2025
Intratumoral IL12 mRNA administration activates innate and adaptive pathways in checkpoint inhibitor-resistant tumors resulting in complete responses
Lakshmipathi J, Santha S, Li M, Qian Y, Roy S, Luheshi N, Politi K, Bosenberg M, Eyles J, Muthusamy V. Intratumoral IL12 mRNA administration activates innate and adaptive pathways in checkpoint inhibitor-resistant tumors resulting in complete responses. Cancer Immunology, Immunotherapy 2025, 74: 250. PMID: 40560386, PMCID: PMC12198101, DOI: 10.1007/s00262-025-04105-0.Peer-Reviewed Original ResearchConceptsAnti-tumor immune responseTumor-associated macrophagesCytotoxic T cellsImmune responseActivity of checkpoint inhibitorsAnti-PD-L1 antibodyPhagocytosis of tumor cellsAnti-PD-L1Enhanced anti-tumorAntigen presentation machineryCell-based immune responsesMurine tumor modelsTh1-type cytokinesColorectal carcinoma tumorsICI resistanceMurine IL12Checkpoint inhibitorsPresentation machineryIntratumoral deliveryResistant tumorsAdvanced diseaseCarcinoma tumorsTumor microenvironmentMurine tumorsT cellsATP-gated P2x7 receptors express at type II auditory nerves and required for efferent hearing control and noise protection
Liang C, Zhai T, Chen J, Fang S, Zhu Y, Liu L, Yu N, Zhao H. ATP-gated P2x7 receptors express at type II auditory nerves and required for efferent hearing control and noise protection. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2421995122. PMID: 40540593, PMCID: PMC12207453, DOI: 10.1073/pnas.2421995122.Peer-Reviewed Original ResearchConceptsCochlear efferent systemHearing sensitivityATP-gated P2X7 receptorP2X7 receptorOuter hair cellsAuditory nerveInnervate outer hair cellsEfferent systemAuditory brainstem responseSpiral ganglion (SGActive cochlear amplificationActive cochlear mechanicsEfferent nervesP2X7 KO miceIncreased susceptibility to noiseSusceptibility to noiseNeuronal functionAcoustic startle responseHair cellsBrainstem responseHearing lossEfferent suppressionHearing disordersOHC electromotilityNoise exposureVisceral pain-related acute actions of cerulein on mouse and human sensory neurons.
Goyal S, Zurek N, Ehsanian R, Goyal S, Jones D, Shilling M, Desir G, Gorelick F, Westlund K, Alles S. Visceral pain-related acute actions of cerulein on mouse and human sensory neurons. Molecular Pain 2025, 21: 17448069251353346. PMID: 40524328, DOI: 10.1177/17448069251353346.Peer-Reviewed Original ResearchConceptsDorsal root gangliaDRG neuronsPain behaviorCCK-AAcute pancreatitisHuman DRGWhole-cell patch-clamp electrophysiologyIncreased excitabilityHuman dorsal root gangliaDorsal root ganglia neuronsHuman sensory neuronsThoracic DRG neuronsVon Frey testAssess pain behaviorCCK-A receptorsInduce acute pancreatitisPatch-clamp electrophysiologyCCK-B receptorsPre-clinical studiesResponse to ceruleinComplaints of patientsAntagonist of cholecystokininMechanical hypersensitivityPancreatic painCholecystokinin systemsEndothelial CLEC5A drives barrier dysfunction and vascular leakage responsible for lung injury in bacterial pneumonia and sepsis
