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Constitutive Overexpression of Bcl-2, Survivin and ER Stress Chaperone GRP-78 Confers Intrinsic Radioresistance in Human Hepatocellular Carcinoma Cells: Insight into the Mechanistic Pathways Involved

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Journal of Cancer Therapy 2013年第2期4卷 399-407页

作者： Chih-Hsiung Wu Yih-Huei Uen Chun-Te Ho Ya-Ting Tseng Tsan-Zon Liu Jeng-Fong Chiou stephen wan leung Cancer Center and Department of Radiation Oncology Taipei Medical University and Hospital Taipei Chinese Taipei Department of General Surgery Chi-Mei Foundation Medical Center Tainan Chinese Taipei Department of Radiology and Nuclear Medicine Yuan’s General Hospital Kaohsiung Chinese Taipei Department of Surgery Taipei Medical University-Shuang Ho Hospital Taipei Chinese Taipei Graduate Institute of Medical Biotechnology Chang-Gung University Gueishan Chinese Taipei Graduate Institute of Medical Sciences Taipei Medical University Taipei Chinese Taipei

We present evidence here that abundantly expressed b-catenin-triggered NF-kB-dependent upregulation of inducible nitric oxide synthase(iNOS) found in hepatoma Mahlavu cells (RT-resistant variant designated as RR-Mal), but not in Hep 3B cells (RT-sensitive variant designated as RS-3B) is a key element contribrting to the radioresisitance through the activation of two prominent radioprotective pathways. First, high iNOS expression found in RR-Mal, but not in RS-3B cells was found to perturb calcium homeostasis that triggered ER stress response leading to the overproduction of ER chaperone GRP-78 via robust generation of cleaved ATF-6a (50 kDa) subunits and their nuclear translocation. Meanwhile, both abundantly expressed NF-κB and COX-2 found in RR-Mal cells could also provoke an increased production of PGE2 resulting in robust production of Bcl-2. Interestingly, when RR-Mal cells were treated with PDTC (a NF-κB inhibitor) or celecoxib (a COX-2 inhibitor), a concentration-dependent downregulation of Bcl-2 could be demonstrated implying that Bcl-2 overexpression was indeed mediated through NF-κB/Cox-2/PGE2 pathway. Importantly, we also unveiled that siRNA-mediated silencing of survivin in RR-Mal cells could result in a concomitant downregulation of GRP-78 due to a severe inhibition of ATF-6a (50 kDa) expression. Taken together, our data demonstrate that constitutively overexpressed b-catenin/NF-κB/iNOS and NF-κB/COX-2/PGE2 pathways that overproducing GRP-78, survivin and Bcl-2 expressions are responsible for radioresistance acquisition in RR-Mal cells. Thus, both pathways could be served as potential targets for overcoming radioresistance.

关键词： Radioresistance Hepatoma Cells Inducible Nitric Oxide Synthase Bcl-2 Survivin GRP-78

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Alcoholic ketoacidosis in two Chinese patients

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Chinese Medical Journal 2000年第11期113卷 91-93页

作者： Rossa WKChiu Hok-leung Tai and Ching-wan Lam DepartmentofChemicalPathology TheChineseUniversityofHongKongPrinceofWalesHospitalHongKongChinaDepartmentofChemicalPathologyTheChineseUniversityofHongKongPrinceofWalesHospitalHongKongChina

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Risk of stroke after acute myocardial infarction among Chinese

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Chinese Medical Journal 2001年第2期114卷 98-99页

作者： Ping-WingNG Wai-KwongCHAN Patrick Kwok-leung K wan Department of Medicine and Geriatrics United Christian Hospital 130 Hip Wo Street Kwun Tong Kowloon Hong Kong China.

Following an acute myocardial infarction (AMI), patients have an increased risk of stroke. Estimates of risk are mainly derived from AMI treatment trials or secondary prevention studies. The reported incidence of stroke in Caucasians in the early phase after AMI ranged from 0.5% to 2.5%.1-3 Similar assessment of risk in the Chinese population is lacking. As thrombolytic therapy becomes standard treatment for AMI, there is concern that there may be an increase in haemorrhagic stroke complicating AMI treatment, especially since haemorrhagic stroke is more common in Asian populations.

