2023
Nimotuzumab Plus Gemcitabine for K-Ras Wild-Type Locally Advanced or Metastatic Pancreatic Cancer
Qin S, Li J, Bai Y, Wang Z, Chen Z, Xu R, Xu J, Zhang H, Chen J, Yuan Y, Liu T, Yang L, Zhong H, Chen D, Shen L, Hao C, Fu D, Cheng Y, Yang J, Wang Q, Qin B, Pan H, Zhang J, Bai X, Zheng Q. Nimotuzumab Plus Gemcitabine for K-Ras Wild-Type Locally Advanced or Metastatic Pancreatic Cancer. Journal Of Clinical Oncology 2023, 41: 5163-5173. PMID: 37647576, PMCID: PMC10666986, DOI: 10.1200/jco.22.02630.Peer-Reviewed Original ResearchConceptsProgression-free survivalK-ras wild-type tumorMetastatic pancreatic cancerWild-type tumorsOverall survivalPancreatic cancerK-rasMedian progression-free survivalProgression-free survival timePhase III clinical studiesK-ras wild-typeResponse rateIncidence of adverse eventsDisease control rateSecondary end pointsIII clinical studiesPhase IIb trialMean survival timeMedian OSNimotuzumab groupImproved OSPlacebo groupClinical benefitSafety profileAdverse events
2019
Shared and Tissue-Specific Expression Signatures between Bone Marrow from Primary Myelofibrosis and Essential Thrombocythemia
Ishikawa G, Fujiwara N, Hirschfield H, Varricchio L, Hoshida Y, Barosi G, Rosti V, Padilla M, Mazzarini M, Friedman SL, Hoffman R, Migliaccio AR. Shared and Tissue-Specific Expression Signatures between Bone Marrow from Primary Myelofibrosis and Essential Thrombocythemia. Experimental Hematology 2019, 79: 16-25.e3. PMID: 31678370, PMCID: PMC6910948, DOI: 10.1016/j.exphem.2019.10.001.Peer-Reviewed Original ResearchConceptsBone marrowLung fibrosisMyeloproliferative neoplasmsEssential thrombocytopeniaLiver fibrosisPhiladelphia-negative myeloproliferative neoplasmsProtein 1Possible therapeutic targetPrimary myelofibrosis patientsExpression of Id1Extracellular matrix protein 1Poor prognosisIL-8Myelofibrosis patientsEssential thrombocythemiaTherapeutic targetPrimary myelofibrosisFibrosisMegakaryocyte hyperplasiaCholesterol homeostasisBM functionHematopoietic failureMatrix protein 1K-rasPotential target
2012
Abstract 3697: Phase II study of therapy selected by molecular profiling in patients with previously treated metastatic pancreatic cancer - SU2C-001
Barrett M, Lenkiewicz E, Evers L, Holley T, Aziz M, Kiefer J, Maitra A, Hidalgo M, Kumar R, Hlavacek W, Stites E, Posner R, Ramanathan R, Von Hoff D. Abstract 3697: Phase II study of therapy selected by molecular profiling in patients with previously treated metastatic pancreatic cancer - SU2C-001. Cancer Research 2012, 72: 3697-3697. DOI: 10.1158/1538-7445.am2012-3697.Peer-Reviewed Original ResearchComparative genomic hybridizationPhase II studyStudies of therapyMolecular profilingTreating metastatic pancreatic cancerK-rasPanel of xenograftsAneuploid tumour cell populationsMetastatic pancreatic cancerComparative genomic hybridization arrayAmerican Association for Cancer ResearchTherapeutic targetK-ras mutationsTumor cell populationGene expression microarray analysisExpression microarray analysisFocal ampliconsMetastatic lesionsMetastatic biopsiesC-kitGenomic hybridizationPancreatic cancerTumor nucleiHomozygous deletionDrug sensitivity
2011
The oncogenic kinase Pim-1 is modulated by K-Ras signaling and mediates transformed growth and radioresistance in human pancreatic ductal adenocarcinoma cells
