2024
Mucosal sugars delineate pyrazine vs pyrazinone autoinducer signaling in Klebsiella oxytoca
Hamchand R, Wang K, Song D, Palm N, Crawford J. Mucosal sugars delineate pyrazine vs pyrazinone autoinducer signaling in Klebsiella oxytoca. Nature Communications 2024, 15: 8902. PMID: 39406708, PMCID: PMC11480411, DOI: 10.1038/s41467-024-53185-6.Peer-Reviewed Original ResearchConceptsK. oxytocaGeneral carbohydrate metabolismVirulence factor productionPLP-dependent enzymesAssociated with gutEnterobactin biosynthesisAutoinducer signalBacterial virulenceKlebsiella oxytocaSpecific carbohydratesHost immune responseCarbohydrate metabolismAutoinducerMolecular signalsVirulenceHistamine receptor H4BiosynthesisHost signalAcquisition responsesProtease inhibitorsPathwayHostLung pathologyLung isolationImmune responsePreclinical evaluation of avutometinib and defactinib in high‐grade endometrioid endometrial cancer
Hartwich T, Mansolf M, Demirkiran C, Greenman M, Bellone S, McNamara B, Nandi S, Alexandrov L, Yang‐Hartwich Y, Coma S, Pachter J, Santin A. Preclinical evaluation of avutometinib and defactinib in high‐grade endometrioid endometrial cancer. Cancer Medicine 2024, 13: e70210. PMID: 39240189, PMCID: PMC11378359, DOI: 10.1002/cam4.70210.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Combined Chemotherapy ProtocolsBenzamidesCarcinoma, EndometrioidCell Line, TumorCell ProliferationEndometrial NeoplasmsExome SequencingFemaleFocal Adhesion Kinase 1HumansImidazolesMiceNeoplasm GradingOxazepinesProtein Kinase InhibitorsPyrazinesSulfonamidesXenograft Model Antitumor AssaysConceptsFocal adhesion kinaseWhole-exome sequencingEndometrial cancer cell linesVS-4718Cell linesRas/MAPK pathwayPhosphorylated focal adhesion kinaseWestern blot assayWhole-exome sequencing resultsRAF/MEK inhibitionEAC cell linesBlot assayP-FAKGenetic landscapeCell cycleEndometrial cancerGenetic derangementsDefactinibP-MEKGrowth inhibitionRAF/MEKRas/MAPKCell viabilityP-ERKHigh-grade endometrial cancer
2022
Follow-up of patients with R/R FLT3-mutation–positive AML treated with gilteritinib in the phase 3 ADMIRAL trial
Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation–positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood 2022, 139: 3366-3375. PMID: 35081255, PMCID: PMC9197557, DOI: 10.1182/blood.2021011583.Peer-Reviewed Original ResearchConceptsAcute myeloid leukemiaSalvage chemotherapyADMIRAL trialSC armOverall survivalFLT3 mutation-positive acute myeloid leukemiaPositive acute myeloid leukemiaComposite complete remissionStable safety profileAdverse event incidenceCommon adverse eventsLiver transaminase levelsMedian overall survivalSuperior overall survivalLong-term treatment effectsGilteritinib armComplete remissionMaintenance therapyAdverse eventsCumulative incidenceMedian survivalTransaminase levelsEvent incidenceMaintenance treatmentSafety profileClinical outcomes in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib
Perl AE, Hosono N, Montesinos P, Podoltsev N, Martinelli G, Panoskaltsis N, Recher C, Smith CC, Levis MJ, Strickland S, Röllig C, Groß-Langenhoff M, Chou WC, Lee JH, Yokoyama H, Hasabou N, Lu Q, Tiu RV, Altman JK. Clinical outcomes in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib. Blood Cancer Journal 2022, 12: 84. PMID: 35637252, PMCID: PMC9151663, DOI: 10.1038/s41408-022-00677-7.Peer-Reviewed Original ResearchConceptsAcute myeloid leukemiaFLT3-TKIRefractory FLT3TKI exposureSalvage chemotherapyClinical outcomesMyeloid leukemiaR AMLLonger median overall survivalComposite complete remissionHigher CRCS ratesMedian overall survivalTyrosine kinase inhibitor midostaurinKinase inhibitor midostaurinPotential clinical impactADMIRAL trialCRC ratesGilteritinib armPrior sorafenibComplete remissionRemission durationOverall survivalTKI therapyTKI useSurvival outcomesGilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with FLT3 inhibitors
