2024
Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer
Robles-Oteíza C, Hastings K, Choi J, Sirois I, Ravi A, Expósito F, de Miguel F, Knight J, López-Giráldez F, Choi H, Socci N, Merghoub T, Awad M, Getz G, Gainor J, Hellmann M, Caron É, Kaech S, Politi K. Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer. Journal Of Experimental Medicine 2024, 222: e20231106. PMID: 39585348, DOI: 10.1084/jem.20231106.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsNon-small cell lung cancerAcquired resistanceCheckpoint inhibitorsResistant tumorsPatients treated with anti-PD-1/PD-L1 therapyAnti-PD-1/PD-L1 therapyLung cancerResistance to immune checkpoint inhibitorsAssociated with decreased progression-free survivalHypoxia activated pro-drugsTargeting hypoxic tumor regionsTreat non-small cell lung cancerAnti-CTLA-4Anti-PD-1Immune checkpoint inhibitionTumor metabolic featuresProgression-free survivalCell lung cancerResistant cancer cellsHypoxic tumor regionsMHC-II levelsRegions of hypoxiaKnock-outCheckpoint inhibition
2023
LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility
Hwang J, Chai P, Nawaz S, Choi J, Lopez-Giraldez F, Hussain S, Bilguvar K, Mane S, Lifton R, Ahmad W, Zhang K, Chung J. LRRC23 truncation impairs radial spoke 3 head assembly and sperm motility underlying male infertility. ELife 2023, 12: rp90095. PMID: 38091523, PMCID: PMC10721216, DOI: 10.7554/elife.90095.Peer-Reviewed Original ResearchMicroRNA-1 protects the endothelium in acute lung injury
Korde A, Haslip M, Pednekar P, Khan A, Chioccioli M, Mehta S, Lopez-Giraldez F, Bermejo S, Rojas M, Dela Cruz C, Matthay M, Pober J, Pierce R, Takyar S. MicroRNA-1 protects the endothelium in acute lung injury. JCI Insight 2023, 8: e164816. PMID: 37737266, PMCID: PMC10561733, DOI: 10.1172/jci.insight.164816.Peer-Reviewed Original ResearchConceptsAcute respiratory distress syndromeAcute lung injuryVascular endothelial growth factorAngiopoietin-2Lung injuryAcute injuryMiR-1MicroRNA-1Endothelial cell-specific overexpressionSevere endothelial dysfunctionRespiratory distress syndromeSurvival of miceIntrinsic protective effectContext of injuryCell-specific overexpressionEndothelial growth factorFamily member 3Pneumonia cohortMiR-1 targetsEndothelial dysfunctionDistress syndromeBarrier dysfunctionCapillary leakProtective effectSevere formMultiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts
Kundishora A, Allington G, McGee S, Mekbib K, Gainullin V, Timberlake A, Nelson-Williams C, Kiziltug E, Smith H, Ocken J, Shohfi J, Allocco A, Duy P, Elsamadicy A, Dong W, Zhao S, Wang Y, Qureshi H, DiLuna M, Mane S, Tikhonova I, Fu P, Castaldi C, López-Giráldez F, Knight J, Furey C, Carter B, Haider S, Moreno-De-Luca A, Alper S, Gunel M, Millan F, Lifton R, Torene R, Jin S, Kahle K. Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts. Nature Medicine 2023, 29: 667-678. PMID: 36879130, DOI: 10.1038/s41591-023-02238-2.Peer-Reviewed Original ResearchConceptsArachnoid cystCerebral arachnoid cystsDe novo variantsAC pathogenesisDevelopmental brain lesionsStructural brain diseaseAppropriate clinical contextPatients' medical recordsDamaging de novo variantsMedical recordsClinical severityBrain lesionsHealthy individualsAC subtypesBrain diseasesGenetic testingNeurodevelopmental pathologyClinical contextPathogenesisPatient phenotypesNeurodevelopmental programsNovo variantsRNA sequencing transcriptomeHuman brainCysts
2022
Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas
