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Lyng FM, Azzam EI. Abscopal Effects, Clastogenic Effects and Bystander Effects: 70 Years of Non-Targeted Effects of Radiation. Radiat Res 2024; 202:355-367. [PMID: 38986531 DOI: 10.1667/rade-24-00040.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 04/29/2024] [Indexed: 07/12/2024]
Abstract
In vitro and in vivo observations accumulated over several decades have firmly shown that the biological effects of ionizing radiation can spread from irradiated cells/tissues to non-targeted cells/tissues. Redox-modulated intercellular communication mechanisms that include a role for secreted factors and gap junctions, can mediate these non-targeted effects. Clearly, the expression of such effects and their transmission to progeny cells has implications for issues related to radiation protection. Their elucidation is also relevant towards enhancing the efficacy of cancer radiotherapy and reducing its impact on the development of normal tissue toxicities. In addition, the study of non-targeted effects is pertinent to our basic understanding of intercellular communications under conditions of oxidative stress. This review will trace the history of non-targeted effects of radiation starting with early reports of abscopal effects which described radiation induced effects in tissues distant from the site of radiation exposure. A related effect involved the production of clastogenic factors in plasma following irradiation which can induce chromosome damage in unirradiated cells. Despite these early reports suggesting non-targeted effects of radiation, the classical paradigm that a direct deposition of energy in the nucleus was required still dominated. This paradigm was challenged by papers describing radiation induced bystander effects. This review will cover mechanisms of radiation-induced bystander effects and the potential impacts on radiation protection and radiation therapy.
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Affiliation(s)
- Fiona M Lyng
- Radiation and Environmental Science Centre, FOCAS Research Institute
- School of Physics, Clinical and Optometric Sciences, Technological University Dublin, Dublin, Ireland
| | - Edouard I Azzam
- Department of Radiology, Rutgers New Jersey Medical School Cancer Center, Newark, New Jersey
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Sonanini D, Griessinger CM, Schörg BF, Knopf P, Dittmann K, Röcken M, Pichler BJ, Kneilling M. Low-dose total body irradiation facilitates antitumoral Th1 immune responses. Theranostics 2021; 11:7700-7714. [PMID: 34335959 PMCID: PMC8315067 DOI: 10.7150/thno.61459] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 05/16/2021] [Indexed: 12/16/2022] Open
Abstract
CD4+ T helper cells are capable of mediating long-term antitumoral immune responses. We developed a combined immunotherapy (COMBO) using tumor antigen-specific T helper 1 cells (Tag-Th1), dual PD-L1/LAG-3 immune checkpoint blockade, and a low-dose total body irradiation (TBI) of 2 Gy, that was highly efficient in controlling the tumor burden of non-immunogenic RIP1-Tag2 mice with late-stage endogenous pancreatic islet carcinomas. In this study, we aimed to explore the impact of 2 Gy TBI on the treatment efficacy and the underlying mechanisms to boost CD4+ T cell-based immunotherapies. Methods: Heavily progressed RIP1-Tag2 mice underwent COMBO treatment and their survival was compared to a cohort without 2 Gy TBI. Positron emission tomography/computed tomography (PET/CT) with radiolabeled anti-CD3 monoclonal antibodies and flow cytometry were applied to investigate 2 Gy TBI-induced alterations in the biodistribution of endogenous T cells of healthy C3H mice. Migration and homing properties of Cy5-labeled adoptive Tag-Th1 cells were monitored by optical imaging and flow cytometric analyses in C3H and tumor-bearing RIP1-Tag2 mice. Splenectomy or sham-surgery of late-stage RIP1-Tag2 mice was performed before onset of COMBO treatment to elucidate the impact of the spleen on the therapy response. Results: First, we determined a significant longer survival of RIP1-Tag2 mice and an increased CD4+ T cell tumor infiltrate when 2 Gy TBI was applied in addition to Tag-Th1 cell PD-L1/LAG-3 treatment. In non-tumor-bearing C3H mice, TBI induced a moderate host lymphodepletion and a tumor antigen-independent accumulation of Tag-Th1 cells in lymphoid and non-lymphoid organs. In RIP1-Tag2, we found increased numbers of effector memory-like Tag-Th1 and endogenous CD4+ T cells in the pancreatic tumor tissue after TBI, accompanied by a tumor-specific Th1-driven immune response. Furthermore, the spleen negatively regulated T cell effector function by upregulation PD-1/LAG-3/TIM-3 immune checkpoints, providing a further rationale for this combined treatment approach. Conclusion: Low-dose TBI represents a powerful tool to foster CD4+ T cell-based cancer immunotherapies by favoring Th1-driven antitumoral immunity. As TBI is a clinically approved and well-established technique it might be an ideal addition for adoptive cell therapy with CD4+ T cells in the clinical setting.
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Out-of-Field Hippocampus from Partial-Body Irradiated Mice Displays Changes in Multi-Omics Profile and Defects in Neurogenesis. Int J Mol Sci 2021; 22:ijms22084290. [PMID: 33924260 PMCID: PMC8074756 DOI: 10.3390/ijms22084290] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/15/2021] [Accepted: 04/15/2021] [Indexed: 12/11/2022] Open
Abstract
The brain undergoes ionizing radiation exposure in many clinical situations, particularly during radiotherapy for brain tumors. The critical role of the hippocampus in the pathogenesis of radiation-induced neurocognitive dysfunction is well recognized. The goal of this study is to test the potential contribution of non-targeted effects in the detrimental response of the hippocampus to irradiation and to elucidate the mechanisms involved. C57Bl/6 mice were whole body (WBI) or partial body (PBI) irradiated with 0.1 or 2.0 Gy of X-rays or sham irradiated. PBI consisted of the exposure of the lower third of the mouse body, whilst the upper two thirds were shielded. Hippocampi were collected 15 days or 6 months post-irradiation and a multi-omics approach was adopted to assess the molecular changes in non-coding RNAs, proteins and metabolic levels, as well as histological changes in the rate of hippocampal neurogenesis. Notably, at 2.0 Gy the pattern of early molecular and histopathological changes induced in the hippocampus at 15 days following PBI were similar in quality and quantity to the effects induced by WBI, thus providing a proof of principle of the existence of out-of-target radiation response in the hippocampus of conventional mice. We detected major alterations in DAG/IP3 and TGF-β signaling pathways as well as in the expression of proteins involved in the regulation of long-term neuronal synaptic plasticity and synapse organization, coupled with defects in neural stem cells self-renewal in the hippocampal dentate gyrus. However, compared to the persistence of the WBI effects, most of the PBI effects were only transient and tended to decrease at 6 months post-irradiation, indicating important mechanistic difference. On the contrary, at low dose we identified a progressive accumulation of molecular defects that tended to manifest at later post-irradiation times. These data, indicating that both targeted and non-targeted radiation effects might contribute to the pathogenesis of hippocampal radiation-damage, have general implications for human health.
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Mohamed HA, Said RS. Coenzyme Q10 attenuates inflammation and fibrosis implicated in radiation enteropathy through suppression of NF-kB/TGF-β/MMP-9 pathways. Int Immunopharmacol 2021; 92:107347. [PMID: 33418245 DOI: 10.1016/j.intimp.2020.107347] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 12/23/2020] [Accepted: 12/24/2020] [Indexed: 01/01/2023]
Abstract
Radiation enteropathy is one the most common clinical issue for patients receiving radiotherapy for abdominal/pelvic tumors which severely affect the quality of life of cancer patients due to dysplastic lesions (ischemia, ulcer, or fibrosis) that aggravate the radiation damage. Herein, this study demonstrated the prophylactic role of coenzyme Q10 (CoQ10), a powerful antioxidant, against radiotherapy-induced gastrointestinal injury. Male Sprague Dawley rats were divided into four groups: group 1 was defined as control, and group 2 was the irradiated group. Group 3 and 4 were CoQ10 control and radiation plus CoQ10 groups, respectively. CoQ10 (10 mg/kg) was orally administered for 10 days before 10 Gy whole-body radiation and was continued for 4 days post-irradiation. CoQ10 administration protected rats delivered a lethal dose of ϒ-radiation from changes in crypt-villus structures and promoted regeneration of the intestinal epithelium. CoQ10 attenuated radiation-induced oxidative stress by decreasing lipid peroxidation and increasing the antioxidant enzyme catalase activity and reduced glutathione level. CoQ10 also counteracts inflammatory response mediated after radiation exposure through downregulating intestinal NF-ĸB expression which subsequently decreased the level of inflammatory cytokine IL-6 and the expression of COX-2. Radiation-induced intestinal fibrosis confirmed via Masson's trichrome staining occurred through upregulating transforming growth factor (TGF)-β1 and matrix metalloproteinase (MMP)-9 expression, while CoQ10 administration significantly diminishes these effects which further confirmed the anti-fibrotic property of CoQ10. Therefore, CoQ10 is a promising radioprotector that could prevent intestinal complications and enhance the therapeutic ratio of radiotherapy in patients with pelvic tumors through suppressing the NF-kB/TGF-β1/MMP-9 signaling pathway.
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Affiliation(s)
- Heba A Mohamed
- Department of Drug Radiation Research, National Center for Radiation Research & Technology, Atomic Energy Authority, Cairo, Egypt
| | - Riham S Said
- Department of Drug Radiation Research, National Center for Radiation Research & Technology, Atomic Energy Authority, Cairo, Egypt.
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5
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Hu S, Shao C. Research progress of radiation induced bystander and abscopal effects in normal tissue. RADIATION MEDICINE AND PROTECTION 2020. [DOI: 10.1016/j.radmp.2020.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
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Farias VDA, Tovar I, del Moral R, O'Valle F, Expósito J, Oliver FJ, Ruiz de Almodóvar JM. Enhancing the Bystander and Abscopal Effects to Improve Radiotherapy Outcomes. Front Oncol 2020; 9:1381. [PMID: 31970082 PMCID: PMC6960107 DOI: 10.3389/fonc.2019.01381] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 11/22/2019] [Indexed: 12/12/2022] Open
Abstract
In this paper, we summarize published articles and experiences related to the attempt to improve radiotherapy outcomes and, thus, to personalize the radiation treatment according to the individual characteristics of each patient. The evolution of ideas and the study of successively published data have led us to envisage new biophysical models for the interpretation of tumor and healthy normal tissue response to radiation. In the development of the model, we have shown that when mesenchymal stem cells (MSCs) and radiotherapy are administered simultaneously in experimental radiotherapy on xenotumors implanted in a murine model, the results of the treatment show the existence of a synergic mechanism that is able to enhance the local and systemic actions of the radiation both on the treated tumor and on its possible metastasis. We are convinced that, due to the physical hallmarks that characterize the neoplastic tissues, the physical-chemical tropism of MSCs, and the widespread functions of macromolecules, proteins, and exosomes released from activated MSCs, the combination of radiotherapy plus MSCs used intratumorally has the effect of counteracting the pro-tumorigenic and pro-metastatic signals that contribute to the growth, spread, and resistance of the tumor cells. Therefore, we have concluded that MSCs are appropriate for therapeutic use in a clinical trial for rectal cancer combined with radiotherapy, which we are going to start in the near future.
