Sample records for accidental radiation-induced hematopoietic

  1. Hematopoietic stem cell injury induced by ionizing radiation.

    PubMed

    Shao, Lijian; Luo, Yi; Zhou, Daohong

    2014-03-20

    Exposure to ionizing radiation (IR) as the result of nuclear accidents or terrorist attacks is a significant threat and a major medical concern. Hematopoietic stem cell (HSC) injury is the primary cause of death after accidental or intentional exposure to a moderate or high dose of IR. Protecting HSCs from IR should be a primary goal in the development of novel medical countermeasures against radiation. Significant progress has been made in our understanding of the mechanisms by which IR causes HSC damage. The mechanisms include (i) induction of HSC apoptosis via the p53-Puma pathway; (ii) promotion of HSC differentiation via the activation of the G-CSF/Stat3/BATF-dependent differentiation checkpoint; (iii) induction of HSC senescence via the ROS-p38 pathway; and (iv) damage to the HSC niche. Induction of apoptosis in HSCs and hematopoietic progenitor cells is primarily responsible for IR-induced acute bone marrow (BM) injury. Long-term BM suppression caused by IR is mainly attributable to the induction of HSC senescence. However, the promotion of HSC differentiation and damage to the HSC niche can contribute to both the acute and long-term effects of IR on the hematopoietic system. In this review, we have summarized a number of recent findings that provide new insights into the mechanisms whereby IR damages HSCs. These findings will provide new opportunities for developing a mechanism-based strategy to prevent and/or mitigate IR-induced BM suppression. Antioxid.

  2. Hematopoietic Stem Cell Injury Induced by Ionizing Radiation

    PubMed Central

    Shao, Lijian; Luo, Yi

    2014-01-01

    Abstract Significance: Exposure to ionizing radiation (IR) as the result of nuclear accidents or terrorist attacks is a significant threat and a major medical concern. Hematopoietic stem cell (HSC) injury is the primary cause of death after accidental or intentional exposure to a moderate or high dose of IR. Protecting HSCs from IR should be a primary goal in the development of novel medical countermeasures against radiation. Recent Advances: Significant progress has been made in our understanding of the mechanisms by which IR causes HSC damage. The mechanisms include (i) induction of HSC apoptosis via the p53-Puma pathway; (ii) promotion of HSC differentiation via the activation of the G-CSF/Stat3/BATF-dependent differentiation checkpoint; (iii) induction of HSC senescence via the ROS-p38 pathway; and (iv) damage to the HSC niche. Critical Issues: Induction of apoptosis in HSCs and hematopoietic progenitor cells is primarily responsible for IR-induced acute bone marrow (BM) injury. Long-term BM suppression caused by IR is mainly attributable to the induction of HSC senescence. However, the promotion of HSC differentiation and damage to the HSC niche can contribute to both the acute and long-term effects of IR on the hematopoietic system. Future Directions: In this review, we have summarized a number of recent findings that provide new insights into the mechanisms whereby IR damages HSCs. These findings will provide new opportunities for developing a mechanism-based strategy to prevent and/or mitigate IR-induced BM suppression. Antioxid. Redox Signal. 20, 1447–1462. PMID:24124731

  3. Serum microRNAs are early indicators of survival after radiation-induced hematopoietic injury

    PubMed Central

    Acharya, Sanket S.; Fendler, Wojciech; Watson, Jacqueline; Hamilton, Abigail; Pan, Yunfeng; Gaudiano, Emily; Moskwa, Patryk; Bhanja, Payel; Saha, Subhrajit; Guha, Chandan; Parmar, Kalindi; Chowdhury, Dipanjan

    2015-01-01

    Accidental radiation exposure is a threat to human health that necessitates effective clinical planning and diagnosis. Minimally invasive biomarkers that can predict long-term radiation injury are urgently needed for optimal management after a radiation accident. We have identified serum microRNA (miRNA) signatures that indicate long-term impact of total body irradiation (TBI) in mice when measured within 24 hours of exposure. Impact of TBI on the hematopoietic system was systematically assessed to determine a correlation of residual hematopoietic stem cells (HSCs) with increasing doses of radiation. Serum miRNA signatures distinguished untreated mice from animals exposed to radiation and correlated with the impact of radiation on HSCs. Mice exposed to sublethal (6.5 Gy) and lethal (8 Gy) doses of radiation were indistinguishable for 3 to 4 weeks after exposure. A serum miRNA signature detectable 24 hours after radiation exposure consistently segregated these two cohorts. Furthermore, using either a radioprotective agent before, or radiation mitigation after, lethal radiation, we determined that the serum miRNA signature correlated with the impact of radiation on animal health rather than the radiation dose. Last, using humanized mice that had been engrafted with human CD34+ HSCs, we determined that the serum miRNA signature indicated radiation-induced injury to the human bone marrow cells. Our data suggest that serum miRNAs can serve as functional dosimeters of radiation, representing a potential breakthrough in early assessment of radiation-induced hematopoietic damage and timely use of medical countermeasures to mitigate the long-term impact of radiation. PMID:25972001

  4. Mitigation of radiation-induced hematopoietic injury by the polyphenolic acetate 7, 8-diacetoxy-4-methylthiocoumarin in mice

    PubMed Central

    Venkateswaran, Kavya; Shrivastava, Anju; Agrawala, Paban K.; Prasad, Ashok; Kalra, Namita; Pandey, Parvat R.; Manda, Kailash; Raj, Hanumantharao G.; Parmar, Virinder S.; Dwarakanath, Bilikere S.

    2016-01-01

    Protection of the hematopoietic system from radiation damage, and/or mitigation of hematopoietic injury are the two major strategies for developing medical countermeasure agents (MCM) to combat radiation-induced lethality. In the present study, we investigated the potential of 7, 8-diacetoxy-4-methylthiocoumarin (DAMTC) to ameliorate radiation-induced hematopoietic damage and the associated mortality following total body irradiation (TBI) in C57BL/6 mice. Administration of DAMTC 24 hours post TBI alleviated TBI-induced myelo-suppression and pancytopenia, by augmenting lymphocytes and WBCs in the peripheral blood of mice, while bone marrow (BM) cellularity was restored through enhanced proliferation of the stem cells. It stimulated multi-lineage expansion and differentiation of myeloid progenitors in the BM and induced proliferation of splenic progenitors thereby, facilitating hematopoietic re-population. DAMTC reduced the radiation-induced apoptotic and mitotic death in the hematopoietic compartment. Recruitment of pro-inflammatory M1 macrophages in spleen contributed to the immune-protection linked to the mitigation of hematopoietic injury. Recovery of the hematopoietic compartment correlated well with mitigation of mortality at a lethal dose of 9 Gy, leading to 80% animal survival. Present study establishes the potential of DAMTC to mitigate radiation-induced injury to the hematopoietic system by stimulating the re-population of stem cells from multiple lineages. PMID:27849061

  5. Rutin-Enriched Extract from Coriandrum sativum L. Ameliorates Ionizing Radiation-Induced Hematopoietic Injury

    PubMed Central

    Han, Xiaodan; Xue, Xiaolei; Zhao, Yu; Li, Yuan; Liu, Weili; Zhang, Junling; Fan, Saijun

    2017-01-01

    Hematopoietic injury is a major cause of mortality in radiation accidents and a primary side effect in patients undergoing radiotherapy. Ionizing radiation (IR)-induced myelosuppression is largely attributed to the injury of hematopoietic stem and progenitor cells (HSPCs). Coriander is a culinary herb with multiple pharmacological effects and has been widely used in traditional medicine. In this study, flavonoids were identified as the main component of coriander extract with rutin being the leading compound (rutin-enriched coriander extract; RE-CE). We evaluated the radioprotective effect of RE-CE against IR-induced HSPCs injury. Results showed that RE-CE treatment markedly improved survival, ameliorated organ injuries and myelosuppression, elevated HSPCs frequency, and promoted differentiation and proliferation of HSPCs in irradiated mice. The protective role of RE-CE in hematopoietic injury is probably attributed to its anti-apoptotic and anti-DNA damage effect in irradiated HSPCs. Moreover, these changes were associated with reduced reactive oxygen species (ROS) and enhanced antioxidant enzymatic activities in irradiated HSPCs. Collectively, these findings demonstrate that RE-CE is able to ameliorate IR-induced hematopoietic injury partly by reducing IR-induced oxidative stress. PMID:28468251

  6. C/EBPδ deficiency sensitizes mice to ionizing radiation-induced hematopoietic and intestinal injury.

    PubMed

    Pawar, Snehalata A; Shao, Lijian; Chang, Jianhui; Wang, Wenze; Pathak, Rupak; Zhu, Xiaoyan; Wang, Junru; Hendrickson, Howard; Boerma, Marjan; Sterneck, Esta; Zhou, Daohong; Hauer-Jensen, Martin

    2014-01-01

    Knowledge of the mechanisms involved in the radiation response is critical for developing interventions to mitigate radiation-induced injury to normal tissues. Exposure to radiation leads to increased oxidative stress, DNA-damage, genomic instability and inflammation. The transcription factor CCAAT/enhancer binding protein delta (Cebpd; C/EBPδ is implicated in regulation of these same processes, but its role in radiation response is not known. We investigated the role of C/EBPδ in radiation-induced hematopoietic and intestinal injury using a Cebpd knockout mouse model. Cebpd-/- mice showed increased lethality at 7.4 and 8.5 Gy total-body irradiation (TBI), compared to Cebpd+/+ mice. Two weeks after a 6 Gy dose of TBI, Cebpd-/- mice showed decreased recovery of white blood cells, neutrophils, platelets, myeloid cells and bone marrow mononuclear cells, decreased colony-forming ability of bone marrow progenitor cells, and increased apoptosis of hematopoietic progenitor and stem cells compared to Cebpd+/+ controls. Cebpd-/- mice exhibited a significant dose-dependent decrease in intestinal crypt survival and in plasma citrulline levels compared to Cebpd+/+ mice after exposure to radiation. This was accompanied by significantly decreased expression of γ-H2AX in Cebpd-/- intestinal crypts and villi at 1 h post-TBI, increased mitotic index at 24 h post-TBI, and increase in apoptosis in intestinal crypts and stromal cells of Cebpd-/- compared to Cebpd+/+ mice at 4 h post-irradiation. This study uncovers a novel biological function for C/EBPδ in promoting the response to radiation-induced DNA-damage and in protecting hematopoietic and intestinal tissues from radiation-induced injury.

  7. Acute radiation syndrome caused by accidental radiation exposure - therapeutic principles.

    PubMed

    Dörr, Harald; Meineke, Viktor

    2011-11-25

    Fortunately radiation accidents are infrequent occurrences, but since they have the potential of large scale events like the nuclear accidents of Chernobyl and Fukushima, preparatory planning of the medical management of radiation accident victims is very important. Radiation accidents can result in different types of radiation exposure for which the diagnostic and therapeutic measures, as well as the outcomes, differ. The clinical course of acute radiation syndrome depends on the absorbed radiation dose and its distribution. Multi-organ-involvement and multi-organ-failure need be taken into account. The most vulnerable organ system to radiation exposure is the hematopoietic system. In addition to hematopoietic syndrome, radiation induced damage to the skin plays an important role in diagnostics and the treatment of radiation accident victims. The most important therapeutic principles with special reference to hematopoietic syndrome and cutaneous radiation syndrome are reviewed.

  8. Amelioration of radiation-induced hematopoietic and gastrointestinal damage by Ex-RAD® in mice

    PubMed Central

    Ghosh, Sanchita P.; Kulkarni, Shilpa; Perkins, Michael W.; Hieber, Kevin; Pessu, Roli L.; Gambles, Kristen; Maniar, Manoj; Kao, Tzu-Cheg; Seed, Thomas M.; Kumar, K. Sree

    2012-01-01

    The aim of the present study was to assess recovery from hematopoietic and gastrointestinal damage by Ex-RAD®, also known as ON01210.Na (4-carboxystyryl-4-chlorobenzylsulfone, sodium salt), after total body radiation. In our previous study, we reported that Ex-RAD, a small-molecule radioprotectant, enhances survival of mice exposed to gamma radiation, and prevents radiation-induced apoptosis as measured by the inhibition of radiation-induced protein 53 (p53) expression in cultured cells. We have expanded this study to determine best effective dose, dose-reduction factor (DRF), hematological and gastrointestinal protection, and in vivo inhibition of p53 signaling. A total of 500 mg/kg of Ex-RAD administered at 24 h and 15 min before radiation resulted in a DRF of 1.16. Ex-RAD ameliorated radiation-induced hematopoietic damage as monitored by the accelerated recovery of peripheral blood cells, and protection of granulocyte macrophage colony-forming units (GM-CFU) in bone marrow. Western blot analysis on spleen indicated that Ex-RAD treatment inhibited p53 phosphorylation. Ex-RAD treatment reduces terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay (TUNEL)-positive cells in jejunum compared with vehicle-treated mice after radiation injury. Finally, Ex-RAD preserved intestinal crypt cells compared with the vehicle control at 13 and 14 Gy. The results demonstrated that Ex-RAD ameliorates radiation-induced peripheral blood cell depletion, promotes bone marrow recovery, reduces p53 signaling in spleen and protects intestine from radiation injury. PMID:22843617

  9. Loss of β-catenin triggers oxidative stress and impairs hematopoietic regeneration

    PubMed Central

    Lento, William; Ito, Takahiro; Zhao, Chen; Harris, Jeffrey R.; Huang, Wei; Jiang, Chen; Owzar, Kouros; Piryani, Sadhna; Racioppi, Luigi; Chao, Nelson; Reya, Tannishtha

    2014-01-01

    Accidental or deliberate ionizing radiation exposure can be fatal due to widespread hematopoietic destruction. However, little is known about either the course of injury or the molecular pathways that regulate the subsequent regenerative response. Here we show that the Wnt signaling pathway is critically important for regeneration after radiation-induced injury. Using Wnt reporter mice, we show that radiation triggers activation of Wnt signaling in hematopoietic stem and progenitor cells. β-Catenin-deficient mice, which lack the ability to activate canonical Wnt signaling, exhibited impaired hematopoietic stem cell regeneration and bone marrow recovery after radiation. We found that, as part of the mechanism, hematopoietic stem cells lacking β-catenin fail to suppress the generation of reactive oxygen species and cannot resolve DNA double-strand breaks after radiation. Consistent with the impaired response to radiation, β-catenin-deficient mice are also unable to recover effectively after chemotherapy. Collectively, these data indicate that regenerative responses to distinct hematopoietic injuries share a genetic dependence on β-catenin and raise the possibility that modulation of Wnt signaling may be a path to improving bone marrow recovery after damage. PMID:24788518

  10. Epidemiology of accidental radiation exposures.

    PubMed Central

    Cardis, E

    1996-01-01

    Much of the information on the health effects of radiation exposure available to date comes from long-term studies of the atomic bombings in Hiroshima and Nagasaki. Accidental exposures, such as those resulting from the Chernobyl and Kyshtym accidents, have as yet provided little information concerning health effects of ionizing radiation. This paper will present the current state of our knowledge concerning radiation effects, review major large-scale accidental radiation exposures, and discuss information that could be obtained from studies of accidental exposures and the types of studies that are needed. PMID:8781398

  11. The potential benefits of nicaraven to protect against radiation-induced injury in hematopoietic stem/progenitor cells with relative low dose exposures

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ali, Haytham; Department of Medical Physiology and Cell Biology, Qena Faculty of Medicine, South Valley University; Galal, Omima

    Highlights: • Nicaraven mitigated the radiation-induced reduction of c-kit{sup +} stem cells. • Nicaraven enhanced the function of hematopoietic stem/progenitor cells. • Complex mechanisms involved in the protection of nicaraven to radiation injury. - Abstract: Nicaraven, a hydroxyl radical-specific scavenger has been demonstrated to attenuate radiation injury in hematopoietic stem cells with 5 Gy γ-ray exposures. We explored the effect and related mechanisms of nicaraven for protecting radiation injury induced by sequential exposures to a relatively lower dose γ-ray. C57BL/6 mice were given nicaraven or placebo within 30 min before exposure to 50 mGy γ-ray daily for 30 days inmore » sequences (cumulative dose of 1.5 Gy). Mice were victimized 24 h after the last radiation exposure, and the number, function and oxidative stress of hematopoietic stem cells were quantitatively estimated. We also compared the gene expression in these purified stem cells from mice received nicaraven and placebo treatment. Nicaraven increased the number of c-kit{sup +} stem/progenitor cells in bone marrow and peripheral blood, with a recovery rate around 60–90% of age-matched non-irradiated healthy mice. The potency of colony forming from hematopoietic stem/progenitor cells as indicator of function was completely protected with nicaraven treatment. Furthermore, nicaraven treatment changed the expression of many genes associated to DNA repair, inflammatory response, and immunomodulation in c-kit{sup +} stem/progenitor cells. Nicaraven effectively protected against damages of hematopoietic stem/progenitor cells induced by sequential exposures to a relatively low dose radiation, via complex mechanisms.« less

  12. PEGylated IL-11 (BBT-059): A Novel Radiation Countermeasure for Hematopoietic Acute Radiation Syndrome.

    PubMed

    Kumar, Vidya P; Biswas, Shukla; Sharma, Neel K; Stone, Sasha; Fam, Christine M; Cox, George N; Ghosh, Sanchita P

    2018-07-01

    Interleukin-11 was developed to reduce chemotherapy-induced thrombocytopenia; however, its clinical use was limited by severe adverse effects in humans. PEGylated interleukin-11 (BBT-059), developed by Bolder Biotechnology, Inc., exhibited a longer half-life in rodents and induced longer-lasting increases in hematopoietic cells than interleukin-11. A single dose of 1.2 mg kg of BBT-059, administered subcutaneously to CD2F1 mice (12-14 wk, male) was found to be safe in a 14 d toxicity study. The drug demonstrated its efficacy both as a prophylactic countermeasure and a mitigator in CD2F1 mice exposed to Co gamma total-body irradiation. A single dose of 0.3 mg kg, administered either 24 h pre-, 4 h post-, or 24 h postirradiation increased the survival of mice to 70-100% from lethal doses of radiation. Preadministration (-24 h) of the drug conferred a significantly (p < 0.05) higher survival compared to 24 h post-total-body irradiation. There was significantly accelerated recovery from radiation-induced peripheral blood neutropenia and thrombocytopenia in animals pretreated with BBT-059. The drug also increased bone marrow cellularity and megakaryocytes and accelerated multilineage hematopoietic recovery. In addition, BBT-059 inhibited the induction of radiation-induced hematopoietic biomarkers, thrombopoietin, erythropoietin, and Flt-3 ligand. These results indicate that BBT-059 is a promising radiation countermeasure, demonstrating its potential to be used both pre- and postirradiation for hematopoietic acute radiation syndrome with a broad window for medical management in a radiological or nuclear event.

  13. Low-dose radiation (LDR) induces hematopoietic hormesis: LDR-induced mobilization of hematopoietic progenitor cells into peripheral blood circulation.

    PubMed

    Li, Wei; Wang, Guanjun; Cui, Jiuwei; Xue, Lu; Cai, Lu

    2004-11-01

    The aim of this study was to investigate the stimulating effect of low-dose radiation (LDR) on bone marrow hematopoietic progenitor cell (HPC) proliferation and peripheral blood mobilization. Mice were exposed to 25- to 100-mGy x-rays. Bone marrow and peripheral blood HPCs (BFU-E, CFU-GM, and c-kit+ cells) were measured, and GM-CSF, G-CSF, and IL-3 protein and mRNA expression were detected using ELISA, slot blot hybridization, and Northern blot methods. To functionally evaluate LDR-stimulated and -mobilized HPCs, repopulation of peripheral blood cells in lethally irradiated recipients after transplantation of LDR-treated donor HPCs was examined by WBC counts, animal survival, and colony-forming units in the recipient spleens (CFUs-S). 75-mGy x-rays induced a maximal stimulation for bone marrow HPC proliferation (CFU-GM and BFU-E formation) 48 hours postirradiation, along with a significant increase in HPC mobilization into peripheral blood 48 to 72 hours postradiation, as shown by increases in CFU-GM formation and proportion of c-kit+ cells in the peripheral mononuclear cells. 75-mGy x-rays also maximally induced increases in G-CSF and GM-CSF mRNA expression in splenocytes and levels of serum GM-CSF. To define the critical role of these hematopoietic-stimulating factors in HPC peripheral mobilization, direct administration of G-CSF at a dose of 300 microg/kg/day or 150 microg/kg/day was applied and found to significantly stimulate GM-CFU formation and increase c-kit+ cells in the peripheral mononuclear cells. More importantly, 75-mGy x-rays plus 150 microg/kg/day G-CSF (LDR/150-G-CSF) produced a similar effect to that of 300 microg/kg/day G-CSF alone. Furthermore, the capability of LDR-mobilized donor HPCs to repopulate blood cells was confirmed in lethally irradiated recipient mice by counting peripheral WBC and CFUs-S. These results suggest that LDR induces hematopoietic hormesis, as demonstrated by HPC proliferation and peripheral mobilization, providing a

  14. Sensitivity and dose dependency of radiation-induced injury in hematopoietic stem/progenitor cells in mice

    PubMed Central

    Guo, Chang-Ying; Luo, Lan; Urata, Yoshishige; Goto, Shinji; Huang, Wen-Jing; Takamura, Syu; Hayashi, Fumiko; Doi, Hanako; Kitajima, Yuriko; Ono, Yusuke; Ogi, Tomoo; Li, Tao-Sheng

    2015-01-01

    We evaluated the sensitivity and dose dependency of radiation-induced injury in hematopoietic stem/progenitor cells. Adult C57BL/6 mice were daily exposed to 0, 2, 10, 50, and 250 mGy γ-ray for 1 month in succession, respectively. The damage of hematopoietic stem/progenitor cells in bone marrow were investigated within 2 hours (acute phase) or at 3 months (chronic phase) after the last exposure. Daily exposure to over 10 mGy γ-ray significantly decreased the number and colony-forming capacity of hematopoietic stem/progenitor cells at acute phase, and did not completely recover at chronic phase with 250 mGy exposure. Interestingly, the daily exposure to 10 or 50 mGy γ-ray decreased the formation of mixed types of colonies at chronic phase, but the total number of colonies was comparable to control. Immunostaining analysis showed that the formation of 53BP1 foci in c-kit+ stem/progenitor cells was significantly increased with daily exposure to 50 and 250 mGy at acute phase, and 250 mGy at chronic phase. Many genes involved in toxicity responses were up- or down-regulated with the exposures to all doses. Our data have clearly shown the sensitivity and dose dependency of radiation-induced injury in hematopoietic stem/progenitor cells of mice with daily exposures to 2 ~ 250 mGy γ-ray. PMID:25623887

  15. Filgrastim for the treatment of hematopoietic acute radiation syndrome.

    PubMed

    Farese, A M; MacVittie, T J

    2015-09-01

    The U.S. Food and Drug Administration (FDA) recently approved Neupogen(®) (filgrastim) for the treatment of patients with radiation-induced myelosuppression following a radiological/nuclear incident. It is the first medical countermeasure currently approved by the FDA for this indication under the criteria of the FDA "animal rule". This article summarizes the consequences of high-dose radiation exposure, a description of the hematopoietic acute radiation syndrome (H-ARS), the use of hematopoietic growth factors in radiation accident victims and current available treatments for H-ARS with an emphasis on the use of Neupogen in this scenario. Copyright 2015 Prous Science, S.A.U. or its licensors. All rights reserved.

  16. Stromal Progenitor Cells in Mitigation of Non-Hematopoietic Radiation Injuries

    PubMed Central

    Kulkarni, Shilpa; Wang, Timothy C.; Guha, Chandan

    2016-01-01

    Purpose of review Therapeutic exposure to high doses of radiation can severely impair organ function due to ablation of stem cells. Normal tissue injury is a dose-limiting toxicity for radiation therapy (RT). Although advances in the delivery of high precision conformal RT has increased normal tissue sparing, mitigating and therapeutic strategies that could alleviate early and chronic radiation effects are urgently needed in order to deliver curative doses of RT, especially in abdominal, pelvic and thoracic malignancies. Radiation-induced gastrointestinal injury is also a major cause of lethality from accidental or intentional exposure to whole body irradiation in the case of nuclear accidents or terrorism. This review examines the therapeutic options for mitigation of non-hematopoietic radiation injuries. Recent findings We have developed stem cell based therapies for the mitigation of acute radiation syndrome (ARS) and radiation-induced gastrointestinal syndrome (RIGS). This is a promising option because of the robustness of standardized isolation and transplantation of stromal cells protocols, and their ability to support and replace radiation-damaged stem cells and stem cell niche. Stromal progenitor cells (SPC) represent a unique multipotent and heterogeneous cell population with regenerative, immunosuppressive, anti-inflammatory, and wound healing properties. SPC are also known to secrete various key cytokines and growth factors such as platelet derived growth factors (PDGF), keratinocyte growth factor (KGF), R-spondins (Rspo), and may consequently exert their regenerative effects via paracrine function. Additionally, secretory vesicles such as exosomes or microparticles can potentially be a cell-free alternative replacing the cell transplant in some cases. Summary This review highlights the beneficial effects of SPC on tissue regeneration with their ability to (a) target the irradiated tissues, (b) recruit host stromal cells, (c) regenerate endothelium and

  17. 21 CFR 1002.20 - Reporting of accidental radiation occurrences.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Reporting of accidental radiation occurrences... SERVICES (CONTINUED) RADIOLOGICAL HEALTH RECORDS AND REPORTS Manufacturers' Reports on Accidental Radiation Occurrences § 1002.20 Reporting of accidental radiation occurrences. (a) Manufacturers of electronic products...

  18. 21 CFR 1002.20 - Reporting of accidental radiation occurrences.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Reporting of accidental radiation occurrences... SERVICES (CONTINUED) RADIOLOGICAL HEALTH RECORDS AND REPORTS Manufacturers' Reports on Accidental Radiation Occurrences § 1002.20 Reporting of accidental radiation occurrences. (a) Manufacturers of electronic products...

  19. 21 CFR 1002.20 - Reporting of accidental radiation occurrences.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Reporting of accidental radiation occurrences... SERVICES (CONTINUED) RADIOLOGICAL HEALTH RECORDS AND REPORTS Manufacturers' Reports on Accidental Radiation Occurrences § 1002.20 Reporting of accidental radiation occurrences. (a) Manufacturers of electronic products...

  20. Hematopoietic Acute Radiation Syndrome (Bone marrow syndrome, Aplastic Anemia): Molecular Mechanisms of Radiation Toxicity.

    NASA Astrophysics Data System (ADS)

    Popov, Dmitri

    Radiation Toxins (SRD-4) to radiation naive animals in doses 0.1 mg/kg; 0,5 mg/kg; 1 mg/kg; 2 mg/kg; 3 mg/kg up to 30 mg/kg. Results: After I/V or I/M administration of Hematotoxic Radiation Toxins to radiation -naive animals the induction of specific clinical signs was observed- including thrombocytopenia, lymphocytosis followed by lymphocytopenia, granulocytopenia , aplastic anemia, and the clinical manifestations- ecchymosis, hemorrhage and coagulopathy. These observed clinical signs mimic the acute/hematopoietic acute radiation syndrome. Conclusions: Administration of Hematopoietic Radiation Toxins (SRD-4) to radiation naive animals in doses 0.1 mg/kg;0,5 mg/kg; 1 mg/kg; 2 mg/kg; 3 mg/kg up to 30 mg/kg produced specific toxic reactions with the development of signs and symptoms consistent with the hematological form of Acute Radiation Syndromes. Administration of high doses of Hematopoietic Radiation Toxins developed a clinical picture identical to severe Acute Radiation Exposure Syndrome and induces Toxic Multiple Organ Failure (TMOF) and Toxic Multiple Organ Involvement (TMOI) {i.e. pneumonitis, renal failure, renal hypo-perfusion, acute tubular necrosis, hepatic failure, etc.} essentially as which occurs as an acute consequence of radiation toxemia. Aplastic anemia is an important clinical and pathological process which develops after animals receive high doses of both radiation and administered radiation toxins.

  1. The triterpenoid RTA 408 is a robust mitigator of hematopoietic acute radiation syndrome in mice.

    PubMed

    Goldman, Devorah C; Alexeev, Vitali; Lash, Elizabeth; Guha, Chandan; Rodeck, Ulrich; Fleming, William H

    2015-03-01

    Bone marrow suppression due to exposure to ionizing radiation is a significant clinical problem associated with radiation therapy as well as with nonmedical radiation exposure. Currently, there are no small molecule agents available that can enhance hematopoietic regeneration after radiation exposure. Here, we report on the effective mitigation of acute hematopoietic radiation syndrome in mice by the synthetic triterpenoid, RTA 408. The administration of a brief course of RTA 408 treatment, beginning 24 h after lethal doses of radiation to bone marrow, significantly increased overall survival. Importantly, treatment with RTA 408 led to the full recovery of steady state hematopoiesis with normalization of the frequency of hematopoietic stem and progenitor cells. Moreover, hematopoietic stem cells from RTA 408-mitigated mice showed lineage-balanced, long-term, multilineage potential in serial transplantation assays, indicative of their normal self-renewal activity. The potency of RTA 408 in mitigating radiation-induced bone marrow suppression makes it an attractive candidate for potential clinical use in treating both therapy-related and unanticipated radiation exposure.

  2. Hematopoietic recovery of acute radiation syndrome by human superoxide dismutase-expressing umbilical cord mesenchymal stromal cells.

    PubMed

    Gan, Jingyi; Meng, Fanwei; Zhou, Xin; Li, Chan; He, Yixin; Zeng, Xiaoping; Jiang, Xingen; Liu, Jia; Zeng, Guifang; Tang, Yunxia; Liu, Muyun; Mrsny, Randall J; Hu, Xiang; Hu, Jifan; Li, Tao

    2015-04-01

    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. 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. 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. 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. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  3. Sodium orthovanadate (vanadate), a potent mitigator of radiation-induced damage to the hematopoietic system in mice

    PubMed Central

    Wang, Bing; Tanaka, Kaoru; Morita, Akinori; Ninomiya, Yasuharu; Maruyama, Kouichi; Fujita, Kazuko; Hosoi, Yoshio; Nenoi, Mitsuru

    2013-01-01

    Previous in vitro and in vivo studies have shown that sodium orthovanadate (vanadate), an inorganic vanadium compound, could effectively suppress radiation-induced p53-mediated apoptosis via both transcription-dependent and transcription-independent pathways. As a potent radiation protector administered at a dose of 20 mg/kg body weight (20 mg/kg) prior to total body irradiation (TBI) by intra-peritoneal (ip) injection, it completely protected mice from hematopoietic syndrome and partially from gastrointestinal syndrome. In the present study, radiation mitigation effects from vanadate were investigated by ip injection of vanadate after TBI in mice. Results showed that a single administration of vanadate at a dose of 20 mg/kg markedly improved the 30-day survival rate and the peripheral blood hemogram, relieved bone marrow aplasia and decreased occurrence of the bone marrow micronucleated erythrocytes in the surviving animals. The dose reduction factor was 1.2 when a single dose of 20 mg/kg was administered 15 min after TBI in mice using the 30-day survival test as the endpoint. Results also showed that either doubling the vanadate dose (40 mg/kg) in a single administration or continuing the vanadate treatment (after a single administration at 20 mg/kg) from the following day at a dose of 5 mg/kg per day for 4 consecutive days further significantly improved the efficacy for rescuing bone marrow failure in the 30-day survival test. Taken together, these findings indicate that vanadate would be a potent mitigator suppressing the acute lethality (hematopoietic syndrome) and minimizing the detrimental effects (anhematopoiesis and delayed genotoxic effects) induced by TBI in mice. PMID:23349341

  4. Protective Effects of 2-Amino-5,6-dihydro-4H-1,3-thiazine and Its Derivative against Radiation-Induced Hematopoietic and Intestinal Injury in Mice.

    PubMed

    Li, Yuanyuan; Kong, Shaofan; Yang, Fujun; Xu, Wenqing

    2018-05-21

    Ionizing radiation (IR) acts as an external stimulating factor, when it acts on the body, it will activate NF- κ B and cause the up-regulation of inducible nitric oxide synthase (iNOS) and induce a large amount of nitric oxide (NO) production. NO and other reactive nitrogen and oxygen species (RNS and ROS) can cause damage to biological molecules and affect their physiological functions. Our study investigated the protective role of 2-amino-5,6-dihydro-4 H -1,3-thiazine hydrobromide (2-ADT) and 2-acetylamino-5,6-dihydro-4 H -1,3-thiazine hydrobromide (2-AADT), two nitric oxide synthase inhibitors, against radiation-induced hematopoietic and intestinal injury in mice. Pretreatment with 2-ADT and 2-AADT improved the survival of mice exposed to a lethal dose of radiation, especially, the survival rate of the 2-ADT 20 mg/kg group was significantly higher than that of the vehicle group ( p < 0.001). Our findings indicated that the radioprotective actions of 2-ADT and 2-AADT are achieved via accelerating hematopoietic system recovery, decreasing oxidative and nitrosative stress by enhancing the antioxidant defense system and reducing NO as well as peroxynitrite (ONOO − ) content, and mitigating the radiation-induced DNA damage evaluated by comet assay. These results suggest that 2-ADT and 2-AADT may have great application potential in ameliorating the damages of radiotherapy.

  5. In vitro and in vivo assessment of direct effects of simulated solar and galactic cosmic radiation on human hematopoietic stem/progenitor cells.

    PubMed

    Rodman, C; Almeida-Porada, G; George, S K; Moon, J; Soker, S; Pardee, T; Beaty, M; Guida, P; Sajuthi, S P; Langefeld, C D; Walker, S J; Wilson, P F; Porada, C D

    2017-06-01

    Future deep space missions to Mars and near-Earth asteroids will expose astronauts to chronic solar energetic particles (SEP) and galactic cosmic ray (GCR) radiation, and likely one or more solar particle events (SPEs). Given the inherent radiosensitivity of hematopoietic cells and short latency period of leukemias, space radiation-induced hematopoietic damage poses a particular threat to astronauts on extended missions. We show that exposing human hematopoietic stem/progenitor cells (HSC) to extended mission-relevant doses of accelerated high-energy protons and iron ions leads to the following: (1) introduces mutations that are frequently located within genes involved in hematopoiesis and are distinct from those induced by γ-radiation; (2) markedly reduces in vitro colony formation; (3) markedly alters engraftment and lineage commitment in vivo; and (4) leads to the development, in vivo, of what appears to be T-ALL. Sequential exposure to protons and iron ions (as typically occurs in deep space) proved far more deleterious to HSC genome integrity and function than either particle species alone. Our results represent a critical step for more accurately estimating risks to the human hematopoietic system from space radiation, identifying and better defining molecular mechanisms by which space radiation impairs hematopoiesis and induces leukemogenesis, as well as for developing appropriately targeted countermeasures.

  6. In vitro and in vivo assessment of direct effects of simulated solar and galactic cosmic radiation on human hematopoietic stem/progenitor cells

    DOE PAGES

    Rodman, C.; Almeida-Porada, G.; George, S. K.; ...

    2016-11-24

    Future deep space missions to Mars and near-Earth asteroids will expose astronauts to chronic solar energetic particles (SEP) and galactic cosmic ray (GCR) radiation,and likely one or more solar particle events (SPEs).Given the inherent radiosensitivity of hematopoietic cells and short latency period of leukemias, space radiation-induced hematopoietic damage poses a particular threat to astronauts on extended missions.We show that exposing human hematopoietic stem/progenitor cells(HSC) toextended mission-relevant doses of accelerated high-energyprotons andiron ions leads to the following: (1) introduces mutations that are frequently located within genes involved in hematopoiesis and are distinct from those induced by γ-radiation; (2) markedly reduces inmore » vitro colony formation; (3)markedly alters engraftment and lineage commitment in vivo; and (4) leads to the development, in vivo, ofwhat appears to be T-ALL. Sequential exposure to protons and iron ions (as typically occurs in deep space) proved far more deleterious to HSC genome integrity and function than either particle species alone.Our results represent a critical step for more accurately estimating risks to the human hematopoietic system from space radiation, identifying and better defining molecular mechanisms by which space radiation impairs hematopoiesis and induces leukemogenesis, as well as for developing appropriately targeted countermeasures.« less

  7. In vitro and in vivo assessment of direct effects of simulated solar and galactic cosmic radiation on human hematopoietic stem/progenitor cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Rodman, C.; Almeida-Porada, G.; George, S. K.

    Future deep space missions to Mars and near-Earth asteroids will expose astronauts to chronic solar energetic particles (SEP) and galactic cosmic ray (GCR) radiation,and likely one or more solar particle events (SPEs).Given the inherent radiosensitivity of hematopoietic cells and short latency period of leukemias, space radiation-induced hematopoietic damage poses a particular threat to astronauts on extended missions.We show that exposing human hematopoietic stem/progenitor cells(HSC) toextended mission-relevant doses of accelerated high-energyprotons andiron ions leads to the following: (1) introduces mutations that are frequently located within genes involved in hematopoiesis and are distinct from those induced by γ-radiation; (2) markedly reduces inmore » vitro colony formation; (3)markedly alters engraftment and lineage commitment in vivo; and (4) leads to the development, in vivo, ofwhat appears to be T-ALL. Sequential exposure to protons and iron ions (as typically occurs in deep space) proved far more deleterious to HSC genome integrity and function than either particle species alone.Our results represent a critical step for more accurately estimating risks to the human hematopoietic system from space radiation, identifying and better defining molecular mechanisms by which space radiation impairs hematopoiesis and induces leukemogenesis, as well as for developing appropriately targeted countermeasures.« less

  8. Protective Role of Angiogenin Against Hematopoietic Syndrome of the Acute Radiation Syndrome

    DTIC Science & Technology

    2017-05-01

    AWARD NUMBER: W81XWH-15-1-0207 TITLE: “Protective Role of Angiogenin Against Hematopoietic Syndrome of the Acute Radiation Syndrome ...SUBTITLE Protective Role of Angiogenin Against Hematopoietic Syndrome 5a. CONTRACT NUMBER of the Acute Radiation Syndrome 5b. GRANT NUMBER 5c...hematopoietic syndrome of the acute radiation syndrome (H-ARS) and is able to attenuate the effect of residual bone marrow damage (RBMD) after

  9. Pleiotrophin mediates hematopoietic regeneration via activation of RAS.

    PubMed

    Himburg, Heather A; Yan, Xiao; Doan, Phuong L; Quarmyne, Mamle; Micewicz, Eva; McBride, William; Chao, Nelson J; Slamon, Dennis J; Chute, John P

    2014-11-01

    Hematopoietic stem cells (HSCs) are highly susceptible to ionizing radiation-mediated death via induction of ROS, DNA double-strand breaks, and apoptotic pathways. The development of therapeutics capable of mitigating ionizing radiation-induced hematopoietic toxicity could benefit both victims of acute radiation sickness and patients undergoing hematopoietic cell transplantation. Unfortunately, therapies capable of accelerating hematopoietic reconstitution following lethal radiation exposure have remained elusive. Here, we found that systemic administration of pleiotrophin (PTN), a protein that is secreted by BM-derived endothelial cells, substantially increased the survival of mice following radiation exposure and after myeloablative BM transplantation. In both models, PTN increased survival by accelerating the recovery of BM hematopoietic stem and progenitor cells in vivo. PTN treatment promoted HSC regeneration via activation of the RAS pathway in mice that expressed protein tyrosine phosphatase receptor-zeta (PTPRZ), whereas PTN treatment did not induce RAS signaling in PTPRZ-deficient mice, suggesting that PTN-mediated activation of RAS was dependent upon signaling through PTPRZ. PTN strongly inhibited HSC cycling following irradiation, whereas RAS inhibition abrogated PTN-mediated induction of HSC quiescence, blocked PTN-mediated recovery of hematopoietic stem and progenitor cells, and abolished PTN-mediated survival of irradiated mice. These studies demonstrate the therapeutic potential of PTN to improve survival after myeloablation and suggest that PTN-mediated hematopoietic regeneration occurs in a RAS-dependent manner.

  10. Consequences of irradiation on bone and marrow phenotypes, and its relation to disruption of hematopoietic precursors

    PubMed Central

    Green, Danielle E.; Rubin, Clinton T.

    2014-01-01

    The rising levels of radiation exposure, specifically for medical treatments and accidental exposures, have added great concern for the long term risks of bone fractures. Both the bone marrow and bone architecture are devastated following radiation exposure. Even sub-lethal doses cause a deficit to the bone marrow microenvironment, including a decline in hematopoietic cells, and this deficit occurs in a dose dependent fashion. Certain cell phenotypes though are more susceptible to radiation damage, with mesenchymal stem cells being more resilient than the hematopoietic stem cells. The decline in total bone marrow hematopoietic cells is accompanied with elevated adipocytes into the marrow cavity, thereby inhibiting hematopoiesis and recovery of the bone marrow microenvironment. Poor bone marrow is also associated with a decline in bone architectural quality. Therefore, the ability to maintain the bone marrow microenvironment would hinder much of the trabecular bone loss caused by radiation exposure, ultimately decreasing some comorbidities in patients exposed to radiation. PMID:24607941

  11. Combined mitigation of the gastrointestinal and hematopoietic acute radiation syndromes by an LPA2 receptor-specific nonlipid agonist.

    PubMed

    Patil, Renukadevi; Szabó, Erzsébet; Fells, James I; Balogh, Andrea; Lim, Keng G; Fujiwara, Yuko; Norman, Derek D; Lee, Sue-Chin; Balazs, Louisa; Thomas, Fridtjof; Patil, Shivaputra; Emmons-Thompson, Karin; Boler, Alyssa; Strobos, Jur; McCool, Shannon W; Yates, C Ryan; Stabenow, Jennifer; Byrne, Gerrald I; Miller, Duane D; Tigyi, Gábor J

    2015-02-19

    Pharmacological mitigation of injuries caused by high-dose ionizing radiation is an unsolved medical problem. A specific nonlipid agonist of the type 2 G protein coupled receptor for lysophosphatidic acid (LPA2) 2-[4-(1,3-dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl]benzoic acid (DBIBB) when administered with a postirradiation delay of up to 72 hr reduced mortality of C57BL/6 mice but not LPA2 knockout mice. DBIBB mitigated the gastrointestinal radiation syndrome, increased intestinal crypt survival and enterocyte proliferation, and reduced apoptosis. DBIBB enhanced DNA repair by augmenting the resolution of γ-H2AX foci, increased clonogenic survival of irradiated IEC-6 cells, attenuated the radiation-induced death of human CD34(+) hematopoietic progenitors and enhanced the survival of the granulocyte/macrophage lineage. DBIBB also increased the survival of mice suffering from the hematopoietic acute radiation syndrome after total-body irradiation. DBIBB represents a drug candidate capable of mitigating acute radiation syndrome caused by high-dose γ-radiation to the hematopoietic and gastrointestinal system. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Protective Role of Angiogenin Against Hematopoietic Syndrome of the Acute Radiation Syndrome

    DTIC Science & Technology

    2016-09-01

    Syndrome of the Acute Radiation Syndrome PRINCIPAL...SUBTITLE 5a. CONTRACT NUMBER Protective Role of Angiogenin Against Hematopoietic Syndrome of the Acute Radiation Syndrome 5b. GRANT NUMBER W81XWH-15...protective role against hematopoietic syndrome of the acute radiation syndrome (H-ARS) and is able to attenuate the effect of residual bone marrow

  13. Protection of Radiation-Induced Damage to the Hematopoietic System, Small Intestine and Salivary Glands in Rats by JNJ7777120 Compound, a Histamine H4 Ligand

    PubMed Central

    Martinel Lamas, Diego J.; Carabajal, Eliana; Prestifilippo, Juan P.; Rossi, Luis; Elverdin, Juan C.; Merani, Susana; Bergoc, Rosa M.; Rivera, Elena S.; Medina, Vanina A.

    2013-01-01

    Based on previous data on the histamine radioprotective effect on highly radiosensitive tissues, in the present work we aimed at investigating the radioprotective potential of the H4R ligand, JNJ7777120, on ionizing radiation-induced injury and genotoxic damage in small intestine, salivary glands and hematopoietic tissue. For that purpose, rats were divided into 4 groups. JNJ7777120 and JNJ7777120-irradiated groups received a daily subcutaneous JNJ7777120 injection (10 mg/kg) starting 24 h before irradiation. Irradiated groups received a single dose of 5 Gy on whole-body using Cesium-137 source and were sacrificed 3 or 30 days after irradiation. Tissues were removed, fixed, stained with hematoxylin and eosin or PAS staining and histological characteristics were evaluated. Proliferative and apoptotic markers were studied by immunohistochemistry, while micronucleus assay was performed to evaluate DNA damage. Submandibular gland (SMG) function was evaluated by methacholine-induced salivation. Results indicate that JNJ7777120 treatment diminished mucosal atrophy and preserved villi and the number of crypts after radiation exposure (240±8 vs. 165±10, P<0.01). This effect was associated to a reduced apoptosis and DNA damage in intestinal crypts. JNJ7777120 reduced radiation-induced aplasia, preserving medullar components and reducing formation of micronucleus and also it accelerated bone marrow repopulation. Furthermore, it reduced micronucleus frequency in peripheral blood (27±8 vs. 149±22, in 1,000 erythrocytes, P<0.01). JNJ7777120 completely reversed radiation-induced reduced salivation, conserving glandular mass with normal histological appearance and reducing apoptosis and atrophy of SMG. JNJ7777120 exhibits radioprotective effects against radiation-induced cytotoxic and genotoxic damages in small intestine, SMG and hematopoietic tissues and, thus, could be of clinical value for patients undergoing radiotherapy. PMID:23922686

  14. Accelerated hematopoietic recovery with angiotensin-(1-7) after total body radiation.

    PubMed

    Rodgers, Kathleen E; Espinoza, Theresa; Roda, Norma; Meeks, Christopher J; Hill, Colin; Louie, Stan G; Dizerega, Gere S

    2012-06-01

    Angiotensin (1-7) [A(1-7)] is a component of the renin angiotensin system (RAS) that stimulates hematopoietic recovery after myelosuppression. In a Phase I/IIa clinical trial, thrombocytopenia after chemotherapy was reduced by A(1-7). In this study, the ability of A(1-7) to improve recovery after total body irradiation (TBI) is shown with specific attention to radiation-induced hematopoietic injury. Mice were exposed to TBI (doses of 2-7 Gray [Gy]) of cesium 137 gamma rays, followed by treatment with A(1-7), typical doses were 100-1000 μg/kg given once or once daily for a specified number of days depending on the study. Animals are injected subcutaneously via the nape of the neck with 0.1 ml drug in saline. The recovery of blood and bone marrow cells was determined. Effects of TBI and A(1-7) on survival and bleeding time was also evaluated. Daily administration of A(1-7) after radiation exposure improved survival (from 60% to 92-97%) and reduced bleeding time at day 30 after TBI. Further, A(1-7) increased early mixed progenitors (3- to 5-fold), megakaryocyte (2- to 3-fold), myeloid (3- to 6-fold) and erythroid (2- to 5-fold) progenitors in the bone marrow and reduced radiation-induced thrombocytopenia (RIT) (up to 2-fold). Reduction in the number of treatments to 3 per week also improved bone marrow recovery and reduced RIT. As emergency responder and healthcare systems in case of nuclear accident or/and terrorist attack may be overwhelmed, the consequence of delayed initiation of treatment was ascertained. Treatment with A(1-7) can be delayed up to 5 days and still be effective in the reduction of RIT or acceleration of bone marrow recovery. The data presented in this paper indicate that A(1-7) reduces the consequences of critical radiation exposure and can be initiated well after initial exposure with maximal effects on early responding hematopoietic progenitors when treatment is initiated 2 days after exposure and 5 days after exposure for the later responding

  15. Long-term hematopoietic stem cell damage in a murine model of the hematopoietic syndrome of the acute radiation syndrome.

    PubMed

    Chua, Hui Lin; Plett, P Artur; Sampson, Carol H; Joshi, Mandar; Tabbey, Rebeka; Katz, Barry P; MacVittie, Thomas J; Orschell, Christie M

    2012-10-01

    Residual bone marrow damage (RBMD) persists for years following exposure to radiation and is believed to be due to decreased self-renewal potential of radiation-damaged hematopoietic stem cells (HSC). Current literature has examined primarily sublethal doses of radiation and time points within a few months of exposure. In this study, the authors examined RBMD in mice surviving lethal doses of total body ionizing irradiation (TBI) in a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS). Survivors were analyzed at various time points up to 19 mo post-TBI for hematopoietic function. The competitive bone marrow (BM) repopulating potential of 150 purified c-Kit+ Sca-1+ lineage- CD150+ cells (KSLCD150+) remained severely deficient throughout the study compared to KSLCD150+ cells from non-TBI age-matched controls. The minimal engraftment from these TBI HSCs is predominantly myeloid, with minimal production of lymphocytes both in vitro and in vivo. All classes of blood cells as well as BM cellularity were significantly decreased in TBI mice, especially at later time points as mice aged. Primitive BM hematopoietic cells (KSLCD150+) displayed significantly increased cell cycling in TBI mice at all time points, which may be a physiological attempt to maintain HSC numbers in the post-irradiation state. Taken together, these data suggest that the increased cycling among primitive hematopoietic cells in survivors of lethal radiation may contribute to long-term HSC exhaustion and subsequent RBMD, exacerbated by the added insult of aging at later time points.

  16. Linking Doses with Clinical Scores of Hematopoietic Acute Radiation Syndrome.

    PubMed

    Hu, Shaowen

    2016-10-01

    In radiation accidents, determining the radiation dose the victim received is a key step for medical decision making and patient prognosis. To reconstruct and evaluate the absorbed dose, researchers have developed many physical devices and biological techniques during the last decades. However, using the physical parameter "absorbed dose" alone is not sufficient to predict the clinical development of the various organs injured in an individual patient. In operational situations for radiation accidents, medical responders need more urgently to classify the severity of the radiation injury based on the signs and symptoms of the patient. In this work, the author uses a unified hematopoietic model to describe dose-dependent dynamics of granulocytes, lymphocytes, and platelets, and the corresponding clinical grading of hematopoietic acute radiation syndrome. This approach not only visualizes the time course of the patient's probable outcome in the form of graphs but also indirectly gives information of the remaining stem and progenitor cells, which are responsible for the autologous recovery of the hematopoietic system. Because critical information on the patient's clinical evolution can be provided within a short time after exposure and only peripheral cell counts are required for the simulation, these modeling tools will be useful to assess radiation exposure and injury in human-involved radiation accident/incident scenarios.

  17. Hematopoietic cell differentiation from embryonic and induced pluripotent stem cells

    PubMed Central

    2013-01-01

    Pluripotent stem cells, both embryonic stem cells and induced pluripotent stem cells, are undifferentiated cells that can self-renew and potentially differentiate into all hematopoietic lineages, such as hematopoietic stem cells (HSCs), hematopoietic progenitor cells and mature hematopoietic cells in the presence of a suitable culture system. Establishment of pluripotent stem cells provides a comprehensive model to study early hematopoietic development and has emerged as a powerful research tool to explore regenerative medicine. Nowadays, HSC transplantation and hematopoietic cell transfusion have successfully cured some patients, especially in malignant hematological diseases. Owing to a shortage of donors and a limited number of the cells, hematopoietic cell induction from pluripotent stem cells has been regarded as an alternative source of HSCs and mature hematopoietic cells for intended therapeutic purposes. Pluripotent stem cells are therefore extensively utilized to facilitate better understanding in hematopoietic development by recapitulating embryonic development in vivo, in which efficient strategies can be easily designed and deployed for the generation of hematopoietic lineages in vitro. We hereby review the current progress of hematopoietic cell induction from embryonic stem/induced pluripotent stem cells. PMID:23796405

  18. Pleiotrophin mediates hematopoietic regeneration via activation of RAS

    PubMed Central

    Himburg, Heather A.; Yan, Xiao; Doan, Phuong L.; Quarmyne, Mamle; Micewicz, Eva; McBride, William; Chao, Nelson J.; Slamon, Dennis J.; Chute, John P.

    2014-01-01

    Hematopoietic stem cells (HSCs) are highly susceptible to ionizing radiation–mediated death via induction of ROS, DNA double-strand breaks, and apoptotic pathways. The development of therapeutics capable of mitigating ionizing radiation–induced hematopoietic toxicity could benefit both victims of acute radiation sickness and patients undergoing hematopoietic cell transplantation. Unfortunately, therapies capable of accelerating hematopoietic reconstitution following lethal radiation exposure have remained elusive. Here, we found that systemic administration of pleiotrophin (PTN), a protein that is secreted by BM-derived endothelial cells, substantially increased the survival of mice following radiation exposure and after myeloablative BM transplantation. In both models, PTN increased survival by accelerating the recovery of BM hematopoietic stem and progenitor cells in vivo. PTN treatment promoted HSC regeneration via activation of the RAS pathway in mice that expressed protein tyrosine phosphatase receptor-zeta (PTPRZ), whereas PTN treatment did not induce RAS signaling in PTPRZ-deficient mice, suggesting that PTN-mediated activation of RAS was dependent upon signaling through PTPRZ. PTN strongly inhibited HSC cycling following irradiation, whereas RAS inhibition abrogated PTN-mediated induction of HSC quiescence, blocked PTN-mediated recovery of hematopoietic stem and progenitor cells, and abolished PTN-mediated survival of irradiated mice. These studies demonstrate the therapeutic potential of PTN to improve survival after myeloablation and suggest that PTN-mediated hematopoietic regeneration occurs in a RAS-dependent manner. PMID:25250571

  19. Use of Proteomic and Hematology Biomarkers for Prediction of Hematopoietic Acute Radiation Syndrome Severity in Baboon Radiation Models.

    PubMed

    Blakely, William F; Bolduc, David L; Debad, Jeff; Sigal, George; Port, Matthias; Abend, Michael; Valente, Marco; Drouet, Michel; Hérodin, Francis

    2018-07-01

    Use of plasma proteomic and hematological biomarkers represents a promising approach to provide useful diagnostic information for assessment of the severity of hematopoietic acute radiation syndrome. Eighteen baboons were evaluated in a radiation model that underwent total-body and partial-body irradiations at doses of Co gamma rays from 2.5 to 15 Gy at dose rates of 6.25 cGy min and 32 cGy min. Hematopoietic acute radiation syndrome severity levels determined by an analysis of blood count changes measured up to 60 d after irradiation were used to gauge overall hematopoietic acute radiation syndrome severity classifications. A panel of protein biomarkers was measured on plasma samples collected at 0 to 28 d after exposure using electrochemiluminescence-detection technology. The database was split into two distinct groups (i.e., "calibration," n = 11; "validation," n = 7). The calibration database was used in an initial stepwise regression multivariate model-fitting approach followed by down selection of biomarkers for identification of subpanels of hematopoietic acute radiation syndrome-responsive biomarkers for three time windows (i.e., 0-2 d, 2-7 d, 7-28 d). Model 1 (0-2 d) includes log C-reactive protein (p < 0.0001), log interleukin-13 (p < 0.0054), and procalcitonin (p < 0.0316) biomarkers; model 2 (2-7 d) includes log CD27 (p < 0.0001), log FMS-related tyrosine kinase 3 ligand (p < 0.0001), log serum amyloid A (p < 0.0007), and log interleukin-6 (p < 0.0002); and model 3 (7-28 d) includes log CD27 (p < 0.0012), log serum amyloid A (p < 0.0002), log erythropoietin (p < 0.0001), and log CD177 (p < 0.0001). The predicted risk of radiation injury categorization values, representing the hematopoietic acute radiation syndrome severity outcome for the three models, produced least squares multiple regression fit confidences of R = 0.73, 0.82, and 0.75, respectively. The resultant algorithms support the proof of concept that plasma proteomic biomarkers can supplement

  20. Inhibiting glycogen synthase kinase-3 mitigates the hematopoietic acute radiation syndrome in mice.

    PubMed

    Lee, Chang-Lung; Lento, William E; Castle, Katherine D; Chao, Nelson J; Kirsch, David G

    2014-05-01

    Exposure to a nuclear accident or radiological attack can cause death from acute radiation syndrome (ARS), which results from radiation injury to vital organs such as the hematopoietic system. However, the U.S. Food and Drug Administration (FDA) has not approved any medical countermeasures for this specific purpose. With growing concern over nuclear terrorism, there is an urgent need to develop small molecule deliverables that mitigate mortality from ARS. One emerging modulator of hematopoietic stem/progenitor cell (HSPC) activity is glycogen synthase kinase-3 (GSK-3). The inhibition of GSK-3 has been shown to augment hematopoietic repopulation in mouse models of bone marrow transplantation. In this study, we performed an in vitro screen using irradiated bone marrow mononuclear cells (BM-MNCs) to test the effects of four GSK-3 inhibitors: CHIR99021; 6-Bromoindirubin-3'-oxime (BIO); SB415286; and SB216763. This screen showed that SB216763 significantly increased the frequency of c-Kit(+) Lin(-) Sca1(+) (KLS) cells and hematopoietic colony-forming cells in irradiated BM-MNCs. Importantly, administration of a single dose of SB216763 to C57BL/6J mice by subcutaneous injection 24 h after total-body irradiation significantly improved hematopoietic recovery and mitigated hematopoietic ARS. Collectively, our results demonstrate that the GSK-3 inhibitor SB216763 is an effective medical countermeasure against acute radiation injury of the hematopoietic system.

  1. Mitigation of lung injury after accidental exposure to radiation.

    PubMed

    Mahmood, J; Jelveh, S; Calveley, V; Zaidi, A; Doctrow, S R; Hill, R P

    2011-12-01

    There is a serious need to develop effective mitigators against accidental radiation exposures. In radiation accidents, many people may receive nonuniform whole-body or partial-body irradiation. The lung is one of the more radiosensitive organs, demonstrating pneumonitis and fibrosis that are believed to develop at least partially because of radiation-induced chronic inflammation. Here we addressed the crucial questions of how damage to the lung can be mitigated and whether the response is affected by irradiation to the rest of the body. We examined the widely used dietary supplement genistein given at two dietary levels (750 or 3750 mg/kg) to Fischer rats irradiated with 12 Gy to the lung or 8 Gy to the lung + 4 Gy to the whole body excluding the head and tail (whole torso). We found that genistein had promising mitigating effects on oxidative damage, pneumonitis and fibrosis even at late times (36 weeks) when drug treatment was initiated 1 week after irradiation and stopped at 28 weeks postirradiation. The higher dose of genistein showed no greater beneficial effect. Combined lung and whole-torso irradiation caused more lung-related severe morbidity resulting in euthanasia of the animals than lung irradiation alone.

  2. Potential for a pluripotent adult stem cell treatment for acute radiation sickness

    PubMed Central

    Rodgerson, Denis O; Reidenberg, Bruce E; Harris, Alan G; Pecora, Andrew L

    2012-01-01

    Accidental radiation exposure and the threat of deliberate radiation exposure have been in the news and are a public health concern. Experience with acute radiation sickness has been gathered from atomic blast survivors of Hiroshima and Nagasaki and from civilian nuclear accidents as well as experience gained during the development of radiation therapy for cancer. This paper reviews the medical treatment reports relevant to acute radiation sickness among the survivors of atomic weapons at Hiroshima and Nagasaki, among the victims of Chernobyl, and the two cases described so far from the Fukushima Dai-Ichi disaster. The data supporting the use of hematopoietic stem cell transplantation and the new efforts to expand stem cell populations ex vivo for infusion to treat bone marrow failure are reviewed. Hematopoietic stem cells derived from bone marrow or blood have a broad ability to repair and replace radiation induced damaged blood and immune cell production and may promote blood vessel formation and tissue repair. Additionally, a constituent of bone marrow-derived, adult pluripotent stem cells, very small embryonic like stem cells, are highly resistant to ionizing radiation and appear capable of regenerating radiation damaged tissue including skin, gut and lung. PMID:24520532

  3. 21 CFR 1002.20 - Reporting of accidental radiation occurrences.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... the Director, Center for Devices and Radiological Health, all accidental radiation occurrences... grounds include, but are not necessarily limited to, professional, scientific, or medical facts or... occurred. (b) Such reports shall be addressed to the Center for Devices and Radiological Health, ATTN...

  4. 21 CFR 1002.20 - Reporting of accidental radiation occurrences.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... the Director, Center for Devices and Radiological Health, all accidental radiation occurrences... grounds include, but are not necessarily limited to, professional, scientific, or medical facts or... occurred. (b) Such reports shall be addressed to Food and Drug Administration, Center for Devices and...

  5. Cebpd Is Essential for Gamma-Tocotrienol Mediated Protection against Radiation-Induced Hematopoietic and Intestinal Injury

    PubMed Central

    Banerjee, Sudip; Shah, Sumit K.; Melnyk, Stepan B.; Hauer-Jensen, Martin

    2018-01-01

    Gamma-tocotrienol (GT3) confers protection against ionizing radiation (IR)-induced injury. However, the molecular targets that underlie the protective functions of GT3 are not yet known. We have reported that mice lacking CCAAT enhancer binding protein delta (Cebpd−/−) display increased mortality to IR due to injury to the hematopoietic and intestinal tissues and that Cebpd protects from IR-induced oxidative stress and cell death. The purpose of this study was to investigate whether Cebpd mediates the radio protective functions of GT3. We found that GT3-treated Cebpd−/− mice showed partial recovery of white blood cells compared to GT3-treated Cebpd+/+ mice at 2 weeks post-IR. GT3-treated Cebpd−/− mice showed an increased loss of intestinal crypt colonies, which correlated with increased expression of inflammatory cytokines and chemokines, increased levels of oxidized glutathione (GSSG), S-nitrosoglutathione (GSNO) and 3-nitrotyrosine (3-NT) after exposure to IR compared to GT3-treated Cebpd+/+ mice. Cebpd is induced by IR as well as a combination of IR and GT3 in the intestine. Studies have shown that granulocyte-colony stimulating factor (G-CSF), mediates the radioprotective functions of GT3. Interestingly, we found that IR alone as well as the combination of IR and GT3 caused robust augmentation of plasma G-CSF in both Cebpd+/+ and Cebpd−/− mice. These results identify a novel role for Cebpd in GT3-mediated protection against IR-induced injury, in part via modulation of IR-induced inflammation and oxidative/nitrosative stress, which is independent of G-CSF. PMID:29642403

  6. Metastatic angiosarcoma of the spleen after accidental radiation exposure: a case report.

    PubMed

    Geffen, D B; Zirkin, H J; Mermershtain, W; Cohen, Y; Ariad, S

    1998-04-01

    Angiosarcoma is a rare malignant tumor arising from endothelial cells of blood vessels or lymphatic channels. Therapeutic irradiation, thoriumdioxide administration, pyothorax, and polyvinyl chloride exposure have been shown to be predisposing factors for developing angiosarcoma. Accidental radiation exposure has not been associated with angiosarcoma. We present an unusual case of angiosarcoma of the spleen, with metastases to bone, liver, breast, and bone marrow, in a woman who lived near the Chernobyl nuclear facility in the former Soviet Union at the time of the reactor accident in 1986. To the best of our knowledge, this is the first report of metastatic angiosarcoma after accidental radiation exposure.

  7. Mitigating the effects of Xuebijing injection on hematopoietic cell injury induced by total body irradiation with γ rays by decreasing reactive oxygen species levels.

    PubMed

    Li, Deguan; Lu, Lu; Zhang, Junling; Wang, Xiaochun; Xing, Yonghua; Wu, Hongying; Yang, Xiangdong; Shi, Zhexin; Zhao, Mingfeng; Fan, Saijun; Meng, Aimin

    2014-06-12

    Hematopoietic injury is the most common side effect of radiotherapy. However, the methods available for the mitigating of radiation injury remain limited. Xuebijing injection (XBJ) is a traditional Chinese medicine used to treat sepsis in the clinic. In this study, we investigated the effects of XBJ on the survival rate in mice with hematopoietic injury induced by γ ray ionizing radiation (IR). Mice were intraperitoneally injected with XBJ daily for seven days after total body irradiation (TBI). Our results showed that XBJ (0.4 mL/kg) significantly increased 30-day survival rates in mice exposed to 7.5 Gy TBI. This effect may be attributable to improved preservation of white blood cells (WBCs) and hematopoietic cells, given that bone marrow (BM) cells from XBJ-treated mice produced more granulocyte-macrophage colony forming units (CFU-GM) than that in the 2 Gy/TBI group. XBJ also decreased the levels of reactive oxygen species (ROS) by increasing glutathione (GSH) and superoxide dismutase (SOD) levels in serum and attenuated the increased BM cell apoptosis caused by 2 Gy/TBI. In conclusion, these findings suggest that XBJ enhances the survival rate of irradiated mice and attenuates the effects of radiation on hematopoietic injury by decreasing ROS production in BM cells, indicating that XBJ may be a promising therapeutic candidate for reducing hematopoietic radiation injury.

  8. Insulin-Like Growth Factor 1 Mitigates Hematopoietic Toxicity After Lethal Total Body Irradiation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Zhou, Dunhua; Deoliveira, Divino; Kang, Yubin

    2013-03-15

    Purpose: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. Methods and Materials: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. Results: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) inmore » the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. Conclusions: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells.« less

  9. Estimating Risk of Hematopoietic Acute Radiation Syndrome in Children.

    PubMed

    Adams, Tim G; Sumner, Louise E; Casagrande, Rocco

    2017-12-01

    Following a radiological terrorist attack or radiation accident, the general public may be exposed to radiation. Historically, modeling efforts have focused on radiation effects on a "reference man"-a 70-kg, 180-cm-tall, 20- to 30-y-old male-which does not adequately reflect radiation hazard to special populations, particularly children. This work examines the radiosensitivity of children with respect to reference man to develop a set of parameters for modeling hematopoetic acute radiation syndrome in children. This analysis was performed using animal studies and the results verified using data from medical studies. Overall, the hematopoietic system in children is much more radiosensitive than that in adults, with the LD50 for children being 56% to 91% of the LD50 of adults, depending on age.

  10. [Cutaneous radiation syndrome after accidental skin exposure to ionizing radiation].

    PubMed

    Peter, R U

    2013-12-01

    Accidental exposure of the human skin to single doses of ionizing radiation greater than 3 Gy results in a distinct clinical picture, which is characterized by a transient and faint erythema after a few hours, then followed by severe erythema, blistering and necrosis. Depending on severity of damage, the latter generally occurs 10-30 days after exposure, but in severe cases may appear within 48 hrs. Between three and 24 months after exposure, epidermal atrophy combined with progressive dermal and subcutaneous fibrosis is the predominant clinical feature. Even years and decades after exposure, atrophy of epidermis, sweat and sebaceous glands; telangiectases; and dermal and subcutaneous fibrosis may be found and even continue to progress. For this distinct pattern of deterministic effects following cutaneous accidental radiation exposure the term "cutaneous radiation syndrome (CRS)" was coined in 1993 and has been accepted by all international authorities including IAEA and WHO since 2000. In contrast to the classical concept that inhibition of epidermal stem cell proliferation accounts for the clinical symptomatology, research of the last three decades has demonstrated the additional crucial role of inflammatory processes in the etiology of both acute and chronic sequelae of the CRS. Therefore, therapeutic approaches should include topical and systemic anti-inflammatory measures at the earliest conceivable point, and should be maintained throughout the acute and subacute stages, as this reduces the need for surgical intervention, once necrosis has occurred. If surgical intervention is planned, it should be executed with a conservative approach; no safety margins are needed. Antifibrotic measures in the chronic stage should address the chronic inflammatory nature of this process, in which over-expression TGF beta-1 may be a target for therapeutic intervention. Life-long follow-up often is required for management of delayed effects and for early detection of secondary

  11. RADIATION INDUCED AGING IN MICE

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Curtis, H.J.; Gebhard, K.L.

    1958-10-31

    . Experiments were undertaken in an effort to determine the degree of similarity between natural and radiation induced aging, and to determine the causes for the latter. Several severe non-specific stresses were applied to mice either as single massive doses or as smaller doses administered over a large fraction of the life span of the animals. Stresses used included typhoid vaccine, tetanus toxin and tetanus toxoid and turpentine. None of these produced any premature aging comparable to that produced by radiation. The somatic mutation theory of aging and expecially radiationinduced aging has been tested by applying the chemical mutatgen, nitrogenmore » mustard, either as a massive single dose or as smaller single doses repeated over long periods of time. No shortening of the life span has been observed and it is concluded that the somatic mutation theory is untenable. Experiments designed to determine the organ system responsible for radiation induced aging have demonstrated that the hematopoietic system is not primarily involved in this phenomenon. (auth)« less

  12. Challenges in Clinical Management of Radiation-Induced Illnesses in Exploration Spaceflight

    NASA Technical Reports Server (NTRS)

    Blue, Rebecca; Chancellor, Jeffery; Suresh, Rahul; Carnell, Lisa; Reyes, David; Nowadly, Craig; Antonsen, Erik

    2018-01-01

    Historical solar particle events (SPEs) provide context for some understanding of acute radiation exposure risk to astronauts traveling outside of low Earth orbit. Modeling of potential doses delivered to exploration crewmembers anticipates limited radiation-induced health impacts, including prodromal symptoms of nausea, emesis, and fatigue, but suggests that more severe clinical manifestations are unlikely. Recent large animal-model research in space-analogs closely mimicking SPEs has identified coagulopathic events independent of the hematopoietic sequelae of higher radiation doses, similar in manifestation to disseminated intravascular coagulation (DIC). We explored the challenges of clinical management of radiation-related clinical manifestations, using currently accepted modeling techniques and anticipated physiological sequelae, to identify medical capabilities needed to successfully manage SPE-induced radiation illnesses during exploration spaceflight.

  13. Radiation-Induced Leukemia at Doses Relevant to Radiation Therapy: Modeling Mechanisms and Estimating Risks

    NASA Technical Reports Server (NTRS)

    Shuryak, Igor; Sachs, Rainer K.; Hlatky, Lynn; Mark P. Little; Hahnfeldt, Philip; Brenner, David J.

    2006-01-01

    Because many cancer patients are diagnosed earlier and live longer than in the past, second cancers induced by radiation therapy have become a clinically significant issue. An earlier biologically based model that was designed to estimate risks of high-dose radiation induced solid cancers included initiation of stem cells to a premalignant state, inactivation of stem cells at high radiation doses, and proliferation of stem cells during cellular repopulation after inactivation. This earlier model predicted the risks of solid tumors induced by radiation therapy but overestimated the corresponding leukemia risks. Methods: To extend the model to radiation-induced leukemias, we analyzed in addition to cellular initiation, inactivation, and proliferation a repopulation mechanism specific to the hematopoietic system: long-range migration through the blood stream of hematopoietic stem cells (HSCs) from distant locations. Parameters for the model were derived from HSC biologic data in the literature and from leukemia risks among atomic bomb survivors v^ ho were subjected to much lower radiation doses. Results: Proliferating HSCs that migrate from sites distant from the high-dose region include few preleukemic HSCs, thus decreasing the high-dose leukemia risk. The extended model for leukemia provides risk estimates that are consistent with epidemiologic data for leukemia risk associated with radiation therapy over a wide dose range. For example, when applied to an earlier case-control study of 110000 women undergoing radiotherapy for uterine cancer, the model predicted an excess relative risk (ERR) of 1.9 for leukemia among women who received a large inhomogeneous fractionated external beam dose to the bone marrow (mean = 14.9 Gy), consistent with the measured ERR (2.0, 95% confidence interval [CI] = 0.2 to 6.4; from 3.6 cases expected and 11 cases observed). As a corresponding example for brachytherapy, the predicted ERR of 0.80 among women who received an inhomogeneous low

  14. Estrogen signaling selectively induces apoptosis of hematopoietic progenitors and myeloid neoplasms without harming steady-state hematopoiesis.

    PubMed

    Sánchez-Aguilera, Abel; Arranz, Lorena; Martín-Pérez, Daniel; García-García, Andrés; Stavropoulou, Vaia; Kubovcakova, Lucia; Isern, Joan; Martín-Salamanca, Sandra; Langa, Xavier; Skoda, Radek C; Schwaller, Jürg; Méndez-Ferrer, Simón

    2014-12-04

    Estrogens are potent regulators of mature hematopoietic cells; however, their effects on primitive and malignant hematopoietic cells remain unclear. Using genetic and pharmacological approaches, we observed differential expression and function of estrogen receptors (ERs) in hematopoietic stem cell (HSC) and progenitor subsets. ERα activation with the selective ER modulator (SERM) tamoxifen induced apoptosis in short-term HSCs and multipotent progenitors. In contrast, tamoxifen induced proliferation of quiescent long-term HSCs, altered the expression of self-renewal genes, and compromised hematopoietic reconstitution after myelotoxic stress, which was reversible. In mice, tamoxifen treatment blocked development of JAK2(V617F)-induced myeloproliferative neoplasm in vivo, induced apoptosis of human JAK2(V617F+) HSPCs in a xenograft model, and sensitized MLL-AF9(+) leukemias to chemotherapy. Apoptosis was selectively observed in mutant cells, and tamoxifen treatment only had a minor impact on steady-state hematopoiesis in disease-free animals. Together, these results uncover specific regulation of hematopoietic progenitors by estrogens and potential antileukemic properties of SERMs. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Accelerated hematopoietic toxicity by high energy (56)Fe radiation.

    PubMed

    Datta, Kamal; Suman, Shubhankar; Trani, Daniela; Doiron, Kathryn; Rotolo, Jimmy A; Kallakury, Bhaskar V S; Kolesnick, Richard; Cole, Michael F; Fornace, Albert J

    2012-03-01

    There is little information on the relative toxicity of highly charged (Z) high-energy (HZE) radiation in animal models compared to γ or X-rays, and the general assumption based on in vitro studies has been that acute toxicity is substantially greater. C57BL/6J mice were irradiated with (56)Fe ions (1 GeV/nucleon), and acute (within 30 d) toxicity compared to that of γ rays or protons (1 GeV). To assess relative hematopoietic and gastrointestinal toxicity, the effects of (56)Fe ions were compared to γ rays using complete blood count (CBC), bone marrow granulocyte-macrophage colony forming unit (GM-CFU), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay for apoptosis in bone marrow, and intestinal crypt survival. Although onset was more rapid, (56)Fe ions were only slightly more toxic than γ rays or protons with lethal dose (LD)(50/30) (a radiation dose at which 50% lethality occurs at 30-day) values of 5.8, 7.25, and 6.8 Gy, respectively, with relative biologic effectiveness for (56)Fe ions of 1.25 and 1.06 for protons. (56)Fe radiation caused accelerated and more severe hematopoietic toxicity. Early mortality correlated with more profound leukopenia and subsequent sepsis. Results indicate that there is selective enhanced toxicity to bone marrow progenitor cells, which are typically resistant to γ rays, and bone marrow stem cells, because intestinal crypt cells did not show increased HZE toxicity.

  16. A nonhuman primate model of the hematopoietic acute radiation syndrome plus medical management.

    PubMed

    Farese, Ann M; Cohen, Melanie V; Katz, Barry P; Smith, Cassandra P; Jackson, William; Cohen, Daniel M; MacVittie, Thomas J

    2012-10-01

    The development of medical countermeasures against the hematopoietic subsyndrome of the acute radiation syndrome requires well characterized and validated animal models. The model must define the radiation dose- and time-dependent relationships for mortality and major signs of morbidity to include other organ damage that may contribute to morbidity and mortality. Herein, the authors define these parameters for a nonhuman primate exposed to total body radiation and administered medical management. A blinded, randomized study (n = 48 rhesus macaques) determined the lethal dose-response relationship using bilateral 6 MV linear accelerator photon radiation to doses in the range of 7.20 to 8.90 Gy at 0.80 Gy min(-1). Following irradiation, animals were monitored for complete bloodcounts, body weight, temperature, diarrhea, and hydration status for 60 d. Animals were administered medical management consisting of intravenous fluids, prophylactic antibiotics, blood transfusions, anti-diarrheals, analgesics, and nutrition. The primary endpoint was survival at 60 d post-irradiation; secondary endpoints included hematopoietic-related parameters, number of transfusions, incidence of documented infection, febrile neutropenia, severity of diarrhea, mean survival time of decedents, and tissue histology. The study defined an LD30/60 of 7.06 Gy, LD50/60 of 7.52 Gy, and an LD70/60 of 7.99 Gy with a relatively steep slope of 1.13 probits per linear dose. This study establishes a rhesus macaque model of the hematopoietic acute radiation syndrome and shows the marked effect of medical management on increased survival and overall mean survival time for decedents. Furthermore, following a nuclear terrorist event, medical management may be the only treatment administered at its optimal schedule.

  17. Lnk adaptor suppresses radiation resistance and radiation-induced B-cell malignancies by inhibiting IL-11 signaling

    PubMed Central

    Louria-Hayon, Igal; Frelin, Catherine; Ruston, Julie; Gish, Gerald; Jin, Jing; Kofler, Michael M.; Lambert, Jean-Philippe; Adissu, Hibret A.; Milyavsky, Michael; Herrington, Robert; Minden, Mark D.; Dick, John E.; Gingras, Anne-Claude; Iscove, Norman N.; Pawson, Tony

    2013-01-01

    The Lnk (Sh2b3) adaptor protein dampens the response of hematopoietic stem cells and progenitors (HSPCs) to a variety of cytokines by inhibiting JAK2 signaling. As a consequence, Lnk−/− mice develop hematopoietic hyperplasia, which progresses to a phenotype resembling the nonacute phase of myeloproliferative neoplasm. In addition, Lnk mutations have been identified in human myeloproliferative neoplasms and acute leukemia. We find that Lnk suppresses the development of radiation-induced acute B-cell malignancies in mice. Lnk-deficient HSPCs recover more effectively from irradiation than their wild-type counterparts, and this resistance of Lnk−/− HSPCs to radiation underlies the subsequent emergence of leukemia. A search for the mechanism responsible for radiation resistance identified the cytokine IL-11 as being critical for the ability of Lnk−/− HSPCs to recover from irradiation and subsequently become leukemic. In IL-11 signaling, wild-type Lnk suppresses tyrosine phosphorylation of the Src homology region 2 domain-containing phosphatase-2/protein tyrosine phosphatase nonreceptor type 11 and its association with the growth factor receptor-bound protein 2, as well as activation of the Erk MAP kinase pathway. Indeed, Src homology region 2 domain-containing phosphatase-2 has a binding motif for the Lnk Src Homology 2 domain that is phosphorylated in response to IL-11 stimulation. IL-11 therefore drives a pathway that enhances HSPC radioresistance and radiation-induced B-cell malignancies, but is normally attenuated by the inhibitory adaptor Lnk. PMID:24297922

  18. Accelerated Hematopoietic Toxicity by High Energy 56Fe Radiation

    PubMed Central

    Datta, Kamal; Suman, Shubhankar; Trani, Daniela; Doiron, Kathryn; Rotolo, Jimmy A.; Kallakury, Bhaskar V. S.; Kolesnick, Richard; Cole, Michael F.; Fornace, Albert J.

    2013-01-01

    Purpose There is little information on the relative toxicity of highly charged (Z) high-energy (HZE) radiation in animal models compared to γ or x-rays, and the general assumption based on in vitro studies has been that acute toxicity is substantially greater. Methods C57BL/6J mice were irradiated with 56Fe ions (1 GeV/nucleon), and acute (within 30 d) toxicity compared to that of γ rays or protons (1 GeV). To assess relative hematopoietic and gastrointestinal toxicity, the effects of 56Fe ions were compared to γ rays using complete blood count (CBC), bone marrow granulocyte-macrophage colony forming unit (GM-CFU), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay for apoptosis in bone marrow, and intestinal crypt survival. Results Although onset was more rapid, 56Fe ions were only slightly more toxic than γ rays or protons with lethal dose (LD)50/30 (a radiation dose at which 50% lethality occurs at 30-day) values of 5.8, 7.25, and 6.8 Gy respectively with relative biologic effectiveness for 56Fe ions of 1.25 and 1.06 for protons. Conclusions 56Fe radiation caused accelerated and more severe hematopoietic toxicity. Early mortality correlated with more profound leukopenia and subsequent sepsis. Results indicate that there is selective enhanced toxicity to bone marrow progenitor cells, which are typically resistant to γ rays, and bone marrow stem cells, because intestinal crypt cells did not show increased HZE toxicity. PMID:22077279

  19. Accidental and experimentally induced 5-fluorouracil toxicity in dogs.

    PubMed

    Sayre, Rebecca S; Barr, James W; Bailey, E Murl

    2012-10-01

    To summarize the literature involving 5-fluorouracil (5-FU) toxicosis in dogs. 5-Fluorouracil's mechanism of action revolves around the metabolism of 5-FU into fluorouridine triphosphate which then interferes with RNA synthesis and function as well as the inhibition of thymidylate synthase which ultimately impairs DNA stability. Toxicity of 5-FU is the most pronounced on rapidly dividing cells. Toxicity manifests itself mainly in the neurologic, gastrointestinal, respiratory, or hematopoietic systems. History of accidental exposure to 5-FU-containing products. Therapy for 5-FU toxicosis involves typical decontamination procedures and symptomatic therapy for the subsequent toxicity. Seizure control and treatment of the severe gastrointestinal signs that follow are the primary goals in the acute setting. As the disease progresses, management of the sequelae to bone marrow suppression and pulmonary complications are essential. The prognosis for dogs with ingestion of 5-FU is dependent on the amount consumed, with severe intoxication carrying a poor prognosis. Toxic doses can be as little as 5 mg/kg, and doses ≥40 mg/kg are reported to be uniformly fatal. © Veterinary Emergency and Critical Care Society 2012.

  20. Radiation-induced hematopoietic myelosuppression and genotoxicity get significantly countered by active principles of Podophyllum hexandrum: A study in strain 'A' mice.

    PubMed

    Verma, Savita; Gupta, Manju Lata

    2015-01-01

    To investigate the protective role of a novel formulation, prepared by a combination of three active principles isolated from Podophyllum hexandrum (G-002M), against radiation- mediated hematopoietic suppression and cytogenetic aberrations in lethally irradiated mice. G-002M, a combination of podophyllotoxin, podophyllotoxin-β-D glucoside and rutin, was administered intramuscularly in mice (- 1 h) to radiation (9 Gy) exposure. The animals were autopsied at different time intervals for further studies. Loss of bone marrow progenitor cells, altered myeloid/erythroid ratio, serum erythropoietin and pancytopenia in irradiated mice was found significantly (p < 0.001) ameliorated in G-002M pre-administered mice within 30 d. Bcl-2 (B-cell lymphoma 2) and BAX (Bcl-2-associated X) protein expression was also positively (p < 0.001) countered in these mice. Chromosomal aberrations in 30 d were found remarkably (p < 0.001) reduced in marrow of G-002M pretreated mice. Accelerated antioxidants, reduced DNA damage, stimulated lymphocyte proliferation and minimal cellular atrophy in spleen were some of the other key features observed in G-002M administered mice. Reduction in hematopoietic aplasia and chromosomal aberrations, besides, early recovery in bone marrow and spleen of G-002M pretreated mice, could be attributed to its free radical scavenging, DNA protecting and apoptotic proteins modulating ability against radiation.

  1. Selective Insulin-like Growth Factor Resistance Associated with Heart Hemorrhages and Poor Prognosis in a Novel Preclinical Model of the Hematopoietic Acute Radiation Syndrome.

    PubMed

    Kenchegowda, Doreswamy; Legesse, Betre; Hritzo, Bernadette; Olsen, Cara; Aghdam, Saeed; Kaur, Amandeep; Culp, William; Derrien-Colemyn, Alexandrine; Severson, Grant; Moroni, Maria

    2018-05-29

    Although bone marrow aplasia has been considered for the past decades as the major contributor of radiation-induced blood disorders, cytopenias alone are insufficient to explain differences in the prevalence of bleeding. In this study, the minipig was used as a novel preclinical model of hematopoietic acute radiation syndrome to assess if factors other than platelet counts correlated with bleeding and survival. We sought to determine whether radiation affected the insulin-like growth factor-1 (IGF-1) pathway, a growth hormone with cardiovascular and radioprotective features. Gottingen and Sinclair minipigs were exposed to ionizing radiation at hematopoietic doses. The smaller Gottingen minipig strain was more sensitive to radiation; differences in IGF-1 levels were minimal, suggesting that increased sensitivity could depend on weak response to the hormone. Radiation caused IGF-1 selective resistance by inhibiting the anti-inflammatory anti-oxidative stress IRS/PI3K/Akt but not the pro-inflammatory MAPK kinase pathway, shifting IGF-1 signaling towards a pro-oxidant, pro-inflammatory environment. Selective IGF-1 resistance associated with hemorrhages in the heart, poor prognosis, increase in C-reactive protein and NADPH oxidase 2, uncoupling of endothelial nitric oxide synthase, inhibition of nitric oxide (NO) synthesis and imbalance between the vasodilator NO and the vasoconstrictor endothelin-1 molecules. Selective IGF-1 resistance is a novel mechanism of radiation injury, associated with a vicious cycle amplifying reactive oxygen species-induced damage, inflammation and endothelial dysfunction. In the presence of thrombocytopenia, selective inhibition of IGF-1 cardioprotective function may contribute to the development of hemostatic disorders. This finding may be particularly relevant for individuals with low IGF-1 activity, such as the elderly or those with cardiometabolic dysfunctions.

  2. Novel Radiomitigator for Radiation-Induced Bone Loss

    NASA Technical Reports Server (NTRS)

    Schreurs, A-S; Shirazi-fard, Y.; Terada, M.; Alwood, J. S.; Steczina, S.; Medina, C.; Tahimic, C. G. T.; Globus, R. K.

