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Sample records for radiation-induced tissue structure

  1. Structure-function relationships in radiation-induced cell and tissue lesions: special references to the contributions of scanning electron microscopy and hematopoietic tissue responses

    SciTech Connect

    Seed, T.M.

    1987-03-01

    Contributions of scanning electron microscopy to the field of radiation biology are briefly reviewed and presented in terms of an overall goal to identify and characterize the structural features of radiation-induced lesions in vital cell and tissue targets. In the context of lesion production, the major radiation-elicited response sequences, the types and nature of measured end points, and governing temporal and radiobiological parameters are discussed and illustrated by using results derived from both in vitro cell systems and in vivo studies that measured tissue responses from various organ systems (respiratory, digestive, circulatory, and central nervous systems). Work in our laboratory on the nature of early and late hematopathologic tissue responses (aplastic anemia and myeloid leukemia) induced by protracted radiation exposure and the bridging effect of repair processes relative to the expression of these pathologies is highlighted.

  2. Imaging radiation-induced normal tissue injury.

    PubMed

    Robbins, Mike E; Brunso-Bechtold, Judy K; Peiffer, Ann M; Tsien, Christina I; Bailey, Janet E; Marks, Lawrence B

    2012-04-01

    Technological developments in radiation therapy and other cancer therapies have led to a progressive increase in five-year survival rates over the last few decades. Although acute effects have been largely minimized by both technical advances and medical interventions, late effects remain a concern. Indeed, the need to identify those individuals who will develop radiation-induced late effects, and to develop interventions to prevent or ameliorate these late effects is a critical area of radiobiology research. In the last two decades, preclinical studies have clearly established that late radiation injury can be prevented/ameliorated by pharmacological therapies aimed at modulating the cascade of events leading to the clinical expression of radiation-induced late effects. These insights have been accompanied by significant technological advances in imaging that are moving radiation oncology and normal tissue radiobiology from disciplines driven by anatomy and macrostructure to ones in which important quantitative functional, microstructural, and metabolic data can be noninvasively and serially determined. In the current article, we review use of positron emission tomography (PET), single photon emission tomography (SPECT), magnetic resonance (MR) imaging and MR spectroscopy to generate pathophysiological and functional data in the central nervous system, lung, and heart that offer the promise of, (1) identifying individuals who are at risk of developing radiation-induced late effects, and (2) monitoring the efficacy of interventions to prevent/ameliorate them.

  3. Radioprotectors and Mitigators of Radiation-Induced Normal Tissue Injury

    PubMed Central

    Cotrim, Ana P.; Hyodo, Fuminori; Baum, Bruce J.; Krishna, Murali C.; Mitchell, James B.

    2010-01-01

    Radiation is used in the treatment of a broad range of malignancies. Exposure of normal tissue to radiation may result in both acute and chronic toxicities that can result in an inability to deliver the intended therapy, a range of symptoms, and a decrease in quality of life. Radioprotectors are compounds that are designed to reduce the damage in normal tissues caused by radiation. These compounds are often antioxidants and must be present before or at the time of radiation for effectiveness. Other agents, termed mitigators, may be used to minimize toxicity even after radiation has been delivered. Herein, we review agents in clinical use or in development as radioprotectors and mitigators of radiation-induced normal tissue injury. Few agents are approved for clinical use, but many new compounds show promising results in preclinical testing. PMID:20413641

  4. Radiation-induced structural changes, 4

    NASA Astrophysics Data System (ADS)

    Hama, Yoshimasa; Matsuyama, Tomochika; Ogasawara, Masaaki

    1993-10-01

    This seminar was held for discussion on recent progress in experimental investigation of positron and its application to material science. Fundamental characteristics of positronium, measuring method, molecular structure of positronium, and its annihilation and reaction, in liquid phase positronium chemistry are reported. The nonthermal positrons (0.25-2.5 keV) are occurred in KURRI-LINAC, slow positrons are found out by moderating with solid xenon film. Positronium formation in insulating materials are reported. Positron lifetime and insulating rupture strength are measured with epoxy resin and fluororesin changing bridging density, experimental materials temperature, gamma ray dose Free-volume studies on polymer in multiphase systems are evaluated using the method of spin labeling, the molecular dynamics of polymer chains are discussed. The anisotropy diffusion process on structural relaxation of linear polymers are described, introducing the molecular dynamics simulation of polarization and stress relaxation of ferroelectric polymers.

  5. Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications.

    PubMed

    Zhao, Weiling; Robbins, Mike E C

    2009-01-01

    The threat of radiation-induced late normal tissue injury limits the dose of radiation that can be delivered safely to cancer patients presenting with solid tumors. Tissue dysfunction and failure, associated with atrophy, fibrosis and/or necrosis, as well as vascular injury, have been reported in late responding normal tissues, including the central nervous system, gut, kidney, liver, lung, and skin. The precise mechanisms involved in the pathogenesis of radiation-induced late normal tissue injury have not been fully elucidated. It has been proposed recently that the radiation-induced late effects are caused, in part, by chronic oxidative stress and inflammation. Increased production of reactive oxygen species, which leads to lipid peroxidation, oxidation of DNA and proteins, as well as activation of pro-inflammatory factors has been observed in vitro and in vivo. In this review, we will present direct and indirect evidence to support this hypothesis. To improve the long-term survival and quality of life for radiotherapy patients, new approaches have been examined in preclinical models for their efficacy in preventing or mitigating the radiation-induced chronic normal tissue injury. We and others have tested drugs that can either attenuate inflammation or reduce chronic oxidative stress in animal models of late radiation-induced normal tissue injury. The effectiveness of renin-angiotensin system blockers, peroxisome proliferator-activated receptor (PPAR) gamma agonists, and antioxidants/antioxidant enzymes in preventing or mitigating the severity of radiation-induced late effects indicates that radiation-induced chronic injury can be prevented and/or treated. This provides a rationale for the design and development of anti-inflammatory-based interventional approaches for the treatment of radiation-induced late normal tissue injury.

  6. Physiology of Hormone Autonomous Tissue Lines Derived From Radiation-Induced Tumors of Arabidopsis thaliana 1

    PubMed Central

    Campell, Bruce R.; Town, Christopher D.

    1991-01-01

    γ-Radiation-induced tumors of Arabidopsis thaliana L. have been produced as a novel approach to isolation of genes that regulate plant development. Tumors excised from irradiated plants are hormone autonomous in culture and have been maintained on hormone-free medium for up to 4 years. Five tumor tissue lines having different morphologies and growth rates were analyzed for auxin, cytokinin, and 1-aminocyclopropane-1-carboxylic acid (ACC) content, ethylene production, and response to exogenous growth regulators. Normal tissues and two crown gall tissue lines were analyzed for comparison. Rosettes and whole seedlings each contained approximately 30 nanograms· (gram fresh weight)−1 free indoleacetic acid (IAA), 150 nanograms· (gram fresh weight)−1 ester-conjugated IAA, and 10 to 20 micrograms· (gram fresh weight)−1 amide-conjugated IAA. The crown gall lines contained similar amounts of free and ester-conjugated IAA but less amide conjugates. Whereas three of the radiation-induced tumor lines had IAA profiles similar to normal tissues, one line had 10- to 100-fold more free IAA and three- to 10-fold less amide-conjugated IAA. The fifth line had normal free IAA levels but more conjugated IAA than control tissues. Whole seedlings contained approximately 2 nanograms· (gram fresh weight)−1 of both zeatin riboside and isopentenyladenosine. The crown gall lines had 100- to 1000-fold higher levels of each cytokinin. In contrast, the three radiation-induced tumor lines analyzed contained cytokinin levels similar to the control tissue. The radiation-induced tumor tissues produced very little ethylene, although each contained relatively high levels of ACC. Normal callus contained similar amounts of ACC but produced several times more ethylene than the radiation-induced tumor lines. Each of the radiation-induced tumor tissues displayed a unique set of responses to exogenously supplied growth regulators. Only one tumor line showed the same response as normal callus to

  7. Effect of MPG on radiation-induced odontogenic tissue metaplasia

    SciTech Connect

    Geist, J.R.; Kafrawy, A.H.; Shupe, R.E.

    1988-01-01

    This investigation monitored the effect of 2-mercaptopropionylglycine (MPG) in reducing radiation damage to the tooth-forming tissues. Fifty rats were exposed to x-ray doses of between 3 and 19 Gy directed toward the maxillary incisor germinal centers. Half of the animals were given an injection of MPG before irradiation, while the other rats were injected with saline solution. Administration of MPG did not significantly reduce the frequency of dentinal niche formation relative to the control teeth. The average lengths and percentage depths of the apicoincisal niches were statistically smaller in the groups treated with MPG. Although statistically significant, the mild protective effect of MPG was not clinically important because damage to the irradiated teeth was still extensive.

  8. Chromatin Structure and Radiation-Induced Intrachromosome Exchange

    NASA Technical Reports Server (NTRS)

    Mangala; Zhang, Ye; Hada, Megumi; Cucinotta, Francis A.; Wu, Honglu

    2011-01-01

    We have recently investigated the location of breaks involved in intrachromosomal type exchange events, using the multicolor banding in situ hybridization (mBAND) technique for human chromosome 3. In human epithelial cells exposed to both low- and high-LET radiations in vitro, intrachromosome exchanges were found to occur preferentially between a break in the 3p21 and one in the 3q11. Exchanges were also observed between a break in 3p21 and one in 3q26, but few exchanges were observed between breaks in 3q11 and 3q26, even though the two regions were on the same arm of the chromosome. To explore the relationships between intrachromosome exchanges and chromatin structure, we used probes that hybridize the three regions of 3p21, 3q11 and 3q26, and measured the distance between two of the three regions in interphase cells. We further analyzed fragile sites on the chromosome that have been identified in various types of cancers. Our results demonstrated that the distribution of breaks involved in radiation-induced intrachromosome aberrations depends upon both the location of fragile sites and the folding of chromatins

  9. In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury

    PubMed Central

    Rannou, Emilie; François, Agnès; Toullec, Aurore; Guipaud, Olivier; Buard, Valérie; Tarlet, Georges; Mintet, Elodie; Jaillet, Cyprien; Iruela-Arispe, Maria Luisa; Benderitter, Marc; Sabourin, Jean-Christophe; Milliat, Fabien

    2015-01-01

    The pathophysiological mechanism involved in side effects of radiation therapy, and especially the role of the endothelium remains unclear. Previous results showed that plasminogen activator inhibitor-type 1 (PAI-1) contributes to radiation-induced intestinal injury and suggested that this role could be driven by an endothelium-dependent mechanism. We investigated whether endothelial-specific PAI-1 deletion could affect radiation-induced intestinal injury. We created a mouse model with a specific deletion of PAI-1 in the endothelium (PAI-1KOendo) by a Cre-LoxP system. In a model of radiation enteropathy, survival and intestinal radiation injury were followed as well as intestinal gene transcriptional profile and inflammatory cells intestinal infiltration. Irradiated PAI-1KOendo mice exhibited increased survival, reduced acute enteritis severity and attenuated late fibrosis compared with irradiated PAI-1flx/flx mice. Double E-cadherin/TUNEL labeling confirmed a reduced epithelial cell apoptosis in irradiated PAI-1KOendo. High-throughput gene expression combined with bioinformatic analyses revealed a putative involvement of macrophages. We observed a decrease in CD68+cells in irradiated intestinal tissues from PAI-1KOendo mice as well as modifications associated with M1/M2 polarization. This work shows that PAI-1 plays a role in radiation-induced intestinal injury by an endothelium-dependent mechanism and demonstrates in vivo that the endothelium is directly involved in the progression of radiation-induced enteritis. PMID:26510580

  10. Dynamics of wound healing signaling as a potential therapeutic target for radiation-induced tissue damage.

    PubMed

    Chung, Yih-Lin; Pui, Newman N M

    2015-01-01

    We hypothesized the histone deacetylase inhibitor phenylbutyrate (PB) has beneficial effects on radiation-induced injury by modulating the expression of DNA repair and wound healing genes. Hamsters received a radiosurgical dose of radiation (40 Gy) to the cheek and were treated with varying PB dosing regimens. Gross alteration of the irradiated cheeks, eating function, histological changes, and gene expression during the course of wound healing were compared between treatment groups. Pathological analysis showed decreased radiation-induced mucositis, facilitated epithelial cell growth, and preventing ulcerative wound formation, after short-term PB treatment, but not after vehicle or sustained PB. The radiation-induced wound healing gene expression profile exhibited a sequential transition from the inflammatory and DNA repair phases to the tissue remodeling phase in the vehicle group. Sustained PB treatment resulted in a prolonged wound healing gene expression profile and delayed the wound healing process. Short-term PB shortened the duration of inflammatory cytokine expression, triggered repeated pulsed expression of cell cycle and DNA repair-regulating genes, and promoted earlier oscillatory expression of tissue remodeling genes. Distinct gene expression patterns between sustained and short-term treatment suggest dynamic profiling of wound healing gene expression can be an important part of a biological therapeutic strategy to mitigate radiation-related tissue injury. © 2015 by the Wound Healing Society.

  11. Radiation-Induced Topological Disorder in Irradiated Network Structures

    SciTech Connect

    Hobbs, Linn W.

    2002-12-21

    This report summarizes results of a research program investigating the fundamental principles underlying the phenomenon of topological disordering in a radiation environment. This phenomenon is known popularly as amorphization, but is more formally described as a process of radiation-induced structural arrangement that leads in crystals to loss of long-range translational and orientational correlations and in glasses to analogous alteration of connectivity topologies. The program focus has been on a set compound ceramic solids with directed bonding exhibiting structures that can be described as networks. Such solids include SiO2, Si3N4, SiC, which are of interest to applications in fusion energy production, nuclear waste storage, and device manufacture involving ion implantation or use in radiation fields. The principal investigative tools comprise a combination of experimental diffraction-based techniques, topological modeling, and molecular-dynamics simulations that have proven a rich source of information in the preceding support period. The results from the present support period fall into three task areas. The first comprises enumeration of the rigidity constraints applying to (1) more complex ceramic structures (such as rutile, corundum, spinel and olivine structures) that exhibit multiply polytopic coordination units or multiple modes of connecting such units, (2) elemental solids (such as graphite, silicon and diamond) for which a correct choice of polytope is necessary to achieve correct representation of the constraints, and (3) compounds (such as spinel and silicon carbide) that exhibit chemical disorder on one or several sublattices. With correct identification of the topological constraints, a unique correlation is shown to exist between constraint and amorphizability which demonstrates that amorphization occurs at a critical constraint loss. The second task involves the application of molecular dynamics (MD) methods to topologically-generated models

  12. The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury.

    PubMed

    Hu, Bo; Jin, Chengcheng; Li, Hua-Bing; Tong, Jiyu; Ouyang, Xinshou; Cetinbas, Naniye Malli; Zhu, Shu; Strowig, Till; Lam, Fred C; Zhao, Chen; Henao-Mejia, Jorge; Yilmaz, Omer; Fitzgerald, Katherine A; Eisenbarth, Stephanie C; Elinav, Eran; Flavell, Richard A

    2016-11-11

    Acute exposure to ionizing radiation induces massive cell death and severe damage to tissues containing actively proliferating cells, including bone marrow and the gastrointestinal tract. However, the cellular and molecular mechanisms underlying this pathology remain controversial. Here, we show that mice deficient in the double-stranded DNA sensor AIM2 are protected from both subtotal body irradiation-induced gastrointestinal syndrome and total body irradiation-induced hematopoietic failure. AIM2 mediates the caspase-1-dependent death of intestinal epithelial cells and bone marrow cells in response to double-strand DNA breaks caused by ionizing radiation and chemotherapeutic agents. Mechanistically, we found that AIM2 senses radiation-induced DNA damage in the nucleus to mediate inflammasome activation and cell death. Our results suggest that AIM2 may be a new therapeutic target for ionizing radiation exposure. Copyright © 2016, American Association for the Advancement of Science.

  13. Radiation-induced trapped charge in metal-nitride-oxide-semiconductor structure

    SciTech Connect

    Takahashi, Y.; Ohnishi, K.; Fujimaki, T.; Yoshikawa, M.

    1999-12-01

    The radiation-induced trapped charge in insulation layer of metal-nitride-oxide-semiconductor (MNOS) structure has been investigated. The mechanism of charge trapping under irradiation is studied by the radiation-induced mid-gap voltage shift using a simple charge trap model. The depth profile of fixed charge in insulator before irradiation was evaluated by the mid-gap voltage of MNOS structures with varying insulator thicknesses using slanted etching method. The irradiation tests were carried out using Co-60 gamma ray source up to 1 Mrad(Si) with the gate voltage of +6 or {minus}6 V. The calculated results using the model can be fitted well to the experimental results, and the authors confirmed the model is very useful to discuss the radiation-induced trapped charge. By simulating the mid-gap voltage shift of MNOS structures, they considered the possibility for radiation hardened device.

  14. Quantitative Ultrasonic Evaluation of Radiation-Induced Late Tissue Toxicity: Pilot Study of Breast Cancer Radiotherapy

    SciTech Connect

    Liu Tian; Zhou Jun; Yoshida, Emi J.; Woodhouse, Shermian A.; Schiff, Peter B.; Wang, Tony J.C.; Lu Zhengfeng; Pile-Spellman, Eliza; Zhang Pengpeng; Kutcher, Gerald J.

    2010-11-01

    Purpose: To investigate the use of advanced ultrasonic imaging to quantitatively evaluate normal-tissue toxicity in breast-cancer radiation treatment. Methods and Materials: Eighteen breast cancer patients who received radiation treatment were enrolled in an institutional review board-approved clinical study. Radiotherapy involved a radiation dose of 50.0 to 50.4 Gy delivered to the entire breast, followed by an electron boost of 10.0 to 16.0 Gy delivered to the tumor bed. Patients underwent scanning with ultrasound during follow-up, which ranged from 6 to 94 months (median, 22 months) postradiotherapy. Conventional ultrasound images and radio-frequency (RF) echo signals were acquired from treated and untreated breasts. Three ultrasound parameters, namely, skin thickness, Pearson coefficient, and spectral midband fit, were computed from RF signals to measure radiation-induced changes in dermis, hypodermis, and subcutaneous tissue, respectively. Ultrasound parameter values of the treated breast were compared with those of the untreated breast. Ultrasound findings were compared with clinical assessment using Radiation Therapy Oncology Group (RTOG) late-toxicity scores. Results: Significant changes were observed in ultrasonic parameter values of the treated vs. untreated breasts. Average skin thickness increased by 27.3%, from 2.05 {+-} 0.22mm to 2.61 {+-} 0.52mm; Pearson coefficient decreased by 31.7%, from 0.41 {+-} 0.07 to 0.28 {+-} 0.05; and midband fit increased by 94.6%, from -0.92 {+-} 7.35 dB to 0.87 {+-} 6.70 dB. Ultrasound evaluations were consistent with RTOG scores. Conclusions: Quantitative ultrasound provides a noninvasive, objective means of assessing radiation-induced changes to the skin and subcutaneous tissue. This imaging tool will become increasingly valuable as we continue to improve radiation therapy technique.

  15. HZE particle radiation induces tissue-specific and p53-dependent mutagenesis in transgenic animals

    NASA Technical Reports Server (NTRS)

    Chang, P. Y.; Kanazawa, N.; Lutze-Mann, L.; Winegar, R.

    2001-01-01

    Transgenic animals, with the integrated target gene, provide a unique approach for measuring and characterizing mutations in any tissue of the animal. We are using the plasmid-based lacZ transgenic mice with different p53 genetic background to examine radiation-induced genetic damage resulting from exposure to heavy particle radiation. We measured lacZ mutation frequencies (MF) in the brain and spleen tissues at various times after exposing animals to an acute dose of 1 Gy of 1GeV/amu iron particles. MF in the spleen of p53+/+ animals increased up to 2.6-fold above spontaneous levels at 8 weeks post irradiation. In contrast, brain MF from the same animals increased 1.7-fold above controls in the same period. In the p53-/- animals, brain MF increased to 2.2-fold above spontaneous levels at 1 week after treatment, but returned to control levels thereafter. Radiation also induced alterations in the spectrum of mutants in both tissues, accompanied by changes in the frequency of mutants with deletions extending past the transgene into mouse genomic DNA. Our results indicate that the accumulation of transgene MF after radiation exposure is dependant on the tissue examined as well as the p53 genetic background of the animals.

  16. Semiquantitative probe for radiation-induced normal tissue damage at the molecular level

    SciTech Connect

    Miller, G.; Siemann, D.; Scott, P.; Dawson, D.; Muldrew, K.; Trepanier, P.; McGann, L.

    1986-01-01

    Sheep antibodies to bovine type I collagen were employed in the immunohistochemical detection of type I collagen in lung tissue sections of irradiated LAF1 mice. A video image digitizing system was developed to estimate collagen levels, by assigning a numerical value (0-63) to each of approximately 53,800 picture elements (pixels) in the microscope field, according to the collagen-dependent fluorescence intensity at each locus. For lungs harvested 52 weeks subsequent to graded doses of 60Co gamma radiation between 0 and 10 Gy, a dose-dependent increase in type I collagen was observed in the alveolar walls. A reproducible increase was evident for doses as low as 5 Gy: doses of 7 to 10 Gy elicited type I collagen levels significantly elevated with respect to those of age-matched controls. These results are consistent with a role for type I collagen in the development of radiation-induced pulmonary fibrosis. The assay system developed here will be used to explore the role of connective tissue macromolecules in the development of radiation pneumonitis and fibrosis.

  17. Roles of Sensory Nerves in the Regulation of Radiation-Induced Structural and Functional Changes in the Heart

    SciTech Connect

    Sridharan, Vijayalakshmi; Tripathi, Preeti; Sharma, Sunil; Moros, Eduardo G.; Zheng, Junying; Hauer-Jensen, Martin; Boerma, Marjan

    2014-01-01

    Purpose: Radiation-induced heart disease (RIHD) is a chronic severe side effect of radiation therapy of intrathoracic and chest wall tumors. The heart contains a dense network of sensory neurons that not only are involved in monitoring of cardiac events such as ischemia and reperfusion but also play a role in cardiac tissue homeostasis, preconditioning, and repair. The purpose of this study was to examine the role of sensory nerves in RIHD. Methods and Materials: Male Sprague-Dawley rats were administered capsaicin to permanently ablate sensory nerves, 2 weeks before local image-guided heart x-ray irradiation with a single dose of 21 Gy. During the 6 months of follow-up, heart function was assessed with high-resolution echocardiography. At 6 months after irradiation, cardiac structural and molecular changes were examined with histology, immunohistochemistry, and Western blot analysis. Results: Capsaicin pretreatment blunted the effects of radiation on myocardial fibrosis and mast cell infiltration and activity. By contrast, capsaicin pretreatment caused a small but significant reduction in cardiac output 6 months after irradiation. Capsaicin did not alter the effects of radiation on cardiac macrophage number or indicators of autophagy and apoptosis. Conclusions: These results suggest that sensory nerves, although they play a predominantly protective role in radiation-induced cardiac function changes, may eventually enhance radiation-induced myocardial fibrosis and mast cell activity.

  18. Chromatin structure and ionizing-radiation-induced chromosome aberrations

    SciTech Connect

    Muehlmann-Diaz, M.C.

    1993-01-01

    The possible influence of chromatic structure or activity on chromosomal radiosensitivity was studied. A cell line was isolated which contained some 10[sup 5] copies of an amplified plasmid in a single large mosquito artificial chromosome (MAC). This chromosome was hypersensitive to DNase I. Its radiosensitivity was some three fold greater than normal mosquito chromosomes in the same cell. In cultured human cells irradiated during G[sub 0], the initial breakage frequency in chromosome 4, 19 and the euchromatic and heterochromatic portions of the Y chromosome were measured over a wide range of doses by inducing Premature Chromosome Condensation (PCC) immediately after irradiation with Cs-137 gamma rays. No evidence was seen that Y heterochromatin or large fragments of it remained unbroken. The only significant deviation from the expected initial breakage frequency per Gy per unit length of chromosome was that observed for the euchromatic portion of the Y chromosome, with breakage nearly twice that expected. The development of aberrations involving X and Y chromosomes at the first mitosis after irradation was also studied. Normal female cells sustained about twice the frequency of aberrations involving X chromosomes for a dose of 7.3 Gy than the corresponding male cells. Fibroblasts from individuals with supernumerary X chromosomes did not show any further increase in X aberrations for this dos. The frequency of aberrations involving the heterochromatic portion of the long arm of the Y chromosome was about what would be expected for a similar length of autosome, but the euchromatic portion of the Y was about 3 times more radiosensitive per unit length. 5-Azacytidine treatment of cultured human female fibroblasts or fibroblasts from a 49,XXXXY individual, reduced the methylation of cytosine residues in DNA, and resulted in an increased chromosomal radiosensitivity in general, but it did not increase the frequency of aberrations involving the X chromosomes.

  19. Effect of top electrode material on radiation-induced degradation of ferroelectric thin film structures

    SciTech Connect

    Brewer, Steven J.; Bassiri-Gharb, Nazanin; Deng, Carmen Z.; Callaway, Connor P.; Paul, McKinley K.; Fisher, Kenzie J.; Guerrier, Jonathon E.; Jones, Jacob L.; Rudy, Ryan Q.; Polcawich, Ronald G.; Glaser, Evan R.; Cress, Cory D.

    2016-07-14

    The effects of gamma irradiation on the dielectric and piezoelectric responses of Pb[Zr{sub 0.52}Ti{sub 0.48}]O{sub 3} (PZT) thin film stacks were investigated for structures with conductive oxide (IrO{sub 2}) and metallic (Pt) top electrodes. The samples showed, generally, degradation of various key dielectric, ferroelectric, and electromechanical responses when exposed to 2.5 Mrad (Si) {sup 60}Co gamma radiation. However, the low-field, relative dielectric permittivity, ε{sub r}, remained largely unaffected by irradiation in samples with both types of electrodes. Samples with Pt top electrodes showed substantial degradation of the remanent polarization and overall piezoelectric response, as well as pinching of the polarization hysteresis curves and creation of multiple peaks in the permittivity-electric field curves post irradiation. The samples with oxide electrodes, however, were largely impervious to the same radiation dose, with less than 5% change in any of the functional characteristics. The results suggest a radiation-induced change in the defect population or defect energy in PZT with metallic top electrodes, which substantially affects motion of internal interfaces such as domain walls. Additionally, the differences observed for stacks with different electrode materials implicate the ferroelectric–electrode interface as either the predominant source of radiation-induced effects (Pt electrodes) or the site of healing for radiation-induced defects (IrO{sub 2} electrodes).

  20. Protective Effect of Pyruvate Against Radiation-Induced Damage in Collagenized Tissues

    NASA Technical Reports Server (NTRS)

    Griko, Y. V.; Yan, Xiaoli

    2016-01-01

    Exposure to high doses of ionizing radiation produces both acute and late effects on the collagenized tissues and have profound effects on wound healing. Because of the crucial practical importance for new radioprotective agents, our study has been focused on evaluation of the efficacy of non-toxic naturally occurring compounds to protect tissue integrity against high-dose gamma radiation. Here, we demonstrate that molecular integrity of collagen may serve as a sensitive biological marker for quantitative evaluation of molecular damage to collagenized tissue and efficacy of radioprotective agents. Increasing doses of gamma radiation (0-50kGy) result in progressive destruction of the native collagen fibrils, which provide a structural framework, strength, and proper milieu for the regenerating tissue. The strategy used in this study involved the thermodynamic specification of all structural changes in collagenized matrix of skin, aortic heart valve, and bone tissue induced by different doses and conditions of g-irradiation. This study describes a simple biophysical approach utilizing the Differential Scanning Calorimetry (DSC) to characterize the structural resistance of the aortic valve matrix exposed to different doses of g-irradiation. It allows us to identify the specific response of each constituent as well as to determine the influence of the different treatments on the characteristic parameters of protein structure. We found that pyruvate, a substance that naturally occurs in the body, provide significant protection (up to 80%) from biochemical and biomechanical damage to the collagenized tissue through the effective targeting of reactive oxygen species. The recently discovered role of pyruvate in the cell antioxidant defense to O2 oxidation, and its essential constituency in the daily human diet, indicate that the administration of pyruvate-based radioprotective formulations may provide safe and effective protection from deleterious effects of ionizing

  1. Characterization of Network Structure of Polyacrylamide Based Hydrogels Prepared By Radiation Induced Polymerization

    SciTech Connect

    Mahmudi, Naim; Sen, Murat; Gueven, Olgun; Rendevski, Stojan

    2007-04-23

    In this study network structure of polyacrylamide based hydrogels prepared by radiation induced polymerization has been investigated. Polyacrylamide based hydrogels in the rod form were prepared by copolymerization of acrylamide(AAm) with hydroxyl ethyl methacrylate(HEMA) and methyl acrylamide(MAAm) in the presence of cross-linking agent and water by gamma rays at ambient temperature. Molecular weight between cross-links and effective cross-link density of hydrogels were calculated from swelling as well as shear modulus data obtained from compression tests. The results have shown that simple compression analyses can be used for the determination of effective cross-link density of hydrogels without any need to some polymer-solvent based parameters as in the case of swelling based determinations. Diffusion of water into hydrogels was examined by analyzing water absorption kinetics and the effect of network, structure on the diffusion type and coefficient was discussed.

  2. Dissecting the Molecular Mechanism of Ionizing Radiation-Induced Tissue Damage in the Feather Follicle

    PubMed Central

    Chen, Xi; Liao, Chunyan; Chu, Qiqi; Zhou, Guixuan; Lin, Xiang; Li, Xiaobo; Lu, Haijie; Xu, Benhua; Yue, Zhicao

    2014-01-01

    Ionizing radiation (IR) is a common therapeutic agent in cancer therapy. It damages normal tissue and causes side effects including dermatitis and mucositis. Here we use the feather follicle as a model to investigate the mechanism of IR-induced tissue damage, because any perturbation of feather growth will be clearly recorded in its regular yet complex morphology. We find that IR induces defects in feather formation in a dose-dependent manner. No abnormality was observed at 5 Gy. A transient, reversible perturbation of feather growth was induced at 10 Gy, leading to defects in the feather structure. This perturbation became irreversible at 20 Gy. Molecular and cellular analysis revealed P53 activation, DNA damage and repair, cell cycle arrest and apoptosis in the pathobiology. IR also induces patterning defects in feather formation, with disrupted branching morphogenesis. This perturbation is mediated by cytokine production and Stat1 activation, as manipulation of cytokine levels or ectopic Stat1 over-expression also led to irregular feather branching. Furthermore, AG-490, a chemical inhibitor of Stat1 signaling, can partially rescue IR-induced tissue damage. Our results suggest that the feather follicle could serve as a useful model to address the in vivo impact of the many mechanisms of IR-induced tissue damage. PMID:24586618

  3. Dissecting the molecular mechanism of ionizing radiation-induced tissue damage in the feather follicle.

    PubMed

    Chen, Xi; Liao, Chunyan; Chu, Qiqi; Zhou, Guixuan; Lin, Xiang; Li, Xiaobo; Lu, Haijie; Xu, Benhua; Yue, Zhicao

    2014-01-01

    Ionizing radiation (IR) is a common therapeutic agent in cancer therapy. It damages normal tissue and causes side effects including dermatitis and mucositis. Here we use the feather follicle as a model to investigate the mechanism of IR-induced tissue damage, because any perturbation of feather growth will be clearly recorded in its regular yet complex morphology. We find that IR induces defects in feather formation in a dose-dependent manner. No abnormality was observed at 5 Gy. A transient, reversible perturbation of feather growth was induced at 10 Gy, leading to defects in the feather structure. This perturbation became irreversible at 20 Gy. Molecular and cellular analysis revealed P53 activation, DNA damage and repair, cell cycle arrest and apoptosis in the pathobiology. IR also induces patterning defects in feather formation, with disrupted branching morphogenesis. This perturbation is mediated by cytokine production and Stat1 activation, as manipulation of cytokine levels or ectopic Stat1 over-expression also led to irregular feather branching. Furthermore, AG-490, a chemical inhibitor of Stat1 signaling, can partially rescue IR-induced tissue damage. Our results suggest that the feather follicle could serve as a useful model to address the in vivo impact of the many mechanisms of IR-induced tissue damage.

  4. Amifostine, a radioprotectant agent, protects rat brain tissue lipids against ionizing radiation induced damage: An FTIR microspectroscopic imaging study

    SciTech Connect

    Cakmak G.; Miller L.; Zorlu, F.; Severcan, F.

    2012-03-03

    Amifostine is the only approved radioprotective agent by FDA for reducing the damaging effects of radiation on healthy tissues. In this study, the protective effect of amifostine against the damaging effects of ionizing radiation on the white matter (WM) and grey matter (GM) regions of the rat brain were investigated at molecular level. Sprague-Dawley rats, which were administered amifostine or not, were whole-body irradiated at a single dose of 800 cGy, decapitated after 24 h and the brain tissues of these rats were analyzed using Fourier transform infrared microspectroscopy (FTIRM). The results revealed that the total lipid content and CH{sub 2} groups of lipids decreased significantly and the carbonyl esters, olefinic=CH and CH{sub 3} groups of lipids increased significantly in the WM and GM after exposure to ionizing radiation, which could be interpreted as a result of lipid peroxidation. These changes were more prominent in the WM of the brain. The administration of amifostine before ionizing radiation inhibited the radiation-induced lipid peroxidation in the brain. In addition, this study indicated that FTIRM provides a novel approach for monitoring ionizing radiation induced-lipid peroxidation and obtaining different molecular ratio images can be used as biomarkers to detect lipid peroxidation in biological systems.

