2023
606 IMpower110: Tertiary lymphoid structures (TLS) and clinical outcomes in advanced non-small cell lung cancer (NSCLC) treated with first-line atezolizumab or chemotherapy
Srivastava M, Gayevskiy V, Ma V, Estay I, Rodas M, Rajendran B, Hoang T, Ballinger M, Amin R, Herbst R, Marinis F, Giaccone G, Jassem J, Spigel D, Schalper K, Koeppen H, Shames D, Johnston R, Giltnane J, Nabet B. 606 IMpower110: Tertiary lymphoid structures (TLS) and clinical outcomes in advanced non-small cell lung cancer (NSCLC) treated with first-line atezolizumab or chemotherapy. 2023, a690-a690. DOI: 10.1136/jitc-2023-sitc2023.0606.Peer-Reviewed Original Research
2020
Biomarkers Associated with Beneficial PD-1 Checkpoint Blockade in Non–Small Cell Lung Cancer (NSCLC) Identified Using High-Plex Digital Spatial Profiling
Zugazagoitia J, Gupta S, Liu Y, Fuhrman K, Gettinger S, Herbst RS, Schalper KA, Rimm DL. Biomarkers Associated with Beneficial PD-1 Checkpoint Blockade in Non–Small Cell Lung Cancer (NSCLC) Identified Using High-Plex Digital Spatial Profiling. Clinical Cancer Research 2020, 26: 4360-4368. PMID: 32253229, PMCID: PMC7442721, DOI: 10.1158/1078-0432.ccr-20-0175.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerPD-1 checkpoint blockadeCell lung cancerCheckpoint blockadeLung cancerAdvanced non-small cell lung cancerUnivariate unadjusted analysisProgression-free survivalImmune cell countsMinority of patientsRobust predictive biomarkersBiomarkers of responseLarge independent cohortsSpatial profiling technologyDigital spatial profilingDigital spatial profiling (DSP) technologyOverall survivalClinical outcomesImmune predictorsHigher CD56NSCLC casesPredictive biomarkersUnadjusted analysesImmune parametersTissue microarrayLongitudinal analyses reveal immunological misfiring in severe COVID-19
Lucas C, Wong P, Klein J, Castro TBR, Silva J, Sundaram M, Ellingson MK, Mao T, Oh JE, Israelow B, Takahashi T, Tokuyama M, Lu P, Venkataraman A, Park A, Mohanty S, Wang H, Wyllie AL, Vogels CBF, Earnest R, Lapidus S, Ott IM, Moore AJ, Muenker MC, Fournier JB, Campbell M, Odio CD, Casanovas-Massana A, Herbst R, Shaw A, Medzhitov R, Schulz W, Grubaugh N, Dela Cruz C, Farhadian S, Ko A, Omer S, Iwasaki A. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature 2020, 584: 463-469. PMID: 32717743, PMCID: PMC7477538, DOI: 10.1038/s41586-020-2588-y.Peer-Reviewed Original ResearchConceptsSevere COVID-19Moderate COVID-19Immune signaturesDisease outcomeCOVID-19Disease trajectoriesInterleukin-5Early immune signaturesInnate cell lineagesType 2 effectorsT cell numbersPoor clinical outcomeWorse disease outcomesImmune response profileCoronavirus disease 2019Distinct disease trajectoriesCytokine levelsImmunological correlatesImmune profileClinical outcomesEarly elevationImmune profilingIL-13Immunoglobulin EDisease 2019Immune profiling and clinical outcomes in patients treated with ramucirumab and pembrolizumab in phase I study JVDF.