Zhang H, Li B, Huang Q, López-Giráldez F, Tanaka Y, Lin Q, Mehta S, Wang G, Graham M, Liu X, Park I, Eichmann A, Min W, Zhou J. Mitochondrial dysfunction induces ALK5-SMAD2-mediated hypovascularization and arteriovenous malformations in mouse retinas. Nature Communications 2022, 13: 7637. PMID: 36496409, PMCID: PMC9741628, DOI: 10.1038/s41467-022-35262-w.Peer-Reviewed Original ResearchConceptsMitochondrial dysfunctionThioredoxin 2Single-cell RNA-seq analysisRNA-seq analysisMutant miceNuclear genesMitochondrial proteinsMitochondrial localizationHuman retinal diseasesTranscriptional factorsGene expressionMutant retinasMitochondrial activityExtracellular matrixNovel mechanismVascular maturationArteriovenous malformationsGenetic deficiencyVessel growthSmad2Mouse retinaVascular malformationsMechanistic studiesBasement membraneRetinal vascular malformations
2021
Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake
Habtemichael EN, Li DT, Camporez JP, Westergaard XO, Sales CI, Liu X, López-Giráldez F, DeVries SG, Li H, Ruiz DM, Wang KY, Sayal BS, González Zapata S, Dann P, Brown SN, Hirabara S, Vatner DF, Goedeke L, Philbrick W, Shulman GI, Bogan JS. Insulin-stimulated endoproteolytic TUG cleavage links energy expenditure with glucose uptake. Nature Metabolism 2021, 3: 378-393. PMID: 33686286, PMCID: PMC7990718, DOI: 10.1038/s42255-021-00359-x.Peer-Reviewed Original ResearchConceptsTUG cleavageGlucose uptakeProtein degradation pathwaysGLUT4 glucose transportersCoactivator PGC-1αC-terminal cleavage productInsulin-stimulated glucose uptakeAte1 arginyltransferaseGene expressionPhysiological relevanceWhole-body energy expenditureGlucose transporterPeroxisome proliferator-activated receptorCell surfacePGC-1αProtein 1Proliferator-activated receptorDegradation pathwayEffect of insulinCleavage pathwayAdipose cellsCleavage productsPathwayCleavageEnergy expenditure
2020
Dermal Adipocyte Lipolysis and Myofibroblast Conversion Are Required for Efficient Skin Repair
Shook BA, Wasko RR, Mano O, Rutenberg-Schoenberg M, Rudolph MC, Zirak B, Rivera-Gonzalez GC, López-Giráldez F, Zarini S, Rezza A, Clark DA, Rendl M, Rosenblum MD, Gerstein MB, Horsley V. Dermal Adipocyte Lipolysis and Myofibroblast Conversion Are Required for Efficient Skin Repair. Cell Stem Cell 2020, 26: 880-895.e6. PMID: 32302523, PMCID: PMC7853423, DOI: 10.1016/j.stem.2020.03.013.Peer-Reviewed Original ResearchConceptsSingle-cell RNA sequencingDermal adipocytesGenetic lineage tracingMammary gland biologyMature adipocytesGenetic mouse studiesAdipocyte-derived lipidsGenetic experimentsTissue homeostasisRNA sequencingLineage tracingECM-producing myofibroblastsDefective wound healingAdipocyte lipolysisMyofibroblast conversionAdipocyte functionEssential roleLipid releaseAdipocytesFatty acidsMacrophage inflammationInflammatory diseasesMultiple aspectsSkin repairMouse studiesTumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6
Arnal-Estapé A, Cai WL, Albert AE, Zhao M, Stevens LE, López-Giráldez F, Patel KD, Tyagi S, Schmitt EM, Westbrook TF, Nguyen DX. Tumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6. Oncogene 2020, 39: 3726-3737. PMID: 32157212, PMCID: PMC7190573, DOI: 10.1038/s41388-020-1246-z.Peer-Reviewed Original ResearchConceptsChromatin landscapeTranscription factorsBone morphogenetic protein (BMP) signalingDiverse transcriptional programsAlters chromatin accessibilityMultiple genomic lociMorphogenetic protein signalingDistal enhancer elementsSelective transcription factorsEpithelial cell typesSurfactant protein CChromatin accessibilityGenomic lociTranscriptional programsLung adenocarcinoma progressionTumor progressionEpigenetic mechanismsProtein signalingBiological functionsLUAD progressionLUAD cellsEnhancer elementsLineage dependencyTumor suppressionLung cancer cells
2019
Progenitor-derived human endothelial cells evade alloimmunity by CRISPR/Cas9-mediated complete ablation of MHC expression