Zhang T, Huang X, Goodwin J, Wen R, Liu Y, Yang Y, Zhang T, Zheng Y, Chen A, Hao P, Tong X, Yang N, Liu C. Endothelial CLEC5A drives barrier dysfunction and vascular leakage responsible for lung injury in bacterial pneumonia and sepsis. Science Advances 2025, 11: eadt7589. PMID: 40498836, PMCID: PMC12154197, DOI: 10.1126/sciadv.adt7589.Peer-Reviewed Original ResearchConceptsVascular leakagePuncture (CLP)-induced polymicrobial sepsisRegulating endothelial barrier functionCLP-challenged miceEndothelial barrier dysfunctionTrans-endothelial electrical resistanceEndothelial barrier functionLipopolysaccharide (LPS)-induced endotoxemiaVascular endothelial cellsPattern recognition receptorsSurvival benefitMultiorgan failurePolymicrobial sepsisTrans-endothelial migrationCecal ligationBacterial pneumoniaLung injuryBarrier dysfunctionVascular injurySingle-cell RNA sequencingDecreased mortalityInflammatory stormBacterial infectionsHeterogeneity of vascular endothelial cellsSepsisNeuronal ALKAL2 and its ALK receptor contribute to the development of colitis-associated colorectal cancer
Delanne-Cuménal M, Defaye M, Delanne-Cuménal A, Ahmed M, Ho V, Abdullah N, Alhassoun M, Svendsen K, Mager L, Schlessinger J, Hirota S, Altier C. Neuronal ALKAL2 and its ALK receptor contribute to the development of colitis-associated colorectal cancer. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2500632122. PMID: 40493183, PMCID: PMC12184428, DOI: 10.1073/pnas.2500632122.Peer-Reviewed Original ResearchConceptsColitis-associated colorectal cancerAnaplastic lymphoma kinaseColorectal cancerAnaplastic lymphoma kinase activityColitis-associated colorectal cancer progressionAnaplastic lymphoma kinase receptorTRPV1+ nociceptorsDevelopment of colitis-associated colorectal cancerMouse colonic organoidsALK signalingInflammatory painTumor burdenTreatment resistanceSensory neuronsTumor growthColonic organoidsALKAL2Colonic mucosaOverall inflammationCancer progressionCancerIn vivoTRPV1NeuronsInflammationSystemic 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 systemRedundancy of the OST catalytic subunit facilitates therapeutic targeting of N-glycosylation
Baro M, Lee H, Kelley V, Lou R, Phoomak C, Politi K, Zeiss C, Van Zandt M, Contessa J. Redundancy of the OST catalytic subunit facilitates therapeutic targeting of N-glycosylation. Cell Chemical Biology 2025, 32: 839-853.e6. PMID: 40494352, DOI: 10.1016/j.chembiol.2025.05.005.Peer-Reviewed Original ResearchConceptsN-glycosylationTrafficking of cell surface receptorsInhibits N-glycosylationCell surface receptorsGlycan synthesisCatalytic subunitOligosaccharyltransferaseEnzymatic activitySurface receptorsSTT3BSTT3ACharacterized in vitroDownstream effectsLung cancer xenograftsTherapeutic targetPatient-derivedBiological activityTumor regressionCancer xenograftsSmall moleculesGrowth delayTherapeutic agentsGlycansHeterozygosity for neurodevelopmental disorder-associated TRIO variants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice
Ishchenko Y, Jeng A, Feng S, Nottoli T, Manriquez-Rodriguez C, Nguyen K, Carrizales M, Vitarelli M, Corcoran E, Greer C, Myers S, Koleske A. Heterozygosity for neurodevelopmental disorder-associated TRIO variants yields distinct deficits in behavior, neuronal development, and synaptic transmission in mice. ELife 2025, 13: rp103620. PMID: 40488445, PMCID: PMC12148328, DOI: 10.7554/elife.103620.Peer-Reviewed Original ResearchConceptsAutism spectrum disorderGuanine nucleotide exchange factorNeurodevelopmental disordersPresynaptic glutamate releaseLayer 5 pyramidal neuronsAssociated with neurodevelopmental disordersIntellectual disabilitySpectrum disorderMouse behaviorCognitive behaviorNucleotide exchange factorNeuronal developmentBrain developmentGlutamate releaseIncreased Rac1 activityBrain sizeSynaptic functionControlling neuronal developmentSchizophreniaImpaired abilityAssociated with increased levelsNeurodevelopmental eventsActive GTPaseGEF Tiam1Exchange factorDesign and Evaluation of Novel Ginger 6‑Shogaol-Inspired Phospholipase C Inhibitors to Enhance β‑Agonist-Induced Relaxation in Human Airway Smooth Muscle
