2025
Dynamic interaction of spliceosomal snRNPs with coilin explains Cajal body characteristics
Basello D, Blažíková M, Roithová A, Hálová M, Radivojević N, Neugebauer K, Staněk D. Dynamic interaction of spliceosomal snRNPs with coilin explains Cajal body characteristics. Journal Of Cell Biology 2025, 224: e202309128. PMID: 40560171, PMCID: PMC12189012, DOI: 10.1083/jcb.202309128.Peer-Reviewed Original ResearchA genetic modifier links integrin α5 to the phenotypic variation in fibronectin 1a mutant zebrafish.
Capon S, Maroufidou A, Feltes M, Xu Y, Matharoo D, Jülich D, Holley S, Farber S, Stainier D. A genetic modifier links integrin α5 to the phenotypic variation in fibronectin 1a mutant zebrafish. PLOS Genetics 2025, 21: e1011747. PMID: 40549824, PMCID: PMC12212883, DOI: 10.1371/journal.pgen.1011747.Peer-Reviewed Original ResearchConceptsMutant phenotypePhenotypic variationNonsense mutationGenetic modifiersDouble mutant analysisWhole-genome sequencingITGA5 expressionSevere phenotypeIntegrin alpha 5Mutant analysisMutant larvaeProximal promoterMutantsMutant zebrafishCardia bifidaGene expressionIntegrin A5Genetic backgroundAlpha 5PhenotypeMutationsExpression levelsFibronectinFunctional cardiovascular systemZebrafishSystemic in utero gene editing as a treatment for cystic fibrosis
Ricciardi A, Barone C, Putman R, Quijano E, Gupta A, Nguyen R, Mandl H, Piotrowski-Daspit A, Lopez-Giraldez F, Luks V, Freedman-Weiss M, Farrelly J, Ahle S, Lynn A, Glazer P, Saltzman W, Stitelman D, Egan M. Systemic in utero gene editing as a treatment for cystic fibrosis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2418731122. PMID: 40493185, PMCID: PMC12184489, DOI: 10.1073/pnas.2418731122.Peer-Reviewed Original ResearchConceptsUtero gene editingCystic fibrosisCF transmembrane conductance regulatorTreat CF patientsTransmembrane conductance regulatorWild-type miceIrreversible organ damageNormal organ developmentTreat monogenic diseasesCFTR activityCF patientsConductance regulatorDisease-causing genesMultiorgan diseaseDisease improvementOrgan damageGene editingMonogenic diseasesMutation correctionPolymeric nanoparticlesGastrointestinal tissuesDiseaseBirthFibrosisReproductive systemORCHARD: Osimertinib Plus Necitumumab in Patients With Epidermal Growth Factor Receptor–Mutated Advanced Non–Small Cell Lung Cancer With a Secondary Epidermal Growth Factor Receptor Alteration Whose Disease Had Progressed on First-Line Osimertinib
Riess J, de Langen A, Ponce S, Goldberg S, Piotrowska Z, Goldman J, Le X, Cho B, Yoneshima Y, Ambrose H, Cavazzina R, Tang K, Lau J, Yu H. ORCHARD: Osimertinib Plus Necitumumab in Patients With Epidermal Growth Factor Receptor–Mutated Advanced Non–Small Cell Lung Cancer With a Secondary Epidermal Growth Factor Receptor Alteration Whose Disease Had Progressed on First-Line Osimertinib. JCO Precision Oncology 2025, 9: e2400818. PMID: 40466026, DOI: 10.1200/po-24-00818.Peer-Reviewed Original ResearchConceptsAdvanced non-small cell lung cancerNon-small cell lung cancerCell lung cancerLung cancerEpidermal growth factor receptor alterationsFirst-line osimertinibSafety of osimertinibProgression-free survivalDuration of responseNovel drug combinationsData cutoffPartial responseOsimertinib resistanceRisk-benefit analysisOverall survivalReceptor alterationsDiscontinued treatmentInvestigator assessmentClinical benefitNecitumumabSafety profileOsimertinibReport final resultsAdverse eventsDrug combinationsMore than just another IDH inhibitor: Insights from the HMPL-306 phase 1 trial
Getz T, Bewersdorf J. More than just another IDH inhibitor: Insights from the HMPL-306 phase 1 trial. Med 2025, 6: 100600. PMID: 40516517, DOI: 10.1016/j.medj.2025.100600.Peer-Reviewed Original ResearchPrediction of Lymph Node Metastasis in Non–Small Cell Lung Carcinoma Using Primary Tumor Somatic Mutation Data
