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Novel therapeutic targets for pancreatic cancer

World Journal of Gastroenterology 2014年第31期20卷 10825-10844页

作者： Shing-Chun Tang Yang-Chao Chen school of biomedical sciences Faculty of Medicine the Chinese University of Hong Kong Shenzhen Research institute The Chinese University of Hong Kong

Pancreatic cancer has become the fourth leading cause of cancer death in the last two decades. Only 3%-15% of patients diagnosed with pancreatic cancer had 5 year survival rate. Drug resistance, high metastasis, poor prognosis and tumour relapse contributed to the malignancies and difficulties in treating pancreatic cancer. The current standard chemotherapy for pancreatic cancer is gemcitabine, however its efficacy is far from satisfactory, one of the reasons is due to the complex tumour microenvironment which decreases effective drug delivery to target cancer cell. Studies of the molecular pathology of pancreatic cancer have revealed that activation of KRAS, overexpression of cyclooxygenase-2, inactivation of p16INK4A and loss of p53 activities occurred in pancreatic cancer. Co-administration of gemcitabine and targeting the molecular pathological events happened in pancreatic cancer has brought an enhanced therapeutic effectiveness of gemcitabine. Therefore, studies looking for novel targets in hindering pancreatic tumour growth are emerging rapidly. In order to give a better understanding of the current findings and to seek the direction in future pancreatic cancer research; in this review we will focus on targets suppressing tumour metastatsis and progression, KRAS activated downstream effectors, the relationship of Notch signaling and Nodal/Activin signaling with pancreatic cancer cells, the current findings of non-coding RNAs in inhibiting pancreatic cancer cell proliferation, brief discussion in transcription remodeling by epigenetic modifiers (e.g., HDAC, BMI1, EZH2) and the plausible therapeutic applications of cancer stem cell and hyaluronan in tumour environment.

关键词： Pancreatic cancer CTHRC1 RAC1 RalGEF-RAl Notch Signaling Nodal/Activin Signaling NDRG1 Hypoxic condition DR5 PAR2 HER3 IAP Non-coding RNA HDAC BMI1 EZH2 Pancreatic cancer stem cell Tumour microenvironment

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Clinical significance of exosomes as potential biomarkers in cancer

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World Journal of Clinical Cases 2019年第2期7卷 171-190页

作者： Chi-Hin Wong Yang-Chao Chen school of biomedical sciences Faculty of Medicine The Chinese University of Hong Kong Shenzhen Research institute The Chinese University of Hong Kong

BACKGROUND Exosomes are microvesicles, measuring 30-100 nm in diameter. They are widely distributed in body fluids, including blood, bile, urine and saliva. Cancer-derived exosomes carry a wide variety of DNA, RNA, proteins and lipids, and may serve as novel biomarkers in *** To summarize the performance of exosomal biomarkers in cancer diagnosis and *** Relevant publications in the literature were identified by search of the "PubMed"database up to September 11, 2018. The quality of the included studies was assessed by QUADAS-2 and REMARK. For assessment of diagnostic biomarkers,47 biomarkers and 2240 patients from 30 studies were *** Our results suggested that these exosomal biomarkers had excellent diagnostic ability in various types of cancer, with good sensitivity and specificity. For assessment of prognostic markers, 50 biomarkers and 4797 patients from 42 studies were included. We observed that exosomal biomarkers had prognostic values in overall survival, disease-free survival and recurrence-free *** Exosomes can function as potential biomarkers in cancer diagnosis and prognosis.

关键词： Exosome Biomarker Cancer Diagnosis Prognosis

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Therapeutic potential of targeting acinar cell reprogramming in pancreatic cancer

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World Journal of Gastroenterology 2016年第31期22卷 7046-7057页

作者： Chi-Hin Wong You-Jia Li Yang-Chao Chen school of biomedical sciences Faculty of Medicine The Chinese University of Hong Kong Shenzhen Research institute The Chinese University of Hong Kong