  5. Normal tissue complication probability modeling of radiation-induced sensorineural hearing loss after head-and-neck radiation therapy.

    PubMed

    Cheraghi, Susan; Nikoofar, Alireza; Bakhshandeh, Mohsen; Khoei, Samideh; Farahani, Saeid; Abdollahi, Hamid; Mahdavi, Seied Rabi

    2017-10-02

    The aim of this study was to generate the dose-response curves by six normal tissue complication probability (NTCP) models and ranking the models for prediction of radiation induced sensorineural hearing loss (SNHL) caused by head and neck radiation therapy (RT). Pure tone audiometry (PTA) was performed on 70 ears of patients for 12 months after the completion of radiation therapy. The SNHL was defined as a threshold shift ≤15 dB at 2 contiguous frequencies according to the common toxicity criteria for adverse events scoring system. The models evaluated were: Lyman and Logit; Mean Dose; Relative Seriality; Individual Critical Volume; and Population Critical Volume models. Maximum likelihood analysis was used to fit the models to experimental data. The appropriateness of the fit was determined by the 2-sample Kolmogorov-Smirnov test. Ranking of the models was made according to Akaike's information criterion. The dose of 50% complication rate (D50) was 51-60 Gy. Three of the examined models fitted well with clinical data in a 95% confidence interval. The relative seriality model was ranked as the best model of prediction for radiation induced SNHL. Cochlea shows a different behaviour against different NTCP models; it's may be due to its small size.

  6. The effect of interferon gamma on conventional fractionated radiation-induced damage and fibrosis in the pelvic tissue of rabbits

    PubMed Central

    Yang, Yunyi; Liu, Zi; Wang, Juan; Chai, Yanlan; Su, Jin; Shi, Fan; Wang, Jiquan; Che, Shao Min

    2016-01-01

    We aim to investigate the effect of interferon gamma (IFN-γ) on conventional fractionated radiation–induced damage and fibrosis in ureter and colorectal mucosa. Fifty-two rabbits were randomly divided into three groups comprising a conventional radiation group, an IFN-γ group, and a control group. X-rays were used to irradiate the pelvic tissues of the rabbits in the IFN-γ and conventional radiation groups. Five days after radiation exposure, the rabbits in the IFN-γ group were administered 250,000 U/kg IFN-γ intramuscularly once a week for 5 weeks. The rabbits in the conventional radiation group received 5.0 mL/kg saline. The rabbits were sacrificed at 4, 8, 12, and 16 weeks postradiation, and the rectal and ureteral tissues within the radiation areas were collected. The results showed that the morphology of rectal and ureteral tissues was changed by X-ray radiation. The degree of damage at 4, 8, and 12 weeks, but not at 16 weeks, postradiation was significantly different between the IFN-γ and conventional radiation groups. The expression of transforming growth factor beta 1 mRNA in the ureter and colorectal mucosa of the IFN-γ group was significantly lower than that in the conventional radiation group at 4, 8, 12, and 16 weeks postradiation, but it was still higher than that in the control group. There were significant differences in the expression of collagen III among the three groups. IFN-γ can inhibit the radiation-induced upregulation of transforming growth factor beta 1 mRNA and collagen III protein in the ureter and colorectal mucosa and attenuate radiation-induced damage and fibrosis. PMID:27274263

  7. Radiation induced COX-2 expression and mutagenesis at non-targeted lung tissues of gpt delta transgenic mice

    PubMed Central

    Chai, Y; Calaf, G M; Zhou, H; Ghandhi, S A; Elliston, C D; Wen, G; Nohmi, T; Amundson, S A; Hei, T K

    2013-01-01

    Background: Although radiation-induced bystander effects have been confirmed using a variety of endpoints, the mechanism(s) underlying these effects are not well understood, especially for in vivo study. Methods: A 1-cm2 area (1 cm × 1 cm) in the lower abdominal region of gpt delta transgenic mice was irradiated with 5 Gy of 300 keV X-rays, and changes in out-of-field lung and liver were observed. Results: Compared with sham-treated controls, the Spi− mutation frequency increased 2.4-fold in non-targeted lung tissues at 24 h after partial body irradiation (PBIR). Consistent with dramatic Cyclooxygenase 2 (COX-2) induction in the non-targeted bronchial epithelial cells, increasing levels of prostaglandin, together with 8-hydroxydeoxyguanosine, in the out-of-field lung tissues were observed after PBIR. In addition, DNA double-strand breaks and apoptosis were induced in bystander lung tissues after PBIR. Conclusion: The PBIR induces DNA damage and mutagenesis in non-targeted lung tissues, especially in bronchial epithelial cells, and COX-2 has an essential role in bystander mutagenesis. PMID:23321513

  8. Investigation of gamma radiation induced changes in local structure of borosilicate glass by TDPAC and EXAFS

    NASA Astrophysics Data System (ADS)

    Kumar, Ashwani; Nayak, C.; Rajput, P.; Mishra, R. K.; Bhattacharyya, D.; Kaushik, C. P.; Tomar, B. S.

    2016-12-01

    Gamma radiation induced changes in local structure around the probe atom (Hafnium) were investigated in sodium barium borosilicate (NBS) glass, used for immobilization of high level liquid waste generated from the reprocessing plant at Trombay, Mumbai. The (NBS) glass was doped with 181Hf as a probe for time differential perturbed angular correlation (TDPAC) spectroscopy studies, while for studies using extended X-ray absorption fine structure (EXAFS) spectroscopy, the same was doped with 0.5 and 2 % (mole %) hafnium oxide. The irradiated as well as un-irradiated glass samples were studied by TDPAC and EXAFS techniques to obtain information about the changes (if any) around the probe atom due to gamma irradiation. TDPAC spectra of unirradiated and irradiated glasses were similar and reminescent of amorphous materials, indicating negligible effect of gamma radiation on the microstructure around Hafnium probe atom, though the quaqdrupole interaction frequency ( ω Q) and asymmetry parameter ( η) did show a marginal decrease in the irradiated glass compared to that in the unirradiated glass. EXAFS measurements showed a slight decrease in the Hf-O bond distance upon gamma irradiation of Hf doped NBS glass indicating densification of the glass matrix, while the cordination number around hafnium remains unchanged.

  9. TGF-.beta. antagonists as mitigators of radiation-induced tissue damage

    DOEpatents

    Barcellos-Hoff, Mary H.

    1997-01-01

    A method for treating tissue damage caused by radiation is described by use of a TGF-.beta. antagonist, such as an anti-TGF-.beta. antibody or a TGF-.beta. latency associated protein. It is administered not more than a week after exposure, and is particularly useful in mitigating the side effects of breast cancer therapy.

  10. TGF-{beta} antagonists as mitigators of radiation-induced tissue damage

    DOEpatents

    Barcellos-Hoff, M.H.

    1997-04-01

    A method for treating tissue damage caused by radiation is described by use of a TGF-{beta} antagonist, such as an anti-TGF-{beta} antibody or a TGF-{beta} latency associated protein. It is administered not more than a week after exposure, and is particularly useful in mitigating the side effects of breast cancer therapy.

  11. Modulation of radiation-induced alterations in oxidative stress and cytokine expression in lung tissue by Panax ginseng extract.

    PubMed

    Jang, Seong Soon; Kim, Hyeong Geug; Han, Jong Min; Lee, Jin Seok; Choi, Min Kyung; Huh, Gil Ja; Son, Chang Gue

    2015-02-01

    We investigated the modulating effect of Panax ginseng extract (PGE) on radiation-induced lung injury (RILI) by measuring early changes in oxidative stress levels, cytokine expression, and the histopathology of mouse lung tissue treated with high dose of X-ray radiation. The mice were pretreated with 25, 50, and 100-mg/kg doses of PGE orally for four consecutive days, and their thoraces were then exposed to 15-Gy X-ray radiation 1 h after the last administration of PGE on day 4. The pretreatments with 50 and 100 mg/kg PGE led to significant reductions in the elevation of lipid peroxidation levels at 2 and 10 days, respectively, after irradiation. The mice pretreated with PGE exhibited dose-dependent reductions in the irradiation-induced production of tumor necrosis factor α and transforming growth factor β1 cytokines 10 days after irradiation, with these reductions nearly reaching the control levels after the 100-mg/kg dose. Furthermore, together with providing significant protection against reductions in catalase activity and glutathione content, pretreatment with 100 mg/kg PGE resulted in a marked attenuation of the severity of inflammatory changes in lung tissue 10 days after irradiation. A high pretreatment dose of PGE may be a useful pharmacological approach for protection against RILI.

  12. Mobilization of LINE-1 in irradiated mammary gland tissue may potentially contribute to low dose radiation-induced genomic instability.

    PubMed

    Luzhna, Lidia; Ilnytskyy, Yaroslav; Kovalchuk, Olga

    2015-01-01

    It is known that cellular stresses such as ionizing radiation activate LINE-1 (long interspersed nuclear element type 1, L1), but the molecular mechanisms of LINE-1 activation have not been fully elucidated. There is a possibility that DNA methylation changes induced by genotoxic stresses might contribute to LINE-1 activation in mammalian cells. L1 insertions usually cause major genomic rearrangements, such as deletions, transductions, the intrachromosomal homologous recombination between L1s, and the generation of pseudogenes, which could lead to genomic instability. The purpose of this study was to evaluate the effects of low and high doses of ionizing radiation on the DNA methylation status of LINE-1 transposable elements in rat mammary glands. Here we describe radiation-induced hypomethylation and activation of LINE-1 ORF1 in rat mammary gland tissues. We show that radiation exposure has also led to the translation of the LINE-1 element, whereby the 148 kDa LINE-1 protein level was increased 96 hours after treatment with a low dose and low energy level radiation and remained elevated for 24 weeks after treatment. The mobilization of LINE-1 in irradiated tissue may potentially contribute to genomic instability. The observed activation of mobile elements in response to radiation exposure is consistently discussed as a plausible mechanism of cancer etiology and development.

  13. Radiation-induced changes in intestinal and tissue-nonspecific alkaline phosphatase: implications for recovery after radiation therapy.

    PubMed

    Rentea, Rebecca M; Lam, Vy; Biesterveld, Ben; Fredrich, Katherine M; Callison, Jennifer; Fish, Brian L; Baker, John E; Komorowski, Richard; Gourlay, David M; Otterson, Mary F

    2016-10-01

    Exogenous replacement of depleted enterocyte intestinal alkaline phosphatase (IAP) decreases intestinal injury in models of colitis. We determined whether radiation-induced intestinal injury could be mitigated by oral IAP supplementation and the impact on tissue-nonspecific AP. WAG/RjjCmcr rats (n = 5 per group) received lower hemibody irradiation (13 Gy) followed by daily gavage with phosphate-buffered saline or IAP (40 U/kg/d) for 4 days. Real-time polymerase chain reaction, AP activity, and microbiota analysis were performed on intestine. Lipopolysaccharide and cytokine analysis was performed on serum. Data were expressed as a mean ± SEM with P greater than .05 considered significant. Intestine of irradiated animals demonstrates lower hemibody irradiation and is associated with upregulation of tissue-nonspecific AP, downregulation of IAP, decreased AP activity, and altered composition of the intestinal microbiome. Supplemental IAP after radiation may be beneficial in mitigating intestinal radiation syndrome as evidenced by improved histologic injury, decreased acute intestinal inflammation, and normalization of intestinal microbiome. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Dependence on grain boundary structure of radiation induced segregation in a 9 wt.% Cr model ferritic/martensitic steel

    NASA Astrophysics Data System (ADS)

    Field, Kevin G.; Barnard, Leland M.; Parish, Chad M.; Busby, Jeremy T.; Morgan, Dane; Allen, Todd R.

    2013-04-01

    Ferritic/Martensitic (F/M) steels containing 9 wt.% Cr are candidates for structural and cladding components in the next generation of advanced nuclear fission and fusion reactors. Although it is known these alloys exhibit radiation-induced segregation (RIS) at grain boundaries (GBs) while in-service, little is known about the mechanism behind RIS in F/M steels. The classical understanding of RIS in F/M steels presents a mechanism where point defects migrate to GBs acting as perfect sinks. However, variation in grain boundary structure may influence the sink efficiency and these migration processes. A proton irradiated 9 wt.% Cr model alloy steel was investigated using STEM/EDS spectrum imaging and GB misorientation analysis to determine the role of GB structure on RIS at different GBs. An ab initio based rate theory model was developed and compared to the experimental findings. This investigation found Cr preferentially segregates to specific GB structures. The preferential segregation to specific GB structures suggests GB structure plays a key role in the mechanism behind radiation-induced segregation, showing that not all grain boundaries in F/M steels act as perfect sinks. The study also found how irradiation dose and temperature impact the radiation-induced segregation response in F/M steels.

  15. A mechanistic description of radiation-induced damage to normal tissue and its healing kinetics

    NASA Astrophysics Data System (ADS)

    Hanin, Leonid; Zaider, Marco

    2013-02-01

    We introduce a novel mechanistic model of the yield of tissue damage at the end of radiation treatment and of the subsequent healing kinetics. We find explicit expressions for the total number of functional proliferating cells as well as doomed (functional but non-proliferating) cells as a function of time post treatment. This leads to the possibility of estimating—for any given cohort of patients undergoing radiation therapy—the probability distribution of those kinetic parameters (e.g. proliferation rates) that determine times to injury onset and ensuing resolution. The model is suitable for tissues with simple duplication organization, meaning that functionally competent cells are also responsible for tissue renewal or regeneration following injury. An extension of the model to arbitrary temporal patterns of dose rate is presented. To illustrate the practical utility of the model, as well as its limitations, we apply it to data on the time course of urethral toxicity following fractionated radiation treatment and brachytherapy for prostate cancer.

  16. Structural effects of radiation-induced volumetric expansion on unreinforced concrete biological shields

    DOE PAGES

    Le Pape, Y.

    2015-11-22

    Limited literature (Pomaro et al., 2011, Mirhosseini et al., 2014, Salomoni et al., 2014 and Andreev and Kapliy, 2014) is available on the structural analysis of irradiated concrete biological shield (CBS), although extended operations of nuclear powers plants may lead to critical neutron exposure above 1.0 × 10+19 n cm₋2. To the notable exception of Andreev and Kapliy, available structural models do not account for radiation-induced volumetric expansion, although it was found to develop important linear dimensional change of the order of 1%, and, can lead to significant concrete damage (Le Pape et al., 2015). A 1D-cylindrical model of an unreinforced CBS accounting for temperature and irradiation effects is developed. Irradiated concrete properties are characterized probabilistically using the updated database collected by Oak Ridge National Laboratory (Field et al., 2015). The overstressed concrete ratio (OCR) of the CBS, i.e., the proportion of the wall thickness being subject to stresses beyond the resistance of concrete, is derived by deterministic and probabilistic analysis assuming that irradiated concrete behaves as an elastic materials. In the bi-axial compressive zone near the reactor cavity, the OCR is limited to 5.7%, i.e., 8.6 cm (3more » $$_2^1$$ in.), whereas, in the tension zone, the OCR extends to 72%, i.e., 1.08 m (42$$_2^1$$ in.). Finally, we find that these results, valid for a maximum neutron fluence on the concrete surface of 3.1 × 10+19 n cm₋2 (E > 0.1 MeV) and, obtained after 80 years of operation, give an indication of the potential detrimental effects of prolonged irradiation of concrete in nuclear power plants.« less

  17. Structural effects of radiation-induced volumetric expansion on unreinforced concrete biological shields

    SciTech Connect

    Le Pape, Y.

    2015-11-22

    Limited literature (Pomaro et al., 2011, Mirhosseini et al., 2014, Salomoni et al., 2014 and Andreev and Kapliy, 2014) is available on the structural analysis of irradiated concrete biological shield (CBS), although extended operations of nuclear powers plants may lead to critical neutron exposure above 1.0 × 10+19 n cm₋2. To the notable exception of Andreev and Kapliy, available structural models do not account for radiation-induced volumetric expansion, although it was found to develop important linear dimensional change of the order of 1%, and, can lead to significant concrete damage (Le Pape et al., 2015). A 1D-cylindrical model of an unreinforced CBS accounting for temperature and irradiation effects is developed. Irradiated concrete properties are characterized probabilistically using the updated database collected by Oak Ridge National Laboratory (Field et al., 2015). The overstressed concrete ratio (OCR) of the CBS, i.e., the proportion of the wall thickness being subject to stresses beyond the resistance of concrete, is derived by deterministic and probabilistic analysis assuming that irradiated concrete behaves as an elastic materials. In the bi-axial compressive zone near the reactor cavity, the OCR is limited to 5.7%, i.e., 8.6 cm (3$_2^1$ in.), whereas, in the tension zone, the OCR extends to 72%, i.e., 1.08 m (42$_2^1$ in.). Finally, we find that these results, valid for a maximum neutron fluence on the concrete surface of 3.1 × 10+19 n cm₋2 (E > 0.1 MeV) and, obtained after 80 years of operation, give an indication of the potential detrimental effects of prolonged irradiation of concrete in nuclear power plants.

  18. The Chernobyl Tissue Bank: integrating research on radiation-induced thyroid cancer.

    PubMed

    Thomas, G A

    2012-03-01

    The only unequivocal radiological effect of the Chernobyl accident on human health is the increase in thyroid cancer in those exposed in childhood or early adolescence. Cancer is a complicated disease and it is unclear whether the mechanism by which radiation gives rise to cancer differs from that involved in the generation of cancers of the same type by other environmental stimuli. The Chernobyl Tissue Bank was established in response to the scientific interest in studying the molecular biology of thyroid cancer after Chernobyl to address this question. The project is supported by the governments of Ukraine and Russia, and financially supported (in total around US$3 million) by the European Commission, the National Cancer Institute of the USA and the Sasakawa Memorial Health Foundation of Japan. The project began collecting a variety of biological samples from patients on 1 October 1988, and has supplied material to 23 research projects in Japan, the USA and Europe. The establishment of the Chernobyl Tissue Bank has facilitated co-operation between these research projects and the combination of clinical and research data provides a paradigm for cancer research in the molecular biological age.

  19. Modeling the risk of radiation-induced lung fibrosis: Irradiated heart tissue is as important as irradiated lung.

    PubMed

    Cella, Laura; D'Avino, Vittoria; Palma, Giuseppe; Conson, Manuel; Liuzzi, Raffaele; Picardi, Marco; Pressello, Maria Cristina; Boboc, Genoveva Ionela; Battistini, Roberta; Donato, Vittorio; Pacelli, Roberto

    2015-10-01

    We used normal tissue complication probability (NTCP) modeling to explore the impact of heart irradiation on radiation-induced lung fibrosis (RILF). We retrospectively reviewed for RILF 148 consecutive Hodgkin lymphoma (HL) patients treated with sequential chemo-radiotherapy (CHT-RT). Left, right, total lung and heart dose-volume and dose-mass parameters along with clinical, disease and treatment-related characteristics were analyzed. NTCP modeling by multivariate logistic regression analysis using bootstrapping was performed. Models were evaluated by Spearman Rs coefficient and ROC area. At a median time of 13months, 18 out of 115 analyzable patients (15.6%) developed RILF after treatment. A three-variable predictive model resulted to be optimal for RILF. The two models most frequently selected by bootstrap included increasing age and mass of heart receiving >30Gy as common predictors, in combination with left lung V5 (Rs=0.35, AUC=0.78), or alternatively, the lungs near maximum dose D2% (Rs=0.38, AUC=0.80). CHT-RT may cause lung injury in a small, but significant fraction of HL patients. Our results suggest that aging along with both heart and lung irradiation plays a fundamental role in the risk of developing RILF. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Microbeam Radiation-Induced Tissue Damage Depends on the Stage of Vascular Maturation

    SciTech Connect

    Sabatasso, Sara; Laissue, Jean Albert; Hlushchuk, Ruslan; Graber, Werner; Bravin, Alberto; Braeuer-Krisch, Elke; Corde, Stephanie; Blattmann, Hans; Gruber, Guenther; Djonov, Valentin

    2011-08-01

    Purpose: To explore the effects of microbeam radiation (MR) on vascular biology, we used the chick chorioallantoic membrane (CAM) model of an almost pure vascular system with immature vessels (lacking periendothelial coverage) at Day 8 and mature vessels (with coverage) at Day 12 of development. Methods and Materials: CAMs were irradiated with microplanar beams (width, {approx}25 {mu}m; interbeam spacing, {approx}200 {mu}m) at entrance doses of 200 or 300 Gy and, for comparison, with a broad beam (seamless radiation [SLR]), with entrance doses of 5 to 40 Gy. Results: In vivo monitoring of Day-8 CAM vasculature 6 h after 200 Gy MR revealed a near total destruction of the immature capillary plexus. Conversely, 200 Gy MR barely affected Day-12 CAM mature microvasculature. Morphological evaluation of Day-12 CAMs after the dose was increased to 300 Gy revealed opened interendothelial junctions, which could explain the transient mesenchymal edema immediately after irradiation. Electron micrographs revealed cytoplasmic vacuolization of endothelial cells in the beam path, with disrupted luminal surfaces; often the lumen was engorged with erythrocytes and leukocytes. After 30 min, the capillary plexus adopted a striated metronomic pattern, with alternating destroyed and intact zones, corresponding to the beam and the interbeam paths within the array. SLR at a dose of 10 Gy caused growth retardation, resulting in a remarkable reduction in the vascular endpoint density 24 h postirradiation. A dose of 40 Gy damaged the entire CAM vasculature. Conclusions: The effects of MR are mediated by capillary damage, with tissue injury caused by insufficient blood supply. Vascular toxicity and physiological effects of MR depend on the stage of capillary maturation and appear in the first 15 to 60 min after irradiation. Conversely, the effects of SLR, due to the arrest of cell proliferation, persist for a longer time.

  1. Consecutive CT-guided core needle tissue biopsy of lung lesions in the same dog at different phases of radiation-induced lung injury

    PubMed Central

    Yin, Zhongyuan; Deng, Sisi; Liang, Zhiwen; Wang, Qiong

    2016-01-01

    This project aimed to set up a Beagle dog model of radiation-induced lung injury in order to supply fresh lung tissue samples in the different injury phases for gene and protein research. Three dogs received 18 Gy X-ray irradiation in one fraction, another three dogs received 8 Gy in each of three fractions at weekly intervals, and one control dog was not irradiated. Acute pneumonitis was observed during the first 3 months after radiation, and chronic lung fibrosis was found during the next 4–12 months in all the dogs exposed to radiation. CT-guided core needle lung lesion biopsies were extracted from each dog five times over the course of 1 year. The dogs remained healthy after each biopsy, and 50–100 mg fresh lung lesion tissues were collected in each operation. The incidence of pneumothorax and hemoptysis was 20% and 2.8%, respectively, in the 35 tissue biopsies. A successful and stable radiation-induced lung injury dog model was established. Lung lesion tissue samples from dogs in acute stage, recovery stage and fibrosis stage were found to be sufficient to support cytology, genomics and proteomics research. This model safely supplied fresh tissue samples that would allow future researchers to more easily explore and develop treatments for radiation-induced lung injury. PMID:27422930

  2. The Correlation of Interphase Chromatin Structure with the Radiation-Induced Inter- and Intrachromosome Exchange Hotspots

    NASA Technical Reports Server (NTRS)

    Zhang, Ye; Mangala, Lingegowda S.; Purgason, Ashley M.; Hada, Megumi; Cucinotta, Francis A.; Wu, Honglu

    2011-01-01

    To investigate the relationship between chromosome aberrations induced by radiation and chromatin folding, we reconstructed three dimensional structure of chromosome 3 and measured the physical distances between different regions of the chromosome. Previously, we have investigated the location of breaks involved in inter- and intrachromosomal type exchange events in human chromosome 3, using the multicolor banding in situ hybridization (mBAND) technique. In human epithelial cells exposed to both low- and high-LET radiations in vitro, we reported that intra-chromosome exchanges occurred preferentially between a break in the 3p21 and one in the 3q11 regions, and the breaks involving in inter-chromosome exchanges occurred in two regions towards the telomeres of the chromosome. Exchanges were also observed between a break in 3p21 and one in 3q26, but few exchanges were observed between breaks in 3q11 and 3q26, even though the two regions are located on the same arm of the chromosome. In this study, human epithelial cells were fixed at G1 phase and the interphase cells were hybridized using the XCyte3 mBAND kit from MetaSystems. The z-section images of chromosome 3 were captured with a Leica and an LSM 510 Meta laser scanning confocal microscopes. A total of 100 chromosomes were analyzed. The reconstruction of three dimensional structure of interphase chromosome 3 with six different colored regions was achieved using the Imaris software. The relative distance between different regions was measured as well. We further analyzed fragile sites on the chromosome that have been identified in various types of cancers. The data showed that, in majority of the cells, the regions containing 3p21 and 3q11 are colocalized in the center of the chromosome, whereas, the regions towards the telomeres of the chromosome are either physically wrapping outside the chromosome center or with arms sticking out. Our results demonstrated that the distribution of breaks involved in radiation-induced

  3. Radiation-Induced Bioradicals

    NASA Astrophysics Data System (ADS)

    Mondelaers, Win; Lahorte, Philippe

    This chapter is part one of a review in which the production and application of radiation-induced bioradicals is discussed. Bioradicals play a pivotal role in the complex chain of processes starting with the absorption of radiation in biological materials and ending with the radiation-induced biological after-effects. The general aspects of the four consecutive stages (physical, physicochemical, chemical and biological) are discussed from an interdisciplinary point of view. The close relationship between radiation dose and track structure, induced DNA damage and cell survival or killing is treated in detail. The repair mechanisms that cells employ, to insure DNA stability following irradiation, are described. Because of their great biomedical importance tumour suppressor genes involved in radiation-induced DNA repair and in checkpoint activation will be treated briefly, together with the molecular genetics of radiosensitivity. Part two of this review will deal with modern theoretical methods and experimental instrumentation for quantitative studies in this research field. Also an extensive overview of the applications of radiation-induced bioradicals will be given. A comprehensive list of references allows further exploration of this research field, characterised in the last decade by a substantial advance, both in fundamental knowledge and in range of applications.

  4. Hyperbaric oxygen therapy for late radiation-induced tissue toxicity: prospectively patient-reported outcome measures in breast cancer patients.

    PubMed

    Teguh, David N; Bol Raap, René; Struikmans, Henk; Verhoef, Cees; Koppert, Linetta B; Koole, Arne; Huang, Yadi; van Hulst, Rob A

    2016-09-29

    This study examines patient reported outcome measures of women undergoing hyperbaric oxygen treatment (HBOT) after breast-conserving therapy. Included were 57 women treated with HBOT for late radiation-induced tissue toxicity (LRITT) referred in the period January 2014-December 2015. HBOT consisted of (on average) 47 sessions. In total, 80 min of 100 % O2 was administered under increased pressure of 2.4 ATA. Quality of life was assessed before and after treatment using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-BR23, and a NRS pain score. Fifty-seven women were available for evaluation before and after treatment. Before HBOT, patients had severe complaints of pain in the arm/shoulder (46 %), swollen arm/hand (14 %), difficulty to raise arm or move it sideways (45 %), pain in the area of the affected breast (67 %), swollen area of the affected breast (45 %), oversensitivity of the affected breast (54 %), and skin problems on/in the area of the affected breast (32 %); post HBOT, severe complaints were still experienced in 17, 7, 22, 15, 13, 15, and 11 % of the women, respectively. Differences were all significant. The NRS pain score improved at least 1 point (range 0-10) in 81 % of the patients (p < 0.05). In these breast cancer patients treated with HBOT for LRITT, the patient-reported outcomes were positive and improvements were observed. HBOT was a well-tolerated treatment for LRITT and its side-effects were both minimal and reversible.

  5. Accumulation of radiation-induced charge in MNOS structures with different oxide thicknesses

    SciTech Connect

    Gurtov, V.A.; Evdokimov, V.D.; Nazarov, A.I.; Khrustalev, V.A.

    1986-05-01

    The authors attempt to answer questions regarding the dosimetry of x-ray radiation sources, especially in the region of high exposure doses, using silicon nitride. SiO/sub 2/ was obtained by thermal oxidation in dry oxygen or in a mixture of oxygen and argon. Silicon nitride was obtained by ammonolysis of silicon tetrachloride. Aluminum was used for the gate. The magnitude of the radiation-induced space charge was determined from the shift in the flat-band voltage on the high-frequency volt-faraday curves.

  6. Normal Tissue Complication Probability Modeling of Radiation-Induced Hypothyroidism After Head-and-Neck Radiation Therapy

    SciTech Connect

    Bakhshandeh, Mohsen; Hashemi, Bijan; Mahdavi, Seied Rabi Mehdi; Nikoofar, Alireza; Vasheghani, Maryam; Kazemnejad, Anoshirvan

    2013-02-01

    Purpose: To determine the dose-response relationship of the thyroid for radiation-induced hypothyroidism in head-and-neck radiation therapy, according to 6 normal tissue complication probability models, and to find the best-fit parameters of the models. Methods and Materials: Sixty-five patients treated with primary or postoperative radiation therapy for various cancers in the head-and-neck region were prospectively evaluated. Patient serum samples (tri-iodothyronine, thyroxine, thyroid-stimulating hormone [TSH], free tri-iodothyronine, and free thyroxine) were measured before and at regular time intervals until 1 year after the completion of radiation therapy. Dose-volume histograms (DVHs) of the patients' thyroid gland were derived from their computed tomography (CT)-based treatment planning data. Hypothyroidism was defined as increased TSH (subclinical hypothyroidism) or increased TSH in combination with decreased free thyroxine and thyroxine (clinical hypothyroidism). Thyroid DVHs were converted to 2 Gy/fraction equivalent doses using the linear-quadratic formula with {alpha}/{beta} = 3 Gy. The evaluated models included the following: Lyman with the DVH reduced to the equivalent uniform dose (EUD), known as LEUD; Logit-EUD; mean dose; relative seriality; individual critical volume; and population critical volume models. The parameters of the models were obtained by fitting the patients' data using a maximum likelihood analysis method. The goodness of fit of the models was determined by the 2-sample Kolmogorov-Smirnov test. Ranking of the models was made according to Akaike's information criterion. Results: Twenty-nine patients (44.6%) experienced hypothyroidism. None of the models was rejected according to the evaluation of the goodness of fit. The mean dose model was ranked as the best model on the basis of its Akaike's information criterion value. The D{sub 50} estimated from the models was approximately 44 Gy. Conclusions: The implemented normal tissue

  7. Ionizing Radiation-Induced Endothelial Cell Senescence and Cardiovascular Diseases

    PubMed Central

    Wang, Yingying; Boerma, Marjan; Zhou, Daohong

    2016-01-01

    Exposure to ionizing radiation induces not only apoptosis but also senescence. While the role of endothelial cell apoptosis in mediating radiation-induced acute tissue injury has been extensively studied, little is known about the role of endothelial cell senescence in the pathogenesis of radiation-induced late effects. Senescent endothelial cells exhibit decreased production of nitric oxide and expression of thrombomodulin, increased expression of adhesion molecules, elevated production of reactive oxygen species and inflammatory cytokines and an inability to proliferate and form capillary-like structures in vitro. These findings suggest that endothelial cell senescence can lead to endothelial dysfunction by dysregulation of vasodilation and hemostasis, induction of oxidative stress and inflammation and inhibition of angiogenesis, which can potentially contribute to radiation-induced late effects such as cardiovascular diseases (CVDs). In this article, we discuss the mechanisms by which radiation induces endothelial cell senescence, the roles of endothelial cell senescence in radiation-induced CVDs and potential strategies to prevent, mitigate and treat radiation-induced CVDs by targeting senescent endothelial cells. PMID:27387862

  8. Mitigating HZE Radiation-Induced Deficits in Marrow-Derived Mesenchymal Progenitor Cells and Skeletal Structure

    NASA Technical Reports Server (NTRS)

    Globus, Ruth K.; Schreurs, Ann-Sofie; Shirazi-Fard, Yasaman; Terada, Masahiro; Alwood, Joshua; Halloran, Bernard; Tahimic, Candice

    2016-01-01

    Future long-duration space exploration beyond the earths magnetosphere will increase human exposure to space radiation and associated risks to skeletal health. We hypothesize that oxidative stress resulting from radiation exposure causes progressive bone loss and dysfunction in associated tissue. In animal studies, increased free radical formation is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility.

  9. Radiation-induced cardiovascular effects

    NASA Astrophysics Data System (ADS)

    Tapio, Soile

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

  10. Association between Single Nucleotide Polymorphisms in XRCC3 and Radiation-Induced Adverse Effects on Normal Tissue: A Meta-Analysis.