Xu D, Allsop S, Witherspoon S, Snider J, Yeh J, Fiordalisi J, White C, Williams D, Cox A, Baines A. The oncogenic kinase Pim-1 is modulated by K-Ras signaling and mediates transformed growth and radioresistance in human pancreatic ductal adenocarcinoma cells. Carcinogenesis 2011, 32: 488-495. PMID: 21262926, PMCID: PMC3066419, DOI: 10.1093/carcin/bgr007.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomabcl-Associated Death ProteinCarcinoma, Pancreatic DuctalCell Line, TumorCell ProliferationCyclin-Dependent Kinase Inhibitor p27HumansNeoplasm InvasivenessPancreatic NeoplasmsPhosphorylationProto-Oncogene ProteinsProto-Oncogene Proteins c-pim-1Proto-Oncogene Proteins p21(ras)Radiation Toleranceras ProteinsSignal TransductionConceptsShRNA-mediated suppressionK-Ras signalingPim-1 expressionPancreatic ductal adenocarcinoma cell linesPim-1 kinasePro-apoptotic protein BadCell growthOncogenic K-Ras signalingK-rasPim-1 protein levelsCyclin-dependent kinase inhibitor p27Kip1Immortalized cell modelGrowth transformationHuman pancreatic ductal adenocarcinoma cellsCell linesPancreatic ductal adenocarcinomaPim-1Pancreatic ductal adenocarcinoma cell growthMutant K-rasPim-1 activityPim-1 proteinProtein BadOncogenic K-RasPancreatic ductal adenocarcinoma cellsKinase activity
2007
Low-Dose BBR3610 Toxicity in Colon Cancer Cells Is p53-Independent and Enhanced by Inhibition of Epidermal Growth Factor Receptor (ERBB1)-Phosphatidyl Inositol 3 Kinase Signaling
Mitchell C, Kabolizadeh P, Ryan J, Roberts JD, Yacoub A, Curiel DT, Fisher PB, Hagan MP, Farrell NP, Grant S, Dent P. Low-Dose BBR3610 Toxicity in Colon Cancer Cells Is p53-Independent and Enhanced by Inhibition of Epidermal Growth Factor Receptor (ERBB1)-Phosphatidyl Inositol 3 Kinase Signaling. Molecular Pharmacology 2007, 72: 704-714. PMID: 17578896, DOI: 10.1124/mol.107.038406.Peer-Reviewed Original ResearchConceptsColon cancer cellsEpidermal growth factor receptorGrowth factor receptorActive AktC-FLIPMolecular inhibitionCaspase-8 functionsPhosphatidyl inositol 3 kinaseActivation of BaxDominant-negative AktErbB1 inhibitorsFactor receptorHuman colon cancer cellsOverexpression of XIAPCancer cellsSmall moleculesKinase signalingPI3K inhibitorsAkt activityCaspase-9Bcl-xLNull cellsMcl-1SW480 cellsK-ras
2003
Use of avian retroviral vectors to introduce transcriptional regulators into mammalian cells for analyses of tumor maintenance
Pao W, Klimstra D, Fisher G, Varmus H. Use of avian retroviral vectors to introduce transcriptional regulators into mammalian cells for analyses of tumor maintenance. Proceedings Of The National Academy Of Sciences Of The United States Of America 2003, 100: 8764-8769. PMID: 12857957, PMCID: PMC166387, DOI: 10.1073/pnas.1133333100.Peer-Reviewed Original ResearchConceptsTumor maintenanceTransgenic miceAvian retroviral receptorTVA transgenic miceTranscriptional regulationMammalian cellsStudy of oncogenesisInfection of cellsProtein coding sequencesGenetic complementation assayDox withdrawalSomatic mammalian cellsAvian retroviral vectorRetroviral vectorsRetroviral receptorTemporally controlled gene expressionOncogenic transgenesNude miceRCAS virusesMurine embryonic fibroblastsTumor initiationMouse modelTumorGenetic lesionsK-rasRole of the DPC4 Tumor Suppressor Gene in Adenocarcinoma of the Ampulla of Vater: Analysis of 140 Cases
McCarthy D, Hruban R, Argani P, Howe J, Conlon K, Brennan M, Zahurak M, Wilentz R, Cameron J, Yeo C, Kern S, Klimstra D. Role of the DPC4 Tumor Suppressor Gene in Adenocarcinoma of the Ampulla of Vater: Analysis of 140 Cases. Modern Pathology 2003, 16: 272-278. PMID: 12640108, DOI: 10.1097/01.mp.0000057246.03448.26.Peer-Reviewed Original ResearchConceptsLoss of Dpc4 expressionDpc4 expressionK-ras gene mutationAmpulla of VaterK-ras oncogeneK-rasPancreatic adenocarcinomaAreas of high-grade dysplasiaGene mutationsDPC4 tumor suppressor genesAssociated with shorter survivalDPC4 gene productLoss of DPC4Resected ampullary adenocarcinomaHigh-grade dysplasiaPredictor of prognosisDevelopment of adenocarcinomaLymph node metastasisActivating point mutationsIntestinal-type tumorsTumor suppressor geneK-ras geneComplete lossInvasive carcinomaAmpullary adenocarcinoma
