2022
Mitochondrial fitness and cancer risk
Kossenkov AV, Milcarek A, Notta F, Jang GH, Wilson JM, Gallinger S, Zhou DC, Ding L, Ghosh JC, Perego M, Morotti A, Locatelli M, Robert ME, Vaira V, Altieri DC. Mitochondrial fitness and cancer risk. PLOS ONE 2022, 17: e0273520. PMID: 36223343, PMCID: PMC9555630, DOI: 10.1371/journal.pone.0273520.Peer-Reviewed Original ResearchConceptsPancreatic ductal adenocarcinomaSenescence-Associated Secretory PhenotypeIndependent patient cohortsPoor patient outcomesAggressive disease variantFolfirinox failureLocal inflammationPatient cohortDuctal adenocarcinomaPatient outcomesPatient riskMultiple malignanciesCancer riskMitochondrial fitnessSecretory phenotypeGene signatureHallmarks of cancerMetastatic propensityNormal tissuesHuman tumorsInterferon SignalingTumorsInner membrane mitochondrial proteinMalignancyMolecular signaturesImmune cells and their inflammatory mediators modify beta cells and cause checkpoint inhibitor-induced diabetes
Perdigoto AL, Deng S, Du KC, Kuchroo M, Burkhardt DB, Tong A, Israel G, Robert ME, Weisberg SP, Kirkiles-Smith N, Stamatouli AM, Kluger HM, Quandt Z, Young A, Yang ML, Mamula MJ, Pober JS, Anderson MS, Krishnaswamy S, Herold KC. Immune cells and their inflammatory mediators modify beta cells and cause checkpoint inhibitor-induced diabetes. JCI Insight 2022, 7: e156330. PMID: 35925682, PMCID: PMC9536276, DOI: 10.1172/jci.insight.156330.Peer-Reviewed Original ResearchConceptsCheckpoint inhibitorsΒ-cellsPD-1/PD-L1 pathwayT-lymphocyte antigen-4PD-1 blockadePD-L1 pathwayDeath ligand 1NOD mouse modelDevelopment of diabetesHuman β-cellsAutoimmune complicationsNOD miceΒ-cell populationDeath-1Diabetes mellitusImmune infiltratesInflammatory mediatorsPancreatic inflammationPD-L1Induced diabetesLymphocytic infiltrationInflammatory cytokinesAntigen-4Immune cellsT cellsComprehensive molecular profiling of pancreatic ductal adenocarcinoma in FNA, biopsy, and resection specimens
Razzano D, Bouza SJ, Hernandez PV, Wang M, Robert ME, Walther Z, Cai G. Comprehensive molecular profiling of pancreatic ductal adenocarcinoma in FNA, biopsy, and resection specimens. Cancer Cytopathology 2022, 130: 726-734. PMID: 35511415, DOI: 10.1002/cncy.22589.Peer-Reviewed Original ResearchConceptsFine-needle aspirationFine-needle biopsyPancreatic ductal adenocarcinomaOncomine Comprehensive AssayResection specimensMolecular alterationsMolecular testingFNB samplesDuctal adenocarcinomaTherapeutic implicationsSuccess rateComprehensive molecular analysisComprehensive molecular testingComprehensive molecular profilingPotential therapeutic implicationsSimilar success ratesResection casesKRAS mutationsFNB specimensFNA materialFNA specimensAmplification analysisMolecular profilingFusion assessmentGene mutationsCytoskeletal dynamics regulates stromal invasion behavior of distinct liver cancer subtypes
Nguyen RY, Xiao H, Gong X, Arroyo A, Cabral AT, Fischer TT, Flores KM, Zhang X, Robert ME, Ehrlich BE, Mak M. Cytoskeletal dynamics regulates stromal invasion behavior of distinct liver cancer subtypes. Communications Biology 2022, 5: 202. PMID: 35241781, PMCID: PMC8894393, DOI: 10.1038/s42003-022-03121-5.Peer-Reviewed Original ResearchGhost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability
Ghosh JC, Perego M, Agarwal E, Bertolini I, Wang Y, Goldman AR, Tang HY, Kossenkov AV, Landis CJ, Languino LR, Plow EF, Morotti A, Ottobrini L, Locatelli M, Speicher DW, Caino MC, Cassel J, Salvino JM, Robert ME, Vaira V, Altieri DC. Ghost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2115624119. PMID: 35177476, PMCID: PMC8872753, DOI: 10.1073/pnas.2115624119.Peer-Reviewed Original ResearchMeSH KeywordsCell DeathCell Line, TumorCell MovementCell ProliferationEpithelial-Mesenchymal TransitionHumansMitochondriaMitochondrial DynamicsMitochondrial ProteinsMuscle ProteinsNeoplasm InvasivenessNeoplasm MetastasisNeoplasmsNeoplastic ProcessesProtein Serine-Threonine KinasesProto-Oncogene Proteins c-aktReactive Oxygen SpeciesSignal TransductionConceptsEpithelial-mesenchymal transitionGene expression programsTherapeutic vulnerabilitiesTumor cell movementCytokine/chemokine signalingExpression programsTherapeutic targetCell movementMitochondrial dynamicsEssential scaffoldMitochondrial structureSurvival signalingMitochondrial integrityCancer metabolismStress responseActionable therapeutic targetsCell deathChemokine signalingMitochondriaSmall-molecule drug screensCell proliferationOxidative damageInnate immunityMetastatic disseminationHuman tumors
2021
Renalase is a novel tissue and serological biomarker in pancreatic ductal adenocarcinoma
Gao Y, Wang M, Guo X, Hu J, Chen TM, Finn S, Lacy J, Kunstman JW, H. C, Bellin MD, Robert ME, Desir GV, Gorelick FS. Renalase is a novel tissue and serological biomarker in pancreatic ductal adenocarcinoma. PLOS ONE 2021, 16: e0250539. PMID: 34587190, PMCID: PMC8480607, DOI: 10.1371/journal.pone.0250539.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overBiomarkers, TumorCarcinoma, Pancreatic DuctalCase-Control StudiesFemaleGene Expression Regulation, NeoplasticHumansMaleMiddle AgedMonoamine OxidaseNeoplasm GradingPancreatic NeoplasmsPrognosisProspective StudiesRetrospective StudiesSurvival AnalysisUp-RegulationYoung AdultConceptsPlasma renalase levelsBorderline resectable PDACRenalase levelsPDAC precursor lesionsOverall survivalPDAC tissuesTumor characteristicsResectable PDACChronic pancreatitisPrecursor lesionsNormal pancreasPancreatic ductal adenocarcinoma growthAdvanced tumor characteristicsVaried clinical stagesWorse tumor characteristicsNode-positive diseasePancreatic ductal adenocarcinomaNormal pancreatic headSpindle-shaped cellsPlasma renalaseRenalase expressionUnderwent resectionAbdominal traumaPancreatic headPositive diseaseTrefoil factor 2 secreted from damaged hepatocytes activates hepatic stellate cells to induce fibrogenesis
Zhang B, Lapenta K, Wang Q, Nam JH, Chung D, Robert ME, Nathanson MH, Yang X. Trefoil factor 2 secreted from damaged hepatocytes activates hepatic stellate cells to induce fibrogenesis. Journal Of Biological Chemistry 2021, 297: 100887. PMID: 34146542, PMCID: PMC8267550, DOI: 10.1016/j.jbc.2021.100887.Peer-Reviewed Original ResearchConceptsHepatic stellate cellsTrefoil factor 2Liver injuryStellate cellsActivation of HSCsPrimary hepatic stellate cellsPlatelet-derived growth factor receptor betaChronic liver diseaseGrowth factor receptor betaProcess of fibrogenesisLiver-specific deletionFactor 2Spontaneous fibrosisLiver diseaseLiver fibrosisFibrogenic processReceptor betaFibrogenesisWT hepatocytesProtein expressionFibrosisHepatocytesInjuryNovel factorActivationCheckpoint Inhibitor Colitis Shows Drug-Specific Differences in Immune Cell Reaction That Overlap With Inflammatory Bowel Disease and Predict Response to Colitis Therapy