关键词： acute myocardial infarction thrombolytic therapy Chinese population

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Chemical biology investigation of a triple-action,smart-decomposition antimicrobial booster based-combination therapy against“ESKAPE”pathogens

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Science China Chemistry 2024年第9期67卷 3071-3082页

作者： Min wang Huangsheng Pu Yangfan Xu Chenxuan Wu Yuanxin Gu Qingyun Cai Guoxing Yin Peng Yin Chunhui Zhang Wing-leung Wong Muyang wan Yugang Bai Xinxin Feng State Key Laboratory of Chem-/Bio-Sensing and Chemometrics Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biologyand School of Chemistry and Chemical EngineeringHunan UniversityChangsha 410082China College of Biology Hunan UniversityChangsha 410082China College of Advanced Interdisciplinary Studies&Hunan Provincial Key Laboratory of Novel Nano Optoelectronic Information Materials and Devices National University of Defense TechnologyChangsha 410073China Nanhu Laser Laboratory National University of Defense TechnologyChangsha 410073China Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research(Ministry of Education) College of Chemistry and Chemical EngineeringHunan Normal UniversityChangsha 410081China State Key Laboratory of Chemical Biology and Drug Discovery Department of Applied Biology and Chemical TechnologyThe Hong Kong Polytechnic UniversityHong Kong SAR 999077China Hunan Provincial Key Laboratory of Anti-Resistance Microbial Drugs The Third Hospital of Changsha(The Affiliated Changsha Hospital of Hunan University)Changsha 410015China

The global antibiotic resistance crisis necessitates urgent *** innovative approach involves potentiating antibiotics and non-antibiotic drugs with adjuvants or boosters.A major drawback of these membrane-active boosters is their limited biocompatibility,as they struggle to differentiate between prokaryotic and eukaryotic *** study reports the chemical biology investigation of a dual-action oligoamidine(OA1)booster with a glutathione-triggered decomposition ***1,when combined with other antimicrobial molecules,exhibits a triple-targeting mechanism including cell membrane disruption,DNA targeting,and intracellular enzyme *** multi-targeting mechanism not only enhances the in vitro and in vivo eradication of antibiotic-resistant“ESKAPE”pathogens,but also suppresses the development of bacterial ***,OA1 maintains its activity in bacterial cells by creating an oxidative environment,while it quickly decomposes in mammalian cells due to high glutathione *** mechanistic insights and design principles may provide a feasible approach to develop novel antimicrobial agents and effective anti-resistance combination therapies.

关键词： antimicrobial booster oligoamidine membrane disruption DNA targeting triggered degradation anti-resistance

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Review on applications of metastatic lymph node based radiomic assessment in nasopharyngeal carcinoma

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Journal of Cancer Metastasis and Treatment 2023年第1期9卷 328-341页

作者： Po Ling Chan wan Shun leung Varut Vardhanabhuti Shara W.Y.Lee Jason Y.K.Chan Department of Otorhinolaryngology Head and Neck SurgeryThe Chinese University of Hong KongHong KongChina Department of Health Technology and Informatics The Hong Kong Polytechnic UniversityHong KongChina Department of Diagnostic Radiology The University of Hong KongHong KongChina

Nasopharyngeal carcinoma(NPC)has a distinct geographical prevalence in Southern China and Southeast Asia with a high overall survival rate(>90%)in the early stage of the ***,almost 85%of patients suffer from the locally advanced disease with nodal metastasis at *** overall survival rate would drastically drop to 63%.In addition to the generic tumor,nodal,and metastasis(TNM)staging,radiomic studies focusing on primary nasopharyngeal tumors have gained attention in precision medicine with artificial *** the heterogeneous presentation of cervical lymphadenopathy in locally advanced NPC is regarded as the same clinical stage under TNM criteria,radiomic analysis provides more insights into risk stratification,treatment differentiation,and survival *** appears to be a lack of a review that consolidates radiomics-related studies on lymph node metastasis in *** aim of this paper is to summarize the state-of-the-art of radiomics for lymph node analysis in NPC,including its potential use in prognostic prediction,treatment response,and overall survival for this cohort of patients.