    PubMed

    Song, Yu-Zhe; Han, Fu-Jun; Liu, Min; Xia, Cheng-Cheng; Shi, Wei-Yan; Dong, Li-Hua

    2015-01-01

    The X-ray repair cross-complementing group 3 (XRCC3) protein plays an important role in the repair of DNA double-strand breaks. The relationship between XRCC3 polymorphisms and the risk of radiation-induced adverse effects on normal tissue remains inconclusive. Thus, we performed a meta-analysis to elucidate the association between XRCC3 polymorphisms and radiation-induced adverse effects on normal tissue. All eligible studies up to December 2014 were identified through a search of the PubMed, Embase and Web of Science databases. Seventeen studies involving 656 cases and 2193 controls were ultimately included in this meta-analysis. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to evaluate the association between XRCC3 polymorphisms and the risk of radiation-induced normal tissue adverse effects. We found that the XRCC3 p.Thr241Met (rs861539) polymorphism was significantly associated with early adverse effects induced by radiotherapy (OR = 1.99, 95%CI: 1.31-3.01, P = 0.001). A positive association lacking statistical significance with late adverse effects was also identified (OR = 1.28, 95%CI: 0.97-1.68, P = 0.08). In addition, the rs861539 polymorphism was significantly correlated with a higher risk of adverse effects induced by head and neck area irradiation (OR = 2.41, 95%CI: 1.49-3.89, p = 0.0003) and breast irradiation (OR = 1.41, 95%CI: 1.02-1.95, p = 0.04), whereas the correlation was not significant for lung irradiation or pelvic irradiation. Furthermore, XRCC3 rs1799794 polymorphism may have a protective effect against late adverse effects induced by radiotherapy (OR = 0.47, 95%CI: 0.26-0.86, P = 0.01). Well-designed large-scale clinical studies are required to further validate our results.

  11. Structure and properties of the radiation-induced intermediates produced from HCN in noble gas matrices

    NASA Astrophysics Data System (ADS)

    Kameneva, Svetlana V.; Tyurin, Daniil A.; Feldman, Vladimir I.

    2016-07-01

    In this work we report the results of systematic studies on the radiation-induced transformations in HCN/Ng systems (Ng=Ne, Ar, Kr or Xe) at 7 K using a combination of FTIR and EPR spectroscopy. It was shown that HCN underwent efficient decomposition producing H atoms, CN radicals and HNC isomer. The thermally induced reactions of H atoms in different matrices result in the formation of two isomeric radicals, H2CN and trans-HCNH, the former being predominated. The temperature dependent dynamics of CN and H2CN radicals in a krypton matrix was observed by EPR spectroscopy in solid krypton. The vibrational frequencies, IR intensities and magnetic resonance parameters of H2CN and trans-HCNH radicals calculated at the CCSD(T) level are in reasonable agreement with the experimental results. It was found that HCNH radical could be effectively bleached with visible light. The comparison of experimental and computational data made it possible to assign a new vibrational band at 918 cm-1 in an Ar matrix (and the corresponding bands in Kr and Xe) to trans-HCNH radical. In addition, HKrCN was found in the case of krypton, whereas HXeCN and HXeNC were produced in solid xenon. The reaction mechanisms and contribution of different channels are discussed.

  12. Radiation Induced Enhancement of Hydrogen Influence on Luminescent Properties of nc-Si/SiO2 Structures

    NASA Astrophysics Data System (ADS)

    Lisovskyy, Igor; Voitovych, Mariia; Litovchenko, Volodymyr; Voitovych, Vasyl; Nasieka, Iurii; Bratus, Viktor

    2016-12-01

    Using photo-luminescence, infrared spectroscopy, and electron spin resonance technique, the silicon dioxide films with embedded silicon nanocrystals (nc-Si/SiO2 structures) have been investigated after γ-irradiation with the dose 2 × 107 rad and subsequent annealing at 450 °C in hydrogen ambient. For the first time, it was shown that such a radiation-thermal treatment results in significant increase of the luminescence intensity, in a red shift of the photoluminescence spectra, and in disappearance of the electron-spin resonance signal related to silicon broken bonds. This effect has been explained by passivation of silicon broken bonds at the nc-Si-SiO2 interface with hydrogen and by generation of new luminescence centers, these centers being created at elevated temperatures due to transformation of radiation-induced defects.

  13. Novobiocin treatment reverses radiation-induced alterations in higher-order DNA structure in L5178Y nucleoids

    SciTech Connect

    Kapiszewska, M.; Lange, C.S. )

    1991-09-01

    The authors have studied the effect of novobiocin treatment on radiation-induced damage and its repair in higher-order DNA structure in two mouse leukemia cell lines differing in their radiosensitivity, L5178Y-R (LY-R) and L5178Y-S (LY-S). They used the fluorescent halo technique to measure alterations in the superhelical density and the topological constraints of DNA in LY-R and LY-S nucleoids. The results for untreated cells show that both cell lines reached maximal DNA unwinding at the same concentration of propidium iodide (PI), whereas LY-S nucleoids were less efficient in their ability to rewind their DNA. The loop size did not differ significantly between the cell lines. Incubation of LY-R and LY-S cells with novobiocin at a concentration which does not influence survival (0.1 mM for 45 min), but inhibits DNA synthesis in LY-R cells (by 28%) to a greater extent than in LY-S cells (by 10%), also causes more DNA unwinding in LY-R nucleoids than in LY-S nucleoids. However, a decreased superhelical density was observed in nucleoids from both cell lines. Novobiocin applied before, and present during, irradiation prevents radiation-induced alterations in DNA supercoiling more efficiently in LY-R than in LY-S cells. The presence of novobiocin during the repair period increased DNA rewinding to levels not significantly different from control values in nucleoids from both cell lines.

  14. Tissue-specific effects of acute aluminium exposure on the radiation-induced bystander effect in rainbow trout (Oncorhynchus mykiss, Walbaum).

    PubMed

    Smith, Richard W; Seymour, Colin B; Moccia, Richard D; Mothersill, Carmel E

    2015-01-01

    To investigate if aluminium (Al) modifies the rainbow trout response to radiation exposure and/or the induction of a radiation-induced bystander effect. Rainbow trout were exposed to 100 or 200 μg l(-1) Al (for 3 h), a 0.5 Gy X-ray dose or Al followed immediately by irradiation. The exposed fish were then swum with completely untreated bystander fish. A human reporter cell clonogenic assay was used to determine whether Al exposure modified the effects of irradiation on the skin and gills from directly exposed fish and also the radiation-induced bystander effect in untreated fish. Al exposure did not modify the response to direct irradiation by the skin, or the gill. Al did not modify the bystander effect in the skin. However Al did modify the bystander effect in the gill. Gills of bystander fish swum with fish exposed to 200 μg l(-1) Al, followed by irradiation, caused a greater reduction in HPV-G cell survival than was caused by irradiation only. Interestingly Al exposure only also caused a bystander effect (reduced HPV-G survival) in the gill. This study shows that, in a multiple stressor scenario, the communication of radiation-induced stress signals is modified on a tissue-specific basis by acute Al exposure. Aside from the implications this has for radiological protection this response may also have potential for environmental monitoring where detection of the bystander effect could act as an indicator of radiation exposure when direct exposure responses are not evident.

  15. Variation of normal tissue complication probability (NTCP) estimates of radiation-induced hypothyroidism in relation to changes in delineation of the thyroid gland.

    PubMed

    Rønjom, Marianne F; Brink, Carsten; Lorenzen, Ebbe L; Hegedüs, Laszlo; Johansen, Jørgen

    2015-01-01

    To examine the variations of risk-estimates of radiation-induced hypothyroidism (HT) from our previously developed normal tissue complication probability (NTCP) model in patients with head and neck squamous cell carcinoma (HNSCC) in relation to variability of delineation of the thyroid gland. In a previous study for development of an NTCP model for HT, the thyroid gland was delineated in 246 treatment plans of patients with HNSCC. Fifty of these plans were randomly chosen for re-delineation for a study of the intra- and inter-observer variability of thyroid volume, Dmean and estimated risk of HT. Bland-Altman plots were used for assessment of the systematic (mean) and random [standard deviation (SD)] variability of the three parameters, and a method for displaying the spatial variation in delineation differences was developed. Intra-observer variability resulted in a mean difference in thyroid volume and Dmean of 0.4 cm(3) (SD ± 1.6) and -0.5 Gy (SD ± 1.0), respectively, and 0.3 cm(3) (SD ± 1.8) and 0.0 Gy (SD ± 1.3) for inter-observer variability. The corresponding mean differences of NTCP values for radiation-induced HT due to intra- and inter-observer variations were insignificantly small, -0.4% (SD ± 6.0) and -0.7% (SD ± 4.8), respectively, but as the SDs show, for some patients the difference in estimated NTCP was large. For the entire study population, the variation in predicted risk of radiation-induced HT in head and neck cancer was small and our NTCP model was robust against observer variations in delineation of the thyroid gland. However, for the individual patient, there may be large differences in estimated risk which calls for precise delineation of the thyroid gland to obtain correct dose and NTCP estimates for optimized treatment planning in the individual patient.

  16. Monte Carlo simulation of ionizing radiation induced DNA strand breaks utilizing coarse grained high-order chromatin structures

    NASA Astrophysics Data System (ADS)

    Liang, Ying; Yang, Gen; Liu, Feng; Wang, Yugang

    2016-01-01

    Ionizing radiation threatens genome integrity by causing DNA damage. Monte Carlo simulation of the interaction of a radiation track structure with DNA provides a powerful tool for investigating the mechanisms of the biological effects. However, the more or less oversimplification of the indirect effect and the inadequate consideration of high-order chromatin structures in current models usually results in discrepancies between simulations and experiments, which undermine the predictive role of the models. Here we present a biophysical model taking into consideration factors that influence indirect effect to simulate radiation-induced DNA strand breaks in eukaryotic cells with high-order chromatin structures. The calculated yields of single-strand breaks and double-strand breaks (DSBs) for photons are in good agreement with the experimental measurements. The calculated yields of DSB for protons and α particles are consistent with simulations by the PARTRAC code, whereas an overestimation is seen compared with the experimental results. The simulated fragment size distributions for 60Co γ irradiation and α particle irradiation are compared with the measurements accordingly. The excellent agreement with 60Co irradiation validates our model in simulating photon irradiation. The general agreement found in α particle irradiation encourages model applicability in the high linear energy transfer range. Moreover, we demonstrate the importance of chromatin high-order structures in shaping the spectrum of initial damage.

  17. The influence of oxygen on radiation-induced structural and functional changes in glyceraldehyde-3-phosphate dehydrogenase and lactate dehydrogenase

    NASA Astrophysics Data System (ADS)

    Rodacka, Aleksandra; Serafin, Eligiusz; Bubinski, Michal; Krokosz, Anita; Puchala, Mieczyslaw

    2012-07-01

    Proteins are major targets for oxidative damage due to their abundance in cells and high reactivity with free radicals. In the present study we examined the influence of oxygen on radiation-induced inactivation and structural changes of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and lactate dehydrogenase (LDH). We chose these two enzymes because they occur at high concentrations and participate in the most important processes in organisms; furthermore, they show considerable similarity in their structure. Protein solutions were irradiated with X-rays in doses ranging from 0.1 to 0.7 kGy, in air and N2O. The much higher radiation inactivation of GAPDH as compared to LDH is correlated with substantially greater structural changes in this protein, mainly involving the loss of free thiol groups (-SH). Of lesser importance in the differentiation of the radiosensitivity of the studied enzymes are tryptophan residues. Molecular oxygen, present during irradiation, increased to a significantly greater extent the inactivation and structural changes of GAPDH than that of LDH. The results suggest that the greater effect of oxygen on GAPDH is due to the higher efficiency of the superoxide radical, the higher amount of hydroperoxides generated, and the higher degree of unfolding of this protein.

  18. Association between Single Nucleotide Polymorphisms in XRCC3 and Radiation-Induced Adverse Effects on Normal Tissue: A Meta-Analysis

    PubMed Central

    Song, Yu-Zhe; Han, Fu-Jun; Liu, Min; Xia, Cheng-Cheng; Shi, Wei-Yan; Dong, Li-Hua

    2015-01-01

    The X-ray repair cross-complementing group 3 (XRCC3) protein plays an important role in the repair of DNA double-strand breaks. The relationship between XRCC3 polymorphisms and the risk of radiation-induced adverse effects on normal tissue remains inconclusive. Thus, we performed a meta-analysis to elucidate the association between XRCC3 polymorphisms and radiation-induced adverse effects on normal tissue. All eligible studies up to December 2014 were identified through a search of the PubMed, Embase and Web of Science databases. Seventeen studies involving 656 cases and 2193 controls were ultimately included in this meta-analysis. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to evaluate the association between XRCC3 polymorphisms and the risk of radiation-induced normal tissue adverse effects. We found that the XRCC3 p.Thr241Met (rs861539) polymorphism was significantly associated with early adverse effects induced by radiotherapy (OR = 1.99, 95%CI: 1.31–3.01, P = 0.001). A positive association lacking statistical significance with late adverse effects was also identified (OR = 1.28, 95%CI: 0.97–1.68, P = 0.08). In addition, the rs861539 polymorphism was significantly correlated with a higher risk of adverse effects induced by head and neck area irradiation (OR = 2.41, 95%CI: 1.49–3.89, p = 0.0003) and breast irradiation (OR = 1.41, 95%CI: 1.02–1.95, p = 0.04), whereas the correlation was not significant for lung irradiation or pelvic irradiation. Furthermore, XRCC3 rs1799794 polymorphism may have a protective effect against late adverse effects induced by radiotherapy (OR = 0.47, 95%CI: 0.26–0.86, P = 0.01). Well-designed large-scale clinical studies are required to further validate our results. PMID:26091483

  19. Correlation Between Interphase Chromatin Structure and - and High-Let Radiation-Induced - and Intra-Chromosome Exchange Hotspots

    NASA Astrophysics Data System (ADS)

    Zhang, Ye; Wu, Honglu; Mangala, Lingegowda; Asaithamby, Aroumougame; Chen, David

    2012-07-01

    CORRELATION BETWEEN INTERPHASE CHROMATIN STRUCTURE AND LOW- AND HIGH-LET RADIATION-INDUCED INTER- AND INTRA-CHROMOSOME EXCHANGE HOTSPOTS Ye Zhang1,2, Lingegowda S. Mangala1,3, Aroumougame Asaithamby4, David J. Chen4, and Honglu Wu1 1 NASA Johnson Space Center, Houston, Texas, USA 2 Wyle Integrated Science and Engineering Group, Houston, Texas, USA 3 University of Houston Clear Lake, Houston, Texas, USA 4 University of Texas, Southwestern Medical Center, Dallas, Texas, USA To investigate the relationship between chromosome aberrations induced by low- and high-LET radiation and chromatin folding, we reconstructed the three dimensional structure of chromosome 3 and measured the physical distances between different regions of this chromosome. Previously, we investigated the location of breaks involved in inter- and intrachromosomal type exchange events in chromosome 3 of human epithelial cells, using the multicolor banding in situ hybridization (mBAND) technique. After exposure to both low- and high-LET radiations in vitro, intra-chromosome exchanges occurred preferentially between a break in the 3p21 and one in the 3q11 regions, and the breaks involved in inter-chromosome exchanges occurred in two regions near the telomeres of the chromosome. In this study, human epithelial cells were fixed in G1 phase and interphase chromosomes hybridized with an mBAND probe for chromosome 3 were captured with a laser scanning confocal microscope. The 3-dimensional structure of interphase chromosome 3 with different colored regions was reconstructed, and the distance between different regions was measured. We show that, in most of the G1 cells, the regions containing 3p21 and 3q11 are colocalized in the center of the chromosome domain, whereas, the regions towards the telomeres of the chromosome are located in the peripherals of the chromosome domain. Our results demonstrate that the distribution of breaks involved in radiation-induced inter and intra-chromosome aberrations depends

  20. Structural Stability of Human Fibroblast Growth Factor-1 Is Essential for Protective Effects Against Radiation-Induced Intestinal Damage

    SciTech Connect

    Nakayama, Fumiaki; Umeda, Sachiko; Yasuda, Takeshi; Asada, Masahiro; Motomura, Kaori; Suzuki, Masashi; Zakrzewska, Malgorzata; Imamura, Toru; Imai, Takashi

    2013-02-01

    Purpose: Human fibroblast growth factor-1 (FGF1) has radioprotective effects on the intestine, although its structural instability limits its potential for practical use. Several stable FGF1 mutants were created increasing stability in the order, wild-type FGF1, single mutants (Q40P, S47I, and H93G), Q40P/S47I, and Q40P/S47I/H93G. This study evaluated the contribution of the structural stability of FGF1 to its radioprotective effect. Methods and Materials: Each FGF1 mutant was administered intraperitoneally to BALB/c mice in the absence of heparin 24 h before or after total body irradiation (TBI) with {gamma}-rays at 8-12 Gy. Several radioprotective effects were examined in the jejunum. Results: Q40P/S47I/H93G could activate all subtypes of FGF receptors in vitro much more strongly than the wild-type without endogenous or exogenous heparin. Preirradiation treatment with Q40P/S47I/H93G significantly increased crypt survival more than wild-type FGF1 after TBI at 10 or 12 Gy, and postirradiation treatment with Q40P/S47I/H93G was effective in promoting crypt survival after TBI at 10, 11, or 12 Gy. In addition, crypt cell proliferation, crypt depth, and epithelial differentiation were significantly promoted by postirradiation treatment with Q40P/S47I/H93G. The level of stability of FGF1 mutants correlated with their mitogenic activities in vitro in the absence of heparin; however, preirradiation treatment with the mutants increased the crypt number to almost the same level as Q40P/S47I/H93G. When given 24 h after TBI at 10 Gy, all FGF1 mutants increased crypt survival more than wild-type FGF1, and Q40P/S47I/H93G had the strongest mitogenic effects in intestinal epithelial cells after radiation damage. Moreover, Q40P/S47I/H93G prolonged mouse survival after TBI because of the repair of intestinal damage. Conclusion: These findings suggest that the structural stability of FGF1 can contribute to the enhancement of protective effects against radiation-induced intestinal

  1. High-frequency detection of the formation and stabilization of a radiation-induced defect cluster in semiconductor structures

    SciTech Connect

    Puzanov, A. S.; Obolenskiy, S. V. Kozlov, V. A.; Volkova, E. V.; Paveliev, D. G.

    2015-12-15

    The processes of the formation and stabilization of a radiation-induced defect cluster upon the arrival of a fast neutron to the space-charge region of a semiconductor diode are analyzed. The current pulse formed by secondary electrons is calculated and the spectrum of the signal generated by the diode (detector) under the action of an instantaneous neutron flux of the fission spectrum is determined. The possibility of experimental detection of the picosecond radiation-induced transition processes is discussed.

  2. The influence of chromatin structure on the frequency of radiation-induced DNA strand breaks: a study using nuclear and nucleoid monolayers

    SciTech Connect

    Ljungman, M. )

    1991-04-01

    To assess the influence of chromatin structure on the frequency of radiation-induced DNA strand breaks, the alkaline unwinding technique was applied to nuclear and nucleoid monolayers. These chromatin substrates were prepared by treating human fibroblasts grown as monolayers with the nonionic detergent Triton X-100 and varying concentrations of cations. The chromatin structure was modified either by a stepwise removal of DNA-bound proteins by extraction in increasing concentrations of monovalent salt, or by the addition or deletion of mono- and divalent cations to condense or decondense the chromatin, respectively. It was found that the stepwise removal of DNA-bound proteins from the chromatin dramatically increased the frequency of radiation-induced DNA strand breaks. The DNA-bound proteins showed a qualitative difference in their ability to protect the DNA where proteins removed by salt concentrations above 1.0 M exerted the greatest protection. Furthermore, the frequency of radiation-induced DNA strand breaks was found to be 6 times lower in condensed chromatin than in decondensed chromatin and about 80 times lower than in protein-depleted chromatin. It is concluded that the presence of DNA-bound proteins and the folding of the chromatin into higher-order structures protect the DNA against radiation-induced strand breaks.

  3. Chemical structure and physical properties of radiation-induced crosslinking of polytetrafluoroethylene

    NASA Astrophysics Data System (ADS)

    Oshima, Akihiro; Ikeda, Shigetoshi; Katoh, Etsuko; Tabata, Yoneho

    2001-07-01

    The chemical structure and physical properties of polytetrafluoroethylene (PTFE) that has been crosslinked by radiation have been studied by various methods. It has been found that a Y-type crosslinking structure and a Y-type structure incorporating a double bond (modified Y-type) is formed in PTFE by radiation-crosslinking in the molten state. In addition, various types of double bond structures, excluding the crosslinking site, have been identified. The crosslinked PTFE has a good light transparency due to the loss of crystallites, whilst it retains the excellent properties of electrical insulation and heat resistance. The coefficient of abrasion and the permanent creep are also greatly improved by crosslinking.

  4. A Tocotrienol-Enriched Formulation Protects against Radiation-Induced Changes in Cardiac Mitochondria without Modifying Late Cardiac Function or Structure

    PubMed Central

    Sridharan, Vijayalakshmi; Tripathi, Preeti; Aykin-Burns, Nukhet; Krager, Kimberly J; Sharma, Sunil K.; Moros, Eduardo G.; Melnyk, Stepan B.; Pavliv, Oleksandra; Hauer-Jensen, Martin; Boerma, Marjan

    2015-01-01

    Radiation-induced heart disease (RIHD) is a common and sometimes severe late side effect of radiation therapy for intrathoracic and chest wall tumors. We have previously shown that local heart irradiation in a rat model caused prolonged changes in mitochondrial respiration and increased susceptibility to mitochondrial permeability transition pore (mPTP) opening. Because tocotrienols are known to protect against oxidative stress-induced mitochondrial dysfunction, in this study, we examined the effects of tocotrienols on radiation-induced alterations in mitochondria, and structural and functional manifestations of RIHD. Male Sprague-Dawley rats received image-guided localized X irradiation to the heart to a total dose of 21 Gy. Twenty-four hours before irradiation, rats received a tocotrienol-enriched formulation or vehicle by oral gavage. Mitochondrial function and mitochondrial membrane parameters were studied at 2 weeks and 28 weeks after irradiation. In addition, cardiac function and histology were examined at 28 weeks. A single oral dose of the tocotrienol-enriched formulation preserved Bax/Bcl2 ratios and prevented mPTP opening and radiation-induced alterations in succinate-driven mitochondrial respiration. Nevertheless, the late effects of local heart irradiation pertaining to myocardial function and structure were not modified. Our studies suggest that a single dose of tocotrienols protects against radiation-induced mitochondrial changes, but these effects are not sufficient against long-term alterations in cardiac function or remodeling. PMID:25710576

  5. Radiation-Induced Bioradicals

    NASA Astrophysics Data System (ADS)

    Lahorte, Philippe; Mondelaers, Wim

    This chapter represents the second part of a review in which the production and application of radiation-induced radicals in biological matter are discussed. In part one the general aspects of the four stages (physical, physicochemical, chemical and biological) of interaction of radiation with matter in general and biological matter in particular, were discussed. Here an overview is presented of modem technologies and theoretical methods available for studying these radiation effects. The relevance is highlighted of electron paramagnetic resonance spectroscopy and quantum chemical calculations with respect to obtaining structural information on bioradicals, and a survey is given of the research studies in this field. We also discuss some basic aspects of modem accelerator technologies which can be used for creating radicals and we conclude with an overview of applications of radiation processing in biology and related fields such as biomedical and environmental engineering, food technology, medicine and pharmacy.

  6. Semiquinone fraction isolated from Bacillus sp. INM-1 protects hepatic tissues against γ-radiation induced toxicity.

    PubMed

    Mishra, Saurabh; Bansal, Deen Dayal; Malhotra, Poonam; K Reddy, D Sudheer; Jamwal, Vishawdeep S; Patel, Dev Dutt; Gupta, Ashutosh Kumar; Singh, Praveen Kumar; Javed, Saleem; Kumar, Raj

    2014-12-01

    Present study was focused on evaluation of a semiquinone glucoside derivative (SQGD) isolated from radioresistant bacterium Bacillus sp. INM-1 for its ability against γ radiation induced oxidative stress in irradiated mice. Animals were divided into four group, i.e., (i) untreated control mice; (ii) SQGD treated (50 mg/kg b. wt. i.p.) mice; (iii) irradiated (10 Gy) mice; and (iv) irradiated mice which were pre-treated (-2 h) with SQGD (50 mg/kg b. wt. i.p.). Following treatment, liver homogenates of the treated mice were subjected to endogenous antioxidant enzymes estimation. Result indicated that SQGD pre-treatment, significantly (P < 0.05) induced superoxide dismutase (SOD) (19.84 ± 2.18% at 72 h), catalase (CAT) (26.47 ± 3.11% at 12 h), glutathione (33.81 ± 1.99% at 24 h), and glutathione-S-transferase (24.40 ± 2.65% at 6 h) activities in the liver of mice as compared with untreated control. Significant (P < 0.05) induction in SOD (50.04 ± 5.59% at 12 h), CAT (62.22 ± 7.50 at 72 h), glutathione (42.92 ± 2.28% at 24 h), and glutathione-S-transferase (46.65 ± 3.25 at 12 h) was observed in irradiated mice which were pre-treated with SQGD compared with only irradiated mice. Further, significant induction in ABTS(+) radicals (directly proportional to decrease mM Trolox equivalent) was observed in liver homogenate of H2 O2 treated mice which were found to be significantly inhibited in H2 O2 treated mice pre-treated with SQGD. Thus, it can be concluded that SQGD treatment neutralizes oxidative stress caused by irradiation not only by enhancing endogenous antioxidant enzymes but also by improving total antioxidant status of cellular system and thus cumulative effect of the phenomenon may contributes to radioprotection.

  7. Atomistic structures of nano-engineered SiC and radiation-induced amorphization resistance

    SciTech Connect

    Imada, Kenta; Ishimaru, Manabu; Sato, Kazuhisa; Xue, Haizhou; Zhang, Yanwen; Shannon, Steven; Weber, William J.

    2015-06-18

    In this paper, nano-engineered 3C–SiC thin films, which possess columnar structures with high-density stacking faults and twins, were irradiated with 2 MeV Si ions at cryogenic and room temperatures. From cross-sectional transmission electron microscopy observations in combination with Monte Carlo simulations based on the Stopping and Range of Ions in Matter code, it was found that their amorphization resistance is six times greater than bulk crystalline SiC at room temperature. High-angle bright-field images taken by spherical aberration corrected scanning transmission electron microscopy revealed that the distortion of atomic configurations is localized near the stacking faults. Finally, the resultant strain field probably contributes to the enhancement of radiation tolerance of this material.

  8. Atomistic structures of nano-engineered SiC and radiation-induced amorphization resistance

    DOE PAGES

    Imada, Kenta; Ishimaru, Manabu; Sato, Kazuhisa; ...

    2015-06-18

    In this paper, nano-engineered 3C–SiC thin films, which possess columnar structures with high-density stacking faults and twins, were irradiated with 2 MeV Si ions at cryogenic and room temperatures. From cross-sectional transmission electron microscopy observations in combination with Monte Carlo simulations based on the Stopping and Range of Ions in Matter code, it was found that their amorphization resistance is six times greater than bulk crystalline SiC at room temperature. High-angle bright-field images taken by spherical aberration corrected scanning transmission electron microscopy revealed that the distortion of atomic configurations is localized near the stacking faults. Finally, the resultant strain fieldmore » probably contributes to the enhancement of radiation tolerance of this material.« less

  9. In situ observation of radiation induced amorphization of crystals with apatite structure

    SciTech Connect

    Wang, L.M.; Ewing, R.C.; Cameron, M.; Weber, W.J.; Crowley, K.D.

    1993-06-01

    Temperature dependence of amorphization doses for 1.5 MeV Kr ion-irradiated Ca{sub 10}(PO{sub 4}){sub 6}F{sub 2} and Ca{sub 2}La{sub 8}(SiO{sub 4}){sub 6}O{sub 2} were studied with in situ transmission electron microscopy. At low temperatures, Ca{sub 10}(PO{sub 4}){sub 6}F{sub 2} became amorphized at lower dose than Ca{sub 2}La{sub 8}(SiO{sub 4}){sub 6}O{sub 2}. However, the critical amorphization dose increased much more rapidly for the former above 350 K than the latter. At 475 K, Ca{sub 10}(PO{sub 4}){sub 6}F{sub 2} required nearly five times of higher dose to become amorphous than Ca{sub 10}La{sub 8}(SiO{sub 4}){sub 6}O{sub 2}. Based on the dose-temperature curves, activation energies for the crystal structure recovery process were determined to be 0.07 eV for Ca{sub 10}(PO{sub 4}){sub 6}F{sub 2} and 0.13 eV for Ca{sub 2}La{sub 8}(SiO{sub 4}){sub 6}O{sub 2} respectively. The lower critical amorphization dose and lower activation energy for recovery of Ca{sub 10}(PO{sub 4}){sub 6}F{sub 2} are attributed to the weaker P-O bond and the higher fluorine mobility in the structure.

  10. Terahertz radiation induces non-thermal structural changes associated with Fröhlich condensation in a protein crystal

    PubMed Central

    Lundholm, Ida V.; Rodilla, Helena; Wahlgren, Weixiao Y.; Duelli, Annette; Bourenkov, Gleb; Vukusic, Josip; Friedman, Ran; Stake, Jan; Schneider, Thomas; Katona, Gergely

    2015-01-01

    Whether long-range quantum coherent states could exist in biological systems, and beyond low-temperature regimes where quantum physics is known to be applicable, has been the subject to debate for decades. It was proposed by Fröhlich that vibrational modes within protein molecules can order and condense into a lowest-frequency vibrational mode in a process similar to Bose-Einstein condensation, and thus that macroscopic coherence could potentially be observed in biological systems. Despite the prediction of these so-called Fröhlich condensates almost five decades ago, experimental evidence thereof has been lacking. Here, we present the first experimental observation of Fröhlich condensation in a protein structure. To that end, and to overcome the challenges associated with probing low-frequency molecular vibrations in proteins (which has hampered understanding of their role in proteins' function), we combined terahertz techniques with a highly sensitive X-ray crystallographic method to visualize low-frequency vibrational modes in the protein structure of hen-egg white lysozyme. We found that 0.4 THz electromagnetic radiation induces non-thermal changes in electron density. In particular, we observed a local increase of electron density in a long α-helix motif consistent with a subtle longitudinal compression of the helix. These observed electron density changes occur at a low absorption rate indicating that thermalization of terahertz photons happens on a micro- to milli-second time scale, which is much slower than the expected nanosecond time scale due to damping of delocalized low frequency vibrations. Our analyses show that the micro- to milli-second lifetime of the vibration can only be explained by Fröhlich condensation, a phenomenon predicted almost half a century ago, yet never experimentally confirmed. PMID:26798828

  11. Terahertz radiation induces non-thermal structural changes associated with Fröhlich condensation in a protein crystal.

    PubMed

    Lundholm, Ida V; Rodilla, Helena; Wahlgren, Weixiao Y; Duelli, Annette; Bourenkov, Gleb; Vukusic, Josip; Friedman, Ran; Stake, Jan; Schneider, Thomas; Katona, Gergely

    2015-09-01

    Whether long-range quantum coherent states could exist in biological systems, and beyond low-temperature regimes where quantum physics is known to be applicable, has been the subject to debate for decades. It was proposed by Fröhlich that vibrational modes within protein molecules can order and condense into a lowest-frequency vibrational mode in a process similar to Bose-Einstein condensation, and thus that macroscopic coherence could potentially be observed in biological systems. Despite the prediction of these so-called Fröhlich condensates almost five decades ago, experimental evidence thereof has been lacking. Here, we present the first experimental observation of Fröhlich condensation in a protein structure. To that end, and to overcome the challenges associated with probing low-frequency molecular vibrations in proteins (which has hampered understanding of their role in proteins' function), we combined terahertz techniques with a highly sensitive X-ray crystallographic method to visualize low-frequency vibrational modes in the protein structure of hen-egg white lysozyme. We found that 0.4 THz electromagnetic radiation induces non-thermal changes in electron density. In particular, we observed a local increase of electron density in a long α-helix motif consistent with a subtle longitudinal compression of the helix. These observed electron density changes occur at a low absorption rate indicating that thermalization of terahertz photons happens on a micro- to milli-second time scale, which is much slower than the expected nanosecond time scale due to damping of delocalized low frequency vibrations. Our analyses show that the micro- to milli-second lifetime of the vibration can only be explained by Fröhlich condensation, a phenomenon predicted almost half a century ago, yet never experimentally confirmed.

  12. Treatment of Radiation-Induced Urethral Strictures.

    PubMed

    Hofer, Matthias D; Liu, Joceline S; Morey, Allen F

    2017-02-01

    Radiation therapy may result in urethral strictures from vascular damage. Most radiation-induced urethral strictures occur in the bulbomembranous junction, and urinary incontinence may result as a consequence of treatment. Radiation therapy may compromise reconstruction due to poor tissue healing and radionecrosis. Excision and primary anastomosis is the preferred urethroplasty technique for radiation-induced urethral stricture. Principles of posterior urethroplasty for trauma may be applied to the treatment of radiation-induced urethral strictures. Chronic management with suprapubic tube is an option based on patient comorbidities and preference.

  13. Comparison of radiation-induced normal lung tissue density changes for patients from multiple institutions receiving conventional or hypofractionated treatments.

