Whole thorax irradiation of non-human primates induces persistent nuclear damage and gene expression changes in peripheral blood cells

Ghandhi, Shanaz A.; Turner, Helen; Shuryak, Igor; Dugan, Greg; Bourland, J. Daniel; Olson, John D.; Tooze, Janet A.; Morton, Shad R.; Batinić‐Haberle, Ines; Cline, J. Mark; Amundson, Sally A.

doi:10.1371/journal.pone.0191402

Cited by 35 publications

(38 citation statements)

References 63 publications

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“…miR-130b, miR-29c, miR-720, miR-151a-5p, miR-195, miR-212). This observation is in line with a recent publication where another group showed a persistent altered state of the immune system (based on gene expression measurements) up to 30 days after whole thorax irradiation in non-human primates 25 . Noteworthy, immunological alterations have been implicated as a mechanism for persistent fatigue after treatment 18 , 19 , (supplement Table 1 ).…”

Section: Discussionsupporting

confidence: 92%

Persistent mRNA and miRNA expression changes in irradiated baboons

Port¹,

Hérodin²,

Valente³

et al. 2018

Sci Rep

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We examined the transcriptome/post-transcriptome for persistent gene expression changes after radiation exposure in a baboon model. Eighteen baboons were irradiated with a whole body equivalent dose of 2.5 or 5 Gy. Blood samples were taken before, 7, 28 and 75–106 days after radiation exposure. Stage I was a whole genome screening for mRNA combined with a qRT-PCR platform for detection of 667 miRNAs. Candidate mRNAs and miRNAs differentially up- or down-regulated in stage I were chosen for validation in stage II using the remaining samples. Only 12 of 32 candidate genes provided analyzable results with two mRNAs showing significant 3–5-fold differences in gene expression over the reference (p < 0.0001). From 667 candidate miRNAs, 290 miRNA were eligible for analysis with 21 miRNAs independently validated using qRT-PCR. These miRNAs showed persistent expression changes on each day and over days 7–106 days after exposure (n = 7). In particular miR-212 involved in radiosensitivity and immune modulation appeared persistently and 48–77-fold up-regulated over the entire time period. We are finally trying to put our results into a context of clinical implications and provide possible hints on underlying molecular mechanisms to be examined in future studies.

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Section: Discussionsupporting

confidence: 92%

Persistent mRNA and miRNA expression changes in irradiated baboons

Port¹,

Hérodin²,

Valente³

et al. 2018

Sci Rep

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“…Previous work with this model suggests that both C3H mice and C57Bl/6 mice have the tendency to develop pneumonitis while C57Bl/6 mice progress towards pulmonary fibrosis, which was consistent with CT imaging and histology from this study. Characteristic radiation hematologic toxicity exemplified in blood count nadirs and the later compensatory increases in lymphocyte and neutrophil counts seen in our irradiated animals are consistent with the literature on animal models and in humans, as are the other signs of radiation injury that were noted including inadequate weight gain and increased mortality [45]. Interestingly, the overshoot in circulating neutrophils and lymphocytes late after exposure is greater in C57Bl/6 mice than C3H mice Table 1.…”

Section: Plos Onesupporting

confidence: 88%

Identification of miRNA signatures associated with radiation-induced late lung injury in mice

et al. 2020

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Acute radiation exposure of the thorax can lead to late serious, and even life-threatening, pulmonary and cardiac damage. Sporadic in nature, late complications tend to be difficult to predict, which prompted this investigation into identifying non-invasive, tissue-specific biomarkers for the early detection of late radiation injury. Levels of circulating microRNA (miRNA) were measured in C3H and C57Bl/6 mice after whole thorax irradiation at doses yielding approximately 70% mortality in 120 or 180 days, respectively (LD 70/120 or 180). Within the first two weeks after exposure, weight gain slowed compared to sham treated mice along with a temporary drop in white blood cell counts. 52% of C3H (33 of 64) and 72% of C57Bl/6 (46 of 64) irradiated mice died due to late radiation injury. Lung and heart damage, as assessed by computed tomography (CT) and histology at 150 (C3H mice) and 180 (C57Bl/6 mice) days, correlated well with the appearance of a local, miRNA signature in the lung and heart tissue of irradiated animals, consistent with inherent differences in the C3H and C57Bl/6 strains in their propensity for developing radiation-induced pneumonitis or fibrosis, respectively. Radiation-induced changes in the circulating miRNA profile were most prominent within the first 30 days after exposure and included miRNA known to regulate inflammation and fibrosis. Importantly, early changes in plasma miRNA expression predicted survival with reasonable accuracy (88-92%). The miRNA signature that predicted survival in C3H mice, including miR-34a-5p,-100-5p, and-150-5p, were associated with pro-inflammatory NF-κB-mediated signaling pathways, whereas the signature identified in C57Bl/6 mice (miR-34b-3p,-96-5p, and-802-5p) was associated with TGF-β/SMAD signaling. This study supports the hypothesis that plasma miRNA profiles could be used to identify individuals at high risk of organ-specific late radiation damage, with applications for radiation oncology clinical practice or in the context of a radiological incident.

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“…We also investigated total body radiation signatures on predicting exposures with different sources of partial body irradiation expression data: GSE66372 48 and GSE84898 49 . These murine and baboon datasets lacked several genes present in the signatures we derived.…”

Section: Resultsmentioning

confidence: 99%

Predicting ionizing radiation exposure using biochemically-inspired genomic machine learning

Zhao

Mucaki

2018

F1000Res

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Gene signatures derived from transcriptomic data using machine Background: learning methods have shown promise for biodosimetry testing. These signatures may not be sufficiently robust for large scale testing, as their performance has not been adequately validated on external, independent datasets. The present study develops human and murine signatures with biochemically-inspired machine learning that are strictly validated using k-fold and traditional approaches.Gene Expression Omnibus (GEO) datasets of exposed human and Methods: murine lymphocytes were preprocessed via nearest neighbor imputation and expression of genes implicated in the literature to be responsive to radiation exposure (n=998) were then ranked by Minimum Redundancy Maximum Relevance (mRMR). Optimal signatures were derived by backward, complete, and forward sequential feature selection using Support Vector Machines (SVM), and validated using k-fold or traditional validation on independent datasets.The best human signatures we derived exhibit k-fold , and ) when validated over 85 samples. Some human ENO1 PPM1D signatures are specific enough to differentiate between chemotherapy and radiotherapy. Certain multi-class murine signatures have sufficient granularity in dose estimation to inform eligibility for cytokine therapy (assuming these signatures could be translated to humans). We compiled a list of the most frequently appearing genes in the top 20 human and mouse signatures. More frequently appearing genes among an ensemble of signatures may indicate greater impact of these genes on the performance of individual signatures. Several genes in the signatures we derived are present in previously proposed signatures.Gene signatures for ionizing radiation exposure derived by Conclusions: 2018, 7:233 Last updated: 20 MAR 2019 Gene signatures for ionizing radiation exposure derived by Conclusions: machine learning have low error rates in externally validated, independent datasets, and exhibit high specificity and granularity for dose estimation.

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Whole thorax irradiation of non-human primates induces persistent nuclear damage and gene expression changes in peripheral blood cells

Cited by 35 publications

References 63 publications

Persistent mRNA and miRNA expression changes in irradiated baboons

Persistent mRNA and miRNA expression changes in irradiated baboons

Identification of miRNA signatures associated with radiation-induced late lung injury in mice

Predicting ionizing radiation exposure using biochemically-inspired genomic machine learning

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