Lee V, Moore N, Doyle J, Hicks D, Oh P, Bodofsky S, Hossain S, Patel A, Aneja S, Homer R, Park H. Prediction of Lymph Node Metastasis in Non–Small Cell Lung Carcinoma Using Primary Tumor Somatic Mutation Data. JCO Clinical Cancer Informatics 2025, 9: e2400303. PMID: 40446175, DOI: 10.1200/cci-24-00303.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerLymph node metastasisArea under the receiver operating characteristic curveNode metastasisTreatment strategiesNon-small cell lung carcinomaPrediction of lymph node metastasisSurvival analysisSNP dataLymph node metastasis statusAssociated with lymph node metastasisCell lung carcinomaCell lung cancerLymph node metastasis predictionReceiver operating characteristic curveDiagnostic methodsPersonalized treatment strategiesSingle-nucleotide polymorphism (SNPChi-square testMedian AUCLung carcinomaClinical outcomesNon-smallRisk stratificationLogistic regression modelsNeuronal potassium channel activity triggers initiation of mRNA translation through binding of translation regulators
Malone T, Wu J, Zhang Y, Licznerski P, Chen R, Nahiyan S, Pedram M, Jonas E, Kaczmarek L. Neuronal potassium channel activity triggers initiation of mRNA translation through binding of translation regulators. Science Advances 2025, 11: eadv3140. PMID: 40435242, PMCID: PMC12118559, DOI: 10.1126/sciadv.adv3140.Peer-Reviewed Original ResearchConceptsMRNA translationTranslational regulationInitiation of mRNA translationInitiation of translationSevere intellectual disabilityRegulation of translationMRNA translation regulationNeurites of cortical neuronsB-actinChannel activityIntellectual disabilityPotassium channel activityNeuronal activityMolecular mechanismsInhibit initiationMutationsCell linesPharmacological stimulationCortical neuronsMRNABindingRegulationTranslationEIF4ECYFIP1Comprehensive mutational analysis of the sequence–function relationship within a viral internal ribosome entry site
Grunseich S, Strobel S. Comprehensive mutational analysis of the sequence–function relationship within a viral internal ribosome entry site. Nucleic Acids Research 2025, 53: gkaf445. PMID: 40421802, PMCID: PMC12107430, DOI: 10.1093/nar/gkaf445.Peer-Reviewed Original ResearchConceptsCrPV-IRESIRES functionViral internal ribosome entry siteNext-generation sequencing methodsInternal ribosome entry siteSequence-function relationshipsCricket paralysis virusRibosome entry siteCell-free systemComprehensive mutational analysisMechanism of translationHigh-throughput methodRibosome contactsIntergenic regionRNA elementsTranslation initiationSequence requirementsIRES elementsMutation databaseEukaryotic extractsInitiation factorsSequencing methodsExpressed proteinsHelical regionsMutation analysisAPOBEC affects tumor evolution and age at onset of lung cancer in smokers
Zhang T, Sang J, Hoang P, Zhao W, Rosenbaum J, Johnson K, Klimczak L, McElderry J, Klein A, Wirth C, Bergstrom E, Díaz-Gay M, Vangara R, Colon-Matos F, Hutchinson A, Lawrence S, Cole N, Zhu B, Przytycka T, Shi J, Caporaso N, Homer R, Pesatori A, Consonni D, Imielinski M, Chanock S, Wedge D, Gordenin D, Alexandrov L, Harris R, Landi M. APOBEC affects tumor evolution and age at onset of lung cancer in smokers. Nature Communications 2025, 16: 4711. PMID: 40394004, PMCID: PMC12092836, DOI: 10.1038/s41467-025-59923-8.Peer-Reviewed Original ResearchConceptsLung cancerTumor evolutionMulti-omics profilingLung tumor samplesCell of originProgenitor-like cellsMulti-omicsMutagenic processesMutational processesOff-target activityTP53 mutationsMutational burdenSignaling pathwayKRAS mutationsMutagenesisAPOBEC mutagenesisSomatic mutationsSolid tumorsTumor samplesClonal expansionDNA damageTumor developmentCell typesMutationsStemness markersMutations in the SWEET15 Sugar Transporter Gene Affect Response of Citrus to Huanglongbing Disease and Citrus Canker