Luković E, Zhu Y, Zhang Y, Genualdi J, Sang S, Emala C. Design and Evaluation of Novel Ginger 6‑Shogaol-Inspired Phospholipase C Inhibitors to Enhance β‑Agonist-Induced Relaxation in Human Airway Smooth Muscle. Journal Of Medicinal Chemistry 2025, 68: 12626-12640. PMID: 40489244, DOI: 10.1021/acs.jmedchem.5c00378.Peer-Reviewed Original ResearchConceptsStructure-activity analysisHuman airway smooth muscleHuman airway smooth muscle cellsPhenol moietyAirway smooth muscle cellsHuman tracheal tissueHydroxyl groupsAirway smooth musclePhospholipase C inhibitorSmooth muscle cellsMouse lung tissuePoor symptom controlDerivativesIntracellular calciumSmooth muscleMuscle cellsAsthma treatmentLung tissueC inhibitorTherapeutic potentialNovel therapeuticsTracheal tissueEnhanced inhibitionSymptom controlInositol phosphatesFTO inhibition enhances the therapeutic index of radiation therapy in head and neck cancer
Ji L, Pu L, Wang J, Cao H, Melemenidis S, Sinha S, Guan L, Laseinde E, von Eyben R, Richter S, Nam J, Kong C, Casey K, Graves E, Frock R, Le Q, Rankin E. FTO inhibition enhances the therapeutic index of radiation therapy in head and neck cancer. JCI Insight 2025, 10: e184968. PMID: 40485587, DOI: 10.1172/jci.insight.184968.Peer-Reviewed Original ResearchConceptsTherapeutic index of radiation therapyHPV- head and neck squamous cell carcinomaRadiation therapyTherapeutic indexRT responseHead and neck squamous cell carcinomaRadiation-induced oral mucositisNeck squamous cell carcinomaPharmacological inhibitionHead and neck cancerDrug-radiotherapy combinationsOverall survival rateEfficacy of RTSquamous cell carcinomaTherapeutic targetObesity-related genesAssociated with increased DNA damageChemoradiation treatmentOral mucositisCell carcinomaHNSCC treatmentHNSCC cellsNeck cancerPotential therapeutic targetCancer therapeutic targetSeparation of telomere protection from length regulation by two different point mutations at amino acid 492 of RTEL1
Smoom R, May C, Lichtental D, Bar-Ness K, Rangel R, Khoury J, Nachmani D, Avrahami D, Ahangari F, Skordalakes E, Kaminski N, Kaestner K, Tzfati Y. Separation of telomere protection from length regulation by two different point mutations at amino acid 492 of RTEL1. Nucleic Acids Research 2025, 53: gkaf507. PMID: 40530700, PMCID: PMC12203905, DOI: 10.1093/nar/gkaf507.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SubstitutionAnimalsDisease Models, AnimalDNA DamageDNA HelicasesDyskeratosis CongenitaFetal Growth RetardationGrowth DisordersHematopoiesisHumansIntellectual DisabilityLimb Deformities, CongenitalLungMiceMicrocephalyPoint MutationTelomereTelomere HomeostasisX-Linked Intellectual DisabilityConceptsHoyeraal-Hreidarsson syndromeTelomere protectionLength regulationTelomere length regulationTelomere-related diseasesTelomere biology disordersDNA helicaseMouse genomeGenome stabilityMouse modelMouse telomeresAberrant hematopoiesisGenomic instabilityPoint mutationsHouse miceTelomeric DNA damageAnaphase bridgesRTEL1Amino acidsTelomereMechanistic rolesDNA damageMutationsIsoleucine mutationGenomeDevelopment of Mouse Models for Ménétrier's Disease.