Numan Y, Rahman Z, Grenet J, Boisclair S, Bewersdorf JP, Collins C, Barth D, Fraga M, Bixby DL, Zeidan AM, Yilmaz M, Desai P, Mannis G, Deutsch YE, Abaza Y, Dinner S, Frankfurt O, Litzow M, Al‐Kali A, Foran JM, Sproat LZ, Jovanovic B, Daver N, Perl AE, Altman JK. Gilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with FLT3 inhibitors. American Journal Of Hematology 2022, 97: 322-328. PMID: 34981560, DOI: 10.1002/ajh.26447.Peer-Reviewed Original ResearchConceptsAcute myeloid leukemiaMyeloid leukemiaRelapsed/Refractory Acute Myeloid LeukemiaComposite complete remission rateRefractory acute myeloid leukemiaLower median overall survivalComplete remission rateMedian overall survivalStem cell transplantCRC ratesLower CRCRefractory FLT3Median survivalRemission rateIntensive inductionOverall survivalCell transplantCombination therapyFLT3 inhibitorsFLT3 mutationsClinical activityUS CentersRetrospective analysisADMIRAL studyMitogen-activated protein kinase pathway
2021
Gilteritinib vs salvage chemotherapy in FLT3-mutated acute myeloid leukemia: number needed to treat for clinical outcomes per a secondary analysis of the ADMIRAL trial
Zeidan AM, Qi CZ, Yang H, Garnham A, Shah MV, Pandya BJ. Gilteritinib vs salvage chemotherapy in FLT3-mutated acute myeloid leukemia: number needed to treat for clinical outcomes per a secondary analysis of the ADMIRAL trial. Leukemia & Lymphoma 2021, 63: 762-764. PMID: 34749571, DOI: 10.1080/10428194.2021.2001467.Peer-Reviewed Original Research
2019
Temozolomide Sensitizes MGMT-Deficient Tumor Cells to ATR Inhibitors
Jackson CB, Noorbakhsh SI, Sundaram RK, Kalathil AN, Ganesa S, Jia L, Breslin H, Burgenske DM, Gilad O, Sarkaria JN, Bindra RS. Temozolomide Sensitizes MGMT-Deficient Tumor Cells to ATR Inhibitors. Cancer Research 2019, 79: 4331-4338. PMID: 31273061, PMCID: PMC6810597, DOI: 10.1158/0008-5472.can-18-3394.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Agents, AlkylatingAntineoplastic Combined Chemotherapy ProtocolsAtaxia Telangiectasia Mutated ProteinsCell Cycle CheckpointsCell Line, TumorCheckpoint Kinase 1DNA Breaks, Double-StrandedDNA DamageDNA Modification MethylasesDNA Repair EnzymesDrug SynergismFemaleHumansIsoxazolesMice, NudePyrazinesTemozolomideTumor Suppressor ProteinsXenograft Model Antitumor AssaysConceptsMGMT-deficient cells
2018
Radio-sensitizing effects of VE-821 and beyond: Distinct phosphoproteomic and metabolomic changes after ATR inhibition in irradiated MOLT-4 cells
Šalovská B, Janečková H, Fabrik I, Karlíková R, Čecháková L, Ondrej M, Link M, Friedecký D, Tichý A. Radio-sensitizing effects of VE-821 and beyond: Distinct phosphoproteomic and metabolomic changes after ATR inhibition in irradiated MOLT-4 cells. PLOS ONE 2018, 13: e0199349. PMID: 30001349, PMCID: PMC6042708, DOI: 10.1371/journal.pone.0199349.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid MotifsAtaxia Telangiectasia Mutated ProteinsBinding SitesBiomarkersCell Cycle CheckpointsCell Line, TumorComputational BiologyGamma RaysGene OntologyHumansMetabolomeMetabolomicsPhosphoproteinsPhosphorylationProtein BindingProtein Kinase InhibitorsProteomeProteomicsPyrazinesRadiation ToleranceRadiation-Sensitizing AgentsSignal TransductionSulfonesTOR Serine-Threonine KinasesConceptsVE-821MOLT-4 cellsCellular metabolismOncogene-induced replication stressATR inhibitionATM-deficient cellsDNA damage responseATR/Chk1 pathwayCell biology techniquesDownregulation of mTORAnti-cancer strategyCurrent anti-cancer strategiesReplication stressPhosphorylation sitesDamage responseIrradiation-induced oxidative stressQuantitative proteomicsDNA repairChk1 pathwayCellular eventsBiology techniquesSpecific inhibitorMain regulatorTumor-specific abnormalitiesMTOR inhibitionBiodegradable PEG-poly(ω-pentadecalactone-co-p-dioxanone) nanoparticles for enhanced and sustained drug delivery to treat brain tumors