Pancreatic ductal adenocarcinoma(PDAC) is a common pancreatic cancer and the fourth leading cause of cancer death in the United States. Treating this life-threatening disease remains challenging due to the lack of effective prognosis, diagnosis and therapy. Apart from pancreatic duct cells, acinar cells may also be the origin of PDAC. During pancreatitis or combined with activating KRasG12 D mutation, acinar cells lose their cellular identity and undergo a transdifferentiation process called acinarto-ductal-metaplasia(ADM), forming duct cells which may then transform into pancreatic intraepithelial neoplasia(Pan IN) and eventually PDAC. During ADM, the activation of mitogen-activated protein kinases, Wnt, Notch and phosphatidylinositide 3-kinases/Akt signaling inhibits the transcription of acinar-specific genes, including Mist and amylase, but promotes the expression of ductal genes, such as cytokeratin-19. Inhibition of this transdifferentiation process hinders the development of Pan IN and PDAC. In addition, the transdifferentiated cells regain acinar identity, indicating ADM may be a reversible process. This provides a new therapeutic direction in treating PDAC through cancer reprogramming. Many studies have already demonstrated the success of switching Pan IN/PDAC back to normal cells through the use of PD325901, the expression of E47, and the knockdown of Dickkopf-3. In this review, we discuss the signaling pathways involved in ADM and the therapeutic potential of targeting reprogramming in order to treat PDAC.

关键词： Acinar cells Acinar-to-ductal metaplasia Pancreatic ductal adenocarcinoma Signal transduction Reprogramming

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Outlook of PINK1/Parkin signaling in molecular etiology of Parkinson's disease,with insights into Pink1 knockout models

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Zoological Research 2023年第3期44卷 559-576页

作者： Zhangting Wang See-Wing Chan Hui Zhao Kai-Kei Miu Wai-Yee Chan school of biomedical sciences Faculty of MedicineThe Chinese University of Hong KongHong Kong SARChina Kunming institute of Zoology-The chinese university of hong kong(KIZ-CUHK)Joint Laboratory of Bioresources and Molecular Research of Common Diseases Hong Kong SARChina hong kong Branch of CAS Center for Excellence in Animal Evolution and Genetics School of Biomedical SciencesThe Chinese University of Hong KongHong Kong SARChina Key Laboratory for Regenerative medicine Ministry of EducationSchool of Biomedical SciencesThe Chinese University of Hong KongHong Kong SARChina

Parkinson’s disease(PD)relates to defective mitochondrial quality control in the dopaminergic motor *** studies have revealed that PINK1 and Parkin mutations are indicative of a heightened propensity to PD onset,pinpointing mitophagy and inflammation as the culprit pathways involved in neuronal loss in the substantia nigra(SNpc).In a reciprocal manner,LRRK2 functions in the regulation of basal flux and inflammatory responses responsible for PINK1/Parkin-dependent mitophagy *** intervention in these diseasemodifying pathways may facilitate the development of novel PD therapeutics,despite the current lack of an established drug evaluation *** such,we reviewed the feasibility of employing the versatile global Pink1knockout(KO)rat model as a self-sufficient,spontaneous PD model for investigating both disease etiology and drug *** rats retain clinical features encompassing basal mitophagic flux changes with PD *** demonstrate the versatility of this PD rat model based on the incorporation of additional experimental insults to recapitulate the proinflammatory responses observed in PD patients.

关键词： Parkinson’s disease Mitophagy Inflammatory response Genetic model Pink1 KO rats

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ROS does not contribute to acute development of nitroglycerine tolerance in rat aortas

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中国病理生理杂志 2010年第A10期26卷 2065-2066页

作者： WONG SL DOING JH LEE HK LEE WY LAU CW institute of vascular medicine and school of biomedical sciences Departments of Chemistry and Pharmacy Chinese University of Hong Kong

The development of nitroglycerine tolerance limits its clinical efficacy of nitric oxide(NO)donors. Several cellular mechanisms have been proposed to explain this phenomenon,one of which is an exaggerated production of reactive oxygen specious(ROS).The present study examined whether ROS contribute to the occurrence of nitroglycerine tolerance which is induced

关键词： explain limits xanthine impaired contraction incubation relaxation exposed inhibited markedly

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Integrated metabolomics analysis of the effect of PPARδ agonist GW501516 on catabolism of BCAAs and carboxylic acids in diabetic mice

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chinese Chemical Letters 2021年第7期32卷 2197-2202页

作者： Li Xiang Juan Nie Li Wang Yu Wang Jingchun Shi Juntong Wei Chi-Wai Lau Zongwei Cai Yu Huang Heart and vascular institute School of Biomedical Sciences and Shenzhen Research Institute.Chinese University of Hong KongHong KongChina State Key Laboratory of Environmental and Biological Analysis and Department of Chemistry Hong Kong Baptist UniversityHong KongChina

