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Prehospital transdermal glyceryl trinitrate for ultra- acute ischaemic stroke: data from the RIGHT- 2 randomised sham- controlled ambulance trial

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Stroke & Vascular Neurology 2024年第1期9卷 38-49,I0035-I0046页

作者： Jason Philip Appleton Lisa J Woodhouse Craig S Anderson Sandeep Ankolekar Lesley Cala Mark Dixon Timothy J England Kailash Krishnan Grant Mair Keith W Muir John Potter Christopher I Price Marc Randall thompson G robinson Christine Roffe Else C Sandset Jeffrey L Saver Angela Shone Aloysius Niroshan Siriwardena Joanna M Wardlaw Nikola Sprigg Philip M Bath Stroke University Hospitals Birmingham NHS Foundation TrustBirminghamUK Institute of Applied HealthResearch University of Birmingham College of Medical and Dental SciencesBirminghamUK Stroke Trials Unit Mental Health and Clinical NeurosciencesUniversity of NottinghamNottinghamUK Faculty of Medicine The George Institute for Global HealthSydneyNew South WalesAustralia The George Institute China at Peking University Health Science Center BeijingChina Neurology Royal Prince Alfred HospitalSydney Health PartnersSydneyNew South WalesAustralia Department of Neurology King's College Hospital NHS Foundation TrustLondonUK Faculty of Health and Medical Sciences University of Western AustraliaCrawleyWestern AustraliaAustralia East Midlands Ambulance Service NHS Trust NottinghamUK Stroke Queen's Medical CentreNottingham University Hospitals NHS TrustNottinghamUK Centre for Clinical Brain Sciences Dementia Research InstituteUniveristy of EdinburghEdinburghUK Institute of Neurology and Psychology University of GlasgowGlasgowUK Bob Champion Research and Education Building University of East AngliaNorwichUK Institute of Neuroscience Newcastle UniversityNewcastle upon TyneUK Department of Neurology Leeds Teaching Hospitals NHS TrustLeedsUK Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre University of LeicesterLeicesterUK Stroke Research in Stoke Institute for Science and Technology in MedicineKeele UniversityStoke-on TrentUK Department of Neurology Oslo University HospitalOsloNorway Research and Development Norwegian Air Ambulance FoundationOsloNorway Department of Neurology and Comprehensive Stroke Center David Geffen School of MedicineUCLALos AngelesCaliforniaUSA Research and Graduate Services University of NottinghamNottinghamUK Community and Health Research Unit University of LincolnLincolnUK

Background The effect of transdermal glyceryl trinitrate(GTN,a nitrovasodilator)on clinical outcome when administered before hospital admission in suspected stroke patients is ***,we assess the safety and efficacy of GTN in the prespecified subgroup of patients who had an ischaemic stroke within the Rapid Intervention with Glyceryl trinitrate in Hypertensive stroke Trial-2(RIGHT-2).Methods RIGHT-2 was an ambulance-based multicentre sham-controlled blinded-endpoint study with patients randomised within 4hours of *** primary outcome was a shift in scores on the modified Rankin scale(mRS)at day *** outcomes included death;a global analysis(Wei-Lachin test)containing Barthel Index,EuroQol-5D,mRS,telephone interview for cognitive status-modified and Zung depression scale;and neuroimaging-determined‘brain frailty’*** were reported as n(%),mean(SD),median[IQR],adjusted common OR(acOR),mean difference or Mann-Whitney difference(MWD)with 95%*** 597 of 1149(52%)patients had a final diagnosis of ischaemic stroke;age 75(12)years,premorbid mRS>2107(18%),Glasgow Coma Scale 14(2)and time from onset to randomisation 67[45,108]***‘brain frailty’was common:median score 2[2,3](range 0–3).At day 90,GTN did not influence the primary outcome(acOR for increased disability 1.15,95%CI 0.85 to 1.54),death or global analysis(MWD 0.00,95%CI-0.10 to 0.09).In subgroup analyses,there were non-significant interactions suggesting GTN may be associated with more death and dependency in participants randomised within 1hour of symptom onset and in those with more severe *** In patients who had an ischaemic stroke,ultra-acute administration of transdermal GTN in the ambulance did not improve clinical outcomes in a population with more clinical and radiological frailty than seen in previous in-hospital *** IS ALREADY KNOWN ON THIS TOPIC⇒Transdermal glyceryl trinitrate(GTN)was associat-ed with less death and dependency in those w

