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LKB1 depletion-mediated epithelial-mesenchymal transition induces fibroblast activation in lung fibrosis

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Genes & Diseases 2024年第3期11卷 417-426页

作者： Zijian Xu Elizabeth R.Davies Liudi Yao Yilu Zhou Juanjuan Li Aiman Alzetani Ben G.Marshall David Hancock Tim Wallis Julian Downward Rob M.Ewing Donna E.Davies Mark G.Jones Yihua Wang Biological Sciences Faculty of Environmental and Life SciencesUniversity of SouthamptonSouthampton SO171BJUK clinical and Experimental Sciences Faculty of MedicineUniversity of SouthamptonSouthampton SO166YDUK Institute for Life Sciences University of SouthamptonSouthampton SO171BJUK nihr Southampton Biomedical Research Centre University Hospital SouthamptonSouthampton SO166YDUK University Hospital Southampton Southampton SO166YDUK Oncogene Biology The Francis Crick InstituteLondon NW11ATUK

The factors that determine fibrosis progression or normal tissue repair are largely *** previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition(EMT)in human alveolar epithelial type Il(ATIl)cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine ***,we report that liver kinase B1(LKB1)inactivation in ATIl cells inhibits autophagy and induces EMT as a *** IPF lungs,this is caused by the down-regulation of CAB39L,a key subunit within the LKB1 complex.3D co-cultures of ATIl cells and MRC5 lung fibroblasts coupled with RNA sequencing(RNA-seq)confirmed that paracrine signaling between LKB1-depleted ATIl cells and fibroblasts augmented myofibroblast ***,these data suggest that reduced autophagy caused by LKB1 inhibition can induce EMT in ATIl cells and contribute to fibrosis via aberrant epithelial-fibroblast crosstalk.

关键词： CAB39L Crosstalk EMT LKB1 Pulmonary fibrosis

“机械灌注+”应用于扩大标准供肝移植--肝尽其用

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Engineering 2024年第1期32卷 29-40页

作者： Zhoucheng Wang Jack Martin Jiongjie Yu Kai Wang Kourosh Saeb-Parsy Xiao Xu Zhejiang University School of Medicine Hangzhou 310058China Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province Hangzhou 310006China Department of Surgery Cambridge University Hospitals&NHS Foundation TrustCambridge CB22QQ UK Department of Surgery University of Cambridge&NIHR Cambridge Biomedical Research CentreCambridge CB22QQUK Institute of Organ Transplantation Zhejiang UniversityHangzhou 310003China

Transplantation represents the most effective treatment for end-stage liver diseases but is limited by the shortage of healthy donor *** criteria donor(ECD)liver grafts are increasingly utilized in clinical practice to mitigate this ***,impaired ischemic tolerance of these grafts jeopardizes organ viability during cold *** perfusion(MP)was designed to improve organ preservation and reduce posttransplant ***,it is increasingly evident that MP alone may not preserve ECD grafts *** emphasis has thus been placed on modified MP strategies,including the use of different perfusates,modified perfusion modalities,and different therapeutic ***,we introduce a novel term,"MP Plus,"denoting these additional strategies that are designed to restore organ function and potentially enable regeneration of ECD *** this review,we summarize the existing and potential modified MP strategies and discuss their advantages in reconditioning different ECD grafts in clinical settings.

关键词： Liver transplantation Extended criteria donor Machine perfusion plus Organ shortage

British Journal of General Practice论文摘要汇编——精神疾病患者使用急诊服务和全科医生服务预测因素的公共卫生调查

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中国全科医学 2020年第9期23卷 1180-1180页

作者： SAINI P MCINTYRE J CORCORAN R 本刊编辑部(整理) School of Psychology Faculty of Health Liverpool John Moores University Liverpool. Institute of Population Health Sciences University of Liverpool Liverpool. Institute of Population Health Sciences University of Liverpool NIHR ARC NWC Liverpool. nihr arc nwc Liverpool. Cheshire and Wirral NHS Foundation Trust Liverpool. Institute of Public Health Sciences University of Liverpool NIHR ARC NW Liverpool.

