This study demonstrates that mice, similar to humans, have a common mitochondrial DNA deletion (3... more This study demonstrates that mice, similar to humans, have a common mitochondrial DNA deletion (3,860 bp) that encodes 5 transfer RNA genes and 5 polypeptide genes that is related to aging, tissue type and radiotoxicity. Our research indicates that the deletion ratio in the liver was significantly higher than in the brain and gut tissues of 8-month-old mice, as compared to 8-week-old mice. Our results also demonstrate that tissue type, oxidative metabolic capacity and radiosensitivity influence the 3,860-bp deletion level. Therefore, this 3,860-bp deletion content may serve as a biomarker of aging and oxidative damage in mice.
Advances in Experimental Medicine and Biology, Nov 2, 2011
Genomic background helps determine sensitivity to TBI. Since the LD50/30 (the dose that causes de... more Genomic background helps determine sensitivity to TBI. Since the LD50/30 (the dose that causes death in half of exposed mice within 30 days) following TBI varies between murine strains, we tested four murine strains to determine whether TBI sensitivity was associated with different levels of circulating DNA after radiation. The LD50/30 for the mice we tested – BALB/c, NIH Swiss, C3H/HeN, and C57BL/6 – is approximately 5.8 ± 0.3, 7.3 ± 0.2, 7.4 ± 0.3, and 8.5 ± 0.3 Gy, respectively. We estimated the radiation dose at which circulating DNA reached a peak level (peakGy), and mice were subjected to different doses at 1.84 Gy/min. The peakGy was 6, 7, 9, and 9 Gy for BALB/c, NIH Swiss, C3H/HeN, and C57BL/6, which corresponds to each strain’s respective LD50/30. BALB/c, the most sensitive strain, had the lowest DNA concentration at peakGy, while C57BL/6, the most resistant strain, had the highest concentration at peakGy. At 7 Gy, the plasma DNA was approximately 3,754 ± 636, 8,238 ± 2,704, 9,773 ± 2,821, and 22,733 ± 5,914 ng/ml for BALB/c, NIH Swiss, C3H/HeN, and C57BL/6, respectively. These findings support our hypothesis that plasma DNA level is associated with genomic background.
The reactions of free and DNA-bound 2,2,5,5-tetramethylpyrrolidine-N-oxyl (PROXYL) probes with ra... more The reactions of free and DNA-bound 2,2,5,5-tetramethylpyrrolidine-N-oxyl (PROXYL) probes with radicals generated during radiolysis of dilute aqueous solutions of DNA were examined. For the free PROXYL probe in deaerated solution with each of the four nucleotides (dAMP, dCMP, dGMP, and TMP) it was found that the pyrimidine radicals were more reactive toward the probe than were the purine radicals. Reactions of the electron adduct of TMP and the hydroxyl radical adducts of dAMP, dGMP, and TMP with the probe resulted in little or no reduction of the probe. For TMP these results are consistent with the fact that both the protonated electron and hydroxyl radical adducts of TMP will covalently bind to the nitroxide function of the probe. Reduction of the PROXYL probe was observed in reactions with the hydroxyl radical adduct of dCMP and with the electron adducts of dAMP, dCMP, and dGMP. Results of the radiolysis of the free PROXYL probe in deaerated dilute solution of DNA suggest that the PROXYL probe protects the DNA from water radical attack as the ratio of DNA bases to PROXYL probe increases above 50:1. Reactions of DNA-bound probes are dependent on the depth of the nitroxide function in relation to the major groove of the DNA helix. Two probes with tether lengths which are less than the depth of the major groove show an expected increase in reactions with DNA base radicals as compared to a probe with a tether that extends beyond the groove. The longer probe is involved largely in reactions with sugar and water radicals along the periphery of the DNA helix. In the presence of oxygen, there is a dramatic decrease in the loss of both the free and DNA-bound probes due to the lack of reaction of these probes with peroxyl radicals formed by the addition of molecular oxygen to DNA radicals.
