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Role of the forkhead transcription factor fOXO-fOXM1 axis in cancer and drug resistance

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frontiers of Medicine 2012年第4期6卷 376-380页

作者： fung Zhao eric w.-f.lam Department of Surgery and Cancer Imperial College LondonHammersmith Hospital CampusLondon W120NNUK

The forkhead transcription factors fOXO and fOXM1 have pivotal roles in tumorigenesis and in mediating chemotherapy sensitivity and *** research shows that the forkhead transcription factor fOXM1 is a direct transcriptional target repressed by the forkhead protein fOXO3a,a vital downstream effector of the PI3K-AKT-fOXO signaling ***,fOXM1 and fOXO3a also compete for binding to the same gene targets,which have a role in chemotherapeutic drug action and *** understanding of the role and regulation of the fOXO-fOXM1 axis will impact directly on our knowledge of chemotherapeutic drug action and resistance in patients,and provide new insights into the design of novel therapeutic strategy and reliable biomarkers for prediction of drug sensitivity.

关键词： fOXO3a fOXM1 transcription factor cancer drug resistance tumorigenesis

CRISPR/Cas9 screening identifies a kinetochore-microtubule dependent mechanism for Aurora-A inhibitor resistance in breast cancer

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Cancer Communications 2021年第2期41卷 121-139页

作者： Ailin Chen Shijun wen fang Liu Zijian Zhang Meiling Liu Yuanzhong wu Bin He Min Yan Tiebang Kang eric w-f lam Zifeng wang Quentin Liu Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhouGuangdong 510060P.R.China Institute of Cancer Stem Cell Dalian Medical UniversityDalianLiaoning 116044P.R.China Department of Surgery and Cancer Imperial College LondonW120NNLondonUK

Background:Overexpression of Aurora-A(AURKA)is a feature of breast cancer and associates with adverse *** selective Aurora-A inhibitor alisertib(MLN8237)has recently demonstrated promising antitumor responses as a single agent in various cancer types but its phase III clinical trial was reported as a failure since MLN8237 did not show an apparent effect in prolonging the survival of ***,identification of potential targets that could enhance the activity of MLN8237 would provide a rationale for drug combination to achieve better therapeutic ***:Here,we conducted a systematic synthetic lethality CRISPR/Cas9 screening of 507 kinases using MLN8237 in breast cancer cells and identified a number of targetable kinases that displayed synthetic lethality interactions with ***,we performed competitive growth assays,colony formation assays,cell viability assays,apoptosis assays,and xenograft murine model to evaluate the synergistic therapeutic effects of Haspin(GSG2)depletion or inhibition with *** mechanistic studies,immunofluorescence was used to detect the state of microtubules and the localization of Aurora-B and mitotic centromere-associated kinesin(MCAK).Results:Among the hits,we observed that Haspin depletion or inhibition marginally inhibited breast cancer cell growth but could substantially enhance the killing effects of *** studies showed that co-treatment with Aurora-A and Haspin inhibitors abolished the recruitment of Aurora-B and mitotic centromere-associated kinesin(MCAK)to centromeres which were associated with excessive microtubule depolymerization,kinetochore-microtubule(KT-MT)attachment failure,and severe mitotic *** further showed that the combination of MLN8237 and the Haspin inhibitor CHR-6494 synergistically reduced breast cancer cell viability and significantly inhibited both in vitro and in vivo tumor ***:These findings establish Haspin as a synthetic lethal targe

关键词： alisertib Aurora-A breast cancer CHR-6494 CRISPR/Cas9 screening haspin kinetochoremicrotubule mitotic centromere-associated kinesin synthetic lethal xenograft

Endohepatology:Arrival at the frontier of interventional endosonography

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world Journal of Gastroenterology 2024年第18期30卷 2397-2401页

作者： Shane P Selvanderan eric lam Neal Shahidi Department of Medicine University of British ColumbiaVancouver V6Z 1Y6BCCanada