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Affiliation(s)
- Virgínea de Araújo Farias
- Centro de Investigación Biomédica, Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, PTS Granada, Granada, Spain
- CIBERONC (Instituto de Salud Carlos III), Granada, Spain
- Instituto de Parasitología y Biomedicina “López Neyra”, Consejo Superior de Investigaciones Científicas, PTS Granada, Granada, Spain
| | - Isabel Tovar
- Complejo Hospitalario de Granada, Servicio Andaluz de Salud, PTS Granada, Granada, Spain
| | - Rosario del Moral
- Complejo Hospitalario de Granada, Servicio Andaluz de Salud, PTS Granada, Granada, Spain
| | - Francisco O'Valle
- Centro de Investigación Biomédica, Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, PTS Granada, Granada, Spain
- CIBERONC (Instituto de Salud Carlos III), Granada, Spain
- Instituto de Parasitología y Biomedicina “López Neyra”, Consejo Superior de Investigaciones Científicas, PTS Granada, Granada, Spain
- Departamento de Anatomía Patológica, Facultad de Medicina, Universidad de Granada, PTS Granada, Granada, Spain
| | - José Expósito
- Complejo Hospitalario de Granada, Servicio Andaluz de Salud, PTS Granada, Granada, Spain
| | - Francisco Javier Oliver
- CIBERONC (Instituto de Salud Carlos III), Granada, Spain
- Instituto de Parasitología y Biomedicina “López Neyra”, Consejo Superior de Investigaciones Científicas, PTS Granada, Granada, Spain
| | - José Mariano Ruiz de Almodóvar
- Centro de Investigación Biomédica, Instituto Universitario de Investigación en Biopatología y Medicina Regenerativa, PTS Granada, Granada, Spain
- CIBERONC (Instituto de Salud Carlos III), Granada, Spain
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7
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Naqvi SMH, Kim Y. Epigenetic modification by galactic cosmic radiation as a risk factor for lung cancer: real world data issues. Transl Lung Cancer Res 2019; 8:116-118. [PMID: 31106121 DOI: 10.21037/tlcr.2019.01.01] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
| | - Youngchul Kim
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA
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Yamashita T, Kato T, Isogai T, Gu Y, Ma N. Protective Effects of Taurine on the Radiation Exposure Induced Cellular Damages in the Mouse Intestine. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1155:443-450. [DOI: 10.1007/978-981-13-8023-5_41] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Lierova A, Jelicova M, Nemcova M, Proksova M, Pejchal J, Zarybnicka L, Sinkorova Z. Cytokines and radiation-induced pulmonary injuries. JOURNAL OF RADIATION RESEARCH 2018; 59:709-753. [PMID: 30169853 PMCID: PMC6251431 DOI: 10.1093/jrr/rry067] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 07/11/2018] [Indexed: 05/20/2023]
Abstract
Radiation therapy is one of the most common treatment strategies for thorax malignancies. One of the considerable limitations of this therapy is its toxicity to normal tissue. The lung is the major dose-limiting organ for radiotherapy. That is because ionizing radiation produces reactive oxygen species that induce lesions, and not only is tumor tissue damaged, but overwhelming inflammatory lung damage can occur in the alveolar epithelium and capillary endothelium. This damage may result in radiation-induced pneumonitis and/or fibrosis. While describing the lung response to irradiation generally, the main focus of this review is on cytokines and their roles and functions within the individual stages. We discuss the relationship between radiation and cytokines and their direct and indirect effects on the formation and development of radiation injuries. Although this topic has been intensively studied and discussed for years, we still do not completely understand the roles of cytokines. Experimental data on cytokine involvement are fragmented across a large number of experimental studies; hence, the need for this review of the current knowledge. Cytokines are considered not only as molecular factors involved in the signaling network in pathological processes, but also for their diagnostic potential. A concentrated effort has been made to identify the significant immune system proteins showing positive correlation between serum levels and tissue damages. Elucidating the correlations between the extent and nature of radiation-induced pulmonary injuries and the levels of one or more key cytokines that initiate and control those damages may improve the efficacy of radiotherapy in cancer treatment and ultimately the well-being of patients.
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Affiliation(s)
- Anna Lierova
- Department of Radiobiology, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
| | - Marcela Jelicova
- Department of Radiobiology, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
| | - Marketa Nemcova
- Department of Radiobiology, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
| | - Magdalena Proksova
- Department of Molecular Pathology and Biology, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
| | - Jaroslav Pejchal
- Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
| | - Lenka Zarybnicka
- Department of Radiobiology, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
| | - Zuzana Sinkorova
- Department of Radiobiology, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
- Corresponding author. Department of Radiobiology, Faculty of Military Health Sciences, University of Defence in Brno, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Tel.: +420 973 253 219.
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Leung HW, Wang SY, Jin-Jhih H, Chan AL. Abscopal effect of radiation on bone metastases of breast cancer: A case report. Cancer Biol Ther 2017; 19:20-24. [PMID: 29281479 DOI: 10.1080/15384047.2017.1394545] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The abscopal effect is defined as the clearance of distant tumors after applying localized irradiation to a particular tumor site. It has been proposed that a mechanism for the abscopal effect might be the activation of the immune system, which leads to immunogenic tumor cell death. Here, we describe a woman with advanced breast cancer that received modified ablative radiation therapy that targeted her primary breast tumor. She experienced an apparent regression of metastatic mass in the thoracic spine. This case supported the hypothesis that the abscopal effect might be attributable to an activation of the systemic immune response.
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Affiliation(s)
- Henry Wc Leung
- a Department of Radiation Oncology , An-Nan Hospital, China Medical University , No. 66, Sec. 2, Changhe Rd., Annan Dist., Tainan , Taiwan
| | - Shyh-Yau Wang
- b Department of Radiology , An Nan Hospital, China Medical University , No. 66, Sec. 2, Changhe Rd., Annan Dist., Tainan , Taiwan
| | - Huang Jin-Jhih
- a Department of Radiation Oncology , An-Nan Hospital, China Medical University , No. 66, Sec. 2, Changhe Rd., Annan Dist., Tainan , Taiwan.,c Department of Pharmacy , An Nan Hospital, China Medical University , No. 66, Sec. 2, Changhe Rd., Annan Dist., Tainan , Taiwan
| | - Agnes Lf Chan
- c Department of Pharmacy , An Nan Hospital, China Medical University , No. 66, Sec. 2, Changhe Rd., Annan Dist., Tainan , Taiwan
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Alteration of murine duodenal morphology and redox signalling events by reactive oxygen species generated after whole body γ-irradiation and its prevention by ferulic acid. Free Radic Res 2017; 51:886-910. [DOI: 10.1080/10715762.2017.1388916] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Tong L, Zhu G, Wang J, Sun R, He F, Zhai J. Suppressing angiogenesis regulates the irradiation-induced stimulation on osteoclastogenesis in vitro. J Cell Physiol 2017; 233:3429-3438. [PMID: 28941279 DOI: 10.1002/jcp.26196] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 09/15/2017] [Indexed: 01/08/2023]
Abstract
Ionizing radiation-induced bone loss is a potential health concern in radiotherapy, occupational exposure, and astronauts. Although impaired bone vasculature and reduced proliferation of bone-forming osteoblasts has been implicated in this process, it has not been clearly characterized that whether radiation affects the growth of bone-resorbing osteoclasts. The molecular crosstalk between different cell populations in the skeletal system has not yet been elucidated in detail, especially between the increased bone resorption at early stage of post-irradiation and bone marrow-derived endothelial progenitor cells (BM-EPCs). In order to further understand the mechanisms involved in radiation-induced bone loss at the cellular level, we assessed the effects of irradiation on angiogenesis of BM-EPCs and osteoclastogenesis of receptor activator for nuclear factor-κB ligand (RANKL)-stimulated RAW 264.7 cells and crosstalk between these cell populations. We herein found significantly dysfunction of BM-EPCs in response to irradiation at a dose of 2 Gy, including inhibited proliferation, migration, tube-forming abilities, and downregulated expression of pro-angiogenesis vascular endothelial growth factors A (VEGF A). Meanwhile, we observed that irradiation promoted osteoclastogenesis of RANKL-stimulated RAW 264.7 cells directly or indirectly. These results provide quantitative evidences of irradiation induced osteoclastogenesis at a cellular level, and strongly suggest the involvement of osteoclastogenesis, angiogenesis and crosstalk between bone marrow cells in the radiation-induced bone loss. This study may provide new insights for the early diagnosis and intervention of bone loss post-irradiation.
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Affiliation(s)
- Ling Tong
- Institute of Radiation Medicine, Fudan University, Shanghai, P.R. China
| | - Guoying Zhu
- Institute of Radiation Medicine, Fudan University, Shanghai, P.R. China
| | - Jianping Wang
- Institute of Radiation Medicine, Fudan University, Shanghai, P.R. China
| | - Ruilian Sun
- Institute of Radiation Medicine, Fudan University, Shanghai, P.R. China
| | - Feilong He
- Institute of Radiation Medicine, Fudan University, Shanghai, P.R. China
| | - Jianglong Zhai
- Institute of Radiation Medicine, Fudan University, Shanghai, P.R. China
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Diegeler S, Hellweg CE. Intercellular Communication of Tumor Cells and Immune Cells after Exposure to Different Ionizing Radiation Qualities. Front Immunol 2017. [PMID: 28638385 PMCID: PMC5461334 DOI: 10.3389/fimmu.2017.00664] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Ionizing radiation can affect the immune system in many ways. Depending on the situation, the whole body or parts of the body can be acutely or chronically exposed to different radiation qualities. In tumor radiotherapy, a fractionated exposure of the tumor (and surrounding tissues) is applied to kill the tumor cells. Currently, mostly photons, and also electrons, neutrons, protons, and heavier particles such as carbon ions, are used in radiotherapy. Tumor elimination can be supported by an effective immune response. In recent years, much progress has been achieved in the understanding of basic interactions between the irradiated tumor and the immune system. Here, direct and indirect effects of radiation on immune cells have to be considered. Lymphocytes for example are known to be highly radiosensitive. One important factor in indirect interactions is the radiation-induced bystander effect which can be initiated in unexposed cells by expression of cytokines of the irradiated cells and by direct exchange of molecules via gap junctions. In this review, we summarize the current knowledge about the indirect effects observed after exposure to different radiation qualities. The different immune cell populations important for the tumor immune response are natural killer cells, dendritic cells, and CD8+ cytotoxic T-cells. In vitro and in vivo studies have revealed the modulation of their functions due to ionizing radiation exposure of tumor cells. After radiation exposure, cytokines are produced by exposed tumor and immune cells and a modulated expression profile has also been observed in bystander immune cells. Release of damage-associated molecular patterns by irradiated tumor cells is another factor in immune activation. In conclusion, both immune-activating and -suppressing effects can occur. Enhancing or inhibiting these effects, respectively, could contribute to modified tumor cell killing after radiotherapy.
