2024
Intranasal neomycin evokes broad-spectrum antiviral immunity in the upper respiratory tract
Mao T, Kim J, Peña-Hernández M, Valle G, Moriyama M, Luyten S, Ott I, Gomez-Calvo M, Gehlhausen J, Baker E, Israelow B, Slade M, Sharma L, Liu W, Ryu C, Korde A, Lee C, Monteiro V, Lucas C, Dong H, Yang Y, Initiative Y, Gopinath S, Wilen C, Palm N, Dela Cruz C, Iwasaki A, Vogels C, Hahn A, Chen N, Breban M, Koch T, Chaguza C, Tikhonova I, Castaldi C, Mane S, De Kumar B, Ferguson D, Kerantzas N, Peaper D, Landry M, Schulz W, Grubaugh N. Intranasal neomycin evokes broad-spectrum antiviral immunity in the upper respiratory tract. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2319566121. PMID: 38648490, PMCID: PMC11067057, DOI: 10.1073/pnas.2319566121.Peer-Reviewed Original ResearchConceptsInterferon-stimulated genesRespiratory infectionsStrains of influenza A virusTreatment of respiratory viral infectionsRespiratory virus infectionsInfluenza A virusMouse model of COVID-19Respiratory viral infectionsNeomycin treatmentExpression of interferon-stimulated genesUpper respiratory infectionInterferon-stimulated gene expressionLower respiratory infectionsBroad spectrum of diseasesAdministration of neomycinRespiratory viral diseasesDisease to patientsUpper respiratory tractIntranasal deliveryCongenic miceIntranasal applicationNasal mucosaSevere acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2A virusThe chemokine receptor CXCR3 promotes CD8+ T cell–dependent lung pathology during influenza pathogenesis
Guo K, Yombo D, Wang Z, Navaeiseddighi Z, Xu J, Schmit T, Ahamad N, Tripathi J, De Kumar B, Mathur R, Hur J, Sun J, Olszewski M, Khan N. The chemokine receptor CXCR3 promotes CD8+ T cell–dependent lung pathology during influenza pathogenesis. Science Advances 2024, 10: eadj1120. PMID: 38170765, PMCID: PMC10776024, DOI: 10.1126/sciadv.adj1120.Peer-Reviewed Original ResearchConceptsLung pathologyT cellsLung injuryCytotoxic responsePeak viral loadChemokine receptor CXCR3Wild-type CD8Robust cytotoxic responseSingle-cell RNA sequencing analysisCXCR3 blockadeAdoptive transferEffector potentialT subpopulationsT effectorsViral clearanceViral loadEffector subsetsReceptor CXCR3Influenza pathogenesisCD8Therapeutic effectMurine lungInfluenza controlCentral memoryCXCR3
2023
Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survival
Sun Z, Zhang Z, Banu K, Gibson I, Colvin R, Yi Z, Zhang W, De Kumar B, Reghuvaran A, Pell J, Manes T, Djamali A, Gallon L, O'Connell P, He J, Pober J, Heeger P, Menon M. Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survival. Journal Of Clinical Investigation 2023, 133: e170420. PMID: 37676733, PMCID: PMC10617779, DOI: 10.1172/jci170420.Peer-Reviewed Original ResearchConceptsDeath-censored graft lossHuman leukocyte antigenExpression quantitative trait lociT cellsTGF-β1TGF-β1/Smad pathwayDonor-recipient differencesKidney allograft lossChronic allograft rejectionKidney transplant survivalDonor-recipient mismatchActive TGF-β1Allograft lossGraft lossAllograft rejectionTransplant cohortPeripheral bloodLeukocyte antigenClinical trialsImmune cellsHaplotype mismatchGenome-wide scaleTransplant survivalQuantitative trait lociSingle nucleotide polymorphism dataEnhanced inhibition of MHC-I expression by SARS-CoV-2 Omicron subvariants
