2023
Pericytes are protective in experimental pneumococcal meningitis through regulating leukocyte infiltration and blood–brain barrier function
Teske N, Dyckhoff-Shen S, Beckenbauer P, Bewersdorf J, Engelen-Lee J, Hammerschmidt S, Kälin R, Pfister H, Brouwer M, Klein M, Glass R, van de Beek D, Koedel U. Pericytes are protective in experimental pneumococcal meningitis through regulating leukocyte infiltration and blood–brain barrier function. Journal Of Neuroinflammation 2023, 20: 267. PMID: 37978545, PMCID: PMC10655320, DOI: 10.1186/s12974-023-02938-z.Peer-Reviewed Original ResearchConceptsModel of pneumococcal meningitisPneumococcal meningitisLeukocyte infiltrationAnimal model of pneumococcal meningitisPrevented blood-brain barrierToll-like receptor inhibitorsDegree of leukocyte infiltrationSerotypes of Streptococcus pneumoniaeUnfavorable disease courseBlood-brain barrier disruptionHuman pericytesExperimental pneumococcal meningitisBlood-brain barrier integrityRegulating leukocyte infiltrationBlood-brain barrier functionRegulation of cerebral blood flowAdult mouse modelInfection in vivoUpregulation of chemokine expressionIncreased cerebral edemaMaintenance of blood-brain barrier integrityBlood-brain barrierCerebral blood flowMouse meningitis modelIn vitro studiesCurrent landscape of translational and clinical research in myelodysplastic syndromes/neoplasms (MDS): Proceedings from the 1st International Workshop on MDS (iwMDS) Of the International Consortium for MDS (icMDS)
Bewersdorf J, Xie Z, Bejar R, Borate U, Boultwood J, Brunner A, Buckstein R, Carraway H, Churpek J, Daver N, Porta M, DeZern A, Fenaux P, Figueroa M, Gore S, Griffiths E, Halene S, Hasserjian R, Hourigan C, Kim T, Komrokji R, Kuchroo V, List A, Loghavi S, Majeti R, Odenike O, Patnaik M, Platzbecker U, Roboz G, Sallman D, Santini V, Sanz G, Sekeres M, Stahl M, Starczynowski D, Steensma D, Taylor J, Abdel-Wahab O, Xu M, Savona M, Wei A, Zeidan A. Current landscape of translational and clinical research in myelodysplastic syndromes/neoplasms (MDS): Proceedings from the 1st International Workshop on MDS (iwMDS) Of the International Consortium for MDS (icMDS). Blood Reviews 2023, 60: 101072. PMID: 36934059, DOI: 10.1016/j.blre.2023.101072.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsImmune checkpoint inhibitorsSpecific molecular alterationsNovel animal modelInnate immune systemCheckpoint inhibitorsImmune dysregulationMDS patientsClinical trialsNovel therapiesTherapeutic strategiesAnimal modelsGermline predispositionImmune systemMolecular alterationsClinical researchInternational ConsortiumNeoplasmsClinical workGenetic landscapeInternational WorkshopPatientsCurrent landscapePathogenesisTherapyDiseasePlasma renalase levels are associated with the development of acute pancreatitis
Wang M, Weiss F, Guo X, Kolodecik T, Bewersdorf J, Laine L, Lerch M, Desir G, Gorelick F. Plasma renalase levels are associated with the development of acute pancreatitis. Pancreatology 2023, 23: 158-162. PMID: 36697349, DOI: 10.1016/j.pan.2023.01.001.Peer-Reviewed Original ResearchConceptsAcute pancreatitisSevere diseasePlasma renalase levelsAcute pancreatitis patientsSevere acute pancreatitisAcute pancreatitis modelPlasma renalaseRenalase levelsSignificant morbidityPancreatitis patientsPlasma levelsHealthy controlsPancreatitis modelPancreatitisPatientsPlasma samplesRenalaseDiseaseNonparametric statistical analysisSecretory proteinsMorbidityStatistical analysisMortalityLevels