关键词： Nasopharyngeal carcinoma radiomics deep learning NPC nodal metastasis artificial intelligence review head and neck oncology cervical lymphadenopathy

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Aurone derivatives as Vps34 inhibitors that modulate autophagy

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Acta Pharmaceutica Sinica B 2019年第3期9卷 537-544页

作者： Guodong Li Joshua William Boyle Chung-Nga Ko Wu Zeng Vincent Kam Wai Wong Jian-Bo wan Philip Wai Hong Chan Dik-Lung Ma Chung-Hang leung State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao999078China School of Chemistry Monash UniversityClayton3800Australia Department of Chemistry Hong Kong Baptist UniversityHong Kong999077China State Key Laboratory of Quality Research in Chinese Medicine Macao University of Science and TechnologyMacao999078China Department of Chemistry University of WarwickCoventry CV47ALUK

We report in this study the identification of a natural product-like antagonist(1a) of Vps34 as a potent autophagy modulator via structure-based virtual screening. Aurone derivative 1a strongly inhibited Vps34 activity in cell-free and cell-based assays. Significantly, 1a prevents autophagy in human cells induced either by starvation or by an mT OR inhibitor. In silico modeling and kinetic data revealed that 1a could function as an ATP-competitive inhibitor of Vps34. Moreover, it suppressed autophagy in vivo and without inducing heart or liver damage in mice. 1a could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases.

关键词： Autophagy Natural products Vps34 Inhibitor Structure-based virtual screening Vesicle trafficking Heart or liver damage Aurone derivative

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Traditional Chinese Medicine as a Treatment for Rheumatoid Arthritis:From Empirical Practice to Evidence-Based Therapy

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Engineering 2019年第5期5卷 895-906页

作者： Hu-Dan Pan Yao Xiao wan-Ying wang Ru-Tong Ren Elaine Lai-Han leung Liang Liu State Key Laboratory of Quality Research in Chinese Medicine Macao Institute for Applied Research in Medicine and HealthMacao University of Science and TechnologyMacaoChina State Key Laboratory of Respiratory Disease Guangzhou Institute of Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China Department of Respiratory and Critical Care Medicine Affiliated Taihe Hospital of Hubei University of MedicineHubei 442000China

Rheumatoid arthritis(RA)is a common autoimmune condition with an elusive *** and biological disease-modifying drugs sometimes fail or produce only partial *** Chinese medicine(TCM)has long been used in China as a treatment for RA and is achieving everincreasing acceptance *** treatments are traditionally guided by the theory of treatment based on TCM syndrome differentiation;however,they remain a matter of empirical practice relying on TCM theories and doctors’own experience,which places severe restrictions on worldwide TCM ***,TCM is a treasure trove for drug discovery,particularly as a treatment for complicated human *** discoveries of artemisinin as a treatment for malaria and of TCM–arsenic trioxide(As2O3)combination therapy as a treatment for acute promyelocytic leukemia(APL)are excellent examples of the great value of *** RA treatments,many Chinese medicinal herbs and their formulas,extracts,ingredients,and even single compounds have been used in clinical *** Chinese proprietary medicines(CPMs)derived from TCM formulas or herbal bioactive components,such as the controlled-release ZhengQingFengTongNing(ZQFTN)Tablets,Tripterygium Glycoside Tablets,and Total Glucosides of Peony(TGP)Capsules,have been included in the National Health Insurance Directory of China,and show comparable therapeutic efficacies to those of western chemical drugs with fewer side *** TCM research has advanced,particularly in the use of multidisciplinary technologies,the scientific foundations and characteristics of the use of TCM to treat RA have been revealed,and the quality of TCM treatments have been increasingly ***,TCM generally lacks sufficient clinical and laboratory data to be consistent with international standards for quality,safety,and efficacy in order to support its application ***,intensive basic and clinical studies on TCM are required.I

关键词： Traditional Chinese medicine Rheumatoid arthritis Evidence-based therapy Perspective

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Impact of extended-infusion piperacillin-tazobactam in a Canadian community hospital

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Infectious Medicine 2023年第1期2卷 31-35页

作者： April J.Chan Gerald Lebovic Michael wan Yan Chen Elizabeth leung Bradley J.Langford Jenny Seah Linda R.Taggart Mark Downing Department of Pharmacy Unity Health TorontoTorontoOntarioCanada University of Toronto TorontoOntarioCanada Division of Infectious Diseases Unity Health TorontoTorontoOntarioCanada Public Health Ontario TorontoOntarioCanada Hotel Dieu Shaver Health and Rehabilitation Centre St.CatharinesOntarioCanada