    PubMed

    Diot, Quentin; Marks, Lawrence B; Bentzen, Soren M; Senan, Suresh; Kavanagh, Brian D; Lawrence, Michael V; Miften, Moyed; Palma, David A

    2014-07-01

    To quantitatively assess changes in computed tomography (CT)-defined normal lung tissue density after conventional and hypofractionated radiation therapy (RT). The pre-RT and post-RT CT scans from 118 and 111 patients receiving conventional and hypofractionated RT, respectively, at 3 institutions were registered to each other and to the 3-dimensional dose distribution to quantify dose-dependent changes in normal lung tissue density. Dose-response curves (DRC) for groups of patients receiving conventional and hypofractionated RT were generated for each institution, and the frequency of density changes >80 Hounsfield Units (HU) was modeled depending on the fractionation type using a Probit model for different follow-up times. For the pooled data from all institutions, there were significant differences in the DRC between the conventional and hypofractionated groups; the respective doses resulting in 50% complication risk (TD50) were 62 Gy (95% confidence interval [CI] 57-67) versus 36 Gy (CI 33-39) at <6 months, 48 Gy (CI 46-51) versus 31 Gy (CI 28-33) at 6-12 months, and 47 Gy (CI 45-49) versus 35 Gy (32-37) at >12 months. The corresponding m values (slope of the DRC) were 0.52 (CI 0.46-0.59) versus 0.31 (CI 0.28-0.34) at <6 months, 0.46 (CI 0.42-0.51) versus 0.30 (CI 0.26-0.34) at 6-12 months, and 0.45 (CI 0.42-0.50) versus 0.31 (CI 0.27-0.35) at >12 months (P<.05 for all comparisons). Compared with conventional fractionation, hypofractionation has a lower TD50 and m value, both suggesting an increased degree of normal tissue density sensitivity with hypofractionation. Copyright © 2014 Elsevier Inc. All rights reserved.

  14. Comparison of Radiation-Induced Normal Lung Tissue Density Changes for Patients From Multiple Institutions Receiving Conventional or Hypofractionated Treatments

    SciTech Connect

    Diot, Quentin; Marks, Lawrence B.; Bentzen, Soren M.; Senan, Suresh; Kavanagh, Brian D.; Lawrence, Michael V.; Miften, Moyed; Palma, David A.

    2014-07-01

    Purpose: To quantitatively assess changes in computed tomography (CT)–defined normal lung tissue density after conventional and hypofractionated radiation therapy (RT). Methods and Materials: The pre-RT and post-RT CT scans from 118 and 111 patients receiving conventional and hypofractionated RT, respectively, at 3 institutions were registered to each other and to the 3-dimensional dose distribution to quantify dose-dependent changes in normal lung tissue density. Dose-response curves (DRC) for groups of patients receiving conventional and hypofractionated RT were generated for each institution, and the frequency of density changes >80 Hounsfield Units (HU) was modeled depending on the fractionation type using a Probit model for different follow-up times. Results: For the pooled data from all institutions, there were significant differences in the DRC between the conventional and hypofractionated groups; the respective doses resulting in 50% complication risk (TD{sub 50}) were 62 Gy (95% confidence interval [CI] 57-67) versus 36 Gy (CI 33-39) at <6 months, 48 Gy (CI 46-51) versus 31 Gy (CI 28-33) at 6-12 months, and 47 Gy (CI 45-49) versus 35 Gy (32-37) at >12 months. The corresponding m values (slope of the DRC) were 0.52 (CI 0.46-0.59) versus 0.31 (CI 0.28-0.34) at <6 months, 0.46 (CI 0.42-0.51) versus 0.30 (CI 0.26-0.34) at 6-12 months, and 0.45 (CI 0.42-0.50) versus 0.31 (CI 0.27-0.35) at >12 months (P<.05 for all comparisons). Conclusion: Compared with conventional fractionation, hypofractionation has a lower TD{sub 50} and m value, both suggesting an increased degree of normal tissue density sensitivity with hypofractionation.

  15. A model of the radiation-induced bystander effect based on an analogy with ferromagnets. Application to modelling tissue response in a uniform field

    NASA Astrophysics Data System (ADS)

    Vassiliev, O. N.

    2014-12-01

    We propose a model of the radiation-induced bystander effect based on an analogy with magnetic systems. The main benefit of this approach is that it allowed us to apply powerful methods of statistical mechanics. The model exploits the similarity between how spin-spin interactions result in correlations of spin states in ferromagnets, and how signalling from a damaged cell reduces chances of survival of neighbour cells, resulting in correlated cell states. At the root of the model is a classical Hamiltonian, similar to that of an Ising ferromagnet with long-range interactions. The formalism is developed in the framework of the Mean Field Theory. It is applied to modelling tissue response in a uniform radiation field. In this case the results are remarkably simple and at the same time nontrivial. They include cell survival curves, expressions for the tumour control probability and effects of fractionation. The model extends beyond of what is normally considered as bystander effects. It offers an insight into low-dose hypersensitivity and into mechanisms behind threshold doses for deterministic effects.

  16. Ionizing radiation induces upregulation of cellular procoagulability and tissue factor expression in human peripheral blood mononuclear cells.

    PubMed

    Goldin-Lang, Petra; Niebergall, Florian; Antoniak, Silvio; Szotowski, Bjoern; Rosenthal, Peter; Pels, Klaus; Schultheiss, Heinz-Peter; Rauch, Ursula

    2007-01-01

    The therapeutic application of ionizing radiation is associated with thrombotic events, but the exact underlying molecular mechanisms are still unclear. Tissue factor (TF), the primary initiator of blood coagulation, is essentially involved in the pathophysiology of thrombosis. Circulating monocytes have been identified to upregulate TF under inflammatory conditions and, thereby, enhance blood thrombogenicity. The study examines the effect of irradiation on the cellular procoagulability and TF protein expression of human peripheral blood mononuclear cells (PBMNCs) in a time period of 7 days. Human PBMNCs were irradiated with 20 Gy. Procoagulability of PBMNCs, released microparticles and microparticle-free cell supernatant was analyzed by a chromogenic assay and TF protein expression quantified by TF ELISA. To determine whether irradiated PBMNCs and shed microparticles initiate plasma clotting, a one stage clotting assay was performed. We found a significant increase of PBMNC-associated procoagulant activity over a time period of 7 days post irradiation. Moreover, 3 days post irradiation PBMNCs initiated the plasma clotting faster than non-irradiated cells. An enhanced cellular TF protein concentration was persistently observed throughout the investigated time up to 7 days post irradiation. Microparticle-associated TF activity significantly increased 3 days post irradiation compared with the non-irradiated controls. PBMNC-derived microparticles post irradiation also initiated the plasma clotting faster than microparticles derived from controls. The results show irradiation to induce TF expression and to increase procoagulability of PBMNCs and cell-derived microparticles. This could be a possible mechanism by which ionizing radiation enhances blood thrombogenicity.

  17. Inhibition of Radiation-Induced Oxidative Damage in the Lung Tissue: May Acetylsalicylic Acid Have a Positive Role?

    PubMed

    Demirel, Can; Kilciksiz, Sevil Cagiran; Gurgul, Serkan; Erdal, Nurten; Yigit, Seyran; Tamer, Lulufer; Ayaz, Lokman

    2016-02-01

    The lung is relatively sensitive to irradiation. It is shown that acetylsalicylic acid (ASA) might reduce oxidative injury and that it has a place in protection from cancer. The aim of this study is to evaluate the potential radioprotective effects of ASA. Whole-body irradiation (6 Gy, single dose) was applied to the rats. Glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) levels in the lung tissue were measured. Control (C), Radiation (R), Radiation + ASA (R + ASA; received irradiation and 25 mg/kg of ASA intraperitoneally (i.p.)), and Radiation + Amifostine (R + WR-2721; received irradiation and 200 mg/kg of WR-2721 i.p.) groups were used. The MPO levels decreased statistically significantly in the group administered ASA. Histopathologically, a radioprotective effect of ASA was more evident in the R + ASA group. ASA is an agent which has not been used as a radioprotector in the clinic yet, and it is worth supporting with more advanced studies.

  18. Spectrum of Radiation-Induced Clustered Non-DSB Damage - A Monte Carlo Track Structure Modeling and Calculations.

    PubMed

    Watanabe, Ritsuko; Rahmanian, Shirin; Nikjoo, Hooshang

    2015-05-01

    The aim of this report is to present the spectrum of initial radiation-induced cellular DNA damage [with particular focus on non-double-strand break (DSB) damage] generated by computer simulations. The radiation types modeled in this study were monoenergetic electrons (100 eV-1.5 keV), ultrasoft X-ray photons Ck, AlK and TiK, as well as some selected ions including 3.2 MeV/u proton; 0.74 and 2.4 MeV/u helium ions; 29 MeV/u nitrogen ions and 950 MeV/u iron ions. Monte Carlo track structure methods were used to simulate damage induction by these radiation types in a cell-mimetic condition from a single-track action. The simulations took into account the action of direct energy deposition events and the reaction of hydroxyl radicals on atomistic linear B-DNA segments of a few helical turns including the water of hydration. Our results permitted the following conclusions: a. The absolute levels of different types of damage [base damage, simple and complex single-strand breaks (SSBs) and DSBs] vary depending on the radiation type; b. Within each damage class, the relative proportions of simple and complex damage vary with radiation type, the latter being higher with high-LET radiations; c. Overall, for both low- and high-LET radiations, the ratios of the yields of base damage to SSBs are similar, being about 3.0 ± 0.2; d. Base damage contributes more to the complexity of both SSBs and DSBs, than additional SSB damage and this is true for both low- and high-LET radiations; and e. The average SSB/DSB ratio for low-LET radiations is about 18, which is about 5 times higher than that for high-LET radiations. The hypothesis that clustered DNA damage is more difficult for cells to repair has gained currency among radiobiologists. However, as yet, there is no direct in vivo experimental method to validate the dependence of kinetics of DNA repair on DNA damage complexity (both DSB and non-DSB types). The data on the detailed spectrum of DNA damage presented here, in particular

  19. Radiation-induced gliomas

    PubMed Central

    Prasad, Gautam; Haas-Kogan, Daphne A.

    2013-01-01

    Radiation-induced gliomas represent a relatively rare but well-characterized entity in the neuro-oncologic literature. Extensive retrospective cohort data in pediatric populations after therapeutic intracranial radiation show a clearly increased risk in glioma incidence that is both patient age- and radiation dose/volume-dependent. Data in adults are more limited but show heightened risk in certain groups exposed to radiation. In both populations, there is no evidence linking increased risk associated with routine exposure to diagnostic radiation. At the molecular level, recent studies have found distinct genetic differences between radiation-induced gliomas and their spontaneously-occurring counterparts. Clinically, there is understandable reluctance on the part of clinicians to re-treat patients due to concern for cumulative neurotoxicity. However, available data suggest that aggressive intervention can lead to improved outcomes in patients with radiation-induced gliomas. PMID:19831840

  20. Structural changes caused by radiation-induced reduction and radiolysis: the effect of X-ray absorbed dose in a fungal multicopper oxidase

    SciTech Connect

    De la Mora, Eugenio; Lovett, Janet E.; Blanford, Christopher F.; Garman, Elspeth F.; Valderrama, Brenda; Rudino-Pinera, Enrique

    2012-05-01

    Radiation-induced reduction, radiolysis of copper sites and the effect of pH value together with the concomitant geometrical distortions of the active centres were analysed in several fungal (C. gallica) laccase structures collected at cryotemperature. This study emphasizes the importance of careful interpretation when the crystallographic structure of a metalloprotein is described. X-ray radiation induces two main effects at metal centres contained in protein crystals: radiation-induced reduction and radiolysis and a resulting decrease in metal occupancy. In blue multicopper oxidases (BMCOs), the geometry of the active centres and the metal-to-ligand distances change depending on the oxidation states of the Cu atoms, suggesting that these alterations are catalytically relevant to the binding, activation and reduction of O{sub 2}. In this work, the X-ray-determined three-dimensional structure of laccase from the basidiomycete Coriolopsis gallica (Cg L), a high catalytic potential BMCO, is described. By combining spectroscopic techniques (UV–Vis, EPR and XAS) and X-ray crystallography, structural changes at and around the active copper centres were related to pH and absorbed X-ray dose (energy deposited per unit mass). Depletion of two of the four active Cu atoms as well as low occupancies of the remaining Cu atoms, together with different conformations of the metal centres, were observed at both acidic pH and high absorbed dose, correlating with more reduced states of the active coppers. These observations provide additional evidence to support the role of flexibility of copper sites during O{sub 2} reduction. This study supports previous observations indicating that interpretations regarding redox state and metal coordination need to take radiation effects explicitly into account.

  1. Radiation-induced pneumothorax

    SciTech Connect

    Epstein, D.M.; Littman, P.; Gefter, W.B.; Miller, W.T.; Raney, R.B. Jr.

    1983-01-01

    Pneumothorax is an uncommon complication of radiation therapy to the chest. The proposed pathogenesis is radiation-induced fibrosis promoting subpleural bleb formation that ruptures resulting in pneumothorax. We report on two young patients with primary sarcomas without pulmonary metastases who developed spontaneous pneumothorax after irradiation. Neither patient had antecedent radiographic evidence of pulmonary fibrosis.

  2. Ionizing radiation induces structural and functional damage on the molecules of rat brain homogenate membranes: a Fourier transform infrared (FT-IR) spectroscopic study.

    PubMed

    Demir, Pinar; Akkas, Sara B; Severcan, Mete; Zorlu, Faruk; Severcan, Feride

    2015-01-01

    Humans can be exposed to ionizing radiation, due to various reasons, whose structural effects on biological membranes are not well defined. The current study aims to understand the ionizing radiation-induced structural and functional alterations in biomolecules of brain membranes using Fourier transform infrared (FT-IR) spectroscopy using rat animal models. For this purpose, 1000 cGy of ionizing radiation was specifically directed to the head of Sprague Dawley rats. The rats were decapitated after 24 h. The results revealed that the lipid-to-protein ratio decreased and that irradiation caused lipid peroxidation and increases in the amounts of olefinic =CH, carbonyl, and methylene groups of lipids. In addition, ionizing radiation induced a decrease in membrane fluidity, disordering of membrane lipids, strengthening of the hydrogen bonding of the phosphate groups of lipid head-groups, and weakening in the hydrogen bonding of the interfacial carbonyl groups of lipids. Radiation further caused significant decrements in the α-helix and turns, and significant increments in the β-sheet and random coil contents in the protein structure. Hierarchical cluster analyses, performed in the whole region (3030-1000 cm(-1)), lipid (3030-2800 cm(-1)), and protein (1700-1600 cm(-1)) regions separately, successfully differentiated the control and irradiated groups of rat brain membranes and showed that proteins in the membranes are affected more than lipids from the damages induced with ionizing radiation. As a result, the current study showed that FT-IR spectroscopy can be used successfully as a novel method to monitor radiation-induced alterations on biological membranes.

  3. TLR4-dependent immune response promotes radiation-induced liver disease by changing the liver tissue interstitial microenvironment during liver cancer radiotherapy.

    PubMed

    Zhi-Feng, Wu; Le-Yuan, Zhou; Xiao-Hui, Zhou; Ya-Bo, Gao; Jian-Ying, Zhang; Yong, Hu; Zhao-Chong, Zeng

    2014-12-01

    Liver tissue interstitial fluid (TIF) a special microenvironment around liver cells, which may play a vital role in cell communication during liver injury. Moreover, toll-like receptor 4 (TLR4) is an important trigger of the immune response that may also play a role in liver injuries, including radiation-induced liver disease (RILD). Therefore, the purpose of this study was to identify the roles of the TLR4-dependent immune response and TIFs in RILD after radiation therapy (RT) for liver cancer. This study consisted of two phases, and in the primary phase, the livers of TLR4 mutant (TLR4(-)) and normal (TLR4(+)) mice were irradiated with 30 Gy. TIF was then obtained from mouse livers and assessed by cytokine array analysis 20 days after irradiation, and cytokines in the TIFs, TLR4 and RILD were analyzed. In the second or validation phase, hepatocytes were isolated from TLR4(+) or TLR4(-) mice irradiated with 8 Gy and were co-cultured with TIFs from mouse livers, apoptosis of the hepatocytes was then measured using flow cytometry. We found that severe RILD was accompanied by higher expression of granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-related apoptosis inducing ligand (TRAIL) and vascular endothelial growth factor receptor 2(VEGFR-2) in liver TIFs, from in TLR4(+) mice compared with TLR4(-) mice (P < 0.05). In both TLR4(+) and TLR4(-) hepatocytes, apoptosis after irradiaton was increased significantly after co-culture in TIFs from TLR4(+) mice that had their livers irradiated, compared with TIFs from TLR4(-) mice that had their livers irradiated or TIFs from unirradiated mice (P < 0.05). In summary, these findings indicate that the TLR4-dependent immune response may promote RILD by enhancing the expression of GM-CSF, VEGFR-2 and TRAIL in liver TIFs.

  4. The effects of anti-angiogenic therapy on the formation of radiation-induced microbleeds in normal brain tissue of patients with glioma†

    PubMed Central

    Lupo, Janine M.; Molinaro, Annette M.; Essock-Burns, Emma; Butowski, Nicholas; Chang, Susan M.; Cha, Soonmee; Nelson, Sarah J.

    2016-01-01

    Background Radiotherapy (RT) is an integral component in managing patients with glioma, but the damage it may cause to healthy brain tissue and quality of life is of concern. Susceptibility-weighted imaging (SWI) is highly sensitive to the detection of microbleeds that occur years after RT. This study's goals were to characterize the evolution of radiation-induced microbleeds in normal-appearing brain and determine whether the administration of an anti-angiogenic agent altered this process. Methods Serial high-resolution SWI was acquired on 17 patients with high-grade glioma between 8 months and 4.5 years posttreatment with RT and adjuvant chemotherapy. Nine of these patients were also treated with the anti-angiogenic agent enzastaurin. Microbleeds were identified as discrete foci of susceptibility not corresponding to vessels, tumor, or postoperative infarct, and counted in normal-appearing brain. Analysis of covariance was performed to compare slopes of regression of individual patients' microbleed counts over time, Wilcoxon rank-sum tests examined significant differences in rates of microbleed formation between groups, and linear and quadratic mixed-effects models were employed. Results The number of microbleeds increased with time for all patients, with initial onset occurring at 8–22 months. No microbleeds disappeared once formed. The average rate of microbleed formation significantly increased after 2 years post-RT (P < .001). Patients receiving anti-angiogenic therapy exhibited fewer microbleeds overall (P < .05) and a significant reduction in initial rate of microbleed appearance (P = .01). Conclusions We have demonstrated a dramatic increase in microbleed formation after 2 years post-RT that was decelerated by the concomitant administration of anti-angiogenic therapy, which may aid in determining brain regions susceptible to RT. PMID:26206774

  5. Structural changes caused by radiation-induced reduction and radiolysis: the effect of X-ray absorbed dose in a fungal multicopper oxidase.

    PubMed

    De la Mora, Eugenio; Lovett, Janet E; Blanford, Christopher F; Garman, Elspeth F; Valderrama, Brenda; Rudino-Pinera, Enrique

    2012-05-01

    X-ray radiation induces two main effects at metal centres contained in protein crystals: radiation-induced reduction and radiolysis and a resulting decrease in metal occupancy. In blue multicopper oxidases (BMCOs), the geometry of the active centres and the metal-to-ligand distances change depending on the oxidation states of the Cu atoms, suggesting that these alterations are catalytically relevant to the binding, activation and reduction of O(2). In this work, the X-ray-determined three-dimensional structure of laccase from the basidiomycete Coriolopsis gallica (Cg L), a high catalytic potential BMCO, is described. By combining spectroscopic techniques (UV-Vis, EPR and XAS) and X-ray crystallography, structural changes at and around the active copper centres were related to pH and absorbed X-ray dose (energy deposited per unit mass). Depletion of two of the four active Cu atoms as well as low occupancies of the remaining Cu atoms, together with different conformations of the metal centres, were observed at both acidic pH and high absorbed dose, correlating with more reduced states of the active coppers. These observations provide additional evidence to support the role of flexibility of copper sites during O(2) reduction. This study supports previous observations indicating that interpretations regarding redox state and metal coordination need to take radiation effects explicitly into account.

  6. Molecular and genetic characterization of a radiation-induced structural rearrangement in mouse chromosome 2 causing mutations at the limb deformity and agouti loci.

    PubMed

    Woychik, R P; Generoso, W M; Russell, L B; Cain, K T; Cacheiro, N L; Bultman, S J; Selby, P B; Dickinson, M E; Hogan, B L; Rutledge, J C

    1990-04-01

    Molecular characterization of mutations in the mouse, particularly those involving agent-induced major structural alterations, is proving to be useful for correlating the structure and expression of individual genes with their function in the whole organism. Here we present the characterization of a radiation-induced mutation that simultaneously generated distinct alleles of both the limb deformity (ld) and agouti (a) loci, two developmentally important regions of chromosome 2 normally separated by 20 centimorgans. Cytogenetic analysis revealed that an interstitial segment of chromosome 17 (17B- 17C; or, possibly, 17A2-17B) had been translocated into the distal end of chromosome 2, resulting in a smaller-than-normal chromosome 17 (designated 17del) and a larger form of chromosome 2 (designated 2(17). Additionally, a large interstitial segment of the 2(17) chromosome, immediately adjacent and proximal to the insertion site, did not match bands 2E4-2H1 at corresponding positions on a normal chromosome 2. Molecular analysis detected a DNA rearrangement in which a portion of the ld locus was joined to sequences normally tightly linked to the a locus. This result, along with the genetic and cytogenetic data, suggests that the alleles of ld and a in this radiation-induced mutation, designated ldIn2 and ajIn2, were associated with DNA breaks caused by an inversion of an interstitial segment in the 2(17) chromosome.

  7. Structural changes caused by radiation-induced reduction and radiolysis: the effect of X-ray absorbed dose in a fungal multicopper oxidase

    PubMed Central

    De la Mora, Eugenio; Lovett, Janet E.; Blanford, Christopher F.; Garman, Elspeth F.; Valderrama, Brenda; Rudino-Pinera, Enrique

    2012-01-01

    X-ray radiation induces two main effects at metal centres contained in protein crystals: radiation-induced reduction and radiolysis and a resulting decrease in metal occupancy. In blue multicopper oxidases (BMCOs), the geometry of the active centres and the metal-to-ligand distances change depending on the oxidation states of the Cu atoms, suggesting that these alterations are catalytically relevant to the binding, activation and reduction of O2. In this work, the X-ray-determined three-dimensional structure of laccase from the basidiomycete Coriolopsis gallica (Cg L), a high catalytic potential BMCO, is described. By combining spectroscopic techniques (UV–Vis, EPR and XAS) and X-ray crystallography, structural changes at and around the active copper centres were related to pH and absorbed X-­ray dose (energy deposited per unit mass). Depletion of two of the four active Cu atoms as well as low occupancies of the remaining Cu atoms, together with different conformations of the metal centres, were observed at both acidic pH and high absorbed dose, correlating with more reduced states of the active coppers. These observations provide additional evidence to support the role of flexibility of copper sites during O2 reduction. This study supports previous observations indicating that interpretations regarding redox state and metal coordination need to take radiation effects explicitly into account. PMID:22525754

  8. Prospective Study Validating Inter- and Intraobserver Variability of Tissue Compliance Meter in Breast Tissue of Healthy Volunteers: Potential Implications for Patients With Radiation-Induced Fibrosis of the Breast

    SciTech Connect

    Wernicke, A. Gabriella; Parashar, Bhupesh; Kulidzhanov, Fridon; Riley, Lillian; Christos, Paul J.; Fischer, Andrew; Nori, Dattatreyudu; Chao, K.S. Clifford

    2011-05-01

    Purpose: Accurate detection of radiation-induced fibrosis (RIF) is crucial in management of breast cancer survivors. Tissue compliance meter (TCM) has been validated in musculature. We validate TCM in healthy breast tissue with respect to interobserver and intraobserver variability before applying it in RIF. Methods and Materials: Three medical professionals obtained three consecutive TCM measurements in each of the four quadrants of the right and left breasts of 40 women with no breast disease or surgical intervention. The intraclass correlation coefficient (ICC) assessed interobserver variability. The paired t test and Pearson correlation coefficient (r) were used to assess intraobserver variability within each rater. Results: The median age was 45 years (range, 24-68 years). The median bra size was 35C (range, 32A-40DD). Of the participants, 27 were white (67%), 4 black (10%), 5 Asian (13%), and 4 Hispanic (10%). ICCs indicated excellent interrater reliability (low interobserver variability) among the three raters, by breast and quadrant (all ICC {>=}0.99). The paired t test and Pearson correlation coefficient both indicated low intraobserver variability within each rater (right vs. left breast), stratified by quadrant (all r{>=} 0.94, p < 0.0001). Conclusions: The interobserver and intraobserver variability is small using TCM in healthy mammary tissue. We are now embarking on a prospective study using TCM in women with breast cancer at risk of developing RIF that may guide early detection, timely therapeutic intervention, and assessment of success of therapy for RIF.

  9. Measurement of changes in impedance of DNA nanowires due to radiation induced structural damage. A novel approach for a DNA-based radiosensitive device

    NASA Astrophysics Data System (ADS)

    Heimbach, Florian; Arndt, Alexander; Nettelbeck, Heidi; Langner, Frank; Giesen, Ulrich; Rabus, Hans; Sellner, Stefan; Toppari, Jussi; Shen, Boxuan; Baek, Woon Yong

    2017-08-01

    The ability of DNA to conduct electric current has been the topic of numerous investigations over the past few decades. Those investigations indicate that this ability is dependent on the molecular structure of the DNA. Radiation-induced damages, which lead to an alteration of the molecular structure, should therefore change the electrical impedance of a DNA molecule. In this paper, the damage due to ionising radiation is shown to have a direct effect on the electrical transport properties of DNA. Impedance measurements of DNA samples were carried out by an AC impedance spectrometer before, during and after irradiation. The samples comprised of DNA segments, which were immobilized between gold electrodes with a gap of 12 μm. The impedance of all DNA samples exhibited rising capacitive behaviour with increasing absorbed dose.

  10. Radiation-induced amorphization of intermetallic compounds

    NASA Astrophysics Data System (ADS)

    Lam, N. Q.; Sabochick, M. J.; Okamoto, P. R.

    1994-06-01

    In the present paper, important results of our recent computer simulation of radiation-induced amorphization in the ordered compounds CuTi and Cu4Ti3 are summarized. The energetic, structural, thermodynamic and mechanical responses of these intermetallics during chemical disordering, point-defect production and heating were simulated, using molecular dynamics and embedded-atom potentials. From the atomistic details obtained, the critical role of radiation-induced structural disorder in driving the crystalline-to-amorphous phase transformation is discussed.

  11. Radiation-Induced Oral Mucositis

    PubMed Central

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

    2017-01-01

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

  12. Radiation-Induced Oral Mucositis.

    PubMed

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

    2017-01-01

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

  13. Radiation Induced Oral Mucositis

    PubMed Central

    PS, Satheesh Kumar; Balan, Anita; Sankar, Arun; Bose, Tinky

    2009-01-01

    Patients receiving radiotherapy or chemotherapy will receive some degree of oral mucositis The incidence of oral mucositis was especially high in patients: (i) With primary tumors in the oral cavity, oropharynx, or nasopharynx; (ii) who also received concomitant chemotherapy; (iii) who received a total dose over 5,000 cGy; and (iv) who were treated with altered fractionation radiation schedules. Radiation-induced oral mucositis affects the quality of life of the patients and the family concerned. The present day management of oral mucositis is mostly palliative and or supportive care. The newer guidelines are suggesting Palifermin, which is the first active mucositis drug as well as Amifostine, for radiation protection and cryotherapy. The current management should focus more on palliative measures, such as pain management, nutritional support, and maintenance, of good oral hygiene PMID:20668585

  14. The effect of radiation-induced reactive oxygen species (ROS) on the structural and functional properties of yeast alcohol dehydrogenase (YADH).

    PubMed

    Rodacka, Aleksandra

    2016-01-01

    To determine the mechanism underlying oxidative modifications caused by radiation-induced reactive oxygen species (ROS) and elucidate their effect on the structure and function of yeast alcohol dehydrogenase (YADH), a zinc-containing protein. YADH was exposed to water radiolysis products in an air atmosphere. YADH oxidation products were determined by spectrophotometric and spectrofluorimetric methods. The extent to which oxidative modifications affected enzyme activity was also studied. Water radiolysis products oxidized thiol groups leading to the release of zinc ions and the destruction of tryptophan and tyrosine residues. Those processes were accompanied by alterations in protein structure such as increased surface hydrophobicity, greater tryptophan accessibility to acrylamide, and changes in the secondary structure. Structural modifications were correlated with lower enzyme activity. During the process of functional and structural changes in YADH exposed to reactive oxygen species, a key part is the oxidation of cysteine residues attached to zinc and the release of zinc ions from the molecule. It may be assumed that ROS induce similar changes in many other zinc-containing proteins.

  15. Radiation Induced Genomic Instability

    SciTech Connect

    Morgan, William F.

    2011-03-01

    Radiation induced genomic instability can be observed in the progeny of irradiated cells multiple generations after irradiation of parental cells. The phenotype is well established both in vivo (Morgan 2003) and in vitro (Morgan 2003), and may be critical in radiation carcinogenesis (Little 2000, Huang et al. 2003). Instability can be induced by both the deposition of energy in irradiated cells as well as by signals transmitted by irradiated (targeted) cells to non-irradiated (non-targeted) cells (Kadhim et al. 1992, Lorimore et al. 1998). Thus both targeted and non-targeted cells can pass on the legacy of radiation to their progeny. However the radiation induced events and cellular processes that respond to both targeted and non-targeted radiation effects that lead to the unstable phenotype remain elusive. The cell system we have used to study radiation induced genomic instability utilizes human hamster GM10115 cells. These cells have a single copy of human chromosome 4 in a background of hamster chromosomes. Instability is evaluated in the clonal progeny of irradiated cells and a clone is considered unstable if it contains three or more metaphase sub-populations involving unique rearrangements of the human chromosome (Marder and Morgan 1993). Many of these unstable clones have been maintained in culture for many years and have been extensively characterized. As initially described by Clutton et al., (Clutton et al. 1996) many of our unstable clones exhibit persistently elevated levels of reactive oxygen species (Limoli et al. 2003), which appear to be due dysfunctional mitochondria (Kim et al. 2006, Kim et al. 2006). Interestingly, but perhaps not surprisingly, our unstable clones do not demonstrate a “mutator phenotype” (Limoli et al. 1997), but they do continue to rearrange their genomes for many years. The limiting factor with this system is the target – the human chromosome. While some clones demonstrate amplification of this chromosome and thus lend

  16. Long-term melatonin administration attenuates low-LET γ-radiation-induced lymphatic tissue injury during the reproductively active and inactive phases of Indian palm squirrels (Funambulus pennanti)

    PubMed Central

    Sharma, S; Haldar, C; Chaube, S K; Laxmi, T; Singh, S S

    2010-01-01

    A comparative analysis of low linear energy transfer (LET) γ-radiation-induced damage in the lymphatic tissue of a tropical seasonal breeder, Indian palm squirrel (Funambulus pennanti), during its reproductively active phase (RAP) and inactive phase (RIP) was performed with simultaneous investigation of the effects of long-term melatonin pre-treatment (100 μg/100 g body weight). A total of 120 squirrels (60 during RAP and 60 during RIP) were divided into 12 groups and sacrificed at 4, 24, 48, 72 and 168 h following 5 Gy γ-radiation exposure; control groups were excluded from exposure. Total leukocyte count and absolute lymphocyte count (ALC) and melatonin only of peripheral blood, stimulation index, thiobarbituric-acid-reactive substances (TBARS) level, superoxide dismutase (SOD) activity, and the apoptotic index of spleen as analysed by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labelling (TUNEL) noted at observed time-points were significantly reduced in melatonin pre-treated groups during RAP and RIP. Long-term melatonin pre-treatment mitigated radiation-induced alterations more prominently during RIP, as assessed by ALC, TBARS, SOD, TUNEL and caspase-3 activity, at some time-points. Our results demonstrate an inhibitory role of melatonin on caspase-3 activity in splenocytes during RAP and RIP following γ-radiation-induced caspase-mediated apoptosis. Hence, we propose that melatonin might preserve the viability of immune cells of a seasonal breeder against background radiation, which is constantly present in the environment. PMID:20139262

  17. Simulations of DSB Yields and Radiation-induced Chromosomal Aberrations in Human Cells Based on the Stochastic Track Structure Induced by HZE Particles

    NASA Technical Reports Server (NTRS)

    Ponomarev, Artem; Plante, Ianik; George, Kerry; Wu, Honglu

    2014-01-01

    The formation of double-strand breaks (DSBs) and chromosomal aberrations (CAs) is of great importance in radiation research and, specifically, in space applications. We are presenting a new particle track and DNA damage model, in which the particle stochastic track structure is combined with the random walk (RW) structure of chromosomes in a cell nucleus. The motivation for this effort stems from the fact that the model with the RW chromosomes, NASARTI (NASA radiation track image) previously relied on amorphous track structure, while the stochastic track structure model RITRACKS (Relativistic Ion Tracks) was focused on more microscopic targets than the entire genome. We have combined chromosomes simulated by RWs with stochastic track structure, which uses nanoscopic dose calculations performed with the Monte-Carlo simulation by RITRACKS in a voxelized space. The new simulations produce the number of DSBs as function of dose and particle fluence for high-energy particles, including iron, carbon and protons, using voxels of 20 nm dimension. The combined model also calculates yields of radiation-induced CAs and unrejoined chromosome breaks in normal and repair deficient cells. The joined computational model is calibrated using the relative frequencies and distributions of chromosomal aberrations reported in the literature. The model considers fractionated deposition of energy to approximate dose rates of the space flight environment. The joined model also predicts of the yields and sizes of translocations, dicentrics, rings, and more complex-type aberrations formed in the G0/G1 cell cycle phase during the first cell division after irradiation. We found that the main advantage of the joined model is our ability to simulate small doses: 0.05-0.5 Gy. At such low doses, the stochastic track structure proved to be indispensable, as the action of individual delta-rays becomes more important.