The peroxisome proliferator-activated receptor(PPARδ)agonists are reported to improve insulin sensitivity,reduce glucose levels,and alleviate dysfunctional lipid metabolism in animal models of type 2 diabetes ***,the underlying mechanisms remain incompletely *** plays an essential role in the biological *** of metabolic changes in response to disease conditions or drug treatment is critical for better understanding of the pathophysiological *** this study,metabolic profiling analysis by gas chromatography-mass spectrometry integrated with targeted analysis by liquid chro matography-mass spectrometry was carried out in plasma samples of db/db diabetic mice after six-week treatment of PPARδagonist ***501516 treatment significantly altered levels of metabolites,such as branched-chain amino acids(BCAAs),BCAA metabolites(3-hydroxyisobutyric acid and 3-hydroxyisovaleric acid),long-chain fatty acids,uric acid and ketone bodies(3-hydroxybutyric acid and 2-hydroxybutyric acid)which are all associated with the impaired systemic insulin *** pre sent results indicate the beneficial effect of PPARδagonist in alleviating insulin resistance of diabetic mice by favorably modulating metabolic profile,thus providing valuable information in understanding the therapeutic potential of PPARδagonists in correcting metabolic dysfunction in diabetes.

关键词： PPARδ BCAAs BCAA metabolites Metabolomics Diabetic mice

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Facile and rapid fabrication of a novel 3D-printable,visible light-crosslinkable and bioactive polythiourethane for large-to-massive rotator cuff tendon repair

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Bioactive Materials 2024年第7期37卷 439-458页

作者： Xu Zhang Ke Li Chenyang Wang Ying Rao Rocky STuan Dan Michelle Wang Dai Fei Elmer Ker institute for Tissue Engineering and Regenerative medicine The Chinese University of Hong KongNew TerritoriesHong Kong SARChina school of biomedical sciences Faculty of MedicineThe Chinese University of Hong KongNew TerritoriesHong Kong SARChina Center for Neuromusculoskeletal Restorative medicine Hong Kong Science ParkHong Kong SARChina Ministry of Education Key Laboratory for Regenerative medicine School of Biomedical SciencesFaculty of MedicineThe Chinese University of Hong KongNew TerritoriesHong Kong SARChina Department of Orthopaedics and Traumatology Faculty of MedicineThe Chinese University of Hong KongNew TerritoriesHong Kong SARChina

Facile and rapid 3D fabrication of strong,bioactive materials can address challenges that impede repair of large-to-massive rotator cuff tears including personalized grafts,limited mechanical support,and inadequate tissue ***,we developed a facile and rapid methodology that generates visible light-crosslinkable polythiourethane(PHT)pre-polymer resin(~30 min at room temperature),yielding 3D-printable scaffolds with tendon-like mechanical attributes capable of delivering tenogenic bioactive *** vivo characterization confirmed successful fabrication,robust human supraspinatus tendon(SST)-like tensile properties(strength:23 MPa,modulus:459 MPa,at least 10,000 physiological loading cycles without failure),excellent suture retention(8.62-fold lower than acellular dermal matrix(ADM)-based clinical graft),slow degradation,and controlled release of fibroblast growth factor-2(FGF-2)and transforming growth factor-β3(TGF-β3).In vitro studies showed cytocompatibility and growth factor-mediated tenogenic-like differentiation of mesenchymal stem *** vivo studies demonstrated biocompatibility(3-week mouse subcutaneous implantation)and ability of growth factor-containing scaffolds to notably regenerate at least 1-cm of tendon with native-like biomechanical attributes as uninjured shoulder(8-week,large-to-massive 1-cm gap rabbit rotator cuff injury).This study demonstrates use of a 3D-printable,strong,and bioactive material to provide mechanical support and pro-regenerative cues for challenging injuries such as large-to-massive rotator cuff tears.