Lo YC, Price C, Blenman K, Patil P, Zhang X, Robert ME. Checkpoint Inhibitor Colitis Shows Drug-Specific Differences in Immune Cell Reaction That Overlap With Inflammatory Bowel Disease and Predict Response to Colitis Therapy. American Journal Of Clinical Pathology 2021, 156: 214-228. PMID: 33555016, DOI: 10.1093/ajcp/aqaa217.Peer-Reviewed Original ResearchConceptsInflammatory bowel diseaseCD8/FOXP3 ratioBiopsy specimensCPI patientsPD-1CD68 scoreFOXP3 ratioBowel diseasePD-L1Antibody-treated patientsCheckpoint inhibitor colitisPD-L1 groupInitial biopsy specimensPD-L1 expressionImmune cell reactionsColonic biopsy specimensDrug-specific differencesIBD groupCheckpoint inhibitorsChronicity scoreActivity scoreImmune phenotypeTherapeutic responseColitisShared pathophysiology
2020
Frontiers in Celiac Disease
Patel N, Robert ME. Frontiers in Celiac Disease. The American Journal Of Surgical Pathology 2020, 46: e43-e54. PMID: 33739793, DOI: 10.1097/pas.0000000000001639.Peer-Reviewed Original ResearchConceptsCeliac diseaseType II refractory celiac diseaseMonoclonal T-cell populationChildhood viral infectionsDuodenal mucosal histologyImportant autoimmune diseasesRefractory celiac diseaseCommon autoimmune disorderT cell populationsCeliac disease patientsCeliac disease pathogenesisEvaluation of responseCeliac disease manifestationsGluten toleranceDietary glutenGluten exposureMechanisms of diseaseAutoimmune conditionsHLA-DQ2Mucosal histologySymptomatic diseaseInflammatory cascadeInitial diagnosisPatient's symptomsAutoimmune disordersNeutrophils interact with cholangiocytes to cause cholestatic changes in alcoholic hepatitis
Takeuchi M, Vidigal PT, Guerra MT, Hundt MA, Robert ME, Olave-Martinez M, Aoki S, Khamphaya T, Kersten R, Kruglov E, de la Rosa Rodriguez R, Banales JM, Nathanson MH, Weerachayaphorn J. Neutrophils interact with cholangiocytes to cause cholestatic changes in alcoholic hepatitis. Gut 2020, 70: 342-356. PMID: 33214166, PMCID: PMC7906004, DOI: 10.1136/gutjnl-2020-322540.Peer-Reviewed Original ResearchConceptsBile ductCholestatic changesLimited treatment optionsPresence of cholestasisAbility of neutrophilsLife-threatening diseaseNew therapeutic targetsHuman bile ductIntracellular calcium channelsAlcoholic hepatitisLiver biopsyControl neutrophilsPathological findingsHepatocellular damageHistological findingsTreatment optionsCell adhesion moleculeHistological parametersDisease altersITPR3 expressionTherapeutic targetAnimal modelsCalcium channelsNeutrophilsPatientsOGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance
Yang Y, Li X, Luan HH, Zhang B, Zhang K, Nam JH, Li Z, Fu M, Munk A, Zhang D, Wang S, Liu Y, Albuquerque JP, Ong Q, Li R, Wang Q, Robert ME, Perry RJ, Chung D, Shulman GI, Yang X. OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 16616-16625. PMID: 32601203, PMCID: PMC7368321, DOI: 10.1073/pnas.1916121117.Peer-Reviewed Original ResearchConceptsRibosomal protein S6 kinase beta-1Macrophage proinflammatory activationGlcNAc signalingProinflammatory activationUnexpected roleWhole-body metabolismNutrient fluxesLipid accumulationImmune cell activationGlcNAcHomeostatic mechanismsMetabolic disturbancesBeta 1Cell activationDiet-induced metabolic dysfunctionDiet-induced obese miceActivationWhole-body insulin resistanceMacrophage inflammationGlcNAcylationOGTPeripheral tissuesPhosphorylationEnhanced inflammationInsulin resistanceSmooth muscle tumors of the gastrointestinal tract: an analysis of prognostic features in 407 cases
Alpert L, Al-Sabti R, Graham RP, Pai RK, Gonzalez RS, Zhang X, Smith V, Wang HL, Westbrook L, Goldblum JR, Bakhshwin A, Shetty S, Klimstra DS, Shia J, Askan G, Robert ME, Thomas C, Frankel WL, Alsomali M, Hagen C, Mostafa ME, Feely MM, Assarzadegan N, Misdraji J, Shih AR, Agostini-Vulaj D, Meis JM, Tang S, Chatterjee D, Kang LI, Hart J, Lee SM, Smith T, Yantiss RK, Hissong EM, Gao ZH, Wu J, Resnick MB, Wu EY, Pai RK, Zhao L, Doyle LA, Chopra S, Panarelli NC, Hu S, Longacre TA, Raghavan SS, Lauwers GY, Ghayouri M, Cooper HS, Nagarathinam R, Bellizzi AM, Kakar S, Hosseini M, Rong J, Greenson JK, Lamps LW, Dong Z, Bronner MP. Smooth muscle tumors of the gastrointestinal tract: an analysis of prognostic features in 407 cases. Modern Pathology 2020, 33: 1410-1419. PMID: 32051556, PMCID: PMC8405135, DOI: 10.1038/s41379-020-0492-5.Peer-Reviewed Original ResearchConceptsSmooth muscle tumorsGastrointestinal smooth muscle tumorsMuscle tumorsPrognostic featuresSmall bowelGastrointestinal tractNon-progressive tumorsProgression-free survivalSlight female predominanceDisease-related deathKaplan-Meier plotsReceiver operator characteristic analysisSoft tissue pathologistsPotential prognostic featuresOperator characteristic analysisMucosal ulcerationSerosal involvementFemale predominanceLocal recurrenceMargin statusPathologic featuresTumor sizeLarge tumorsEsophageal tumorsTumor necrosisPolycystin 2 is increased in disease to protect against stress-induced cell death
Brill AL, Fischer TT, Walters JM, Marlier A, Sewanan LR, Wilson PC, Johnson EK, Moeckel G, Cantley LG, Campbell SG, Nerbonne JM, Chung HJ, Robert ME, Ehrlich BE. Polycystin 2 is increased in disease to protect against stress-induced cell death. Scientific Reports 2020, 10: 386. PMID: 31941974, PMCID: PMC6962458, DOI: 10.1038/s41598-019-57286-x.Peer-Reviewed Original ResearchConceptsPolycystin-2General cellular homeostasisCell deathStress-induced cell deathPathological cell deathAutosomal dominant polycystic kidney diseaseEndoplasmic reticulum membraneCellular homeostasisCellular stressPrimary ciliaUbiquitous expressionExpression changesCell stressReticulum membraneTransient receptor potential cation channelHuman diseasesMultiple tissuesEndogenous roleDominant polycystic kidney diseaseTissue typesCation channelsPolycystic kidney diseaseDifferent pathological statesMultiple diseasesKidney disease
2019
O-GlcNAc transferase suppresses necroptosis and liver fibrosis