  18. Simulations of DSB Yields and Radiation-induced Chromosomal Aberrations in Human Cells Based on the Stochastic Track Structure iIduced by HZE Particles

    NASA Technical Reports Server (NTRS)

    Ponomarev, Artem; Plante, Ianik; George, Kerry; Wu, Honglu

    2014-01-01

    The formation of double-strand breaks (DSBs) and chromosomal aberrations (CAs) is of great importance in radiation research and, specifically, in space applications. We are presenting a new particle track and DNA damage model, in which the particle stochastic track structure is combined with the random walk (RW) structure of chromosomes in a cell nucleus. The motivation for this effort stems from the fact that the model with the RW chromosomes, NASARTI (NASA radiation track image) previously relied on amorphous track structure, while the stochastic track structure model RITRACKS (Relativistic Ion Tracks) was focused on more microscopic targets than the entire genome. We have combined chromosomes simulated by RWs with stochastic track structure, which uses nanoscopic dose calculations performed with the Monte-Carlo simulation by RITRACKS in a voxelized space. The new simulations produce the number of DSBs as function of dose and particle fluence for high-energy particles, including iron, carbon and protons, using voxels of 20 nm dimension. The combined model also calculates yields of radiation-induced CAs and unrejoined chromosome breaks in normal and repair deficient cells. The joined computational model is calibrated using the relative frequencies and distributions of chromosomal aberrations reported in the literature. The model considers fractionated deposition of energy to approximate dose rates of the space flight environment. The joined model also predicts of the yields and sizes of translocations, dicentrics, rings, and more complex-type aberrations formed in the G0/G1 cell cycle phase during the first cell division after irradiation. We found that the main advantage of the joined model is our ability to simulate small doses: 0.05-0.5 Gy. At such low doses, the stochastic track structure proved to be indispensable, as the action of individual delta-rays becomes more important.

  19. Radiation induced structural and magnetic transformations in nanoparticle MnxZn(1-x)Fe2O4 ferrites

    NASA Astrophysics Data System (ADS)

    Naik, P. P.; Tangsali, R. B.; Sonaye, B.; Sugur, S.

    2015-07-01

    Nanoparticle magnetic materials are suitable for multiple modern high end medical applications like targeted drug delivery, gene therapy, hyperthermia and MR thermometry imaging. Majority of these applications are confined to use of Mn-Zn ferrite nanoparticles. These nanoparticles are normally left in the body after their requisite application. Preparing these nanoparticles is usually a much involved job. However with the development of the simple technique MnxZn1-xFe2O4 nanoparticles could be prepared with much ease. The nanoparticles of MnxZn1-xFe2O4 with (x=1.0, 0.7, 0.5, 0.3, 0.0) were prepared and irradiated with gamma radiation of various intensities ranging between 500 R to 10,000 R, after appropriate structural and magnetic characterization. Irradiated samples were investigated for structural and magnetic properties, as well as for structural stability and cation distribution. The irradiated nanoparticles exhibited structural stability with varied cation distribution and magnetic properties, dependent on gamma radiation dose. Surprisingly samples also exhibited quenching of lattice parameter and particle size. The changes introduced in the cation distribution, lattice constant, particle size and magnetic properties were found to be irreversible with time lapse and were of permanent nature exhibiting good stability even after several months. Thus the useful properties of nanoparticles could be enhanced on modifying the cation distribution inside the nanoparticles by application of gamma radiation.

  20. Quercetin inhibits radiation-induced skin fibrosis.

    PubMed

    Horton, Jason A; Li, Fei; Chung, Eun Joo; Hudak, Kathryn; White, Ayla; Krausz, Kristopher; Gonzalez, Frank; Citrin, Deborah

    2013-08-01

    Radiation induced fibrosis of the skin is a late toxicity that may result in loss of function due to reduced range of motion and pain. The current study sought to determine if oral delivery of quercetin mitigates radiation-induced cutaneous injury. Female C3H/HeN mice were fed control chow or quercetin-formulated chow (1% by weight). The right hind leg was exposed to 35 Gy of X rays and the mice were followed serially to assess acute toxicity and hind leg extension. Tissue samples were collected for assessment of soluble collagen and tissue cytokines. Human and murine fibroblasts were subjected to clonogenic assays to determine the effects of quercetin on radiation response. Contractility of fibroblasts was assessed with a collagen contraction assay in the presence or absence of quercetin and transforming growth factor-β (TGF-β). Western blotting of proteins involved in fibroblast contractility and TGF-β signaling were performed. Quercetin treatment significantly reduced hind limb contracture, collagen accumulation and expression of TGF-β in irradiated skin. Quercetin had no effect on the radioresponse of fibroblasts or murine tumors, but was capable of reducing the contractility of fibroblasts in response to TGF-β, an effect that correlated with partial stabilization of phosphorylated cofilin. Quercetin is capable of mitigating radiation induced skin fibrosis and should be further explored as a therapy for radiation fibrosis.

  1. Quercetin Inhibits Radiation-Induced Skin Fibrosis

    PubMed Central

    Horton, Jason A.; Li, Fei; Chung, Eun Joo; Hudak, Kathryn; White, Ayla; Krausz, Kristopher; Gonzalez, Frank; Citrin, Deborah

    2013-01-01

    Radiation induced fibrosis of the skin is a late toxicity that may result in loss of function due to reduced range of motion and pain. The current study sought to determine if oral delivery of quercetin mitigates radiation-induced cutaneous injury. Female C3H/HeN mice were fed control chow or quercetin-formulated chow (1% by weight). The right hind leg was exposed to 35 Gy of X rays and the mice were followed serially to assess acute toxicity and hind leg extension. Tissue samples were collected for assessment of soluble collagen and tissue cytokines. Human and murine fibroblasts were subjected to clonogenic assays to determine the effects of quercetin on radiation response. Contractility of fibroblasts was assessed with a collagen contraction assay in the presence or absence of quercetin and transforming growth factor-β (TGF-β). Western blotting of proteins involved in fibroblast contractility and TGF-β signaling were performed. Quercetin treatment significantly reduced hind limb contracture, collagen accumulation and expression of TGF-β in irradiated skin. Quercetin had no effect on the radioresponse of fibroblasts or murine tumors, but was capable of reducing the contractility of fibroblasts in response to TGF-β, an effect that correlated with partial stabilization of phosphorylated cofilin. Quercetin is capable of mitigating radiation induced skin fibrosis and should be further explored as a therapy for radiation fibrosis. PMID:23819596

  2. Radiation induced structural and motional changes occurring in silica filled silicone polymer foams as probed by multinuclear NMR

    SciTech Connect

    Maxwell, R.S.; Balazs, B.; Chien, A.; LeMay, J.

    1999-10-14

    The aging of polymeric composite materials through factors such as thermal and mechanical stresses, environment, radiation, and chemical attack can affect the length of time for which a given material can maintain its engineering performance. Iterative interactions and cumulative reactions may result in the material or device reaching a critical age where its properties fail unexpectedly and catastrophically. The mechanical poperty changes associated with multi-mechanism aging may be subtle, and may not necessarily change linearly as a function of time in service. Since such linear relationships are often used in lifetime predictions, there is a fundamental need to develop and employ spectroscopic methods to investigate the structural and motional changes that occur in these organic-inorganic materials as a result of aging in chemically, thermally, or radioactively harsh environments. Silica filled polydimethylsiloxane (PDMS) composite systems are of technological interest due to their chemical and environmental resilience. Silica is usually chosen as the filler phase due to the significant reinforcement of the composite material through hydrogen bonding between the polymer chains and the surface groups on the filler. Unfilled PDMS is known to crosslink when exposed to high-energy radiation. The presence of a silica filler phase, which has a higher electron density than the polymer matrix, has been proposed to result in an increased incidence of crosslinking or scission due to backscatter of the incident radiation. Cohen-Addad has used {sup 1}H relaxation times to characterized cross-link density in unirradiated filled PDMS and Charlesby has reported {sup 1}H relaxation studies of irradiation induced changes in unfilled PDMS systems of average molccular weights up to 1 MDalton. However, no specific studies have been reported on aging of silica-filled PDMS based polymers systems. To this end the authors have applied Nuclear Magnetic Resonance (NMR) methods to gain

  3. Tissue compliance meter is a more reproducible method of measuring radiation-induced fibrosis than late effects of normal tissue-subjective objective management analytical in patients treated with intracavitary brachytherapy accelerated partial breast irradiation: results of a prospective trial.

    PubMed

    Wernicke, A Gabriella; Greenwood, Eleni A; Coplowitz, Shana; Parashar, Bhupesh; Kulidzhanov, Fridon; Christos, Paul J; Fischer, Andrew; Nori, Dattatreyudu; Chao, Kun S Clifford

    2013-01-01

    Identification of radiation-induced fibrosis (RIF) remains a challenge with Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA). Tissue compliance meter (TCM), a non-invasive applicator, may render a more reproducible tool for measuring RIF. In this study, we prospectively quantify RIF after intracavitary brachytherapy (IB) accelerated partial breast irradiation (APBI) with TCM and compare it with LENT-SOMA. Thirty-nine women with American Joint Committee on Cancer Stages 0-I breast cancer, treated with lumpectomy and intracavitary brachytherapy delivered by accelerated partial breast irradiation (IBAPBI), were evaluated by two raters in a prospective manner pre-IBAPBI and every 6 months post-IBAPBI for development of RIF, using TCM and LENT-SOMA. TCM classification scale grades RIF as 0 = none, 1 = mild, 2 = moderate, and 3 = severe, corresponding to a change in TCM (ΔTCM) between the IBAPBI and nonirradiated breasts of ≤2.9, 3.0-5.9, 6.0-8.9, ≥9.0 mm, respectively. LENT-SOMA scale employs clinical palpation to grade RIF as 0 = none, 1 = mild, 2 = moderate, and 3 = severe. Correlation coefficients-Intraclass (ICC), Pearson (r), and Cohen's kappa (κ)-were employed to assess reliability of TCM and LENT-SOMA. Multivariate and univariate linear models explored the relationship between RIF and anatomical parameters [bra cup size], antihormonal therapy, and dosimetric factors [balloon diameter, skin-to-balloon distance (SBD), V150, and V200]. Median time to follow-up from completion of IBAPBI is 3.6 years (range, 0.8-4.9 years). Median age is 69 years (range, 47-82 years). Median breast cup size is 39D (range, 34B-44DDD). Median balloon size is 41.2 cc (range, 37.6-50.0 cc), and median SBD is 1.4 cm (range, 0.2-5.5 cm). At pre-IBAPBI, TCM measurements demonstrate high interobserver agreement between two raters in all four quadrants of both breasts ICC ≥ 0.997 (95% CI 0.994-1.000). After 36 months, RIF is graded by TCM scale as 0

  4. The Impact of the Geometrical Structure of the DNA on Parameters of the Track-Event Theory for Radiation Induced Cell Kill.

    PubMed

    Schneider, Uwe; Vasi, Fabiano; Besserer, Jürgen

    2016-01-01

    When fractionation schemes for hypofractionation and stereotactic body radiotherapy are considered, a reliable cell survival model at high dose is needed for calculating doses of similar biological effectiveness. An alternative to the LQ-model is the track-event theory which is based on the probabilities for one- and two two-track events. A one-track-event (OTE) is always represented by at least two simultaneous double strand breaks. A two-track-event (TTE) results in one double strand break. Therefore at least two two-track-events on the same or different chromosomes are necessary to produce an event which leads to cell sterilization. It is obvious that the probabilities of OTEs and TTEs must somehow depend on the geometrical structure of the chromatin. In terms of the track-event theory the ratio ε of the probabilities of OTEs and TTEs includes the geometrical dependence and is obtained in this work by simple Monte Carlo simulations. For this work it was assumed that the anchors of loop forming chromatin are most sensitive to radiation induced cell deaths. Therefore two adjacent tetranucleosomes representing the loop anchors were digitized. The probability ratio ε of OTEs and TTEs was factorized into a radiation quality dependent part and a geometrical part: ε = εion ∙ εgeo. εgeo was obtained for two situations, by applying Monte Carlo simulation for DNA on the tetranucleosomes itself and for linker DNA. Low energy electrons were represented by randomly distributed ionizations and high energy electrons by ionizations which were simulated on rays. εion was determined for electrons by using results from nanodosimetric measurements. The calculated ε was compared to the ε obtained from fits of the track event model to 42 sets of experimental human cell survival data. When the two tetranucleosomes are in direct contact and the hits are randomly distributed εgeo and ε are 0.12 and 0.85, respectively. When the hits are simulated on rays εgeo and ε are 0

  5. [Update in radiation-induced neoplasms: genetic studies].

    PubMed

    Chauveinc, Laurent; Lefevre, Sandrine; Malfoy, Bernard; Dutrillaux, Bernard

    2002-02-01

    Radiation induced tumors are a possible (very) late complications of radiotherapy. The evaluation of the risks of radiation-induced tumors has been presented in different epidemiological studies, with the evaluation of the relative risk for different tissues. But, the genetic studies are rare, and no global theory exists. Two cytogenetic profiles are described, one with translocations and one with genetic material losses, evoking two different genetic evolutions. Two questions are stated. What are the radiation-induced genetic mechanisms? Is it possible to differentiate the radiation-induced and spontaneous tumors with genetic approaches? With 37 cytogenetic cases, 12 analyzed in our laboratory, the radiation-induced tumors were characterized by genetic material losses. An anti-oncogenic evolution is probable. A new molecularly study confirm these results. Only thyroid tumors do not have this evolution. For tumors with simple karyotype, like meningioma, radiation-induced tumors seem to be more complex than spontaneous tumors. But for the others, the differentiation is impossible to be done with cytogenetic. The mechanism of the chromosomic material losses in unknown, but some hypothesis are discussed.

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

    NASA Astrophysics Data System (ADS)

    Bednarz, Bryan; Besemer, Abigail

    2017-09-01

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

  7. A Preliminary Study on Racial Differences in HMOX1, NFE2L2 and TGFβ1 Gene Polymorphisms and Radiation Induced Late Normal Tissue Toxicity

    PubMed Central

    Alam, Asim; Mukhopadhyay, Nitai D.; Ning, Yi; Reshko, Leonid B.; Cardnell, Robert J.G.; Alam, Omair; Rabender, Christopher S.; Yakovlev, Vasily A.; Walker, Linda; Anscher, Mitchell S.; Mikkelsen, Ross B.

    2015-01-01

    Purpose This study tests whether racial differences in genetic polymorphisms of four genes involved in wound repair and response to radiation can be used to predict the occurrence of normal tissue late effects of radiotherapy and indicate potential therapeutic targets. Methods and Materials This prospective study examines genetic polymorphisms that modulate the expression of four genes involved in inflammation and fibrosis and response to radiation (HMOX1, NFE2L2, NOS3 and TGFβ1). DNA from blood samples of 179 patients (~80% breast and head and neck) collected at the time of diagnosis by their radiation oncologist as exhibiting late normal tissue toxicity was used for the analysis. Patient demographics were: 56% Caucasian, 43% African-American, 1% other. Allelic frequencies of the different polymorphisms of the participants were compared to those of the general American population stratified by race. Twenty-six additional patients treated with radiation, but without toxicity at 3 months or later post-therapy, were also analyzed. Results Increased frequency of a long GT repeat in the HMOX1 promoter was associated with late effects in both African-American and Caucasian populations. The single nucleotide polymorphisms (SNP) rs1800469 in the TGFβ1 promoter and the rs6721961 SNP in the NFE2L2 promoter were also found to significantly associate with late effects in African-Americans but not Caucasians. A combined analysis of these polymorphisms revealed that >90% of African-American patients with late effects had at least one and 58% two or more of these minor alleles. No statistical significance was found relating the studied NOS3 polymorphisms and normal tissue toxicity. Conclusions These results support a strong association between wound repair and late toxicities of radiation. The presence of these genetic risk factors can vary significantly among different ethnic groups, as demonstrated for some of the SNPs. Future studies should account for the possibility of

  8. A Preliminary Study on Racial Differences in HMOX1, NFE2L2, and TGFβ1 Gene Polymorphisms and Radiation-Induced Late Normal Tissue Toxicity

    SciTech Connect

    Alam, Asim; Mukhopadhyay, Nitai D.; Ning, Yi; Reshko, Leonid B.; Cardnell, Robert J.G.; Alam, Omair; Rabender, Christopher S.; Yakovlev, Vasily A.; Walker, Linda; Anscher, Mitchell S.; Mikkelsen, Ross B.

    2015-10-01

    Purpose: This study tested whether racial differences in genetic polymorphisms of 4 genes involved in wound repair and response to radiation can be used to predict the occurrence of normal tissue late effects of radiation therapy and indicate potential therapeutic targets. Methods and Materials: This prospective study examined genetic polymorphisms that modulate the expression of 4 genes involved in inflammation and fibrosis and response to radiation (HMOX1, NFE2L2, NOS3, and TGFβ1). DNA from blood samples of 179 patients (∼80% breast and head and neck) collected at the time of diagnosis by their radiation oncologist as exhibiting late normal tissue toxicity was used for the analysis. Patient demographics were as follows: 56% white, 43% African American, 1% other. Allelic frequencies of the different polymorphisms of the participants were compared with those of the general American population stratified by race. Twenty-six additional patients treated with radiation, but without toxicity at 3 months or later after therapy, were also analyzed. Results: Increased frequency of a long GT repeat in the HMOX1 promoter was associated with late effects in both African American and white populations. The single nucleotide polymorphisms (SNP) rs1800469 in the TGFβ1 promoter and the rs6721961 SNP in the NFE2L2 promoter were also found to significantly associate with late effects in African Americans but not whites. A combined analysis of these polymorphisms revealed that >90% of African American patients with late effects had at least 1 of these minor alleles, and 58% had 2 or more. No statistical significance was found relating the studied NOS3 polymorphisms and normal tissue toxicity. Conclusions: These results support a strong association between wound repair and late toxicities of radiation. The presence of these genetic risk factors can vary significantly among different ethnic groups, as demonstrated for some of the SNPs. Future studies should account for the

  9. Role of Oxidative Damage in Radiation-Induced Bone Loss

    NASA Technical Reports Server (NTRS)

    Schreurs, Ann-Sofie; Alwood, Joshua S.; Limoli, Charles L.; Globus, Ruth K.

    2014-01-01

    used an array of countermeasures (Antioxidant diets and injections) to prevent the radiation-induced bone loss, although these did not prevent bone loss, analysis is ongoing to determine if these countermeasure protected radiation-induced damage to other tissues.

  10. Prediction of radiation-induced liver disease by Lyman normal-tissue complication probability model in three-dimensional conformal radiation therapy for primary liver carcinoma

    SciTech Connect

    Xu ZhiYong; Liang Shixiong; Zhu Ji; Zhu Xiaodong; Zhao Jiandong; Lu Haijie; Yang Yunli; Chen Long; Wang Anyu; Fu Xiaolong; Jiang Guoliang . E-mail: jianggl@21cn.com

    2006-05-01

    Purpose: To describe the probability of RILD by application of the Lyman-Kutcher-Burman normal-tissue complication (NTCP) model for primary liver carcinoma (PLC) treated with hypofractionated three-dimensional conformal radiotherapy (3D-CRT). Methods and Materials: A total of 109 PLC patients treated by 3D-CRT were followed for RILD. Of these patients, 93 were in liver cirrhosis of Child-Pugh Grade A, and 16 were in Child-Pugh Grade B. The Michigan NTCP model was used to predict the probability of RILD, and then the modified Lyman NTCP model was generated for Child-Pugh A and Child-Pugh B patients by maximum-likelihood analysis. Results: Of all patients, 17 developed RILD in which 8 were of Child-Pugh Grade A, and 9 were of Child-Pugh Grade B. The prediction of RILD by the Michigan model was underestimated for PLC patients. The modified n, m, TD{sub 5} (1) were 1.1, 0.28, and 40.5 Gy and 0.7, 0.43, and 23 Gy for patients with Child-Pugh A and B, respectively, which yielded better estimations of RILD probability. The hepatic tolerable doses (TD{sub 5}) would be MDTNL of 21 Gy and 6 Gy, respectively, for Child-Pugh A and B patients. Conclusions: The Michigan model was probably not fit to predict RILD in PLC patients. A modified Lyman NTCP model for RILD was recommended.

  11. The Impact of the Geometrical Structure of the DNA on Parameters of the Track-Event Theory for Radiation Induced Cell Kill

    PubMed Central

    Vasi, Fabiano; Besserer, Jürgen

    2016-01-01

    Background and Purpose When fractionation schemes for hypofractionation and stereotactic body radiotherapy are considered, a reliable cell survival model at high dose is needed for calculating doses of similar biological effectiveness. An alternative to the LQ-model is the track-event theory which is based on the probabilities for one- and two two-track events. A one-track-event (OTE) is always represented by at least two simultaneous double strand breaks. A two-track-event (TTE) results in one double strand break. Therefore at least two two-track-events on the same or different chromosomes are necessary to produce an event which leads to cell sterilization. It is obvious that the probabilities of OTEs and TTEs must somehow depend on the geometrical structure of the chromatin. In terms of the track-event theory the ratio ε of the probabilities of OTEs and TTEs includes the geometrical dependence and is obtained in this work by simple Monte Carlo simulations. Materials and Methods For this work it was assumed that the anchors of loop forming chromatin are most sensitive to radiation induced cell deaths. Therefore two adjacent tetranucleosomes representing the loop anchors were digitized. The probability ratio ε of OTEs and TTEs was factorized into a radiation quality dependent part and a geometrical part: ε = εion ∙ εgeo. εgeo was obtained for two situations, by applying Monte Carlo simulation for DNA on the tetranucleosomes itself and for linker DNA. Low energy electrons were represented by randomly distributed ionizations and high energy electrons by ionizations which were simulated on rays. εion was determined for electrons by using results from nanodosimetric measurements. The calculated ε was compared to the ε obtained from fits of the track event model to 42 sets of experimental human cell survival data. Results When the two tetranucleosomes are in direct contact and the hits are randomly distributed εgeo and ε are 0.12 and 0.85, respectively

  12. Radiation-induced genomic instability

    NASA Technical Reports Server (NTRS)

    Kronenberg, A.

    1994-01-01

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

  13. Radiation-induced genomic instability

    NASA Technical Reports Server (NTRS)

    Kronenberg, A.

    1994-01-01

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

  14. Radiation induced detwinning in nanotwinned Cu

    SciTech Connect

    Chen, Youxing; Wang, Haiyan; Kirk, Mark A.; Li, Meimei; Wang, Jian; Zhang, Xinghang

    2016-11-15

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

  15. Epigenetics in radiation-induced fibrosis.

    PubMed

    Weigel, C; Schmezer, P; Plass, C; Popanda, O

    2015-04-23

    Radiotherapy is a major cancer treatment option but dose-limiting side effects such as late-onset fibrosis in the irradiated tissue severely impair quality of life in cancer survivors. Efforts to explain radiation-induced fibrosis, for example, by genetic variation remained largely inconclusive. Recently published molecular analyses on radiation response and fibrogenesis showed a prominent role of epigenetic gene regulation. This review summarizes the current knowledge on epigenetic modifications in fibrotic disease and radiation response, and it points out the important role for epigenetic mechanisms such as DNA methylation, microRNAs and histone modifications in the development of this disease. The synopsis illustrates the complexity of radiation-induced fibrosis and reveals the need for investigations to further unravel its molecular mechanisms. Importantly, epigenetic changes are long-term determinants of gene expression and can therefore support those mechanisms that induce and perpetuate fibrogenesis even in the absence of the initial damaging stimulus. Future work must comprise the interconnection of acute radiation response and long-lasting epigenetic effects in order to assess their role in late-onset radiation fibrosis. An improved understanding of the underlying biology is fundamental to better comprehend the origin of this disease and to improve both preventive and therapeutic strategies.

  16. Prosthodontic management of radiation induced xerostomic patient using flexible dentures

    PubMed Central

    Murthy, Varsha; V, Yuvraj; Nair, Preeti P; Thomas, Shaji

    2012-01-01

    Xerostomia causes discomfort for complete denture wearers as the tissues become dry and friable due to lack of lubricating properties of saliva. Common problems faced by such patients are glossitis, mucositis, angular chelitis, dysgeusia and difficulty in chewing and swallowing. This case report describes a new method in addressing such issues by using flexible complete denture construction in radiation induced xerostomic patient with minimal tissue damage during and after denture construction procedures. PMID:22605708

  17. The structural, biochemical, and genetic characterization of a new radiation-induced, variegated leaf mutant of soybean [Glycine max (L.) Merr].

    PubMed

    Cheng, T S; Chandlee, J M

    1999-01-01

    A variegated leaf mutant in soybean [Glycine max (L.) Merr.] has been identified and characterized. E25-10 was derived by exposure of seeds of the "Williams' 82" cultivar to gamma-radiation. In this mutant, yellow leaf sectors contain defective chloroplasts, in which the thylakoid membranes are presented as long, parallel structures with little or no overlap. No starch grains have been detected in the mutant chloroplasts. Small vesicles and plastoglobuli can be found within the defective chloroplasts. Genetic studies revealed that a single nuclear-encoded gene is responsible for the mutation in E25-10. The total chlorophyll content is reduced in yellow leaf tissue by 70-80%. However, the chlorophyll a/b ratio is not altered. The absorbance spectrum of pigments in the mutant leaf tissue differed from that of the green extracts in the range of 400-500 nm. This reduction in total chlorophyll and the change in the absorbance spectrum pattern in the yellow tissue is related to a loss of certain photosynthetic complexes. Green gel analysis revealed that four major pigment-protein complexes (CP1, LHCP1, LHCP2, and CPa) of the thylakoid membranes were absent in the E25-10 mutant. Lithium dodecyl sulphate polyacrylamide gel analysis showed that at least 5-6 polypeptides (51, 44, 25, 15, 13, and 12 kDa) were missing in the thylakoid membranes of chloroplasts from the yellow tissue. Changes in chloroplast- and nuclear-encoded gene message levels were detected. The psaA transcripts which code for the P700 apoprotein in PSI were reduced in chloroplasts from the E25-10 mutant yellow tissue. The levels of the large subunit of ribulose bisphosphate carboxylase (rbcL) and light harvest complex protein (LHCP) of PSII mRNA appeared to be reduced slightly in the mutant plants. However, a much more significant reduction in the 16S rRNA and the small subunit of ribulose bisphosphate carboxylase (rbcS) expression was detected in the yellow leaf sectors. Our results suggest that the

  18. Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice

    PubMed Central

    Wei, Liang; Leibowitz, Brian J.; Wang, Xinwei; Epperly, Michael; Greenberger, Joel; Zhang, Lin

    2016-01-01

    Radiotherapy causes dose-limiting toxicity and long-term complications in rapidly renewing tissues, including the gastrointestinal tract. Currently, there is no FDA-approved agent for the prevention or treatment of radiation-induced intestinal injury. In this study, we have shown that PD 0332991 (PD), an FDA-approved selective inhibitor of cyclin-dependent kinase 4/6 (CDK4/6), prevents radiation-induced lethal intestinal injury in mice. Treating mice with PD or a structurally distinct CDK4/6 inhibitor prior to radiation blocked proliferation and crypt apoptosis and improved crypt regeneration. PD treatment also enhanced LGR5+ stem cell survival and regeneration after radiation. PD was an on-target inhibitor of RB phosphorylation and blocked G1/S transition in the intestinal crypts. PD treatment strongly but reversibly inhibited radiation-induced p53 activation, which blocked p53-upregulated modulator of apoptosis–dependent (PUMA-dependent) apoptosis without affecting p21-dependent suppression of DNA damage accumulation, with a repair bias toward nonhomologous end joining. Further, deletion of PUMA synergized with PD treatment for even greater intestinal radioprotection. Our results demonstrate that the cell cycle critically regulates the DNA damage response and survival of intestinal stem cells and support the concept that pharmacological quiescence is a potentially highly effective and selective strategy for intestinal radioprotection. PMID:27701148

  19. Radiation-induced human endogenous retrovirus (HERV)-R env gene expression by epigenetic control.

    PubMed

    Lee, Ja-Rang; Ahn, Kung; Kim, Yun-Ji; Jung, Yi-Deun; Kim, Heui-Soo

    2012-11-01

    It is commonly accepted that ionizing radiation induces genomic instability by changes in genomic structure, epigenetic regulation and gene expression. Human endogenous retroviruses (HERV)-R also are often differentially expressed between normal and disease tissues under unstable genomic conditions and are implicated in the pathogenesis of several human diseases. To understand the influence of ionizing radiation on HERV-R expression, we performed quantitative reverse transcription-polymerase chain reaction (RT-PCR) analyses using γ-irradiated normal human cells. Compared to nonirradiated cells, HERV-R expression was up-regulated in γ-irradiated cells. The regulatory mechanism of HERV-R expression in irradiated cells was investigated by methylation analyses of HERV-R 5'LTRs and treatment with garcinol. These data indicated that the up-regulated transcription of HERV-R may be regulated by radiation-induced epigenetic changes induced by histone modification, and thus could be of great importance for understanding the relationship between radiation-induced biological effects and transposable elements.

  20. Radiation-induced bladder carcinoma

    SciTech Connect

    Uyama, T.; Nakamura, S.; Moriwaki, S.

    1981-01-01

    Two cases are presented of radiation-induced bladder carcinoma which followed prior irradiation for cervical carcinoma of the uterus. One was a sixty-eight-year-old woman with bladder carcinoma fourteen years after irradiation (total dose of 4,500 rad) for cervical carcinoma of the uterus. The other was a sixty-four-year-old woman with bladder carcinoma twenty-five years after irradiation with 150-K volt apparatus for cervical carcinoma of the uterus. From the late radiation change of the skin, it was estimated that the total dose of prior radiation might be 4,000 rad or more. Both had high-grade, high-stage transitional cell bladder carcinoma, and the former was with marked mucus-forming adenomatous metaplasia.

  1. Radiation-induced mutations and plant breeding

    SciTech Connect

    Naqvi, S.H.M.

    1985-01-01

    Ionizing radiation could cause genetic changes in an organism and could modify gene linkages. The induction of mutation through radiation is random and the probability of getting the desired genetic change is low but can be increased by manipulating different parameters such as dose rate, physical conditions under which the material has been irradiated, etc. Induced mutations have been used as a supplement to conventional plant breeding, particularly for creating genetic variability for specific characters such as improved plant structure, pest and disease resistance, and desired changes in maturity period; more than 200 varieties of crop plants have been developed by this technique. The Pakistan Atomic Energy Commission has used this technique fruitfully to evolve better germplasm in cotton, rice, chickpea, wheat and mungbean; some of the mutants have become popular commercial varieties. This paper describes some uses of radiation induced mutations and the results achieved in Pakistan so far.

  2. Transesophageal Echocardiography and Radiation-induced Damages

    PubMed Central

    Cottini, Marzia; Polizzi, Vincenzo; Pino, Paolo Giuseppe; Buffa, Vitaliano; Musumeci, Francesco

    2016-01-01

    The long-term sequelae of mantle therapy include, especially lung and cardiac disease but also involve the vessels and the organs in the neck and thorax (such as thyroid, aorta, and esophagus). We presented the case of 66-year-old female admitted for congestive heart failure in radiation-induced heart disease. The patient had undergone to massive radiotherapy 42 years ago for Hodgkin's disease (type 1A). Transesophageal echocardiography was performed unsuccessfully with difficulty because of the rigidity and impedance of esophageal walls. Our case is an extraordinary report of radiotherapy's latency effect as a result of dramatic changes in the structure of mediastinum, in particular in the esophagus, causing unavailability of a transesophageal echocardiogram. PMID:27867461

  3. Radiation-induced xerostomia: pathophysiology, clinical course and supportive treatment.

    PubMed

    Guchelaar, H J; Vermes, A; Meerwaldt, J H

    1997-07-01

    Xerostomia, or oral dryness, is one of the most common complaints experienced by patients who have had radiotherapy of the oral cavity and neck region. The hallmarks of radiation-induced damage are acinar atrophy and chronic inflammation of the salivary glands. The early response, resulting in atrophy of the secretory cells without inflammation might be due to radiation-induced apoptosis. In contrast, the late response with inflammation could be a result of radiation-induced necrosis. The subjective complaint of a dry mouth appears to be poorly correlated with objective findings of salivary gland dysfunction. Xerostomia, with secondary symptoms of increased dental caries, difficulty in chewing, swallowing and speaking, and an increased incidence of oral candidiasis, can have a significant effect on the quality of life. At present there is no causal treatment for radiation-induced xerostomia. Temporary symptomatic relief can be offered by moistening agents and saliva substitutes, and is the only option for patients without residual salivary function. In patients with residual salivary function, oral administration of pilocarpine 5-10 mg three times a day is effective in increasing salivary flow and improving the symptoms of xerostomia, and this therapy should be considered as the treatment of choice. Effectiveness of sialogogue treatment requires residual salivary function, which emphasizes the potential benefit from sparing normal tissue during irradiation. The hypothesis concerning the existence of early apoptotic and late necrotic effects of irradiation on the salivary glands theoretically offers a way of achieving this goal.

