{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:15:55Z","timestamp":1772172955652,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009504","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T00:00:00Z","timestamp":1644192000000}}],"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T00:00:00Z","timestamp":1643155200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA254271"],"award-info":[{"award-number":["R01CA254271"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01NS115971"],"award-info":[{"award-number":["R01NS115971"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01NS115971"],"award-info":[{"award-number":["R01NS115971"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30CA033572"],"award-info":[{"award-number":["P30CA033572"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100019408","name":"Marcus Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100019408","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007557","name":"California Institute of Regenerative Medicine","doi-asserted-by":"publisher","award":["CLIN2-10248"],"award-info":[{"award-number":["CLIN2-10248"]}],"id":[{"id":"10.13039\/100007557","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Chimeric antigen receptor (CAR) T-cell therapy is potentially an effective targeted immunotherapy for glioblastoma, yet there is presently little known about the efficacy of CAR T-cell treatment when combined with the widely used anti-inflammatory and immunosuppressant glucocorticoid, dexamethasone. Here we present a mathematical model-based analysis of three patient-derived glioblastoma cell lines treated\n                    <jats:italic>in vitro<\/jats:italic>\n                    with CAR T-cells and dexamethasone. Advanced\n                    <jats:italic>in vitro<\/jats:italic>\n                    experimental cell killing assay technologies allow for highly resolved temporal dynamics of tumor cells treated with CAR T-cells and dexamethasone, making this a valuable model system for studying the rich dynamics of nonlinear biological processes with translational applications. We model the system as a nonautonomous, two-species predator-prey interaction of tumor cells and CAR T-cells, with explicit time-dependence in the clearance rate of dexamethasone. Using time as a bifurcation parameter, we show that (1) dexamethasone destabilizes coexistence equilibria between CAR T-cells and tumor cells in a dose-dependent manner and (2) as dexamethasone is cleared from the system, a stable coexistence equilibrium returns in the form of a Hopf bifurcation. With the model fit to experimental data, we demonstrate that high concentrations of dexamethasone antagonizes CAR T-cell efficacy by exhausting, or reducing the activity of CAR T-cells, and by promoting tumor cell growth. Finally, we identify a critical threshold in the ratio of CAR T-cell death to CAR T-cell proliferation rates that predicts eventual treatment success or failure that may be used to guide the dose and timing of CAR T-cell therapy in the presence of dexamethasone in patients.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1009504","type":"journal-article","created":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T13:37:40Z","timestamp":1643204260000},"page":"e1009504","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["Dose-dependent thresholds of dexamethasone destabilize CAR T-cell treatment efficacy"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8776-0939","authenticated-orcid":true,"given":"Alexander B.","family":"Brummer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7094-626X","authenticated-orcid":true,"given":"Margarita","family":"Gutova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4915-8207","authenticated-orcid":true,"given":"Christine E.