Moriyama M, Lucas C, Monteiro V, Initiative Y, Iwasaki A, Chen N, Breban M, Hahn A, Pham K, Koch T, Chaguza C, Tikhonova I, Castaldi C, Mane S, De Kumar B, Ferguson D, Kerantzas N, Peaper D, Landry M, Schulz W, Vogels C, Grubaugh N. Enhanced inhibition of MHC-I expression by SARS-CoV-2 Omicron subvariants. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2221652120. PMID: 37036977, PMCID: PMC10120007, DOI: 10.1073/pnas.2221652120.Peer-Reviewed Original ResearchConceptsMHC-I expressionBreakthrough infectionsSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variantsMajor histocompatibility complex class I expressionCell-mediated immunityInfluenza virus infectionSARS-CoV-2 VOCsMHC-I upregulationClass I expressionSARS-CoV-2T cell recognitionVirus infectionMHC II expressionSpike proteinEnhanced inhibitionInfectionCell recognitionCommon mutationsReinfectionE proteinAntibodiesViral genesSubvariantsExpressionUtility of promoter hypermethylation in malignant risk stratification of intraductal papillary mucinous neoplasms
Chhoda A, Sharma A, Sailo B, Tang H, Ruzgar N, Tan W, Ying L, Khatri R, Narayanan A, Mane S, De Kumar B, Wood L, Iacobuzio-Donahue C, Wolfgang C, Kunstman J, Salem R, Farrell J, Ahuja N. Utility of promoter hypermethylation in malignant risk stratification of intraductal papillary mucinous neoplasms. Clinical Epigenetics 2023, 15: 28. PMID: 36803844, PMCID: PMC9942382, DOI: 10.1186/s13148-023-01429-5.Peer-Reviewed Original ResearchConceptsPapillary mucinous neoplasmMalignant risk stratificationCACNA1G geneRisk stratificationMucinous neoplasmsBiomarker panelBackgroundIntraductal papillary mucinous neoplasmIntraductal papillary mucinous neoplasmEarly detectionPrevious case-control studyHigh-grade dysplasiaCase-control studyPancreatic cancer precursorsReceiver Operating Characteristic (ROC) curve analysisSignificant diagnostic challengeCross-sectional imagingCharacteristic curve analysisOperating Characteristic curve analysisG geneHigh diagnostic specificityPrior validation studiesSignificant procedural riskIPMN tissuesSurgical resectionAdvanced neoplasiaAge-dependent impairment in antibody responses elicited by a homologous CoronaVac booster dose
Filardi B, Monteiro V, Schwartzmann P, do Prado Martins V, Zucca L, Baiocchi G, Malik A, Silva J, Hahn A, Chen N, Pham K, Pérez-Then E, Miric M, Brache V, Cochon L, Larocca R, Della Rosa Mendez R, Silveira D, Pinto A, Croda J, Yildirim I, Omer S, Ko A, Vermund S, Grubaugh N, Iwasaki A, Lucas C, Initiative Y, Vogels C, Breban M, Koch T, Chaguza C, Tikhonova I, Castaldi C, Mane S, De Kumar B, Ferguson D, Kerantzas N, Peaper D, Landry M, Schulz W. Age-dependent impairment in antibody responses elicited by a homologous CoronaVac booster dose. Science Translational Medicine 2023, 15: eade6023. PMID: 36791210, DOI: 10.1126/scitranslmed.ade6023.Peer-Reviewed Original ResearchConceptsBooster doseAntibody responseNeutralization titersVirus-specific IgG titersOlder adultsAntiviral humoral immunityPlasma antibody responsesHigh-risk populationSARS-CoV-2 spikeYears of ageAge-dependent impairmentHeterologous regimensBooster dosesBooster vaccineCoronaVac vaccineIgG titersProtective immunityHumoral immunityHumoral responseCoronaVacOmicron waveBooster strategyAge groupsEarly controlVaccineAccelerated SARS-CoV-2 intrahost evolution leading to distinct genotypes during chronic infection