    2016-01-01

    Radiation-induced bone loss can occur with radiotherapy patients, accidental radiation exposure and during long-term spaceflight. Bone loss due to radiation is due to an early increase in oxidative stress, inflammation and bone resorption, resulting in an imbalance in bone remodeling. Furthermore, exposure to high-Linear Energy Transfer (LET) radiation will impair the bone forming progenitors and reduce bone formation. Radiation can be classified as high-LET or low-LET based on the amount of energy released. Dried Plum (DP) diet prevents bone loss in mice exposed to total body irradiation with both low-LET and high-LET radiation. DP prevents the early radiation-induced bone resorption, but furthermore, we show that DP protects the bone forming osteoblast progenitors from high-LET radiation. These results provide insight that DP re-balances the bone remodeling by preventing resorption and protecting the bone formation capacity. This data is important considering that most of the current osteoporosis treatments only block the bone resorption but do not protect bone formation. In addition, DP seems to act on both the oxidative stress and inflammation pathways. Finally, we have preliminary data showing the potential of DP to be radio-protective at a systemic effect and could possible protect other tissues at risk of total body-irradiation such as skin, brain and heart.

  3. Protracted Oxidative Alterations in the Mechanism of Hematopoietic Acute Radiation Syndrome

    PubMed Central

    Gorbunov, Nikolai V.; Sharma, Pushpa

    2015-01-01

    The biological effects of high-dose total body ionizing irradiation [(thereafter, irradiation (IR)] are attributed to primary oxidative breakage of biomolecule targets, mitotic, apoptotic and necrotic cell death in the dose-limiting tissues, clastogenic and epigenetic effects, and cascades of functional and reactive responses leading to radiation sickness defined as the acute radiation syndrome (ARS). The range of remaining and protracted injuries at any given radiation dose as well as the dynamics of post-IR alterations is tissue-specific. Therefore, functional integrity of the homeostatic tissue barriers may decline gradually within weeks in the post-IR period culminating with sepsis and failure of organs and systems. Multiple organ failure (MOF) leading to moribundity is a common sequela of the hemotapoietic form of ARS (hARS). Onset of MOF in hARS can be presented as “two-hit phenomenon” where the “first hit” is the underlying consequences of the IR-induced radiolysis in cells and biofluids, non-septic inflammation, metabolic up-regulation of pro-oxidative metabolic reactions, suppression of the radiosensitive hematopoietic and lymphoid tissues and the damage to gut mucosa and vascular endothelium. While the “second hit” derives from bacterial translocation and spread of the bacterial pathogens and inflammagens through the vascular system leading to septic inflammatory, metabolic responses and a cascade of redox pro-oxidative and adaptive reactions. This sequence of events can create a ground for development of prolonged metabolic, inflammatory, oxidative, nitrative, and carbonyl, electrophilic stress in crucial tissues and thus exacerbate the hARS outcomes. With this perspective, the redox mechanisms, which can mediate the IR-induced protracted oxidative post-translational modification of proteins, oxidation of lipids and carbohydrates and their countermeasures in hARS are subjects of the current review. Potential role of ubiquitous, radioresistant

  4. Protracted Oxidative Alterations in the Mechanism of Hematopoietic Acute Radiation Syndrome.

    PubMed

    Gorbunov, Nikolai V; Sharma, Pushpa

    2015-02-27

    The biological effects of high-dose total body ionizing irradiation [(thereafter, irradiation (IR)] are attributed to primary oxidative breakage of biomolecule targets, mitotic, apoptotic and necrotic cell death in the dose-limiting tissues, clastogenic and epigenetic effects, and cascades of functional and reactive responses leading to radiation sickness defined as the acute radiation syndrome (ARS). The range of remaining and protracted injuries at any given radiation dose as well as the dynamics of post-IR alterations is tissue-specific. Therefore, functional integrity of the homeostatic tissue barriers may decline gradually within weeks in the post-IR period culminating with sepsis and failure of organs and systems. Multiple organ failure (MOF) leading to moribundity is a common sequela of the hemotapoietic form of ARS (hARS). Onset of MOF in hARS can be presented as "two-hit phenomenon" where the "first hit" is the underlying consequences of the IR-induced radiolysis in cells and biofluids, non-septic inflammation, metabolic up-regulation of pro-oxidative metabolic reactions, suppression of the radiosensitive hematopoietic and lymphoid tissues and the damage to gut mucosa and vascular endothelium. While the "second hit" derives from bacterial translocation and spread of the bacterial pathogens and inflammagens through the vascular system leading to septic inflammatory, metabolic responses and a cascade of redox pro-oxidative and adaptive reactions. This sequence of events can create a ground for development of prolonged metabolic, inflammatory, oxidative, nitrative, and carbonyl, electrophilic stress in crucial tissues and thus exacerbate the hARS outcomes. With this perspective, the redox mechanisms, which can mediate the IR-induced protracted oxidative post-translational modification of proteins, oxidation of lipids and carbohydrates and their countermeasures in hARS are subjects of the current review. Potential role of ubiquitous, radioresistant mesenchymal

  5. Radioprotective effect of Rapana thomasiana hemocyanin in gamma induced acute radiation syndrome

    PubMed Central

    Kindekov, Ivan; Mileva, Milka; Krastev, Dimo; Vassilieva, Vladimira; Raynova, Yuliana; Doumanova, Lyuba; Aljakov, Mitko; Idakieva, Krassimira

    2014-01-01

    The radioprotective effect of Rapana thomasiana hemocyanin (RtH) against radiation-induced injuries (stomach ulcers, survival time and endogenous haemopoiesis) and post-radiation recovery was investigated in male albino mice (C3H strain). Radiation course was in a dose of 7.5 Gy (LD 100/30 – dose that kills 100% of the mice at 30 days) from 137Cs with a dose of 2.05 Gy/min. Radiation injuries were manifested by inducing а hematopoietic form of acute radiation syndrome. RtH was administered intraperitoneally in a single dose of 50, 100, 150 and 200 mg/kg body weight (b. w.) once a day for five consecutive days before irradiation. The results obtained showed that radiation exposure led to (1) 100% mortality rate, (2) ulceration in the stomach mucosa and (3) decrease formation of spleen colonies as a marker of endogenous haemopoiesis. Administration of RtH at a dose of 200 mg/kg provided better protection against radiation-induced stomach ulceration, mitigated the lethal effects of radiation exposure and recovered endogenous haemopoiesis versus irradiated but not supplemented mice. It could be expected that RtH will find a use in mitigating radiation induced injury and enhanced radiorecovery. PMID:26019540

  6. Radioprotective effect of Rapana thomasiana hemocyanin in gamma induced acute radiation syndrome.

    PubMed

    Kindekov, Ivan; Mileva, Milka; Krastev, Dimo; Vassilieva, Vladimira; Raynova, Yuliana; Doumanova, Lyuba; Aljakov, Mitko; Idakieva, Krassimira

    2014-05-04

    The radioprotective effect of Rapana thomasiana hemocyanin (RtH) against radiation-induced injuries (stomach ulcers, survival time and endogenous haemopoiesis) and post-radiation recovery was investigated in male albino mice (C3H strain). Radiation course was in a dose of 7.5 Gy (LD 100/30 - dose that kills 100% of the mice at 30 days) from 137 Cs with a dose of 2.05 Gy/min. Radiation injuries were manifested by inducing а hematopoietic form of acute radiation syndrome. RtH was administered intraperitoneally in a single dose of 50, 100, 150 and 200 mg/kg body weight (b. w.) once a day for five consecutive days before irradiation. The results obtained showed that radiation exposure led to (1) 100% mortality rate, (2) ulceration in the stomach mucosa and (3) decrease formation of spleen colonies as a marker of endogenous haemopoiesis. Administration of RtH at a dose of 200 mg/kg provided better protection against radiation-induced stomach ulceration, mitigated the lethal effects of radiation exposure and recovered endogenous haemopoiesis versus irradiated but not supplemented mice. It could be expected that RtH will find a use in mitigating radiation induced injury and enhanced radiorecovery.

  7. Relieved residual damage in the hematopoietic system of mice rescued by radiation-induced adaptive response (Yonezawa Effect)

    PubMed Central

    Wang, Bing; Tanaka, Kaoru; Ninomiya, Yasuharu; Maruyama, Kouichi; VarèS, Guillaume; Eguchi-Kasai, Kiyomi; Nenoi, Mitsuru

    2013-01-01

    Existence of adaptive response (AR) was previously demonstrated in C57BL/6J mice. Irradiations were performed by delivering a priming low dose of X-rays (0.50 Gy) in combination with a challenge high dose of accelerated carbon or neon ion particles. AR was characterized by significantly decreased mortality in the 30-day survival test. This mouse AR model (‘Yonezawa Effect’) was originally established by using X-rays as both the priming and challenge irradiations. The underlying mechanism was due to radio-resistance occurring in blood-forming tissues. In this study, we verified the existence of AR and further investigated residual damage in the hematopoietic system in surviving animals. Results showed that the priming low dose of X-rays could relieve the detrimental effects on the hematopoietic system. We observed both an improvement in the blood platelet count and the ratio of polychromatic erythrocytes (PCEs) to the sum of PCEs and normochromatic erythrocytes (NCEs) and a marked reduction of the incidences of micronucleated PCEs and micronucleated NCEs. These findings suggest that the priming low dose of low linear energy transfer (LET) X-rays induced a protective effect on the hematopoietic system, which may play an important role in both rescue from acute lethal damage (mouse killing) and prevention of late detrimental consequences (residual anhematopoiesis and delayed genotoxic effects) caused by exposure to a high challenge dose from low-LET (X-ray) or high-LET (carbon and neon ion) irradiations. These findings provide new knowledge of the characterization of the Yonezawa Effect by providing new insight into the mechanistic study of AR in vivo. PMID:22923746

  8. Clustered DNA damages induced in human hematopoietic cells by low doses of ionizing radiation

    NASA Technical Reports Server (NTRS)

    Sutherland, Betsy M.; Bennett, Paula V.; Cintron-Torres, Nela; Hada, Megumi; Trunk, John; Monteleone, Denise; Sutherland, John C.; Laval, Jacques; Stanislaus, Marisha; Gewirtz, Alan

    2002-01-01

    Ionizing radiation induces clusters of DNA damages--oxidized bases, abasic sites and strand breaks--on opposing strands within a few helical turns. Such damages have been postulated to be difficult to repair, as are double strand breaks (one type of cluster). We have shown that low doses of low and high linear energy transfer (LET) radiation induce such damage clusters in human cells. In human cells, DSB are about 30% of the total of complex damages, and the levels of DSBs and oxidized pyrimidine clusters are similar. The dose responses for cluster induction in cells can be described by a linear relationship, implying that even low doses of ionizing radiation can produce clustered damages. Studies are in progress to determine whether clusters can be produced by mechanisms other than ionizing radiation, as well as the levels of various cluster types formed by low and high LET radiation.

  9. Genistein protects hematopoietic stem cells against G-CSF-induced DNA damage.

    PubMed

    Souza, Liliana R; Silva, Erica; Calloway, Elissa; Kucuk, Omer; Rossi, Michael; McLemore, Morgan L

    2014-05-01

    Granulocyte colony-stimulating factor (G-CSF) has been used to treat neutropenia in various clinical settings. Although clearly beneficial, there are concerns that the chronic use of G-CSF in certain conditions increases the risk of myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The most striking example is in severe congenital neutropenia (SCN). Patients with SCN develop MDS/AML at a high rate that is directly correlated to the cumulative lifetime dosage of G-CSF. Myelodysplastic syndrome and AML that arise in these settings are commonly associated with chromosomal deletions. We have demonstrated in this study that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell (HSC) population. In addition, primitive hematopoietic progenitors from G-CSF-treated mice show evidence of DNA damage as demonstrated by an increase in double-strand breaks and recurrent chromosomal deletions. Concurrent treatment with genistein, a natural soy isoflavone, limits DNA damage in this population. The protective effect of genistein seems to be related to its preferential inhibition of G-CSF-induced proliferation of HSCs. Importantly, genistein does not impair G-CSF-induced proliferation of committed hematopoietic progenitors, nor diminishes neutrophil production. The protective effect of genistein was accomplished with plasma levels that are attainable through dietary supplementation.

  10. Amelioration of Radiation-Induced Hematopoietic and Gastrointestinal Damage by Ex-RAD (trademark) in Mice

    DTIC Science & Technology

    2012-06-06

    recovery from radiation-induced neutropenia Figure 3 shows the protective effects of Ex-RAD prophy- laxis on acute radiation-induced cytopenia. We used a... neutropenia on Day 4 post-TBI. For platelets, the nadir was observed between Days 7 to 17 post-TBI in the vehicle-treated group (Fig. 3d). Peripheral blood cell...recovery from neutropenia and restored blood Fig. 7. TUNEL staining in the jejunum sections from Ex-RAD-treated and vehicle-treated groups 24 h post

  11. Donor Dependent Variations in Hematopoietic Differentiation among Embryonic and Induced Pluripotent Stem Cell Lines

    PubMed Central

    Féraud, Olivier; Valogne, Yannick; Melkus, Michael W.; Zhang, Yanyan; Oudrhiri, Noufissa; Haddad, Rima; Daury, Aurélie; Rocher, Corinne; Larbi, Aniya; Duquesnoy, Philippe; Divers, Dominique; Gobbo, Emilie; Brunet de la Grange, Philippe; Louache, Fawzia; Bennaceur-Griscelli, Annelise; Mitjavila-Garcia, Maria Teresa

    2016-01-01

    Hematopoiesis generated from human embryonic stem cells (ES) and induced pluripotent stem cells (iPS) are unprecedented resources for cell therapy. We compared hematopoietic differentiation potentials from ES and iPS cell lines originated from various donors and derived them using integrative and non-integrative vectors. Significant differences in differentiation toward hematopoietic lineage were observed among ES and iPS. The ability of engraftment of iPS or ES-derived cells in NOG mice varied among the lines with low levels of chimerism. iPS generated from ES cell-derived mesenchymal stem cells (MSC) reproduce a similar hematopoietic outcome compared to their parental ES cell line. We were not able to identify any specific hematopoietic transcription factors that allow to distinguish between good versus poor hematopoiesis in undifferentiated ES or iPS cell lines. There is a relatively unpredictable variation in hematopoietic differentiation between ES and iPS cell lines that could not be predicted based on phenotype or gene expression of the undifferentiated cells. These results demonstrate the influence of genetic background in variation of hematopoietic potential rather than the reprogramming process. PMID:26938212

  12. The Hematopoietic System in the Context of Regenerative Medicine

    PubMed Central

    Porada, Christopher D.; Atala, Anthony J.; Almeida-Porada, Graça

    2015-01-01

    Hematopoietic stem cells (HSC) represent the prototype stem cell within the body. Since their discovery, HSC have been the focus of intensive research, and have proven invaluable clinically to restore hematopoiesis following inadvertent radiation exposure and following radio/chemotherapy to eliminate hematologic tumors. While they were originally discovered in the bone marrow, HSC can also be isolated from umbilical cord blood and can be “mobilized” peripheral blood, making them readily available in relatively large quantities. While their ability to repopulate the entire hematopoietic system would already guarantee HSC a valuable place in regenerative medicine, the finding that hematopoietic chimerism can induce immunological tolerance to solid organs and correct autoimmune diseases has dramatically broadened their clinical utility. The demonstration that these cells, through a variety of mechanisms, can also promote repair/regeneration of non-hematopoietic tissues as diverse as liver, heart, and brain has further increased their clinical value. The goal of this review is to provide the reader with a brief glimpse into the remarkable potential HSC possess, and to highlight their tremendous value as therapeutics in regenerative medicine. PMID:26319943

  13. Evidence for Radiation-Induced Disseminated Intravascular Coagulation as a Major Cause of Radiation-Induced Death in Ferrets

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Krigsfeld, Gabriel S.; Savage, Alexandria R.; Billings, Paul C.

    Purpose: The studies reported here were performed as part of a program in space radiation biology in which proton radiation like that present in solar particle events, as well as conventional gamma radiation, were being evaluated in terms of the ability to affect hemostasis. Methods and Materials: Ferrets were exposed to 0 to 2 Gy of whole-body proton or gamma radiation and monitored for 30 days. Blood was analyzed for blood cell counts, platelet clumping, thromboelastometry, and fibrin clot formation. Results: The lethal dose of radiation to 50% of the population (LD{sub 50}) of the ferrets was established at ∼1.5 Gy, with 100%more » mortality at 2 Gy. Hypocoagulability was present as early as day 7 postirradiation, with animals unable to generate a stable clot and exhibiting signs of platelet aggregation, thrombocytopenia, and fibrin clots in blood vessels of organs. Platelet counts were at normal levels during the early time points postirradiation when coagulopathies were present and becoming progressively more severe; platelet counts were greatly reduced at the time of the white blood cell nadir of 13 days. Conclusions: Data presented here provide evidence that death at the LD{sub 50} in ferrets is most likely due to disseminated intravascular coagulation (DIC). These data question the current hypothesis that death at relatively low doses of radiation is due solely to the cell-killing effects of hematopoietic cells. The recognition that radiation-induced DIC is the most likely mechanism of death in ferrets raises the question of whether DIC is a contributing mechanism to radiation-induced death at relatively low doses in large mammals.« less

  14. Evidence for radiation-induced disseminated intravascular coagulation as a major cause of radiation-induced death in ferrets.

    PubMed

    Krigsfeld, Gabriel S; Savage, Alexandria R; Billings, Paul C; Lin, Liyong; Kennedy, Ann R

    2014-03-15

    The studies reported here were performed as part of a program in space radiation biology in which proton radiation like that present in solar particle events, as well as conventional gamma radiation, were being evaluated in terms of the ability to affect hemostasis. Ferrets were exposed to 0 to 2 Gy of whole-body proton or gamma radiation and monitored for 30 days. Blood was analyzed for blood cell counts, platelet clumping, thromboelastometry, and fibrin clot formation. The lethal dose of radiation to 50% of the population (LD50) of the ferrets was established at ∼ 1.5 Gy, with 100% mortality at 2 Gy. Hypocoagulability was present as early as day 7 postirradiation, with animals unable to generate a stable clot and exhibiting signs of platelet aggregation, thrombocytopenia, and fibrin clots in blood vessels of organs. Platelet counts were at normal levels during the early time points postirradiation when coagulopathies were present and becoming progressively more severe; platelet counts were greatly reduced at the time of the white blood cell nadir of 13 days. Data presented here provide evidence that death at the LD50 in ferrets is most likely due to disseminated intravascular coagulation (DIC). These data question the current hypothesis that death at relatively low doses of radiation is due solely to the cell-killing effects of hematopoietic cells. The recognition that radiation-induced DIC is the most likely mechanism of death in ferrets raises the question of whether DIC is a contributing mechanism to radiation-induced death at relatively low doses in large mammals. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. MMR Deficiency Does Not Sensitize or Compromise the Function of Hematopoietic Stem Cells to Low and High LET Radiation.

    PubMed

    Patel, Rutulkumar; Qing, Yulan; Kennedy, Lucy; Yan, Yan; Pink, John; Aguila, Brittany; Desai, Amar; Gerson, Stanton L; Welford, Scott M

    2018-04-14

    One of the major health concerns on long-duration space missions will be radiation exposure to the astronauts. Outside the earth's magnetosphere, astronauts will be exposed to galactic cosmic rays (GCR) and solar particle events that are principally composed of protons and He, Ca, O, Ne, Si, Ca, and Fe nuclei. Protons are by far the most common species, but the higher atomic number particles are thought to be more damaging to biological systems. Evaluation and amelioration of risks from GCR exposure will be important for deep space travel. The hematopoietic system is one of the most radiation-sensitive organ systems, and is highly dependent on functional DNA repair pathways for survival. Recent results from our group have demonstrated an acquired deficiency in mismatch repair (MMR) in human hematopoietic stem cells (HSCs) with age due to functional loss of the MLH1 protein, suggesting an additional risk to astronauts who may have significant numbers of MMR deficient HSCs at the time of space travel. In the present study, we investigated the effects gamma radiation, proton radiation, and 56 Fe radiation on HSC function in Mlh1 +/+ and Mlh1 -/- marrow from mice in a variety of assays and have determined that while cosmic radiation is a major risk to the hematopoietic system, there is no dependence on MMR capacity. Stem Cells Translational Medicine 2018. © 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  16. Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion.

    PubMed

    He, Shenghui; Roberts, Patrick J; Sorrentino, Jessica A; Bisi, John E; Storrie-White, Hannah; Tiessen, Renger G; Makhuli, Karenann M; Wargin, William A; Tadema, Henko; van Hoogdalem, Ewoud-Jan; Strum, Jay C; Malik, Rajesh; Sharpless, Norman E

    2017-04-26

    Conventional cytotoxic chemotherapy is highly effective in certain cancers but causes dose-limiting damage to normal proliferating cells, especially hematopoietic stem and progenitor cells (HSPCs). Serial exposure to cytotoxics causes a long-term hematopoietic compromise ("exhaustion"), which limits the use of chemotherapy and success of cancer therapy. We show that the coadministration of G1T28 (trilaciclib), which is a small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), contemporaneously with cytotoxic chemotherapy protects murine hematopoietic stem cells (HSCs) from chemotherapy-induced exhaustion in a serial 5-fluorouracil treatment model. Consistent with a cell-intrinsic effect, we show directly preserved HSC function resulting in a more rapid recovery of peripheral blood counts, enhanced serial transplantation capacity, and reduced myeloid skewing. When administered to healthy human volunteers, G1T28 demonstrated excellent in vivo pharmacology and transiently inhibited bone marrow (BM) HSPC proliferation. These findings suggest that the combination of CDK4/6 inhibitors with cytotoxic chemotherapy should provide a means to attenuate therapy-induced BM exhaustion in patients with cancer. Copyright © 2017, American Association for the Advancement of Science.

  17. Prostaglandin E2 increases hematopoietic stem cell survival and accelerates hematopoietic recovery after radiation injury

    PubMed Central

    Porter, Rebecca L.; Georger, Mary; Bromberg, Olga; McGrath, Kathleen E.; Frisch, Benjamin J.; Becker, Michael W.; Calvi, Laura M.

    2013-01-01

    Hematopoietic stem and progenitor cells (HSPCs), which continuously maintain all mature blood cells, are regulated within the marrow microenvironment. We previously reported that pharmacologic treatment of naïve mice with prostaglandin E2 (PGE2) expands HSPCs. However, the cellular mechanisms mediating this expansion remain unknown. Here we demonstrate that PGE2 treatment in naïve mice inhibits apoptosis of HSPCs without changing their proliferation rate. In a murine model of sub-lethal total body irradiation (TBI), in which HSPCs are rapidly lost, treatment with a long-acting PGE2 analogue (dmPGE2) reversed the apoptotic program initiated by TBI. dmPGE2 treatment in vivo decreased the loss of functional HSPCs following radiation injury, as demonstrated both phenotypically and by their increased reconstitution capacity. The antiapoptotic effect of dmPGE2 on HSPCs did not impair their ability to differentiate in vivo, resulting instead in improved hematopoietic recovery after TBI. dmPGE2 also increased microenvironmental cyclooxygenase-2 expression and expanded the α-SMA+ subset of marrow macrophages, thus enhancing the bone marrow microenvironmental response to TBI. Therefore, in vivo treatment with PGE2 analogues may be particularly beneficial to HSPCs in the setting of injury by targeting them both directly and also through their niche. The current data provide rationale for in vivo manipulation of the HSPC pool as a strategy to improve recovery after myelosuppression. PMID:23169593

  18. Involvement of the histamine H{sub 4} receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Goto, Aya; Mouri, Akihiro; Nagai, Tomoko

    Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100 μM)more » and doxorubicin (0.2 µM) decreased the cell survival rate, but olanzapine (1–100 µM) did not. Under granulocytic differentiation for 5 days, clozapine, even at a concentration of 25 μM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H{sub 4} receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H{sub 4} receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H{sub 4} receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H{sub 4} receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic

  19. The Gottingen minipig is a model of the hematopoietic acute radiation syndrome: G-CSF stimulates hematopoiesis and enhances survival from lethal total-body gamma-irradiation

    PubMed Central

    Moroni, Maria; Ngudiankama, Barbara F.; Christensen, Christine; Olsen, Cara H.; Owens, Rossitsa; Lombardini, Eric D.; Holt, Rebecca K.; Whitnall, Mark H.

    2013-01-01

    Purpose We are characterizing the Gottingen minipig as an additional large animal model for advanced drug testing for the Acute Radiation Syndrome (ARS), to enhance discovery and development of novel radiation countermeasures. Among the advantages provided by this model, the similarities to human hematological parameters and dynamics of cell loss/recovery following irradiation provide a convenient means to compare efficacy of drugs known to affect bone marrow cellularity and hematopoiesis. Methods and Materials Male Gottingen minipigs, 4–5 months old and weighing 9–11 kg were used for this study. We tested the standard off-label treatment for ARS, rhG-CSF (Neupogen®, 10 μg/kg/day for 17 days), at the estimated LD70/30 total-body gamma-irradiation (TBI) radiation dose for the hematopoietic syndrome, starting 24 hours after irradiation. Results Results indicate G-CSF enhanced survival, stimulated recovery from neutropenia, and induced mobilization of hematopoietic progenitor cells. In addition, administration of G-CSF resulted in maturation of monocytes/macrophages. Conclusion These results support continuing efforts toward validation of the minipig as a large animal model for advanced testing of radiation countermeasures and characterization of the pathophysiology of ARS, and suggest that the efficacy of G-CSF in improving survival after total body irradiation may involve mechanisms other than increasing numbers of circulating granulocytes. PMID:23845847

  20. Countermeasures for Space Radiation Induced Malignancies and Acute Biological Effects

    NASA Astrophysics Data System (ADS)

    Kennedy, Ann

    The hypothesis being evaluated in this research program is that control of radiation induced oxidative stress will reduce the risk of radiation induced adverse biological effects occurring as a result of exposure to the types of radiation encountered during space travel. As part of this grant work, we have evaluated the protective effects of several antioxidants and dietary supplements and observed that a mixture of antioxidants (AOX), containing L-selenomethionine, N-acetyl cysteine (NAC), ascorbic acid, vitamin E succinate, and alpha-lipoic acid, is highly effective at reducing space radiation induced oxidative stress in both in vivo and in vitro systems, space radiation induced cytotoxicity and malignant transformation in vitro [1-7]. In studies designed to determine whether the AOX formulation could affect radiation induced mortality [8], it was observed that the AOX dietary supplement increased the 30-day survival of ICR male mice following exposure to a potentially lethal dose (8 Gy) of X-rays when given prior to or after animal irradiation. Pretreatment of animals with antioxidants resulted in significantly higher total white blood cell and neutrophil counts in peripheral blood at 4 and 24 hours following exposure to doses of 1 Gy and 8 Gy. Antioxidant treatment also resulted in increased bone marrow cell counts following irradiation, and prevented peripheral lymphopenia following 1 Gy irradiation. Supplementation with antioxidants in irradiated animals resulted in several gene expression changes: the antioxidant treatment was associated with increased Bcl-2, and decreased Bax, caspase-9 and TGF-β1 mRNA expression in the bone marrow following irradiation. These results suggest that modulation of apoptosis may be mechanistically involved in hematopoietic system radioprotection by antioxidants. Maintenance of the antioxidant diet was associated with improved recovery of the bone marrow following sub-lethal or potentially lethal irradiation. Taken together

  1. Rebamipide alleviates radiation-induced colitis through improvement of goblet cell differentiation in mice.

    PubMed

    Jang, Hyosun; Park, Sunhoo; Lee, Janet; Myung, Jae Kyung; Jang, Won-Suk; Lee, Sun-Joo; Myung, Hyunwook; Lee, Changsun; Kim, Hyewon; Lee, Seung-Sook; Jin, Young-Woo; Shim, Sehwan

    2018-04-01

    Radiation-induced colitis is a common clinical problem associated with radiotherapy and accidental exposure to ionizing radiation. Goblet cells play a pivotal role in the intestinal barrier against pathogenic bacteria. Rebamipide, an anti-gastric ulcer drug, has the effects to promote goblet cell proliferation. The aim of this study was to investigate whether radiation-induced colonic injury could be alleviated by rebamipide. This study orally administered rebamipide for 6 days to mice, which were subjected to 13 Gy abdominal irradiation, to evaluate the therapeutic effects of rebamipide against radiation-induced colitis. To confirm the effects of rebamipide on irradiated colonic epithelial cells, this study used the HT29 cell line. Rebamipide clearly alleviated the acute radiation-induced colitis, as reflected by the histopathological data, and significantly increased the number of goblet cells. The drug also inhibited intestinal inflammation and protected from bacterial translocation during acute radiation-induced colitis. Furthermore, rebamipide significantly increased mucin 2 expression in both the irradiated mouse colon and human colonic epithelial cells. Additionally, rebamipide accelerated not only the recovery of defective tight junctions but also the differentiation of impaired goblet cells in an irradiated colonic epithelium, which indicates that rebamipide has beneficial effects on the colon. Rebamipide is a therapeutic candidate for radiation-induced colitis, owing to its ability to inhibit inflammation and protect the colonic epithelial barrier. © 2017 The Authors Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  2. Nitrogen-containing bisphosphonate induces a newly discovered hematopoietic structure in the omentum of an anemic mouse model by stimulating G-CSF production.

    PubMed

    Otsuka, Hirotada; Yagi, Hideki; Endo, Yasuo; Soeta, Satoshi; Nonaka, Naoko; Nakamura, Masanori

    2017-02-01

    We previously reported that the injection of nitrogen-containing bisphosphonate (NBP) induced the site of erythropoiesis to shift from the bone marrow (BM) to the spleen. Our previous study established a severely anemic mouse model that was treated with a combination of NBP with phenylhydrazine (PHZ), which induced newly discovered hematopoietic organs in the omentum. No reports have shown that new hematopoietic organs form under any condition. We characterized the structures and factors related to the formation of these new organs. Splenectomized mice were treated with NBP to inhibit erythropoiesis in the BM and then injected with PHZ to induce hemolytic anemia. The mice showed severe anemia and wine-colored structures appeared in the omentum. Some hematopoietic cells, including megakaryocytes, and well-developed sinuses were observed in these structures. Numerous TER119-positive erythroblasts were located with cells positive for PCNA, a cell proliferation marker. C-kit-positive cells were detected and mRNAs related to hematopoiesis were expressed in these structures. Moreover, TER119-positive erythroblasts emerged and formed clusters and hematopoiesis-related factors were detected in the omentum of mice treated with NBP and PHZ. The levels of G-CSF in the serum and hematopoietic progenitor cells (HPCs) in the peripheral blood were increased upon treatment with both NBP and PHZ. These results suggest that the induced hematopoietic structures act as the sites of erythropoiesis and that NBP-induced G-CSF production causes HPC mobilization, homing and colonization in the omentum because they constitutively express some factors, including SDF-1; thus, the newly discovered hematopoietic structure in this study might be formed.

  3. Circulating hematopoietic progenitor cells in patients affected by Chornobyl accident.

    PubMed

    Bilko, N M; Dyagil, I S; Russu, I Z; Bilko, D I

    2016-12-01

    High radiation sensitivity of stem cells and their ability to accumulate sublethal radiation damage provides the basis for investigation of hematopoietic progenitors using in vivo culture methodology. Unique samples of peripheral blood and bone marrow were derived from the patients affected by Chornobyl accident during liquidation campaign. To investigate functional activity of circulating hematopoietic progenitor cells from peripheral blood and bone marrow of cleanup workers in early and remote periods after the accident at Chornobyl nuclear power plant (CNPP). The assessment of the functional activity of circulating hematopoietic progenitor cells was performed in samples of peripheral blood and bone marrow of 46 cleanup workers, who were treated in the National Scientific Center for Radiation Medicine of the Academy of Medical Sciences of Ukraine alongside with 35 non radiated patients, who served as a control. Work was performed by culturing peripheral blood and bone marrow mononuclear cells in the original gel diffusion capsules, implanted into the peritoneal cavity of CBA mice. It was shown that hematopoietic progenitor cells could be identified in the peripheral blood of liquidators of CNPP accident. At the same time the number of functionally active progenitor cells of the bone marrow was significantly decreased and during the next 10 years after the accident, counts of circulating progenitor cells in the peripheral blood as well as functionally active hematopoietic cells in bone marrow returned to normal levels. It was shown that hematopoietic progenitor cells are detected not only in the bone marrow but also in the peripheral blood of liquidators as a consequence of radiation exposure associated with CNPP accident. This article is a part of a Special Issue entitled "The Chornobyl Nuclear Accident: Thirty Years After".

  4. Sulforaphane mitigates genotoxicity induced by radiation and anticancer drugs in human lymphocytes.

    PubMed

    Katoch, Omika; Kumar, Arun; Adhikari, Jawahar S; Dwarakanath, Bilikere S; Agrawala, Paban K

    2013-12-12

    Sulforaphane, present in cruciferous vegetables such as broccoli, is a dietary anticancer agent. Sulforaphane, added 2 or 20 h following phytohemaglutinin stimulation to cultured peripheral blood lymphocytes of individuals accidentally exposed to mixed γ and β-radiation, reduced the micronucleus frequency by up to 70%. Studies with whole blood cultures obtained from healthy volunteers confirmed the ability of sulforaphane to ameliorate γ-radiation-induced genotoxicity and to reduce micronucleus induction by other DNA-damaging anticancer agents, such as bleomycin and doxorubicin. This reduction in genotoxicity in lymphocytes treated at the G(0) or G(1) stage suggests a role for sulforaphane in modulating DNA repair. Sulforaphane also countered the radiation-induced increase in lymphocyte HDAC activity, to control levels, when cells were treated 2 h after exposure, and enhanced histone H4 acetylation status. Sulforaphane post-irradiation treatment enhanced the CD 34(+)Lin(-) cell population in culture. Sulforaphane has therapeutic potential for management of the late effects of radiation. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. The Gottingen minipig is a model of the hematopoietic acute radiation syndrome: G-colony stimulating factor stimulates hematopoiesis and enhances survival from lethal total-body γ-irradiation.

    PubMed

    Moroni, Maria; Ngudiankama, Barbara F; Christensen, Christine; Olsen, Cara H; Owens, Rossitsa; Lombardini, Eric D; Holt, Rebecca K; Whitnall, Mark H

    2013-08-01

    We are characterizing the Gottingen minipig as an additional large animal model for advanced drug testing for the acute radiation syndrome (ARS) to enhance the discovery and development of novel radiation countermeasures. Among the advantages provided by this model, the similarities to human hematologic parameters and dynamics of cell loss/recovery after irradiation provide a convenient means to compare the efficacy of drugs known to affect bone marrow cellularity and hematopoiesis. Male Gottingen minipigs, 4 to 5 months old and weighing 9 to 11 kg, were used for this study. We tested the standard off-label treatment for ARS, rhG-CSF (Neupogen, 10 μg/kg/day for 17 days), at the estimated LD70/30 total-body γ-irradiation (TBI) radiation dose for the hematopoietic syndrome, starting 24 hours after irradiation. The results indicated that granulocyte colony stimulating factor (G-CSF) enhanced survival, stimulated recovery from neutropenia, and induced mobilization of hematopoietic progenitor cells. In addition, the administration of G-CSF resulted in maturation of monocytes/macrophages. These results support continuing efforts toward validation of the minipig as a large animal model for advanced testing of radiation countermeasures and characterization of the pathophysiology of ARS, and they suggest that the efficacy of G-CSF in improving survival after total body irradiation may involve mechanisms other than increasing the numbers of circulating granulocytes. Published by Elsevier Inc.

  6. Sodium Caseinate (CasNa) Induces Mobilization of Hematopoietic Stem Cells in a BALB/c Mouse Model

    PubMed Central

    Santiago-Osorio, Edelmiro; Ledesma-Martínez, Edgar; Aguiñiga-Sánchez, Itzen; Poblano-Pérez, Ignacio; Weiss-Steider, Benny; Montesinos-Montesinos, Juan José; de Lourdes Mora-García, María

    2015-01-01

    Background Hematopoietic stem cells transplantation has high clinical potential against a wide variety of hematologic, metabolic, and autoimmune diseases and solid tumors. Clinically, hematopoietic stem cells derived from peripheral blood are currently used more than those obtained from sources such as bone marrow. However, mobilizing agents used in the clinic tend to fail in high rates, making the number of mobilized cells insufficient for transplantation. We investigated whether sodium caseinate induces functional mobilization of hematopoietic stem cells into peripheral blood of Balb/c mice. Material/Methods Using a mouse model, we administrated sodium caseinate or Plerixafor, a commercial mobilizing agent, and analyzed counts of hematopoietic stem cells in peripheral blood, and then cells were transplanted into lethally irradiated mice to restore hematopoiesis. All assays were performed at least twice. Results We found that sodium caseinate increases the number of mononuclear cells in peripheral blood with the immunophenotype of hematopoietic stem cells (0.2 to 0.5% LSK cells), allowing them to form colonies of various cell lineages in semisolid medium (p<0.05). This effect is similar to that of Plerixafor, and cells transplanted into lethally irradiated mice can restore hematopoiesis at higher percentages than mononuclear cells mobilized by Plerixafor (40% vs. 20%, respectively). Further, a secondary transplant rescued a separate group of irradiated mice from death, proving definitive evidence of hematopoietic reconstitution after hematopoietic stem cells transplantation. Data are presented as mean ± standard deviation. To determine significant differences between the data, one-way ANOVA and the Tukey test were used. Conclusions Collectively these results show the utility of sodium caseinate as a mobilizer of hematopoietic stem cells and its potential clinical application in transplantation settings. PMID:26409928

  7. Sodium Caseinate (CasNa) Induces Mobilization of Hematopoietic Stem Cells in a BALB/c Mouse Model.

    PubMed

    Santiago-Osorio, Edelmiro; Ledesma-Martínez, Edgar; Aguiñiga-Sánchez, Itzen; Poblano-Pérez, Ignacio; Weiss-Steider, Benny; Montesinos-Montesinos, Juan José; Mora-García, María de Lourdes

    2015-09-25

    BACKGROUND Hematopoietic stem cells transplantation has high clinical potential against a wide variety of hematologic, metabolic, and autoimmune diseases and solid tumors. Clinically, hematopoietic stem cells derived from peripheral blood are currently used more than those obtained from sources such as bone marrow. However, mobilizing agents used in the clinic tend to fail in high rates, making the number of mobilized cells insufficient for transplantation. We investigated whether sodium caseinate induces functional mobilization of hematopoietic stem cells into peripheral blood of Balb/c mice. MATERIAL AND METHODS Using a mouse model, we administrated sodium caseinate or Plerixafor, a commercial mobilizing agent, and analyzed counts of hematopoietic stem cells in peripheral blood, and then cells were transplanted into lethally irradiated mice to restore hematopoiesis. All assays were performed at least twice. RESULTS We found that sodium caseinate increases the number of mononuclear cells in peripheral blood with the immunophenotype of hematopoietic stem cells (0.2 to 0.5% LSK cells), allowing them to form colonies of various cell lineages in semisolid medium (p<0.05). This effect is similar to that of Plerixafor, and cells transplanted into lethally irradiated mice can restore hematopoiesis at higher percentages than mononuclear cells mobilized by Plerixafor (40% vs. 20%, respectively). Further, a secondary transplant rescued a separate group of irradiated mice from death, proving definitive evidence of hematopoietic reconstitution after hematopoietic stem cells transplantation. Data are presented as mean ± standard deviation. To determine significant differences between the data, one-way ANOVA and the Tukey test were used. CONCLUSIONS Collectively these results show the utility of sodium caseinate as a mobilizer of hematopoietic stem cells and its potential clinical application in transplantation settings.

  8. Impact of p53 status on heavy-ion radiation-induced micronuclei in circulating erythrocytes

    NASA Technical Reports Server (NTRS)

    Chang, P. Y.; Torous, D.; Lutze-Mann, L.; Winegar, R.

    2000-01-01

    Transgenic mice that differed in their p53 genetic status were exposed to an acute dose of highly charged and energetic (HZE) iron particle radiation. Micronuclei (MN) in two distinct populations of circulating peripheral blood erythrocytes, the immature reticulocytes (RETs) and the mature normochromatic erythrocytes (NCEs), were measured using a simple and efficient flow cytometric procedure. Our results show significant elevation in the frequency of micronucleated RETs (%MN-RETs) at 2 and 3 days post-radiation. At 3 days post-irradiation, the magnitude of the radiation-induced MN-RET was 2.3-fold higher in the irradiated p53 wild-type animals compared to the unirradiated controls, 2.5-fold higher in the p53 hemizygotes and 4.3-fold higher in the p53 nullizygotes. The persistence of this radiation-induced elevation of MN-RETs is dependent on the p53 genetic background of the animal. In the p53 wild-type and p53 hemizygotes, %MN-RETs returned to control levels by 9 days post-radiation. However, elevated levels of %MN-RETs in p53 nullizygous mice persisted beyond 56 days post-radiation. We also observed elevated MN-NCEs in the peripheral circulation after radiation, but the changes in radiation-induced levels of MN-NCEs appear dampened compared to those of the MN-RETs for all three strains of animals. These results suggest that the lack of p53 gene function may play a role in the iron particle radiation-induced genomic instability in stem cell populations in the hematopoietic system.

  9. 28Si total body irradiation injures bone marrow hematopoietic stem cells via induction of cellular apoptosis

    NASA Astrophysics Data System (ADS)

    Chang, Jianhui; Feng, Wei; Wang, Yingying; Allen, Antiño R.; Turner, Jennifer; Stewart, Blair; Raber, Jacob; Hauer-Jensen, Martin; Zhou, Daohong; Shao, Lijian

    2017-05-01

    Long-term space mission exposes astronauts to a radiation environment with potential health hazards. High-energy charged particles (HZE), including 28Si nuclei in space, have deleterious effects on cells due to their characteristics with high linear energy transfer and dense ionization. The influence of 28Si ions contributes more than 10% to the radiation dose equivalent in the space environment. Understanding the biological effects of 28Si irradiation is important to assess the potential health hazards of long-term space missions. The hematopoietic system is highly sensitive to radiation injury and bone marrow (BM) suppression is the primary life-threatening injuries after exposure to a moderate dose of radiation. Therefore, in the present study we investigated the acute effects of low doses of 28Si irradiation on the hematopoietic system in a mouse model. Specifically, 6-month-old C57BL/6 J mice were exposed to 0.3, 0.6 and 0.9 Gy 28Si (600 MeV) total body irradiation (TBI). The effects of 28Si TBI on BM hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) were examined four weeks after the exposure. The results showed that exposure to 28Si TBI dramatically reduced the frequencies and numbers of HSCs in irradiated mice, compared to non-irradiated controls, in a radiation dose-dependent manner. In contrast, no significant changes were observed in BM HPCs regardless of radiation doses. Furthermore, irradiated HSCs exhibited a significant impairment in clonogenic ability. These acute effects of 28Si irradiation on HSCs may be attributable to radiation-induced apoptosis of HSCs, because HSCs, but not HPCs, from irradiated mice exhibited a significant increase in apoptosis in a radiation dose-dependent manner. However, exposure to low doses of 28Si did not result in an increased production of reactive oxygen species and DNA damage in HSCs and HPCs. These findings indicate that exposure to 28Si irradiation leads to acute HSC damage.

  10. The Gottingen Minipig Is a Model of the Hematopoietic Acute Radiation Syndrome: G-Colony Stimulating Factor Stimulates Hematopoiesis and Enhances Survival From Lethal Total-Body γ-Irradiation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Moroni, Maria, E-mail: maria.moroni@usuhs.edu; Ngudiankama, Barbara F.; Christensen, Christine

    Purpose: We are characterizing the Gottingen minipig as an additional large animal model for advanced drug testing for the acute radiation syndrome (ARS) to enhance the discovery and development of novel radiation countermeasures. Among the advantages provided by this model, the similarities to human hematologic parameters and dynamics of cell loss/recovery after irradiation provide a convenient means to compare the efficacy of drugs known to affect bone marrow cellularity and hematopoiesis. Methods and Materials: Male Gottingen minipigs, 4 to 5 months old and weighing 9 to 11 kg, were used for this study. We tested the standard off-label treatment formore » ARS, rhG-CSF (Neupogen, 10 μg/kg/day for 17 days), at the estimated LD70/30 total-body γ-irradiation (TBI) radiation dose for the hematopoietic syndrome, starting 24 hours after irradiation. Results: The results indicated that granulocyte colony stimulating factor (G-CSF) enhanced survival, stimulated recovery from neutropenia, and induced mobilization of hematopoietic progenitor cells. In addition, the administration of G-CSF resulted in maturation of monocytes/macrophages. Conclusions: These results support continuing efforts toward validation of the minipig as a large animal model for advanced testing of radiation countermeasures and characterization of the pathophysiology of ARS, and they suggest that the efficacy of G-CSF in improving survival after total body irradiation may involve mechanisms other than increasing the numbers of circulating granulocytes.« less

  11. The suppression of radiation-induced NF-{kappa}B activity by dexamethasone correlates with increased cell death in vivo

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nam, Seon Young; Chung, Hee-Yong

    2005-10-21

    In this study, we show that dexamethasone treatment increases ionizing radiation-induced cell death by inducing the inhibitory {kappa}B{alpha} (I{kappa}B{alpha}) pathway in mice. The effect of dexamethasone on radiation-induced cell death was assessed by changes in total spleen cellularity and bone marrow colony-forming unit-granulocyte-macrophage (CFU-GM) contents after total body irradiation. While in vivo treatment of mice with dexamethasone alone (1 mg/kg/day, for 2 days) failed to elicit cell death in spleen cells, the combined treatment with dexamethasone (1 mg/kg/day, for 2 days) and {gamma}-rays (1 or 5 Gy) caused a 50-80% reduction in total cellularity in spleen and CFU-GM contents inmore » bone marrow. These results demonstrate that dexamethasone has a synergistic effect on radiation-induced cellular damages in vivo. Immunoblot analysis showed that dexamethasone treatment significantly increases I{kappa}B{alpha} expression in the spleens of irradiated mice. In addition, the dexamethasone treatment significantly reduced radiation-induced nuclear translocation of the nucleus factor-{kappa}B in the spleens of irradiated mice. These results indicate that dexamethasone treatment in vivo may increase radiation-induced cell damages by increasing I{kappa}B{alpha} expression in hematopoietic organs such as spleen and bone marrow.« less

  12. TGFβ restores hematopoietic homeostasis after myelosuppressive chemotherapy

    PubMed Central

    Brenet, Fabienne; Kermani, Pouneh; Spektor, Roman; Rafii, Shahin

    2013-01-01

    Myelosuppression is a life-threatening complication of antineoplastic therapy, but treatment is restricted to a few cytokines with unilineage hematopoietic activity. Although hematopoietic stem cells (HSCs) are predominantly quiescent during homeostasis, they are rapidly recruited into cell cycle by stresses, including myelosuppressive chemotherapy. Factors that induce HSCs to proliferate during stress have been characterized, but it is not known how HSC quiescence is then reestablished. In this study, we show that TGFβ signaling is transiently activated in hematopoietic stem and progenitor cells (HSPCs) during hematopoietic regeneration. Blockade of TGFβ signaling after chemotherapy accelerates hematopoietic reconstitution and delays the return of cycling HSCs to quiescence. In contrast, TGFβ blockade during homeostasis fails to induce cycling of HSPCs. We identified the cyclin-dependent kinase inhibitor Cdkn1c (p57) as a key downstream mediator of TGFβ during regeneration because the recovery of chimeric mice, incapable of expressing p57 in HSPCs, phenocopies blockade of TGFβ signaling after chemotherapy. This study demonstrates that context-dependent activation of TGFβ signaling is central to an unrecognized counterregulatory mechanism that promotes homeostasis once hematopoiesis has sufficiently recovered from myelosuppressive chemotherapy. These results open the door to new, potentially superior, approaches to promote multilineage hematopoietic recovery by blocking the TGFβ signaling that dampens regeneration. PMID:23440043

  13. Murine thymic lymphoma is associated with a species-specific hematopoietic progenitor cell subpopulation

    NASA Technical Reports Server (NTRS)

    Irons, R. D.; Colagiovanni, D. B.; Stillman, W. S.; Clarkson, T. W. (Principal Investigator)

    1996-01-01

    Many strains of laboratory mouse are uniquely susceptible to the development of T cell lymphoma/leukemia, either spontaneously or as a result of chemical or radiation exposure. In contrast, T cell leukemias or lymphomas which are relatively uncommon in human populations, are not easily induced by radiation, and are not generally associated with chemotherapy or chemical exposure. Evidence is presented to suggest that differences in the susceptibility to the development of these malignancies is related to subtle but important variations in the regulation of hematopoietic stem cell differentiation between these two species.

  14. A genotoxic analysis of the hematopoietic system after mobile phone type radiation exposure in rats.

    PubMed

    Kumar, Gaurav; McIntosh, Robert L; Anderson, Vitas; McKenzie, Ray J; Wood, Andrew W

    2015-08-01

    In our earlier study we reported that 900 MHz continuous wave (CW) radiofrequency radiation (RFR) exposure (2 W/kg specific absorption rate [SAR]) had no significant effect on the hematopoietic system of rats. In this paper we extend the scope of the previous study by testing for possible effects at: (i) different SAR levels; (ii) both 900 and 1800 MHz, and; (iii) both CW and pulse modulated (PM) RFR. Excised long bones from rats were placed in medium and RFR exposed in (i) a Transverse Electromagnetic (TEM) cell or (ii) a waveguide. Finite-difference time-domain (FDTD) numerical analyses were used to estimate forward power needed to produce nominal SAR levels of 2/10 and 2.5/12.4 W/kg in the bone marrow. After exposure, the lymphoblasts were extracted and assayed for proliferation rate, and genotoxicity. Our data did not indicate any significant change in these end points for any combination of CW/PM exposure at 900/1800 MHz at SAR levels of nominally 2/10 W/kg or 2.5/12.4 W/kg. No significant changes were observed in the hematopoietic system of rats after the exposure of CW/PM wave 900 MHz/1800 MHz RF radiations at different SAR values.

  15. Hematopoietic tissue repair under chronic low daily dose irradiation

    NASA Astrophysics Data System (ADS)

    Seed, T. M.

    The capacity of the hematopoietic system to repair constantly accruing cellular damage under chronic, low daily dose gamma irradiation is essential for the maintenance of a functional hematopoietic system, and, in turn, long term survival. In certain individuals, however, such continuous cycles of damage and repair provide an essential inductive environment for selected types of hematopathologies, e.g., myeloid leukemia (ML). In our laboratory we have been studying temporal and causal relationships between hematopoietic capacity, associated repair functions, and propensities for hematologic disease in canines under variable levels of chronic radiation stress (0.3-26.3 cGy d^-1). Results indicate that the maximum exposure rate tolerated by the hematopoietic system is highly individual-specific (three major responding subgroups identified) and is based largely on the degree to which repair capacity, and, in turn, hematopoietic restoration, is augmented under chronic exposure. In low-tolerance individuals (prone to aplastic anemia, subgroup 1), the failure to augment basic repair functions seemingly results in a progressive accumulation of genetic and cellular damage within vital progenitorial marrow compartments (particularly marked within erythroid compartments) that results in loss of reproductive capacity and ultimately in collapse of the hematopoietic system. The high-tolerance individuals (radioaccommodated and either prone- or not prone to ML, subgroup 2 & 3) appear to minimize the accumulating damage effect of daily exposures by extending repair functions, which preserves reproductive integrity and fosters regenerative hematopoietic responses. As the strength of the regenerative response manifests the extent of repair augmentation, the relatively strong response of high-tolerance individuals progressing to patent ML suggests an insufficiency of repair quality rather than repair quantity. The kinetics of these repair-mediated, regenerative hematopoietic

  16. Thrombomodulin Contributes to Gamma Tocotrienol-Mediated Lethality Protection and Hematopoietic Cell Recovery in Irradiated Mice

    PubMed Central

    Pathak, Rupak; Shao, Lijian; Ghosh, Sanchita P.; Zhou, Daohong; Boerma, Marjan; Weiler, Hartmut; Hauer-Jensen, Martin

    2015-01-01

    Systemic administration of recombinant thrombomodulin (TM) confers radiation protection partly by accelerating hematopoietic recovery. The uniquely potent radioprotector gamma tocotrienol (GT3), in addition to being a strong antioxidant, inhibits the enzyme hydroxy-methyl-glutaryl-coenzyme A reductase (HMGCR) and thereby likely modulates the expression of TM. We hypothesized that the mechanism underlying the exceptional radioprotective properties of GT3 partly depends on the presence of endothelial TM. In vitro studies confirmed that ionizing radiation suppresses endothelial TM (about 40% at 4 hr after 5 Gy γ-irradiation) and that GT3 induces TM expression (about 2 fold at the mRNA level after 5 μM GT3 treatment for 4 hr). In vivo survival studies showed that GT3 was significantly more effective as a radioprotector in TM wild type (TM+/+) mice than in mice with low TM function (TMPro/-). After exposure to 9 Gy TBI, GT3 pre-treatment conferred 85% survival in TM+/+ mice compared to only 50% in TMPro/-. Thus, GT3-mediated radiation lethality protection is partly dependent on endothelial TM. Significant post-TBI recovery of hematopoietic cells, particularly leukocytes, was observed in TM+/+ mice (p = 0.003), but not in TMPro/- mice, despite the fact that GT3 induced higher levels of granulocyte colony stimulating factor (G-CSF) in TMPro/- mice (p = 0.0001). These data demonstrate a critical, G-CSF-independent, role for endothelial TM in GT3-mediated lethality protection and hematopoietic recovery after exposure to TBI and may point to new strategies to enhance the efficacy of current medical countermeasures in radiological/nuclear emergencies. PMID:25860286

  17. Generating autologous hematopoietic cells from human-induced pluripotent stem cells through ectopic expression of transcription factors.

    PubMed

    Hwang, Yongsung; Broxmeyer, Hal E; Lee, Man Ryul

    2017-07-01

    Hematopoietic cell transplantation (HCT) is a successful treatment modality for patients with malignant and nonmalignant disorders, usually when no other treatment option is available. The cells supporting long-term reconstitution after HCT are the hematopoietic stem cells (HSCs), which can be limited in numbers. Moreover, finding an appropriate human leukocyte antigen-matched donor can be problematic. If HSCs can be stably produced in large numbers from autologous or allogeneic cell sources, it would benefit HCT. Induced pluripotent stem cells (iPSCs) established from patients' own somatic cells can be differentiated into hematopoietic cells in vitro. This review will highlight recent methods for regulating human (h) iPSC production of HSCs and more mature blood cells. Advancements in transcription factor-mediated regulation of the developmental stages of in-vivo hematopoietic lineage commitment have begun to provide an understanding of the molecular mechanism of hematopoiesis. Such studies involve not only directed differentiation in which transcription factors, specifically expressed in hematopoietic lineage-specific cells, are overexpressed in iPSCs, but also direct conversion in which transcription factors are introduced into patient-derived somatic cells which are dedifferentiated to hematopoietic cells. As iPSCs derived from patients suffering from genetically mutated diseases would express the same mutated genetic information, CRISPR-Cas9 gene editing has been utilized to differentiate genetically corrected iPSCs into normal hematopoietic cells. IPSCs provide a model for molecular understanding of disease, and also may function as a cell population for therapy. Efficient differentiation of patient-specific iPSCs into HSCs and progenitor cells is a potential means to overcome limitations of such cells for HCT, as well as for providing in-vitro drug screening templates as tissue-on-a-chip models.

  18. Recovery from radiation-induced bone marrow damage by HSP25 through Tie2 signaling.

    PubMed

    Lee, Hae-June; Kwon, Hee-Chung; Chung, Hee-Yong; Lee, Yoon-Jin; Lee, Yun-Sil

    2012-09-01

    Whole-body radiation therapy can cause severe injury to the hematopoietic system, and therefore it is necessary to identify a novel strategy for overcoming this injury. Mice were irradiated with 4.5 Gy after heat shock protein 25 (HSP25) gene transfer using an adenoviral vector. Then, peripheral blood cell counts, histopathological analysis, and Western blotting on bone marrow (BM) cells were performed. The interaction of HSP25 with Tie2 was investigated with mouse OP9 and human BM-derived mesenchymal stem cells to determine the mechanism of HSP25 in the hematopoietic system. HSP25 transfer increased BM regeneration and reduced apoptosis following whole-body exposure to ionizing radiation (IR). The decrease in Tie2 protein expression that followed irradiation of the BM was blocked by HSP25 transfer, and Tie2-positive cells were more abundant among the BM cells of HSP25-transferred mice, even after IR exposure. Following systemic RNA interference of Tie2 before IR, HSP25-mediated radioprotective effects were partially blocked in both mice and cell line systems. Stability of Tie2 was increased by HSP25, a response mediated by the interaction of HSP25 with Tie2. IR-induced tyrosine phosphorylation of Tie2 was augmented by HSP25 overexpression; downstream events in the Tie2 signaling pathway, including phosphorylation of AKT and EKR1/2, were also activated. HSP25 protects against radiation-induced BM damage by interacting with and stabilizing Tie2. This may be a novel strategy for HSP25-mediated radioprotection in BM. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Benzene-Induced Aberrant miRNA Expression Profile in Hematopoietic Progenitor Cells in C57BL/6 Mice.

    PubMed

    Wei, Haiyan; Zhang, Juan; Tan, Kehong; Sun, Rongli; Yin, Lihong; Pu, Yuepu

    2015-11-12

    Benzene is a common environmental pollutant that causes hematological alterations. MicroRNAs (miRNAs) may play a role in benzene-induced hematotoxicity. In this study, C57BL/6 mice showed significant hematotoxicity after exposure to 150 mg/kg benzene for 4 weeks. Benzene exposure decreased not only the number of cells in peripheral blood but also hematopoietic progenitor cells in the bone marrow. Meanwhile, RNA from Lin(-) cells sorted from the bone marrow was applied to aberrant miRNA expression profile using Illumina sequencing. We found that 5 miRNAs were overexpressed and 45 miRNAs were downregulated in the benzene exposure group. Sequencing results were confirmed through qRT-PCR. Furthermore, we also identified five miRNAs which significantly altered in Lin(-)c-Kit⁺ cells obtained from benzene-exposed mice, including mmu-miR-34a-5p; mmu-miR-342-3p; mmu-miR-100-5p; mmu-miR-181a-5p; and mmu-miR-196b-5p. In summary, we successfully established a classical animal model to induce significant hematotoxicity by benzene injection. Benzene exposure may cause severe hematotoxicity not only to blood cells in peripheral circulation but also to hematopoietic cells in bone marrow. Benzene exposure also alters miRNA expression in hematopoietic progenitor cells. This study suggests that benzene induces alteration in hematopoiesis and hematopoiesis-associated miRNAs.

  20. ICRP publication 112. A report of preventing accidental exposures from new external beam radiation therapy technologies.

    PubMed

    Ortiz López, P; Cosset, J M; Dunscombe, P; Holmberg, O; Rosenwald, J C; Pinillos Ashton, L; Vilaragut Llanes, J J; Vatnitsky, S

    2009-08-01

    Disseminating the knowledge and lessons learned from accidental exposures is crucial in preventing re-occurrence. This is particularly important in radiation therapy; the only application of radiation in which very high radiation doses are deliberately given to patients to achieve cure or palliation of disease. Lessons from accidental exposures are, therefore, an invaluable resource for revealing vulnerable aspects of the practice of radiotherapy, and for providing guidance for the prevention of future occurrences. These lessons have successfully been applied to avoid catastrophic events with conventional technologies and techniques. Recommendations, for example, include the independent verification of beam calibration and independent calculation of the treatment times and monitor units for external beam radiotherapy, and the monitoring of patients and their clothes immediately after brachytherapy. New technologies are meant to bring substantial improvement to radiation therapy. However, this is often achieved with a considerable increase in complexity, which in turn brings opportunities for new types of human error and problems with equipment. Dissemination of information on these errors or mistakes as soon as it becomes available is crucial in radiation therapy with new technologies. In addition, information on circumstances that almost resulted in serious consequences (near-misses) is also important, as the same type of events may occur elsewhere. Sharing information about near-misses is thus a complementary important aspect of prevention. Lessons from retrospective information are provided in Sections 2 and 4 of this report. Disseminating lessons learned for serious incidents is necessary but not sufficient when dealing with new technologies. It is of utmost importance to be proactive and continually strive to answer questions such as 'What else can go wrong', 'How likely is it?' and 'What kind of cost-effective choices do I have for prevention?'. These

  1. Relationship between spontaneous γH2AX foci formation and progenitor functions in circulating hematopoietic stem and progenitor cells among atomic-bomb survivors.

    PubMed

    Kajimura, Junko; Kyoizumi, Seishi; Kubo, Yoshiko; Misumi, Munechika; Yoshida, Kengo; Hayashi, Tomonori; Imai, Kazue; Ohishi, Waka; Nakachi, Kei; Weng, Nan-Ping; Young, Lauren F; Shieh, Jae-Hung; Moore, Malcolm A; van den Brink, Marcel R M; Kusunoki, Yoichiro

    2016-05-01

    Accumulated DNA damage in hematopoietic stem cells is a primary mechanism of aging-associated dysfunction in human hematopoiesis. About 70 years ago, atomic-bomb (A-bomb) radiation induced DNA damage and functional decreases in the hematopoietic system of A-bomb survivors in a radiation dose-dependent manner. The peripheral blood cell populations then recovered to a normal range, but accompanying cells derived from hematopoietic stem cells still remain that bear molecular changes possibly caused by past radiation exposure and aging. In the present study, we evaluated radiation-related changes in the frequency of phosphorylated (Ser-139) H2AX (γH2AX) foci formation in circulating CD34-positive/lineage marker-negative (CD34+Lin-) hematopoietic stem and progenitor cells (HSPCs) among 226Hiroshima A-bomb survivors. An association between the frequency of γH2AX foci formation in HSPCs and the radiation dose was observed, but the γH2AX foci frequency was not significantly elevated by past radiation. We found a negative correlation between the frequency of γH2AX foci formation and the length of granulocyte telomeres. A negative interaction effect between the radiation dose and the frequency of γH2AX foci was suggested in a proportion of a subset of HSPCs as assessed by the cobblestone area-forming cell assay (CAFC), indicating that the self-renewability of HSPCs may decrease in survivors who were exposed to a higher radiation dose and who had more DNA damage in their HSPCs. Thus, although many years after radiation exposure and with advancing age, the effect of DNA damage on the self-renewability of HSPCs may be modified by A-bomb radiation exposure. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Relationship between spontaneous γH2AX foci formation and progenitor functions in circulating hematopoietic stem and progenitor cells among atomic-bomb survivors

    PubMed Central

    Kajimura, Junko; Kyoizumi, Seishi; Kubo, Yoshiko; Misumi, Munechika; Yoshida, Kengo; Hayashi, Tomonori; Imai, Kazue; Ohishi, Waka; Nakachi, Kei; Weng, Nan-ping; Young, Lauren F.; Shieh, Jae-Hung; Moore, Malcolm A.; van den Brink, Marcel R.M.; Kusunoki, Yoichiro

    2016-01-01

    Accumulated DNA damage in hematopoietic stem cells is a primary mechanism of aging-associated dysfunction in human hematopoiesis. About 70 years ago, atomic-bomb (A-bomb) radiation induced DNA damage and functional decreases in the hematopoietic system of A-bomb survivors in a radiation dose-dependent manner. The peripheral blood cell populations then recovered to a normal range, but accompanying cells derived from hematopoietic stem cells still remain that bear molecular changes possibly caused by past radiation exposure and aging. In the present study, we evaluated radiation-related changes in the frequency of phosphorylated (Ser-139) H2AX (γH2AX) foci formation in circulating CD34-positive/lineage marker-negative (CD34 + Lin−) hematopoietic stem and progenitor cells (HSPCs) among 226Hiroshima A-bomb survivors. An association between the frequency of γH2AX foci formation in HSPCs and the radiation dose was observed, but the γH2AX foci frequency was not significantly elevated by past radiation. We found a negative correlation between the frequency of γH2AX foci formation and the length of granulocyte telomeres. A negative interaction effect between the radiation dose and the frequency of γH2AX foci was suggested in a proportion of a subset of HSPCs as assessed by the cobblestone area-forming cell assay (CAFC), indicating that the self-renewability of HSPCs may decrease in survivors who were exposed to a higher radiation dose and who had more DNA damage in their HSPCs. Thus, although many years after radiation exposure and with advancing age, the effect of DNA damage on the self-renewability of HSPCs may be modified by A-bomb radiation exposure. PMID:27169377

  3. CCM-AMI, a Polyethylene Glycol Micelle with Amifostine, as an Acute Radiation Syndrome Protectant in C57BL/6 Mice.

    PubMed

    Chen, Chia-Hung; Kuo, Min-Liang; Wang, Jen-Ling; Liao, Wei-Chuan; Chang, Li-Ching; Chan, Leong-Perng; Lin, Johnson

    2015-09-01

    Acute radiation syndrome results from radiation exposure, such as in accidental nuclear disasters. Safe and effective radioprotectants, mitigators, and treatment drugs must be developed as medical countermeasures against radiation exposure. Here, the authors evaluated CCM-Ami, a novel polyethylene glycol micelle encapsulated with amifostine, for its radioprotective properties after total-body irradiation from a 60Co source. Male C57BL/6 mice (6-8 wk old) were intravenously injected with 45 mg kg(-1) of CCM-Ami 90 min before exposure to 7.2 and 8.5 Gy irradiation at a dose rate of 0.04 Gy min(-1). Both survival benefit and hematopoietic protection were observed after prophylactic CCM-Ami administration when compared with the effects measured in excipient control and amifostine groups. Pharmacokinetic results showed that after the intravenous injection, the plasma concentration of WR-1065, the active form of amifostine, was higher in CCM-Ami-treated mice than in amifostine-treated mice. These findings suggest that CCM-Ami-mediated hematopoietic protection plays a key role in enhancing survival of mice exposed to radiation toxicity and thus indicate that CCM-Ami is a radioprotectant that can be used safely and effectively in nuclear disasters.

  4. Role of drugs in the prevention and amelioration of radiation induced toxic effects.

    PubMed

    Patyar, Rakesh Raman; Patyar, Sazal

    2018-01-15

    As the use of radiation technology for nuclear warfare or for the benefits of mankind (e.g. in radiotherapy or radio-diagnosis) is increasing tremendously, the risk of associated side effects is becoming a cause of concern. These effects, ranging from nausea/vomiting to death, may result from accidental or deliberate exposure and begin in seconds. Through this review paper, efforts have been done to critically review different compounds which have been investigated as radioprotectors and radiation mitigators. Radioprotectors are compounds which are administered just before or at the time of irradiation so as to minimize the radiation induced damage to normal tissues. And radiation mitigators are the compounds which can even minimize or ameliorate post irradiaion-toxicity provided they are administered before the onset of toxic symptoms. A variety of agents have been investigated for their preventive and ameliorative potential against radiation induced toxic effects. This review article has focused on various aspects of the promising representative agents belonging to different classes of radioprotectors and mitigators. Many compounds have shown promising results, but till date only amifostine and palifermin are clinically approved by FDA. To fill this void in pharmacological armamentarium, focus should be shifted towards novel approaches. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Cutting the brakes on hematopoietic regeneration by blocking TGFβ to limit chemotherapy-induced myelosuppression

    PubMed Central

    Brenet, Fabienne; Scandura, Joseph M

    2015-01-01

    Hematopoietic stressors such as infection, bleeding, or toxic injury trigger a hematopoietic adaptation that sacrifices hematopoietic stem and progenitor cell (HSPC) quiescence to meet an urgent need for new blood cell production. Once the hematopoietic demands are adequately met, homeostasis must be restored. Transforming growth factor β (TGFβ) signaling is a central mediator mandating the return of HSPCs to quiescence after stress. Blockade of TGFβ signaling after hematopoietic stress delays the return of cycling HSPCs to quiescence and in so doing promotes hematopoietic stem cell (HSC) self-renewal and accelerates hematopoietic reconstitution. These findings open the door to new therapeutics that modulate the hematopoietic adaptation to stress. In this review, we will discuss the complex context-dependent activities of TGFβ in hematopoiesis and the potential benefits and limitations of using TGFβ pathway inhibitors to promote multilineage hematopoietic reconstitution after myelosuppressive chemotherapy. PMID:27308454

  6. Benzene-Induced Aberrant miRNA Expression Profile in Hematopoietic Progenitor Cells in C57BL/6 Mice

    PubMed Central

    Wei, Haiyan; Zhang, Juan; Tan, Kehong; Sun, Rongli; Yin, Lihong; Pu, Yuepu

    2015-01-01

    Benzene is a common environmental pollutant that causes hematological alterations. MicroRNAs (miRNAs) may play a role in benzene-induced hematotoxicity. In this study, C57BL/6 mice showed significant hematotoxicity after exposure to 150 mg/kg benzene for 4 weeks. Benzene exposure decreased not only the number of cells in peripheral blood but also hematopoietic progenitor cells in the bone marrow. Meanwhile, RNA from Lin− cells sorted from the bone marrow was applied to aberrant miRNA expression profile using Illumina sequencing. We found that 5 miRNAs were overexpressed and 45 miRNAs were downregulated in the benzene exposure group. Sequencing results were confirmed through qRT-PCR. Furthermore, we also identified five miRNAs which significantly altered in Lin−c-Kit+ cells obtained from benzene-exposed mice, including mmu-miR-34a-5p; mmu-miR-342-3p; mmu-miR-100-5p; mmu-miR-181a-5p; and mmu-miR-196b-5p. In summary, we successfully established a classical animal model to induce significant hematotoxicity by benzene injection. Benzene exposure may cause severe hematotoxicity not only to blood cells in peripheral circulation but also to hematopoietic cells in bone marrow. Benzene exposure also alters miRNA expression in hematopoietic progenitor cells. This study suggests that benzene induces alteration in hematopoiesis and hematopoiesis-associated miRNAs. PMID:26569237

  7. Spectral analysis of paramagnetic centers induced in human tooth enamel by x-rays and gamma radiation

    NASA Astrophysics Data System (ADS)

    Kirillov, V. A.; Kuchuro, I. I.

    2010-03-01

    Based on study of spectral and relaxation characteristics, we have established that paramagnetic centers induced in tooth enamel by x-rays and gamma radiation are identical in nature. We show that for the same exposure dose, the intensity of the electron paramagnetic resonance (EPR) signal induced by x-radiation with effective energy 34 keV is about an order of magnitude higher than the amplitude of the signal induced by gamma radiation. We have identified a three-fold attenuation of the EPR signal along the path of the x-radiation from the buccal to the lingual side of a tooth, which is evidence that the individual had undergone diagnostic x-ray examination of the dentition or skull. We have shown that the x-ray exposure doses reconstructed from the EPR spectra are an order of magnitude higher than the applied doses, while the dose loads due to gamma radiation are equal to the applied doses. The data obtained indicate that for adequate reconstruction of individual absorbed doses from EPR spectra of tooth enamel in the population subjected to the combined effect of x-radiation and accidental external gamma radiation as a result of the disaster at the Chernobyl nuclear power plant, we need to take into account the contribution to the dose load from diagnostic x-rays in examination of the teeth, jaw, or skull.

  8. Radiologic Differences between Bone Marrow Stromal and Hematopoietic Progenitor Cell Lines from Fanconi Anemia (Fancd2−/−) Mice

    PubMed Central

    Berhane, Hebist; Epperly, Michael W.; Goff, Julie; Kalash, Ronny; Cao, Shaonan; Franicola, Darcy; Zhang, Xichen; Shields, Donna; Houghton, Frank; Wang, Hong; Wipf, Peter; Parmar, Kalindi; Greenberger, Joel S.

    2014-01-01

    FancD2 plays a central role in the human Fanconi anemia DNA damage response (DDR) pathway. Fancd2−/− mice exhibit many features of human Fanconi anemia including cellular DNA repair defects. Whether the DNA repair defect in Fancd2−/− mice results in radiologic changes in all cell lineages is unknown. We measured stress of hematopoiesis in long-term marrow cultures and radiosensitivity in clonogenic survival curves, as well as comet tail intensity, total antioxidant stores and radiation-induced gene expression in hematopoietic progenitor compared to bone marrow stromal cell lines. We further evaluated radioprotection by a mitochondrial-targeted antioxidant GS-nitroxide, JP4-039. Hematopoiesis longevity in Fancd2−/− mouse long-term marrow cultures was diminished and bone marrow stromal cell lines were radiosensitive compared to Fancd2+/+ stromal cells (Fancd2−/− D0 = 1.4 ± 0.1 Gy, ñ = 5.0 ± 0.6 vs. Fancd2+/+ D0 = 1.6 ± 0.1 Gy, ñ = 6.7 ± 1.6), P = 0.0124 for D0 and P = 0.0023 for ñ, respectively). In contrast, Fancd2−/− IL-3-dependent hematopoietic progenitor cells were radioresistant (D0 = 1.71 ± 0.04 Gy and ñ = 5.07 ± 0.52) compared to Fancd2+/+ (D0 = 1.39 ± 0.09 Gy and ñ = 2.31 ± 0.85, P = 0.001 for D0). CFU-GM from freshly explanted Fancd2−/− marrow was also radioresistant. Consistent with radiosensitivity, irradiated Fancd2−/− stromal cells had higher DNA damage by comet tail intensity assay compared to Fancd2+/+ cells (P < 0.0001), slower DNA damage recovery, lower baseline total antioxidant capacity, enhanced radiation-induced depletion of antioxidants, and increased CDKN1A-p21 gene transcripts and protein. Consistent with radioresistance, Fancd2−/− IL-3-dependent hematopoietic cells had higher baseline and post irradiation total antioxidant capacity. While, there was no detectable alteration of radiation-induced cell cycle arrest with Fancd2−/− stromal cells, hematopoietic progenitor cells showed reduced G2/M

  9. Regulated Apoptosis of Genetically-Modified Hematopoietic Stem and Progenitor Cells via an Inducible Caspase-9 Suicide Gene in Rhesus Macaques

    PubMed Central

    Barese, Cecilia N.; Felizardo, Tania C.; Sellers, Stephanie E.; Keyvanfar, Keyvan; Di Stasi, Antonio; Metzger, Mark E.; Krouse, Allen E.; Donahue, Robert E.; Spencer, David M.; Dunbar, Cynthia E.

    2014-01-01

    The high risk of insertional oncogenesis reported in clinical trials utilizing integrating retroviral vectors to genetically-modify hematopoietic stem and progenitor cells (HSPC) requires the development of safety strategies to minimize risks associated with novel cell and gene therapies. The ability to ablate genetically modified cells in vivo is desirable, should an abnormal clone emerge. Inclusion of “suicide genes” in vectors to facilitate targeted ablation of vector-containing abnormal clones in vivo is one potential safety approach. We tested whether the inclusion of the “inducible Caspase-9” (iCasp9) suicide gene in a gamma-retroviral vector facilitated efficient elimination of vector-containing HSPCs and their hematopoietic progeny in vivo long-term, in an autologous non-human primate transplantation model. Following stable engraftment of iCasp9 expressing hematopoietic cells in rhesus macaques, administration of AP1903, a chemical inducer of dimerization able to activate iCasp9, specifically eliminated vector-containing cells in all hematopoietic lineages long-term, suggesting activity at the HSPC level. Between 75–94% of vector-containing cells were eliminated by well-tolerated AP1903 dosing, but lack of complete ablation was linked to lower iCasp9 expression in residual cells. Further investigation of resistance mechanisms demonstrated upregulation of Bcl-2 in hematopoietic cell lines transduced with the vector and resistant to AP1903 ablation. These results demonstrate both the potential and the limitations of safety approaches utilizing iCasp9 to HSPC-targeted gene therapy settings, in a model with great relevance to clinical development. PMID:25330775

  10. Differential Requirements for c-Myc in Chronic Hematopoietic Hyperplasia and Acute Hematopoietic Malignancies in Pten-null Mice

    PubMed Central

    Zhang, Jun; Xiao, Yechen; Guo, Yinshi; Breslin, Peter; Zhang, Shubin; Wei, Wei; Zhang, Zhou; Zhang, Jiwang

    2011-01-01

    Myeloproliferative disorders (MPDs), lymphoproliferative disorders (LPDs), acute T-lymphocytic or myeloid leukemia and T-lymphocytic lymphoma were developed in inducible Pten-knockout (Pten−/−) mice. The appearance of these multiple diseases in one animal model provides an opportunity to study the pathogenesis of multiple diseases simultaneously. To study whether Myc function is required for the development of these hematopoietic disorders in Pten−/− mice, we generated inducible Pten/Myc double-knockout mice (Pten−/−/Myc−/−). By comparing the hematopoietic phenotypes of these double-knockout mice with those of Pten−/− mice, we found that both sets of animals developed MPDs and LPDs. However, none of the compound-mutant mice developed acute leukemia or lymphoma. Interestingly, in contrast to the MPDs which developed in Pten−/− mice which are dominated by granulocytes, megakaryocytes predominate in the MPDs of Pten−/−/Myc−/− mice. Our study suggests that the deregulation of PI3K/Akt signaling in Pten−/− hematopoietic cells protects these cells from apoptotic cell death, resulting in chronic proliferative disorders. But due to the differential requirement for Myc in granulocyte as compared to megakaryocyte proliferation, Myc deletion converts Pten−/− MPDs from granulocyte-dominated to megakaryocyte-dominated conditions. Myc is absolutely required for the development of acute hematopoietic malignancies. PMID:21926961

  11. Sensitive Detection of Radiation-Induced Medulloblastomas after Acute or Protracted Gamma-Ray Exposures in Ptch1 Heterozygous Mice Using a Radiation-Specific Molecular Signature.

    PubMed

    Tsuruoka, Chizuru; Blyth, Benjamin J; Morioka, Takamitsu; Kaminishi, Mutsumi; Shinagawa, Mayumi; Shimada, Yoshiya; Kakinuma, Shizuko

    2016-10-01

    Recently reported studies have led to a heightened awareness of the risks of cancer induced by diagnostic radiological imaging, and in particular, the risk of brain cancer after childhood CT scans. One feature of Ptch1 +/- mice is their sensitivity to radiation-induced medulloblastomas (an embryonic cerebellar tumor) during a narrow window of time centered on the days around birth. Little is known about the dynamics of how dose protraction interacts with such narrow windows of sensitivity in individual tissues. Using medulloblastomas from irradiated Ptch1 +/- mice with a hybrid C3H × C57BL/6 F1 genetic background, we previously showed that the alleles retained on chromosome 13 (which harbors the Ptch1 gene) reveal two major mechanisms of loss of the wild-type allele. The loss of parental alleles from the telomere extending up to or past the Ptch1 locus by recombination (spontaneous type) accounts for almost all medulloblastomas in nonirradiated mice, while tumors in irradiated mice often exhibited interstitial deletions, which start downstream of the wild-type Ptch1 and extend up varying lengths towards the centromere (radiation type). In this study, Ptch1 +/- mice were exposed to an acute dose of either 100 or 500 mGy gamma rays in utero or postnatally, or the same radiation doses protracted over a four-day period, and were monitored for medulloblastoma development. The results showed dose- and age-dependent radiation-induced type tumors. Furthermore, the size of the radiation-induced deletion differed with the dose rate. The results of this work suggest that tumor latency may be related to the size of the deletion. In this study, 500 mGy exposure produced radiation-induced type tumors at all ages and dose rates, while 100 mGy exposure did not significantly produce radiation-induced type tumors. The radiation signature allows for unique mechanistic insight into the action of radiation to induce DNA lesions with known causal relationship to a specific tumor type

  12. Mice Lacking RIP3 Kinase are not Protected from Acute Radiation Syndrome.

    PubMed

    Castle, Katherine D; Daniel, Andrea R; Moding, Everett J; Luo, Lixia; Lee, Chang-Lung; Kirsch, David G

    2018-06-01

    Exposure to high doses of ionizing radiation can cause lethal injury to normal tissue, thus inducing acute radiation syndrome. Acute radiation syndrome is caused by depletion of bone marrow cells (hematopoietic syndrome) and irreparable damage to the epithelial cells in the gastrointestinal tract (gastrointestinal syndrome). Although radiation initiates apoptosis in the hematopoietic and gastrointestinal compartments within the first few hours after exposure, alternative mechanisms of cell death may contribute to injury in these radiosensitive tissues. In this study, we utilized mice lacking a critical regulator of necroptosis, receptor interacting protein 3 (RIP3) kinase, to characterize the role of RIP3 in normal tissue toxicity after irradiation. Our results suggest that RIP3-mediated signaling is not a critical driver of acute radiation syndrome.

  13. Influence of radiation quality on mouse chromosome 2 deletions in radiation-induced acute myeloid leukaemia.

    PubMed

    Brown, Natalie; Finnon, Rosemary; Manning, Grainne; Bouffler, Simon; Badie, Christophe

    2015-11-01

    Leukaemia is the prevailing neoplastic disorder of the hematopoietic system. Epidemiological analyses of the survivors of the Japanese atomic bombings show that exposure to ionising radiation (IR) can cause leukaemia. Although a clear association between radiation exposure and leukaemia development is acknowledged, the underlying mechanisms remain incompletely understood. A hemizygous deletion on mouse chromosome 2 (del2) is a common feature in several mouse strains susceptible to radiation-induced acute myeloid leukaemia (rAML). The deletion is an early event detectable 24h after exposure in bone marrow cells. Ultimately, 15-25% of exposed animals develop AML with 80-90% of cases carrying del2. Molecular mapping of leukaemic cell genomes identified a minimal deleted region (MDR) on chromosome 2 (chr2) in which a tumour suppressor gene, Sfpi1 is located, encoding the transcription factor PU.1, essential in haematopoiesis. The remaining copy of Sfpi1 has a point mutation in the coding sequence for the DNA-binding domain of the protein in 70% of rAML, which alters a single CpG sequence in the codon for arginine residue R235. In order to identify chr2 deletions and Sfpi.1/PU.1 loss, we performed array comparative genomic hybridization (aCGH) on a unique panel of 79rAMLs. Using a custom made CGH array specifically designed for mouse chr2, we analysed at unprecedentedly high resolution (1.4M array- 148bp resolution) the size of the MDR in low LET and high-LET induced rAMLs (32 X-ray- and 47 neutron-induced). Sequencing of Sfpi1/PU.1DNA binding domain identified the presence of R235 point mutations, showing no influence of radiation quality on R235 type or frequency. We identified for the first time rAML cases with complex del2 in a subset of neutron-induced AMLs. This study allowed us to re-define the MDR to a much smaller 5.5Mb region (still including Sfpi1/PU.1), identical regardless of radiation quality. Crown Copyright © 2015. Published by Elsevier B.V. All rights

  14. Improved hematopoietic differentiation efficiency of gene-corrected beta-thalassemia induced pluripotent stem cells by CRISPR/Cas9 system.

    PubMed

    Song, Bing; Fan, Yong; He, Wenyin; Zhu, Detu; Niu, Xiaohua; Wang, Ding; Ou, Zhanhui; Luo, Min; Sun, Xiaofang

    2015-05-01

    The generation of beta-thalassemia (β-Thal) patient-specific induced pluripotent stem cells (iPSCs), subsequent homologous recombination-based gene correction of disease-causing mutations/deletions in the β-globin gene (HBB), and their derived hematopoietic stem cell (HSC) transplantation offers an ideal therapeutic solution for treating this disease. However, the hematopoietic differentiation efficiency of gene-corrected β-Thal iPSCs has not been well evaluated in the previous studies. In this study, we used the latest gene-editing tool, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9), to correct β-Thal iPSCs; gene-corrected cells exhibit normal karyotypes and full pluripotency as human embryonic stem cells (hESCs) showed no off-targeting effects. Then, we evaluated the differentiation efficiency of the gene-corrected β-Thal iPSCs. We found that during hematopoietic differentiation, gene-corrected β-Thal iPSCs showed an increased embryoid body ratio and various hematopoietic progenitor cell percentages. More importantly, the gene-corrected β-Thal iPSC lines restored HBB expression and reduced reactive oxygen species production compared with the uncorrected group. Our study suggested that hematopoietic differentiation efficiency of β-Thal iPSCs was greatly improved once corrected by the CRISPR/Cas9 system, and the information gained from our study would greatly promote the clinical application of β-Thal iPSC-derived HSCs in transplantation.

  15. Effect of SCG, 1,3-beta-D-glucan from Sparassis crispa on the hematopoietic response in cyclophosphamide induced leukopenic mice.

    PubMed

    Harada, Toshie; Miura, Noriko; Adachi, Yoshiyuki; Nakajima, Mitsuhiro; Yadomae, Toshiro; Ohn, Naohito

    2002-07-01

    Sparassis crispa Fr. is an edible mushroom recently cultivable in Japan. It contains a remarkably high content of 6-branched 1,3-beta-D-glucan showing antitumor activity. Using ion-exchange chromatography, a purified beta-glucan preparation, SCG, was prepared. In this study, we examined the hematopoietic response by SCG in cyclophosphamide (CY)-induced leukopenic mice. SCG enhanced the hematopoietic response in CY induced leukopenic mice by intraperitoneal routes over a wide range of concentrations. SCG enhanced the hematopoietic response in CY-treated mice by prior or post administration. Analyzing the leukocyte population by flow cytometry, monocytes and granulocytes in the peritoneal cavity, liver, spleen and bone marrow (BM) recovered faster than in the control group. The ratio of natural killer cells and gammadelta T cells in the liver, spleen and peritoneal cavity was also increased. In contrast, CD4+ CD8+ cells in the thymus were temporarily significantly decreased by the administration of SCG. Interleukin-6 (IL-6) production of CY+SCG-treated peritoneal exdated cells (PECs), spleen cells and bone marrow cells (BMCs) were higher than that of the CY-treated group. By in vitro culture of CY-treated PEC and spleen cells, IL-6 production was enhanced by the addition of SCG. These facts suggested the possibility that IL-6 might be a key cytokine for the enhanced hematopoietic response by SCG.