2022
Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia
Tanaka A, Nakano T, Nomura M, Yamazaki H, Bewersdorf J, Mulet-Lazaro R, Hogg S, Liu B, Penson A, Yokoyama A, Zang W, Havermans M, Koizumi M, Hayashi Y, Cho H, Kanai A, Lee S, Xiao M, Koike Y, Zhang Y, Fukumoto M, Aoyama Y, Konuma T, Kunimoto H, Inaba T, Nakajima H, Honda H, Kawamoto H, Delwel R, Abdel-Wahab O, Inoue D. Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia. Blood 2022, 140: 875-888. PMID: 35709354, PMCID: PMC9412007, DOI: 10.1182/blood.2021015325.Peer-Reviewed Original ResearchConceptsAcute myeloid leukemiaMyeloid leukemiaEVI1 isoformsSF3B1 mutationsAberrant 3' splice sitesSelf-renewal of hematopoietic stem cellsSplicing factor SF3B1Zinc finger domainExonic splicing enhancerIn-frame insertionCryptic branch pointPathogenesis of myeloid leukemiaPatient-derived cell linesHematopoietic stem cellsRNA-splicingSplicing enhancerSplice siteEpigenomic analysesMutant SF3B1Promoter usageExon 13Leukemic transformationSplice variantsGenomic alterationsUpregulated transcriptsSynthetic introns enable splicing factor mutation-dependent targeting of cancer cells
North K, Benbarche S, Liu B, Pangallo J, Chen S, Stahl M, Bewersdorf J, Stanley R, Erickson C, Cho H, Pineda J, Thomas J, Polaski J, Belleville A, Gabel A, Udy D, Humbert O, Kiem H, Abdel-Wahab O, Bradley R. Synthetic introns enable splicing factor mutation-dependent targeting of cancer cells. Nature Biotechnology 2022, 40: 1103-1113. PMID: 35241838, PMCID: PMC9288984, DOI: 10.1038/s41587-022-01224-2.Peer-Reviewed Original ResearchConceptsBreast cancerExpression of herpes simplex virus thymidine kinaseHerpes simplex virus thymidine kinaseCancer cellsPancreatic cancer cells in vitroWild-type cellsCancer cells in vitroCancer gene therapyTargeting of cancer cellsTumor-specific changesUveal melanoma cellsTreatment in vivoSynthetic intronChange-of-function mutationsCells in vitroUveal melanomaSF3B1 mutationsHSV-tkGene therapyTumor cellsIsogenic wild-type cellsMelanoma cellsRNA splicing factorsCancerHost survivalPhase 1 study of anti-CD47 monoclonal antibody CC-90002 in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes
Zeidan AM, DeAngelo DJ, Palmer J, Seet CS, Tallman MS, Wei X, Raymon H, Sriraman P, Kopytek S, Bewersdorf JP, Burgess MR, Hege K, Stock W. Phase 1 study of anti-CD47 monoclonal antibody CC-90002 in patients with relapsed/refractory acute myeloid leukemia and high-risk myelodysplastic syndromes. Annals Of Hematology 2022, 101: 557-569. PMID: 34981142, PMCID: PMC9414073, DOI: 10.1007/s00277-021-04734-2.Peer-Reviewed Original ResearchConceptsAnti-drug antibodiesAcute myeloid leukemiaDose-limiting toxicityRefractory acute myeloid leukemiaHigh-risk myelodysplastic syndromeMyelodysplastic syndromeMyeloid leukemiaCommon treatment-emergent adverse eventsTreatment-emergent adverse eventsADA-positive patientsPhase 2 dosePresence/frequencyUnexpected safety findingsPhase 1 studyAnti-CD47 antibodyCD47-SIRPα interactionMacrophage-mediated killingHematological cancer cell linesFebrile neutropeniaMonotherapy activityCancer cell linesPrimary endpointSecondary endpointsAdverse eventsObjective response
2020
Hyperleukocytosis and Leukostasis in Acute Myeloid Leukemia: Can a Better Understanding of the Underlying Molecular Pathophysiology Lead to Novel Treatments?