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Affiliation(s)
- Sebastian Diegeler
- Division of Radiation Biology, Institute of Aerospace Medicine, German Aerospace Center (DLR), Köln, Germany
| | - Christine E Hellweg
- Division of Radiation Biology, Institute of Aerospace Medicine, German Aerospace Center (DLR), Köln, Germany
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Yuce Sari S, Yazici G, Yuce D, Karabulut E, Cengiz M, Ozyigit G. The effect of glutamine and arginine-enriched nutritional support on quality of life in head and neck cancer patients treated with IMRT. Clin Nutr ESPEN 2016; 16:30-35. [PMID: 28531452 DOI: 10.1016/j.clnesp.2016.08.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Revised: 06/24/2016] [Accepted: 08/16/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND AND AIMS Oral mucositis and esophagitis are common acute toxicities of radiotherapy (RT) for head and neck cancer (HNC). In order to decrease the rates of these toxicities, we compared quality of life in HNC patients that did and did not receive a glutamine and arginine-enriched solution (GAES) during RT. METHODS A total of 29 patients received intensity-modulated radiotherapy (IMRT); 15 used GAES b.i.d. during the treatment, and a matched cohort of 14 patients did not. Patients were administered the EORTC QLQ-C30, QLQ-H&N35 and QLQ-OES18 questionnaires on the 1st, 15th, and last days of IMRT. RESULTS The global health status, functional and symptom scale scores were similar in both groups on the 1st day of IMRT. On the 15th and last days, the scores of social functions (p = 0.01 and p = 0.012), pain (p = 0.002 and p = 0.002), appetite (p = 0.01 and p = 0.02), dry mouth (p = 0.001 and p = 0.03), sticky saliva (p = 0.003 and p = 0.04), trouble with taste (p = 0.001 and p = 0.03), trouble with social eating (p = 0.004 and p = 0.006), and swallowing problems (p = 0.002 and p = 0.046) were significantly worse in the control group. CONCLUSIONS Quality of life is negatively affected by IMRT; however, use of GAES may mediate this negative effect.
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Affiliation(s)
- Sezin Yuce Sari
- Hacettepe University, Faculty of Medicine, Department of Radiation Oncology, Ankara, Turkey.
| | - Gozde Yazici
- Hacettepe University, Faculty of Medicine, Department of Radiation Oncology, Ankara, Turkey
| | - Deniz Yuce
- Hacettepe University, Faculty of Medicine, Department of Preventive Oncology, Ankara, Turkey
| | - Erdem Karabulut
- Hacettepe University, Faculty of Medicine, Department of Biostatistics, Ankara, Turkey
| | - Mustafa Cengiz
- Hacettepe University, Faculty of Medicine, Department of Radiation Oncology, Ankara, Turkey
| | - Gokhan Ozyigit
- Hacettepe University, Faculty of Medicine, Department of Radiation Oncology, Ankara, Turkey
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Menon N, Rogers CJ, Lukaszewicz AI, Axtelle J, Yadav M, Song F, Chakravarti A, Jacob NK. Detection of Acute Radiation Sickness: A Feasibility Study in Non-Human Primates Circulating miRNAs for Triage in Radiological Events. PLoS One 2016; 11:e0167333. [PMID: 27907140 PMCID: PMC5132176 DOI: 10.1371/journal.pone.0167333] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Accepted: 11/11/2016] [Indexed: 11/19/2022] Open
Abstract
Development of biomarkers capable of estimating absorbed dose is critical for effective triage of affected individuals after radiological events. Levels of cell-free circulating miRNAs in plasma were compared for dose-response analysis in non-human primates (NHP) exposed to lethal (6.5 Gy) and sub-lethal (1 and 3 Gy) doses over a 7 day period. The doses and test time points were selected to mimic triage needs in the event of a mass casualty radiological event. Changes in miRNA abundance in irradiated animals were compared to a non-irradiated cohort and a cohort experiencing acute inflammation response from exposure to lipopolysaccharide (LPS). An amplification-free, hybridization-based direct digital counting method was used for evaluation of changes in microRNAs in plasma from all animals. Consistent with previous murine studies, circulating levels of miR-150-5p exhibited a dose- and time-dependent decrease in plasma. Furthermore, plasma miR-150-5p levels were found to correlate well with lymphocyte and neutrophil depletion kinetics. Additionally, plasma levels of several other evolutionarily and functionally conserved miRNAs were found altered as a function of dose and time. Interestingly, miR-574-5p exhibited a distinct, dose-dependent increase 24 h post irradiation in NHPs with lethal versus sub-lethal exposure before returning to the baseline level by day 3. This particular miRNA response was not detected in previous murine studies but was observed in animals exposed to LPS, indicating distinct molecular and inflammatory responses. Furthermore, an increase in low-abundant miR-126, miR-144, and miR-21 as well as high-abundant miR-1-3p and miR-206 was observed in irradiated animals on day 3 and/or day 7. The data from this study could be used to develop a multi-marker panel with known tissue-specific origin that could be used for developing rapid assays for dose assessment and evaluation of radiation injury on multiple organs. Furthermore this approach may be utilized to screen for tissue toxicity in patients who receive myeloablative and therapeutic radiation.
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Affiliation(s)
- Naresh Menon
- ChromoLogic LLC, Monrovia, California, United States of America
| | | | | | - James Axtelle
- ChromoLogic LLC, Monrovia, California, United States of America
| | - Marshleen Yadav
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center Columbus, Ohio, United States of America
| | - Feifei Song
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center Columbus, Ohio, United States of America
| | - Arnab Chakravarti
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center Columbus, Ohio, United States of America
| | - Naduparambil K. Jacob
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center Columbus, Ohio, United States of America
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16
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Lock M, Muinuddin A, Kocha WI, Dinniwell R, Rodrigues G, D'souza D. Abscopal Effects: Case Report and Emerging Opportunities. Cureus 2015; 7:e344. [PMID: 26623199 PMCID: PMC4641721 DOI: 10.7759/cureus.344] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The abscopal effect is a phenomenon observed in the treatment of metastatic cancer where localized irradiation of a particular tumor site causes a response in a site distant to the irradiated volume. The mechanisms of the abscopal effect are speculated to be of several origins, including distant effects on p53, elaboration of inflammatory agents including cytokines, and, most recently, secondary to immune mechanisms. In this case report, we present a rare report of a patient with hepatocellular carcinoma with lung metastases who, after receiving radiation treatment to the liver, had a treatment response in the liver and a complete response in the lung. Recent advances in the understanding of the primary role of immune-modulated cytotoxicity, especially with the success of immune checkpoint inhibitors, have the potential to turn the abscopal effect from a rare phenomenon into a tool to guide antineoplastic therapy and provide a new line of research.
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Affiliation(s)
- Michael Lock
- Department of Radiation Oncology, London Regional Cancer Program, London, Ontario, CA; Schulich School of Medicine & Dentistry, Western University, London, Ontario, CA
| | | | | | - Robert Dinniwell
- Cancer Clinical Research Unit (CCRU), Princess Margaret Cancer Centre
| | - George Rodrigues
- Department of Radiation Oncology, London Regional Cancer Program, London, Ontario, CA; Schulich School of Medicine & Dentistry, Western University, London, Ontario, CA
| | - David D'souza
- Department of Radiation Oncology, London Regional Cancer Program, London, Ontario, CA; Schulich School of Medicine & Dentistry, Western University, London, Ontario, CA
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17
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Abramyuk A, Hietschold V, Appold S, von Kummer R, Abolmaali N. Radiochemotherapy-induced changes of tumour vascularity and blood supply estimated by dynamic contrast-enhanced CT and fractal analysis in malignant head and neck tumours. Br J Radiol 2015; 88:20140412. [PMID: 25412001 DOI: 10.1259/bjr.20140412] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
OBJECTIVE To investigate radiochemotherapy (RChT)-induced changes of transfer coefficient (K(trans)) and relative tumour blood volume (rTBV) estimated by dynamic contrast-enhanced CT (DCE-CT) and fractal analysis in head and neck tumours (HNTs). METHODS DCE-CT was performed in 15 patients with inoperable HNTs before RChT, and after 2 and 5 weeks. The dynamics of K(trans) and rTBV as well as lacunarity, slope of log(lacunarity) vs log(box size), and fractal dimension were compared with tumour behaviour during RChT and in the 24-month follow-up. RESULTS In 11 patients, an increase of K(trans) and/or rTBV after 20 Gy followed by a decrease of both parameters after 50 Gy was noted. Except for one local recurrence, no tumour residue was found during the follow-up. In three patients with partial tumour reduction during RChT, a decrease of K(trans) accompanied by an increase in rTBV between 20 and 50 Gy was detected. In one patient with continuous elevation of both parameters, tumour progressed after RChT. Pre-treatment difference in intratumoral heterogeneity with its decline under RChT for the responders vs non-responders was observed. CONCLUSION Initial growth of K(trans) and/or rTBV followed by further reduction of both parameters along with the decline of the slope of log(lacunarity) vs log(box size) was associated with positive radiochemotherapeutic response. Increase of K(trans) and/or rTBV under RChT indicated a poor outcome. ADVANCES IN KNOWLEDGE The modification of K(trans) and rTBV as measured by DCE-CT may be applied for the assessment of tumour sensitivity to chose RChT regimen and, consequently, to reveal clinical impact allowing individualization of RChT strategy in patients with HNT.