  16. Assessment of Benzene-Induced Hematotoxicity Using a Human-Like Hematopoietic Lineage in NOD/Shi-scid/IL-2Rγnull Mice

    PubMed Central

    Takahashi, Masayuki; Tsujimura, Noriyuki; Yoshino, Tomoko; Hosokawa, Masahito; Otsuka, Kensuke; Matsunaga, Tadashi; Nakasono, Satoshi

    2012-01-01

    Despite recent advancements, it is still difficult to evaluate in vivo responses to toxicants in humans. Development of a system that can mimic the in vivo responses of human cells will enable more accurate health risk assessments. A surrogate human hematopoietic lineage can be established in NOD/Shi-scid/IL-2Rγnull (NOG) mice by transplanting human hematopoietic stem/progenitor cells (Hu-NOG mice). Here, we first evaluated the toxic response of human-like hematopoietic lineage in NOG mice to a representative toxic agent, benzene. Flow cytometric analysis showed that benzene caused a significant decrease in the number of human hematopoietic stem/progenitor cells in the bone marrow and the number of human leukocytes in the peripheral blood and hematopoietic organs. Next, we established chimeric mice by transplanting C57BL/6 mouse-derived bone marrow cells into NOG mice (Mo-NOG mice). A comparison of the degree of benzene-induced hematotoxicity in donor-derived hematopoietic lineage cells within Mo-NOG mice indicated that the toxic response of Hu-NOG mice reflected interspecies differences in susceptibilities to benzene. Responses to the toxic effects of benzene were greater in lymphoid cells than in myeloid cells in Mo-NOG and Hu-NOG mice. These findings suggested that Hu-NOG mice may be a powerful in vivo tool for assessing hematotoxicity in humans, while accounting for interspecies differences. PMID:23226520

  17. Radiobiology of the acute radiation syndrome.

    PubMed

    Macià I Garau, Miquel; Lucas Calduch, Anna; López, Enric Casanovas

    2011-07-06

    ACUTE RADIATION SYNDROME OR ACUTE RADIATION SICKNESS IS CLASSICALLY SUBDIVIDED INTO THREE SUBSYNDROMES: the hematopoietic, gastrointestinal and neurovascular syndrome but many other tissues can be damaged. The time course and severity of clinical signs and symptoms are a function of the overall body volume irradiated, the inhomogeneity of dose exposure, the particle type, the absorbed dose and the dose rate. Classical pathophysiology explain the failure of each of these organs and the timing of appearance of their signs and symptoms due to radiation-induced cytocidal effects of a great number of parenchymal cells of hierarchically organized tissues. Contemporaneously, many other radiation-induced effects has been described and all of them may lead to tissue injury with their corresponding signs and symptoms that can be expressed after short or long period of time. Radiation-induced multi-organ involvement is thought to be due to radiation-induced systemic inflammatory response mediated by released pro-inflammatory cytokines.

  18. Modeling Hematopoiesis and Responses to Radiation Countermeasures in a Bone Marrow-on-a-Chip.

    PubMed

    Torisawa, Yu-Suke; Mammoto, Tadanori; Jiang, Elisabeth; Jiang, Amanda; Mammoto, Akiko; Watters, Alexander L; Bahinski, Anthony; Ingber, Donald E

    2016-05-01

    Studies on hematopoiesis currently rely on animal models because in vitro culture methods do not accurately recapitulate complex bone marrow physiology. We recently described a bone marrow-on-a-chip microfluidic device that enables the culture of living hematopoietic bone marrow and mimics radiation toxicity in vitro. In the present study, we used this microdevice to demonstrate continuous blood cell production in vitro and model bone marrow responses to potential radiation countermeasure drugs. The device maintained mouse hematopoietic stem and progenitor cells in normal proportions for at least 2 weeks in culture. Increases in the number of leukocytes and red blood cells into the microfluidic circulation also could be detected over time, and addition of erythropoietin induced a significant increase in erythrocyte production. Exposure of the bone marrow chip to gamma radiation resulted in reduction of leukocyte production, and treatment of the chips with two potential therapeutics, granulocyte-colony stimulating factor or bactericidal/permeability-increasing protein (BPI), induced significant increases in the number of hematopoietic stem cells and myeloid cells in the fluidic outflow. In contrast, BPI was not found to have any effect when analyzed using static marrow cultures, even though it has been previously shown to accelerate recovery from radiation-induced toxicity in vivo. These findings demonstrate the potential value of the bone marrow-on-a-chip for modeling blood cell production, monitoring responses to hematopoiesis-modulating drugs, and testing radiation countermeasures in vitro.

  19. Hematopoietic stem cell loss and hematopoietic failure in severe aplastic anemia is driven by macrophages and aberrant podoplanin expression.

    PubMed

    McCabe, Amanda; Smith, Julianne N P; Costello, Angelica; Maloney, Jackson; Katikaneni, Divya; MacNamara, Katherine C

    2018-05-17

    Severe aplastic anemia results from profound hematopoietic stem cell loss. T cells and interferon gamma have long been associated with severe aplastic anemia, yet the underlying mechanisms driving hematopoietic stem cell loss remain unknown. Using a mouse model of severe aplastic anemia, we demonstrate that interferon gamma-dependent hematopoietic stem cell loss required macrophages. Interferon gamma was necessary for bone marrow macrophage persistence, despite loss of other myeloid cells and hematopoietic stem cells. Depleting macrophages or abrogating interferon gamma signaling specifically in macrophages did not impair T cell activation or interferon gamma production in the bone marrow but rescued hematopoietic stem cells and reduced mortality. Thus, macrophages are not required for induction of interferon gamma in severe aplastic anemia and rather act as sensors of interferon gamma. Macrophage depletion rescued thrombocytopenia, increased bone marrow megakaryocytes, preserved platelet-primed stem cells, and increased the platelet-repopulating capacity of transplanted hematopoietic stem cells. In addition to the hematopoietic effects, severe aplastic anemia induced loss of non-hematopoietic stromal populations, including podoplanin-positive stromal cells. However, a subset of podoplanin-positive macrophages was increased during disease, and blockade of podoplanin in mice was sufficient to rescue disease. Our data further our understanding of disease pathogenesis demonstrating a novel role for macrophages as sensors of interferon gamma, thus illustrating an important role for the microenvironment in pathogenesis of severe aplastic anemia. Copyright © 2018, Ferrata Storti Foundation.

  20. Oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients.

    PubMed

    Aisa, Yoshinobu; Mori, Takehiko; Kudo, Masumi; Yashima, Tomoko; Kondo, Sakiko; Yokoyama, Akihiro; Ikeda, Yasuo; Okamoto, Shinichiro

    2005-04-01

    The purpose of this study was to evaluate the efficacy of oral cryotherapy to prevent high-dose melphalan-induced stomatitis. Eighteen consecutive recipients of allogeneic hematopoietic stem cell transplant conditioned with high-dose melphalan (140 mg/m2) in combination with fludarabine alone or with fludarabine and additional chemotherapy or radiation were enrolled. The severity of stomatitis was graded according to the National Cancer Institute Common Toxicity Criteria. Patients were kept on oral cryotherapy using ice chips and ice-cold water shortly before, during, and for additional 90 min after completion of melphalan administration. Only two of 18 patients (11.1%) developed grade 2 or 3 stomatitis while six of seven patients in the historical control developed it (85.7%; P=0.001). These results suggested that oral cryotherapy could effectively prevent stomatitis caused by high-dose melphalan, and we recommend that it should be incorporated into the conditioning regimen with high-dose melphalan.

  1. Strategies for Discovery of Small Molecule Radiation Protectors and Radiation Mitigators

    PubMed Central

    Greenberger, Joel S.; Clump, David; Kagan, Valerian; Bayir, Hülya; Lazo, John S.; Wipf, Peter; Li, Song; Gao, Xiang; Epperly, Michael W.

    2011-01-01

    Mitochondrial targeted radiation damage protectors (delivered prior to irradiation) and mitigators (delivered after irradiation, but before the appearance of symptoms associated with radiation syndrome) have been a recent focus in drug discovery for (1) normal tissue radiation protection during fractionated radiotherapy, and (2) radiation terrorism counter measures. Several categories of such molecules have been discovered: nitroxide-linked hybrid molecules, including GS-nitroxide, GS-nitric oxide synthase inhibitors, p53/mdm2/mdm4 inhibitors, and pharmaceutical agents including inhibitors of the phosphoinositide-3-kinase pathway and the anti-seizure medicine, carbamazepine. Evaluation of potential new radiation dose modifying molecules to protect normal tissue includes: clonogenic radiation survival curves, assays for apoptosis and DNA repair, and irradiation-induced depletion of antioxidant stores. Studies of organ specific radioprotection and in total body irradiation-induced hematopoietic syndrome in the mouse model for protection/mitigation facilitate rational means by which to move candidate small molecule drugs along the drug discovery pipeline into clinical development. PMID:22655254

  2. Patents for Toll-like receptor ligands as radiation countermeasures for acute radiation syndrome.

    PubMed

    Singh, Vijay K; Pollard, Harvey B

    2015-01-01

    Acute radiation exposure induces apoptosis of tissues in the hematopoietic, digestive, cutaneous, cardiovascular and nervous systems; extensive apoptosis of these tissues ultimately leads to acute radiation syndrome. A novel strategy for developing radiation countermeasures has been to imitate the genetic mechanisms acquired by radiation-resistant tumors. Two mechanisms that underlie this ability of tumor cells are the p53 and NF-κB pathways. The loss of p53 function results in the inactivation of pro-apoptotic control mechanisms, while constitutive activation of NF-κB results in the up-regulation of anti-apoptotic genes. Various Toll-like receptor ligands are capable of up regulating the NF-κB pathway, which increases radio-resistance and reduces radiation-induced apoptosis in various tissues. Several Toll-like receptor ligands have been patented and are currently under development as radiation countermeasures for acute radiation syndrome. Ongoing studies suggest that a few of these attractive agents are progressing well along the US FDA approval pathway to become radiation countermeasures.

  3. Patents for Toll-like receptor ligands as radiation countermeasures for acute radiation syndrome

    PubMed Central

    Singh, Vijay K; Pollard, Harvey B

    2015-01-01

    Acute radiation exposure induces apoptosis of tissues in the hematopoietic, digestive, cutaneous, cardiovascular and nervous systems; extensive apoptosis of these tissues ultimately leads to acute radiation syndrome. A novel strategy for developing radiation countermeasures has been to imitate the genetic mechanisms acquired by radiation-resistant tumors. Two mechanisms that underlie this ability of tumor cells are the p53 and NF-κB pathways. The loss of p53 function results in the inactivation of pro-apoptotic control mechanisms, while constitutive activation of NF-κB results in the up-regulation of anti-apoptotic genes. Various Toll-like receptor ligands are capable of up regulating the NF-κB pathway, which increases radio-resistance and reduces radiation-induced apoptosis in various tissues. Several Toll-like receptor ligands have been patented and are currently under development as radiation countermeasures for acute radiation syndrome. Ongoing studies suggest that a few of these attractive agents are progressing well along the US FDA approval pathway to become radiation countermeasures. PMID:26135043

  4. Surgical treatment and optical coherence tomographic evaluation for accidental laser-induced full-thickness macular holes.

    PubMed

    Qi, Y; Wang, Y; You, Q; Tsai, F; Liu, W

    2017-07-01

    PurposeTo report OCT appearance and surgical outcomes of full-thickness macular holes (MHs) accidentally caused by laser devices.Patients and methodsThis retrospective case series included 11 eyes of 11 patients with laser-induced MHs treated by pars plana vitrectomy, internal limiting membrane (ILM) peeling, and gas or silicone oil tamponade. Evaluations included a full ophthalmic examination, macular spectral-domain optical coherence tomography (SD-OCT), and fundus photography. Main outcome measures is MH closure and final visual acuity; the secondary outcome was the changes of retinal pigment epithelium and photoreceptor layer evaluated by sequential post-operative SD-OCT images.ResultsFive patients were accidentally injured by a yttrium aluminum garnet (YAG) laser and six patients by handheld laser. MH diameters ranged from 272 to 815 μm (mean, 505.5±163.0 μm) preoperatively. Best-corrected visual acuity (BCVA) improved from a mean of 0.90 logMAR (range, counting finger-8/20) preoperatively to a mean of 0.34 logMAR (range, a counting finger-20/20) postoperatively (P=0.001, t=4.521). Seven of 11 patients (63.6%) achieved a BCVA better than 10/20. Ten patients had a subfoveal hyperreflectivity and four patients had a focal choroidal depression subfoveal preoperatively. At the last follow-up, all 11 eyes demonstrated the following: closure of the macular hole, variable degrees of disruption of external limiting membrane (ELM) and outer photoreceptor ellipsoid and interdigitation bands. In 10 eyes, the disruption was in the form of focal defects in the outer retina. After surgery, the subfoveal hyperreflectivity and focal choroidal depression remained.ConclusionAccidental laser-induced full-thickness macular holes can be successfully closed with surgery. Inadvertent retinal injury from laser devices, especially handheld laser injury has occurred with increasing frequency in recent years. However, there is a paucity of data regarding these types of injuries

  5. Involvement of hypoxia-inducible factor-1 α (HIF-1α) in inhibition of benzene on mouse hematopoietic system.

    PubMed

    Meng, Xing; Zhang, Juan; Yin, Lihong; Pu, Yuepu

    2016-01-01

    Benzene is an occupational and environmental pollutant that damages the hematopoietic system through oxidant mechanisms. The aims of this study were to assess the role of oxidation in benzene-mediated damage by determination of the levels of reactive oxygen species (ROS) and to evaluate the role of hypoxia-inducible factor-1α (HIF-1α) in this process. C57BL/6 mice were exposed to benzene at varying concentrations of 60, 150, or 300 mg/kg/d for 15 d. Mice in the benzene groups displayed weight loss, and hematologic consequences including decreased red and white blood cell counts, reduced platelet count, diminished hemoglobin content, and lower number of hematopoietic stem cells in bone marrow (BM). There was an elevated proportional neutrophil count and decrease in relative thymus weight. In BM there was a significant increase in ROS levels at 150 mg/kg benzene. However, as a result of diminished cellular viability, ROS levels were not markedly different between the 300-mg/kg benzene dose and the control, as the number of hematopoietic stem cells was reduced. HIF-1α expression and protein levels were decreased in BM cells at all doses of benzene. In conclusion, data indicated that HIF-1α may be involved in benzene-induced inhibition of mouse hematopoiesis and that oxidative stress may play a role in the observed toxicity.

  6. Comparison of degradation effects induced by gamma radiation and electron beam radiation in two cable jacketing materials

    NASA Astrophysics Data System (ADS)

    Bartoníček, B.; Plaček, V.; Hnát, V.

    2007-05-01

    The radiation degradation behavior of commercial low density polyethylene (LDPE) and ethylene-vinylacetate (EVA) cable materials has been investigated. The changes of mechanical properties, thermooxidative stability and density exhibit different radiation stability towards 60Co-gamma radiation and 160 keV electron beam radiation. This difference reflects much higher penetration of the gamma radiation through the polymeric material as a function of sample thickness. These results are discussed with respect to the role of beta radiation during design basis events in a nuclear power plants. In case when total accidental design basis event (DBE) dose (involving about 80% soft beta radiation) is simulated by 60Co-gamma radiation the conservatism is reached.

  7. Brief report: a human induced pluripotent stem cell model of cernunnos deficiency reveals an important role for XLF in the survival of the primitive hematopoietic progenitors.

    PubMed

    Tilgner, Katarzyna; Neganova, Irina; Singhapol, Chatchawan; Saretzki, Gabriele; Al-Aama, Jumana Yousuf; Evans, Jerome; Gorbunova, Vera; Gennery, Andrew; Przyborski, Stefan; Stojkovic, Miodrag; Armstrong, Lyle; Jeggo, Penny; Lako, Majlinda

    2013-09-01

    Cernunnos (also known as XLF) deficiency syndrome is a rare recessive autosomal disorder caused by mutations in the XLF gene, a key factor involved in the end joining step of DNA during nonhomologous end joining (NHEJ) process. Human patients with XLF mutations display microcephaly, developmental and growth delays, and severe immunodeficiency. While the clinical phenotype of DNA damage disorders, including XLF Syndrome, has been described extensively, the underlying mechanisms of disease onset, are as yet, undefined. We have been able to generate an induced pluripotent stem cell (iPSC) model of XLF deficiency, which accurately replicates the double-strand break repair deficiency observed in XLF patients. XLF patient-specific iPSCs (XLF-iPSC) show typical expression of pluripotency markers, but have altered in vitro differentiation capacity and an inability to generate teratomas comprised of all three germ layers in vivo. Our results demonstrate that XLF-iPSCs possess a weak NHEJ-mediated DNA repair capacity that is incapable of coping with the DNA lesions introduced by physiological stress, normal metabolism, and ionizing radiation. XLF-iPSC lines are capable of hematopoietic differentiation; however, the more primitive subsets of hematopoietic progenitors display increased apoptosis in culture and an inability to repair DNA damage. Together, our findings highlight the importance of NHEJ-mediated-DNA repair in the maintenance of a pristine pool of hematopoietic progenitors during human embryonic development. © AlphaMed Press.

  8. Generation of induced pluripotent stem cells as a potential source of hematopoietic stem cells for transplant in PNH patients.

    PubMed

    Phondeechareon, Tanapol; Wattanapanitch, Methichit; U-Pratya, Yaowalak; Damkham, Chanapa; Klincumhom, Nuttha; Lorthongpanich, Chanchao; Kheolamai, Pakpoom; Laowtammathron, Chuti; Issaragrisil, Surapol

    2016-10-01

    Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by lack of CD55 and CD59 on blood cell membrane leading to increased sensitivity of blood cells to complement. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for PNH, however, lack of HLA-matched donors and post-transplant complications are major concerns. Induced pluripotent stem cells (iPSCs) derived from patients are an attractive source for generating autologous HSCs to avoid adverse effects resulting from allogeneic HSCT. The disease involves only HSCs and their progeny; therefore, other tissues are not affected by the mutation and may be used to produce disease-free autologous HSCs. This study aimed to derive PNH patient-specific iPSCs from human dermal fibroblasts (HDFs), characterize and differentiate to hematopoietic cells using a feeder-free protocol. Analysis of CD55 and CD59 expression was performed before and after reprogramming, and hematopoietic differentiation. Patients' dermal fibroblasts expressed CD55 and CD59 at normal levels and the normal expression remained after reprogramming. The iPSCs derived from PNH patients had typical pluripotent properties and differentiation capacities with normal karyotype. After hematopoietic differentiation, the differentiated cells expressed early hematopoietic markers (CD34 and CD43) with normal CD59 expression. The iPSCs derived from HDFs of PNH patients have normal levels of CD55 and CD59 expression and hold promise as a potential source of HSCs for autologous transplantation to cure PNH patients.

  9. Mesenchymal stromal cell derived extracellular vesicles rescue radiation damage to murine marrow hematopoietic cells

    PubMed Central

    Wen, Sicheng; Dooner, Mark; Cheng, Yan; Papa, Elaine; Del Tatto, Michael; Pereira, Mandy; Deng, Yanhui; Goldberg, Laura; Aliotta, Jason; Chatterjee, Devasis; Stewart, Connor; Carpanetto, Andrea; Collino, Federica; Bruno, Stefania; Camussi, Giovanni; Quesenberry, Peter

    2016-01-01

    Mesenchymal stromal cells (MSC) have been shown to reverse radiation damage to marrow stem cells. We have evaluated the capacity of MSC-derived extracellular vesicles (MSC-EVs) to mitigate radiation injury to marrow stem cells at 4 hours to 7 days after irradiation. Significant restoration of marrow stem cell engraftment at 4, 24 and 168 hours post-irradiation by exposure to MSC-EVs was observed at 3 weeks to 9 months after transplant and further confirmed by secondary engraftment. Intravenous injection of MSC-EVs to 500cGy exposed mice led to partial recovery of peripheral blood counts and restoration of the engraftment of marrow. The murine hematopoietic cell line, FDC-P1 exposed to 500 cGy, showed reversal of growth inhibition, DNA damage and apoptosis on exposure to murine or human MSC-EVs. Both murine and human MSC-EVs reverse radiation damage to murine marrow cells and stimulate normal murine marrow stem cell/progenitors to proliferate. A preparation with both exosomes and microvesicles was found to be superior to either microvesicles or exosomes alone. Biologic activity was seen in freshly isolated vesicles and in vesicles stored for up to 6 months in 10% DMSO at −80°C. These studies indicate that MSC-EVs can reverse radiation damage to bone marrow stem cells. PMID:27150009

  10. Protective effects of HemoHIM on immune and hematopoietic systems against γ-irradiation.

    PubMed

    Park, Hae-Ran; Jo, Sung-Kee; Jung, Uhee; Yee, Sung-Tae; Kim, Sung-Ho

    2014-02-01

    We examined the effect of HemoHIM on the protective efficacy of hematopoietic stem cells and on the recovery of immune cells against sublethal doses of ionizing radiation. Two-month-old mice were exposed to γ-rays at a dose of 8, 6.5, or 5 Gy for a30-day survival study, endogenous spleen colony formation, or other experiments, respectively. HemoHIM was injected intraperitoneally before and after irradiation. Our results showed that HemoHIM significantly decreased the mortality of sublethally irradiated mice. The HemoHIM administration decreased the apoptosis of bone marrow cells in irradiated mice. On the other hand, HemoHIM increased the formation of endogenous spleen colony in irradiated mice. In irradiated mice, the recovery of total leukocytes in the peripheral blood and lymphocytes in the spleen were enhanced significantly by HemoHIM. Moreover, the function of B cells, T cells, and NK cells regenerated in irradiated mice were significantly improved by the administration of HemoHIM. HemoHIM showed an ideal radioprotector for protecting hematopoietic stem cells and for accelerating the recovery of immune cells. We propose HemoHIM as a beneficial supplement drug during radiotherapy to alleviate adverse radiation-induced effects for cancer patients. Copyright © 2013 John Wiley & Sons, Ltd.

  11. Single low-dose rHuIL-12 safely triggers multilineage hematopoietic and immune-mediated effects

    PubMed Central

    2014-01-01

    Background Recombinant human interleukin 12 (rHuIL-12) regulates hematopoiesis and cell-mediated immunity. Based on these hematopoietic and immunomodulatory activities, a recombinant human IL-12 (rHuIL-12) is now under development to address the unmet need for a medical countermeasure against the hematopoietic syndrome of the acute radiation syndrome (HSARS) that occurs in individuals exposed to lethal radiation, and also to serve as adjuvant therapy that could provide dual hematopoietic and immunotherapeutic benefits in patients with cancer receiving chemotherapy. We sought to demonstrate in healthy subjects the safety of rHuIL-12 at single, low doses that are appropriate for use as a medical countermeasure for humans exposed to lethal radiation and as an immunomodulatory anti-cancer agent. Methods Two placebo-controlled, double-blinded studies assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of rHuIL-12. The first-in-human (FIH) dose-escalation study randomized subjects to single subcutaneous injections of placebo or rHuIL-12 at 2, 5, 10, and 20 μg doses. Due to toxicity, dose was reduced to 15 μg and then to 12 μg. The phase 1b expansion study randomized subjects to the highest safe and well tolerated dose of 12 μg. Results Thirty-two subjects were enrolled in the FIH study: 4 active and 2 placebo at rHuIL-12 doses of 2, 5, 10, 12, and 15 μg; 1 active and 1 placebo at 20 μg. Sixty subjects were enrolled in the expansion study: 48 active and 12 placebo at 12 μg dose of rHuIL-12. In both studies, the most common adverse events (AEs) related to rHuIL-12 were headache, dizziness, and chills. No immunogenicity was observed. Elimination of rHuIL-12 was biphasic, suggesting significant distribution into extravascular spaces. rHuIL-12 triggered transient changes in neutrophils, platelets, reticulocytes, lymphocytes, natural killer cells, and CD34+ hematopoietic progenitor cells, and induced increases in interferon-γ and C-X-C motif

  12. Small Molecule Protection of Bone Marrow Hematopoietic Stem Cells

    DTIC Science & Technology

    2015-10-01

    several recently identified small molecules can protect hematopoietic stem cells (HSCs) from damage or killing by endogenous aldehydes . Proof-of-concept...anemia bone marrow failure CD34+ hematopoietic stem cells aldehydes formaldehyde DNA damage DNA base adduct DNA-protein crosslink mass...below. Revised Specific Aim 1: Small molecule protection of human cells from aldehyde - induced killing (in vitro studies - no mice or human subjects

  13. Melanoma induced immunosuppression is mediated by hematopoietic dysregulation.

    PubMed

    Kamran, Neha; Li, Youping; Sierra, Maria; Alghamri, Mahmoud S; Kadiyala, Padma; Appelman, Henry D; Edwards, Marta; Lowenstein, Pedro R; Castro, Maria G

    2018-01-01

    Tumors are associated with expansion of immunosuppressive cells such as tumor associated macrophages (TAMs), regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs). These cells promote tumor growth, angiogenesis, metastasis and immune escape. Cancer patients frequently present symptoms such as anemia, leukocytosis and/or cytopenia; associated with poor prognosis. To uncover tumor-mediated hematopoietic abnormalities and identify novel targets that can be harnessed to improve tumor-specific immune responses, we investigated the hematopoietic stem and progenitor cell compartment in melanoma bearing mice. We show that melanoma growth results in expansion of myeloid lineages such as MDSCs, macrophages and DCs along with a reduction in mature RBCs and platelets. Mature B lymphocytes in the blood and BM of melanoma mice were also reduced. Mice bearing melanoma showed extramedullary hematopoiesis in the spleen. Increased expansion of myeloid lineages occurred directly at the level of stem and progenitor cells. The reduction in mature B lymphocytes resulted from a block at the Pro-B cell stage in the bone marrow. Addition of recombinant IL-3 to bone marrow cells resulted in the expansion of committed myeloid progenitors including common myeloid precursors, granulocyte-monocyte precursors and megakaryocyte-erythrocyte precursors. In vivo , IL-3 receptor stimulation in melanoma bearing mice using an IL-3 antibody also resulted in a robust expansion of committed myeloid progenitors and hematopoietic stem cells. Collectively our findings demonstrate that tumor growth plays a pivotal role in reprogramming the host immune system by impacting hematopoiesis directly at the level of stem cell compartment.

  14. Radiation-induced radioresistance of mammals and risk assessment

    NASA Astrophysics Data System (ADS)

    Smirnova, O.; Yonezawa, M.

    It is shown experimentally that a preliminary low dose exposure can induce radioresistance in mice in two (early and late) periods after preirradiation. The manifestation of such effects is reduced mortality of pre-exposed specimens after challenge acute irradiation, the reason of the animal death being the hematopoietic subsyndrome of the acute radiation syndrome. Therefore, proceeding from the radiobiological concept of the critical system, the theoretical investigation of the influence of preirradiation on mammalian radiosensitivity is conducted by making use of mathematical models of the vital body system, hematopoiesis. Modeling results make it possible to elucidate the mechanisms of the radioprotection effect of low level priming irradiation on mammals. Specifically, the state of acquired radioresistance in mice is caused by reduced radiosensitivity of lymphopoietic and thrombocytopoietic systems in the early period and by reduced radiosensitivity of granulocytopoietic system in the late period after preirradiation. It is important to emphasize that the evaluations of the duration of the early and late periods of postirradiation radioresistance in mice, carried out on the basis of the modeling and experimental investigations, practically coincide. All this demonstrates the effectiveness of joint modeling and experimental methods in studies and predictions of modification effects of preirradiation on mammalian radiosensitivity. The results obtained show the importance of accounting such effects in radiation risk assessments for cosmonauts and astronauts on long-term missions.

  15. The Hematopoietic Syndrome of the Acute Radiation Syndrome in Rhesus Macaques: A Systematic Review of the Lethal Dose Response Relationship.

    PubMed

    MacVittie, Thomas J; Farese, Ann M; Jackson, William

    2015-11-01

    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 U.S. Food and Drug Administration "animal rule." Development of a model requires the determination of the radiation dose response relationship and time course of mortality and morbidity across the hematopoietic acute radiation syndrome. The nonhuman primate, rhesus macaque, is a relevant animal model that may be used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality at selected lethal doses of total body irradiation. A systematic review of relevant studies that determined the dose response relationship for the hematopoietic acute radiation syndrome in the rhesus macaque relative to radiation quality, dose rate, and exposure uniformity has never been performed. The selection of data cohorts was made from the following sources: Ovid Medline (1957-present), PubMed (1954-present), AGRICOLA (1976-present), Web of Science (1954-present), and U.S. HHS REPORT (2002 to present). The following terms were used: Rhesus, total body-irradiation, total body x irradiation, TBI, irradiation, gamma radiation, hematopoiesis, LD50/60, Macaca mulatta, whole-body irradiation, nonhuman primate, NHP, monkey, primates, hematopoietic radiation syndrome, mortality, and nuclear radiation. The reference lists of all studies, published and unpublished, were reviewed for additional studies. The total number of hits across all search sites was 3,001. There were a number of referenced, unpublished, non-peer reviewed government reports that were unavailable for review. Fifteen studies, 11 primary (n = 863) and four secondary (n = 153) studies [n = 1,016 total nonhuman primates (NHP), rhesus Macaca mulatta] were evaluated to provide an informative and consistent review. The dose response relationships (DRRs) were determined for uniform or non-uniform total

  16. PEGylated G-CSF (BBT-015), GM-CSF (BBT-007), and IL-11 (BBT-059) analogs enhance survival and hematopoietic cell recovery in a mouse model of the hematopoietic syndrome of the acute radiation syndrome.

    PubMed

    Plett, Paul Artur; Chua, Hui Lin; Sampson, Carol H; Katz, Barry P; Fam, Christine M; Anderson, Lana J; Cox, George N; Orschell, Christie M

    2014-01-01

    Hematopoietic growth factors (HGF) are recommended therapy for high dose radiation exposure, but unfavorable administration schedules requiring early and repeat dosing limit the logistical ease with which they can be used. In this report, using a previously described murine model of H-ARS, survival efficacy and effect on hematopoietic recovery of unique PEGylated HGF were investigated. The PEGylated-HGFs possess longer half-lives and more potent hematopoietic properties than corresponding non-PEGylated-HGFs. C57BL/6 mice underwent single dose lethal irradiation (7.76-8.72 Gy, Cs, 0.62-1.02 Gy min) and were treated with various dosing regimens of 0.1, 0.3, and 1.0 mg kg of analogs of human PEG-G-CSF, murine PEG-GM-CSF, or human PEG-IL-11. Mice were administered one of the HGF analogs at 24-28 h post irradiation, and in some studies, additional doses given every other day (beginning with the 24-28 h dose) for a total of three or nine doses. Thirty-day (30 d) survival was significantly increased with only one dose of 0.3 mg kg of PEG-G-CSF and PEG-IL-11 or three doses of 0.3 mg kg of PEG-GM-CSF (p ≤ 0.006). Enhanced survival correlated with consistently and significantly enhanced WBC, NE, RBC, and PLT recovery for PEG-G- and PEG-GM-CSF, and enhanced RBC and PLT recovery for PEG-IL-11 (p ≤ 0.05). Longer administration schedules or higher doses did not provide a significant additional survival benefit over the shorter, lower dose, schedules. These data demonstrate the efficacy of BBT's PEG-HGF to provide significantly increased survival with fewer injections and lower drug doses, which may have significant economic and logistical value in the aftermath of a radiation event.

  17. Accidental Predissociation: A Special Case of Photo-Induced Isotope Fractionation Effect and Possible Occurrence in Nature

    NASA Astrophysics Data System (ADS)

    Chakraborty, S.; Thiemens, M. H.

    2009-12-01

    Photo-Induced Isotope Fractionation Effects (PHIFE) are known to produce isotopic frac-tionation in some photo-dissociating molecules (1-2). The PHIFE formalism is based on the Born-Oppenheimer approximation and the Reflection Principle. The isotopic fractionation arises principally from the spectral shift induced by the small difference in zero point energy between isotopologues and the contraction of the wave function due to isotopic substitution, consequently, the associated isotopic fractionations depends on the reduced mass of the isotopically substi-tuted species. The PHIFE formalism is only applicable to the molecules which undergo direct photo-dissociation that possess continuous absorption spectra. Simple molecules (N2, O2, CO) however do not follow a direct dissociation pathway and dissociate through an indirect process termed predissociation, which occurs when the molecule is excited to a quasi-bound state energetically above the dissociation continuum. The PHIFE formalism is not applicable when the absorption spectra are discrete. The assumption that the lightest isotopologues are preferentially predissociated is only valid for restricted predissociation cases. There is a special case of predissociation known as ‘accidental predissociation’ (3), which takes place through an intermediate bound state in two steps (i) leakage to an intermediate bound state (coupled through spin orbit interaction) and, (ii) predissociation to a third quasi-bound state from the intermediate state. Line broadening at an accidental predissociation is a function of the magnitude of coupling matrix elements and the linewidths are strongly influenced by isotopic substitution (4). An anomalous isotopic effect in accidental predissociation was spectroscopically observed in CO (5), N2 (4) and BeH (6). We measured the isotopic fractionation for the first time in two accidental predissociating states of CO through VUV photodissociation using the 9.0.2 beamline at ALS (7-8). In

  18. Radiation-induced genomic instability

    NASA Technical Reports Server (NTRS)

    Kronenberg, A.

    1994-01-01

    Quantitative assessment of the heritable somatic effects of ionizing radiation exposures has relied upon the assumption that radiation-induced lesions were 'fixed' in the DNA prior to the first postirradiation mitosis. Lesion conversion was thought to occur during the initial round of DNA replication or as a consequence of error-prone enzymatic processing of lesions. The standard experimental protocols for the assessment of a variety of radiation-induced endpoints (cell death, specific locus mutations, neoplastic transformation and chromosome aberrations) evaluate these various endpoints at a single snapshot in time. In contrast with the aforementioned approaches, some studies have specifically assessed radiation effects as a function of time following exposure. Evidence has accumulated in support of the hypothesis that radiation exposure induces a persistent destabilization of the genome. This instability has been observed as a delayed expression of lethal mutations, as an enhanced rate of accumulation of non-lethal heritable alterations, and as a progressive intraclonal chromosomal heterogeneity. The genetic controls and biochemical mechanisms underlying radiation-induced genomic instability have not yet been delineated. The aim is to integrate the accumulated evidence that suggests that radiation exposure has a persistent effect on the stability of the mammalian genome.

  19. Accelerated hematopoietic syndrome after radiation doses bridging hematopoietic (H-ARS) and gastrointestinal (GI-ARS) acute radiation syndrome: early hematological changes and systemic inflammatory response syndrome in minipig.

    PubMed

    Moroni, Maria; Elliott, Thomas B; Deutz, Nicolaas E; Olsen, Cara H; Owens, Rossitsa; Christensen, Christine; Lombardini, Eric D; Whitnall, Mark H

    2014-05-01

    To characterize acute radiation syndrome (ARS) sequelae at doses intermediate between the bone marrow (H-ARS) and full gastrointestinal (GI-ARS) syndrome. Male minipigs, approximately 5 months old, 9-12 kg in weight, were irradiated with Cobalt-60 (total body, bilateral gamma irradiation, 0.6 Gy/min). Endpoints were 10-day survival, gastrointestinal histology, plasma citrulline, bacterial translocation, vomiting, diarrhea, vital signs, systemic inflammatory response syndrome (SIRS), febrile neutropenia (FN). We exposed animals to doses (2.2-5.0 Gy) above those causing H-ARS (1.6-2.0 Gy), and evaluated development of ARS. Compared to what was observed during H-ARS (historical data: Moroni et al. 2011a , 2011c ), doses above 2 Gy produced signs of increasingly severe pulmonary damage, faster deterioration of clinical conditions, and faster increases in levels of C-reactive protein (CRP). In the range of 4.6-5.0 Gy, animals died by day 9-10; signs of the classic GI syndrome, as measured by diarrhea, vomiting and bacterial translocation, did not occur. At doses above 2 Gy we observed transient reduction in circulating citrulline levels, and animals exhibited earlier depletion of blood elements and faster onset of SIRS and FN. An accelerated hematopoietic subsyndrome (AH-ARS) is observed at radiation doses between those producing H-ARS and GI-ARS. It is characterized by early onset of SIRS and FN, and greater lung damage, compared to H-ARS.

  20. NOS2 deficiency has no influence on the radiosensitivity of the hematopoietic system.

    PubMed

    Li, Chengcheng; Luo, Yi; Shao, Lijian; Meng, Aimin; Zhou, Daohong

    2018-01-01

    Previous studies have shown that inhibition of inducible NO synthase (NOS2 or iNOS) with an inhibitor can selectively protect several normal tissues against radiation during radiotherapy. However, the role of NOS2 in ionizing radiation (IR)-induced bone marrow (BM) suppression is unknown and thus was investigated in the present study using NOS2 - / - and wild-type mice 14 days after they were exposed to a sublethal dose of total body irradiation (TBI). The effects of different doses of IR (1, 2 and 4 Gy) on the apoptosis and colony-forming ability of bone marrow cells from wild-type (WT) and NOS2 - / - mice were investigated in vitro. In addition, we exposed NOS2 - / - mice and WT mice to 6-Gy TBI or sham irradiation. They were euthanized 14 days after TBI for analysis of peripheral blood cell counts and bone marrow cellularity. Colony-forming unit-granulocyte and macrophage, burst-forming unit-erythroid and CFU-granulocyte, erythroid, macrophage in bone marrow cells from the mice were determined to evaluate the function of hematopoietic progenitor cells (HPCs), and the ability of hematopoietic stem cells (HSCs) to self-renew was analysed by the cobblestone area forming cell assay. The cell cycling of HPCs and HSCs were measured by flow cytometry. Exposure to 2 and 4 Gy IR induced bone marrow cell apoptosis and inhibited the proliferation of HPCs in vitro. However, there was no difference between the cells from WT mice and NOS2 - / - mice in response to IR exposure in vitro. Exposure of WT mice and NOS2 - / - mice to 6 Gy TBI decreased the white blood cell, red blood cell, and platelet counts in the peripheral blood and bone marrow mononuclear cells, and reduced the colony-forming ability of HPCs (P < 0.05), damaged the clonogenic function of HSCs. However, these changes were not significantly different in WT and NOS2 - / - mice. These data suggest that IR induces BM suppression in a NOS2-independent manner.

  1. Development of hematopoietic stem and progenitor cells from human pluripotent stem cells.

    PubMed

    Chen, Tong; Wang, Fen; Wu, Mengyao; Wang, Zack Z

    2015-07-01

    Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), provide a new cell source for regenerative medicine, disease modeling, drug discovery, and preclinical toxicity screening. Understanding of the onset and the sequential process of hematopoietic cells from differentiated hPSCs will enable the achievement of personalized medicine and provide an in vitro platform for studying of human hematopoietic development and disease. During embryogenesis, hemogenic endothelial cells, a specified subset of endothelial cells in embryonic endothelium, are the primary source of multipotent hematopoietic stem cells. In this review, we discuss current status in the generation of multipotent hematopoietic stem and progenitor cells from hPSCs via hemogenic endothelial cells. We also review the achievements in direct reprogramming from non-hematopoietic cells to hematopoietic stem and progenitor cells. Further characterization of hematopoietic differentiation in hPSCs will improve our understanding of blood development and expedite the development of hPSC-derived blood products for therapeutic purpose. © 2015 Wiley Periodicals, Inc.

  2. Inflammation- and tumor-induced anorexia and weight loss require MyD88 in hematopoietic/myeloid cells but not in brain endothelial or neural cells.

    PubMed

    Ruud, Johan; Wilhelms, Daniel Björk; Nilsson, Anna; Eskilsson, Anna; Tang, Yan-Juan; Ströhle, Peter; Caesar, Robert; Schwaninger, Markus; Wunderlich, Thomas; Bäckhed, Fredrik; Engblom, David; Blomqvist, Anders

    2013-05-01

    Loss of appetite is a hallmark of inflammatory diseases. The underlying mechanisms remain undefined, but it is known that myeloid differentiation primary response gene 88 (MyD88), an adaptor protein critical for Toll-like and IL-1 receptor family signaling, is involved. Here we addressed the question of determining in which cells the MyD88 signaling that results in anorexia development occurs by using chimeric mice and animals with cell-specific deletions. We found that MyD88-knockout mice, which are resistant to bacterial lipopolysaccharide (LPS)-induced anorexia, displayed anorexia when transplanted with wild-type bone marrow cells. Furthermore, mice with a targeted deletion of MyD88 in hematopoietic or myeloid cells were largely protected against LPS-induced anorexia and displayed attenuated weight loss, whereas mice with MyD88 deletion in hepatocytes or in neural cells or the cerebrovascular endothelium developed anorexia and weight loss of similar magnitude as wild-type mice. Furthermore, in a model for cancer-induced anorexia-cachexia, deletion of MyD88 in hematopoietic cells attenuated the anorexia and protected against body weight loss. These findings demonstrate that MyD88-dependent signaling within the brain is not required for eliciting inflammation-induced anorexia. Instead, we identify MyD88 signaling in hematopoietic/myeloid cells as a critical component for acute inflammatory-driven anorexia, as well as for chronic anorexia and weight loss associated with malignant disease.

  3. Global gene expression analyses of hematopoietic stem cell-like cell lines with inducible Lhx2 expression

    PubMed Central

    Richter, Karin; Wirta, Valtteri; Dahl, Lina; Bruce, Sara; Lundeberg, Joakim; Carlsson, Leif; Williams, Cecilia

    2006-01-01

    Background Expression of the LIM-homeobox gene Lhx2 in murine hematopoietic cells allows for the generation of hematopoietic stem cell (HSC)-like cell lines. To address the molecular basis of Lhx2 function, we generated HSC-like cell lines where Lhx2 expression is regulated by a tet-on system and hence dependent on the presence of doxycyclin (dox). These cell lines efficiently down-regulate Lhx2 expression upon dox withdrawal leading to a rapid differentiation into various myeloid cell types. Results Global gene expression of these cell lines cultured in dox was compared to different time points after dox withdrawal using microarray technology. We identified 267 differentially expressed genes. The majority of the genes overlapping with HSC-specific databases were those down-regulated after turning off Lhx2 expression and a majority of the genes overlapping with those defined as late progenitor-specific genes were the up-regulated genes, suggesting that these cell lines represent a relevant model system for normal HSCs also at the level of global gene expression. Moreover, in situ hybridisations of several genes down-regulated after dox withdrawal showed overlapping expression patterns with Lhx2 in various tissues during embryonic development. Conclusion Global gene expression analysis of HSC-like cell lines with inducible Lhx2 expression has identified genes putatively linked to self-renewal / differentiation of HSCs, and function of Lhx2 in organ development and stem / progenitor cells of non-hematopoietic origin. PMID:16600034

  4. Human radiation tolerance

    NASA Technical Reports Server (NTRS)

    Lushbaugh, C. C.

    1974-01-01

    The acute radiation syndrome in man is clinically bounded by death at high dose levels and by the prodromal syndrome of untoward physiological effects at minimal levels of clinically effective exposure. As in lower animals, man experiences principally three acute modes of death from radiation exposure (Bond et al., 1965). These are known collectively as the lethal radiation syndromes: central nervous system death, gastrointestinal death, and hematopoietic death. The effect of multiple exposure on lethality, the effect of multiple exposure on hematopoietic recovery, and quantitative aspects of cell and tissue repair are discussed.

  5. Intercellular communications-redox interactions in radiation toxicity; potential targets for radiation mitigation.

    PubMed

    Farhood, Bagher; Goradel, Nasser Hashemi; Mortezaee, Keywan; Khanlarkhani, Neda; Salehi, Ensieh; Nashtaei, Maryam Shabani; Shabeeb, Dheyauldeen; Musa, Ahmed Eleojo; Fallah, Hengameh; Najafi, Masoud

    2018-06-17

    Nowadays, using ionizing radiation (IR) is necessary for clinical, agricultural, nuclear energy or industrial applications. Accidental exposure to IR after a radiation terror or disaster poses a threat to human. In contrast to the old dogma of radiation toxicity, several experiments during the last two recent decades have revealed that intercellular signaling and communications play a key role in this procedure. Elevated level of cytokines and other intercellular signals increase oxidative damage and inflammatory responses via reduction/oxidation interactions (redox system). Intercellular signals induce production of free radicals and inflammatory mediators by some intermediate enzymes such as cyclooxygenase-2 (COX-2), nitric oxide synthase (NOS), NADPH oxidase, and also via triggering mitochondrial ROS. Furthermore, these signals facilitate cell to cell contact and increasing cell toxicity via cohort effect. Nitric oxide is a free radical with ability to act as an intercellular signal that induce DNA damage and changes in some signaling pathways in irradiated as well as non-irradiated adjacent cells. Targeting of these mediators by some anti-inflammatory agents or via antioxidants such as mitochondrial ROS scavengers opens a window to mitigate radiation toxicity after an accidental exposure. Experiments which have been done so far suggests that some cytokines such as IL-1β, TNF-α, TGF-β, IL-4 and IL-13 are some interesting targets that depend on irradiated organs and may help mitigate radiation toxicity. Moreover, animal experiments in recent years indicated that targeting of toll like receptors (TLRs) may be more useful for radioprotection and mitigation. In this review, we aimed to describe the role of intercellular interactions in oxidative injury, inflammation, cell death and killing effects of IR. Moreover, we described evidence on potential mitigation of radiation injury via targeting of these mediators.

  6. Smad, but not MAPK, pathway mediates the expression of type I collagen in radiation induced fibrosis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yano, Hiroyuki; Division of Radioisotope Research, Department of Research Support, Research Promotion Project, Oita University, 1-1 Idaigaoka Hasama-machi, Yufu, Oita 879-5593; Hamanaka, Ryoji

    Highlights: Black-Right-Pointing-Pointer We examine how radiation affects the expression level and signal pathway of collagen. Black-Right-Pointing-Pointer TGF-{beta}1 mRNA is elevated earlier than those of collagen genes after irradiation. Black-Right-Pointing-Pointer Smad pathway mediates the expression of collagen in radiation induced fibrosis. Black-Right-Pointing-Pointer MAPK pathways are not affected in the expression of collagen after irradiation. -- Abstract: Radiation induced fibrosis occurs following a therapeutic or accidental radiation exposure in normal tissues. Tissue fibrosis is the excessive accumulation of collagen and other extracellular matrix components. This study investigated how ionizing radiation affects the expression level and signal pathway of type I collagen. Realmore » time RT-RCR showed that both {alpha}1and {alpha}2 chain of type I collagen mRNA were elevated from 48 h after irradiation with 10 Gy in NIH3T3 cells. The relative luciferase activities of both genes and type I collagen marker were elevated at 72 h. TGF-{beta}1 mRNA was elevated earlier than those of type I collagen genes. A Western blot analysis showed the elevation of Smad phosphorylation at 72 h. Conversely, treatment with TGF-{beta} receptor inhibitor inhibited the mRNA and relative luciferase activity of type I collagen. The phosphorylation of Smad was repressed with the inhibitor, and the luciferase activity was cancelled using a mutant construct of Smad binding site of {alpha}2(I) collagen gene. However, the MAPK pathways, p38, ERK1/2 and JNK, were not affected with specific inhibitors or siRNA. The data showed that the Smad pathway mediated the expression of type I collagen in radiation induced fibrosis.« less

  7. Social evaluation of intentional, truly accidental, and negligently accidental helpers and harmers by 10-month-old infants.

    PubMed

    Woo, Brandon M; Steckler, Conor M; Le, Doan T; Hamlin, J Kiley

    2017-11-01

    Whereas adults largely base their evaluations of others' actions on others' intentions, a host of research in developmental psychology suggests that younger children privilege outcome over intention, leading them to condemn accidental harm. To date, this question has been examined only with children capable of language production. In the current studies, we utilized a non-linguistic puppet show paradigm to examine the evaluation of intentional and accidental acts of helping or harming in 10-month-old infants. In Experiment 1 (n=64), infants preferred intentional over accidental helpers but accidental over intentional harmers, suggestive that by this age infants incorporate information about others' intentions into their social evaluations. In Experiment 2 (n=64), infants did not distinguish "negligently" accidental from intentional helpers or harmers, suggestive that infants may find negligent accidents somewhat intentional. In Experiment 3 (n=64), we found that infants preferred truly accidental over negligently accidental harmers, but did not reliably distinguish negligently accidental from truly accidental helpers, consistent with past work with adults and children suggestive that humans are particularly sensitive to negligently accidental harm. Together, these results imply that infants engage in intention-based social evaluation of those who help and harm accidentally, so long as those accidents do not stem from negligence. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Medical management of the acute radiation syndrome.

    PubMed

    López, Mario; Martín, Margarita

    2011-07-13

    The acute radiation syndrome (ARS) occurs after whole-body or significant partial-body irradiation (typically at a dose of >1 Gy). ARS can involve the hematopoietic, cutaneous, gastrointestinal and the neurovascular organ systems either individually or in combination. There is a correlation between the severity of clinical signs and symptoms of ARS and radiation dose. Radiation induced multi-organ failure (MOF) describes the progressive dysfunction of two or more organ systems over time. Radiation combined injury (RCI) is defined as radiation injury combined with blunt or penetrating trauma, burns, blast, or infection. The classic syndromes are: hematopoietic (doses >2-3 Gy), gastrointestinal (doses 5-12 Gy) and cerebrovascular syndrome (doses 10-20 Gy). There is no possibility to survive after doses >10-12 Gy. The Phases of ARS are-prodromal: 0-2 days from exposure, latent: 2-20 days, and manifest illness: 21-60 days from exposure. Granulocyte-colony stimulating factor (G-CSF) at a dose of 5 μg/kg body weight per day subcutaneously has been recommended as treatment of neutropenia, and antibiotics, antiviral and antifungal agents for prevention or treatment of infections. If taken within the first hours of contamination, stable iodine in the form of nonradioactive potassium iodide (KI) saturates iodine binding sites within the thyroid and inhibits incorporation of radioiodines into the gland. Finally, if severe aplasia persists under cytokines for more than 14 days, the possibility of a hematopoietic stem cell (HSC) transplantation should be evaluated. This review will focus on the clinical aspects of the ARS, using the European triage system (METREPOL) to evaluate the severity of radiation injury, and scoring groups of patients for the general and specific management of the syndrome.

  9. Exposure of the Bone Marrow Microenvironment to Simulated Solar and Galactic Cosmic Radiation Induces Biological Bystander Effects on Human Hematopoiesis.

    PubMed

    Almeida-Porada, Graça; Rodman, Christopher; Kuhlman, Bradford; Brudvik, Egil; Moon, John; George, Sunil; Guida, Peter; Sajuthi, Satria P; Langefeld, Carl D; Walker, Stephen J; Wilson, Paul F; Porada, Christopher D

    2018-04-26

    The stem cell compartment of the hematopoietic system constitutes one of the most radiosensitive tissues of the body and leukemias represent one of the most frequent radiogenic cancers with short latency periods. As such, leukemias may pose a particular threat to astronauts during prolonged space missions. Control of hematopoiesis is tightly governed by a specialized bone marrow (BM) microenvironment/niche. As such, any environmental insult that damages cells of this niche would be expected to produce pronounced effects on the types and functionality of hematopoietic/immune cells generated. We recently reported that direct exposure of human hematopoietic stem cells (HSC) to simulated solar energetic particle (SEP) and galactic cosmic ray (GCR) radiation dramatically altered the differentiative potential of these cells, and that simulated GCR exposures can directly induce DNA damage and mutations within human HSC, which led to leukemic transformation when these cells repopulated murine recipients. In this study, we performed the first in-depth examination to define changes that occur in mesenchymal stem cells present in the human BM niche following exposure to accelerated protons and iron ions and assess the impact these changes have upon human hematopoiesis. Our data provide compelling evidence that simulated SEP/GCR exposures can also contribute to defective hematopoiesis/immunity through so-called "biological bystander effects" by damaging the stromal cells that comprise the human marrow microenvironment, thereby altering their ability to support normal hematopoiesis.

  10. Proliferation of multipotent hematopoietic cells controlled by a truncated erythropoietin receptor transgene.

    PubMed Central

    Kirby, S L; Cook, D N; Walton, W; Smithies, O

    1996-01-01

    The long-term efficacy of gene therapy using bone marrow transplantation requires the engraftment of genetically altered totipotent hematopoietic stem cells (THSCs). Ex vivo expansion of corrected THSCs is one way to increase the efficiency of the procedure. Similarly, selective in vivo expansion of the therapeutic THSCs rather than the endogenous THSCs could favor the transplant. To test whether a conferred proliferative advantage gene can facilitate the in vitro and in vivo expansion of hematopoietic stem cells, we have generated transgenic mice expressing a truncated receptor for the growth factor erythropoietin. These mice are phenotypically normal, but when treated in vivo with exogenous erythropoietin they exhibit a marked increase in multipotent, clonogenic hematopoietic cells [colony-forming units in the spleen (CFU-S) and CFUs that give rise to granulocytes, erythroid cells, macrophages, and megakaryocytes within the same colony (CFU-GEMM)] in comparison with the wild-type mice. In addition, long-term in vitro culture of tEpoR transgenic bone marrow in the presence of erythropoietin induces exponential expansion of trilineage hematopoietic stem cells not seen with wild-type bone marrow. Thus, the truncated erythropoietin receptor gene shows promise as a means for obtaining cytokine-inducible hematopoietic stem cell proliferation to facilitate the direct targeting of THSCs and to provide a competitive repopulation advantage for transplanted therapeutic stem cells. Images Fig. 3 PMID:8790342

  11. Placenta-Derived Adherent Stromal Cell Therapy for Hematopoietic Disorders: A Case Study of PLX-R18.

    PubMed

    Sher, Noa; Ofir, Racheli

    2018-01-01

    The ephemeral placenta provides a noncontroversial source of young, healthy cells of both maternal and fetal origin from which cell therapy products can be manufactured. The 2 advantages of using live cells as therapeutic entities are: (a) in their environmental-responsive, multifactorial secretion profile and (b) in their activity as a "slow-release drug delivery system," releasing secretions over a long time frame. A major difficulty in translating cell therapy to the clinic involves challenges of large-scale, robust manufacturing while maintaining product characteristics, identity, and efficacy. To address these concerns early on, Pluristem developed the PLacental eXpanded (PLX) platform, the first good manufacturing practice-approved, 3-dimensional bioreactor-based cell growth platform, to enable culture of mesenchymal-like adherent stromal cells harvested from the postpartum placenta. One of the products produced by Pluristem on this platform is PLX-R18, a product mainly comprising placental fetal cells, which is proven in vivo to alleviate radiation-induced lethality and to enhance hematopoietic cell counts after bone marrow (BM) failure. The identified mechanism of action of PLX-R18 cells is one of the cell-derived systemic pro-hematopoietic secretions, which upregulate endogenous secretions and subsequently rescue BM and peripheral blood cellularity, thereby boosting survival. PLX-R18 is therefore currently under study to treat both the hematopoietic syndrome of acute radiation (under the US Food and Drug Administration [FDA]'s Animal Rule) and the incomplete engraftment after BM transplantation (in a phase I study). In the future, they could potentially address additional hematological indications, such as aplastic anemia, myelodysplastic syndrome, primary graft failure, and acute or chronic graft versus host disease.

  12. Generating Human Hematopoietic Stem Cells In Vitro: Exploring Endothelial To Hematopoietic Transition As A Portal For Stemness Acquisition

    PubMed Central

    Slukvin, Igor I.

    2016-01-01

    Advances in cellular reprogramming technologies have created alternative platforms for the production of blood cells, either through inducing pluripotency in somatic cells or by way of direct conversion of non-hematopoietic cells into blood cells. However, de novo generation of hematopoietic stem cells (HSCs) with robust and sustained multilineage engraftment potential remains a significant challenge. Hemogenic endothelium (HE) has been recognized as a unique transitional stage of blood development from mesoderm at which HSCs arise in certain embryonic locations. The major aim of this review is to summarize historical perspectives and recent advances in the investigation of endothelial-hematopoietic transition (EHT) and HSC formation in the context of aiding in vitro approaches to instruct HSC fate from human pluripotent stem cells. In addition, direct conversion of somatic cells to blood and HSCs and progression of this conversion through HE stage are discussed. A thorough understanding of the intrinsic and microenvironmental regulators of EHT that lead to the acquisition of self-renewal potential by emerging blood cells, is essential to advance the technologies for HSC production and expansion. PMID:27391301

  13. The possible role of liver kinase B1 in hydroquinone-induced toxicity of murine fetal liver and bone marrow hematopoietic stem cells.

    PubMed

    Li, Zhen; Wang, Chunhong; Zhu, Jie; Bai, YuE; Wang, Wei; Zhou, Yanfeng; Zhang, Shaozun; Liu, Xiangxiang; Zhou, Sheng; Huang, Wenting; Bi, Yongyi; Wang, Hong

    2016-07-01

    Epidemiological studies suggest that the increasing incidence of childhood leukemia may be due to maternal exposure to benzene, which is a known human carcinogen; however, the mechanisms involved remain unknown. Liver Kinase B1 (LKB1) acts as a regulator of cellular energy metabolism and functions to regulate hematopoietic stem cell (HSC) homeostasis. We hypothesize that LKB1 contributes to the deregulation of fetal or bone hematopoiesis caused by the benzene metabolite hydroquinone (HQ). To evaluate this hypothesis, we compared the effects of HQ on murine fetal liver hematopoietic stem cells (FL-HSCs) and bone marrow hematopoietic stem cells (BM-HSCs). FL-HSCs and BM-HSCs were isolated and enriched by a magnetic cell sorting system and exposed to various concentrations of HQ (0, 1.25, 2.5, 5, 10, 20, and 40 μM) for 24 h. We found that the inhibition of differentiation and growth, as well as the apoptosis rate of FL-HSCs, induced by HQ were consistent with the changes in BM-HSCs. Furthermore, G1 cell cycle arrest was observed in BM-HSCs and FL-HSCs in response to HQ. Importantly, FL-HSCs were more sensitive than BM-HSCs after exposure to HQ. The highest induction of LKB1 and adenosine monophosphate-activated protein kinase (AMPK) was observed with a much lower concentration of HQ in FL-HSCs than in BM-HSCs. LKB1 may play a critical role in apoptosis and cell cycle arrest of HQ-treated HSCs. This research has developed innovative ideas concerning benzene-induced hematopoietic toxicity or embryotoxicity, which can provide a new experimental evidence for preventing childhood leukemia. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 830-841, 2016. © 2014 Wiley Periodicals, Inc.

  14. Radiation-induced genomic instability: radiation quality and dose response

    NASA Technical Reports Server (NTRS)

    Smith, Leslie E.; Nagar, Shruti; Kim, Grace J.; Morgan, William F.

    2003-01-01

    Genomic instability is a term used to describe a phenomenon that results in the accumulation of multiple changes required to convert a stable genome of a normal cell to an unstable genome characteristic of a tumor. There has been considerable recent debate concerning the importance of genomic instability in human cancer and its temporal occurrence in the carcinogenic process. Radiation is capable of inducing genomic instability in mammalian cells and instability is thought to be the driving force responsible for radiation carcinogenesis. Genomic instability is characterized by a large collection of diverse endpoints that include large-scale chromosomal rearrangements and aberrations, amplification of genetic material, aneuploidy, micronucleus formation, microsatellite instability, and gene mutation. The capacity of radiation to induce genomic instability depends to a large extent on radiation quality or linear energy transfer (LET) and dose. There appears to be a low dose threshold effect with low LET, beyond which no additional genomic instability is induced. Low doses of both high and low LET radiation are capable of inducing this phenomenon. This report reviews data concerning dose rate effects of high and low LET radiation and their capacity to induce genomic instability assayed by chromosomal aberrations, delayed lethal mutations, micronuclei and apoptosis.

  15. RADIATION INJURY OF MYELOPOIESIS IN MONKEYS,

    DTIC Science & Technology

    RADIATION EFFECTS, *HEMATOPOIETIC SYSTEM, RADIATION INJURIES, GAMMA RAYS, LEUKOCYTES, BLOOD COUNTS, HEMOGLOBIN, MORTALITY RATE, BONE MARROW, LEUKEMIA, ANEMIAS , RADIATION SICKNESS, RADIATION DOSAGE, USSR.

  16. Hematopoietic stem cell transplantation for HIV cure.

    PubMed

    Kuritzkes, Daniel R

    2016-02-01

    The apparent cure of an HIV-infected person following hematopoietic stem cell transplantation (HSCT) from an allogeneic donor homozygous for the ccr5Δ32 mutation has stimulated the search for strategies to eradicate HIV or to induce long-term remission without requiring ongoing antiretroviral therapy. A variety of approaches, including allogeneic HSCT from CCR5-deficient donors and autologous transplantation of genetically modified hematopoietic stem cells, are currently under investigation. This Review covers the experience with HSCT in HIV infection to date and provides a survey of ongoing work in the field. The challenges of developing HSCT for HIV cure in the context of safe, effective, and convenient once-daily antiretroviral therapy are also discussed.

  17. Radiation-induced leukemia: lessons from history.

    PubMed

    Finch, Stuart C

    2007-03-01

    Beginning in 1895, with the discovery of x-rays, alpha and beta radiation, uranium, radium, thorium, and polonium, the fascinating story of the beginning of knowledge concerning the existence of ionizing radiation unfolds. This brief history of radiation and leukemia is divided into two main parts: the first 50 years, which deals with the confusion regarding radiation effects and the failure to clearly recognize that exposure to ionizing radiation may induce leukemia. The second part focuses on the last 60 years, when the radiation induction of leukemia was accepted and some progress achieved in understanding the clinical and pathophysiological characteristics of radiation-induced leukemia. Particular attention in this is paid to the effects of radiation on the survivors of Hiroshima and Nagasaki. The discussion in this section also covers some concepts of radiation-induced cell damage and ruminations on unanswered questions.

  18. Plasticity and Maintenance of Hematopoietic Stem Cells During Development

    PubMed Central

    Kanji, Suman; Pompili, Vincent J.; Das, Hiranmoy

    2012-01-01

    Maintenance of hematopoietic stem cells (HSCs) pool depends on fine balance between self-renewal and differentiation of HSCs. HSCs normally reside within the bone marrow niche of an adult mammal. The embryonic development of HSCs is a complex process that involves the migration of developing HSCs in multiple anatomical sites. Throughout the process, developing HSCs receive internal (transcriptional program) and external (HSC niche) signals, which direct them to maintain balance between self-renewal and differentiation, also to generate a pool of HSCs. In physiological condition HSCs differentiate into all mature cell types present in the blood. However, in pathological condition they may differentiate into non-hematological cells according to the need of the body. It was shown that HSCs can transdifferentiate into cell types that do not belong to the hematopoietic system suggests a complete paradigm shift of the hierarchical hematopoietic tree. This review describes the developmental origins and regulation of HSCs focusing on developmental signals that induce the adult hematopoietic stem cell program, as these informations are very critical for manipulating conditions for expansion of HSCs in ex vivo condition. This review also states clinical application and related patents using HSC. PMID:21517745

  19. Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment

    PubMed Central

    Kovtonyuk, Larisa V.; Fritsch, Kristin; Feng, Xiaomin; Manz, Markus G.; Takizawa, Hitoshi

    2016-01-01

    All hematopoietic and immune cells are continuously generated by hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) through highly organized process of stepwise lineage commitment. In the steady state, HSCs are mostly quiescent, while HPCs are actively proliferating and contributing to daily hematopoiesis. In response to hematopoietic challenges, e.g., life-threatening blood loss, infection, and inflammation, HSCs can be activated to proliferate and engage in blood formation. The HSC activation induced by hematopoietic demand is mediated by direct or indirect sensing mechanisms involving pattern recognition receptors or cytokine/chemokine receptors. In contrast to the hematopoietic challenges with obvious clinical symptoms, how the aging process, which involves low-grade chronic inflammation, impacts hematopoiesis remains undefined. Herein, we summarize recent findings pertaining to functional alternations of hematopoiesis, HSCs, and the bone marrow (BM) microenvironment during the processes of aging and inflammation and highlight some common cellular and molecular changes during the processes that influence hematopoiesis and its cells of origin, HSCs and HPCs, as well as the BM microenvironment. We also discuss how age-dependent alterations of the immune system lead to subclinical inflammatory states and how inflammatory signaling might be involved in hematopoietic aging. Our aim is to present evidence supporting the concept of “Inflamm-Aging,” or inflammation-associated aging of hematopoiesis. PMID:27895645

  20. Serum Proteome Analysis for Profiling Predictive Protein Markers Associated with the Severity of Skin Lesions Induced by Ionizing Radiation.

    PubMed

    Chaze, Thibault; Hornez, Louis; Chambon, Christophe; Haddad, Iman; Vinh, Joelle; Peyrat, Jean-Philippe; Benderitter, Marc; Guipaud, Olivier

    2013-07-10

    The finding of new diagnostic and prognostic markers of local radiation injury, and particularly of the cutaneous radiation syndrome, is crucial for its medical management, in the case of both accidental exposure and radiotherapy side effects. Especially, a fast high-throughput method is still needed for triage of people accidentally exposed to ionizing radiation. In this study, we investigated the impact of localized irradiation of the skin on the early alteration of the serum proteome of mice in an effort to discover markers associated with the exposure and severity of impending damage. Using two different large-scale quantitative proteomic approaches, 2D-DIGE-MS and SELDI-TOF-MS, we performed global analyses of serum proteins collected in the clinical latency phase (days 3 and 7) from non-irradiated and locally irradiated mice exposed to high doses of 20, 40 and 80 Gy which will develop respectively erythema, moist desquamation and necrosis. Unsupervised and supervised multivariate statistical analyses (principal component analysis, partial-least square discriminant analysis and Random Forest analysis) using 2D-DIGE quantitative protein data allowed us to discriminate early between non-irradiated and irradiated animals, and between uninjured/slightly injured animals and animals that will develop severe lesions. On the other hand, despite a high number of animal replicates, PLS-DA and Random Forest analyses of SELDI-TOF-MS data failed to reveal sets of MS peaks able to discriminate between the different groups of animals. Our results show that, unlike SELDI-TOF-MS, the 2D-DIGE approach remains a powerful and promising method for the discovery of sets of proteins that could be used for the development of clinical tests for triage and the prognosis of the severity of radiation-induced skin lesions. We propose a list of 15 proteins which constitutes a set of candidate proteins for triage and prognosis of skin lesion outcomes.

  1. Serum Proteome Analysis for Profiling Predictive Protein Markers Associated with the Severity of Skin Lesions Induced by Ionizing Radiation

    PubMed Central

    Chaze, Thibault; Hornez, Louis; Chambon, Christophe; Haddad, Iman; Vinh, Joelle; Peyrat, Jean-Philippe; Benderitter, Marc; Guipaud, Olivier

    2013-01-01

    The finding of new diagnostic and prognostic markers of local radiation injury, and particularly of the cutaneous radiation syndrome, is crucial for its medical management, in the case of both accidental exposure and radiotherapy side effects. Especially, a fast high-throughput method is still needed for triage of people accidentally exposed to ionizing radiation. In this study, we investigated the impact of localized irradiation of the skin on the early alteration of the serum proteome of mice in an effort to discover markers associated with the exposure and severity of impending damage. Using two different large-scale quantitative proteomic approaches, 2D-DIGE-MS and SELDI-TOF-MS, we performed global analyses of serum proteins collected in the clinical latency phase (days 3 and 7) from non-irradiated and locally irradiated mice exposed to high doses of 20, 40 and 80 Gy which will develop respectively erythema, moist desquamation and necrosis. Unsupervised and supervised multivariate statistical analyses (principal component analysis, partial-least square discriminant analysis and Random Forest analysis) using 2D-DIGE quantitative protein data allowed us to discriminate early between non-irradiated and irradiated animals, and between uninjured/slightly injured animals and animals that will develop severe lesions. On the other hand, despite a high number of animal replicates, PLS-DA and Random Forest analyses of SELDI-TOF-MS data failed to reveal sets of MS peaks able to discriminate between the different groups of animals. Our results show that, unlike SELDI-TOF-MS, the 2D-DIGE approach remains a powerful and promising method for the discovery of sets of proteins that could be used for the development of clinical tests for triage and the prognosis of the severity of radiation-induced skin lesions. We propose a list of 15 proteins which constitutes a set of candidate proteins for triage and prognosis of skin lesion outcomes. PMID:28250398

  2. Protective Effects of Hydrogen against Low-Dose Long-Term Radiation-Induced Damage to the Behavioral Performances, Hematopoietic System, Genital System, and Splenic Lymphocytes in Mice

    PubMed Central

    Lei, Xiao; Zhao, Hainan; Liu, Pengfei; Xu, Yang; Chen, Yuanyuan; Chuai, Yunhai

    2016-01-01

    Molecular hydrogen (H2) has been previously reported playing an important role in ameliorating damage caused by acute radiation. In this study, we investigated the effects of H2 on the alterations induced by low-dose long-term radiation (LDLTR). All the mice in hydrogen-treated or radiation-only groups received 0.1 Gy, 0.5 Gy, 1.0 Gy, and 2.0 Gy whole-body gamma radiation, respectively. After the last time of radiation exposure, all the mice were employed for the determination of the body mass (BM) observation, forced swim test (FST), the open field test (OFT), the chromosome aberration (CA), the peripheral blood cells parameters analysis, the sperm abnormality (SA), the lymphocyte transformation test (LTT), and the histopathological studies. And significant differences between the treatment group and the radiation-only groups were observed, showing that H2 could diminish the detriment induced by LDLTR and suggesting the protective efficacy of H2 in multiple systems in mice against LDLTR. PMID:27774116

  3. Altered microRNA expression patterns in irradiated hematopoietic tissues suggest a sex-specific protective mechanism

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ilnytskyy, Yaroslav; Zemp, Franz J.; Koturbash, Igor

    To investigate involvement of miRNAs in radiation responses we used microRNAome profiling to analyze the sex-specific response of radiation sensitive hematopoietic lymphoid tissues. We show that radiation exposure resulted in a significant and sex-specific deregulation of microRNA expression in murine spleen and thymus tissues. Among the regulated miRNAs, we found that changes in expression of miR-34a and miR-7 may be involved in important protective mechanisms counteracting radiation cytotoxicity. We observed a significant increase in the expression of tumor-suppressor miR-34a, paralleled by a decrease in the expression of its target oncogenes NOTCH1, MYC, E2F3 and cyclin D1. Additionally, we show thatmore » miR-7 targets the lymphoid-specific helicase LSH, a pivotal regulator of DNA methylation and genome stability. While miR-7 was significantly down-regulated LSH was significantly up-regulated. These cellular changes may constitute an attempt to counteract radiation-induced hypomethylation. Tissue specificity of miRNA responses and possible regulation of miRNA expression upon irradiation are discussed.« less

  4. Hematopoietic Stem Cells from Ts65Dn Mice Are Deficient in the Repair of DNA Double-Strand Breaks.

    PubMed

    Wang, Yingying; Chang, Jianhui; Shao, Lijian; Feng, Wei; Luo, Yi; Chow, Marie; Du, Wei; Meng, Aimin; Zhou, Daohong

    2016-06-01

    Down syndrome (DS) is a genetic disorder caused by the presence of an extra partial or whole copy of chromosome 21. In addition to musculoskeletal and neurodevelopmental abnormalities, children with DS exhibit various hematologic disorders and have an increased risk of developing acute lymphoblastic leukemia and acute megakaryocytic leukemia. Using the Ts65Dn mouse model, we investigated bone marrow defects caused by trisomy for 132 orthologs of the genes on human chromosome 21. The results showed that, although the total bone marrow cellularity as well as the frequency of hematopoietic progenitor cells (HPCs) was comparable between Ts65Dn mice and their age-matched euploid wild-type (WT) control littermates, human chromosome 21 trisomy led to a significant reduction in hematopoietic stem cell (HSC) numbers and clonogenic function in Ts65Dn mice. We also found that spontaneous DNA double-strand breaks (DSBs) were significantly increased in HSCs from the Ts65Dn mice, which was correlated with the significant reduction in HSC clonogenic activity compared to those from WT controls. Moreover, analysis of the repair kinetics of radiation-induced DSBs revealed that HSCs from Ts65Dn mice were less proficient in DSB repair than the cells from WT controls. This deficiency was associated with a higher sensitivity of Ts65Dn HSCs to radiation-induced suppression of HSC clonogenic activity than that of euploid HSCs. These findings suggest that an additional copy of genes on human chromosome 21 may selectively impair the ability of HSCs to repair DSBs, which may contribute to DS-associated hematological abnormalities and malignancies.

  5. Hematopoietic Stem Cells from Ts65Dn Mice Are Deficient in the Repair of DNA Double-Strand Breaks

    PubMed Central

    Wang, Yingying; Chang, Jianhui; Shao, Lijian; Feng, Wei; Luo, Yi; Chow, Marie; Du, Wei; Meng, Aimin; Zhou, Daohong

    2016-01-01

    Down syndrome (DS) is a genetic disorder caused by the presence of an extra partial or whole copy of chromosome 21. In addition to musculoskeletal and neurodevelopmental abnormalities, children with DS exhibit various hematologic disorders and have an increased risk of developing acute lymphoblastic leukemia and acute megakaryocytic leukemia. Using the Ts65Dn mouse model, we investigated bone marrow defects caused by trisomy for 132 orthologs of the genes on human chromosome 21. The results showed that, although the total bone marrow cellularity as well as the frequency of hematopoietic progenitor cells (HPCs) was comparable between Ts65Dn mice and their age-matched euploid wild-type (WT) control littermates, human chromosome 21 trisomy led to a significant reduction in hematopoietic stem cell (HSC) numbers and clonogenic function in Ts65Dn mice. We also found that spontaneous DNA double-strand breaks (DSBs) were significantly increased in HSCs from the Ts65Dn mice, which was correlated with the significant reduction in HSC clonogenic activity compared to those from WT controls. Moreover, analysis of the repair kinetics of radiation-induced DSBs revealed that HSCs from Ts65Dn mice were less proficient in DSB repair than the cells from WT controls. This deficiency was associated with a higher sensitivity of Ts65Dn HSCs to radiation-induced suppression of HSC clonogenic activity than that of euploid HSCs. These findings suggest that an additional copy of genes on human chromosome 21 may selectively impair the ability of HSCs to repair DSBs, which may contribute to DS-associated hematological abnormalities and malignancies. PMID:27243896

  6. Accidental sodium hypochlorite-induced skin injury during endodontic treatment.

    PubMed

    Serper, Ahmet; Ozbek, Murat; Calt, Semra

    2004-03-01

    A case of accidental skin injury caused by leakage of sodium hypochlorite solution from the rubber dam during root canal preparation is reported. After placement of a rubber dam and initiation of root canal treatment, the patient complained of a burning sensation with sodium hypochlorite irrigation. The complaints were ignored by the practitioner, and a skin rash developed on and around the patient's chin, followed by scab formation. The patient required medical treatment with topical Hamamelis virginiana extract for 2 weeks, with full recovery.

  7. Protein Malnutrition Induces Bone Marrow Mesenchymal Stem Cells Commitment to Adipogenic Differentiation Leading to Hematopoietic Failure

    PubMed Central

    Cunha, Mayara Caldas Ramos; Lima, Fabiana da Silva; Vinolo, Marco Aurélio Ramirez; Hastreiter, Araceli; Curi, Rui; Borelli, Primavera; Fock, Ricardo Ambrósio

    2013-01-01

    Protein malnutrition (PM) results in pathological changes that are associated with peripheral leukopenia, bone marrow (BM) hypoplasia and alterations in the BM microenvironment leading to hematopoietic failure; however, the mechanisms involved are poorly understood. In this context, the BM mesenchymal stem cells (MSCs) are cells intimately related to the formation of the BM microenvironment, and their differentiation into adipocytes is important because adipocytes are cells that have the capability to negatively modulate hematopoiesis. Two-month-old male Balb/c mice were subjected to protein-energy malnutrition with a low-protein diet containing 2% protein, whereas control animals were fed a diet containing 12% protein. The hematopoietic parameters and the expression of CD45 and CD117 positive cells in the BM were evaluated. MSCs were isolated from BM, and their capability to produce SCF, IL-3, G-CSF and GM-CSF were analyzed. The expression of PPAR-γ and C/EBP-α as well as the expression of PPAR-γ and SREBP mRNAs were evaluated in MSCs together with their capability to differentiate into adipocytes in vitro. The malnourished animals had anemia and leukopenia as well as spleen and bone marrow hypoplasia and a reduction in the expression of CD45 and CD117 positive cells from BM. The MSCs of the malnourished mice presented an increased capability to produce SCF and reduced production of G-CSF and GM-CSF. The MSCs from the malnourished animals showed increased expression of PPAR-γ protein and PPAR-γ mRNA associated with an increased capability to differentiate into adipocytes. The alterations found in the malnourished animals allowed us to conclude that malnutrition committed MSC differentiation leading to adipocyte decision and compromised their capacity for cytokine production, contributing to an impaired hematopoietic microenvironment and inducing the bone marrow failure commonly observed in protein malnutrition states. PMID:23516566

  8. Erythro-Myeloid Progenitors: “definitive” hematopoiesis in the conceptus prior to the emergence of hematopoietic stem cells

    PubMed Central

    Frame, Jenna M.; McGrath, Kathleen E.; Palis, James

    2013-01-01

    Erythro-myeloid progenitors (EMP) serve as a major source of hematopoiesis in the developing conceptus prior to the formation of a permanent blood system. In this review, we summarize the current knowledge regarding the emergence, fate, and potential of this hematopoietic stem cell (HSC)-independent wave of hematopoietic progenitors, focusing on the murine embryo as a model system. A better understanding of the temporal and spatial control of hematopoietic emergence in the embryo will ultimately improve our ability to derive hematopoietic stem and progenitor cells from embryonic stem cells and induced pluripotent stem cells to serve therapeutic purposes. PMID:24095199

  9. Adenosine signaling promotes hematopoietic stem and progenitor cell emergence

    PubMed Central

    Jing, Lili; Tamplin, Owen J.; Chen, Michael J.; Deng, Qing; Patterson, Shenia; Kim, Peter G.; Durand, Ellen M.; McNeil, Ashley; Green, Julie M.; Matsuura, Shinobu; Ablain, Julien; Brandt, Margot K.; Schlaeger, Thorsten M.; Huttenlocher, Anna; Daley, George Q.; Ravid, Katya

    2015-01-01

    Hematopoietic stem cells (HSCs) emerge from aortic endothelium via the endothelial-to-hematopoietic transition (EHT). The molecular mechanisms that initiate and regulate EHT remain poorly understood. Here, we show that adenosine signaling regulates hematopoietic stem and progenitor cell (HSPC) development in zebrafish embryos. The adenosine receptor A2b is expressed in the vascular endothelium before HSPC emergence. Elevated adenosine levels increased runx1+/cmyb+ HSPCs in the dorsal aorta, whereas blocking the adenosine pathway decreased HSPCs. Knockdown of A2b adenosine receptor disrupted scl+ hemogenic vascular endothelium and the subsequent EHT process. A2b adenosine receptor activation induced CXCL8 via cAMP–protein kinase A (PKA) and mediated hematopoiesis. We further show that adenosine increased multipotent progenitors in a mouse embryonic stem cell colony-forming assay and in embryonic day 10.5 aorta-gonad-mesonephros explants. Our results demonstrate that adenosine signaling plays an evolutionary conserved role in the first steps of HSPC formation in vertebrates. PMID:25870200

  10. Hematopoietic Stem Cell Therapy to Countermeasure Cancer in Astronauts during Exploration of Deep Space

    NASA Technical Reports Server (NTRS)

    Ohi, S.; Kindred, R. P.; Roach, A-N.; Edossa, A.; Kim, B. C.; Gonda, S. R.; Emami, K.

    2004-01-01

    Exposure to cosmic radiation can cause chromosomal mutations, which may lead to cancer in astronauts engaged in space exploration. Therefore, our goals are to develop countermeasures to prevent space-induced cancer using hematopoietic stem cell therapy (HSCT) and gene therapy. This presentation focuses on HSCT for cancer. Our previous experiments on a simulated, space-induced immuno-deficiency model (mouse hind limb unloading ) indicated that transplanted hematopoietic stem cells (HSCs) could enhance the host's immunity by effectively eliminating bacterial infection (Ohi S, et. al. J Grav Physiol 10, P63-64, 2003; Ohi S, et. al. Proceedings of the Space Technology and Applications International Forum (STAIF) . American Institute of Physics, New York, pp. 938-950, 2004). Hence, we hypothesized that the HSCs might be effective in combating cancer as well. Studies of cocultured mouse HSCs with beta-galactosidase marked rat gliosarcoma spheroids (9L/lacZ), a cancer model, indicated antagonistic interactions , resulting in destruction of the spheroids by HSCs. Trypan Blue dye-exclusion assays were consistent with the conclusion. These results show potential usehlness of HSCT for cancer. Currently, the NASA Hydrodynamic Focusing Bioreactor (HFB), a space analog tissue/cell culture system, is being used to study invasion of the gliosarcoma (GS) spheroids into mouse brain with or without co-cultured HSCs. This may simulate the metastasis of gliosarcoma to brain. There is a tendency for the HSCs to inhibit invasion of GS spheroids into brain, as evidenced by the X-gal staining.

  11. Mitigative Effects of a Combination of Multiple Pharmaceutical Drugs on the Survival of Mice Exposed to Lethal Ionizing Radiation.

    PubMed

    Hirouchi, Tokuhisa; Ito, Koichi; Nakano, Manabu; Monzen, Satoru; Yoshino, Hironori; Chiba, Mitsuru; Hazawa, Masaharu; Nakano, Akira; Ishikawa, Junya; Yamaguchi, Masaru; Tanaka, Kimio; Kashiwakura, Ikuo

    2015-01-01

    It is important to establish an easy-to-use therapeutic protocol for the emergency medical care of patients involved in radiation accidents to reduce the radiation-related casualties. The present study aimed to establish an optimum therapeutic protocol using currently approved pharmaceutical drugs to increase the survival of victims exposed to lethal radiation. Different combinations of four drugs-recombinant human erythropoietin (EPO), granulocyte-colony stimulating factor (G-CSF), c-mpl receptor agonist romiplostim (RP) and nandrolone decanoate (ND)-were administered to mice within 2 h after exposure to a lethal 7 Gy dose of γ-irradiation. On day 30 after irradiation, the condition of the mice was analyzed using various hematological parameters, such as the number of peripheral blood cells, bone marrow cells, hematopoietic progenitor cells and the expression of cell surface antigens. Approximately 10% of the untreated irradiated control mice survived for 21 days, but all of the control mice died by day 30. The combined administration of G-CSF, EPO and RP for five days immediately after irradiation led to a complete survival of the irradiated mice until day 30. However, the treatment with G-CSF, EPO and RP with ND led to only 75% survival at day 30. The hematological analyses showed that the numbers of almost all of hematopoietic cells in the surviving mice treated with effective medications recovered to the levels of non-irradiated mice. The present findings show that the combination of G-CSF, EPO and RP may be a useful countermeasure for victims exposed to accidental lethal irradiation.

  12. Hematopoietic Stem Cell Regeneration Enhanced by Ectopic Expression of ROS-detoxifying Enzymes in Transplant Mice

    PubMed Central

    Miao, Weimin; XuFeng, Richard; Park, Moo-Rim; Gu, Haihui; Hu, Linping; Kang, Jin Wook; Ma, Shihui; Liang, Paulina H; Li, Yanxin; Cheng, Haizi; Yu, Hui; Epperly, Michael; Greenberger, Joel; Cheng, Tao

    2013-01-01

    High levels of reactive oxygen species (ROS) can exhaust hematopoietic stem cells (HSCs). Thus, maintaining a low state of redox in HSCs by modulating ROS-detoxifying enzymes may augment the regeneration potential of HSCs. Our results show that basal expression of manganese superoxide dismutase (MnSOD) and catalase were at low levels in long-term and short-term repopulating HSCs, and administration of a MnSOD plasmid and lipofectin complex (MnSOD-PL) conferred radiation protection on irradiated recipient mice. To assess the intrinsic role of elevated MnSOD or catalase in HSCs and hematopoietic progenitor cells, the MnSOD or catalase gene was overexpressed in mouse hematopoietic cells via retroviral transduction. The impact of MnSOD and catalase on hematopoietic progenitor cells was mild, as measured by colony-forming units (CFUs). However, overexpressed catalase had a significant beneficial effect on long-term engraftment of transplanted HSCs, and this effect was further enhanced after an insult of low-dose γ-irradiation in the transplant mice. In contrast, overexpressed MnSOD exhibited an insignificant effect on long-term engraftment of transplanted HSCs, but had a significant beneficial effect after an insult of sublethal irradiation. Taken together, these results demonstrate that HSC function can be enhanced by ectopic expression of ROS-detoxifying enzymes, especially after radiation exposure in vivo. PMID:23295952

  13. Hematopoietic Effects of Paeoniflorin and Albiflorin on Radiotherapy-Induced Myelosuppression Mice

    PubMed Central

    Zhu, Yingli; Wang, Linyuan; Yang, Zhihui; Wang, Jingxia; Li, Wei; Zhou, Jianyu; Zhang, Jianjun

    2016-01-01

    Paeonia lactiflora root (baishao in Chinese) is a commonly used herb in traditional Chinese medicine (TCM). Paeoniflorin (PF) and albiflorin (AF) are two major active constituents of P. lactiflora. In this paper, we aimed to investigate the hematopoietic effects of PF and AF on myelosuppression mice induced by radiotherapy and to explore the underlying mechanism. The finding indicated that PF and AF significantly increased the numbers of white blood cells (WBC) and reversed the atrophy of thymus. Furthermore, PF and AF increased the levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) and reduced the levels of tumor necrosis factor-α (TNF-α) in serum and increased the level of colony-stimulating factor (G-CSF) in plasma. Lastly, PF and AF not only enhanced the mRNA levels of GM-CSF and G-CSF in the spleens, but also increased the protein levels of G-CSF and GM-CSF in bone marrow. Our results suggest that PF and AF may promote the recovery of bone marrow hemopoietic function in a myelosuppressed mouse model. PMID:27313650

  14. European consensus on the medical management of acute radiation syndrome and analysis of the radiation accidents in Belgium and Senegal.

