Combined Analysis of Gamma-H2AX/53BP1 Foci and Caspase Activation in Lymphocyte Subsets Detects Recent and More Remote Radiation Exposures

Horn, Simon; Barnard, Stephen; Brady, Darren; Prise, Kevin M.; Rothkamm, Kai

doi:10.1667/rr13342.1

Cited by 24 publications

(22 citation statements)

References 37 publications

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“…The disappearance of RIF at later time-points could also have been caused potentially by elimination of damaged cells. However, while high dose rate acute photon irradiation has been shown to induce apoptotic cell death in blood samples irradiated ex vivo [ 24 , 25 ] and in minipigs exposed to partial body γ-irradiation with 50 Gy [ 23 ], we only occasionally noted apoptotic leucocytes in our in-vivo samples exposed to low doses and low dose rates. Therefore, we consider it unlikely that a preferential elimination of damaged cells influenced the repair time courses observed.…”

Section: Discussionmentioning

confidence: 60%

DNA damage in blood leucocytes of prostate cancer patients during therapy with 177Lu-PSMA

Schumann

Scherthan

Lapa

et al. 2019

Eur J Nucl Med Mol Imaging

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Purpose The aim of this study was to investigate the time- and dose-dependency of DNA double-strand break (DSB) induction and repair in peripheral blood leucocytes of prostate cancer patients during therapy with 177 Lu-PSMA. Methods Blood samples from 16 prostate cancer patients receiving their first 177 Lu-PSMA therapy were taken before and at seven time-points (between 1 h and 96 h) after radionuclide administration. Absorbed doses to the blood were calculated using integrated time–activity curves of the blood and the whole-body. For DSB quantification, leucocytes were isolated, fixed in ethanol and immunostained with γ-H2AX and 53BP1 antibodies. Colocalizing foci of both DSB markers were manually counted in a fluorescence microscope. Results The average number of radiation-induced foci (RIF) per cell increased within the first 4 h after administration, followed by a decrease indicating DNA repair. The number of RIF during the first 2.6 h correlated linearly with the absorbed dose to the blood ( R 2 = 0.58), in good agreement with previously published in-vitro data. At late time-points (48 h and 96 h after administration), the number of RIF correlated linearly with the absorbed dose rate ( R 2 = 0.56). In most patients, DNA DSBs were repaired effectively. However, in some patients RIF did not disappear completely even 96 h after administration. Conclusion The general pattern of the time- and dose-dependent induction and disappearance of RIF during 177 Lu-PSMA therapy is similar to that of other radionuclide therapies.

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Section: Discussionmentioning

confidence: 60%

DNA damage in blood leucocytes of prostate cancer patients during therapy with 177Lu-PSMA

Schumann

Scherthan

Lapa

et al. 2019

Eur J Nucl Med Mol Imaging

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“…With this personalized approach the chance of cure could be increased in sensitive, normal and resistant patients. The molecular mechanisms for the known hypersensitivity still remain obscure and there are no universally valid predictive biomarkers for radio-sensitivity available (Akervall et al, 2014;Chua and Rothkamm, 2013;Horn et al, 2013;Mabert et al, 2014;Pernot et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

The inter-individual variability outperforms the intra-individual variability of differentially expressed proteins prior and post irradiation in lymphoblastoid cell lines

Guertler

Hauptmann

Pautz

et al. 2014

Archives of Physiology and Biochemistry

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“…DDB2 is a protein associated with nucleotide excision repair and has a key role in DNA damage recognition 14 . FDXR is a mitochondrial flavoprotein transferring electron from NADPH to cytochrome P450 which can be induced by DNA damage and is involved in p53 and oxidative stress-mediated apoptosis 11,15 . TSPYL2 is important for G1 checkpoint maintenance upon DNA damage 16 .…”

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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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Combined Analysis of Gamma-H2AX/53BP1 Foci and Caspase Activation in Lymphocyte Subsets Detects Recent and More Remote Radiation Exposures

Cited by 24 publications

References 37 publications

DNA damage in blood leucocytes of prostate cancer patients during therapy with 177Lu-PSMA

DNA damage in blood leucocytes of prostate cancer patients during therapy with 177Lu-PSMA

The inter-individual variability outperforms the intra-individual variability of differentially expressed proteins prior and post irradiation in lymphoblastoid cell lines

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

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