关键词： Glasgow nitrate random

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Characteristics,management and response to alteplase in China versus non-China participants of the ENCHANTED trial

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Stroke & Vascular Neurology 2017年第2期2卷 53-58页

作者： Lily Song Xia Wang thompson robinson Richard I Lindley Hisatomi Arima Pablo M Lavados Xiaoying Chen John Chalmers Craig S Anderson The George Institute for Global Health at Peking University Health Science Center BeijingChina Department of Neurology 85 Hospital of People’s Liberation ArmyShanghaiChina The George Institute for Global Health The University of New South WalesSydneyAustralia Department of Cardiovascular Sciences and NIHR Biomedical Research Unit for Cardiovascular Sciences University of LeicesterLeicesterUK Department of Preventive Medicine and Public Health Faculty of MedicineFukuoka UniversityFukuokaJapan Clínica Alemana de Santiago Universidad del DesarrolloConcepciónChile Departamento de Ciencias Neurológicas Facultad de MedicinaUniversidad de ChileConcepciónChile Neurology Department Royal Prince Alfred HospitalSydneyAustralia

Background The characteristics of patients with acute ischaemic stroke(AIS)and their management vary across regions,which may influence *** examined for differential patterns of outcome between China and non-China participants of the ENhanced Control of Hypertension And Thrombolysis strokE stuDy(ENCHANTED),which tested different alteplase doses in *** ENCHANTED was an international,multicentre,open,blinded-endpoint trial of the effects of low-dose(0.6 mg/kg)versus standard-dose(0.9 mg/kg)intravenous alteplase on 90-day disability outcomes and symptomatic intracerebral haemorrhage(sICH)in 3310 patients with *** Participants(n=1419,48%)in China were younger,and more often male,hypertensive and with prior stroke and coronary artery disease,but less likely to have atrial fibrillation and use antihypertensive,antithrombotic and lipid-lowering agents,compared with non-China patients with *** China participants had more AIS due to large artery occlusion,were treated later and had differing ancillary management,there was no significant difference in 90-day modified Rankin scale scores 2–6(55.6% vs 47.8%;OR,adjusted for baseline and management factors 0.87(95%CI 0.71 to 1.07;p=0.20))and risk of sICH(Safe Implementation of Thrombolysis in Stroke-Monitoring Study criteria:1.4% vs 1.8%;p=0.12)compared with non-China *** was no heterogeneity in the treatment effects of low-dose versus standard-dose alteplase between China and non-China *** Patients with AIS recruited to the ENCHANTED trial in China had similar outcomes in response to thrombolysis treatment despite significantly differing demographic,clinical and management factors to patients with AIS in other regions.

关键词： hypertensive doses younger

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Smoking influences outcome in patients who had thrombolysed ischaemic stroke:the ENCHANTED study

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Stroke & Vascular Neurology 2021年第3期6卷 395-401,I0033,I0034页