    PubMed

    Gourmelon, Patrick; Benderitter, Marc; Bertho, Jean Marc; Huet, Christelle; Gorin, Norbert Claude; De Revel, Patrick

    2010-06-01

    A European consensus concerning the medical management of mass radiation exposure was obtained in 2005 during a conference held by the European Group for Blood and Bone Marrow Transplantation, the Institute of Radioprotection and Nuclear Safety, and the University of Ulm. At the conference, a two-step triage strategy to deal with large masses of radiation-exposed patients was designed. The first step of this strategy concerns the first 48 h and involves scoring the patients exclusively on the basis of their clinical symptoms and biological data. This allows the non-irradiated bystanders and outpatient candidates to be identified. The remaining patients are hospitalized and diagnosis is confirmed after the first 48-h period according to the METREPOL (Medical Treatment Protocols for radiation accident victims) scale. This grades the patients according to the severity of their symptoms. It was also agreed that in the case of acute radiation syndrome (ARS), emergency hematopoietic stem cell (HSC) transplantation is not necessary. Instead, cytokines that promote hematological reconstruction should be administered as early as possible for 14-21 d. Crucial tests for determining whether the patient has residual hematopoiesis are physical dose reconstructions combined with daily blood count analyses. It was agreed that HSC transplantation should only be considered if severe aplasia persists after cytokine treatment. Two recent cases of accidental radiation exposure that were managed successfully by following the European consensus with modification are reviewed here. Thus, a European standard for the evaluation and treatment of ARS victims is now available. This standard may be suitable for application around the world.

  15. Establishing a murine model of the hematopoietic syndrome of the acute radiation syndrome.

    PubMed

    Plett, P Artur; Sampson, Carol H; Chua, Hui Lin; Joshi, Mandar; Booth, Catherine; Gough, Alec; Johnson, Cynthia S; Katz, Barry P; Farese, Ann M; Parker, Jeffrey; MacVittie, Thomas J; Orschell, Christie M

    2012-10-01

    The authors have developed a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS) for efficacy testing of medical countermeasures (MCM) against radiation according to the FDA Animal Rule. Ten- to 12-wk-old male and female C57BL/6 mice were exposed to the LD50/30-LD70/30 dose of total body irradiation (TBI, (137)Cs, 0.62-0.67 Gy min(-1)) in the morning hours when mice were determined to be most radiosensitive, and they were assessed for 30-d survival and mean survival time (MST). Antibiotics were delivered in drinking water on days 4-30 post-TBI at a concentration based on the amount of water that lethally-irradiated mice were found to consume. The fluoroquinolones, ciprofloxacin and levofloxacin, as well as the tetracycline doxycycline, and aminoglycoside neomycin, all significantly increased MST of decedent mice, while ciprofloxacin (p = 0.061) and doxycycline + neomycin (p = 0.005) showed at least some efficacy to increase 30-d survival. Blood sampling (30 μL/mouse every fifth day) was found to negatively impact 30-d survival. Histopathology of tissues harvested from nonmoribund mice showed expected effects of lethal irradiation, while moribund mice were largely septicemic with a preponderance of enteric organisms. Kinetics of loss and recovery of peripheral blood cells in untreated mice and those treated with two MCM, granulocyte-colony stimulating factor and Amifostine further characterized and validated this model for use in screening studies and pivotal efficacy studies of candidate MCM for licensure to treat irradiated individuals suffering from H-ARS.

  16. Composite accidental axions

    NASA Astrophysics Data System (ADS)

    Redi, Michele; Sato, Ryosuke

    2016-05-01

    We present several models where the QCD axion arises accidentally. Confining gauge theories can generate axion candidates whose properties are uniquely determined by the quantum numbers of the new fermions under the Standard Model. The Peccei-Quinn symmetry can emerge accidentally if the gauge theory is chiral. We generalise previous constructions in a unified framework. In some cases these models can be understood as the deconstruction of 5-dimensional gauge theories where the Peccei-Quinn symmetry is protected by locality but more general constructions are possible.

  17. Breaking the rules? X-ray examination of hematopoietic stem cell grafts at international airports.

    PubMed

    Petzer, Andreas L; Speth, Hans-Georg; Hoflehner, Elisabeth; Clausen, Johannes; Nachbaur, David; Gastl, Günther; Gunsilius, Eberhard

    2002-06-15

    Hematopoietic stem cell grafts from unrelated donors are commonly transported by aircraft. They must not be subjected to x-rays during security checks, which may cause inconvenient discussions between the courier and the airport security staff. We exposed hematopoietic stem cells from mobilized peripheral blood to a widely used x-ray hand-luggage control system. Cell viability as well as growth in vitro of mature progenitor cells (colony-forming cells), primitive progenitor cells (long-term culture-initiating cells), and lymphocytes were not altered even after 10 passages through the hand-luggage control system. Thus, repeated exposure to the low radiation dose of hand-luggage control systems (1.5 +/- 0.6 microSv per exposure) seems to be harmless for hematopoietic stem cells, which should simplify the international transport of stem cell grafts.

  18. Modulation of occluding junctions alters the hematopoietic niche to trigger immune activation

    PubMed Central

    Khadilkar, Rohan J; Vogl, Wayne; Goodwin, Katharine

    2017-01-01

    Stem cells are regulated by signals from their microenvironment, or niche. During Drosophila hematopoiesis, a niche regulates prohemocytes to control hemocyte production. Immune challenges activate cell-signalling to initiate the cellular and innate immune response. Specifically, certain immune challenges stimulate the niche to produce signals that induce prohemocyte differentiation. However, the mechanisms that promote prohemocyte differentiation subsequent to immune challenges are poorly understood. Here we show that bacterial infection induces the cellular immune response by modulating occluding-junctions at the hematopoietic niche. Occluding-junctions form a permeability barrier that regulates the accessibility of prohemocytes to niche derived signals. The immune response triggered by infection causes barrier breakdown, altering the prohemocyte microenvironment to induce immune cell production. Moreover, genetically induced barrier ablation provides protection against infection by activating the immune response. Our results reveal a novel role for occluding-junctions in regulating niche-hematopoietic progenitor signalling and link this mechanism to immune cell production following infection. PMID:28841136

  19. Radiation-induced instability and its relation to radiation carcinogenesis

    NASA Technical Reports Server (NTRS)

    Ullrich, R. L.; Ponnaiya, B.

    1998-01-01

    PURPOSE: A model that identifies radiation-induced genetic instability as the earliest cellular event in the multi-step sequence leading to radiation-induced cancer was previously proposed. In this paper ongoing experiments are discussed which are designed to test this model and its predictions in mouse mammary epithelial cells. RESULTS: Several lines of evidence are presented that appear to support this model: first, the development of delayed mutations in p53 following irradiation in altered growth variants; secondly, the high frequencies for the induction of both instability and transformation following irradiation in mammary epithelial cells; and finally, the demonstration that susceptibility to the induction of cytogenetic instability is a heritable trait that correlates with susceptibility to transformation and radiation-induced mammary cancer. Mice resistant to transformation and mammary cancer development are also resistant to the development of instability after irradiation. In contrast, mice sensitive to transformation and cancer are also sensitive to the development of cytogenetic instability. CONCLUSIONS: Data from this laboratory and from the studies cited above suggest a specific, and perhaps unique, role for radiation-induced instability as a critical early event associated with initiation of the carcinogenic process.

  20. Accidental hanging by a T-shirt collar in a man with morphine intoxication: an unusual case.

    PubMed

    Kodikara, Sarathchandra; Alagiyawanna, Ramesh

    2011-09-01

    Accidental hanging is rare across all age groups, and it is even rarer in the adult population except in autoerotic asphyxia. Few cases have been reported in the literature, which describe unusual patterns of accidental hanging. This article focuses on an unusual pattern of accidental hanging of a 25-year-old man, who was in a state of morphine-induced central nervous system depression and found dead in a sitting position with the collar of his T-shirt hanging off a jutting-out root of a tree. The hanged collar acted as a ligature compressing the neck.

  1. 5 CFR 870.206 - Accidental death and dismemberment.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 5 Administrative Personnel 2 2010-01-01 2010-01-01 false Accidental death and dismemberment. 870....206 Accidental death and dismemberment. (a) (1) Accidental death and dismemberment coverage is an automatic part of Basic and Option A insurance for employees. (2) There is no accidental death and...

  2. 5 CFR 870.206 - Accidental death and dismemberment.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 5 Administrative Personnel 2 2014-01-01 2014-01-01 false Accidental death and dismemberment. 870....206 Accidental death and dismemberment. (a)(1) Accidental death and dismemberment coverage is an automatic part of Basic and Option A insurance for employees. (2) There is no accidental death and...

  3. 5 CFR 870.206 - Accidental death and dismemberment.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 5 Administrative Personnel 2 2011-01-01 2011-01-01 false Accidental death and dismemberment. 870....206 Accidental death and dismemberment. (a)(1) Accidental death and dismemberment coverage is an automatic part of Basic and Option A insurance for employees. (2) There is no accidental death and...

  4. 5 CFR 870.206 - Accidental death and dismemberment.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 5 Administrative Personnel 2 2013-01-01 2013-01-01 false Accidental death and dismemberment. 870....206 Accidental death and dismemberment. (a)(1) Accidental death and dismemberment coverage is an automatic part of Basic and Option A insurance for employees. (2) There is no accidental death and...

  5. 5 CFR 870.206 - Accidental death and dismemberment.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 5 Administrative Personnel 2 2012-01-01 2012-01-01 false Accidental death and dismemberment. 870....206 Accidental death and dismemberment. (a)(1) Accidental death and dismemberment coverage is an automatic part of Basic and Option A insurance for employees. (2) There is no accidental death and...

  6. Fancb deficiency impairs hematopoietic stem cell function

    PubMed Central

    Du, Wei; Amarachintha, Surya; Erden, Ozlem; Wilson, Andrew; Meetei, Amom Ruhikanta; Andreassen, Paul R.; Namekawa, Satoshi H.; Pang, Qishen

    2015-01-01

    Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure, variable congenital malformations and a predisposition to malignancies. FANCB (also known as FAAP95), is the only X-linked FA gene discovered thus far. In the present study, we investigated hematopoiesis in adult Fancb deficient (Fancb−/y) mice and found that Fancb−/y mice have decreased hematopoietic stem cell (HSC) quiescence accompanied by reduced progenitor activity in vitro and reduced repopulating capacity in vivo. Like other FA mouse models previously reported, the hematopoietic system of Fancb−/y mice is hypersensitive to DNA cross-linking agent mitomycin C (MMC), which induces bone marrow failure in Fancb−/y mice. Furthermore, Fancb−/y BM exhibits slower recovery kinetics and less tolerance to myelotoxic stress induced by 5-fluorouracil than wild-type littermates. RNA-seq analysis reveals altered expression of genes involved in HSC function and cell cycle regulation in Fancb−/y HSC and progenitor cells. Thus, this Fancb−/y mouse model provides a novel approach for studying the critical role of the FA pathway not only in germ cell development but also in the maintenance of HSC function. PMID:26658157

  7. Hydrogen-Rich Water Ameliorates Total Body Irradiation-Induced Hematopoietic Stem Cell Injury by Reducing Hydroxyl Radical

    PubMed Central

    Xue, Xiaolei; Han, Xiaodan; Li, Yuan; Lu, Lu; Li, Deguan

    2017-01-01

    We examined whether consumption of hydrogen-rich water (HW) could ameliorate hematopoietic stem cell (HSC) injury in mice with total body irradiation (TBI). The results indicated that HW alleviated TBI-induced HSC injury with respect to cell number alteration and to the self-renewal and differentiation of HSCs. HW specifically decreased hydroxyl radical (∙OH) levels in the c-kit+ cells of 4 Gy irradiated mice. Proliferative bone marrow cells (BMCs) increased and apoptotic c-kit+ cells decreased in irradiated mice uptaken with HW. In addition, the mean fluorescence intensity (MFI) of γ-H2AX and percentage of 8-oxoguanine positive cells significantly decreased in HW-treated c-kit+ cells, indicating that HW can alleviate TBI-induced DNA damage and oxidative DNA damage in c-kit+ cells. Finally, the cell cycle (P21), cell apoptosis (BCL-XL and BAK), and oxidative stress (NRF2, HO-1, NQO1, SOD, and GPX1) proteins were significantly altered by HW in irradiated mouse c-kit+ cells. Collectively, the present results suggest that HW protects against TBI-induced HSC injury. PMID:28243358

  8. Hydrogen-Rich Water Ameliorates Total Body Irradiation-Induced Hematopoietic Stem Cell Injury by Reducing Hydroxyl Radical.

    PubMed

    Zhang, Junling; Xue, Xiaolei; Han, Xiaodan; Li, Yuan; Lu, Lu; Li, Deguan; Fan, Saijun

    2017-01-01

    We examined whether consumption of hydrogen-rich water (HW) could ameliorate hematopoietic stem cell (HSC) injury in mice with total body irradiation (TBI). The results indicated that HW alleviated TBI-induced HSC injury with respect to cell number alteration and to the self-renewal and differentiation of HSCs. HW specifically decreased hydroxyl radical ( ∙ OH) levels in the c-kit + cells of 4 Gy irradiated mice. Proliferative bone marrow cells (BMCs) increased and apoptotic c-kit + cells decreased in irradiated mice uptaken with HW. In addition, the mean fluorescence intensity (MFI) of γ -H2AX and percentage of 8-oxoguanine positive cells significantly decreased in HW-treated c-kit + cells, indicating that HW can alleviate TBI-induced DNA damage and oxidative DNA damage in c-kit + cells. Finally, the cell cycle (P21), cell apoptosis (BCL-XL and BAK), and oxidative stress (NRF2, HO-1, NQO1, SOD, and GPX1) proteins were significantly altered by HW in irradiated mouse c-kit + cells. Collectively, the present results suggest that HW protects against TBI-induced HSC injury.

  9. Epigenomics in hematopoietic transplantation: novel treatment strategies.

    PubMed

    Engel, Nicole; Rank, Andreas

    2011-10-01

    Allogeneic hematopoietic stem cell transplantation is a high risk but curative treatment option for leukemia, myelodysplasia and other hematological malignancies. After high dose radio- or chemo-therapy, recipient's hematopoiesis is replaced by a new immunosystem and residual malignant cells are eliminated by the graft-versus-leukemia reaction. The benefit of this immunological effect is limited by the most frequent complication of hematopoietic stem cell transplantation: graft-versus-host disease. In addition to their well-known anti-tumor activity, epigenetic drugs mediate immunotolerance without reducing alloreactivity or even enhance graft-versus-leukemia effect without inducing graft-versus-host disease by regulating cytokine release, increasing the circulating number of regulatory T cells and interacting with natural killer cells. We focus on the use of epigenetic drugs in the allogeneic transplantation setting in relation to their anti-tumor and immunomodulatory potential.

  10. Vascular niche promotes hematopoietic multipotent progenitor formation from pluripotent stem cells

    PubMed Central

    Gori, Jennifer L.; Butler, Jason M.; Chan, Yan-Yi; Chandrasekaran, Devikha; Poulos, Michael G.; Ginsberg, Michael; Nolan, Daniel J.; Elemento, Olivier; Wood, Brent L.; Adair, Jennifer E.; Rafii, Shahin; Kiem, Hans-Peter

    2015-01-01

    Pluripotent stem cells (PSCs) represent an alternative hematopoietic stem cell (HSC) source for treating hematopoietic disease. The limited engraftment of human PSC–derived (hPSC-derived) multipotent progenitor cells (MPP) has hampered the clinical application of these cells and suggests that MPP require additional cues for definitive hematopoiesis. We hypothesized that the presence of a vascular niche that produces Notch ligands jagged-1 (JAG1) and delta-like ligand-4 (DLL4) drives definitive hematopoiesis. We differentiated hes2 human embryonic stem cells (hESC) and Macaca nemestrina–induced PSC (iPSC) line-7 with cytokines in the presence or absence of endothelial cells (ECs) that express JAG1 and DLL4. Cells cocultured with ECs generated substantially more CD34+CD45+ hematopoietic progenitors compared with cells cocultured without ECs or with ECs lacking JAG1 or DLL4. EC-induced cells exhibited Notch activation and expressed HSC-specific Notch targets RUNX1 and GATA2. EC-induced PSC-MPP engrafted at a markedly higher level in NOD/SCID/IL-2 receptor γ chain–null (NSG) mice compared with cytokine-induced cells, and low-dose chemotherapy-based selection further increased engraftment. Long-term engraftment and the myeloid-to-lymphoid ratio achieved with vascular niche induction were similar to levels achieved for cord blood–derived MPP and up to 20-fold higher than those achieved with hPSC-derived MPP engraftment. Our findings indicate that endothelial Notch ligands promote PSC-definitive hematopoiesis and production of long-term engrafting CD34+ cells, suggesting these ligands are critical for HSC emergence. PMID:25664855

  11. Soy isoflavone aglycone modulates a hematopoietic response in combination with soluble beta-glucan: SCG.

    PubMed

    Harada, Toshie; Masuda, Susumu; Arii, Masayuki; Adachi, Yoshiyuki; Nakajima, Mitsuhiro; Yadomae, Toshiro; Ohno, Naohito

    2005-12-01

    Soy isoflavone aglycones (IFAs) have a wide range of biological actions that suggest they may be of use in cancer prevention. On the other hand, a branched beta-glucan from Sparassis crispa (SCG) is a major 6-branched 1,3-beta-D-glucan in an edible/medicinal mushroom: Sparassis crispa showing antitumor activity. We have previously reported that both oral and intraperitoneal administration of SCG enhanced the hematopoietic response in cyclophosphamide (CY)-induced leukopenic mice. In this study, we investigated the hematopoietic response due to IFA in combination with SCG in CY-induced leukopenic mice. The oral administration of IFA in combination with SCG synergistically enhanced the number of white blood cells, and increased spleen weight. Analyzing the leukocyte population by flow cytometry, the combination of IFA and SCG increased the number of monocytes and granulocytes in the spleen. Taken together, the combination of IFA and SCG synergistically provides the hematopoietic responses that are enhanced over IFA or SCG alone.

  12. Radiation-induced genomic instability and bystander effects: related inflammatory-type responses to radiation-induced stress and injury? A review.

    PubMed

    Lorimore, S A; Wright, E G

    2003-01-01

    To review studies of radiation responses in the haemopoietic system in the context of radiation-induced genomic instability, bystander effects and inflammatory-type processes. There is considerable evidence that cells that themselves are not exposed to ionizing radiation but are the progeny of cells irradiated many cell divisions previously may express a high frequency of gene mutations, chromosomal aberrations and cell death. These effects are collectively known as radiation-induced genomic instability. A second untargeted effect results in non-irradiated cells exhibiting responses typically associated with direct radiation exposure but occurs as a consequence of contact with irradiated cells or by receiving soluble signals from irradiated cells. These effects are collectively known as radiation-induced bystander effects. Reported effects include increases or decreases in damage-inducible and stress-related proteins; increases or decreases in reactive oxygen species, cell death or cell proliferation, and induction of mutations and chromosome aberrations. This array of responses is reminiscent of effects mediated by cytokines and other similar regulatory factors that may involve, but do not necessarily require, gap junction-mediated transfer, have multiple inducers and a variety of context-dependent consequences in different cell systems. That chromosomal instability in haemopoietic cells can be induced by an indirect bystander-type mechanism both in vitro and in vivo provides a potential link between these two untargeted effects and there are radiation responses in vivo consistent with the microenvironment contributing secondary cell damage as a consequence of an inflammatory-type response to radiation-induced injury. Intercellular signalling, production of cytokines and free radicals are features of inflammatory responses that have the potential for both bystander-mediated and persisting damage as well as for conferring a predisposition to malignancy. The

  13. MicroRNAs enriched in hematopoietic stem cells differentially regulate long-term hematopoietic output.

    PubMed

    O'Connell, Ryan M; Chaudhuri, Aadel A; Rao, Dinesh S; Gibson, William S J; Balazs, Alejandro B; Baltimore, David

    2010-08-10

    The production of blood cells depends on a rare hematopoietic stem-cell (HSC) population, but the molecular mechanisms underlying HSC biology remain incompletely understood. Here, we identify a subset of microRNAs (miRNAs) that is enriched in HSCs compared with other bone-marrow cells. An in vivo gain-of-function screen found that three of these miRNAs conferred a competitive advantage to engrafting hematopoietic cells, whereas other HSC miRNAs attenuated production of blood cells. Overexpression of the most advantageous miRNA, miR-125b, caused a dose-dependent myeloproliferative disorder that progressed to a lethal myeloid leukemia in mice and also enhanced hematopoietic engraftment in human immune system mice. Our study identifies an evolutionarily conserved subset of miRNAs that is expressed in HSCs and functions to modulate hematopoietic output.

  14. Whole-Body Proton Irradiation Causes Long-Term Damage to Hematopoietic Stem Cells in Mice

    PubMed Central

    Chang, Jianhui; Feng, Wei; Wang, Yingying; Luo, Yi; Allen, Antiño R.; Koturbash, Igor; Turner, Jennifer; Stewart, Blair; Raber, Jacob; Hauer-Jensen, Martin; Zhou, Daohong; Shao, Lijian

    2016-01-01

    Space flight poses certain health risks to astronauts, including exposure to space radiation, with protons accounting for more than 80% of deep-space radiation. Proton radiation is also now being used with increasing frequency in the clinical setting to treat cancer. For these reasons, there is an urgent need to better understand the biological effects of proton radiation on the body. Such improved understanding could also lead to more accurate assessment of the potential health risks of proton radiation, as well as the development of improved strategies to prevent and mitigate its adverse effects. Previous studies have shown that exposure to low doses of protons is detrimental to mature leukocyte populations in peripheral blood, however, the underlying mechanisms are not known. Some of these detriments may be attributable to damage to hematopoietic stem cells (HSCs) that have the ability to self-renew, proliferate and differentiate into different lineages of blood cells through hematopoietic progenitor cells (HPCs). The goal of this study was to investigate the long-term effects of low-dose proton irradiation on HSCs. We exposed C57BL/6J mice to 1.0 Gy whole-body proton irradiation (150 MeV) and then studied the effects of proton radiation on HSCs and HPCs in the bone marrow (BM) 22 weeks after the exposure. The results showed that mice exposed to 1.0 Gy whole-body proton irradiation had a significant and persistent reduction of BM HSCs compared to unirradiated controls. In contrast, no significant changes were observed in BM HPCs after proton irradiation. Furthermore, irradiated HSCs and their progeny exhibited a significant impairment in clonogenic function, as revealed by the cobblestone area-forming cell (CAFC) and colony-forming cell assays, respectively. These long-term effects of proton irradiation on HSCs may be attributable to the induction of chronic oxidative stress in HSCs, because HSCs from irradiated mice exhibited a significant increase in NADPH

  15. Epidemiology of radiation-induced cancer.

    PubMed Central

    Radford, E P

    1983-01-01

    The epidemiology of radiation-induced cancer is important for theoretical and practical insights that these studies give to human cancer in general and because we have more evidence from radiation-exposed populations than for any other environmental carcinogen. On theoretical and experimental grounds, the linear no-threshold dose-response relationship is a reasonable basis for extrapolating effects to low doses. Leukemia is frequently the earliest observed radiogenic cancer but is now considered to be of minor importance, because the radiation effect dies out after 25 or 30 years, whereas solid tumors induced by radiation develop later and the increased cancer risk evidently persists for the remaining lifetime. Current estimates of the risk of particular cancers from radiation exposure cannot be fully evaluated until the population under study have been followed at least 40 or 50 years after exposure. Recent evidence indicates that for lung cancer induction, combination of cigarette smoking and radiation exposure leads to risks that are not multiplicative but rather nearly additive. PMID:6653538

  16. Novel pathways to erythropoiesis induced by dimerization of intracellular C-Mpl in human hematopoietic progenitors.

    PubMed

    Parekh, Chintan; Sahaghian, Arineh; Kim, William; Scholes, Jessica; Ge, Shundi; Zhu, Yuhua; Asgharzadeh, Shahab; Hollis, Roger; Kohn, Donald; Ji, Lingyun; Malvar, Jemily; Wang, Xiaoyan; Crooks, Gay

    2012-04-01

    The cytokine thrombopoietin (Tpo) plays a critical role in hematopoiesis by binding to the extracellular domain and inducing homodimerization of the intracellular signaling domain of its receptor, c-Mpl. Mpl homodimerization can also be accomplished by binding of a synthetic ligand to a constitutively expressed fusion protein F36VMpl consisting of a ligand binding domain (F36V) and the intracellular signaling domain of Mpl. Unexpectedly, in contrast to Tpo stimulation, robust erythropoiesis is induced after dimerization of F36VMpl in human CD34+ progenitor cells. The goal of this study was to define the hematopoietic progenitor stages at which dimerization of intracellular Mpl induces erythropoiesis and the downstream molecular events that mediate this unanticipated effect. Dimerization (in the absence of erythropoietin and other cytokines) in human common myeloid progenitors and megakaryocytic erythroid progenitors caused a significant increase in CD34+ cells (p < .01) and induced all stages of erythropoiesis including production of enucleated red blood cells. In contrast, erythropoiesis was not seen with Tpo stimulation. CD34+ cell expansion was the result of increased cell cycling and survival (p < .05). Microarray profiling of CD34+ cells demonstrated that a unique transcriptional pattern is activated in progenitors by F36VMpl dimerization. Ligand-inducible dimerization of intracellular Mpl in human myeloerythroid progenitors induces progenitor expansion and erythropoiesis through molecular mechanisms that are not shared by Tpo stimulation of endogenous Mpl. Copyright © 2012 AlphaMed Press.

  17. Wnt5a Regulates Hematopoietic Stem Cell Proliferation and Repopulation Through the Ryk Receptor

    PubMed Central

    Povinelli, Benjamin J.; Nemeth, Michael J.

    2017-01-01

    Proper regulation of the balance between hematopoietic stem cell (HSC) proliferation, self-renewal, and differentiation is necessary to maintain hematopoiesis throughout life. The Wnt family of ligands has been implicated as critical regulators of these processes through a network of signaling pathways. Previously, we have demonstrated that the Wnt5a ligand can induce HSC quiescence through a noncanonical Wnt pathway, resulting in an increased ability to reconstitute hematopoiesis. In this study, we tested the hypothesis that the Ryk protein, a Wnt ligand receptor that can bind the Wnt5a ligand, regulated the response of HSCs to Wnt5a. We observed that inhibiting Ryk blocked the ability of Wnt5a to induce HSC quiescence and enhance short-term and long-term hematopoietic repopulation. We found that Wnt5a suppressed production of reactive oxygen species, a known inducer of HSC proliferation. The ability of Wnt5a to inhibit ROS production was also regulated by Ryk. From these data, we propose that Wnt5a regulates HSC quiescence and hematopoietic repopulation through the Ryk receptor and that this process is mediated by suppression of reactive oxygen species. PMID:23939973

  18. Wnt5a regulates hematopoietic stem cell proliferation and repopulation through the Ryk receptor.

    PubMed

    Povinelli, Benjamin J; Nemeth, Michael J

    2014-01-01

    Proper regulation of the balance between hematopoietic stem cell (HSC) proliferation, self-renewal, and differentiation is necessary to maintain hematopoiesis throughout life. The Wnt family of ligands has been implicated as critical regulators of these processes through a network of signaling pathways. Previously, we have demonstrated that the Wnt5a ligand can induce HSC quiescence through a noncanonical Wnt pathway, resulting in an increased ability to reconstitute hematopoiesis. In this study, we tested the hypothesis that the Ryk protein, a Wnt ligand receptor that can bind the Wnt5a ligand, regulated the response of HSCs to Wnt5a. We observed that inhibiting Ryk blocked the ability of Wnt5a to induce HSC quiescence and enhance short-term and long-term hematopoietic repopulation. We found that Wnt5a suppressed production of reactive oxygen species, a known inducer of HSC proliferation. The ability of Wnt5a to inhibit ROS production was also regulated by Ryk. From these data, we propose that Wnt5a regulates HSC quiescence and hematopoietic repopulation through the Ryk receptor and that this process is mediated by suppression of reactive oxygen species. © 2013 AlphaMed Press.

  19. Radiation-induced cardiovascular effects

    NASA Astrophysics Data System (ADS)

    Tapio, Soile

    Recent epidemiological studies indicate that exposure to ionising radiation enhances the risk of cardiovascular mortality and morbidity in a moderate but significant manner. Our goal is to identify molecular mechanisms involved in the pathogenesis of radiation-induced cardiovascular disease using cellular and mouse models. Two radiation targets are studied in detail: the vascular endothelium that plays a pivotal role in the regulation of cardiac function, and the myocardium, in particular damage to the cardiac mitochondria. Ionising radiation causes immediate and persistent alterations in several biological pathways in the endothelium in a dose- and dose-rate dependent manner. High acute and cumulative doses result in rapid, non-transient remodelling of the endothelial cytoskeleton, as well as increased lipid peroxidation and protein oxidation of the heart tissue, independent of whether exposure is local or total body. Proteomic and functional changes are observed in lipid metabolism, glycolysis, mitochondrial function (respiration, ROS production etc.), oxidative stress, cellular adhesion, and cellular structure. The transcriptional regulators Akt and PPAR alpha seem to play a central role in the radiation-response of the endothelium and myocardium, respectively. We have recently started co-operation with GSI in Darmstadt to study the effect of heavy ions on the endothelium. Our research will facilitate the identification of biomarkers associated with adverse cardiac effects of ionising radiation and may lead to the development of countermeasures against radiation-induced cardiac damage.

  20. Direct Reprogramming of Murine Fibroblasts to Hematopoietic Progenitor Cells

    PubMed Central

    Batta, Kiran; Florkowska, Magdalena; Kouskoff, Valerie; Lacaud, Georges

    2014-01-01

    Summary Recent reports have shown that somatic cells, under appropriate culture conditions, could be directly reprogrammed to cardiac, hepatic, or neuronal phenotype by lineage-specific transcription factors. In this study, we demonstrate that both embryonic and adult somatic fibroblasts can be efficiently reprogrammed to clonal multilineage hematopoietic progenitors by the ectopic expression of the transcription factors ERG, GATA2, LMO2, RUNX1c, and SCL. These reprogrammed cells were stably expanded on stromal cells and possessed short-term reconstitution ability in vivo. Loss of p53 function facilitated reprogramming to blood, and p53−/− reprogrammed cells efficiently generated erythroid, megakaryocytic, myeloid, and lymphoid lineages. Genome-wide analyses revealed that generation of hematopoietic progenitors was preceded by the appearance of hemogenic endothelial cells expressing endothelial and hematopoietic genes. Altogether, our findings suggest that direct reprogramming could represent a valid alternative approach to the differentiation of embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) for disease modeling and autologous blood cell therapies. PMID:25466247

  1. Recombinant TAT-BMI-1 fusion protein induces ex vivo expansion of human umbilical cord blood-derived hematopoietic stem cells.

    PubMed

    Codispoti, Bruna; Rinaldo, Nicola; Chiarella, Emanuela; Lupia, Michela; Spoleti, Cristina Barbara; Marafioti, Maria Grazia; Aloisio, Annamaria; Scicchitano, Stefania; Giordano, Marco; Nappo, Giovanna; Lucchino, Valeria; Moore, Malcolm A S; Zhou, Pengbo; Mesuraca, Maria; Bond, Heather Mandy; Morrone, Giovanni

    2017-07-04

    Transplantation of hematopoietic stem cells (HSCs) is a well-established therapeutic approach for numerous disorders. HSCs are typically derived from bone marrow or peripheral blood after cytokine-induced mobilization. Umbilical cord blood (CB) represents an appealing alternative HSC source, but the small amounts of the individual CB units have limited its applications. The availability of strategies for safe ex vivo expansion of CB-derived HSCs (CB-HSCs) may allow to extend the use of these cells in adult patients and to avoid the risk of insufficient engraftment or delayed hematopoietic recovery.Here we describe a system for the ex vivo expansion of CB-HSCs based on their transient exposure to a recombinant TAT-BMI-1 chimeric protein. BMI-1 belongs to the Polycomb family of epigenetic modifiers and is recognized as a central regulator of HSC self-renewal. Recombinant TAT-BMI-1 produced in bacteria was able to enter the target cells via the HIV TAT-derived protein transduction peptide covalently attached to BMI-1, and conserved its biological activity. Treatment of CB-CD34+ cells for 3 days with repeated addition of 10 nM purified TAT-BMI-1 significantly enhanced total cell expansion as well as that of primitive hematopoietic progenitors in culture. Importantly, TAT-BMI-1-treated CB-CD34+ cells displayed a consistently higher rate of multi-lineage long-term repopulating activity in primary and secondary xenotransplants in immunocompromised mice. Thus, recombinant TAT-BMI-1 may represent a novel, effective reagent for ex vivo expansion of CB-HSC for therapeutic purposes.

  2. Recombinant TAT-BMI-1 fusion protein induces ex vivo expansion of human umbilical cord blood-derived hematopoietic stem cells

    PubMed Central

    Codispoti, Bruna; Rinaldo, Nicola; Chiarella, Emanuela; Lupia, Michela; Spoleti, Cristina Barbara; Marafioti, Maria Grazia; Aloisio, Annamaria; Scicchitano, Stefania; Giordano, Marco; Nappo, Giovanna; Lucchino, Valeria; Moore, Malcolm A.S.; Zhou, Pengbo; Mesuraca, Maria

    2017-01-01

    Transplantation of hematopoietic stem cells (HSCs) is a well-established therapeutic approach for numerous disorders. HSCs are typically derived from bone marrow or peripheral blood after cytokine-induced mobilization. Umbilical cord blood (CB) represents an appealing alternative HSC source, but the small amounts of the individual CB units have limited its applications. The availability of strategies for safe ex vivo expansion of CB-derived HSCs (CB-HSCs) may allow to extend the use of these cells in adult patients and to avoid the risk of insufficient engraftment or delayed hematopoietic recovery. Here we describe a system for the ex vivo expansion of CB-HSCs based on their transient exposure to a recombinant TAT-BMI-1 chimeric protein. BMI-1 belongs to the Polycomb family of epigenetic modifiers and is recognized as a central regulator of HSC self-renewal. Recombinant TAT-BMI-1 produced in bacteria was able to enter the target cells via the HIV TAT-derived protein transduction peptide covalently attached to BMI-1, and conserved its biological activity. Treatment of CB-CD34+ cells for 3 days with repeated addition of 10 nM purified TAT-BMI-1 significantly enhanced total cell expansion as well as that of primitive hematopoietic progenitors in culture. Importantly, TAT-BMI-1-treated CB-CD34+ cells displayed a consistently higher rate of multi-lineage long-term repopulating activity in primary and secondary xenotransplants in immunocompromised mice. Thus, recombinant TAT-BMI-1 may represent a novel, effective reagent for ex vivo expansion of CB-HSC for therapeutic purposes. PMID:28187462

  3. Hematopoietic responses under protracted exposures to low daily dose gamma irradiation

    NASA Astrophysics Data System (ADS)

    Seed, T. M.; Fritz, T. E.; Tolle, D. V.; Jackson, W. E.

    In attempting to evaluate the possible health consequences of chronic ionizing radiation exposure during extended space travel (e.g., Mars Mission), ground-based experimental studies of the clinical and pathological responses of canines under low daily doses of 60Co gamma irradiation (0.3-26.3 cGy d -1) have been examined. Specific reference was given to responses of the blood forming system. Results suggest that the daily dose rate of 7.5 cGy d -1 represents a threshold below which the hematopoietic system can retain either partial or full trilineal cell-producing capacity (erythropoiesis, myelopoiesis, and megakaryopoiesis) for extended periods of exposure (> 1yr). Trilineal capacity was fully retained for several years of exposure at the lowest dose-rate tested (0.3 cGy d -1) but was completely lost within several hundred days at the highest dose-rate (26.3 cGy d -1). Retention of hematopoietic capacity under chronic exposure has been demonstrated to be mediated by hematopoietic progenitors with acquired radioresistance and repair functions, altered cytogenetics, and cell-cycle characteristics. Radiological, biological, and temporal parameters responsible for these vital acquisitions by hematopoietic progenitors have been partially characterized. These parameters, along with threshold responses, are described and discussed in relation to potential health risks of the space traveler under chronic stress of low-dose irradiation.

  4. Hematopoietic responses under protracted exposures to low daily dose gamma irradiation.

    PubMed

    Seed, T M; Fritz, T E; Tolle, D V; Jackson, W E

    2002-01-01

    In attempting to evaluate the possible health consequences of chronic ionizing radiation exposure during extended space travel (e.g., Mars Mission), ground-based experimental studies of the clinical and pathological responses of canines under low daily doses of 60Co gamma irradiation (0.3-26.3 cGy d-1) have been examined. Specific reference was given to responses of the blood forming system. Results suggest that the daily dose rate of 7.5 cGy d-1 represents a threshold below which the hematopoietic system can retain either partial or full trilineal cell-producing capacity (erythropoiesis, myelopoiesis, and megakaryopoiesis) for extended periods of exposure (>1 yr). Trilineal capacity was fully retained for several years of exposure at the lowest dose-rate tested (0.3 cGy d-1) but was completely lost within several hundred days at the highest dose-rate (26.3 cGy d-1). Retention of hematopoietic capacity under chronic exposure has been demonstrated to be mediated by hematopoietic progenitors with acquired radioresistance and repair functions, altered cytogenetics, and cell-cycle characteristics. Radiological, biological, and temporal parameters responsible for these vital acquisitions by hematopoietic progenitors have been partially characterized. These parameters, along with threshold responses, are described and discussed in relation to potential health risks of the space traveler under chronic stress of low-dose irradiation. Published by Elsevier Science Ltd on behalf of COSPAR.

  5. Hematopoietic stem cell-specific GFP-expressing transgenic mice generated by genetic excision of a pan-hematopoietic reporter gene.

    PubMed

    Perez-Cunningham, Jessica; Boyer, Scott W; Landon, Mark; Forsberg, E Camilla

    2016-08-01

    Selective labeling of specific cell types by expression of green fluorescent protein (GFP) within the hematopoietic system would have great utility in identifying, localizing, and tracking different cell populations in flow cytometry, microscopy, lineage tracing, and transplantation assays. In this report, we describe the generation and characterization of a new transgenic mouse line with specific GFP labeling of all nucleated hematopoietic cells and platelets. This new "Vav-GFP" mouse line labels the vast majority of hematopoietic cells with GFP during both embryonic development and adulthood, with particularly high expression in hematopoietic stem and progenitor cells (HSPCs). With the exception of transient labeling of fetal endothelial cells, GFP expression is highly selective for hematopoietic cells and persists in donor-derived progeny after transplantation of HSPCs. Finally, we also demonstrate that the loxP-flanked reporter allows for specific GFP labeling of different hematopoietic cell subsets when crossed to various Cre reporter lines. By crossing Vav-GFP mice to Flk2-Cre mice, we obtained robust and highly selective GFP expression in hematopoietic stem cells (HSCs). These data describe a new mouse model capable of directing GFP labeling exclusively of hematopoietic cells or exclusively of HSCs. Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  6. Adoptive immunotherapy against kidney targets in dog-leukocyte antigen-identical mixed hematopoietic canine chimeras.

    PubMed

    Junghanss, Christian; Takatu, Alessandra; Little, Marie-Terese; Maciej Zaucha, J; Zellmer, Eustacia; Yunusov, Murad; Sale, George; Georges, George E; Storb, Rainer

    2003-02-15

    Stable mixed-donor-host-hematopoietic chimerism can serve as a platform for adoptive immunotherapy. Infusions of donor lymphocytes (DLI) sensitized against hematopoietic cells converted mixed hematopoietic into full-donor chimerism in dog-leukocyte antigen (DLA)-identical littermates. Whether sensitization against tissue of solid organs leads to organ-specific immunity that can be transferred by DLI was unknown and was investigated in these experiments using the kidney as target. DLA-identical recipients with established stable mixed-donor-host-hematopoietic chimerism were used. In five pairs, hematopoietic stem-cell transplant (HSCT) donors were sensitized by kidney transplantation from the respective chimeras. In a second group, five HSCT donors received vaccinations that were generated from kidney cells of the respective mixed chimeras. Twenty-eight days after sensitization, DLI were administered to the mixed-hematopoietic chimeras. All HSCT donors rejected their kidney grafts from their mixed-chimeric recipients within 22 to 45 days. DLI caused no sustained graft-versus-kidney effects in the mixed-chimeric recipients. However, DLI donors sensitized by kidney transplantation converted 4 of 5 mixed chimeras into virtually complete (>95%) donor-type chimeras, compared with 1 of 5 mixed chimeras given DLI by vaccination from sensitized donors. Although DLA-identical kidney grafts from mixed-hematopoietic chimeras were readily rejected by their HSCT donors, subsequent transfusions of sensitized-donor lymphocytes into mixed chimeras converted mixed to all-donor chimerism but failed to induce graft-versus-kidney effects. Vaccination strategies in lieu of kidney grafts failed to convert mixed chimerism.

  7. Accidental sulfur mustard exposure: A case report.

    PubMed

    Schmidt, Annette; Steinritz, Dirk; Rudolf, Klaus-Dieter; Thiermann, Horst; Striepling, Enno

    2018-09-01

    The clinical progression following a sulfur mustard-induced skin exposure is well documented in the literature. Upon skin contact and a characteristic latency period, sulfur mustard (SM) causes erythema, blister formation and ulceration, which is associated with wound healing disorders that may require surgical treatment. Here, we present a case report of accidental exposure to SM in a laboratory setting which required surgical treatment of the skin. The case was illustrated at close intervals over a period of two years and underlines that exposure to SM has to be taken into account when typical clinical symptoms occur. Moreover skin grafts appear to be effective in SM-induced non healing skin ulcerations. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Transformation of human mesenchymal cells and skin fibroblasts into hematopoietic cells.

    PubMed

    Harris, David M; Hazan-Haley, Inbal; Coombes, Kevin; Bueso-Ramos, Carlos; Liu, Jie; Liu, Zhiming; Li, Ping; Ravoori, Murali; Abruzzo, Lynne; Han, Lin; Singh, Sheela; Sun, Michael; Kundra, Vikas; Kurzrock, Razelle; Estrov, Zeev

    2011-01-01

    Patients with prolonged myelosuppression require frequent platelet and occasional granulocyte transfusions. Multi-donor transfusions induce alloimmunization, thereby increasing morbidity and mortality. Therefore, an autologous or HLA-matched allogeneic source of platelets and granulocytes is needed. To determine whether nonhematopoietic cells can be reprogrammed into hematopoietic cells, human mesenchymal stromal cells (MSCs) and skin fibroblasts were incubated with the demethylating agent 5-azacytidine (Aza) and the growth factors (GF) granulocyte-macrophage colony-stimulating factor and stem cell factor. This treatment transformed MSCs to round, non-adherent cells expressing T-, B-, myeloid-, or stem/progenitor-cell markers. The transformed cells engrafted as hematopoietic cells in bone marrow of immunodeficient mice. DNA methylation and mRNA array analysis suggested that Aza and GF treatment demethylated and activated HOXB genes. Indeed, transfection of MSCs or skin fibroblasts with HOXB4, HOXB5, and HOXB2 genes transformed them into hematopoietic cells. Further studies are needed to determine whether transformed MSCs or skin fibroblasts are suitable for therapy.

  9. Transformation of Human Mesenchymal Cells and Skin Fibroblasts into Hematopoietic Cells

    PubMed Central

    Harris, David M.; Hazan-Haley, Inbal; Coombes, Kevin; Bueso-Ramos, Carlos; Liu, Jie; Liu, Zhiming; Li, Ping; Ravoori, Murali; Abruzzo, Lynne; Han, Lin; Singh, Sheela; Sun, Michael; Kundra, Vikas; Kurzrock, Razelle; Estrov, Zeev

    2011-01-01

    Patients with prolonged myelosuppression require frequent platelet and occasional granulocyte transfusions. Multi-donor transfusions induce alloimmunization, thereby increasing morbidity and mortality. Therefore, an autologous or HLA-matched allogeneic source of platelets and granulocytes is needed. To determine whether nonhematopoietic cells can be reprogrammed into hematopoietic cells, human mesenchymal stromal cells (MSCs) and skin fibroblasts were incubated with the demethylating agent 5-azacytidine (Aza) and the growth factors (GF) granulocyte-macrophage colony-stimulating factor and stem cell factor. This treatment transformed MSCs to round, non-adherent cells expressing T-, B-, myeloid-, or stem/progenitor-cell markers. The transformed cells engrafted as hematopoietic cells in bone marrow of immunodeficient mice. DNA methylation and mRNA array analysis suggested that Aza and GF treatment demethylated and activated HOXB genes. Indeed, transfection of MSCs or skin fibroblasts with HOXB4, HOXB5, and HOXB2 genes transformed them into hematopoietic cells. Further studies are needed to determine whether transformed MSCs or skin fibroblasts are suitable for therapy. PMID:21731684

  10. Radiation-induced vaginal stenosis: current perspectives

    PubMed Central

    Morris, Lucinda; Do, Viet; Chard, Jennifer; Brand, Alison H

    2017-01-01

    Treatment of gynecological cancer commonly involves pelvic radiation therapy (RT) and/or brachytherapy. A commonly observed side effect of such treatment is radiation-induced vaginal stenosis (VS). This review analyzed the incidence, pathogenesis, clinical manifestation(s) and assessment and grading of radiation-induced VS. In addition, risk factors, prevention and treatment options and follow-up schedules are also discussed. The limited available literature on many of these aspects suggests that additional studies are required to more precisely determine the best management strategy of this prevalent group after RT. PMID:28496367

  11. Role of neurotensin in radiation-induced hypothermia in rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kandasamy, S.B.; Hunt, W.A.; Harris, A.H.

    1991-05-01

    The role of neurotensin in radiation-induced hypothermia was examined. Intracerebroventricular (ICV) administration of neurotensin produced dose-dependent hypothermia. Histamine appears to mediate neurotensin-induced hypothermia because the mast cell stabilizer disodium cromoglycate and antihistamines blocked the hypothermic effects of neurotensin. An ICV pretreatment with neurotensin antibody attenuated neurotensin-induced hypothermia, but did not attenuate radiation-induced hypothermia, suggesting that radiation-induced hypothermia was not mediated by neurotensin.

  12. HIV-1 infection depletes human CD34+CD38- hematopoietic progenitor cells via pDC-dependent mechanisms.

    PubMed

    Li, Guangming; Zhao, Juanjuan; Cheng, Liang; Jiang, Qi; Kan, Sheng; Qin, Enqiang; Tu, Bo; Zhang, Xin; Zhang, Liguo; Su, Lishan; Zhang, Zheng

    2017-07-01

    Chronic human immunodeficiency virus-1 (HIV-1) infection in patients leads to multi-lineage hematopoietic abnormalities or pancytopenia. The deficiency in hematopoietic progenitor cells (HPCs) induced by HIV-1 infection has been proposed, but the relevant mechanisms are poorly understood. We report here that both human CD34+CD38- early and CD34+CD38+ intermediate HPCs were maintained in the bone marrow (BM) of humanized mice. Chronic HIV-1 infection preferentially depleted CD34+CD38- early HPCs in the BM and reduced their proliferation potential in vivo in both HIV-1-infected patients and humanized mice, while CD34+CD38+ intermediate HSCs were relatively unaffected. Strikingly, depletion of plasmacytoid dendritic cells (pDCs) prevented human CD34+CD38- early HPCs from HIV-1 infection-induced depletion and functional impairment and restored the gene expression profile of purified CD34+ HPCs in humanized mice. These findings suggest that pDCs contribute to the early hematopoietic suppression induced by chronic HIV-1 infection and provide a novel therapeutic target for the hematopoiesis suppression in HIV-1 patients.

  13. Evaluating the risk of death via the hematopoietic syndrome mode for prolonged exposure of nuclear workers to radiation delivered at very low rates.

    PubMed

    Scott, B R; Lyzlov, A F; Osovets, S V

    1998-05-01

    During a Phase-I effort, studies were planned to evaluate deterministic (nonstochastic) effects of chronic exposure of nuclear workers at the Mayak atomic complex in the former Soviet Union to relatively high levels (> 0.25 Gy) of ionizing radiation. The Mayak complex has been used, since the late 1940's, to produce plutonium for nuclear weapons. Workers at Site A of the complex were involved in plutonium breeding using nuclear reactors, and some were exposed to relatively large doses of gamma rays plus relatively small neutron doses. The Weibull normalized-dose model, which has been set up to evaluate the risk of specific deterministic effects of combined, continuous exposure of humans to alpha, beta, and gamma radiations, is here adapted for chronic exposure to gamma rays and neutrons during repeated 6-h work shifts--as occurred for some nuclear workers at Site A. Using the adapted model, key conclusions were reached that will facilitate a Phase-II study of deterministic effects among Mayak workers. These conclusions include the following: (1) neutron doses may be more important for Mayak workers than for Japanese A-bomb victims in Hiroshima and can be accounted for using an adjusted dose (which accounts for neutron relative biological effectiveness); (2) to account for dose-rate effects, normalized dose X (a dimensionless fraction of an LD50 or ED50) can be evaluated in terms of an adjusted dose; (3) nonlinear dose-response curves for the risk of death via the hematopoietic mode can be converted to linear dose-response curves (for low levels of risk) using a newly proposed dimensionless dose, D = X(V), in units of Oklad (where D is pronounced "deh"), and V is the shape parameter in the Weibull model; (4) for X < or = Xo, where Xo is the threshold normalized dose, D = 0; (5) unlike absorbed dose, the dose D can be averaged over different Mayak workers in order to calculate the average risk of death via the hematopoietic mode for the population exposed at Site A

  14. [Accidental hanging during auto-erotic practices].

    PubMed

    Vieira, D N; da Silva, A G

    1989-01-01

    An unusual case of accidental hanging during autoerotic practices in a 25-year-old male student is described and the autoerotic asphyxia syndrome briefly discussed. The authors stressed the importance of a correct diagnostic of accidental death in these cases.

  15. Radiation-induced genomic instability and its implications for radiation carcinogenesis

    NASA Technical Reports Server (NTRS)

    Huang, Lei; Snyder, Andrew R.; Morgan, William F.

    2003-01-01

    Radiation-induced genomic instability is characterized by an increased rate of genetic alterations including cytogenetic rearrangements, mutations, gene amplifications, transformation and cell death in the progeny of irradiated cells multiple generations after the initial insult. Chromosomal rearrangements are the best-characterized end point of radiation-induced genomic instability, and many of the rearrangements described are similar to those found in human cancers. Chromosome breakage syndromes are defined by chromosome instability, and individuals with these diseases are cancer prone. Consequently, chromosomal instability as a phenotype may underlie some fraction of those changes leading to cancer. Here we attempt to relate current knowledge regarding radiation-induced chromosome instability with the emerging molecular information on the chromosome breakage syndromes. The goal is to understand how genetic and epigenetic factors might influence the onset of chromosome instability and the role of chromosomal instability in carcinogenesis.

  16. Reducing Toxicity of Radiation Treatment of Advanced Prostate Cancer

    DTIC Science & Technology

    2015-10-01

    steady state hematopoiesis with normalization of the frequency of hematopoietic stem and progenitor cells. Moreover, hematopoietic stem cells from RTA...ongoing. 7 KEY RESEARCH ACCOMPLISHMENTS: • Identified radiation protection of different organ systems (GI tract, skin and hematopoiesis ) by RTA

  17. Failure of hepatocyte marker-expressing hematopoietic progenitor cells to efficiently convert into hepatocytes in vitro.

    PubMed

    Lian, Gewei; Wang, Chengyan; Teng, Chunbo; Zhang, Cong; Du, Liying; Zhong, Qian; Miao, Chenglin; Ding, Mingxiao; Deng, Hongkui

    2006-03-01

    Whether bone marrow (BM) hematopoietic stem/progenitor cells can directly differentiate into nonhematopoietic cells remains controversial. The aim of this study is to further investigate the potentiality of BM hematopoietic progenitor cells to convert into hepatocytes in vitro. Different subsets of BM cells from C57/BL6 mice were isolated using markers of hematopoietic stem cells by magnetic cell sorting and by flow cytometry. These cells were induced to transdifferentiate to hepatocytes in vitro in the presence of various cytokines or of hepatocytes (or tissue) from damaged liver, which have been reported to stimulate the conversion. Hepatic gene markers in freshly isolated or cultured BM cells were determined by reverse transcriptase polymerase chain reaction and immunofluorescence. Freshly isolated hematopoietic progenitor cells (HPC) expressed a low level of messenger RNAs of hepatic cell-specific markers including albumin and alpha-fetoprotein (AFP), but did not significantly upregulate expression of these markers, even in the presence of cytokines or cocultured hepatocytes (or tissue). HPCs induced in vitro did not express the message of alpha-anti-trypsin-a mature hepatocyte marker. At protein level, the specific staining of AFP was not detected in the HPCs, either freshly isolated or in vitro induced. Albumin protein was detected in freshly isolated albumin mRNA-positive and -negative BM cell subpopulations. Albumin-stained BM cells disappeared after being induced for 5 days, but restained if mouse serum was supplemented in medium for a 24-hour extended culture, suggesting that albumin was absorbed by BM cells instead of de novo expression. HPCs expressed mRNAs of hepatic cell markers, but could not efficiently convert into hepatocytes in vitro under our experimental conditions. Our observation raises a cautionary note in determining whether in vitro transdifferentiation of BM cells to hepatocytes can actually take place.

  18. Safety and efficacy of intravenous administration for tranexamic acid-induced emesis in dogs with accidental ingestion of foreign substances.

    PubMed

    Orito, Kensuke; Kawarai-Shimamura, Asako; Ogawa, Atsushi; Nakamura, Atsushi

    2017-12-22

    A prospective observational study was performed in canine clinical medicine to evaluate the emetic action and adverse effects of tranexamic acid. Veterinarians treated 137 dogs with a single dose of tranexamic acid (50 mg/kg, IV) after accidental ingestion of foreign substances. If needed, a second (median, 50 mg/kg; range, 20-50 mg/kg, IV) or third dose (median, 50 mg/kg; range, 25-50 mg/kg, IV) was administered. Tranexamic acid induced emesis in 116 of 137 (84.7%) dogs. Median time to onset of emesis was 116.5 sec (range, 26-370 sec), median duration of emesis was 151.5 sec (range, 30-780 sec), and median number of emesis episodes was 2 (range, 1-8). Second and third administrations of tranexamic acid induced emesis in 64.7 and 66.7% of dogs, respectively. In total, IV administration of tranexamic acid successfully induced emesis in 129 of 137 (94.2%) dogs. Adverse effects included a tonic-clonic convulsion and hemostatic disorder in two different dogs, both of which recovered after receiving medical care. Tranexamic acid induced emesis in most dogs following a single-dose. When a single dose was not sufficient, an additional dosage effectively induced emesis. Overall, adverse effects were considered low and self-limiting.

  19. Radar detection of radiation-induced ionization in air

    DOEpatents

    Gopalsami, Nachappa; Heifetz, Alexander; Chien, Hual-Te; Liao, Shaolin; Koehl, Eugene R.; Raptis, Apostolos C.

    2015-07-21

    A millimeter wave measurement system has been developed for remote detection of airborne nuclear radiation, based on electromagnetic scattering from radiation-induced ionization in air. Specifically, methods of monitoring radiation-induced ionization of air have been investigated, and the ionized air has been identified as a source of millimeter wave radar reflection, which can be utilized to determine the size and strength of a radiation source.

  20. BMS 493 Modulates Retinoic Acid-Induced Differentiation During Expansion of Human Hematopoietic Progenitor Cells for Islet Regeneration.

    PubMed

    Elgamal, Ruth M; Bell, Gillian I; Krause, Sarah C T; Hess, David A

    2018-06-06

    Cellular therapies are emerging as a novel treatment strategy for diabetes. Thus, the induction of endogenous islet regeneration in situ represents a feasible goal for diabetes therapy. Umbilical cord blood-derived hematopoietic progenitor cells (HPCs), isolated by high aldehyde dehydrogenase activity (ALDH hi ), have previously been shown to reduce hyperglycemia after intrapancreatic (iPan) transplantation into streptozotocin (STZ)-treated nonobese diabetic (NOD)/severe combined immunodeficiency (SCID) mice. However, these cells are rare and require ex vivo expansion to reach clinically applicable numbers for human therapy. Therefore, we investigated whether BMS 493, an inverse retinoic acid receptor agonist, could prevent retinoic acid-induced differentiation and preserve islet regenerative functions during expansion. After 6-day expansion, BMS 493-treated cells showed a twofold increase in the number of ALDH hi cells available for transplantation compared with untreated controls. Newly expanded ALDH hi cells showed increased numbers of CD34 and CD133-positive cells, as well as a reduction in CD38 expression, a marker of hematopoietic cell differentiation. BMS 493-treated cells showed similar hematopoietic colony-forming capacity compared with untreated cells, with ALDH hi subpopulations producing more colonies than low aldehyde dehydrogenase activity subpopulations for expanded cells. To determine if the secreted proteins of these cells could augment the survival and/or proliferation of β-cells in vitro, conditioned media (CM) from cells expanded with or without BMS 493 was added to human islet cultures. The total number of proliferating β-cells was increased after 3- or 7-day culture with CM generated from BMS 493-treated cells. In contrast to freshly isolated ALDH hi cells, 6-day expansion with or without BMS 493 generated progeny that were unable to reduce hyperglycemia after iPan transplantation into STZ-treated NOD/SCID mice. Further strategies to reduce

  1. Accidental poisoning with deadly nightshade berries: a case report.

    PubMed

    Trabattoni, G; Visintini, D; Terzano, G M; Lechi, A

    1984-12-01

    A case of acute accidental poisoning with deadly nightshade (Atropa belladonna) berries is reported. The patient was an elderly but healthy man who soon recovered. On the one hand, the clinical picture looked similar to that of delirium tremens; on the other, there were myoclonic jerks and signs of extrapyramidal involvement to suggest the onset of subacute dementia. The electroencephalogram findings confirmed those already reported during experimentally induced intoxication after ingestion of atropine in man.

  2. [THREE CASES OF ACCIDENTAL AUTO-INJECTION OF ADRENALINE].

    PubMed

    Yanagida, Noriyuki; Iikura, Katsuhito; Ogura, Kiyotake; Wang, Ling-jen; Asaumi, Tomoyuki; Sato, Sakura; Ebisawa, Motohiro

    2015-12-01

    Reports on accidental auto-injection of adrenaline are few. We encountered three cases of accidental injection of adrenaline. In this study, we have examined and reported the clinical courses and symptoms of our cases. CASE 1 involved a female physician in her 50s who had attended an explanatory meeting on auto-injection of adrenaline. She mistook EpiPen® to be the EpiPen trainer and accidentally injected herself with 0.3 mg EpiPen®. Her systolic/diastolic pressure peaked at 7 min to reach 144/78 mmHg and decreased to 120/77 mmHg at 14 min. Except for palpitation after 7 min, the only subjective symptom was local pain at the injection site. CASE 2 was noted in a 6-year-old boy. He accidentally pierced his right forefinger with 0.15 mg EpiPen®, and after 20 min, his right forefinger was swollen. The swelling improved 80 min after the accidental injection. CASE 3 was noted in a 4-year-old girl. She accidentally injected herself with 0.15 mg EpiPen®. Her systolic/diastolic pressure peaked at 23 min to reach 123/70 mmHg and decreased to 96/86 mmHg at 28 min. Severe adverse effects of accidental auto-injection of adrenaline were not observed in these three cases. Our findings suggest that while handling adrenaline auto-injectors, we should keep in mind the possibility of accidental injection.

  3. Pyruvate metabolism: A therapeutic opportunity in radiation-induced skin injury

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Yoo, Hyun; Kang, Jeong Wook; Lee, Dong Won

    Ionizing radiation is used to treat a range of cancers. Despite recent technological progress, radiation therapy can damage the skin at the administration site. The specific molecular mechanisms involved in this effect have not been fully characterized. In this study, the effects of pyruvate, on radiation-induced skin injury were investigated, including the role of the pyruvate dehydrogenase kinase 2 (PDK2) signaling pathway. Next generation sequencing (NGS) identified a wide range of gene expression differences between the control and irradiated mice, including reduced expression of PDK2. This was confirmed using Q-PCR. Cell culture studies demonstrated that PDK2 overexpression and a highmore » cellular pyruvate concentration inhibited radiation-induced cytokine expression. Immunohistochemical studies demonstrated radiation-induced skin thickening and gene expression changes. Oral pyruvate treatment markedly downregulated radiation-induced changes in skin thickness and inflammatory cytokine expression. These findings indicated that regulation of the pyruvate metabolic pathway could provide an effective approach to the control of radiation-induced skin damage. - Highlights: • The effects of radiation on skin thickness in mice. • Next generation sequencing revealed that radiation inhibited pyruvate dehydrogenase kinase 2 expression. • PDK2 inhibited irradiation-induced cytokine gene expression. • Oral pyruvate treatment markedly downregulated radiation-induced changes in skin thickness.« less

  4. Evaluation of hematopoietic potential generated by transplantation of muscle-derived stem cells in mice.

    PubMed

    Farace, Francoise; Prestoz, Laetitita; Badaoui, Sabrina; Guillier, Martine; Haond, Celine; Opolon, Paule; Thomas, Jean-Leon; Zalc, Bernard; Vainchenker, William; Turhan, Ali G

    2004-02-01

    Muscle tissue of adult mice has been shown to contain stem cells with hematopoietic repopulation ability in vivo. To determine the functional characteristics of stem cells giving rise to this hematopoietic activity, we have performed hematopoietic reconstitution experiments by the use of muscle versus marrow transplantation in lethally irradiated mice and followed the fate of transplanted cells by Y-chimerism using PCR and fluorescence in situ hybridization (FISH) analysis. We report here that transplantation of murine muscle generate a major hematopoietic chimerism at the level of CFU-C, CFU-S, and terminally-differentiated cells in three generations of lethally irradiated mice followed up to 1 year after transplantation. This potential is totally abolished when muscle grafts were performed by the use of muscle from previously irradiated mice. As compared to marrow transplantation, muscle transplants were able to generate similar potencies to give rise to myeloid, T, B, and natural killer (NK) cells. Interestingly, marrow stem cells that have been generated in primary and then in secondary recipients were able to contribute efficiently to myofibers in the muscle tissue of tertiary recipients. Altogether, our data demonstrate that muscle-derived stem cells present a major hematopoietic repopulating ability with evidence of self-replication in vivo. They are radiation-sensitive and similar to marrow-derived stem cells in terms of their ability to generate multilineage hematopoiesis. Finally, our data demonstrate that muscle-derived hematopoietic stem cells do not lose their ability to contribute to myofiber generation after at least two rounds of serial transplantation, suggesting a potential that is probably equivalent to that generated by marrow transplantation.

  5. Evaluation of γ-radiation-induced DNA damage in two species of bivalves and their relative sensitivity using comet assay.

    PubMed

    Praveen Kumar, M K; Shyama, S K; Sonaye, B S; Naik, U Roshini; Kadam, S B; Bipin, P D; D'costa, A; Chaubey, R C

    2014-05-01

    Ionizing radiation is known to induce genetic damage in diverse groups of organisms. Under accidental situations, large quantities of radioactive elements get released into the environment and radiation emitted from these radionuclides may adversely affect both the man and the non-human biota. The present study is aimed (a) to know the genotoxic effect of gamma radiation on aquatic fauna employing two species of selected bivalves, (b) to evaluate the possible use of 'Comet assay' for detecting genetic damage in haemocytes of bivalves as a biomarker for environmental biomonitoring and also (c) to compare the relative sensitivity of two species of bivalves viz. Paphia malabarica and Meretrix casta to gamma radiation. The comet assays was optimized and validated using different concentrations (18, 32 and 56 mg/L) of ethyl methanesulfonate (EMS), a direct-acting reference genotoxic agent, to which the bivalves were exposed for various times (24, 48 and 72 h). Bivalves were irradiated (single acute exposure) with 5 different doses (viz. 2, 4, 6, 8 and 10 Gy) of gamma radiation and their genotoxic effects on the haemocytes were studied using the comet assay. Haemolymph was collected from the adductor muscle at 24, 48 and 72 h of both EMS-exposed and irradiated bivalves and comet assay was carried out using standard protocol. A significant increase in DNA damage was observed as indicated by an increase in % tail DNA damage at different concentrations of EMS and all the doses of gamma radiation as compared to controls in both bivalve species. This showed a dose-dependent increase of genetic damage induced in bivalves by EMS as well as gamma radiation. Further, the highest DNA damage was observed at 24h. The damage gradually decreased with time, i.e. was smaller at 48 and 72 h than at 24h post irradiation in both species of bivalves. This may indicate repair of the damaged DNA and/or loss of heavily damaged cells as the post irradiation time advanced. The present study

  6. Modulation of Radiation-Induced Apoptosis by Thiolamines

    NASA Technical Reports Server (NTRS)

    Warters, R. L.; Roberts, J. C.; Wilmore, B. H.; Kelley, L. L.

    1997-01-01

    Exposure to the thiolamine radioprotector N-(2-mercaptoethyl)-1,3-propanediamine (WR-1065) induced apoptosis in the mouse TB8-3 hybridoma after 60-minute (LD(sub50) = 4.5mM) or during a 20-hour (LD(sub50) = 0.15 mM) exposure. In contrast, a 20-hour exposure to 17 mM L-cysteine or 10 mM cysteamine was required to induce 50 percent apoptosis within 20 hours. Apoptosis was not induced by either a 60-minute or 20-hour exposure to 10 mM of the thiazolidime prodrugs ribose-cysteine (RibCys) or ribose-cysteamine (RibCyst). Thiolamine-induced apoptosis appeared to be a p53-independent process since it was induced by WR-1065 exposure in human HL60 cells. Exposure to WR-1065 (4mM for 15 minutes) or cysteine (10mM for 60 minutes) before and during irradiation protected cells against the induction of both DNA double-strand breaks and apoptosis, while exposure to RibCys (10 mM for 3 hours) did not. Treatment with either WR-1065, cysteine, RibCys or RibCyst for 60 minutes beginning 60 minutes after irradiation did not affect the level of radiation-induced apoptosis. In contrast, treatment with either cysteine, cysteamine or RibCys for 20 hours beginning 60 minutes after irradiation enhanced radiation-induced apoptosis. Similar experiments could not be conducted with WR-1065 because of its extreme toxicity. Our results indicate that thiolamine enhancement of radiation-induced apoptosis is not involved in their previously reported capacity to reduce radiation-induced mutations.

  7. The Effects of Hematopoietic Growth Factors on Neurite Outgrowth

    PubMed Central

    Su, Ye; Cui, Lili; Piao, Chunshu; Li, Bin; Zhao, Li-Ru

    2013-01-01

    Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) are initially discovered as the essential hematopoietic growth factors regulating bone marrow stem cell proliferation and differentiation, and SCF in combination with G-CSF (SCF+G-CSF) has synergistic effects on bone marrow stem cell mobilization. In this study we have determined the effect of SCF and G-CSF on neurite outgrowth in rat cortical neurons. Using molecular and cellular biology and live cell imaging approaches, we have revealed that receptors for SCF and G-CSF are expressed on the growth core of cortical neurons, and that SCF+G-CSF synergistically enhances neurite extension through PI3K/AKT and NFκB signaling pathways. Moreover, SCF+G-CSF induces much greater NFκB activation, NFκB transcriptional binding and brain-derived neurotrophic factor (BDNF) production than SCF or G-CSF alone. In addition, we have also observed that BDNF, the target gene of NFκB, is required for SCF+G-CSF-induced neurite outgrowth. These data suggest that SCF+G-CSF has synergistic effects to promote neurite growth. This study provides new insights into the contribution of hematopoietic growth factors in neuronal plasticity. PMID:24116056

  8. Apatinib in refractory radiation-induced brain edema

    PubMed Central

    Hu, Wei Guo; Weng, Yi Ming; Dong, Yi; Li, Xiang Pan; Song, Qi-Bin

    2017-01-01

    Abstract Rationale: Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, which has observed to be effective and safe in refractory radiation-induced brain edema, like Avastin did. Till now, there is no case report after apatinib came in the market. Patient concerns: Two patients who received brain radiotherapy developed clinical manifestations of brain edema, including dizziness, headache, limb activity disorder, and so on. Diagnoses: Two patients were both diagnosed as refractory radiation-induced brain edema. Interventions: Two patients received apatinib (500 mg/day) for 2 and 4 weeks. Outcomes: Two patients got symptomatic improvements from apatinib in different degrees. Magnetic resonance imaging after apatinib treatments showed that compared with pre-treatment imaging, the perilesional edema reduced dramatically. However, the toxicity of apatinib was controllable and tolerable. Lessons: Apatinib can obviously relieve the symptoms of refractory radiation-induced brain edema and improve the quality of life, which offers a new method for refractory radiation-induced brain edema in clinical practices. But that still warrants further investigation in the prospective study. PMID:29145238

  9. Radiation-induced sarcoma of the thyroid

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Griem, K.L.; Robb, P.K.; Caldarelli, D.D.

    1989-08-01

    A 23-year-old white man presented with a thyroid mass 12 years after receiving high-dose radiotherapy for a T2 and N1 lymphoepithelioma of the nasopharynx. Following subtotal thyroidectomy, a histopathologic examination revealed liposarcoma of the thyroid gland. The relationship between sarcomas and irradiation is described and Cahan and colleagues' criteria for radiation-induced sarcomas are reviewed. To our knowledge, we are presenting the first such case of a radiation-induced sarcoma of the thyroid gland.

  10. Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression.

    PubMed

    Guo, Peipei; Poulos, Michael G; Palikuqi, Brisa; Badwe, Chaitanya R; Lis, Raphael; Kunar, Balvir; Ding, Bi-Sen; Rabbany, Sina Y; Shido, Koji; Butler, Jason M; Rafii, Shahin

    2017-12-01

    Angiocrine factors, such as Notch ligands, supplied by the specialized endothelial cells (ECs) within the bone marrow and splenic vascular niche play an essential role in modulating the physiology of adult hematopoietic stem and progenitor cells (HSPCs). However, the relative contribution of various Notch ligands, specifically jagged-2, to the homeostasis of HSPCs is unknown. Here, we show that under steady state, jagged-2 is differentially expressed in tissue-specific vascular beds, but its expression is induced in hematopoietic vascular niches after myelosuppressive injury. We used mice with EC-specific deletion of the gene encoding jagged-2 (Jag2) to demonstrate that while EC-derived jagged-2 was dispensable for maintaining the capacity of HSPCs to repopulate under steady-state conditions, by activating Notch2 it did contribute to the recovery of HSPCs in response to myelosuppressive conditions. Engraftment and/or expansion of HSPCs was dependent on the expression of endothelial-derived jagged-2 following myeloablation. Additionally, jagged-2 expressed in bone marrow ECs regulated HSPC cell cycle and quiescence during regeneration. Endothelial-deployed jagged-2 triggered Notch2/Hey1, while tempering Notch2/Hes1 signaling in HSPCs. Collectively, these data demonstrate that EC-derived jagged-2 activates Notch2 signaling in HSPCs to promote hematopoietic recovery and has potential as a therapeutic target to accelerate balanced hematopoietic reconstitution after myelosuppression.

  11. Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression

    PubMed Central

    Guo, Peipei; Poulos, Michael G.; Palikuqi, Brisa; Badwe, Chaitanya R.; Lis, Raphael; Kunar, Balvir; Ding, Bi-Sen; Rabbany, Sina Y.; Butler, Jason M.

    2017-01-01

    Angiocrine factors, such as Notch ligands, supplied by the specialized endothelial cells (ECs) within the bone marrow and splenic vascular niche play an essential role in modulating the physiology of adult hematopoietic stem and progenitor cells (HSPCs). However, the relative contribution of various Notch ligands, specifically jagged-2, to the homeostasis of HSPCs is unknown. Here, we show that under steady state, jagged-2 is differentially expressed in tissue-specific vascular beds, but its expression is induced in hematopoietic vascular niches after myelosuppressive injury. We used mice with EC-specific deletion of the gene encoding jagged-2 (Jag2) to demonstrate that while EC-derived jagged-2 was dispensable for maintaining the capacity of HSPCs to repopulate under steady-state conditions, by activating Notch2 it did contribute to the recovery of HSPCs in response to myelosuppressive conditions. Engraftment and/or expansion of HSPCs was dependent on the expression of endothelial-derived jagged-2 following myeloablation. Additionally, jagged-2 expressed in bone marrow ECs regulated HSPC cell cycle and quiescence during regeneration. Endothelial-deployed jagged-2 triggered Notch2/Hey1, while tempering Notch2/Hes1 signaling in HSPCs. Collectively, these data demonstrate that EC-derived jagged-2 activates Notch2 signaling in HSPCs to promote hematopoietic recovery and has potential as a therapeutic target to accelerate balanced hematopoietic reconstitution after myelosuppression. PMID:29058691

  12. Acute radiation risk models

    NASA Astrophysics Data System (ADS)

    Smirnova, Olga

    Biologically motivated mathematical models, which describe the dynamics of the major hematopoietic lineages (the thrombocytopoietic, lymphocytopoietic, granulocytopoietic, and erythropoietic systems) in acutely/chronically irradiated humans are developed. These models are implemented as systems of nonlinear differential equations, which variables and constant parameters have clear biological meaning. It is shown that the developed models are capable of reproducing clinical data on the dynamics of these systems in humans exposed to acute radiation in the result of incidents and accidents, as well as in humans exposed to low-level chronic radiation. Moreover, the averaged value of the "lethal" dose rates of chronic irradiation evaluated within models of these four major hematopoietic lineages coincides with the real minimal dose rate of lethal chronic irradiation. The demonstrated ability of the models of the human thrombocytopoietic, lymphocytopoietic, granulocytopoietic, and erythropoietic systems to predict the dynamical response of these systems to acute/chronic irradiation in wide ranges of doses and dose rates implies that these mathematical models form an universal tool for the investigation and prediction of the dynamics of the major human hematopoietic lineages for a vast pattern of irradiation scenarios. In particular, these models could be applied for the radiation risk assessment for health of astronauts exposed to space radiation during long-term space missions, such as voyages to Mars or Lunar colonies, as well as for health of people exposed to acute/chronic irradiation due to environmental radiological events.

  13. Principals Of Radiation Toxicology: Important Aspects.

    NASA Astrophysics Data System (ADS)

    Popov, Dmitri; Maliev, Slava; Jones, Jeffrey

    “All things are poison, and nothing is without poison; only the dose permits something not to be poisonous.” Paracelsus Key Words: Radiation Toxins (RT), Radiation Toxicants (RTc), Radiation Poisons (RP), Radiation Exposure (RE), Radiation Toxicology is the science about radiation poisons. [D.Popov et al. 2012,J.Zhou et al. 2007,] Radiation Toxins is a specific proteins with high enzymatic activity produced by living irradiated mammals. [D.Popov et al. 2012,] Radiation Toxicants is a substances that produce radiomimetics effects, adverse biological effects which specific for radiation. [D.Popov et al. 2012,] Radiation Toxic agent is specific proteins that can produce pathological biological effects specific for physical form of radiation.[D.Popov et al. 1990,2012,V. Maliev 2007] Different Toxic Substances isolated from cells or from blood or lymph circulation. [Kudriashov I. et al. 1970, D.Popov et al. 1990,2012,V. Maliev et al. 2007,] Radiation Toxins may affects many organs or specific organ, tissue, specific group of cells. [Kudriashov I. et al. 1970, D.Popov et al. 1990,2012,V. Maliev et al. 2007] For example: Radiation Toxins could induce collective toxic clinical states to include: systemic inflammatory response syndrome (SIRS),toxic multiple organ injury (TMOI), toxic multiple organ dysfunction syndromes (TMODS),and finally, toxic multiple organ failure (TMOF). [T. Azizova et al. 2005, Konchalovsky et al., 2005, D. Popov et al 2012] However, Radiation Toxins could induce specific injury of organs or tissue and induce Acute Radiation Syndromes such as Acute Radiation Cerebrovascular Syndrome, Acute Radiation Cardiovascular Syndrome, Acute Radiation Hematopoietic Syndrome, Acute Radiation GastroIntestinal Syndrome. [ D.Popov et al. 1990, 2012, V. Maliev et al. 2007] Radiation Toxins correlates with Radiation Exposure and the dose-response relationship is a fundamental and essential concept in classic Toxicology and Radiation Toxicology.[ D.Popov et al

  14. The characterization and evaluation of accidental explosions

    NASA Technical Reports Server (NTRS)

    Strehlow, R. A.; Baker, W. E.

    1975-01-01

    Accidental explosions are discussed from a number of viewpoints. First, all accidental explosions, intentional explosions and natural explosions are characterized by type. Second, the nature of the blast wave produced by an ideal (point source or HE) explosion is discussed to form a basis for describing how other explosion processes yield deviations from ideal blast wave behavior. The current status blast damage mechanism evaluation is also discussed. Third, the current status of our understanding of each different category of accidental explosions is discussed in some detail.

  15. HEMATOPOIETIC STEM CELL INFUSION/TRANSPLANTATION FOR INDUCTION OF ALLOGRAFT TOLERANCE

    PubMed Central

    Granados, Jose M. Marino; Benichou, Gilles; Kawai, Tatsuo

    2015-01-01

    Purpose of review This review updates the current status of basic, preclinical, and clinical research on donor hematopoietic stem cell infusion for allograft tolerance induction. Recent findings Recent basic studies in mice provide evidence of significant involvement of both central deletional and peripheral regulatory mechanisms in induction and maintenance of allograft tolerance effected through a mixed chimerism approach with donor hematopoietic stem cell infusion. The presence of heterologous memory T cells in primates hampers the induction of persistent chimerism. Durable mixed chimerism, however, now has been recently induced in inbred major histocompatibility complex-mismatched swine, resulting in tolerance of vascularized composite tissue allografts. In clinical transplantation, allograft tolerance has been achieved in human leukocyte antigen-mismatched kidney transplantation after the induction of transient mixed chimerism or persistent full donor chimerism. Summary Tolerance induction in clinical kidney transplantation has been achieved by donor hematopoietic stem cell infusion. Improving the consistency and safety of tolerance induction and extending successful protocols to other organs, as well as to organs from deceased donors, are critical next steps to bringing tolerance to a wider range of clinical applications. PMID:25563992

  16. Dose-independent confusion induced by voriconazole in a patient with Asian ancestry after allogeneic hematopoietic stem cell transplant.

    PubMed

    Hui, John

    2016-02-01

    This is the case of a 71-year-old man with Asian ancestry who had myelodysplastic syndrome admitted for allogeneic hematopoietic stem cell transplant. This case suggests that voriconazole-induced confusion is probably dose-independent and reversible with no residual symptoms after discontinuation of voriconazole. Patient can experience confusion even voriconazole is ordered according to package insert and serum voriconazole level is within therapeutic range (1-6 µg/mL). The onset of confusion can be delayed and sudden after seven days of voriconazole therapy. Genotyping of CYP2C19 can be tested for Asian populations since 15-20% of them could be poor metabolizers of voriconazole. © The Author(s) 2014.

  17. Cord blood-derived CD34+ hematopoietic cells with low mitochondrial mass are enriched in hematopoietic repopulating stem cell function.

    PubMed

    Romero-Moya, Damia; Bueno, Clara; Montes, Rosa; Navarro-Montero, Oscar; Iborra, Francisco J; López, Luis Carlos; Martin, Miguel; Menendez, Pablo

    2013-07-01

    The homeostasis of the hematopoietic stem/progenitor cell pool relies on a fine-tuned balance between self-renewal, differentiation and proliferation. Recent studies have proposed that mitochondria regulate these processes. Although recent work has contributed to understanding the role of mitochondria during stem cell differentiation, it remains unclear whether the mitochondrial content/function affects human hematopoietic stem versus progenitor function. We found that mitochondrial mass correlates strongly with mitochondrial membrane potential in CD34(+) hematopoietic stem/progenitor cells. We, therefore, sorted cord blood CD34(+) cells on the basis of their mitochondrial mass and analyzed the in vitro homeostasis and clonogenic potential as well as the in vivo repopulating potential of CD34(+) cells with high (CD34(+) Mito(High)) versus low (CD34(+) Mito(Low)) mitochondrial mass. The CD34(+) Mito(Low) fraction contained 6-fold more CD34(+)CD38(-) primitive cells and was enriched in hematopoietic stem cell function, as demonstrated by its significantly greater hematopoietic reconstitution potential in immuno-deficient mice. In contrast, the CD34(+) Mito(High) fraction was more enriched in hematopoietic progenitor function with higher in vitro clonogenic capacity. In vitro differentiation of CD34(+) Mito(Low) cells was significantly delayed as compared to that of CD34(+) Mito(High) cells. The eventual complete differentiation of CD34(+) Mito(Low) cells, which coincided with a robust expansion of the CD34(-) differentiated progeny, was accompanied by mitochondrial adaptation, as shown by significant increases in ATP production and expression of the mitochondrial genes ND1 and COX2. In conclusion, cord blood CD34(+) cells with low levels of mitochondrial mass are enriched in hematopoietic repopulating stem cell function whereas high levels of mitochondrial mass identify hematopoietic progenitors. A mitochondrial response underlies hematopoietic stem/progenitor cell

  18. Safety and efficacy of intravenous administration for tranexamic acid-induced emesis in dogs with accidental ingestion of foreign substances

    PubMed Central

    ORITO, Kensuke; KAWARAI-SHIMAMURA, Asako; OGAWA, Atsushi; NAKAMURA, Atsushi

    2017-01-01

    A prospective observational study was performed in canine clinical medicine to evaluate the emetic action and adverse effects of tranexamic acid. Veterinarians treated 137 dogs with a single dose of tranexamic acid (50 mg/kg, IV) after accidental ingestion of foreign substances. If needed, a second (median, 50 mg/kg; range, 20–50 mg/kg, IV) or third dose (median, 50 mg/kg; range, 25–50 mg/kg, IV) was administered. Tranexamic acid induced emesis in 116 of 137 (84.7%) dogs. Median time to onset of emesis was 116.5 sec (range, 26–370 sec), median duration of emesis was 151.5 sec (range, 30–780 sec), and median number of emesis episodes was 2 (range, 1–8). Second and third administrations of tranexamic acid induced emesis in 64.7 and 66.7% of dogs, respectively. In total, IV administration of tranexamic acid successfully induced emesis in 129 of 137 (94.2%) dogs. Adverse effects included a tonic-clonic convulsion and hemostatic disorder in two different dogs, both of which recovered after receiving medical care. Tranexamic acid induced emesis in most dogs following a single-dose. When a single dose was not sufficient, an additional dosage effectively induced emesis. Overall, adverse effects were considered low and self-limiting. PMID:29093310

  19. Radiation-Induced Second Cancer Risk Estimates From Radionuclide Therapy

    NASA Astrophysics Data System (ADS)

    Bednarz, Bryan; Besemer, Abigail

    2017-09-01

    The use of radionuclide therapy in the clinical setting is expected to increase significantly over the next decade. There is an important need to understand the radiation-induced second cancer risk associated with these procedures. In this study the radiation-induced cancer risk in five radionuclide therapy patients was investigated. These patients underwent serial SPECT imaging scans following injection as part of a clinical trial testing the efficacy of a 131Iodine-labeled radiopharmaceutical. Using these datasets the committed absorbed doses to multiple sensitive structures were calculated using RAPID, which is a novel Monte Carlo-based 3D dosimetry platform developed for personalized dosimetry. The excess relative risk (ERR) for radiation-induced cancer in these structures was then derived from these dose estimates following the recommendations set forth in the BEIR VII report. The radiation-induced leukemia ERR was highest among all sites considered reaching a maximum value of approximately 4.5. The radiation-induced cancer risk in the kidneys, liver and spleen ranged between 0.3 and 1.3. The lifetime attributable risks (LARs) were also calculated, which ranged from 30 to 1700 cancers per 100,000 persons and were highest for leukemia and the liver for both males and females followed by radiation-induced spleen and kidney cancer. The risks associated with radionuclide therapy are similar to the risk associated with external beam radiation therapy.