Bewersdorf JP, Zeidan AM. Hyperleukocytosis and Leukostasis in Acute Myeloid Leukemia: Can a Better Understanding of the Underlying Molecular Pathophysiology Lead to Novel Treatments? Cells 2020, 9: 2310. PMID: 33080779, PMCID: PMC7603052, DOI: 10.3390/cells9102310.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsTumor lysis syndromeAcute myeloid leukemiaLeukemic blastsMyeloid leukemiaCell adhesion moleculeAggressive intravenous fluid hydrationWhite blood cell countEndothelial cellsAdhesion moleculesDevelopment of leukostasisIntravenous fluid hydrationManagement of DICMainstay of therapyLife-threatening complicationsBlood cell countLeukemic stem cell survivalBone marrow microenvironmentIntensive chemotherapyIntravascular coagulationLysis syndromeFluid hydrationSupportive treatmentAdverse prognosisAML patientsInflammatory cytokines
2019
The minimal that kills: Why defining and targeting measurable residual disease is the “Sine Qua Non” for further progress in management of acute myeloid leukemia
Bewersdorf JP, Shallis RM, Boddu PC, Wood B, Radich J, Halene S, Zeidan AM. The minimal that kills: Why defining and targeting measurable residual disease is the “Sine Qua Non” for further progress in management of acute myeloid leukemia. Blood Reviews 2019, 43: 100650. PMID: 31883804, DOI: 10.1016/j.blre.2019.100650.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsAcute myeloid leukemiaMyeloid leukemiaHard clinical outcomesClinical trial evidenceMeasurable residual diseaseResidual leukemic cellsRisk of relapseApprovable endpointsMRD statusDeep remissionMorphologic remissionMRD assessmentOverall survivalMRD levelsClinical outcomesDisease relapseInitial treatmentResidual diseaseTrial evidenceClinical trialsTreatment decisionsSurrogate endpointsBone marrowPreemptive interventionLeukemic cellsHedgehog pathway inhibition as a therapeutic target in acute myeloid leukemia
Shallis RM, Bewersdorf JP, Boddu PC, Zeidan AM. Hedgehog pathway inhibition as a therapeutic target in acute myeloid leukemia. Expert Review Of Anticancer Therapy 2019, 19: 717-729. PMID: 31422721, DOI: 10.1080/14737140.2019.1652095.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsAcute myeloid leukemiaHh pathway inhibitorsMyeloid leukemiaSurvival of AMLPathway inhibitorHh pathwayPoor-risk diseaseHedgehog pathway inhibitionStem cellsCombination therapyClinical trialsFirst approvalTherapeutic strategiesTherapeutic targetPathway inhibitionHematopoietic stem cellsNeoplasm therapyOlder populationTherapyHedgehog pathwayFurther studiesLeukemiaNormal hematopoiesisAdult stem cellsInhibitorsTransforming growth factor (TGF)-β pathway as a therapeutic target in lower risk myelodysplastic syndromes
Bewersdorf JP, Zeidan AM. Transforming growth factor (TGF)-β pathway as a therapeutic target in lower risk myelodysplastic syndromes. Leukemia 2019, 33: 1303-1312. PMID: 30962581, DOI: 10.1038/s41375-019-0448-2.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsErythropoiesis stimulating agentsMyelodysplastic syndromeGrowth factorIneffective erythropoiesisLower-risk myelodysplastic syndromesTGF-β pathway inhibitorLR-MDS patientsFurther therapeutic optionsRisk myelodysplastic syndromesLimited therapy optionsTGF-β receptor activationPromising therapeutic approachPhysiologic conditionsTGF-β pathwayAberrant TGFImmunomodulator lenalidomideLR-MDSMyelosuppressive effectsTherapeutic optionsTherapy optionsLife impairmentAdditional potential targetsClinical dataMDS pathogenesisTherapeutic approachesGetting personal with myelodysplastic syndromes: is now the right time?
Chokr N, Pine AB, Bewersdorf JP, Shallis RM, Stahl M, Zeidan AM. Getting personal with myelodysplastic syndromes: is now the right time? Expert Review Of Hematology 2019, 12: 215-224. PMID: 30977414, PMCID: PMC6540985, DOI: 10.1080/17474086.2019.1592673.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsMyelodysplastic syndromeNext-generation sequencingTherapy selectionPrognosis of MDSRole of NGSPrognosis of patientsRoutine clinical practiceMinimal residual diseaseRecurrent genetic abnormalitiesResidual diseaseBlood countDisease stagePeripheral bloodHematologic malignanciesPrognostic evaluationMDS pathogenesisRoutine managementTherapy decisionsHealthy individualsBone marrowClinical practiceCytological examinationPatientsScoring systemDiagnostic accuracyImmune checkpoint-based therapy in myeloid malignancies: a promise yet to be fulfilled
Bewersdorf JP, Stahl M, Zeidan AM. Immune checkpoint-based therapy in myeloid malignancies: a promise yet to be fulfilled. Expert Review Of Anticancer Therapy 2019, 19: 393-404. PMID: 30887841, PMCID: PMC6527485, DOI: 10.1080/14737140.2019.1589374.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsImmune checkpoint-based therapyImmune checkpoint inhibitorsAcute myeloid leukemiaMyelodysplastic syndromeNon-small cell lung cancerMultiple immune checkpoint inhibitorsTumor microenvironmentHematopoietic stem cell transplantAdvanced solid malignanciesStem cell transplantCell lung cancerInhibitory immune checkpointsImmunosuppressive tumor microenvironmentType of therapyMinimal residual diseaseInduction chemotherapyMonotherapy useRefractory settingCheckpoint inhibitorsImmune checkpointsTumor cell survivalCell transplantResidual diseaseSafety profileImmune system evasionCalcium Influx through Plasma-Membrane Nanoruptures Drives Axon Degeneration in a Model of Multiple Sclerosis
Witte M, Schumacher A, Mahler C, Bewersdorf J, Lehmitz J, Scheiter A, Sánchez P, Williams P, Griesbeck O, Naumann R, Misgeld T, Kerschensteiner M. Calcium Influx through Plasma-Membrane Nanoruptures Drives Axon Degeneration in a Model of Multiple Sclerosis. Neuron 2019, 101: 615-624.e5. PMID: 30686733, PMCID: PMC6389591, DOI: 10.1016/j.neuron.2018.12.023.Peer-Reviewed Original ResearchConceptsAxonal lossModel of multiple sclerosisSodium-calcium exchangerCytoplasmic calcium levelsMultiple sclerosis modelMultiple sclerosis patientsCalcium entryCalcium influxCalcium levelsCalcium imagingCalcium accumulationGlutamate excitotoxicityPersistent disabilityAxonal degenerationMultiple sclerosisAxonsPlasma membraneEndoplasmic reticulumCalcium
2018
Immunotherapy in acute myeloid leukemia and myelodysplastic syndromes: The dawn of a new era?