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Affiliation(s)
- A Abramyuk
- 1 Department of Neuroradiology, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, Germany
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18
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Sato T, Kinoshita M, Yamamoto T, Ito M, Nishida T, Takeuchi M, Saitoh D, Seki S, Mukai Y. Treatment of irradiated mice with high-dose ascorbic acid reduced lethality. PLoS One 2015; 10:e0117020. [PMID: 25651298 PMCID: PMC4317183 DOI: 10.1371/journal.pone.0117020] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 12/17/2014] [Indexed: 02/01/2023] Open
Abstract
Ascorbic acid is an effective antioxidant and free radical scavenger. Therefore, it is expected that ascorbic acid should act as a radioprotectant. We investigated the effects of post-radiation treatment with ascorbic acid on mouse survival. Mice received whole body irradiation (WBI) followed by intraperitoneal administration of ascorbic acid. Administration of 3 g/kg of ascorbic acid immediately after exposure significantly increased mouse survival after WBI at 7 to 8 Gy. However, administration of less than 3 g/kg of ascorbic acid was ineffective, and 4 or more g/kg was harmful to the mice. Post-exposure treatment with 3 g/kg of ascorbic acid reduced radiation-induced apoptosis in bone marrow cells and restored hematopoietic function. Treatment with ascorbic acid (3 g/kg) up to 24 h (1, 6, 12, or 24 h) after WBI at 7.5 Gy effectively improved mouse survival; however, treatments beyond 36 h were ineffective. Two treatments with ascorbic acid (1.5 g/kg × 2, immediately and 24 h after radiation, 3 g/kg in total) also improved mouse survival after WBI at 7.5 Gy, accompanied with suppression of radiation-induced free radical metabolites. In conclusion, administration of high-dose ascorbic acid might reduce radiation lethality in mice even after exposure.
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Affiliation(s)
- Tomohito Sato
- Military Medicine Research Unit, Test and Evaluation Command, Ground Self-Defense Force, Setagaya, Tokyo, Japan
| | - Manabu Kinoshita
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Saitama, Japan
- * E-mail:
| | - Tetsuo Yamamoto
- Military Medicine Research Unit, Test and Evaluation Command, Ground Self-Defense Force, Setagaya, Tokyo, Japan
| | - Masataka Ito
- Department of Developmental Anatomy and Regenerative Biology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Takafumi Nishida
- Military Medicine Research Unit, Test and Evaluation Command, Ground Self-Defense Force, Setagaya, Tokyo, Japan
| | - Masaru Takeuchi
- Department of Ophthalmology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Daizoh Saitoh
- Division of Traumatology, Research Institute, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Shuhji Seki
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Yasuo Mukai
- Military Medicine Research Unit, Test and Evaluation Command, Ground Self-Defense Force, Setagaya, Tokyo, Japan
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19
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Mirzoeva S, Paunesku T, Wanzer MB, Shirvan A, Kaempfer R, Woloschak GE, Small W. Single administration of p2TA (AB103), a CD28 antagonist peptide, prevents inflammatory and thrombotic reactions and protects against gastrointestinal injury in total-body irradiated mice. PLoS One 2014; 9:e101161. [PMID: 25054224 PMCID: PMC4108308 DOI: 10.1371/journal.pone.0101161] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Accepted: 06/03/2014] [Indexed: 01/19/2023] Open
Abstract
The goal of this study was to elucidate the action of the CD28 mimetic peptide p2TA (AB103) that attenuates an excessive inflammatory response in mitigating radiation-induced inflammatory injuries. BALB/c and A/J mice were divided into four groups: Control (C), Peptide (P; 5 mg/kg of p2TA peptide), Radiation (R; total body irradiation with 8 Gy γ-rays), and Radiation + Peptide (RP; irradiation followed by p2TA peptide 24 h later). Gastrointestinal tissue damage was evaluated by analysis of jejunum histopathology and immunohistochemistry for cell proliferation (Cyclin D1) and inflammation (COX-2) markers, as well as the presence of macrophages (F4/80). Pro-inflammatory cytokines IL-6 and KC as well as fibrinogen were quantified in plasma samples obtained from the same mice. Our results demonstrated that administration of p2TA peptide significantly reduced the irradiation-induced increase of IL-6 and fibrinogen in plasma 7 days after exposure. Seven days after total body irradiation with 8 Gy of gamma rays numbers of intestinal crypt cells were reduced and villi were shorter in irradiated animals compared to the controls. The p2TA peptide delivery 24 h after irradiation led to improved morphology of villi and crypts, increased Cyclin D1 expression, decreased COX-2 staining and decreased numbers of macrophages in small intestine of irradiated mice. Our study suggests that attenuation of CD28 signaling is a promising therapeutic approach for mitigation of radiation-induced tissue injury.
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Affiliation(s)
- Salida Mirzoeva
- Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Tatjana Paunesku
- Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - M. Beau Wanzer
- Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | | | - Raymond Kaempfer
- Department of Biochemistry and Molecular Biology, Institute of Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | - Gayle E. Woloschak
- Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - William Small
- Department of Radiation Oncology, Loyola University Stritch School of Medicine, Chicago, Illinois, United States of America
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20
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Yagi M, Arentsen L, Shanley RM, Rosen CJ, Kidder LS, Sharkey LC, Yee D, Koizumi M, Ogawa K, Hui SK. A dual-radioisotope hybrid whole-body micro-positron emission tomography/computed tomography system reveals functional heterogeneity and early local and systemic changes following targeted radiation to the murine caudal skeleton. Calcif Tissue Int 2014; 94:544-52. [PMID: 24562595 PMCID: PMC3987955 DOI: 10.1007/s00223-014-9839-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Accepted: 01/17/2014] [Indexed: 12/27/2022]
Abstract
The purpose of this study was to develop a longitudinal non-invasive functional imaging method using a dual-radioisotope hybrid micro-positron emission tomography/computed tomography (PET/CT) scanner in order to assess both the skeletal metabolic heterogeneity and the effect of localized radiation that models therapeutic cancer treatment on marrow and bone metabolism. Skeletally mature BALB/c female mice were given clinically relevant local radiation (16 Gy) to the hind limbs on day 0. Micro-PET/CT acquisition was performed serially for the same mice on days -5 and +2 with FDG and days -4 and +3 with NaF. Serum levels of pro-inflammatory cytokines were measured. Significant differences (p < 0.0001) in marrow metabolism (measured by FDG) and bone metabolism (measured by NaF) were observed among bones before radiation, which demonstrates functional heterogeneity in the marrow and mineralized bone throughout the skeleton. Radiation significantly (p < 0.0001) decreased FDG uptake but increased NaF uptake (p = 0.0314) in both irradiated and non-irradiated bones at early time points. An increase in IL-6 was observed with a significant abscopal (distant) effect on marrow and bone metabolic function. Radiation significantly decreased circulating IGF-1 (p < 0.01). Non-invasive longitudinal imaging with dual-radioisotope micro-PET/CT is feasible to investigate simultaneous changes in marrow and bone metabolic function at local and distant skeletal sites in response to focused radiation injury. Distinct local and remote changes may be affected by several cytokines activated early after local radiation exposure. This approach has the potential for longer-term studies to clarify the effects of radiation on marrow and bone.
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Affiliation(s)
- Masashi Yagi
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
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21
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Camara-Lemarroy CR. Remote ischemic preconditioning as treatment for non-ischemic gastrointestinal disorders: Beyond ischemia-reperfusion injury. World J Gastroenterol 2014; 20:3572-3581. [PMID: 24707140 PMCID: PMC3974524 DOI: 10.3748/wjg.v20.i13.3572] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 10/23/2013] [Accepted: 01/02/2014] [Indexed: 02/06/2023] Open
Abstract
Common gastrointestinal diseases such as radiation enteritis (RE), acute pancreatitis, inflammatory bowel diseases (IBD) and drug-induced hepatotoxicity share pathophysiological mechanisms at the molecular level, mostly involving the activation of many pathways of the immune response, ultimately leading to tissue injury. Increased oxidative stress, inflammatory cytokine release, inflammatory cell infiltration and activation and the up-regulation of inflammatory transcription factors participate in the pathophysiology of these complex entities. Treatment varies in each specific disease, but at least in the cases of RE and IBD immunosuppressors are effective. However, full therapeutic responses are not always achieved. The pathophysiology of ischemia-reperfusion (IR) injury shares many of these mechanisms. Brief and repetitive periods of ischemia in an organ or limb have been shown to protect against subsequent major IR injury in distant organs, a phenomenon called remote ischemic preconditioning (RIP). This procedure has been shown to protect the gut, pancreas and liver by modulating many of the same inflammatory mechanisms. Since RIP is safe and tolerable, and has shown to be effective in some recent clinical trials, I suggest that RIP could be used as a physiologically relevant adjunct treatment for non-ischemic gastrointestinal inflammatory conditions.
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22
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Holley AK, Miao L, St Clair DK, St Clair WH. Redox-modulated phenomena and radiation therapy: the central role of superoxide dismutases. Antioxid Redox Signal 2014; 20:1567-89. [PMID: 24094070 PMCID: PMC3942704 DOI: 10.1089/ars.2012.5000] [Citation(s) in RCA: 101] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
SIGNIFICANCE Ionizing radiation is a vital component in the oncologist's arsenal for the treatment of cancer. Approximately 50% of all cancer patients will receive some form of radiation therapy as part of their treatment regimen. DNA is considered the major cellular target of ionizing radiation and can be damaged directly by radiation or indirectly through reactive oxygen species (ROS) formed from the radiolysis of water, enzyme-mediated ROS production, and ROS resulting from altered aerobic metabolism. RECENT ADVANCES ROS are produced as a byproduct of oxygen metabolism, and superoxide dismutases (SODs) are the chief scavengers. ROS contribute to the radioresponsiveness of normal and tumor tissues, and SODs modulate the radioresponsiveness of tissues, thus affecting the efficacy of radiotherapy. CRITICAL ISSUES Despite its prevalent use, radiation therapy suffers from certain limitations that diminish its effectiveness, including tumor hypoxia and normal tissue damage. Oxygen is important for the stabilization of radiation-induced DNA damage, and tumor hypoxia dramatically decreases radiation efficacy. Therefore, auxiliary therapies are needed to increase the effectiveness of radiation therapy against tumor tissues while minimizing normal tissue injury. FUTURE DIRECTIONS Because of the importance of ROS in the response of normal and cancer tissues to ionizing radiation, methods that differentially modulate the ROS scavenging ability of cells may prove to be an important method to increase the radiation response in cancer tissues and simultaneously mitigate the damaging effects of ionizing radiation on normal tissues. Altering the expression or activity of SODs may prove valuable in maximizing the overall effectiveness of ionizing radiation.