  20. Protection from radiation-induced pneumonitis using cerium oxide nanoparticles.

    PubMed

    Colon, Jimmie; Herrera, Luis; Smith, Joshua; Patil, Swanand; Komanski, Chris; Kupelian, Patrick; Seal, Sudipta; Jenkins, D Wayne; Baker, Cheryl H

    2009-06-01

    In an effort to combat the harmful effects of radiation exposure, we propose that rare-earth cerium oxide (CeO(2)) nanoparticles (free-radical scavengers) protect normal tissue from radiation-induced damage. Preliminary studies suggest that these nanoparticles may be a therapeutic regenerative nanomedicine that will scavenge reactive oxygen species, which are responsible for radiation-induced cell damage. The effectiveness of CeO(2) nanoparticles in radiation protection in murine models during high-dose radiation exposure is investigated, with the ultimate goal of offering a new approach to radiation protection, using nanotechnology. We show that CeO(2) nanoparticles are well tolerated by live animals, and they prevent the onset of radiation-induced pneumonitis when delivered to live animals exposed to high doses of radiation. In the end, these studies provide a tremendous potential for radioprotection and can lead to significant benefits for the preservation of human health and the quality of life for humans receiving radiation therapy.

  1. Seabuckthron (Hippophae rhamnoides L.) leaf extract ameliorates the gamma radiation mediated DNA damage and hepatic alterations.

    PubMed

    Khan, Amitava; Manna, Krishnendu; Chinchubose; Das, Dipesh Kr; Sinha, Mahuya; Kesh, Swaraj Bandhu; Das, Ujjal; Dey, Rakhi Sharma; Banerji, Asoke; Dey, Sanjit

    2014-10-01

    In vitro assessment showed that H. rhamnoides (HrLE) extract possessed free radical scavenging activities and can protect gamma (gamma) radiation induced supercoiled DNA damage. For in vivo study, Swiss albino mice were administered with HrLE (30 mg/kg body weight) for 15 consecutive days before exposing them to a single dose of 5 Gy of beta radiation. HrLE significantly prevented the radiation induced genomic DNA damage indicated as a significant reduction in the comet parameters. The lipid peroxidation, liver function enzymes, expression of phosphorylated NFkappaB (p65) and IkappaBalpha increased whereas the endogenous antioxidants diminished upon radiation exposure compared to control. Pretreatment of HrLE extract ameliorated these changes. Based on the present results it can be concluded that H. rhamnoides possess a potential preventive element in planned and accidental nuclear exposures.

  2. Chromosome aberrations induced by high-LET radiations

    NASA Technical Reports Server (NTRS)

    Kawata, Tetsuya; Ito, Hisao; George, Kerry; Wu, Honglu; Cucinotta, Francis A.

    2004-01-01

    Measurements of chromosome aberrations in peripheral blood lymphocytes are currently the most sensitive and reliable indicator of radiation exposure that can be used for biological dosimetry. This technique has been implemented recently to study radiation exposures incurred by astronauts during space flight, where a significant proportion of the dose is delivered by high-LET particle exposure. Traditional methods for the assessing of cytogenetic damage in mitotic cells collected at one time point after exposure may not be suitable for measuring high-LET radiation effects due to the drastic cell cycle perturbations and interphase cell death induced by this type of exposure. In this manuscript we review the recent advances in methodology used to study high-LET induced cytogenetic effects and evaluate the use of chemically-induced Premature Chromosome Condensation (PCC) as an alternative to metaphase analysis. Published data on the cytogenetic effects of in vitro exposures of high-LET radiation is reviewed, along with biodosimetry results from astronauts after short or long space missions.

  3. Gemcitabine-induced rectus abdominus radiation recall.

    PubMed

    Fakih, Marwan G

    2006-05-09

    Radiation recall has been described in the context of gemcitabine chemotherapy. However, this phenomenon has been largely limited to skin. We hereby report a case of radiation recall dermatitis and myositis occurring on gemcitabine monotherapy, five months after completing chemoradiation for locally advanced pancreatic cancer. Radiation recall resolved spontaneously with withdrawal of gemcitabine. This is the second case report that describes gemcitabine-induced radiation recall in rectus abdominus muscles after gemcitabine-based radiation therapy. Given the wide use of gemcitabine following chemoradiation for pancreatic cancer, providers should be aware of this potential complication.

  4. Treatment of radiation-induced cystitis with hyperbaric oxygen

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Weiss, J.P.; Boland, F.P.; Mori, H.

    The effects of hyperbaric oxygen on radiation cystitis have been documented in 3 patients with radiation-induced hemorrhagic cystitis refractory to conventional therapy. Cessation of gross hematuria and reversal of cystoscopic bladder changes were seen in response to a series of hyperbaric oxygen treatments of 2 atmosphere absolute pressure for 2 hours. To our knowledge this is the first report of cystoscopically documented healing of radiation-induced bladder injury.

  5. Circulating Hematopoietic Stem and Progenitor Cells in Aging Atomic Bomb Survivors.

    PubMed

    Kyoizumi, Seishi; Kubo, Yoshiko; Misumi, Munechika; Kajimura, Junko; Yoshida, Kengo; Hayashi, Tomonori; Imai, Kazue; Ohishi, Waka; Nakachi, Kei; Young, Lauren F; Shieh, Jae-Hung; Moore, Malcolm A; van den Brink, Marcel R M; Kusunoki, Yoichiro

    2016-01-01

    It is not yet known whether hematopoietic stem and progenitor cells (HSPCs) are compromised in the aging population of atomic bomb (A-bomb) survivors after their exposure nearly 70 years ago. To address this, we evaluated age- and radiation-related changes in different subtypes of circulating HSPCs among the CD34-positive/lineage marker-negative (CD34(+)Lin(-)) cell population in 231 Hiroshima A-bomb survivors. We enumerated functional HSPC subtypes, including: cobblestone area-forming cells; long-term culture-initiating cells; erythroid burst-forming units; granulocyte and macrophage colony-forming units; and T-cell and natural killer cell progenitors using cell culture. We obtained the count of each HSPC subtype per unit volume of blood and the proportion of each HSPC subtype in CD34(+)Lin(-) cells to represent the lineage commitment trend. Multivariate analyses, using sex, age and radiation dose as variables, showed significantly decreased counts with age in the total CD34(+)Lin(-) cell population and all HSPC subtypes. As for the proportion, only T-cell progenitors decreased significantly with age, suggesting that the commitment to the T-cell lineage in HSPCs continuously declines with age throughout the lifetime. However, neither the CD34(+)Lin(-) cell population, nor HSPC subtypes showed significant radiation-induced dose-dependent changes in counts or proportions. Moreover, the correlations of the proportions among HSPC subtypes in the survivors properly revealed the hierarchy of lineage commitments. Taken together, our findings suggest that many years after exposure to radiation and with advancing age, the number and function of HSPCs in living survivors as a whole may have recovered to normal levels.

  6. Circulating Hematopoietic Stem and Progenitor Cells in Aging Atomic Bomb Survivors

    PubMed Central

    Kyoizumi, Seishi; Kubo, Yoshiko; Misumi, Munechika; Kajimura, Junko; Yoshida, Kengo; Hayashi, Tomonori; Imai, Kazue; Ohishi, Waka; Nakachi, Kei; Young, Lauren F.; Shieh, Jae-Hung; Moore, Malcolm A.; van den Brink, Marcel R. M.; Kusunoki, Yoichiro

    2016-01-01

    It is not yet known whether hematopoietic stem and progenitor cells (HSPCs) are compromised in the aging population of atomic bomb (A-bomb) survivors after their exposure nearly 70 years ago. To address this, we evaluated age- and radiation-related changes in different subtypes of circulating HSPCs among the CD34-positive/lineage marker-negative (CD34+Lin− ) cell population in 231 Hiroshima A-bomb survivors. We enumerated functional HSPC subtypes, including: cobblestone area-forming cells; long-term culture-initiating cells; erythroid burst-forming units; granulocyte and macrophage colony-forming units; and T-cell and natural killer cell progenitors using cell culture. We obtained the count of each HSPC subtype per unit volume of blood and the proportion of each HSPC subtype in CD34+Lin− cells to represent the lineage commitment trend. Multivariate analyses, using sex, age and radiation dose as variables, showed significantly decreased counts with age in the total CD34+Lin− cell population and all HSPC subtypes. As for the proportion, only T-cell progenitors decreased significantly with age, suggesting that the commitment to the T-cell lineage in HSPCs continuously declines with age throughout the lifetime. However, neither the CD34+Lin− cell population, nor HSPC subtypes showed significant radiation-induced dose-dependent changes in counts or proportions. Moreover, the correlations of the proportions among HSPC subtypes in the survivors properly revealed the hierarchy of lineage commitments. Taken together, our findings suggest that many years after exposure to radiation and with advancing age, the number and function of HSPCs in living survivors as a whole may have recovered to normal levels. PMID:26720799

  7. AML1/ETO induces self-renewal in hematopoietic progenitor cells via the Groucho-related amino-terminal AES protein.

    PubMed

    Steffen, Björn; Knop, Markus; Bergholz, Ulla; Vakhrusheva, Olesya; Rode, Miriam; Köhler, Gabriele; Henrichs, Marcel-Philipp; Bulk, Etmar; Hehn, Sina; Stehling, Martin; Dugas, Martin; Bäumer, Nicole; Tschanter, Petra; Brandts, Christian; Koschmieder, Steffen; Berdel, Wolfgang E; Serve, Hubert; Stocking, Carol; Müller-Tidow, Carsten

    2011-04-21

    The most frequent translocation t(8;21) in acute myeloid leukemia (AML) generates the chimeric AML1/ETO protein, which blocks differentiation and induces self-renewal in hematopoietic progenitor cells. The underlying mechanisms mediating AML1/ETO-induced self-renewal are largely unknown. Using expression microarray analysis, we identified the Groucho-related amino-terminal enhancer of split (AES) as a consistently up-regulated AML1/ETO target. Elevated levels of AES mRNA and protein were confirmed in AML1/ETO-expressing leukemia cells, as well as in other AML specimens. High expression of AES mRNA or protein was associated with improved survival of AML patients, even in the absence of t(8;21). On a functional level, knockdown of AES by RNAi in AML1/ETO-expressing cell lines inhibited colony formation. Similarly, self-renewal induced by AML1/ETO in primary murine progenitors was inhibited when AES was decreased or absent. High levels of AES expression enhanced formation of immature colonies, serial replating capacity of primary cells, and colony formation in colony-forming unit-spleen assays. These findings establish AES as a novel AML1/ETO-induced target gene that plays an important role in the self-renewal phenotype of t(8;21)-positive AML.

  8. Novel Tissue Protective Agents for the Treatment of Acute Radiation-induced BMF

    DTIC Science & Technology

    2013-03-01

    induced apoptosis in the following hematopoietic cell lines: HL-60, NB-4 cells, 32Dc13 and EML cell line. Experimental design and methods: HL-60, a...et al., 1999). EML Cell line (ATCC CRL-11691), a bone marrow cell line obtained by immortalizing bone marrow cells from male BDF1 mice with a...Membrane preparations were made from HL-60, NB-4, 32Dc13 and EML cells attempts were made to co-immunoprecipitate the CD131 molecule with EPOR in

  9. Early Hematopoietic Zinc Finger Protein Prevents Tumor Cell Recognition by Natural Killer Cells1

    PubMed Central

    La Rocca, Rosanna; Fulciniti, Mariateresa; Lakshmikanth, Tadepally; Mesuraca, Maria; Ali, Talib Hassan; Mazzei, Valerio; Amodio, Nicola; Catalano, Lucio; Rotoli, Bruno; Ouerfelli, Ouathek; Grieco, Michele; Gulletta, Elio; Bond, Heather M.; Morrone, Giovanni; Ferrone, Soldano; Carbone, Ennio

    2009-01-01

    Early hematopoietic zinc finger/zinc finger protein 521 (EHZF/ZNF521) is a novel zinc finger protein expressed in hematopoietic stem and progenitor cells and is down-regulated during their differentiation. Its transcript is also abundant in some hematopoietic malignancies. Analysis of the changes in the antigenic profile of cells transfected with EHZF cDNA revealed up-regulation of HLA class I cell surface expression. This phenotypic change was associated with an increased level of HLA class I H chain, in absence of detectable changes in the expression of other Ag-processing machinery components. Enhanced resistance of target cells to NK cell-mediated cytotoxicity was induced by enforced expression of EHZF in the cervical carcinoma cell line HeLa and in the B lymphoblastoid cell line IM9. Preincubation of transfected cells with HLA class I Ag-specific mAb restored target cell susceptibility to NK cell-mediated lysis, indicating a specific role for HLA class I Ag up-regulation in the NK resistance induced by EHZF. A potential clinical significance of these findings is further suggested by the inverse correlation between EHZF and MHC class I expression levels, and autologous NK susceptibility of freshly explanted multiple myeloma cells. PMID:19342626

  10. EPIDEMIOLOGY OF ACCIDENTAL POISONING

    PubMed Central

    Bissell, D. M.; McInnes, Robert S.

    1960-01-01

    In San Jose, California, studies of cases of accidental poisoning showed that the greatest hazard was to children 1 through 3 years of age. Drugs accounted for half the cases, household products for another third, and insecticides and rodenticides and others for the remainder. Most often poison material was within easy reach of the children. An analysis of families in which an accident occurred indicated that accidental poisoning might happen to any family. Since there was little after-effect of poisoning in cases in which treatment was obtained promptly, education directed toward getting prompt treatment seems most advisable. Community agencies interested in poison control need to focus their attention on parents of pre-school children. PMID:13801023

  11. Radiation-Induced Immune Modulation in Prostate Cancer

    DTIC Science & Technology

    2008-01-01

    cancers. 15. SUBJECT TERMS Radiation, Dendritic Cells , Cytokines, PSA 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18...radiation is more than a cytotoxic agent. Our recent study has shown that radiation modulates the immune system by affecting dendritic cell (DC...translate radiation-induced tumor cell death into generation of tumor immunity in the hope of optimizing therapy for localized and disseminated prostate

  12. BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells

    PubMed Central

    Schemionek, Mirle; Elling, Christian; Steidl, Ulrich; Bäumer, Nicole; Hamilton, Ashley; Spieker, Tilmann; Göthert, Joachim R.; Stehling, Martin; Wagers, Amy; Huettner, Claudia S.; Tenen, Daniel G.; Tickenbrock, Lara; Berdel, Wolfgang E.; Serve, Hubert; Holyoake, Tessa L.; Müller-Tidow, Carsten

    2010-01-01

    In a previously developed inducible transgenic mouse model of chronic myeloid leukemia, we now demonstrate that the disease is transplantable using BCR-ABL+ Lin−Sca-1+c-kit+ (LSK) cells. Interestingly, the phenotype is more severe when unfractionated bone marrow cells are transplanted, yet neither progenitor cells (Lin−Sca-1−c-kit+), nor mature granulocytes (CD11b+Gr-1+), nor potential stem cell niche cells (CD45−Ter119−) are able to transmit the disease or alter the phenotype. The phenotype is largely independent of BCR-ABL priming before transplantation. However, prolonged BCR-ABL expression abrogates the potential of LSK cells to induce full-blown disease in secondary recipients and increases the fraction of multipotent progenitor cells at the expense of long-term hematopoietic stem cells (LT-HSCs) in the bone marrow. BCR-ABL alters the expression of genes involved in proliferation, survival, and hematopoietic development, probably contributing to the reduced LT-HSC frequency within BCR-ABL+ LSK cells. Reversion of BCR-ABL, or treatment with imatinib, eradicates mature cells, whereas leukemic stem cells persist, giving rise to relapsed chronic myeloid leukemia on reinduction of BCR-ABL, or imatinib withdrawal. Our results suggest that BCR-ABL induces differentiation of LT-HSCs and decreases their self-renewal capacity. PMID:20053753

  13. Malignant diseases of hematopoietic and lymphoid tissues in Chernobyl clean-up workers.

    PubMed

    Gluzman, Daniel; Imamura, Nobutaka; Sklyarenko, Lylia; Nadgornaya, Valentina; Zavelevich, Michael; Machilo, Vasily

    2005-01-01

    The question as to whether the incidence of leukemias and malignant lymphomas among the clean-up workers increased in 18 years after the catastrophe is still a point of much controversy. Precise diagnosis of the main forms of hematopoietic malignancies and comparison of these data with those in the general population will be helpful in estimating thr relative contribution of the radiation factor to the overall incidence of such pathologies. In all, 187 consecutive cases of malignant diseases of hematopoietic and lymphoid tissues in Chernobyl clean-up workers were analyzed in Ukrainian Reference Laboratory in 1996-2003. A total of 1942 consecutive patients of general population, mainly the residents of Kyiv city and district, diagnosed in References Laboratory at the same period comprised the group of comparison. The morphology and cytochemistry of bone marrow and peripheral blood cells were studied. Immunocytochemical techniques (PAP, APAAP, ABC) and the panel of monoclonal antibodies to differentiation antigens of leukocytes were employed for immunophenotyping leukemic cells. Various types of malignant disease of hematopoietic and lymphoid tissues were registered in Chernobyl clean-up workers under study including myelodysplastic syndromes (nine patients), acute lymphoblastic leukemia (eight) and acute myeloblastic leukemia (31), chromic myeloid leukemia (17), multiple myeloma (17) and other forms of chromic myeloproliferative and lymphoproliferative disease including B-cell chromic lymphocytic leukemia (49 patients). The verified diagnosis of tumors of hematopoietic malignancies according to modern classification (EGIL, WHO) could be the prerequisite for further analytical epidemiology study of leukemias that may be related to the Chernobyl accident.

  14. Accidental death in autoerotic maneuvers.

    PubMed

    Focardi, Martina; Gualco, Barbara; Norelli, GianAristide

    2008-03-01

    The authors from the Florence Forensic Department present a case that demonstrates the paradigms attached to accidental deaths while performing autoerotic maneuvers. The incidents of such practices are underestimated and are only the tip of the iceberg since they do not represent the cases that are never reported due to successful practice. After analyzing the statistic data, the authors describe the case and discuss about the element that prove the accidental nature of the death and the importance of the correct application of forensic methodology at the scene and in the mortuary.

  15. Interleukin-7-induced Stat-5 acts in synergy with Flt-3 signaling to stimulate expansion of hematopoietic progenitor cells.

    PubMed

    Åhsberg, Josefine; Tsapogas, Panagiotis; Qian, Hong; Zetterblad, Jenny; Zandi, Sasan; Månsson, Robert; Jönsson, Jan-Ingvar; Sigvardsson, Mikael

    2010-11-19

    The development of lymphoid cells from bone marrow progenitors is dictated by interplay between internal cues such as transcription factors and external signals like the cytokines Flt-3 ligand and Il-7. These proteins are both of large importance for normal lymphoid development; however, it is unclear if they act in direct synergy to expand a transient Il-7R(+)Flt-3(+) population or if the collaboration is created through sequential activities. We report here that Flt-3L and Il-7 synergistically stimulated the expansion of primary Il-7R(+)Flt-3(+) progenitor cells and a hematopoietic progenitor cell line ectopically expressing the receptors. The stimulation resulted in a reduced expression of pro-apoptotic genes and also mediated survival of primary progenitor cells in vitro. However, functional analysis of single cells suggested that the anti-apoptotic effect was additive indicating that the synergy observed mainly depends on stimulation of proliferation. Analysis of downstream signaling events suggested that although Il-7 induced Stat-5 phosphorylation, Flt-3L caused activation of the ERK and AKT signaling pathways. Flt-3L could also drive proliferation in synergy with ectopically expressed constitutively active Stat-5. This synergy could be inhibited with either receptor tyrosine kinase or MAPK inhibitors suggesting that Flt-3L and Il-7 act in synergy by activation of independent signaling pathways to expand early hematopoietic progenitors.

  16. Hematopoietic stem cells derived from human umbilical cord ameliorate cisplatin-induced acute renal failure in rats

    PubMed Central

    Shalaby, Rokaya H; Rashed, Laila A; Ismaail, Alaa E; Madkour, Naglaa K; Elwakeel, Sherien H

    2014-01-01

    Injury to a target organ can be sensed by bone marrow stem cells that migrate to the site of damage, undergo differentiation, and promote structural and functional repair. This remarkable stem cell capacity prompted an investigation of the potential of mesenchymal and hematopoietic stem cells to cure acute renal failure. On the basis of the recent demonstration that hematopoietic stem cells (HSCs) can differentiate into renal cells, the current study tested the hypothesis that HSCs can contribute to the regeneration of renal tubular epithelial cells after renal injury. HSCs from human umbilical cord blood which isolated and purified by magnetic activated cell sorting were transplanted intraperitoneal into acute renal failure (ARF) rats which was established by a single dose of cisplatin 5 mg/kg for five days. The Study was carried on 48 male white albino rats, of average weight 120-150 gm. The animals were divided into 4 groups, Group one Served as control and received normal saline throughout the experiments. Group two (model control) received a single dose of cisplatin. Group three and four male-albino rats with induced ARF received interapritoneally (HSCs) at two week and four week respectively. Injection of a single dose of cisplatin resulted in a significant increase in serum creatinine and urea levels, histo-pathological examination of kidney tissue from cisplatin showed severe nephrotoxicity in which 50-75% of glomeruli and renal tubules exhibited massive degenerative change. Four weeks after HSC transplantation, Serum creatinine and urea nitrogen decreased 3.5 times and 2.1 times as well as HGF, IGF-1, VEGF and P53 using quantitative real-time PCR increased 4.3 times, 3.2, 2.4 and 4.2 times compared to ARF groups, respectively. The proliferation of cell nuclear antigen (PCNA)-positive cells (500.083±35.167) was higher than that in the cisplatin groups (58.612±15.743). In addition, the transplanted umbilical cord hematopoietic stem cells UC-HSCs could

  17. A Model for Precise and Uniform Pelvic- and Limb-Sparing Abdominal Irradiation to Study the Radiation-Induced Gastrointestinal Syndrome in Mice Using Small Animal Irradiation Systems.

    PubMed

    Brodin, N Patrik; Velcich, Anna; Guha, Chandan; Tomé, Wolfgang A

    2017-01-01

    Currently, no readily available mitigators exist for acute abdominal radiation injury. Here, we present an animal model for precise and homogenous limb-sparing abdominal irradiation (LSAIR) to study the radiation-induced gastrointestinal syndrome (RIGS). The LSAIR technique was developed using the small animal radiation research platform (SARRP) with image guidance capabilities. We delivered LSAIR at doses between 14 and 18 Gy on 8- to 10-week-old male C57BL/6 mice. Histological analysis was performed to confirm that the observed mortality was due to acute abdominal radiation injury. A steep dose-response relationship was found for survival, with no deaths seen at doses below 16 Gy and 100% mortality at above 17 Gy. All deaths occurred between 6 and 10 days after irradiation, consistent with the onset of RIGS. This was further confirmed by histological analysis showing clear differences in the number of regenerative intestinal crypts between animals receiving sublethal (14 Gy) and 100% lethal (18 Gy) radiation. The developed LSAIR technique provides uniform dose delivery with a clear dose response, consistent with acute abdominal radiation injury on histological examination. This model can provide a useful tool for researchers investigating the development of mitigators for accidental or clinical high-dose abdominal irradiation.

  18. Radiation-Induced Oral Mucositis

    PubMed Central

    Maria, Osama Muhammad; Eliopoulos, Nicoletta; Muanza, Thierry

    2017-01-01

    Radiation-induced oral mucositis (RIOM) is a major dose-limiting toxicity in head and neck cancer patients. It is a normal tissue injury caused by radiation/radiotherapy (RT), which has marked adverse effects on patient quality of life and cancer therapy continuity. It is a challenge for radiation oncologists since it leads to cancer therapy interruption, poor local tumor control, and changes in dose fractionation. RIOM occurs in 100% of altered fractionation radiotherapy head and neck cancer patients. In the United Sates, its economic cost was estimated to reach 17,000.00 USD per patient with head and neck cancers. This review will discuss RIOM definition, epidemiology, impact and side effects, pathogenesis, scoring scales, diagnosis, differential diagnosis, prevention, and treatment. PMID:28589080

  19. Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro.

    PubMed

    Torisawa, Yu-suke; Spina, Catherine S; Mammoto, Tadanori; Mammoto, Akiko; Weaver, James C; Tat, Tracy; Collins, James J; Ingber, Donald E

    2014-06-01

    Current in vitro hematopoiesis models fail to demonstrate the cellular diversity and complex functions of living bone marrow; hence, most translational studies relevant to the hematologic system are conducted in live animals. Here we describe a method for fabricating 'bone marrow-on-a-chip' that permits culture of living marrow with a functional hematopoietic niche in vitro by first engineering new bone in vivo, removing it whole and perfusing it with culture medium in a microfluidic device. The engineered bone marrow (eBM) retains hematopoietic stem and progenitor cells in normal in vivo-like proportions for at least 1 week in culture. eBM models organ-level marrow toxicity responses and protective effects of radiation countermeasure drugs, whereas conventional bone marrow culture methods do not. This biomimetic microdevice offers a new approach for analysis of drug responses and toxicities in bone marrow as well as for study of hematopoiesis and hematologic diseases in vitro.

  20. Mdm2 is required for survival of hematopoietic stem cells/progenitors via dampening of ROS-induced p53 activity

    USDA-ARS?s Scientific Manuscript database

    Mdm2 is an E3 ubiquitin ligase that targets p53 for degradation. p53(515C) (encoding p53R172P) is a hypomorphic allele of p53 that rescues the embryonic lethality of Mdm2(-/-) mice. Mdm2(-/-) p53(515C/515C) mice, however, die by postnatal day 13 resulting from hematopoietic failure. Hematopoietic st...

  1. 2-O, 3-O desulfated heparin mitigates murine chemotherapy- and radiation-induced thrombocytopenia

    PubMed Central

    Tkaczynski, Elizabeth; Arulselvan, Abinaya; Tkaczynski, John; Avery, Stephen; Xiao, Liqing; Torok-Storb, Beverly; Abrams, Kraig; Rao, Narayanam V.; Johnson, Gregory; Poncz, Mortimer

    2018-01-01

    Thrombocytopenia is a significant complication of chemotherapy and radiation therapy. Platelet factor 4 (PF4; CXCL4) is a negative paracrine of megakaryopoiesis. We have shown that PF4 levels are inversely related to steady-state platelet counts, and to the duration and severity of chemotherapy- and radiation-induced thrombocytopenia (CIT and RIT, respectively). Murine studies suggest that blocking the effect of PF4 improves megakaryopoiesis, raising nadir platelet counts and shortening the time to platelet count recovery. We examined the ability of 2-O, 3-O desulfated heparin (ODSH), a heparin variant with little anticoagulant effects, to neutralize PF4’s effects on megakaryopoiesis. Using megakaryocyte colony assays and liquid cultures, we show that ODSH restored megakaryocyte proliferation in PF4-treated Cxcl4−/− murine and human CD34+-derived megakaryocyte cultures (17.4% megakaryocyte colonies, P < .01 compared with PF4). In murine CIT and RIT models, ODSH, started 24 hours after injury, was examined for the effect on hematopoietic recovery demonstrating higher platelet count nadirs (9% ± 5% treated vs 4% ± 4% control) and significantly improved survival in treated animals (73% treated vs 36% control survival). Treatment with ODSH was able to reduce intramedullary free PF4 concentrations by immunohistochemical analysis. In summary, ODSH mitigated CIT and RIT in mice by neutralizing the intramedullary negative paracrine PF4. ODSH, already in clinical trials in humans as an adjuvant to chemotherapy, may be an important, clinically relevant therapeutic for CIT and RIT. PMID:29599195

  2. Exposure of the Bone Marrow Microenvironment to Simulated Solar and Galactic Cosmic Radiation Induces Biological Bystander Effects on Human Hematopoiesis

    DOE PAGES

    Almeida-Porada, Graca; Rodman, Christopher; Kuhlman, Bradford; ...

    2018-04-26

    The stem cell compartment of the hematopoietic system constitutes one of the most radiosensitive tissues of the body and leukemias represent one of the most frequent radiogenic cancers with short latency periods. As such, leukemias may pose a particular threat to astronauts during prolonged space missions. Control of hematopoiesis is tightly governed by a specialized bone marrow (BM) microenvironment/niche. As such, any environmental insult that damages cells of this niche would be expected to produce pronounced effects on the types and functionality of hematopoietic/immune cells generated. We recently reported that direct exposure of human HSC to simulated SEP and GCRmore » radiation dramatically altered the differentiative potential of these cells, and that simulated GCR exposures can directly induce DNA damage and mutations within human HSC, which led to leukemic transformation when these cells repopulated murine recipients. In the present study, we performed the first in depth examination to define changes that occur in mesenchymal stem cells (MSC) present in the human BM niche following exposure to accelerated protons and iron ions, and assess the impact these changes have upon human hematopoiesis. Here, our data thus provides compelling evidence that simulated SEP/GCR exposures can also contribute to defective hematopoiesis/immunity through so-called “biological bystander effects” by damaging the stromal cells that comprise the human marrow microenvironment, thereby altering their ability to support normal hematopoiesis.« less

  3. Exposure of the Bone Marrow Microenvironment to Simulated Solar and Galactic Cosmic Radiation Induces Biological Bystander Effects on Human Hematopoiesis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Almeida-Porada, Graca; Rodman, Christopher; Kuhlman, Bradford

    The stem cell compartment of the hematopoietic system constitutes one of the most radiosensitive tissues of the body and leukemias represent one of the most frequent radiogenic cancers with short latency periods. As such, leukemias may pose a particular threat to astronauts during prolonged space missions. Control of hematopoiesis is tightly governed by a specialized bone marrow (BM) microenvironment/niche. As such, any environmental insult that damages cells of this niche would be expected to produce pronounced effects on the types and functionality of hematopoietic/immune cells generated. We recently reported that direct exposure of human HSC to simulated SEP and GCRmore » radiation dramatically altered the differentiative potential of these cells, and that simulated GCR exposures can directly induce DNA damage and mutations within human HSC, which led to leukemic transformation when these cells repopulated murine recipients. In the present study, we performed the first in depth examination to define changes that occur in mesenchymal stem cells (MSC) present in the human BM niche following exposure to accelerated protons and iron ions, and assess the impact these changes have upon human hematopoiesis. Here, our data thus provides compelling evidence that simulated SEP/GCR exposures can also contribute to defective hematopoiesis/immunity through so-called “biological bystander effects” by damaging the stromal cells that comprise the human marrow microenvironment, thereby altering their ability to support normal hematopoiesis.« less

  4. Cellular innate immunity and restriction of viral infection: implications for lentiviral gene therapy in human hematopoietic cells.

    PubMed

    Kajaste-Rudnitski, Anna; Naldini, Luigi

    2015-04-01

    Hematopoietic gene therapy has tremendous potential to treat human disease. Nevertheless, for gene therapy to be efficacious, effective gene transfer into target cells must be reached without inducing detrimental effects on their biological properties. This remains a great challenge for the field as high vector doses and prolonged ex vivo culture conditions are still required to reach significant transduction levels of clinically relevant human hematopoietic stem and progenitor cells (HSPCs), while other potential target cells such as primary macrophages can hardly be transduced. The reasons behind poor permissiveness of primary human hematopoietic cells to gene transfer partly reside in the retroviral origin of lentiviral vectors (LVs). In particular, host antiviral factors referred to as restriction factors targeting the retroviral life cycle can hamper LV transduction efficiency. Furthermore, LVs may activate innate immune sensors not only in differentiated hematopoietic cells but also in HSPCs, with potential consequences on transduction efficiency as well as their biological properties. Therefore, better understanding of the vector-host interactions in the context of hematopoietic gene transfer is important for the development of safer and more efficient gene therapy strategies. In this review, we briefly summarize the current knowledge regarding innate immune recognition of lentiviruses in primary human hematopoietic cells as well as discuss its relevance for LV-based ex vivo gene therapy approaches.

  5. Soluble factor(s) from bone marrow cells can rescue lethally irradiated mice by protecting endogenous hematopoietic stem cells.

    PubMed

    Zhao, Yi; Zhan, Yuxia; Burke, Kathleen A; Anderson, W French

    2005-04-01

    Ionizing radiation-induced myeloablation can be rescued via bone marrow transplantation (BMT) or administration of cytokines if given within 2 hours after radiation exposure. There is no evidence for the existence of soluble factors that can rescue an animal after a lethal dose of radiation when administered several hours postradiation. We established a system that could test the possibility for the existence of soluble factors that could be used more than 2 hours postirradiation to rescue animals. Animals with an implanted TheraCyte immunoisolation device (TID) received lethal-dose radiation and then normal bone marrow Lin- cells were loaded into the device (thereby preventing direct interaction between donor and recipient cells). Animal survival was evaluated and stem cell activity was tested with secondary bone marrow transplantation and flow cytometry analysis. Donor cell gene expression of five antiapoptotic cytokines was examined. Bone marrow Lin- cells rescued lethally irradiated animals via soluble factor(s). Bone marrow cells from the rescued animals can rescue and repopulate secondary lethally irradiated animals. Within the first 6 hours post-lethal-dose radiation, there is no significant change of gene expression of the known radioprotective factors TPO, SCF, IL-3, Flt-3 ligand, and SDF-1. Hematopoietic stem cells can be protected in lethally irradiated animals by soluble factors produced by bone marrow Lin- cells.

  6. Radiation-induced valvular heart disease.

    PubMed

    Gujral, Dorothy M; Lloyd, Guy; Bhattacharyya, Sanjeev

    2016-02-15

    Radiation to the mediastinum is a key component of treatment with curative intent for a range of cancers including Hodgkin's lymphoma and breast cancer. Exposure to radiation is associated with a risk of radiation-induced heart valve damage characterised by valve fibrosis and calcification. There is a latent interval of 10-20 years between radiation exposure and development of clinically significant heart valve disease. Risk is related to radiation dose received, interval from exposure and use of concomitant chemotherapy. Long-term outlook and the risk of valve surgery are related to the effects of radiation on mediastinal structures including pulmonary fibrosis and pericardial constriction. Dose prediction models to predict the risk of heart valve disease in the future and newer radiation techniques to reduce the radiation dose to the heart are being developed. Surveillance strategies for this cohort of cancer survivors at risk of developing significant heart valve complications are required. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  7. Orally administered fructose increases the numbers of peripheral lymphocytes reduced by exposure of mice to gamma or SPE-like proton radiation

    NASA Astrophysics Data System (ADS)

    Romero-Weaver, A. L.; Ni, J.; Lin, L.; Kennedy, A. R.

    2014-07-01

    Exposure of the whole body or a major portion of the body to ionizing radiation can result in Acute Radiation Sickness (ARS), which can cause symptoms that range from mild to severe, and include death. One of the syndromes that can occur during ARS is the hematopoietic syndrome, which is characterized by a reduction in bone marrow cells as well as the number of circulating blood cells. Doses capable of causing this syndrome can result from conventional radiation therapy and accidental exposure to ionizing radiation. It is of concern that this syndrome could also occur during space exploration class missions in which astronauts could be exposed to significant doses of solar particle event (SPE) radiation. Of particular concern is the reduction of lymphocytes and granulocytes, which are major components of the immune system. A significant reduction in their numbers can compromise the immune system, causing a higher risk for the development of infections which could jeopardize the success of the mission. Although there are no specific countermeasures utilized for the ARS resulting from exposure to space radiation(s), granulocyte colony-stimulating factor (G-CSF) has been proposed as a countermeasure for the low number of neutrophils caused by SPE radiation, but so far no countermeasure exists for a reduced number of circulating lymphocytes. The present study demonstrates that orally administered fructose significantly increases the number of peripheral lymphocytes reduced by exposure of mice to 2 Gy of gamma- or SPE-like proton radiation, making it a potential countermeasure for this biological end-point.

  8. Effectiveness of the herbal medicine daikenchuto for radiation-induced enteritis.

    PubMed

    Takeda, Takashi; Kamiura, Shouji; Kimura, Tadashi

    2008-07-01

    Radiation-induced enteritis is a serious clinical problem for which there is currently no recommended standard management. Daikenchuto (DKT) is a Japanese herbal medicine that has been used to treat adhesive bowel obstruction in Japan. This report describes a patient with radiation-induced enteritis whose clinical symptoms were much improved by treatment with DKT. The patient was administered DKT, a traditional Japanese herbal formula, orally (2.5 g 3 times daily). Abdominal distention was evaluated objectively with computed tomography. Gastrointestinal symptoms associated with radiation-induced enteritis were controlled successfully with DKT treatment. DKT treatment may be useful for the management of radiation-induced enteritis.

  9. Crosstalk between telomere maintenance and radiation effects: A key player in the process of radiation-induced carcinogenesis

    PubMed Central

    Shim, Grace; Ricoul, Michelle; Hempel, William M.; Azzam, Edouard I.; Sabatier, Laure

    2014-01-01

    It is well established that ionizing radiation induces chromosomal damage, both following direct radiation exposure and via non-targeted (bystander) effects, activating DNA damage repair pathways, of which the proteins are closely linked to telomeric proteins and telomere maintenance. Long-term propagation of this radiation-induced chromosomal damage during cell proliferation results in chromosomal instability. Many studies have shown the link between radiation exposure and radiation-induced changes in oxidative stress and DNA damage repair in both targeted and non-targeted cells. However, the effect of these factors on telomeres, long established as guardians of the genome, still remains to be clarified. In this review, we will focus on what is known about how telomeres are affected by exposure to low- and high-LET ionizing radiation and during proliferation, and will discuss how telomeres may be a key player in the process of radiation-induced carcinogenesis. PMID:24486376

  10. Radiation induced detwinning in nanotwinned Cu

    DOE PAGES

    Chen, Youxing; Wang, Haiyan; Kirk, Mark A.; ...

    2016-11-15

    Superior radiation tolerance has been experimentally examined in nanotwinned metals. The stability of nanotwinned structure under radiation is the key factor for advancing the application of nanotwinned metals for nuclear reactors. We thus performed in situ radiation tests for nanotwinned Cu with various twin thicknesses inside a transmission electron microscope. We found that there is a critical twin thickness (10 nm), below which, radiation induced detwinning is primarily accomplished through migration of incoherent twin boundaries. Lastly, detwinning is faster for thinner twins in this range, while thicker twins are more stable.

  11. Pharmacological countermeasures for the acute radiation syndrome.

    PubMed

    Xiao, Mang; Whitnall, Mark H

    2009-01-01

    The acute radiation syndrome (ARS) is defined as the signs and symptoms that occur within several months after exposure to ionizing radiation (IR). This syndrome develops after total- or partial-body irradiation at a relatively high dose (above about 1 Gy in humans) and dose rate. Normal tissue injuries induced by IR differ depending on the target organ and cell type. Organs and cells with high sensitivity to radiation include the skin, the hematopoietic system, the gut, the spermatogenic cells and the vascular system. Exposure to IR causes damage to DNA, protein, and lipids in mammalian cells, as well as increased mitochondria-dependent generation of reactive oxygen species (ROS), with subsequent cell cycle checkpoint arrest, apoptosis, and stress-related responses. DNA double strand breaks (DSBs) are a primary lethal lesion induced by IR. The cellular response to damage is complex and relies on simultaneous activation of a number of signaling networks. Among these, the activation of DNA non-homologous end-joining (NHEJ) and homologous recombination (HR), and signaling pathways containing ataxia telangiectasia mutated (ATM), play important roles. The transcription factor NFkappaB has emerged as a pro-survival actor in response to IR in ATM and p53-induced protein with a death domain (PIDD) cascades. Although radiation-induced ARS has been well documented at the clinical level, and mechanistic information is accumulating, successful prophylaxis and treatment for ARS is problematic, even with the use of supportive care and growth factors. There is a pressing need to develop radiation countermeasures that can be used both in the clinic, for small-scale incidents, and outside the clinic, in mass casualty scenarios. In this review we summarize recent information on intracellular and extracellular signaling pathways relevant to radiation countermeasure research.

  12. Protection from radiation-induced apoptosis by the radioprotector amifostine (WR-2721) is radiation dose dependent.

    PubMed

    Ormsby, Rebecca J; Lawrence, Mark D; Blyth, Benjamin J; Bexis, Katrina; Bezak, Eva; Murley, Jeffrey S; Grdina, David J; Sykes, Pamela J

    2014-02-01

    The radioprotective agent amifostine is a free radical scavenger that can protect cells from the damaging effects of ionising radiation when administered prior to radiation exposure. However, amifostine has also been shown to protect cells from chromosomal mutations when administered after radiation exposure. As apoptosis is a common mechanism by which cells with mutations are removed from the cell population, we investigated whether amifostine stimulates apoptosis when administered after radiation exposure. We chose to study a relatively low dose which is the maximum radiation dose for radiation emergency workers (0.25 Gy) and a high dose relevant to radiotherapy exposures (6 Gy). Mice were administered 400 mg/kg amifostine 30 min before, or 3 h after, whole-body irradiation with 0.25 or 6 Gy X-rays and apoptosis was analysed 3 or 7 h later in spleen and bone marrow. We observed a significant increase in radiation-induced apoptosis in the spleen of mice when amifostine was administered before or after 0.25 Gy X-rays. In contrast, when a high dose of radiation was used (6 Gy), amifostine caused a reduction in radiation-induced apoptosis 3 h post-irradiation in spleen and bone marrow similar to previously published studies. This is the first study to investigate the effect of amifostine on radiation-induced apoptosis at a relatively low radiation dose and the first to demonstrate that while amifostine can reduce apoptosis from high doses of radiation, it does not mediate the same effect in response to low-dose exposures. These results suggest that there may be a dose threshold at which amifostine protects from radiation-induced apoptosis and highlight the importance of examining a range of radiation doses and timepoints.

  13. Radiation-induced alternative transcripts as detected in total and polysome-bound mRNA.

    PubMed

    Wahba, Amy; Ryan, Michael C; Shankavaram, Uma T; Camphausen, Kevin; Tofilon, Philip J

    2018-01-02

    Alternative splicing is a critical event in the posttranscriptional regulation of gene expression. To investigate whether this process influences radiation-induced gene expression we defined the effects of ionizing radiation on the generation of alternative transcripts in total cellular mRNA (the transcriptome) and polysome-bound mRNA (the translatome) of the human glioblastoma stem-like cell line NSC11. For these studies, RNA-Seq profiles from control and irradiated cells were compared using the program SpliceSeq to identify transcripts and splice variations induced by radiation. As compared to the transcriptome (total RNA) of untreated cells, the radiation-induced transcriptome contained 92 splice events suggesting that radiation induced alternative splicing. As compared to the translatome (polysome-bound RNA) of untreated cells, the radiation-induced translatome contained 280 splice events of which only 24 were overlapping with the radiation-induced transcriptome. These results suggest that radiation not only modifies alternative splicing of precursor mRNA, but also results in the selective association of existing mRNA isoforms with polysomes. Comparison of radiation-induced alternative transcripts to radiation-induced gene expression in total RNA revealed little overlap (about 3%). In contrast, in the radiation-induced translatome, about 38% of the induced alternative transcripts corresponded to genes whose expression level was affected in the translatome. This study suggests that whereas radiation induces alternate splicing, the alternative transcripts present at the time of irradiation may play a role in the radiation-induced translational control of gene expression and thus cellular radioresponse.

  14. About Assessment Criteria of Driver's Accidental Abilities

    ERIC Educational Resources Information Center

    Lobanova, Yuliya I.; Glushko, Kirill V.

    2016-01-01

    The article points at the importance of studying the human factor as a cause of accidents of drivers, especially in loosely structured traffic situations. The description of the experiment on the measurement of driver's accidental abilities is given. Under accidental ability is meant the capability to ensure the security of driving as a behavior…

  15. Accidental awareness during general anaesthesia - a narrative review.

    PubMed

    Tasbihgou, S R; Vogels, M F; Absalom, A R

    2018-01-01

    Unintended accidental awareness during general anaesthesia represents failure of successful anaesthesia, and so has been the subject of numerous studies during the past decades. As return to consciousness is both difficult to describe and identify, the reported incidence rates vary widely. Similarly, a wide range of techniques have been employed to identify cases of accidental awareness. Studies which have used the isolated forearm technique to identify responsiveness to command during intended anaesthesia have shown remarkably high incidences of awareness. For example, the ConsCIOUS-1 study showed an incidence of responsiveness around the time of laryngoscopy of 1:25. On the other hand, the 5th Royal College of Anaesthetists National Audit Project, which reported the largest ever cohort of patients who had experienced accidental awareness, used a system to identify patients who spontaneously self-reported accidental awareness. In this latter study, the incidence of accidental awareness was 1:19,600. In the recently published SNAP-1 observational study, in which structured postoperative interviews were performed, the incidence was 1:800. In almost all reported cases of intra-operative responsiveness, there was no subsequent explicit recall of intra-operative events. To date, there is no evidence that this occurrence has any psychological consequences. Among patients who experience accidental awareness and can later remember details of their experience, the consequences are better known. In particular, when awareness occurs in a patient who has been given neuromuscular blocking agents, it may result in serious sequelae such as symptoms of post-traumatic stress disorder and a permanent aversion to surgery and anaesthesia, and is feared by patients and anaesthetists. In this article, the published literature on the incidence, consequences and management of accidental awareness under general anaesthesia with subsequent recall will be reviewed. © 2017 The Association

  16. Endothelial transplantation rejuvenates aged hematopoietic stem cell function

    PubMed Central

    Poulos, Michael G.; Gutkin, Michael C.; Llanos, Pierre; Gilleran, Katherine; Rabbany, Sina Y.; Butler, Jason M.

    2017-01-01

    Age-related changes in the hematopoietic compartment are primarily attributed to cell-intrinsic alterations in hematopoietic stem cells (HSCs); however, the contribution of the aged microenvironment has not been adequately evaluated. Understanding the role of the bone marrow (BM) microenvironment in supporting HSC function may prove to be beneficial in treating age-related functional hematopoietic decline. Here, we determined that aging of endothelial cells (ECs), a critical component of the BM microenvironment, was sufficient to drive hematopoietic aging phenotypes in young HSCs. We used an ex vivo hematopoietic stem and progenitor cell/EC (HSPC/EC) coculture system as well as in vivo EC infusions following myelosuppressive injury in mice to demonstrate that aged ECs impair the repopulating activity of young HSCs and impart a myeloid bias. Conversely, young ECs restored the repopulating capacity of aged HSCs but were unable to reverse the intrinsic myeloid bias. Infusion of young, HSC-supportive BM ECs enhanced hematopoietic recovery following myelosuppressive injury and restored endogenous HSC function in aged mice. Coinfusion of young ECs augmented aged HSC engraftment and enhanced overall survival in lethally irradiated mice by mitigating damage to the BM vascular microenvironment. These data lay the groundwork for the exploration of EC therapies that can serve as adjuvant modalities to enhance HSC engraftment and accelerate hematopoietic recovery in the elderly population following myelosuppressive regimens. PMID:29035282

  17. Factors perceived as being related to accidental falls by persons with multiple sclerosis.

    PubMed

    Nilsagård, Ylva; Denison, Eva; Gunnarsson, Lars-Gunnar; Boström, Katrin

    2009-01-01

    This study explores and describes factors that persons with multiple sclerosis (MS) perceive as being related to accidental falls. A qualitative content analysis with primarily deductive approach was conducted using the International Classification of Functioning, Disability and Health. Twelve persons with MS, and identified as fallers, were interviewed. Factors perceived to cause accidental falls that had not previously been targeted in MS populations in relation to falls were identified as divided attention, reduced muscular endurance, fatigue and heat sensitivity. Previously reported risk factors such as changed gait pattern, limited walking ability, impaired proprioception, vision and spasticity were supported. Activities involving walking, recreation and leisure, maintaining and changing body position, lifting or carrying, taking care of the home, washing the body, moving around, preparing meals and housekeeping were limited and considered to be risk activities. Supportive persons and assistive device reduced falls, and unsuitable physical environments and climate conditions induced falls. Several preventative strategies were described as partially compensating for the impairments, limitations and restrictions. Investigating accidental falls using the perspective of the patient gave important information about variables not earlier targeted in MS research.

  18. Radiation-induced schwannomas

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Rubinstein, A.B.; Reichenthal, E.; Borohov, H.

    1989-06-01

    The histopathology and clinical course of three patients with schwannomas of the brain and high cervical cord after therapeutic irradiation for intracranial malignancy and for ringworm of the scalp are described. Earlier reports in the literature indicated that radiation of the scalp may induce tumors in the head and neck. It is therefore suggested that therapeutic irradiation in these instances was a causative factor in the genesis of these tumors.

  19. Simulating Space Radiation-Induced Breast Tumor Incidence Using Automata.

    PubMed

    Heuskin, A C; Osseiran, A I; Tang, J; Costes, S V

    2016-07-01

    Estimating cancer risk from space radiation has been an ongoing challenge for decades primarily because most of the reported epidemiological data on radiation-induced risks are derived from studies of atomic bomb survivors who were exposed to an acute dose of gamma rays instead of chronic high-LET cosmic radiation. In this study, we introduce a formalism using cellular automata to model the long-term effects of ionizing radiation in human breast for different radiation qualities. We first validated and tuned parameters for an automata-based two-stage clonal expansion model simulating the age dependence of spontaneous breast cancer incidence in an unexposed U.S. We then tested the impact of radiation perturbation in the model by modifying parameters to reflect both targeted and nontargeted radiation effects. Targeted effects (TE) reflect the immediate impact of radiation on a cell's DNA with classic end points being gene mutations and cell death. They are well known and are directly derived from experimental data. In contrast, nontargeted effects (NTE) are persistent and affect both damaged and undamaged cells, are nonlinear with dose and are not well characterized in the literature. In this study, we introduced TE in our model and compared predictions against epidemiologic data of the atomic bomb survivor cohort. TE alone are not sufficient for inducing enough cancer. NTE independent of dose and lasting ∼100 days postirradiation need to be added to accurately predict dose dependence of breast cancer induced by gamma rays. Finally, by integrating experimental relative biological effectiveness (RBE) for TE and keeping NTE (i.e., radiation-induced genomic instability) constant with dose and LET, the model predicts that RBE for breast cancer induced by cosmic radiation would be maximum at 220 keV/μm. This approach lays the groundwork for further investigation into the impact of chronic low-dose exposure, inter-individual variation and more complex space radiation

  20. Hepatocyte nuclear factor-4alpha induces transdifferentiation of hematopoietic cells into hepatocytes.

    PubMed

    Khurana, Satish; Jaiswal, Amit K; Mukhopadhyay, Asok

    2010-02-12

    Hematopoietic stem cells can directly transdifferentiate into hepatocytes because of cellular plasticity, but the molecular basis of transdifferentiation is not known. Here, we show the molecular basis using lineage-depleted oncostatin M receptor beta-expressing (Lin(-)OSMRbeta(+)) mouse bone marrow cells in a hepatic differentiation culture system. Differentiation of the cells was marked by the expression of albumin. Hepatocyte nuclear factor (HNF)-4alpha was expressed and translocated into the nuclei of the differentiating cells. Suppression of its activation in OSM-neutralized culture medium inhibited cellular differentiation. Ectopic expression of full-length HNF4alpha in 32D myeloid cells resulted in decreased myeloid colony-forming potential and increased expression of hepatocyte-specific genes and proteins. Nevertheless, the neohepatocytes produced in culture expressed active P450 enzyme. The obligatory role of HNF4alpha in hepatic differentiation was confirmed by transfecting Lin(-)OSMRbeta(+) cells with dominant negative HNF4alpha in the differentiation culture because its expression inhibited the transcription of the albumin and tyrosine aminotransferase genes. The loss and gain of functional activities strongly suggested that HNF4alpha plays a central role in the transdifferentiation process. For the first time, this report demonstrates the mechanism of transdifferentiation of hematopoietic cells into hepatocytes, in which HNF4alpha serves as a molecular switch.

  1. Three Mile Island epidemiologic radiation dose assessment revisited: 25 years after the accident.

    PubMed

    Field, R William

    2005-01-01

    Over the past 25 years, public health concerns following the Three Mile Island (TMI) accident prompted several epidemiologic investigations in the vicinity of TMI. One of these studies is ongoing. This commentary suggests that the major source of radiation exposure to the population has been ignored as a potential confounding factor or effect modifying factor in previous and ongoing TMI epidemiologic studies that explore whether or not TMI accidental plant radiation releases caused an increase in lung cancer in the community around TMI. The commentary also documents the observation that the counties around TMI have the highest regional radon potential in the United States and concludes that radon progeny exposure should be included as part of the overall radiation dose assessment in future studies of radiation-induced lung cancer resulting from the TMI accident.

  2. [Effects of radiation exposure on human body].

    PubMed

    Kamiya, Kenji; Sasatani, Megumi

    2012-03-01

    There are two types of radiation health effect; acute disorder and late on-set disorder. Acute disorder is a deterministic effect that the symptoms appear by exposure above a threshold. Tissues and cells that compose the human body have different radiation sensitivity respectively, and the symptoms appear in order, from highly radiosensitive tissues. The clinical symptoms of acute disorder begin with a decrease in lymphocytes, and then the symptoms appear such as alopecia, skin erythema, hematopoietic damage, gastrointestinal damage, central nervous system damage with increasing radiation dose. Regarding the late on-set disorder, a predominant health effect is the cancer among the symptoms of such as cancer, non-cancer disease and genetic effect. Cancer and genetic effect are recognized as stochastic effects without the threshold. When radiation dose is equal to or more than 100 mSv, it is observed that the cancer risk by radiation exposure increases linearly with an increase in dose. On the other hand, the risk of developing cancer through low-dose radiation exposure, less 100 mSv, has not yet been clarified scientifically. Although uncertainty still remains regarding low level risk estimation, ICRP propound LNT model and conduct radiation protection in accordance with LNT model in the low-dose and low-dose rate radiation from a position of radiation protection. Meanwhile, the mechanism of radiation damage has been gradually clarified. The initial event of radiation-induced diseases is thought to be the damage to genome such as radiation-induced DNA double-strand breaks. Recently, it is clarified that our cells could recognize genome damage and induce the diverse cell response to maintain genome integrity. This phenomenon is called DNA damage response which induces the cell cycle arrest, DNA repair, apoptosis, cell senescence and so on. These responses act in the direction to maintain genome integrity against genome damage, however, the death of large number of

  3. Mechanisms of Radiation-Induced Conditioned Taste Aversion Learning

    DTIC Science & Technology

    1986-01-01

    to Walter A. Hunt. 86 4 21 144 . J Jr -.W U *’ = 7 . 7 .: M: W. ,WLW;i , .-, -’ .’P. %k T .- - ’ .: ’W ; .a --,.-" -. t .:-. , 56 RABIN AND HUNT can...8217. 7m. U RADIATION-INDUCED TASTE AVERSIONS 57 induced CTA 11021. Alternatively, when the antihistamine is [ 21 . A radiation-induced CTA can be...in rats. Pharmmad psychioactive drugs. J (omp Phvsiod Pvchld .;’: 21 -26. 1972. Biochem Behav 17: 305-311. 1982. 4. Berger. B. D.. C. D. Wise and L

  4. A report on radiation-induced gliomas

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Salvati, M.; Artico, M.; Caruso, R.

    1991-01-15

    Radiation-induced gliomas are uncommon, with only 73 cases on record to date. The disease that most frequently occasioned radiation therapy has been acute lymphoblastic leukemia (ALL). Three more cases are added here, two after irradiation for ALL and one after irradiation for tinea capitis. In a review of the relevant literature, the authors stress the possibility that the ALL-glioma and the retinoblastoma-glioma links point to syndromes in their own right that may occur without radiation therapy.56 references.

  5. Epigenetic Analysis of Heavy-ion Radiation Induced Bystander Effects in Mice

    NASA Astrophysics Data System (ADS)

    Zhang, Meng; Sun, Yeqing; Cui, Changna; Xue, Bei

    Abstract: Radiation-induced bystander effect was defined as the induction of damage in neighboring non-hit cells by signals released from directly-irradiated cells. Recently, low dose of high LET radiation induced bystander effects in vivo have been reported more and more. It has been indicated that radiation induced bystander effect was localized not only in bystander tissues but also in distant organs. Genomic, epigenetic and proteomics plays significant roles in regulating heavy-ion radiation stress responses in mice. To identify the molecular mechanism that underlies bystander effects of heavy-ion radiation, the male Balb/c and C57BL mice were exposed head-only to 40, 200, 2000mGy dose of (12) C heavy-ion radiation, while the rest of the animal body was shielded. Directly radiation organ ear and the distant organ liver were detected on 1h, 6h, 12h and 24h after radiation, respectively. Methylation-sensitive amplification polymorphism (MSAP) was used to monitor the level of polymorphic genomic DNA methylation changed with dose and time effects. The results show that heavy-ion irradiated mouse head could induce genomic DNA methylation changes significantly in both the directly radiation organ ear and the distant organ liver. The percent of DNA methylation changes were time-dependent and tissue-specific. Demethylation polymorphism rate was highest separately at 1 h in 200 mGy and 6 h in 2000 mGy after irradiation. The global DNA methylation changes tended to occur in the CG sites. The results illustrated that genomic methylation changes of heavy ion radiation-induced bystander effect in liver could be obvious 1 h after radiation and achieved the maximum at 6 h, while the changes could recover gradually at 12 h. The results suggest that mice head exposed to heavy-ion radiation can induce damage and methylation pattern changed in both directly radiation organ ear and distant organ liver. Moreover, our findings are important to understand the molecular mechanism of

  6. Lack of Phenotypical and Morphological Evidences of Endothelial to Hematopoietic Transition in the Murine Embryonic Head during Hematopoietic Stem Cell Emergence.

    PubMed

    Iizuka, Kazuhide; Yokomizo, Tomomasa; Watanabe, Naoki; Tanaka, Yosuke; Osato, Motomi; Takaku, Tomoiku; Komatsu, Norio

    2016-01-01

    During mouse ontogeny, hematopoietic cells arise from specialized endothelial cells, i.e., the hemogenic endothelium, and form clusters in the lumen of arterial vessels. Hemogenic endothelial cells have been observed in several embryonic tissues, such as the dorsal aorta, the placenta and the yolk sac. Recent work suggests that the mouse embryonic head also produces hematopoietic stem cells (HSCs)/progenitors. However, a histological basis for HSC generation in the head has not yet been determined because the hematopoietic clusters and hemogenic endothelium in the head region have not been well characterized. In this study, we used whole-mount immunostaining and 3D confocal reconstruction techniques to analyze both c-Kit+ hematopoietic clusters and Runx1+ hemogenic endothelium in the whole-head vasculature. The number of c-Kit+ hematopoietic cells was 20-fold less in the head arteries than in the dorsal aorta. In addition, apparent nascent hematopoietic cells, which are characterized by a "budding" structure and a Runx1+ hemogenic endothelium, were not observed in the head. These results suggest that head HSCs may not be or are rarely generated from the endothelium in the same manner as aortic HSCs.

  7. Lack of Phenotypical and Morphological Evidences of Endothelial to Hematopoietic Transition in the Murine Embryonic Head during Hematopoietic Stem Cell Emergence

    PubMed Central

    Iizuka, Kazuhide; Yokomizo, Tomomasa; Watanabe, Naoki; Tanaka, Yosuke; Osato, Motomi; Takaku, Tomoiku; Komatsu, Norio

    2016-01-01

    During mouse ontogeny, hematopoietic cells arise from specialized endothelial cells, i.e., the hemogenic endothelium, and form clusters in the lumen of arterial vessels. Hemogenic endothelial cells have been observed in several embryonic tissues, such as the dorsal aorta, the placenta and the yolk sac. Recent work suggests that the mouse embryonic head also produces hematopoietic stem cells (HSCs)/progenitors. However, a histological basis for HSC generation in the head has not yet been determined because the hematopoietic clusters and hemogenic endothelium in the head region have not been well characterized. In this study, we used whole-mount immunostaining and 3D confocal reconstruction techniques to analyze both c-Kit+ hematopoietic clusters and Runx1+ hemogenic endothelium in the whole-head vasculature. The number of c-Kit+ hematopoietic cells was 20-fold less in the head arteries than in the dorsal aorta. In addition, apparent nascent hematopoietic cells, which are characterized by a “budding” structure and a Runx1+ hemogenic endothelium, were not observed in the head. These results suggest that head HSCs may not be or are rarely generated from the endothelium in the same manner as aortic HSCs. PMID:27227884

  8. Acute Radiation Disease : Cutaneous Syndrome and Toxic properties of Radiomimetics -Radiation Neurotoxins and Hematotoxins.

    NASA Astrophysics Data System (ADS)

    Popov, Dmitri; Maliev, Slava

    Cutaneous injury is an important complication of a general or local acute irradiation. A type of a skin and tissues lesions depends on a type, intensity, and period of irradiation. Also, the clinical picture, signs, and manifestations of the cutaneous syndrome depend on a type of the radiation toxins circulated in lymph and blood of irradiated mammals. Radiation Toxins were isolated from lymph of the mammals that were irradiated and developed different forms of the Acute Radiation Syndromes (ARS) -Cerebrovascular, Cardiovascular, Gastrointestinal, and Hematopoietic. Radiation Toxins can be divided into the two important types of toxins (Neu-rotoxins and Hematotoxins) or four groups. The effects of Radiation Neurotoxins include severe damages and cell death of brain, heart, gastrointestinal tissues and endothelial cells of blood and lymphatic vessels. The hematotoxicity of Hematotoxic Radiation Toxins includes lym-phopenia, leukopenia, thrombocytopenia, and anemia in the blood circulation and transitory lymphocytosis and leukocytosis in the Central Lymphatic System. In all cases, administration of the Radiomimetics (Radiation Toxins) intramuscularly or intravenously to healthy, radiation naive mammals had induced and developed the typical clinical manifestations of the ARS. In all cases, administration of Radiomimetics by subtoxic doses had demonstrated development of typical clinical signs of the cutaneous syndrome such as hair loss, erythema, swelling, desqua-mation, blistering and skin necrosis. In animal-toxic models, we have activated development of the local skin and tissue injury after injection of Radiation Toxins with cytoxic properties.

  9. Antioxidant Supplementation: A Linchpin in Radiation-Induced Enteritis

    PubMed Central

    Anwar, Mumtaz; Ahmad, Shabeer; Akhtar, Reyhan; Mahmood, Akhtar

    2017-01-01

    Radiation enteritis is one of the most feared complications of abdominal and pelvic regions. Thus, radiation to abdominal or pelvic malignancies unavoidably injures the intestine. Because of rapid cell turnover, the intestine is highly sensitive to radiation injury, which is the limiting factor in the permissible dosage of irradiation. Bowel injuries such as fistulas, strictures, and chronic malabsorption are potentially life-threatening complications and have an impact on patient quality of life. The incidence of radiation enteritis is increasing because of the current trend of combined chemotherapy and radiation. The consequences of radiation damage to the intestine may result in considerable morbidity and even mortality. The observed effects of ionizing radiation are mediated mainly by oxygen-free radicals that are generated by its action on water and are involved in several steps of signal transduction cascade, leading to apoptosis. The oxyradicals also induce DNA strand breaks and protein oxidation. An important line of defense against free radical damage is the presence of antioxidants. Therefore, administration of antioxidants may ameliorate the radiation-induced damage to the intestine. PMID:28532242

  10. Scaling and Multifractality in Road Accidental Distances

    NASA Astrophysics Data System (ADS)

    Qiu, Tian; Wan, Chi; Zou, Xiang-Xiang; Wang, Xiao-Fan

    Accidental distance dynamics is investigated, based on the road accidental data of the Great Britain. The distance distribution of all the districts as an ensemble presents a power law tail, which is different from that of the individual district. A universal distribution is found for different districts, by rescaling the distribution functions of individual districts, which can be well fitted by the Weibull distribution. The male and female drivers behave similarly in the distance distribution. The multifractal characteristic is further studied for the individual district and all the districts as an ensemble, and different behaviors are also revealed between them. The accidental distances of the individual district show a weak multifractality, whereas of all the districts present a strong multifractality when taking them as an ensemble.

  11. Are hematopoietic stem cells involved in hepatocarcinogenesis?

    PubMed

    Facciorusso, Antonio; Antonino, Matteo; Del Prete, Valentina; Neve, Viviana; Scavo, Maria Principia; Barone, Michele

    2014-08-01

    THE LIVER HAS THREE CELL LINEAGES ABLE TO PROLIFERATE AFTER A HEPATIC INJURY: the mature hepatocyte, the ductular "bipolar" progenitor cell termed "oval cell" and the putative periductular stem cell. Hepatocytes can only produce other hepatocytes whereas ductular progenitor cells are considerate bipolar since they can give rise to biliary cells or hepatocytes. Periductular stem cells are rare in the liver, have a very long proliferation potential and may be multipotent, being this aspect still under investigation. They originate in the bone marrow since their progeny express genetic markers of donor hematopoietic cells after bone marrow transplantation. Since the liver is the hematopoietic organ of the fetus, it is possible that hematopoietic stem cells may reside in the liver of the adult. This assumption is proved by the finding that oval cells express hematopoietic markers like CD34, CD45, CD 109, Thy-1, c-kit, and others, which are also expressed by bone marrow-derived hematopoietic stem cells (BMSCs). Few and discordant studies have evaluated the role of BMSC in hepatocarcinogenesis so far and further studies in vitro and in vivo are warranted in order to definitively clarify such an issue.

  12. Are hematopoietic stem cells involved in hepatocarcinogenesis?

    PubMed Central

    Antonino, Matteo; Del Prete, Valentina; Neve, Viviana; Scavo, Maria Principia; Barone, Michele

    2014-01-01

    The liver has three cell lineages able to proliferate after a hepatic injury: the mature hepatocyte, the ductular “bipolar” progenitor cell termed “oval cell” and the putative periductular stem cell. Hepatocytes can only produce other hepatocytes whereas ductular progenitor cells are considerate bipolar since they can give rise to biliary cells or hepatocytes. Periductular stem cells are rare in the liver, have a very long proliferation potential and may be multipotent, being this aspect still under investigation. They originate in the bone marrow since their progeny express genetic markers of donor hematopoietic cells after bone marrow transplantation. Since the liver is the hematopoietic organ of the fetus, it is possible that hematopoietic stem cells may reside in the liver of the adult. This assumption is proved by the finding that oval cells express hematopoietic markers like CD34, CD45, CD 109, Thy-1, c-kit, and others, which are also expressed by bone marrow-derived hematopoietic stem cells (BMSCs). Few and discordant studies have evaluated the role of BMSC in hepatocarcinogenesis so far and further studies in vitro and in vivo are warranted in order to definitively clarify such an issue. PMID:25202697

  13. Adult hematopoietic stem cells lacking Hif-1α self-renew normally

    PubMed Central

    Vukovic, Milica; Sepulveda, Catarina; Subramani, Chithra; Guitart, Amélie V.; Mohr, Jasmine; Allen, Lewis; Panagopoulou, Theano I.; Paris, Jasmin; Lawson, Hannah; Villacreces, Arnaud; Armesilla-Diaz, Alejandro; Gezer, Deniz; Holyoake, Tessa L.; Ratcliffe, Peter J.

    2016-01-01

    The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed β subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1α is essential for HSC maintenance, whereby Hif-1α–deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2α is dispensable for cell-autonomous HSC maintenance, both under steady-state conditions and following transplantation. Given these unexpected findings, we set out to revisit the role of Hif-1α in cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1α has no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1α efficiently self-renew and sustain long-term multilineage hematopoiesis upon serial transplantation. Finally, Hif-1α–deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the bone marrow microenvironment, Hif-1α is dispensable for cell-autonomous HSC maintenance. PMID:27060169

  14. Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia.

    PubMed

    Wang, Wenwen; Stiehl, Thomas; Raffel, Simon; Hoang, Van T; Hoffmann, Isabel; Poisa-Beiro, Laura; Saeed, Borhan R; Blume, Rachel; Manta, Linda; Eckstein, Volker; Bochtler, Tilmann; Wuchter, Patrick; Essers, Marieke; Jauch, Anna; Trumpp, Andreas; Marciniak-Czochra, Anna; Ho, Anthony D; Lutz, Christoph

    2017-09-01

    In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse. Copyright© 2017 Ferrata Storti Foundation.

  15. Course Management Systems for Learning: Beyond Accidental Pedagogy

    ERIC Educational Resources Information Center

    McGee, Patricia; Carmean, Colleen; Jafari, Ali

    2005-01-01

    "Course Management Systems for Learning: Beyond Accidental Pedagogy" is a comprehensive overview of standards, practices and possibilities of course management systems in higher education. "Course Management Systems for Learning: Beyond Accidental Pedagogy" focuses on what the current knowledge is (in best practices, research, standards and…

  16. Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation

    PubMed Central

    Jones, Morgan; Osawa, Gail; Regal, Joshua A.; Weinberg, Daniel N.; Taggart, James; Kocak, Hande; Friedman, Ann; Ferguson, David O.; Keegan, Catherine E.; Maillard, Ivan

    2013-01-01

    The shelterin complex plays dual functions in telomere homeostasis by recruiting telomerase and preventing the activation of a DNA damage response at telomeric ends. Somatic stem cells require telomerase activity, as evidenced by progressive stem cell loss leading to bone marrow failure in hereditary dyskeratosis congenita. Recent work demonstrates that dyskeratosis congenita can also arise from mutations in specific shelterin genes, although little is known about shelterin functions in somatic stem cells. We found that mouse hematopoietic stem cells (HSCs) are acutely sensitive to inactivation of the shelterin gene Acd, encoding TPP1. Homozygosity for a hypomorphic acd allele preserved the emergence and expansion of fetal HSCs but led to profoundly defective function in transplantation assays. Upon complete Acd inactivation, HSCs expressed p53 target genes, underwent cell cycle arrest, and were severely depleted within days, leading to hematopoietic failure. TPP1 loss induced increased telomeric fusion events in bone marrow progenitors. However, unlike in epidermal stem cells, p53 deficiency did not rescue TPP1-deficient HSCs, indicating that shelterin dysfunction has unique effects in different stem cell populations. Because the consequences of telomere shortening are progressive and unsynchronized, acute loss of shelterin function represents an attractive alternative for studying telomere crisis in hematopoietic progenitors. PMID:24316971

  17. The Accidental Transgressor: Morally Relevant Theory of Mind

    PubMed Central

    Killen, Melanie; Mulvey, Kelly Lynn; Richardson, Cameron; Jampol, Noah

    2014-01-01

    To test young children’s false belief theory of mind in a morally relevant context, two experiments were conducted. In Experiment 1, children (N = 162) at 3.5, 5.5, and 7.5 years of age were administered 3 tasks: prototypic moral transgression task, false belief theory of mind task (ToM), and an “accidental transgressor” task, which measured a morally relevant false belief theory of mind (MoToM). Children who did not pass false belief ToM were more likely to attribute negative intentions to an accidental transgressor than children who passed false belief ToM, and to use moral reasons when blaming the accidental transgressor. In Experiment 2, children (N = 46) who did not pass false belief ToM viewed it as more acceptable to punish the accidental transgressor than did participants who passed false belief ToM. Findings are discussed in light of research on the emergence of moral judgment and theory of mind. PMID:21377148

  18. The Effects of Gamma and Proton Radiation Exposure on Hematopoietic Cell Counts in the Ferret Model

    PubMed Central

    Sanzari, Jenine K.; Wan, X. Steven; Krigsfeld, Gabriel S.; Wroe, Andrew J.; Gridley, Daila S.; Kennedy, Ann R.

    2014-01-01

    Exposure to total-body radiation induces hematological changes, which can detriment one's immune response to wounds and infection. Here, the decreases in blood cell counts after acute radiation doses of γ-ray or proton radiation exposure, at the doses and dose-rates expected during a solar particle event (SPE), are reported in the ferret model system. Following the exposure to γ-ray or proton radiation, the ferret peripheral total white blood cell (WBC) and lymphocyte counts decreased whereas neutrophil count increased within 3 hours. At 48 hours after irradiation, the WBC, neutrophil, and lymphocyte counts decreased in a dose-dependent manner but were not significantly affected by the radiation type (γ-rays verses protons) or dose rate (0.5 Gy/minute verses 0.5 Gy/hour). The loss of these blood cells could accompany and contribute to the physiological symptoms of the acute radiation syndrome (ARS). PMID:25356435

  19. Methylglyoxal-bis(guanylhydrazone), a polyamine analogue, sensitized γ-radiation-induced cell death in HL-60 leukemia cells Sensitizing effect of MGBG on γ-radiation-induced cell death.

    PubMed

    Kim, Jin Sik; Lee, Jin; Chung, Hai Won; Choi, Han; Paik, Sang Gi; Kim, In Gyu

    2006-09-01

    Methylglyoxal-bis(guanylhydrazone) (MGBG), a polyamine analogue, has been known to inhibit the biosynthesis of polyamines, which are important in cell proliferation. We showed that MGBG treatment significantly affected γ-radiation-induced cell cycle transition (G(1)/G(0)→S→G(2)/M) and thus γ-radiation-induced cell death. As determined by micronuclei and comet assay, we showed that it sensitized the cytotoxic effect induced by γ-radiation. One of the reasons is that polyamine depletion by MGBG treatment did not effectively protect against the chemical (OH) or physical damage to DNA caused by γ-radiation. Through in vitro experiment, we confirmed that DNA strand breaks induced by γ-radiation was prevented more effectively in the presence of polyamines (spermine and spermidine) than in the absence of polyamines. MGBG also blocks the cell cycle transition caused by γ-radiation (G(2) arrest), which helps protect cells by allowing time for DNA repair before entry into mitosis or apoptosis, via the down regulation of cyclin D1, which mediates the transition from G(1) to S phase of cell cycle, and ataxia telangiectasia mutated, which is involved in the DNA sensing, repair and cell cycle check point. Therefore, the abrogation of G(2) arrest sensitizes cells to the effect of γ-radiation. As a result, γ-radiation-induced cell death increased by about 2.5-3.0-fold in cells treated with MGBG. However, exogenous spermidine supplement partially relieved this γ-radiation-induced cytotoxicity and cell death. These findings suggest a potentially therapeutic strategy for increasing the cytotoxic efficacy of γ-radiation.

  20. [The occupational radiation-induced cataract in five industrial radiographers].

    PubMed

    Benzarti Mezni, A; Loukil, I; Hriz, N; Kallel, K; Mlaiki, N; Ben Jemaâ, A

    2012-04-01

    The industrial uses of ionizing radiation in Tunisia are expanding, especially in industry and most particularly in the nondestructive testing of welds. Thus workers operating in the non-destructive testing of welds may develop a radiation-induced cataract varying in time to onset depending on the dose. To describe the characteristics of the radiation-induced cataract in patients exposed to ionizing radiation, determine the risk factors of radiation-induced cataracts. This was an anamnestic, clinical, and environmental study of five cases of radiation-induced cataract in workers employed in non-destructive testing of welds. This series of five cases had a mean age of 30.2 years and 5.53 years of work experience, ranging from 14 months to 15 years. All the patients were male and industrial radiographers specialized in nondestructive testing of welds. The average duration of exposure to ionizing radiation was 5.53 years. None of the patients had worn protective gear such as eye goggles. The ophthalmic check-up for the five special industrial radiographers showed punctuate opacities in three cases, punctiform opacities in one eye in one case, and phacosclerosis with bilateral lens multiple crystalline stromal opacities in a case of micro-lens opacities in both eyes with opalescence of both eyes in one case. These cataracts had been declared as occupational diseases. The value of a specialized ophthalmologic surveillance among these workers and the early diagnosis of lens opacities must be emphasized. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  1. Biology and flow cytometry of proangiogenic hematopoietic progenitors cells.

    PubMed

    Rose, Jonathan A; Erzurum, Serpil; Asosingh, Kewal

    2015-01-01

    During development, hematopoiesis and neovascularization are closely linked to each other via a common bipotent stem cell called the hemangioblast that gives rise to both hematopoietic cells and endothelial cells. In postnatal life, this functional connection between the vasculature and hematopoiesis is maintained by a subset of hematopoietic progenitor cells endowed with the capacity to differentiate into potent proangiogenic cells. These proangiogenic hematopoietic progenitors comprise a specific subset of bone marrow (BM)-derived cells that homes to sites of neovascularization and possess potent paracrine angiogenic activity. There is emerging evidence that this subpopulation of hematopoietic progenitors plays a critical role in vascular health and disease. Their angiogenic activity is distinct from putative "endothelial progenitor cells" that become structural cells of the endothelium by differentiation into endothelial cells. Proangiogenic hematopoietic progenitor cell research requires multidisciplinary expertise in flow cytometry, hematology, and vascular biology. This review provides a comprehensive overview of proangiogenic hematopoietic progenitor cell biology and flow cytometric methods to detect these cells in the peripheral blood circulation and BM. © 2014 International Society for Advancement of Cytometry.

  2. Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function.

    PubMed

    Mgbemena, Victoria E; Signer, Robert A J; Wijayatunge, Ranjula; Laxson, Travis; Morrison, Sean J; Ross, Theodora S

    2017-01-24

    BRCA1 is a well-known DNA repair pathway component and a tissue-specific tumor suppressor. However, its role in hematopoiesis is uncertain. Here, we report that a cohort of patients heterozygous for BRCA1 mutations experienced more hematopoietic toxicity from chemotherapy than those with BRCA2 mutations. To test whether this reflects a requirement for BRCA1 in hematopoiesis, we generated mice with Brca1 mutations in hematopoietic cells. Mice homozygous for a null Brca1 mutation in the embryonic hematopoietic system (Vav1-iCre;Brca1 F22-24/F22-24 ) developed hematopoietic defects in early adulthood that included reduced hematopoietic stem cells (HSCs). Although mice homozygous for a huBRCA1 knockin allele (Brca1 BRCA1/BRCA1 ) were normal, mice with a mutant huBRCA1/5382insC allele and a null allele (Mx1-Cre;Brca1 F22-24/5382insC ) had severe hematopoietic defects marked by a complete loss of hematopoietic stem and progenitor cells. Our data show that Brca1 is necessary for HSC maintenance and normal hematopoiesis and that distinct mutations lead to different degrees of hematopoietic dysfunction. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  3. Erythroid differentiation of human induced pluripotent stem cells is independent of donor cell type of origin.

    PubMed

    Dorn, Isabel; Klich, Katharina; Arauzo-Bravo, Marcos J; Radstaak, Martina; Santourlidis, Simeon; Ghanjati, Foued; Radke, Teja F; Psathaki, Olympia E; Hargus, Gunnar; Kramer, Jan; Einhaus, Martin; Kim, Jeong Beom; Kögler, Gesine; Wernet, Peter; Schöler, Hans R; Schlenke, Peter; Zaehres, Holm

    2015-01-01

    Epigenetic memory in induced pluripotent stem cells, which is related to the somatic cell type of origin of the stem cells, might lead to variations in the differentiation capacities of the pluripotent stem cells. In this context, induced pluripotent stem cells from human CD34(+) hematopoietic stem cells might be more suitable for hematopoietic differentiation than the commonly used fibroblast-derived induced pluripotent stem cells. To investigate the influence of an epigenetic memory on the ex vivo expansion of induced pluripotent stem cells into erythroid cells, we compared induced pluripotent stem cells from human neural stem cells and human cord blood-derived CD34(+) hematopoietic stem cells and evaluated their potential for differentiation into hematopoietic progenitor and mature red blood cells. Although genome-wide DNA methylation profiling at all promoter regions demonstrates that the epigenetic memory of induced pluripotent stem cells is influenced by the somatic cell type of origin of the stem cells, we found a similar hematopoietic induction potential and erythroid differentiation pattern of induced pluripotent stem cells of different somatic cell origin. All human induced pluripotent stem cell lines showed terminal maturation into normoblasts and enucleated reticulocytes, producing predominantly fetal hemoglobin. Differences were only observed in the growth rate of erythroid cells, which was slightly higher in the induced pluripotent stem cells derived from CD34(+) hematopoietic stem cells. More detailed methylation analysis of the hematopoietic and erythroid promoters identified similar CpG methylation levels in the induced pluripotent stem cell lines derived from CD34(+) cells and those derived from neural stem cells, which confirms their comparable erythroid differentiation potential. Copyright© Ferrata Storti Foundation.

  4. Radiation-induced lichen sclerosus of the vulva : First report in the medical literature.

    PubMed

    Edwards, Lisa R; Privette, Emily D; Patterson, James W; Tchernev, Georgi; Chokoeva, Anastasiya Atanasova; Wollina, Uwe; Lotti, Torello; Wilson, Barbara B

    2017-03-01

    A 67-year-old woman presented with a firm plaque in the perineal region, 16 months after diagnosis of a high-grade basaloid squamous cell carcinoma of the vagina and treatment by external beam radiation therapy and vaginal cuff brachytherapy. The differential diagnosis included radiation-induced morphea, radiation dermatitis, or, possibly, radiation-induced lichen sclerosus. Biopsy findings, including special staining, confirmed the diagnosis of radiation-induced lichen sclerosus. To our knowledge, this is the first report of radiation-induced lichen sclerosus of the vulvar region.

  5. Real-space analysis of radiation-induced specific changes with independent component analysis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Borek, Dominika; Bromberg, Raquel; Hattne, Johan

    A method of analysis is presented that allows for the separation of specific radiation-induced changes into distinct components in real space. The method relies on independent component analysis (ICA) and can be effectively applied to electron density maps and other types of maps, provided that they can be represented as sets of numbers on a grid. Here, for glucose isomerase crystals, ICA was used in a proof-of-concept analysis to separate temperature-dependent and temperature-independent components of specific radiation-induced changes for data sets acquired from multiple crystals across multiple temperatures. ICA identified two components, with the temperature-independent component being responsible for themore » majority of specific radiation-induced changes at temperatures below 130 K. The patterns of specific temperature-independent radiation-induced changes suggest a contribution from the tunnelling of electron holes as a possible explanation. In the second case, where a group of 22 data sets was collected on a single thaumatin crystal, ICA was used in another type of analysis to separate specific radiation-induced effects happening on different exposure-level scales. Here, ICA identified two components of specific radiation-induced changes that likely result from radiation-induced chemical reactions progressing with different rates at different locations in the structure. In addition, ICA unexpectedly identified the radiation-damage state corresponding to reduced disulfide bridges rather than the zero-dose extrapolated state as the highest contrast structure. The application of ICA to the analysis of specific radiation-induced changes in real space and the data pre-processing for ICA that relies on singular value decomposition, which was used previously in data space to validate a two-component physical model of X-ray radiation-induced changes, are discussed in detail. This work lays a foundation for a better understanding of protein-specific radiation

  6. Modeling radiation induced segregation in Iron-Chromium alloys

    DOE PAGES

    Senninger, Oriane; Soisson, Frederic; Martinez Saez, Enrique; ...

    2015-10-16

    Radiation induced segregation in ferritic Fe-Cr alloys is studied by Atomistic Kinetic Monte Carlo simulations that include di usion of chemical species by vacancy and interstitial migration, recombination, and elimination at sinks. The parameters of the di usion model are tted to DFT calculations. Transport coe cients that control the coupling between di usion of defects and chemical species are measured in dilute and concentrated alloys. Radiation induced segregation near grain boundaries is directly simulated with this model. We nd that the di usion of vacancies toward sinks leads to a Cr depletion. Meanwhile, the di usion of self-interstitials causesmore » an enrichment of Cr in the vicinity of sinks. For concentrations lower than 15%Cr, we predict that sinks will be enriched with Cr for temperatures lower than a threshold. When the temperature is above this threshold value, the sinks will be depleted in Cr. These results are compared to previous experimental studies and models. Cases of radiation induced precipitation and radiation accelerated precipitation are considered.« less

  7. Space Radiation and the Brain

    NASA Astrophysics Data System (ADS)

    Hampson, R. E.

    Solar and cosmic radiation pose a number of physiological challenges to human spaceflight outside the protective region of Earth's magnetosphere. Aside from well-described effects of radiation on the blood-forming tissues of the hematopoietic system, there is increasing evidence of direct effects of radiation on the brain as evidenced by studies showing longitudinal decline in memory and cognitive function following radiation specifically directed at brain tissue. These indications strengthen the need to more fully research effects of radiation - particular those components associated with solar wind and galactic cosmic radiation - on the nervous system of mammals from rodents to humans.

  8. NEW APPLICATIONS OF ADAPTOGENS TO REDUCE RADIATION SIDE EFFECTS.

    PubMed

    Alekseeva, S N; Antipina, U D; Arzhakova, L I; Protodyakonov, S V

    2015-01-01

    One of the live medical issues today is to find medication to prevent adverse effects of ionizing radiation on the immune and hematopoietic systems. In Yakutia where in most of its regions the overall environmental situation is getting worse due to the development of natural deposits including radioactive deposits, this problem remains vital. The purpose of this work is to study radioprotective properties of adaptogens in the case of the hematopoietic system under irradiation. The studies were conducted on certain groups of hybrid mice. We used the methods of radiation exposure by a radiological apparatus RUM-25 on hybrid mice followed by studying the cellularity of bone marrow, spleen and thymus. The functional activity of all compartments of early hematopoiesis (bone marrow hematopoiesis) was identified by the exogenous colony forming method. The study found that the extracts of reindeer and moose antlers have a stimulating effect on the functional activity of the hematopoietic precursors in response to radiation. The study medication stimulates regeneration processes in the thymus and bone marrow after irradiation. Further, the adaptogens stimulatory effect on CFU functional activity was identified. The most pronounced effect has the extracts of reindeer antlers "Epsorin".