Herbst R, Arkenau H, Calvo E, Bendell J, Penel N, Fuchs C, McNeely S, Rasmussen E, Wang H, Oliveira J, Ferry D, Chau I. Immune profiling and clinical outcomes in patients treated with ramucirumab and pembrolizumab in phase I study JVDF. Journal Of Clinical Oncology 2020, 38: 3089-3089. DOI: 10.1200/jco.2020.38.15_suppl.3089.Peer-Reviewed Original ResearchNon-small cell lung cancerPD-L1 protein expressionObjective response rateBiliary tract cancerProgression-free survivalClinical outcomesOverall survivalUrothelial carcinomaProtein expressionDako PD-L1 IHC 22C3 pharmDxAdvanced non-small cell lung cancerDay 1Phase 1a/b trialImmune checkpoint-related genesPD-L1 IHC 22C3 pharmDxPD-L1 negative tumorsPD-L1 positive tumorsMyeloid-derived suppressor cellsPD-L1 gene expressionTumor microenvironmentPanCancer Immune Profiling PanelImmune-related gene signatureImmune-related gene expressionBaseline tumor samplesGastroesophageal junction adenocarcinoma
2019
LBA79 Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials
Herbst R, Lopes G, Kowalski D, Nishio M, Wu Y, de Castro G, Baas P, Kim D, Gubens M, Cristescu R, Aurora-Garg D, Albright A, Ayers M, Loboda A, Lunceford J, Kobie J, Lubiniecki G, Pietanza M, Piperdi B, Mok T. LBA79 Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials. Annals Of Oncology 2019, 30: v916-v917. DOI: 10.1093/annonc/mdz394.077.Peer-Reviewed Original ResearchBristol-Myers SquibbTissue TMBGenentech/RocheSubsidiary of MerckDohme Corp.KEYNOTE-010KEYNOTE-042PD-L1Merck SeronoBoehringer IngelheimMerck SharpAdvanced NSCLCClinical outcomesEli LillyOno PharmaceuticalCox proportional hazards modelPositive advanced NSCLCResults Baseline characteristicsSubset of ptsOpen-label trialTotal study populationProportional hazards modelRoche/GenentechMultiple tumor typesWhole-exome sequencingMA11.11 STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC
Skoulidis F, Arbour K, Hellmann M, Patil P, Marmarelis M, Owen D, Awad M, Murray J, Levy B, Hellyer J, Gainor J, Stewart T, Goldberg S, Dimou A, Bestvina C, Cummings A, Elamin Y, Lam V, Zhang J, Shu C, Riess J, Blakely C, Pecot C, Mezquita L, Tabbò F, Sacher A, Scheffler M, Ricciuti B, Venkatraman D, Rizvi H, Liu C, Johnston R, Ni Y, Azok J, Kier M, Katz S, Davies K, Segal J, Ritterhouse L, Shaish H, Lacroix L, Memmott R, Madrigal J, Goldman J, Lau S, Killam J, Walther Z, Carter B, Woodcock M, Roth J, Swisher S, Leighl N, Digumarthy S, Mooradian M, Rotow J, Wolf J, Scagliotti G, Planchard D, Besse B, Bivona T, Gandara D, Garon E, Rizvi N, Camidge D, Schalper K, Herbst R, Shaw A, Neal J, Wakelee H, Brahmer J, Jänne P, Carbone D, Aggarwal C, Pennell N, Rudin C, Papadimitrakopoulou V, Heymach J. MA11.11 STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC. Journal Of Thoracic Oncology 2019, 14: s294-s295. DOI: 10.1016/j.jtho.2019.08.591.Peer-Reviewed Original Research
2018
Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC): A Statement Paper from the IASLC