Chaguza C, Hahn A, Petrone M, Zhou S, Ferguson D, Breban M, Pham K, Peña-Hernández M, Castaldi C, Hill V, Initiative Y, Billig K, Earnest R, Fauver J, Kalinch C, Kerantzas N, Koch T, De Kumar B, Landry M, Ott I, Peaper D, Tikhonova I, Vogels C, Schulz W, Swanstrom R, Roberts S, Grubaugh N. Accelerated SARS-CoV-2 intrahost evolution leading to distinct genotypes during chronic infection. Cell Reports Medicine 2023, 4: 100943. PMID: 36791724, PMCID: PMC9906997, DOI: 10.1016/j.xcrm.2023.100943.Peer-Reviewed Original ResearchConceptsChronic infectionEvolutionary ratesGenetic diversityIntrahost evolutionDistinct genotypesHigher viral genome copiesVirus evolutionary ratesSARS-CoV-2 evolutionUntreated chronic infectionAdvantageous mutationsNucleotide substitutionsViral genome copiesDivergent variantsInfection hypothesisVariant emergenceViral populationsInfectious virusInfectionHallmark changesGenome copiesDifferent genotypesDiversityGenotypesTemporal dynamicsEvolutionDNA methylation of the promoter region at the CREB1 binding site is a mechanism for the epigenetic regulation of brain-specific PKMζ
Pramio D, Vieceli F, Varella-Branco E, Goes C, Kobayashi G, da Silva Pelegrina D, de Moraes B, El Allam A, De Kumar B, Jara G, Farfel J, Bennett D, Kundu S, Viapiano M, Reis E, de Oliveira P, Dos Santos E Passos-Bueno M, Rothlin C, Ghosh S, Schechtman D. DNA methylation of the promoter region at the CREB1 binding site is a mechanism for the epigenetic regulation of brain-specific PKMζ. Biochimica Et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 2023, 1866: 194909. PMID: 36682583, PMCID: PMC10037092, DOI: 10.1016/j.bbagrm.2023.194909.Peer-Reviewed Original ResearchConceptsInduced pluripotent stem cellsInternal promoterNeuronal differentiationEpigenetic mechanismsDNA methylationUpstream promoterProtein kinase C ζHuman neuronal differentiationSite-specific hypermethylationAberrant DNA hypermethylationPluripotent stem cellsEpigenetic regulationSame epigenetic mechanismsLong-term memory formationDNA hypermethylationDemethylated regionsEpigenetic factorsPromoter regionTissue specificityMolecular mechanismsPRKCZ geneDifferentiated neuronsPromoterProtein kinase M zetaLong-term potentiation
2022
Cellular Heterogeneity and Molecular Reprogramming of the Host Response during Influenza Acute Lung Injury
Guo K, Yombo D, Schmit T, Wang Z, Navaeiseddighi Z, Sathish V, Mathur R, Wu M, De Kumar B, Hur J, Khan N. Cellular Heterogeneity and Molecular Reprogramming of the Host Response during Influenza Acute Lung Injury. Journal Of Virology 2022, 96: e01246-22. PMID: 36286482, PMCID: PMC9645213, DOI: 10.1128/jvi.01246-22.Peer-Reviewed Original ResearchConceptsAcute lung injuryLung injuryIAV infectionHost responseDysregulated host responseExuberant host responseOutcome of interferonTotal immune cellsMonocyte-derived macrophagesSingle-cell RNA sequencing analysisChemokine responsesAcute injuryCellular levelImmune cellsNonimmune cellsBarrier integrityMyeloid cellsTherapeutic interventionsCellular heterogeneityInjuryChemokine signalingNonhematopoietic cellsInfectionRNA sequencing analysisMechanistic associationRapid emergence of SARS-CoV-2 Omicron variant is associated with an infection advantage over Delta in vaccinated persons