Background:Studies have demonstrated improved clinical outcomes with extended infusion(EI)piperacillin/tazobactam(TZP)compared to standard infusion(SI).However,there is less evidence on its benefits in noncritically-ill ***-wide EI TZP was implemented at our site on February 21,*** objectives were to compare clinical,safety and economic outcomes between EI and SI ***:A retrospective cohort study of all adult patients who received EI TZP(3.375 g IV q8h infused over 4 hours and SI TZP for≥48 hours during 3 years pre-and postimplementation was *** primary study outcome was 14-day mortality while secondary outcomes included length of hospital stay(LOS),nursing plus pharmacy cost,occurrence of Clostridioides difficile infection,readmission within 30 days and change in Pseudomonas aeruginosa minimum inhibitory concentration(MIC)distribution for *** primary outcome and binary secondary outcomes were analyzed using a logistic regression *** was examined using time to event *** was examined using linear regression ***:Overall,2034 patients received EI TZP and 1364 patients received SI *** TZP was associated with lower odds of mortality(OR 0.76,95%CI 0.63-0.91),lower odds of *** infection(OR 0.59,95%CI 0.41-0.84)and 8%lower cost(estimate 0.92,95%CI 0.87-0.98)compared to SI ***:Hospital-wide implementation of EI TZP was associated with lower odds of 14-day mortality and incidence of *** infection with cost savings at our institution.

关键词： Antimicrobial stewardship Piperacillin/tazobactam Extended-infusion

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一类定性控制系统的稳定性分析

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控制理论与应用 2000年第2期17卷 175-179页

作者：刘林运万百五梁天培西安交通大学系统工程研究所西安710049 香港理工大学机械工程系

对一类非线性对象提出了定性稳定性的定义 ,并对其闭环自治系统的定性稳定性提出一个充分性判据 ,然后给出一种用变量梯度法构造李亚普诺夫函数的步骤 .最后以一个二阶非线性对象为例 ,给出了一种以全部定性状态作为反馈的定性控制 ,讨... 详细信息

对一类非线性对象提出了定性稳定性的定义 ,并对其闭环自治系统的定性稳定性提出一个充分性判据 ,然后给出一种用变量梯度法构造李亚普诺夫函数的步骤 .最后以一个二阶非线性对象为例 ,给出了一种以全部定性状态作为反馈的定性控制 ,讨论了闭环控制系统的定性稳定性 .

关键词：定性量定性控制系统稳定性分析定性控制器

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Quantitative and qualitative subgenomic RNA profiles of SARS-CoV-2 in respiratory samples: A comparison between Omicron BA.2 and non-VOC-D614G

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Virologica Sinica 2024年第2期39卷 218-227页

作者： Zigui Chen Rita Way Yin Ng Grace Lui Lowell Ling Agnes S.Y.leung Chit Chow Siaw Shi Boon Wendy C.S.Ho Maggie Haitian wang Renee wan Yi Chan Albert Martin Li David Shu Cheong Hui Paul Kay Sheung Chan Department of Microbiology Faculty of MedicineThe Chinese University of Hong KongHong KongChina Department of Medicine and Therapeutics Faculty of MedicineThe Chinese University of Hong KongHong KongChina Department of Anaesthesia and Intensive Care Faculty of MedicineThe Chinese University of Hong KongHong KongChina Department of Paediatrics Faculty of MedicineThe Chinese University of Hong KongHong KongChina Department of Anatomical and Cellular Pathology Faculty of MedicineThe Chinese University of Hong KongHong KongChina Jockey Club School of Public Health and Primary Care Faculty of MedicineThe Chinese University of Hong KongHong KongChina Stanley Ho Centre for Emerging Infectious Diseases Faculty of MedicineThe Chinese University of Hong KongHong KongChina

The SARS-CoV-2 Omicron variants are notorious for their transmissibility,but little is known about their subgenomic RNA(sgRNA)*** study applied RNA-seq to delineate the quantitative and qualitative profiles of canonical sgRNA of 118 respiratory samples collected from patients infected with Omicron BA.2 and compared with 338 patients infected with non-variant of concern(non-VOC)-D614G.A unique characteristic profile depicted by the relative abundance of 9 canonical sgRNAs was reproduced by both BA.2 and non-VOCD614G regardless of host gender,age and presence of ***,such profile was lost in samples with low viral load,suggesting a potential application of sgRNA pattern to indicate viral activity of individual patient at a specific time point.A characteristic qualitative profile of canonical sgRNAs was also reproduced by both BA.2 and *** presence of a full set of canonical sgRNAs carried a coherent correlation with crude viral load(AUC¼0.91,95%CI 0.88–0.94),and sgRNA ORF7b was identified to be the best surrogate marker allowing feasible routine application in characterizing the infection status of individual *** potentials in using sgRNA as a target for vaccine and antiviral development are worth pursuing.

关键词： Coronavirus SARS-CoV-2 Omicron BA.2 Non-VOC-D614G RNA-seq Subgenomic RNA(sgRNA)

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