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Breath Biopsy^(®) to Identify Exhaled Volatile Organic Compounds Biomarkers for liver Cirrhosis Detection

Journal of Clinical and Translational Hepatology 2023年第3期11卷 638-648页

作者： Giuseppe Ferrandino Giovanna De Palo Antonio Murgia Owen Birch Ahmed Tawfike Rob Smith Irene Debiram-Beecham Olga Gandelman Graham Kibble Anne Marie Lydon Alice Groves Agnieszka Smolinska Max Allsworth Billy Boyle Marc P.van der Schee Michael Allison Rebecca C.Fitzgerald Matthew Hoare Victoria K.Snowdon Owlstone Medical CambridgeUK Department of Oncology University of CambridgeHutchison/MRC Research CentreCambridgeUK Department of Pharmacology and Toxicology School for Nutrition and Translational Research in Metabo-lism(NUTRIM)Maastricht University Medical Centerthe Netherlands Department of Medicine University of CambridgeAddenbrooke’s HospitalCambridgeUK Addenbrookes Hepatology and liver Transplantation Unit Addenbrookes Hospi-talCambridgeUK mrc Cancer Unit Hutchison/MRC Research CentreUniversity of CambridgeCambridgeUK CRUK Cambridge Institute CambridgeUK

Background and Aims:The prevalence of chronic liver dis-ease in adults exceeds 30%in some countries and there is significant interest in developing tests and treatments to help control disease progression and reduce healthcare *** is a rich sampling matrix that offers non-invasive so-lutions suitable for early-stage detection and disease *** previously investigated targeted analysis of a single biomarker,here we investigated a multiparametric approach to breath testing that would provide more robust and reliable results for clinical ***:To identify can-didate biomarkers we compared 46 breath samples from cir-rhosis patients and 42 from *** and analysis used Breath Biopsy OMNI™,maximizing signal and contrast to background to provide high confidence biomarker detec-tion based upon gas chromatography mass spectrometry(GC-MS).Blank samples were also analyzed to provide de-tailed information on background volatile organic compounds(VOCs)***:A set of 29 breath VOCs differed significantly between cirrhosis and controls.A classification model based on these VOCs had an area under the curve(AUC)of 0.95±0.04 in cross-validated test *** seven best performing VOCs were sufficient to maximize classifica-tion performance.A subset of 11 VOCs was correlated with blood metrics of liver function(bilirubin,albumin,prothrom-bin time)and separated patients by cirrhosis severity using principal component ***:A set of seven VOCs consisting of previously reported and novel candidates show promise as a panel for liver disease detection and mon-itoring,showing correlation to disease severity and serum biomarkers at late stage.

关键词： Breath Biopsy Non-invasive Biomarker Cirrhosis liver function test.

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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

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Associations of PNPLA3 and LEP genetic polymorphisms with metabolic-associated fatty liver disease in Thai people living with human immunodeficiency virus

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World Journal of Hepatology 2024年第3期16卷 366-378页

作者： Kanuengnit Choochuay Punna Kunhapan Apichaya Puangpetch Sissades Tongsima Pornpen Srisawasdi Abhasnee Sobhonslidsuk Somnuek Sungkanuparph Mohitosh Biswas Chonlaphat Sukasem Program in Translational Medicine Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand School of Pharmacy Walailak UniversityNakhon Si Thammarat 80161Thailand Laboratory for Pharmacogenomics Division of Pharmacogenomics and Personalized MedicineSomdech Phra Debaratana Medical CenterDepartment of PathologyFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand Department of Medical Sciences Ministry of Public HealthNonthaburi 11000Thailand National Biobank of Thailand National Center for Genetic Engineering and BiotechnologyPathum Thani 12120Thailand Division of Clinical Chemistry Department of PathologyFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand Division of Gastroenterology and Hepatology Department of MedicineFaculty of Medicine Ramathibodi HospitalMahidol UniversityBangkok 10400Thailand Chakri Naruebodindra Medical Institute Faculty of Medicine Ramathibodi HospitalMahidol UniversitySamut Prakan 10540Thailand Department of Pharmacy University of RajshahiRajshahi 6205Bangladesh Pharmacogenomics Clinic Bumrungrad Genomic Medicine InstituteBumrungrad International HospitalBangkok 10110Thailand research and Development Laboratory Bumrungrad International HospitalBangkok 10110Thailand mrc centre for Drug Safety Science Department of Pharmacology and TherapeuticsInstitute of SystemsMolecular and Integrative BiologyUniversity of Liverpool Liverpool L693GLUnited Kingdom Faculty of Pharmaceutical Sciences Burapha UniversityChonburi 20131Thailand