Endohepatology describes the emerging field where diagnostic and therapeutic endoscopic ultrasound(EUS)are used for the diagnosis and management of liver disease and its *** this editorial we comment on the article by Gadour et *** spectrum of EUS-guided procedures includes liver parenchymal and lesional biopsy,abscess drainage,treatment of focal liver lesions,diagnosis of portal hypertension and management of gastric *** data suggest that the application of EUS to hepatology is technically feasible and safe,heralding the arrival at a new frontier for *** data,specifically randomised trials comparing EUS to interventional radiology techniques,and continued partnership between endoscopy and hepatology are required to see this field establish itself outside expert tertiary centres.

关键词： Cancer Cirrhosis Endoscopy Endoscopic ultrasound Liver disease

Cancer cell employs a microenvironmental neural signal transactivating nucleus-mitochondria coordination to acquire stemness

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Signal Transduction and Targeted Therapy 2023年第8期8卷 3818-3836页

作者： Bin He Rui Gao Shasha Lv Ailin Chen Junxiu Huang Luoxuan wang Yunxiu feng Jiesi feng Bing Liu Jie Lei Bing Deng Bin He Bai Cui fei Peng Min Yan Zifeng wang eric w-f lam Bilian Jin Zhiming Shao Yulong Li Jianwei Jiao Xi wang Quentin Liu State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer CenterGuangzhou 510060PR China Department of Medical Oncology The Seventh Affiliated HospitalSun Yat-sen UniversityShenzhen 510275PR China Institute of Cancer Stem Cell Cancer CenterDalian Medical UniversityDalian 116023PR China Zhongshan School of Medicine Sun Yat-sen UniversityGuangzhou 510080PR China State Key Laboratory of Membrane Biology Peking University School of Life SciencesBeijing 100871PR China Department of Surgery and Cancer Imperial College LondonLondon W120NNUK Department of Breast Surgery Precision Cancer Medicine CenterFudan University Shanghai Cancer CenterShanghai 200032PR China State Key Laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101PR China

Cancer cell receives extracellular signal inputs to obtain a stem-like status,yet how tumor microenvironmental(TME)neural signals steer cancer stemness to establish the hierarchical tumor architectures remains ***,a pan-cancer transcriptomic screening for 10852 samples of 33 TCGA cancer types reveals that cAMP-responsive element(CRE)transcription factors are convergent activators for cancer *** of transcriptomic profiles,specification of neural markers and illustration of norepinephrine dynamics uncover a bond between TME neural signals and cancer-cell CRE ***,neural signal norepinephrine potentiates the stemness of proximal cancer cells by activating cAMP-CRE axis,where ATf1 serves as a conserved *** activation by norepinephrine,ATf1 potentiates cancer stemness by coordinated trans-activation of both nuclear pluripotency factors MYC/NANOG and mitochondrial biogenesis regulators NRf1/TfAM,thereby orchestrating nuclear reprograming and mitochondrial ***,single-cell transcriptomes confirm the coordinated activation of nuclear pluripotency with mitochondrial biogenesis in cancer stem-like *** findings elucidate that cancer cell acquires stemness via a norepinephrine-ATf1 driven nucleus-mitochondria collaborated program,suggesting a spatialized stemness acquisition by hijacking microenvironmental neural signals.

关键词： Cancer neural architectures

Effects of length alteration of OPE-containing mono- and dinuclear alkynylplatinum(II) terpyridine complexes on photophysical, structural and morphological properties

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Nano Research 2024年第10期17卷 8893-8903页

作者： Jason Koon-lam Poon Sammual Yu-Lut Leung eric Ka-Ho wong Vivian wing-wah Yam Institute of Molecular functional Materials State Key Laboratory of Synthetic Chemistry and Department of ChemistryThe University of Hong KongHong Kong 999077China

A series of mononuclear complexes and unsymmetric dinuclear alkynylplatinum(II)terpyridine complexes with oligo(paraphenylene ethynylene)(OPE)-derived backbone with a variation of the lengths of alkoxy chains and OPE backbones was *** morphological properties,packing lattice and gelation behaviors of the mononuclear complexes were systematically studied,and the thermodynamic parameters and packing lattices of the dinuclear complexes were also investigated,providing further insights into the roles of the non-covalent interactions and their delicate balance in constructing sophisticated supramolecular *** and nanotube formation have been observed upon a delicate control of the intermolecular interactions by altering the lengths and structural dimensions of the complexes.