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Affiliation(s)
- Aaron K Holley
- 1 Graduate Center for Toxicology, University of Kentucky , Lexington, Kentucky
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23
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Wang H, Zhang L, Shi Y, Javidiparsijani S, Wang G, Li X, Ouyang W, Zhou J, Zhao L, Wang X, Zhang X, Gao F, Liu J, Luo J, Tang J. Abscopal antitumor immune effects of magnet-mediated hyperthermia at a high therapeutic temperature on Walker-256 carcinosarcomas in rats. Oncol Lett 2014; 7:764-770. [PMID: 24527084 PMCID: PMC3919910 DOI: 10.3892/ol.2014.1803] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 12/20/2013] [Indexed: 11/11/2022] Open
Abstract
The abscopal effect has previously been described in various tumors and is associated with radiation therapy and hyperthermia, with possible underlying mechanisms explaining each observed case. In the present study, we aimed to investigate the antitumor effects of magnet-mediated hyperthermia on Walker-256 carcinosarcomas in rats at two different temperature ranges (42–46°C and 50–55°C). We also aimed to identify whether a higher therapeutic temperature of magnetic-mediated hyperthermia improves the abscopal antitumor effects, where localised irradiation of the tumor causes not only the irradiated tumor to shrink, but also tumors located far from the area of irradiation. Following induction of carcinosarcoma in both sides of the body, magnet-mediated hyperthermia was applied to one side only, leaving the other side as a control. The changes in tumor growth were observed. Our results demonstrated that magnet-mediated hyperthermia at a higher temperature inhibited the growth of carcinosarcoma at the site of treatment. Furthermore, the growth of the carcinosarcoma on the untreated side was also inhibited. The expression levels of proliferating cell nuclear antigen were decreased in the hyperthermia group, which was more significant in the higher temperature test group. Flow cytometric analysis showed an increased number of CD4- and CD8-positive T cells, and enzyme-linked immunosorbent assay showed increased levels of interferon-γ and interleukin-2 in the higher temperature group. These results suggested that magnet-mediated hyperthermia at a higher temperature (50–55°C) can improve the abscopal antitumor effects and stimulate a greater endogenous immune response in carcinosarcoma-bearing rats.
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Affiliation(s)
- Hui Wang
- Department of Radiation Oncology, The Affiliated Hunan Provincial Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China ; Department of Radiation Oncology, The Affiliated Xiangya Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Li Zhang
- Department of Engineering Physics, Tsinghua University Key Laboratory of Particle and Radiation Imaging, Ministry of Education, Haidian, Beijing 100084, P.R. China
| | - Yingrui Shi
- Department of Radiation Oncology, The Affiliated Hunan Provincial Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | | | - Guirong Wang
- Department of Surgery, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Xiao Li
- Department of Radiation Oncology, The Affiliated Xiangya Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Weiwei Ouyang
- Department of Thoracic Oncology, Guizhou Cancer Hospital, Guiyang, Guizhou 550004, P.R. China
| | - Jumei Zhou
- Department of Radiation Oncology, The Affiliated Hunan Provincial Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Lingyun Zhao
- Department of Radiation Oncology, The Affiliated Xiangya Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Xiaowen Wang
- Department of Radiation Oncology, The Affiliated Xiangya Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Xiaodong Zhang
- Department of Radiation Oncology, The Affiliated Xiangya Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Fuping Gao
- Department of Radiation Oncology, The Affiliated Xiangya Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
| | - Jingshi Liu
- Department of Anesthesiology, Hunan Provincial Tumor Hospital, The Affiliated Tumor Hospital of Xiangya Medical School of Central South University, Changsha, Hunan 410013, P.R. China
| | - Junming Luo
- Department of Radiation Oncology, The Affiliated Hunan Provincial Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China ; Department of Pathology, Qinghai Provincial People's Hospital, Xining, Qinghai 810007, P.R. China
| | - Jintian Tang
- Department of Radiation Oncology, The Affiliated Xiangya Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China
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24
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Ito Y, Kinoshita M, Yamamoto T, Sato T, Obara T, Saitoh D, Seki S, Takahashi Y. A combination of pre- and post-exposure ascorbic acid rescues mice from radiation-induced lethal gastrointestinal damage. Int J Mol Sci 2013; 14:19618-35. [PMID: 24084715 PMCID: PMC3821576 DOI: 10.3390/ijms141019618] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Revised: 09/09/2013] [Accepted: 09/13/2013] [Indexed: 12/13/2022] Open
Abstract
The development of an effective therapy for radiation-induced gastrointestinal damage is important, because it is currently a major complication of treatment and there are few effective therapies available. Although we have recently demonstrated that pretreatment with ascorbic acid attenuates lethal gastrointestinal damage in irradiated mice, more than half of mice eventually died, thus indicating that better approach was needed. We then investigated a more effective therapy for radiation-induced gastrointestinal damage. Mice receiving abdominal radiation at 13 Gy were orally administered ascorbic acid (250 mg/kg/day) for three days before radiation (pretreatment), one shot of engulfment (250 mg/kg) at 8 h before radiation, or were administered the agent for seven days after radiation (post-treatment). None of the control mice survived the abdominal radiation at 13 Gy due to severe gastrointestinal damage (without bone marrow damage). Neither pretreatment with ascorbic acid (20% survival), engulfment (20%), nor post-treatment (0%) was effective in irradiated mice. However, combination therapy using ascorbic acid, including pretreatment, engulfment and post-treatment, rescued all of the mice from lethal abdominal radiation, and was accompanied by remarkable improvements in the gastrointestinal damage (100% survival). Omitting post-treatment from the combination therapy with ascorbic acid markedly reduced the mouse survival (20% survival), suggesting the importance of post-treatment with ascorbic acid. Combination therapy with ascorbic acid may be a potent therapeutic tool for radiation-induced gastrointestinal damage.
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Affiliation(s)
- Yasutoshi Ito
- Military Medicine Research Unit, Test and Evaluation Command, Ground Self-Defense Force, 1-2-24 Ikejiri, Setagaya, Tokyo 154-8566, Japan; E-Mails: (Y.I.); (T.Y.); (T.S.); (T.O.); (Y.T.)
| | - Manabu Kinoshita
- Department of Immunology and Microbiology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8613, Japan; E-Mail:
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +81-4-2995-1541; Fax: +81-4-2996-5194
| | - Tetsuo Yamamoto
- Military Medicine Research Unit, Test and Evaluation Command, Ground Self-Defense Force, 1-2-24 Ikejiri, Setagaya, Tokyo 154-8566, Japan; E-Mails: (Y.I.); (T.Y.); (T.S.); (T.O.); (Y.T.)
| | - Tomohito Sato
- Military Medicine Research Unit, Test and Evaluation Command, Ground Self-Defense Force, 1-2-24 Ikejiri, Setagaya, Tokyo 154-8566, Japan; E-Mails: (Y.I.); (T.Y.); (T.S.); (T.O.); (Y.T.)
| | - Takeyuki Obara
- Military Medicine Research Unit, Test and Evaluation Command, Ground Self-Defense Force, 1-2-24 Ikejiri, Setagaya, Tokyo 154-8566, Japan; E-Mails: (Y.I.); (T.Y.); (T.S.); (T.O.); (Y.T.)
| | - Daizoh Saitoh
- Division of Traumatology, Research Institute, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8613, Japan; E-Mail:
| | - Shuhji Seki
- Department of Immunology and Microbiology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8613, Japan; E-Mail:
| | - Yukihiro Takahashi
- Military Medicine Research Unit, Test and Evaluation Command, Ground Self-Defense Force, 1-2-24 Ikejiri, Setagaya, Tokyo 154-8566, Japan; E-Mails: (Y.I.); (T.Y.); (T.S.); (T.O.); (Y.T.)
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25
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Lara PC, López-Peñalver JJ, Farias VDA, Ruiz-Ruiz MC, Oliver FJ, Ruiz de Almodóvar JM. Direct and bystander radiation effects: a biophysical model and clinical perspectives. Cancer Lett 2013; 356:5-16. [PMID: 24045041 DOI: 10.1016/j.canlet.2013.09.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Revised: 09/03/2013] [Accepted: 09/08/2013] [Indexed: 12/12/2022]
Abstract
In planning treatment for each new patient, radiation oncologists pay attention to the aspects that they control. Thus their attention is usually focused on volume and dose. The dilemma for the physician is how to protract the treatment in a way that maximizes control of the tumor and minimizes normal tissue injury. The initial radiation-induced damage to DNA may be a biological indicator of the quantity of energy transferred to the DNA. However, until now the biophysical models proposed cannot explain either the early or the late adverse effects of radiation, and a more general theory appears to be required. The bystander component of tumor cell death after radiotherapy measured in many experimental works highlights the importance of confirming these observations in a clinical situation.
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Affiliation(s)
- Pedro Carlos Lara
- Radiation Oncology Department, Hospital Universitario de Gran Canaria Dr Negrín, Barranco de La Ballena s/n, Las Palmas de Gran Canaria, CP 35010, Spain
| | - Jesús Joaquín López-Peñalver
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Avda. Conocimiento 2, 18016 Granada, Spain
| | - Virgínea de Araújo Farias
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Avda. Conocimiento 2, 18016 Granada, Spain
| | - M Carmen Ruiz-Ruiz
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Avda. Conocimiento 2, 18016 Granada, Spain
| | - Francisco Javier Oliver
- Instituto de Parasitología y Biomedicina López Neyra, CSIC, Avda. Conocimiento 4, 18016 Granada, Spain
| | - José Mariano Ruiz de Almodóvar
- Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Avda. Conocimiento 2, 18016 Granada, Spain; Hospital Universitario San Cecilio, Avda. Dr. Olóriz s/n, 18012 Granada, Spain.
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Spontaneous regression of thoracic metastases while progression of brain metastases after stereotactic radiosurgery and stereotactic body radiotherapy for metastatic renal cell carcinoma: abscopal effect prevented by the blood-brain barrier? Clin Genitourin Cancer 2012; 10:196-8. [PMID: 22409865 DOI: 10.1016/j.clgc.2012.01.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Revised: 01/18/2012] [Accepted: 01/19/2012] [Indexed: 01/06/2023]
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LI XUFANG, ZHU GUOYING, WANG JIANPING, WANG YU. Inhibitory effects of autologous γ-irradiated cell conditioned medium on osteoblasts in vitro. Mol Med Rep 2012; 12:273-80. [DOI: 10.3892/mmr.2015.3354] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Accepted: 01/15/2015] [Indexed: 11/05/2022] Open
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Ozel Turkcu U, Cakmak GK, Demir EO, Bakkal H, Oner MO, Okyay RD, Bassorgun IC, Ciftcioglu MA. The effect of erythropoietin on anastomotic healing of irradiated rats. J INVEST SURG 2011; 25:127-35. [PMID: 22149012 DOI: 10.3109/08941939.2011.611583] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
AIM The aim of the present study is to evaluate the possible protective effects of erythropoietin (EPO) on anastomotic wound healing after preoperative radiotherapy according to its pleiotropic mechanism of action. METHODS Thirty-two male Wistar albino rats were randomized into four groups containing eight rats each: ANAS group, standard resection plus anastomosis; RT+ANAS group, radiation plus standard resection plus anastomosis; ANAS+EPO group, standard resection plus anastomosis plus EPO; RT+ANAS+EPO, radiation plus standard resection plus anastomosis plus EPO. All animals were sacrificed by cardiac puncture, and anastomotic healing was measured by bursting pressure, hydroxyproline (OHP) levels, myeloperoxidase (MPO) activity and histopathological evaluations. Malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), and matrix metalloproteinase-9 (MMP-9) were also measured in serum specimens. RESULTS OHP levels in the RT+ANAS + EPO group were significantly increased compared with other groups (p < .05). In contrast, MPO activity in the RT+ANAS+EPO group was significantly decreased compared with other groups (p < .05). Serum MDA levels were found to be decreased in the ANAS+EPO and RT+ANAS+EPO groups (p < .05). Group comparisons demonstrated that bursting pressure was significantly higher in EPO treated rats (p < .05). The histopathology results revealed that EPO treatment improves anastomotic wound healing though decreased necrosis and inflammatory cell infiltration and increased fibroblast activity. CONCLUSION The findings of the present study indicate that EPO contributes to wound healing and the strength of colon anastomosis following radiation due to its antioxidant and anti-inflammatory effects, but further studies are needed to explore the significance of these effects.