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1557-159X","authenticated-orcid":true,"given":"Russell C.","family":"Rockne","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,1,26]]},"reference":[{"issue":"26","key":"pcbi.1009504.ref001","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1056\/NEJMoa1610497","article-title":"Regression of glioblastoma after chimeric antigen receptor T-cell therapy","volume":"375","author":"CE Brown","year":"2016","journal-title":"New England Journal of Medicine"},{"issue":"8","key":"pcbi.1009504.ref002","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1001\/jamaoncol.2017.0184","article-title":"HER2-Specific Chimeric Antigen Receptor\u2013Modified Virus-Specific T Cells for Progressive Glioblastoma: A Phase 1 Dose-Escalation Trial","volume":"3","author":"N Ahmed","year":"2017","journal-title":"JAMA Oncology"},{"issue":"399","key":"pcbi.1009504.ref003","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aaa0984","article-title":"A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma","volume":"9","author":"DM O\u2019Rourke","year":"2017","journal-title":"Science Translational Medicine"},{"issue":"1","key":"pcbi.1009504.ref004","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1111\/imr.12773","article-title":"CAR T cells for brain tumors: Lessons learned and road ahead","volume":"290","author":"D Akhavan","year":"2019","journal-title":"Immunological Reviews"},{"issue":"5","key":"pcbi.1009504.ref005","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/neuonc\/noz150","article-title":"CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012\u20132016","volume":"21","author":"QT Ostrom","year":"2019","journal-title":"Neuro-Oncology"},{"key":"pcbi.1009504.ref006","first-page":"1","article-title":"Using chimeric antigen receptor T-cell therapy to fight glioblastoma multiforme: past, present and future developments","author":"DC Soler","year":"2021","journal-title":"Journal of Neuro-Oncology"},{"issue":"10","key":"pcbi.1009504.ref007","doi-asserted-by":"crossref","first-page":"e77769","DOI":"10.1371\/journal.pone.0077769","article-title":"Glioma IL13R\u03b12 is associated with mesenchymal signature gene expression and poor patient prognosis","volume":"8","author":"CE Brown","year":"2013","journal-title":"PloS one"},{"issue":"1","key":"pcbi.1009504.ref008","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.ymthe.2017.10.002","article-title":"Optimization of IL13R\u03b12-targeted chimeric antigen receptor T cells for improved anti-tumor efficacy against glioblastoma","volume":"26","author":"CE Brown","year":"2018","journal-title":"Molecular Therapy"},{"issue":"18","key":"pcbi.1009504.ref009","doi-asserted-by":"crossref","first-page":"4062","DOI":"10.1158\/1078-0432.CCR-15-0428","article-title":"Bioactivity and safety of IL13R\u03b12-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma","volume":"21","author":"CE Brown","year":"2015","journal-title":"Clinical cancer research"},{"issue":"Supplement_5","key":"pcbi.1009504.ref010","doi-asserted-by":"crossref","first-page":"v108","DOI":"10.1093\/noajnl\/vdab107","article-title":"A review of neurotoxicities associated with immunotherapy and a framework for evaluation","volume":"3","author":"LB Burton","year":"2021","journal-title":"Neuro-Oncology Advances"},{"issue":"162","key":"pcbi.1009504.ref011","doi-asserted-by":"crossref","first-page":"20190734","DOI":"10.1098\/rsif.2019.0734","article-title":"Mathematical deconvolution of CAR T-cell proliferation and exhaustion from real-time killing assay data","volume":"17","author":"P Sahoo","year":"2020","journal-title":"Journal of the Royal Society Interface"},{"key":"pcbi.1009504.ref012","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3389\/fnmol.2019.00065","article-title":"Dexamethasone in glioblastoma multiforme therapy: mechanisms and controversies","volume":"12","author":"M Cenciarini","year":"2019","journal-title":"Frontiers in Molecular Neuroscience"},{"issue":"2","key":"pcbi.1009504.ref013","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/S0092-8240(05)80260-5","article-title":"Nonlinear dynamics of immunogenic tumors: parameter estimation and global bifurcation analysis","volume":"56","author":"VA Kuznetsov","year":"1994","journal-title":"Bulletin of mathematical biology"},{"issue":"4","key":"pcbi.1009504.ref014","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.jtbi.2003.11.024","article-title":"A mathematical model for chronic myelogenous leukemia (CML) and T cell interaction","volume":"227","author":"H Moore","year":"2004","journal-title":"Journal of theoretical biology"},{"issue":"1","key":"pcbi.1009504.ref015","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3934\/dcdsb.2014.19.55","article-title":"Mathematical modeling on helper T cells in a tumor immune system","volume":"19","author":"Y Dong","year":"2014","journal-title":"Discrete & Continuous Dynamical