2023
Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment
Chiorazzi M, Martinek J, Krasnick B, Zheng Y, Robbins K, Qu R, Kaufmann G, Skidmore Z, Juric M, Henze L, Brösecke F, Adonyi A, Zhao J, Shan L, Sefik E, Mudd J, Bi Y, Goedegebuure S, Griffith M, Griffith O, Oyedeji A, Fertuzinhos S, Garcia-Milian R, Boffa D, Detterbeck F, Dhanasopon A, Blasberg J, Judson B, Gettinger S, Politi K, Kluger Y, Palucka K, Fields R, Flavell R. Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment. Journal For ImmunoTherapy Of Cancer 2023, 11: e006921. PMID: 37487666, PMCID: PMC10373695, DOI: 10.1136/jitc-2023-006921.Peer-Reviewed Original ResearchConceptsHuman tumor microenvironmentTumor microenvironmentTumor-immune interactionsSolid tumorsAdaptive immune activationAdaptive immune populationsIndividual tumor microenvironmentsPatient's hematopoietic systemPatient-derived xenograft tissuesVascular endothelial growth factorBone marrow hematopoietic stemBone marrow aspiratePreclinical drug testingEndothelial growth factorHematopoietic systemAutologous tumorPDX modelingPDX miceImmune activationImmune populationsMarrow aspiratesAutologous systemIndividual patientsLittermate controlsPreclinical predictionsThe age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques
Kabir I, Zhang X, Dave J, Chakraborty R, Qu R, Chandran R, Ntokou A, Gallardo-Vara E, Aryal B, Rotllan N, Garcia-Milian R, Hwa J, Kluger Y, Martin K, Fernández-Hernando C, Greif D. The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques. Nature Aging 2023, 3: 64-81. PMID: 36743663, PMCID: PMC9894379, DOI: 10.1038/s43587-022-00342-5.Peer-Reviewed Original ResearchConceptsAtherosclerotic plaquesBone marrowSmooth muscle-derived cellsSMC progenitorsAtherosclerotic plaque cellsSmooth muscle cell progenitorsPredominant risk factorCause of deathNovel therapeutic strategiesTNF receptor 1Muscle-derived cellsAged bone marrowAged BMEffect of agePlaque burdenAged miceRisk factorsTumor necrosisTherapeutic strategiesPlaque cellsMyeloid cellsReceptor 1Integrin β3Cell progenitorsAtherosclerosis
2022
Examining sex differences in responses to footshock stress and the role of the metabotropic glutamate receptor 5: an [18F]FPEB and positron emission tomography study in rats
Asch RH, Pothula S, Toyonaga T, Fowles K, Groman SM, Garcia-Milian R, DiLeone RJ, Taylor JR, Esterlis I. Examining sex differences in responses to footshock stress and the role of the metabotropic glutamate receptor 5: an [18F]FPEB and positron emission tomography study in rats. Neuropsychopharmacology 2022, 48: 489-497. PMID: 36100654, PMCID: PMC9852230, DOI: 10.1038/s41386-022-01441-y.Peer-Reviewed Original ResearchLiver metabolomics identifies bile acid profile changes at early stages of alcoholic liver disease in mice
Charkoftaki G, Tan WY, Berrios-Carcamo P, Orlicky DJ, Golla JP, Garcia-Milian R, Aalizadeh R, Thomaidis NS, Thompson DC, Vasiliou V. Liver metabolomics identifies bile acid profile changes at early stages of alcoholic liver disease in mice. Chemico-Biological Interactions 2022, 360: 109931. PMID: 35429548, PMCID: PMC9364420, DOI: 10.1016/j.cbi.2022.109931.Peer-Reviewed Original ResearchConceptsAlcoholic liver diseaseEthanol-consuming miceAlcohol consumptionLiver diseaseDevelopment of ALDBile acid changesChronic alcohol drinkingChronic alcohol consumptionLieber-DeCarli dietAlcohol-induced alterationsGlobal healthcare problemBile acid biosynthesisAlcohol drinkingLiver histopathologyTissue injuryClinical consequencesUntargeted metabolomics analysisEarly stagesComplex pathologyMinimal changesUntargeted metabolomics approachEarly onsetHealthcare problemMiceLiver
2021
Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis
Chandran RR, Xie Y, Gallardo-Vara E, Adams T, Garcia-Milian R, Kabir I, Sheikh AQ, Kaminski N, Martin KA, Herzog EL, Greif DM. Distinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis. Nature Communications 2021, 12: 7179. PMID: 34893592, PMCID: PMC8664937, DOI: 10.1038/s41467-021-27499-8.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell ProliferationDisease Models, AnimalDown-RegulationExtracellular MatrixFemaleFibroblastsFibrosisHumansKruppel-Like Factor 4LungLung InjuryMaleMesenchymal Stem CellsMiceMice, Inbred C57BLMyofibroblastsReceptor, Platelet-Derived Growth Factor betaRespiratory Tract DiseasesSignal TransductionTransforming Growth Factor betaConceptsMesenchymal cell typesPlatelet-derived growth factor receptorSmooth muscle actinLung fibrosisKruppel-like factor 4Forkhead box M1Growth factor receptorCell transitionCell typesExtracellular matrixDistinct rolesKLF4Box M1C chemokine ligandMesenchymal cell subtypesFactor receptorPro-fibrotic effectsFactor 4PDGFRMesenchymeCellsMacrophage accumulationKLF4 levelsChemokine ligandLung fibrogenesisImpaired GSH biosynthesis disrupts eye development, lens morphogenesis and PAX6 function
