Candidate protein markers for radiation biodosimetry in the hematopoietically humanized mouse model

Lee, Younghyun; Pujol-Canadell, Mònica; Shuryak, Igor; Perrier, Jay R.; Taveras, M.; Patel, Purvi; Koller, Antonius; Smilenov, Lubomir B.; Brenner, David J.; Chen, Emily I.; Turner, Helen

doi:10.1038/s41598-018-31740-8

Cited by 40 publications

(46 citation statements)

References 48 publications

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“…Previously, we used Hu-NSG mice as an alternative model to validate human radiation biodosimetry standards and used the human hematopoietic system to investigate candidate protein marker expression in vivo after radiation exposure 8,34 . In the present study, we engrafted NSG mice with human fetal CD34+ stem cells to enrich the number of human cells in the mouse blood 41 .…”

Section: Discussionmentioning

confidence: 99%

“…The results show that although human cell engraftment levels were similar to our earlier study 8 , the NSG mice engrafted with human fetal cells showed a larger percentage of surviving human leukocytes; approximately 50% as opposed to 25% using the human cord blood stem cell model measured 3 days after 1 Gy X-ray exposure. This allowed for the use of CD45+ cells from the peripheral blood of the Hu-NSG mice mouse as opposed to the mouse spleen in previous study 8 . Table 1 and Supplementary Figure S1 show the performance of the highest-ranking protein panel to estimate delivered dose in human peripheral blood leukocytes.…”

Section: Discussionmentioning

confidence: 99%

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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%

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

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“…Equal numbers of female and male mice were used to study gender differences. Prior to irradiation, mice (8)(9)(10) week-old males, [10][11][12] week-old females) were randomized into groups for an average body weight of 29 ± 1 g. Mice were anesthetized using an intraperitoneal injection a mixture of ketamine and xylazine (80 mg/kg ketamine and 4 mg/kg xylazine) and an ophthalmic ointment was applied to prevent corneal drying (Puralube 1 vet ointment, Dechra Veterinary Products, Northwich, UK). Anesthetized mice were placed in a jig (S1 Fig) with the thorax positioned so that a 2.75 cm wide strip was exposed to X-rays administered vertically with a focus-to-surface distance of 32 cm with the rest of the body shielded with 3 mm lead that gives 99.5% attenuation.…”

Section: Whole Thorax Lung Irradiation (Wtli)mentioning

confidence: 99%

“…Biomarkers to predict both acute and late adverse outcomes of radiation exposure are critically needed to identify individuals at risk after a radiological incident, especially since early therapeutic intervention can dramatically improve survival rates in the context of ARS [1][2][3][4][5][6], and perhaps late disease [2]. Efforts into monitoring changes in blood or plasma have yielded encouraging data and identified potential biomarkers of radiation exposure, including proteins [7][8][9][10], mRNA [11][12][13][14][15][16], non-coding RNA [17], and microRNA (miRNA) [18][19][20][21][22][23][24]. Because circulating miRNA are protected from degradation in extracellular vesicles or protein complexes, and are stable at room temperature for hours to days, they are exceptionally well suited for triage in the field [25].…”

Section: Introductionmentioning

confidence: 99%

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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“…This methodology has been validated through several NATO and RENEB exercises (16,18,19). A single gene expression analysis [e.g., ferredoxin reductase, (FDXR), also reported to be a protein biomarker of radiation exposure, (20)] can offer accurate information on dose received in vivo in humans across a large range of doses from CT scan to total-body exposure (14). However, a radiation signature can provide further information about homogeneity of exposure (21), mixed exposure (22) or dose rate (11).…”

Section: Introductionmentioning

confidence: 99%

Generation of a Transcriptional Radiation Exposure Signature in Human Blood Using Long-Read Nanopore Sequencing

et al. 2019

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Candidate protein markers for radiation biodosimetry in the hematopoietically humanized mouse model

Cited by 40 publications

References 48 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

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

Generation of a Transcriptional Radiation Exposure Signature in Human Blood Using Long-Read Nanopore Sequencing

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