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dc.contributor.authorKini, Lohith G.
dc.contributor.authorHerrero-Jimenez, Pablo
dc.contributor.authorSanghvi, Jayodita
dc.contributor.authorGutierrez, Efren
dc.contributor.authorKusko, Rebecca
dc.contributor.authorRexer, Karl
dc.contributor.authorKurzweil, Ray
dc.contributor.authorRefinetti, Paulo
dc.contributor.authorMorgenthaler, Stephan
dc.contributor.authorGostjeva, Elena V.
dc.contributor.authorKamath, Tushar V.
dc.contributor.authorHensle, David, 1981-
dc.contributor.authorKogel, John, 1981-
dc.contributor.authorKoledova, Vera V
dc.contributor.authorThilly, William G
dc.date.accessioned2014-09-10T16:18:13Z
dc.date.available2014-09-10T16:18:13Z
dc.date.issued2013-10
dc.date.submitted2013-05
dc.identifier.issn2234-943X
dc.identifier.urihttp://hdl.handle.net/1721.1/89414
dc.description.abstractAdult age-specific colorectal cancer incidence rates increase exponentially from maturity, reach a maximum, then decline in extreme old age. Armitage and Doll (1) postulated that the exponential increase resulted from “n” mutations occurring throughout adult life in normal “cells at risk” that initiated the growth of a preneoplastic colony in which subsequent “m” mutations promoted one of the preneoplastic “cells at risk” to form a lethal neoplasia. We have reported cytologic evidence that these “cells at risk” are fetal/juvenile organogenic, then preneoplastic metakaryotic stem cells. Metakaryotic cells display stem-like behaviors of both symmetric and asymmetric nuclear divisions and peculiarities such as bell shaped nuclei and amitotic nuclear fission that distinguish them from embryonic, eukaryotic stem cells. Analyses of mutant colony sizes and numbers in adult lung epithelia supported the inferences that the metakaryotic organogenic stem cells are constitutively mutator/hypermutable and that their contributions to cancer initiation are limited to the fetal/juvenile period. We have amended the two-stage model of Armitage and Doll and incorporated these several inferences in a computer program CancerFit v.5.0. We compared the expectations of the amended model to adult (15–104 years) age-specific colon cancer rates for European-American males born 1890–99 and observed remarkable concordance. When estimates of normal colonic fetal/juvenile APC and OAT gene mutation rates (∼2–5 × 10[superscript −5] per stem cell doubling) and preneoplastic colonic gene loss rates (∼8 × 10[superscript −3]) were applied, the model was in accordance only for the values of n = 2 and m = 4 or 5.en_US
dc.description.sponsorshipUnited Therapeutics Corporationen_US
dc.language.isoen_US
dc.publisherFrontiers Research Foundationen_US
dc.relation.isversionofhttp://dx.doi.org/10.3389/fonc.2013.00267en_US
dc.rightsCreative Commons Attributionen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.sourceFrontiersen_US
dc.titleMutator/Hypermutable Fetal/Juvenile Metakaryotic Stem Cells and Human Colorectal Carcinogenesisen_US
dc.typeArticleen_US
dc.identifier.citationKini, Lohith G., Pablo Herrero-Jimenez, Tushar Kamath, Jayodita Sanghvi, Efren Gutierrez, David Hensle, John Kogel, et al. “Mutator/Hypermutable Fetal/Juvenile Metakaryotic Stem Cells and Human Colorectal Carcinogenesis.” Front. Oncol. 3 (2013).en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorKini, Lohith G.en_US
dc.contributor.mitauthorKamath, Tushar V.en_US
dc.contributor.mitauthorKoledova, Vera V.en_US
dc.contributor.mitauthorGostjeva, Elena V.en_US
dc.contributor.mitauthorThilly, William G.en_US
dc.relation.journalFrontiers in Oncologyen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsKini, Lohith G.; Herrero-Jimenez, Pablo; Kamath, Tushar; Sanghvi, Jayodita; Gutierrez, Efren; Hensle, David; Kogel, John; Kusko, Rebecca; Rexer, Karl; Kurzweil, Ray; Refinetti, Paulo; Morgenthaler, Stephan; Koledova, Vera V.; Gostjeva, Elena V.; Thilly, William G.en_US
dc.identifier.orcidhttps://orcid.org/0000-0003-2581-6092
mit.licensePUBLISHER_CCen_US
mit.metadata.statusComplete


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