Zhang B, Li MD, Yin R, Liu Y, Yang Y, Mitchell-Richards KA, Nam JH, Li R, Wang L, Iwakiri Y, Chung D, Robert ME, Ehrlich BE, Bennett AM, Yu J, Nathanson MH, Yang X. O-GlcNAc transferase suppresses necroptosis and liver fibrosis. JCI Insight 2019, 4: e127709. PMID: 31672932, PMCID: PMC6948774, DOI: 10.1172/jci.insight.127709.Peer-Reviewed Original ResearchConceptsReceptor-interacting protein kinase 3Liver fibrosisLiver diseaseHepatocyte necroptosisEthanol-induced liver injuryAlcoholic liver cirrhosisChronic liver diseaseMultiple liver diseasesWeeks of ageProtein expression levelsPortal inflammationLiver cirrhosisLiver injuryBallooning degenerationElevated protein expression levelsSpontaneous genetic modelFibrosisKey suppressorKey mediatorMiceProtein kinase 3CirrhosisExpression levelsGlcNAc levelsMixed lineage kinaseHistopathology Scoring Systems of Stenosis Associated With Small Bowel Crohn’s Disease: A Systematic Review
Gordon IO, Bettenworth D, Bokemeyer A, Srivastava A, Rosty C, de Hertogh G, Robert ME, Valasek MA, Mao R, Kurada S, Harpaz N, Borralho P, Pai RK, Pai RK, Odze R, Feakins R, Parker CE, Nguyen T, Jairath V, Baker ME, Bruining DH, Fletcher JG, Feagan BG, Rieder F, Consortium S. Histopathology Scoring Systems of Stenosis Associated With Small Bowel Crohn’s Disease: A Systematic Review. Gastroenterology 2019, 158: 137-150.e1. PMID: 31476299, PMCID: PMC7649049, DOI: 10.1053/j.gastro.2019.08.033.Peer-Reviewed Original ResearchConceptsSmall bowel Crohn's diseaseCrohn's diseaseSystematic reviewScoring systemFibromuscular stenosisComputed tomography enterographyMEDLINE of studiesEffective medical therapyCross-sectional imaging techniquesStudy of patientsHistologic scoring systemSemiquantitative histologic evaluationSame scoring systemImportant pathologic componentHistopathology indexSymptomatic stricturesTomography enterographyCommon complicationMedical therapyResection specimenHistologic findingsAntifibrotic agentsFibrotic alterationsHistologic evaluationHistopathologic gradingSyntaphilin Is a Novel Biphasic Biomarker of Aggressive Prostate Cancer and a Metastasis Predictor
Hwang MJ, Bryant KG, Seo JH, Liu Q, Humphrey PA, Melnick MAC, Altieri DC, Robert ME. Syntaphilin Is a Novel Biphasic Biomarker of Aggressive Prostate Cancer and a Metastasis Predictor. American Journal Of Pathology 2019, 189: 1180-1189. PMID: 31079810, PMCID: PMC6560381, DOI: 10.1016/j.ajpath.2019.02.009.Peer-Reviewed Original ResearchConceptsProstate cancerTumor bulkInvasive frontHigh Gleason grade prostate cancerLocalized prostate cancerGrade prostate cancerAggressive prostate cancerCell proliferationKi-67 labelingTumor cell proliferationMetastasis predictorMetastatic diseaseDistant metastasisGleason gradeAccessible biomarkersProstate tumorsMetastatic potentialNovel markerCancerBiphasic patternProliferative rateHigh expressionOxidative metabolismReduced levelsTumorsEffects of Endotoxin on Type 3 Inositol 1,4,5‐Trisphosphate Receptor in Human Cholangiocytes