BACKGROUND The prevalence of metabolic-associated fatty liver disease(MAFLD)is a growing public health issue in people living with human immunodeficiency virus(PLWH).However,the pathophysiology of MAFLD is still unknown,and the role of genetic variables is only now becoming *** To evaluate the associations of gene-polymorphism-related MAFLD in *** The study employed transient elastography with a controlled attenuation parameter≥248 dB/m to identify MAFLD in patients from a Super Tertiary Hospital in central *** single-nucleotide polymorphisms(SNPs)were genotyped using TaqMan®MGB probe 5'nuclease assays for seven MAFLD-related *** analyses included SNP frequency analysis,Fisher's Exact and Chi-square tests,odds ratio calculations,and multivariable logistic *** The G-allele carriers of PNPLA3(rs738409)exhibited a two-fold rise in MAFLD,increasing by 2.5 times in MAFLD with human immunodeficiency virus *** clinical features and genetic patterns imply that LEP rs7799039 A-allele carriers had a nine times(P=0.001)more significant chance of developing aberrant triglyceride among *** The current study shows an association between PNPLA3 rs738409 and LEP rs7799039 with MAFLD in PLWH.

关键词： PNPLA3 LEP Metabolic-associated fatty liver disease People living with HIV Thai

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Plasma angiopoietin 2 as a novel prognostic biomarker in alcohol- related cirrhosis and hepatitis

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liver research 2022年第1期6卷 21-29页

作者： Victoria Tatiana Kronsten Josepmaria Argemi Ada Sera Kurt Godhev Mannakat Vijay Jennifer Marie Ryan Ramon Bataller Debbie Lindsay Shawcross Institute of liver Studies Department of Inflammation BiologySchool of Immunology and Microbial SciencesFaculty of Life Sciences and MedicineKing's College LondonUK Division of Gastroenterology Hepatology and NutritionPittsburgh Liver Research CenterUniversity of Pittsburgh Medical CenterPittsburghPAUSA liver Unit.University of Navarra Clinic Hepatology Program.Center for Applied Medical Research(CIMA)Navarra Research InstitutePamplonaSpain Department of Hepatology Royal Free HospitalLondonUK

Background and aim:Severe alcoholic hepatitis(SAH),the most florid form of alcohol-related liver dis-ease(ALD),has a mortality rate of 16%at 28 *** angiopoietin-Tie 2 system regulates angiogenesis and inflammation,both of which are implicated in the pathogenesis of *** study examined plasma and hepatic gene expression of angiopoietin 1(ANG1)and angiopoietin 2(ANG2)in patients with SAH and ALD and investigated their roles as prognostic ***:A case-control study was performed measuring plasma levels of ANG1 and ANG2 by enzyme-linked immunosorbent assay(ELISA)from 30 patients with SAH(Maddrey's discriminant function32),32 patients with ALD cirrhosis and 15 healthy controls(HC).RNA sequencing for ANG1,ANG2,TIE1(codes for Tie1 receptor)and TEK(codes for Tie2 receptor)gene expression from a separate cohort study of 79 patients was also ***:Plasma levels of ANG1 were lower(P=0.010)and ANG2 were higher(Pliver disease(MELD)score(r=0.30,P=0.020),Child-Pugh score(r=0.38,P=0.003),international normalized ratio(r=0.41,P=0.001)and white blood cell count(r=0.28,P=0.040)and inversely correlated with albumin(r=0.26,P=0.040).ANG1 gene expression from liver biopsies was higher in SAH than that in HC(P<0.0001),and greater in severe disease(P<0.0001).ANG2 gene expression trended towards being lower in SAH than that in HC(P=0.070)though was upregulated in severe disease(P=0.0003).Conclusions:Plasma ANG2 is raised in SAH and ALD and could be useful as a prognostic biomarker in this patient population.

