2024
Modulation of canonical Wnt signaling regulates peribiliary mesenchymal identity during homeostasis and injury
Singh S, Budiman T, Redmond D, Gupta V. Modulation of canonical Wnt signaling regulates peribiliary mesenchymal identity during homeostasis and injury. Hepatology Communications 2024, 8: e0368. PMID: 38251878, PMCID: PMC10805418, DOI: 10.1097/hc9.0000000000000368.Peer-Reviewed Original ResearchConceptsT-box transcription factorTranscription factorsMesenchymal gene expressionSignaling effectorsGene expressionGli transcription factorsGene transcription programUpregulation of TBX2Gain of functionSingle-cell sequencingExtrahepatic bile ductCellular identityTranscriptome analysisTranscriptional programsReceptor-ligand analysisMyofibroblast transdifferentiationIn vivo approachesB-cateninT-boxSignaling pathwayBile ductTbx3 expressionTbx3Primary sclerosing cholangitisBile duct ligation
2023
PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants
Baysac K, Sun G, Nakano H, Schmitz E, Cruz A, Fisher C, Bailey A, Group P, Abbott J, Becerra J, Allenspach E, Assing K, Atkinson T, Bargir U, Baxter S, Bergerson J, Bista R, Blanche S, Buckley L, Butte M, Carcamo B, Chandrakala S, Chen K, Chervinskiy S, Chinn I, Chong H, Coffey K, Copland A, Cowen E, Cros G, De Bruycker J, de la Morena M, Ehlayel M, Satter L, Gelfand E, Gilliaux O, Glover S, Gorman M, Griffin T, Grimbacher B, Gru A, Haddad E, Hadjadj J, Hajjar J, Hauck F, Hautala T, Holland S, Hsieh E, Hsu F, Jacquemin E, Jindal A, Kahn S, Keller M, Kobayashi R, Krupski C, Larkin A, Lawrence M, Madkaikar M, Malphettes M, Martelius, Mehta M, Metcalfe D, Meyts I, Nannapaneni N, Vinyals J, Olivier K, Ombrello A, Orange J, Rabinovitch N, Rauscher C, Redfern A, Reynolds P, Rieux-Laucat F, Secord E, Seeborg F, Seppänen M, Sereti I, Shin D, Shin J, Snapper S, Suri D, Tangcheewinsirikul S, Thatayatikom A, Torgerson T, Touzot F, Uzel G, Varjosalo M, Vasconcelos D, von Bernuth H, Walsh T, Walter J, Ward B, Wittkowski H, Wysocki C, Mace E, Milner J, Ombrello M. PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants. Journal Of Allergy And Clinical Immunology 2023, 153: 230-242. PMID: 37769878, PMCID: PMC11337301, DOI: 10.1016/j.jaci.2023.08.036.Peer-Reviewed Original ResearchConceptsImmune dysregulationPhospholipase C gamma 2Gain of functionB cellsNatural killer cell dysfunctionCalcium fluxLoF variantsNatural killer cellsHumoral immune deficiencyDistinct clinical presentationsPrimary patient cellsExtracellular signal-regulated kinase (ERK) phosphorylationB cell activationSignal-regulated kinase phosphorylationPLCG2 mutationsAntibody deficiencyKiller cellsClinical presentationImmune deficiencyCell dysfunctionClinical dataStandardized questionnaireFunctional alterationsSporadic casesPathogenic variantsUterine leiomyosarcomas harboring MAP2K4 gene amplification are sensitive in vivo to PLX8725, a novel MAP2K4 inhibitor
McNamara B, Harold J, Manavella D, Bellone S, Mutlu L, Hartwich T, Zipponi M, Yang-Hartwich Y, Demirkiran C, Verzosa M, Yang K, Choi J, Dong W, Buza N, Hui P, Altwerger G, Huang G, Andikyan V, Clark M, Ratner E, Azodi M, Schwartz P, Burton E, Inagaki H, Albers A, Zhang C, Bollag G, Schlessinger J, Santin A. Uterine leiomyosarcomas harboring MAP2K4 gene amplification are sensitive in vivo to PLX8725, a novel MAP2K4 inhibitor. Gynecologic Oncology 2023, 172: 65-71. PMID: 36958197, PMCID: PMC10192120, DOI: 10.1016/j.ygyno.2023.03.009.Peer-Reviewed Original ResearchConceptsUterine leiomyosarcomaPDX modelsGain of functionMedian overall survivalPhase I trialOral gavage dailyVivo activityTumor growth inhibitionTumor volume differencesTumor cell proliferationOverall survivalTolerable toxicityI trialOral treatmentTreatment cohortsGavage dailyAggressive tumorsSCID miceULMS patientsPK studiesTumor samplesWestern blotCell proliferationControl vehicleLeiomyosarcoma