关键词： Photo-crosslinkable biomaterials Polyurethane Click reactions 3D-printing Growth factors Rotator cuff tendon tissue engineering

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“Slow walk”mimetic tensile loading maintains human meniscus tissue resident progenitor cells homeostasis in photocrosslinked gelatin hydrogel

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Bioactive Materials 2023年第7期25卷 256-272页

作者： Jing Sun Yau Tsz Chan Ki Wai Kevin Ho Li Zhang Liming Bian Rocky S.Tuan Yangzi Jiang institute for Tissue Engineering and Regenerative medicine School of Biomedical SciencesFaculty of MedicineThe Chinese University of Hong KongShatinHong Kong Special Administrative Region of China school of biomedical sciences Faculty of MedicineThe Chinese University of Hong KongShatinHong Kong Special Administrative Region of China Department of Orthopaedics&Traumatology Faculty of MedicineThe Chinese University of Hong KongAnd Prince of Wales HospitalShatinHong Kong Special Administrative Region of China Department of Mechanical and Automation Engineering Faculty of EngineeringThe Chinese University of Hong KongShatinHong Kong Special Administrative Region of China Department of biomedical Engineering Faculty of EngineeringThe Chinese University of Hong KongShatinHong Kong Special Administrative Region of China Center for Neuromusculoskeletal Restorative medicine Hong Kong Special Administrative Region of China

Meniscus,the cushion in knee joint,is a load-bearing tissue that transfers mechanical forces to extracellular matrix(ECM)and tissue resident *** mechanoresponse of human tissue resident stem/progenitor cells in meniscus(hMeSPCs)is significant to tissue homeostasis and regeneration but is not well *** study reports that a mild cyclic tensile loading regimen of~1800 loads/day on hMeSPCs seeded in 3-dimensional(3D)photocrosslinked gelatin methacryloyl(GelMA)hydrogel is critical in maintaining cellular ***,a“slow walk”biomimetic cyclic loading regimen(10%tensile strain,0.5 Hz,1 h/day,up to 15 days)is applied to hMeSPCs encapsulated in GelMA hydrogel with a magnetic force-controlled loading *** loading significantly increases cell differentiation and fibrocartilage-like ECM deposition without affecting cell *** analysis reveals 332 mechanoresponsive genes,clustered into cell senescence,mechanical sensitivity,and ECM dynamics,associated with interleukins,integrins,and collagens/matrix metalloproteinase *** cell-GelMA constructs show active ECM remodeling,traced using a green fluorescence tagged(GFT)-GelMA *** enhances nascent pericellular matrix production by the encapsulated hMeSPCs,which gradually compensates for the hydrogel loss in the *** findings demonstrate the strong tissue-forming ability of hMeSPCs,and the importance of mechanical factors in maintaining meniscus homeostasis.

关键词： Human meniscus progenitor cells 3D cell-based constructs Biomimetic cyclic loading GelMA hydrogel Extracellular matrix

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Would integrated Western and traditional chinese medicine have more benefits for stroke rehabilitation? A systematic review and meta-analysis

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Stroke & vascular Neurology 2022年第1期7卷 77-85页

作者： Linda LD Zhong Ya Zheng Alexander Y Lau Norman Wong Liang Yao Xingyao Wu Tengteng Shao Zhenxing Lu Huijuan Li Chun Sum Yuen Jianwen Guo Suzanne Lo Janita Chau Kam Wa Chan Bacon Fung Leung Ng Zhaoxiang Bian Edwin Chau-leung Yu hong kong chinese medicine Clinical Study Centre School of Chinese MedicineHong Kong Baptist UniversityHong Kong SARChina Department of medicine and Therapeutics and hong kong institute of Integrative medicine Prince of Wales HospitalFaculty of MedicineThe Chinese University of Hong KongHong Kong SARChina Department of Health Research Methods Evidence and ImpactMcMaster UniversityHamiltonOntarioCanada Clinical Laboratory Shanghai Traditional Chinese Medicine Integrated Institute of Vascular AbnomaliesShanghaiChina institute of Medical Research Northwestern Polytechnical UniversityXi'anShanxiChina Evidence Based medicine Center School of Basic Medical SciencesLanzhou UniversityLanzhouChina school of chinese medicine Hong Kong Baptist UniversityHong Kong SARChina Brain Center Guangdong Procincial Hospital of Traditional Chinese MedicineGuangdong University of Chinese MedicineGuangzhouChina The Nethersole school of Nuring Faculty of Medicinethe Chinese University of Hong KongHong Kong SARChina Department of medicine Li Ka Shing Faculty of Medicinethe University of Hong KongHong Kong SARChina Department of Rehabilitation sciences Hong Kong Polytechnic UniversityHong Kong SARChina hong kong Association for Integration of chinese-Western medicine Limited Hong Kong SARChina