作者： Lingli Sun Lili Song Jie Yang Richard I Lindley thompson robinson Pablo M Lavados Candice Delcourt Hisatomi Arima Bruce Ovbiagele John Chalmers Craig S Anderson Xia Wang The George Institute for Global Health Peking University Health Science CentreBeijingChina The George Institute for Global Health University of New South WalesSydneyNSWAustralia Department of Neurology The First Affiliated Hospital of Chengdu Medical CollegeChengduChina Faculty of Medicine University of SydneySydneyNSWAustralia Department of Cardiovascular Sciences and NIHR Biomedical Research Unit for Cardiovascular Sciences University of LeicesterLeicesterUK Clínica Alemana de Santiago Universidad del DesarrolloSantiago de ChileRegion Metropolitana de SChile Department of Preventive Medicine and Public Health Faculty of MedicineFukuoka UniversityFukuokaJapan San Francisco VA Healthcare System University of CaliforniaSan FranciscoCaliforniaUSA

Background and purpose As studies vary in defining the prognostic significance of smoking in acute ischaemic stroke(AIS),we aimed to determine the relation of smoking and key outcomes in patient participants who had thrombolysed AIS of the international quasi-factorial randomised Enhanced Control of Hypertension and Thrombolysis Stroke Study(ENCHANTED).Methods Post-hoc analyses of ENCHANTED,an international quasi-factorial randomised evaluation of intravenous alteplase-dose comparison and levels of blood pressure control in patients who had thrombolysed *** logistic regression models with inverse probability of treatment weighting(IPTW)propensity scores were used to determine associations of self-reported smoking status and clinical outcomes,according to 90-day modified Rankin Scale(mRS)scores and symptomatic intracerebral haemorrhage(sICH).Results Of 4540 patients who had an AIS,there were 1008(22.2%)current smokers who were younger and predominantly male,with more comorbidities of hypertension,coronary artery disease,atrial fibrillation and diabetes mellitus,and greater baseline neurological impairment,compared with *** univariate analysis,current smokers had a higher likelihood of a favourable shift in mRS scores(OR 0.88,95%CI 0.77 to 0.99;p=0.038)but this association reversed in a fully adjusted model with IPTW(adjusted OR 1.15,95%CI 1.04 to 1.28;p=0.009).A similar trend was also apparent for dichotomised poor outcome(mRS scores 2–6:OR 1.18,95%CI 1.05 to 1.33;p=0.007),but not with the risk of sICH across standard *** Smoking predicts poor functional recovery in patients who had thrombolysed *** registration number NCT01422616.

关键词： patients smoke acute

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Current status of intravenous tissue plasminogen activator dosage for acute ischaemic stroke:an updated systematic review

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Stroke & Vascular Neurology 2018年第1期3卷 28-33页

作者： Xia Wang Shoujiang You Shoichiro Sato Jie Yang Cheryl Carcel Danni Zheng Sohei Yoshimura Craig S Anderson Else Charlotte Sandset thompson robinson John Chalmers Vijay K Sharma The George Institute for Global Health NewtownNew South WalesAustralia Sydney Medical School The University of SydneySydneyNew South WalesAustralia Department of Neurology The Second Affiliated Hospital of Soochow UniversitySuzhouChina Department of Cerebrovascular Medicine National Cerebral and Cardiovascular CenterOsakaJapan Department of Neurology The First Affiliated Hospital of Chengdu Medical CollegeChengduChina Royal Prince Alfred Hospital CamperdownNew South WalesAustralia The George Institute China Peking University Health Science CenterBeijingChina Department of Neurology Oslo University HospitalOsloNorway Department of Cardiovascular Sciences and NIHR Biomedical Research Unit for Cardiovascular Diseases University of LeicesterLeicesterUK Yong Loo Lin School of Medicine National University of SingaporeSingapore Division of Neurology National University HospitalSingapore

