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DC Field | Value | Language |
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dc.citation.endPage | 801 | - |
dc.citation.number | 2 | - |
dc.citation.startPage | 786 | - |
dc.citation.title | JOURNAL OF CLINICAL INVESTIGATION | - |
dc.citation.volume | 129 | - |
dc.contributor.author | Bodo, Sahra | - |
dc.contributor.author | Campagne, Cecile | - |
dc.contributor.author | Thin, Tin Htwe | - |
dc.contributor.author | Higgins, Daniel S. | - |
dc.contributor.author | Vargas, H. Alberto | - |
dc.contributor.author | Hua, Guoqiang | - |
dc.contributor.author | Fuller, John D. | - |
dc.contributor.author | Ackerstaff, Ellen | - |
dc.contributor.author | Russel, James | - |
dc.contributor.author | Kingler, Stefan | - |
dc.contributor.author | Cho, Hyungjoon | - |
dc.contributor.author | Kaag, Matthew G. | - |
dc.contributor.author | Mazaheri, Yousef | - |
dc.contributor.author | Rimner, Andreas | - |
dc.contributor.author | Manova Todovora, Katia | - |
dc.contributor.author | Epel, Boris | - |
dc.contributor.author | Zatcky, Joan | - |
dc.contributor.author | Cleary, Critian R. | - |
dc.contributor.author | Rao, Shyam S. | - |
dc.contributor.author | Yamada, Yoshiya | - |
dc.contributor.author | Zelefsky, Michael J, | - |
dc.contributor.author | Halpern, Howard J. | - |
dc.contributor.author | Koutcher, Jason A. | - |
dc.contributor.author | Cordon Cardo, Carlos | - |
dc.contributor.author | Greco, Carlo | - |
dc.contributor.author | Haimovitz Freidman, Adriana | - |
dc.contributor.author | Sala, Evis | - |
dc.contributor.author | Powell, Simon N. | - |
dc.contributor.author | Kolesnick, Richard | - |
dc.contributor.author | Fuks, Zvi | - |
dc.date.accessioned | 2023-12-21T19:39:23Z | - |
dc.date.available | 2023-12-21T19:39:23Z | - |
dc.date.created | 2018-10-12 | - |
dc.date.issued | 2019-02 | - |
dc.description.abstract | Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell-autonomous gradual buildup of DNA double strand break (DSB) misrepair. Here we report single dose radiotherapy (SDRT), a disruptive technique that ablates >90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase (ASMase)-mediated microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcirculatory vasoconstriction post-SDRT conferred an ischemic stress response within parenchymal tumor cells, with reactive oxygen species triggering the evolutionarily conserved SUMO Stress Response, specifically depleting chromatin-associated free SUMO3. Whereas SUMO3, but not SUMO2, was indispensible for homology-directed repair (HDR) of DSBs, HDR loss-of-function post-SDRT yielded DSB unrepair, chromosomal aberrations and tumor clonogen demise. Vasoconstriction blockade with the endothelin-1 inhibitor BQ-123, or ROS scavenging post-SDRT using peroxiredoxin-6 overexpression or the SOD-mimetic tempol, prevented chromatin SUMO3 depletion, HDR loss-of-function and SDRT tumor ablation. We also provide evidence of mouse to human translation of this biology in a randomized clinical trial, showing 24Gy SDRT, but not 3x9Gy fractionation, coupled early tumor ischemia/reperfusion to human cancer ablation. The SDRT biology provides opportunities for mechanism-based selective tumor radiosensitization via accessing SDRT/ASMase signaling, as current studies indicate this pathway is tractable to pharmacologic intervention. | - |
dc.identifier.bibliographicCitation | JOURNAL OF CLINICAL INVESTIGATION, v.129, no.2, pp.786 - 801 | - |
dc.identifier.doi | 10.1172/JCI97631 | - |
dc.identifier.issn | 0021-9738 | - |
dc.identifier.scopusid | 2-s2.0-85060892415 | - |
dc.identifier.uri | https://scholarworks.unist.ac.kr/handle/201301/25019 | - |
dc.identifier.url | https://www.jci.org/articles/view/97631 | - |
dc.identifier.wosid | 000457479300035 | - |
dc.language | 영어 | - |
dc.publisher | AMER SOC CLINICAL INVESTIGATION INC | - |
dc.title | Single-dose radiotherapy disables tumor cell homologous recombination via ischemia/reperfusion injury | - |
dc.type | Article | - |
dc.description.isOpenAccess | FALSE | - |
dc.relation.journalWebOfScienceCategory | Medicine, Research & Experimental | - |
dc.relation.journalResearchArea | Research & Experimental Medicine | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.subject.keywordPlus | DOUBLE-STRAND BREAKS | - |
dc.subject.keywordPlus | BODY RADIATION-THERAPY | - |
dc.subject.keywordPlus | INTENSITY-MODULATED RADIOTHERAPY | - |
dc.subject.keywordPlus | PHASE I/II TRIAL | - |
dc.subject.keywordPlus | EXTRACRANIAL OLIGOMETASTASES | - |
dc.subject.keywordPlus | STROMAL SENSITIVITY | - |
dc.subject.keywordPlus | GAMMA-H2AX FOCI | - |
dc.subject.keywordPlus | OXYGEN-TENSION | - |
dc.subject.keywordPlus | CERAMIDE | - |
dc.subject.keywordPlus | STRESS | - |
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