关键词： supramolecular chemistry self-assembled nanostructures platinum(II)complexes metallogel

Targeting cancer cell plasticity by HDAC inhibition to reverse EBV-induced dedifferentiation in nasopharyngeal carcinoma

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Signal Transduction and Targeted Therapy 2021年第10期6卷 3045-3061页

作者： Jiajun Xie Zifeng wang wenjun fan Youping Liu fang Liu Xiangbo wan Meiling Liu Xuan wang Deshun Zeng Van wang Bin He Min Yan Zijian Zhang Mengjuan Zhang Zhijie Hou Chunli wang Zhijie Kang wenfeng fang Li Zhang eric w-f lam Xiang Guo Jinsong Yan Yixin Zeng Mingyuan Chen Quentin Liu Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and TherapyGuangzhouChina Institute of Cancer Stem Cell Cancer CenterDalian Medical UniversityDalianChina Department of Hematology Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational MedicineLiaoning Medical Center for Hematopoietic Stem Cell TransplantationDalian Key Laboratory of HematologyDiamond Bay Institute of HematologyThe Affiliated Second Hospital of Dalian Medical UniversityDalianChina Department of Radiation Oncology The Sixth Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina Sun Yat-sen Institute of Hematology The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina

Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been *** carci noma(NPC)is a distinctive cancer with poor differe ntiatio n and high prevalenee of Epstein-Barr virus(EBV)***,we show that the expressi on of EBV latent protein LMP1 in duces dediffere ntiated and stem-like status with high plasticity through the transcriptional inhibition of ***,LMP1 upregulates STAT5A and recruits HDAC 1/2 to the CEBPA locus to reduce its histone *** inhibition restored CEBPA expression,reversing cellular dedifferentiation and stem-like status in mouse xeno graft *** fin dings provide a novel mecha nistic epigenetic-based in sight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.

关键词： LMP1 cancer plasticity

An automated multiwell plate reading flim microscope for live cell autofluorescence lifetime assays

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Journal of Innovative Optical Health Sciences 2014年第5期7卷 99-113页

作者： Douglas J.Kelly Sean C.warren Sunil Kumar Joao L.Lagarto Benjamin T.Dyer Anca Margineanu eric w.-f.lam Chris Dunsby Paul M.w.french Photonics Group Department of PhysicsImperial College London South Kensington CampusLondonSW72AZUK Institute of Chemical Biology Department of Chemistry Imperial College LondonSouth Kensington Campus LondonSWT 2AZUK National Heart&Lung Institute Imperial Centre for Eaperimental&Translational Medicine Du Cane Road LondonW12 ONNUK Department of Surgery and Cancer Imperial Cllege London Du Cane RoadLondonW12 ONNUK Centre for Histopathology Imperial College London Du Cane RoadLondonW120NNUK

fluorescence lifetime imaging(fLIM)is increasingly used to read out cellular autofluorescenceoriginating from the coenzyme NADH in the context of investigating cell metabolic *** here an automated multiwell plate reading fLIM microscope optimized for UV illumi-nation with the goal of extending high content fluorescence lifetime asays to readouts ofmetabolism,we demonstrate its application to automated cellular autofluorescence lifetime imaging and discuss the key practical issues associated with its *** particular,weillustrate its capability to read out the NADH-lifetime response of cells to metabolic modulators,thereby illustrating the potential of the instrument for cytotoxicity studies,assays for drugdiscovery and stratified medicine.