  4. Immunohistochemical analysis of radiation-induced non-healing dermal wounds of the head and neck.

    PubMed

    Riedel, Frank; Philipp, Katrin; Sadick, Haneen; Goessler, Ullrich; Hörmann, Karl; Verse, Thomas

    2005-01-01

    Persistent, poorly healing wounds are a significant clinical problem in patients who have had previous irradiation. The pathology of chronic dermal ulcers is characterised by excessive proteolytic activity which degrades the extracellular matrix (required for cell migration) and growth factors and their receptors. Interestingly, the molecular basis of radiation-induced dermal wounds is poorly understood. The aim of this study was to investigate, by immunohistochemistry, the expression of the endothelial marker vWF, of angiogenic bFGF, VEGF and IL-8, of collagenases MMP-2 and MMP-9 and their inhibitors TIMP-1 and TIMP-2, in tissue samples from radiation-induced chronic dermal wounds and healthy control skin. Performing immunohistochemical detection of microvessels, an equivalent density of microvessels was observed within tissue samples from normal healthy skin and from radiation-induced non-healing cutaneous wounds. Investigation of angiogenic bFGF and VEGF demonstrated a decreased expression of both factors in the radiation-induced dermal wounds. The expression of angiogenic IL-8 was weak in both the healthy skin samples and the radiation-induced wounds. In addition, an increased expression of collagenases MMP-2 and MMP-9 protein within the radiation-induced wounds was demonstrated. While the expression of TIMP-1 showed no difference of expression between normal control skin and tissue samples from radiation-induced wounds, TIMP-2 expression was slightly increased compared to healthy controls. Our data suggest that radiation-induced dermal injuries often fail to heal because of decreased angiogenesis and persistently high concentrations of MMPs with an imbalance of their tissue inhibitors. The basic mechanisms of wound healing in radiation-induced dermal wounds at the molecular level need to be understood further for the development of innovative treatment strategies.

  5. Detection and early phase assessment of radiation-induced lung injury in mice using micro-CT.

    PubMed

    Saito, Shigeyoshi; Murase, Kenya

    2012-01-01

    Radiation therapy is an important therapeutic modality for thoracic malignancies. However, radiation-induced pulmonary injuries such as radiation pneumonitis and fibrosis are major dose-limiting factors. Previous research shows that micro-computed tomography (micro-CT) can detect radiation-induced lung injuries a few months following irradiation, but studies to assess the early response of lung tissue are lacking. The aim of this study was to determine if micro-CT could be used to detect and assess early-phase radiation-induced lung injury in mice. Twenty-one animals were divided into three groups: normal (n = 7), one day after x-ray exposure (n = 7), and at four days after x-ray exposure (n = 7). The x-ray-exposed groups received a single dose of 20 Gy, to the whole lung. Histology showed enlargements of the air space (Lm: mean chord length) following irradiation. 40.5 ± 3.8 µm and 60.0 ± 6.9 µm were observed after one and four days, respectively, compared to 26.5 ± 3.1 µm in normal mice. Three-dimensional micro-CT images were constructed and histograms of radiodensity - Hounsfield Units (HU) - were used to assess changes in mouse lungs. Radiation-induced lung injury was observed in irradiated mice, by the use of two parameters which were defined as shifts in peak HU between -200 to -800 HU (Peak(HU)) and increase in the number of pixels at -1000 HU (Number(-1000)). These parameters were correlated with histological changes. The results demonstrate that micro-CT can be used for the early detection and assessment of structural and histopathological changes resulting from radiation-induced lung injury in mice. Micro-CT has the advantage, over traditional histological techniques, of allowing longitudinal studies of lung disease progression and assessment of the entire lung, while reducing the number of animals required for such studies.

  6. Cerenkov radiation-induced phototherapy for depth-independent cancer treatment (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Akers, Walter J.; Achilefu, Samuel; Kotagiri, Nalinikanth

    2017-02-01

    Light emitted as the result of high-energy particle transport through biological tissues (Cerenkov radiation) can be exploited for noninvasive diagnostic imaging using high sensitivity scientific cameras. We have investigated the energy transfer potential of Cerenkov radiation, discovering a new phototherapeutic technique for treatment of localized and disseminated cancers. This technique, Cerenkov radiation-induced phototherapy (CRIT), like photodynamic therapy, requires the presence of both light and photosensitive agent together to induce cytotoxicity and effective cancer treatment. But unlike conventional phototherapy strategies in which tissue ablation or activation of photoactive molecules is limited to superficial structures, radiation-induced phototherapy enables phototherapy delivery to the tumor sites throughout the body. Titanium oxide nanoparticles, which produce cytotoxic reactive oxygen species upon irradiation with UV light, were targeted to tumor tissue by surface decoration with transferrin. Subsequent administration of tumor-avid radiotracer, 18-fluorodeoxyglucose (18FDG) provided localized UV light source via Cerenkov radiation. Treatment of tumor-bearing mice with the combination of Titanium nanoparticles and 18FDG resulted in effective reduction in tumor growth, while individual agents were not therapeutic. This new strategy in cancer therapy extends the reach of phototherapy beyond what was previously possible, with potential for treatment of cancer metastases and rescue from treatment resistance.

  7. Radiation-induced moyamoya syndrome

    SciTech Connect

    Desai, Snehal S.; Paulino, Arnold C. . E-mail: apaulino@tmh.tmc.edu; Mai, Wei Y.; Teh, Bin S.

    2006-07-15

    Purpose: The moyamoya syndrome is an uncommon late complication after radiotherapy (RT). Methods and Materials: A PubMed search of English-language articles, with radiation, radiotherapy, and moyamoya syndrome used as search key words, yielded 33 articles from 1967 to 2002. Results: The series included 54 patients with a median age at initial RT of 3.8 years (range, 0.4 to 47). Age at RT was less than 5 years in 56.3%, 5 to 10 years in 22.9%, 11 to 20 years in 8.3%, 21 to 30 years in 6.3%, 31 to 40 years in 2.1%, and 41 to 50 years in 4.2%. Fourteen of 54 patients (25.9%) were diagnosed with neurofibromatosis type 1 (NF-1). The most common tumor treated with RT was low-grade glioma in 37 tumors (68.5%) of which 29 were optic-pathway glioma. The average RT dose was 46.5 Gy (range, 22-120 Gy). For NF-1-positive patients, the average RT dose was 46.5 Gy, and for NF-1-negative patients, it was 58.1 Gy. The median latent period for development of moyamoya syndrome was 40 months after RT (range, 4-240). Radiation-induced moyamoya syndrome occurred in 27.7% of patients by 2 years, 53.2% of patients by 4 years, 74.5% of patients by 6 years, and 95.7% of patients by 12 years after RT. Conclusions: Patients who received RT to the parasellar region at a young age (<5 years) are the most susceptible to moyamoya syndrome. The incidence for moyamoya syndrome continues to increase with time, with half of cases occurring within 4 years of RT and 95% of cases occurring within 12 years. Patients with NF-1 have a lower radiation-dose threshold for development of moyamoya syndrome.

  8. The effect of tianeptine in the prevention of radiation-induced neurocognitive impairment.

    PubMed

    Akyurek, Serap; Senturk, Vesile; Oncu, Bedriye; Ozyigit, Gokhan; Yilmaz, Sercan; Gokce, Saban Cakir

    2008-12-01

    Radiation-induced neurocognitive impairment is an undesirable radiation-induced toxicity and a common health problem in patients with primary or metastatic brain tumor. It greatly impairs quality of life for long-term brain tumor survivors. Hippocampus is the most important brain structure for neurocognitive functions. It has been shown that radiation affects the hippocampal neurogenesis due to either induce the apoptosis or reduce the precursor cell proliferation in the hippocampus. Radiation-induced microglial inflammatory response is also negative regulator of neurogenesis. Tianeptine is a clinically effective antidepressant that induces neurogenesis. It has also been shown that tianeptine is able to reduce apoptosis and cytoprotective against the effects of proinflammatory cytokines in the hippocampus. Given the putative role of impaired hippocampal neurogenesis in radiation-induced neurocognitive impairment we think that tianeptine can be effective for preventing radiation-induced neurocognitive impairment by increasing hippocampal neurogenesis.

  9. Radiation-induced accelerated coronary arteriosclerosis

    SciTech Connect

    Mittal, B.; Deutsch, M.; Thompson, M.; Dameshek, H.L.

    1986-07-01

    There is a paucity of information on radiation-induced coronary heart disease. A young patient with myocardial infarction following mediastinal irradiation is described. The role of radiotherapy and chemotherapy on the subsequent development of coronary heart disease is discussed.

  10. Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice.

    PubMed

    Lee, Seung Jun; Yi, Chin-ok; Heo, Rok Won; Song, Dae Hyun; Cho, Yu Ji; Jeong, Yi Yeong; Kang, Ki Mun; Roh, Gu Seob; Lee, Jong Deog

    2015-01-01

    Radiation-induced lung injury (RILI) is a common and unavoidable complication of thoracic radiotherapy. The current study was conducted to evaluate the ability of clarithromycin (CLA) to prevent radiation-induced pneumonitis, oxidative stress, and lung fibrosis in an animal model. C57BL/6J mice were assigned to control, irradiation only, irradiation plus CLA, and CLA only groups. Test mice received single thoracic exposures to radiation and/or oral CLA (100 mg/kg/day). Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group. On a microscopic level, CLA inhibited macrophage influx, alveolar fibrosis, parenchymal collapse, consolidation, and epithelial cell changes. The concentration of collagen in lung tissue was lower in irradiation plus CLA mice. Radiation-induced expression of tumor necrosis factor (TNF)-α, TNF receptor 1, acetylated nuclear factor kappa B, cyclooxygenase 2, vascular cell adhesion molecule 1, and matrix metallopeptidase 9 were also attenuated by CLA. Expression levels of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1, transforming growth factor-β1, connective tissue growth factor, and type I collagen in radiation-treated lungs were also attenuated by CLA. These findings indicate that CLA ameliorates the deleterious effects of thoracic irradiation in mice by reducing pulmonary inflammation, oxidative damage, and fibrosis.

  11. Clarithromycin Attenuates Radiation-Induced Lung Injury in Mice

    PubMed Central

    Lee, Seung Jun; Yi, Chin-ok; Heo, Rok Won; Song, Dae Hyun; Cho, Yu Ji; Jeong, Yi Yeong; Kang, Ki Mun; Roh, Gu Seob; Lee, Jong Deog

    2015-01-01

    Radiation-induced lung injury (RILI) is a common and unavoidable complication of thoracic radiotherapy. The current study was conducted to evaluate the ability of clarithromycin (CLA) to prevent radiation-induced pneumonitis, oxidative stress, and lung fibrosis in an animal model. C57BL/6J mice were assigned to control, irradiation only, irradiation plus CLA, and CLA only groups. Test mice received single thoracic exposures to radiation and/or oral CLA (100 mg/kg/day). Histopathologic findings and markers of inflammation, fibrosis, and oxidative stress were compared by group. On a microscopic level, CLA inhibited macrophage influx, alveolar fibrosis, parenchymal collapse, consolidation, and epithelial cell changes. The concentration of collagen in lung tissue was lower in irradiation plus CLA mice. Radiation-induced expression of tumor necrosis factor (TNF)-α, TNF receptor 1, acetylated nuclear factor kappa B, cyclooxygenase 2, vascular cell adhesion molecule 1, and matrix metallopeptidase 9 were also attenuated by CLA. Expression levels of nuclear factor erythroid 2-related factor 2 and heme oxygenase 1, transforming growth factor-β1, connective tissue growth factor, and type I collagen in radiation-treated lungs were also attenuated by CLA. These findings indicate that CLA ameliorates the deleterious effects of thoracic irradiation in mice by reducing pulmonary inflammation, oxidative damage, and fibrosis. PMID:26114656

  12. Radiation-induced sarcoma of the thyroid

    SciTech Connect

    Griem, K.L.; Robb, P.K.; Caldarelli, D.D.; Templeton, A.C. )

    1989-08-01

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

  13. Lipotransfer for radiation-induced skin fibrosis.

    PubMed

    Kumar, R; Griffin, M; Adigbli, G; Kalavrezos, N; Butler, P E M

    2016-07-01

    Radiation-induced fibrosis (RIF) is a late complication of radiotherapy that results in progressive functional and cosmetic impairment. Autologous fat has emerged as an option for soft tissue reconstruction. There are also sporadic reports suggesting regression of fibrosis following regional lipotransfer. This systematic review aimed to identify cellular mechanisms driving RIF, and the potential role of lipotransfer in attenuating these processes. PubMed, OVID and Google Scholar databases were searched to identify all original articles regarding lipotransfer for RIF. All articles describing irradiated fibroblast or myofibroblast behaviour were included. Data elucidating the mechanisms of RIF, role of lipotransfer in RIF and methods to quantify fibrosis were extracted. Ninety-eight studies met the inclusion criteria. A single, definitive model of RIF is yet to be established, but four cellular mechanisms were identified through in vitro studies. Twenty-one studies identified connective tissue growth factor and transforming growth factor β1 cytokines as drivers of fibrotic cascades. Hypoxia was demonstrated to propagate fibrogenesis in three studies. Oxidative stress from the release of reactive oxygen species and free radicals was also linked to RIF in 11 studies. Purified autologous fat grafts contain cellular and non-cellular properties that potentially interact with these processes. Six methods for quantifying fibrotic changes were evaluated including durometry, ultrasound shear wave elastography, thermography, dark field imaging, and laser Doppler and laser speckle flowmetry. Understanding how lipotransfer causes regression of RIF remains unclear; there are a number of new hypotheses for future research. © 2016 BJS Society Ltd Published by John Wiley & Sons Ltd.

  14. Delayed Radiation-Induced Vasculitic Leukoencephalopathy

    SciTech Connect

    Rauch, Philipp J.; Park, Henry S.; Knisely, Jonathan P.S.; Chiang, Veronica L.; Vortmeyer, Alexander O.

    2012-05-01

    Purpose: Recently, single-fraction, high-dosed focused radiation therapy such as that administered by Gamma Knife radiosurgery has been used increasingly for the treatment of metastatic brain cancer. Radiation therapy to the brain can cause delayed leukoencephalopathy, which carries its own significant morbidity and mortality. While radiosurgery-induced leukoencephalopathy is known to be clinically different from that following fractionated radiation, pathological differences are not well characterized. In this study, we aimed to integrate novel radiographic and histopathologic observations to gain a conceptual understanding of radiosurgery-induced leukoencephalopathy. Methods and Materials: We examined resected tissues of 10 patients treated at Yale New Haven Hospital between January 1, 2009, and June 30, 2010, for brain metastases that had been previously treated with Gamma Knife radiosurgery, who subsequently required surgical management of a symptomatic regrowing lesion. None of the patients showed pathological evidence of tumor recurrence. Clinical and magnetic resonance imaging data for each of the 10 patients were then studied retrospectively. Results: We provide evidence to show that radiosurgery-induced leukoencephalopathy may present as an advancing process that extends beyond the original high-dose radiation field. Neuropathologic examination of the resected tissue revealed traditionally known leukoencephalopathic changes including demyelination, coagulation necrosis, and vascular sclerosis. Unexpectedly, small and medium-sized vessels revealed transmural T-cell infiltration indicative of active vasculitis. Conclusions: We propose that the presence of a vasculitic component in association with radiation-induced leukoencephalopathy may facilitate the progressive nature of the condition. It may also explain the resemblance of delayed leukoencephalopathy with recurring tumor on virtually all imaging modalities used for posttreatment follow-up.

  15. Mouse models of radiation-induced cancers.

    PubMed

    Rivina, Leena; Schiestl, Robert

    2013-01-01

    Radiation-induced (RI) secondary cancers were not a major clinical concern even as little as 15 years ago. However, advances in cancer diagnostics, therapy, and supportive care have saved numerous lives and many former cancer patients are now living for 5, 10, 20, and more years beyond their initial diagnosis. The majority of these patients have received radiotherapy as a part of their treatment regimen and are now beginning to develop secondary cancers arising from normal tissue exposure to damaging effects of ionizing radiation. Because historically patients rarely survived past the extended latency periods inherent to these RI cancers, very little effort was channeled towards the research leading to the development of therapeutic agents intended to prevent or ameliorate oncogenic effects of normal tissue exposure to radiation. The number of RI cancers is expected to increase very rapidly in the near future, but the field of cancer biology might not be prepared to address important issues related to this phenomena. One such issue is the ability to accurately differentiate between primary tumors and de novo arising secondary tumors in the same patient. Another issue is the lack of therapeutic agents intended to reduce such cancers in the future. To address these issues, large-scale epidemiological studies must be supplemented with appropriate animal modeling studies. This work reviews relevant mouse (Mus musculus) models of inbred and F1 animals and methodologies of induction of most relevant radiation-associated cancers: leukemia, lymphoma, and lung and breast cancers. Where available, underlying molecular pathologies are included. © 2013 Elsevier Inc. All rights reserved.

  16. Ionizing radiation induces senescence and differentiation of human dental pulp stem cells.

    PubMed

    Havelek, R; Soukup, T; Ćmielová, J; Seifrtová, M; Suchánek, J; Vávrová, J; Mokrý, J; Muthná, D; Řezáčová, M

    2013-01-01

    Head and neck cancer is one of the most common cancers in Europe. Many current anti-cancer treatments, including ionizing radiation, induce apoptosis via DNA damage. Unfortunately, such treatments are non-selective to cancer cells and produce similar toxicity in normal cells, including adult stem cells. One of the fundamental properties of an adult stem cell is that it does not have any tissue-specific structures that allow it to perform specialized functions. However, under certain stimuli, unspecialized adult stem cells can give rise to specialized cells to generate replacements for cells that are lost during one's life or due to injury or disease. Nevertheless, specialization of stem cells must be controlled by specific milieu and also initiated at the proper time, making the entire process beneficial for tissue recovery and maintaining it for a long time. In this paper we assess whether irradiated dental pulp stem cells have maintained open their options to mature into specialized cells, or whether they have lost their unspecialized (immature) state following irradiation. Our findings showed radiation-induced premature differentiation of dental pulp stem cells towards odonto-/osteoblast lineages in vitro. Matrix calcification was visualized from Day 6 or Day 9 following irradiation of cells expressing low or high levels of CD146, respectively.

  17. Radiation-induced segregation, hardening, and IASCC

    SciTech Connect

    Eason, E.D.; Nelson, E.E.

    1995-12-31

    Intergranular cracking has been discovered after extended radiation exposure in several boiling water reactor (BWR) internal components made of austenitic stainless steel and nickel-based alloys. There are fewer field observations of intergranular cracking in pressurized water reactors (PWR), but failures have occurred in bolts, springs, and fuel cladding. There is concern for other PWR components, some of which will receive greater radiation doses than BWR components during the plant lifetime. This paper presents the results of an investigation on the connection between radiation induced segregation, hardening and irradiation-assisted stress corrosion cracking (IASCC). A data base was developed containing the available data on austenitic stainless steel where the grain boundary composition was measured by Field Emission Gun-Scanning Transmission Election Microscopy (FEG-STEM), the stress corrosion susceptibility was measured by constant extension rate tests (CERT) in light water reactor environments, some estimate of irradiated strength was available and the irradiation was conducted in a power reactor. The data base was analyzed using advanced data analysis techniques, including tree-structured pattern recognition and transformation analysis codes. The most sensitive variables and optimal modeling forms were identified using these techniques, then preliminary models were calibrated using nonlinear least squares. The results suggest that more than one mechanism causes IASCC.

  18. Radiation-induced valvular heart disease.

    PubMed

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

    2016-02-15

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

  19. Follistatin attenuates radiation-induced fibrosis in a murine model

    PubMed Central

    Forrester, Helen B.; de Kretser, David M.; Leong, Trevor; Hagekyriakou, Jim; Sprung, Carl N.

    2017-01-01

    Purpose Fibrosis can be a disabling, severe side effect of radiotherapy that can occur in patients, and for which there is currently no effective treatment. The activins, proteins which are members of the TGFβ superfamily, have a major role in stimulating the inflammatory response and subsequent fibrosis. Follistatin is an endogenous protein that binds the activins virtually irreversibly and inhibits their actions. These studies test if follistatin can attenuate the fibrotic response using a murine model of radiation-induced fibrosis. Experimental design C57BL/6 mice were subcutaneously injected with follistatin 24 hours prior to irradiation. Mice were irradiated in a 10 x 10 mm square area of the right hind leg with 35 Gy and were given follistatin 24 hours before radiation and three times a week for six months following. Leg extension was measured, and tissue was collected for histological and molecular analysis to evaluate the progression of the radiation-induced fibrosis. Results Leg extension was improved in follistatin treated mice compared to vehicle treated mice at six months after irradiation. Also, epidermal thickness and cell nucleus area of keratinocytes were decreased by the follistatin treatment compared to the cells in irradiated skin of control mice. Finally, the gene expression of transforming growth factor β1 (Tgfb1), and smooth muscle actin (Acta2) were decreased in the irradiated skin and Acta2 and inhibin βA subunit (Inhba) were decreased in the irradiated muscle of the follistatin treated mice. Conclusions Follistatin attenuated the radiation-induced fibrotic response in irradiated mice. These studies provide the data to support further investigation of the use of follistatin to reduce radiation-induced fibrosis in patients undergoing radiotherapy for cancer. PMID:28301516

  20. Follistatin attenuates radiation-induced fibrosis in a murine model.

    PubMed

    Forrester, Helen B; de Kretser, David M; Leong, Trevor; Hagekyriakou, Jim; Sprung, Carl N

    2017-01-01

    Fibrosis can be a disabling, severe side effect of radiotherapy that can occur in patients, and for which there is currently no effective treatment. The activins, proteins which are members of the TGFβ superfamily, have a major role in stimulating the inflammatory response and subsequent fibrosis. Follistatin is an endogenous protein that binds the activins virtually irreversibly and inhibits their actions. These studies test if follistatin can attenuate the fibrotic response using a murine model of radiation-induced fibrosis. C57BL/6 mice were subcutaneously injected with follistatin 24 hours prior to irradiation. Mice were irradiated in a 10 x 10 mm square area of the right hind leg with 35 Gy and were given follistatin 24 hours before radiation and three times a week for six months following. Leg extension was measured, and tissue was collected for histological and molecular analysis to evaluate the progression of the radiation-induced fibrosis. Leg extension was improved in follistatin treated mice compared to vehicle treated mice at six months after irradiation. Also, epidermal thickness and cell nucleus area of keratinocytes were decreased by the follistatin treatment compared to the cells in irradiated skin of control mice. Finally, the gene expression of transforming growth factor β1 (Tgfb1), and smooth muscle actin (Acta2) were decreased in the irradiated skin and Acta2 and inhibin βA subunit (Inhba) were decreased in the irradiated muscle of the follistatin treated mice. Follistatin attenuated the radiation-induced fibrotic response in irradiated mice. These studies provide the data to support further investigation of the use of follistatin to reduce radiation-induced fibrosis in patients undergoing radiotherapy for cancer.

  1. Heavy-ion radiation induced bystander effect in mice

    NASA Astrophysics Data System (ADS)

    Liang, Shujian; Sun, Yeqing; Zhang, Meng; Wang, Wei; Cui, Changna

    2012-07-01

    Radiation-induced bystander effect is defined as the induction of damage in neighboring non-hit cells by signals released from directly-irradiated cells. Recently, Low dose of high LET radiation induced bystander effects in vivo have been reported more and more. It has been indicated that radiation induced bystander effect was localized not only in bystander tissues but also in distant organs. Genomic, epigenetic, metabolomics and proteomics play significant roles in regulating heavy-ion radiation stress responses in mice. To identify the molecular mechanism that underlies bystander effects of heavy-ion radiation, the male mice head were exposed to 2000mGy dose of 12C heavy-ion radiation and the distant organ liver was detected on 1h, 6h, 12h and 24h after radiation, respectively. MSAP was used to monitor the level of polymorphic DNA methylation changes. The results show that heavy-ion irradiate mouse head can induce liver DNA methylation changes significantly. The percent of DNA methylation changes are time-dependent and highest at 6h after radiation. We also prove that the hypo-methylation changes on 1h and 6h after irradiation. But the expression level of DNA methyltransferase DNMT3a is not changed. UPLC/Synapt HDMS G2 was employed to detect the proteomics of bystander liver 1h after irradiation. 64 proteins are found significantly different between treatment and control group. GO process show that six of 64 which were unique in irradiation group are associated with apoptosis and DNA damage response. The results suggest that mice head exposed to heavy-ion radiation can induce damage and methylation pattern changed in distant organ liver. Moreover, our findings are important to understand the molecular mechanism of radiation induced bystander effects in vivo.

  2. Hardwiring Stem Cell Communication through Tissue Structure.

    PubMed

    Xin, Tianchi; Greco, Valentina; Myung, Peggy

    2016-03-10

    Adult stem cells across diverse organs self-renew and differentiate to maintain tissue homeostasis. How stem cells receive input to preserve tissue structure and function largely relies on their communication with surrounding cellular and non-cellular elements. As such, how tissues are organized and patterned not only reflects organ function, but also inherently hardwires networks of communication between stem cells and their environment to direct tissue homeostasis and injury repair. This review highlights how different methods of stem cell communication reflect the unique organization and function of diverse tissues. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Hardwiring stem cell communication through tissue structure

    PubMed Central

    Xin, Tianchi; Greco, Valentina; Myung, Peggy

    2016-01-01

    Adult stem cells across diverse organs self-renew and differentiate to maintain tissue homeostasis. How stem cells receive input to preserve tissue structure and function largely relies on their communication with surrounding cellular and non-cellular elements. As such, how tissues are organized and patterned not only reflects organ function but also inherently hardwires networks of communication between stem cells and their environment to direct tissue homeostasis and injury repair. This review highlights how different methods of stem cell communication reflect the unique organization and function of diverse tissues. PMID:26967287

  4. Investigation of high temperature annealing effectiveness for recovery of radiation-induced structural changes and properties of 18Cr-10Ni-Ti austenitic stainless steels

    NASA Astrophysics Data System (ADS)

    Gurovich, B. A.; Kuleshova, E. A.; Frolov, A. S.; Maltsev, D. A.; Prikhodko, K. E.; Fedotova, S. V.; Margolin, B. Z.; Sorokin, A. A.

    2015-10-01

    A complex study of structural state and properties of 18Cr-10Ni-Ti austenitic stainless steel after irradiation in BOR-60 fast research reactor (in the temperature range 330-400 °С up to damaging doses of 145 dpa) and in VVER-1000 light water reactor (at temperature ∼320 °С and damaging doses ∼12-14 dpa) was performed. The possibility of recovery of structural-phase state and mechanical properties to the level almost corresponding to the initial state by the recovery annealing was studied. The principal possibility of the recovery annealing of pressurized water reactor internals that ensures almost complete recovery of its mechanical properties and microstructure was shown. The optimal mode of recovery annealing was established: 1000 °C during 120 h.

  5. Biodegradable polymeric fiber structures in tissue engineering.

    PubMed

    Tuzlakoglu, Kadriye; Reis, Rui L

    2009-03-01

    Tissue engineering offers a promising new approach to create biological alternatives to repair or restore function of damaged or diseased tissues. To obtain three-dimensional tissue constructs, stem or progenitor cells must be combined with a highly porous three-dimensional scaffold, but many of the structures purposed for tissue engineering cannot meet all the criteria required by an adequate scaffold because of lack of mechanical strength and interconnectivity, as well as poor surface characteristics. Fiber-based structures represent a wide range of morphological and geometric possibilities that can be tailored for each specific tissue-engineering application. The present article overviews the research data on tissue-engineering therapies based on the use of biodegradable fiber architectures as a scaffold.

  6. Impact of G-quadruplex structures and intronic polymorphisms rs17878362 and rs1642785 on basal and ionizing radiation-induced expression of alternative p53 transcripts

    PubMed Central

    Perriaud, Laury; Marcel, Virginie; Sagne, Charlotte; Favaudon, Vincent; Guédin, Aurore; De Rache, Aurore; Guetta, Corinne; Hamon, Florian; Teulade-Fichou, Marie-Paule; Hainaut, Pierre; Mergny, Jean-Louis; Hall, Janet

    2014-01-01

    G-quadruplex (G4) structures in intron 3 of the p53 pre-mRNA modulate intron 2 splicing, altering the balance between the fully spliced p53 transcript (FSp53, encoding full-length p53) and an incompletely spliced transcript retaining intron 2 (p53I2 encoding the N-terminally truncated Δ40p53 isoform). The nucleotides forming G4s overlap the polymorphism rs17878362 (A1 wild-type allele, A2 16-base pair insertion) which is in linkage disequilibrium with rs1642785 in intron 2 (c.74+38 G>C). Biophysical and biochemical analyses show rs17878362 A2 alleles form similar G4 structures as A1 alleles although their position is shifted with respect to the intron 2 splice acceptor site. In addition basal FSp53 and p53I2 levels showed allele specific differences in both p53-null cells transfected with reporter constructs or lymphoblastoid cell lines. The highest FSp53 and p53I2 levels were associated with combined rs1642785-GG/rs17878362-A1A1 alleles, whereas the presence of rs1642785-C with either rs17878362 allele was associated with lower p53 pre-mRNA, total TP53, FSp53 and p53I2 levels, due to the lower stability of transcripts containing rs1642785-C. Treatment of lymphoblastoid cell with the G4 binding ligands 360A or PhenDC3 or with ionizing radiation increased FSp53 levels only in cells with rs17878362 A1 alleles, suggesting that under this G4 configuration full splicing is favoured. These results demonstrate the complex effects of intronic TP53 polymorphisms on G4 formation and identify a new role for rs1642785 on mRNA splicing and stability, and thus on the differential expression of isoform-specific transcripts of the TP53 gene. PMID:25269805

  7. Radiation-induced vaginal stenosis: current perspectives

    PubMed Central

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

    2017-01-01

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

  8. A setup for synchrotron-radiation-induced total reflection X-ray fluorescence and X-ray absorption near-edge structure recently commissioned at BESSY II BAMline.

    PubMed

    Fittschen, U; Guilherme, A; Böttger, S; Rosenberg, D; Menzel, M; Jansen, W; Busker, M; Gotlib, Z P; Radtke, M; Riesemeier, H; Wobrauschek, P; Streli, C

    2016-05-01

    An automatic sample changer chamber for total reflection X-ray fluorescence (TXRF) and X-ray absorption near-edge structure (XANES) analysis in TXRF geometry was successfully set up at the BAMline at BESSY II. TXRF and TXRF-XANES are valuable tools for elemental determination and speciation, especially where sample amounts are limited (<1 mg) and concentrations are low (ng ml(-1) to µg ml(-1)). TXRF requires a well defined geometry regarding the reflecting surface of a sample carrier and the synchrotron beam. The newly installed chamber allows for reliable sample positioning, remote sample changing and evacuation of the fluorescence beam path. The chamber was successfully used showing accurate determination of elemental amounts in the certified reference material NIST water 1640. Low limits of detection of less than 100 fg absolute (10 pg ml(-1)) for Ni were found. TXRF-XANES on different Re species was applied. An unknown species of Re was found to be Re in the +7 oxidation state.

  9. Skeletal Scintigraphy in Radiation-Induced Fibrosis With Lymphedema.

    PubMed

    Wang, Jieqi; Iranmanesh, Arya M; Oates, M Elizabeth

    2017-03-01

    Despite increasing reliance on CT, MRI, and FDG PET/CT for oncological imaging, whole-body skeletal scintigraphy remains a frontline modality for staging and surveillance of osseous metastatic disease. We present a 54-year-old woman with metastatic breast cancer who received palliative external-beam radiation to the left ilium. Serial follow-up Tc-MDP bone scans demonstrated progressive soft-tissue uptake in her left lower extremity, extending from thigh to leg, with associated enlargement and skin thickening, consistent with lymphedema related to radiation-induced fibrosis. Correlative abdominopelvic CT scans confirmed fibrotic changes in the left thigh.

  10. Facial reconstruction for radiation-induced skin cancer

    SciTech Connect

    Panje, W.R.; Dobleman, T.J. )

    1990-04-01

    Radiation-induced skin cancers can be difficult to diagnose and treat. Typically, a patient who has received orthovoltage radiotherapy for disorders such as acne, eczema, tinea capitis, skin tuberculosis, and skin cancer can expect that aggressive skin cancers and chronic radiodermatitis may develop subsequently. Cryptic facial cancers can lead to metastases and death. Prophylactic widefield excision of previously irradiated facial skin that has been subject to multiple recurrent skin cancers is suggested as a method of deterring future cutaneous malignancy and metastases. The use of tissue expanders and full-thickness skin grafts offers an expedient and successful method of subsequent reconstruction.