The optimal dose of recombinant tissue plasminogen activator(rtPA)for acute ischaemic stroke(AIS)remains controversial,especially in Asian *** aimed to update the evidence regarding the use of low-dose versus standard-dose *** performed a systematic literature search across MEDLINE,Embase,Cochrane Central Register of Controlled Trials(CENTRAL),PsycINFO and Cumulative Index to Nursing and Allied Health Literature(CINAHL)from inception to 22 August 2016 to identify all related *** outcomes were death or disability(defined by modified Rankin Scale 2-6),death,and symptomatic intracerebral haemorrhage(sICH).Where possible,data were pooled for meta-analysis with ORs and corresponding 95% CIs by means of random-effects or fixed-effects *** included 26 observational studies and 1 randomised controlled trial with a total of 23210 *** doses of rtPA were used for thrombolysis of AIS in ***-analysis shows that low-dose rtPA was not associated with increased risk of death or disability(OR 1.13,95% CI 0.95 to 1.33),or death(OR 0.86,95% CI 0.74 to 1.01),or decreased risk of sICH(OR 1.06,95% CI 0.65 to 1.72).The results remained consistent when sensitivity analyses were performed including only low-dose and standard-dose rtPA or only Asian *** review shows small difference between the outcomes or the risk profile in the studies using low-dose and/or standard-dose rtPA for ***-dose rtPA was not associated with lower risk of death or disability,death alone,or sICH.

关键词： dosage doses acute

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The decision-making process for senior cancer patients: treatment allocation of older women with operable breast cancer in the UK

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Cancer Biology & Medicine 2015年第4期12卷 308-315页

作者： Jenna L.Morgan Paul Richards Osama Zaman Sue Ward Karen Collins thompson robinson Kwok-Leung Cheung Riccardo A.Audisio Malcolm W.Reed Lynda Wyld on behalf of the Bridging the Age Gap in Breast Cancer Trial Management Team Academic Unit of Surgical Oncology University of Sheffield Medical School Health Economics and Decision Science School for Health and Related Research University of Sheffield Center for Health and Social Care Research Sheffield Hallam University Collegiate Crescent Department of Cardiovascular Sciences University of Leicester School of Medicine University of Nottingham Royal Derby Hospital Center Department of Surgery University of Liverpool St Helens Teaching Hospital Brighton and Sussex Medical School University of Sussex

Objective: Up to 40% of women over 70 years with primary operable breast cancer in the UK are treated with primary endocrine therapy(PET) as an alternative to surgery. A variety of factors are important in determining treatment for older breast cancer patients. This study aimed to identify the patient and tumor factors associated with treatment allocation in this ***: Prospectively collected data on treatment received(surgery vs. PET) were analysed with multivariable logistic regression using the variables age, modified Charlson Comorbidity Index(CCI), activities of daily living(ADL) score, Mini-Mental State Examination(MMSE) score, HER2 status, tumour size, grade and nodal status. Results: Data were available for 1,122 cancers in 1,098 patients recruited between February 2013 and June 2015 from 51 UK hospitals. About 78% of the population were treated surgically, with the remainder being treated with PET. Increasing patient age at diagnosis, increasing CCI score, large tumor size(5 cm or more) and dependence in one or more ADL categories were all strongly associated with non-surgical treatment(P<0.05).Conclusion: Increasing comorbidity, large tumor size and reduced functional ability are associated with reduced likelihood of surgical treatment of breast cancer in older patients. However, age itself remains a significant factor for non-surgical treatment; reinforcing the need for evidence-based guidelines.

关键词： Frail elderly breast neoplasms decision-making

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No benefit of flat head positioning in early moderate-severe acute ischaemic stroke: a HeadPoST study subgroup analysis

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Stroke & Vascular Neurology 2020年第4期5卷 406-409页