Khadgi A, Zayed O, Sagawa C, Zhang F, Seymour D, Irish V. Mutations in the SWEET15 Sugar Transporter Gene Affect Response of Citrus to Huanglongbing Disease and Citrus Canker. Molecular Plant Pathology 2025, 26: e70094. PMID: 40369935, PMCID: PMC12078760, DOI: 10.1111/mpp.70094.Peer-Reviewed Original ResearchConceptsSecretion systemCitrus cankerSusceptibility genesEffector proteinsType III secretion systemSec secretion systemIII secretion systemBacterial secretion systemsBacterial diseasesXanthomonas citri pvSusceptibility to citrus cankerCitrus cultivarsCandidatus Liberibacter asiaticusSusceptibility gene expressionPlant immunityInfected plantsBacterial pathogensSucrose transportGene activationLiberibacter asiaticusPromote pathogenesisExported TransportersSWEET15Lemon plantsCankerExploring the complexity of MECP2 function in Rett syndrome
Liu Y, Whitfield T, Bell G, Guo R, Flamier A, Young R, Jaenisch R. Exploring the complexity of MECP2 function in Rett syndrome. Nature Reviews Neuroscience 2025, 26: 379-398. PMID: 40360671, DOI: 10.1038/s41583-025-00926-1.Peer-Reviewed Original ResearchConceptsMethylated DNA binding protein MeCP2Neuronal gene regulationReview recent insightsChromatin structureTranscriptional regulationGene regulationInteraction hubProtein MeCP2Cofactor interactionsTranscription factorsEpigenetic regulationRett syndromeProteomic studiesDiverse processesMolecular mechanismsMeCP2 functionTherapeutic designMeCP2Neuronal functionRegulationModel systemNeurodevelopmental disordersRepressorChromatinMechanistic studiesGenomic landscape and homologous recombination repair deficiency signature in stage I-III and de novo stage IV primary breast cancers
Jeon J, Chen K, Madison R, Schrock A, Sokol E, Levy M, Rozenblit M, Huang R, Pusztai L. Genomic landscape and homologous recombination repair deficiency signature in stage I-III and de novo stage IV primary breast cancers. The Oncologist 2025, 30: oyaf089. PMID: 40421962, PMCID: PMC12107548, DOI: 10.1093/oncolo/oyaf089.Peer-Reviewed Original ResearchConceptsHomologous recombination deficiencyDe novo stage IV breast cancerStage IV breast cancerPrimary breast cancerIV breast cancerStage I-III cancerStage I-IIIBreast cancerGenomic alterationsFrequency of genomic alterationsHER2+ cancersI-IIITargetable genomic alterationsGenomic landscapePlatinum-based treatmentWild-type cancersHR repairCancer-related genesER+/HER2- cancersLate relapsePrimary tumorFoundation MedicinePIK3CA mutationsMutation statusNo significant differenceCharacterization and Clinical Implications of p53 Dysfunction in Patients With Myelodysplastic Syndromes
Zampini M, Riva E, Lanino L, Sauta E, Dos Reis R, Ejarque R, Maggioni G, Termanini A, Merlotti A, Campagna A, Dall’Olio L, Kulasekararaj A, Calvi M, Di Vito C, Bonometti A, Rahal D, Croci G, Boveri E, Gianelli U, Ponzoni M, Caselli R, Albertazzi S, Todisco G, Ubezio M, Crisafulli L, Frigo A, Lugli E, Mosca E, Acha P, Ghisletti S, Nicassio F, Santoro A, Diez-Campelo M, Solé F, Ades L, Platzbecker U, Santini V, Fenaux P, Haferlach T, Sallman D, Garcia-Manero G, Mavilio D, Remondini D, Castellani G, D'Amico S, Zeidan A, Komrokji R, Kordasti S, Ficara F, Della Porta M, Consortium C, Russo A, Travaglino E, Delleani M, Asti G, Ventura D, Tentori C, Buizza A, Brindisi M, Pinocchio N, Pesce F. Characterization and Clinical Implications of p53 Dysfunction in Patients With Myelodysplastic Syndromes. Journal Of Clinical Oncology 2025, 43: 2069-2083. PMID: 40315418, PMCID: PMC12169866, DOI: 10.1200/jco-24-02394.Peer-Reviewed Original ResearchConceptsMyelodysplastic syndromeP53 dysfunctionPhenotype of immune cellsClassification of myeloid neoplasmsIdentified high-risk patientsImpaired antigen presentationOptimal timing of therapeutic interventionsAbnormal p53 proteinHigh-risk patientsSubsets of patientsBone marrow progenitorsTiming of therapeutic interventionDesign of clinical trialsRecognition of patientsTumor protein 53Variant allele frequencyNF-kB pathwayInnovative immunotherapyMyeloid neoplasmsDismal outcomeMarrow progenitorsImmune dysregulationBiallelic inactivationImmune cellsPoor prognosisVAC14 oligomerization is essential for the function of the FAB1/PIKfyve-VAC14-FIG4 complex.