Thompson B, Chen Y, Davidson EA, Garcia-Milian R, Golla JP, Apostolopoulos N, Orlicky DJ, Schey K, Thompson DC, Vasiliou V. Impaired GSH biosynthesis disrupts eye development, lens morphogenesis and PAX6 function. The Ocular Surface 2021, 22: 190-203. PMID: 34425299, PMCID: PMC8560581, DOI: 10.1016/j.jtos.2021.08.010.Peer-Reviewed Original ResearchConceptsHEK293T cellsEye developmentGSH biosynthesisTransactivation activityPax6 functionReactive oxygen speciesSubsequent gene ontologyCell identity genesButhionine sulfoximineEpithelial cell identityRNA-seq analysisIngenuity Pathway AnalysisKey upstream regulatorIdentity genesCell identityGene OntologyRNA-seqImmune response genesBioinformatics analysisResponse genesGlutathione biosynthesisLens morphogenesisMolecular consequencesUpstream regulatorMicrophthalmia phenotypeIdentification of Dose-Dependent DNA Damage and Repair Responses From Subchronic Exposure to 1,4-Dioxane in Mice Using a Systems Analysis Approach
Charkoftaki G, Golla JP, Santos-Neto A, Orlicky DJ, Garcia-Milian R, Chen Y, Rattray NJW, Cai Y, Wang Y, Shearn CT, Mironova V, Wang Y, Johnson CH, Thompson DC, Vasiliou V. Identification of Dose-Dependent DNA Damage and Repair Responses From Subchronic Exposure to 1,4-Dioxane in Mice Using a Systems Analysis Approach. Toxicological Sciences 2021, 183: 338-351. PMID: 33693819, PMCID: PMC8921626, DOI: 10.1093/toxsci/kfab030.Peer-Reviewed Original ResearchConceptsDX exposureBile acid quantificationRepair responseBDF-1 miceDNA damageDose-dependent DNA damageEffects of exposureHistopathological studySubchronic exposureImmunohistochemical analysisLiver carcinogenLiver carcinogenicityLiver transcriptomicsDrinking waterMetabolomic profilingMicePotential mechanismsLiverEnvironmental chemicalsState maximum contaminant levelToxic effectsCell deathExposureOxidative stress responsePresent study
2020
Glucocorticoids and serum- and glucocorticoid-inducible kinase 1 are potent regulators of CFTR in the native intestine: implications for stress-induced diarrhea
Ahsan MK, Figueroa-Hall L, Baratta V, Garcia-Milian R, Lam TT, Hoque K, Salas PJ, Ameen NA. Glucocorticoids and serum- and glucocorticoid-inducible kinase 1 are potent regulators of CFTR in the native intestine: implications for stress-induced diarrhea. AJP Gastrointestinal And Liver Physiology 2020, 319: g121-g132. PMID: 32567324, PMCID: PMC7500270, DOI: 10.1152/ajpgi.00076.2020.Peer-Reviewed Original Research14-3-3 ProteinsAnimalsBacterial ToxinsCystic Fibrosis Transmembrane Conductance RegulatorDexamethasoneDiarrheaDimethyl SulfoxideEnterotoxinsEscherichia coli ProteinsGene Expression RegulationImmediate-Early ProteinsMaleNedd4 Ubiquitin Protein LigasesPhosphatidylinositol 3-KinasesProtein Serine-Threonine KinasesProtein TransportProto-Oncogene Proteins c-aktPyruvate Dehydrogenase Acetyl-Transferring KinaseRatsRats, Sprague-DawleySodium-Hydrogen Exchanger 3
2019
Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune response
Sahraei M, Chaube B, Liu Y, Sun J, Kaplan A, Price NL, Ding W, Oyaghire S, García-Milian R, Mehta S, Reshetnyak YK, Bahal R, Fiorina P, Glazer PM, Rimm DL, Fernández-Hernando C, Suárez Y. Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune response. Journal Of Clinical Investigation 2019, 129: 5518-5536. PMID: 31710308, PMCID: PMC6877327, DOI: 10.1172/jci127125.Peer-Reviewed Original ResearchConceptsTumor-associated macrophagesMiR-21 expressionTumor growthMiR-21Immune responseCytotoxic T cell responsesC motif chemokine 10Antitumor immune responseT cell responsesAntitumoral immune responseTumor immune infiltratesInduction of cytokinesPotential therapeutic implicationsMiR-21 inhibitionStages of carcinogenesisAngiostatic phenotypeTumor cell deathIL-12Immune infiltratesTherapeutic implicationsSolid tumorsTumor neovascularizationTumor progressionTumor microenvironmentTumor pathogenesisGlutathione deficiency-elicited reprogramming of hepatic metabolism protects against alcohol-induced steatosis
