New Approaches for Quantitative Reconstruction of Radiation Dose in Human Blood Cells

Ghandhi, Shanaz A.; Shuryak, Igor; Morton, Shad R.; Amundson, Sally A.; Brenner, David J.

doi:10.1101/640052

Cited by 6 publications

(9 citation statements)

References 36 publications

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“…that are better suited to estimate low doses only (< 0.1 Gy) 11 . At the gene transcription level, all the biomarkers tested here have been shown to be radiation responsive markers in multiple tissue types 11 , 13 , 45 , 46 while several of them (BAX, FDXR, DDB2 and p53) have been used in the development of a gene expression-based signature for the reconstruction of dose in human peripheral blood 45 , 47 – 50 . We consider that future studies should further investigate the gene to protein relationship of these blood biomarkers for radiation biodosimetry.…”

Section: Discussionmentioning

confidence: 99%

Development of the FAST-DOSE assay system for high-throughput biodosimetry and radiation triage

Wang

Lee

Shuryak

et al. 2020

Sci Rep

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Following a large-scale radiological incident, there is a need for FDA-approved biodosimetry devices and biomarkers with the ability to rapidly determine past radiation exposure with sufficient accuracy for early population triage and medical management. Towards this goal, we have developed FAST-DOSE (Fluorescent Automated Screening Tool for Dosimetry), an immunofluorescent, biomarkerbased system designed to reconstruct absorbed radiation dose in peripheral blood samples collected from potentially exposed individuals. The objective of this study was to examine the performance of the FAST-DOSE assay system to quantify intracellular protein changes in blood leukocytes for early biodosimetry triage from humanized NOD-scid-gamma (Hu-NSG) mice and non-human primates (NHPs) exposed to ionizing radiation up to 8 days after radiation exposure. In the Hu-NSG mice studies, the FAST-DOSE biomarker panel was able to generate delivered dose estimates at days 1, 2 and 3 post exposure, whereas in the NHP studies, the biomarker panel was able to successfully classify samples by dose categories below or above 2 Gy up to 8 days after total body exposure. These results suggest that the FAST-DOSE bioassay has large potential as a useful diagnostic tool for rapid and reliable screening of potentially exposed individuals to aid early triage decisions within the first week post-exposure. In the event of a large-scale radiological incident or accident, hundreds of thousands of people may be exposed to ionizing radiation. There is an important need for the development of FDA-approved point-of-care radiation biodosimeters and in vitro diagnostic devices (IVDs) with the ability to rapidly determine past radiation exposure with sufficient accuracy for early population triage and medical management. Biodosimetry technologies may be designed for early in-the-field triage (usually qualitative) or for more clinical evaluation and medical management that includes dose level confirmation (usually quantitative or semi-quantitative) 1. We have recently developed a new high-throughput biodosimetry assay system called FAST-DOSE (Fluorescent Automated Screening Tool for Dosimetry) which is designed for rapid immune-detection and quantitation of radiation responsive protein biomarkers and reconstruction of dose in human peripheral blood leukocytes. This biomarker-based triage assay has large potential as a useful diagnostic tool for the mass-screening of potentially exposed individuals and offers a short "time-to-result" since cell culture is not required compared with the gold standard micronucleus and dicentric biodosimetry assays 2-4. The FAST-DOSE assay device is based on imaging flow cytometry (IFC) 5-7 and a panel of intracellular biomarkers identified by earlier proteomic study 8 to rapidly quantify the upregulation of biomarker expression in blood leukocytes using fluorescent imagery and algorithms for the estimation of absorbed dose. The advantage of IFC (ImageStream, Luminex, Austin, TX) technology is that it combines the speed and quantifica...