Franca A, Filho A, Guerra MT, Weerachayaphorn J, dos Santos M, Njei B, Robert M, Lima C, Vidigal P, Banales JM, Ananthanarayanan M, Leite MF, Nathanson MH. Effects of Endotoxin on Type 3 Inositol 1,4,5‐Trisphosphate Receptor in Human Cholangiocytes. Hepatology 2019, 69: 817-830. PMID: 30141207, PMCID: PMC6351171, DOI: 10.1002/hep.30228.Peer-Reviewed Original ResearchConceptsToll-like receptor 4Alcoholic hepatitisEffect of endotoxinBile duct cellsNF-κBInhibition of TLR4Human cholangiocytesStimulation of TLR4Duct cellsSevere alcoholic hepatitisCholestasis of sepsisForms of cholestasisNF-κB subunitsP65/p50Trisphosphate receptorReceptor 4Clinical conditionsBicarbonate secretionHepatocellular changesITPR3 expressionCholestasisType 3 inositolLPS receptorAgonist stimulusSepsisClinical Insignficance of Monoclonal T-Cell Populations and Duodenal Intraepithelial T-Cell Phenotypes in Celiac and Nonceliac Patients
Celli R, Hui P, Triscott H, Bogardus S, Gibson J, Hwang M, Robert ME. Clinical Insignficance of Monoclonal T-Cell Populations and Duodenal Intraepithelial T-Cell Phenotypes in Celiac and Nonceliac Patients. The American Journal Of Surgical Pathology 2019, 43: 151-160. PMID: 30334829, DOI: 10.1097/pas.0000000000001172.Peer-Reviewed Original ResearchConceptsRefractory celiac diseaseT cell populationsMonoclonal T-cell populationRCD IRCD IICeliac diseasePersistent symptomsCD patientsIntraepithelial lymphocytesType II refractory celiac diseaseCD8-positive intraepithelial lymphocytesClonal T-cell populationsT-cell receptor gene rearrangementsAbnormal intraepithelial lymphocytesT-cell phenotypeReceptor gene rearrangementsParaffin-embedded biopsiesParaffin-embedded tissuesCD8 stainingLymphocyte phenotypingNonceliac patientsVillous bluntingDuodenal biopsiesRare conditionSpecialized centers
2018
Hepatocellular Carcinoma Outcome is Predicted by Expression of Neuronal Calcium Sensor 1
Schuette D, Moore LM, Robert ME, Taddei TH, Ehrlich BE. Hepatocellular Carcinoma Outcome is Predicted by Expression of Neuronal Calcium Sensor 1. Cancer Epidemiology Biomarkers & Prevention 2018, 27: cebp.0167.2018. PMID: 29789326, PMCID: PMC8465775, DOI: 10.1158/1055-9965.epi-18-0167.Peer-Reviewed Original ResearchConceptsNeuronal calcium sensor-1Hepatocellular carcinomaDisease outcomePrognostic biomarkerIncidence of HCCWorse disease outcomesCancer-related deathLiver cancer cohortExpression levelsFurther functional assessmentEarly tumor detectionProspective cohortAsian patientsPatient survivalVariety of Ca2Tumor microarrayHCC patientsMetastatic cancerBreast cancerCancer cohortAggressive phenotypeNovel biomarkersFunctional assessmentPredictive valueTumor progressionStatement on Best Practices in the Use of Pathology as a Diagnostic Tool for Celiac Disease
Robert ME, Crowe SE, Burgart L, Yantiss RK, Lebwohl B, Greenson JK, Guandalini S, Murray JA. Statement on Best Practices in the Use of Pathology as a Diagnostic Tool for Celiac Disease. The American Journal Of Surgical Pathology 2018, 42: e44-e58. PMID: 29923907, DOI: 10.1097/pas.0000000000001107.Peer-Reviewed Original ResearchConceptsDuodenal mucosal biopsiesCeliac diseaseMucosal biopsiesPossible celiac diseaseUse of pathologySpecific serological testsUse of endoscopyEndoscopic findingsIntraepithelial lymphocytesPathologic assessmentPathologic findingsVillous architectureNorth American AssociationPathology formsBiopsy interpretationBiopsySerological testsTissue samplingDiseasePatientsDiagnostic toolDiagnosisAmerican AssociationPathologistsCritical appraisal