Chaguza C, Coppi A, Earnest R, Ferguson D, Kerantzas N, Warner F, Young HP, Breban MI, Billig K, Koch RT, Pham K, Kalinich CC, Ott IM, Fauver JR, Hahn AM, Tikhonova IR, Castaldi C, De Kumar B, Pettker CM, Warren JL, Weinberger DM, Landry ML, Peaper DR, Schulz W, Vogels CBF, Grubaugh ND. Rapid emergence of SARS-CoV-2 Omicron variant is associated with an infection advantage over Delta in vaccinated persons. Med 2022, 3: 325-334.e4. PMID: 35399324, PMCID: PMC8983481, DOI: 10.1016/j.medj.2022.03.010.Peer-Reviewed Original ResearchConceptsSpike gene target failureSARS-CoV-2 Omicron variantPositivity rateOmicron variantOmicron infectionVaccine dosesVaccine-induced immunityNumber of dosesTest positivity rateOdds of infectionSARS-CoV-2Significant reductionDominant Delta variantUnvaccinated personsVaccination statusHigher oddsDelta variantInfectionVaccine manufacturersDisease controlVirus copiesDosesPCR testOddsTarget failureComparative transmissibility of SARS-CoV-2 variants Delta and Alpha in New England, USA
Earnest R, Uddin R, Matluk N, Renzette N, Turbett SE, Siddle KJ, Loreth C, Adams G, Tomkins-Tinch CH, Petrone ME, Rothman JE, Breban MI, Koch RT, Billig K, Fauver JR, Vogels CBF, Bilguvar K, De Kumar B, Landry ML, Peaper DR, Kelly K, Omerza G, Grieser H, Meak S, Martha J, Dewey HB, Kales S, Berenzy D, Carpenter-Azevedo K, King E, Huard RC, Novitsky V, Howison M, Darpolor J, Manne A, Kantor R, Smole SC, Brown CM, Fink T, Lang AS, Gallagher GR, Pitzer VE, Sabeti PC, Gabriel S, MacInnis BL, Team N, Altajar A, DeJesus A, Brito A, Watkins A, Muyombwe A, Blumenstiel B, Neal C, Kalinich C, Liu C, Loreth C, Castaldi C, Pearson C, Bernard C, Nolet C, Ferguson D, Buzby E, Laszlo E, Reagan F, Vicente G, Rooke H, Munger H, Johnson H, Tikhonova I, Ott I, Razeq J, Meldrim J, Brown J, Wang J, Vostok J, Beauchamp J, Grimsby J, Hall J, Messer K, Larkin K, Vernest K, Madoff L, Green L, Webber L, Gagne L, Ulcena M, Ray M, Fisher M, Barter M, Lee M, DeFelice M, Cipicchio M, Smith N, Lennon N, Fitzgerald N, Kerantzas N, Hui P, Harrington R, Downing R, Haye R, Lynch R, Anderson S, Hennigan S, English S, Cofsky S, Clancy S, Mane S, Ash S, Baez S, Fleming S, Murphy S, Chaluvadi S, Alpert T, Rivard T, Schulz W, Mandese Z, Tewhey R, Adams M, Park D, Lemieux J, Grubaugh N. Comparative transmissibility of SARS-CoV-2 variants Delta and Alpha in New England, USA. Cell Reports Medicine 2022, 3: 100583. PMID: 35480627, PMCID: PMC8913280, DOI: 10.1016/j.xcrm.2022.100583.Peer-Reviewed Original ResearchConceptsEnhanced transmissibilitySARS-CoV-2 variant DeltaSARS-CoV-2 Delta variantViral RNA copiesPublic health programsAlpha infectionDelta infectionEffective reproductive numberDelta variantHealth programsVariant DeltaRNA copiesInfectionAlphaReproductive numberTransmissibilityEpidemiological dynamicsAssessment of Clinical Effectiveness of BNT162b2 COVID-19 Vaccine in US Adolescents
Oliveira CR, Niccolai LM, Sheikha H, Elmansy L, Kalinich CC, Grubaugh ND, Shapiro ED, Billig K, Breban M, Brito A, Earnest R, Fauver J, Koch T, Ott I, Petrone M, Vogels C, Pham K, Tikhonova I, Castaldi C, Mane S, Bilguvar K, De Kumar B, Ferguson D, Kerantzas N, Landry M, Peaper D, Schulz W. Assessment of Clinical Effectiveness of BNT162b2 COVID-19 Vaccine in US Adolescents. JAMA Network Open 2022, 5: e220935. PMID: 35238933, PMCID: PMC8895259, DOI: 10.1001/jamanetworkopen.2022.0935.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 infectionCase-control studyVaccine effectivenessBNT162b2 vaccineSARS-CoV-2Medical recordsAsymptomatic SARS-CoV-2 infectionBNT162b2 COVID-19 vaccineRetrospective case-control studyRT-PCR test resultsSARS-CoV-2 testUS adolescentsReverse transcription polymerase chain reaction testConditional logistic regression modelsTranscription polymerase chain reaction testDoses of vaccineControl participantsClinical trial populationsRelevant clinical dataCase participantsCOVID-19 vaccinePositive test resultsChain reaction testCounty of residenceNegative test results