2002
Solid-Pseudopapillary Tumors of the Pancreas Are Genetically Distinct from Pancreatic Ductal Adenocarcinomas and Almost Always Harbor β-catenin Mutations
Abraham S, Klimstra D, Wilentz R, Yeo C, Conlon K, Brennan M, Cameron J, Wu T, Hruban R. Solid-Pseudopapillary Tumors of the Pancreas Are Genetically Distinct from Pancreatic Ductal Adenocarcinomas and Almost Always Harbor β-catenin Mutations. American Journal Of Pathology 2002, 160: 1361-1369. PMID: 11943721, PMCID: PMC1867216, DOI: 10.1016/s0002-9440(10)62563-1.Peer-Reviewed Original ResearchConceptsSolid pseudopapillary tumorDNA sequencesAPC/beta-catenin pathwayAPC/beta-cateninDPC4 tumor suppressor genesPancreatic ductal adenocarcinomaK-rasDuctal adenocarcinomaAccumulation of beta-catenin proteinCyclin D1Beta-catenin exon 3Cell cycle proteinsTumor suppressor genePathways of neoplastic progressionPancreatic neoplasmsBeta-catenin proteinNuclear accumulation of beta-catenin proteinNeoplasm of low malignant potentialBeta-catenin dysregulationMutation cluster regionGenetic pathwaysLow malignant potentialImmunohistochemical labelingBeta-catenin mutationsAcinar cell carcinoma
2001
Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes
Fisher G, Wellen S, Klimstra D, Lenczowski J, Tichelaar J, Lizak M, Whitsett J, Koretsky A, Varmus H. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes & Development 2001, 15: 3249-3262. PMID: 11751631, PMCID: PMC312852, DOI: 10.1101/gad.947701.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAdenomaAnimalsApoptosisBromodeoxyuridineCyclin-Dependent Kinase Inhibitor p16DNA PrimersGene Expression Regulation, NeoplasticGenes, rasGenes, Tumor SuppressorGenotypeIn Situ Nick-End LabelingLung NeoplasmsMiceMice, KnockoutMice, TransgenicModels, GeneticNeoplasm Recurrence, LocalReverse Transcriptase Polymerase Chain ReactionTetracyclineTransgenesTumor Suppressor Protein p53ConceptsTumor suppressor geneType II pneumocytesApoptotic regressionLung adenocarcinomaProliferative lesionsPresence of tumor suppressor genesSuppressor geneHistological features of malignancyActivated K-ras geneK-rasControl of doxycyclineFeatures of malignancyViability of tumor cellsFocal proliferative lesionsAlveolar type II pneumocytesK-ras geneEarly proliferative lesionsMonths of inductionMutant K-rasMagnetic resonance imagingTumor burdenPulmonary tumorsP53 geneFocal invasionTumor cellsDistinctive Molecular Genetic Alterations in Sporadic and Familial Adenomatous Polyposis-Associated Pancreatoblastomas Frequent Alterations in the APC/β-Catenin Pathway and Chromosome 11p
Abraham S, Wu T, Klimstra D, Finn L, Lee J, Yeo C, Cameron J, Hruban R. Distinctive Molecular Genetic Alterations in Sporadic and Familial Adenomatous Polyposis-Associated Pancreatoblastomas Frequent Alterations in the APC/β-Catenin Pathway and Chromosome 11p. American Journal Of Pathology 2001, 159: 1619-1627. PMID: 11696422, PMCID: PMC1867075, DOI: 10.1016/s0002-9440(10)63008-8.Peer-Reviewed Original ResearchMeSH KeywordsAdenomatous Polyposis ColiAdenomatous Polyposis Coli ProteinAllelesBase Sequencebeta CateninChildChild, PreschoolChromosomes, Human, Pair 11Cytoskeletal ProteinsDNA-Binding ProteinsFemaleGenes, p53Genes, rasHumansLoss of HeterozygosityMaleMiddle AgedMolecular BiologyMutationNeoplasms, Germ Cell and EmbryonalPancreatic NeoplasmsSmad4 ProteinTrans-ActivatorsConceptsChromosome 11pDNA sequencesPancreatic ductal adenocarcinomaDPC4 tumor suppressor genesGenetic alterationsBeta-CateninFamilial adenomatous polyposisK-rasAllelic loss assaysAccumulation of beta-catenin proteinDpc4 protein expressionDuctal adenocarcinomaAdenomatous polyposis coli (APC)/beta-catenin pathwaySequencing of exon 3DNA sequencing of exon 3Tumor suppressor geneBeta-catenin oncogeneBeta-catenin proteinAbnormal nuclear accumulationMolecular genetic alterationsMutation cluster regionNuclear accumulation of beta-catenin proteinExon 1 of K-rasBeta-catenin geneAllelic lossDetection of the Mutated K-Ras Biomarker in Colorectal Carcinoma