Gabriel T, Park J, Madala S, Coffey R, Huh W. Development of Mouse Models for Ménétrier's Disease. Journal Of Visualized Experiments 2025 PMID: 40549725, DOI: 10.3791/67981.Peer-Reviewed Original ResearchConceptsSpasmolytic polypeptide-expressing metaplasiaLoss of parietal cellsMouse modelFeatures of MDMouse linesFoveolar hyperplasiaParietal cellsEGF receptorTransforming growth factor-aEGFR-neutralizing antibodyChief cellsDevelopment of mouse modelsChief cell differentiationDecreased acid secretionGiant rugal foldsTransgenic mouse linesInducible mouse modelGrowth factor AModel of MDIn vivo modelsMist1 expressionHistological remissionClinical improvementHistopathological featuresTreatment optionsLKB1 regulates ILC3 postnatal development and effector function through metabolic programming
Zhang H, Zhao L, Zhang Q, Hu L, Su X, Sun J, Shen L. LKB1 regulates ILC3 postnatal development and effector function through metabolic programming. Frontiers In Immunology 2025, 16: 1587256. PMID: 40539052, PMCID: PMC12176730, DOI: 10.3389/fimmu.2025.1587256.Peer-Reviewed Original ResearchMeSH KeywordsAMP-Activated Protein Kinase KinasesAMP-Activated Protein KinasesAnimalsCitrobacter rodentiumEnterobacteriaceae InfectionsImmunity, InnateInterleukin-22InterleukinsIntestinal MucosaIntestinesLymphocytesMetabolic ReprogrammingMiceMice, Inbred C57BLMice, KnockoutProtein Serine-Threonine KinasesConceptsLiver kinase B1Intestinal immune homeostasisEffector functionsPostnatal developmentImmune homeostasisFlow cytometryGroup 3 innate lymphoid cellsMetabolic regulationIntestinal immunityLKB1 deficiencyIL-22 productionLKB1-deficient miceConditional knockout miceIntestinal inflammatory responsePotential therapeutic implicationsImpaired cell metabolismILC3 numbersIntestinal ILC3sLymphoid cellsILC3 functionCytokine productionILC3sKnockout miceMitochondrial massILC3 activationCysteine depletion triggers adipose tissue thermogenesis and weight loss
Lee A, Orliaguet L, Youm Y, Maeda R, Dlugos T, Lei Y, Coman D, Shchukina I, Andhey P, Smith S, Ravussin E, Stadler K, Chen B, Artyomov M, Hyder F, Horvath T, Schneeberger M, Sugiura Y, Dixit V. Cysteine depletion triggers adipose tissue thermogenesis and weight loss. Nature Metabolism 2025, 7: 1204-1222. PMID: 40461845, PMCID: PMC12198010, DOI: 10.1038/s42255-025-01297-8.Peer-Reviewed Original ResearchConceptsWeight lossWhite adipose tissueAdipose browningCaloric restrictionAdipose tissueDietary amino acidsCysteine depletionSulphur amino acids cysteineIncreased energy expenditureAdipose tissue thermogenesisIncreased fat utilizationMetabolic inflammationNoradrenaline signalingOrganismal metabolismAdipose thermogenesisObese miceBrowning of adipocytesIncreased heat productionBrownRemoval of cysteineCore body temperatureAmino acidsEnergy expenditureAmino acid cysteineFat utilizationEvidence of secondary Notch signaling within the rat small intestine.