Merola J, Reschke M, Pierce RW, Qin L, Spindler S, Baltazar T, Manes TD, Lopez-Giraldez F, Li G, Bracaglia LG, Xie C, Kirkiles-Smith N, Saltzman WM, Tietjen GT, Tellides G, Pober JS. Progenitor-derived human endothelial cells evade alloimmunity by CRISPR/Cas9-mediated complete ablation of MHC expression. JCI Insight 2019, 4 PMID: 31527312, PMCID: PMC6824302, DOI: 10.1172/jci.insight.129739.Peer-Reviewed Original ResearchMeSH KeywordsAllograftsAnimalsBeta 2-MicroglobulinCD4-Positive T-LymphocytesCD8-Positive T-LymphocytesCell DifferentiationCells, CulturedCRISPR-Cas SystemsDisease Models, AnimalEndothelial CellsEndothelial Progenitor CellsFemaleFetal BloodGene Knockout TechniquesGraft RejectionHealthy VolunteersHumansIsoantibodiesKiller Cells, NaturalLymphocyte ActivationMiceMicrovesselsNuclear ProteinsOrgan TransplantationPrimary Cell CultureTissue EngineeringTrans-ActivatorsConceptsDonor-specific antibodiesClass II transactivatorEndothelial cellsMHC expressionAllogeneic natural killer (NK) cellsT effector memory cellsEffector memory T cellsClass IClass II major histocompatibility complex moleculesEffector memory cellsMHC molecule expressionMemory T cellsNatural killer cellsAlloreactive cytotoxic T lymphocytesAllogeneic endothelial cellsMajor histocompatibility complex moleculesCytotoxic T lymphocytesClass I MHC moleculesHistocompatibility complex moleculesI MHC moleculesAllogeneic CD4Donor leukocytesHuman endothelial cellsGraft perfusionKiller cells
2018
Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair
Shook BA, Wasko RR, Rivera-Gonzalez GC, Salazar-Gatzimas E, López-Giráldez F, Dash BC, Muñoz-Rojas AR, Aultman KD, Zwick RK, Lei V, Arbiser JL, Miller-Jensen K, Clark DA, Hsia HC, Horsley V. Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair. Science 2018, 362 PMID: 30467144, PMCID: PMC6684198, DOI: 10.1126/science.aar2971.Peer-Reviewed Original ResearchConceptsDifferential gene expressionAdipocyte precursorsExtracellular matrix moleculesGene expressionTransplantation assaysMatrix moleculesFactor C.Factor 1Insulin-like growth factor-1Cell populationsTissue resilienceDistinct subpopulationsGrowth factor-1Profibrotic cellsTissue repairMultiple mouse modelsECM depositionSkin repairTissue dysfunctionProliferationMouse modelMyofibroblastsWoundingMacrophagesRepairIn utero nanoparticle delivery for site-specific genome editing
Ricciardi AS, Bahal R, Farrelly JS, Quijano E, Bianchi AH, Luks VL, Putman R, López-Giráldez F, Coşkun S, Song E, Liu Y, Hsieh WC, Ly DH, Stitelman DH, Glazer PM, Saltzman WM. In utero nanoparticle delivery for site-specific genome editing. Nature Communications 2018, 9: 2481. PMID: 29946143, PMCID: PMC6018676, DOI: 10.1038/s41467-018-04894-2.Peer-Reviewed Original ResearchConceptsSite-specific genome editingReversal of splenomegalyPeptide nucleic acidIntra-amniotic administrationBlood hemoglobin levelsMonogenic disordersNanoparticle deliveryPolymeric nanoparticlesPostnatal elevationGestational ageHemoglobin levelsImproved survivalPediatric morbidityDisease improvementHuman β-thalassemiaReticulocyte countNormal organ developmentMouse modelNormal rangeEarly interventionGenome editingOff-target mutationsPostnatal growthGene editingVersatile method
2016
In vivo correction of anaemia in β-thalassemic mice by γPNA-mediated gene editing with nanoparticle delivery
Bahal R, Ali McNeer N, Quijano E, Liu Y, Sulkowski P, Turchick A, Lu YC, Bhunia DC, Manna A, Greiner DL, Brehm MA, Cheng CJ, López-Giráldez F, Ricciardi A, Beloor J, Krause DS, Kumar P, Gallagher PG, Braddock DT, Mark Saltzman W, Ly DH, Glazer PM. In vivo correction of anaemia in β-thalassemic mice by γPNA-mediated gene editing with nanoparticle delivery. Nature Communications 2016, 7: 13304. PMID: 27782131, PMCID: PMC5095181, DOI: 10.1038/ncomms13304.Peer-Reviewed Original ResearchConceptsNanoparticle deliveryGene correctionReversal of splenomegalyPeptide nucleic acidLow off-target effectsVivo correctionGenome editingOff-target effectsGene editingHaematopoietic stem cellsNucleic acidsDonor DNAStem cellsΓPNAΒ-thalassaemiaNanoparticlesDeliveryEditingSCF treatmentTriplex formation