  11. Radiation-Induced Intraspinal Chondrosarcoma: A Case Report

    PubMed Central

    Obid, Peter; Vierbuchen, Mathias; Wolf, Eduard; Reichl, Michael; Niemeyer, Thomas; Übeyli, Hüseyin; Richter, Alexander

    2015-01-01

    Study Design Case report and review of the literature. Objective To report a unique case of an intraspinal chondrosarcoma that was diagnosed 18 years after radiotherapy for a cervical carcinoma and its remarkably unusual clinical presentation. Methods A retrospective case description of an intraspinal mass lesion that occurred 6 weeks after previous spinal surgery. Results Within ∼9 weeks, the tumor had infiltrated the peritoneal cavity and reached the lumbar subcutaneous tissue. Conclusion Radiation-induced sarcomas are rare, are highly aggressive, and may be difficult to diagnose. Furthermore, the only means of achieving long-term survival is through early and extensive surgery. PMID:26430606

  12. Pathology and biology of radiation-induced cardiac disease

    PubMed Central

    Tapio, Soile

    2016-01-01

    Heart disease is the leading global cause of death. The risk for this disease is significantly increased in populations exposed to ionizing radiation, but the mechanisms are not fully elucidated yet. This review aims to gather and discuss the latest data about pathological and biological consequences in the radiation-exposed heart in a comprehensive manner. A better understanding of the molecular and cellular mechanisms underlying radiation-induced damage in heart tissue and cardiac vasculature will provide novel targets for therapeutic interventions. These may be valuable for individuals clinically or occupationally exposed to varying doses of ionizing radiation. PMID:27422929

  13. Metformin Attenuates Radiation-Induced Pulmonary Fibrosis in a Murine Model.

    PubMed

    Wang, Jian; Wang, Ye; Han, Jun; Mei, Hong; Yu, Dandan; Ding, Qian; Zhang, Tao; Wu, Gang; Peng, Gang; Lin, Zhenyu

    2017-07-01

    While radiotherapy continues to be a major cancer treatment option, its dose-limiting side effects, such as pulmonary fibrosis, severely impair the quality of life in these patients. In this study, we evaluated the radioprotective effects of metformin, a commonly used biguanide antidiabetic medication, in a murine model of pulmonary damage. Sprague Dawley(®) rats received whole lung 20 Gy irradiation with or without metformin treatment. Computed tomography (CT) was performed and Hounsfield units (HU) were determined during the observation period. Histological analysis and evaluation of fibrosis/inflammatory markers by Western blot were performed at 12 weeks postirradiation. CCK-8 and colony formation assays were used to explore the effects of metformin on non-small cell lung cancer cells A549 and H460. Results of this study showed that metformin reduced radiological and histological signs of fibrosis, inflammatory infiltration, alterations to alveolar structures and radiation-induced HU lung density. In addition, metformin was found to significantly decrease collagen 1a and TGF-β expression and inhibit p-Smad2 and p-Smad3 expression compared to that of the irradiated group alone. Moreover, metformin reduced A549 and H460 cell growth and clonogenic survival. In conclusion, metformin exerted a protective effect on normal tissues from radiation-induced pulmonary injury, and shows promise as a radioprotective agent in the treatment of lung cancer.

  14. Sensitivity to Radiation-Induced Cancer in Hemochromatosis

    SciTech Connect

    Bull. Richard J.; Anderson, Larry E.

    2000-06-01

    The objectives of this pilot project using HFE-knockout homozygotes and heterozygotes are to (1) determine whether the knock-out mice have greater sensitivity to radiation-induced cancer of the colon, liver and breast, (2) establish the dependence of this sensitivity on the accumulation of iron, (3) determine the extent to which cell replication and apoptosis occur in these target tissues with varying iron load, and (4) correlate the increases in sensitivity with changes in insulin-related signaling in tumors and normal tissue from each target organ. Three experimental designs will be used in the pilot project. The sequence of experiments is designed to first explore the influence of iron load on the response and demonstrate that HFE knockout mice are more sensitive than the wild type to radiation-induced cancer in one or more of three target tissues (liver, colon and breast). The dose response relationships with a broader set of radiation doses will be explored in the second experiment. The final experiment is designed to explore the extent to which heterozygotes display the increased susceptibility to cancer induction and to independently assess the importance of iron load to the initiation versus promotion of tumors.

  15. PAI-1-Dependent Endothelial Cell Death Determines Severity of Radiation-Induced Intestinal Injury

    PubMed Central

    Abderrahmani, Rym; François, Agnes; Buard, Valerie; Tarlet, Georges; Blirando, Karl; Hneino, Mohammad; Vaurijoux, Aurelie; Benderitter, Marc; Sabourin, Jean-Christophe; Milliat, Fabien

    2012-01-01

    Normal tissue toxicity still remains a dose-limiting factor in clinical radiation therapy. Recently, plasminogen activator inhibitor type 1 (SERPINE1/PAI-1) was reported as an essential mediator of late radiation-induced intestinal injury. However, it is not clear whether PAI-1 plays a role in acute radiation-induced intestinal damage and we hypothesized that PAI-1 may play a role in the endothelium radiosensitivity. In vivo, in a model of radiation enteropathy in PAI-1 −/− mice, apoptosis of radiosensitive compartments, epithelial and microvascular endothelium was quantified. In vitro, the role of PAI-1 in the radiation-induced endothelial cells (ECs) death was investigated. The level of apoptotic ECs is lower in PAI-1 −/− compared with Wt mice after irradiation. This is associated with a conserved microvascular density and consequently with a better mucosal integrity in PAI-1 −/− mice. In vitro, irradiation rapidly stimulates PAI-1 expression in ECs and radiation sensitivity is increased in ECs that stably overexpress PAI-1, whereas PAI-1 knockdown increases EC survival after irradiation. Moreover, ECs prepared from PAI-1 −/− mice are more resistant to radiation-induced cell death than Wt ECs and this is associated with activation of the Akt pathway. This study demonstrates that PAI-1 plays a key role in radiation-induced EC death in the intestine and suggests that this contributes strongly to the progression of radiation-induced intestinal injury. PMID:22563394

  16. Factors that modify radiation-induced carcinogenesis.

    PubMed

    Kennedy, Ann R

    2009-11-01

    It is known that numerous factors can influence radiation carcinogenesis in animals; these factors include the specific characteristics of the radiation (radiation type and dose, dose-rate, dose-fractionation, dose distribution, etc.) as well as many other contributing elements that are not specific to the radiation exposure, such as animal genetic characteristics and age, the environment of the animal, dietary factors and whether specific modifying agents for radiation carcinogenesis have been utilized in the studies. This overview focuses on the modifying factors for radiation carcinogenesis, in both in vivo and in vitro systems, and includes a discussion of agents that enhance (e.g., promoting agents) or suppress (e.g., cancer preventive agents) radiation-induced carcinogenesis. The agents that enhance or suppress radiation carcinogenesis in experimental model systems have been shown to lead to effects equally as large as other known modifying factors for radiation-induced carcinogenesis (e.g., dose-rate, dose-fractionation, linear energy transfer). It is known that dietary factors play an important role in determining the yields of radiation-induced cancers in animal model systems, and it is likely that they also influence radiation-induced cancer risks in human populations.

  17. Molecular pathways: radiation-induced cognitive impairment.

    PubMed

    Greene-Schloesser, Dana; Moore, Elizabeth; Robbins, Mike E

    2013-05-01

    Each year, approximately 200,000 patients in the United States will receive partial- or whole-brain irradiation for the treatment of primary or metastatic brain cancer. Early and delayed radiation effects are transient and reversible with modern therapeutic standards; yet, late radiation effects (≥6 months postirradiation) remain a significant risk, resulting in progressive cognitive impairment. These risks include functional deficits in memory, attention, and executive function that severely affect the patient's quality of life. The mechanisms underlying radiation-induced cognitive impairment remain ill defined. Classically, radiation-induced alterations in vascular and neuroinflammatory glial cell clonogenic populations were hypothesized to be responsible for radiation-induced brain injury. Recently, preclinical studies have focused on the hippocampus, one of two sites of adult neurogenesis within the brain, which plays an important role in learning and memory. Radiation ablates hippocampal neurogenesis, alters neuronal function, and induces neuroinflammation. Neuronal stem cells implanted into the hippocampus prevent the decrease in neurogenesis and improve cognition after irradiation. Clinically prescribed drugs, including PPARα and PPARγ agonists, as well as RAS blockers, prevent radiation-induced neuroinflammation and cognitive impairment independent of improved neurogenesis. Translating these exciting findings to the clinic offers the promise of improving the quality of life of brain tumor patients who receive radiotherapy. ©2013 AACR.

  18. Radiation-induced lung injury

    SciTech Connect

    Rosiello, R.A.; Merrill, W.W. )

    1990-03-01

    The use of radiation therapy is limited by the occurrence of the potentially fatal clinical syndromes of radiation pneumonitis and fibrosis. Radiation pneumonitis usually becomes clinically apparent from 2 to 6 months after completion of radiation therapy. It is characterized by fever, cough, dyspnea, and alveolar infiltrates on chest roentgenogram and may be difficult to differentiate from infection or recurrent malignancy. The pathogenesis is uncertain, but appears to involve both direct lung tissue toxicity and an inflammatory response. The syndrome may resolve spontaneously or may progress to respiratory failure. Corticosteroids may be effective therapy if started early in the course of the disease. The time course for the development of radiation fibrosis is later than that for radiation pneumonitis. It is usually present by 1 year following irradiation, but may not become clinically apparent until 2 years after radiation therapy. It is characterized by the insidious onset of dyspnea on exertion. It most often is mild, but can progress to chronic respiratory failure. There is no known successful treatment for this condition. 51 references.

  19. [Quantification of radiation-induced genetic risk].

    PubMed

    Ehling, U H

    1987-05-01

    Associated with technical advances of our civilization is a radiation- and chemically-induced increase in the germ cell mutation rate in man. This would result in an increase in the frequency of genetic diseases and would be detrimental to future generations. It is the duty of our generation to keep this risk as low as possible. The estimation of the radiation-induced genetic risk of human populations is based on the extrapolation of results from animal experiments. Radiation-induced mutations are stochastic events. The probability of the event depends on the dose; the degree of the damage does not. The different methods to estimate the radiation-induced genetic risk will be discussed. The accuracy of the predicted results will be evaluated by a comparison with the observed incidence of dominant mutations in offspring born to radiation exposed survivors of the Hiroshima and Nagasaki atomic bombings. These methods will be used to predict the genetic damage from the fallout of the reactor accident at Chernobyl. For the exposure dose we used the upper limits of the mean effective life time equivalent dose from the fallout values in the Munich region. According to the direct method for the risk estimation we will expect for each 100 to 500 spontaneous dominant mutations one radiation-induced mutation in the first generation. With the indirect method we estimate a ratio of 100 dominant spontaneous mutations to one radiation-induced dominant mutation. The possibilities and the limitations of the different methods to estimate the genetic risk will be discussed. The discrepancy between the high safety standards for radiation protection and the low level of knowledge for the toxicological evaluation of chemical mutagens will be emphasized.

  20. Ultraviolet radiation induced discharge laser

    DOEpatents

    Gilson, Verle A.; Schriever, Richard L.; Shearer, James W.

    1978-01-01

    An ultraviolet radiation source associated with a suitable cathode-anode electrode structure, disposed in a gas-filled cavity of a high pressure pulsed laser, such as a transverse electric atmosphere (TEA) laser, to achieve free electron production in the gas by photoelectric interaction between ultraviolet radiation and the cathode prior to the gas-exciting cathode-to-anode electrical discharge, thereby providing volume ionization of the gas. The ultraviolet radiation is produced by a light source or by a spark discharge.

  1. Radiation-Induced Liver Damage: Correlation of Histopathology with Hepatobiliary Magnetic Resonance Imaging, a Feasibility Study

    SciTech Connect

    Seidensticker, Max; Burak, Miroslaw; Kalinski, Thomas; Garlipp, Benjamin; Koelble, Konrad; Wust, Peter; Antweiler, Kai; Seidensticker, Ricarda; Mohnike, Konrad; Pech, Maciej; Ricke, Jens

    2015-02-15

    PurposeRadiotherapy of liver malignancies shows promising results (radioembolization, stereotactic irradiation, interstitial brachytherapy). Regardless of the route of application, a certain amount of nontumorous liver parenchyma will be collaterally damaged by radiation. The functional reserve may be significantly reduced with an impact on further treatment planning. Monitoring of radiation-induced liver damage by imaging is neither established nor validated. We performed an analysis to correlate the histopathological presence of radiation-induced liver damage with functional magnetic resonance imaging (MRI) utilizing hepatobiliary contrast media (Gd-BOPTA).MethodsPatients undergoing local high-dose-rate brachytherapy for whom a follow-up hepatobiliary MRI within 120 days after radiotherapy as well as an evaluable liver biopsy from radiation-exposed liver tissue within 7 days before MRI were retrospectively identified. Planning computed tomography (CT)/dosimetry was merged to the CT-documentation of the liver biopsy and to the MRI. Presence/absence of radiation-induced liver damage (histopathology) and Gd-BOPTA uptake (MRI) as well as the dose applied during brachytherapy at the site of tissue sampling was determined.ResultsFourteen biopsies from eight patients were evaluated. In all cases with histopathological evidence of radiation-induced liver damage (n = 11), no uptake of Gd-BOPTA was seen. In the remaining three, cases no radiation-induced liver damage but Gd-BOPTA uptake was seen. Presence of radiation-induced liver damage and absence of Gd-BOPTA uptake was correlated with a former high-dose exposition.ConclusionsAbsence of hepatobiliary MRI contrast media uptake in radiation-exposed liver parenchyma may indicate radiation-induced liver damage. Confirmatory studies are warranted.

  2. Radiation-induced brain injury: A review

    PubMed Central

    Greene-Schloesser, Dana; Robbins, Mike E.; Peiffer, Ann M.; Shaw, Edward G.; Wheeler, Kenneth T.; Chan, Michael D.

    2012-01-01

    Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive long enough (>6 months) to experience radiation-induced brain injury. Prior to 1970, the human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after single doses >30 Gy; white matter necrosis occurs at fractionated doses >60 Gy. Although white matter necrosis is uncommon with modern techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become important, because they have profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. Given its central role in memory and neurogenesis, the majority of these studies have focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis. These data have been interpreted to suggest that shielding the hippocampus will prevent clinical radiation-induced cognitive impairment. However, this interpretation may be overly simplistic. Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of demyelination and/or white matter necrosis similar to what is observed clinically, suggesting that more subtle molecular, cellular and/or microanatomic modifications are involved in this radiation-induced brain injury. Given that radiation-induced cognitive impairment likely reflects damage to both hippocampal- and non-hippocampal-dependent domains, there is a critical need to investigate the microanatomic and functional effects of radiation in various brain regions as well as their

  3. A PPAR-gamma agonist protects from radiation-induced intestinal toxicity

    PubMed Central

    Sottili, Mariangela; Gerini, Chiara; Desideri, Isacco; Bastida, Cinzia; Pallotta, Stefania; Castiglione, Francesca; Bonomo, Pierluigi; Meattini, Icro; Greto, Daniela; Cappelli, Sabrina; Di Brina, Lucia; Loi, Mauro; Biti, Giampaolo; Livi, Lorenzo

    2016-01-01

    Objective Because of its anti-inflammatory, anti-fibrotic, anti-apoptotic and anti-neoplastic properties, the PPAR-γ agonist rosiglitazone is an interesting drug for investigating for use in the prevention and treatment of radiation-induced intestinal damage. We aimed to evaluate the radioprotective effect of rosiglitazone in a murine model of acute intestinal damage, assessing whether radioprotection is selective for normal tissues or also occurs in tumour cells. Methods Mice were total-body irradiated (12 Gy), with or without rosiglitazone (5 mg/kg/day). After 24 and 72 hours, mice were sacrificed and the jejunum was collected. HT-29 human colon cancer cells were irradiated with a single dose of 2 (1000 cells), 4 (1500 cells) or 6 (2000 cells) Gy, with or without adding rosiglitazone (20 µM) 1 hour before irradiation. HT-29-xenografted CD1 mice were irradiated (16 Gy) with or without rosiglitazone; tumour volumes were measured for 33 days. Results Rosiglitazone markedly reduced histological signs of altered bowel structures, that is, villi shortening, submucosal thickening, necrotic changes in crypts, oedema, apoptosis, and inflammatory infiltrate induced by irradiation. Rosiglitazone significantly decreased p-NF-kB p65 phosphorylation and TGFβ protein expression at 24 and 72 hours post-irradiation and significantly decreased gene expression of Collagen1, Mmp13, Tnfα and Bax at 24 hours and p53 at 72 hours post-irradiation. Rosiglitazone reduced HT-29 clonogenic survival, but only produced a slight reduction of xenograft tumour growth. Conclusion Rosiglitazone exerts a protective effect on normal tissues and reduces alterations in bowel structures and inflammation in a radiation-induced bowel toxicity model, without interfering with the radiation effect on HT-29 cancer cells. PPAR-γ agonists should be further investigated for their application in abdominal and pelvic irradiation. PMID:28344789

  4. Effects of CTGF Blockade on Attenuation and Reversal of Radiation-Induced Pulmonary Fibrosis.

    PubMed

    Bickelhaupt, Sebastian; Erbel, Christian; Timke, Carmen; Wirkner, Ute; Dadrich, Monika; Flechsig, Paul; Tietz, Alexandra; Pföhler, Johanna; Gross, Wolfgang; Peschke, Peter; Hoeltgen, Line; Katus, Hugo A; Gröne, Hermann-Josef; Nicolay, Nils H; Saffrich, Rainer; Debus, Jürgen; Sternlicht, Mark D; Seeley, Todd W; Lipson, Kenneth E; Huber, Peter E

    2017-08-01

    Radiotherapy is a mainstay for the treatment of lung cancer that can induce pneumonitis or pulmonary fibrosis. The matricellular protein connective tissue growth factor (CTGF) is a central mediator of tissue remodeling. A radiation-induced mouse model of pulmonary fibrosis was used to determine if transient administration of a human antibody to CTGF (FG-3019) started at different times before or after 20 Gy thoracic irradiation reduced acute and chronic radiation toxicity. Mice (25 mice/group; 10 mice/group in a confirmation study) were examined by computed tomography, histology, gene expression changes, and for survival. In vitro experiments were performed to directly study the interaction of CTGF blockade and radiation. All statistical tests were two-sided. Administration of FG-3019 prevented (∼50%-80%) or reversed (∼50%) lung remodeling, improved lung function, improved mouse health, and rescued mice from lethal irradiation ( P < .01). Importantly, when antibody treatment was initiated at 16 weeks after thoracic irradiation, FG-3019 reversed established lung remodeling and restored lung function. CTGF blockade abrogated M2 polarized macrophage influx, normalized radiation-induced gene expression changes, and reduced myofibroblast abundance and Osteopontin expression. These results indicate that blocking CTGF attenuates radiation-induced pulmonary remodeling and can reverse the process after initiation. CTGF has a central role in radiation-induced fibrogenesis, and FG-3019 may benefit patients with radiation-induced pulmonary fibrosis or patients with other forms or origin of chronic fibrotic diseases.

  5. Radiation-induced meningiomas in pediatric patients

    SciTech Connect

    Moss, S.D.; Rockswold, G.L.; Chou, S.N.; Yock, D.; Berger, M.S.

    1988-04-01

    Radiation-induced meningiomas rarely have latency periods short enough from the time of irradiation to the clinical presentation of the tumor to present in the pediatric patient. Three cases of radiation-induced intracranial meningiomas in pediatric patients are presented. The first involved a meningioma of the right frontal region in a 10-year-old boy 6 years after the resection and irradiation of a 4th ventricular medulloblastoma. Review of our pediatric tumor cases produced a second case of a left temporal fossa meningioma presenting in a 15-year-old boy with a history of irradiation for retinoblastoma at age 3 years and a third case of a right frontoparietal meningioma in a 15-year-old girl after irradiation for acute lymphoblastic leukemia. Only three cases of meningiomas presenting in the pediatric age group after radiation therapy to the head were detected in our review of the literature.

  6. Bile acids in radiation-induced diarrhea

    SciTech Connect

    Arlow, F.L.; Dekovich, A.A.; Priest, R.J.; Beher, W.T.

    1987-10-01

    Radiation-induced bowel disease manifested by debilitating diarrhea is an unfortunate consequence of therapeutic irradiation for pelvic malignancies. Although the mechanism for this diarrhea is not well understood, many believe it is the result of damage to small bowel mucosa and subsequent bile acid malabsorption. Excess amounts of bile acids, especially the dihydroxy components, are known to induce water and electrolyte secretion and increase bowel motility. We have directly measured individual and total bile acids in the stool samples of 11 patients with radiation-induced diarrhea and have found bile acids elevated two to six times normal in eight of them. Our patients with diarrhea and increased bile acids in their stools had prompt improvement when given cholestyramine. They had fewer stools and returned to a more normal life-style.

  7. Radiation-induced meningiomas in pediatric patients.

    PubMed

    Moss, S D; Rockswold, G L; Chou, S N; Yock, D; Berger, M S

    1988-04-01

    Radiation-induced meningiomas rarely have latency periods short enough from the time of irradiation to the clinical presentation of the tumor to present in the pediatric patient. Three cases of radiation-induced intracranial meningiomas in pediatric patients are presented. The first involved a meningioma of the right frontal region in a 10-year-old boy 6 years after the resection and irradiation of a 4th ventricular medulloblastoma. Review of our pediatric tumor cases produced a second case of a left temporal fossa meningioma presenting in a 15-year-old boy with a history of irradiation for retinoblastoma at age 3 years and a third case of a right frontoparietal meningioma in a 15-year-old girl after irradiation for acute lymphoblastic leukemia. Only three cases of meningiomas presenting in the pediatric age group after radiation therapy to the head were detected in our review of the literature.

  8. Study of chemical and radiation induced carcinogenesis

    SciTech Connect

    Chmura, A.

    1995-11-01

    The study of chemical and radiation induced carcinogenesis has up to now based many of its results on the detection of genetic aberrations using the fluorescent in situ hybridization (FISH) technique. FISH is time consuming and this tends to hinder its use for looking at large numbers of samples. We are currently developing new technological advances which will increase the speed, clarity and functionality of the FISH technique. These advances include multi-labeled probes, amplification techniques, and separation techniques.

  9. Radiation-induced heart disease in rats

    SciTech Connect

    Lauk, S.; Kiszel, Z.; Buschmann, J.; Trott, K.R.

    1985-04-01

    After local irradiation of the rat heart with X ray doses of over 10 Gy (single dose), animals developed symptoms of radiation-induced heart disease, which at higher doses would lead to fatal cardiac failure. The LD 50 at 1 year was between 15 Gy and 20 Gy. The pericardium and epicardium responded to irradiation with exudative pericarditis after 4 months. Focal myocardial damage was secondary to progressive capillary damage.

  10. Radiation induced fracture of the scapula

    SciTech Connect

    Riggs, J.H. III; Schultz, G.D.; Hanes, S.A. )

    1990-10-01

    A case of radiation induced osteonecrosis resulting in a fracture of the scapula in a 76-yr-old female patient with a history of breast carcinoma is presented. Diagnostic imaging, laboratory recommendations and clinical findings are discussed along with an algorithm for the safe management of patients with a history of cancer and musculoskeletal complaints. This case demonstrates the necessity of a thorough investigation of musculoskeletal complaints in patients with previous bone-seeking carcinomas.

  11. Biomimetic electrospun nanofibrous structures for tissue engineering

    PubMed Central

    Wang, Xianfeng; Ding, Bin; Li, Bingyun

    2013-01-01

    Biomimetic nanofibrous scaffolds mimicking important features of the native extracellular matrix provide a promising strategy to restore functions or achieve favorable responses for tissue regeneration. This review provides a brief overview of current state-of-the-art research designing and using biomimetic electrospun nanofibers as scaffolds for tissue engineering. It begins with a brief introduction of electrospinning and nanofibers, with a focus on issues related to the biomimetic design aspects. The review next focuses on several typical biomimetic nanofibrous structures (e.g. aligned, aligned to random, spiral, tubular, and sheath membrane) that have great potential for tissue engineering scaffolds, and describes their fabrication, advantages, and applications in tissue engineering. The review concludes with perspectives on challenges and future directions for design, fabrication, and utilization of scaffolds based on electrospun nanofibers. PMID:25125992

  12. Synthesis and Characterization of a Rosmarinic Acid Derivative that Targets Mitochondria and Protects against Radiation-Induced Damage In Vitro.

    PubMed

    Zhang, Yu-Rui; Li, Yuan-Yuan; Wang, Jun-Ying; Wang, Hua-Wei; Wang, Hua-Nan; Kang, Xiao-Meng; Xu, Wen-Qing

    2017-09-01

    Mitochondrial dysfunction plays an important role in gamma-radiation-induced mediating oxidative stress. Scavenging radiation-induced reactive oxygen species (ROS) can help mitochondria to maintain their physiological function. Rosmarinic acid is a polyphenol antioxidant that can scavenge radiation-induced ROS, but the structure prevents it from accumulating in mitochondria. In this study, we designed and synthesized a novel rosmarinic acid derivative (Mito-RA) that could use the mitochondrial membrane potential to enter the organelle and scavenge ROS. The DCFH-DA assay revealed that Mito-RA was more effective than rosmarinic acid at scavenging ROS. DNA double-strand breaks, chromosomal aberration, micronucleus and comet assays demonstrated the ability of Mito-RA to protect against radiation-induced oxidative stress in vitro. These findings demonstrate the potential of Mito-RA as an antioxidant, which can penetrate mitochondria, scavenge ROS and protect cells against radiation-induced oxidative damage.

  13. Atorvastatin Ameliorates Radiation-Induced Cardiac Fibrosis in Rats.

    PubMed

    Zhang, KunYi; He, XuYu; Zhou, Yingling; Gao, Lijuan; Qi, Zhengyu; Chen, Jiyan; Gao, Xiuren

    2015-12-01

    Radiation-induced heart injury is one of the major side effects of radiotherapy for thoracic malignancies. Previous studies have shown that radiotherapy induced myocardial fibrosis and intensified myocardial remodeling. In this study, we investigated whether atorvastatin could inhibit radiation-induced heart fibrosis in Sprague-Dawley rats, which were randomly divided into six groups: control; radiation only; and four treatment groups receiving atorvastatin plus radiation (E1, E2, E3 and E4). All rats, except the control group, received local heart irradiation in 7 daily fractions of 3 Gy for a total of 21 Gy. Rats in groups E1 (10 mg/kg/day) and E2 (20 mg/kg/day) received atorvastatin and radiation treatment until week 12 after exposure. Rats in groups E3 (10 mg/kg/day) and E4 (20 mg/kg/day) received atorvastatin treatment from 3 months before irradiation to week 12 after irradiation. The expressions of TGF-β1, Smad2, Smad3, fibronectin, ROCK I and p-Akt in heart tissues were evaluated using real-time PCR or Western blot analyses. Atorvastatin significantly reduced the expression of TGF-β1, Smad3/P-Smad3, ROCK I and p-Akt in rats of the E1-E4 groups and in a dose-dependent manner. Fibronectin exhibited a similar pattern of expression changes. In addition, echocardiography showed that atorvastatin treatment can inhibit the increase of left ventricular end-diastolic dimension, left ventricular end-systolic diameter and left ventricular posterior wall thickness, and prevent the decrease of ejection fraction and fraction shortening in E1-E4 groups compared with the radiation only group. This study demonstrated that radiation exposure increased the expression of fibronectin in cardiac fibroblasts and induced cardiac fibrosis through activation of the TGF-β1/Smad3, RhoA/ROCK, and PI3K/AKT signaling pathways. Statins ameliorated radiation-induced cardiac fibrosis in Sprague-Dawley rats. Our results suggest that atorvastatin is effective for the treatment of radiation-induced

  14. Novel Radiomitigator for Radiation-Induced Bone Loss

    NASA Technical Reports Server (NTRS)

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

    2016-01-01

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

  15. DNA damage in cells exhibiting radiation-induced genomic instability

    SciTech Connect

    Keszenman, Deborah J.; Kolodiuk, Lucia; Baulch, Janet E.

    2015-02-22

    Cells exhibiting radiation induced genomic instability exhibit varied spectra of genetic and chromosomal aberrations. Even so, oxidative stress remains a common theme in the initiation and/or perpetuation of this phenomenon. Isolated oxidatively modified bases, abasic sites, DNA single strand breaks and clustered DNA damage are induced in normal mammalian cultured cells and tissues due to endogenous reactive oxygen species generated during normal cellular metabolism in an aerobic environment. While sparse DNA damage may be easily repaired, clustered DNA damage may lead to persistent cytotoxic or mutagenic events that can lead to genomic instability. In this study, we tested the hypothesis that DNA damage signatures characterised by altered levels of endogenous, potentially mutagenic, types of DNA damage and chromosomal breakage are related to radiation-induced genomic instability and persistent oxidative stress phenotypes observed in the chromosomally unstable progeny of irradiated cells. The measurement of oxypurine, oxypyrimidine and abasic site endogenous DNA damage showed differences in non-double-strand breaks (DSB) clusters among the three of the four unstable clones evaluated as compared to genomically stable clones and the parental cell line. These three unstable clones also had increased levels of DSB clusters. The results of this study demonstrate that each unstable cell line has a unique spectrum of persistent damage and lead us to speculate that alterations in DNA damage signaling and repair may be related to the perpetuation of genomic instability.

  16. DNA damage in cells exhibiting radiation-induced genomic instability

    DOE PAGES

    Keszenman, Deborah J.; Kolodiuk, Lucia; Baulch, Janet E.

    2015-02-22

    Cells exhibiting radiation induced genomic instability exhibit varied spectra of genetic and chromosomal aberrations. Even so, oxidative stress remains a common theme in the initiation and/or perpetuation of this phenomenon. Isolated oxidatively modified bases, abasic sites, DNA single strand breaks and clustered DNA damage are induced in normal mammalian cultured cells and tissues due to endogenous reactive oxygen species generated during normal cellular metabolism in an aerobic environment. While sparse DNA damage may be easily repaired, clustered DNA damage may lead to persistent cytotoxic or mutagenic events that can lead to genomic instability. In this study, we tested the hypothesismore » that DNA damage signatures characterised by altered levels of endogenous, potentially mutagenic, types of DNA damage and chromosomal breakage are related to radiation-induced genomic instability and persistent oxidative stress phenotypes observed in the chromosomally unstable progeny of irradiated cells. The measurement of oxypurine, oxypyrimidine and abasic site endogenous DNA damage showed differences in non-double-strand breaks (DSB) clusters among the three of the four unstable clones evaluated as compared to genomically stable clones and the parental cell line. These three unstable clones also had increased levels of DSB clusters. The results of this study demonstrate that each unstable cell line has a unique spectrum of persistent damage and lead us to speculate that alterations in DNA damage signaling and repair may be related to the perpetuation of genomic instability.« less

  17. Radiation Induced DNA Double-Strand Breaks in Radiology.

    PubMed

    Kuefner, M A; Brand, M; Engert, C; Schwab, S A; Uder, M

    2015-10-01

    Shortly after the discovery of X-rays, their damaging effect on biological tissues was observed. The determination of radiation exposure in diagnostic and interventional radiology is usually based on physical measurements or mathematical algorithms with standardized dose simulations. γ-H2AX immunofluorescence microscopy is a reliable and sensitive method for the quantification of radiation induced DNA double-strand breaks (DSB) in blood lymphocytes. The detectable amount of these DNA damages correlates well with the dose received. However, the biological radiation damage depends not only on dose but also on other individual factors like radiation sensitivity and DNA repair capacity. Iodinated contrast agents can enhance the x-ray induced DNA damage level. After their induction DSB are quickly repaired. A protective effect of antioxidants has been postulated in experimental studies. This review explains the prinicple of the γ-H2AX technique and provides an overview on studies evaluating DSB in radiologic examinations. Radiologic examinations including CT and angiography induce DNA double-strand breaks. Even after mammography a slight but significant increase is detectable in peripheral blood lymphocytes. The number of radiation induced double-strand breaks correlates well with the radiation dose. Individual factors including radiation sensitivity, DNA repair capacity and the application of iodinated contrast media has an influence on the DNA damage level. © Georg Thieme Verlag KG Stuttgart · New York.

  18. Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression.

    PubMed

    Klein, Diana; Steens, Jennifer; Wiesemann, Alina; Schulz, Florian; Kaschani, Farnusch; Röck, Katharina; Yamaguchi, Masahiro; Wirsdörfer, Florian; Kaiser, Markus; Fischer, Jens W; Stuschke, Martin; Jendrossek, Verena

    2017-04-10

    Radiation-induced normal tissue toxicity is closely linked to endothelial cell (EC) damage and dysfunction (acute effects). However, the underlying mechanisms of radiation-induced adverse late effects with respect to the vascular compartment remain elusive, and no causative radioprotective treatment is available to date. The importance of injury to EC for radiation-induced late toxicity in lungs after whole thorax irradiation (WTI) was investigated using a mouse model of radiation-induced pneumopathy. We show that WTI induces EC loss as long-term complication, which is accompanied by the development of fibrosis. Adoptive transfer of mesenchymal stem cells (MSCs) either derived from bone marrow or aorta (vascular wall-resident MSCs) in the early phase after irradiation limited the radiation-induced EC loss and fibrosis progression. Furthermore, MSC-derived culture supernatants rescued the radiation-induced reduction in viability and long-term survival of cultured lung EC. We further identified the antioxidant enzyme superoxide dismutase 1 (SOD1) as a MSC-secreted factor. Importantly, MSC treatment restored the radiation-induced reduction of SOD1 levels after WTI. A similar protective effect was achieved by using the SOD-mimetic EUK134, suggesting that MSC-derived SOD1 is involved in the protective action of MSC, presumably through paracrine signaling. In this study, we explored the therapeutic potential of MSC therapy to prevent radiation-induced EC loss (late effect) and identified the protective mechanisms of MSC action. Adoptive transfer of MSCs early after irradiation counteracts radiation-induced vascular damage and EC loss as late adverse effects. The high activity of vascular wall-derived MSCs for radioprotection may be due to their tissue-specific action. Antioxid. Redox Signal. 26, 563-582.