2021
Autocrine GMCSF Signaling Contributes to Growth of HER2+ Breast Leptomeningeal CarcinomatosisGMCSF Contributes to Breast Leptomeningeal Carcinomatosis
Ansari K, Bhan A, Saotome M, Tyagi A, De Kumar B, Chen C, Takaku M, Jandial R. Autocrine GMCSF Signaling Contributes to Growth of HER2+ Breast Leptomeningeal CarcinomatosisGMCSF Contributes to Breast Leptomeningeal Carcinomatosis. Cancer Research 2021, 81: 4723-4735. PMID: 34247146, PMCID: PMC8986153, DOI: 10.1158/0008-5472.can-21-0259.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutocrine CommunicationBreast NeoplasmsCell Line, TumorCell ProliferationCell SurvivalDisease Models, AnimalGene ExpressionGranulocyte-Macrophage Colony-Stimulating FactorHumansMeningeal CarcinomatosisMiceOncogene ProteinsProtein Kinase InhibitorsReceptor, ErbB-2Signal TransductionXenograft Model Antitumor AssaysConceptsOligodendrocyte progenitor cellsLeptomeningeal carcinomatosisLC growthPan-Aurora kinase inhibitorKinase inhibitorsSuppression of HER2Growth of HER2Central nervous system cell typesProliferation of HER2Nervous system cell typesBreast cancer cellsPrimary HER2Targetable axisOminous complicationIntrathecal deliveryMolecular mechanismsTreatment optionsDire prognosisSpinal cordBreast cancerHER2LC developmentLeptomeningesLC/MS-MSCarcinomatosisThe Hox protein conundrum: The “specifics” of DNA binding for Hox proteins and their partners
De Kumar B, Darland D. The Hox protein conundrum: The “specifics” of DNA binding for Hox proteins and their partners. Developmental Biology 2021, 477: 284-292. PMID: 34102167, PMCID: PMC8846413, DOI: 10.1016/j.ydbio.2021.06.002.Peer-Reviewed Original ResearchConceptsProtein binding specificityHox proteinsAnterior-posterior body axisTranscription factor-DNA interactionsBinding specificityHox protein functionMulti-protein interactionsHomeodomain transcription factorHomeotic genesSegmental identityUnique target specificityProtein functionTranscription factorsCooperative binding modelGene expressionBody axisMolecular characterizationTarget specificityProteinDNAMouse systemRecent studiesSubsequent alterationDrosophilaGenes
2020
Cancer-specific mutation of GATA3 disrupts the transcriptional regulatory network governed by Estrogen Receptor alpha, FOXA1 and GATA3
Takaku M, Grimm S, De Kumar B, Bennett B, Wade P. Cancer-specific mutation of GATA3 disrupts the transcriptional regulatory network governed by Estrogen Receptor alpha, FOXA1 and GATA3. Nucleic Acids Research 2020, 48: 4756-4768. PMID: 32232341, PMCID: PMC7229857, DOI: 10.1093/nar/gkaa179.Peer-Reviewed Original ResearchConceptsRegulatory networksAltered chromatin architectureTranscriptional regulatory networksDifferential gene expressionEpithelial cell biologyTranscription factor FOXA1Mammary epithelial cellsEstrogen receptor alphaCancer-specific mutationsMammary gland developmentChromatin architectureChromatin localizationGenomic localizationReceptor alphaMutant cellsGenomic analysisNetwork downstreamGene setsCell biologyEstrogen receptorGene expressionGATA3 mutationsGland developmentSimilar mutationsFOXA1
2019
Hox genes: Downstream “effectors” of retinoic acid signaling in vertebrate embryogenesis