Zhang L, Uygun T, Hahn H, Liu Y, Rivero-Ríos P, Li D, Navratna V, Bristow E, Luo G, Kovarzin A, Bo Y, Gadde S, Côté M, Ko D, Mosalaganti S, Reinisch K, Weisman L. VAC14 oligomerization is essential for the function of the FAB1/PIKfyve-VAC14-FIG4 complex. Molecular Biology Of The Cell 2025, 36: ar78. PMID: 40305106, DOI: 10.1091/mbc.e24-11-0490.Peer-Reviewed Original ResearchMeSH KeywordsCryoelectron MicroscopyFlavoproteinsHexosyltransferasesHumansIntracellular Signaling Peptides and ProteinsMembrane ProteinsMutationPhosphatidylinositol 3-KinasesPhosphatidylinositol PhosphatesPhosphoric Monoester HydrolasesPhosphotransferases (Alcohol Group Acceptor)Protein BindingProtein MultimerizationSaccharomyces cerevisiaeSaccharomyces cerevisiae ProteinsVesicular Transport ProteinsConceptsPatient mutationsFluorescence-detection size-exclusion chromatographyPI(3,5)P<sub>2</sub>Phosphatidylinositol 3,5-bisphosphatePull-down assaysMedium-resolution structureYeast mutationsPediatric neurodegenerative diseaseVac14Signaling lipidsCell lysatesMutationsOligomerizationNeurodegenerative diseasesElectron microscopy mappingKnockoutFab1/PIKfyveYeastEndosomesFIG4PIKfyveLysatesColocalizationComplexRegulationBlocking Nitrosylation Induces Immunogenic Cell Death by Sensitizing NRAS-Mutant Melanoma to MEK Inhibitors
Srivastava J, Yadav V, Jimenez R, Phadatare P, Inamdar N, Young M, Bacchiocchi A, Halaban R, Fang B, de Mingo Pulido A, Tsai K, Smalley K, Koomen J, Rodriguez P, Premi S. Blocking Nitrosylation Induces Immunogenic Cell Death by Sensitizing NRAS-Mutant Melanoma to MEK Inhibitors. Cancer Research 2025, 85: 2268-2287. PMID: 40287947, PMCID: PMC12167936, DOI: 10.1158/0008-5472.can-24-0693.Peer-Reviewed Original ResearchConceptsInduce immunogenic cell deathNRAS-mutant melanomaDamage-associated molecular patternsImmunogenic cell deathMEK inhibitorsDendritic cellsRepertoire of CD8+ T cellsCocultures of dendritic cellsCD8+ T cellsCell deathActivating NRAS mutationsAntimelanoma immune responsesImmunocompetent mouse modelInnovative treatment strategiesMEK-ERK signalingAntitumor immunityNRAS mutationsMelanoma subtypesERK MAPK pathwayTargeted therapyTumor microenvironmentT cellsT lymphocytesMelanoma growthTherapeutic resistanceMis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias
Kim W, Crosse E, De Neef E, Etxeberria I, Sabio E, Wang E, Bewersdorf J, Lin K, Lu S, Belleville A, Fox N, Castro C, Zhang P, Fujino T, Lewis J, Rahman J, Zhang B, Winick J, Lewis A, Stanley R, DeWolf S, Urben B, Takizawa M, Krause T, Molina H, Chaligne R, Koppikar P, Molldrem J, Gigoux M, Merghoub T, Daniyan A, Chandran S, Greenbaum B, Klebanoff C, Bradley R, Abdel-Wahab O. Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias. Cell 2025, 188: 3422-3440.e24. PMID: 40273911, PMCID: PMC12204805, DOI: 10.1016/j.cell.2025.03.047.Peer-Reviewed Original ResearchConceptsT cell receptorT cellsCurative allogeneic stem cell transplantationVirus-reactive T cellsAllogeneic stem cell transplantationCD8<sup>+</sup> T cellsCognate T cell receptorsStem cell transplantationBlood of patientsImpaired cytotoxic functionPeptide-major histocompatibility complexMyeloid malignanciesCell transplantationActive cancerCytotoxic functionMyeloid leukemiaHealthy donorsPublic neoantigensNeoantigensHistocompatibility complexSplicing alterationsLeukemiaMis-splicing eventsRNA splicing factorsPatientsDecoding the Complex Functional Landscape of the ykkC Riboswitches