2022
Identification of growth hormone receptor as a relevant target for precision medicine in low‐EGFR expressing glioblastoma
Verreault M, Vilchis I, Rosenberg S, Lemaire N, Schmitt C, Guehennec J, Royer‐Perron L, Thomas J, Lam TT, Dingli F, Loew D, Ducray F, Paris S, Carpentier C, Marie Y, Laigle‐Donadey F, Rousseau A, Pigat N, Boutillon F, Bielle F, Mokhtari K, Frank SJ, de Reyniès A, Hoang‐Xuan K, Sanson M, Goffin V, Idbaih A. Identification of growth hormone receptor as a relevant target for precision medicine in low‐EGFR expressing glioblastoma. Clinical And Translational Medicine 2022, 12: e939. PMID: 35808822, PMCID: PMC9270581, DOI: 10.1002/ctm2.939.Peer-Reviewed Original ResearchConceptsEpidermal growth factor receptorGrowth hormone receptorPatient-derived cell linesOncogenic mechanismsGene expression profilesCell linesGain of functionHormone receptorsExpression of proteinsCellular movementGrowth factor receptorHuman GBM samplesExpression profilesCell migrationCommon oncogenic mechanismThird of patientsDistinct molecular subsetsGBM samplesPromoter hypermethylationNew therapeutic approachesFactor receptorCell proliferationPharmacological inhibitionRelevant targetsOverexpression
2021
Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function
Kumar M, Molkentine D, Molkentine J, Bridges K, Xie T, Yang L, Hefner A, Gao M, Bahri R, Dhawan A, Frederick MJ, Seth S, Abdelhakiem M, Beadle BM, Johnson F, Wang J, Shen L, Heffernan T, Sheth A, Ferris RL, Myers JN, Pickering CR, Skinner HD. Inhibition of histone acetyltransferase function radiosensitizes CREBBP/EP300 mutants via repression of homologous recombination, potentially targeting a gain of function. Nature Communications 2021, 12: 6340. PMID: 34732714, PMCID: PMC8566594, DOI: 10.1038/s41467-021-26570-8.Peer-Reviewed Original ResearchMeSH KeywordsAcetylationAnimalsApoptosisBiomarkers, TumorBRCA1 ProteinCell Line, TumorCREB-Binding ProteinE1A-Associated p300 ProteinGain of Function MutationHistone AcetyltransferasesHomologous RecombinationHumansMaleMice, NudeMutationNeoplasmsProtein DomainsSquamous Cell Carcinoma of Head and NeckXenograft Model Antitumor AssaysEndothelial SIRT3 regulates myofibroblast metabolic shifts in diabetic kidneys
Srivastava SP, Li J, Takagaki Y, Kitada M, Goodwin JE, Kanasaki K, Koya D. Endothelial SIRT3 regulates myofibroblast metabolic shifts in diabetic kidneys. IScience 2021, 24: 102390. PMID: 33981977, PMCID: PMC8086030, DOI: 10.1016/j.isci.2021.102390.Peer-Reviewed Original ResearchDiabetic kidney fibrosisDiabetic kidneyEndothelial cellsKidney fibrosisDefective metabolismRenal tubular epithelial cellsTubular epithelial cellsKidney functionDiabetic miceFibrogenic pathwaysFibrogenic processDisease processLoss of functionMesenchymal transitionKidneyMouse strainsEpithelial cellsGain of functionSIRT3Metabolic reprogrammingMesenchymal transformationFibrosisSIRT3 geneMetabolismCells
2018
Epstein–Barr Virus Susceptibility in Activated PI3Kδ Syndrome (APDS) Immunodeficiency