2015
E2F8 as a Novel Therapeutic Target for Lung Cancer
Park SA, Platt J, Lee JW, López-Giráldez F, Herbst RS, Koo JS. E2F8 as a Novel Therapeutic Target for Lung Cancer. Journal Of The National Cancer Institute 2015, 107: djv151. PMID: 26089541, PMCID: PMC4651101, DOI: 10.1093/jnci/djv151.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic AgentsCCAAT-Enhancer-Binding ProteinsCell Line, TumorCell ProliferationCell SurvivalChromatin ImmunoprecipitationFluorescent Antibody TechniqueGene Expression Regulation, NeoplasticHumansImmunoblottingKaplan-Meier EstimateLung NeoplasmsMiceMolecular Targeted TherapyNeoplastic Stem CellsPromoter Regions, GeneticRepressor ProteinsTissue Array AnalysisUbiquitin-Protein LigasesUp-RegulationXenograft Model Antitumor AssaysConceptsTarget genesCell cycle regulationNovel therapeutic targetPromoter activity assaysCell proliferationCancer cellsExpression of UHRF1Transcription activatorAntisense morpholinoChromatin immunoprecipitationCycle regulationTherapeutic targetEmbryonic developmentE2F membersHuman lung cancer cellsMicroarray analysisInvasion analysisLung cancer cellsDirect bindingTumor growthE2F8Activity assaysPublic databasesColony formationUHRF1
2014
Single-stranded γPNAs for in vivo site-specific genome editing via Watson-Crick recognition.
Bahal R, Quijano E, McNeer NA, Liu Y, Bhunia DC, Lopez-Giraldez F, Fields RJ, Saltzman WM, Ly DH, Glazer PM. Single-stranded γPNAs for in vivo site-specific genome editing via Watson-Crick recognition. Current Gene Therapy 2014, 14: 331-42. PMID: 25174576, PMCID: PMC4333085, DOI: 10.2174/1566523214666140825154158.Peer-Reviewed Original ResearchConceptsGene editingSite-specific genome editingEfficient intracellular deliverySite-specific formationIntracellular deliveryGamma PNAsGenome editingAltered helical structureGenomic DNANext generationDonor DNAΓPNANovel strategyMouse bone marrow cellsNanoparticlesDNA repairEditingMouse bone marrowHomopurine sitesSequence restrictionDetectable toxicityBone marrow cellsDNAHereinHelical structure
2013
Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm
Song Y, Nagy M, Ni W, Tyagi NK, Fenton WA, López-Giráldez F, Overton JD, Horwich AL, Brady ST. Molecular chaperone Hsp110 rescues a vesicle transport defect produced by an ALS-associated mutant SOD1 protein in squid axoplasm. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 5428-5433. PMID: 23509252, PMCID: PMC3619309, DOI: 10.1073/pnas.1303279110.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAxonal TransportBacterial ProteinsDecapodiformesGene Expression ProfilingHSP110 Heat-Shock ProteinsHumansLuminescent ProteinsMAP Kinase Kinase Kinase 5MiceMice, TransgenicMutation, MissenseP38 Mitogen-Activated Protein KinasesPhosphorylationProtein FoldingProteomicsRecombinant Fusion ProteinsSpinal CordSuperoxide DismutaseSuperoxide Dismutase-1Transport VesiclesConceptsMutant SOD1 proteinTransport defectSOD1 proteinApoptosis signal-regulating kinase 1 inhibitorsPhosphorylation of kinesinNucleotide exchange factorsMolecular chaperone Hsc70Different oligomeric statesYellow fluorescent proteinTransgenic miceProtein disaggregationChaperone Hsc70Exchange factorMAPK cascadePhosphorylation of p38Oligomeric stateDiminished phosphorylationKinase 1 inhibitorFusion proteinFluorescent proteinP38 inhibitorP38 MAPKPhosphorylationHsp110Cu/Zn