关键词： High content analysis fLIM NADH metabolism cisplatin.

Comparing 11 early warning scores and three shock indices in early sepsis prediction in the emergency department

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world Journal of Emergency Medicine 2024年第4期15卷 273-282页

作者： Rex Pui Kin lam Zonglin Dai eric Ho Yin Lau Carrie Yuen Ting Ip Ho Ching Chan Lingyun Zhao Tat ChiTsang Matthew Sik Hon Tsui Timothy Hudson Rainer Department of Emergency Medicine School of Clinical MedicineLi Ka Shing Faculty of Medicinethe University of Hong KongHong KongChina School of Public Health Li Ka Shing Faculty of Medicinethe University of Hong KongHong KongChina Accident and Emergency Department Queen Mary HospitalHong KongChina

BACKGROUND:This study aimed to evaluate the discriminatory performance of 11 vital sign-based early warning scores(EwSs)and three shock indices in early sepsis prediction in the emergency department(ED).METHODS:we performed a retrospective study on consecutive adult patients with an infection over 3 months in a public ED in Hong *** primary outcome was sepsis(Sepsis-3 definition)within 48 h of ED *** c-statistics and the DeLong test,we compared 11 EwSs,including the National Early warning Score 2(NEwS2),Modified Early warning Score,and worthing Physiological Scoring System(wPS),etc.,and three shock indices(the shock index[SI],modified shock index[MSI],and diastolic shock index[DSI]),with Systemic Inflammatory Response Syndrome(SIRS)and quick Sequential Organ failure Assessment(qSOfA)in predicting the primary outcome,intensive care unit admission,and mortality at different time ***:we analyzed 601 patients,of whom 166(27.6%)developed ***2 had the highest point estimate(area under the receiver operating characteristic curve[AUROC]0.75,95%CI 0.70-0.79)and was significantly better than SIRS,qSOfA,other EwSs and shock indices,except wPS,at predicting the primary ***,the pooled sensitivity and specificity of NEwS2≥5 for the prediction of sepsis were 0.45(95%CI 0.37-0.52)and 0.88(95%CI 0.85-0.91),*** discriminatory performance of all EwSs and shock indices declined when used to predict mortality at a more remote time ***:NEwS2 compared favorably with other EwSs and shock indices in early sepsis prediction but its low sensitivity at the usual cut-off point requires further modification for sepsis screening.

关键词： Sepsis Emergency department Clinical prediction rule Early warning score Shock index

Thermomechanical Modelling of Industrial Vessels that Contain Refractory Masonry Linings

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China's Refractories 2024年第3期33卷 1-8页

作者： Alain GASSER eric BLOND Thomas SAYET Univ.Orléans Univ.ToursINSA-CVLLaMé(EA 7494)Orléans 45072France

Some refractory linings that protect metallic vessels from the hot temperature of the products they contain are made of masonries with or without *** joints play an important role,reducing the stresses in the masonries during ***,the presence of these joints makes the behaviour of the masonry nonlinear and *** perform a thermomechanical simulation using a finite element method of an industrial vessel that contains hundreds or thousands of bricks and joints,microscopic models are not suitable due to the high computational time and the management of the behaviour of the joints(opening/closing)which affects the *** overcome these problems,it is proposed to replace the masonry by a homogeneous material that has a behaviour equivalent to the set of bricks and joints,using a periodic homogenization *** the joints can be closed or open,the equivalent material will have a different behaviour according to the joint ***,refractory materials have an elastic-viscoplastic behaviour at high ***,the equivalent material will have an orthotropic elastic-viscoplastic behaviour,requiring a nonlinear homogenisation *** overview of this approach developed at University of Orléans is presented with two industrial applications(blast-furnace and steel ladle).

关键词： thermomechanical simulation refractory masonry homogenization elastic-viscoplastic behaviour