作者： Alejandro M Brunser Menglu Ouyang Hisatomi Arima Pablo M Lavados thompson robinson Paula Munoz-Venturelli Veronica V Olavarria Laurent Billot Marre L Hackett Lili Song Sandy Middleton Octavio Pontes-Neto Tsong-Hai Lee Caroline Watkins Craig S Anderson Department of General Emergency Clinica Alemana de SantiagoClinica Alemana Universidad del DesarrolloSantiagoChile Department of Neurology and Psychiatry Clinica Alemana de SantiagoFaculty of MedicineClinica Alemana Universidad del DesarrolloSantiagoChile The George Institute for Global Health University of New South WalesSidneyNew South WalesAustralia The George Institute in China Peking University Health Science CenterBeijingChina Department of Preventive Medicine and Public Health Fukuoka UniversityFukuokaJapan Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre University of LeicesterLeicesterUnited Kingdom Faculty of Health and Wellbeing University of Central LancashirePrestonLancashireUnited Kingdom Nursing Research Institute St Vincent's Health Network Sydney AustraliaAustralian Catholic UniversitySydneyNew South WalesAustralia Stroke Service-Neurology Division Department of Neuroscience and Behavioral SciencesRibeirao Preto Medical SchoolUniversity of Sao PauloSao PauloBrazil Stroke Center and Department of Neurology Linkou Chang Gung Memorial Hospital and College of MedicineChang Gung UniversityTaoyuanTaiwan

background Although the Head Positioning in acute Stroke Trial(HeadPoST)showed no effect of the flat head position(FP;vs sitting up head position(SUP))on functional outcome,we hypothesised that it could still offer benefits if commenced early in those with acute ischaemic stroke(AIS)of at least moderate *** Subgroup analysis of HeadPoST in participants with National Institutes of Health Stroke Scale(NIHSS)scores≥7,≥10 and≥14,randomised to FP or SUP<4.5 hours of AIS onset on functional outcomes defined by a shift in scores on the modified Rankin scale(mRS)and death/disability(mRS scores 3-6),and any cardiovascular serious adverse *** regression analyses were undertaken adjusted for study design and baseline risk *** There was no significant differential treatment effect in patient subgroups defined by increasing baseline NIHSS scores:adjusted OR and 95%CI for ordinal shift and binary(3-6)mRS scores:for NIHSS≥7(n=867)0.92(0.67 to 1.25)and 0.74(0.52 to 1.04);NIHSS≥10(n=606)0.80(0.58 to 1.10)and 0.77(0.49 to 1.19);NIHSS≥14(n=378)0.82(0.54 to 1.24)and 1.22(0.69 to 2.14).Conclusions Early FP had no significant effect in patients with moderate-severe AIS.

关键词： acute analysis effect

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Modelling and Characterization of Basalt/Vinyl Ester/SiC Micro-and Nano-hybrid Biocomposites Properties Using Novel ANN–GA Approach

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Journal of Bionic Engineering 2024年第2期21卷 938-952页

作者： Yesudhasan Thooyavan Lakshmi Annamali Kumaraswamidhas robinson Dhas Edwin Raj Joseph Selvi Binoj Bright Brailson Mansingh Antony Sagai Francis Britto Alamry Ali Department of Mechanical Engineering Indian Institute of Technology Dhanbad(ISM)DhanbadJharkhand826004India Gati Shakti Vishwavidyalaya(GSV-A Central University Funded By GoI in the Ministry of Railways) LalbaugVadodaraGujarat390004India Institute of Mechanical Engineering Saveetha School of EngineeringSaveetha Institute of Medical and Technical Sciences(SIMATS)Saveetha UniversityChennaiTamilnadu602105India Metal Joining Research Centre Department of Mechanical EngineeringSri Ramakrishna Engineering CollegeCoimbatoreTamilnadu641022India Department of Mechanical Engineering Rohini College of Engineering and TechnologyPalkulamTamil Nadu629401India Department of Mechanical Engineering College of Engineering in Al-KharjPrince Sattam Bin Abdulaziz University11942Al-KharjSaudi Arabia