【摘要】背景在英国,当前一个重要的问题是人们对卫生服务呈现大量需求,部分体现在精神疾病患者对急诊服务和全科医疗服务的使用率快速增加,而且这些服务的费用不菲。目的探讨精神疾病患者使用卫生服务的社会决定因素。设计与场所本研... 详细信息

【摘要】背景在英国,当前一个重要的问题是人们对卫生服务呈现大量需求,部分体现在精神疾病患者对急诊服务和全科医疗服务的使用率快速增加,而且这些服务的费用不菲。目的探讨精神疾病患者使用卫生服务的社会决定因素。设计与场所本研究在位于英国西北海岸的28个社区开展。每个社区拥有5000~10000例不同贫困程度的人口。方法对研究人群进行全面的公共卫生调查,涉及住房、身体健康、心理健康、生活方式、社会问题、环境、工作和经济等问题。在调整相关社会经济和生活方式因素之后,采用泊松回归模型对精神疾病共病、身体和精神疾病共病和个体心理健康症状对急诊服务和全科医疗服务应用的影响进行分析。

关键词：精神疾病患者卫生服务全科医疗服务全科医生社会决定因素急诊服务公共卫生预测因素

Metabolic reprogramming by Syntenin-1 directs RA FLS and endothelial cell-mediated inflammation and angiogenesis

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Cellular & Molecular Immunology 2024年第1期21卷 33-46页

作者： Anja Meyer Stephanie R.Zack Wes Nijim Adel Burgos Vishwa Patel Brian Zanotti Michael V.Volin M.Asif Amin Myles J.Lewis Costantino Pitzalis Shiva Arami Joseph A.Karam Nadera J.Sweiss Shiva Shahrara Jesse Brown VA Medical Center ChicagoILUSA Department of Medicine Division of RheumatologyThe University of Illinois at ChicagoChicagoILUSA Department of Microbiology and Immunology Midwestern UniversityDowners GroveILUSA Division of Rheumatology and Clinical Autoimmunity Center of Excellence University of MichiganAnn ArborMIUSA Centre for Experimental Medicine and Rheumatology William Harvey Research InstituteBarts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUnited Kingdom Centre for Experimental Medicine&Rheumatology William Harvey Research InstituteQueen Mary University of London and Barts NIHR BRC&NHS TrustLondonUK Department of Biomedical Sciences Humanitas Universityand Humanitas Research HospitalMilanItaly Department of Orthopedic Surgery the University of Illinois at ChicagoChicagoILUSA

A novel rheumatoid arthritis(RA)synovial fluid protein,Syntenin-1,and its receptor,Syndecan-1(SDC-1),are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes(FLS).Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9,IL-1β,IL-6,and CCL2 through SDC-1 ligation and HIF1α,or mTOR ***,Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR *** Syntenin-1 reprogrammed endothelial cells,the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors,AMPK,PGC-1α,citrate,and inactive oxidative ***,RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP *** enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 *** found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS,which are also represented in RA *** to RA explants,morphological and transcriptome studies authenticated the importance of VEGFR1/2,Notch1,RAPTOR,and HIF1αpathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient ***,dysregulation of SDC-1,mTOR,and HIF1αnegated Syntenin-1 inflammatory phenotype in RA explants,while inhibition of HIF1αimpaired synovial angiogenic imprint amplified by *** conclusion,since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood,targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy.