Chen Y, Manna SK, Golla S, Krausz KW, Cai Y, Garcia-Milian R, Chakraborty T, Chakraborty J, Chatterjee R, Thompson DC, Gonzalez FJ, Vasiliou V. Glutathione deficiency-elicited reprogramming of hepatic metabolism protects against alcohol-induced steatosis. Free Radical Biology And Medicine 2019, 143: 127-139. PMID: 31351176, PMCID: PMC6848780, DOI: 10.1016/j.freeradbiomed.2019.07.025.Peer-Reviewed Original ResearchMeSH KeywordsAcetyl Coenzyme AAlcohol DrinkingAMP-Activated Protein KinasesAnimalsEthanolFatty AcidsFatty LiverGlucuronic AcidGlutamate-Cysteine LigaseGlutamatesGlutathioneHomeostasisLipogenesisLiverMaleMiceMice, Inbred C57BLMice, KnockoutOligonucleotide Array Sequence AnalysisOxidation-ReductionOxidative StressPentose Phosphate PathwayProtective AgentsTranscription, GeneticConceptsGlutamate-cysteine ligase modifier subunit geneProtein kinase pathwayAcetyl-CoA fluxMultiple cellular pathwaysAlcohol-induced steatosisCellular stressNucleotide biosynthesisLiver microarray analysisGlobal profilingSubunit geneCellular pathwaysMetabolic reprogrammingKinase pathwayMicroarray analysisMolecular mechanismsGSH poolCellular responsesMetabolic pathwaysLower GSHMolecular pathwaysMetabolic homeostasisAmino acidsDepletion of glutathioneCritical pathogenic eventGlucuronate pathwayDetermining the endocrine disruption potential of industrial chemicals using an integrative approach: Public databases, in vitro exposure, and modeling receptor interactions
Alofe O, Kisanga E, Inayat-Hussain SH, Fukumura M, Garcia-Milian R, Perera L, Vasiliou V, Whirledge S. Determining the endocrine disruption potential of industrial chemicals using an integrative approach: Public databases, in vitro exposure, and modeling receptor interactions. Environment International 2019, 131: 104969. PMID: 31310931, PMCID: PMC6728168, DOI: 10.1016/j.envint.2019.104969.Peer-Reviewed Original ResearchConceptsEstrogen receptorEstradiol-mediated inductionLow-dose combinationIshikawa cell lineLow-dose effectsDirect stimulatoryPotential of chemicalsRate of proliferationOccupational exposureIshikawa cellsAnimal modelsHuman studiesReproductive toxicityCarcinogenic effectsInhibitory effectToxicology testingEndocrineCell proliferationEndocrine disruption potentialDose effectReceptor interactionIndustrial chemicalsCell linesPublic healthAdditive effectRegulated necrosis and failed repair in cisplatin-induced chronic kidney disease
Landau SI, Guo X, Velazquez H, Torres R, Olson E, Garcia-Milian R, Moeckel GW, Desir GV, Safirstein R. Regulated necrosis and failed repair in cisplatin-induced chronic kidney disease. Kidney International 2019, 95: 797-814. PMID: 30904067, PMCID: PMC6543531, DOI: 10.1016/j.kint.2018.11.042.Peer-Reviewed Original ResearchConceptsChronic kidney diseaseKidney diseaseKidney injuryCisplatin-induced chronic kidney diseaseCisplatin-induced acute kidney injuryToll-like receptor 2Regulated necrosis pathwaysReversible kidney injuryAcute kidney injuryChronic kidney injuryProximal tubular damageKidney injury markersDoses of cisplatinEvidence of fibrosisMechanisms of progressionEffective chemotherapeutic agentWestern blot analysisFirst doseInjury markersIntraperitoneal cisplatinSignificant nephrotoxicityTubular damageKidney functionSecond doseCisplatin administrationHepatic metabolic adaptation in a murine model of glutathione deficiency
Chen Y, Golla S, Garcia-Milian R, Thompson DC, Gonzalez FJ, Vasiliou V. Hepatic metabolic adaptation in a murine model of glutathione deficiency. Chemico-Biological Interactions 2019, 303: 1-6. PMID: 30794799, PMCID: PMC6743730, DOI: 10.1016/j.cbi.2019.02.015.Peer-Reviewed Original ResearchConceptsCellular non-protein thiolsMetabolic adaptationGlutamate-cysteine ligase modifier subunitNon-protein thiolsHepatic metabolic adaptationCellular redoxGlobal profilingGSH homeostasisModifier subunitLiver developmentBiochemical mechanismsMetabolic homeostasisAmino acidsGclm null miceDefense mechanismsEnvironmental insultsOxidative damageFatty liver developmentNull miceSpectrum of changesNucleic acidsMetabolic signaturesPivotal roleHomeostasisGlutathione deficiency