Liu Y, Bewersdorf JP, Stahl M, Zeidan AM. Immunotherapy in acute myeloid leukemia and myelodysplastic syndromes: The dawn of a new era? Blood Reviews 2018, 34: 67-83. PMID: 30553527, DOI: 10.1016/j.blre.2018.12.001.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsHematopoietic stem cell transplantAcute myeloid leukemiaImmune checkpoint inhibitorsMyelodysplastic syndromeCheckpoint inhibitorsCell-based therapiesMyeloid leukemiaAllogeneic hematopoietic stem cell transplantCytotoxic T-lymphocyte-associated protein 4T-lymphocyte-associated protein 4Cell death protein 1Cell-based vaccinesNK cell therapyApplication of immunotherapyDeath protein 1Stem cell transplantAntibody-targeted therapyChimeric antigen receptorAntibody-based therapiesGemtuzumab ozogamicinDendritic cellsCell transplantImmunotherapeutic drugsT cellsClinical developmentMast Cells Are Activated by Streptococcus pneumoniae In Vitro but Dispensable for the Host Defense Against Pneumococcal Central Nervous System Infection In Vivo
Fritscher J, Amberger D, Dyckhoff S, Bewersdorf J, Masouris I, Voelk S, Hammerschmidt S, Schmetzer H, Klein M, Pfister H, Koedel U. Mast Cells Are Activated by Streptococcus pneumoniae In Vitro but Dispensable for the Host Defense Against Pneumococcal Central Nervous System Infection In Vivo. Frontiers In Immunology 2018, 9: 550. PMID: 29616039, PMCID: PMC5867309, DOI: 10.3389/fimmu.2018.00550.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBacterial ProteinsCell DegranulationCells, CulturedCentral Nervous SystemCromolyn SodiumHumansImmunity, InnateMaleMast CellsMeningitis, PneumococcalMiceMice, Inbred C57BLMice, TransgenicMutationPneumococcal InfectionsProto-Oncogene Proteins c-kitStreptococcus pneumoniaeStreptolysinsConceptsBone marrow-derived mast cellsCentral nervous systemSystemic infection in vivoMast cellsBone-marrow-derived mast cell degranulationMast cell engraftmentMouse bone marrow-derived mast cellsBacterial infectionsMarrow-derived mast cellsCerebrospinal fluidMutant mouse strainsMast cell-deficientExperimental pneumococcal meningitisMast cell stabilizerSystemic bacterial infectionInfection in vivoDisease phenotypeCell deficiencyCSF pleocytosisPneumococcal serotypesC-kitCell engraftmentPneumococcal meningitisMouse strainsNervous systemNovel and preclinical treatment strategies in pneumococcal meningitis
Bewersdorf J, Grandgirard D, Koedel U, Leib S. Novel and preclinical treatment strategies in pneumococcal meningitis. Current Opinion In Infectious Diseases 2018, 31: 85-92. PMID: 29095719, DOI: 10.1097/qco.0000000000000416.Peer-Reviewed Original ResearchConceptsAdjuvant therapyPneumococcal meningitisNew adjuvant therapiesSystematic clinical testingProtein-based pneumococcal vaccinesPreclinical treatment strategiesPneumococcal conjugate vaccineAnti-inflammatory therapyImprove disease outcomesToxic bacterial productsMatrix metalloproteinase inhibitorsNonbacteriolytic antibioticsAdjuvant dexamethasoneLife-threatening diseaseMeningeal inflammationBacterial meningitisSerotype replacementTreatment optionsConjugate vaccinePneumococcal vaccineMorbidity rateComplement inhibitorsTreatment strategiesSuppress inflammationMeningitis