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Section: Discussionmentioning

confidence: 99%

Development of the FAST-DOSE assay system for high-throughput biodosimetry and radiation triage

Wang

Lee

Shuryak

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…38,43 Among them, CDKN1A , DDB2 , FDXR , GADD45A , PCNA , and TNFRSF10B are known radiation-response genes, which have a sustained radiation dose–response and a strong positive correlation with dose. 44 Therefore, these genes may be part of the main circulating biomarkers of IR damage. If this is confirmed, it will be able to help us identify and understand IR-related risks associated with radiological examinations and radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

Blood Gene Expression Profile Study Revealed the Activation of Apoptosis and p53 Signaling Pathway May Be the Potential Molecular Mechanisms of Ionizing Radiation Damage and Radiation-Induced Bystander Effects

Tang

Xie

et al. 2020

Dose-Response

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Radiotherapy is an effective treatment for local solid tumors, but the mechanism of damage to human body caused by radiation therapy needs further study. In this study, gene expression profiles of human peripheral blood samples exposed to different doses and rates of ionizing radiation (IR) were used for bioinformatics analysis to investigate the mechanism of IR damage and radiation-induced bystander effect (RIBE). Differentially expressed genes analysis, weighted gene correlation network analysis, functional enrichment analysis, hypergeometric test, gene set enrichment analysis, and gene set variation analysis were applied to analyze the data. Moreover, receiver operating characteristic curve analysis was performed to identify core genes of IR damage. Weighted gene correlation network analysis identified 3 modules associated with IR damage, 2 were positively correlated and 1 was negatively correlated. The analysis showed that the positively correlated modules were significantly involved in apoptosis and p53 signaling pathway, and ESR1, ATM, and MYC were potential transcription factors regulating these modules. Thus, the study suggested that apoptosis and p53 signaling pathway may be the potential molecular mechanisms of IR damage and RIBE, which could be driven by ESR1, ATM, and MYC.

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“…We used a novel approach to quantitatively reconstruct radiation dose, initially developed using human blood cells [Ghandhi et al, 2019], based on the gene expression data.…”

Section: Discussionmentioning

confidence: 99%

Effect of age and sex on gene expression-based radiation biodosimetry using mouse peripheral blood

Broustas

Shuryak

Duval

et al. 2022

Preprint

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Blood-based gene expression profiles that can reconstruct radiation exposure are being developed as a practical approach to radiation biodosimetry. However, age and sex could potentially limit the accuracy of the approach. In this study, we determined the impact of age on the peripheral blood cell gene expression profile of female mice exposed to radiation and identified differences and similarities with a previously obtained transcriptomic signature of male mice. Young (2 months) and old (24 months) female mice were irradiated with 4 Gy X-rays, total RNA was isolated from blood 24hr later and subjected to whole genome microarray analysis. Dose reconstruction analyses using a gene signature trained on gene expression data from irradiated young male mice showed accurate reconstruction of 0 or 4 Gy doses with root mean square error of +/- 0.75 Gy (R^2 = 0.90) in young female mice. Although dose reconstruction for irradiated old female mice was less accurate than young female mice, the deviation from the actual radiation dose was not statistically significant. Pathway analysis of differentially expressed genes revealed that after irradiation, apoptosis-related functions were overrepresented, whereas functions related to quantities of various immune cell subtypes were underrepresented, among differentially expressed genes from young female mice, but not older animals. Furthermore, young mice significantly upregulated genes involved in phagocytosis, a process that eliminates apoptotic cells and preserves tissue homeostasis. Both functions were also overrepresented in young, but not old, male mice following 4 Gy X-irradiation. Lastly, functions associated with neutrophil activation that is essential for killing invading pathogens and regulating the inflammatory response were predicted to be uniquely enriched in young but not old female mice. This work supports the concept that peripheral blood gene expression profiles can be identified in mice that accurately predict physical radiation dose exposure irrespective of age and sex. However, inclusion of age and sex as biological factors is essential for effectively predicting radiation injury and for developing radiation medical countermeasures.

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New Approaches for Quantitative Reconstruction of Radiation Dose in Human Blood Cells

Cited by 6 publications

References 36 publications

Development of the FAST-DOSE assay system for high-throughput biodosimetry and radiation triage

Development of the FAST-DOSE assay system for high-throughput biodosimetry and radiation triage

Blood Gene Expression Profile Study Revealed the Activation of Apoptosis and p53 Signaling Pathway May Be the Potential Molecular Mechanisms of Ionizing Radiation Damage and Radiation-Induced Bystander Effects

Effect of age and sex on gene expression-based radiation biodosimetry using mouse peripheral blood

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