Chen EM, Quijano AR, Seo YE, Jackson C, Josowitz AD, Noorbakhsh S, Merlettini A, Sundaram RK, Focarete ML, Jiang Z, Bindra RS, Saltzman WM. Biodegradable PEG-poly(ω-pentadecalactone-co-p-dioxanone) nanoparticles for enhanced and sustained drug delivery to treat brain tumors. Biomaterials 2018, 178: 193-203. PMID: 29936153, PMCID: PMC6082184, DOI: 10.1016/j.biomaterials.2018.06.024.Peer-Reviewed Original Research
2016
Pyrazinone protease inhibitor metabolites from Photorhabdus luminescens
Park HB, Crawford JM. Pyrazinone protease inhibitor metabolites from Photorhabdus luminescens. The Journal Of Antibiotics 2016, 69: 616-621. PMID: 27353165, PMCID: PMC5003743, DOI: 10.1038/ja.2016.79.Peer-Reviewed Original ResearchConceptsSpecialized metabolitesNew specialized metabolitesMutualistic associationAmino acid levelsInsect pathogenesisInsect preyGalleria mellonella larvaePhotorhabdus genusP. luminescensPhenotypic variationFamilies HeterorhabditidaeNematode developmentEntomopathogenic bacteriumProtease inhibitory activityFree amino acid levelsRich mediumAmino acidsMellonella larvaePhenotypic variantsMarfey's analysisPhotorhabdusCirculatory fluidCulture extractsMetabolitesHeterorhabditidae
2015
Tetramethylpyrazine protects CoCl2-induced apoptosis in human umbilical vein endothelial cells by regulating the PHD2/HIF/1α-VEGF pathway
Yang C, Xu Y, Zhou H, Yang L, Yu S, Gao Y, Huang Y, Lu L, Liang X. Tetramethylpyrazine protects CoCl2-induced apoptosis in human umbilical vein endothelial cells by regulating the PHD2/HIF/1α-VEGF pathway. Molecular Medicine Reports 2015, 13: 1287-1296. PMID: 26676934, DOI: 10.3892/mmr.2015.4679.Peer-Reviewed Original Research
2014
Phase I Trial of Bortezomib (PS-341; NSC 681239) and “Nonhybrid” (Bolus) Infusion Schedule of Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-cell Neoplasms
Holkova B, Kmieciak M, Perkins EB, Bose P, Baz RC, Roodman GD, Stuart RK, Ramakrishnan V, Wan W, Peer CJ, Dawson J, Kang L, Honeycutt C, Tombes MB, Shrader E, Weir-Wiggins C, Wellons M, Sankala H, Hogan KT, Colevas AD, Doyle LA, Figg WD, Coppola D, Roberts JD, Sullivan D, Grant S. Phase I Trial of Bortezomib (PS-341; NSC 681239) and “Nonhybrid” (Bolus) Infusion Schedule of Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-cell Neoplasms. Clinical Cancer Research 2014, 20: 5652-5662. PMID: 25248382, PMCID: PMC4233160, DOI: 10.1158/1078-0432.ccr-14-0805.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityCombination of bortezomibCommon hematologic toxicityCommon nonhematologic toxicitiesIndolent B-cell neoplasmsRefractory multiple myelomaDose-escalation designNon-Hodgkin lymphomaTotal response rateB-cell malignanciesB-cell neoplasmsPharmacodynamic study resultsNonhematologic toxicitySchedule regimenStable diseaseComplete remissionHematologic toxicityPartial remissionClinical responseInvestigator's discretionDosing regimenI trialPharmacokinetic findingsSensory neuropathyInfusion scheduleDipeptidyl‐Peptidase 4 Inhibition and the Vascular Effects of Glucagon‐like Peptide‐1 and Brain Natriuretic Peptide in the Human Forearm