  9. bantam miRNA is important for Drosophila blood cell homeostasis and a regulator of proliferation in the hematopoietic progenitor niche

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Lam, Victoria; Tokusumi, Tsuyoshi; Tokusumi, Yumiko

    Highlights: • bantam miRNA is endogenously expressed in the hematopoietic progenitor niche. • bantam is necessary and sufficient to induce cellular proliferation in the PSC. • bantam is upstream of the Insulin Receptor signaling pathway. • A model for positive regulation of hematopoietic niche growth is proposed. - Abstract: The Drosophila hematopoietic system is utilized in this study to gain novel insights into the process of growth control of the hematopoietic progenitor niche in blood development. The niche microenvironment is an essential component controlling the balance between progenitor populations and differentiated, mature blood cells and has been shown to leadmore » to hematopoietic malignancies in humans when misregulated. MicroRNAs are one class of regulators associated with blood malignancies; however, there remains a relative paucity of information about the role of miRNAs in the niche. Here we demonstrate that bantam miRNA is endogenously active in the Drosophila hematopoietic progenitor niche, the posterior signaling center (PSC), and functions in the primary hematopoietic organ, the lymph gland, as a positive regulator of growth. Loss of bantam leads to a significant reduction in the PSC and overall lymph gland size, as well as a loss of the progenitor population and correlative premature differentiation of mature hemocytes. Interestingly, in addition to being essential for proper lymph gland development, we have determined bantam to be a novel upstream component of the insulin signaling cascade in the PSC and have unveiled dMyc as one factor central to bantam activity. These important findings identify bantam as a new hematopoietic regulator, place it in an evolutionarily conserved signaling pathway, present one way in which it is regulated, and provide a mechanism through which it facilitates cellular proliferation in the hematopoietic niche.« less

  10. Countermeasures for space radiation induced adverse biologic effects

    NASA Astrophysics Data System (ADS)

    Kennedy, A. R.; Wan, X. S.

    2011-11-01

    Radiation exposure in space is expected to increase the risk of cancer and other adverse biological effects in astronauts. The types of space radiation of particular concern for astronaut health are protons and heavy ions known as high atomic number and high energy (HZE) particles. Recent studies have indicated that carcinogenesis induced by protons and HZE particles may be modifiable. We have been evaluating the effects of proton and HZE particle radiation in cultured human cells and animals for nearly a decade. Our results indicate that exposure to proton and HZE particle radiation increases oxidative stress, cytotoxicity, cataract development and malignant transformation in in vivo and/or in vitro experimental systems. We have also shown that these adverse biological effects can be prevented, at least partially, by treatment with antioxidants and some dietary supplements that are readily available and have favorable safety profiles. Some of the antioxidants and dietary supplements are effective in preventing radiation induced malignant transformation in vitro even when applied several days after the radiation exposure. Our recent progress is reviewed and discussed in the context of the relevant literature.

  11. Adenosine Kinase Inhibition Protects against Cranial Radiation-Induced Cognitive Dysfunction

    PubMed Central

    Acharya, Munjal M.; Baulch, Janet E.; Lusardi, Theresa A.; Allen, Barrett. D.; Chmielewski, Nicole N.; Baddour, Al Anoud D.; Limoli, Charles L.; Boison, Detlev

    2016-01-01

    Clinical radiation therapy for the treatment of CNS cancers leads to unintended and debilitating impairments in cognition. Radiation-induced cognitive dysfunction is long lasting; however, the underlying molecular and cellular mechanisms are still not well established. Since ionizing radiation causes microglial and astroglial activation, we hypothesized that maladaptive changes in astrocyte function might be implicated in radiation-induced cognitive dysfunction. Among other gliotransmitters, astrocytes control the availability of adenosine, an endogenous neuroprotectant and modulator of cognition, via metabolic clearance through adenosine kinase (ADK). Adult rats exposed to cranial irradiation (10 Gy) showed significant declines in performance of hippocampal-dependent cognitive function tasks [novel place recognition, novel object recognition (NOR), and contextual fear conditioning (FC)] 1 month after exposure to ionizing radiation using a clinically relevant regimen. Irradiated rats spent less time exploring a novel place or object. Cranial irradiation also led to reduction in freezing behavior compared to controls in the FC task. Importantly, immunohistochemical analyses of irradiated brains showed significant elevation of ADK immunoreactivity in the hippocampus that was related to astrogliosis and increased expression of glial fibrillary acidic protein (GFAP). Conversely, rats treated with the ADK inhibitor 5-iodotubercidin (5-ITU, 3.1 mg/kg, i.p., for 6 days) prior to cranial irradiation showed significantly improved behavioral performance in all cognitive tasks 1 month post exposure. Treatment with 5-ITU attenuated radiation-induced astrogliosis and elevated ADK immunoreactivity in the hippocampus. These results confirm an astrocyte-mediated mechanism where preservation of extracellular adenosine can exert neuroprotection against radiation-induced pathology. These innovative findings link radiation-induced changes in cognition and CNS functionality to altered

  12. Comparison of Toxicity of Benzene Metabolite Hydroquinone in Hematopoietic Stem Cells Derived from Murine Embryonic Yolk Sac and Adult Bone Marrow

    PubMed Central

    Zhu, Jie; Wang, Hong; Yang, Shuo; Guo, Liqiao; Li, Zhen; Wang, Wei; Wang, Suhan; Huang, Wenting; Wang, Liping; Yang, Tan; Ma, Qiang; Bi, Yongyi

    2013-01-01

    Benzene is an occupational toxicant and an environmental pollutant that potentially causes hematotoxicity and leukemia in exposed populations. Epidemiological studies suggest an association between an increased incidence of childhood leukemia and benzene exposure during the early stages of pregnancy. However, experimental evidence supporting the association is lacking at the present time. It is believed that benzene and its metabolites target hematopoietic stem cells (HSCs) to cause toxicity and cancer in the hematopoietic system. In the current study, we compared the effects of hydroquinone (HQ), a major metabolite of benzene in humans and animals, on mouse embryonic yolk sac hematopoietic stem cells (YS-HSCs) and adult bone marrow hematopoietic stem cells (BM-HSCs). YS-HSCs and BM-HSCs were isolated and enriched, and were exposed to HQ at increasing concentrations. HQ reduced the proliferation and the differentiation and colony formation, but increased the apoptosis of both YS-HSCs and BM-HSCs. However, the cytotoxic and apoptotic effects of HQ were more apparent and reduction of colony formation by HQ was more severe in YS-HSCs than in BM-HSCs. Differences in gene expression profiles were observed in HQ-treated YS-HSCs and BM-HSCs. Cyp4f18 was induced by HQ both in YS-HSCs and BM-HSCs, whereas DNA-PKcs was induced in BM-HSCs only. The results revealed differential effects of benzene metabolites on embryonic and adult HSCs. The study established an experimental system for comparison of the hematopoietic toxicity and leukemogenicity of benzene and metabolites during mouse embryonic development and adulthood. PMID:23940708

  13. Radiation-induced cerebrovascular disease in children

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wright, T.L.; Bresnan, M.J.

    1976-06-01

    Radiation-induced internal carotid artery occlusion has not been well recognized previously as a cause of childhood cerebrovascular disease. A child who had received radiation as a neonate for a hemangioma involving the left orbit at the age of 6 years experienced a recurrent right-sided paresis, vascular headaches, and speech difficulties. Angiography showed a hypoplastic left carotid artery with occlusion of both the anterior and middle cerebral arteries. Collateral vessels bypassed the occluded-stenotic segments. Review of the literature showed two additional cases of large vessel occlusion in childhood associated with anastomatic telangiectatic vessel development following early radiation therapy of facial hemangioma.

  14. CD44-mediated hyaluronan binding marks proliferating hematopoietic progenitor cells and promotes bone marrow engraftment

    PubMed Central

    Lee-Sayer, Sally S. M.; Dougan, Meghan N.; Cooper, Jesse; Sanderson, Leslie; Dosanjh, Manisha; Maxwell, Christopher A.

    2018-01-01

    CD44 is a widely expressed cell adhesion molecule that binds to the extracellular matrix component, hyaluronan. However, this interaction is not constitutive in most immune cells at steady state, as the ability of CD44 to engage hyaluronan is highly regulated. While activated T cells and macrophages gain the ability to bind hyaluronan by CD44, the status in other immune cells is less studied. Here we found a percentage of murine eosinophils, natural killer and natural killer T cells were capable of interacting with hyaluronan at steady state. To further investigate the consequences of hyaluronan binding by CD44 in the hematopoietic system, point mutations of CD44 that either cannot bind hyaluronan (LOF-CD44) or have an increased affinity for hyaluronan (GOF-CD44) were expressed in CD44-deficient bone marrow. Competitive bone marrow reconstitution of irradiated mice revealed an early preference for GOF-CD44 over WT-CD44 expressing cells, and for WT-CD44 over LOF-CD44 expressing cells, in the hematopoietic progenitor cell compartment. The advantage of the hyaluronan-binding cells was observed in the hematopoietic stem and progenitor populations, and was maintained throughout the immune system. Hematopoietic stem cells bound minimal hyaluronan at steady state, and this was increased when the cells were induced to proliferate whereas multipotent progenitors had an increased ability to bind hyaluronan at steady state. In vitro, the addition of hyaluronan promoted their proliferation. Thus, proliferating hematopoietic progenitors bind hyaluronan, and hyaluronan binding cells have a striking competitive advantage in bone marrow engraftment. PMID:29684048

  15. Thrombopoietin contributes to the formation and the maintenance of hematopoietic progenitor-containing cell clusters in the aorta-gonad-mesonephros region.

    PubMed

    Harada, Kaho; Nobuhisa, Ikuo; Anani, Maha; Saito, Kiyoka; Taga, Tetsuya

    2017-07-01

    In the midgestation mouse embryo, hematopoietic cell clusters containing hematopoietic stem/progenitor cells arise in the aorta-gonad-mesonephros (AGM) region. We have previously reported that forced expression of the Sox17 transcription factor in CD45 low c-Kit high AGM cells, which are the hematopoietic cellular component of the cell clusters, and subsequent coculture with OP9 stromal cells in the presence of three cytokines, stem cell factor (SCF), interleukin-3 (IL-3), and thrombopoietin (TPO), led to the formation and the maintenance of cell clusters with cells at an undifferentiated state in vitro. In this study, we investigated the role of each cytokine in the formation of hematopoietic cell clusters. We cultured Sox17-transduced AGM cells with each of the 7 possible combinations of the three cytokines. The size and the number of Sox17-transduced cell clusters in the presence of TPO, either alone or in combination, were comparable to that observed with the complete set of the three cytokines. Expression of TPO receptor, c-Mpl was almost ubiquitously expressed and maintained in Sox17-transduced hematopoietic cell clusters. In addition, the expression level of c-Mpl was highest in the CD45 low c-Kit high cells among the Sox17-transduced cell clusters. Moreover, c-Mpl protein was highly expressed in the intra-aortic hematopoietic cell clusters in comparison with endothelial cells of dorsal aorta. Finally, stimulation of the endothelial cells prepared from the AGM region by TPO induced the production of hematopoietic cells. These results suggest that TPO contributes to the formation and the maintenance of hematopoietic cell clusters in the AGM region. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Adult hematopoietic stem cells lacking Hif-1α self-renew normally.

    PubMed

    Vukovic, Milica; Sepulveda, Catarina; Subramani, Chithra; Guitart, Amélie V; Mohr, Jasmine; Allen, Lewis; Panagopoulou, Theano I; Paris, Jasmin; Lawson, Hannah; Villacreces, Arnaud; Armesilla-Diaz, Alejandro; Gezer, Deniz; Holyoake, Tessa L; Ratcliffe, Peter J; Kranc, Kamil R

    2016-06-09

    The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed β subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1α is essential for HSC maintenance, whereby Hif-1α-deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2α is dispensable for cell-autonomous HSC maintenance, both under steady-state conditions and following transplantation. Given these unexpected findings, we set out to revisit the role of Hif-1α in cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1α has no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1α efficiently self-renew and sustain long-term multilineage hematopoiesis upon serial transplantation. Finally, Hif-1α-deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the bone marrow microenvironment, Hif-1α is dispensable for cell-autonomous HSC maintenance. © 2016 by The American Society of Hematology.

  17. Pluripotent stem cell models of Shwachman-Diamond syndrome reveal a common mechanism for pancreatic and hematopoietic dysfunction

    PubMed Central

    Tulpule, Asmin; Kelley, James M.; Lensch, M. William; McPherson, Jade; Park, In Hyun; Hartung, Odelya; Nakamura, Tomoka; Schlaeger, Thorsten M.; Shimamura, Akiko; Daley, George Q.

    2013-01-01

    Summary Shwachman-Diamond syndrome (SDS), a rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency and hematopoietic dysfunction, is caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. We created human pluripotent stem cell models of SDS by knock-down of SBDS in human embryonic stem cells (hESCs) and generation of induced pluripotent stem cell (iPSC) lines from two SDS patients. SBDS-deficient hESCs and iPSCs manifest deficits in exocrine pancreatic and hematopoietic differentiation in vitro, enhanced apoptosis and elevated protease levels in culture supernatants, which could be reversed by restoring SBDS protein expression through transgene rescue or by supplementing culture media with protease inhibitors. Protease-mediated auto-digestion provides a mechanistic link between the pancreatic and hematopoietic phenotypes in SDS, highlighting the utility of hESCs and iPSCs in obtaining novel insights into human disease. PMID:23602541

  18. Accidental poisoning with "Chinese chalk".

    PubMed

    Martínez-Navarrete, Juan; Loria-Castellanos, Jorge; Nava-Ocampo, Alejandro A

    2008-04-01

    We present a 1.5-year old, 11 kg, female infant with a history of bronchial hyper-responsiveness who accidentally ingested half of a "Chinese chalk". A day later, the infant showed vomiting, cough, fever, drowsiness, and irritability and her clinical conditions progressively worsened. She was admitted to the emergency department with cough, respiratory distress, and hepatomegaly. It has been reported that the chalk may contain deltamethrin and cypermethrin. The patient was successfully treated with supportive therapy. This report identifies "Chinese chalk" as a potential source of accidental poisoning in children and should be considered as part of the differential diagnoses in the emergency rooms since poisoning with these compounds may be misdiagnosed as organophosphate poisoning due to the presentation of similar symptoms.

  19. Free iron catalyzes oxidative damage to hematopoietic cells/mesenchymal stem cells in vitro and suppresses hematopoiesis in iron overload patients.

    PubMed

    Lu, Wenyi; Zhao, Mingfeng; Rajbhandary, Sajin; Xie, Fang; Chai, Xiao; Mu, Juan; Meng, Juanxia; Liu, Yongjun; Jiang, Yan; Xu, Xinnv; Meng, Aimin

    2013-09-01

    Transfusional iron overload is of major concern in hematological disease. Iron-overload-related dyserythropoiesis and reactive oxygen species (ROS)-related damage to hematopoietic stem cell (HSC) function are major setbacks in treatment for such disorders. We therefore aim to investigate the effect of iron overload on hematopoiesis in the patients and explore the role of ROS in iron-induced oxidative damage in hematopoietic cells and microenvironment in vitro. The hematopoietic colony-forming capacity and ROS level of bone marrow cells were tested before and after iron chelation therapy. In vitro, we first established an iron overload model of bone marrow mononuclear cells (BMMNC) and umbilical cord-derived mesenchymal stem cells (UC-MSC). ROS level, cell cycle, and apoptosis were measured by FACS. Function of cells was individually studied by Colony-forming cell (CFC) assay and co-culture system. Finally, ROS-related signaling pathway was also detected by Western blot. After administering deferoxamine (DFO), reduced blood transfusion, increased neutrophil, increased platelet, and improved pancytopenia were observed in 76.9%, 46.2%, 26.9%, and 15.4% of the patients, respectively. Furthermore, the colony-forming capacity of BMMNC from iron overload patient was deficient, and ROS level was higher, which were partially recovered following iron chelation therapy. In vitro, exposure of BMMNC to ferric ammonium citrate (FAC) for 24 h decreased the ratio of CD34(+) cell from 0.91 ± 0.12% to 0.39 ± 0.07%. Excessive iron could also induce apoptosis, arrest cell cycle, and decrease function of BMMNC and UC-MSC, which was accompanied by increased ROS level and stimulated p38MAPK, p53 signaling pathway. More importantly, N-acetyl-L-cysteine (NAC) or DFO could partially attenuate cell injury and inhibit the signaling pathway induced by excessive iron. Our study shows that iron overload injures the hematopoiesis by damaging hematopoietic cell and hematopoietic

  20. Involvement of Prolonged Ras Activation in Thrombopoietin-Induced Megakaryocytic Differentiation of a Human Factor-Dependent Hematopoietic Cell Line

    PubMed Central

    Matsumura, Itaru; Nakajima, Koichi; Wakao, Hiroshi; Hattori, Seisuke; Hashimoto, Koji; Sugahara, Hiroyuki; Kato, Takashi; Miyazaki, Hiroshi; Hirano, Toshio; Kanakura, Yuzuru

    1998-01-01

    Thrombopoietin (TPO) is a hematopoietic growth factor that plays fundamental roles is both megakaryopoiesis and thrombopoiesis through binding to its receptor, c-mpl. Although TPO has been shown to activate various types of intracellular signaling molecules, such as the Janus family of protein tyrosine kinases, signal transducers and activators of transcription (STATs), and ras, the precise mechanisms underlying TPO-induced proliferation and differentiation remain unknown. In an effort to clarify the mechanisms of TPO-induced proliferation and differentiation, c-mpl was introduced into F-36P, a human interleukin-3 (IL-3)-dependent erythroleukemia cell line, and the effects of TPO on the c-mpl-transfected F-36P (F-36P-mpl) cells were investigated. F-36P-mpl cells were found to proliferate and differentiate at a high rate into mature megakaryocytes in response to TPO. Dominant-negative (dn) forms of STAT1, STAT3, STAT5, and ras were inducibly expressed in F-36P-mpl cells, and their effects on TPO-induced proliferation and megakaryocytic differentiation were analyzed. Among these dn molecules, both dn ras and dn STAT5 reduced TPO- or IL-3-induced proliferation of F-36P-mpl cells by ∼30%, and only dn ras could inhibit TPO-induced megakaryocytic differentiation. In accord with this result, overexpression of activated ras (H-rasG12V) for 5 days led to megakaryocytic differentiation of F-36P-mpl cells. In a time course analysis on H-rasG12V-induced differentiation, activation of the ras pathway for 24 to 28 h was required and sufficient to induce megakaryocytic differentiation. Consistent with this result, the treatment of F-36P-mpl cells with TPO was able to induce prolonged activation of ras for more than 24 h, whereas IL-3 had only a transient effect. These results suggest that prolonged ras activation may be involved in TPO-induced megakaryocytic differentiation. PMID:9632812

  1. Accidental Nuclear War: The Growing Peril. Part I [and] Part II.

    ERIC Educational Resources Information Center

    Newcombe, Alan, Ed.

    1984-01-01

    Two volumes designed to increase awareness of accidental nuclear war dangers are presented. The first of 5 sections in volume I proposes that although accidental war is preventable, the current arms race and secrecy about accidents and false alarms increase the possibility of an accidental war. Section 2 posits that decreased decision-making time…

  2. Pathophysiology of Radiation-Induced Dysphagia in Head and Neck Cancer

    PubMed Central

    King, Suzanne N.; Dunlap, Neal E.; Tennant, Paul A.; Pitts, Teresa

    2017-01-01

    Oncologic treatments, such as curative radiotherapy and chemoradiation, for head and neck cancer can cause long-term swallowing impairments (dysphagia) that negatively impact quality of life. Radiation-induced dysphagia is comprised of a broad spectrum of structural, mechanical, and neurologic deficits. An understanding of the biomolecular effects of radiation on the time course of wound healing and underlying morphological tissue responses that precede radiation damage will improve options available for dysphagia treatment. The goal of this review is to discuss the pathophysiology of radiation-induced injury and elucidate areas that need further exploration. PMID:27098922

  3. Pathophysiology of Radiation-Induced Dysphagia in Head and Neck Cancer.

    PubMed

    King, Suzanne N; Dunlap, Neal E; Tennant, Paul A; Pitts, Teresa

    2016-06-01

    Oncologic treatments, such as curative radiotherapy and chemoradiation, for head and neck cancer can cause long-term swallowing impairments (dysphagia) that negatively impact quality of life. Radiation-induced dysphagia comprised a broad spectrum of structural, mechanical, and neurologic deficits. An understanding of the biomolecular effects of radiation on the time course of wound healing and underlying morphological tissue responses that precede radiation damage will improve options available for dysphagia treatment. The goal of this review is to discuss the pathophysiology of radiation-induced injury and elucidate areas that need further exploration.

  4. Advancement Is Seldom Accidental.

    ERIC Educational Resources Information Center

    Frantzreb, Arthur C.

    1981-01-01

    Success in college goals and programs for institutional advancement is seldom accidental: success in philanthropic support is seen as 90 percent planning and 10 percent implementation. Trustee membership, long-range plans, the motivational case, experienced staff, adequate budgets, prospect research, supportive communication all meld into a plan…

  5. Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors

    PubMed Central

    Kermani, Pouneh; Rafii, Dahlia; Jin, David K.; Whitlock, Paul; Schaffer, Wendy; Chiang, Anne; Vincent, Loic; Friedrich, Matthias; Shido, Koji; Hackett, Neil R.; Crystal, Ronald G.; Rafii, Shahin; Hempstead, Barbara L.

    2005-01-01

    The neurotrophin brain-derived neurotrophic factor (BDNF) is required for the maintenance of cardiac vessel wall stability during embryonic development through direct angiogenic actions on endothelial cells expressing the tropomysin receptor kinase B (TrkB). However, the role of BDNF and a related neurotrophin ligand, neurotrophin-4 (NT-4), in the regulation of revascularization of the adult tissues is unknown. To study the potential angiogenic capacity of BDNF in mediating the neovascularization of ischemic and non-ischemic adult mouse tissues, we utilized a hindlimb ischemia and a subcutaneous Matrigel model. Recruitment of endothelial cells and promotion of channel formation within the Matrigel plug by BDNF and NT-4 was comparable to that induced by VEGF-A. The introduction of BDNF into non-ischemic ears or ischemic limbs induced neoangiogenesis, with a 2-fold increase in the capillary density. Remarkably, treatment with BDNF progressively increased blood flow in the ischemic limb over 21 days, similar to treatment with VEGF-A. The mechanism by which BDNF enhances capillary formation is mediated in part through local activation of the TrkB receptor and also by recruitment of Sca-1+CD11b+ pro-angiogenic hematopoietic cells. BDNF induces a potent direct chemokinetic action on subsets of marrow-derived Sca-1+ hematopoietic cells co-expressing TrkB. These studies suggest that local regional delivery of BDNF may provide a novel mechanism for inducing neoangiogenesis through both direct actions on local TrkB-expressing endothelial cells in skeletal muscle and recruitment of specific subsets of TrkB+ bone marrow–derived hematopoietic cells to provide peri-endothelial support for the newly formed vessels. PMID:15765148

  6. Protective effects of dietary antioxidants on proton total-body irradiation-mediated hematopoietic cell and animal survival.

    PubMed

    Wambi, Chris O; Sanzari, Jenine K; Sayers, Carly M; Nuth, Manunya; Zhou, Zhaozong; Davis, James; Finnberg, Niklas; Lewis-Wambi, Joan S; Ware, Jeffrey H; El-Deiry, Wafik S; Kennedy, Ann R

    2009-08-01

    Abstract Dietary antioxidants have radioprotective effects after gamma-radiation exposure that limit hematopoietic cell depletion and improve animal survival. The purpose of this study was to determine whether a dietary supplement consisting of l-selenomethionine, vitamin C, vitamin E succinate, alpha-lipoic acid and N-acetyl cysteine could improve survival of mice after proton total-body irradiation (TBI). Antioxidants significantly increased 30-day survival of mice only when given after irradiation at a dose less than the calculated LD(50/30); for these data, the dose-modifying factor (DMF) was 1.6. Pretreatment of animals with antioxidants resulted in significantly higher serum total white blood cell, polymorphonuclear cell and lymphocyte cell counts at 4 h after 1 Gy but not 7.2 Gy proton TBI. Antioxidants significantly modulated plasma levels of the hematopoietic cytokines Flt-3L and TGFbeta1 and increased bone marrow cell counts and spleen mass after TBI. Maintenance of the antioxidant diet resulted in improved recovery of peripheral leukocytes and platelets after sublethal and potentially lethal TBI. Taken together, oral supplementation with antioxidants appears to be an effective approach for radioprotection of hematopoietic cells and improvement of animal survival after proton TBI.

  7. Radiation-induced chondrosarcoma of the maxilla 7-year after combined chemoradiation for tonsillar lymphoma.

    PubMed

    Mohammadianpanah, M; Gramizadeh, B; Omidvari, Sh; Mosalaei, A

    2004-01-01

    Radiation-induced sarcoma is a rare complication of radiation therapy. We report a case of radiation-induced chondrosarcoma of the maxilla. An 80-year-old Persian woman developed radiation-induced chondrosarcoma of the left maxilla 7 years after combined chemotherapy and external beam radiation therapy for the Ann Arbor stage IE malignant lymphoma of the right tonsil. She underwent suboptimal tumour resection and died due to extensive locoregional disease 8 months later. An English language literature search of Medline using the terms chondrosarcoma, radiation-induced sarcoma and maxilla revealed only one earlier reported case. We describe the clinical and pathological features of this case and review the literature on radiation-induced sarcomas.

  8. Do autologous peripheral blood cell transplants provide more than hematopoietic recovery?

    PubMed

    Kessinger, A

    1995-07-01

    Bone marrow damage caused by myeloablative radiation therapy and/or chemotherapy can be repaired by intravenously infusing viable stem/progenitor cells collected from either blood or bone marrow. The hematopoietic graft product contains both stem/progenitor cells and populations of hematopoietic and nonhematopoietic (accessory) cells. The frequency of accessory cell types varies with the source of the graft product; marrow or blood. Reinfusion of these accessory cells causes effects other than the hematopoietic restoration provided by the stem/progenitor cells such as graft versus host disease and graft versus leukemia effect after allogeneic transplants. Effects of infused accessory cells in the autologous setting are less well studied and could provide ancillary advantages and/or disadvantages to the patient. Do these additional effects actually occur, and, if they do, are they more likely to appear following peripheral blood cell transplants (PBCT) or after autologous bone marrow transplants (AMBT)? Preliminary data are beginning to accumulate which suggest that reinfusion of occult tumor cells is less likely with PBCT, that immune reconstitution is different depending on the source of the autograft and that, for certain diseases, patient event-free survival following PBCT rather than ABMT may be better. However, infusion of occult tumor cells may result in re-establishment of the malignancy. If the accessory cells (including potential occult tumor cells) are eliminated from the product before transplant, will the patient have a better clinical outcome, or would benefits provided by infused accessory cells outweigh the risks of infused occult tumor cells? These controversial issues are in the very early stages of investigation.

  9. Toxic properties of specific radiation determinant molecules, derived from radiated species

    NASA Astrophysics Data System (ADS)

    Popov, Dmitri; Maliev, Vecheslav; Kedar, Prasad; Casey, Rachael; Jones, Jeffrey

    Introduction: High doses of radiation induce the formation of radiation toxins in the organs of irradiated mammals. After whole body irradiation, cellular macromolecules and cell walls are damaged as a result of long-lived radiation-induced free radicals, reactive oxygen species, and fast, charged particles of radiation. High doses of radiation induce breaks in the chemical bonds of macromolecules and cross-linking reactions via chemically active processes. These processes result in the creation of novel modified macromolecules that possess specific toxic and antigenic properties defined by the type and dose of irradiation by which they are generated. Radiation toxins isolated from the lymph of irradiated animals are classified as hematotoxic, neurotoxic, and enteric non-bacterial (GI) radiation toxins, and they play an important role in the development of hematopoietic, cerebrovascular, and gastrointestinal acute radiation syndromes (ARS). Seven distinct toxins derived from post-irradiated animals have been designated as Specific Radiation Determinants (SRD): SRD-1 (neurotoxic radiation toxin generated by the cerebrovascular form of ARS), SRD-3 (enteric non-bacterial radiation toxins generated by the gastrointestinal form of ARS), and SRD-4 (hematotoxic radiation toxins generated by the hematological, bone marrow form of ARS). SRD-4 is further subdivided into four groups depending on the severity of the ARS induced: SRD-4/1, mild ARS; SRD-4/2, moderate ARS; SRD-4/3, severe ARS; and SRD-4/4, extremely severe ARS. The seventh SRD, SRD-2 is a toxic extract derived from animals suffering from a fourth form of ARS, as described in European literature and produces toxicity primarily in the autonimic nervous system. These radiation toxins have been shown to be responsible for the induction of important pathophysiological, immunological, and biochemical reactions in ARS. Materials and Methods: These studies incorporated the use of statistically significant numbers of a

  10. Pathophysiological Responses in Rat and Mouse Models of Radiation-Induced Brain Injury.

    PubMed

    Yang, Lianhong; Yang, Jianhua; Li, Guoqian; Li, Yi; Wu, Rong; Cheng, Jinping; Tang, Yamei

    2017-03-01

    The brain is the major dose-limiting organ in patients undergoing radiotherapy for assorted conditions. Radiation-induced brain injury is common and mainly occurs in patients receiving radiotherapy for malignant head and neck tumors, arteriovenous malformations, or lung cancer-derived brain metastases. Nevertheless, the underlying mechanisms of radiation-induced brain injury are largely unknown. Although many treatment strategies are employed for affected individuals, the effects remain suboptimal. Accordingly, animal models are extremely important for elucidating pathogenic radiation-associated mechanisms and for developing more efficacious therapies. So far, models employing various animal species with different radiation dosages and fractions have been introduced to investigate the prevention, mechanisms, early detection, and management of radiation-induced brain injury. However, these models all have limitations, and none are widely accepted. This review summarizes the animal models currently set forth for studies of radiation-induced brain injury, especially rat and mouse, as well as radiation dosages, dose fractionation, and secondary pathophysiological responses.

  11. Hsp70- and p53-reponses after heat treatment and/or X-irradiation mediate the susceptibility of hematopoietic cells to undergo apoptosis.

    PubMed

    Nijhuis, E H A; Poot, A A; Feijen, J; Vermes, I

    2008-02-01

    The effect of heat treatment in combination with X-irradiation was examined with regard to expression of p53, a tumor suppressor gene product, and Hsp70, a heat-shock protein, in association with the occurrence of programmed cell death (apoptosis). Three hematopoietic cell lines (HSB2, HL60 and Kasumi-1), which differ in p53 status, were exposed to 42.5 degrees C during one hour and/or X-radiation (total dose 8 Gy). After exposure, both mRNA and protein expression levels of Hsp70 and p53 were investigated by real-time PCR (polymerase chain reaction) and Western blotting. Apoptosis was simultaneously analyzed by observation of cell morphology as well as flowcytometric determination of Annexin V binding to phosphatidylserine and propidium iodide exclusion. Both HL60 and HSB2 cell lines with a low p53 status and a quick response to heat treatment with Hsp70 over-expression are less susceptible to heat-induced apoptosis compared to Kasumi-1 cells with wild-type p53 protein and no Hsp70 response. The combination of first applying X-irradiation followed by heat treatment resulted in the most effective induction of apoptosis due to impairment of the Hsp70 response in all three cell lines. These results indicate that the Hsp70 response and p53 status mediate the susceptibility of hematopoietic cells to undergo heat-induced apoptosis. Therefore, these parameters can be used as markers to predict the effectiveness of hyperthermia in cancer treatment.

  12. Parasitic Infections in Hematopoietic Stem Cell Transplantation

    PubMed Central

    Jarque, Isidro; Salavert, Miguel; Pemán, Javier

    2016-01-01

    Parasitic infections are rarely documented in hematopoietic stem cell transplant recipients. However they may be responsible for fatal complications that are only diagnosed at autopsy. Increased awareness of the possibility of parasitic diseases both in autologous and allogeneic stem cell transplant patients is relevant not only for implementing preventive measures but also for performing an early diagnosis and starting appropriate therapy for these unrecognized but fatal infectious complications in hematopoietic transplant recipients. In this review, we will focus on parasitic diseases occurring in this population especially those with major clinical relevance including toxoplasmosis, American trypanosomiasis, leishmaniasis, malaria, and strongyloidiasis, among others, highlighting the diagnosis and management in hematopoietic transplant recipients. PMID:27413527

  13. Ionizing radiation-induced mutagenesis: radiation studies in Neurospora predictive for results in mammalian cells

    NASA Technical Reports Server (NTRS)

    Evans, H. H.; DeMarini, D. M.

    1999-01-01

    Ionizing radiation was the first mutagen discovered and was used to develop the first mutagenicity assay. In the ensuing 70+ years, ionizing radiation became a fundamental tool in understanding mutagenesis and is still a subject of intensive research. Frederick de Serres et al. developed and used the Neurospora crassa ad-3 system initially to explore the mutagenic effects of ionizing radiation. Using this system, de Serres et al. demonstrated the dependence of the frequency and spectra of mutations induced by ionizing radiation on the dose, dose rate, radiation quality, repair capabilities of the cells, and the target gene employed. This work in Neurospora predicted the subsequent observations of the mutagenic effects of ionizing radiation in mammalian cells. Modeled originally on the mouse specific-locus system developed by William L. Russell, the N. crassa ad-3 system developed by de Serres has itself served as a model for interpreting the results in subsequent systems in mammalian cells. This review describes the primary findings on the nature of ionizing radiation-induced mutagenesis in the N. crassa ad-3 system and the parallel observations made years later in mammalian cells.

  14. Successful Thrombolysis and Spasmolysis of Acute Leg Ischemia after Accidental Intra-arterial Injection of Dissolved Flunitrazepam Tablets

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Radeleff, B., E-mail: Boris_radeleff@med.uni-heidelberg.de; Stampfl, U.; Sommer, C.-M.

    2011-10-15

    A 37-year-old man with known intravenous drug abuse presented in the surgical ambulatory care unit with acute leg ischemia after accidental intra-arterial injection of dissolved flunitrazepam tablets into the right femoral artery. A combination of anticoagulation, vasodilatation, and local selective and superselective thrombolysis with urokinase was performed to salvage the leg. As a result of the severe ischemia-induced pain, the patient had to be monitored over the complete therapy period on the intensive care unit with permanent administration of intravenous fluid and analgetics. We describe the presenting symptoms and the interventional technique, and we discuss the recent literature regarding themore » management of accidental intra-arterial injection of dissolved flunitrazepam tablets.« less

  15. Degos disease: a new simulator of non-accidental injury.

    PubMed

    Moss, Celia; Wassmer, Evangeline; Debelle, Geoff; Hackett, Scott; Goodyear, Helen; Malcomson, Roger; Ryder, Clive; Sgouros, Spyros; Shahidullah, Hossain

    2009-08-01

    Recent high-profile cases have made paediatricians very aware of the serious implications of either missing or wrongly diagnosing non-accidental injury. Subdural fluid collections in non-mobile infants usually represent haemorrhage caused by non-accidental injury. We report a 6-month-old male who presented to the Accident and Emergency Department of Birmingham Heartlands Hospital with bilateral subdural fluid collections and skin ulcers resembling cigarette burns. Non-accidental injury was considered to be the most likely diagnosis. However, while under observation in hospital, the child's neurological condition deteriorated with progressive cerebral infarctions, and serial photographs of the skin lesions showed failure to heal. The revised diagnosis, confirmed histologically, was Degos disease, an extremely rare and often fatal occlusive vasculopathy. The child was treated palliatively and died 8 weeks after presentation. This report informs doctors of a new simulator of non-accidental injury to be considered in infants with otherwise unexplained subdural fluid collections.

  16. Comparative study of microwave radiation-induced magnetoresistive oscillations induced by circularly- and linearly- polarized photo-excitation

    PubMed Central

    Ye, Tianyu; Liu, Han-Chun; Wang, Zhuo; Wegscheider, W.; Mani, Ramesh G.

    2015-01-01

    A comparative study of the radiation-induced magnetoresistance oscillations in the high mobility GaAs/AlGaAs heterostructure two dimensional electron system (2DES) under linearly- and circularly- polarized microwave excitation indicates a profound difference in the response observed upon rotating the microwave launcher for the two cases, although circularly polarized microwave radiation induced magnetoresistance oscillations observed at low magnetic fields are similar to the oscillations observed with linearly polarized radiation. For the linearly polarized radiation, the magnetoresistive response is a strong sinusoidal function of the launcher rotation (or linear polarization) angle, θ. For circularly polarized radiation, the oscillatory magnetoresistive response is hardly sensitive to θ. PMID:26450679

  17. Comparative study of microwave radiation-induced magnetoresistive oscillations induced by circularly- and linearly- polarized photo-excitation.

    PubMed

    Ye, Tianyu; Liu, Han-Chun; Wang, Zhuo; Wegscheider, W; Mani, Ramesh G

    2015-10-09

    A comparative study of the radiation-induced magnetoresistance oscillations in the high mobility GaAs/AlGaAs heterostructure two dimensional electron system (2DES) under linearly- and circularly- polarized microwave excitation indicates a profound difference in the response observed upon rotating the microwave launcher for the two cases, although circularly polarized microwave radiation induced magnetoresistance oscillations observed at low magnetic fields are similar to the oscillations observed with linearly polarized radiation. For the linearly polarized radiation, the magnetoresistive response is a strong sinusoidal function of the launcher rotation (or linear polarization) angle, θ. For circularly polarized radiation, the oscillatory magnetoresistive response is hardly sensitive to θ.

  18. Gamma radiation at a human relevant low dose rate is genotoxic in mice

    NASA Astrophysics Data System (ADS)

    Graupner, Anne; Eide, Dag M.; Instanes, Christine; Andersen, Jill M.; Brede, Dag A.; Dertinger, Stephen D.; Lind, Ole C.; Brandt-Kjelsen, Anicke; Bjerke, Hans; Salbu, Brit; Oughton, Deborah; Brunborg, Gunnar; Olsen, Ann K.

    2016-09-01

    Even today, 70 years after Hiroshima and accidents like in Chernobyl and Fukushima, we still have limited knowledge about the health effects of low dose rate (LDR) radiation. Despite their human relevance after occupational and accidental exposure, only few animal studies on the genotoxic effects of chronic LDR radiation have been performed. Selenium (Se) is involved in oxidative stress defence, protecting DNA and other biomolecules from reactive oxygen species (ROS). It is hypothesised that Se deficiency, as it occurs in several parts of the world, may aggravate harmful effects of ROS-inducing stressors such as ionising radiation. We performed a study in the newly established LDR-facility Figaro on the combined effects of Se deprivation and LDR γ exposure in DNA repair knockout mice (Ogg1-/-) and control animals (Ogg1+/-). Genotoxic effects were seen after continuous radiation (1.4 mGy/h) for 45 days. Chromosomal damage (micronucleus), phenotypic mutations (Pig-a gene mutation of RBCCD24-) and DNA lesions (single strand breaks/alkali labile sites) were significantly increased in blood cells of irradiated animals, covering three types of genotoxic activity. This study demonstrates that chronic LDR γ radiation is genotoxic in an exposure scenario realistic for humans, supporting the hypothesis that even LDR γ radiation may induce cancer.

  19. Low doses of oxygen ion irradiation cause long-term damage to bone marrow hematopoietic progenitor and stem cells in mice

    PubMed Central

    Wang, Yingying; Chang, Jianhui; Li, Xin; Pathak, Rupak; Sridharan, Vijayalakshmi; Jones, Tamako; Mao, Xiao Wen; Nelson, Gregory; Boerma, Marjan; Hauer-Jensen, Martin; Zhou, Daohong

    2017-01-01

    During deep space missions, astronauts will be exposed to low doses of charged particle irradiation. The long-term health effects of these exposures are largely unknown. We previously showed that low doses of oxygen ion (16O) irradiation induced acute damage to the hematopoietic system, including hematopoietic progenitor and stem cells in a mouse model. However, the chronic effects of low dose 16O irradiation remain undefined. In the current study, we investigated the long-term effects of low dose 16O irradiation on the mouse hematopoietic system. Male C57BL/6J mice were exposed to 0.05 Gy, 0.1 Gy, 0.25 Gy and 1.0 Gy whole body 16O (600 MeV/n) irradiation. The effects of 16O irradiation on bone marrow (BM) hematopoietic progenitor cells (HPCs) and hematopoietic stem cells (HSCs) were examined three months after the exposure. The results showed that the frequencies and numbers of BM HPCs and HSCs were significantly reduced in 0.1 Gy, 0.25 Gy and 1.0 Gy irradiated mice compared to 0.05 Gy irradiated and non-irradiated mice. Exposure of mice to low dose 16O irradiation also significantly reduced the clongenic function of BM HPCs determined by the colony-forming unit assay. The functional defect of irradiated HSCs was detected by cobblestone area-forming cell assay after exposure of mice to 0.1 Gy, 0.25 Gy and 1.0 Gy of 16O irradiation, while it was not seen at three months after 0.5 Gy and 1.0 Gy of γ-ray irradiation. These adverse effects of 16O irradiation on HSCs coincided with an increased intracellular production of reactive oxygen species (ROS). However, there were comparable levels of cellular apoptosis and DNA damage between irradiated and non-irradiated HPCs and HSCs. These data suggest that exposure to low doses of 16O irradiation induces long-term hematopoietic injury, primarily via increased ROS production in HSCs. PMID:29232383

  20. Radiation protection and mitigation by natural antioxidants and flavonoids; implications to radiotherapy and radiation disasters.

    PubMed

    Yahyapour, Rasoul; Shabeeb, Dheyauldeen; Cheki, Mohsen; Musa, Ahmed Eleojo; Farhood, Bagher; Rezaeyan, Abolhasan; Amini, Peyman; Fallah, Hengameh; Najafi, Masoud

    2018-06-19

    Nowadays, ionizing radiations are used for various medical and terroristic aims. These purposes involve exposure to ionizing radiations. Hence, people are at risk for acute or late effects. Annually, millions of cancer patients undergo radiotherapy during their course of treatment. Also, some radiological or nuclear events in recent years pose a threat to people, hence the need for radiation mitigation strategies. Amifostine, the first FDA approved radioprotector, has shown some toxicities that limit its usage and efficiency. Due to these side effects, scientists have researched for other agents with less toxicity for better radioprotection and possible mitigation of the lethal effects of ionizing radiations after an accidental exposure. Flavonoids have shown promising results for radioprotection and can be administered in higher doses with less toxicity. Studies for mitigation of ionizing radiation-induced toxicities has concentrated on natural antioxidants. Detoxification of free radicals, management of inflammatory responses and attenuation of apoptosis signaling pathways in radiosensitive organs are the main mechanisms for radiation protection and mitigation with flavonoids and natural antioxidants. However, several studies have proposed that a combination in the form of some antioxidants may alleviate radiation toxicities more effectively in comparison to a single form of antioxidants. In this review, we focus on recent findings about natural radioprotectors and mitigators which are clinically applicable for radiotherapy patients, as well as injured people in possible radiation accidents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. Lack of photoprotection against UVB-induced erythema by immediate pigmentation induced by 382 nm radiation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Black, G.; Matzinger, E.; Gange, R.W.

    Immediate pigment darkening (IPD) was induced on the backs of 11 human volunteers of skin types III and IV by exposing the skin to UVA radiation (382 nm). The minimum erythema dose (MED) of UVB radiation was also determined by exposing sites to graduated doses of 304 nm radiation. The order of exposure of distinct anatomic areas was as follow: UVB followed by IPD induction; IPD induction followed by UVB; IPD induction followed 3 h later by UVB; and UVB only. Erythema responses induced by UVB were graded by inspection 24 h later and the MEDs in the 4 areasmore » were compared. The induction of IPD before UVB exposure caused no significant change in the MED compared to sites receiving UVB only, or receiving UVA radiation after UVB, confirming that the IPD reaction does not protect against UVB-induced erythema. There was also no evidence of photorecovery, i.e., an increase in the MED of UVB resulting from exposure to longer wavelength, UV or visible radiation following UVB exposure.« less

  2. Hyperbaric oxygen: Primary treatment of radiation-induced hemorrhagic cystitis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Weiss, J.P.; Neville, E.C.

    Of 8 patients with symptoms of advanced cystitis due to pelvic radiation treated with hyperbaric oxygen 7 are persistently improved during followup. All 6 patients treated for gross hematuria requiring hospitalization have been free of symptoms for an average of 24 months (range 6 to 43 months). One patient treated for stress incontinence currently is dry despite little change in bladder capacity, implying salutary effect from hyperbaric oxygen on the sphincter mechanism. One patient with radiation-induced prostatitis failed to respond. This experience suggests that hyperbaric oxygen should be considered the primary treatment for patients with symptomatic radiation-induced hemorrhagic cystitis.

  3. Characterization of radiation-induced emesis in the ferret

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    King, G.L.

    1988-06-01

    Forty-eight ferrets (Mustela putorius furo) were individually head-shielded and radiated with bilateral /sup 60/Co gamma radiation at 100 cGy min-1 at doses ranging between 49 and 601 cGy. The emetic threshold was observed at 69 cGy, the ED50 was calculated at 77 cGy, and 100% incidence of emesis occurred at 201 cGy. With increasing doses of radiation, the latency to first emesis after radiation decreased dramatically, whereas the duration of the prodromal period increased. Two other sets of experiments suggest that dopaminergic mechanisms play a minor role in radiation-induced emesis in the ferret. Twenty-two animals were injected either intravenously ormore » subcutaneously with 30 to 300 micrograms/kg of apomorphine. Fewer than 50% of the animals vomited to 300 micrograms/kg apomorphine; central dopaminergic receptor activation was apparent at all doses. Another eight animals received 1 mg/kg domperidone prior to either 201 (n = 4) or 401 (n = 4) cGy radiation and their emetic responses were compared with NaCl-injected-irradiated controls (n = 8). At 201 cGy, domperidone significantly reduced only the total time in emetic behavior. At 401 cGy, domperidone had no salutary effect on radiation-induced emesis. The emetic responses of the ferret to radiation and apomorphine are compared with these responses in other vomiting species.« less

  4. Characterization of radiation-induced emesis in the ferret

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    King, G.L.

    1988-01-01

    Forty-eight ferrets (Mustela putorius furo) were individually head-shielded and radiated with bilateral cobalt 60 gamma radiation at 100 cGy min at doses ranging between 49 and 601 cGy. The emetic threshold was observed at 69 cGy, the ED 50 was calculated as 77 cGy, and 100% incidence of emesis occurred at 201 cGy. With increasing doses of radiation, the latency to first emesis after radiation decreased dramatically, whereas the duration of the prodromal period increased. Two other sets of experiments suggest that dopaminergic mechanisms play a minor role in radiation-induced emesis in the ferret. Twenty-two animals were injected either intravenouslymore » or subcutaneously with 30 to 300 micrograms /kg of apomorphine. Fewer than 50% of the animals vomited to 300 micrograms/kg apomorphine; central dopaminergic receptor activation was apparent at all doses. Another eight animals received 1 mg/kg domperidone prior to either 201 (n=4) or 401 (n=4) cGy radiation and their emetic responses were compared with NaCi-injected-irradiated controls (n=8). At 201 cGy, domperidone significantly reduced only the total time in emetic behavior. At 401 cGy, domperidone had no salutary effect on radiation-induced emesis. The emetic responses of the ferret to radiation and apomorphine are compared with these responses in other vomiting species.« less

  5. Low dose radiation induced senescence of human mesenchymal stromal cells and impaired the autophagy process

    PubMed Central

    Alessio, Nicola; Del Gaudio, Stefania; Capasso, Stefania; Di Bernardo, Giovanni; Cappabianca, Salvatore; Cipollaro, Marilena; Peluso, Gianfranco; Galderisi, Umberto

    2015-01-01

    Low doses of radiation may have profound effects on cellular function. Individuals may be exposed to low doses of radiation either intentionally for medical purposes or accidentally, such as those exposed to radiological terrorism or those who live near illegal radioactive waste dumpsites. We studied the effects of low dose radiation on human bone marrow mesenchymal stromal cells (MSC), which contain a subpopulation of stem cells able to differentiate in bone, cartilage, and fat; support hematopoiesis; and contribute to body's homeostasis. The main outcome of low radiation exposure, besides reduction of cell cycling, is the triggering of senescence, while the contribution to apoptosis is minimal. We also showed that low radiation affected the autophagic flux. We hypothesize that the autophagy prevented radiation deteriorative processes, and its decline contributed to senescence. An increase in ATM staining one and six hours post-irradiation and return to basal level at 48 hours, along with persistent gamma-H2AX staining, indicated that MSC properly activated the DNA repair signaling, though some damages remained unrepaired, mainly in non-cycling cells. This suggested that the impaired DNA repair capacity of irradiated MSC seemed mainly related to the reduced activity of a non-homologous end-joining (NHEJ) system rather than HR (homologous recombination). PMID:25544750

  6. Vitamin A-Retinoic Acid Signaling Regulates Hematopoietic Stem Cell Dormancy.

    PubMed

    Cabezas-Wallscheid, Nina; Buettner, Florian; Sommerkamp, Pia; Klimmeck, Daniel; Ladel, Luisa; Thalheimer, Frederic B; Pastor-Flores, Daniel; Roma, Leticia P; Renders, Simon; Zeisberger, Petra; Przybylla, Adriana; Schönberger, Katharina; Scognamiglio, Roberta; Altamura, Sandro; Florian, Carolina M; Fawaz, Malak; Vonficht, Dominik; Tesio, Melania; Collier, Paul; Pavlinic, Dinko; Geiger, Hartmut; Schroeder, Timm; Benes, Vladimir; Dick, Tobias P; Rieger, Michael A; Stegle, Oliver; Trumpp, Andreas

    2017-05-18

    Dormant hematopoietic stem cells (dHSCs) are atop the hematopoietic hierarchy. The molecular identity of dHSCs and the mechanisms regulating their maintenance or exit from dormancy remain uncertain. Here, we use single-cell RNA sequencing (RNA-seq) analysis to show that the transition from dormancy toward cell-cycle entry is a continuous developmental path associated with upregulation of biosynthetic processes rather than a stepwise progression. In addition, low Myc levels and high expression of a retinoic acid program are characteristic for dHSCs. To follow the behavior of dHSCs in situ, a Gprc5c-controlled reporter mouse was established. Treatment with all-trans retinoic acid antagonizes stress-induced activation of dHSCs by restricting protein translation and levels of reactive oxygen species (ROS) and Myc. Mice maintained on a vitamin A-free diet lose HSCs and show a disrupted re-entry into dormancy after exposure to inflammatory stress stimuli. Our results highlight the impact of dietary vitamin A on the regulation of cell-cycle-mediated stem cell plasticity. VIDEO ABSTRACT. Copyright © 2017. Published by Elsevier Inc.

  7. MicroRNA profiling of the murine hematopoietic system

    PubMed Central

    Monticelli, Silvia; Ansel, K Mark; Xiao, Changchun; Socci, Nicholas D; Krichevsky, Anna M; Thai, To-Ha; Rajewsky, Nikolaus; Marks, Debora S; Sander, Chris; Rajewsky, Klaus; Rao, Anjana; Kosik, Kenneth S

    2005-01-01

    Background MicroRNAs (miRNAs) are a class of recently discovered noncoding RNA genes that post-transcriptionally regulate gene expression. It is becoming clear that miRNAs play an important role in the regulation of gene expression during development. However, in mammals, expression data are principally based on whole tissue analysis and are still very incomplete. Results We used oligonucleotide arrays to analyze miRNA expression in the murine hematopoietic system. Complementary oligonucleotides capable of hybridizing to 181 miRNAs were immobilized on a membrane and probed with radiolabeled RNA derived from low molecular weight fractions of total RNA from several different hematopoietic and neuronal cells. This method allowed us to analyze cell type-specific patterns of miRNA expression and to identify miRNAs that might be important for cell lineage specification and/or cell effector functions. Conclusion This is the first report of systematic miRNA gene profiling in cells of the hematopoietic system. As expected, miRNA expression patterns were very different between hematopoietic and non-hematopoietic cells, with further subtle differences observed within the hematopoietic group. Interestingly, the most pronounced similarities were observed among fully differentiated effector cells (Th1 and Th2 lymphocytes and mast cells) and precursors at comparable stages of differentiation (double negative thymocytes and pro-B cells), suggesting that in addition to regulating the process of commitment to particular cellular lineages, miRNAs might have an important general role in the mechanism of cell differentiation and maintenance of cell identity. PMID:16086853

  8. The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease.

    PubMed

    Singbrant, Sofie; Wall, Meaghan; Moody, Jennifer; Karlsson, Göran; Chalk, Alistair M; Liddicoat, Brian; Russell, Megan R; Walkley, Carl R; Karlsson, Stefan

    2014-04-01

    The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced a gene signature associated with hematopoietic stem cells and myeloid differentiation, as well as hepatocyte growth factor signaling. Here we demonstrate that, in contrast to what has generally been assumed, the significant impact of SKI on hematopoiesis is independent of its ability to inhibit TGF-beta signaling. Instead, myeloid progenitors expressing SKI are partially dependent on functional hepatocyte growth factor signaling. Collectively our results demonstrate that SKI is an important regulator of hematopoietic stem cell activity and its overexpression leads to myeloproliferative disease.

  9. The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease

    PubMed Central

    Singbrant, Sofie; Wall, Meaghan; Moody, Jennifer; Karlsson, Göran; Chalk, Alistair M.; Liddicoat, Brian; Russell, Megan R.; Walkley, Carl R.; Karlsson, Stefan

    2014-01-01

    The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced a gene signature associated with hematopoietic stem cells and myeloid differentiation, as well as hepatocyte growth factor signaling. Here we demonstrate that, in contrast to what has generally been assumed, the significant impact of SKI on hematopoiesis is independent of its ability to inhibit TGF-beta signaling. Instead, myeloid progenitors expressing SKI are partially dependent on functional hepatocyte growth factor signaling. Collectively our results demonstrate that SKI is an important regulator of hematopoietic stem cell activity and its overexpression leads to myeloproliferative disease. PMID:24415629

  10. [Induced thymus aging: radiation model and application perspective for low intensive laser radiation].

    PubMed

    Sevost'ianova, N N; Trofimov, A V; Lin'kova, N S; Poliakova, V O; Kvetnoĭ, I M

    2010-01-01

    The influence of gamma-radiation on morphofunctional state of thymus is rather like as natural thymus aging. However gamma-radiation model of thymus aging widely used to investigate geroprotectors has many shortcomings and limitations. Gamma-radiation can induce irreversible changes in thymus very often. These changes are more intensive in comparison with changes, which can be observed at natural thymus aging. Low intensive laser radiation can not destroy structure of thymus and its effects are rather like as natural thymus aging in comparison with gamma-radiation effects. There are many parameters of low intensive laser radiation, which can be changed to improve morphofunctional thymus characteristics in aging model. Using low intensive laser radiation in thymus aging model can be very perspective for investigations of aging immune system.

  11. Chronic intermittent hypobaric hypoxia attenuates radiation induced heart damage in rats.

    PubMed

    Wang, Jun; Wu, Yajing; Yuan, Fang; Liu, Yixian; Wang, Xuefeng; Cao, Feng; Zhang, Yi; Wang, Sheng

    2016-09-01

    Radiation-induced heart damage (RIHD) is becoming an increasing concern for patients and clinicians due to the use of radiotherapy for thoracic tumor. Chronic intermittent hypobaric hypoxia (CIHH) preconditioning has been documented to exert a cardioprotective effect. Here we hypothesized that CIHH was capable of attenuating functional and structural damage in a rat model of RIHD. Male adult Sprague-Dawley rats were randomly divided into 4 groups: control, radiation, CIHH and CIHH plus radiation. Cardiac function was measured using Langendorff perfusion in in vitro rat hearts. Cardiac fibrosis, oxidative stress and endoplasmic reticulum stress (ERS) was assessed by quantitative analysis of protein expression. No significant difference between any two groups was observed in baseline cardiac function as assessed by left ventricular end diastolic pressure (LVEDP), left ventricular developing pressure (LVDP) and the derivative of left ventricular pressure (±LVdp/dt). When challenged by ischemia/reperfusion, LVEDP was increased but LVDP and ±LVdp/dt was decreased significantly in radiation group compared with controls, accompanied by an enlarged infarct size and decreased coronary flow. Importantly, CIHH dramatically improved radiation-induced damage of cardiac function and blunted radiation-induced cardiac fibrosis in the perivascular and interstitial area. Furthermore, CIHH abrogated radiation-induced increase in malondialdehyde and enhanced total superoxide dismutase activity, as well as downregulated expression levels of ERS markers like GRP78 and CHOP. CIHH pretreatment alleviated radiation-induced damage of cardiac function and fibrosis. Such a protective effect was closely associated with suppression of oxidative stress and ERS responses. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Rebamipide ameliorates radiation-induced intestinal injury in a mouse model.

    PubMed

    Shim, Sehwan; Jang, Hyo-Sun; Myung, Hyun-Wook; Myung, Jae Kyung; Kang, Jin-Kyu; Kim, Min-Jung; Lee, Seung Bum; Jang, Won-Suk; Lee, Sun-Joo; Jin, Young-Woo; Lee, Seung-Sook; Park, Sunhoo

    2017-08-15

    Radiation-induced enteritis is a major side effect in cancer patients undergoing abdominopelvic radiotherapy. Radiation exposure produces an uncontrolled inflammatory cascade and epithelial cell loss leading to impaired epithelial barrier function. The goal of this study was to determine the effect of rebamipide on regeneration of the intestinal epithelia after radiation injury. The abdomens of C57BL/6 mice were exposed to 13Gy of irradiation (IR) and then the mice were treated with rebamipide. Upon IR, intestinal epithelia were destroyed structurally at the microscopic level and bacterial translocation was increased. The intestinal damage reached a maximum level on day 6 post-IR and intestinal regeneration occurred thereafter. We found that rebamipide significantly ameliorated radiation-induced intestinal injury. In mice treated with rebamipide after IR, intestinal barrier function recovered and expression of the tight junction components of the intestinal barrier were upregulated. Rebamipide administration reduced radiation-induced intestinal mucosal injury. The levels of proinflammatory cytokines and matrix metallopeptidase 9 (MMP9) were significantly reduced upon rebamipide administration. Intestinal cell proliferation and β-catenin expression also increased upon rebamipide administration. These data demonstrate that rebamipide reverses impairment of the intestinal barrier by increasing intestinal cell proliferation and attenuating the inflammatory response by inhibiting MMP9 and proinflammatory cytokine expression in a murine model of radiation-induced enteritis. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Hematopoietic organs of Manduca sexta and hemocyte lineages.

    PubMed

    Nardi, James B; Pilas, Barbara; Ujhelyi, Elizabeth; Garsha, Karl; Kanost, Michael R

    2003-10-01

    Cells of the moth immune system are derived from organs that loosely envelop the four wing imaginal discs. The immune response in these insects is believed to depend on the activities of two main classes of hemocytes: plasmatocytes and granular cells. The fates of cells that arise from these hematopoietic organs have been followed by immunolabeling with plasmatocyte-specific and granular-cell-specific antibodies. Cells within each hematopoietic organ differ in their coherence and in their expression of two plasmatocyte-specific surface proteins, integrin and neuroglian. Within an organ there is no overlap in the expression of these two surface proteins; neuroglian is found on the surfaces of the coherent cells while integrin is expressed on cells that are losing coherence, rounding up, and dispersing. A granular-cell-specific marker for the protein lacunin labels the basal lamina that delimits each organ but only a small number of granular cells that lie on or near the periphery of the hematopoietic organ. When organs are cultured in the absence of hemolymph, all cells derived from hematopoietic organs turn out to immunolabel with the plasmatocyte-specific antibody MS13. The circulating plasmatocytes derived from hematopoietic organs have higher ploidy levels than the granular cells and represent a separate lineage of hemocytes.

  14. Autologous hematopoietic stem cells for refractory Crohn's disease.

    PubMed

    DiNicola, C A; Zand, A; Hommes, D W

    2017-05-01

    Autologous hematopoietic stem cells are gaining ground as an effective and safe treatment for treating severe refractory Crohn's disease (CD). Autologous hematopoietic stem cell therapy (AHSCT) induces resetting of the immune system by de novo regeneration of T-cell repertoire and repopulation of epithelial cells by bone-marrow derived cells to help patients achieve clinical and endoscopic remission. Areas covered: Herein, the authors discuss the use of AHSCT in treating patients with CD. Improvements in disease activity have been seen in patients with severe autoimmune disease and patients with severe CD who underwent AHSCT for a concomitant malignant hematological disease. Clinical and endoscopic remission has been achieved in patients treated with AHSCT for CD. The only randomized trial published to date, the ASTIC Trial, did not support further use of AHSCT to treat CD. Yet, critics of this trial have deemed AHSCT as a promising treatment for severe refractory CD. Expert opinion: Even with the promising evidence presented for HSCT for refractory CD, protocols need to be refined through the collaboration of GI and hemato-oncology professionals. The goal is to incorporate safe AHSCT and restore tolerance by delivering an effective immune 'cease fire' as a treatment option for severe refractory CD.

  15. Regulation of long-term repopulating hematopoietic stem cells by EPCR/PAR1 signaling

    PubMed Central

    Gur-Cohen, Shiri; Kollet, Orit; Graf, Claudine; Esmon, Charles T.; Ruf, Wolfram; Lapidot, Tsvee

    2016-01-01

    The common developmental origin of endothelial and hematopoietic cells is manifested by coexpression of several cell surface receptors. Adult murine bone marrow (BM) long-term repopulating hematopoietic stem cells (LT-HSCs), endowed with the highest repopulation and self-renewal potential, express endothelial protein C receptor (EPCR), which is used as a marker to isolate them. EPCR/PAR1 signaling in endothelial cells has anticoagulant and anti-inflammatory roles, while thrombin/PAR1 signaling induces coagulation and inflammation. Recent studies define two new PAR1-mediated signaling cascades that regulate EPCR+ LT-HSC BM retention and egress. EPCR/PAR1 signaling facilitates LT-HSC BM repopulation, retention, survival, and chemotherapy resistance by restricting nitric oxide (NO) production, maintaining NOlow LT-HSC BM retention with increased VLA4 expression, affinity, and adhesion. Conversely, acute stress and clinical mobilization upregulate thrombin generation and activate different PAR1 signaling which overcomes BM EPCR+ LT-HSC retention, inducing their recruitment to the bloodstream. Thrombin/PAR1 signaling induces NO generation, TACE-mediated EPCR shedding, and upregulation of CXCR4 and PAR1, leading to CXCL12-mediated stem and progenitor cell mobilization. This review discusses new roles for factors traditionally viewed as coagulation related, which independently act in the BM to regulate PAR1 signaling in bone- and blood-forming progenitor cells, navigating their fate by controlling NO production. PMID:26928241

  16. Apatinib in refractory radiation-induced brain edema: A case report.

    PubMed

    Hu, Wei Guo; Weng, Yi Ming; Dong, Yi; Li, Xiang Pan; Song, Qi-Bin

    2017-11-01

    Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, which has observed to be effective and safe in refractory radiation-induced brain edema, like Avastin did. Till now, there is no case report after apatinib came in the market. Two patients who received brain radiotherapy developed clinical manifestations of brain edema, including dizziness, headache, limb activity disorder, and so on. Two patients were both diagnosed as refractory radiation-induced brain edema. Two patients received apatinib (500 mg/day) for 2 and 4 weeks. Two patients got symptomatic improvements from apatinib in different degrees. Magnetic resonance imaging after apatinib treatments showed that compared with pre-treatment imaging, the perilesional edema reduced dramatically. However, the toxicity of apatinib was controllable and tolerable. Apatinib can obviously relieve the symptoms of refractory radiation-induced brain edema and improve the quality of life, which offers a new method for refractory radiation-induced brain edema in clinical practices. But that still warrants further investigation in the prospective study.

  17. Comparative study of microwave radiation-induced magnetoresistive oscillations induced by circularly- and linearly- polarized photo-excitation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ye, Tianyu; Liu, Han -Chun; Wang, Zhuo

    A comparative study of the radiation-induced magnetoresistance oscillations in the high mobility GaAs/AlGaAs heterostructure two dimensional electron system (2DES) under linearly- and circularly- polarized microwave excitation indicates a profound difference in the response observed upon rotating the microwave launcher for the two cases, although circularly polarized microwave radiation induced magnetoresistance oscillations observed at low magnetic fields are similar to the oscillations observed with linearly polarized radiation. For the linearly polarized radiation, the magnetoresistive response is a strong sinusoidal function of the launcher rotation (or linear polarization) angle, θ. As a result, for circularly polarized radiation, the oscillatory magnetoresistive response ismore » hardly sensitive to θ.« less

  18. Comparative study of microwave radiation-induced magnetoresistive oscillations induced by circularly- and linearly- polarized photo-excitation

    DOE PAGES

    Ye, Tianyu; Liu, Han -Chun; Wang, Zhuo; ...

    2015-10-09

    A comparative study of the radiation-induced magnetoresistance oscillations in the high mobility GaAs/AlGaAs heterostructure two dimensional electron system (2DES) under linearly- and circularly- polarized microwave excitation indicates a profound difference in the response observed upon rotating the microwave launcher for the two cases, although circularly polarized microwave radiation induced magnetoresistance oscillations observed at low magnetic fields are similar to the oscillations observed with linearly polarized radiation. For the linearly polarized radiation, the magnetoresistive response is a strong sinusoidal function of the launcher rotation (or linear polarization) angle, θ. As a result, for circularly polarized radiation, the oscillatory magnetoresistive response ismore » hardly sensitive to θ.« less

  19. Impact of Abbreviated Filgrastim Schedule on Survival and Hematopoietic Recovery after Irradiation in Four Mouse Strains with Different Radiosensitivity

    PubMed Central

    Satyamitra, Merriline; Kumar, Vidya P.; Biswas, Shukla; Cary, Lynnette; Dickson, Leonora; Venkataraman, Srinivasan; Ghosh, Sanchita P.

    2017-01-01

    Filgrastim (Neupogen®, granulocyte-colony stimulating factor) is among the few countermeasures recommended for management of patients in the event of lethal total-body irradiation. Despite the plethora of studies using filgrastim as a radiation countermeasure, relatively little is known about the optimal dose schedule of filgrastim to mitigate radiation lethality. We evaluated the efficacy of filgrastim in improving 30-day survival of CD2F1 mice irradiated with a lethal dose (LD70/30) in the AFRRI cobalt-60 facility. We tested different schedules of 1, 3, 5,10 or 16 once-daily injections of filgrastim initiated one day after irradiation. Time optimization studies with filgrastim treatment were also performed, beginning 6–48 h postirradiation. Maximum survival was observed with 3 daily doses of 0.17 mg/kg filgrastim. Survival efficacy of the 3-day treatment was compared against the conventional 16-day filgrastim treatment after irradiation in four mouse strains with varying radiation sensitivities: C3H/HeN, C57BL/6, B6C3F1 and CD2F1. Blood indices, bone marrow histopathology and colony forming unit assays were also evaluated. Filgrastim significantly increased 30-day survival (P < 0.001) with a 3-day treatment compared to 16-day treatment. Filgrastim did not prevent cytopenia nadirs, but facilitated faster recovery of white blood cells, neutrophils, red blood cells, platelets, lymphocytes and hematocrits in all four strains. Accelerated hematopoietic recovery was also reflected in faster bone marrow reconstitution and significant increase in hematopoietic progenitors (P < 0.001) in all four mouse strains. These data indicate that prompt and abbreviated filgrastim treatment has potential benefit for triage in the event of a radiological incident for treating acute hematopoietic syndrome. PMID:28362168

  20. HZE Radiation Leukemogenesis in Mice

    NASA Astrophysics Data System (ADS)

    Peng, Yuanlin

    Radiation exposure is a risk factor for acute myeloid leukemia (AML). The Leukemogenesis NSCOR was developed to compare this risk for low LET vs HZE radiations as a means to better assess the leukemia risk to astronauts posed by space radiation. Individual projects within the NSCOR explore HZE radiation leukemogenesis in murine model systems and extend the findings to AML in humans. AML sensitive CBA/CaJ mice have been irradiated with 1 GeV 56 Fe particles at NSRL and with 137 Cs gamma-rays at Colorado State University and followed to 800 days of age for the development of AML. Molecular and cytogenetic analyses of HZE- and gamma-induced AML, including assays for chromosomal aberrations, PU.1 deletion, gene expression, array CGH and microsatellite instability are ongoing. Preliminary data indicate that 56 Fe particles are no more effective in inducing AML or shortening lifespan than gamma-rays. Studies designed to address the individual molecular steps in leukemogenesis and determine the effects of radiation and genetic background on each step have been initiated using knockout mice. Deletion of the PU.1 gene on mouse chromosome 2 is a critical step in this murine model of radiation leukemogenesis. Two of the three HZE-induced AMLs that could be assayed and thirteen of fourteen γ-induced AMLs had PU.1 loss as determined by Fluorescence in Situ Hybridization (FISH). We have found that AML sensitive CBA/CaJ mice have a higher incidence of Chr. 2 deletion in bone marrow cells following 56 Fe irradiation than AML resistant C57BL/6 mice. This study is being extended to proton irradiated mice. Our preliminary results indicate that microsatellite instability may be common in HZE irradiated progenitor cells. To determine if these cytogenetic changes can be induced in human myeloid progenitor cells by gamma, proton or HZE irradiation we are generating NOD/SCID mice that have been "humanized" by being transplanted with human hematopoietic stem cells. We are currently

  1. The potential influence of radiation-induced microenvironments in neoplastic progression

    NASA Technical Reports Server (NTRS)

    Barcellos-Hoff, M. H.; Chatterjee, A. (Principal Investigator)

    1998-01-01

    Ionizing radiation is a complete carcinogen, able both to initiate and promote neoplastic progression and is a known carcinogen of human and murine mammary gland. Tissue response to radiation is a composite of genetic damage, cell death and induction of new gene expression patterns. Although DNA damage is believed to initiate carcinogenesis, the contribution of these other aspects of radiation response are beginning to be explored. Our studies demonstrate that radiation elicits rapid and persistent global alterations in the mammary gland microenvironment. We postulate that radiation-induced microenvironments may affect epithelial cells neoplastic transformation by altering their number or susceptibility. Alternatively, radiation induced microenvironments may exert a selective force on initiated cells and/or be conducive to progression. A key impetus for these studies is the possibility that blocking these events could be a strategy to interrupt neoplastic progression.

  2. Mitigation of the hematopoietic and gastrointestinal acute radiation syndrome by octadecenyl thiophosphate, a small molecule mimic of lysophosphatidic acid.

    PubMed

    Deng, Wenlin; Kimura, Yasuhiro; Gududuru, Veeresh; Wu, Wenjie; Balogh, Andrea; Szabo, Erzsebet; Thompson, Karin Emmons; Yates, C Ryan; Balazs, Louisa; Johnson, Leonard R; Miller, Duane D; Strobos, Jur; McCool, W Shannon; Tigyi, Gabor J

    2015-04-01

    We have previously demonstrated that the small molecule octadecenyl thiophosphate (OTP), a synthetic mimic of the growth factor-like mediator lysophosphatidic acid (LPA), showed radioprotective activity in a mouse model of total-body irradiation (TBI) when given orally or intraperitoneally 30 min before exposure to 9 Gy γ radiation. In the current study, we evaluated the effects of OTP, delivered subcutaneously, for radioprotection or radiomitigation from -24 h before to up to +72 h postirradiation using a mouse TBI model with therapeutic doses at around 1 mg/kg. OTP was injected at 10 mg/kg without observable toxic side effects in mice, providing a comfortable safety margin. Treatment of C57BL/6 mice with a single dose of OTP over the time period from -12 h before to +26 h after a lethal dose of TBI reduced mortality by 50%. When administered at +48 h to +72 h postirradiation (LD50/30 to LD100/30), OTP reduced mortality by ≥34%. OTP administered at +24 h postirradiation significantly elevated peripheral white blood cell and platelet counts, increased crypt survival in the jejunum, enhanced intestinal glucose absorption and reduced endotoxin seepage into the blood. In the 6.4-8.6 Gy TBI range using LD50/10 as the end point, OTP yielded a dose modification factor of 1.2. The current data indicate that OTP is a potent radioprotector and radiomitigator ameliorating the mortality and tissue injury of acute hematopoietic as well as acute gastrointestinal radiation syndrome.

  3. Spontaneous hematologic recovery from bone marrow aplasia after accidental tenfold overdosage with radiophosphorus

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gmuer, J.; Bischof, B.; Coninx, S.

    1983-04-01

    Two patients with polycythemia vera received intravenously an accidental tenfold overdosage of radiophosphorus therapy (60 and 50 mCi 32P, respectively). In both patients, the occurrence of hemorrhagic complications 3 wk after the 32P medication led to detection of the error and referral to our hospital. Upon admission they showed an agranulocytosis, severe thrombocytopenia, and bone marrow aplasia. In both cases, spontaneous recovery of the hematopoiesis was observed from day 40 posttreatment onward. In one patient, a slow but ultimately complete normalization of blood counts and marrow morphology took place, whereas in the other, a mild thrombocytopenia persists. Nearly 5 yrmore » after the accidental overdosage, both patients are clinically well. Symptoms of polycythemia vera have not reappeared up to now. Attempts were made to evaluate the radiation dose absorbed by the bone marrow. In the first patient, the daily 32P excretion was determined from day 22 to day 60, whereas in the other patient a whole body count was performed on day 78 after administration. From these results, an approximate cumulative bone marrow dose of 10 Sv (1000 rem) could be calculated.« less

  4. Neuroprotective effects of Quercetin on radiation-induced brain injury in rats.

    PubMed

    Kale, Aydemir; Piskin, Özcan; Bas, Yilmaz; Aydin, Bengü Gülhan; Can, Murat; Elmas, Özlem; Büyükuysal, Çagatay

    2018-04-24

    Extensive research has been focused on radiation-induced brain injury. Animal and human studies have shown that flavonoids have remarkable toxicological profiles. This study aims to investigate the neuroprotective effects of quercetin in an experimental radiation-induced brain injury. A total of 32 adult male Wistar-Albino rats were randomly divided into four groups (control, quercetin, radiation, and radiation+quercetin groups, with eight rats in each group). Doses (50 mg/kg) of quercetin were administered to the animals in the quercetin and radiation+quercetin groups; radiation and radiation+quercetin groups were exposed to a dose of 20 Gy to the cranium region. Tissue samples, and biochemical levels of tissue injury markers in the four groups were compared. In all measured parameters of oxidative stress, administration of quercetin significantly demonstrated favorable effects. Both plasma and tissue levels of malondialdehyde and total antioxidant status significantly changed in favor of antioxidant activity. Histopathological evaluation of the tissues also demonstrated a significant decrease in cellular degeneration and infiltration parameters after quercetin administration. Quercetin demonstrated significant neuroprotection after radiation-induced brain injury. Further studies of neurological outcomes under different experimental settings are required in order to achieve conclusive results.

  5. [Hematopoietic reconstitution after transplantation of uncontrolled-rate cryopreservation autologous peripheral blood hematopoietic stem cells using -80 °C mechanical freezer].

    PubMed

    Liu, Mo; Zhao, Yu; Sun, Jing-Fen; Zhao, Wei; Wang, Li-Li; Yu, Li

    2015-02-01

    This study was to identify the efficacy of -80°C cryopreservated peripheral blood hemato-poietic stem cell (PBHSC) transplantation for hematopoietic reanstitution in patients. The efficacy of 104 patients underwent autologous peripheral blood hematopoietic stem cell transplantation using uncontrolled-rate freezing and storage at -80°C was evaluated. This cryopreservation method could effectively cryopreserve peripheral blood stem cells. Out of 104 patients only 2 patients died, other patients got hematologic reconstition satisfactorily, the median engrafement times of neutrophils and platelet were 12 and 14 days respectively, the activity of cells after rehabilitation was 94%, the mean recovery rates of CD34(+) cells and mononuclear cells (MNC) were 86% and 80.3% respectively. There were no significant influences on engrafement time in sex, chemotherapy circles and radiotherapy. The engrafement of leukocytes associated with amount of CD34(+) cells. This simple uncontrolled-rate freezing PBHSC at -80°C is safe, effective and economic, and can meet clinical needs. As compared with the classical cryopreservation, there were no significant differences in hematopoietic reconstitution. Therefore, this method worth to popularize and apply in clinic.

  6. Shear Stress Regulates Adhesion and Rolling of CD44+ Leukemic and Hematopoietic Progenitor Cells on Hyaluronan

    PubMed Central

    Christophis, Christof; Taubert, Isabel; Meseck, Georg R.; Schubert, Mario; Grunze, Michael; Ho, Anthony D.; Rosenhahn, Axel

    2011-01-01

    Leukemic cells and human hematopoietic progenitor cells expressing CD44 receptors have the ability to attach and roll on hyaluronan. We investigated quantitatively the adhesion behavior of leukemic cell lines and hematopoietic progenitor cells on thin films of the polysaccharides hyaluronan and alginate in a microfluidic system. An applied flow enhances the interaction between CD44-positive cells and hyaluronan if a threshold shear stress of 0.2 dyn/cm2 is exceeded. At shear stress ∼1 dyn/cm2, the cell rolling speed reaches a maximum of 15 μm/s. Leukemic Jurkat and Kasumi-1 cells lacking CD44-expression showed no adhesion or rolling on the polysaccharides whereas the CD44-expressing leukemic cells KG-1a, HL-60, K-562, and hematopoietic progenitor cells attached and rolled on hyaluronan. Interestingly, the observations of flow-induced cell rolling are related to those found in the recruitment of leukocytes to inflammatory sites and the mechanisms of stem-cell homing into the bone marrow. PMID:21806926

  7. Hazards of Improper Dispensary: Literature Review and Report of an Accidental Chloroform Injection.

    PubMed

    Verma, Prashant; Tordik, Patricia; Nosrat, Ali

    2018-06-01

    Several clear, transparent solutions are used in endodontics. Inappropriate dispensing methods can lead to accidental injection or accidental irrigation. These accidents can cause permanent tissue damage including damage to the bone, periodontium, nerves, and vasculature. This article reports on the consequences of an accidental chloroform injection. Nonsurgical retreatment of tooth #8 was planned as part of a restorative treatment plan in a 69-year-old woman. The dentist accidentally injected chloroform instead of local anesthesia because chloroform was loaded into the anesthetic syringe. The patient experienced severe pain and swelling and soft tissue necrosis and suffered permanent sensory and motor nerve damage. A review of the literature was performed on accidents caused by improper dispensary, namely accidental injections and accidental irrigations. The data were extracted and summarized. Sodium hypochlorite, chlorhexidine, formalin, formocresol, 1:1000 adrenaline, benzalkonium chloride, and lighter fuel were accidentally injected as an intraoral nerve block or as infiltration injections. Bone and soft tissue necrosis, tooth loss, and sensory nerve damage (anesthesia and paresthesia) were the most common consequences reported. Such disastrous events can be prevented by appropriate labeling and separate dispensing methods for each solution. There is a need for disseminating information on toxicity and biocompatibility of materials/solutions used in endodontics. The authors recommend training dental students and endodontic residents on immediate and long-term therapeutic management of patients when an accidental injection or accidental irrigation occurs. Copyright © 2018 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  8. Mistakes in diagnosing non-accidental injury: 10 years' experience

    PubMed Central

    Wheeler, David M; Hobbs, Christopher J

    1988-01-01

    Fifty children who were referred to the child abuse team in Leeds over the 10 years 1976-86 with suspected non-accidental injury were found to have conditions which mimicked non-accidental injury. These included impetigo (nine children) and blue spots (five children). Five children who presented with multiple bruising had haemostatic disorders. Eight children had disorders of the bone. Five children had been previously abused physically. Four showed evidence of neglect. One had evidence of non-accidental injury as well as the condition mimicking abuse. It is emphasised that when child abuse is suspected a sensitive and thorough assessment should be carried out by a paediatrician who is experienced in this. ImagesFIG 1 PMID:3133026

  9. Radiation exposure from work-related medical X-rays at the Portsmouth Naval Shipyard.

    PubMed

    Daniels, Robert D; Kubale, Travis L; Spitz, Henry B

    2005-03-01

    Previous analyses suggest that worker radiation dose may be significantly increased by routine occupational X-ray examinations. Medical exposures are investigated for 570 civilian workers employed at the Portsmouth Naval Shipyard (PNS) at Kittery, Maine. The research objective was to determine the radiation exposure contribution of work-related chest X-rays (WRX) relative to conventional workplace radiation sources. Methods were developed to estimate absorbed doses to the active (hematopoietic) bone marrow from X-ray examinations and workplace exposures using data extracted from worker dosimetry records (8,468) and health records (2,453). Dose distributions were examined for radiation and non-radiation workers. Photofluorographic chest examinations resulted in 82% of the dose from medical sources. Radiation workers received 26% of their collective dose from WRX and received 66% more WRX exposure than non-radiation workers. WRX can result in a significant fraction of the total dose, especially for radiation workers who were more likely to be subjected to routine medical monitoring. Omission of WRX from the total dose is a likely source of bias that can lead to dose category misclassification and may skew the epidemiologic dose-response assessment for cancers induced by the workplace.

  10. Chromosome Instability Underlies Hematopoietic Stem Cell Dysfunction and Lymphoid Neoplasia Associated with Impaired Fbw7-Mediated Cyclin E Regulation

    PubMed Central

    Siu, Ka Tat; Xu, Yanfei; Swartz, Kelsey L.; Bhattacharyya, Mitra; Gurbuxani, Sandeep; Hua, Youjia

    2014-01-01

    The Fbw7 ubiquitin ligase critically regulates hematopoietic stem cell (HSC) function, though the precise contribution of individual substrate ubiquitination pathways to HSC homeostasis is unknown. In the work reported here, we used a mouse model in which we introduced two knock-in mutations (T74A and T393A [changes of T to A at positions 74 and 393]) to disrupt Fbw7-dependent regulation of cyclin E, its prototypic substrate, and to examine the consequences of cyclin E dysregulation for HSC function. Serial transplantation revealed that cyclin ET74A T393A HSCs self-renewed normally; however, we identified defects in their multilineage reconstituting capacity. By inducing hematologic stress, we exposed an impaired self-renewal phenotype in cyclin E knock-in HSCs that was associated with defective cell cycle exit and the emergence of chromosome instability (CIN). Importantly, p53 deletion induced both defects in self-renewal and multilineage reconstitution in cyclin E knock-in HSCs with serial transplantation and CIN in hematopoietic stem and progenitor cells. Moreover, CIN was a feature of fatal T-cell malignancies that ultimately developed in recipients of cyclin ET74A T393A; p53-null HSCs. Together, our findings demonstrate the importance of Fbw7-dependent cyclin E control to the hematopoietic system and highlight CIN as a characteristic feature of HSC dysfunction and malignancy induced by deregulated cyclin E. PMID:24958101

  11. Modulating factors in the expression of radiation-induced oncogenic transformation.

    PubMed Central

    Hall, E J; Hei, T K

    1990-01-01

    Many assays for oncogenic transformation have been developed ranging from those in established rodent cell lines where morphological alteration is scored, to those in human cells growing in nude mice where tumor invasiveness is scored. In general, systems that are most quantitative are also the least relevant in terms of human carcinogenesis and human risk estimation. The development of cell culture systems has made it possible to assess at the cellular level the oncogenic potential of a variety of chemical, physical and viral agents. Cell culture systems afford the opportunity to identify factors and conditions that may prevent or enhance cellular transformation by radiation and chemicals. Permissive and protective factors in radiation-induced transformation include thyroid hormone and the tumor promoter TPA that increase the transformation incidence for a given dose of radiation, and retinoids, selenium, vitamin E, and 5-aminobenzamide that inhibit the expression of transformation. Densely ionizing alpha-particles, similar to those emitted by radon daughters, are highly effective in inducing transformations and appear to interact in a supra-additive fashion with asbestos fibers. The activation of a known dominant oncogene has not yet been demonstrated in radiation-induced oncogenic transformation. The most likely mechanism for radiation activation of an oncogene would be via the production of a chromosomal translocation. Radiation also efficiently induces deletions and may thus lead to the loss of a suppressor gene. Images FIGURE 4. PMID:2272310

  12. Dietary eicosapentaenoic acid prevents systemic immunosuppression in mice induced by UVB radiation.

    PubMed

    Moison, R M; Beijersbergen Van Henegouwen, G M

    2001-07-01

    Moison, R. M. W. and Beijersbergen van Henegouwen, G. M. J. Dietary Eicosapentaenoic Acid Prevents Systemic Immunosuppression in Mice Induced by UVB Radiation. Radiat. Res. 156, 36-44 (2001). Reactive oxygen species (ROS) contribute to the immunosuppression induced by UVB radiation. Omega-3 fatty acids in fish oil, e.g. eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can modulate immunoresponsiveness, but because of their susceptibility to ROS-induced damage, they can also challenge the epidermal antioxidant defense system. The influence of dietary supplementation with different omega-3 fatty acids on systemic immunosuppression induced in mice by UVB radiation was studied using the contact hypersensitivity response to trinitrochlorobenzene. In an attempt to study the mechanisms involved, UVB-radiation-induced changes in epidermal antioxidant status were also studied. Mice received high-fat (25% w/w) diets enriched with either oleic acid (control diet), EPA, DHA, or EPA + DHA (MaxEPA). Immunosuppression induced by UVB radiation was 53% in mice fed the oleic acid diet and 69% in mice fed the DHA diet. In contrast, immunosuppression was only 4% and 24% in mice fed the EPA and MaxEPA diets, respectively. Increased lipid peroxidation and decreased vitamin E levels (P < 0.05) were found in unirradiated mice fed the MaxEPA and DHA diets. For all diets, exposure to UVB radiation increased lipid peroxidation (P < 0.05), but levels of glutathione (P < 0.05) and vitamin C (P > 0.05) decreased only in the mice given fish oil. UVB irradiation did not influence vitamin E levels. In conclusion, dietary EPA, but not DHA, protects against UVB-radiation-induced immunosuppression in mice. The degree of protection appears to be related to the amount of EPA incorporated and the ability of the epidermis to maintain an adequate antioxidant level after irradiation.