Rolfo C, Mack PC, Scagliotti GV, Baas P, Barlesi F, Bivona TG, Herbst RS, Mok TS, Peled N, Pirker R, Raez LE, Reck M, Riess JW, Sequist LV, Shepherd FA, Sholl LM, Tan D, Wakelee HA, Wistuba II, Wynes MW, Carbone DP, Hirsch FR, Gandara DR. Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC): A Statement Paper from the IASLC. Journal Of Thoracic Oncology 2018, 13: 1248-1268. PMID: 29885479, DOI: 10.1016/j.jtho.2018.05.030.Peer-Reviewed Original ResearchConceptsLiquid biopsyAdvanced non-small cell lungClinical practiceNon-small cell lungResistance mutationsAdvanced NSCLC patientsTumor DNA (ctDNA) assaysCurrent available evidenceCell-free tumor DNALiquid biopsy approachesMultiple cancer typesNSCLC patientsClinical outcomesCell lungLung cancerThoracic oncologyClinical managementMultidisciplinary panelBiopsy approachUnmet needBiopsyPatient careStatement paperTumor DNATumor samplesChapter 6 Management of Advanced Non–Small Cell Lung Cancer Noncurative Intent Treatment
Xia B, Herbst R. Chapter 6 Management of Advanced Non–Small Cell Lung Cancer Noncurative Intent Treatment. 2018, 99-115. DOI: 10.1016/b978-0-323-48565-4.00006-0.Peer-Reviewed Original ResearchNon-small cell lung cancerPD-L1 expressionPlatinum-based chemotherapyTreatment optionsLung cancerFirst-line systemic treatment optionMolecular alterationsSecond-line settingSystemic treatment optionsTime of diagnosisMain treatment optionCell lung cancerCancer-related mortalityBiomarkers of responseEfficacy of treatmentAbstract Lung cancerAdenocarcinoma histologyIntent treatmentMetastatic diseaseMost patientsClinical outcomesNoninvasive testingClinical trialsNovel therapiesTreatment strategies
2017
The HGF/c-MET Pathway Is a Driver and Biomarker of VEGFR-inhibitor Resistance and Vascular Remodeling in Non–Small Cell Lung Cancer
Cascone T, Xu L, Lin HY, Liu W, Tran HT, Liu Y, Howells K, Haddad V, Hanrahan E, Nilsson MB, Cortez MA, Giri U, Kadara H, Saigal B, Park YY, Peng W, Lee JS, Ryan AJ, Jüergensmeier JM, Herbst RS, Wang J, Langley RR, Wistuba II, Lee JJ, Heymach JV. The HGF/c-MET Pathway Is a Driver and Biomarker of VEGFR-inhibitor Resistance and Vascular Remodeling in Non–Small Cell Lung Cancer. Clinical Cancer Research 2017, 23: 5489-5501. PMID: 28559461, PMCID: PMC5600821, DOI: 10.1158/1078-0432.ccr-16-3216.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarcinoma, Non-Small-Cell LungCell Line, TumorClinical Trials, Phase II as TopicClinical Trials, Phase III as TopicDisease Models, AnimalDrug Resistance, NeoplasmGene Expression ProfilingHepatocyte Growth FactorHumansHypoxiaKaplan-Meier EstimateLung NeoplasmsMaleMiceMolecular Targeted TherapyMulticenter Studies as TopicNeovascularization, PathologicPrognosisProtein Kinase InhibitorsProto-Oncogene Proteins c-metReceptors, Vascular Endothelial Growth FactorSignal TransductionXenograft Model Antitumor AssaysConceptsNon-small cell lung cancerHepatocyte growth factorC-MetHGF/c-Met pathwayHuman non-small cell lung cancerResistance of NSCLCAngiogenic factor levelsHGF plasma levelsCancer cellsTumor microvascular densityCell lung cancerEffect of therapyTortuous blood vesselsTumor vascular bedC-Met pathwayTyrosine kinase inhibitorsTumor-associated stromaClin Cancer ResHuman lung adenocarcinomaMurine xenograft modelVEGFR-TKIClinical outcomesLung cancerPlasma levelsMicrovascular densityInterplay between immune infiltration and tumor progression and survival in non-small cell lung cancer: An analysis of institutional and public data.