关键词： Alcohol-related cirrhosis Alcoholic hepatitis Alcohol-related liver disease(ALD) Angiopoietin 1(ANG1) Angiopoietin 2(ANG2)

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Extracellular vesicles as mediators of alloimmunity and their therapeutic potential in liver transplantation

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World Journal of Transplantation 2020年第11期10卷 330-344页

作者： Sotiris Mastoridis Marc Martinez-Llordella Alberto Sanchez-Fueyo Department ofSurgery Oxford University HospitalsOxford OX37LEUnited Kingdom Institute of liver Studies King's College HospitalMedical Research Council(MRC)Centre for TransplantationLondon SE59NUUnited Kingdom Department of liver Sciences King's College HospitalMedical Research Council(MRC)Centre for TransplantationLondon SE59NUUnited Kingdom

Extracellular vesicles(EVs)are a heterogenous group of nanosized,membranebound particles which are released by most cell *** are known to play an essential role in cellular communication by way of their varied cargo which includes selectively enriched proteins,lipids,and nucleic *** the last two decades,wide-ranging evidence has established the involvement of EVs in the regulation of immunity,with EVs released by immune and non-immune cells shown to be capable of mediating immune stimulation or suppression and to drive inflammatory,autoimmune,and infectious disease *** recently,studies have demonstrated the involvement of allograft-derived EVs in alloimmune responses following transplantation,with EVs shown to be capable of eliciting allograft rejection as well as promoting *** insights are necessitating the reassessment of standard paradigms of T cell *** this article,we explore the latest understanding of the impact of EVs on alloresponses following transplantation and we highlight the recent technological advances which have enabled the study of EVs in clinical ***,we discuss the rapid progress afoot in the development of EVs as novel therapeutic vehicles in clinical transplantation with particular focus on liver transplantation.

关键词： Extracellular vesicle Transplantation liver Alloimmunity Tolerance Therapy

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Regional variation in routes to diagnosis of cholangiocarcinoma in England from 2006 to 2017

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World Journal of Gastroenterology 2023年第24期29卷 3825-3842页

作者： Amy Zalin-Miller Sophie Jose Craig Knott Lizz Paley Daniela Tataru Helen Morement Mireille B Toledano Shahid A Khan Department of Analytics Health Data Insight CICCambridge CB215XEUnited Kingdom Disease Registration Service NHS EnglandLondon E144PUUnited Kingdom CEO AMMFLondon CM241QWUnited Kingdom mrc centre for Environment and Health School of Public HealthImperial College LondonLondon SW72BXUnited Kingdom liver Unit Division of Digestive DiseasesImperial College LondonLondon W21NYUnited Kingdom

BACKGROUND Incidence of cholangiocarcinoma(CCA)is rising,with overall prognosis remaining very *** for the high mortality of CCA include its late presentation in most patients,when curative options are no longer feasible,and poor response to systemic therapies for advanced *** presentation presents a large barrier to improving outcomes and is often associated with diagnosis via mergency presentation(EP).Earlier diagnoses may be made by Two Week Wait(TWW)referrals through General practitioner(GP).We hypothesise that TWW referrals and EP routes to diagnosis differ across regions in *** To investigate routes to diagnosis of CCA over time,regional variation and influencing *** We linked patient records from the National Cancer Registration Dataset to Hospital Episode Statistics,Cancer Waiting Times and Cancer Screening Programme datasets to define routes to diagnosis and certain patient characteristics for patients diagnosed 2006-2017 in *** used linear probability models to investigate geographic variation by assessing the proportions of patients diagnosed via TWW referral or EP across Cancer Alliances in England,adjusting for potential *** between the proportion of people diagnosed by TWW referral and EP was investigated with Spearman’s correlation *** Of 23632 patients diagnosed between 2006-2017 in England,the most common route to diagnosis was EP(49.6%).Non-TWW GP referrals accounted for 20.5%of diagnosis routes,13.8%were diagnosed by TWW referral,and the remainder 16.2%were diagnosed via an‘other’or Unknown *** proportion diagnosed via a TWW referral doubled between 2006-2017 rising from 9.9%to 19.8%,conversely EP diagnosis route declined,falling from 51.3%to 46.0%.Statistically significant variation in both the TWW referral and EP proportions was found across Cancer ***,presence of comorbidity and underlying liver disease were independently associated with both a lowe