  13. Entanglement-induced quantum radiation

    NASA Astrophysics Data System (ADS)

    Iso, Satoshi; Tatsukawa, Rumi; Ueda, Kazushige; Yamamoto, Kazuhiro

    2017-08-01

    Quantum entanglement of the Minkowski vacuum state between left and right Rindler wedges generates thermal behavior in the right Rindler wedge, which is known as the Unruh effect. In this paper, we show that there is another consequence of this entanglement, namely entanglement-induced quantum radiation emanating from a uniformly accelerated object. We clarify why it is in agreement with our intuition that incoming and outgoing energy fluxes should cancel each other out in a thermalized state.

  14. Doctor Ward's Accidental Terrarium.

    ERIC Educational Resources Information Center

    Hershey, David R.

    1996-01-01

    Presents the story of the accidental invention of the Wardian case, or terrarium, by Nathaniel Bagshaw Ward. Advocates the use of this story in teaching precollege biology as an illustration of how a chance event can lead to a major scientific advancement and as an example of the common occurrence of multiple discovery in botany. Contains 34…

  15. Generation of Transgenic Mouse Fluorescent Reporter Lines for Studying Hematopoietic Development

    PubMed Central

    Vacaru, Andrei M.; Vitale, Joseph; Nieves, Johnathan; Baron, Margaret H.

    2015-01-01

    During the development of the hematopoietic system, at least 8 distinct lineages are generated in the mouse embryo. Transgenic mice expressing fluorescent proteins at various points in the hematopoietic hierarchy, from hematopoietic stem cell to multipotent progenitors to each of the final differentiated cell types, have provided valuable tools for tagging, tracking, and isolating these cells. In this chapter, we discuss general considerations in designing a transgene, survey available fluorescent probes, and methods for confirming and analyzing transgene expression in the hematopoietic systems of the embryo, fetus, and postnatal/adult animal. PMID:25064110

  16. Computer Aided Dosimetry and Verification of Exposure to Radiation

    DTIC Science & Technology

    2002-06-01

    Event matrix 2. Hematopoietic * Absolute blood counts * Relative blood counts 3. Dosimetry * TLD * EPDQuantitative * Radiation survey * Whole body...EI1 Defence Research and Recherche et developpement Development Canada pour la d6fense Canada DEFENCE •mI•DEFENSE Computer Aided Dosimetry and...Aided Dosimetry and Verification of Exposure to Radiation Edward Waller SAIC Canada Robert Z Stodilka Radiation Effects Group, Space Systems and

  17. RIP1 and RIP3 complex regulates radiation-induced programmed necrosis in glioblastoma.

    PubMed

    Das, Arabinda; McDonald, Daniel G; Dixon-Mah, Yaenette N; Jacqmin, Dustin J; Samant, Vikram N; Vandergrift, William A; Lindhorst, Scott M; Cachia, David; Varma, Abhay K; Vanek, Kenneth N; Banik, Naren L; Jenrette, Joseph M; Raizer, Jeffery J; Giglio, Pierre; Patel, Sunil J

    2016-06-01

    Radiation-induced necrosis (RN) is a relatively common side effect of radiation therapy for glioblastoma. However, the molecular mechanisms involved and the ways RN mechanisms differ from regulated cell death (apoptosis) are not well understood. Here, we compare the molecular mechanism of cell death (apoptosis or necrosis) of C6 glioma cells in both in vitro and in vivo (C6 othotopically allograft) models in response to low and high doses of X-ray radiation. Lower radiation doses were used to induce apoptosis, while high-dose levels were chosen to induce radiation necrosis. Our results demonstrate that active caspase-8 in this complex I induces apoptosis in response to low-dose radiation and inhibits necrosis by cleaving RIP1 and RI. When activation of caspase-8 was reduced at high doses of X-ray radiation, the RIP1/RIP3 necrosome complex II is formed. These complexes induce necrosis through the caspase-3-independent pathway mediated by calpain, cathepsin B/D, and apoptosis-inducing factor (AIF). AIF has a dual role in apoptosis and necrosis. At high doses, AIF promotes chromatinolysis and necrosis by interacting with histone H2AX. In addition, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. Analysis of inflammatory markers in matched plasma and cerebrospinal fluid (CSF) isolated from in vivo specimens demonstrated the upregulation of chemokines and cytokines during the necrosis phase. Using RIP1/RIP3 kinase specific inhibitors (Nec-1, GSK'872), we also establish that the RIP1-RIP3 complex regulates programmed necrosis after either high-dose radiation or TNF-α-induced necrosis requires RIP1 and RIP3 kinases. Overall, our data shed new light on the relationship between RIP1/RIP3-mediated programmed necrosis and AIF-mediated caspase-independent programmed necrosis in glioblastoma.

  18. Reactive oxygen species-dependent Toll/NF-κB activation in the Drosophila hematopoietic niche confers resistance to wasp parasitism.

    PubMed

    Louradour, Isabelle; Sharma, Anurag; Morin-Poulard, Ismael; Letourneau, Manon; Vincent, Alain; Crozatier, Michèle; Vanzo, Nathalie

    2017-11-01

    Hematopoietic stem/progenitor cells in the adult mammalian bone marrow ensure blood cell renewal. Their cellular microenvironment, called 'niche', regulates hematopoiesis both under homeostatic and immune stress conditions. In the Drosophila hematopoietic organ, the lymph gland, the posterior signaling center (PSC) acts as a niche to regulate the hematopoietic response to immune stress such as wasp parasitism. This response relies on the differentiation of lamellocytes, a cryptic cell type, dedicated to pathogen encapsulation and killing. Here, we establish that Toll/NF-κB pathway activation in the PSC in response to wasp parasitism non-cell autonomously induces the lymph gland immune response. Our data further establish a regulatory network where co-activation of Toll/NF-κB and EGFR signaling by ROS levels in the PSC/niche controls lymph gland hematopoiesis under parasitism. Whether a similar regulatory network operates in mammals to control emergency hematopoiesis is an open question.

  19. Biological impact of low dose-rate simulated solar particle event radiation in vivo.

    PubMed

    Chang, P Y; Doppalapudi, R; Bakke, J; Wang, A; Menda, S; Davis, Z

    2010-08-01

    C57Bl6-lacZ animals were exposed to a range of low dose-rate simulated solar particle event (sSPE) radiation at the NASA-sponsored Research Laboratory (NSRL) at Brookhaven National Laboratory (BNL). Peripheral blood was harvested from animals from 1 to 12 days after total body irradiation (TBI) to quantify the level of circulating reticulocytes (RET) and micronucleated reticulocytes (MN-RET) as an early indicator of radiation-induced genotoxicity. Bone marrow lymphocytes and hippocampal tissues from each animal were collected at 12 days and up to two months, to evaluate dose-dependent late effects after sSPE exposure. Early hematopoietic changes show that the % RET was reduced up to 3 days in response to radiation exposure but recovered at 12 days postirradiation. The % MN-RET in peripheral blood was temporally regulated and dependant on the total accumulated dose. Total chromosome aberrations in lymphocytes increased linearly with dose within a week after radiation and remained significantly higher than the control values at 4 weeks after exposure. The level of aberrations in the irradiated animals returned to control levels by 8 weeks postirradiation. Measurements of chromosome 2 and 8 specific aberrations indicate that, consistent with conventional giemsa-staining methods, the level of aberrations is also not significantly higher than in control animals at 8 weeks postirradiation. The hippocampus was surveyed for differential transcriptional regulation of genes known to be associated with neurogenesis. Our results showed differential expression of neurotrophin and their associated receptor genes within 1 week after sSPE exposure. Progressive changes in the profile of expressed genes known to be involved in neurogenic signaling pathways were dependent on the sSPE dose. Our results to date suggest that radiation-induced changes in the hematopoietic system, i.e., chromosome aberrations in lymphocytes, are transient and do not persist past 4 weeks after radiation

  20. Lineage-related cytotoxicity and clonogenic profile of 1,4-benzoquinone-exposed hematopoietic stem and progenitor cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chow, Paik Wah; Toxicology Laboratory, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur; Abdul Hamid, Zariyantey, E-mail: zyantey@ukm.edu.my

    Hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) are sensitive targets for benzene-induced hematotoxicity and leukemogenesis. The impact of benzene exposure on the complex microenvironment of HSCs and HPCs remains elusive. This study aims to investigate the mechanism linking benzene exposure to targeting HSCs and HPCs using phenotypic and clonogenic analyses. Mouse bone marrow (BM) cells were exposed ex vivo to the benzene metabolite, 1,4-benzoquinone (1,4-BQ), for 24 h. Expression of cellular surface antigens for HSC (Sca-1), myeloid (Gr-1, CD11b), and lymphoid (CD45, CD3e) populations were confirmed by flow cytometry. The clonogenicity of cells was studied using the colony-formingmore » unit (CFU) assay for multilineage (CFU-GM and CFU-GEMM) and single-lineage (CFU-E, BFU-E, CFU-G, and CFU-M) progenitors. 1,4-BQ demonstrated concentration-dependent cytotoxicity in mouse BM cells. The percentage of apoptotic cells increased (p < 0.05) following 1,4-BQ exposure. Exposure to 1,4-BQ showed no significant effect on CD3e{sup +} cells but reduced the total counts of Sca-1{sup +}, CD11b{sup +}, Gr-1{sup +}, and CD45{sup +} cells at 7 and 12 μM (p < 0.05). Furthermore, the CFU assay showed reduced (p < 0.05) clonogenicity in 1,4-BQ-treated cells. 1,4-BQ induced CFU-dependent cytotoxicity by significantly inhibiting colony growth for CFU-E, BFU-E, CFU-G, and CFU-M starting at a low concentration of exposure (5 μM); whereas for the CFU-GM and CFU-GEMM, the inhibition of colony growth was remarkable only at 7 and 12 μM of 1,4-BQ, respectively. Taken together, 1,4-BQ caused lineage-related cytotoxicity in mouse HPCs, demonstrating greater toxicity in single-lineage progenitors than in those of multi-lineage. - Highlights: • We examine 1,4-BQ toxicity targeting mouse hematopoietic cell lineages. • 1,4-BQ induces concentration-dependent cytotoxicity in bone marrow (BM) cells. • 1,4-BQ shows lineage-related toxicity on hematopoietic stem and

  1. Statins induce apoptosis through inhibition of Ras signaling pathways and enhancement of Bim and p27 expression in human hematopoietic tumor cells.

    PubMed

    Fujiwara, Daichiro; Tsubaki, Masanobu; Takeda, Tomoya; Tomonari, Yoshika; Koumoto, Yu-Ichi; Sakaguchi, Katsuhiko; Nishida, Shozo

    2017-10-01

    Recently, statins have been demonstrated to improve cancer-related mortality or prognosis in patients of various cancers. However, the details of the apoptosis-inducing mechanisms remain unknown. This study showed that the induction of apoptosis by statins in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate biosynthesis. In addition, statins decreased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin through suppressing Ras prenylation. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin by statins induced Bim expression via inhibition of Bim phosphorylation and ubiquitination and cell-cycle arrest at G1 phase via enhancement of p27 expression. Moreover, combined treatment of U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, and rapamycin, a mammalian target of rapamycin inhibitor, induced Bim and p27 expressions. The present results suggested that statins induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, enhancing Bim expression, and inducing cell-cycle arrest at G1 phase through inhibition of Ras/extracellular signal-regulated kinase and Ras/mammalian target of rapamycin pathways. Therefore, our findings support the use of statins as potential anticancer agents or concomitant drugs of adjuvant therapy.

  2. Deficiency of transcription factor RelB perturbs myeloid and DC development by hematopoietic-extrinsic mechanisms

    PubMed Central

    Briseño, Carlos G.; Gargaro, Marco; Durai, Vivek; Davidson, Jesse T.; Theisen, Derek J.; Anderson, David A.; Novack, Deborah V.; Murphy, Theresa L.; Murphy, Kenneth M.

    2017-01-01

    RelB is an NF-κB family transcription factor activated in the noncanonical pathway downstream of NF-κB–inducing kinase (NIK) and TNF receptor family members including lymphotoxin-β receptor (LTβR) and CD40. Early analysis suggested that RelB is required for classical dendritic cell (cDC) development based on a severe reduction of cDCs in Relb−/− mice associated with profound myeloid expansion and perturbations in B and T cells. Subsequent analysis of radiation chimeras generated from wild-type and Relb−/− bone marrow showed that RelB exerts cell-extrinsic actions on some lineages, but it has remained unclear whether the impact of RelB on cDC development is cell-intrinsic or -extrinsic. Here, we reevaluated the role of RelB in cDC and myeloid development using a series of radiation chimeras. We found that there was no cell-intrinsic requirement for RelB for development of most cDC subsets, except for the Notch2- and LTβR-dependent subset of splenic CD4+ cDC2s. These results identify a relatively restricted role of RelB in DC development. Moreover, the myeloid expansion in Relb−/− mice resulted from hematopoietic-extrinsic actions of RelB. This result suggests that there is an unrecognized but critical role for RelB within the nonhematopoietic niche that controls normal myelopoiesis. PMID:28348230

  3. Low-Dose Radiation Cataract and Genetic Determinants of Radiosensitivity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kleiman, Norman Jay

    The lens of the eye is one of the most radiosensitive tissues in the body. Ocular ionizing radiation exposure results in characteristic, dose related, progressive lens changes leading to cataract formation. While initial, early stages of lens opacification may not cause visual disability, the severity of such changes progressively increases with dose until vision is impaired and cataract extraction surgery may be required. Because of the transparency of the eye, radiation induced lens changes can easily be followed non-invasively over time. Thus, the lens provides a unique model system in which to study the effects of low dose ionizing radiationmore » exposure in a complex, highly organized tissue. Despite this observation, considerable uncertainties remain surrounding the relationship between dose and risk of developing radiation cataract. For example, a growing number of human epidemiological findings suggest significant risk among various groups of occupationally and accidentally exposed individuals and confidence intervals that include zero dose. Nevertheless, questions remain concerning the relationship between lens opacities, visual disability, clinical cataract, threshold dose and/or the role of genetics in determining radiosensitivity. Experimentally, the response of the rodent eye to radiation is quite similar to that in humans and thus animal studies are well suited to examine the relationship between radiation exposure, genetic determinants of radiosensitivity and cataractogenesis. The current work has expanded our knowledge of the low-dose effects of X-irradiation or high-LET heavy ion exposure on timing and progression of radiation cataract and has provided new information on the genetic, molecular, biochemical and cell biological features which contribute to this pathology. Furthermore, findings have indicated that single and/or multiple haploinsufficiency for various genes involved in DNA repair and cell cycle checkpoint control, such as Atm, Brca1

  4. Hematopoiesis and hematopoietic organs in arthropods.

    PubMed

    Grigorian, Melina; Hartenstein, Volker

    2013-03-01

    Hemocytes (blood cells) are motile cells that move throughout the extracellular space and that exist in all clades of the animal kingdom. Hemocytes play an important role in shaping the extracellular environment and in the immune response. Developmentally, hemocytes are closely related to the epithelial cells lining the vascular system (endothelia) and the body cavity (mesothelia). In vertebrates and insects, common progenitors, called hemangioblasts, give rise to the endothelia and blood cells. In the adult animal, many differentiated hemocytes seem to retain the ability to proliferate; however, in most cases investigated closely, the bulk of hemocyte proliferation takes place in specialized hematopoietic organs. Hematopoietic organs provide an environment where undifferentiated blood stem cells are able to self-renew, and at the same time generate offspring that differentiate into different blood cell types. Hematopoiesis in vertebrates, taking place in the bone marrow, has been subject to intensive research by immunologists and stem cell biologists. Much less is known about blood cell formation in invertebrate animals. In this review, we will survey structural and functional properties of invertebrate hematopoietic organs, with a main focus on insects and other arthropod taxa. We will then discuss similarities, at the molecular and structural level, that are apparent when comparing the development of blood cells in hematopoietic organs of vertebrates and arthropods. Our comparative review is intended to elucidate aspects of the biology of blood stem cells that are more easily missed when focusing on one or a few model species.

  5. Are pre-hospital deaths from accidental injury preventable?

    PubMed Central

    Hussain, L. M.; Redmond, A. D.

    1994-01-01

    OBJECTIVE--To determine what proportion of pre-hospital deaths from accidental injury--deaths at the scene of the accident and those that occur before the person has reached hospital--are preventable. DESIGN--Retrospective study of all deaths from accidental injury that occurred between 1 January 1987 and 31 December 1990 and were reported to the coroner. SETTING--North Staffordshire. MAIN OUTCOME MEASURES--Injury severity score, probability of survival (probit analysis), and airway obstruction. RESULTS--There were 152 pre-hospital deaths from accidental injury (110 males and 42 females). In the same period there were 257 deaths in hospital from accidental injury (136 males and 121 females). The average age at death was 41.9 years for those who died before reaching hospital, and their average injury severity score was 29.3. In contrast, those who died in hospital were older and equally likely to be males or females. Important neurological injury occurred in 113 pre-hospital deaths, and evidence of airway obstruction in 59. Eighty six pre-hospital deaths were due to road traffic accidents, and 37 of these were occupants in cars. On the basis of the injury severity score and age, death was found to have been inevitable or highly likely in 92 cases. In the remaining 60 cases death had not been inevitable and airway obstruction was present in up to 51 patients with injuries that they might have survived. CONCLUSION--Death was potentially preventable in at least 39% of those who died from accidental injury before they reached hospital. Training in first aid should be available more widely, and particularly to motorists as many pre-hospital deaths that could be prevented are due to road accidents. PMID:8173428

  6. 3D ultrasound Nakagami imaging for radiation-induced vaginal fibrosis

    NASA Astrophysics Data System (ADS)

    Yang, Xiaofeng; Rossi, Peter; Shelton, Joseph; Bruner, Debrorah; Tridandapani, Srini; Liu, Tian

    2014-03-01

    Radiation-induced vaginal fibrosis is a debilitating side-effect affecting up to 80% of women receiving radiotherapy for their gynecological (GYN) malignancies. Despite the significant incidence and severity, little research has been conducted to identify the pathophysiologic changes of vaginal toxicity. In a previous study, we have demonstrated that ultrasound Nakagami shape and PDF parameters can be used to quantify radiation-induced vaginal toxicity. These Nakagami parameters are derived from the statistics of ultrasound backscattered signals to capture the physical properties (e.g., arrangement and distribution) of the biological tissues. In this paper, we propose to expand this Nakagami imaging concept from 2D to 3D to fully characterize radiation-induced changes to the vaginal wall within the radiation treatment field. A pilot study with 5 post-radiotherapy GYN patients was conducted using a clinical ultrasound scanner (6 MHz) with a mechanical stepper. A serial of 2D ultrasound images, with radio-frequency (RF) signals, were acquired at 1 mm step size. The 2D Nakagami shape and PDF parameters were calculated from the RF signal envelope with a sliding window, and then 3D Nakagami parameter images were generated from the parallel 2D images. This imaging method may be useful as we try to monitor radiation-induced vaginal injury, and address vaginal toxicities and sexual dysfunction in women after radiotherapy for GYN malignancies.

  7. Formation and hematopoietic differentiation of human embryoid bodies by suspension and hanging drop cultures.

    PubMed

    Cerdan, Chantal; Hong, Seok Ho; Bhatia, Mickie

    2007-10-01

    The in vitro aggregation of human embryonic stem cells (hESCs) into clusters termed embryoid bodies (EBs) allows for the spontaneous differentiation of cells representing endoderm, mesoderm, and ectoderm lineages. This stochastic process results however, in the generation of low numbers of differentiated cells, and can be enhanced to some extent by the addition of exogenous growth factors or overexpression of regulatory genes. In the authors' laboratory, the use of hematopoietic cytokines in combination with the mesoderm inducer bone morphogenetic protein-4 (BMP-4) was able to generate up to 90% of CD45(+) hematopoietic cells with colony-forming unit (CFU) activity. This unit describes two protocols that have been successfully applied in the authors' laboratory for the generation of EBs in (1) suspension and (2) hanging drop (HD) cultures from enzymatically digested clumps of undifferentiated hESC colonies.

  8. Radiation-Induced Breast Cancer Incidence and Mortality From Digital Mammography Screening: A Modeling Study.

    PubMed

    Miglioretti, Diana L; Lange, Jane; van den Broek, Jeroen J; Lee, Christoph I; van Ravesteyn, Nicolien T; Ritley, Dominique; Kerlikowske, Karla; Fenton, Joshua J; Melnikow, Joy; de Koning, Harry J; Hubbard, Rebecca A

    2016-02-16

    Estimates of risk for radiation-induced breast cancer from mammography screening have not considered variation in dose exposure or diagnostic work-up after abnormal screening results. To estimate distributions of radiation-induced breast cancer incidence and mortality from digital mammography screening while considering exposure from screening and diagnostic mammography and dose variation among women. 2 simulation-modeling approaches. U.S. population. Women aged 40 to 74 years. Annual or biennial digital mammography screening from age 40, 45, or 50 years until age 74 years. Lifetime breast cancer deaths averted (benefits) and radiation-induced breast cancer incidence and mortality (harms) per 100,000 women screened. Annual screening of 100,000 women aged 40 to 74 years was projected to induce 125 breast cancer cases (95% CI, 88 to 178) leading to 16 deaths (CI, 11 to 23), relative to 968 breast cancer deaths averted by early detection from screening. Women exposed at the 95th percentile were projected to develop 246 cases of radiation-induced breast cancer leading to 32 deaths per 100,000 women. Women with large breasts requiring extra views for complete examination (8% of population) were projected to have greater radiation-induced breast cancer risk (266 cancer cases and 35 deaths per 100,000 women) than other women (113 cancer cases and 15 deaths per 100,000 women). Biennial screening starting at age 50 years reduced risk for radiation-induced cancer 5-fold. Life-years lost from radiation-induced breast cancer could not be estimated. Radiation-induced breast cancer incidence and mortality from digital mammography screening are affected by dose variability from screening, resultant diagnostic work-up, initiation age, and screening frequency. Women with large breasts may have a greater risk for radiation-induced breast cancer. Agency for Healthcare Research and Quality, U.S. Preventive Services Task Force, National Cancer Institute.

  9. Clinical and dosimetric factors of radiation-induced esophageal injury: radiation-induced esophageal toxicity.

    PubMed

    Qiao, Wen-Bo; Zhao, Yan-Hui; Zhao, Yan-Bin; Wang, Rui-Zhi

    2005-05-07

    To analyze the clinical and dosimetric predictive factors for radiation-induced esophageal injury in patients with non-small-cell lung cancer (NSCLC) during three-dimensional conformal radiotherapy (3D-CRT). We retrospectively analyzed 208 consecutive patients (146 men and 62 women) with NSCLC treated with 3D-CRT. The median age of the patients was 64 years (range 35-87 years). The clinical and treatment parameters including gender, age, performance status, sequential chemotherapy, concurrent chemotherapy, presence of carinal or subcarinal lymph nodes, pretreatment weight loss, mean dose to the entire esophagus, maximal point dose to the esophagus, and percentage of volume of esophagus receiving >55 Gy were studied. Clinical and dosimetric factors for radiation-induced acute and late grade 3-5 esophageal injury were analyzed according to Radiation Therapy Oncology Group (RTOG) criteria. Twenty-five (12%) of the two hundred and eight patients developed acute or late grade 3-5 esophageal injury. Among them, nine patients had both acute and late grade 3-5 esophageal injury, two died of late esophageal perforation. Concurrent chemotherapy and maximal point dose to the esophagus > or =60 Gy were significantly associated with the risk of grade 3-5 esophageal injury. Fifty-four (26%) of the two hundred and eight patients received concurrent chemotherapy. Among them, 25 (46%) developed grade 3-5 esophageal injury (P = 0.0001<0.01). However, no grade 3-5 esophageal injury occurred in patients who received a maximal point dose to the esophagus <60 Gy (P = 0.0001<0.01). Concurrent chemotherapy and the maximal esophageal point dose > or =60 Gy are significantly associated with the risk of grade 3-5 esophageal injury in patients with NSCLC treated with 3D-CRT.

  10. Differences in lymphocyte developmental potential between human embryonic stem cell and umbilical cord blood-derived hematopoietic progenitor cells.

    PubMed

    Martin, Colin H; Woll, Petter S; Ni, Zhenya; Zúñiga-Pflücker, Juan Carlos; Kaufman, Dan S

    2008-10-01

    Hematopoietic progenitor cells derived from human embryonic stem cells (hESCs) develop into diverse mature hematopoietic lineages, including lymphocytes. Whereas functional natural killer (NK) cells can be efficiently generated in vitro from hESC-derived CD34(+) cells, studies of T- and B-cell development from hESCs have been much more limited. Here, we demonstrate that despite expressing functional Notch-1, CD34(+) cells from hESCs did not derive T cells when cocultured with OP9 cells expressing Delta-like 1, or in fetal thymus organ culture. hESC-derived CD34(+) cells also did not produce B cells in vitro. In contrast, CD34(+) cells isolated from UCB routinely generated T and B cells when cultured in the same conditions. Notably, both undifferentiated hESCs, and sorted hESC-derived populations with hematopoietic developmental potential exhibited constitutive expression of ID family genes and of transcriptional targets of stem cell factor-induced signaling. These pathways both inhibit T-cell development and promote NK-cell development. Together, these results demonstrate fundamental differences between hESC-derived hematopoietic progenitors and analogous primary human cells. Therefore, hESCs can be more readily supported to differentiate into certain cell types than others, findings that have important implications for derivation of defined lineage-committed populations from hESCs.

  11. Impact of modeled microgravity on migration, differentiation, and cell cycle control of primitive human hematopoietic progenitor cells.

    PubMed

    Plett, P Artur; Abonour, Rafat; Frankovitz, Stacy M; Orschell, Christie M

    2004-08-01

    Migration, proliferation, and differentiation of bone marrow (BM) hematopoietic stem cells (HSC) are important factors in maintaining hematopoietic homeostasis. Homeostatic control of erythrocytes and lymphocytes is perturbed in humans exposed to microgravity (micro-g), resulting in space flight-induced anemia and immunosuppression. We sought to determine whether any of these anomalies can be explained by micro-g-induced changes in migration, proliferation, and differentiation of human BM CD34+ cells, and whether such changes can begin to explain any of the shifts in hematopoietic homeostasis observed in astronauts. BM CD34+ cells were cultured in modeled micro-g (mmicro-g) using NASA's rotating wall vessels (RWV), or in control cultures at earth gravity for 2 to 18 days. Cells were harvested at different times and CD34+ cells assessed for migration potential, cell-cycle kinetics and regulatory proteins, and maturation status. Culture of BM CD34+ cells in RWV for 2 to 3 days resulted in a significant reduction of stromal cell-derived factor 1 (SDF-1alpha)-directed migration, which correlated with decreased expression of F-actin. Modeled micro-g induced alterations in cell-cycle kinetics that were characterized by prolonged S phase and reduced cyclin A expression. Differentiation of primitive CD34+ cells cultured for 14 to 18 days in RWV favored myeloid cell development at the expense of erythroid development, which was significantly reduced compared to controls. These results illustrate that mmicro-g significantly inhibits the migration potential, cell-cycle progression, and differentiation patterns of primitive BM CD34+ cells, which may contribute to some of the hematologic abnormalities observed in humans during space flight.

  12. Spacesuit Radiation Shield Design Methods

    NASA Technical Reports Server (NTRS)

    Wilson, John W.; Anderson, Brooke M.; Cucinotta, Francis A.; Ware, J.; Zeitlin, Cary J.

    2006-01-01

    Meeting radiation protection requirements during EVA is predominantly an operational issue with some potential considerations for temporary shelter. The issue of spacesuit shielding is mainly guided by the potential of accidental exposure when operational and temporary shelter considerations fail to maintain exposures within operational limits. In this case, very high exposure levels are possible which could result in observable health effects and even be life threatening. Under these assumptions, potential spacesuit radiation exposures have been studied using known historical solar particle events to gain insight on the usefulness of modification of spacesuit design in which the control of skin exposure is a critical design issue and reduction of blood forming organ exposure is desirable. Transition to a new spacesuit design including soft upper-torso and reconfigured life support hardware gives an opportunity to optimize the next generation spacesuit for reduced potential health effects during an accidental exposure.

  13. The effect of gamma radiation on the Common carp (Cyprinus carpio): In vivo genotoxicity assessment with the micronucleus and comet assays.

    PubMed

    M K, Praveen Kumar; Soorambail K, Shyama; Bhagatsingh Harisingh, Sonaye; D'costa, Avelyno; Ramesh Chandra, Chaubey

    2015-10-01

    Radioactive wastes may be leached into freshwater, either accidentally or in industrial effluents. We have studied gamma radiation-induced DNA damage in the freshwater fish Cyprinus carpio. Fish were irradiated with 2-10Gy gamma radiation and genotoxic effects in blood cells were studied with the micronucleus (MN) and comet assays. Micronuclei and a dose-dependent increase in comet-tail DNA were seen in dose- and time-dependent studies. The highest % tail DNA was observed at 24h, declining until 72h, which may indicate the repair of radiation-induced DNA single-strand breaks after gamma radiation. However, double-stranded DNA damage may not have been repaired, as indicated by increased micronuclei at later periods. A positive correlation was observed between the comet and micronucleus assay results. This study confirms the mutagenic/genotoxic potential of gamma radiation in the Common carp, as well as the possible combined use of the micronucleus and comet assays for in vivo laboratory studies with fresh-water fish for screening the genotoxic potential of radioactive pollution. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Hydroquinone induces DNA hypomethylation-independent overexpression of retroelements in human leukemia and hematopoietic stem cells.

    PubMed

    Conti, Anastasia; Rota, Federica; Ragni, Enrico; Favero, Chiara; Motta, Valeria; Lazzari, Lorenza; Bollati, Valentina; Fustinoni, Silvia; Dieci, Giorgio

    2016-06-10

    Hydroquinone (HQ) is an important benzene-derived metabolite associated with acute myelogenous leukemia risk. Although altered DNA methylation has been reported in both benzene-exposed human subjects and HQ-exposed cultured cells, the inventory of benzene metabolite effects on the epigenome is only starting to be established. In this study, we used a monocytic leukemia cell line (THP-1) and hematopoietic stem cells (HSCs) from cord blood to investigate the effects of HQ treatment on the expression of the three most important families of retrotransposons in the human genome: LINE-1, Alu and Endogenous retroviruses (HERVs), that are normally subjected to tight epigenetic silencing. We found a clear tendency towards increased retrotransposon expression in response to HQ exposure, more pronounced in the case of LINE-1 and HERV. Such a partial loss of silencing, however, was generally not associated with HQ-induced DNA hypomethylation. On the other hand, retroelement derepression was also observed in the same cells in response to the hypomethylating agent decitabine. These observations suggest the existence of different types of epigenetic switches operating at human retroelements, and point to retroelement activation in response to benzene-derived metabolites as a novel factor deserving attention in benzene carcinogenesis studies. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Accidental introductions are an important source of invasive plants in the continental United States.

    PubMed

    Lehan, Nora E; Murphy, Julia R; Thorburn, Lukas P; Bradley, Bethany A

    2013-07-01

    Preventing new plant invasions is critical for reducing large-scale ecological change. Most studies have focused on the deliberate introduction of nonnatives via the ornamental plant trade. However, accidental introduction may be an important source of nonnative, invasive plants. Using Web and literature searches, we compiled pathways of introduction to the United States for 1112 nonnative plants identified as invasive in the continental United States. We assessed how the proportion of accidentally and deliberately introduced invasive plants varies over time and space and by growth habit across the lower 48 states. Deliberate introductions of ornamentals are the primary source of invasive plants in the United States, but accidental introductions through seed contaminants are an important secondary source. Invasive forbs and grasses are the most likely to have arrived accidentally through seed contaminants, while almost all nonnative, invasive trees were introduced deliberately. Nonnative plants invading eastern states primarily arrived deliberately as ornamentals, while a high proportion of invasive plants in western states arrived accidentally as seed contaminants. Accidental introductions may be increasing in importance through time. Before 1850, 10 of 89 (11%) of invasive plants arrived accidentally. After 1900, 20 of 65 (31%) arrived accidentally. Recently enacted screening protocols and weed risk assessments aim to reduce the number of potentially invasive species arriving to the United States via deliberate introduction pathways. Increasing proportions of accidentally introduced invasive plants, particularly associated with contaminated seed imports across the western states, suggest that accidental introduction pathways also need to be considered in future regulatory decisions.

  16. Imitation of Intentional and Accidental Actions by Children with Autism

    ERIC Educational Resources Information Center

    D'Entremont, Barbara; Yazbek, Aimee

    2007-01-01

    To determine whether children with autism (CWA) would selectively imitate intentional, as opposed to accidental actions, an experimenter demonstrated either an "intentional" and an "accidental" action or two "intentional" actions on the same toy [Carpenter, Akhtar, & Tomasello ("1998a") "Infant Behavior and Development, 21," 315-330]. CWA tended…

  17. Hematopoietic progenitors express neural genes

    PubMed Central

    Goolsby, James; Marty, Marie C.; Heletz, Dafna; Chiappelli, Joshua; Tashko, Gerti; Yarnell, Deborah; Fishman, Paul S.; Dhib-Jalbut, Suhayl; Bever, Christopher T.; Pessac, Bernard; Trisler, David

    2003-01-01

    Bone marrow, or cells selected from bone marrow, were reported recently to give rise to cells with a neural phenotype after in vitro treatment with neural-inducing factors or after delivery into the brain. However, we showed previously that untreated bone marrow cells express products of the neural myelin basic protein gene, and we demonstrate here that a subset of ex vivo bone marrow cells expresses the neurogenic transcription factor Pax-6 as well as neuronal genes encoding neurofilament H, NeuN (neuronal nuclear protein), HuC/HuD (Hu-antigen C/Hu-antigen D), and GAD65 (glutamic acid decarboxylase 65), as well as the oligodendroglial gene encoding CNPase (2′,3′ cyclic nucleotide 3′-phosphohydrolase). In contrast, astroglial glial fibrillary acidic protein (GFAP) was not detected. These cells also were CD34+, a marker of hematopoietic stem cells. Cultures of these highly proliferative CD34+ cells, derived from adult mouse bone marrow, uniformly displayed a phenotype comparable with that of hematopoietic progenitor cells (CD45+, CD34+, Sca-1+, AA4.1+, cKit+, GATA-2+, and LMO-2+). The neuronal and oligodendroglial genes expressed in ex vivo bone marrow also were expressed in all cultured CD34+ cells, and GFAP was not observed. After CD34+ cell transplantation into adult brain, neuronal or oligodendroglial markers segregated into distinct nonoverlapping cell populations, whereas astroglial GFAP appeared, in the absence of other neural markers, in a separate set of implanted cells. Thus, neuronal and oligodendroglial gene products are present in a subset of bone marrow cells, and the expression of these genes can be regulated in brain. The fact that these CD34+ cells also express transcription factors (Rex-1 and Oct-4) that are found in early development elicits the hypothesis that they may be pluripotent embryonic-like stem cells. PMID:14634211

  18. Radiation-Induced Breast Cancer Incidence and Mortality from Digital Mammography Screening: A Modeling Study

    PubMed Central

    Miglioretti, Diana L.; Lange, Jane; van den Broek, Jeroen J.; Lee, Christoph I.; van Ravesteyn, Nicolien T.; Ritley, Dominique; Kerlikowske, Karla; Fenton, Joshua J.; Melnikow, Joy; de Koning, Harry J.; Hubbard, Rebecca A.

    2016-01-01

    Background Estimates of radiation-induced breast cancer risk from mammography screening have not previously considered dose exposure variation or diagnostic work-up after abnormal screening. Objective To estimate distributions of radiation-induced breast cancer incidence and mortality from digital mammography screening, considering exposure from screening and diagnostic mammography and dose variation across women. Design Two simulation-modeling approaches using common data on screening mammography from the Breast Cancer Surveillance Consortium and radiation dose from mammography from the Digital Mammographic Imaging Screening Trial. Setting U.S. population. Patients Women aged 40–74 years. Interventions Annual or biennial digital mammography screening from age 40, 45, or 50 until 74. Measurements Lifetime breast cancer deaths averted (benefits) and radiation-induced breast cancer incidence and mortality per 100,000 women screened (harms). Results On average, annual screening of 100,000 women aged 40 to 74 years was projected to induce 125 breast cancers (95% confidence interval [CI]=88–178) leading to 16 deaths (95% CI=11–23) relative to 968 breast cancer deaths averted by early detection from screening. Women exposed at the 95th percentile were projected to develop 246 radiation-induced breast cancers leading to 32 deaths per 100,000 women. Women with large breasts requiring extra views for complete breast examination (8% of population) were projected to have higher radiation-induced breast cancer incidence and mortality (266 cancers, 35 deaths per 100,000 women), compared to women with small or average breasts (113 cancers, 15 deaths per 100,000 women). Biennial screening starting at age 50 reduced risk of radiation-induced cancers 5-fold. Limitations We were unable to estimate years of life lost from radiation-induced breast cancer. Conclusions Radiation-induced breast cancer incidence and mortality from digital mammography screening are impacted by dose

  19. Low dose or low dose rate ionizing radiation-induced health effect in the human.

    PubMed

    Tang, Feng Ru; Loganovsky, Konstantin

    2018-06-05

    The extensive literature review on human epidemiological studies suggests that low dose ionizing radiation (LDIR) (≤100 mSv) or low dose rate ionizing radiation (LDRIR) (<6mSv/H) exposure could induce either negative or positive health effects. These changes may depend on genetic background, age (prenatal day for embryo), sex, nature of radiation exposure, i.e., acute or chronic irradiation, radiation sources (such as atomic bomb attack, fallout from nuclear weapon test, nuclear power plant accidents, 60 Co-contaminated building, space radiation, high background radiation, medical examinations or procedures) and radionuclide components and human epidemiological experimental designs. Epidemiological and clinical studies show that LDIR or LDRIR exposure may induce cancer, congenital abnormalities, cardiovascular and cerebrovascular diseases, cognitive and other neuropsychiatric disorders, cataracts and other eye and somatic pathology (endocrine, bronchopulmonary, digestive, etc). LDIR or LDRIR exposure may also reduce mutation and cancer mortality rates. So far, the mechanisms of LDIR- or LDRIR -induced health effect are poorly understood. Further extensive studies are still needed to clarify under what circumstances, LDIR or LDRIR exposure may induce positive or negative effects, which may facilitate development of new therapeutic approaches to prevent or treat the radiation-induced human diseases or enhance radiation-induced positive health effect. Copyright © 2018 Elsevier Ltd. All rights reserved.

  20. Individual dose due to radioactivity accidental release from fusion reactor.

    PubMed

    Nie, Baojie; Ni, Muyi; Wei, Shiping

    2017-04-05

    As an important index shaping the design of fusion safety system, evaluation of public radiation consequences have risen as a hot topic on the way to develop fusion energy. In this work, the comprehensive public early dose was evaluated due to unit gram tritium (HT/HTO), activated dust, activated corrosion products (ACPs) and activated gases accidental release from ITER like fusion reactor. Meanwhile, considering that we cannot completely eliminate the occurrence likelihood of multi-failure of vacuum vessel and tokamak building, we conservatively evaluated the public radiation consequences and environment restoration after the worst hypothetical accident preliminarily. The comparison results show early dose of different unit radioactivity release under different conditions. After further performing the radiation consequences, we find it possible that the hypothetical accident for ITER like fusion reactor would result in a level 6 accident according to INES, not appear level 7 like Chernobyl or Fukushima accidents. And from the point of environment restoration, we need at least 69 years for case 1 (1kg HTO and 1000kg dust release) and 34-52years for case 2 (1kg HTO and 10kg-100kg dust release) to wait the contaminated zone drop below the general public safety limit (1mSv per year) before it is suitable for human habitation. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Chemotaxis of primitive hematopoietic cells in response to stromal cell–derived factor-1

    PubMed Central

    Jo, Deog-Yeon; Rafii, Shahin; Hamada, Tsuneyoshi; Moore, Malcolm A.S.

    2000-01-01

    Stromal cell–derived factor-1 (SDF-1) provides a potent chemotactic stimulus for CD34+ hematopoietic cells. We cultured mobilized peripheral blood (PB) and umbilical cord blood (CB) for up to 5 weeks and examined the migratory activity of cobblestone area–forming cells (CAFCs) and long-term culture–initiating cells (LTC-ICs) in a transwell assay. In this system, SDF-1 or MS-5 marrow stromal cells placed in the lower chamber induced transmembrane and transendothelial migration by 2- and 5-week-old CAFCs and LTC-ICs in 3 hours. Transmigration was blocked by preincubation of input CD34+ cells with antibody to CXCR4. Transendothelial migration of CB CAFCs and LTC-ICs was higher than that of PB. We expanded CD34+ cells from CB in serum-free medium with thrombopoietin, flk-2 ligand, and c-kit ligand, with or without IL-3 and found that CAFCs cultured in the absence of IL-3 had a chemotactic response equivalent to noncultured cells, even after 5 weeks. However, addition of IL-3 to the culture reduced this response by 20–50%. These data indicate that SDF-1 induces chemotaxis of primitive hematopoietic cells signaling through CXCR4 and that the chemoattraction could be downmodulated by culture ex vivo. PMID:10619866

  2. Non-radiation induced signals in TL dosimetry.

    PubMed

    German, U; Weinstein, M

    2002-01-01

    One source of background signals, which are non-radiation related, is the reader system and it includes dark current, external contaminants and electronic spikes. These factors can induce signals equivalent to several hundredths of mSv. Mostly, the effects are minimised by proper design of the TLD reader, but some effects are dependent on proper operation of the system. The other main group of background signals originates in the TL crystal and is due to tribothermoluminescence, dirt, chemical reactions and stimulation by visible or UV light. These factors can have a significant contribution, equivalent to over several mSv, depending on whether the crystal is bare or protected by PTFE. Working in clean environments, monitoring continuously the glow curves and performing glow curve deconvolution are suggested to minimise non-radiation induced spurious signals.

  3. Trichostatin A inhibits radiation-induced epithelial-to-mesenchymal transition in the alveolar epithelial cells

    PubMed Central

    Nagarajan, Devipriya; Wang, Lei; Zhao, Weiling; Han, Xiaochen

    2017-01-01

    Radiation-induced pneumonitis and fibrosis are major complications following thoracic radiotherapy. Epithelial-to-mesenchymal transition (EMT) plays an important role in tissue injury leading to organ fibrosis, including lung. Our previous studies have reported that radiation can induce EMT in the type II alveolar epithelial cells in both in vitro and in vivo. HDAC inhibitors are a new family of anti-cancer agents currently being used in several clinical trials. In addition to their intrinsic anti-tumor properties, HDAC inhibition is also important in other human diseases, including fibrosis and radiation-induced damage. In this study, we evaluated the effect of Trichostatin A (TSA), a HDAC inhibitor, on radiation-induced EMT in type II alveolar epithelial cells (RLE-6TN). Pre-treatment of RLE-6TN cells with TSA inhibited radiation-induced EMT-like morphological alterations including elevated protein level of α-SMA and Snail, reduction of E-cadherin expression, enhanced phosphorylation of GSK3β and ERK1/2, increased generation of ROS. Radiation enhanced the protein level of TGF-β1, which was blocked by N-acetylcysteine, an antioxidant. Treating cells with SB-431542, TGF-β1 type I receptor inhibitor, diminished radiation-induced alterations in the protein levels of p-GSK-3β, Snail-1 and α-SMA, suggesting a regulatory role of TGF-β1 in EMT. Pre-incubation of cells with TSA showed significant decrease in the level of TGF-β1 compared to radiation control. Collectively, these results demonstrate that i] radiation-induced EMT in RLE-6TN cells is mediated by ROS/MEK/ERK and ROS/TGF-β1 signaling pathways and ii] the inhibitory role of TSA in radiation-induced EMT appears to be due, at least in part, to its action of blocking ROS and TGF-β1 signaling. PMID:29254201

  4. Alectinib induced CNS radiation necrosis in an ALK+NSCLC patient with a remote (7 years) history of brain radiation.

    PubMed

    Ou, Sai-Hong Ignatius; Weitz, Michael; Jalas, John R; Kelly, Daniel F; Wong, Vanessa; Azada, Michele C; Quines, Oliver; Klempner, Samuel J

    2016-06-01

    Alectinib is a second generation ALK inhibitor that has significant clinical activity in central nervous system (CNS) metastases in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Pseudoprogression (PsP) due to radiation necrosis during alecitnib treatment of central nervous system (CNS) metastases from ALK-rearranged NSCLC as been reported. Hence, distinguishing radiation-related PsP from alectinib-induced radiographic changes is important to avoid erroneous early trial discontinuation and abandonment of an effective treatment. However, it remains difficult to assess casuality of radiation necrosis is related to recent direct radiation or induced by alectinib treatment or both. It is also unknown how long from previous radiation can alectinib still induce radiation necrosis. Here we reported a crizotinib-refractory ALK-positive NSCLC patient who develop radiation necrosis in one of his metastatic CNS lesions after approximately 12 months of alectinib treatment who otherwise had on-going CNS response on alectinib. His most recent radiation to his CNS metastases was 7 years prior to the start of alectinib. This case illustrates that in the setting of pror CNS radiation, given the significant clinical activity of alectinib in CNS metastases in ALK-positive NSCLC patients the risk of CNS radiation necrosis remains long after previous radiation to the CNS metastases has been completed and can occur after durable response of treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Fanca-/- hematopoietic stem cells demonstrate a mobilization defect which can be overcome by administration of the Rac inhibitor NSC23766.

    PubMed

    Milsom, Michael D; Lee, Andrew W; Zheng, Yi; Cancelas, Jose A

    2009-07-01

    Fanconi anemia is a severe bone marrow failure syndrome resulting from inactivating mutations of Fanconi anemia pathway genes. Gene and cell therapy trials using hematopoietic stem cells and progenitors have been hampered by poor mobilization of HSC to peripheral blood in response to G-CSF. Using a murine model of Fanconi anemia (Fanca(-/-) mice), we found that the Fanca deficiency was associated with a profound defect in hematopoietic stem cells and progenitors mobilization in response to G-CSF in absence of bone marrow failure, which correlates with the findings of clinical trials in Fanconi anemia patients. This mobilization defect was overcome by co-administration of the Rac inhibitor NSC23766, suggesting that Rac signaling is implicated in the retention of Fanca(-/-) hematopoietic stem cells and progenitors in the bone marrow. In view of these data, we propose that targeting Rac signaling may enhance G-CSF-induced HSC mobilization in Fanconi anemia.

  6. Experiences of Causing an Accidental Death: An Interpretative Phenomenological Analysis

    ERIC Educational Resources Information Center

    Rassool, Sara B.; Nel, Pieter W.

    2012-01-01

    Accidentally killing or feeling responsible for another person's death constitutes an event that is different from many typical traumatic stressors in that the responsibility for causing the trauma is located in the person themselves, rather than another person or persons. Research exploring the perspective of those who have accidentally caused a…

  7. Hematopoietic Project - SEER Registrars

    Cancer.gov

    Use this manual and corresponding database for coding cases diagnosed January 1, 2010 and forward. The changes do not require recoding of old cases. Contains data collection rules for hematopoietic and lymphoid neoplasms (2010+). Access a database and coding manual.

  8. The biochemistry of hematopoietic stem cell development.

    PubMed

    Kaimakis, P; Crisan, M; Dzierzak, E

    2013-02-01

    The cornerstone of the adult hematopoietic system and clinical treatments for blood-related disease is the cohort of hematopoietic stem cells (HSC) that is harbored in the adult bone marrow microenvironment. Interestingly, this cohort of HSCs is generated only during a short window of developmental time. In mammalian embryos, hematopoietic progenitor and HSC generation occurs within several extra- and intraembryonic microenvironments, most notably from 'hemogenic' endothelial cells lining the major vasculature. HSCs are made through a remarkable transdifferentiation of endothelial cells to a hematopoietic fate that is long-lived and self-renewable. Recent studies are beginning to provide an understanding of the biochemical signaling pathways and transcription factors/complexes that promote their generation. The focus of this review is on the biochemistry behind the generation of these potent long-lived self-renewing stem cells of the blood system. Both the intrinsic (master transcription factors) and extrinsic regulators (morphogens and growth factors) that affect the generation, maintenance and expansion of HSCs in the embryo will be discussed. The generation of HSCs is a stepwise process involving many developmental signaling pathways, morphogens and cytokines. Pivotal hematopoietic transcription factors are required for their generation. Interestingly, whereas these factors are necessary for HSC generation, their expression in adult bone marrow HSCs is oftentimes not required. Thus, the biochemistry and molecular regulation of HSC development in the embryo are overlapping, but differ significantly from the regulation of HSCs in the adult. HSC numbers for clinical use are limiting, and despite much research into the molecular basis of HSC regulation in the adult bone marrow, no panel of growth factors, interleukins and/or morphogens has been found to sufficiently increase the number of these important stem cells. An understanding of the biochemistry of HSC

  9. Ten years of iPSC: clinical potential and advances in vitro hematopoietic differentiation.

    PubMed

    Paes, Bárbara Cristina Martins Fernandes; Moço, Pablo Diego; Pereira, Cristiano Gonçalves; Porto, Geciane Silveira; de Sousa Russo, Elisa Maria; Reis, Luiza Cunha Junqueira; Covas, Dimas Tadeu; Picanço-Castro, Virginia

    2017-06-01

    Ten years have passed since the first publication announcing the generation of induced pluripotent stem cells (iPSCs). Issues related to ethics, immune rejection, and cell availability seemed to be solved following this breakthrough. The development of iPSC technology allows advances in in vitro cell differentiation for cell therapy purpose and other clinical applications. This review provides a perspective on the iPSC potential for cell therapies, particularly for hematological applications. We discuss the advances in in vitro hematopoietic differentiation, the possibilities to employ iPSC in hematology studies, and their potential clinical application in hematologic diseases. The generation of red blood cells and functional T cells and the genome editing technology applied to mutation correction are also covered. We highlight some of the requirements and obstacles to be overcome before translating these cells from research to the clinic, for instance, iPSC variability, genotoxicity, the differentiation process, and engraftment. Also, we evaluate the patent landscape and compile the clinical trials in the field of pluripotent stem cells. Currently, we know much more about iPSC than in 2006, but there are still challenges that must be solved. A greater understanding of molecular mechanisms underlying the generation of hematopoietic stem cells is necessary to produce suitable and transplantable hematopoietic stem progenitor cells from iPSC.

  10. NLRP3 inflammasome activation mediates radiation-induced pyroptosis in bone marrow-derived macrophages

    PubMed Central

    Liu, Yan-gang; Chen, Ji-kuai; Zhang, Zi-teng; Ma, Xiu-juan; Chen, Yong-chun; Du, Xiu-ming; Liu, Hong; Zong, Ying; Lu, Guo-cai

    2017-01-01

    A limit to the clinical benefit of radiotherapy is not an incapacity to eliminate tumor cells but rather a limit on its capacity to do so without destroying normal tissue and inducing inflammation. Recent evidence reveals that the inflammasome is essential for mediating radiation-induced cell and tissue damage. In this study, using primary cultured bone marrow-derived macrophages (BMDM) and a mouse radiation model, we explored the role of NLRP3 inflammasome activation and the secondary pyroptosis underlying radiation-induced immune cell death. We observed an increasing proportion of pyroptosis and elevating Caspase-1 activation in 10 and 20 Gy radiation groups. Nlrp3 knock out significantly diminished the quantity of cleaved-Caspase-1 (p10) and IL-1β as well as the proportion of pyroptosis. Additionally, in vivo research shows that 9.5 Gy of radiation promotes Caspase-1 activation in marginal zone cells and induces death in mice, both of which can be significantly inhibited by knocking out Nlrp3. Thus, based on these findings, we conclude that the NLRP3 inflammasome activation mediates radiation-induced pyroptosis in BMDMs. Targeting NLRP3 inflammasome and pyroptosis may serve as effective strategies to diminish injury caused by radiation. PMID:28151471

  11. Association of Hematological Nadirs and Survival in a Nonhuman Primate Model of Hematopoietic Syndrome of Acute Radiation Syndrome.

    PubMed

    Gluzman-Poltorak, Zoya; Vainstein, Vladimir; Basile, Lena A

    2015-08-01

    Recombinant human interleukin-12 (rHuIL-12) mitigates the hematopoietic subsyndrome of acute radiation syndrome (HSARS) after total body irradiation (TBI) in a nonhuman primate (NHP) model of HSARS. The mechanism for this effect appears to involve multiple effects of rHuIL-12 on hematopoiesis. We conducted a meta-analysis to examine hematological nadirs and survival across our three NHP completed studies. Animals were irradiated (700 cGy) and treated with a single subcutaneous injection of vehicle (n = 64) or rHuIL-12 (50-500 ng/kg; n = 108) 24-25 h after irradiation, or with daily subcutaneous injections of granulocyte-colony stimulating factor (G-CSF; 10 μg/kg/day) for 18 days starting 24-25 h after exposure (n = 26). Blood samples were obtained at various time points up to day 60 after TBI. Lymphocytes, neutrophils and platelets were significantly lower in nonsurvivors than in survivors in the overall sample and in each treatment group (P < 0.001 for each comparison, Wilcoxon rank-sum test). Lymphocyte nadir was the strongest and most consistent predictor of death by Spearman's rank correlation. Receiver operating characteristic (ROC) curve analysis of death and threshold hematologic nadir values (where nadir values less than or equal the threshold are predictive of death) showed that a threshold of 0.08 × 10(9)/L for lymphocytes had the largest positive predictive value of death (97.2% and 92.5% for the control and rHuIL-12 groups, respectively) and high sensitivity (76.1% and 62.7%, respectively), consistent with human radiation victims data. The current findings suggest that enhanced early bone marrow regeneration resulting in increases in nadir values for all major blood cell types may be the main mechanism of action by which rHuIL-12 mitigates the lethality of HSARS.

  12. Neural Crossroads in the Hematopoietic Stem Cell Niche.

    PubMed

    Agarwala, Sobhika; Tamplin, Owen J

    2018-05-29

    The hematopoietic stem cell (HSC) niche supports steady-state hematopoiesis and responds to changing needs during stress and disease. The nervous system is an important regulator of the niche, and its influence is established early in development when stem cells are specified. Most research has focused on direct innervation of the niche, however recent findings show there are different modes of neural control, including globally by the central nervous system (CNS) and hormone release, locally by neural crest-derived mesenchymal stem cells, and intrinsically by hematopoietic cells that express neural receptors and neurotransmitters. Dysregulation between neural and hematopoietic systems can contribute to disease, however new therapeutic opportunities may be found among neuroregulator drugs repurposed to support hematopoiesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

  13. Antiradiation Vaccine: Immunological neutralization of Radiation Toxins at Acute Radiation Syndromes.

    NASA Astrophysics Data System (ADS)

    Popov, Dmitri; Maliev, Slava

    . Material and Methods: The SRD molecules were isolated from Lymphatic Systems of animals that were irradiated with high doses of irradiation and had a clinical and laboratory picture of the Cerebral Acute Radia-tion Syndrome, Cardiovascular Acute Radiation Syndrome, Gastrointestinal Acute Radiation Syndrome, and Hematological Acute Radiation Syndrome. Our classification of radiation tox-ins includes 4 major groups: 1.SRD-1, Cerebrovascular neurotoxic Radiation Toxins (CvARS); 2.SRD-2, Cardiovascular Radiation Toxins(CrARS); 3.SRD-3,Gastrointestinal neurotoxic Ra-diation Toxins (GiARS); 4.SRD-4, Hematopietic Radiation Toxins (HpARS). Radiation tox-ins possess both toxic and immunological properties. But mechanisms of immune-toxicity by which radiation toxins stimulate development of the ARS are poorly understood. We have studied lethal toxicity of radiation toxins and an ability of specific antibodies to neutralize toxic activity of radiation toxins by specific antibodies. Results: The Blocking Antiradiation Antibodies induce an immunologically specific effect and inhibiting effects on radiation induced neuro-toxicity, vascular-toxicity, gastrointestinal toxcity, hematopoietic toxicity. Antiradiation Antibodies prevent the radiation induced cytolysis of selected groups of cells that are sensitive to radiation. The Blocking Antiradiation Antibodies are immunologically specific and can be produced by immunization with the different radiation toxins isolated from irradiated mam-mals. We propose that Specific Antiradiation Antibodies targeted against the radiation induced Toxins. Specific Antiradiation Antibodies neutralize toxic properties of radiation toxins. Anti-radiation Antibodies in different phases of the Acute Radiation Syndromes can compete with cytotoxic lymphocytes and prevent cytolysis mediated by cytotoxic lymphocytes. Conclusions: Immunological inhibition of cytotoxic and neurotoxic properties of Specific Radiation Toxins are significant factors for improving

  14. Reduced Erg Dosage Impairs Survival of Hematopoietic Stem and Progenitor Cells.

    PubMed

    Xie, Ying; Koch, Mia Lee; Zhang, Xin; Hamblen, Melanie J; Godinho, Frank J; Fujiwara, Yuko; Xie, Huafeng; Klusmann, Jan-Henning; Orkin, Stuart H; Li, Zhe

    2017-07-01

    ERG, an ETS family transcription factor frequently overexpressed in human leukemia, has been implicated as a key regulator of hematopoietic stem cells. However, how ERG controls normal hematopoiesis, particularly at the stem and progenitor cell level, and how it contributes to leukemogenesis remain incompletely understood. Using homologous recombination, we generated an Erg knockdown allele (Erg kd ) in which Erg expression can be conditionally restored by Cre recombinase. Erg kd/kd animals die at E10.5-E11.5 due to defects in endothelial and hematopoietic cells, but can be completely rescued by Tie2-Cre-mediated restoration of Erg in these cells. In Erg kd/+ mice, ∼40% reduction in Erg dosage perturbs both fetal liver and bone marrow hematopoiesis by reducing the numbers of Lin - Sca-1 + c-Kit + (LSK) hematopoietic stem and progenitor cells (HSPCs) and megakaryocytic progenitors. By genetic mosaic analysis, we find that Erg-restored HSPCs outcompete Erg kd/+ HSPCs for contribution to adult hematopoiesis in vivo. This defect is in part due to increased apoptosis of HSPCs with reduced Erg dosage, a phenotype that becomes more drastic during 5-FU-induced stress hematopoiesis. Expression analysis reveals that reduced Erg expression leads to changes in expression of a subset of ERG target genes involved in regulating survival of HSPCs, including increased expression of a pro-apoptotic regulator Bcl2l11 (Bim) and reduced expression of Jun. Collectively, our data demonstrate that ERG controls survival of HSPCs, a property that may be used by leukemic cells. Stem Cells 2017;35:1773-1785. © 2017 AlphaMed Press.

  15. Accidental degeneracies in nonlinear quantum deformed systems

    NASA Astrophysics Data System (ADS)

    Aleixo, A. N. F.; Balantekin, A. B.

    2011-09-01

    We construct a multi-parameter nonlinear deformed algebra for quantum confined systems that includes many other deformed models as particular cases. We demonstrate that such systems exhibit the property of accidental pairwise energy level degeneracies. We also study, as a special case of our multi-parameter deformation formalism, the extension of the Tamm-Dancoff cutoff deformed oscillator and the occurrence of accidental pairwise degeneracy in the energy levels of the deformed system. As an application, we discuss the case of a trigonometric Rosen-Morse potential, which is successfully used in models for quantum confined systems, ranging from electrons in quantum dots to quarks in hadrons.

  16. Related-to-receptor tyrosine kinase receptor regulates hematopoietic stem and progenitor sensitivity to myelosuppressive injury in mice.

    PubMed

    Povinelli, Benjamin J; Srivastava, Pragya; Nemeth, Michael J

    2015-03-01

    Maintaining a careful balance between quiescence and proliferation of hematopoietic stem and progenitor cells (HSPCs) is necessary for lifelong blood formation. Previously, we demonstrated that the Wnt5a ligand inhibits HSPC proliferation through a functional interaction with a noncanonical Wnt ligand receptor termed 'related-to-receptor tyrosine kinase' (Ryk). Expression of Ryk on HSPCs in vivo is associated with a lower rate of proliferation, and, following treatment with fluorouracil (5-FU), the percentage of Ryk(+/high) HSPCs increased and the percentage of Ryk(-/low) HSPCs decreased. Based on these data, we hypothesized that one function of the Ryk receptor is to protect HSPCs from the effects of myeloablative agents. We found that Ryk expression on HSPCs is associated with lower rates of apoptosis following 5-FU and radiation. Transient inhibition of Ryk signaling in vivo resulted in increased hematopoietic-stem-cell proliferation and decreased hematopoietic-stem-cell function in bone marrow transplant assays. Furthermore, inhibition of Ryk signaling sensitized HSPCs to 5-FU treatment in association with increased levels of reactive oxygen species. Together, these results demonstrated an association between Ryk expression and survival of HSPCs following suppressive injury. Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

  17. WORKSHOP REPORT: MOLECULAR & CELLULAR BIOLOGY OF MODERATE DOSE (1-10 GY) RADIATION & POTENTIAL MECHANISMS OF RADIATION PROTECTION

    EPA Science Inventory

    EXECUTIVE SUMMARY

    Normal tissue response and injury after exposure to ionizing radiation are of great importance to patients with cancer, populations potentially subjected to military, accidental or intentional exposure including bioterrorism, and workers in the nuclear po...

  18. Ionizing radiation-induced acoustics for radiotherapy and diagnostic radiology applications.

    PubMed

    Hickling, Susannah; Xiang, Liangzhong; Jones, Kevin C; Parodi, Katia; Assmann, Walter; Avery, Stephen; Hobson, Maritza; El Naqa, Issam

    2018-04-21

    Acoustic waves are induced via the thermoacoustic effect in objects exposed to a pulsed beam of ionizing radiation. This phenomenon has interesting potential applications in both radiotherapy dosimetry and treatment guidance as well as low dose radiological imaging. After initial work in the field in the 1980s and early 1990s, little research was done until 2013 when interest was rejuvenated, spurred on by technological advances in ultrasound transducers and the increasing complexity of radiotherapy delivery systems. Since then, many studies have been conducted and published applying ionizing radiation-induced acoustic principles into three primary research areas: Linear accelerator photon beam dosimetry, proton therapy range verification, and radiological imaging. This review article introduces the theoretical background behind ionizing radiation-induced acoustic waves, summarizes recent advances in the field, and provides an outlook on how the detection of ionizing radiation-induced acoustic waves can be used for relative and in vivo dosimetry in photon therapy, localization of the Bragg peak in proton therapy, and as a low-dose medical imaging modality. Future prospects and challenges for clinical implementation of these techniques are discussed. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  19. Molecular, Cellular and Functional Effects of Radiation-Induced Brain Injury: A Review

    PubMed Central

    Balentova, Sona; Adamkov, Marian

    2015-01-01

    Radiation therapy is the most effective non-surgical treatment of primary brain tumors and metastases. Preclinical studies have provided valuable insights into pathogenesis of radiation-induced injury to the central nervous system. Radiation-induced brain injury can damage neuronal, glial and vascular compartments of the brain and may lead to molecular, cellular and functional changes. Given its central role in memory and adult neurogenesis, the majority of studies have focused on the hippocampus. These findings suggested that hippocampal avoidance in cranial radiotherapy prevents radiation-induced cognitive impairment of patients. However, multiple rodent studies have shown that this problem is more complex. As the radiation-induced cognitive impairment reflects hippocampal and non-hippocampal compartments, it is of critical importance to investigate molecular, cellular and functional modifications in various brain regions as well as their integration at clinically relevant doses and schedules. We here provide a literature overview, including our previously published results, in order to support the translation of preclinical findings to clinical practice, and improve the physical and mental status of patients with brain tumors. PMID:26610477

  20. The effect of radiation dose on the onset and progression of radiation-induced brain necrosis in the rat model.

    PubMed

    Hartl, Brad A; Ma, Htet S W; Hansen, Katherine S; Perks, Julian; Kent, Michael S; Fragoso, Ruben C; Marcu, Laura

    2017-07-01

    To provide a comprehensive understanding of how the selection of radiation dose affects the temporal and spatial progression of radiation-induced necrosis in the rat model. Necrosis was induced with a single fraction of radiation exposure, at doses ranging between 20 and 60 Gy, to the right hemisphere of 8-week-old Fischer rats from a linear accelerator. The development and progression of necrosis in the rats was monitored and quantified every other week with T1- and T2-weighted gadolinium contrast-enhanced MRI studies. The time to onset of necrosis was found to be dose-dependent, but after the initial onset, the necrosis progression rate and total volume generated was constant across different doses ranging between 30 and 60 Gy. Radiation doses less than 30 Gy did not develop necrosis within 33 weeks after treatment, indicating a dose threshold existing between 20 and 30 Gy. The highest dose used in this study led to the shortest time to onset of radiation-induced necrosis, while producing comparable disease progression dynamics after the onset. Therefore, for the radiation-induced necrosis rat model using a linear accelerator, the most optimum results were generated from a dose of 60 Gy.

  1. [Radiation-induced bystander effect: the important part of ionizing radiation response. Potential clinical implications].

    PubMed

    Wideł, Maria; Przybyszewski, Waldemar; Rzeszowska-Wolny, Joanna

    2009-08-18

    It has long been a central radiobiological dogma that the damaging effects of ionizing radiation, such as cell death, cytogenetic changes, apoptosis, mutagenesis, and carcinogenesis, are the results of the direct ionization of cell structures, particularly DNA, or indirect damage via water radiolysis products. However, several years ago attention turned to a third mechanism of radiation, termed the "bystander effect" or "radiation-induced bystander effect" (RIBE). This is induced by agents and signals emitted by directly irradiated cells and manifests as a lowering of survival, cytogenetic damage, apoptosis enhancement, and biochemical changes in neighboring non-irradiated cells. The bystander effect is mainly observed in in vitro experiments using very low doses of alpha particles (range; mGy, cGy), but also after conventional irradiation (X-rays, gamma rays) at low as well as conventional doses. The mechanisms responsible for the bystander effect are complex and still poorly understood. It is believed that molecular signals released from irradiated cells induce different signaling ways in non-irradiated neighboring cells, leading to the observed events. The molecular signals may be transmitted through gap junction intercellular communication and through a medium transfer mechanism. The nature of these transmitted factors are diverse, and still not definitely established. It seems that RIBE may have important clinical implications for health risk associated with radiation exposure. Potentially, this effect may have important implications in the creation of whole-body or localized side effects in tissues beyond the irradiation field and also in low-dose radiological and radioisotope diagnostics. Factors emitted by irradiated cells may result in the risk of genetic instability, mutations, and second primary cancer induction. They might also have their own part in inducing and extending post-radiation side effects in normal tissue. The bystander effect may be a

  2. Characteristics of Myeloid Differentiation and Maturation Pathway Derived from Human Hematopoietic Stem Cells Exposed to Different Linear Energy Transfer Radiation Types

    PubMed Central

    Monzen, Satoru; Yoshino, Hironori; Kasai-Eguchi, Kiyomi; Kashiwakura, Ikuo

    2013-01-01

    Exposure of hematopoietic stem/progenitor cells (HSPCs) to ionizing radiation causes a marked suppression of mature functional blood cell production in a linear energy transfer (LET)- and/or dose-dependent manner. However, little information about LET effects on the proliferation and differentiation of HSPCs has been reported. With the aim of characterizing the effects of different types of LET radiations on human myeloid hematopoiesis, in vitro hematopoiesis in Human CD34+ cells exposed to carbon-ion beams or X-rays was compared. Highly purified CD34+ cells exposed to each form of radiation were plated onto semi-solid culture for a myeloid progenitor assay. The surviving fractions of total myeloid progenitors, colony-forming cells (CFC), exposed to carbon-ion beams were significantly lower than of those exposed to X-rays, indicating that CFCs are more sensitive to carbon-ion beams (D 0 = 0.65) than to X-rays (D 0 = 1.07). Similar sensitivities were observed in granulocyte-macrophage and erythroid progenitors, respectively. However, the sensitivities of mixed-type progenitors to both radiation types were similar. In liquid culture for 14 days, no significant difference in total numbers of mononuclear cells was observed between non-irradiated control culture and cells exposed to 0.5 Gy X-rays, whereas 0.5 Gy carbon-ion beams suppressed cell proliferation to 4.9% of the control, a level similar to that for cells exposed to 1.5 Gy X-rays. Cell surface antigens associated with terminal maturation, such as CD13, CD14, and CD15, on harvest from the culture of X-ray-exposed cells were almost the same as those from the non-irradiated control culture. X-rays increased the CD235a+ erythroid-related fraction, whereas carbon-ion beams increased the CD34+CD38− primitive cell fraction and the CD13+CD14+/−CD15− fraction. These results suggest that carbon-ion beams inflict severe damage on the clonal growth of myeloid HSPCs, although the intensity of cell surface

  3. Photo- and radiation chemical induced degradation of lignin model compounds.

    PubMed

    Lanzalunga; Bietti, M

    2000-07-01

    The basic mechanistic aspects of the photo- and radiation chemistry of lignin model compounds (LMCs) are discussed with respect to important processes related to lignin degradation. Several reactions occur after direct irradiation, photosensitized or radiation chemically induced oxidation of LMCs. Direct irradiation studies on LMCs have provided supportive evidence for the involvement of hydrogen abstraction reactions from phenols, beta-cleavage of substituted alpha-aryloxyacetophenones and cleavage of ketyl radicals (formed by photoreduction of aromatic ketones or hydrogen abstraction from arylglycerol beta-aryl ethers) in the photoyellowing of lignin rich pulps. Photosensitized and radiation chemically induced generation of reactive oxygen species and their reaction with LMCs are reviewed. The side-chain reactivity of LMC radical cations, generated by radiation chemical means, is also discussed in relation with the enzymatic degradation of lignin.

  4. Caspase-independent cell death mediated by apoptosis-inducing factor (AIF) nuclear translocation is involved in ionizing radiation induced HepG2 cell death

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Sun, Hengwen; Yang, Shana; Li, Jianhua

    Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. The aim of radiotherapy is to eradicate cancer cells with ionizing radiation. Except for the caspase-dependent mechanism, several lines of evidence demonstrated that caspase-independent mechanism is directly involved in the cell death responding to irradiation. For this reason, defining the contribution of caspase-independent molecular mechanisms represents the main goal in radiotherapy. In this study, we focused on the role of apoptosis-inducing factor (AIF), the caspase-independent molecular, in ionizing radiation induced hepatocellular carcinoma cell line (HepG2) cell death. We found that ionizing radiation has no function on AIF expressionmore » in HepG2 cells, but could induce AIF release from the mitochondria and translocate into nuclei. Inhibition of AIF could reduce ionizing radiation induced HepG2 cell death. These studies strongly support a direct relationship between AIF nuclear translocation and radiation induced cell death. What's more, AIF nuclear translocation is caspase-independent manner, but not caspase-dependent manner, in this process. These new findings add a further attractive point of investigation to better define the complex interplay between caspase-independent cell death and radiation therapy. - Highlights: • AIF nuclear translocation is involved in ionizing radiation induced hepatocellular carcinoma cell line HepG2 cell death. • AIF mediated cell death induced by ionizing radiation is caspase-independent. • Caspase-independent pathway is involved in ionzing radiation induced HepG2 cell death.« less

  5. Non-targeted and delayed effects of exposure to ionizing radiation: I. Radiation-induced genomic instability and bystander effects in vitro

    NASA Technical Reports Server (NTRS)

    Morgan, William F.

    2003-01-01

    A long-standing dogma in the radiation sciences is that energy from radiation must be deposited in the cell nucleus to elicit a biological effect. A number of non-targeted, delayed effects of ionizing radiation have been described that challenge this dogma and pose new challenges to evaluating potential hazards associated with radiation exposure. These effects include induced genomic instability and non-targeted bystander effects. The in vitro evidence for non-targeted effects in radiation biology will be reviewed, but the question as to how one extrapolates from these in vitro observations to the risk of radiation-induced adverse health effects such as cancer remains open.

  6. γ-Tocotrienol as a Promising Countermeasure for Acute Radiation Syndrome: Current Status.

    PubMed

    Singh, Vijay K; Hauer-Jensen, Martin

    2016-05-03

    The hazard of ionizing radiation exposure due to nuclear accidents or terrorist attacks is ever increasing. Despite decades of research, still, there is a shortage of non-toxic, safe and effective medical countermeasures for radiological and nuclear emergency. To date, the U.S. Food and Drug Administration (U.S. FDA) has approved only two growth factors, Neupogen (granulocyte colony-stimulating factor (G-CSF), filgrastim) and Neulasta (PEGylated G-CSF, pegfilgrastim) for the treatment of hematopoietic acute radiation syndrome (H-ARS) following the Animal Efficacy Rule. Promising radioprotective efficacy results of γ-tocotrienol (GT3; a member of the vitamin E family) in the mouse model encouraged its further evaluation in the nonhuman primate (NHP) model. These studies demonstrated that GT3 significantly aided the recovery of radiation-induced neutropenia and thrombocytopenia compared to the vehicle controls; these results particularly significant after exposure to 5.8 or 6.5 Gray (Gy) whole body γ-irradiation. The stimulatory effect of GT3 on neutrophils and thrombocytes (platelets) was directly and positively correlated with dose; a 75 mg/kg dose was more effective compared to 37.5 mg/kg. GT3 was also effective against 6.5 Gy whole body γ-irradiation for improving neutrophils and thrombocytes. Moreover, a single administration of GT3 without any supportive care was equivalent, in terms of improving hematopoietic recovery, to multiple doses of Neupogen and two doses of Neulasta with full supportive care (including blood products) in the NHP model. GT3 may serve as an ultimate radioprotector for use in humans, particularly for military personnel and first responders. In brief, GT3 is a promising radiation countermeasure that ought to be further developed for U.S. FDA approval for the ARS indication.

  7. γ-Tocotrienol as a Promising Countermeasure for Acute Radiation Syndrome: Current Status

    PubMed Central

    Singh, Vijay K.; Hauer-Jensen, Martin

    2016-01-01

    The hazard of ionizing radiation exposure due to nuclear accidents or terrorist attacks is ever increasing. Despite decades of research, still, there is a shortage of non-toxic, safe and effective medical countermeasures for radiological and nuclear emergency. To date, the U.S. Food and Drug Administration (U.S. FDA) has approved only two growth factors, Neupogen (granulocyte colony-stimulating factor (G-CSF), filgrastim) and Neulasta (PEGylated G-CSF, pegfilgrastim) for the treatment of hematopoietic acute radiation syndrome (H-ARS) following the Animal Efficacy Rule. Promising radioprotective efficacy results of γ-tocotrienol (GT3; a member of the vitamin E family) in the mouse model encouraged its further evaluation in the nonhuman primate (NHP) model. These studies demonstrated that GT3 significantly aided the recovery of radiation-induced neutropenia and thrombocytopenia compared to the vehicle controls; these results particularly significant after exposure to 5.8 or 6.5 Gray (Gy) whole body γ-irradiation. The stimulatory effect of GT3 on neutrophils and thrombocytes (platelets) was directly and positively correlated with dose; a 75 mg/kg dose was more effective compared to 37.5 mg/kg. GT3 was also effective against 6.5 Gy whole body γ-irradiation for improving neutrophils and thrombocytes. Moreover, a single administration of GT3 without any supportive care was equivalent, in terms of improving hematopoietic recovery, to multiple doses of Neupogen and two doses of Neulasta with full supportive care (including blood products) in the NHP model. GT3 may serve as an ultimate radioprotector for use in humans, particularly for military personnel and first responders. In brief, GT3 is a promising radiation countermeasure that ought to be further developed for U.S. FDA approval for the ARS indication. PMID:27153057

  8. UV-B Radiation Induces Root Bending Through the Flavonoid-Mediated Auxin Pathway in Arabidopsis.

    PubMed

    Wan, Jinpeng; Zhang, Ping; Wang, Ruling; Sun, Liangliang; Wang, Wenying; Zhou, Huakun; Xu, Jin

    2018-01-01

    Ultraviolet (UV)-B radiation-induced root bending has been reported; however, the underlying mechanisms largely remain unclear. Here, we investigate whether and how auxin and flavonoids are involved in UV-B radiation-induced root bending in Arabidopsis using physiological, pharmacological, and genetic approaches. UV-B radiation modulated the direction of root growth by decreasing IAA biosynthesis and affecting auxin distribution in the root tips, where reduced auxin accumulation and asymmetric auxin distribution were observed. UV-B radiation increased the distribution of auxin on the nonradiated side of the root tips, promoting growth and causing root bending. Further analysis indicated that UV-B induced an asymmetric accumulation of flavonoids; this pathway is involved in modulating the accumulation and asymmetric distribution of auxin in root tips and the subsequent redirection of root growth by altering the distribution of auxin carriers in response to UV-B radiation. Taken together, our results indicate that UV-B radiation-induced root bending occurred through a flavonoid-mediated phototropic response to UV-B radiation.

  9. Visual sensations induced by Cherenkov radiation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    McNulty, P.J.; Pease, V.P.; Bond, V.P.

    1975-08-01

    Pulses of relativistic singly charged particles entering the eyeball induce a variety of visual phenomena by means of Cerenkov radiation generated during their passage through the vitreous. These phenomena are similar in appearance to many of the visual sensations experienced by Apollo astronauts exposed to the cosmic rays in deep space. (auth)

  10. Protective effects of L-selenomethionine on space radiation induced changes in gene expression.

    PubMed

    Stewart, J; Ko, Y-H; Kennedy, A R

    2007-06-01

    Ionizing radiation can produce adverse biological effects in astronauts during space travel. Of particular concern are the types of radiation from highly energetic, heavy, charged particles known as HZE particles. The aims of our studies are to characterize HZE particle radiation induced biological effects and evaluate the effects of L-selenomethionine (SeM) on these adverse biological effects. In this study, microarray technology was used to measure HZE radiation induced changes in gene expression, as well as to evaluate modulation of these changes by SeM. Human thyroid epithelial cells (HTori-3) were irradiated (1 GeV/n iron ions) in the presence or in the absence of 5 microM SeM. At 6 h post-irradiation, all cells were harvested for RNA isolation. Gene Chip U133Av2 from Affymetrix was used for the analysis of gene expression, and ANOVA and EASE were used for a determination of the genes and biological processes whose differential expression is statistically significant. Results of this microarray study indicate that exposure to small doses of radiation from HZE particles, 10 and 20 cGy from iron ions, induces statistically significant differential expression of 196 and 610 genes, respectively. In the presence of SeM, differential expression of 77 out of 196 genes (exposure to 10 cGy) and 336 out of 610 genes (exposure to 20 cGy) is abolished. In the presence or in the absence of SeM, radiation from HZE particles induces differential expression of genes whose products have roles in the induction of G1/S arrest during the mitotic cell cycle, as well as heat shock proteins. Some of the genes, whose expressions were affected by radiation from HZE particles and were unchanged in irradiated cells treated with SeM, have been shown to have altered expression levels in cancer cells. The conclusions of this report are that radiation from HZE particles can induce differential expression of many genes, some of which are known to play roles in the same processes that have

  11. Stem cell niches and other factors that influence the sensitivity of bone marrow to radiation-induced bone cancer and leukaemia in children and adults

    PubMed Central

    Richardson, Richard B

    2011-01-01

    Purpose: This paper reviews and reassesses the internationally accepted niches or ‘targets’ in bone marrow that are sensitive to the induction of leukaemia and primary bone cancer by radiation. Conclusions: The hypoxic conditions of the 10 μm thick endosteal/osteoblastic niche where preleukemic stem cells and hematopoietic stem cells (HSC) reside provides a radioprotective microenvironment that is 2-to 3-fold less radiosensitive than vascular niches. This supports partitioning the whole marrow target between the low haematological cancer risk of irradiating HSC in the endosteum and the vascular niches within central marrow. There is a greater risk of induced bone cancer when irradiating a 50 μm thick peripheral marrow adjacent to the remodelling/reforming portion of the trabecular bone surface, rather than marrow next to the quiescent bone surface. This choice of partitioned bone cancer target is substantiated by the greater radiosensitivity of: (i) Bone with high remodelling rates, (ii) the young, (iii) individuals with hypermetabolic benign diseases of bone, and (iv) the epidemiology of alpha-emitting exposures. Evidence is given to show that the absence of excess bone-cancer in atomic-bomb survivors may be partially related to the extremely low prevalence among Japanese of Paget's disease of bone. Radiation-induced fibrosis and the wound healing response may be implicated in not only radiogenic bone cancers but also leukaemia. A novel biological mechanism for adaptive response, and possibility of dynamic targets, is advocated whereby stem cells migrate from vascular niches to stress-mitigated, hypoxic niches. PMID:21204614

  12. Hematopoietic Stem Cells as a Novel Source of Dental Tissue Cells.

    PubMed

    Wilson, Katie R; Kang, In-Hong; Baliga, Uday; Xiong, Ying; Chatterjee, Shilpak; Moore, Emily; Parthiban, Beneta; Thyagarajan, Krishnamurthy; Borke, James L; Mehrotra, Shikhar; Kirkwood, Keith L; LaRue, Amanda C; Ogawa, Makio; Mehrotra, Meenal

    2018-05-23

    While earlier studies have suggested that cells positive for hematopoietic markers can be found in dental tissues, it has yet to be confirmed. To conclusively demonstrate this, we utilized a unique transgenic model in which all hematopoietic cells are green fluorescent protein + (GFP + ). Pulp, periodontal ligament (PDL) and alveolar bone (AvB) cell culture analysis demonstrated numerous GFP + cells, which were also CD45 + (indicating hematopoietic origin) and co-expressed markers of cellular populations in pulp (dentin matrix protein-1, dentin sialophosphoprotein, alpha smooth muscle actin [ASMA], osteocalcin), in PDL (periostin, ASMA, vimentin, osteocalcin) and in AvB (Runx-2, bone sialoprotein, alkaline phosphatase, osteocalcin). Transplantation of clonal population derived from a single GFP + hematopoietic stem cell (HSC), into lethally irradiated recipient mice, demonstrated numerous GFP + cells within dental tissues of recipient mice, which also stained for markers of cell populations in pulp, PDL and AvB (used above), indicating that transplanted HSCs can differentiate into cells in dental tissues. These hematopoietic-derived cells deposited collagen and can differentiate in osteogenic media, indicating that they are functional. Thus, our studies demonstrate, for the first time, that cells in pulp, PDL and AvB can have a hematopoietic origin, thereby opening new avenues of therapy for dental diseases and injuries.

  13. Ionizing Radiation-Induced Immune and Inflammatory Reactions in the Brain

    PubMed Central

    Lumniczky, Katalin; Szatmári, Tünde; Sáfrány, Géza

    2017-01-01

    Radiation-induced late brain injury consisting of vascular abnormalities, demyelination, white matter necrosis, and cognitive impairment has been described in patients subjected to cranial radiotherapy for brain tumors. Accumulating evidence suggests that various degrees of cognitive deficit can develop after much lower doses of ionizing radiation, as well. The pathophysiological mechanisms underlying these alterations are not elucidated so far. A permanent deficit in neurogenesis, chronic microvascular alterations, and blood–brain barrier dysfunctionality are considered among the main causative factors. Chronic neuroinflammation and altered immune reactions in the brain, which are inherent complications of brain irradiation, have also been directly implicated in the development of cognitive decline after radiation. This review aims to give a comprehensive overview on radiation-induced immune alterations and inflammatory reactions in the brain and summarizes how these processes can influence cognitive performance. The available data on the risk of low-dose radiation exposure in the development of cognitive impairment and the underlying mechanisms are also discussed. PMID:28529513

  14. Gamma Radiation Induces Micronucleated Reticulocytes in 3-D Bone Marrow Bioreactors in Vitro

    PubMed Central

    Sun, Hongliang; Dertinger, Stephen D.; Hyrien, Ollivier; David Wu, J. H.; Chen, Yuhchyau

    2009-01-01

    Radiation injury to the bone marrow is potentially lethal due to the potent DNA-damaging effects on cells of the hematopoietic system, including bone marrow stem cell, progenitor, and the precursor cell populations. Investigation of radiation genotoxic effects on bone marrow progenitor/precursor cells has been challenged by the lack of optimal in vitro surrogate organ culture systems, and the overall difficulty to sustain lineage-specific proliferation and differentiation of hematopoiesis in vitro. We report the investigation of radiation genotoxic effects in bone marrow cultures of C57Bl/6 mice established in 3-D bioreactors, which sustain long-term bone marrow cultures. For these studies, genotoxicity is measured by the induction of micronucleated reticulocytes (MN-RET). The kinetics and dose-response relationship of MN-RET induction in response to gamma-radiation of bioreactor-maintained bone marrow cultures are presented. Our data showed that 3-D long-term bone marrow cultures had sustained erythropoiesis capable of generating reticulocytes up to 8 weeks. The peak time-interval of viable cell output and percentage of reticulocytes increased steadily and reached the initial peak between the 14th to 21st days after inoculations. This was followed by a rebound or staying relatively constant until week 8. The percentage of MN-RET reached the maximum between 24 and 32 hours post 1 Gy gamma-ray. There was a near linear MN-RET induction by gamma radiation from 0 Gy to 1.0 Gy, followed by an attenuated increase to 1.5 – 2.0 Gy. The MN-RET response showed a downtrend beyond 2 Gy. Our data suggest that bone marrow culture in the 3-D bioreactor may be a useful organ culture system for the investigation of radiation genotoxic effect in vitro. PMID:19786117

  15. Photoprotection beyond ultraviolet radiation--effective sun protection has to include protection against infrared A radiation-induced skin damage.

