Microarray analysis of miRNA expression profiles following whole body irradiation in a mouse model

<p><b>Context:</b> Accidental exposure to life-threatening radiation in a nuclear event is a major concern; there is an enormous need for identifying biomarkers for radiation biodosimetry to triage populations and treat critically exposed individuals.</p> <p><b>Objective:</b> To identify dose-differentiating miRNA signatures from whole blood samples of whole body irradiated mice.</p> <p><b>Methods:</b> Mice were whole body irradiated with X-rays (2 Gy–15 Gy); blood was collected at various time-points post-exposure; total RNA was isolated; miRNA microarrays were performed; miRNAs differentially expressed in irradiated vs. unirradiated controls were identified; feature extraction and classification models were applied to predict dose-differentiating miRNA signature.</p> <p><b>Results:</b> We observed a time and dose responsive alteration in the expression levels of miRNAs. Maximum number of miRNAs were altered at 24-h and 48-h time-points post-irradiation. A 23-miRNA signature was identified using feature selection algorithms and classifier models. An inverse correlation in the expression level changes of miR-17 members, and their targets were observed in whole body irradiated mice and non-human primates.</p> <p><b>Conclusion:</b> Whole blood-based miRNA expression signatures might be used for predicting radiation exposures in a mass casualty nuclear incident.</p

Determination of the VEGF content in plasma samples.

<p>The concentration of VEGF for each group. Results are expressed in pg/mL of VEGF, mean ± SD; comparison of the VEGF content in the LNC¹⁸⁸Re-SSS versus the sham group (*p<0.05; **p<0.01), ¹⁸⁸ReO₄^- group (^$$p<0.01), and blank LNC (^£p<0.05; ^££p<0.01).</p

Descriptive and statistical data from the survival study.

<p>The increase in the median survival time (IMST%) is calculated in comparison to the sham and the ¹⁸⁸Re-perrhenate groups. Comparisons of survival data using the log-rank test (Mantel-Cox test) versus sham group (*<i>p</i><0.05), blank LNC (^£<i>p</i><0.05), ¹⁸⁸Re0₄^- group (^$<i>p</i><0.05), LNC¹⁸⁸Re-SSS – 80 MBq (^§<i>p</i><0.05), LNC¹⁸⁸Re-SSS – 120 MBq (^#<i>p</i><0.05).</p

Kaplan-Meier survival curves of rats with induced HCC.

<p>On D10, rats were treated with 80 MBq (n = 12) and 120 MBq (n = 11) of LNC¹⁸⁸Re-SSS, sham rats (n = 12), blank LNC (n = 8) and 80 MBq of ¹⁸⁸Re-perrhenate solution (n = 4).</p

ALT Kinetics.

<p>The determination of the ALT content in plasma samples for LNC¹⁸⁸Re-SSS (80 MBq and 120 MBq groups), sham, ¹⁸⁸ReO₄^-, and blank LNC groups at D12, D18, D24, D25, D30, D45, D55, D65, D80, D90, D105, D130, and D152 after the end of tumor induction. Results are expressed in IU/mL of AST, mean ± SD. Comparisons of ALT content versus healthy rats (*<i>p</i><0.05; **<i>p</i><0.01).</p

AST kinetics.

<p>The determination of the AST content in plasma samples for LNC¹⁸⁸Re-SSS (80 MBq and 120 MBq groups), sham, ¹⁸⁸ReO₄^-, and blank LNC groups at D12, D18, D24, D25, D30, D45, D55, D65, D80, D90, D105, D130, and D152 after the end of tumor induction. Results are expressed in IU/mL of AST, mean ± SD. Comparisons of AST content versus healthy rats (*<i>p</i><0.05; **<i>p</i><0.01).</p

Physico-chemical characteristics of blank and ¹⁸⁸Re-SSS LNCs.

<p>Physico-chemical characteristics of blank and ¹⁸⁸Re-SSS LNCs.</p

Tumor volume assessment by MRI.

<p>A and B represent macroscopic views at 188Re-SSS rats, respectively; T2-weighted images of control rats (C) and LNC¹⁸⁸Re-SSS (D) at D100 after the end of tumor induction. Tumors appear as hypersignals (i arrows); healthy liver (ii arrow).</p