Basalt fiber reinforcement in polymer matrix composites is becoming more and more popular because of its environmental friendliness and mechanical qualities that are comparable to those of synthetic *** fiber strengthened vinyl ester matrix polymeric composite with filler addition of nano-and micro-sized silicon carbide(SiC)element spanning from 2 weight percent to 10 weight percent was studied for its mechanical and wear *** application of Artificial Neural Network(ANN)to correlate the filler addition composition for optimum mechanical properties is required due to the non-linear mechanical and tribological features of *** stuffing blend and composition of the composite are optimized using the hybrid model and Genetic Algorithm(GA)to maximize the mechanical and wear-resistant *** predicted and tested ANN–GA optimal values obtained for the composite combination had a tensile,flexural,impact resilience,hardness and wear properties of 202.93 MPa,501.67 MPa,3.460 J/s,43 HV and 0.196 g,respectively,for its optimum combination of filler and *** can be noted that the nano-sized SiC filler particle enhances most of the properties of the composite which diversifies its *** predicted mechanical and wear values of the developed ANN–GA model were in closer agreement with the experimental values which validate the model.

关键词： Hybrid polymer composite Prediction Process modelling Artificial neural networks Genetic algorithm

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Highly efficient and stable organic solar cells with SnO_(2)electron transport layer enabled by UV-curing acrylate oligomers

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Journal of Energy Chemistry 2024年第5期92卷 124-131页

作者： Mwende Mbilo Du Hyeon Ryu Seungjin Lee Muhammad Haris Julius Mwakondo Mwabora robinson Juma Musembi Hang Ken Lee Sang Kyu Lee Chang Eun Song Won Suk Shin Department of Physics Faculty of Science and TechnologyUniversity of Nairobi(UoN)P.O.Box 30197-00100NairobiKenya Advanced Energy Materials Research Center Korea Research Institute of Chemical Technology(KRICT)Daejeon 34114Republic of Korea Advanced Materials and Chemical Engineering University of Science and Technology(UST)Daejeon 34113Republic of Korea

The interfaces between the inorganic metal oxide and organic photoactive layer are of outmost importance for efficiency and stability in organic solar cells(OSCs).Tin oxide(SnO_(2))is one of the promising candidates for the electron transport layer(ETL)in high-performance inverted *** a solution-processed SnO_(2)ETL is employed,however,the presence of interfacial defects and suboptimal interfacial contact can lower the power conversion efficiency(PCE)and operational stability of ***,highly efficient and stable inverted OSCs by modification of the SnO_(2)surface with ultraviolet(UV)-curable acrylate oligomers(SAR and OCS)are *** highest PCEs of 16.6%and 17.0%are achieved in PM6:Y6-BO OSCs with the SAR and OCS,respectively,outperforming a device with a bare SnO_(2)ETL(PCE 13.8%).The remarkable enhancement of PCEs is attributed to the optimized interfacial contact,leading to mitigated surface *** strikingly,improved light-soaking and thermal stability strongly correlated with the interfacial defects are demonstrated for OSCs based on SnO_(2)/UV cross-linked resins compared to OSCs utilizing bare SnO_(2).We believe that UV cross-linking oligomers will play a key role as interfacial modifiers in the future fabrication of large-area and flexible OSCs with high efficiency and stability.

关键词： Organic solar cells SnO_(2) Surface defects Ultraviolet resins Stability Cross-linking oligomers Non-halogenated solvent

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High association strengths are linked to phenotypic similarity,including plumage color and patterns,of participants in mixed-species bird flocks of southwestern China

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Current Zoology 2024年第1期70卷 34-44页

作者： Liping Zhou Christos Mammides Youfang Chen Wenyi Zhou Wenzhang Dai Edward L.Braun Rebecca T.Kimball Yang Liu Scott K.robinson Eben Goodale Guangxi Key Laboratory of Forest Ecology and Conservation College of ForestryGuangxi UniversityNanning 530004China Kunming Natural History Museum of Zoology Kunming Institute of ZoologyChinese Academy of SciencesKunming 650223China Nature Conservation Unit Frederick University7Yianni Frederickou StreetPallouriotissaNicosia 1036Cyprus State Key Laboratory of Vegetation and Environmental Change Institute of BotanyChinese Academy of SciencesBeijing 100093China Florida Museum of Natural History University of FloridaGainesvilleFL 34201USA Department of Biology University of FloridaGainesvilleFL 34201USA School of Life Science and Institute of Wetland Ecology Nanjing UniversityNanjing 210000China State Key Laboratory of Biocontrol School of EcologySun-Yatsen UniversityGuangzhou 510275China Department of Health and Environmental Science Xi'an Jiaotong Liverpool UniversitySuzhou 215123China