Systems-B"},{"issue":"3-4","key":"pcbi.1009504.ref016","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S0895-7177(00)00143-6","article-title":"Modelling and mathematical problems related to tumor evolution and its interaction with the immune system","volume":"32","author":"N Bellomo","year":"2000","journal-title":"Mathematical and Computer Modelling"},{"issue":"17","key":"pcbi.1009504.ref017","doi-asserted-by":"crossref","first-page":"7950","DOI":"10.1158\/0008-5472.CAN-05-0564","article-title":"A validated mathematical model of cell-mediated immune response to tumor growth","volume":"65","author":"LG de Pillis","year":"2005","journal-title":"Cancer research"},{"issue":"3","key":"pcbi.1009504.ref018","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s002850050127","article-title":"Modeling immunotherapy of the tumor\u2013immune interaction","volume":"37","author":"D Kirschner","year":"1998","journal-title":"Journal of mathematical biology"},{"issue":"2","key":"pcbi.1009504.ref019","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1080\/10273660108833067","article-title":"A mathematical tumor model with immune resistance and drug therapy: an optimal control approach","volume":"3","author":"LG De Pillis","year":"2001","journal-title":"Computational and Mathematical Methods in Medicine"},{"issue":"5","key":"pcbi.1009504.ref020","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s10928-014-9386-9","article-title":"Modeling cancer-immune responses to therapy","volume":"41","author":"L DePillis","year":"2014","journal-title":"Journal of pharmacokinetics and pharmacodynamics"},{"issue":"5","key":"pcbi.1009504.ref021","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1007\/s11538-017-0263-8","article-title":"Ordinary differential equation models for adoptive immunotherapy","volume":"80","author":"A Talkington","year":"2018","journal-title":"Bulletin of mathematical biology"},{"key":"pcbi.1009504.ref022","doi-asserted-by":"crossref","first-page":"105684","DOI":"10.1016\/j.cnsns.2020.105684","article-title":"CAR T cells for T-cell leukemias: Insights from mathematical models","volume":"96","author":"VM P\u00e9rez-Garc\u00eda","year":"2021","journal-title":"Communications in Nonlinear Science and Numerical Simulation"},{"issue":"12","key":"pcbi.1009504.ref023","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.3390\/cancers13122941","article-title":"CARTmath\u2014A Mathematical Model of CAR-T Immunotherapy in Preclinical Studies of Hematological Cancers","volume":"13","author":"LR Barros","year":"2021","journal-title":"Cancers"},{"issue":"20","key":"pcbi.1009504.ref024","doi-asserted-by":"crossref","DOI":"10.3390\/cancers13205171","article-title":"A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor T Cell Combination Therapy","volume":"13","author":"V Adhikarla","year":"2021","journal-title":"Cancers"},{"issue":"5","key":"pcbi.1009504.ref025","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11538-021-00869-5","article-title":"Modeling CAR T-Cell Therapy with Patient Preconditioning","volume":"83","author":"K Owens","year":"2021","journal-title":"Bulletin of Mathematical Biology"},{"issue":"8","key":"pcbi.1009504.ref026","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.1158\/1078-0432.CCR-11-1669","article-title":"Stem-like tumor-initiating cells isolated from IL13R\u03b12 expressing gliomas are targeted and killed by IL13-zetakine\u2013redirected T cells","volume":"18","author":"CE Brown","year":"2012","journal-title":"Clinical Cancer Research"},{"issue":"2","key":"pcbi.1009504.ref027","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s10616-014-9692-5","article-title":"Dynamic assessment of cell viability, proliferation and migration using real time cell analyzer system (RTCA)","volume":"67","author":"MR Moniri","year":"2015","journal-title":"Cytotechnology"},{"issue":"6","key":"pcbi.1009504.ref028","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/j.tiv.2005.12.008","article-title":"Microelectronic cell sensor assay for detection of cytotoxicity and prediction of acute toxicity","volume":"20","author":"JZ Xing","year":"2006","journal-title":"Toxicology in vitro"},{"issue":"1","key":"pcbi.1009504.ref029","first-page":"1","article-title":"Comparison between xCELLigence biosensor technology and conventional cell culture system for real-time monitoring human tenocytes