Abstract:Development of biomarkers capable of estimating absorbed dose is critical for effective triage of affected individuals after radiological events. Levels of cell-free circulating miRNAs in plasma were compared for dose-response analysis in non-human primates (NHP) exposed to lethal (6.5 Gy) and sub-lethal (1 and 3 Gy) doses over a 7 day period. The doses and test time points were selected to mimic triage needs in the event of a mass casualty radiological event. Changes in miRNA abundance in irradiated animals w… Show more
“…Plasma miR-150-5p levels were found to correlate well with lymphocyte and neutrophil depletion kinetics [122]. Also, miR-574-5p exhibited a dose-dependent increase 24 h post irradiation in NHPs with lethal versus sub-lethal exposure and returned to the baseline level by d 3.…”
Section: Biomarkers For Radiation Injury and Efficacy Of Radiationmentioning
Introduction
Despite significant scientific advances over the past six decades toward the development of safe and effective radiation countermeasures for humans using animal models, only two pharmaceutical agents have been approved by United States Food and Drug Administration (US FDA) for hematopoietic acute radiation syndrome (H-ARS). Additional research efforts are needed to further develop large animal models for improving the prediction of clinical safety and effectiveness of radiation countermeasures for ARS and delayed effects of acute radiation exposure (DEARE) in humans.
Area covered
The authors review the suitability of animal models for the development of radiation countermeasures for ARS following the FDA Animal Rule with a special focus on nonhuman primate (NHP) models of ARS. There are seven centers in the United States currently conducting studies with irradiated NHPs, with the majority of studies being conducted with rhesus monkeys.
Expert opinion
The NHP model is considered the gold standard animal model for drug development and approval by the FDA. The lack of suitable substitutes to NHP models for predicting response in humans serves as a bottleneck for the development of radiation countermeasures. Additional large animal models need to be characterized to support the development and FDA-approval of new radiation countermeasures.
“…Plasma miR-150-5p levels were found to correlate well with lymphocyte and neutrophil depletion kinetics [122]. Also, miR-574-5p exhibited a dose-dependent increase 24 h post irradiation in NHPs with lethal versus sub-lethal exposure and returned to the baseline level by d 3.…”
Section: Biomarkers For Radiation Injury and Efficacy Of Radiationmentioning
Introduction
Despite significant scientific advances over the past six decades toward the development of safe and effective radiation countermeasures for humans using animal models, only two pharmaceutical agents have been approved by United States Food and Drug Administration (US FDA) for hematopoietic acute radiation syndrome (H-ARS). Additional research efforts are needed to further develop large animal models for improving the prediction of clinical safety and effectiveness of radiation countermeasures for ARS and delayed effects of acute radiation exposure (DEARE) in humans.
Area covered
The authors review the suitability of animal models for the development of radiation countermeasures for ARS following the FDA Animal Rule with a special focus on nonhuman primate (NHP) models of ARS. There are seven centers in the United States currently conducting studies with irradiated NHPs, with the majority of studies being conducted with rhesus monkeys.
Expert opinion
The NHP model is considered the gold standard animal model for drug development and approval by the FDA. The lack of suitable substitutes to NHP models for predicting response in humans serves as a bottleneck for the development of radiation countermeasures. Additional large animal models need to be characterized to support the development and FDA-approval of new radiation countermeasures.
“…MiR-150-5p was identified as a circulating miRNA that correlated with delivered dose within a dose range of 1-12 Gy 24-48 h after irradiation. Due to its abundance in lymphocytes, miR-150-5p was proposed as a sensitive marker for lymphocyte depletion and BM damage and a useful bioindicator for radiation biodosimetry (Jacob et al 2013;Menon et al 2016). It was also reported that expression of miR-150-5p in exosomes secreted by non-small cell lung cancer cells and stromal cells decreased with radiation but increased intracellularly both in cancer cells and stromal cells, suggesting that exosomal export of these miRNAs may be downregulated in these cells in response to radiation (Dinh et al 2016;Menon et al 2016).…”
“…At higher radiation doses in the mouse (~10 Gy and above), damage resulting from radiation exposure can be observed in the GI system in addition to bone marrow, and weight loss; and diarrhea are typically observed, which can lead to dehydration and mortality 6 . There is an increasing traction about determining the role of serum miRNAs in responding to radiation, particularly in the context of biodosimetry 7,8 . A number of reviews highlighted the potential utility of miRNAs as predictors of carcinoma prognosis 9,10 and of drug efficacy 11,12 .…”
mentioning
confidence: 99%
“…Cross-species validated radiation marker for time-and dose-dependent reduction in expression in plasma8 . We found subsequent reduction in expressions in the Mid (−1.31) and Late phases (−1.53).…”
Lethal total body irradiation (TBI) triggers multifactorial health issues in a potentially short time frame. Hence, early signatures of TBI would be of great clinical value. Our study aimed to interrogate microRnA (miRNA) and metabolites, two biomolecules available in blood serum, in order to comprehend the immediate impacts of TBI. Mice were exposed to a lethal dose (9.75 Gy) of Cobalt-60 gamma radiation and euthanized at four time points, namely, days 1, 3, 7 and 9 post-TBI. Serum miRNA libraries were sequenced using the Illumina small RNA sequencing protocol, and metabolites were screened using a mass spectrometer. The degree of early impacts of irradiation was underscored by the large number of miRNAs and metabolites that became significantly expressed during the Early phase (day 0 and 1 post-TBI). Radiation-induced inflammatory markers for bone marrow aplasia and pro-sepsis markers showed early elevation with longitudinal increment. Functional analysis integrating miRNA-proteinmetabolites revealed inflammation as the overarching host response to lethal TBI. Early activation of the network linked to the synthesis of reactive oxygen species was associated with the escalated regulation of the fatty acid metabolism network. In conclusion, we assembled a list of time-informed critical markers and mechanisms of significant translational potential in the context of a radiation exposure event.
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