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Hei TK, Zhou H, Chai Y, Ponnaiya B, Ivanov VN. Radiation induced non-targeted response: mechanism and potential clinical implications. Curr Mol Pharmacol 2011; 4:96-105. [PMID: 21143185 DOI: 10.2174/1874467211104020096] [Citation(s) in RCA: 167] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2010] [Indexed: 02/06/2023]
Abstract
Generations of students in radiation biology have been taught that heritable biological effects require direct damage to DNA. Radiation-induced non-targeted/bystander effects represent a paradigm shift in our understanding of the radiobiological effects of ionizing radiation in that extranuclear and extracellular effects may also contribute to the biological consequences of exposure to low doses of radiation. Although radiation induced bystander effects have been well documented in a variety of biological systems, including 3D human tissue samples and whole organisms, the mechanism is not known. There is recent evidence that the NF-κB-dependent gene expression of interleukin 8, interleukin 6, cyclooxygenase-2, tumor necrosis factor and interleukin 33 in directly irradiated cells produced the cytokines and prostaglandin E2 with autocrine/paracrine functions, which further activated signaling pathways and induced NF-κB-dependent gene expression in bystander cells. The observations that heritable DNA alterations can be propagated to cells many generations after radiation exposure and that bystander cells exhibit genomic instability in ways similar to directly hit cells indicate that the low dose radiation response is a complex interplay of various modulating factors. The potential implication of the non-targeted response in radiation induced secondary cancer is discussed. A better understanding of the mechanism of the non-targeted effects will be invaluable to assess its clinical relevance and ways in which the bystander phenomenon can be manipulated to increase therapeutic gain in radiotherapy.
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Affiliation(s)
- Tom K Hei
- Center for Radiological Research, Department of Radiation Oncology, Columbia University Medical Center, Vanderbilt Clinic, New York, USA.
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Jia D, Gaddy D, Suva LJ, Corry PM. Rapid loss of bone mass and strength in mice after abdominal irradiation. Radiat Res 2011; 176:624-35. [PMID: 21859327 DOI: 10.1667/rr2505.1] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Localized irradiation is a common treatment modality for malignancies in the pelvic-abdominal cavity. We report here on the changes in bone mass and strength in mice 7-14 days after abdominal irradiation. Male C57BL/6 mice of 10-12 weeks of age were given a single-dose (0, 5, 10, 15 or 20 Gy) or fractionated (3 Gy × 2 per day × 7.5 days) X rays to the abdomen and monitored daily for up to 14 days. A decrease in the serum bone formation marker and ex vivo osteoblast differentiation was detected 7 days after a single dose of radiation, with little change in the serum bone resorption marker and ex vivo osteoclast formation. A single dose of radiation elicited a loss of bone mineral density (BMD) within 14 days of irradiation. The BMD loss was up to 4.1% in the whole skeleton, 7.3% in tibia, and 7.7% in the femur. Fractionated abdominal irradiation induced similar extents of BMD loss 10 days after the last fraction: 6.2% in the whole skeleton, 5.1% in tibia, and 13.8% in the femur. The loss of BMD was dependent on radiation dose and was more profound in the trabecula-rich regions of the long bones. Moreover, BMD loss in the total skeleton and the femurs progressed with time. Peak load and stiffness in the mid-shaft tibia from irradiated mice were 11.2-14.2% and 11.5-25.0% lower, respectively, than sham controls tested 7 days after a single-dose abdominal irradiation. Our data demonstrate that abdominal irradiation induces a rapid loss of BMD in the mouse skeleton. These effects are bone type- and region-specific but are independent of radiation fractionation. The radiation-induced abscopal damage to the skeleton is manifested by the deterioration of biomechanical properties of the affected bone.
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Affiliation(s)
- Dan Jia
- Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
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Anti-apoptotic, anti-inflammatory, and immunomodulatory activities of 3,3′-diselenodipropionic acid in mice exposed to whole body γ-radiation. Arch Toxicol 2011; 85:1395-405. [DOI: 10.1007/s00204-011-0687-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2010] [Accepted: 02/17/2011] [Indexed: 10/18/2022]
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Kachikwu EL, Iwamoto KS, Liao YP, DeMarco JJ, Agazaryan N, Economou JS, McBride WH, Schaue D. Radiation enhances regulatory T cell representation. Int J Radiat Oncol Biol Phys 2010; 81:1128-35. [PMID: 21093169 DOI: 10.1016/j.ijrobp.2010.09.034] [Citation(s) in RCA: 319] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2010] [Revised: 08/27/2010] [Accepted: 09/03/2010] [Indexed: 12/11/2022]
Abstract
PURPOSE Immunotherapy could be a useful adjunct to standard cytotoxic therapies such as radiation in patients with micrometastatic disease, although successful integration of immunotherapy into treatment protocols will require further understanding of how standard therapies affect the generation of antitumor immune responses. This study was undertaken to evaluate the impact of radiation therapy (RT) on immunosuppressive T regulatory (Treg) cells. METHODS AND MATERIALS Treg cells were identified as a CD4(+)CD25(hi)Foxp3(+) lymphocyte subset, and their fate was followed in a murine TRAMP C1 model of prostate cancer in mice with and without RT. RESULTS CD4(+)CD25(hi)Foxp3(+) Treg cells increased in immune organs after local leg or whole-body radiation. A large part, but not all, of this increase after leg-only irradiation could be ascribed to radiation scatter and Treg cells being intrinsically more radiation resistant than other lymphocyte subpopulations, resulting in their selection. Their functional activity on a per-cell basis was not affected by radiation exposure. Similar findings were made with mice receiving local RT to murine prostate tumors growing in the leg. The importance of the Treg cell population in the response to RT was shown by systemic elimination of Treg cells, which greatly enhanced radiation-induced tumor regression. CONCLUSIONS We conclude that Treg cells are more resistant to radiation than other lymphocytes, resulting in their preferential increase. Treg cells may form an important homeostatic mechanism for tissues injured by radiation, and in a tumor context, they may assist in immune evasion during therapy. Targeting this population may allow enhancement of radiotherapeutic benefit through immune modulation.
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Affiliation(s)
- Evelyn L Kachikwu
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1714, USA
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Drouet M, Hérodin F. Radiation victim management and the haematologist in the future: time to revisit therapeutic guidelines? Int J Radiat Biol 2010; 86:636-48. [PMID: 20597842 DOI: 10.3109/09553001003789604] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE The use of nuclear/radiation devices against the civilian population is now a realistic scenario. Haematopoietic syndrome is the primary therapeutic challenge in the case of whole body acute exposure over 2 Grays (Gy) whereas burns and combined injuries would be frequently observed in myelo-suppressed patients. Optimisation of scoring and treatments are important goals to achieve. CONCLUSION The European Response Category (RC) concept represents an attempt to integratively assess haematological/extrahematological radiation-induced lesions. Based on the frequently observed heterogeneity of bone marrow damage in accidental/intentional irradiations, the stimulation of residual stem cells using granulocyte Colony-stimulating factor remains the therapeutic standard after exposure to less than the lethal dose 50 % (Haematopoietic[H] score 3-H3). Allogeneic stem cell transplantation is indicated in case of medullary eradication (Haematopoietic score 4-H4) whereas extramedullary toxicity may determine the outcome. Especially in case of numerous casualties exhibiting acute radiation syndrome, the administration of survival factor combinations remains questionable, at least as a palliative treatment. In addition pleiotropic cytokines injection such as erythropoietin and keratinocyte growth factor and grafting multipotent mesenchymal stem cells - from underexposed bone marrow areas or fat tissues - could be proposed to prevent multiple organ failure syndrome development. Multi-disciplinary teams should be prepared to manage such patients.
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Jia D, Koonce NA, Griffin RJ, Jackson C, Corry PM. Prevention and mitigation of acute death of mice after abdominal irradiation by the antioxidant N-acetyl-cysteine (NAC). Radiat Res 2010; 173:579-89. [PMID: 20426657 DOI: 10.1667/rr2030.1] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Gastrointestinal (GI) injury is a major cause of acute death after total-body exposure to large doses of ionizing radiation, but the cellular and molecular explanations for GI death remain dubious. To address this issue, we developed a murine abdominal irradiation model. Mice were irradiated with a single dose of X rays to the abdomen, treated with daily s.c. injection of N-acetyl-l-cysteine (NAC) or vehicle for 7 days starting either 4 h before or 2 h after irradiation, and monitored for up to 30 days. Separately, mice from each group were assayed 6 days after irradiation for bone marrow reactive oxygen species (ROS), ex vivo colony formation of bone marrow stromal cells, and histological changes in the duodenum. Irradiation of the abdomen caused dose-dependent weight loss and mortality. Radiation-induced acute death was preceded not only by a massive loss of duodenal villi but also, surprisingly, abscopal suppression of stromal cells and elevation of ROS in the nonirradiated bone marrow. NAC diminished these radiation-induced changes and improved 10- and 30-day survival rates to >50% compared with <5% in vehicle-treated controls. Our data establish a central role for abscopal stimulation of bone marrow ROS in acute death in mice after abdominal irradiation.
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Affiliation(s)
- Dan Jia
- Department of Radiation Oncology, University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas 72205, USA
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Williams JP, Brown SL, Georges GE, Hauer-Jensen M, Hill RP, Huser AK, Kirsch DG, Macvittie TJ, Mason KA, Medhora MM, Moulder JE, Okunieff P, Otterson MF, Robbins ME, Smathers JB, McBride WH. Animal models for medical countermeasures to radiation exposure. Radiat Res 2010; 173:557-78. [PMID: 20334528 DOI: 10.1667/rr1880.1] [Citation(s) in RCA: 329] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Since September 11, 2001, there has been the recognition of a plausible threat from acts of terrorism, including radiological or nuclear attacks. A network of Centers for Medical Countermeasures against Radiation (CMCRs) has been established across the U.S.; one of the missions of this network is to identify and develop mitigating agents that can be used to treat the civilian population after a radiological event. The development of such agents requires comparison of data from many sources and accumulation of information consistent with the "Animal Rule" from the Food and Drug Administration (FDA). Given the necessity for a consensus on appropriate animal model use across the network to allow for comparative studies to be performed across institutions, and to identify pivotal studies and facilitate FDA approval, in early 2008, investigators from each of the CMCRs organized and met for an Animal Models Workshop. Working groups deliberated and discussed the wide range of animal models available for assessing agent efficacy in a number of relevant tissues and organs, including the immune and hematopoietic systems, gastrointestinal tract, lung, kidney and skin. Discussions covered the most appropriate species and strains available as well as other factors that may affect differential findings between groups and institutions. This report provides the workshop findings.