Jalali A, Wang J, Lee W, Zhang J, Wu C, Gibbons D, Tang X, Kalhor N, Izzo J, Behrens C, Fossella F, Tsao A, Lee J, Swisher S, Heymach J, Futreal A, Wistuba I, Herbst R, Papadimitrakopoulou V, Zhang J. Interplay between immune infiltration and tumor progression and survival in non-small cell lung cancer: An analysis of institutional and public data. Journal Of Clinical Oncology 2017, 35: 8538-8538. DOI: 10.1200/jco.2017.35.15_suppl.8538.Peer-Reviewed Original ResearchNon-small cell lung cancerImmune infiltration scoreTumor immune infiltrationCell lung cancerImmune infiltrationLung cancerImmune responseAdvanced non-small cell lung cancerStage I/II diseaseTumor progressionStage I/IIStage III/IVInfiltration of tumorsInflammatory cell countsHigher median survivalLung Cancer ProjectPrimary tumor specimensLung adenocarcinoma samplesTypes of cancerMeans of CD3Tumor coreEstimate packageMedian survivalNSCLC patientsClinical outcomesMutation profiles in early-stage lung squamous cell carcinoma with clinical follow-up and correlation with markers of immune function
Choi M, Kadara H, Zhang J, Parra ER, Rodriguez-Canales J, Gaffney SG, Zhao Z, Behrens C, Fujimoto J, Chow C, Kim K, Kalhor N, Moran C, Rimm D, Swisher S, Gibbons DL, Heymach J, Kaftan E, Townsend JP, Lynch TJ, Schlessinger J, Lee J, Lifton RP, Herbst RS, Wistuba II. Mutation profiles in early-stage lung squamous cell carcinoma with clinical follow-up and correlation with markers of immune function. Annals Of Oncology 2017, 28: 83-89. PMID: 28177435, PMCID: PMC6246501, DOI: 10.1093/annonc/mdw437.Peer-Reviewed Original ResearchConceptsLung squamous cell carcinomaEarly stage lung squamous cell carcinomaNon-small cell lung cancerSquamous cell carcinomaWhole-exome sequencingImmune markersClinical outcomesCell carcinomaPIK3CA mutationsExact testPoor recurrence-free survivalProportional hazards regression modelsTumoral PD-L1 expressionPD-L1 expressionRecurrence-free survivalCell lung cancerComprehensive immune profilingTP53 mutant tumorsHazards regression modelsNormal lung tissuesFisher's exact testLUSC cohortAdjuvant therapyImmune profilingPoor prognosisWhole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up
Kadara H, Choi M, Zhang J, Parra ER, Rodriguez-Canales J, Gaffney SG, Zhao Z, Behrens C, Fujimoto J, Chow C, Yoo Y, Kalhor N, Moran C, Rimm D, Swisher S, Gibbons DL, Heymach J, Kaftan E, Townsend JP, Lynch TJ, Schlessinger J, Lee J, Lifton RP, Wistuba II, Herbst RS. Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up. Annals Of Oncology 2017, 28: 75-82. PMID: 27687306, PMCID: PMC5982809, DOI: 10.1093/annonc/mdw436.Peer-Reviewed Original ResearchConceptsRecurrence-free survivalPoor recurrence-free survivalWhole-exome sequencingEarly-stage lung adenocarcinomaMutant lung adenocarcinomaLung adenocarcinomaImmune markersClinical outcomesExact testNatural killer cell infiltrationProportional hazards regression modelsGranzyme B levelsImmune marker analysisImmune profiling analysisPD-L1 expressionImmune-based therapiesTumoral PD-L1Hazards regression modelsKRAS mutant tumorsNormal lung tissuesMajority of deathsFisher's exact testHigh mutation burdenAnalysis of immunophenotypeRelevant molecular markers