关键词： Cholangiocarcinoma Route to diagnosis Two Week Wait Emergency presentation Regional variation

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Cohort study to assess geographical variation in cholangiocarcinoma treatment in England

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World Journal of Gastrointestinal Oncology 2023年第12期15卷 2077-2092页

作者： Sophie Jose Amy Zalin-Miller Craig Knott Lizz Paley Daniela Tataru Helen Morement Mireille B Toledano Shahid A Khan Health Data Analysis Health Data Insight CICCambridge CB215XEUnited Kingdom National Disease Registration Service National Health Service EnglandLondon SE18UGUnited Kingdom Department of Executive AMMF-The Cholangiocarcinoma CharityEssex CM241QWUnited Kingdom mrc centre for Environment and Health Imperial College LondonLondon SW72BXUnited Kingdom Mohn centre for Children's Health and Wellbeing Imperial College LondonLondon SW72BXUnited Kingdom liver Unit Division of Digestive DiseasesImperial College LondonLondon SW72BXUnited Kingdom

BACKGROUND Outcomes for cholangiocarcinoma(CCA)are extremely poor owing to the complexities in diagnosing and managing a rare disease with heterogenous *** curative surgery,which is only an option for a minority of patients diagnosed at an early stage,few systemic therapy options are currently recommended to relieve symptoms and prolong *** insertion to manage disease complications requires highly specialised *** is lacking as to how CCA patients are managed in a real-world setting and whether there is any variation in treatments received by CCA *** To assess geographic variation in treatments received amongst CCA patients in *** Data used in this cohort study were drawn from the National Cancer Registration Dataset(NCRD),Hospital Episode Statistics and the Systemic Anti-Cancer Therapy Dataset.A cohort of 8853 CCA patients diagnosed between 2014-2017 in the National Health Service in England was identified from the *** curative surgery for all patients and systemic therapy and stent insertion for 7751 individuals who did not receive surgery were identified as three end-points of *** probability models assessed variation in each of the three treatment modalities according to Cancer Alliance of residence at diagnosis,and for socio-demographic and clinical characteristics at *** Of 8853 CCA patients,1102(12.4%)received potentially curative *** mean[95%confidence interval(CI)]percentage-point difference from the population average ranged from-3.96(-6.34 to-1.59)%to 3.77(0.54 to 6.99)%across Cancer Alliances in England after adjustment for patient sociodemographic and clinical characteristics,showing statistically significant *** 7751 who did not receive surgery,1542(19.9%)received systemic therapy,with mean[95%CI]percentage-point difference from the population average between-3.84(-8.04 to 0.35)%to 9.28(1.76 to 16.80)%across Cancer Alliances after adjustm

关键词： Cholangiocarcinoma Biliary tract cancer liver cancer Treatment Surgery Systemic therapy Chemotherapy Stent England

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Viral hepatitis in 2021:The challenges remaining and how we should tackle them

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World Journal of Gastroenterology 2022年第1期28卷 76-95页

作者： Rebecca Dunn Aaron Wetten Stuart McPherson Mhairi C Donnelly Gastroenterology University Hospital of North TeesStockton on Tees TS198PEUnited Kingdom liver Unit Freeman HospitalNewcastle NE77DNUnited Kingdom Translational and Clinical research Institute Newcastle UniversityNewcastle NE17RUUnited Kingdom

Viral hepatitis results in 1.4 million deaths *** World Health Organization(WHO)set an ambitious target to eliminate viral hepatitis by 2030,but significant challenges *** include inequalities in access to healthcare,reaching at risk populations and providing access to screening and effective *** around viral hepatitis persists and must be *** WHO goal of global elimination by 2030 is a worthy aim,but remains ambitious and the coronavirus 2019 pandemic undoubtedly has set back *** review article will focus on hepatitis A to E,highlighting problems that have been resolved in the field over the past decade,those that remain to be resolved and suggest directions for future problem solving and research.