Devin JK, Pretorius M, Nian H, Yu C, Billings FT, Brown NJ. Dipeptidyl‐Peptidase 4 Inhibition and the Vascular Effects of Glucagon‐like Peptide‐1 and Brain Natriuretic Peptide in the Human Forearm. Journal Of The American Heart Association 2014, 3: e001075. PMID: 25158865, PMCID: PMC4310400, DOI: 10.1161/jaha.114.001075.Peer-Reviewed Original ResearchConceptsGlucagon-like peptide-1Brain natriuretic peptideForearm blood flowNatriuretic peptideDPP4 inhibitionBlood flowPeptide-1Placebo-controlled crossover studyDipeptidyl peptidase-4 inhibitorsDipeptidyl peptidase-4 inhibitionForearm vascular resistanceDose-dependent vasodilationMean arterial pressureGLP-1 concentrationsHuman forearmSitagliptin useDirect vasodilatorVascular resistanceVasodilator responseVascular effectsArterial pressureBrachial arteryDiabetes mellitusGlycemic controlNorepinephrine releaseRadiosensitization of Human Leukemic HL-60 Cells by ATR Kinase Inhibitor (VE-821): Phosphoproteomic Analysis
Šalovská B, Fabrik I, Ďurišová K, Link M, Vávrová J, Řezáčová M, Tichý A. Radiosensitization of Human Leukemic HL-60 Cells by ATR Kinase Inhibitor (VE-821): Phosphoproteomic Analysis. International Journal Of Molecular Sciences 2014, 15: 12007-12026. PMID: 25003641, PMCID: PMC4139827, DOI: 10.3390/ijms150712007.Peer-Reviewed Original ResearchConceptsDNA-dependent protein kinaseVE-821HL-60 cellsNano-liquid chromatography-tandem mass spectrometry analysisCell cycleSequence motif analysisDNA damage responseRadiation-induced double-strand breaksATR kinase inhibitorsDNA damage repairDNA damaging agentsHuman leukemic HL-60 cellsDouble-strand breaksSpecific ATR inhibitorActivity of kinasesInhibitor VE-821Leukemic HL-60 cellsCell cycle arrestQuantitative phosphoproteomicsATR kinaseMotif analysisPhosphorylation sitesCellular processesDamage responsePhosphoproteomic analysisEffect of bortezomib on the efficacy of AAV9.SERCA2a treatment to preserve cardiac function in a rat pressure-overload model of heart failure
Chaanine A, Nonnenmacher M, Kohlbrenner E, Jin D, Kovacic J, Akar F, Hajjar R, Weber T. Effect of bortezomib on the efficacy of AAV9.SERCA2a treatment to preserve cardiac function in a rat pressure-overload model of heart failure. Gene Therapy 2014, 21: 379-386. PMID: 24572786, PMCID: PMC3976435, DOI: 10.1038/gt.2014.7.Peer-Reviewed Original ResearchConceptsHeart failureCardiac functionRodent heart failure modelsRat cardiomyocytesHeart failure modelPressure overload modelEffect of bortezomibProteasome inhibitor bortezomibNeonatal rat cardiomyocytesAdult rat cardiomyocytesWestern blot analysisSERCA2a proteinPressure-volume analysisSERCA2a levelsBortezomib treatmentConcurrent treatmentSERCA2a mRNAInhibitor bortezomibBortezomibHeart samplesHuman SERCA2aSerotype 1Proteasome inhibitorsAAV serotypes 1Proteasome inhibitionSubstance P Increases Sympathetic Activity During Combined Angiotensin-Converting Enzyme and Dipeptidyl Peptidase-4 Inhibition
Devin JK, Pretorius M, Nian H, Yu C, Billings FT, Brown NJ. Substance P Increases Sympathetic Activity During Combined Angiotensin-Converting Enzyme and Dipeptidyl Peptidase-4 Inhibition. Hypertension 2014, 63: 951-957. PMID: 24516103, PMCID: PMC3984385, DOI: 10.1161/hypertensionaha.113.02767.Peer-Reviewed Original ResearchMeSH KeywordsAdultAngiotensin-Converting Enzyme InhibitorsBlood PressureBradykininCross-Over StudiesDipeptidyl Peptidase 4Double-Blind MethodEnalaprilatEnzyme InhibitorsFemaleHeart RateHumansMaleMiddle AgedNeurotransmitter AgentsNorepinephrinePeptidyl-Dipeptidase APyrazinesSitagliptin PhosphateSubstance PSympathetic Nervous SystemTriazolesVascular ResistanceConceptsDipeptidyl peptidase-4 