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Affiliation(s)
- Jacqueline P Williams
- Department of Radiation Oncology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 647, Rochester, NY 14642, USA.
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Mihaescu A, Santen S, Jeppsson B, Thorlacius H. p38 Mitogen-activated protein kinase signalling regulates vascular inflammation and epithelial barrier dysfunction in an experimental model of radiation-induced colitis. Br J Surg 2010; 97:226-34. [PMID: 20034051 DOI: 10.1002/bjs.6811] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND : Microvascular injury and epithelial barrier dysfunction are rate-limiting aspects in radiation enteropathy. This study examined the role of p38 mitogen-activated protein kinase (p38 MAPK) signalling in radiation-induced colitis in an experimental model. METHODS : The p38 MAPK inhibitor SB239063 was administered to mice immediately before exposure to 20 Gy radiation. Leucocyte- and platelet-endothelium interactions in the colonic microcirculation were assessed by intravital microscopy. Levels of myeloperoxidase (MPO) and CXC chemokines (macrophage inflammatory protein (MIP) 2 and cytokine-induced neutrophil chemoattractant (KC)), and albumin leakage were quantified 16 h after irradiation. RESULTS : Irradiation induced an increase in leucocyte and platelet recruitment, MPO activity, CXC chemokine levels and intestinal leakage. Inhibition of p38 MAPK by SB239063 decreased radiation-induced leucocyte and platelet recruitment (leucocyte rolling and adhesion by 70 and 90 per cent, both P < 0.001; that of platelets by 70 and 74 per cent, both P < 0.001). It also reduced radiation-provoked increases in colonic MPO activity by 88 per cent (P < 0.001), formation of MIP-2 and KC by 72 and 74 per cent respectively (P = 0.003 and P < 0.001), and intestinal leakage by 81 per cent (P < 0.001). CONCLUSION : p38 MAPK is an important signalling pathway in radiation-induced colitis.
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Affiliation(s)
- A Mihaescu
- Department of Surgery, Malmö University Hospital, Lund University, 205 02 Malmö, Sweden
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Prasanna PG, Moroni M, Pellmar TC. Triage dose assessment for partial-body exposure: dicentric analysis. HEALTH PHYSICS 2010; 98:244-51. [PMID: 20065689 PMCID: PMC2806648 DOI: 10.1097/01.hp.0000348020.14969.4] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
Partial-body biodosimetry is likely to be required after a radiological or nuclear exposure. Clinical signs and symptoms, distribution of dicentrics in circulating blood cells, organ-specific biomarkers, and physical signals in teeth and fingernails all can provide indications of non-homogeneous exposures. Organ specific biomarkers may provide early warning regarding physiological systems at risk after radiation injury. Use of a combination of markers and symptoms will be needed for clinical insights for therapeutic approaches. Analysis of dicentrics, a marker specific for radiation injury, is the "gold standard" of biodosimetry and can reveal partial-body exposures. Automation of sample processing for dicentric analysis can increase throughput with customization of off-the-shelf technologies for cytogenetic sample processing and information management. Automated analysis of the metaphase spreads is currently limited, but improvements are in development. The efforts described here bridge the technological gaps to allow the use of dicentric chromosome assay (DCA) for risk-based stratification of mass casualties. This article summarizes current knowledge on partial-body cytogenetic dose assessment, synthesizing information leading to the proposal of an approach to triage dose prediction in radiation mass casualties that is based on equivalent whole-body doses under partial-body exposure conditions and assesses the validity of using this model. An initial screening using only 20 metaphase spreads per subject can confirm irradiation above 2 Gy. A subsequent increase to 50 metaphases improves dose determination to allow risk stratification for clinical triage. Metaphases evaluated for inhomogeneous distribution of dicentrics can reveal partial-body exposures. The authors tested the validity of this approach in an in vitro model that simulates partial-body irradiation by mixing irradiated and un-irradiated lymphocytes in various proportions. Preliminary results support the notion that this approach will be effective under a range of conditions including some partial-body exposures, but may have limitations with low doses or small proportions of irradiated parts of the body. These studies address an important problem in the diagnosis of partial-body irradiation and dose assessment in mass casualties and propose a solution. However, additional work is needed to fully develop and validate the application of DCA to partial-body exposures.
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Affiliation(s)
- Pataje G.S. Prasanna
- Armed Forces Radiobiology Research Institute, 8901 Wisconsin Ave, Bldg. 42, Bethesda, MD 20889-5603, Tel: (301) 295-9210; Fax: (301) 295-6857, E-mail:
| | - Maria Moroni
- Armed Forces Radiobiology Research Institute, 8901 Wisconsin Ave, Bldg. 42, Bethesda, MD 20889-5603, Tel: (301) 295-9210; Fax: (301) 295-6857, E-mail:
| | - Terry C. Pellmar
- Armed Forces Radiobiology Research Institute, 8901 Wisconsin Ave, Bldg. 42, Bethesda, MD 20889-5603, Tel: (301) 295-9210; Fax: (301) 295-6857, E-mail:
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Prasanna PGS, Blakely WF, Bertho JM, Chute JP, Cohen EP, Goans RE, Grace MB, Lillis-Hearne PK, Lloyd DC, Lutgens LCHW, Meineke V, Ossetrova NI, Romanyukha A, Saba JD, Weisdorf DJ, Wojcik A, Yukihara EG, Pellmar TC. Synopsis of partial-body radiation diagnostic biomarkers and medical management of radiation injury workshop. Radiat Res 2010; 173:245-53. [PMID: 20095857 PMCID: PMC8914528 DOI: 10.1667/rr1993.1] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/28/2023]
Abstract
Radiation exposures from accidents, nuclear detonations or terrorist incidents are unlikely to be homogeneous; however, current biodosimetric approaches are developed and validated primarily in whole-body irradiation models. A workshop was held at the Armed Forces Radiobiology Research Institute in May 2008 to draw attention to the need for partial-body biodosimetry, to discuss current knowledge, and to identify the gaps to be filled. A panel of international experts and the workshop attendees discussed the requirements and concepts for a path forward. This report addresses eight key areas identified by the Workshop Program Committee for future focus: (1) improved cytogenetics, (2) clinical signs and symptoms, (3) cutaneous bioindicators, (4) organ-specific biomarkers, (5) biophysical markers of dose, (6) integrated diagnostic approaches, (7) confounding factors, and (8) requirements for post-event medical follow-up. For each area, the status, advantages and limitations of existing approaches and suggestions for new directions are presented.
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Affiliation(s)
- Pataje G. S. Prasanna
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889
| | - William F. Blakely
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889
| | - Jean-Marc Bertho
- Institut de Radioprotection et de Sûreté Nucléaire, 92262 Fontenay aux roses cedex, France
| | - John P. Chute
- Division of Cellular Therapy and Stem Cell Transplantation, Duke University Medical Center, Durham, North Carolina 27710
| | - Eric P. Cohen
- Medical College of Wisconsin, Milwaukee, Wisconsin 53226
| | - Ronald E. Goans
- MJW Corp., Amherst, New York 14228, and Radiation Emergency Assistance Center/Training Site, Oak Ridge, Tennessee, 37830
| | - Marcy B. Grace
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889
| | - Patricia K. Lillis-Hearne
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889
| | - David C. Lloyd
- UK Health Protection Agency, Centre for Radiation, Chemical, and Environmental Hazards, Chilton, OX11 0RQ, United Kingdom
| | - Ludy C. H. W. Lutgens
- Maastricht Radiotherapy and Oncology Clinic (MAASTRO Clinic), Maastricht, the Netherlands
| | - Viktor Meineke
- Bundeswehr Institute of Radiobiology, D-80937 Munich, Germany
| | - Natalia I. Ossetrova
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889
| | - Alexander Romanyukha
- Naval Dosimetry Center, Bethesda, Maryland 20889, and Uniformed Services University, Bethesda, Maryland 20814
| | - Julie D. Saba
- Children's Hospital Oakland Research Institute (CHORI), Oakland, California 94609
| | | | | | | | - Terry C. Pellmar
- Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889
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Pawlik A, Delmar P, Bosse S, Sainz L, Petat C, Pietu G, Thierry D, Tronik-Le Roux D. Changes in transcriptome after in vivo exposure to ionising radiation reveal a highly specialised liver response. Int J Radiat Biol 2009; 85:656-71. [PMID: 19637078 DOI: 10.1080/09553000903020024] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
PURPOSE To identify transcriptional gene-networks involved in the early in vivo response of liver cells to radiation exposure and improve our understanding of the molecular processes responsible for tissue radiosensitivity. MATERIALS AND METHODS Transcriptome variations of liver RNA samples were measured 3 hours post-irradiation using microarray technology. The results were confirmed and extended using real-time polymerase-chain-reaction (RT-PCR). RESULTS We identified quantitative changes in the expression of 126 genes, most of which were observed for the first time. We show that some modifications, such as the upregulation of the cyclin-dependent kinase inhibitor 1A (Cdkn1A) gene, persisted for at least two months after the initial exposure. Other genes regulated by the transformation-related protein 53 (Trp53/p53) such as Bcl2-associated X protein (Bax) or etoposide-induced-2.4 (Ei24/PIG8) were not upregulated. Grouping differentially expressed genes into functional categories revealed that the primary response of liver cells to radiation exposure was the enhancement of oxidoreductase activity and inhibition of cell proliferation, involving cell cycle progression and apoptosis-related genes. CONCLUSIONS The data provides evidence of gene expression modifications associated with the hepatic response to radiation exposure. One of the main differences observed with radiation-sensitive tissues such as the spleen was cell proliferation. The comparison of our data with transcriptome modifications in different biological models enabled the identification of networks of genes that might be co-regulated. Overall, our expression data revealed genes and cellular pathways that might help to improve our understanding of the molecular basis underlying tissue radiosensitivity and to identify possible targets for novel therapeutic strategies.