Doolittle B, Emanuel J, Tuttle C, Costa J. Detection of the Mutated K-Ras Biomarker in Colorectal Carcinoma. Experimental And Molecular Pathology 2001, 70: 289-301. PMID: 11418008, DOI: 10.1006/exmp.2001.2364.Peer-Reviewed Original ResearchMeSH KeywordsBiomarkers, TumorColorectal NeoplasmsDeoxyribonuclease EcoRIDNADNA, NeoplasmFecesGenes, rasHumansIndicators and ReagentsMutationPolymerase Chain ReactionPolymorphism, Single-Stranded ConformationalQuaternary Ammonium CompoundsReference ValuesReproducibility of ResultsSite-Specific DNA-Methyltransferase (Adenine-Specific)Trimethyl Ammonium CompoundsConceptsColorectal carcinomaStool samplesHealthy patientsK-rasReliable screening testDouble-blind formatK-ras mutationsWild-type K-rasK-ras oncogeneK-ras sequencesCommon malignancyCRC tumorsPolymerase chain reactionEarly lesionsStool DNANoninvasive screenScreening testTumor tissueGenetic biomarkersHuman stoolPatientsEarly detectionHigh false positive rateSingle-strand conformation polymorphismTissue DNAColloid (Mucinous Noncystic) Carcinoma of the Pancreas
Adsay N, Pierson C, Sarkar F, Abrams J, Weaver D, Conlon K, Brennan M, Klimstra D. Colloid (Mucinous Noncystic) Carcinoma of the Pancreas. The American Journal Of Surgical Pathology 2001, 25: 26-42. PMID: 11145249, DOI: 10.1097/00000478-200101000-00003.Peer-Reviewed Original ResearchConceptsIntraductal papillary mucinous neoplasmOrdinary ductal adenocarcinomaMucinous cystic neoplasmsLymph node metastasisMucinous cystadenocarcinomaDuctal adenocarcinomaIncisional biopsyColloid carcinomaK-ras genePerineurial invasionNode metastasisCodon 12Clinicopathological characteristics of CCPatients died of diseaseRegional lymph node metastasisK-rasSignet-ring cell adenocarcinomaBasal aspectDied of thromboembolismFive-year survivalPapillary mucinous neoplasmSignet-ring cellsPools of mucinPrognosis of CCIncidence of mutations
2000
Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype
Toyota M, Ohe-Toyota M, Ahuja N, Issa J. Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. Proceedings Of The National Academy Of Sciences Of The United States Of America 2000, 97: 710-715. PMID: 10639144, PMCID: PMC15395, DOI: 10.1073/pnas.97.2.710.Peer-Reviewed Original ResearchMeSH KeywordsAdenomaBase SequenceColorectal NeoplasmsCpG IslandsDNA MethylationDNA Mutational AnalysisDNA, NeoplasmGenes, p16Genes, p53Genes, rasHumansMicrosatellite RepeatsMutationPhenotypePoint MutationPolymorphism, Single-Stranded ConformationalProtein Serine-Threonine KinasesReceptor, Transforming Growth Factor-beta Type IIReceptors, Transforming Growth Factor betaSequence DeletionTumor Cells, CulturedConceptsCpG island methylator phenotypeColorectal cancerK-ras mutationsDifferent genetic lesionsActivation of oncogenesTumor suppressor geneMultiple CpG islandsColorectal tumorsMethylator phenotypeCpG islandsDistinct genetic profilesP53 mutationsEpigenetic alterationsMolecular diversitySuppressor geneGenetic lesionsNovel pathwayGroup of tumorsGenetic alterationsK-rasMutationsCancer developmentSimultaneous methylationGenes
1999
Analysis of K-ras, N-ras, H-ras, and p53 in Lung Neuroendocrine Neoplasms
