_(HCC)stratified HCC patients with different outcomes in subgroups.The prognostic accuracy of IGS_(HCC)was better than three reported prognostic signatures.The IGS_(HCC)-based nomogram had high accuracy and significant clinical benefits in predicting 3-and 5-year OS.IGS_(HCC)reflected distinct immunosuppressive phenotypes in low-and high-score groups.Patients with low IGS_(HCC)scores were more likely than those with high scores to benefit from immunotherapy.Conclusions:IGS_(HCC)predicted HCC prognosis and response to immunotherapy,and contributed to individualized clinical management.

关键词： Hepatocellular carcinoma Gene signature Immune microenvironment Prognosis Immunotherapy

PARP inhibitors as precision medicine for cancer treatment

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National Science Review 2017年第4期4卷 576-592页

作者： Yi Du Hirohito Yamaguchi Jennifer L.Hsu mien-chie hung Department of Molecular and Cellular Oncology The University of Texas MD Anderson Cancer Center Graduate Institute of Biomedical Sciences and Center for Molecular Medicine China Medical University Department of Biotechnology Asia University Graduate Institute of Biomedical Sciences and Center for Molecular Medicine China Medical UniversityTaichung

Personalized or precision medicine is an emerging treatment approach tailored to individuals or certain groups of patients based on their unique characteristics. These types of therapies guided by biomarkers tend to be more effective than traditional approaches, especially in cancer. The inhibitor against poly(ADP-ribose) polymerase(PARP), olaparib(Lynparza, Astra Zeneca), which was approved by the US Food and Drug Administration(FDA) in 2014, demonstrated efficacy specifically for ovarian cancer patients harboring mutations in BRCA genes, which encode proteins in DNA double-strand break repairs.However, the response to PARP inhibitors has been less encouraging in other cancer types that also carry defects in the BRCA genes. Thus, furthering our understanding of the underlying mechanism of PARP inhibitors and resistance is critical to improve their efficacy. In this review, we summarize the results of preclinical studies and the clinical application of PARP inhibitors, and discuss the future direction of PARP inhibitors as a potential marker-guided personalized medicine for cancer treatment.

关键词： PARP inhibitor kinase DNA damage precision medicine combination therapy

Identifying Brand Consistency by Product Differentiation Using CNN

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Computer Modeling in Engineering & Sciences 2024年第7期140卷 685-709页

作者： hung-Hsiang Wang Chih-Ping Chen Department of Industrial Design National Taipei University of TechnologyTaipeiTaiwan Department of Product Design Ming Chuan UniversityTaoyuanTaiwan

This paper presents a new method of using a convolutional neural network(CNN)in machine learning to identify brand consistency by product appearance variation.In Experiment 1,we collected fifty mouse devices from the past thirty-five years from a renowned company to build a dataset consisting of product pictures with pre-defined design features of their appearance and functions.Results show that it is a challenge to distinguish periods for the subtle evolution of themouse devices with such traditionalmethods as time series analysis and principal component analysis(PCA).In Experiment 2,we applied deep learning to predict the extent to which the product appearance variation ofmouse devices of various brands.The investigation collected 6,042 images ofmouse devices and divided theminto the Early Stage and the Late Stage.Results show the highest accuracy of 81.4%with the CNNmodel,and the evaluation score of brand style consistency is 0.36,implying that the brand consistency score converted by the CNN accuracy rate is not always perfect in the real world.The relationship between product appearance variation,brand style consistency,and evaluation score is beneficial for predicting new product styles and future product style roadmaps.In addition,the CNN heat maps highlight the critical areas of design features of different styles,providing alternative clues related to the blurred boundary.The study provides insights into practical problems for designers,manufacturers,and marketers in product design.It not only contributes to the scientific understanding of design development,but also provides industry professionals with practical tools and methods to improve the design process and maintain brand consistency.Designers can use these techniques to find features that influence brand style.Then,capture these features as innovative design elements and maintain core brand values.

关键词： Machine learning product differentiation brand consistency principal component analysis convolutional neural network computer mouse

Data-Driven Modeling of Partially Observed Biological Systems

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Communications on Applied Mathematics and Computation 2024年第1期6卷 739-754页

作者： Wei-hung Su Ching-Shan Chou Dongbin Xiu Department of Mathematics The Ohio State UniversityColumbusOH43221USA

We present a numerical approach for modeling unknown dynamical systems using partially observed data,with a focus on biological systems with(relatively)complex dynamical behavior.As an extension of the recently developed deep neural network(DNN)learning methods,our approach is particularly suitable for practical situations when(i)measurement data are available for only a subset of the state variables,and(ii)the system parameters cannot be observed or measured at all.We demonstrate that,with a properly designed DNN structure with memory terms,effective DNN models can be learned from such partially observed data containing hidden parameters.The learned DNN model serves as an accurate predictive tool for system analysis.Through a few representative biological problems,we demonstrate that such DNN models can capture qualitative dynamical behavior changes in the system,such as bifurcations,even when the parameters controlling such behavior changes are completely unknown throughout not only the model learning process but also the system prediction process.The learned DNN model effectively creates a“closed”model involving only the observables when such a closed-form model does not exist mathematically.

关键词： Deep neural network(DNN) Governing equation discovery Biological system Partial observation

Autolysosomal acidification impairment as a mediator for TNFR1 induced neuronal necroptosis in Alzheimer’s disease

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Neural Regeneration Research 2024年第9期19卷 1869-1870页

作者： Evridiki Asimakidou Richard Reynolds Anna M.Barron Chih hung Lo Department of Clinical Neurosciences University of CambridgeCambridgeUK Department of Brain Sciences Faculty of MedicineImperial College LondonLondonUK Lee Kong Chian School of Medicine Nanyang Technological UniversitySingaporeSingapore

Neuronal necroptosis-an emerging form of regulated cell death associated with neuroinflammatory signaling:Alzheimer’s disease(AD)is characterized by the presence of extracellular amyloid-β(Aβ)plaques and intracellular tau neurofibrillary tangles as well as progressive neuronal loss.Recent evidence has suggested that prolonged neuroinflammation with increased levels of cytokines,arising from neuronal injury,innate immune responses from glial cells,and peripheral inflammation,leads to neuronal death and AD progression.

关键词： Alzheimer death tau Aβ

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Study of relationship between motion of mechanisms in gas operated weapon and its shock absorber

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Defence Technology（防务技术） 2024年第3期33卷 42-54页

作者： Jiri Balla Roman Vitek Dung Nguyen Van Zbynek Krist hung Nguyen Van Department of Weapons and Ammunition University of Defence BrnoCzech Republic Department of Weapons Le Quy Don Technical UniversityHanoiViet Nam Department of Design and Special Engineering Alexander Dubcek University of TrencinSlovakia

The article deals with the motion of the breech block carrier and the weapon casing of an automatic weapon mounted on a flexible carriage and the base of the weapon.Earlier works,which did not consider the dynamic properties of the base of the weapon,did not allow to reconcile the calculated and experimental results of the weapon casing displacement when shooting from firing rests.For the analysis of the motion of individual parts,the methods of mathematical modelling and firing experiments using a high-speed camera were chosen.Calculations show the best accord with experiment when modelling the system with 4 degrees of freedom.The oscillation of the system regarding the movement of the breech block carrier and the weapon casing was investigated under changed conditions of rate of fire,the use of a muzzle brake and different types of shock absorbers.The velocities and displacements of the weapon casing and the breech block carrier at different values of the impulse of the gases to the breech block carrier were determined.

关键词： Shock absorber Gas-operated weapon Force-impulse diagram Recoil system Breech block carrier

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