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Acute Radiation Syndrome

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Vijay K. Singh – One of the best experts on this subject based on the ideXlab platform.

  • Entolimod as a Radiation countermeasure for Acute Radiation Syndrome.
    Drug discovery today, 2020
    Co-Authors: Vijay K. Singh, Thomas M. Seed
    Abstract:

    High doses of total-body or partial-body Radiation exposure can result in a life-threatening Acute Radiation Syndrome as manifested by severe morbidity. Entolimod (CBLB502) is effective in protecting against, and mitigating the development of, the hematopoietic and gastrointestinal subSyndromes of the Acute Radiation Syndrome in rodents and nonhuman primates. Entolimod treatment reduces Radiation-induced apoptosis and accelerates the regeneration of progenitors in Radiation-damaged tissues. The drug has been evaluated clinically for its pharmacokinetics (PK), toxicity, and biomarkers. The US Food and Drug Administration (FDA) has granted investigational new drug, fast-track, and orphan drug statuses to entolimod. Its safety, efficacy, and animal-to-human dose conversion data allowed its progression with a pre-emergency use authorization application submission.

  • BIO 300: a promising Radiation countermeasure under advanced development for Acute Radiation Syndrome and the delayed effects of Acute Radiation exposure.
    Expert opinion on investigational drugs, 2020
    Co-Authors: Vijay K. Singh, Thomas M. Seed
    Abstract:

    There are no radioprotectors currently approved by the United States Food and Drug Administration (US FDA) for either the hematopoietic Acute Radiation Syndrome (H-ARS) or for the Acute Radiation g…

  • The efficacy and safety of amifostine for the Acute Radiation Syndrome
    Expert opinion on drug safety, 2019
    Co-Authors: Vijay K. Singh, Thomas M. Seed
    Abstract:

    Introduction: A Radiation countermeasure that can be used prior to Radiation exposure to protect the population from the harmful effects of Radiation exposure remains a major unmet medical need and is recognized as an important area for research. Despite substantial advances in the research and development for finding nontoxic, safe, and effective prophylactic countermeasures for the Acute Radiation Syndrome (ARS), no such agent has been approved by the United States Food and Drug Administration (FDA). Area covered: Despite the progress made to improve the effectiveness of amifostine as a radioprotector for ARS, none of the strategies have resolved the issue of its toxicity/side effects. Thus, the FDA has approved amifostine for limited clinical indications, but not for non-clinical uses. This article reviews recent strategies and progress that have been made to move forward this potentially useful countermeasure for ARS. Expert opinion: Although the recent investigations have been promising for fielding safe and effective Radiation countermeasures, additional work is needed to improve and advance drug design and delivery strategies to get FDA approval for broadened, non-clinical use of amifostine during a radiological/nuclear scenario.

Yunxia Tang – One of the best experts on this subject based on the ideXlab platform.

  • hematopoietic recovery of Acute Radiation Syndrome by human superoxide dismutase expressing umbilical cord mesenchymal stromal cells
    Cytotherapy, 2015
    Co-Authors: Jingyi Gan, Yunxia Tang, Fanwei Meng, Xin Zhou, Xiaoping Zeng, Xingen Jiang, Jia Liu, Guifang Zeng, Muyun Liu, Randall J Mrsny
    Abstract:

    Abstract Background aims Acute Radiation Syndrome (ARS) leads to pancytopenia and multi-organ failure. Transplantation of hematopoietic stem cells provides a curative option for Radiation-induced aplasia, but this therapy is limited by donor availability. Methods We examined an alternative therapeutic approach to ARS with the use of human extracellular superoxide dismutase (ECSOD)-modified umbilical cord mesenchymal stromal cells (UCMSCs). This treatment combines the unique regenerative role of UCMSCs with the anti-oxidative activity of ECSOD. Results We demonstrated that systemically administered ECSOD-UCMSCs are able to protect mice from sub-lethal doses of Radiation and improve survival by promoting multilineage hematopoietic recovery. The therapeutic effect of this treatment is related to the decrease in Radiation-induced O 2 – and apoptosis. Conclusions Our data highlight the clinical potential of this two-pronged approach to the treatment of ARS, thereby serving as a rapid and effective first-line strategy to combat the hematopoietic failure resulting from a Radiation accident, nuclear terrorism and other radiologic emergencies.