An effective medical response to a large-scale radiation event requires prompt and effective init... more An effective medical response to a large-scale radiation event requires prompt and effective initial triage so that appropriate care can be provided to individuals with significant risk for severe acute radiation injury. Arguably, it would be advantageous to use injury rather than radiation dose for the initial assessment, i.e., use bioassays of biological damage. Such assays would be based on changes in intrinsic biological response elements, e.g., up- or down-regulation of genes, proteins, metabolites, blood cell counts, chromosomal aberrations, micronuclei, micro-RNA, cytokines, or transcriptomes. Using a framework to evaluate the feasibility of biodosimetry for triaging up to a million people in less than a week following a major radiation event, Part 1 analyzes the logistical feasibility and clinical needs for ensuring that biomarkers of organ-specific injury could be effectively utilized in this context. We conclude that the decision to use biomarkers of organ-specific injury would greatly benefit by first having independent knowledge of whether the person’s exposure was heterogeneous and, if so, what was the dose distribution (to determine which organs were exposed to high doses). In Part 2 we describe how these two essential needs for prior information (heterogeneity and dose distribution) could be obtained by using in vivo nail dosimetry. This novel physical biodosimetry method can also meet the needs for initial triage, providing non-invasive, point-of-care measurements made by non-experts with immediate dose estimates for 4 separate anatomical sites. Additionally, it uniquely provides immediate information as to whether the exposure was homogeneous and, if not, can estimate the dose distribution. We conclude that combining the capability of methods such as in vivo EPR nail dosimetry with bioassays to predict organ-specific damage would together allow effective use of medical resources to save lives.
International Journal of Radiation Biology, Nov 17, 2021
PURPOSE Based on the experience of biodosimetry laboratories during the COVID-19 pandemic, the pu... more PURPOSE Based on the experience of biodosimetry laboratories during the COVID-19 pandemic, the purpose of this paper is to describe the challenges of providing biodosimetry service in the event of a major radiation incident during a pandemic. This includes describing some of the preparations and planning made by biodosimetry laboratories and special challenges in maintaining a state of readiness while adhering to safety protocols and balancing the need to assist with the COVID-19 response where possible. Experiences of several biodosimetry laboratories will be described and lessons learned will be outlined that could be applied to any large population-scale emergencies. CONCLUSIONS There are many challenges that arise when maintaining capacity and capabilities for biodosimetry when faced with a global pandemic such as COVID-19. The key is to be prepared for anything within reason. This includes, but is not limited to, maintaining flexibility, shifting and reorganizing deployment of staff between pandemic response and biodosimetry needs, strengthening networks to be able to provide assistance to other laboratories, managing staff in the face of possible infections and preparing protocols for the handling of potentially infected biological samples according to regulatory requirements. By implementing these recommendations, international biodosimetry networks can be prepared to address large-scale radiological incidents within the context of a pandemic and ensure the safety of biodosimetry personnel as well as victims in such dual emergencies.
Background: Hemorrhagic cystitis from chemical or radiation bladder injury can cause life-threate... more Background: Hemorrhagic cystitis from chemical or radiation bladder injury can cause life-threatening bleeding and/or urothelial cancer. Fibroblast growth factor 7 (FGF7) blocks urothelial apoptosis induced by cyclophosphamide (CPP) or radiation, but there are limitations to its use in patients, including an inability to apply it by direct bladder infusion and the high cost due to the large size of the protein (18.8 kDa). Purpose: We previously identified a small peptide that equaled or exceeded the mitigation effect of full length FGF2 on acute radiation syndrome. Benefits of developing a similar FGF7 biomimetic peptide include lower likelihood of inflammation, longer shelf life, higher purity, and lower cost than the full-length protein. Methods: Based on the 3-dimensional structure of FGF2 peptide, a corresponding FGF7 peptide (FGF7p) consisting of 19 amino acids was identified and synthesized. FGF7p or vehicle was given subcutaneously (SQ) to female mice subjected to sham injury...