Carpier JM, Lucas CL. Epstein–Barr Virus Susceptibility in Activated PI3Kδ Syndrome (APDS) Immunodeficiency. Frontiers In Immunology 2018, 8: 2005. PMID: 29387064, PMCID: PMC5776011, DOI: 10.3389/fimmu.2017.02005.Peer-Reviewed Original ResearchPrimary immunodeficiency diseasesAPDS patientsEpstein-Barr virus infectionDefective immunoglobulin productionCell-mediated cytotoxicityRecurrent sinopulmonary infectionsFunction mutationsEBV susceptibilityPI3Kδ syndromeEBV infectionPID patientsLymphoproliferative diseaseSinopulmonary infectionsImmunoglobulin productionB lymphocyte developmentImmune disordersImmunodeficiency diseaseT cellsVirus infectionPatientsLymphocyte biologySenescence markersAntigen receptorGain of functionInfection
2016
Somatic Mutations in NEK9 Cause Nevus Comedonicus
Levinsohn JL, Sugarman JL, Genomics Y, McNiff JM, Antaya RJ, Choate KA. Somatic Mutations in NEK9 Cause Nevus Comedonicus. American Journal Of Human Genetics 2016, 98: 1030-1037. PMID: 27153399, PMCID: PMC4863661, DOI: 10.1016/j.ajhg.2016.03.019.Peer-Reviewed Original ResearchConceptsWhole-exome sequencingNevus comedonicusAcne vulgarisNormal follicular differentiationFirst-degree relativesFollicular plugsRare disorderSevere diseaseNormal folliclesFollicular differentiationComedo formationGain of functionMost adolescentsAffected tissuesKeratin 10Differentiation markersComedonesFollicular homeostasisSomatic mutationsCystsFolliclesGenetic determinantsKinase activationPotential regulatorEctopic expressionNovel targeted therapies in uterine serous carcinoma, an aggressive variant of endometrial cancer.
Menderes G, Clark M, Santin AD. Novel targeted therapies in uterine serous carcinoma, an aggressive variant of endometrial cancer. Discovery Medicine 2016, 21: 293-303. PMID: 27232515.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntineoplastic AgentsClass I Phosphatidylinositol 3-KinasesCyclin ECystadenocarcinoma, SerousEndometrial NeoplasmsEpothilonesExomeFemaleHumansMolecular Targeted TherapyMutationNeoplasm Recurrence, LocalOncogene ProteinsPrognosisProtein Kinase InhibitorsProtein Phosphatase 2RadioimmunotherapyReceptor, ErbB-2Sequence Analysis, DNASignal TransductionTOR Serine-Threonine KinasesTubulin ModulatorsTumor Suppressor Protein p53Uterine NeoplasmsVascular Endothelial Growth Factor AConceptsUterine serous carcinomaEndometrial cancerSerous carcinomaTreatment of USCPIK3CA/AKT/mTOREndometrial cancer casesRecent whole-exome sequencing studiesHER2/neu geneNovel therapeutic targetAkt/mTORBiologic therapyAggressive variantDismal prognosisAggressive subtypeWhole-exome sequencing studiesCancer casesTherapeutic targetSubsequent deathDriver mutationsNeu geneGain of functionCarcinomaTherapyCancerSequencing studies
2015
Quinidine in the treatment of KCNT1‐positive epilepsies
Mikati MA, Jiang YH, Carboni M, Shashi V, Petrovski S, Spillmann R, Milligan CJ, Li M, Grefe A, McConkie A, Berkovic S, Scheffer I, Mullen S, Bonner M, Petrou S, Goldstein D. Quinidine in the treatment of KCNT1‐positive epilepsies. Annals Of Neurology 2015, 78: 995-999. PMID: 26369628, PMCID: PMC4811613, DOI: 10.1002/ana.24520.Peer-Reviewed Original ResearchConceptsEpilepsy of infancySecondary generalized seizuresDrug-resistant epilepsySeizure frequencyGeneralized seizuresFocal seizuresKCNT1 mutationsSeizure evaluationSeizure diariesTargeted drugsTherapeutic benefitDevelopmental regressionEpilepsyGain of functionQuinidineEarly childhoodSeizuresPatientsMutations
