{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T02:40:26Z","timestamp":1790563226940,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2016,6,16]],"date-time":"2016-06-16T00:00:00Z","timestamp":1466035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NASA","award":["#NNX12AK19G"],"award-info":[{"award-number":["#NNX12AK19G"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA133470"],"award-info":[{"award-number":["R01CA133470"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R21NS087406-01"],"award-info":[{"award-number":["1R21NS087406-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R03CA180548"],"award-info":[{"award-number":["R03CA180548"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1P42ES023720-01"],"award-info":[{"award-number":["1P42ES023720-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1P30ES013508-02"],"award-info":[{"award-number":["1P30ES013508-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Spaceflight occasionally requires multiple extravehicular activities (EVA) that potentially subject astronauts to repeated changes in ambient oxygen superimposed on those of space radiation exposure. We thus developed a novel in vitro model system to test lung cell damage following repeated exposure to radiation and hyperoxia. Non-tumorigenic murine alveolar type II epithelial cells (C10) were exposed to &gt;95% O2 for 8 h only (O2), 0.25 Gy ionizing \u03b3-radiation (IR) only, or a double-hit combination of both challenges (O2 + IR) followed by 16 h of normoxia (ambient air containing 21% O2 and 5% CO2) (1 cycle = 24 h, 2 cycles = 48 h). Cell survival, DNA damage, apoptosis, and indicators of oxidative stress were evaluated after 1 and 2 cycles of exposure. We observed a significant (p &lt; 0.05) decrease in cell survival across all challenge conditions along with an increase in DNA damage, determined by Comet analysis and H2AX phosphorylation, and apoptosis, determined by Annexin-V staining, relative to cells unexposed to hyperoxia or radiation. DNA damage (GADD45\u03b1 and cleaved-PARP), apoptotic (cleaved caspase-3 and BAX), and antioxidant (HO-1 and Nqo1) proteins were increased following radiation and hyperoxia exposure after 1 and 2 cycles of exposure. Importantly, exposure to combination challenge O2 + IR exacerbated cell death and DNA damage compared to individual exposures O2 or IR alone. Additionally levels of cell cycle proteins phospho-p53 and p21 were significantly increased, while levels of CDK1 and Cyclin B1 were decreased at both time points for all exposure groups. Similarly, proteins involved in cell cycle arrest was more profoundly changed with the combination challenges as compared to each stressor alone. These results correlate with a significant 4- to 6-fold increase in the ratio of cells in G2\/G1 after 2 cycles of exposure to hyperoxic conditions. We have characterized a novel in vitro model of double-hit, low-level radiation and hyperoxia exposure that leads to oxidative lung cell injury, DNA damage, apoptosis, and cell cycle arrest.<\/jats:p>","DOI":"10.3390\/ijms17060953","type":"journal-article","created":{"date-parts":[[2016,6,16]],"date-time":"2016-06-16T10:23:20Z","timestamp":1466072600000},"page":"953","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Novel Double-Hit Model of Radiation and Hyperoxia-Induced Oxidative Cell Damage Relevant to Space Travel"],"prefix":"10.3390","volume":"17","author":[{"given":"Ralph","family":"Pietrofesa","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine and the Department of Medicine, University of Pennsylvania Perelman School of Medicine, 3450 Hamilton Walk, Edward J. Stemmler Hall 2nd Floor, Office Suite 227, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Velalopoulou","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine and the Department of Medicine, University of Pennsylvania Perelman School of Medicine, 3450 Hamilton Walk, Edward J. Stemmler Hall 2nd Floor, Office Suite 227, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey","family":"Lehman","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evguenia","family":"Arguiri","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine and the Department of Medicine, University of Pennsylvania Perelman School of Medicine, 3450 Hamilton Walk, Edward J. Stemmler Hall 2nd Floor, Office Suite 227, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pantelis","family":"Solomides","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine and the Department of Medicine, University of Pennsylvania Perelman School of Medicine, 3450 Hamilton Walk, Edward J. Stemmler Hall 2nd Floor, Office Suite 227, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Koch","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Om","family":"Mishra","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine and the Department of Medicine, University of Pennsylvania Perelman School of Medicine, 3450 Hamilton Walk, Edward J. Stemmler Hall 2nd Floor, Office Suite 227, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantinos","family":"Koumenis","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Goodwin","sequence":"additional","affiliation":[{"name":"The National Aeronautics and Space Administration (NASA) Johnson Space Center, Houston, TX 77058, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5945-6569","authenticated-orcid":false,"given":"Melpo","family":"Christofidou-Solomidou","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine and the Department of Medicine, University of Pennsylvania Perelman School of Medicine, 3450 Hamilton Walk, Edward J. Stemmler Hall 2nd Floor, Office Suite 227, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2016,6,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1097\/01.HP.0000339020.92837.61","article-title":"Modeling the acute health effects of astronauts from exposure to large solar particle events","volume":"96","author":"Hu","year":"2009","journal-title":"Health Phys."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1093\/rpd\/nci141","article-title":"Implications of the space radiation environment for human exploration in deep space","volume":"115","author":"Townsend","year":"2005","journal-title":"Radiat. Prot. Dosim."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Holloway, R.J., Leong, G.F., Ainsworth, E.J., Albright, M.L., and Baum, S.J. (1967). Recovery from radiation injury in the hamster as evaluated by the split-dose technique. Usnrdl-tr-1111. Res. Dev. Tech. Rep., 1\u201326.","DOI":"10.2307\/3572240"},{"key":"ref_4","unstructured":"Leong, G.F., Page, N.P., Ainsworth, E.J., and Hanks, G.E. (1966). Injury accumulation in sheep during protracted gamma radiation. Usnrdl-tr-998. Res. Dev. Tech. Rep., 1\u201313."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.ccm.2005.05.008","article-title":"The lung in space","volume":"26","author":"Prisk","year":"2005","journal-title":"Clin. Chest Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1007\/s11306-013-0556-3","article-title":"Personalized medicine in human space flight: Using omics based analyses to develop individualized countermeasures that enhance astronaut safety and performance","volume":"9","author":"Schmidt","year":"2013","journal-title":"Metabolomics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1152\/ajplegacy.1972.223.2.431","article-title":"Hematologic responses to hypobaric hyperoxia","volume":"223","author":"Larkin","year":"1972","journal-title":"Am. J. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"41","DOI":"10.3357\/ASEM.2610.2010","article-title":"Endothelial function and stress response after simulated dives to 18 msw breathing air or oxygen","volume":"81","author":"Madden","year":"2010","journal-title":"Aviat. Space Environ. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00114-006-0204-0","article-title":"Getting ready for the manned mission to mars: The astronauts\u2019 risk from space radiation","volume":"94","author":"Hellweg","year":"2007","journal-title":"Naturwissenschaften"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1667\/RR1330.1","article-title":"Physical and biological organ dosimetry analysis for international space station astronauts","volume":"170","author":"Cucinotta","year":"2008","journal-title":"Radiat. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"L416","DOI":"10.1152\/ajplung.00260.2014","article-title":"Space radiation-associated lung injury in a murine model","volume":"308","author":"Pietrofesa","year":"2015","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_12","first-page":"1000158","article-title":"Oxidative lung damage resulting from repeated exposure to radiation and hyperoxia associated with space exploration","volume":"3","author":"Pietrofesa","year":"2013","journal-title":"J. Pulm. Respir. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1000215","DOI":"10.4172\/2161-105X.1000215","article-title":"Flaxseed mitigates acute oxidative lung damage in a mouse model of repeated radiation and hyperoxia exposure associated with space exploration","volume":"4","author":"Pietrofesa","year":"2014","journal-title":"J. Pulm. Respir. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1378\/chest.111.4.1061","article-title":"Pulmonary radiation injury","volume":"111","author":"Movsas","year":"1997","journal-title":"Chest"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1080\/15287398409530500","article-title":"Alterations in lung structure caused by inhalation of oxidants","volume":"13","author":"Crapo","year":"1984","journal-title":"J. Toxicol. Environ. Health"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"L1050","DOI":"10.1152\/ajplung.00067.2006","article-title":"Dissociation between alveolar transmigration of neutrophils and lung injury in hyperoxia","volume":"291","author":"Perkowski","year":"2006","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.radonc.2006.09.013","article-title":"Systemic polyethylene glycol-modified (pegylated) superoxide dismutase and catalase mixture attenuates radiation pulmonary fibrosis in the c57\/bl6 mouse","volume":"81","author":"Machtay","year":"2006","journal-title":"Radiother. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"356","DOI":"10.3390\/toxins3040356","article-title":"Cycle inhibiting factors (cifs): Cyclomodulins that usurp the ubiquitin-dependent degradation pathway of host cells","volume":"3","author":"Taieb","year":"2011","journal-title":"Toxins (Basel)"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"35511","DOI":"10.1074\/jbc.M113.512640","article-title":"The cyclin-dependent kinase inhibitor p16ink4a physically interacts with transcription factor sp1 and cyclin-dependent kinase 4 to transactivate microrna-141 and microrna-146b-5p spontaneously and in response to ultraviolet light-induced DNA damage","volume":"288","author":"Mohideen","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/S0300-483X(02)00460-2","article-title":"Cell cycle checkpoint signaling: Cell cycle arrest versus apoptosis","volume":"181\u2013182","author":"Pietenpol","year":"2002","journal-title":"Toxicology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1080\/09674845.2004.11732652","article-title":"Links between apoptosis, proliferation and the cell cycle","volume":"61","author":"Alenzi","year":"2004","journal-title":"Br. J. Biomed. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"823","DOI":"10.4161\/cbt.8.9.8143","article-title":"Sensitization to \u03b3-irradiation-induced cell cycle arrest and apoptosis by the histone deacetylase inhibitor trichostatin a in non-small cell lung cancer (NSCLC) cells","volume":"8","author":"Zhang","year":"2009","journal-title":"Cancer Biol. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1158\/1535-7163.MCT-06-0596","article-title":"Radiation-induced cell signaling: Inside-out and outside-in","volume":"6","author":"Valerie","year":"2007","journal-title":"Mol. Cancer Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1002\/lsm.1900080108","article-title":"Laser balloon angioplasty: Effect of tissue temperature on weld strength of human postmortem intima-media separations","volume":"8","author":"Jenkins","year":"1988","journal-title":"Lasers Surg. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/0003-2697(88)90359-4","article-title":"Real time computer tracking of free-swimming and tethered rotating cells","volume":"175","author":"Poole","year":"1988","journal-title":"Anal. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4488","DOI":"10.1128\/MCB.25.11.4488-4500.2005","article-title":"GADD45\u03b1 expression induces bim dissociation from the cytoskeleton and translocation to mitochondria","volume":"25","author":"Tong","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"32672","DOI":"10.1016\/S0021-9258(18)31687-9","article-title":"Characterization of human GADD45, a p53-regulated protein","volume":"269","author":"Carrier","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8800","DOI":"10.1073\/pnas.85.23.8800","article-title":"DNA damage-inducible transcripts in mammalian cells","volume":"85","author":"Fornace","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1038\/sj.cdd.4400851","article-title":"Characterization of the necrotic cleavage of poly(ADP-ribose) polymerase (PARP-1): Implication of lysosomal proteases","volume":"8","author":"Gobeil","year":"2001","journal-title":"Cell Death Differ."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1038\/sj.jcbfm.9600335","article-title":"Pyruvate improves recovery after PARP-1-associated energy failure induced by oxidative stress in neonatal rat cerebrocortical slices","volume":"27","author":"Zeng","year":"2007","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1038\/sj.onc.1204252","article-title":"Regulation of the G2\/M transition by p53","volume":"20","author":"Taylor","year":"2001","journal-title":"Oncogene"},{"key":"ref_32","first-page":"L589","article-title":"Mitogen-activated protein kinase pathway mediates hyperoxia-induced apoptosis in cultured macrophage cells","volume":"277","author":"Petrache","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/1465-9921-12-68","article-title":"Effect of recombinant IL-10 on cultured fetal rat alveolar type II cells exposed to 65%-hyperoxia","volume":"12","author":"Lee","year":"2011","journal-title":"Respir. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1165\/ajrcmb.19.4.3173","article-title":"Oxygen toxicity in mouse lung: Pathways to cell death","volume":"19","author":"Barazzone","year":"1998","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1006\/mgme.2000.3046","article-title":"Signal transduction pathways in hyperoxia-induced lung cell death","volume":"71","author":"Mantell","year":"2000","journal-title":"Mol. Genet. Metabol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1186\/s13014-014-0266-7","article-title":"Endothelial perturbations and therapeutic strategies in normal tissue radiation damage","volume":"9","author":"Korpela","year":"2014","journal-title":"Radiat. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1093\/nar\/gks1038","article-title":"Novel smad proteins localize to ir-induced double-strand breaks: Interplay between tgfbeta and atm pathways","volume":"41","author":"Wang","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/j.dnarep.2013.10.004","article-title":"Investigation of switch from atm to atr signaling at the sites of DNA damage induced by low and high let radiation","volume":"12","author":"Saha","year":"2013","journal-title":"DNA Repair. (Amst.)"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.mrgentox.2013.04.011","article-title":"Smad7 foci are present in micronuclei induced by heavy particle radiation","volume":"756","author":"Wang","year":"2013","journal-title":"Mutat. Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Velalopoulou, A., Tyagi, S., Pietrofesa, R.A., Arguiri, E., and Christofidou-Solomidou, M. (2015). The flaxseed-derived lignan phenolic secoisolariciresinol diglucoside (SDG) protects non-malignant lung cells from radiation damage. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17010007"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"869","DOI":"10.3109\/01902148809064180","article-title":"Patterns of progression and markers of lung injury in rodents and subhuman primates exposed to hyperoxia","volume":"14","author":"Fracica","year":"1988","journal-title":"Exp. Lung Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"356","DOI":"10.4161\/cbt.8.4.7432","article-title":"Development of a three-dimensional model of lung cancer using cultured transformed lung cells","volume":"8","author":"Vertrees","year":"2009","journal-title":"Cancer Biol. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"404","DOI":"10.4161\/cbt.7.3.5368","article-title":"Cellular differentiation in three-dimensional lung cell cultures","volume":"7","author":"Vertrees","year":"2008","journal-title":"Cancer Biol. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0300-483X(97)00108-X","article-title":"Mouse lung epithelial cell lines\u2014Tools for the study of differentiation and the neoplastic phenotype","volume":"123","author":"Malkinson","year":"1997","journal-title":"Toxicology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1080\/01902140119724","article-title":"Inactivation of both Rb and p53 pathways in mouse lung epithelial cell lines","volume":"27","author":"Herzog","year":"2001","journal-title":"Exp. Lung Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"434","DOI":"10.2307\/3576294","article-title":"A thin-film culturing technique allowing rapid gas-liquid equilibration (6 s) with no toxicity to mammalian cells","volume":"97","author":"Koch","year":"1984","journal-title":"Radiat. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"L1021","DOI":"10.1152\/ajplung.2001.281.4.L1021","article-title":"Limitations to oxygen diffusion and equilibration in in vitro cell exposure systems in hyperoxia and hypoxia","volume":"281","author":"Allen","year":"2001","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"L255","DOI":"10.1152\/ajplung.00138.2007","article-title":"Dietary flaxseed enhances antioxidant defenses and is protective in a mouse model of lung ischemia-reperfusion injury","volume":"294","author":"Lee","year":"2008","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1667\/RR2980.1","article-title":"Radioprotective role in lung of the flaxseed lignan complex enriched in the phenolic secoisolariciresinol diglucoside (SDG)","volume":"178","author":"Tyagi","year":"2012","journal-title":"Radiat. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1093\/carcin\/bgv174","article-title":"Flaxseed lignans enriched in secoisolariciresinol diglucoside prevent acute asbestos-induced peritoneal inflammation in mice","volume":"37","author":"Pietrofesa","year":"2016","journal-title":"Carcinogenesis"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/6\/953\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:25:34Z","timestamp":1760210734000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/6\/953"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,16]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2016,6]]}},"alternative-id":["ijms17060953"],"URL":"https:\/\/doi.org\/10.3390\/ijms17060953","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6,16]]}}}