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Shukla J, Chatterjee S, Thakur VS, Premachandran S, Checker R, Poduval TB. L-Arginine reverses radiation-induced immune dysfunction: the need for optimum treatment window. Radiat Res 2009; 171:180-7. [PMID: 19267543 DOI: 10.1667/rr1241.1] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The aim of the present study was to investigate the protective efficacy of l-arginine in mitigating the injury induced by 2 Gy of total-body gamma radiation (TBI). Mice exposed to radiation (TBI group) had significantly decreased spleen weight, splenocyte numbers and bone marrow cellularity. Administration of l-arginine 2 h after TBI (TBI + l-arginine group) was effective in reducing the radiation-induced depletion of spleen and bone marrow cellularity but was not effective when administered before TBI (l-arginine + TBI group). The radiation-induced decrease in Con A-induced spleen cell proliferation, specific antibody response of spleen B cells to sheep red blood cells, and spleen RNA content was reversed in mice in the TBI + l-arginine group. The radiation-induced increase in serum TNF-alpha levels, serum nitrate/nitrite (NOx) levels, spleen DNA fragmentation, spleen nitric oxide synthase (NOS) activity, spleen inducible NOS (iNOS) activity, and hepatic iNOS activity was reversed in mice in the TBI + l-arginine group. l-Arginine administered before TBI could not reverse these changes. Mice in the TBI + l-arginine group had significantly increased spleen arginase activity compared to mice from either the TBI or l-arginine + TBI group. The results suggest the importance of the time of administration of l-arginine and the l-arginine pathway in mitigating the radiation-induced host immune dysfunction.
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Affiliation(s)
- Jyoti Shukla
- Immunology and Hyperthermia Section, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai - 400 085, India
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Abstract
About half of people with cancer are treated with radiation therapy; however, normal tissue toxicity still remains a dose-limiting factor for this treatment. The skin response to ionizing radiation may involve multiple inflammatory outbreaks. The endothelium is known to play a critical role in radiation-induced vascular injury. Furthermore, endothelial dysfunction reflects a decreased availability of nitric oxide. Statins have been reported to preserve endothelial function through their antioxidant and anti-inflammatory activities. In this study, wild type and endothelial nitric oxide synthase (eNOS)(-/-) mice were subjected to dorsal skin irradiation and treated with pravastatin for 28 days. We demonstrated that pravastatin has a therapeutic effect on skin lesions and abolishes radiation-induced vascular functional activation by decreasing interactions between leukocytes and endothelium. Pravastatin limits the radiation-induced increase of blood CCL2 and CXCL1 production expression of inflammatory adhesion molecules such as E-selectin and intercellular adhesion molecule-1, and inflammatory cell migration in tissues. Pravastatin limits the in vivo and in vitro radiation-induced downregulation of eNOS. Moreover, pravastatin has no effect in eNOS(-/-) mice, demonstrating that eNOS plays a key role in the beneficial effect of pravastatin in radiation-induced skin lesions. In conclusion, pravastatin may be a good therapeutic approach to prevent or reduce radiation-induced skin damage.
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Moriconi F, Christiansen H, Raddatz D, Dudas J, Hermann RM, Rave-Fränk M, Sheikh N, Saile B, Hess CF, Ramadori G. Effect of radiation on gene expression of rat liver chemokines: in vivo and in vitro studies. Radiat Res 2008; 169:162-9. [PMID: 18220462 DOI: 10.1667/rr1006.1] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2007] [Accepted: 10/11/2007] [Indexed: 11/03/2022]
Abstract
The aim of the study was to analyze the effect of a single irradiation on chemokine gene expression in the rat liver and in isolated rat hepatocytes. RNA extracted from livers and from hepatocytes within the first 48 h after irradiation was analyzed by real-time PCR and the Northern blot assay. The chemokine concentrations in the serum of irradiated rats were measured quantitatively by ELISA. A significant radiation-induced increase of CINC1, IP10, MCP1, MIP3alpha, MIP3beta, MIG and ITAC gene expression could be detected at the RNA level in the liver. CINC1, MCP1 and IP10 serum levels were significantly increased. In rat hepatocytes in vitro, only MIP3alpha showed a radiation-induced increase in expression, while CINC1, IP10, MIP3beta, MIG, MIP1alpha, ITAC and SDF1 RNA levels were significantly down-regulated. However, incubation of irradiated hepatocytes in vitro with either TNF-alpha, IL1beta, or IL6 plus TNF-alpha led to up-regulation of MCP1, IP10 and MCP1 or CINC1 and MIP3beta, respectively. Irradiation of the liver induces up-regulation of the genes of the main proinflammatory chemokines, probably through the action of locally synthesized proinflammatory cytokines. The reason for the lack of liver inflammation in this model has still to be clarified.
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Affiliation(s)
- Federico Moriconi
- Department of Gastroenterology and Endocrinology, Gottingen University, 37075 Goettingen, Germany
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Sémont A, François S, Mouiseddine M, François A, Saché A, Frick J, Thierry D, Chapel A. Mesenchymal stem cells increase self-renewal of small intestinal epithelium and accelerate structural recovery after radiation injury. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2007; 585:19-30. [PMID: 17120774 DOI: 10.1007/978-0-387-34133-0_2] [Citation(s) in RCA: 107] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Patients who undergo pelvic or abdominal radiotherapy may develop side effects that can be life threatening. Tissue complications caused by radiation-induced stem cell depletion may result in structural and functional alterations of the gastrointestinal (GI) tract. Stem cell therapy using mesenchymal stem cells (MSC) is a promising approach for replenishment of the depleted stem cell compartment during radiotherapy. There is little information on the therapeutic potential of MSC in injured-GI tract following radiation exposure. In this study, we addressed the ability of MSC to support the structural regeneration of the small intestine after abdominal irradiation. We isolated MSC from human bone marrow and human mesenchymal stem cells (hMSC) were transplanted into immunotolerent NOD/SCID mice with a dose of 5.10(6) cells via the systemic route. Using a model of radiation-induced intestinal injury, we studied the link between damage, hMSC engraftment and the capacity of hMSC to sustain structural recovery. Tissue injury was assessed by histological analysis. hMSC engraftment in tissues was quantified by PCR assay. Following abdominal irradiation, the histological analysis of small intestinal structure confirms the presence of partial and transient (three days) mucosal atrophy. PCR analysis evidences a low but significant hMSC implantation in small intestine (0.17%) but also at all the sites of local irradiation (kidney, stomach and spleen). Finally, in presence of hMSC, the small intestinal structure is already recovered at three days after abdominal radiation exposure. We show a structural recovery accompanied by an increase of small intestinal villus height, three and fifteen days following abdominal radiation exposure. In this study, we show that radiation-induced small intestinal injury may play a role in the recruitment of MSC for the improvement of tissue recovery. This work supports, the use of MSC infusion to repair damaged GI tract in patients subjected to radiotherapy. MSC therapy to avoid extended intestinal crypt sterilization is a promising approach to diminish healthy tissue alterations during the course of pelvic radiotherapy.
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Matsumoto H, Hamada N, Takahashi A, Kobayashi Y, Ohnishi T. Vanguards of paradigm shift in radiation biology: radiation-induced adaptive and bystander responses. JOURNAL OF RADIATION RESEARCH 2007; 48:97-106. [PMID: 17327685 DOI: 10.1269/jrr.06090] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
The risks of exposure to low dose ionizing radiation (below 100 mSv) are estimated by extrapolating from data obtained after exposure to high dose radiation, using a linear no-threshold model (LNT model). However, the validity of using this dose-response model is controversial because evidence accumulated over the past decade has indicated that living organisms, including humans, respond differently to low dose/low dose-rate radiation than they do to high dose/high dose-rate radiation. In other words, there are accumulated findings which cannot be explained by the classical "target theory" of radiation biology. The radioadaptive response, radiation-induced bystander effects, low-dose radio-hypersensitivity, and genomic instability are specifically observed in response to low dose/low dose-rate radiation, and the mechanisms underlying these responses often involve biochemical/molecular signals that respond to targeted and non-targeted events. Recently, correlations between the radioadaptive and bystander responses have been increasingly reported. The present review focuses on the latter two phenomena by summarizing observations supporting their existence, and discussing the linkage between them from the aspect of production of reactive oxygen and nitrogen species.
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Affiliation(s)
- Hideki Matsumoto
- Division of Oncology, Biomedical Imaging Research Center, University of Fukui, Eiheiji, Japan.
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Haksar A, Sharma A, Chawla R, Kumar R, Arora R, Singh S, Prasad J, Gupta M, Tripathi RP, Arora MP, Islam F, Sharma RK. Zingiber officinale exhibits behavioral radioprotection against radiation-induced CTA in a gender-specific manner. Pharmacol Biochem Behav 2006; 84:179-88. [PMID: 16797061 DOI: 10.1016/j.pbb.2006.04.008] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2005] [Revised: 03/30/2006] [Accepted: 04/18/2006] [Indexed: 11/23/2022]
Abstract
At the organismic level, exposure to radiation can produce taste aversion (CTA) learning and emesis, which have been proposed as behavioral endpoints that are mediated by harmful effects of radiations on peripheral systems, primarily the gastrointestinal system. Thus, the aim of the present investigation was to study the gastroprotective action of hydroalcoholic extract of zingiber rhizome (Zingiber officinale Rosc.) against radiation-induced conditioned taste aversion (CTA) in both male and female species of animals, for testing its potential as a behavioral radioprotector. Administration of zingiber extract 1 h before 2-Gy gamma-radiation was significantly effective in blocking the saccharin avoidance response, with 200 and 250 mg/kg b.wt. i.p., being the most effective doses for male and female rats, respectively. A comparison of the efficacy of zingiber extract with two antiemetic drugs, ondansteron and dexamethasone, revealed that the extract rendered comparable protection against radiation-induced CTA. Our experiments also confirmed the existence of sex dichotomy (i.e., the sex of animal greatly influenced response towards radiation exposure) in relation to behavioral responses (CTA) or differential metabolism. The observed gender variations were hypothesized to be a result of hormonal fluctuations and differences in pharmacological parameters in male and female rats. To correlate the mechanism of action, the free-radical-scavenging potential of zingiber extract to scavenge hydroxyl ion and nitric oxide was also tested, in cell-free system and a concentration of 1000 microg/ml, was found to be the most potent, which has been proposed as one the many activities assisting in its overall ability to modulate radiation-induced taste aversion. The results demonstrate that Z. officinale possesses antioxidant, radioprotective and neuromodulatory properties that can be effectively utilized for behavioral radioprotection and for efficiently mitigating radiation-induced CTA in both males and females species.
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Affiliation(s)
- Anupum Haksar
- Division of Radiological Imaging, Bio-informatics and Radiation Biology, Institute of Nuclear Medicine and Allied Sciences, Brig. S. K. Mazumdar Road, Delhi-110054, India
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Gaugler MH. A unifying system: does the vascular endothelium have a role to play in multi-organ failure following radiation exposure? Br J Radiol 2005. [DOI: 10.1259/bjr/24511652] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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