2014
A CACNA1C Variant Associated with Reduced Voltage-Dependent Inactivation, Increased CaV1.2 Channel Window Current, and Arrhythmogenesis
Hennessey JA, Boczek NJ, Jiang YH, Miller JD, Patrick W, Pfeiffer R, Sutphin BS, Tester DJ, Barajas-Martinez H, Ackerman MJ, Antzelevitch C, Kanter R, Pitt GS. A CACNA1C Variant Associated with Reduced Voltage-Dependent Inactivation, Increased CaV1.2 Channel Window Current, and Arrhythmogenesis. PLOS ONE 2014, 9: e106982. PMID: 25184293, PMCID: PMC4153713, DOI: 10.1371/journal.pone.0106982.Peer-Reviewed Original ResearchConceptsSudden unexplained infant deathVoltage-dependent inactivationLong QT syndromeWindow currentTimothy syndromeCav1.2 L-type Ca2Multiple dental cariesLower extremity weaknessGain of functionCertain clinical settingsEpisodes of rhabdomyolysisUnexplained infant deathL-type Ca2Channel window currentAge 5 yearsYears of ageAppreciation of mechanismsMonths of ageCandidate gene sequencingCardiac ion channelsRecurrent VTExtremity weaknessSpastic diplegiaExtracardiac featuresDental cariesA TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8–induced IL-1
Hedl M, Abraham C. A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8–induced IL-1. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 13451-13456. PMID: 25197060, PMCID: PMC4169936, DOI: 10.1073/pnas.1404178111.Peer-Reviewed Original ResearchMeSH KeywordsAcetylmuramyl-Alanyl-IsoglutamineADAM ProteinsADAM17 ProteinCaspase 8Cells, CulturedGenetic Predisposition to DiseaseHumansInterleukin-1LigandsMacrophagesMitogen-Activated Protein KinasesMycobacteriumMyeloid CellsNF-kappa BNod2 Signaling Adaptor ProteinPhosphatidylinositol 3-KinasesPolymorphism, Single NucleotideReceptors, Pattern RecognitionReceptors, Tumor Necrosis Factor, Member 25Signal TransductionSolubilityTissue Inhibitor of Metalloproteinase-3Tumor Necrosis Factor Ligand Superfamily Member 15ConceptsMost risk lociCaspase-8-dependent pathwayCytokine secretionGain of functionIntestinal myeloid cellsInflammatory bowel diseaseRisk lociIL-1 secretionTNFSF15 expressionPI3KPRR responsesBowel diseaseSignalingCytokine productionImmune homeostasisInflammatory diseasesHuman macrophagesIL-1Myeloid cellsAltered functionCytokinesTNFSF15MacrophagesSecretionDiseasePodocyte-Specific VEGF-A Gain of Function Induces Nodular Glomerulosclerosis in eNOS Null Mice
Veron D, Aggarwal PK, Velazquez H, Kashgarian M, Moeckel G, Tufro A. Podocyte-Specific VEGF-A Gain of Function Induces Nodular Glomerulosclerosis in eNOS Null Mice. Journal Of The American Society Of Nephrology 2014, 25: 1814-1824. PMID: 24578128, PMCID: PMC4116059, DOI: 10.1681/asn.2013070752.Peer-Reviewed Original ResearchConceptsNodular glomerulosclerosisGain of functionEndothelial nitric oxide synthase knockout miceNitric oxide synthase knockout miceGlomerular basement membrane thickeningENOS-null miceSynthase knockout miceBasement membrane thickeningWild-type miceCollagen IVArteriolar hyalinosisGlomerular nodulesGlomerular VEGFKimmelstiel-WilsonPronounced albuminuriaCreatinine clearanceRenal failureDiabetic nephropathyENOS deficiencyMassive proteinuriaDiabetic milieuMembrane thickeningPodocyte effacementDeposition of lamininKnockout miceTargeted Therapy in Uterine Serous Carcinoma: An Aggressive Variant of Endometrial Cancer