Barth K, Hiller D, de Andrade G, Kavita K, Fernando C, Breaker R, Strobel S. Decoding the Complex Functional Landscape of the ykkC Riboswitches. Biochemistry 2025, 64: 1983-1995. PMID: 40254862, DOI: 10.1021/acs.biochem.4c00787.Peer-Reviewed Original ResearchConceptsTerminator hairpinSequence changesMutation analysisExtensive mutational analysisAssociated with genesSmall sequence changesBinding site positionsComplex functional landscapeRiboswitch classesPhylogenetic analysisChemically diverse ligandsVariant classesTranscriptional controlAptamer domainRiboswitchNatural riboswitchesLigand specificityFunctional roleFunctional landscapeGMP synthesisDiverse ligandsStructural studiesHairpinSite positionsSequenceScreening single nucleotide changes to tropomyosin to identify novel cardiomyopathy mutants
Wen J, Campbell S, Moore J, Lehman W, Rynkiewicz M. Screening single nucleotide changes to tropomyosin to identify novel cardiomyopathy mutants. Journal Of Molecular And Cellular Cardiology 2025, 203: 82-90. PMID: 40268117, PMCID: PMC12135046, DOI: 10.1016/j.yjmcc.2025.04.009.Peer-Reviewed Original ResearchConceptsDeleterious effects of mutationsTropomyosin-actin interactionsSingle nucleotide mutationsEffects of mutationsThin filament regulationDilated cardiomyopathyTropomyosin sequencesActin interactionNucleotide mutationsFilament regulationMutation-sensitiveSubcellular unitsMutantsPathological cardiac remodelingTropomyosinActinThin filamentsEarly therapeutic interventionFunctional analysisMutationsInherited cardiomyopathyCardiac remodelingCardiac functionRegulatory BCardiomyopathyActivation of a Potassium Channel Mutation That Causes Spinocerebellar Ataxia Promotes Aggregation of the RhoGEF Domain‐Containing Protein Plekhg4
Zhang Y, Andrawis A, Kaczmarek L. Activation of a Potassium Channel Mutation That Causes Spinocerebellar Ataxia Promotes Aggregation of the RhoGEF Domain‐Containing Protein Plekhg4. The FASEB Journal 2025, 39: e70552. PMID: 40249242, DOI: 10.1096/fj.202402809rr.Peer-Reviewed Original ResearchConceptsGuanine nucleotide exchange factorKv3.3 channelsNucleation of actin filamentsPlasma membraneNucleotide exchange factorPurkinje neuronsRegulating Rac1 activitySpinocerebellar ataxiaPotassium channel mutationsAuditory brainstem neuronsCerebellar Purkinje neuronsActin nucleationPurkinje cell activityWild-type channelsExchange factorActin filamentsPotential new therapeutic approachCytoplasmic proteinsTreatment of spinocerebellar ataxiaRac1 activationHAX-1Cytoplasmic aggregatesRegulate excitabilityBrainstem neuronsCHO cellsNatural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes
Rodriguez-Sevilla J, Ganan-Gomez I, Kumar B, Thongon N, Ma F, Chien K, Kim Y, Yang H, Loghavi S, Tan R, Adema V, Li Z, Tanaka T, Uryu H, Kanagal-Shamanna R, Al-Atrash G, Bejar R, Banerjee P, Lynn Cha S, Montalban-Bravo G, Dougherty M, Fernandez Laurita M, Wheeler N, Jia B, Papapetrou E, Izzo F, Dueñas D, McAllen S, Gu Y, Todisco G, Ficara F, Della Porta M, Jain A, Takahashi K, Clise-Dwyer K, Halene S, Bertilaccio M, Garcia-Manero G, Daher M, Colla S. Natural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes. Nature Communications 2025, 16: 3450. PMID: 40216768, PMCID: PMC11992119, DOI: 10.1038/s41467-025-58662-0.Peer-Reviewed Original ResearchConceptsHematopoietic stem cellsMyelodysplastic syndromeImmune escapeMyelodysplastic syndrome hematopoietic stem cellsNatural killer (NK) cellsAberrant hematopoietic stem cellsEarly-stage myelodysplastic syndromeDevelopment of myelodysplastic syndromeStage of myelodysplastic syndromeAdoptive cell therapyFunctional in vitro studiesNatural killer cellsTime of diagnosisPreclinical in vivo studiesPre-malignant clonesDisease-related comorbiditiesPre-malignant stageSlow down disease progressionRegenerate hematopoiesisClonal cytopeniaNK cellsImmune surveillanceKiller cellsHealthy donorsPharmacological therapy
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