This study demonstrates that mice, similar to humans, have a common mitochondrial DNA deletion (3... more This study demonstrates that mice, similar to humans, have a common mitochondrial DNA deletion (3,860 bp) that encodes 5 transfer RNA genes and 5 polypeptide genes that is related to aging, tissue type and radiotoxicity. Our research indicates that the deletion ratio in the liver was significantly higher than in the brain and gut tissues of 8-month-old mice, as compared to 8-week-old mice. Our results also demonstrate that tissue type, oxidative metabolic capacity and radiosensitivity influence the 3,860-bp deletion level. Therefore, this 3,860-bp deletion content may serve as a biomarker of aging and oxidative damage in mice.
Advances in Experimental Medicine and Biology, Nov 2, 2011
Genomic background helps determine sensitivity to TBI. Since the LD50/30 (the dose that causes de... more Genomic background helps determine sensitivity to TBI. Since the LD50/30 (the dose that causes death in half of exposed mice within 30 days) following TBI varies between murine strains, we tested four murine strains to determine whether TBI sensitivity was associated with different levels of circulating DNA after radiation. The LD50/30 for the mice we tested – BALB/c, NIH Swiss, C3H/HeN, and C57BL/6 – is approximately 5.8 ± 0.3, 7.3 ± 0.2, 7.4 ± 0.3, and 8.5 ± 0.3 Gy, respectively. We estimated the radiation dose at which circulating DNA reached a peak level (peakGy), and mice were subjected to different doses at 1.84 Gy/min. The peakGy was 6, 7, 9, and 9 Gy for BALB/c, NIH Swiss, C3H/HeN, and C57BL/6, which corresponds to each strain’s respective LD50/30. BALB/c, the most sensitive strain, had the lowest DNA concentration at peakGy, while C57BL/6, the most resistant strain, had the highest concentration at peakGy. At 7 Gy, the plasma DNA was approximately 3,754 ± 636, 8,238 ± 2,704, 9,773 ± 2,821, and 22,733 ± 5,914 ng/ml for BALB/c, NIH Swiss, C3H/HeN, and C57BL/6, respectively. These findings support our hypothesis that plasma DNA level is associated with genomic background.
The reactions of free and DNA-bound 2,2,5,5-tetramethylpyrrolidine-N-oxyl (PROXYL) probes with ra... more The reactions of free and DNA-bound 2,2,5,5-tetramethylpyrrolidine-N-oxyl (PROXYL) probes with radicals generated during radiolysis of dilute aqueous solutions of DNA were examined. For the free PROXYL probe in deaerated solution with each of the four nucleotides (dAMP, dCMP, dGMP, and TMP) it was found that the pyrimidine radicals were more reactive toward the probe than were the purine radicals. Reactions of the electron adduct of TMP and the hydroxyl radical adducts of dAMP, dGMP, and TMP with the probe resulted in little or no reduction of the probe. For TMP these results are consistent with the fact that both the protonated electron and hydroxyl radical adducts of TMP will covalently bind to the nitroxide function of the probe. Reduction of the PROXYL probe was observed in reactions with the hydroxyl radical adduct of dCMP and with the electron adducts of dAMP, dCMP, and dGMP. Results of the radiolysis of the free PROXYL probe in deaerated dilute solution of DNA suggest that the PROXYL probe protects the DNA from water radical attack as the ratio of DNA bases to PROXYL probe increases above 50:1. Reactions of DNA-bound probes are dependent on the depth of the nitroxide function in relation to the major groove of the DNA helix. Two probes with tether lengths which are less than the depth of the major groove show an expected increase in reactions with DNA base radicals as compared to a probe with a tether that extends beyond the groove. The longer probe is involved largely in reactions with sugar and water radicals along the periphery of the DNA helix. In the presence of oxygen, there is a dramatic decrease in the loss of both the free and DNA-bound probes due to the lack of reaction of these probes with peroxyl radicals formed by the addition of molecular oxygen to DNA radicals.