关键词： Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E COVID-19

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Human hepatic sinusoidal endothelial cells can be distinguished by expression of phenotypic markers related to their specialised functions in vivo

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World Journal of Gastroenterology 2006年第34期12卷 5429-5439页

作者： PF Lalor SM Curbishley S Shetty DH Adams liver research Group Institute of Biomedical Research Division of Medical Science University of Birmingham Birmingham B15 2TT United Kingdom

The hepatic sinusoids are lined by a unique population of hepatic sinusoidal endothelial cells (HSEC), which is one of the first hepatic cell populations to come into contact with blood components. However, HSEC are not simply barrier cells that restrict the access of blood- borne compounds to the parenchyma. They are func- tionally specialised endothelial cells that have complex roles, including not only receptor-mediated clearance of endotoxin, bacteria and other compounds, but also the regulation of inflammation, leukocyte recruitment and host immune responses to pathogens. Thus understand- ing the differentiation and function of HSEC is critical for the elucidation of liver biology and pathophysiology. This article reviews methods for isolating and studying human hepatic endothelial cell populations using in vitro models. We also discuss the expression and functions of phe- notypic markers, such as the presence of fenestrations and expression of VAP-1, Stabilin-1, L-SIGN, which can be used to identify sinusoidal endothelium and to permit discrimination from vascular and lymphatic endothelial cells.

关键词： Human liver Endothelium Sinusoid Phenotype

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Effect of rapamycin on hepatic osteodystrophy in rats with portasystemic shunting

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World Journal of Gastroenterology 2006年第28期12卷 4504-4510页

作者： Schalk W van der Merwe Maria M Conradie Robert Bond Brenda J Olivier Elongo Fritz Martin Nieuwoudt Rhena Delport Tomas Slavik Gert Engelbrecht Del Kahn Enid G Shephard Maritha J Kotze Nico P de Villiers Stephen Hough Department of Internal Medicine and Gastroenterology ImmunologyHepatology and GI- research laboratoryUniversity of PretoriaSouth Africa Department of Internal Medicine and Endocrinology University of StellenboschSouth Africa Department of Internal Medicine and Gastroenterology1 Hepatology and GI- research laboratoryUniversity of PretoriaSouth Africa Department of Hepatology and GI- research laboratory University of PretoriaSouth Africa Department of Chemical Pathology University of PretoriaSouth Africa Department of Ampath pathology PretoriaSouth Africa Department of Surgery Grootte Schuur HospitalUniversity of Cape TownSouth Africa mrc liver research centre Grootte Schuur HospitalUniversity of Cape TownSouth Africa Department of Genecare Molecular Genetics Christiaan Barnard Memorial HospitalCape TownSouth Africa

AIM： TO study if T-cell activation related to portasystemic shunting causes osteoclast-mediated bone loss through RANKL-dependent pathways. We also investigated if T-cell inhibition using rapamycin would protect against bone loss in rats. METHODS： Portasystemic shunting was performed in male Sprague-Dawley rats and rapamycin 0.1 mg/kg was administered for 15 wk by gavage. Rats received powderized chow and supplemental feeds to prevent the effects of malnutrition on bone composition. Weight gain and growth was restored after surgery in shunted animals. At termination, biochemical parameters of bone turnover and quantitative bone histology were assessed. Markers of T-cell activation, inflammatory cytokine production, and RANKL-dependent pathways were measured. In addition, the roles of IGF-1 and hypogonadism were investigated. RESULTS： Portasystemic shunting caused low turnover osteoporosis that was RANKL independent. Bone resorbing cytokine levels, including IL-1, IL-6 and TNFα, were not increased in serum and TNFα and RANKL expression were not upregulated in PBMC. Portasystemic shunting increased the circulating CD8＋ T-cell population. Rapamycin decreased the circulating CD8＋ T-cell population, increased CD8＋ CD25＋ T-regulatory cell population and improved all parameters of bone turnover. CONCLUSION： Osteoporosis caused by portasystemic shunting may be partially ameliorated by rapamycin in the rat model of hepatic osteodystrophy.

关键词： Osteopenia liver disease Portasystemic shunting T-lymphocyte Rapamycin

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