  • Hematopoietic recovery of Acute Radiation Syndrome by human superoxide dismutase–expressing umbilical cord mesenchymal stromal cells
    Cytotherapy, 2015
    Co-Authors: Jingyi Gan, Fanwei Meng, Xin Zhou, Xiaoping Zeng, Xingen Jiang, Jia Liu, Guifang Zeng, Yunxia Tang
    Abstract:

    Abstract Background aims Acute Radiation Syndrome (ARS) leads to pancytopenia and multi-organ failure. Transplantation of hematopoietic stem cells provides a curative option for Radiation-induced aplasia, but this therapy is limited by donor availability. Methods We examined an alternative therapeutic approach to ARS with the use of human extracellular superoxide dismutase (ECSOD)-modified umbilical cord mesenchymal stromal cells (UCMSCs). This treatment combines the unique regenerative role of UCMSCs with the anti-oxidative activity of ECSOD. Results We demonstrated that systemically administered ECSOD-UCMSCs are able to protect mice from sub-lethal doses of Radiation and improve survival by promoting multilineage hematopoietic recovery. The therapeutic effect of this treatment is related to the decrease in Radiation-induced O 2 – and apoptosis. Conclusions Our data highlight the clinical potential of this two-pronged approach to the treatment of ARS, thereby serving as a rapid and effective first-line strategy to combat the hematopoietic failure resulting from a Radiation accident, nuclear terrorism and other radiologic emergencies.

Jingyi Gan – One of the best experts on this subject based on the ideXlab platform.

  • hematopoietic recovery of Acute Radiation Syndrome by human superoxide dismutase expressing umbilical cord mesenchymal stromal cells
    Cytotherapy, 2015
    Co-Authors: Jingyi Gan, Yunxia Tang, Fanwei Meng, Xin Zhou, Xiaoping Zeng, Xingen Jiang, Jia Liu, Guifang Zeng, Muyun Liu, Randall J Mrsny
    Abstract:

    Abstract Background aims Acute Radiation Syndrome (ARS) leads to pancytopenia and multi-organ failure. Transplantation of hematopoietic stem cells provides a curative option for Radiation-induced aplasia, but this therapy is limited by donor availability. Methods We examined an alternative therapeutic approach to ARS with the use of human extracellular superoxide dismutase (ECSOD)-modified umbilical cord mesenchymal stromal cells (UCMSCs). This treatment combines the unique regenerative role of UCMSCs with the anti-oxidative activity of ECSOD. Results We demonstrated that systemically administered ECSOD-UCMSCs are able to protect mice from sub-lethal doses of Radiation and improve survival by promoting multilineage hematopoietic recovery. The therapeutic effect of this treatment is related to the decrease in Radiation-induced O 2 – and apoptosis. Conclusions Our data highlight the clinical potential of this two-pronged approach to the treatment of ARS, thereby serving as a rapid and effective first-line strategy to combat the hematopoietic failure resulting from a Radiation accident, nuclear terrorism and other radiologic emergencies.

  • Hematopoietic recovery of Acute Radiation Syndrome by human superoxide dismutase–expressing umbilical cord mesenchymal stromal cells
    Cytotherapy, 2015
    Co-Authors: Jingyi Gan, Fanwei Meng, Xin Zhou, Xiaoping Zeng, Xingen Jiang, Jia Liu, Guifang Zeng, Yunxia Tang
    Abstract:

    Abstract Background aims Acute Radiation Syndrome (ARS) leads to pancytopenia and multi-organ failure. Transplantation of hematopoietic stem cells provides a curative option for Radiation-induced aplasia, but this therapy is limited by donor availability. Methods We examined an alternative therapeutic approach to ARS with the use of human extracellular superoxide dismutase (ECSOD)-modified umbilical cord mesenchymal stromal cells (UCMSCs). This treatment combines the unique regenerative role of UCMSCs with the anti-oxidative activity of ECSOD. Results We demonstrated that systemically administered ECSOD-UCMSCs are able to protect mice from sub-lethal doses of Radiation and improve survival by promoting multilineage hematopoietic recovery. The therapeutic effect of this treatment is related to the decrease in Radiation-induced O 2 – and apoptosis. Conclusions Our data highlight the clinical potential of this two-pronged approach to the treatment of ARS, thereby serving as a rapid and effective first-line strategy to combat the hematopoietic failure resulting from a Radiation accident, nuclear terrorism and other radiologic emergencies.