Black JD, English DP, Roque DM, Santin AD. Targeted Therapy in Uterine Serous Carcinoma: An Aggressive Variant of Endometrial Cancer. Women's Health 2014, 10: 45-57. PMID: 24328598, PMCID: PMC3984476, DOI: 10.2217/whe.13.72.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic AgentsClass I Phosphatidylinositol 3-KinasesCyclin ECystadenocarcinoma, SerousDrug Resistance, NeoplasmFemaleGenes, erbB-2HumansMolecular Targeted TherapyMutationNeoplasm Recurrence, LocalNeoplasm StagingPhosphatidylinositol 3-KinasesRandomized Controlled Trials as TopicUterine NeoplasmsConceptsUterine serous carcinomaEndometrial cancerAggressive variantSerous carcinomaRecurrent uterine serous carcinomaPIK3CA/AKT/mTORComprehensive surgical stagingRecent whole-exome sequencing studiesHER2/neu geneVaginal cuff brachytherapyNovel therapeutic targetAkt/mTORUSC therapyPaclitaxel chemotherapySurgical stagingBiologic therapyTargeted therapyWhole-exome sequencing studiesTherapeutic targetDriver mutationsTherapyNeu geneCancerGain of functionCarcinoma
2010
Inhibition of pathogen-induced apoptosis by a Coxiella burnetii type IV effector protein
Lührmann A, Nogueira CV, Carey KL, Roy CR. Inhibition of pathogen-induced apoptosis by a Coxiella burnetii type IV effector protein. Proceedings Of The National Academy Of Sciences Of The United States Of America 2010, 107: 18997-19001. PMID: 20944063, PMCID: PMC2973885, DOI: 10.1073/pnas.1004380107.Peer-Reviewed Original ResearchConceptsPathogen-induced apoptosisEffector proteinsMammalian hostsL. pneumophila effector proteinsType IV effector proteinsHost cellsType IV secretion systemMammalian host cellsL. pneumophilaGain of functionProtein repertoireOrganelle traffickingRepeat familyDistinct hostsSecretion systemInfection strategiesProtozoan hostsApoptosis pathwayIntracellular bacteriaIntracellular replicationVirulence determinantsProteinLegionella pneumophilaApoptosisPathogens
2009
Response to Comment on "Human-Specific Gain of Function in a Developmental Enhancer"
Prabhakar S, Visel A, Akiyama J, Shoukry M, Lewis K, Holt A, Plajzer-Frick I, Morrison H, FitzPatrick D, Afzal V, Pennacchio L, Rubin E, Noonan J. Response to Comment on "Human-Specific Gain of Function in a Developmental Enhancer". Science 2009, 323: 714-714. DOI: 10.1126/science.1166571.Peer-Reviewed Original Research
2008
Human-Specific Gain of Function in a Developmental Enhancer
Prabhakar S, Visel A, Akiyama JA, Shoukry M, Lewis KD, Holt A, Plajzer-Frick I, Morrison H, FitzPatrick DR, Afzal V, Pennacchio LA, Rubin EM, Noonan JP. Human-Specific Gain of Function in a Developmental Enhancer. Science 2008, 321: 1346-1350. PMID: 18772437, PMCID: PMC2658639, DOI: 10.1126/science.1159974.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBase SequenceBinding SitesBody PatterningConserved SequenceEmbryonic DevelopmentEnhancer Elements, GeneticEvolution, MolecularExtremitiesGene Expression ProfilingGene Expression Regulation, DevelopmentalHumansLimb BudsMacaca mulattaMiceMice, TransgenicMolecular Sequence DataMutationPan troglodytesPAX9 Transcription FactorSelection, GeneticTranscription FactorsConceptsExpression domainsHuman-specific substitutionsHuman-specific gainsGain of functionOrthologous elementsDevelopmental enhancersAncestral stateGene regulationNoncoding sequencesTerrestrial vertebratesHuman enhancersSynthetic enhancersEnhancer sequencesGene expressionRegulatory functionsDevelopmental stagesVivo analysisEnhancerVivo evidenceTransgenic miceSequenceVertebratesDomainRegulationSubstitution
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