Participants in mixed-species bird flocks(MSFs)have been shown to associate with species that are similar in body size,diet,and evolutionary history,suggesting that facilitation structures these *** addition,several studies have suggested that species in MsFs resemble each other in their plumage,but this question has not been systematically investigated for any MsF *** the nonbreeding season of 2020 and 2021,we sampled 585 MSFs on 14 transects in 2 habitats of Tongbiguang Nature Reserve in western Yunnan Province,*** performed social network analysis and the Multiple Regression Quadratic Assignment Procedure to evaluate the effect of 4 species traits(body size,overall plumage color,distinctive plumage patterns,and diet)and evolutionary history on species association strength at the whole-MSF and within-MSF *** 41 significant relationships showed that species with stronger associations were more similar in their various *** size had the strongest effect on association strength,followed by phylogeny,plumage patterns,and plumage color;diet had the weakest *** results are consistent with the hypotheses that the benefits of associating with phenotypically similar species outweigh the potential costs of interspecific competition,and that trait matching can occur in plumage characteristics,albeit more weakly than in other *** explanations exist as to why similarities in plumage may occur in MSFs,including that they could reduce predators'ability to target phenotypically"odd"*** trait matching in plumage occurs through assortative processes in ecological time or is influenced by co-evolution requires furtherstudy.

关键词： co-evolution interaction networks mixed-species animal groups phenotypic similarity trait convergence

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Metabolic collaboration between cells in the tumor microenvironment has a negligible effect on tumor growth

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The Innovation 2024年第2期5卷 107-114页

作者： Johan Gustafsson Fariba Roshanzamir Anders Hagnestål Sagar M.Patel Oseeyi I.Daudu Donald F.Becker Jonathan L.robinson Jens Nielsen Department of Life Sciences Chalmers University of TechnologySE-41296 GothenburgSweden Hagnesia AB SE-43854 HindåsSweden Department of Biochemistry and Redox Biology Center University of Nebraska-LincolnLincolnNE 68588USA BioInnovation Institute DK2200 CopenhagenDenmark

The tumor microenvironment is composed of a complex mixture of different cell types interacting under conditions of nutrient deprivation,but the metabolism therein is not fully understood due to difficulties in measuring metabolic fluxes and exchange of metabolites between different cell types in ***-scale metabolic modeling enables estimation of such exchange fluxes as well as an opportunity to gain insight into the metabolic behavior of individual cell ***,we estimated the availability of nutrients and oxygen within the tumor microenvironment using concentration measurements from blood together with a metabolite diffusion *** addition,we developed an approach to efficiently apply enzyme usage constraints in a comprehensive metabolic model of human *** combined modeling reproduced severe hypoxic conditions and the Warburg effect,and we found that limitations in enzymatic capacity contribute to cancer cells’preferential use of glutamine as a substrate to the citric acid ***,we investigated the common hypothesis that some stromal cells are exploited by cancer cells to produce metabolites useful for the cancer *** identified over 200 potential metabolites that could support collaboration between cancer cells and cancer-associated fibroblasts,but when limiting to metabolites previously identified to participate in such collaboration,no growth advantage was *** work highlights the importance of enzymatic capacity limitations for cell behaviors and exemplifies the utility of enzyme-constrained models for accurate prediction of metabolism in cells and tumor microenvironments.

关键词： metabolism effect limitations

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