Thomas J. Macvittie – One of the best experts on this subject based on the ideXlab platform.

  • Evaluation of Plasma Biomarker Utility for the Gastrointestinal Acute Radiation Syndrome in Non-human Primates after Partial Body IrRadiation with Minimal Bone Marrow Sparing through Correlation with Tissue and Histological Analyses.
    Health physics, 2020
    Co-Authors: Praveen Kumar, Thomas J. Macvittie, Ann M. Farese, Gregory Tudor, Catherine Booth, Pengcheng Wang, Maureen A. Kane
    Abstract:

    Exposure to total- and partial-body irRadiation following a nuclear or radiological incident result in the potentially lethal Acute Radiation Syndromes of the gastrointestinal and hematopoietic systems in a dose- and time-dependent manner. Radiation-induced damage to the gastrointestinal tract is observed within days to weeks post-irRadiation. Our objective in this study was to evaluate plasma biomarker utility for the gastrointestinal Acute Radiation Syndrome in non-human primates after partial body irRadiation with minimal bone marrow sparing through correlation with tissue and histological analyses. Plasma and jejunum samples from non-human primates exposed to partial body irRadiation of 12 Gy with bone marrow sparing of 2.5% were evaluated at various time points from day 0 to day 21 as part of a natural history study. Additionally, longitudinal plasma samples from non-human primates exposed to 10 Gy partial body irRadiation with 2.5% bone marrow sparing were evaluated at timepoints out to 180 d post-irRadiation. Plasma and jejunum metabolites were quantified via liquid chrochromatography-tandem mass spectrometry and histological analysis consisted of corrected crypt number, an established metric to assess Radiation-induced gastrointestinal damage. A positive correlation of metabolite levels in jejunum and plasma was observed for citrulline, serotonin, acylcarnitine, and multiple species of phosphatidylcholines. Citrulline levels also correlated with injury and regeneration of crypts in the small intestine. These results expand the characterization of the natural history of gastrointestinal Acute Radiation Syndrome in non-human primates exposed to partial body irRadiation with minimal bone marrow sparing and also provide additional data toward the correlation of citrulline with histological endpoints.

  • Lifelong Residual bone Marrow Damage in Murine Survivors of the Hematopoietic Acute Radiation Syndrome (H-ARS): A Compilation of Studies Comprising the Indiana University Experience.
    Health physics, 2019
    Co-Authors: Hui Lin Chua, Thomas J. Macvittie, P. Artur Plett, Alexa Fisher, Carol H. Sampson, Sasidhar Vemula, Hailin Feng, Rajendran Sellamuthu, Christie M. Orschell
    Abstract:

    Accurate analyses of the delayed effects of Acute Radiation exposure in survivors of the hematopoietic Acute Radiation Syndrome are hampered by low numbers of mice for examination due to high lethality from the Acute Syndrome, increased morbidity and mortality in survivors, high cost of husbandry for long-term studies, biological variability, and inconsistencies of models from different laboratories complicating meta-analyses. To address this, a compilation of 38 similar hematopoietic Acute Radiation Syndrome studies conducted over a 7-y period in the authors’ laboratory, comprising more than 1,500 irradiated young adult C57BL/6 mice and almost 600 day-30 survivors, was assessed for hematopoietic delayed effects of Acute Radiation exposure at various times up to 30 mo of age. Significant loss of long-term repopulating potential of phenotypically defined primitive hematopoietic stem cells was documented in hematopoietic Acute Radiation Syndrome survivors, as well as significant decreases in all hematopoietic lineages in peripheral blood, prominent myeloid skew, significantly decreased bone marrow cellularity, and numbers of lineage-negative Sca-1+ cKit+ CD150+ cells (KSL CD150+; the phenotype known to be enriched for hematopoietic stem cells), and increased cycling of KSL CD150+ cells. Studies interrogating the phenotype of bone marrow cells capable of initiation of suspension cultures and engraftment in competitive transplantation assays documented the phenotype of hematopoietic stem cells in hematopoietic Acute Radiation Syndrome survivors to be the same as that in nonirradiated age-matched controls. This compilation study adds rigor and validity to our initial findings of persistent hematopoietic dysfunction in hematopoietic Acute Radiation Syndrome survivors that arises at the level of the hematopoietic stem cell and which affects all classes of hematopoietic cells for the life of the survivor.