Background Stroke is a major cause of death or long-term disability *** patients with stroke receive integrative therapy consisting of Western medicine(WM)and routine rehabilitation in conjunction with chinese medicine(CM),such as acupuncture and chinese herbal ***,there is no available evidence on the effectiveness of the combined use of WM and CM interventions in stroke *** The purpose of this meta-analysis is to evaluate the results of all individual studies to assess the combined use of CM and WM in stroke rehabilitation compared with WM *** The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were ***,EMBASE,Cochrane and China National Knowledge Infrastructure(CNKI)were *** included outcomes were dependency,motor function,depression and swallowing *** analysis was performed,and publication bias was assessed using funnel *** of review 58 studies and 6339 patients were included in the *** analysis revealed that combined therapy comprising both acupuncture and WM had a superior effect on improving dependency and swallowing function compared with standard WM therapy *** superiority of combined therapy comprising CM and WM in improving depression compared with standard WM therapy was also *** Our results indicate that the combined use of CM and WM could be more efficacious in stroke rehabilitation compared with the use of WM therapy ***,most studies were short in duration(2 to 4 weeks)and prone to different types of biases,which prevents making any conclusion regarding the long-term effects and raises concerns regarding true efficacy in context of high likelihood of Hawthorn ***,more randomised controlled trials with more rigorous design and longer duration of treatment and follow-up need to be conducted to compare WM alone versus WM and CM combined.

关键词： acupuncture routine alone

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Meteorin-β/Meteorin like/IL-41 attenuates airway inflammation in house dust mite-induced allergic asthma

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Cellular & Molecular Immunology 2022年第2期19卷 245-259页

作者： Xun Gao Ting-Fan Leung Gary Wing-Kin Wong Wing-Hung Ko Mengyun Cai Ellie Jiayi He Ida Miu-Ting Chu Miranda Sin-Man Tsang Ben Chung-Lap Chan Jiawei Ling Xiao Fan Liwei Lu Christopher Wai-Kei Lam Chun-Kwok Wong Department of Chemical Pathology The Chinese University of Hong KongHong KongChina Department of Paediatrics The Chinese University of Hong KongHong KongChina school of biomedical sciences The Chinese University of Hong KongHong KongChina Emory College of Arts and sciences Emory UniversityAtlantaGAUSA institute of chinese medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants The Chinese University of Hong KongHong KongChina Department of Pathology and Shenzhen institute of Research and Innovation The University of Hong KongHong KongChina Faculty of medicine and State Key Laboratory of Quality Research in chinese medicines Macao University of Science and TechnologyMacaoChina Li Dak Sum Yip Yio Chin R&D Centre for chinese medicine The Chinese University of Hong KongHong KongChina

We sought to examine the regulatory effect of Meteorin-β(Metrnβ)/Meteorin like(Metrnl)/IL-41 on lung inflammation in allergic *** found that Metrnβwas elevated significantly in asthmatic patients and in mice with allergic asthma induced by house dust mite(HDM)*** exposure to HDM,Metrnβwas secreted predominantly by airway epithelial cells and inflammatory cells,including macrophages and *** increased Metrnβeffectively blocked the development of airway hyperreactivity(AHR)and decreased inflammatory cell airway infiltration and type 2 cytokine production,which was associated with downregulated DC-mediated adaptive immune ***,Metrnβimpaired the maturation and function of bone marrow-derived dendritic cells in *** mice adoptively transferred with dendritic cells isolated from Metrnβ-treated allergic mice displayed decreased AHR,airway inflammation,and lung ***βalso displayed anti-inflammatory properties in immunodeficient SCID mice with allergic asthma and in in vitro 3D ALI airway ***,blockade of Metrnβby anti-Metrnβantibody treatment promoted the development of allergic *** results revealed the unappreciated protective roles of Metrnβin alleviating DC-mediated Th2 inflammation in allergic asthma,providing the novel treatment strategy of therapeutic targeting of Metrnβin allergic asthma.

关键词： Metrnβ Eosinophils Dendritic cells Allergic asthma Air-liquid interface

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