Couce M, Bautista D, Costa J, Carter D. Analysis of K-ras, N-ras, H-ras, and p53 in Lung Neuroendocrine Neoplasms. Applied Immunohistochemistry & Molecular Morphology 1999, 8: 71-79. PMID: 10475381, DOI: 10.1097/00019606-199906000-00003.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAllelesDNA Mutational AnalysisExonsFemaleGenes, rasHumansImmunohistochemistryLung NeoplasmsMaleMiddle AgedMutation, MissenseNeuroendocrine TumorsPoint MutationPolymerase Chain ReactionPolymorphism, GeneticPolymorphism, Single-Stranded ConformationalRetrospective StudiesTumor Suppressor Protein p53ConceptsLarge cell neuroendocrine carcinomaPulmonary neuroendocrine tumorsAtypical carcinoidNeuroendocrine tumorsTypical carcinoidP53 geneK-rasCell neuroendocrine carcinomaSingle-strand conformation polymorphismHigh-grade tumorsHigh-grade carcinomaH-ras mutationsLung neuroendocrine neoplasmsN-rasK-ras mutationsH-RasExon 5Neuroendocrine carcinomaPolymerase chain reactionNeuroendocrine neoplasmsPositive immunostainingGenotypic mutationsN-ras geneTumors
1998
K-ras Oncogene Mutations in Osteoclast-like Giant Cell Tumors of the Pancreas and Liver
Westra W, Sturm P, Drillenburg P, Choti M, Klimstra D, Albores-Saavedra J, Montag A, Offerhaus G, Hruban R. K-ras Oncogene Mutations in Osteoclast-like Giant Cell Tumors of the Pancreas and Liver. The American Journal Of Surgical Pathology 1998, 22: 1247-1254. PMID: 9777987, DOI: 10.1097/00000478-199810000-00010.Peer-Reviewed Original ResearchConceptsOsteoclast-like giant cell tumorOsteoclast-like giant cellsK-ras mutationsGiant cell tumorK-ras oncogeneK-rasGiant cellsCell tumorsEpithelial proliferationMononuclear cellsEpithelial markersAtypical intraductal epithelial proliferationEpithelial precursorsK-ras oncogene mutationsIntraductal epithelial proliferationMucinous cystic neoplasmsFinding of K-ras mutationsInfiltrating mononuclear cellsPhagocytize tumor cellsEnigmatic tumorsUndifferentiated carcinomaMesenchymal tumorsAbsent stainingEpithelial lesionsCystic neoplasms
1997
K-ras mutation in adenomas and carcinomas of the ampulla of vater.
Howe J, Klimstra D, Cordon-Cardo C, Paty P, Park P, Brennan M. K-ras mutation in adenomas and carcinomas of the ampulla of vater. Clinical Cancer Research 1997, 3: 129-33. PMID: 9815548.Peer-Reviewed Original ResearchConceptsK-ras mutationsAmpulla of VaterK-ras exon 1Patient survivalK-rasClinicopathological factorsExon 1Tumor size >2 cmAssociated with K-ras mutationK-ras mutation statusAnalysis of K-ras mutationsLog-rank testCox proportional hazards modelsAdjacent to carcinomaSpectrum of mutationsProgression of tumorsProportional hazards modelResected tumorAmpullary tumorsInvasive carcinomaMutation statusAmpullary carcinomaPCR amplificationColorectal neoplasmsPCR products
1994
K-ras mutations and p53 alterations in neoplastic and nonneoplastic lesions associated with longstanding ulcerative colitis.
Chaubert P, Benhattar J, Saraga E, Costa J. K-ras mutations and p53 alterations in neoplastic and nonneoplastic lesions associated with longstanding ulcerative colitis. American Journal Of Pathology 1994, 144: 767-75. PMID: 8160776, PMCID: PMC1887244.Peer-Reviewed Original ResearchConceptsK-ras mutationsLongstanding ulcerative colitisUlcerative colitisP53 alterationsActive colitisDysplastic lesionsK-rasGenetic alterationsP53 gene alterationsP53 genetic alterationsCombination of immunohistochemistryK-ras geneNonneoplastic lesionsColorectal carcinomaInvasive carcinomaColonic carcinomaDysplastic mucosaEpithelial lesionsInvasive tumorsColitisSame patientCarcinomaSporadic carcinomasLesionsNontumor samples
1990
Genetic Abnormalities in Sporadic Parathyroid Adenomas
Friedman E, Bale A, Marx S, Norton J, Arnold A, Tu T, Aurbach G, Spiegel A. Genetic Abnormalities in Sporadic Parathyroid Adenomas. The Journal Of Clinical Endocrinology & Metabolism 1990, 71: 293-297. PMID: 2199477, DOI: 10.1210/jcem-71-2-293.Peer-Reviewed Original Research
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