inhibitionPeptidase-4 inhibitionTissue plasminogen activator releaseSubstance PDipeptidyl peptidase-4Plasminogen activator releaseSympathetic activityPeptidase-4Activator releasePlacebo-controlled crossover studyDipeptidyl peptidase-4 inhibitorsType 2 diabetes mellitusIntra-arterial enalaprilatForearm vascular resistanceForearm blood flowMean arterial pressurePeptidase-4 inhibitorsAngiotensin converting enzymeSubstrates of angiotensinVascular resistanceVasodilator responseArterial pressureBrachial arteryDiabetes mellitusCrossover studyNovel 3-arylethynyl-substituted thieno[3,4- b ]pyrazine derivatives as human transglutaminase 2 inhibitors
Kim N, Kwak H, Lee S, Juvekar V, Lee B, Ahn H, Kim S, Gong Y. Novel 3-arylethynyl-substituted thieno[3,4- b ]pyrazine derivatives as human transglutaminase 2 inhibitors. Organic & Biomolecular Chemistry 2014, 12: 4932-4940. PMID: 24879506, DOI: 10.1039/c4ob00179f.Peer-Reviewed Original Research
2013
Deleterious effect of oltipraz on extrahepatic cholestasis in bile duct-ligated mice
Weerachayaphorn J, Luo Y, Mennone A, Soroka CJ, Harry K, Boyer JL. Deleterious effect of oltipraz on extrahepatic cholestasis in bile duct-ligated mice. Journal Of Hepatology 2013, 60: 160-166. PMID: 23978715, PMCID: PMC4054607, DOI: 10.1016/j.jhep.2013.08.015.Peer-Reviewed Original ResearchConceptsBile duct ligationBDL miceLiver injuryControl miceBile duct-ligated miceBile flow rateBile duct obstructionHepato-protective effectsSmooth muscle actin expressionLiver function markersSevere liver damageBile acid-independent flowHigher bile flowMatrix metalloproteinases-9Hepatic stellate cellsCancer preventive agentsMuscle actin expressionPromising cancer-preventive agentBiliary pressureSerum aminotransferasesLiver histologyBDL groupPhase II detoxificationPortal fibroblastsProfibrogenic genesPhase I trial of bortezomib and dacarbazine in melanoma and soft tissue sarcoma
Poklepovic A, Youseffian L, Winning M, Birdsell CA, Crosby NA, Ramakrishnan V, Ernstoff MS, Roberts JD. Phase I trial of bortezomib and dacarbazine in melanoma and soft tissue sarcoma. Investigational New Drugs 2013, 31: 937-942. PMID: 23315028, PMCID: PMC3844155, DOI: 10.1007/s10637-012-9913-8.Peer-Reviewed Original ResearchConceptsSoft tissue sarcomasPhase I trialTissue sarcomasPartial responseI trialPhase II dosesDurable complete responseAmine precursor uptakeTwenty-eight patientsProteasome inhibitor bortezomibHuman melanoma cell linesMurine xenograft tumor modelXenograft tumor modelCKIT mutationsDecarboxylation (APUD) tumorsProphylactic antiemeticsRECIST v1.0Eight patientsComplete responseMelanoma cell linesWeekly dosesDose escalationAgent dacarbazinePreclinical studiesDose levels
2012
Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis
Shefner J, Cedarbaum JM, Cudkowicz ME, Maragakis N, Lee J, Jones D, Watson ML, Mahoney K, Chen M, Saikali K, Mao J, Russell AJ, Hansen RL, Malik F, Wolff AA, Team F. Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis And Frontotemporal Degeneration 2012, 13: 430-438. PMID: 22591195, DOI: 10.3109/17482968.2012.684214.Peer-Reviewed Original ResearchConceptsAmyotrophic lateral sclerosisSingle dosesGlobal ImpressionLateral sclerosisFast skeletal muscle troponin activatorFrequent adverse eventsDose-related fashionLimb muscle strengthMaximum voluntary ventilationDose-dependent benefitMeasures of enduranceAdverse eventsPulmonary functionVoluntary ventilationGeneral fatigueTroponin activatorMuscle strengthPharmacodynamic markersHandgrip endurancePatientsRandom orderMaximal strengthDosesTolerabilityFurther studies
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