Nolte C, De Kumar B, Krumlauf R. Hox genes: Downstream “effectors” of retinoic acid signaling in vertebrate embryogenesis. Genesis 2019, 57: e23306. PMID: 31111645, DOI: 10.1002/dvg.23306.Peer-Reviewed Original ResearchConceptsHox genesAxial patterningHox gene expressionAnteroposterior axisBasic body planGene regulatory networksVertebrate embryogenesisAnimal developmentPatterning of cellsVertebrate developmentBody planAxial specificationRegulatory networksCombinatorial codeTissue contextGene expressionDirect effectorVertebrate planHematopoietic systemGenesReproductive organsRegulatory processesEmbryogenesisDifferential responseRetinoic acid
2018
Retinoid-Sensitive Epigenetic Regulation of the Hoxb Cluster Maintains Normal Hematopoiesis and Inhibits Leukemogenesis
Qian P, De Kumar B, He X, Nolte C, Gogol M, Ahn Y, Chen S, Li Z, Xu H, Perry J, Hu D, Tao F, Zhao M, Han Y, Hall K, Peak A, Paulson A, Zhao C, Venkatraman A, Box A, Perera A, Haug J, Parmely T, Li H, Krumlauf R, Li L. Retinoid-Sensitive Epigenetic Regulation of the Hoxb Cluster Maintains Normal Hematopoiesis and Inhibits Leukemogenesis. Cell Stem Cell 2018, 22: 740-754.e7. PMID: 29727682, DOI: 10.1016/j.stem.2018.04.012.Peer-Reviewed Original ResearchConceptsHoxb expressionHematopoietic stem cellsDNA methylationCoordinate regulationLoss of HSCsCis-regulatory elementsSpecific DNA methylationDNA methylome analysisHox genesHOXB clusterHox expressionEpigenetic regulationDNA methyltransferasesMethylome analysisHoxb genesCluster expressionLT-HSCsRetinoid signalingNormal hematopoiesisGenesStem cellsLeukemogenesisMethylationReconstitution capacityRegulation
2016
HOXs and lincRNAs: Two sides of the same coin
De Kumar B, Krumlauf R. HOXs and lincRNAs: Two sides of the same coin. Science Advances 2016, 2: e1501402. PMID: 27034976, PMCID: PMC4805430, DOI: 10.1126/sciadv.1501402.Peer-Reviewed Original Research
2012
Poised RNA Polymerase II Changes over Developmental Time and Prepares Genes for Future Expression
Gaertner B, Johnston J, Chen K, Wallaschek N, Paulson A, Garruss A, Gaudenz K, De Kumar B, Krumlauf R, Zeitlinger J. Poised RNA Polymerase II Changes over Developmental Time and Prepares Genes for Future Expression. Cell Reports 2012, 2: 1670-1683. PMID: 23260668, PMCID: PMC3572839, DOI: 10.1016/j.celrep.2012.11.024.Peer-Reviewed Original ResearchConceptsPol IIMammalian embryonic stem cellsGenes de novoDevelopmental control genesPolycomb group repressionFuture gene expressionRNA Pol IIRNA polymerase IIEmbryonic stem cellsTissue-specific fashionChromatin stateDrosophila embryosPolymerase IIExtracellular signalsDevelopmental programStages of differentiationGene expressionControl genesDevelopmental timeSynchronous inductionDynamic expressionGenesStem cellsDe novoFuture expression
2011
Dynamic transcriptional events in embryonic stem cells mediated by the super elongation complex (SEC)
Lin C, Garrett A, De Kumar B, Smith E, Gogol M, Seidel C, Krumlauf R, Shilatifard A. Dynamic transcriptional events in embryonic stem cells mediated by the super elongation complex (SEC). Genes & Development 2011, 25: 1486-1498. PMID: 21764852, PMCID: PMC3143939, DOI: 10.1101/gad.2059211.Peer-Reviewed Original ResearchConceptsSuper elongation complexEmbryonic stem cellsElongation complexPol IIDifferentiation signalsDynamic transcriptional eventsMurine embryonic stem cellsRNA polymerase IIStem cellsGlobal genomic analysisTranscription elongationPolymerase IITranscriptional regulationTranscriptional activationTranscriptional eventsGenomic analysisEnvironmental cuesES cellsGene expressionHuman cellsEnvironmental stimuliGenesEssential roleActivation signalsMajor classes