Early molecular markers for retrospective biodosimetry and prediction of acute health effects

Abend, Michael; Blakely, William F.; Ostheim, Patrick; Schüle, Simone; Port, Matthias

doi:10.1088/1361-6498/ac2434

Cited by 26 publications

(19 citation statements)

References 172 publications

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“…Of note, FDXR was used by all teams, and 78% of correctly reported dose estimates [considering the uncertainty dose interval for triage dosimetry) were based on FDXR measured either solely or in combination with other genes (Table 3). FDXR has been already recognized as a promising gene for dose estimation (for review, see the literature (2,17,24,30,31)]. However, using one gene only for dose estimation (including FDXR) seemed to reduce robustness compared with the combination of certain gene sets and the median summed absolute difference (SAD) calculated over all three blinded, coded reference samples approximately doubled relative to teams employing a combination of genes (Fig.…”

Section: Discussionmentioning

confidence: 99%

RENEB Inter-Laboratory Comparison 2021: The Gene Expression Assay

Abend

Amundson

Badie³

et al. 2023

Radiation Research

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Early and high-throughput individual dose estimates are essential following large-scale radiation exposure events. In the context of the Running the European Network for Biodosimetry and Physical Dosimetry (RENEB) 2021 exercise, gene expression assays were conducted and their corresponding performance for dose-assessment is presented in this publication. Three blinded, coded whole blood samples from healthy donors were exposed to 0, 1.2 and 3.5 Gy X-ray doses (240 kVp, 1 Gy/min) using the X-ray source Yxlon. These exposures correspond to clinically relevant groups of unexposed, low dose (no severe acute health effects expected) and high dose exposed individuals (requiring early intensive medical health care). Samples were sent to eight teams for dose estimation and identification of clinically relevant groups. For quantitative reverse transcription polymerase chain reaction (qRT-PCR) and microarray analyses, samples were lysed, stored at 20°C and shipped on wet ice. RNA isolations and assays were run in each laboratory according to locally established protocols. The time-to-result for both rough early and more precise later reports has been documented where possible. Accuracy of dose estimates was calculated as the difference between estimated and reference doses for all doses (summed absolute difference, SAD) and by determining the number of correctly reported dose estimates that were defined as ±0.5 Gy for reference doses <2.5 Gy and ±1.0 Gy for reference doses >3 Gy, as recommended for triage dosimetry. We also examined the allocation of dose estimates to clinically/diagnostically relevant exposure groups. Altogether, 105 dose estimates were reported by the eight teams, and the earliest report times on dose categories and estimates were 5 h and 9 h, respectively. The coefficient of variation for 85% of all 436 qRT-PCR measurements did not exceed 10%. One team reported dose estimates that systematically deviated several-fold from reported dose estimates, and these outliers were excluded from further analysis. Teams employing a combination of several genes generated about two-times lower median SADs (0.8 Gy) compared to dose estimates based on single genes only (1.7 Gy). When considering the uncertainty intervals for triage dosimetry, dose estimates of all teams together were correctly reported in 100% of the 0 Gy, 50% of the 1.2 Gy and 50% of the 3.5 Gy exposed samples. The order of dose estimates (from lowest to highest) corresponding to three dose categories (unexposed, low dose and highest exposure) were correctly reported by all teams and all chosen genes or gene combinations. Furthermore, if teams reported no exposure or an exposure >3.5 Gy, it was always correctly allocated to the unexposed and the highly exposed group, while low exposed (1.2 Gy) samples sometimes could not be discriminated from highly (3.5 Gy) exposed samples. All teams used FDXR and 78.1% of correct dose estimates used FDXR as one of the predictors. Still, the accuracy of reported dose estimates based on FDXR differed considerably among teams with one team's SAD (0.5 Gy) being comparable to the dose accuracy employing a combination of genes. Using the workflow of this reference team, we performed additional experiments after the exercise on residual RNA and cDNA sent by six teams to the reference team. All samples were processed similarly with the intention to improve the accuracy of dose estimates when employing the same workflow. Re-evaluated dose estimates improved for half of the samples and worsened for the others. In conclusion, this inter-laboratory comparison exercise enabled (1) identification of technical problems and corrections in preparations for future events, (2) confirmed the early and high-throughput capabilities of gene expression, (3) emphasized different biodosimetry approaches using either only FDXR or a gene combination, (4) indicated some improvements in dose estimation with FDXR when employing a similar methodology, which requires further research for the final conclusion and (5) underlined the applicability of gene expression for identification of unexposed and highly exposed samples, supporting medical management in radiological or nuclear scenarios.