proliferation and drugs cytotoxicity screening","volume":"12","author":"CH Chiu","year":"2017","journal-title":"Journal of orthopaedic surgery and research"},{"issue":"3","key":"pcbi.1009504.ref030","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1002\/bdd.2510080302","article-title":"Pharmacokinetics of dexamethasone and its phosphate ester","volume":"8","author":"P Rohdewald","year":"1987","journal-title":"Biopharmaceutics & drug disposition"},{"issue":"1-2","key":"pcbi.1009504.ref031","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.bbamem.2004.01.006","article-title":"Hydrocortisone and dexamethasone in very deformable drug carriers have increased biological potency, prolonged effect, and reduced therapeutic dosage","volume":"1663","author":"G Cevc","year":"2004","journal-title":"Biochimica et Biophysica Acta (BBA)-Biomembranes"},{"issue":"10","key":"pcbi.1009504.ref032","first-page":"4251","article-title":"Glucocorticoids augment survival and proliferation of tumor cells","volume":"32","author":"S Guendisch","year":"2012","journal-title":"Anticancer research"},{"issue":"1","key":"pcbi.1009504.ref033","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.jmaa.2004.02.038","article-title":"Dynamics of a nonautonomous predator\u2013prey system with the Beddington\u2013DeAngelis functional response","volume":"295","author":"M Fan","year":"2004","journal-title":"Journal of Mathematical Analysis and Applications"},{"issue":"9","key":"pcbi.1009504.ref034","doi-asserted-by":"crossref","first-page":"3817","DOI":"10.3934\/dcdsb.2018082","article-title":"A non-autonomous predator-prey model with infected prey","volume":"23","author":"Y Lu","year":"2018","journal-title":"Discrete & Continuous Dynamical Systems-B"},{"key":"pcbi.1009504.ref035","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-03080-7","volume-title":"Nonautonomous dynamical systems in the life sciences","author":"PE Kloeden","year":"2013"},{"key":"pcbi.1009504.ref036","doi-asserted-by":"crossref","unstructured":"Kennedy J, Eberhart R. Particle swarm optimization. In: Proceedings of ICNN\u201995-international conference on neural networks. vol. 4. IEEE; 1995. p. 1942\u20131948.","DOI":"10.1109\/ICNN.1995.488968"},{"key":"pcbi.1009504.ref037","first-page":"217","article-title":"Computational Model Predicts the Effects of Targeting Cellular Metabolism in Pancreatic Cancer","volume":"8","author":"M Roy","year":"2017","journal-title":"Frontiers in Physiology"},{"issue":"17","key":"pcbi.1009504.ref038","doi-asserted-by":"crossref","first-page":"6704","DOI":"10.1158\/0008-5472.CAN-10-0460","article-title":"Identification of optimal drug combinations targeting cellular networks: integrating phospho-proteomics and computational network analysis","volume":"70","author":"S Iadevaia","year":"2010","journal-title":"Cancer research"},{"issue":"1","key":"pcbi.1009504.ref039","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1752-0509-5-159","article-title":"Parameter estimation with bio-inspired meta-heuristic optimization: modeling the dynamics of endocytosis","volume":"5","author":"K Tashkova","year":"2011","journal-title":"BMC systems biology"},{"issue":"2","key":"pcbi.1009504.ref040","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.cmpb.2013.10.003","article-title":"Statistical identifiability and convergence evaluation for nonlinear pharmacokinetic models with particle swarm optimization","volume":"113","author":"S Kim","year":"2014","journal-title":"Computer methods and programs in biomedicine"},{"issue":"10","key":"pcbi.1009504.ref041","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pcbi.1005153","article-title":"Structural Identifiability of Dynamic Systems Biology Models","volume":"12","author":"AF Villaverde","year":"2016","journal-title":"PLOS Computational Biology"},{"key":"pcbi.1009504.ref042","volume-title":"A Treatise on Stability of Autonomous and Non-autonomous Systems: Theory and Illustrative Practical Applications","author":"R Adhikari","year":"2013","edition":"1"},{"issue":"4","key":"pcbi.1009504.ref043","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1137\/20M1316007","article-title":"A Holling Predator-Prey Model with Handling and Searching Predators","volume":"80","author":"SB Hsu","year":"2020","journal-title":"SIAM Journal on Applied