    PubMed

    Schroeder, P; Calles, C; Benesova, T; Macaluso, F; Krutmann, J

    2010-01-01

    Solar radiation is well known to damage human skin, for example by causing premature skin ageing (i.e. photoageing). We have recently learned that this damage does not result from ultraviolet (UV) radiation alone, but also from longer wavelengths, in particular near-infrared radiation (IRA radiation, 760-1,440 nm). IRA radiation accounts for more than one third of the solar energy that reaches human skin. While infrared radiation of longer wavelengths (IRB and IRC) does not penetrate deeply into the skin, more than 65% of the shorter wavelength (IRA) reaches the dermis. IRA radiation has been demonstrated to alter the collagen equilibrium of the dermal extracellular matrix in at least two ways: (a) by leading to an increased expression of the collagen-degrading enzyme matrix metalloproteinase 1, and (b) by decreasing the de novo synthesis of the collagen itself. IRA radiation exposure therefore induces similar biological effects to UV radiation, but the underlying mechanisms are substantially different, specifically, the cellular response to IRA irradiation involves the mitochondrial electron transport chain. Effective sun protection requires specific strategies to prevent IRA radiation-induced skin damage. 2010 S. Karger AG, Basel.

  16. Coordinated and unique functions of the E-selectin ligand ESL-1 during inflammatory and hematopoietic recruitment in mice

    PubMed Central

    Sreeramkumar, Vinatha; Leiva, Magdalena; Stadtmann, Anika; Pitaval, Christophe; Ortega-Rodríguez, Inés; Wild, Martin K.; Lee, Brendan; Zarbock, Alexander; Hidalgo, Andrés

    2013-01-01

    Beyond its well-established roles in mediating leukocyte rolling, E-selectin is emerging as a multifunctional receptor capable of inducing integrin activation in neutrophils, and of regulating various biological processes in hematopoietic precursors. Although these effects suggest important homeostatic contributions of this selectin in the immune and hematologic systems, the ligands responsible for transducing these effects in different leukocyte lineages are not well defined. We have characterized mice deficient in E-selectin ligand-1 (ESL-1), or in both P-selectin glycoprotein-1 (PSGL-1) and ESL-1, to explore and compare the contributions of these glycoproteins in immune and hematopoietic cell trafficking. In the steady state, ESL-1 deficiency resulted in a moderate myeloid expansion that became more prominent when both glycoproteins were eliminated. During inflammation, PSGL-1 dominated E-selectin binding, rolling, integrin activation, and extravasation of mature neutrophils, but only the combined deficiency in PSGL-1 and ESL-1 completely abrogated leukocyte recruitment. Surprisingly, we find that the levels of ESL-1 were strongly elevated in hematopoietic progenitor cells. These elevations correlated with a prominent function of ESL-1 for E-selectin binding and for migration of hematopoietic progenitor cells into the bone marrow. Our results uncover dominant roles for ESL-1 in the immature compartment, and a functional shift toward PSGL-1 dependence in mature neutrophils. PMID:24106206

  17. Coordinated and unique functions of the E-selectin ligand ESL-1 during inflammatory and hematopoietic recruitment in mice.

    PubMed

    Sreeramkumar, Vinatha; Leiva, Magdalena; Stadtmann, Anika; Pitaval, Christophe; Ortega-Rodríguez, Inés; Wild, Martin K; Lee, Brendan; Zarbock, Alexander; Hidalgo, Andrés

    2013-12-05

    Beyond its well-established roles in mediating leukocyte rolling, E-selectin is emerging as a multifunctional receptor capable of inducing integrin activation in neutrophils, and of regulating various biological processes in hematopoietic precursors. Although these effects suggest important homeostatic contributions of this selectin in the immune and hematologic systems, the ligands responsible for transducing these effects in different leukocyte lineages are not well defined. We have characterized mice deficient in E-selectin ligand-1 (ESL-1), or in both P-selectin glycoprotein-1 (PSGL-1) and ESL-1, to explore and compare the contributions of these glycoproteins in immune and hematopoietic cell trafficking. In the steady state, ESL-1 deficiency resulted in a moderate myeloid expansion that became more prominent when both glycoproteins were eliminated. During inflammation, PSGL-1 dominated E-selectin binding, rolling, integrin activation, and extravasation of mature neutrophils, but only the combined deficiency in PSGL-1 and ESL-1 completely abrogated leukocyte recruitment. Surprisingly, we find that the levels of ESL-1 were strongly elevated in hematopoietic progenitor cells. These elevations correlated with a prominent function of ESL-1 for E-selectin binding and for migration of hematopoietic progenitor cells into the bone marrow. Our results uncover dominant roles for ESL-1 in the immature compartment, and a functional shift toward PSGL-1 dependence in mature neutrophils.

  18. Differences in lymphocyte developmental potential between human embryonic stem cell and umbilical cord blood–derived hematopoietic progenitor cells

    PubMed Central

    Martin, Colin H.; Woll, Petter S.; Ni, Zhenya; Zúñiga-Pflücker, Juan Carlos

    2008-01-01

    Hematopoietic progenitor cells derived from human embryonic stem cells (hESCs) develop into diverse mature hematopoietic lineages, including lymphocytes. Whereas functional natural killer (NK) cells can be efficiently generated in vitro from hESC-derived CD34+ cells, studies of T- and B-cell development from hESCs have been much more limited. Here, we demonstrate that despite expressing functional Notch-1, CD34+ cells from hESCs did not derive T cells when cocultured with OP9 cells expressing Delta-like 1, or in fetal thymus organ culture. hESC-derived CD34+ cells also did not produce B cells in vitro. In contrast, CD34+ cells isolated from UCB routinely generated T and B cells when cultured in the same conditions. Notably, both undifferentiated hESCs, and sorted hESC-derived populations with hematopoietic developmental potential exhibited constitutive expression of ID family genes and of transcriptional targets of stem cell factor–induced signaling. These pathways both inhibit T-cell development and promote NK-cell development. Together, these results demonstrate fundamental differences between hESC-derived hematopoietic progenitors and analogous primary human cells. Therefore, hESCs can be more readily supported to differentiate into certain cell types than others, findings that have important implications for derivation of defined lineage-committed populations from hESCs. PMID:18621931

  19. Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia.

    PubMed

    Zambetti, Noemi A; Ping, Zhen; Chen, Si; Kenswil, Keane J G; Mylona, Maria A; Sanders, Mathijs A; Hoogenboezem, Remco M; Bindels, Eric M J; Adisty, Maria N; Van Strien, Paulina M H; van der Leije, Cindy S; Westers, Theresia M; Cremers, Eline M P; Milanese, Chiara; Mastroberardino, Pier G; van Leeuwen, Johannes P T M; van der Eerden, Bram C J; Touw, Ivo P; Kuijpers, Taco W; Kanaar, Roland; van de Loosdrecht, Arjan A; Vogl, Thomas; Raaijmakers, Marc H G P

    2016-11-03

    Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system, but the underlying molecular mechanisms and relevance to human disease remain poorly defined. Here, we show that perturbation of mesenchymal cells in a mouse model of the pre-leukemic disorder Shwachman-Diamond syndrome (SDS) induces mitochondrial dysfunction, oxidative stress, and activation of DNA damage responses in hematopoietic stem and progenitor cells. Massive parallel RNA sequencing of highly purified mesenchymal cells in the SDS mouse model and a range of human pre-leukemic syndromes identified p53-S100A8/9-TLR inflammatory signaling as a common driving mechanism of genotoxic stress. Transcriptional activation of this signaling axis in the mesenchymal niche predicted leukemic evolution and progression-free survival in myelodysplastic syndrome (MDS), the principal leukemia predisposition syndrome. Collectively, our findings identify mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cells through inflammatory signaling as a targetable determinant of disease outcome in human pre-leukemia. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Individual housing-based socioeconomic status predicts risk of accidental falls among adults.

    PubMed

    Ryu, Euijung; Juhn, Young J; Wheeler, Philip H; Hathcock, Matthew A; Wi, Chung-Il; Olson, Janet E; Cerhan, James R; Takahashi, Paul Y

    2017-07-01

    Accidental falls are a major public health concern among people of all ages. Little is known about whether an individual-level housing-based socioeconomic status measure is associated with the risk of accidental falls. Among 12,286 Mayo Clinic Biobank participants residing in Olmsted County, Minnesota, subjects who experienced accidental falls between the biobank enrollment and September 2014 were identified using ICD-9 codes evaluated at emergency departments. HOUSES (HOUsing-based Index of SocioEconomic Status), a socioeconomic status measure based on individual housing features, was also calculated. Cox regression models were utilized to assess the association of the HOUSES (in quartiles) with accidental fall risk. Seven hundred eleven (5.8%) participants had at least one emergency room visit due to an accidental fall during the study period. Subjects with higher HOUSES were less likely to experience falls in a dose-response manner (hazard ratio: 0.58; 95% confidence interval: 0.44-0.76 for comparing the highest to the lowest quartile). In addition, the HOUSES was positively associated with better health behaviors, social support, and functional status. The HOUSES is inversely associated with accidental fall risk requiring emergency care in a dose-response manner. The HOUSES may capture falls-related risk factors through housing features and socioeconomic status-related psychosocial factors. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Procedures, placement, and risks of further abuse after Munchausen syndrome by proxy, non-accidental poisoning, and non-accidental suffocation

    PubMed Central

    Davis, P; McClure, R; Rolfe, K; Chessman, N; Pearson, S; Sibert, J; Meadow, R

    1998-01-01

    OBJECTIVES—To investigate outcome, management, and prevention in Munchausen syndrome by proxy, non-accidental poisoning, and non-accidental suffocation.
DESIGN—Ascertainment through British Paediatric Surveillance Unit and questionnaires to responding paediatricians.
SETTING—The UK and Republic of Ireland, September 1992 to August 1994.
SUBJECTS—Children under 14 years diagnosed with the above.
MAIN OUTCOME MEASURES—Placement and child protection measures for victims and siblings; morbidity and reabuse rates for victims; abuse of siblings; prosecution of perpetrators.
RESULTS—Outcome data for 119 with median follow up of 24 months (range 12 to 44 months). No previously diagnosed factitious disease was found to have been caused by genuine disease. Forty six children were allowed home without conditions at follow up. Children who had suffered from suffocation, non-accidental poisoning, direct harm, and those under 5 years were less likely to go home.
 Twenty seven (24%) children still had symptoms or signs as a result of the abuse at follow up; 108/120 were originally on a child protection register and 35/111 at follow up. Twenty nine per cent (34/118) of the perpetrators had been prosecuted and most convicted; 17% of the milder cases of Munchausen syndrome by proxy allowed home were reabused. Evidence in siblings suggests that in 50% of families with a suffocated child and 40% with non-accidental poisoning there would be further abuse, some fatal.
CONCLUSIONS—This type of abuse is severe with high mortality, morbidity, family disruption, reabuse, and harm to siblings. A very cautious approach for child protection with reintroduction to home only if circumstances are especially favourable is advised. Paediatric follow up by an expert in child protection should also occur.

 PMID:9613350

  2. Are there mechanistic differences between ultraviolet and visible radiation induced skin pigmentation?

    PubMed

    Ramasubramaniam, Rajagopal; Roy, Arindam; Sharma, Bharati; Nagalakshmi, Surendra

    2011-12-01

    Most of the studies on sunlight-induced pigmentation of skin are mainly focused on ultraviolet (UV) radiation-induced pigmentation and ways to prevent it. Recent studies have shown that the visible component of sunlight can also cause significant skin pigmentation. In the current study, the extent of pigmentation induced by UV and visible regions of sunlight in subjects with Fitzpatrick skin type IV-V was measured and compared with pigmentation induced by total sunlight. The immediate pigment darkening (IPD) induced by the visible fraction of sunlight is not significantly different from that induced by the UV fraction. However, the persistent pigment darkening (PPD) induced by visible fraction of sunlight in significantly lower than that induced by the UV fraction. The dose responses of IPD induced by UV, visible light and total sunlight suggest that both UV and visible light interact with the same precursor although UV is 25 times more efficient in inducing pigmentation per J cm(-2) of irradiation compared to visible radiation. The measured diffused reflection spectra and decay kinetics of UV and visible radiation-induced pigmentation are very similar, indicating that the nature of the transient and persistent species involved in both the processes are also likely to be same.

  3. Revisiting therapeutic strategies in radiation casualties.

    PubMed

    Hérodin, Francis; Grenier, Nancy; Drouet, Michel

    2007-04-01

    Nuclear/radiological threats have evolved and scenarios for terrorist attacks involving radioactive material have been identified as complex situations. Mass casualty scenarios may happen, and individuals may be exposed to intentionally hidden sources of high activity, resulting in delayed diagnosis and treatment of acute radiation syndrome (ARS). Moreover, ARS must be considered as an emergency in order to better anticipate delayed radiation toxicity. In this context, therapeutic strategies in radiation casualties have to be revisited and new pharmacological approaches developed. B6D2F1 mice were total-body irradiated (TBI) with a 9 Gy gamma dose and then received intraperitoneal doses of either early (stem cell factor + FLT-3 ligand + thrombopoietin + interleukin-3 [SFT3] +/- keratinocyte growth factor (KGF); stem cell factor + erythropoietin + Peg-filgrastim [SEG]) or delayed treatments (SFT3 +/- KGF, erythropoietin, or hyaluronic acid). Survival was monitored and bone marrow hematopoiesis evaluated at 300 days following early treatments. SFT3 anti-apoptotic cytokine combination administered early (2 hours and 24 hours) after lethal TBI induced 60% survival versus 5% in controls. Early SEG treatment may be an alternative to SFT3 in terms of survival (55%), but SEG benefit might be obtained at the expense of long-term hematopoiesis. SFT3 + KGF induced 75% survival. No effectiveness was observed, over antimicrobial supportive care, when administration of SFT3 or its tested combinations was delayed at 48 hours. As a potentially multi-organ failure, ARS requires global therapy, beyond the hematopoietic syndrome, which may include pleiotropic cytokines such as KGF.

  4. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

    NASA Astrophysics Data System (ADS)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B.; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  5. Radiation induces genomic instability and mammary ductal dysplasia in Atm heterozygous mice

    NASA Technical Reports Server (NTRS)

    Weil, M. M.; Kittrell, F. S.; Yu, Y.; McCarthy, M.; Zabriskie, R. C.; Ullrich, R. L.

    2001-01-01

    Ataxia-telangiectasia (AT) is a genetic syndrome resulting from the inheritance of two defective copies of the ATM gene that includes among its stigmata radiosensitivity and cancer susceptibility. Epidemiological studies have demonstrated that although women with a single defective copy of ATM (AT heterozygotes) appear clinically normal, they may never the less have an increased relative risk of developing breast cancer. Whether they are at increased risk for radiation-induced breast cancer from medical exposures to ionizing radiation is unknown. We have used a murine model of AT to investigate the effect of a single defective Atm allele, the murine homologue of ATM, on the susceptibility of mammary epithelial cells to radiation-induced transformation. Here we report that mammary epithelial cells from irradiated mice with one copy of Atm truncated in the PI-3 kinase domain were susceptible to radiation-induced genomic instability and generated a 10% incidence of dysplastic mammary ducts when transplanted into syngenic recipients, whereas cells from Atm(+/+) mice were stable and formed only normal ducts. Since radiation-induced ductal dysplasia is a precursor to mammary cancer, the results indicate that AT heterozygosity increases susceptibility to radiogenic breast cancer in this murine model system.

  6. Lipoxin A4 inhibits UV radiation-induced skin inflammation and oxidative stress in mice.

    PubMed

    Martinez, R M; Fattori, V; Saito, P; Melo, C B P; Borghi, S M; Pinto, I C; Bussmann, A J C; Baracat, M M; Georgetti, S R; Verri, W A; Casagrande, R

    2018-04-27

    Lipoxin A4 (LXA 4 ) is a metabolic product of arachidonic acid. Despite potent anti-inflammatory and pro-resolution activities, it remains to be determined if LXA 4 has effect on ultraviolet (UV) radiation-induced skin inflammation. To investigate the effects of systemic administration with LXA 4 on UV radiation-induced inflammation and oxidative damage in the skin of mice. Varied parameters of inflammation and oxidative stress in the skin of mice were evaluated after UV radiation (4.14 J/cm 2 ). Pretreatment with LXA 4 significantly inhibited UV radiation-induced skin edema and myeloperoxidase activity. LXA 4 efficacy was enhanced by increasing the time of pre-treatment to up to 72 h. LXA 4 reduced UV radiation-induced skin edema, neutrophil recruitment (myeloperoxidase activity and LysM-eGFP + cells), MMP-9 activity, deposition of collagen fibers, epidermal thickness, sunburn cell counts, and production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-33). Depending on the time point, LXA 4 increased the levels of anti-inflammatory cytokines (TGF-β and IL-10). LXA 4 significantly attenuated UV radiation-induced oxidative damage returning the oxidative status to baseline levels in parameters such as ferric reducing ability, scavenging of free radicals, GSH levels, catalase activity and superoxide anion production. LXA 4 also reduced UV radiation-induced gp91 phox [nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) subunit] mRNA expression and enhanced nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target enzyme nicotinamide adenine dinucleotide (phosphate) quinone oxidoreductase (Nqo1) mRNA expression. LXA 4 inhibited UV radiation-induced skin inflammation by diminishing pro-inflammatory cytokine production and oxidative stress as well as inducing anti-inflammatory cytokines and Nrf2. Copyright © 2018. Published by Elsevier B.V.

  7. Radiation-induced optic neuropathy: A magnetic resonance imaging study

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Guy, J.; Mancuso, A.; Beck, R.

    1991-03-01

    Optic neuropathy induced by radiation is an infrequent cause of delayed visual loss that may at times be difficult to differentiate from compression of the visual pathways by recurrent neoplasm. The authors describe six patients with this disorder who experienced loss of vision 6 to 36 months after neurological surgery and radiation therapy. Of the six patients in the series, two had a pituitary adenoma and one each had a metastatic melanoma, multiple myeloma, craniopharyngioma, and lymphoepithelioma. Visual acuity in the affected eyes ranged from 20/25 to no light perception. Magnetic resonance (MR) imaging showed sellar and parasellar recurrence ofmore » both pituitary adenomas, but the intrinsic lesions of the optic nerves and optic chiasm induced by radiation were enhanced after gadolinium-diethylenetriaminepenta-acetic acid (DTPA) administration and were clearly distinguishable from the suprasellar compression of tumor. Repeated MR imaging showed spontaneous resolution of gadolinium-DTPA enhancement of the optic nerve in a patient who was initially suspected of harboring recurrence of a metastatic malignant melanoma as the cause of visual loss. The authors found the presumptive diagnosis of radiation-induced optic neuropathy facilitated by MR imaging with gadolinium-DTPA. This neuro-imaging procedure may help avert exploratory surgery in some patients with recurrent neoplasm in whom the etiology of visual loss is uncertain.« less

  8. Accidental fetal lacerations during cesarean delivery: experience in an Italian level III university hospital.

    PubMed

    Dessole, Salvatore; Cosmi, Erich; Balata, Antonio; Uras, Luisa; Caserta, Donatella; Capobianco, Giampiero; Ambrosini, Guido

    2004-11-01

    The purpose of this study was to investigate the incidence, type, location, and risk factors of accidental fetal lacerations during cesarean delivery. Total deliveries, cesarean deliveries, and neonatal records for documented accidental fetal lacerations were reviewed retrospectively in our level III university hospital. The gestational age, the presenting part of the fetus, the cesarean delivery indication, the type of incision, and the surgeon who performed the procedure were recorded. Cesarean deliveries were divided into scheduled, unscheduled, and emergency procedures. Fetal lacerations were divided into mild, moderate, and severe. Neonatal follow-up examinations regarding laceration sequelae were available for 6 months. Of 14926 deliveries, 3108 women were delivered by cesarean birth (20.82%). Neonatal records documented 97 accidental fetal lacerations. Of these accidental lacerations, 94 were mild; 2 were moderate, and 1 was severe. The overall rate of accidental fetal laceration per cesarean delivery was 3.12%; the accidental laceration rate in the cohort of fetuses was 2.46%. The crude odds ratios were 0.34 for scheduled procedures, 0.57 for unscheduled procedures, and 1.7 for emergency procedures. The risk for fetal accidental lacerations was higher in fetuses who underwent emergency cesarean birth and lower for unscheduled and scheduled cesarean births (P < .001). Fetal accidental laceration may occur during cesarean delivery; the incidence is significantly higher during emergency cesarean delivery compared with elective procedures. The patient should be counseled about the occurrence of fetal laceration during cesarean delivery to avoid litigation.

  9. UV-B Radiation Induces Root Bending Through the Flavonoid-Mediated Auxin Pathway in Arabidopsis

    PubMed Central

    Wan, Jinpeng; Zhang, Ping; Wang, Ruling; Sun, Liangliang; Wang, Wenying; Zhou, Huakun; Xu, Jin

    2018-01-01

    Ultraviolet (UV)-B radiation-induced root bending has been reported; however, the underlying mechanisms largely remain unclear. Here, we investigate whether and how auxin and flavonoids are involved in UV-B radiation-induced root bending in Arabidopsis using physiological, pharmacological, and genetic approaches. UV-B radiation modulated the direction of root growth by decreasing IAA biosynthesis and affecting auxin distribution in the root tips, where reduced auxin accumulation and asymmetric auxin distribution were observed. UV-B radiation increased the distribution of auxin on the nonradiated side of the root tips, promoting growth and causing root bending. Further analysis indicated that UV-B induced an asymmetric accumulation of flavonoids; this pathway is involved in modulating the accumulation and asymmetric distribution of auxin in root tips and the subsequent redirection of root growth by altering the distribution of auxin carriers in response to UV-B radiation. Taken together, our results indicate that UV-B radiation-induced root bending occurred through a flavonoid-mediated phototropic response to UV-B radiation. PMID:29868074

  10. Notch2 blockade enhances hematopoietic stem cell mobilization and homing.

    PubMed

    Wang, Weihuan; Yu, Shuiliang; Myers, Jay; Wang, Yiwei; Xin, William W; Albakri, Marwah; Xin, Alison W; Li, Ming; Huang, Alex Y; Xin, Wei; Siebel, Christian W; Lazarus, Hillard M; Zhou, Lan

    2017-10-01

    Despite use of newer approaches, some patients being considered for autologous hematopoietic cell transplantation (HCT) may only mobilize limited numbers of hematopoietic progenitor cells (HPCs) into blood, precluding use of the procedure, or being placed at increased risk of complications due to slow hematopoietic reconstitution. Developing more efficacious HPC mobilization regimens and strategies may enhance the mobilization process and improve patient outcome. Although Notch signaling is not essential for homeostasis of adult hematopoietic stem cells (HSCs), Notch-ligand adhesive interaction maintains HSC quiescence and niche retention. Using Notch receptor blocking antibodies, we report that Notch2 blockade, but not Notch1 blockade, sensitizes hematopoietic stem cells and progenitors (HSPCs) to mobilization stimuli and leads to enhanced egress from marrow to the periphery. Notch2 blockade leads to transient myeloid progenitor expansion without affecting HSC homeostasis and self-renewal. We show that transient Notch2 blockade or Notch2-loss in mice lacking Notch2 receptor lead to decreased CXCR4 expression by HSC but increased cell cycling with CXCR4 transcription being directly regulated by the Notch transcriptional protein RBPJ. In addition, we found that Notch2-blocked or Notch2-deficient marrow HSPCs show an increased homing to the marrow, while mobilized Notch2-blocked, but not Notch2-deficient stem cells and progenitors, displayed a competitive repopulating advantage and enhanced hematopoietic reconstitution. These findings suggest that blocking Notch2 combined with the current clinical regimen may further enhance HPC mobilization and improve engraftment during HCT. Copyright© 2017 Ferrata Storti Foundation.

  11. The Development of Countermeasures for Space Radiation Induced Adverse Health Effects

    NASA Astrophysics Data System (ADS)

    Kennedy, Ann

    The Development of Countermeasures for Space Radiation Induced Adverse Health Effects Ann R. Kennedy Department of Radiation Oncology, University of Pennsylvania School of Medicine, 195 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA, United States 19104-6072 The development of countermeasures for radiation induced adverse health effects is a lengthy process, particularly when the countermeasure/drug has not yet been evaluated in human trials. One example of a drug developed from the bench to the clinic is the soybean-derived Bowman-Birk inhibitor (BBI), which has been developed as a countermeasure for radiation induced cancer. It was originally identified as a compound/drug that could prevent the radiation induced carcinogenic process in an in vitro assay system in 1975. The first observation that BBI could inhibit carcinogenesis in animals was in 1985. BBI received Investigational New Drug (IND) Status with the U.S. Food and Drug Administration (FDA) in 1992 (after several years of negotiation with the FDA about the potential IND status of the drug), and human trials began at that time. Phase I, II and III human trials utilizing BBI have been performed under several INDs with the FDA, and an ongoing Phase III trial will be ending in the very near future. Thus, the drug has been in development for 35 years at this point, and it is still not a prescription drug on the market which is available for human use. A somewhat less time-consuming process is to evaluate compounds that are on the GRAS (Generally Recognized as Safe) list. These compounds would include some over-the-counter medications, such as antioxidant vitamins utilized in human trials at the levels for which Recommended Dietary Allowances (RDAs) have been established. To determine whether GRAS substances are able to have beneficial effects on radiation induced adverse health effects, it is still likely to be a lengthy process involving many years to potentially decades of human trial work. The

  12. Hemodialysis as a treatment of severe accidental hypothermia.

    PubMed

    Caluwé, Rogier; Vanholder, Raymond; Dhondt, Annemieke

    2010-03-01

    We describe a case of severe accidental hypothermia (core body temperature 23.2 degrees C) successfully treated with hemodialysis in a diabetic patient with preexisting renal insufficiency. Consensus exists about cardiopulmonary bypass as the treatment of choice in cases of severe accidental hypothermia with cardiac arrest. Prospective randomized controlled trials comparing the different rewarming modalities for hemodynamically stable patients with hypothermia, however, are lacking. In our opinion, the choice of a rewarming technique should be patient tailored, knowing that hemodialysis is an efficient, minimally invasive, and readily available technique with the advantage of providing electrolyte support.

  13. A descriptive study of accidental skeletal injuries and non-accidental skeletal injuries of child maltreatment.

    PubMed

    Ghanem, Maha A H; Moustafa, Tarek A; Megahed, Haidy M; Salama, Naglaa; Ghitani, Sara A

    2018-02-01

    Lack of awareness and recognition of child maltreatment is the major reason behind underreporting. All victims often interact with the health care system for routine or emergency care. In several research works, non-accidental fractures are the second most common injury in maltreated children and it is represented up to one-third of cases. To determine the incidence of different types of accidental and non-accidental skeletal injuries among children, estimate the severity of injuries according to the modified injury severity score and to determine the degree of fractures either closed or opened (Gustiloe-Anderson open fracture classification). Moreover, identifying fractures resulting from child abuse and neglect. This aimed for early recognition of non-accidental nature of fractures in child maltreatment that can prevent further morbidity and mortality. A descriptive study was carried out on all children (109) with skeletal injuries who were admitted to both Main Alexandria and El-Hadara Orthopedic and Traumatology University Hospitals during six months. History, physical examination and investigations were done for the patients. A detailed questionnaire was taken to diagnose child abuse and neglect. Gustiloe-Anderson open fracture classification was used to estimate the degree of open fractures. Out of 109 children, twelve cases (11%) were categorized as child maltreatment. One case was physical abuse, eight cases (7.3%) were child neglect and three cases (2.8%) were labour exploitation. Road traffic accidents (RTA) was the commonest cause of skeletal injuries followed by falling from height. Regarding falls, they included 4 cases of stair falls in neglected children and another four cases of falling from height (balcony/window). The remaining 36 cases of falls were accidental. The skeletal injuries were in the form of fractures in 99 cases, dislocation in two cases, both fracture and/or dislocation in three cases, and bone deformity from brachial plexus injury

  14. 21 CFR 369.9 - General warnings re accidental ingestion by children.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 5 2012-04-01 2012-04-01 false General warnings re accidental ingestion by... SERVICES (CONTINUED) DRUGS FOR HUMAN USE INTERPRETATIVE STATEMENTS RE WARNINGS ON DRUGS AND DEVICES FOR OVER-THE-COUNTER SALE Definitions and Interpretations § 369.9 General warnings re accidental ingestion...

  15. 21 CFR 369.9 - General warnings re accidental ingestion by children.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 5 2011-04-01 2011-04-01 false General warnings re accidental ingestion by... SERVICES (CONTINUED) DRUGS FOR HUMAN USE INTERPRETATIVE STATEMENTS RE WARNINGS ON DRUGS AND DEVICES FOR OVER-THE-COUNTER SALE Definitions and Interpretations § 369.9 General warnings re accidental ingestion...

  16. Cinnamon extract ameliorates ionizing radiation-induced cellular injury in rats.

    PubMed

    Azab, Khaled Sh; Mostafa, Abdel-Halem A; Ali, Ehab M M; Abdel-Aziz, Mohamed A S

    2011-11-01

    The present study aimed to investigate the protective role of cinnamon extract against inflammatory and oxidative injuries in gamma irradiated rats. Rats were subjected to fractionated doses of gamma radiation. Cinnamon extract were daily administrated before starting irradiation and continued after radiation exposure. The results obtained revealed that the administration of cinnamon extract to irradiated rats significantly ameliorated the changes induced in liver antioxidant system; catalase, superoxide dismutase and glutathione peroxidase activities as well as reduced glutathione concentration. The liver's lipid peroxidation and protein oxidation indices were significantly decreased when compared with their equivalent values in irradiated rats. Furthermore, the changes induces in xanthine oxidoreductase system were significantly diminished. In addition, the changes in liver nitric oxide contents, serum tumor necrosis factor alpha and C-reactive protein levels were markedly improved. In conclusion, the administration of cinnamon extract might provide substantial protection against radiation-induced oxidative and inflammatory damages. Copyright © 2011 Elsevier Inc. All rights reserved.

  17. A Cell Kinetic Model of Granulocytopoiesis Under Radiation Exposure: Extension from Murines to Canines and Humans

    NASA Technical Reports Server (NTRS)

    Hu, Shaowen; Cucinotta, Francis A.

    2009-01-01

    Space radiation poses significant challenges to space travel, and it is essential to understand the possible adverse effects from space radiation exposure to the radiosensitive organ systems that are important for immediate survival of human, e.g., the hematopoietic system. In this presentation a biomathematical model of granulocytopoiesis is described and used to analyze the blood granulocyte changes seen in the blood of mammalians under continuous and acute radiation exposure. This is one of a set of hematopoietic models that have been successfully utilized to simulate and interpret the experimental data of acute and chronic radiation on rodents. We discuss the underlying implicit regulation mechanism and the biological relevance of the kinetic parameters estimation method. Extension of the model to predictions in dogs and humans systems indicates that the modeling results are consistent with the cumulative experimental and empirical data from various sources. This implies the potential to integrate the models into one united system for monitoring the hematopoietic response of various species under irradiation. Based on the evidence of threshold responses of dogs to extended periods of low daily dose exposures, we discuss the potential health risks of the space traveler under chronic stress of low-dose irradiation and the possibly encountered Solar Particle Events.

  18. Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury

    PubMed Central

    Azzam, Edouard I.; Jay-Gerin, Jean-Paul; Pain, Debkumar

    2013-01-01

    Cellular exposure to ionizing radiation leads to oxidizing events that alter atomic structure through direct interactions of radiation with target macromolecules or via products of water radiolysis. Further, the oxidative damage may spread from the targeted to neighboring, non-targeted bystander cells through redox-modulated intercellular communication mechanisms. To cope with the induced stress and the changes in the redox environment, organisms elicit transient responses at the molecular, cellular and tissue levels to counteract toxic effects of radiation. Metabolic pathways are induced during and shortly after the exposure. Depending on radiation dose, dose-rate and quality, these protective mechanisms may or may not be sufficient to cope with the stress. When the harmful effects exceed those of homeostatic biochemical processes, induced biological changes persist and may be propagated to progeny cells. Physiological levels of reactive oxygen and nitrogen species play critical roles in many cellular functions. In irradiated cells, levels of these reactive species may be increased due to perturbations in oxidative metabolism and chronic inflammatory responses, thereby contributing to the long-term effects of exposure to ionizing radiation on genomic stability. Here, in addition to immediate biological effects of water radiolysis on DNA damage, we also discuss the role of mitochondria in the delayed outcomes of ionization radiation. Defects in mitochondrial functions lead to accelerated aging and numerous pathological conditions. Different types of radiation vary in their linear energy transfer (LET) properties, and we discuss their effects on various aspects of mitochondrial physiology. These include short and long-term in vitro and in vivo effects on mitochondrial DNA, mitochondrial protein import and metabolic and antioxidant enzymes. PMID:22182453

  19. Lentiviral gene transduction of mouse and human hematopoietic stem cells.

    PubMed

    van Til, Niek P; Wagemaker, Gerard

    2014-01-01

    Lentiviral vectors can be used to genetically modify a broad range of cells. Hematopoietic stem cells (HSCs) are particularly suitable for lentiviral gene augmentation, because these cells can be enriched with relative ease from mouse bone marrow and human hematopoietic sources, and in principle require relatively limited cell numbers to completely reconstitute the hematopoietic system in vivo. Furthermore, lentiviral vectors are very efficient if pseudotyped with broad tropism envelope proteins. This chapter focuses on gene modification by the use of self-inactivating third-generation human immunodeficiency virus-derived lentiviral vectors for ex vivo HSC modification for both mouse and human application.

  20. Radiation-Induced Liver Damage: Correlation of Histopathology with Hepatobiliary Magnetic Resonance Imaging, a Feasibility Study

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Seidensticker, Max, E-mail: max.seidensticker@med.ovgu.de; Burak, Miroslaw; Kalinski, Thomas

    PurposeRadiotherapy of liver malignancies shows promising results (radioembolization, stereotactic irradiation, interstitial brachytherapy). Regardless of the route of application, a certain amount of nontumorous liver parenchyma will be collaterally damaged by radiation. The functional reserve may be significantly reduced with an impact on further treatment planning. Monitoring of radiation-induced liver damage by imaging is neither established nor validated. We performed an analysis to correlate the histopathological presence of radiation-induced liver damage with functional magnetic resonance imaging (MRI) utilizing hepatobiliary contrast media (Gd-BOPTA).MethodsPatients undergoing local high-dose-rate brachytherapy for whom a follow-up hepatobiliary MRI within 120 days after radiotherapy as well as an evaluablemore » liver biopsy from radiation-exposed liver tissue within 7 days before MRI were retrospectively identified. Planning computed tomography (CT)/dosimetry was merged to the CT-documentation of the liver biopsy and to the MRI. Presence/absence of radiation-induced liver damage (histopathology) and Gd-BOPTA uptake (MRI) as well as the dose applied during brachytherapy at the site of tissue sampling was determined.ResultsFourteen biopsies from eight patients were evaluated. In all cases with histopathological evidence of radiation-induced liver damage (n = 11), no uptake of Gd-BOPTA was seen. In the remaining three, cases no radiation-induced liver damage but Gd-BOPTA uptake was seen. Presence of radiation-induced liver damage and absence of Gd-BOPTA uptake was correlated with a former high-dose exposition.ConclusionsAbsence of hepatobiliary MRI contrast media uptake in radiation-exposed liver parenchyma may indicate radiation-induced liver damage. Confirmatory studies are warranted.« less

  1. Donor parity no longer a barrier for female-to-male hematopoietic stem cell transplantation.

    PubMed

    van Halteren, Astrid G S; Dierselhuis, Miranda P; Netelenbos, Tanja; Fechter, Mirjam

    2014-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a widely applied treatment for disorders mainly involving the hematopoietic system. The success of this treatment depends on many different patient- and donor-specific factors. Based on higher CD34+ yields and superior clinical outcomes associated with the use of male donors, males are generally seen as the preferred HSCT donor. In addition, female donors are notorious for bearing memory type lymphocytes induced by previous pregnancies; such alloimmune cells may provoke unwanted immune reactions such as graft-vs.-host disease in transplant recipients. Consequently, many transplant centers try to avoid parous donors, particularly when searching the best unrelated donor for a male patient. We recently showed that parous women with female offspring have an anti-male directed tolerogenic immune status comparable to that of nulliparous donors. As discussed in this article addendum, the sex of the donor's offspring combined with the presence of HY-specific T regulator cells are possibly better selection criteria than parity status per se.

  2. Bone marrow adipocytes as negative regulators of the hematopoietic microenvironment

    PubMed Central

    Naveiras, Olaia; Nardi, Valentina; Wenzel, Pamela L.; Fahey, Frederic; Daley, George Q.

    2009-01-01

    Osteoblasts and endothelium constitute functional niches that support hematopoietic stem cells (HSC) in mammalian bone marrow (BM) 1,2,3 . Adult BM also contains adipocytes, whose numbers correlate inversely with the hematopoietic activity of the marrow. Fatty infiltration of hematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia 4. To explore whether adipocytes influence hematopoiesis or simply fill marrow space, we compared the hematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. By flow cytometry, colony forming activity, and competitive repopulation assay, HSCs and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 “fatless” mice, which are genetically incapable of forming adipocytes8, and in mice treated with the PPARγ inhibitor Bisphenol-A-DiGlycidyl-Ether (BADGE), which inhibits adipogenesis9, post-irradiation marrow engraftment is accelerated relative to wild type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone marrow microenvironment, and suggest that antagonizingmarrow adipogenesis may enhance hematopoietic recovery in clinical bone marrow transplantation. PMID:19516257

  3. Interferon-gamma enhances radiation-induced cell death via downregulation of Chk1

    PubMed Central

    Kim, Kwang Seok; Choi, Kyu Jin; Bae, Sangwoo

    2012-01-01

    Interferon-gamma (IFNγ) is a cytokine with roles in immune responses as well as in tumor control. Interferon is often used in cancer treatment together with other therapies. Here we report a novel approach to enhancement of cancer cell killing by combined treatment of IFNγ with ionizing radiation. We found that IFNγ treatment alone in HeLa cells induced phosphorylation of Chk1 in a time- and dose-dependent manner, and resulted in cell arrest. Moreover IFNγ treatment was correlated with attenuation of Chk1 as the treatment shortened protein half-life of Chk1. As Chk1 is an essential cell cycle regulator for viability after DNA damage, attenuation of Chk1 by IFNγ pre-treatment in HeLa cells resulted in increased cell death following ionizing radiation about 2-folds than ionizing radiation treatment alone whereas IFNγ treatment alone had little effect on cell death. X-linked inhibitor of apoptosis-associated factor 1 (XAF1), an IFN-induced gene, seems to partly regulate IFNγ-induced Chk1 destabilization and radiation sensitivity because transient depletion of XAF1 by siRNA prevented IFNγ-induced Chk1 attenuation and partly protected cells from IFNγ-enhanced radiation cell killing. Therefore the results provide a novel rationale to combine IFNγ pretreatment and DNA-damaging anti-cancer drugs such as ionizing radiation to enhance cancer cell killing. PMID:22825336

  4. Optical imaging of radiation-induced metabolic changes in radiation-sensitive and resistant cancer cells

    NASA Astrophysics Data System (ADS)

    Alhallak, Kinan; Jenkins, Samir V.; Lee, David E.; Greene, Nicholas P.; Quinn, Kyle P.; Griffin, Robert J.; Dings, Ruud P. M.; Rajaram, Narasimhan

    2017-06-01

    Radiation resistance remains a significant problem for cancer patients, especially due to the time required to definitively determine treatment outcome. For fractionated radiation therapy, nearly 7 to 8 weeks can elapse before a tumor is deemed to be radiation-resistant. We used the optical redox ratio of FAD/(FAD+NADH) to identify early metabolic changes in radiation-resistant lung cancer cells. These radiation-resistant human A549 lung cancer cells were developed by exposing the parental A549 cells to repeated doses of radiation (2 Gy). Although there were no significant differences in the optical redox ratio between the parental and resistant cell lines prior to radiation, there was a significant decrease in the optical redox ratio of the radiation-resistant cells 24 h after a single radiation exposure (p=0.01). This change in the redox ratio was indicative of increased catabolism of glucose in the resistant cells after radiation and was associated with significantly greater protein content of hypoxia-inducible factor 1 (HIF-1α), a key promoter of glycolytic metabolism. Our results demonstrate that the optical redox ratio could provide a rapid method of determining radiation resistance status based on early metabolic changes in cancer cells.

  5. Eosinophil-derived CCL-6 impairs hematopoietic stem cell homeostasis

    PubMed Central

    Zhang, Chao; Yi, Weiwei; Li, Fei; Du, Xufei; Wang, Hu; Wu, Ping; Peng, Chao; Luo, Man; Hua, Wen; Wong, Catherine CL; Lee, James J; Li, Wen; Chen, Zhihua; Ying, Songmin; Ju, Zhenyu; Shen, Huahao

    2018-01-01

    Eosinophils (Eos) have been long considered as end-stage effector cells in the hierarchical hematopoietic system. Numerous lines of evidence have suggested that Eos are multifunctional leukocytes with respect to the initiation, propagation and regulation of various inflammatory or immune reactions, especially in allergic diseases. Recent studies have shown that Eos are also required for maintenance of bone marrow plasma cells and differentiation of B cells. However, it remains unclear whether Eos contributes to regulation of hematopoietic stem cell (HSC) homeostasis. Here, we demonstrate that Eos disrupt HSC homeostasis by impairing HSC quiescence and reconstitution ability in wild-type mice following ovalbumin (OVA) challenge and even by causing bone marrow HSC failure and exhaustion in Cd3δ-Il-5 transgenic mice. The impaired maintenance and function of HSCs were associated with Eos-induced redox imbalance (increased oxidative phosphorylation and decreased anti-oxidants levels). More importantly, using mass spectrometry, we determined that CCL-6 is expressed at a high level under eosinophilia. We demonstrate that CCL-6 is Eos-derived and responsible for the impaired HSC homeostasis. Interestingly, blockage of CCL-6 with a specific neutralizing antibody, restored the reconstitution ability of HSCs while exacerbating eosinophilia airway inflammation in OVA-challenged mice. Thus, our study reveals an unexpected function of Eos/CCL-6 in HSC homeostasis. PMID:29327730

  6. Eosinophil-derived CCL-6 impairs hematopoietic stem cell homeostasis.

    PubMed

    Zhang, Chao; Yi, Weiwei; Li, Fei; Du, Xufei; Wang, Hu; Wu, Ping; Peng, Chao; Luo, Man; Hua, Wen; Wong, Catherine Cl; Lee, James J; Li, Wen; Chen, Zhihua; Ying, Songmin; Ju, Zhenyu; Shen, Huahao

    2018-03-01

    Eosinophils (Eos) have been long considered as end-stage effector cells in the hierarchical hematopoietic system. Numerous lines of evidence have suggested that Eos are multifunctional leukocytes with respect to the initiation, propagation and regulation of various inflammatory or immune reactions, especially in allergic diseases. Recent studies have shown that Eos are also required for maintenance of bone marrow plasma cells and differentiation of B cells. However, it remains unclear whether Eos contributes to regulation of hematopoietic stem cell (HSC) homeostasis. Here, we demonstrate that Eos disrupt HSC homeostasis by impairing HSC quiescence and reconstitution ability in wild-type mice following ovalbumin (OVA) challenge and even by causing bone marrow HSC failure and exhaustion in Cd3δ-Il-5 transgenic mice. The impaired maintenance and function of HSCs were associated with Eos-induced redox imbalance (increased oxidative phosphorylation and decreased anti-oxidants levels). More importantly, using mass spectrometry, we determined that CCL-6 is expressed at a high level under eosinophilia. We demonstrate that CCL-6 is Eos-derived and responsible for the impaired HSC homeostasis. Interestingly, blockage of CCL-6 with a specific neutralizing antibody, restored the reconstitution ability of HSCs while exacerbating eosinophilia airway inflammation in OVA-challenged mice. Thus, our study reveals an unexpected function of Eos/CCL-6 in HSC homeostasis.

  7. Antimicrobial fabric adsorbed iodine produced by radiation-induced graft polymerization

    NASA Astrophysics Data System (ADS)

    Aoki, Shoji; Fujiwara, Kunio; Sugo, Takanobu; Suzuki, Koichi

    2013-03-01

    Antimicrobial fabric was synthesized by radiation-induced graft polymerization of N-vinyl pyrrolidone onto polyolefine nonwoven fabric and subsequent adsorption of iodine. In response of the huge request for the antimicrobial material applied to face masks for swine flu in 2009, operation procedure of continuous radiation-induced graft polymerization apparatus was improved. The improved grafting production per week increased 3.8 times compared to the production by former operation procedure. Shipped antimicrobial fabric had reached 130,000 m2 from June until December, 2009.

  8. UV radiation induces CXCL5 expression in human skin.

    PubMed

    Reichert, Olga; Kolbe, Ludger; Terstegen, Lara; Staeb, Franz; Wenck, Horst; Schmelz, Martin; Genth, Harald; Kaever, Volkhard; Roggenkamp, Dennis; Neufang, Gitta

    2015-04-01

    CXCL5 has recently been identified as a mediator of UVB-induced pain in rodents. To compare and to extend previous knowledge of cutaneous CXCL5 regulation, we performed a comprehensive study on the effects of UV radiation on CXCL5 regulation in human skin. Our results show a dose-dependent increase in CXCL5 protein in human skin after UV radiation. CXCL5 can be released by different cell types in the skin. We presumed that, in addition to immune cells, non-immune skin cells also contribute to UV-induced increase in CXCL5 protein. Analysis of monocultured dermal fibroblasts and keratinocytes revealed that only fibroblasts but not keratinocytes displayed up regulated CXCL5 levels after UV stimulation. Whereas UV treatment of human skin equivalents, induced epidermal CXCL5 mRNA and protein expression. Up regulation of epidermal CXCL5 was independent of keratinocyte differentiation and keratinocyte-keratinocyte interactions in epidermal layers. Our findings provide first evidence on the release of CXCL5 in UV-radiated human skin and the essential role of fibroblast-keratinocyte interaction in the regulation of epidermal CXCL5. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Fanca−/− hematopoietic stem cells demonstrate a mobilization defect which can be overcome by administration of the Rac inhibitor NSC23766

    PubMed Central

    Milsom, Michael D.; Lee, Andrew W.; Zheng, Yi; Cancelas, Jose A.

    2009-01-01

    Fanconi anemia is a severe bone marrow failure syndrome resulting from inactivating mutations of Fanconi anemia pathway genes. Gene and cell therapy trials using hematopoietic stem cells and progenitors have been hampered by poor mobilization of HSC to peripheral blood in response to G-CSF. Using a murine model of Fanconi anemia (Fanca−/− mice), we found that the Fanca deficiency was associated with a profound defect in hematopoietic stem cells and progenitors mobilization in response to G-CSF in absence of bone marrow failure, which correlates with the findings of clinical trials in Fanconi anemia patients. This mobilization defect was overcome by co-administration of the Rac inhibitor NSC23766, suggesting that Rac signaling is implicated in the retention of Fanca−/− hematopoietic stem cells and progenitors in the bone marrow. In view of these data, we propose that targeting Rac signaling may enhance G-CSF-induced HSC mobilization in Fanconi anemia. PMID:19491337

  10. Reducing radiation-induced gastrointestinal toxicity — the role of the PHD/HIF axis

    PubMed Central

    Olcina, Monica M.; Giaccia, Amato J.

    2016-01-01

    Radiotherapy is an effective treatment strategy for cancer, but a significant proportion of patients experience radiation-induced toxicity due to damage to normal tissue in the irradiation field. The use of chemical or biological approaches aimed at reducing or preventing normal tissue toxicity induced by radiotherapy is a long-held goal. Hypoxia-inducible factors (HIFs) regulate the production of factors that may protect several cellular compartments affected by radiation-induced toxicity. Pharmacological inhibitors of prolyl hydroxylase domain–containing enzymes (PHDs), which result in stabilization of HIFs, have recently been proposed as a new class of radioprotectors. In this review, radiation-induced toxicity in the gastrointestinal (GI) tract and the main cellular compartments studied in this context will be discussed. The effects of PHD inhibition on GI radioprotection will be described in detail. PMID:27548524

  11. Modeling marrow damage from response data: Evolution from radiation biology to benzene toxicity

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Jones, T.D.; Morris, M.D.; Hasan, J.S.

    1996-12-01

    Consensus principles from radiation biology were used to describe a generic set of nonlinear, first-order differential equations for modeling toxicity-induced compensatory cell kinetics in terms of sublethal injury, repair, direct killing, killing of cells with unrepaired sublethal injury, and repopulation. This cellular model was linked to a probit model of hematopoietic mortality that describes death from infection and/or hemorrhage between 5 and 30 days. Mortality data from 27 experiments with 851 dose-response groups, in which doses were protracted by rate and/or fractionation, were used to simultaneously estimate all rate constants by maximum-likelihood methods. Data used represented 18,940 test animals: 12,827more » mice, 2925 rats, 1676 sheep, 829 swine, 479 dogs, and 204 burros. Although a long-term, repopulating hematopoietic stem cell is ancestral to all lineages needed to restore normal homeostasis, the dose-response data from the protracted irradiations indicate clearly that the particular lineage that is critical to hematopoietic recovery does not resemble stemlike cells with regard to radiosensitivity and repopulation rates. Instead, the weakest link in the chain of hematopoiesis was found to have an intrinsic radioresistance equal to or greater than stromal cells and to repopulate at the same rates. Model validation has been achieved by predicting the LD50 and/or fractional group mortality in 38 protracted-dose experiments (rats and mice) that were not used in the fitting of model coefficients. 29 refs., 5 figs., 5 tabs.« less

  12. New Approaches to Radiation Protection

    PubMed Central

    Rosen, Eliot M.; Day, Regina; Singh, Vijay K.

    2015-01-01

    Radioprotectors are compounds that protect against radiation injury when given prior to radiation exposure. Mitigators can protect against radiation injury when given after exposure but before symptoms appear. Radioprotectors and mitigators can potentially improve the outcomes of radiotherapy for cancer treatment by allowing higher doses of radiation and/or reduced damage to normal tissues. Such compounds can also potentially counteract the effects of accidental exposure to radiation or deliberate exposure (e.g., nuclear reactor meltdown, dirty bomb, or nuclear bomb explosion); hence they are called radiation countermeasures. Here, we will review the general principles of radiation injury and protection and describe selected examples of radioprotectors/mitigators ranging from small-molecules to proteins to cell-based treatments. We will emphasize agents that are in more advanced stages of development. PMID:25653923

  13. DETECTION OF LOW DOSE RADIATION INDUCED DNA DAMAGE USING TEMPERATURE DIFFERENTIAL FLUORESCENCE ASSAY

    EPA Science Inventory

    A rapid and sensitive fluorescence assay for radiation-induced DNA damage is reported. Changes in temperature-induced strand separation in both calf thymus DNA and plasmid DNA (puc 19 plasmid from Escherichia coli) were measured after exposure to low doses of radiation. Exposur...

  14. DETECTION OF LOW DOSE RADIATION INDUCED DNA DAMAGE USING TEMPERATURE DIFFERENNTIAL FLUORESENCE ASSAY

    EPA Science Inventory

    A rapid and sensitive fluorescence assay for radiation-induced DNA damage is reported. Changes in temperature-induced strand separation in both calf thymus DNA and plasmid DNA (puc 19 plasmid from Escherichia coli) were measured after exposure to low doses of radiation. Exposures...

  15. Night work, long work weeks, and risk of accidental injuries. A register-based study.

    PubMed

    Larsen, Ann D; Hannerz, Harald; Møller, Simone V; Dyreborg, Johnny; Bonde, Jens Peter; Hansen, Johnni; Kolstad, Henrik A; Hansen, Åse Marie; Garde, Anne Helene

    2017-11-01

    Objectives The aims of this study were to (i) investigate the association between night work or long work weeks and the risk of accidental injuries and (ii) test if the association is affected by age, sex or socioeconomic status. Methods The study population was drawn from the Danish version of the European Labour Force Survey from 1999-2013. The current study was based on 150 438 participants (53% men and 47% women). Data on accidental injuries were obtained at individual level from national health registers. We included all 20-59-year-old employees working ≥32 hours a week at the time of the interview. We used Poisson regression to estimate the relative rates (RR) of accidental injuries as a function of night work or long work weeks (>40 hours per week) adjusted for year of interview, sex, age, socioeconomic status (SES), industry, and weekly working hours or night work. Age, sex and SES were included as two-way interactions. Results We observed 23 495 cases of accidental injuries based on 273 700 person years at risk. Exposure to night work was statistically significantly associated with accidental injuries (RR 1.11, 99% CI 1.06-1.17) compared to participants with no recent night work. No associations were found between long work weeks (>40 hours) and accidental injuries. Conclusion We found a modest increased risk of accidental injuries when reporting night work. No associations between long work weeks and risk of accidental injuries were observed. Age, sex and SES showed no trends when included as two-way interactions.

  16. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments.

    PubMed

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk. Copyright © 2016 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.

  17. Human hematopoietic progenitors express erythropoietin.

    PubMed

    Stopka, T; Zivny, J H; Stopkova, P; Prchal, J F; Prchal, J T

    1998-05-15

    Erythropoietin (EPO) is a factor essential for erythroid cell proliferation, differentiation, and survival. The production of EPO by the kidneys in response to hypoxia and anemia is well documented. To determine whether EPO is also produced by hematopoietic cells, we analyzed the expression of EPO in normal human hematopoietic progenitors and in their progeny. Undifferentiated CD34(+)lin- hematopoietic progenitors do not have detectable EPO mRNA. Differentiating CD34(+) cells that are stimulated with recombinant human EPO in serum-free liquid cultures express both EPO and EPO receptor (EPOR). Because CD34(+) cells represent a heterogeneous cell population, we analyzed individual burst-forming units-erythroid (BFU-E) and nonerythroid colony-forming unit-granulocyte-macrophage colonies for EPO mRNA. Only BFU-E colonies were positive for EPO mRNA. Lysates from pooled BFU-E colonies stained positively for EPO by immunoblotting. To further confirm the intrinsic nature of erythroid EPO, we replaced extrinsic EPO in erythroid colony cultures with EPO-mimicking peptide (EMP). We show EPO expression in the EMP-stimulated BFU-Es at both mRNA and protein levels. Stimulation of bone marrow mononuclear cells (BMMCs) with EMP upregulated EPO expression. Furthermore, we found EPO and EPOR mRNAs as well as EPO protein in K562 cells, a human erythroleukemia cell line. Stimulation of K562 cells with EMP upregulated EPO expression. We suggest that EPO of erythroid origin may have a role in the regulation of erythropoiesis.

  18. Activating PTEN by COX-2 inhibitors antagonizes radiation-induced AKT activation contributing to radiosensitization

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Meng, Zhen; Department of Oral & Maxillofacial Surgery, Peking University School and Hospital of Stomatology, 22 Zhongguancun Avenue South, Haidian District, Beijing 100081; Gan, Ye-Hua, E-mail: kqyehuagan@bjmu.edu.cn

    2015-05-01

    Radiotherapy is still one of the most effective nonsurgical treatments for many tumors. However, radioresistance remains a major impediment to radiotherapy. Although COX-2 inhibitors can induce radiosensitization, the underlying mechanism is not fully understood. In this study, we showed that COX-2 selective inhibitor celecoxib enhanced the radiation-induced inhibition of cell proliferation and apoptosis in HeLa and SACC-83 cells. Treatment with celecoxib alone dephosphorylated phosphatase and tensin homolog deleted on chromosome ten (PTEN), promoted PTEN membrane translocation or activation, and correspondingly dephosphorylated or inactivated protein kinase B (AKT). By contrast, treatment with radiation alone increased PTEN phosphorylation, inhibited PTEN membrane translocationmore » and correspondingly activated AKT in the two cell lines. However, treatment with celecoxib or another COX-2 selective inhibitor (valdecoxib) completely blocked radiation-induced increase of PTEN phosphorylation, rescued radiation-induced decrease in PTEN membrane translocation, and correspondingly inactivated AKT. Moreover, celecoxib could also upregulate PTEN protein expression by downregulating Sp1 expression, thereby leading to the activation of PTEN transcription. Our results suggested that COX-2 inhibitors could enhance radiosensitization at least partially by activating PTEN to antagonize radiation-induced AKT activation. - Highlights: • COX-2 inhibitor, celecoxib, could enhance radiosensitization. • Radiation induced PTEN inactivation (phosphorylation) and AKT activation. • COX-2 inhibitor induced PTEN expression and activation, and inactivated AKT. • COX-2 inhibitor enhanced radiosensitization through activating PTEN.« less

  19. Radiation-induced cardiomyopathy as a function of radiation beam gating to the cardiac cycle

    NASA Astrophysics Data System (ADS)

    Gladstone, David J.; Flanagan, Michael F.; Southworth, Jean B.; Hadley, Vaughn; Thibualt, Melissa Wei; Hug, Eugen B.; Hoopes, P. Jack

    2004-04-01

    Portions of the heart are often unavoidably included in the primary treatment volume during thoracic radiotherapy, and radiation-induced heart disease has been observed as a treatment-related complication. Such complications have been observed in humans following radiation therapy for Hodgkin's disease and treatment of the left breast for carcinoma. Recent attempts have been made to prevent re-stenosis following angioplasty procedures using external beam irradiation. These attempts were not successful, however, due to the large volume of heart included in the treatment field and subsequent cardiac morbidity. We suggest a mechanism for sparing the heart from radiation damage by synchronizing the radiation beam with the cardiac cycle and delivering radiation only when the heart is in a relatively hypoxic state. We present data from a rat model testing this hypothesis and show that radiation damage to the heart can be altered by synchronizing the radiation beam with the cardiac cycle. This technique may be useful in reducing radiation damage to the heart secondary to treatment for diseases such as Hodgkin's disease and breast cancer.

  20. What do we know about the participation of hematopoietic stem cells in hematopoiesis?

    PubMed

    Drize, Nina; Petinati, Nataliya

    2015-01-01

    The demonstrated presence in adult tissues of cells with sustained tissue regenerative potential has given rise to the concept of tissue stem cells. Assays to detect and measure such cells indicate that they have enormous proliferative potential and usually an ability to produce all or many of the mature cell types that define the specialized functionality of the tissue. In the hematopoietic system, one or only a few cells can restore lifelong hematopoiesis of the whole organism. To what extent is the maintenance of hematopoietic stem cells required during normal hematopoiesis? How does the constant maintenance of hematopoiesis occur and what is the behavior of the hematopoietic stem cells in the normal organism? How many of the hematopoietic stem cells are created during the development of the organism? How many hematopoietic stem cells are generating more mature progeny at any given moment? What happens to the population of hematopoietic stem cells in aging? This review will attempt to describe the results of recent research which contradict some of the ideas established over the past 30 years about how hematopoiesis is regulated.

  1. Irradiated esophageal cells are protected from radiation-induced recombination by MnSOD gene therapy.

    PubMed

    Niu, Yunyun; Wang, Hong; Wiktor-Brown, Dominika; Rugo, Rebecca; Shen, Hongmei; Huq, M Saiful; Engelward, Bevin; Epperly, Michael; Greenberger, Joel S

    2010-04-01

    Radiation-induced DNA damage is a precursor to mutagenesis and cytotoxicity. During radiotherapy, exposure of healthy tissues can lead to severe side effects. We explored the potential of mitochondrial SOD (MnSOD) gene therapy to protect esophageal, pancreatic and bone marrow cells from radiation-induced genomic instability. Specifically, we measured the frequency of homologous recombination (HR) at an integrated transgene in the Fluorescent Yellow Direct Repeat (FYDR) mice, in which an HR event can give rise to a fluorescent signal. Mitochondrial SOD plasmid/liposome complex (MnSOD-PL) was administered to esophageal cells 24 h prior to 29 Gy upper-body irradiation. Single cell suspensions from FYDR, positive control FYDR-REC, and negative control C57BL/6NHsd (wild-type) mouse esophagus, pancreas and bone marrow were evaluated by flow cytometry. Radiation induced a statistically significant increase in HR 7 days after irradiation compared to unirradiated FYDR mice. MnSOD-PL significantly reduced the induction of HR by radiation at day 7 and also reduced the level of HR in the pancreas. Irradiation of the femur and tibial marrow with 8 Gy also induced a significant increase in HR at 7 days. Radioprotection by intraesophageal administration of MnSOD-PL was correlated with a reduced level of radiation-induced HR in esophageal cells. These results demonstrate the efficacy of MnSOD-PL for suppressing radiation-induced HR in vivo.

  2. The big chill: accidental hypothermia.

    PubMed

    Davis, Robert Allan

    2012-01-01

    A potential cause of such emergent issues as cardiac arrhythmias, hypotension, and fluid and electrolyte shifts, accidental hypothermia can be deadly, is common among trauma patients, and is often difficult to recognize. The author discusses predisposing conditions, the classic presentation, and the effects on normal thermoregulatory processes; explains how to conduct a systems assessment of the hypothermic patient; and describes crucial management strategies.

  3. Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials

    PubMed Central

    Jenrow, Kenneth A.; Brown, Stephen L.

    2014-01-01

    To summarize current knowledge regarding mechanisms of radiation-induced normal tissue injury and medical countermeasures available to reduce its severity. Advances in radiation delivery using megavoltage and intensity-modulated radiation therapy have permitted delivery of higher doses of radiation to well-defined tumor target tissues. Injury to critical normal tissues and organs, however, poses substantial risks in the curative treatment of cancers, especially when radiation is administered in combination with chemotherapy. The principal pathogenesis is initiated by depletion of tissue stem cells and progenitor cells and damage to vascular endothelial microvessels. Emerging concepts of radiation-induced normal tissue toxicity suggest that the recovery and repopulation of stromal stem cells remain chronically impaired by long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines/chemokines resulting in progressive damage after radiation exposure. Better understanding the mechanisms mediating interactions among excessive generation of reactive oxygen species, production of pro-inflammatory cytokines and activated macrophages, and role of bone marrow-derived progenitor and stem cells may provide novel insight on the pathogenesis of radiation-induced injury of tissues. Further understanding the molecular signaling pathways of cytokines and chemokines would reveal novel targets for protecting or mitigating radiation injury of tissues and organs. PMID:25324981

  4. Radiation-induced transmissable chromosomal instability in haemopoietic stem cells

    NASA Astrophysics Data System (ADS)

    Kadhim, M. A.; Wright, E. G.

    Heritable radiation-induced genetic alterations have long been assumed to be ``fixed'' within the first cell division. However, there is a growing body of evidence that a considerable fraction of cells surviving radiation exposure appear normal, but a variety of mutational changes arise in their progeny due to a transmissible genomic instability. In our investigations of G-banded metaphases, non-clonal cytogenetic aberrations, predominantly chromatid-type aberrations, have been observed in the clonal descendants of murine and human haemopoietic stem cells surviving low doses (~1 track per cell) of alpha-particle irradiations. The data are consistent with a transmissible genetic instability induced in a stem cell resulting in a diversity of chromosomal aberrations in its clonal progeny many cell divisions later. Recent studies have demonstrated that the instability phenotype persists in vivo and that the expression of chromosomal instability has a strong dependence on the genetic characteristics of the irradiated cell. At the time when cytogenetic aberrations are detected, an increased incidence of hprt mutations and apoptotic cells have been observed in the clonal descendants of alpha-irradiated murine haemopoietic stem cells. Thus, delayed chromosomal abnormalities, delayed cell death by apoptosis and late-arising specific gene mutations may reflect diverse consequences of radiation-induced genomic instability. The relationship, if any, between these effects is not established. Current studies suggest that expression of these delayed heritable effects is determined by the type of radiation exposure, type of cell and a variety of genetic factors.

  5. In vivo engineering of bone tissues with hematopoietic functions and mixed chimerism

    PubMed Central

    Shih, Yu-Ru; Kang, Heemin; Rao, Vikram; Chiu, Yu-Jui; Kwon, Seong Keun; Varghese, Shyni

    2017-01-01

    Synthetic biomimetic matrices with osteoconductivity and osteoinductivity have been developed to regenerate bone tissues. However, whether such systems harbor donor marrow in vivo and support mixed chimerism remains unknown. We devised a strategy to engineer bone tissues with a functional bone marrow (BM) compartment in vivo by using a synthetic biomaterial with spatially differing cues. Specifically, we have developed a synthetic matrix recapitulating the dual-compartment structures by modular assembly of mineralized and nonmineralized macroporous structures. Our results show that these matrices incorporated with BM cells or BM flush transplanted into recipient mice matured into functional bone displaying the cardinal features of both skeletal and hematopoietic compartments similar to native bone tissue. The hematopoietic function of bone tissues was demonstrated by its support for a higher percentage of mixed chimerism compared with i.v. injection and donor hematopoietic cell mobilization in the circulation of nonirradiated recipients. Furthermore, hematopoietic cells sorted from the engineered bone tissues reconstituted the hematopoietic system when transplanted into lethally irradiated secondary recipients. Such engineered bone tissues could potentially be used as ectopic BM surrogates for treatment of nonmalignant BM diseases and as a tool to study hematopoiesis, donor–host cell dynamics, tumor tropism, and hematopoietic cell transplantation. PMID:28484009

  6. In vivo engineering of bone tissues with hematopoietic functions and mixed chimerism.

    PubMed

    Shih, Yu-Ru; Kang, Heemin; Rao, Vikram; Chiu, Yu-Jui; Kwon, Seong Keun; Varghese, Shyni

    2017-05-23

    Synthetic biomimetic matrices with osteoconductivity and osteoinductivity have been developed to regenerate bone tissues. However, whether such systems harbor donor marrow in vivo and support mixed chimerism remains unknown. We devised a strategy to engineer bone tissues with a functional bone marrow (BM) compartment in vivo by using a synthetic biomaterial with spatially differing cues. Specifically, we have developed a synthetic matrix recapitulating the dual-compartment structures by modular assembly of mineralized and nonmineralized macroporous structures. Our results show that these matrices incorporated with BM cells or BM flush transplanted into recipient mice matured into functional bone displaying the cardinal features of both skeletal and hematopoietic compartments similar to native bone tissue. The hematopoietic function of bone tissues was demonstrated by its support for a higher percentage of mixed chimerism compared with i.v. injection and donor hematopoietic cell mobilization in the circulation of nonirradiated recipients. Furthermore, hematopoietic cells sorted from the engineered bone tissues reconstituted the hematopoietic system when transplanted into lethally irradiated secondary recipients. Such engineered bone tissues could potentially be used as ectopic BM surrogates for treatment of nonmalignant BM diseases and as a tool to study hematopoiesis, donor-host cell dynamics, tumor tropism, and hematopoietic cell transplantation.

  7. A prospective cohort study on radiation-induced hypothyroidism: development of an NTCP model.

    PubMed

    Boomsma, Marjolein J; Bijl, Hendrik P; Christianen, Miranda E M C; Beetz, Ivo; Chouvalova, Olga; Steenbakkers, Roel J H M; van der Laan, Bernard F A M; Wolffenbuttel, Bruce H R; Oosting, Sjoukje F; Schilstra, Cornelis; Langendijk, Johannes A

    2012-11-01

    To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced hypothyroidism. The thyroid-stimulating hormone (TSH) level of 105 patients treated with (chemo-) radiation therapy for head-and-neck cancer was prospectively measured during a median follow-up of 2.5 years. Hypothyroidism was defined as elevated serum TSH with decreased or normal free thyroxin (T4). A multivariate logistic regression model with bootstrapping was used to determine the most important prognostic variables for radiation-induced hypothyroidism. Thirty-five patients (33%) developed primary hypothyroidism within 2 years after radiation therapy. An NTCP model based on 2 variables, including the mean thyroid gland dose and the thyroid gland volume, was most predictive for radiation-induced hypothyroidism. NTCP values increased with higher mean thyroid gland dose (odds ratio [OR]: 1.064/Gy) and decreased with higher thyroid gland volume (OR: 0.826/cm(3)). Model performance was good with an area under the curve (AUC) of 0.85. This is the first prospective study resulting in an NTCP model for radiation-induced hypothyroidism. The probability of hypothyroidism rises with increasing dose to the thyroid gland, whereas it reduces with increasing thyroid gland volume. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. γ-radiation induced corrosion of copper in bentonite-water systems under anaerobic conditions

    NASA Astrophysics Data System (ADS)

    Karin Norrfors, K.; Björkbacka, Åsa; Kessler, Amanda; Wold, Susanna; Jonsson, Mats

    2018-03-01

    In this work we have experimentally studied the impact of bentonite clay on the process of radiation-induced copper corrosion in anoxic water. The motivation for this is to further develop our understanding of radiation-driven processes occurring in deep geological repositories for spent nuclear fuel where copper canisters containing the spent nuclear fuel will be embedded in compacted bentonite. Experiments on radiation-induced corrosion in the presence and absence of bentonite were performed along with experiments elucidating the impact irradiation on the Cu2+ adsorption capacity of bentonite. The experiments presented in this work show that the presence of bentonite clay has no or very little effect on the magnitude of radiation-induced corrosion of copper in anoxic aqueous systems. The absence of a protective effect similar to that observed for radiation-induced dissolution of UO2 is attributed to differences in the corrosion mechanism. This provides further support for the previously proposed mechanism where the hydroxyl radical is the key radiolytic oxidant responsible for the corrosion of copper. The radiation effect on the bentonite sorption capacity of Cu2+ (reduced capacity) is in line with what has previously been reported for other cations. The reduced cation sorption capacity is partly attributed to a loss of Al-OH sites upon irradiation.

  9. A Prospective Cohort Study on Radiation-induced Hypothyroidism: Development of an NTCP Model

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Boomsma, Marjolein J.; Bijl, Hendrik P.; Christianen, Miranda E.M.C.

    Purpose: To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced hypothyroidism. Methods and Materials: The thyroid-stimulating hormone (TSH) level of 105 patients treated with (chemo-) radiation therapy for head-and-neck cancer was prospectively measured during a median follow-up of 2.5 years. Hypothyroidism was defined as elevated serum TSH with decreased or normal free thyroxin (T4). A multivariate logistic regression model with bootstrapping was used to determine the most important prognostic variables for radiation-induced hypothyroidism. Results: Thirty-five patients (33%) developed primary hypothyroidism within 2 years after radiation therapy. An NTCP model based on 2 variables, including the mean thyroidmore » gland dose and the thyroid gland volume, was most predictive for radiation-induced hypothyroidism. NTCP values increased with higher mean thyroid gland dose (odds ratio [OR]: 1.064/Gy) and decreased with higher thyroid gland volume (OR: 0.826/cm{sup 3}). Model performance was good with an area under the curve (AUC) of 0.85. Conclusions: This is the first prospective study resulting in an NTCP model for radiation-induced hypothyroidism. The probability of hypothyroidism rises with increasing dose to the thyroid gland, whereas it reduces with increasing thyroid gland volume.« less

  10. Cerenkov radiation-induced phototherapy for depth-independent cancer treatment (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Akers, Walter J.; Achilefu, Samuel; Kotagiri, Nalinikanth

    2017-02-01

    Light emitted as the result of high-energy particle transport through biological tissues (Cerenkov radiation) can be exploited for noninvasive diagnostic imaging using high sensitivity scientific cameras. We have investigated the energy transfer potential of Cerenkov radiation, discovering a new phototherapeutic technique for treatment of localized and disseminated cancers. This technique, Cerenkov radiation-induced phototherapy (CRIT), like photodynamic therapy, requires the presence of both light and photosensitive agent together to induce cytotoxicity and effective cancer treatment. But unlike conventional phototherapy strategies in which tissue ablation or activation of photoactive molecules is limited to superficial structures, radiation-induced phototherapy enables phototherapy delivery to the tumor sites throughout the body. Titanium oxide nanoparticles, which produce cytotoxic reactive oxygen species upon irradiation with UV light, were targeted to tumor tissue by surface decoration with transferrin. Subsequent administration of tumor-avid radiotracer, 18-fluorodeoxyglucose (18FDG) provided localized UV light source via Cerenkov radiation. Treatment of tumor-bearing mice with the combination of Titanium nanoparticles and 18FDG resulted in effective reduction in tumor growth, while individual agents were not therapeutic. This new strategy in cancer therapy extends the reach of phototherapy beyond what was previously possible, with potential for treatment of cancer metastases and rescue from treatment resistance.

  11. Complete prevention of radiation-induced dermatitis using topical adrenergic vasoconstrictors.

    PubMed

    Fahl, William E

    2016-12-01

    Radiation dermatitis is a commonly occurring, painful, side effect of cancer radiotherapy that causes some patients to withdraw from the radiotherapy course. Our goal was to test and optimize topical application of an adrenergic vasoconstrictor to rat skin in a preclinical test to prevent radiation-induced dermatitis. A radiation dermatitis assay was developed in which 17.2 Gy to a 1.5 × 3.0 cm rectangle on the clipped dorsal back of rats yielded Grade 3 radiation dermatitis over the irradiated area 13 days later. Single, topical applications of each of three adrenergic vasoconstrictors, epinephrine, norepinephrine, or phenylephrine, in various vehicle formulations, doses, and application schedules, were tested to determine their efficacy in preventing radiation dermatitis. Each of the three adrenergic agonists conferred 100 % prevention of radiation dermatitis in linear, dose-dependent manners and their EC 50 potencies in preventing radiation dermatitis correlated well with their individual K d association constants for binding to mammalian α-adrenergic receptors. Topical vasoconstrictor application as little as 3-12 min before irradiation gave 80-100 % prevention, respectively, of radiation dermatitis. There was a strong correlation between the extent (0-100 %) of skin blanch present in skin immediately before irradiation and prevention of radiation dermatitis scored 13 days after irradiation. The data presented here demonstrate that topical application of adrenergic vasoconstrictors to rat skin before a large, 17.2 Gy, radiation insult confers 100 % protection against radiation dermatitis and support ongoing clinical trials and commercial development of a vasoconstrictor-based product to prevent radiotherapy-induced dermatitis.

  12. Radiation-Induce Immune Modulation in Prostate Cancer

    DTIC Science & Technology

    2005-01-01

    Prostate-specific antigen Prostate carcinoma Mammoglobin-A Breast carcinoma Overexpressed Alpha - fetoprotein Hepatocellular carcinoma and yolk-sac tumors...Interleukin-3 cooperates with tumor necrosis factor alpha for the development of human dendritic/Langerhans cells from cord blood CD34+ hematopoietic progenitor...additional subsets, e.g. Langerhans cells of the epidermis, and dermal or interstitial DC. PDC are the major interferon- alpha (IFNca) producing cells

  13. Diet-Induced Obesity Modulates Epigenetic Responses to Ionizing Radiation in Mice

    PubMed Central

    Vares, Guillaume; Wang, Bing; Ishii-Ohba, Hiroko; Nenoi, Mitsuru; Nakajima, Tetsuo

    2014-01-01

    Both exposure to ionizing radiation and obesity have been associated with various pathologies including cancer. There is a crucial need in better understanding the interactions between ionizing radiation effects (especially at low doses) and other risk factors, such as obesity. In order to evaluate radiation responses in obese animals, C3H and C57BL/6J mice fed a control normal fat or a high fat (HF) diet were exposed to fractionated doses of X-rays (0.75 Gy ×4). Bone marrow micronucleus assays did not suggest a modulation of radiation-induced genotoxicity by HF diet. Using MSP, we observed that the promoters of p16 and Dapk genes were methylated in the livers of C57BL/6J mice fed a HF diet (irradiated and non-irradiated); Mgmt promoter was methylated in irradiated and/or HF diet-fed mice. In addition, methylation PCR arrays identified Ep300 and Socs1 (whose promoters exhibited higher methylation levels in non-irradiated HF diet-fed mice) as potential targets for further studies. We then compared microRNA regulations after radiation exposure in the livers of C57BL/6J mice fed a normal or an HF diet, using microRNA arrays. Interestingly, radiation-triggered microRNA regulations observed in normal mice were not observed in obese mice. miR-466e was upregulated in non-irradiated obese mice. In vitro free fatty acid (palmitic acid, oleic acid) administration sensitized AML12 mouse liver cells to ionizing radiation, but the inhibition of miR-466e counteracted this radio-sensitization, suggesting that the modulation of radiation responses by diet-induced obesity might involve miR-466e expression. All together, our results suggested the existence of dietary effects on radiation responses (especially epigenetic regulations) in mice, possibly in relationship with obesity-induced chronic oxidative stress. PMID:25171162

  14. Accidental Falls Among Geriatric Patients: Can More Be Prevented?

    PubMed Central

    Johnson, Edwin T.

    1985-01-01

    The potential for accidental falls among geriatric patients is of mounting concern. Two hundred forty-one accidental falls over a 12-month period at the VA Medical Center were analyzed retrospectively and the literature reviewed in order to highlight factors that have bearing on the incidence and severity of falls. If a patient's potential for falling could be identified through a grading system based on these premonitory features, preventive measures might be more clearly focused where needed to reduce this frequent hazard in our hospital population. PMID:4046062

  15. Protective effects of Korean red ginseng against radiation-induced apoptosis in human HaCaT keratinocytes

    PubMed Central

    Chang, Jae Won; Park, Keun Hyung; HWANG, Hye Sook; Shin, Yoo Seob; Oh, Young-Taek; Kim, Chul-Ho

    2014-01-01

    Radiation-induced oral mucositis is a dose-limiting toxic side effect for patients with head and neck cancer. Numerous attempts at improving radiation-induced oral mucositis have not produced a qualified treatment. Ginseng polysaccharide has multiple immunoprotective effects. Our aim was to investigate the effectiveness of Korean red ginseng (KRG) on radiation-induced damage in the human keratinocyte cell line HaCaT and in an in vivo zebrafish model. Radiation inhibited HaCaT cell proliferation and migration in a cell viability assay and wound healing assay, respectively. KRG protected against these effects. KRG attenuated the radiation-induced embryotoxicity in the zebrafish model. Irradiation of HaCaT cells caused apoptosis and changes in mitochondrial membrane potential (MMP). KRG inhibited the radiation-induced apoptosis and intracellular generation of reactive oxygen species (ROS), and stabilized the radiation-induced loss of MMP. Western blots revealed KRG-mediated reduced expression of ataxia telangiectasia mutated protein (ATM), p53, c-Jun N-terminal kinase (JNK), p38 and cleaved caspase-3, compared with their significant increase after radiation treatment. The collective results suggest that KRG protects HaCaT cells by blocking ROS generation, inhibiting changes in MMP, and inhibiting the caspase, ATM, p38 and JNK pathways. PMID:24078877

  16. Protective effects of Korean red ginseng against radiation-induced apoptosis in human HaCaT keratinocytes.

    PubMed

    Chang, Jae Won; Park, Keun Hyung; Hwang, Hye Sook; Shin, Yoo Seob; Oh, Young-Taek; Kim, Chul-Ho

    2014-03-01

    Radiation-induced oral mucositis is a dose-limiting toxic side effect for patients with head and neck cancer. Numerous attempts at improving radiation-induced oral mucositis have not produced a qualified treatment. Ginseng polysaccharide has multiple immunoprotective effects. Our aim was to investigate the effectiveness of Korean red ginseng (KRG) on radiation-induced damage in the human keratinocyte cell line HaCaT and in an in vivo zebrafish model. Radiation inhibited HaCaT cell proliferation and migration in a cell viability assay and wound healing assay, respectively. KRG protected against these effects. KRG attenuated the radiation-induced embryotoxicity in the zebrafish model. Irradiation of HaCaT cells caused apoptosis and changes in mitochondrial membrane potential (MMP). KRG inhibited the radiation-induced apoptosis and intracellular generation of reactive oxygen species (ROS), and stabilized the radiation-induced loss of MMP. Western blots revealed KRG-mediated reduced expression of ataxia telangiectasia mutated protein (ATM), p53, c-Jun N-terminal kinase (JNK), p38 and cleaved caspase-3, compared with their significant increase after radiation treatment. The collective results suggest that KRG protects HaCaT cells by blocking ROS generation, inhibiting changes in MMP, and inhibiting the caspase, ATM, p38 and JNK pathways.

  17. Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress

    PubMed Central

    Rissone, Alberto; Weinacht, Katja Gabriele; la Marca, Giancarlo; Bishop, Kevin; Giocaliere, Elisa; Jagadeesh, Jayashree; Felgentreff, Kerstin; Dobbs, Kerry; Al-Herz, Waleed; Jones, Marypat; Chandrasekharappa, Settara; Kirby, Martha; Wincovitch, Stephen; Simon, Karen Lyn; Itan, Yuval; DeVine, Alex; Schlaeger, Thorsten; Schambach, Axel; Sood, Raman

    2015-01-01

    Adenylate kinases (AKs) are phosphotransferases that regulate the cellular adenine nucleotide composition and play a critical role in the energy homeostasis of all tissues. The AK2 isoenzyme is expressed in the mitochondrial intermembrane space and is mutated in reticular dysgenesis (RD), a rare form of severe combined immunodeficiency (SCID) in humans. RD is characterized by a maturation arrest in the myeloid and lymphoid lineages, leading to early onset, recurrent, and overwhelming infections. To gain insight into the pathophysiology of RD, we studied the effects of AK2 deficiency using the zebrafish model and induced pluripotent stem cells (iPSCs) derived from fibroblasts of an RD patient. In zebrafish, Ak2 deficiency affected hematopoietic stem and progenitor cell (HSPC) development with increased oxidative stress and apoptosis. AK2-deficient iPSCs recapitulated the characteristic myeloid maturation arrest at the promyelocyte stage and demonstrated an increased AMP/ADP ratio, indicative of an energy-depleted adenine nucleotide profile. Antioxidant treatment rescued the hematopoietic phenotypes in vivo in ak2 mutant zebrafish and restored differentiation of AK2-deficient iPSCs into mature granulocytes. Our results link hematopoietic cell fate in AK2 deficiency to cellular energy depletion and increased oxidative stress. This points to the potential use of antioxidants as a supportive therapeutic modality for patients with RD. PMID:26150473

  18. A non-human primate model of radiation-induced cachexia.

    PubMed

    Cui, Wanchang; Bennett, Alexander W; Zhang, Pei; Barrow, Kory R; Kearney, Sean R; Hankey, Kim G; Taylor-Howell, Cheryl; Gibbs, Allison M; Smith, Cassandra P; MacVittie, Thomas J

    2016-03-31

    Cachexia, or muscle wasting, is a serious health threat to victims of radiological accidents or patients receiving radiotherapy. Here, we propose a non-human primate (NHP) radiation-induced cachexia model based on clinical and molecular pathology findings. NHP exposed to potentially lethal partial-body irradiation developed symptoms of cachexia such as body weight loss in a time- and dose-dependent manner. Severe body weight loss as high as 20-25% was observed which was refractory to nutritional intervention. Radiographic imaging indicated that cachectic NHP lost as much as 50% of skeletal muscle. Histological analysis of muscle tissues showed abnormalities such as presence of central nuclei, inflammation, fatty replacement of skeletal muscle, and muscle fiber degeneration. Biochemical parameters such as hemoglobin and albumin levels decreased after radiation exposure. Levels of FBXO32 (Atrogin-1), ActRIIB and myostatin were significantly changed in the irradiated cachectic NHP compared to the non-irradiated NHP. Our data suggest NHP that have been exposed to high dose radiation manifest cachexia-like symptoms in a time- and dose-dependent manner. This model provides a unique opportunity to study the mechanism of radiation-induced cachexia and will aid in efficacy studies of mitigators of this disease.

  19. Analysis of Policy and Doctrine Supporting the Management of Operational Exposures to Ionizing Radiation

    DTIC Science & Technology

    2016-06-01

    discussion of the various subsyndromes of acute radiation syndrome , such as the hematopoietic syndrome , gastrointestinal syndrome , and neurovascular...Protection (Washington, DC: USAF, September 2011), p. 16. 8 probabilities as a function of acute radiation dose. Paragraph 3.d. discusses Risk... syndrome . It includes the use of dosimetry as well as biodosimetry to estimate radiation exposure and prognosis. It also provides guidance on the

  20. Proteomic overview and perspectives of the radiation-induced bystander effects.

    PubMed

    Chevalier, François; Hamdi, Dounia Houria; Saintigny, Yannick; Lefaix, Jean-Louis

    2015-01-01

    Radiation proteomics is a recent, promising and powerful tool to identify protein markers of direct and indirect consequences of ionizing radiation. The main challenges of modern radiobiology is to predict radio-sensitivity of patients and radio-resistance of tumor to be treated, but considerable evidences are now available regarding the significance of a bystander effect at low and high doses. This "radiation-induced bystander effect" (RIBE) is defined as the biological responses of non-irradiated cells that received signals from neighboring irradiated cells. Such intercellular signal is no more considered as a minor side-effect of radiotherapy in surrounding healthy tissue and its occurrence should be considered in adapting radiotherapy protocols, to limit the risk for radiation-induced secondary cancer. There is no consensus on a precise designation of RIBE, which involves a number of distinct signal-mediated effects within or outside the irradiated volume. Indeed, several cellular mechanisms were proposed, including the secretion of soluble factors by irradiated cells in the extracellular matrix, or the direct communication between irradiated and neighboring non-irradiated cells via gap junctions. This phenomenon is observed in a context of major local inflammation, linked with a global imbalance of oxidative metabolism which makes its analysis challenging using in vitro model systems. In this review article, the authors first define the radiation-induced bystander effect as a function of radiation type, in vitro analysis protocols, and cell type. In a second time, the authors present the current status of protein biomarkers and proteomic-based findings and discuss the capacities, limits and perspectives of such global approaches to explore these complex intercellular mechanisms. Copyright © 2014 Elsevier B.V. All rights reserved.