2012
Effect of KRAS Oncogene Substitutions on Protein Behavior: Implications for Signaling and Clinical Outcome
Ihle NT, Byers LA, Kim ES, Saintigny P, Lee JJ, Blumenschein GR, Tsao A, Liu S, Larsen JE, Wang J, Diao L, Coombes KR, Chen L, Zhang S, Abdelmelek MF, Tang X, Papadimitrakopoulou V, Minna JD, Lippman SM, Hong WK, Herbst RS, Wistuba II, Heymach JV, Powis G. Effect of KRAS Oncogene Substitutions on Protein Behavior: Implications for Signaling and Clinical Outcome. Journal Of The National Cancer Institute 2012, 104: 228-239. PMID: 22247021, PMCID: PMC3274509, DOI: 10.1093/jnci/djr523.Peer-Reviewed Original ResearchMeSH KeywordsAspartic AcidCarcinoma, Non-Small-Cell LungCell Line, TumorClinical Trials, Phase II as TopicCysteineDisease-Free SurvivalGene Expression ProfilingGene Expression Regulation, NeoplasticGenes, rasGenetic VectorsGlycineHumansImmunoblottingImmunoprecipitationKaplan-Meier EstimateLentivirusLung NeoplasmsMicroarray AnalysisMolecular Targeted TherapyMutationProto-Oncogene Proteins c-aktRandomized Controlled Trials as TopicSignal TransductionTOR Serine-Threonine KinasesTreatment OutcomeValineConceptsNon-small cell lung cancerKirsten rat sarcoma viral oncogene homologProgression-free survivalNSCLC cell linesWild-type KrasMutant KrasRefractory non-small cell lung cancerWorse progression-free survivalRat sarcoma viral oncogene homologRas2 Kirsten rat sarcoma viral oncogene homologSarcoma viral oncogene homologKaplan-Meier curvesCell lung cancerReverse-phase protein array studiesKRas proteinsHuman bronchial epithelial cellsCancer cell growthPatient tumor samplesCell linesImmortalized human bronchial epithelial cellsBronchial epithelial cellsProtein array studiesTumor gene expressionEvaluable patientsClinical outcomes
2011
Increased VEGFR-2 Gene Copy Is Associated with Chemoresistance and Shorter Survival in Patients with Non–Small-Cell Lung Carcinoma Who Receive Adjuvant Chemotherapy
Yang F, Tang X, Riquelme E, Behrens C, Nilsson MB, Giri U, Varella-Garcia M, Byers LA, Lin HY, Wang J, Raso MG, Girard L, Coombes K, Lee JJ, Herbst RS, Minna JD, Heymach JV, Wistuba II. Increased VEGFR-2 Gene Copy Is Associated with Chemoresistance and Shorter Survival in Patients with Non–Small-Cell Lung Carcinoma Who Receive Adjuvant Chemotherapy. Cancer Research 2011, 71: 5512-5521. PMID: 21724587, PMCID: PMC3159530, DOI: 10.1158/0008-5472.can-10-2614.Peer-Reviewed Original ResearchConceptsCell lung carcinomaHIF-1α levelsAdjuvant therapyLung carcinomaAdjuvant platinum-based chemotherapyVEGFR-2 blockadeNuclear hypoxia inducible factor-1αNSCLC tumor cellsPlatinum-based chemotherapyFavorable overall survivalRisk of deathHypoxia-inducible factor-1αHigher microvessel densityNSCLC tumor specimensNSCLC cell linesInducible factor-1αCell linesVEGF receptor 2Adjuvant chemotherapyOverall survivalClinical outcomesAdenocarcinoma patientsMicrovessel densityShorter SurvivalHigh riskDo elderly chemorefractory NSCLC patients derive benefit from salvage targeted therapy? Subgroup analysis of clinical outcome and toxicity from the BATTLE trial.