Mathematics"},{"key":"pcbi.1009504.ref044","doi-asserted-by":"crossref","first-page":"111346","DOI":"10.1016\/j.chaos.2021.111346","article-title":"The impact of immunotherapy on a glioma immune interaction model","volume":"152","author":"S Khajanchi","year":"2021","journal-title":"Chaos, Solitons & Fractals"},{"key":"pcbi.1009504.ref045","doi-asserted-by":"crossref","first-page":"S147","DOI":"10.1002\/jcph.1691","article-title":"Chimeric Antigen Receptor T Cell Therapies: A Review of Cellular Kinetic-Pharmacodynamic Modeling Approaches","volume":"60","author":"A Chaudhury","year":"2020","journal-title":"The Journal of Clinical Pharmacology"},{"key":"pcbi.1009504.ref046","first-page":"3391","article-title":"Predator-Prey in Tumor-Immune Interactions: A Wrong Model or Just an Incomplete One?","author":"I Kareva","year":"2021","journal-title":"Frontiers in Immunology"},{"issue":"4","key":"pcbi.1009504.ref047","first-page":"362","article-title":"Bench-to-bedside translation of chimeric antigen receptor (CAR) T cells using a multiscale systems pharmacokinetic-pharmacodynamic model: A case study with anti-BCMA CAR-T","volume":"10","author":"AP Singh","year":"2021","journal-title":"CPT: Pharmacometrics & Systems Pharmacology"},{"key":"pcbi.1009504.ref048","article-title":"Sex differences in health and disease: A review of biological sex differences relevant to cancer with a spotlight on glioma","author":"SC Massey","year":"2020","journal-title":"Cancer Letters"},{"issue":"5","key":"pcbi.1009504.ref049","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/S0002-9394(98)00003-8","article-title":"Dexamethasone concentration in vitreous and serum after oral administration","volume":"125","author":"O Weijtens","year":"1998","journal-title":"American journal of ophthalmology"},{"issue":"7738","key":"pcbi.1009504.ref050","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/s41586-018-0792-9","article-title":"Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial","volume":"565","author":"DB Keskin","year":"2019","journal-title":"Nature"},{"key":"pcbi.1009504.ref051","article-title":"IFNg is Critical for CAR T Cell Mediated Myeloid Activation and Induction of Endogenous Immunity","author":"D Alizadeh","year":"2021","journal-title":"Cancer Discovery"},{"issue":"1","key":"pcbi.1009504.ref052","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-020-17175-8","article-title":"Tumor response and endogenous immune reactivity after administration of HER2 CAR T cells in a child with metastatic rhabdomyosarcoma","volume":"11","author":"M Hegde","year":"2020","journal-title":"Nature communications"},{"issue":"57","key":"pcbi.1009504.ref053","doi-asserted-by":"crossref","first-page":"eabd4344","DOI":"10.1126\/sciimmunol.abd4344","article-title":"A cross-talk between CAR T cell subsets and the tumor microenvironment is essential for sustained cytotoxic activity","volume":"6","author":"M Boulch","year":"2021","journal-title":"Science immunology"},{"key":"pcbi.1009504.ref054","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1200\/CCI.21.00023","article-title":"Next-Generation Implementation of Chimeric Antigen Receptor T-Cell Therapy Using Digital Health","volume":"5","author":"R Banerjee","year":"2021","journal-title":"JCO Clinical Cancer Informatics"},{"issue":"5","key":"pcbi.1009504.ref055","doi-asserted-by":"crossref","first-page":"4905","DOI":"10.3934\/mbe.2020267","article-title":"Identifying the spatial and temporal dynamics of molecularly-distinct glioblastoma sub-populations","volume":"17","author":"B Morris","year":"2020","journal-title":"Mathematical Biosciences and Engineering"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1009504","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T00:00:00Z","timestamp":1644192000000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009504","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,17]],"date-time":"2024-09-17T05:48:07Z","timestamp":1726552087000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009504"}},"subtitle":[],"editor":[{"given":"Heiko","family":"Enderling","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,1,26]]},"references-count":55,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1,26]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1009504","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.10.01.462697","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,26]]}}}