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Section: Discussionmentioning

confidence: 99%

RENEB Inter-Laboratory Comparison 2021: The Gene Expression Assay

Abend

Amundson

Badie³

et al. 2023

Radiation Research

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“…As a result, a certain GE change refers to another dose estimate depending on the time. This also applies to protein measurements or radiation-induced blood cell count changes such as neutrophils or lymphocytes [Blakely et al, 2021;Abend et al, 2022]. This fact must be considered in the event of efficient diagnosis or already in identifying appropriate gene signatures.…”

Section: Clinically Relevant Groups Of People In Radiological and Nuc...mentioning

confidence: 99%

“…1) [Hall and Giaccia, 2012;Port et al, 2019a, b]. Besides, examinations on the association of gene expression (GE), particularly with dose, represent the topic of the vast majority of molecular radiobiological publications [reviewed by Abend et al, 2022]. Dose ratedependent GE changes are less examined [Paul et al, 2015;Ghandhi et al, 2019], as well as GE changes related to radiation quality [Unverricht-Yeboah et al, 2018].…”

mentioning

confidence: 99%

Radiation-Induced Gene Expression Changes Used for Biodosimetry and Clinical Outcome Prediction: Challenges and Promises

Abend¹,

Ostheim²,

Port³

2023

Cytogenet Genome Res

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As the war in Ukraine progresses, the radiological and nuclear threat has never been as real as now. The formation of life-threatening acute radiation syndrome (ARS), in particular after the deployment of a nuclear weapon or an attack on a nuclear power station, must be considered realistic. ARS is caused by massive cell death, leading to functional organ deficits and, via systemic inflammatory responses, finally aggravates into multiple organ failure. As a deterministic effect, the severity of the disease dictates the clinical outcome. Hence, predicting ARS severity via biodosimetry or alternative approaches appears straightforward. Because the disease occurs delayed, therapy starting as early as possible has the most significant benefit. A clinically relevant diagnosis should be carried out within the diagnostic time window of about 3 days after exposure. Biodosimetry assays providing retrospective dose estimations within this time frame will support medical management decision-making. However, how closely can dose estimates be associated with the later developing ARS severity degrees when considering dose as one among other determinants of radiation exposure and cell death? From a clinical/triage point of view, ARS severity degrees can be further aggregated into unexposed, weakly diseased (no acute health effects expected), and strongly diseased patient groups, with the latter requiring hospitalization as well as an early and intensive treatment. Radiation-induced gene expression (GE) changes occur early after exposure and can be quickly quantified. GE can be used for biodosimetry purposes. Can GE be used to predict later developing ARS severity degrees and allocate individuals to the three clinically relevant groups as well?

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“…Specifically, measurement of lymphocyte depletion kinetics is a very common test in everyday healthcare and could, therefore, should be useful in triage (see EBMT 2017). Abend et al (2022) emphasise the potential usefulness of molecular protein or gene expression biomarkers for high-throughput and point-of-care diagnosis in the first few days following a radiation accident. They also note that the various potential markers respond differently in relation to characteristics such as radiation quality, dose and dose rate.…”

Section: Biomarkersmentioning

confidence: 99%

Responding to radiation accidents: what more do we need to know?

Thorne¹

2022

J. Radiol. Prot.

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A short review of the various types of radiation incidents and accidents that have occurred is used to provide a context for discussing the findings on medical management of the victims of such incidents and accidents reported in a recent Special Issue of the Journal of Radiological Protection. The review demonstrates that accidents and incidents giving rise to high radiation doses may involve over-exposure of a single individual, a few individuals, or very large numbers. In general, these exposures will be relatively short-term, ranging from a few seconds to a few days, but chronic situations resulting in high exposures can occur. Some of these exposures may be highly localised, whereas others may result in almost uniform whole-body irradiation. This diversity of situations means that it is not feasible to have a single protocol for the diagnosis and treatment of over-exposed individuals. If the over-exposures are limited to one or a few individuals, these can be addressed on a case-by-case basis. However, where large numbers have been exposed or may have been exposed, there is a need to implement a rapid and effective system of triage. Furthermore, this system is likely to have to be implemented by individuals who have little or no direct experience of radiation-induced injuries. For those individuals who may have been significantly exposed, the key consideration is not to determine the radiation dose that they have received, but to establish their present clinical status and how it is likely to develop with time. There is at most a very limited role for bone-marrow transplantation in the treatment of acute radiation syndrome, whereas there are good arguments for administering various treatments to boost bone marrow function together with other supportive interventions, e.g. in control of infections and handling both fluid loss and bleeding. However, there is concern that the focus to date has been only on the licencing of drugs related to the management of haematopoietic effects. Although a great deal is known about the diagnosis and treatment of injuries arising from high dose exposures, this knowledge is biased towards situations in which there is relatively uniform, external whole-body exposure. More attention needs to be given to assessing the implications of various inhomogeneous exposure regimes and to developing medical countermeasures optimised for addressing the complex, multi-organ effects likely to arise from such inhomogeneous exposures.

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Early molecular markers for retrospective biodosimetry and prediction of acute health effects

Cited by 26 publications

References 172 publications

RENEB Inter-Laboratory Comparison 2021: The Gene Expression Assay

RENEB Inter-Laboratory Comparison 2021: The Gene Expression Assay

Radiation-Induced Gene Expression Changes Used for Biodosimetry and Clinical Outcome Prediction: Challenges and Promises

Responding to radiation accidents: what more do we need to know?

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