关键词： Syntenin-1 Syndecan-1 RA FLS RA explants immunometabolism

Hepatic expression and cellular distribution of the glucose transporter family

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World Journal of Gastroenterology 2012年第46期18卷 6771-6781页

作者： Sumera Karim David H Adams Patricia F Lalor Centre for Liver Research and nihr Biomedical Research Unit Institute of Biomedical Research University of Birmingham

Glucose and other carbohydrates are transported into cells using members of a family of integral membrane glucose transporter (GLUT) molecules. To date 14 members of this family, also called the solute carrier 2A proteins have been identified which are divided on the basis of transport characteristics and sequence similarities into several families (Classes 1 to 3). The expression of these different receptor subtypes varies between different species, tissues and cellular subtypes and each has differential sensitivities to stimuli such as insulin. The liver is a contributor to metabolic carbohydrate homeostasis and is a major site for synthesis, storage and redistribution of carbohydrates. Situations in which the balance of glucose homeostasis is upset such as diabetes or the metabolic syndrome can lead metabolic disturbances that drive chronic organ damage and failure, confirming the importance of understanding the molecular regulation of hepatic glucose homeostasis. There is a considerable literature describing the expression and function of receptors that regulate glucose uptake and release by hepatocytes, the most import cells in glucose regulation and glycogen storage. However there is less appreciation of the roles of GLUTs expressed by non parenchymal cell types within the liver, all of which require carbohydrate to function. A better understanding of the detailed cellular distribution of GLUTs in human liver tissue may shed light on mechanisms underlying disease pathogenesis. This review summarises the available literature on hepatocellular expression of GLUTs in health and disease and highlights areas where further investigation is required.

关键词： Hepatic Liver Glucose transporters Glucose Transport Hepatocyte

Era of Barrett’s surveillance: Does equipment matter?

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World Journal of Gastroenterology 2010年第37期16卷 4640-4645页

作者： Jayan Mannath Krish Ragunath Nottingham Digestive Diseases Centre and nihr Biomedical Research Unit Nottingham University Hospitals NHS Trust

Barrett’s esophagus is a consequence of long standing gastro-esophageal reflux disease and predisposes to the development of esophageal adenocarcinoma. Regular surveillance endoscopies can detect curable early neoplasia in asymptomatic patients, which in turn could improve the prognosis compared to symptomatic cancer. Early neoplastic lesions, which are amenable for local therapy, could be treated endoscopically, avoiding a major surgery. However, in the absence of obvious mucosal lesions, random four quadrant biopsies are done, which is associated with significant sampling error. Newer imaging modalities, such as autofluorescence endoscopy, are helpful in detecting subtle lesions that could be examined in detail with narrow band imaging to characterize and target biopsies. This has the potential benefit of reducing the number of random biopsies with a better yield of dysplasia. Confocal endomicroscopy provides "optical biopsies" and is a valuable tool in targeting biopsies to improve dysplasia detection; however, this is technically challenging. Fuji intelligent chromoendoscopy and I-Scan are recent additions to the imaging armamentarium that have produced notable early results. While all these additional new imaging techniques are promising, a thorough examination by high resolution white light endoscopy after clearing the mucosa with mucolytics should be the minimum standard to improve dysplasia detection during Barrett’s surveillance.

关键词： Barrett’s esophagus Endoscopy Autofluorescence imaging Narrowband imaging Early diagnosis of cancer

Dysregulated bidirectional epithelial-mesenchymal crosstalk:A core determinant of lung fibrosis progression

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Chinese Medical Journal Pulmonary and Critical Care Medicine 2024年第1期2卷 27-33页

作者： Liudi Yao Zijian Xu Donna E.Davies Mark G.Jones Yihua Wang Biological Sciences Faculty of Environmental and Life SciencesUniversity of SouthamptonSouthampton SO171BJUK Clinical and Experimental Sciences Faculty of MedicineUniversity of SouthamptonSouthampton SO166YDUK Institute for Life Sciences University of SouthamptonSouthampton SO171BJUK nihr Southampton Biomedical Research Centre University Hospital SouthamptonSouthampton SO166YDUK

Progressive lung fibrosis is characterized by dysregulated extracellular matrix(ECM)***-ing of disease pathogenesis remains limited and has prevented the development of effective *** an abnormal wound-healing response is strongly implicated in lung fibrosis initiation,factors that determine why fi-brosis progresses rather than regular tissue repair occur are not fully *** human lung fibrosis,there is evidence of altered epithelial and mesenchymal populations as well as cells undergoing epithelial-mesenchymal transition(EMT),a dynamic and reversible biological process by which epithelial cells lose their cell polarity and down-regulate cadherin-mediated cell-cell adhesion to gain migratory *** review will focus on the role of EMT and dysregulated epithelial-mesenchymal crosstalk in progressive lung fibrosis.