An effective medical response to a large-scale radiation event requires prompt and effective init... more An effective medical response to a large-scale radiation event requires prompt and effective initial triage so that appropriate care can be provided to individuals with significant risk for severe acute radiation injury. Arguably, it would be advantageous to use injury rather than radiation dose for the initial assessment, i.e., use bioassays of biological damage. Such assays would be based on changes in intrinsic biological response elements, e.g., up- or down-regulation of genes, proteins, metabolites, blood cell counts, chromosomal aberrations, micronuclei, micro-RNA, cytokines, or transcriptomes. Using a framework to evaluate the feasibility of biodosimetry for triaging up to a million people in less than a week following a major radiation event, Part 1 analyzes the logistical feasibility and clinical needs for ensuring that biomarkers of organ-specific injury could be effectively utilized in this context. We conclude that the decision to use biomarkers of organ-specific injury would greatly benefit by first having independent knowledge of whether the person’s exposure was heterogeneous and, if so, what was the dose distribution (to determine which organs were exposed to high doses). In Part 2 we describe how these two essential needs for prior information (heterogeneity and dose distribution) could be obtained by using in vivo nail dosimetry. This novel physical biodosimetry method can also meet the needs for initial triage, providing non-invasive, point-of-care measurements made by non-experts with immediate dose estimates for 4 separate anatomical sites. Additionally, it uniquely provides immediate information as to whether the exposure was homogeneous and, if not, can estimate the dose distribution. We conclude that combining the capability of methods such as in vivo EPR nail dosimetry with bioassays to predict organ-specific damage would together allow effective use of medical resources to save lives.
International Journal of Radiation Biology, Nov 17, 2021
PURPOSE Based on the experience of biodosimetry laboratories during the COVID-19 pandemic, the pu... more PURPOSE Based on the experience of biodosimetry laboratories during the COVID-19 pandemic, the purpose of this paper is to describe the challenges of providing biodosimetry service in the event of a major radiation incident during a pandemic. This includes describing some of the preparations and planning made by biodosimetry laboratories and special challenges in maintaining a state of readiness while adhering to safety protocols and balancing the need to assist with the COVID-19 response where possible. Experiences of several biodosimetry laboratories will be described and lessons learned will be outlined that could be applied to any large population-scale emergencies. CONCLUSIONS There are many challenges that arise when maintaining capacity and capabilities for biodosimetry when faced with a global pandemic such as COVID-19. The key is to be prepared for anything within reason. This includes, but is not limited to, maintaining flexibility, shifting and reorganizing deployment of staff between pandemic response and biodosimetry needs, strengthening networks to be able to provide assistance to other laboratories, managing staff in the face of possible infections and preparing protocols for the handling of potentially infected biological samples according to regulatory requirements. By implementing these recommendations, international biodosimetry networks can be prepared to address large-scale radiological incidents within the context of a pandemic and ensure the safety of biodosimetry personnel as well as victims in such dual emergencies.
Background: Hemorrhagic cystitis from chemical or radiation bladder injury can cause life-threate... more Background: Hemorrhagic cystitis from chemical or radiation bladder injury can cause life-threatening bleeding and/or urothelial cancer. Fibroblast growth factor 7 (FGF7) blocks urothelial apoptosis induced by cyclophosphamide (CPP) or radiation, but there are limitations to its use in patients, including an inability to apply it by direct bladder infusion and the high cost due to the large size of the protein (18.8 kDa). Purpose: We previously identified a small peptide that equaled or exceeded the mitigation effect of full length FGF2 on acute radiation syndrome. Benefits of developing a similar FGF7 biomimetic peptide include lower likelihood of inflammation, longer shelf life, higher purity, and lower cost than the full-length protein. Methods: Based on the 3-dimensional structure of FGF2 peptide, a corresponding FGF7 peptide (FGF7p) consisting of 19 amino acids was identified and synthesized. FGF7p or vehicle was given subcutaneously (SQ) to female mice subjected to sham injury...
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Papers by Steven Swarts