Tsao A, Liu S, Lee J, Alden C, Kim E, Blumenschein G, Herbst R, Lippman S, Wistuba I, Hong W. Do elderly chemorefractory NSCLC patients derive benefit from salvage targeted therapy? Subgroup analysis of clinical outcome and toxicity from the BATTLE trial. Journal Of Clinical Oncology 2011, 29: 7550-7550. DOI: 10.1200/jco.2011.29.15_suppl.7550.Peer-Reviewed Original Research
2010
BATTLE (Biomarker-based Approach of Targeted Therapy for Lung Cancer Elimination)
Hong W, Herbst R, Kim E. BATTLE (Biomarker-based Approach of Targeted Therapy for Lung Cancer Elimination). 2010 DOI: 10.21236/ada542458.Peer-Reviewed Original Research
2009
Classification by Mass Spectrometry Can Accurately and Reliably Predict Outcome in Patients with Non-small Cell Lung Cancer Treated with Erlotinib-Containing Regimen
Salmon S, Chen H, Chen S, Herbst R, Tsao A, Tran H, Sandler A, Billheimer D, Shyr Y, Lee JW, Massion P, Brahmer J, Schiller J, Carbone D, Dang TP. Classification by Mass Spectrometry Can Accurately and Reliably Predict Outcome in Patients with Non-small Cell Lung Cancer Treated with Erlotinib-Containing Regimen. Journal Of Thoracic Oncology 2009, 4: 689-696. PMID: 19404214, PMCID: PMC3563261, DOI: 10.1097/jto.0b013e3181a526b3.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsBevacizumabBiomarkers, TumorCarcinoma, Non-Small-Cell LungCase-Control StudiesCohort StudiesErlotinib HydrochlorideFemaleHumansLung NeoplasmsMaleMiddle AgedNeoplasm Recurrence, LocalPleural Effusion, MalignantPrognosisQuinazolinesReproducibility of ResultsSpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationSurvival RateTreatment OutcomeConceptsNon-small cell lung cancerCell lung cancerLung cancerRefractory non-small cell lung cancerPhase I/II studyUnivariate Cox proportional hazards modelProgression-free survival outcomesCox proportional hazards modelOutcomes of patientsCohort of patientsSelection of patientsVascular endothelial growth factorProportional hazards modelEndothelial growth factorReceptor kinase inhibitorEpidermal growth factor receptorGrowth factor receptorII studyOverall survivalPretreatment serumTreatment cohortsClinical outcomesSurvival outcomesEpidermal growth factor receptor kinase inhibitorsSuch therapy
2008
Tumor Cavitation During Therapy with Antiangiogenesis Agents in Patients with Lung Cancer
Marom EM, Martinez CH, Truong MT, Lei X, Sabloff BS, Munden RF, Gladish GW, Herbst RS, Morice RC, Stewart DJ, Jimenez CA, Blumenschein GR, Onn A. Tumor Cavitation During Therapy with Antiangiogenesis Agents in Patients with Lung Cancer. Journal Of Thoracic Oncology 2008, 3: 351-357. PMID: 18379352, DOI: 10.1097/jto.0b013e318168c7e9.Peer-Reviewed Original ResearchConceptsLung cancer patientsTumor cavitationCancer patientsAntiangiogenesis agentsAdverse eventsLung cancerMD Anderson Cancer CenterChest imaging findingsProgression-free survivalAdditional adverse eventsSquamous cell histologySquamous cell tumorsAnderson Cancer CenterCavitary tumorsPrevious chemotherapyCell histologyOverall survivalClinical outcomesImaging findingsCancer CenterCell tumorsTumor locationMedical recordsClinical dataClinical significance
2005
O-186 Mutations in EGFR, HER2, KRAS and BRAF in NSCLC: Prevalences and correlations with clinical outcomes in patients treated with carboplatin and paclitaxel with or without erlotinib
Eberhard D, Johnson B, Goddard A, Herbst R, Janne P, Johnson D, Klein P, Ostland M, Seshagiri S, Hillan K. O-186 Mutations in EGFR, HER2, KRAS and BRAF in NSCLC: Prevalences and correlations with clinical outcomes in patients treated with carboplatin and paclitaxel with or without erlotinib. Lung Cancer 2005, 49: s62. DOI: 10.1016/s0169-5002(05)80320-4.Peer-Reviewed Original ResearchCorrelation of molecular markers including mutations with clinical outcomes in advanced non small cell lung cancer (NSCLC) patients (pts) treated with gefitinib, chemotherapy or chemotherapy and gefitinib in IDEAL and INTACT clinical trials
Lynch T, Bell D, Haber D, Johnson D, Giaccone G, Fukuoka M, Kris M, Herbst R, Krebs A, Ochs J. Correlation of molecular markers including mutations with clinical outcomes in advanced non small cell lung cancer (NSCLC) patients (pts) treated with gefitinib, chemotherapy or chemotherapy and gefitinib in IDEAL and INTACT clinical trials. Journal Of Clinical Oncology 2005, 23: 7006-7006. DOI: 10.1200/jco.2005.23.16_suppl.7006.Peer-Reviewed Original Research