关键词： Lung fibrosis Epithelial-mesenchymal transition(EMT) Crosstalk

Portal hypertension in polycystic liver disease patients does not affect wait-list or immediate post-liver transplantation outcomes

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World Journal of Gastroenterology 2016年第45期22卷 9966-9973页

作者： Neil Rajoriya Dhiraj Tripathi Joanna A Leithead Bridget K Gunson Sophie Lord James W Ferguson Gideon M Hirschfield Liver Unit Queen Elizabeth Hospital Centre for Liver Research NIHR Birmingham Liver Biomedical Research Unit University of Birmingham

AIM To establish the impact of portal hypertension(PH) on wait-list/post-transplant outcomes in patients with polycystic liver disease(PCLD) listed for liver transplantation. METHODS A retrospective single-centre case controlled study of consecutive patients listed for liver transplantation over 12 years was performed from our centre. PH in the PCLD cohort was defined by the one or more of following parameters:(1) presence of radiological or endoscopic documented varices from our own centre or the referral centre;(2) splenomegaly(> 11 cm) on radiology inabsence of splenic cysts accounting for increased imaging size;(3) thrombocytopenia(platelets < 150 × 109/L); or(4) ascites without radiological evidence of hepatic venous outflow obstruction from a single cyst. RESULTS Forty-seven PCLD patients(F: M = 42: 5) were listed for liver transplantation(LT)(single organ, n = 35; combined liver-kidney transplantation, n = 12) with 19 patients(40.4%) having PH. When comparing the PH group with non-PH group, the mean listing age(PH group, 50.6(6.4); non-PH group, 47.1(7.4) years; P = 0.101), median listing MELD(PH group, 12; non-PH group, 11; P = 0.422) median listing UKELD score(PH group, 48; non-PH group, 46; P = 0.344) and need for renal replacement therapy(P = 0.317) were similar. In the patients who underwent LT alone, there was no difference in the duration of ICU stay(PH, 3 d; non-PH, 2 d; P = 0.188), hospital stay length(PH, 9 d; non-PH, 10 d; P = 0.973), or frequency of renal replacement therapy(PH, 2/8; non-PH, 1/14; P = 0.121) in the immediate post-transplantation period. CONCLUSION Clinically apparent portal hypertension in patients with PCLD listed for liver transplantation does not appear to have a major impact on wait-list or peri-transplant morbidity.

关键词： Polycystic liver disease Portal hypertension Liver transplantation

Barriers and Facilitators to Implementation of Digital Solutions

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Health 2021年第11期13卷 1330-1345页

作者： Elaine Bidmead Catherine McShane nihr arc NENC and Centre for Research in Health and Society Institute of Health University of Cumbria Carlisle Cumbria County Durham and Darlington NHS Foundation Trust Darlington Memorial Hospital Darlington UK

Intro/background: The NHS Long term plan calls for “digital-first” solutions, however, many good innovations fail. Barriers to digital innovation in healthcare are well-rehearsed and often predictable. This paper aims to highlight issues to be considered in implementation. Methods: It is a qualitative study of experiences of telehealth implementation. Findings: Staff engagement is crucial to acceptance;compatibility with existing practises helps but where impossible, pathway redesign is necessary. There is a notion that staff of any grade can become digital champions, yet the role is challenging for staff without power. Funding systems can restrict adoption due to associated savings impacting elsewhere in the system. Organisational support for innovation is often apparent but does not trickle down to service level sufficiently. Conclusions: Senior management needs to lead on and support at a micro level the implementation of digitally enabled health care. Funders and commissioners need to recognise that innovation takes time and that measured approaches are more successful.

关键词： Telehealth Telemonitoring Digital Health Digital Health Adoption Qualitative Research