  • The Gastrointestinal SubSyndrome of the Acute Radiation Syndrome in Rhesus Macaques: A Systematic Review of the Lethal Dose-response Relationship With and Without Medical Management.
    Health physics, 2019
    Co-Authors: Thomas J. Macvittie, Ann M. Farese, Gregory Tudor, Catherine Booth, George A. Parker, William E. Jackson, Kim G. Hankey, Christopher S Potten
    Abstract:

    Well-characterized animal models that mimic the human response to potentially lethal doses of Radiation are required to assess the efficacy of medical countermeasures under the criteria of the US Food and Drug Administration‘s Animal Rule. Development of a model for the gastrointestinal Acute Radiation Syndrome requires knowledge of the Radiation dose-response relationship and time course of mortality and morbidity across the Acute and prolonged gastrointestinal Radiation Syndrome. The nonhuman primate, rhesus macaque, is a relevant animal model that has been used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality relative to the hematopoietic Acute Radiation Syndrome, gastrointestinal Acute Radiation Syndrome, and lung injury. It can be used to assess the natural history of gastrointestinal damage, concurrent multiple organ injury, and aspects of the mechanism of action for Acute Radiation exposure and treatment. A systematic review of relevant studies that determined the dose-response relationship for the gastrointestinal Acute and prolonged Radiation Syndrome in the rhesus macaque relative to Radiation dose, quality, dose rate, exposure uniformity, and use of medical management has never been performed.

Thomas M. Seed – One of the best experts on this subject based on the ideXlab platform.

  • Entolimod as a Radiation countermeasure for Acute Radiation Syndrome.
    Drug discovery today, 2020
    Co-Authors: Vijay K. Singh, Thomas M. Seed
    Abstract:

    High doses of total-body or partial-body Radiation exposure can result in a life-threatening Acute Radiation Syndrome as manifested by severe morbidity. Entolimod (CBLB502) is effective in protecting against, and mitigating the development of, the hematopoietic and gastrointestinal subSyndromes of the Acute Radiation Syndrome in rodents and nonhuman primates. Entolimod treatment reduces Radiation-induced apoptosis and accelerates the regeneration of progenitors in Radiation-damaged tissues. The drug has been evaluated clinically for its pharmacokinetics (PK), toxicity, and biomarkers. The US Food and Drug Administration (FDA) has granted investigational new drug, fast-track, and orphan drug statuses to entolimod. Its safety, efficacy, and animal-to-human dose conversion data allowed its progression with a pre-emergency use authorization application submission.

  • BIO 300: a promising Radiation countermeasure under advanced development for Acute Radiation Syndrome and the delayed effects of Acute Radiation exposure.
    Expert opinion on investigational drugs, 2020
    Co-Authors: Vijay K. Singh, Thomas M. Seed
    Abstract:

    There are no radioprotectors currently approved by the United States Food and Drug Administration (US FDA) for either the hematopoietic Acute Radiation Syndrome (H-ARS) or for the Acute Radiation g…

  • The efficacy and safety of amifostine for the Acute Radiation Syndrome
    Expert opinion on drug safety, 2019
    Co-Authors: Vijay K. Singh, Thomas M. Seed
    Abstract:

    Introduction: A Radiation countermeasure that can be used prior to Radiation exposure to protect the population from the harmful effects of Radiation exposure remains a major unmet medical need and is recognized as an important area for research. Despite substantial advances in the research and development for finding nontoxic, safe, and effective prophylactic countermeasures for the Acute Radiation Syndrome (ARS), no such agent has been approved by the United States Food and Drug Administration (FDA). Area covered: Despite the progress made to improve the effectiveness of amifostine as a radioprotector for ARS, none of the strategies have resolved the issue of its toxicity/side effects. Thus, the FDA has approved amifostine for limited clinical indications, but not for non-clinical uses. This article reviews recent strategies and progress that have been made to move forward this potentially useful countermeasure for ARS. Expert opinion: Although the recent investigations have been promising for fielding safe and effective Radiation countermeasures, additional work is needed to improve and advance drug design and delivery strategies to get FDA approval for broadened, non-clinical use of amifostine during a radiological/nuclear scenario.