Zagoren E, Dias N, Santos A, Smith Z, Ameen N, Sumigray K. Evidence of secondary Notch signaling within the rat small intestine. Development 2025, 152 PMID: 40371707, PMCID: PMC12188240, DOI: 10.1242/dev.204277.Peer-Reviewed Original ResearchConceptsSecretory lineageRegulate luminal pHSecretory cellsNotch signalingSecretory cell typesSmall intestinal epithelial cellsRNA sequencing dataIntestinal epithelial cellsIntestinal stem cellsSmall intestineFate in vivoFibrosis pathophysiologyRat small intestineCrypt progenitorsTranscription factorsEpithelial cellsRat jejunumStem cellsPseudotime trajectory analysisRare populationLuminal pHRatsHigher expressionIntestinal functionIn vitroFrom genes to geometry: Controlling embryo models by programming genomic activation
McNamara H, Sozen B. From genes to geometry: Controlling embryo models by programming genomic activation. Cell Stem Cell 2025, 32: 857-858. PMID: 40480203, DOI: 10.1016/j.stem.2025.04.013.Peer-Reviewed Original ResearchCo-targeting of epigenetic regulators and BCL-XL improves efficacy of immune checkpoint blockade therapy in multiple solid tumors
Senent Y, Fresquet V, Jiménez V, Valencia K, Exposito F, Martín-Úriz P, Camps G, Fernández-Pierola E, de Córdoba B, González-Huarriz M, Tamayo I, Remírez A, Moreno H, Serrano D, Ajona D, Alonso M, Lecanda F, Pineda-Lucena A, Prósper F, Sanmamed M, Calvo A, Martinez-Climent J, Pio R. Co-targeting of epigenetic regulators and BCL-XL improves efficacy of immune checkpoint blockade therapy in multiple solid tumors. Molecular Cancer 2025, 24: 154. PMID: 40442785, PMCID: PMC12123720, DOI: 10.1186/s12943-025-02352-4.Peer-Reviewed Original ResearchConceptsImmune checkpoint blockadeBcl-xL inhibitorsBcl-xLSolid tumorsTumor cell linesHematologic malignanciesSolid tumor cell linesEfficacy of immune checkpoint blockade therapyEpigenetic regulationImmune checkpoint blockade therapyAnti-apoptotic protein Bcl-xLHuman colon cancer modelsPreclinical models of solid tumorsBCL-XL dependencyImmunosuppressive Treg cellsCheckpoint blockade therapyAnti-tumor responsesImmunogenic cell deathProlonged overall survivalProtein Bcl-xLColon cancer modelM1/M2 macrophage ratioMultiple solid tumorsModels of solid tumorsCell linesC/EBPβ increases tumor aggressiveness by enhancing KIFC1 expression in androgen receptor negative triple negative breast cancer
Joshi S, Garlapati C, Nguyen T, Sharma S, Chandrashekar D, Bhattarai S, Varambally S, Krishnamurti U, Li X, Aneja R. C/EBPβ increases tumor aggressiveness by enhancing KIFC1 expression in androgen receptor negative triple negative breast cancer. Cell Communication And Signaling 2025, 23: 255. PMID: 40448099, PMCID: PMC12125945, DOI: 10.1186/s12964-025-02243-7.Peer-Reviewed Original ResearchConceptsHuman epidermal growth factor receptor 2Expression of estrogen receptorAndrogen receptorAggressive characteristicsEpithelial-mesenchymal transitionProgesterone receptorPoor prognosisBreast cancerLack of AR expressionQuadruple-negative breast cancerEpidermal growth factor receptor 2Triple-negative breast tumorsKIFC1 expressionTriple negative breast cancerExpression of therapeutic targetsReduced tumor volumeTherapeutic targetNegative breast cancerRisk predictive biomarkersPromote epithelial-mesenchymal transitionExpression of KIFC1Cancer cell proliferationTumor volumeAR expressionTumor aggressivenessNeuronal 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 neuronsMRNABindingRegulationTranslationEIF4ECYFIP1FTO regulates ELK3-mediated metabolic rewiring and represents a unique therapeutic target in T cell leukemia
Huang H, Li X, Luo J, Gao C, Yang M, Xu J, Xie T, Chen Z, Wang D, Wang Y, Li H, Huang J, Liu Y, Zhang H, Ntziachristos P, Zhao Y, Qing G, Liu H. FTO regulates ELK3-mediated metabolic rewiring and represents a unique therapeutic target in T cell leukemia. Science Advances 2025, 11: eadq3052. PMID: 40435251, PMCID: PMC12118595, DOI: 10.1126/sciadv.adq3052.Peer-Reviewed Original ResearchConceptsT-cell leukemiaT-ALLT-cell acute lymphoblastic leukemiaAcute lymphoblastic leukemiaExpression of glycolytic genesDevelopment of potential therapeutic strategiesPotential therapeutic strategyAntileukemia efficacyLymphoblastic leukemiaLeukemia initiationLymphoid leukemiaTherapeutic strategiesGlycolytic genesPharmacological inhibitionMetabolic rewiringLeukemiaDemethylase FTOHuman cancersN6-methyladenosineMRNA stabilityTherapeutic targetCancerMechanistic analysisMRNAModel system
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