Role of a high throughput biodosimetry test in treatment prioritization after a nuclear incident

Jacobs, Aviva R.; Guyon, Timothy; Headley, Violetta; Nair, M. Pratap; Ricketts, William; Gray, G.; Wong, J.Y.C.; Chao, Nelson J.; Terbrueggen, Robert

doi:10.1080/09553002.2018.1532615

Cited by 30 publications

(33 citation statements)

References 8 publications

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“…One of the challenges for biodosimetry studies is that there is no perfect model for biomarker response indicative of human response days after radiation exposure, thus limiting the development and validation of biodosimeters. To date, the development and validation of radiation responsive biomarkers in vivo has relied heavily on rodent, minipig and more recently NHP models 23,[36][37][38][39][40] . In the present work, we used two animal models, Hu-NSG mouse and NHP to support our FAST-DOSE biodosimetry device to estimate delivered dose using peripheral blood samples for early triage decisions within 8 days after radiation exposure.…”

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

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“…Dose estimates could be provided in a short time from gene expression using different protocols in several multicenter biodosimetry exercises (Badie et al 2013;Abend et al 2016;Manning et al 2017;Polozov et al 2019). The genes selected in the present study, (FDXR, CCNG1, MDM2, PHPT1, APOBEC3H, DDB2, SESN1, P21, PUMA and GADD45), have previously been identified as IR responsive and demonstrated a strong transcriptional response in ex vivo experiments in our laboratory and others (Amundson et al 2004;Kabacik, Mackay, et al 2011;Kabacik, Ortega-Molina, et al 2011;Paul et al 2011;Budworth et al 2012;Manning et al 2013;Ghandhi et al 2015;Cruz-Garcia et al 2018;Jacobs et al 2020;Cruz-Garcia, O'Brien, Sipos, Mayes, Love, et al 2020) and in vivo (Cruz-Garcia et al 2018;O'Brien et al 2018). Previous studies have shown that factors such as inflammation, sex or nutritional components can contribute in the modulation of the biomarker's response to radiation exposure (Budworth et al 2012;Soltani et al 2016;Cruz-Garcia et al 2018;Cruz-Garcia, O'Brien, Sipos, Mayes, Tich y, et al 2020).…”

Section: Discussionmentioning

confidence: 83%

Role of blood derived cell fractions, temperature and sample transport on gene expression-based biological dosimetry

Nasser

Cruz-García

O’Brien

et al. 2021

International Journal of Radiation Biology

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Purpose: For triage purposes following a nuclear accident or a terrorist event, gene expression biomarkers in blood have been demonstrated to be good bioindicators of ionizing radiation (IR) exposure and can be used to assess the dose received by exposed individuals. Many IR-sensitive genes are regulated by the DNA damage response pathway, and modulators of this pathway could potentially affect their expression level and therefore alter accurate dose estimations. In the present study, we addressed the potential influence of temperature, sample transport conditions and the blood cell fraction analyzed on the transcriptional response of the following radiationresponsive genes: FDXR, CCNG1, MDM2, PHPT1, APOBEC3H, DDB2, SESN1, P21, PUMA, and GADD45. Materials and Methods: Whole blood from healthy donors was exposed to a 2 Gy X-ray dose with a dose rate of 0.5 Gy/min (output 13 mA, 250 kV peak, 0.2 mA) and incubated for 24 h at either 37, 22, or 4 C. For mimicking the effect of transport conditions at different temperatures, samples incubated at 37 C for 24 h were kept at 37, 22 or 4 C for another 24 h. Comparisons of biomarker responses to IR between white blood cells (WBCs), peripheral blood mononuclear cells (PBMCs) and whole blood were carried out after a 2 Gy X-ray exposure and incubation at 37 C for 24 hours. Results: Hypothermic conditions (22 or 4 C) following irradiation drastically inhibited transcriptional responses to IR exposure. However, sample shipment at different temperatures did not affect gene expression level except for SESN1. The transcriptional response to IR of specific genes depended on the cell fraction used, apart from FDXR, CCNG1, and SESN1. Conclusion:In conclusion, temperature during the incubation period and cell fraction but not the storing conditions during transport can influence the transcriptional response of specific genes. However, FDXR and CCNG1 showed a consistent response under all the different conditions tested demonstrating their reliability as individual biological dosimetry biomarkers.

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“…The test times are comparable at 6-8 hrs per run and comparable in daily output using multiple instruments to process more than 1000 patient results per 24-hour day. The REDI-Dx test demonstrated a 98.5% sensitivity and 90% specificity at 2 Gy and a 92% sensitivity and 84% specificity for 6 Gy in verification testing (Jacobs et al 2020). Recent data from the Arad test has shown a mean dose correlation between total body fractionated dose irradiated human and non-human primate data (r ¼ 0.99) up to a dose of about 8 Gy.…”

Section: Discussionmentioning

confidence: 90%

Using biodosimetry to enhance the public health response to a nuclear incident

Wathen

Eder

Horwith

et al. 2020

International Journal of Radiation Biology

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Radiation Biodosimetry is a continually developing clinical diagnostic field, which focuses on biological markers that proportionally change in relationship to the amount of ionizing radiation absorbed. Examples of host marker response include changes in white cell count, specific proteins in circulation, RNAs in white blood cells, or chromosome fidelity in affected lymphocytes. Measurements of radiation biomarkers correlate with the approximate radiation dose absorbed and indirectly provide an assessment of the likelihood of developing acute radiation syndrome. The aim of this review is to summarize four biodosimetry programs that are in advanced development, later pipeline stages with funding from the Biomedical Advanced Research and Development Authority (BARDA), an agency under the Assistant Secretary for Preparedness and Response (ASPR) in the U.S. Department of Health and Human Services (HHS). With BARDA financial support, biodosimetry diagnostic assays in development will inform patient management, improve health and psychosocial outcomes, and save lives after a nuclear disaster. These tests include an SRI International developed rapid on-site screening test requiring only a finger stick of blood to triage those who have received little or no radiation from those who have received clinically significant levels of radiation and need further immediate patient management. In addition, multiple laboratory-based, high-throughput quantitative tests, currently under development by MRIGlobal, DxTerity, and ASELL, will more accurately define dose levels and possibly predict cellular and organ-damage and other longer-term effects of radiation. In the future, when clinical and analytical validation of these assays is complete, the data is reviewed by the FDA, and agency use status is obtained, rapid triage and laboratory-based biodosimetry test results will enable emergency medical teams to do the most good for the largest number of people after a nuclear blast.

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Role of a high throughput biodosimetry test in treatment prioritization after a nuclear incident

Cited by 30 publications

References 8 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

Role of blood derived cell fractions, temperature and sample transport on gene expression-based biological dosimetry

Using biodosimetry to enhance the public health response to a nuclear incident

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