  19. Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

    PubMed Central

    Steens, Jennifer; Wiesemann, Alina; Schulz, Florian; Kaschani, Farnusch; Röck, Katharina; Yamaguchi, Masahiro; Wirsdörfer, Florian; Kaiser, Markus; Fischer, Jens W.; Stuschke, Martin; Jendrossek, Verena

    2017-01-01

    Abstract Aims: Radiation-induced normal tissue toxicity is closely linked to endothelial cell (EC) damage and dysfunction (acute effects). However, the underlying mechanisms of radiation-induced adverse late effects with respect to the vascular compartment remain elusive, and no causative radioprotective treatment is available to date. Results: The importance of injury to EC for radiation-induced late toxicity in lungs after whole thorax irradiation (WTI) was investigated using a mouse model of radiation-induced pneumopathy. We show that WTI induces EC loss as long-term complication, which is accompanied by the development of fibrosis. Adoptive transfer of mesenchymal stem cells (MSCs) either derived from bone marrow or aorta (vascular wall-resident MSCs) in the early phase after irradiation limited the radiation-induced EC loss and fibrosis progression. Furthermore, MSC-derived culture supernatants rescued the radiation-induced reduction in viability and long-term survival of cultured lung EC. We further identified the antioxidant enzyme superoxide dismutase 1 (SOD1) as a MSC-secreted factor. Importantly, MSC treatment restored the radiation-induced reduction of SOD1 levels after WTI. A similar protective effect was achieved by using the SOD-mimetic EUK134, suggesting that MSC-derived SOD1 is involved in the protective action of MSC, presumably through paracrine signaling. Innovation: In this study, we explored the therapeutic potential of MSC therapy to prevent radiation-induced EC loss (late effect) and identified the protective mechanisms of MSC action. Conclusions: Adoptive transfer of MSCs early after irradiation counteracts radiation-induced vascular damage and EC loss as late adverse effects. The high activity of vascular wall-derived MSCs for radioprotection may be due to their tissue-specific action. Antioxid. Redox Signal. 26, 563–582. PMID:27572073

  20. ATM Mutations and the Development of Severe Radiation-Induced Morbidity Following Radiotherapy for Breast Cancer

    DTIC Science & Technology

    2006-07-01

    were treated in Aarhus, Denmark with a hypofractionated radiotherapy protocol. Due to a high incidence of late normal tissue complications, the...treated with either a hypofractionated or standard radiotherapy fractionation protocol were screened (80). Since many of these patients received a... hypofractionated treatment, radiation-induced skin fibrosis was relatively common in this cohort. Based on a logistic regression model, a dose

  1. Evolved Cellular Mechanisms to Respond to Genotoxic Insults: Implications for Radiation-Induced Hematologic Malignancies

    PubMed Central

    Fleenor, Courtney J.; Higa, Kelly; Weil, Michael M.; DeGregori, James

    2015-01-01

    Human exposure to ionizing radiation is highly associated with adverse health effects, including reduced hematopoietic cell function and increased risk of carcinogenesis. The hematopoietic deficits manifest across blood cell types and persist for years after radiation exposure, suggesting a long-lived and multi-potent cellular reservoir for radiation-induced effects. As such, research has focused on identifying both the immediate and latent hematopoietic stem cell responses to radiation exposure. Radiation-associated effects on hematopoietic function and malignancy development have generally been attributed to the direct induction of mutations resulting from radiation-induced DNA damage. Other studies have illuminated the role of cellular programs that both limit and enhance radiation-induced tissue phenotypes and carcinogenesis. In this review, distinct but collaborative cellular responses to genotoxic insults are highlighted, with an emphasis on how these programmed responses impact hematopoietic cellular fitness and competition. These radiation-induced cellular programs include apoptosis, senescence and impaired self-renewal within the hematopoietic stem cell (HSC) pool. In the context of sporadic DNA damage to a cell, these cellular responses act in concert to restore tissue function and prevent selection for adaptive oncogenic mutations. But in the contexts of whole-tissue exposure or whole-body exposure to genotoxins, such as radiotherapy or chemotherapy, we propose that these programs can contribute to long-lasting tissue impairment and increased carcinogenesis. PMID:26414506

  2. The structure and micromechanics of elastic tissue.

    PubMed

    Green, Ellen M; Mansfield, Jessica C; Bell, James S; Winlove, C Peter

    2014-04-06

    Elastin is a major component of tissues such as lung and blood vessels, and endows them with the long-range elasticity necessary for their physiological functions. Recent research has revealed the complexity of these elastin structures and drawn attention to the existence of extensive networks of fine elastin fibres in tissues such as articular cartilage and the intervertebral disc. Nonlinear microscopy, allowing the visualization of these structures in living tissues, is informing analysis of their mechanical properties. Elastic fibres are complex in composition and structure containing, in addition to elastin, an array of microfibrillar proteins, principally fibrillin. Raman microspectrometry and X-ray scattering have provided new insights into the mechanisms of elasticity of the individual component proteins at the molecular and fibrillar levels, but more remains to be done in understanding their mechanical interactions in composite matrices. Elastic tissue is one of the most stable components of the extracellular matrix, but impaired mechanical function is associated with ageing and diseases such as atherosclerosis and diabetes. Efforts to understand these associations through studying the effects of processes such as calcium and lipid binding and glycation on the mechanical properties of elastin preparations in vitro have produced a confusing picture, and further efforts are required to determine the molecular basis of such effects.

  3. Radiation-induced brain damage, impact of Michael Robbins' work and the need for predictive biomarkers.

    PubMed

    Prasanna, Pataje G S; Ahmed, Mansoor M; Stone, Helen B; Vikram, Bhadrasain; Mehta, Minesh P; Coleman, C Norman

    2014-09-01

    To review the literature on radiation-induced normal tissue injury in the context of treatment of primary and metastatic brain tumors with a focus on Michael Robbins' work on mechanisms of injury and approaches to mitigation, and also to identify other potential opportunities to improve treatment outcome and quality of life (QOL). Brain tumors remain a significant challenge for patients, their families, the physicians treating them, and researchers seeking more effective treatments. Current treatment of brain tumors involves combinations of radiotherapy with surgery, chemotherapy, and molecularly targeted agents. As patient survival improves with advances in treatment there is an increasing concern for the cognitive deficits that may become apparent months or years after treatment some of which are related to radiation-induced brain damage. One area of Michael Robbins' research was unraveling the mechanisms of radiation-induced cognitive deficits, which formed the basis for the development of some mitigators of radiation injury. Extrapolating from this, new opportunities to identify and develop putative predictive biomarkers of radiation-induced brain damage can be explored. Predictive biomarkers of radiation-induced brain injury may enable stratifying patients for customization of treatment and thus aid in improving the QOL and possibly prolonging survival. Here we discuss the challenges involved in leveraging recent advances in radiation-specific biomarker research and translating them to radiotherapy, which for the foreseeable future is likely to remain a cornerstone of the treatment of brain tumors.

  4. Radiation-induced injury of the esophagus

    SciTech Connect

    Lepke, R.A.; Libshitz, H.I.

    1983-08-01

    Forty patients with functional or morphologic esophageal abnormalities following radiotherapy were identified. Abnormalities included abnormal motility with and without mucosal edema, stricture, ulceration and pseudodiverticulum, and fistula. Abnormal motility occurred 4 to 12 weeks following radiotherapy alone and as early as 1 week after therapy when concomitant chemotherapy had been given. Strictures developed 4 to 8 months following completion of radiotherapy. Ulceration, pseudodiverticulum, and fistula formation did not develop in a uniform time frame. Radiation-induced esophageal injury is more frequent when radiotherapy and chemotherapy are combined than it is with radiotherapy alone.

  5. Radiation-induced esophagitis in lung cancer

    PubMed Central

    Baker, Sarah; Fairchild, Alysa

    2016-01-01

    Radiation-induced esophagitis is the most common local acute toxicity of radiotherapy (RT) delivered for the curative or palliative intent treatment of lung cancer. Although concurrent chemotherapy and higher RT dose are associated with increased esophagitis risk, advancements in RT techniques as well as adherence to esophageal dosimetric constraints may reduce the incidence and severity. Mild acute esophagitis symptoms are generally self-limited, and supportive management options include analgesics, acid suppression, diet modification, treatment for candidiasis, and maintenance of adequate nutrition. Esophageal stricture is the most common late sequela from esophageal irradiation and can be addressed with endoscopic dilatation. Approaches to prevent or mitigate these toxicities are also discussed. PMID:28210168

  6. A report on radiation-induced gliomas

    SciTech Connect

    Salvati, M.; Artico, M.; Caruso, R.; Rocchi, G.; Orlando, E.R.; Nucci, F. )

    1991-01-15

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

  7. Factors that modify risks of radiation-induced cancer

    SciTech Connect

    Fabrikant, J.I.

    1988-11-01

    The collective influence of biologic and physical factors that modify risks of radiation-induced cancer introduces uncertainties sufficient to deny precision of estimates of human cancer risk that can be calculated for low-dose radiation in exposed populations. The important biologic characteristics include the tissue sites and cell types, baseline cancer incidence, minimum latent period, time-to-tumor recognition, and the influence of individual host (age and sex) and competing etiologic influences. Physical factors include radiation dose, dose rate, and radiation quality. Statistical factors include time-response projection models, risk coefficients, and dose-response relationships. Other modifying factors include other carcinogens, and other biological sources (hormonal status, immune status, hereditary factors).

  8. The Dose Window for Radiation-Induced Protective Adaptive Responses

    PubMed Central

    Mitchel, Ronald E. J.

    2009-01-01

    Adaptive responses to low doses of low LET radiation occur in all organisms thus far examined, from single cell lower eukaryotes to mammals. These responses reduce the deleterious consequences of DNA damaging events, including radiation-induced or spontaneous cancer and non-cancer diseases in mice. The adaptive response in mammalian cells and mammals operates within a certain window that can be defined by upper and lower dose thresholds, typically between about 1 and 100 mGy for a single low dose rate exposure. However, these thresholds for protection are not a fixed function of total dose, but also vary with dose rate, additional radiation or non-radiation stressors, tissue type and p53 functional status. Exposures above the upper threshold are generally detrimental, while exposures below the lower threshold may or may not increase either cancer or non-cancer disease risk. PMID:20585438

  9. Radiation induced conductivity in space dielectric materials

    SciTech Connect

    Hanna, R.; Paulmier, T. Belhaj, M.; Dirassen, B.; Molinie, P.; Payan, D.; Balcon, N.

    2014-01-21

    The radiation-induced conductivity of some polymers was described mainly in literature by a competition between ionization, trapping/detrapping, and recombination processes or by radiation assisted ageing mechanisms. Our aim is to revise the effect of the aforementioned mechanisms on the complex evolution of Teflon{sup ®} FEP under space representative ionizing radiation. Through the definition of a new experimental protocol, revealing the effect of radiation dose and relaxation time, we have been able to demonstrate that the trapping/recombination model devised in this study agrees correctly with the observed experimental phenomenology at qualitative level and allows describing very well the evolution of radiation induced conductivity with irradiation time (or received radiation dose). According to this model, the complex behavior observed on Teflon{sup ®} FEP may be basically ascribed to the competition between electron/hole pairs generation and recombination: electrons are deeply trapped and act as recombination centers for free holes. Relaxation effects have been characterized through successive irradiations steps and have been again well described with the defined model at qualitative level: recombination centers created by the irradiation induce long term alteration on the electric properties, especially the effective bulk conductivity. One-month relaxation does not allow a complete recovery of the material initial charging behavior.

  10. Radiation induced conductivity in space dielectric materials

    NASA Astrophysics Data System (ADS)

    Hanna, R.; Paulmier, T.; Molinie, P.; Belhaj, M.; Dirassen, B.; Payan, D.; Balcon, N.

    2014-01-01

    The radiation-induced conductivity of some polymers was described mainly in literature by a competition between ionization, trapping/detrapping, and recombination processes or by radiation assisted ageing mechanisms. Our aim is to revise the effect of the aforementioned mechanisms on the complex evolution of Teflon® FEP under space representative ionizing radiation. Through the definition of a new experimental protocol, revealing the effect of radiation dose and relaxation time, we have been able to demonstrate that the trapping/recombination model devised in this study agrees correctly with the observed experimental phenomenology at qualitative level and allows describing very well the evolution of radiation induced conductivity with irradiation time (or received radiation dose). According to this model, the complex behavior observed on Teflon® FEP may be basically ascribed to the competition between electron/hole pairs generation and recombination: electrons are deeply trapped and act as recombination centers for free holes. Relaxation effects have been characterized through successive irradiations steps and have been again well described with the defined model at qualitative level: recombination centers created by the irradiation induce long term alteration on the electric properties, especially the effective bulk conductivity. One-month relaxation does not allow a complete recovery of the material initial charging behavior.

  11. Mouse models for radiation-induced cancers.

    PubMed

    Rivina, Leena; Davoren, Michael J; Schiestl, Robert H

    2016-09-01

    Potential ionising radiation exposure scenarios are varied, but all bring risks beyond the simple issues of short-term survival. Whether accidentally exposed to a single, whole-body dose in an act of terrorism or purposefully exposed to fractionated doses as part of a therapeutic regimen, radiation exposure carries the consequence of elevated cancer risk. The long-term impact of both intentional and unintentional exposure could potentially be mitigated by treatments specifically developed to limit the mutations and precancerous replication that ensue in the wake of irradiation The development of such agents would undoubtedly require a substantial degree of in vitro testing, but in order to accurately recapitulate the complex process of radiation-induced carcinogenesis, well-understood animal models are necessary. Inbred strains of the laboratory mouse, Mus musculus, present the most logical choice due to the high number of molecular and physiological similarities they share with humans. Their small size, high rate of breeding and fully sequenced genome further increase its value for use in cancer research. This chapter will review relevant m. musculus inbred and F1 hybrid animals of radiation-induced myeloid leukemia, thymic lymphoma, breast and lung cancers. Method of cancer induction and associated molecular pathologies will also be described for each model. © The Author 2016. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  12. Nature of radiation-induced defects in quartz

    SciTech Connect

    Wang, Bu; Yu, Yingtian; Bauchy, Mathieu; Pignatelli, Isabella; Sant, Gaurav

    2015-07-14

    Although quartz (α-form) is a mineral used in numerous applications wherein radiation exposure is an issue, the nature of the atomistic defects formed during radiation-induced damage has not been fully clarified. Especially, the extent of oxygen vacancy formation is still debated, which is an issue of primary importance as optical techniques based on charged oxygen vacancies have been utilized to assess the level of radiation damage in quartz. In this paper, molecular dynamics simulations are applied to study the effects of ballistic impacts on the atomic network of quartz. We show that the defects that are formed mainly consist of over-coordinated Si and O, as well as Si–O connectivity defects, e.g., small Si–O rings and edge-sharing Si tetrahedra. Oxygen vacancies, on the contrary, are found in relatively low abundance, suggesting that characterizations based on E′ centers do not adequately capture radiation-induced structural damage in quartz. Finally, we evaluate the dependence on the incident energy, of the amount of each type of the point defects formed, and quantify unambiguously the threshold displacement energies for both O and Si atoms. These results provide a comprehensive basis to assess the nature and extent of radiation damage in quartz.

  13. Radiation-induced alterations in histone modification patterns and their potential impact on short-term radiation effects

    PubMed Central

    Friedl, Anna A.; Mazurek, Belinda; Seiler, Doris M.

    2012-01-01

    Detection and repair of radiation-induced DNA damage occur in the context of chromatin. An intricate network of mechanisms defines chromatin structure, including DNA methylation, incorporation of histone variants, histone modifications, and chromatin remodeling. In the last years it became clear that the cellular response to radiation-induced DNA damage involves all of these mechanisms. Here we focus on the current knowledge on radiation-induced alterations in post-translational histone modification patterns and their effect on the chromatin accessibility, transcriptional regulation and chromosomal stability. PMID:23050241

  14. Identifying radiation-induced survivorship syndromes affecting bowel health in a cohort of gynecological cancer survivors

    PubMed Central

    Steineck, Gunnar; Skokic, Viktor; Bull, Cecilia; Alevronta, Eleftheria; Dunberger, Gail; Bergmark, Karin; Wilderäng, Ulrica; Oh, Jung Hun; Deasy, Joseph O.; Jörnsten, Rebecka

    2017-01-01

    Background During radiotherapy unwanted radiation to normal tissue surrounding the tumor triggers survivorship diseases; we lack a nosology for radiation-induced survivorship diseases that decrease bowel health and we do not know which symptoms are related to which diseases. Methods Gynecological-cancer survivors were followed-up two to 15 years after having undergone radiotherapy; they reported in a postal questionnaire the frequency of 28 different symptoms related to bowel health. Population-based controls gave the same information. With a modified factor analysis, we determined the optimal number of factors, factor loadings for each symptom, factor-specific factor-loading cutoffs and factor scores. Results Altogether data from 623 survivors and 344 population-based controls were analyzed. Six factors best explain the correlation structure of the symptoms; for five of these a statistically significant difference (P< 0.001, Mann-Whitney U test) was found between survivors and controls concerning factor score quantiles. Taken together these five factors explain 42 percent of the variance of the symptoms. We interpreted these five factors as radiation-induced syndromes that may reflect distinct survivorship diseases. We obtained the following frequencies, defined as survivors having a factor loading above the 95 percent percentile of the controls, urgency syndrome (190 of 623, 30 percent), leakage syndrome (164 of 623, 26 percent), excessive gas discharge (93 of 623, 15 percent), excessive mucus discharge (102 of 623, 16 percent) and blood discharge (63 of 623, 10 percent). Conclusion Late effects of radiotherapy include five syndromes affecting bowel health; studying them and identifying the underlying survivorship diseases, instead of the approximately 30 long-term symptoms they produce, will simplify the search for prevention, alleviation and elimination. PMID:28158314

  15. Late radiation-induced heart disease after radiotherapy. Clinical importance, radiobiological mechanisms and strategies of prevention.

    PubMed

    Andratschke, Nicolaus; Maurer, Jean; Molls, Michael; Trott, Klaus-Rüdiger

    2011-08-01

    The clinical importance of radiation-induced heart disease, in particular in post-operative radiotherapy of breast cancer patients, has been recognised only recently. There is general agreement, that a co-ordinated research effort would be needed to explore all the potential strategies of how to reduce the late risk of radiation-induced heart disease in radiotherapy. This approach would be based, on one hand, on a comprehensive understanding of the radiobiological mechanisms of radiation-induced heart disease after radiotherapy which would require large-scale long-term animal experiments with high precision local heart irradiation. On the other hand - in close co-operation with mechanistic in vivo research studies - clinical studies in patients need to determine the influence of dose distribution in the heart on the risk of radiation-induced heart disease. The aim of these clinical studies would be to identify the critical structures within the organ which need to be spared and their radiation sensitivity as well as a potential volume and dose effect. The results of the mechanistic studies might also provide concepts of how to modify the gradual progression of radiation damage in the heart by drugs or biological molecules. The results of the studies in patients would need to also incorporate detailed dosimetric and imaging studies in order to develop early indicators of impending radiation-induced heart disease which would be a pre-condition to develop sound criteria for treatment plan optimisation. Copyright © 2010. Published by Elsevier Ireland Ltd.

  16. Radiation-Induced Bystander Response: Mechanism and Clinical Implications

    PubMed Central

    Suzuki, Keiji; Yamashita, Shunichi

    2014-01-01

    Significance: Absorption of energy from ionizing radiation (IR) to the genetic material in the cell gives rise to damage to DNA in a dose-dependent manner. There are two types of DNA damage; by a high dose (causing acute or deterministic effects) and by a low dose (related to chronic or stochastic effects), both of which induce different health effects. Among radiation effects, acute cutaneous radiation syndrome results from cell killing as a consequence of high-dose exposure. Recent advances: Recent advances in radiation biology and oncology have demonstrated that bystander effects, which are emerged in cells that have never been exposed, but neighboring irradiated cells, are also involved in radiation effects. Bystander effects are now recognized as an indispensable component of tissue response related to deleterious effects of IR. Critical issues: Evidence has indicated that nonapoptotic premature senescence is commonly observed in various tissues and organs. Senesced cells were found to secrete various proteins, including cytokines, chemokines, and growth factors, most of which are equivalent to those identified as bystander factors. Secreted factors could trigger cell proliferation, angiogenesis, cell migration, inflammatory response, etc., which provide a tissue microenvironment assisting tissue repair and remodeling. Future directions: Understandings of the mechanisms and physiological relevance of radiation-induced bystander effects are quite essential for the beneficial control of wound healing and care. Further studies should extend our knowledge of the mechanisms of bystander effects and mode of cell death in response to IR. PMID:24761341

  17. Survival and Margin Status in Head and Neck Radiation-Induced Sarcomas and De Novo Sarcomas.

    PubMed

    Rosko, Andrew J; Birkeland, Andrew C; Chinn, Steven B; Shuman, Andrew G; Prince, Mark E; Patel, Rajiv M; McHugh, Jonathan B; Spector, Matthew E

    2017-04-01

    Objective To describe histologic subtypes and oncologic outcomes among patients with radiation-induced and de novo sarcomas of the head and neck. Study Design Retrospective case series with chart review. Setting Tertiary academic center. Subject and Methods In total, 166 adult patients with sarcoma of the head and neck treated from January 1, 1985, to January 1, 2010, were included. Tumors were characterized as radiation induced (15.1%) vs de novo sarcomas (84.9%). Clinical and tumor characteristics were compared. The primary outcomes were overall survival (OS) and disease-specific survival (DSS). Results Radiation-induced sarcomas were more likely to be high grade ( P = .006) and advanced stage ( P = .03). Chondrosarcoma was more common in de novo tumors ( P = .02) while leiomyosarcoma ( P = .01), sarcoma not otherwise specified ( P = .02), and undifferentiated pleomorphic sarcoma ( P < .001) were more common in radiation-induced sarcomas. Radiation-induced sarcomas were associated with statistically significantly worse DSS ( P = .019) and OS ( P = .005) compared with de novo sarcomas, but when only high-grade soft tissue sarcomas were analyzed, neither DSS ( P = .48) nor OS ( P = .29) differed. Margin status was a significant predictor of survival as both R0 and R1 resections correlated with statistically better DSS and OS compared with R2 ( P < .001) resections and patients treated with radiation therapy/chemoradiation therapy alone ( P = .005). Conclusion Radiation-induced sarcomas of the head and neck correlate with worse survival compared with de novo tumors; however, when controlling for tumor grade and resection status, there is no statistically significant difference in observed outcomes.

  18. The Lactate Dehydrogenase Inhibitor Gossypol Inhibits Radiation-Induced Pulmonary Fibrosis.

    PubMed

    Judge, Jennifer L; Lacy, Shannon H; Ku, Wei-Yao; Owens, Kristina M; Hernady, Eric; Thatcher, Thomas H; Williams, Jacqueline P; Phipps, Richard P; Sime, Patricia J; Kottmann, R Matthew

    2017-07-01

    Exposure of the lung to ionizing radiation that occurs in radiotherapy, as well as after accidental or intentional mass casualty incident can result in pulmonary fibrosis, which has few treatment options. Pulmonary fibrosis is characterized by an accumulation of extracellular matrix proteins that create scar tissue. Although the mechanisms leading to radiation-induced pulmonary fibrosis remain poorly understood, one frequent observation is the activation of the profibrotic cytokine transforming growth factor-beta (TGF-β). Our laboratory has shown that the metabolite lactate activates latent TGF-β by a reduction in extracellular pH. We recently demonstrated that lactate dehydrogenase-A (LDHA), the enzyme that produces lactate, is upregulated in patients with radiation-induced pulmonary fibrosis. Furthermore, genetic silencing of LDHA or pharmacologic inhibition using the LDHA inhibitor gossypol prevented radiation-induced extracellular matrix secretion in vitro through inhibition of TGF-β activation. In the current study, we hypothesized that LDHA inhibition in vivo prevents radiation-induced pulmonary fibrosis. To test this hypothesis, C57BL/6 mice received 5 Gy total-body irradiation plus 10 Gy thoracic irradiation from a (137)Cs source to induce pulmonary fibrosis. Starting at 4 weeks postirradiation, mice were treated with 5 mg/kg of the LDHA inhibitor gossypol or vehicle daily until sacrifice at 26 weeks postirradiation. Exposure to radiation resulted in pulmonary fibrosis, characterized by an increase in collagen content, fibrosis area, extracellular matrix gene expression and TGF-β activation. Irradiated mice treated with gossypol had significantly reduced fibrosis outcomes, including reduced collagen content in the lungs, reduced expression of active TGF-β, LDHA and the transcription factor hypoxia-inducible factor-1 alpha (HIF-1α). These findings suggest that inhibition of LDHA protects against radiation-induced pulmonary fibrosis, and may be a novel

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

    SciTech Connect

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

    1991-05-01

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

  20. The effect of Halofuginone in the amelioration of radiation induced-lung fibrosis.

    PubMed

    Yavas, Guler; Calik, Mustafa; Calik, Goknil; Yavas, Cagdas; Ata, Ozlem; Esme, Hidir

    2013-04-01

    The lung is one of the most sensitive organs to ionizing radiation, and damage to normal lung tissue remains a major dose limiting factor for patients receiving radiation to the thorax. Radiation induced lung injury (RILI) which is also named as "radiation pneumonpathy" is a continuous process and regarded as the result of an abnormal healing response. It has been shown that transforming growth factor β-1 (TGF-β1) plays an integral role in the radiation induced lung fibrosis formation by promoting the chemoattraction of fibroblasts and their conversion to myofibroblasts. Halofuginone is a, low molecular weight plant derived alkaloid, isolated from the Dichroa febrifuga plant that exhibits antifibrotic activity and inhibition of type I collagen synthesis. Halofuginone has been shown to protect against radiation induced soft tissue fibrosis by virtue of inhibiting various members of TFG-β signaling pathway. By the light of these findings, we hypothesize that Halofuginone may be able to ameliorate the radiation induced lung fibrosis. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. Neurogenic differentiation factor NeuroD confers protection against radiation-induced intestinal injury in mice

    PubMed Central

    Li, Ming; Du, Aonan; Xu, Jing; Ma, Yanchao; Cao, Han; Yang, Chao; Yang, Xiao-Dong; Xing, Chun-Gen; Chen, Ming; Zhu, Wei; Zhang, Shuyu; Cao, Jianping

    2016-01-01

    The gastrointestinal tract, especially the small intestine, is particularly sensitive to radiation, and is prone to radiation-induced injury as a result. Neurogenic differentiation factor (NeuroD) is an evolutionarily-conserved basic helix-loop-helix (bHLH) transcription factor. NeuroD contains a protein transduction domain (PTD), which allows it to be exogenously delivered across the membrane of mammalian cells, whereupon its transcription activity can be unleashed. Whether NeuroD has therapeutic effects for radiation-induced injury remains unclear. In the present study, we prepared a NeuroD-EGFP recombinant protein, and explored its protective effects on the survival and intestinal damage induced by ionizing radiation. Our results showed that NeuroD-EGFP could be transduced into small intestine epithelial cells and tissues. NeuroD-EGFP administration significantly increased overall survival of mice exposed to lethal total body irradiation (TBI). This recombinant NeuroD also reduced radiation-induced intestinal mucosal injury and apoptosis, and improved crypt survival. Expression profiling of NeuroD-EGFP-treated mice revealed upregulation of tissue inhibitor of metalloproteinase 1 (TIMP-1), a known inhibitor of apoptosis in mammalian cells. In conclusion, NeuroD confers protection against radiation-induced intestinal injury, and provides a novel therapeutic clinical option for the prevention of intestinal side effects of radiotherapy and the treatment of victims of incidental exposure. PMID:27436572

  2. Radiation-induced damage to normal tissues after radiotherapy in patients treated for gynecologic tumors: Association with single nucleotide polymorphisms in XRCC1, XRCC3, and OGG1 genes and in vitro chromosomal radiosensitivity in lymphocytes

    SciTech Connect

    Ruyck, Kim de . E-mail: kim.deruyck@UGent.be; Eijkeren, Marc van; Claes, Kathleen; Morthier, Rudy; Paepe, Anne de; Vral, Anne; Ridder, Leo de; Thierens, Hubert

    2005-07-15

    Purpose: To examine the association of polymorphisms in XRCC1 (194Arg/Trp, 280Arg/His, 399Arg/Gln, 632Gln/Gln), XRCC3 (5' UTR 4.541A>G, IVS5-14 17.893A>G, 241Thr/Met), and OGG1 (326Ser/Cys) with the development of late radiotherapy (RT) reactions and to assess the correlation between in vitro chromosomal radiosensitivity and clinical radiosensitivity. Methods and Materials: Sixty-two women with cervical or endometrial cancer treated with RT were included in the study. According to the Common Terminology Criteria for Adverse Events, version 3.0, scale, 22 patients showed late adverse RT reactions. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays were performed to examine polymorphic sites, the G2 assay was used to measure chromosomal radiosensitivity, and patient groups were compared using actuarial methods. Results: The XRCC3 IVS5-14 polymorphic allele was significantly associated with the risk of developing late RT reactions (odds ratio 3.98, p = 0.025), and the XRCC1 codon 194 variant showed a significant protective effect (p = 0.028). Patients with three or more risk alleles in XRCC1 and XRCC3 had a significantly increased risk of developing normal tissue reactions (odds ratio 10.10, p = 0.001). The mean number of chromatid breaks per cell was significantly greater in patients with normal tissue reactions than in patients with no reactions (1.16 and 1.34, respectively; p = 0.002). Patients with high chromosomal radiosensitivity showed a 9.2-fold greater annual risk of complications than patients with intermediate chromosomal radiosensitivity. Combining the G2 analysis with the risk allele model allowed us to identify 23% of the patients with late normal tissue reactions, without false-positive results. Conclusion: The results of the present study showed that clinical radiosensitivity is associated with an enhanced G2 chromosomal radiosensitivity and is significantly associated with a combination of different polymorphisms in

  3. Triptolide Mitigates Radiation-Induced Pulmonary Fibrosis.

    PubMed

    Yang, Shanmin; Zhang, Mei; Chen, Chun; Cao, Yongbin; Tian, Yeping; Guo, Yangsong; Zhang, Bingrong; Wang, Xiaohui; Yin, Liangjie; Zhang, Zhenhuan; O'Dell, Walter; Okunieff, Paul; Zhang, Lurong

    2015-11-01

    Triptolide (TPL) may mitigate radiation-induced late pulmonary side effects through its inhibition of global pro-inflammatory cytokines. In this study, we evaluated the effect of TPL in C57BL/6 mice, the animals were exposed to radiation with vehicle (15 Gy), radiation with TPL (0.25 mg/kg i.v., twice weekly for 1, 2 and 3 months), radiation and celecoxib (CLX) (30 mg/kg) and sham irradiation. Cultured supernatant of irradiated RAW 264.7 and MLE-15 cells and lung lysate in different groups were enzyme-linked immunosorbent assays at 33 h. Respiratory rate, pulmonary compliance and pulmonary density were measured at 5 months in all groups. The groups exposed to radiation with vehicle and radiation with TPL exhibited significant differences in respiratory rate and pulmonary compliance (480 ± 75/min vs. 378 ± 76/min; 0.6 ± 0.1 ml/cm H2O/p kg vs. 0.9 ± 0.2 ml/cm H2O/p kg). Seventeen cytokines were significantly reduced in the lung lysate of the radiation exposure with TPL group at 5 months compared to that of the radiation with vehicle group, including profibrotic cytokines implicated in pulmonary fibrosis, such as IL-1β, TGF- β1 and IL-13. The radiation exposure with TPL mice exhibited a 41% reduction of pulmonary density and a 25% reduction of hydroxyproline in the lung, compared to that of radiation with vehicle mice. The trichrome-stained area of fibrotic foci and pathological scaling in sections of the mice treated with radiation and TPL mice were significantly less than those of the radiation with vehicle-treated group. In addition, the radiation with TPL-treated mice exhibited a trend of improved survival rate compared to that of the radiation with vehicle-treated mice at 5 months (83% vs. 53%). Three radiation-induced profibrotic cytokines in the radiation with vehicle-treated group were significantly reduced by TPL treatment, and this partly contributed to the trend of improved survival rate and pulmonary density and function and the decreased severity of

  4. A molecular dynamics study of radiation induced diffusion in uranium dioxide

    NASA Astrophysics Data System (ADS)

    Martin, G.; Maillard, S.; Brutzel, L. Van; Garcia, P.; Dorado, B.; Valot, C.

    2009-03-01

    The nuclear oxide fuels are submitted 'in-pile' to strong structural and chemical modifications due to the fissions and temperature. The diffusion of species is notably the result of a thermal activation and of radiation induced diffusion. This study proposes to estimate to what extent the radiation induced diffusion contributes to the diffusion of lattice atoms in UO2. Irradiations are simulated using molecular dynamics simulation by displacement cascades induced by uranium primary knock-on atoms between 1 and 80 keV. As atoms are easier to displace when their vibration amplitude increases, the temperature range which have been investigated is 300-1400 K. Cascade overlaps were also simulated. The material is shown to melt at the end of cascades, yielding a reduced threshold energy displacement. The nuclear contribution to the radiation induced diffusion is compared to thermally activated diffusion under in-reactor and long-term storage conditions.

  5. Compositional trends of radiation-induced effects in ternary systems of chalcogenide glasses

    NASA Astrophysics Data System (ADS)

    Kovalskiy, A.

    2003-01-01

    The effect of gamma-irradiation on the optical transmittance spectra of pseudobinary stoichiometric and non-stoichiometric cuts of ternary systems of chalcogenide glasses was studied. The application of chemical-bond approach is proposed to explain the features of compositional dependencies of radiation-induced effects in these materials. It is shown that free volume concept must be taken into consideration at the presence of different radiation-sensitive structural units. The creation processes of coordination defects connected with the formation of free volume and coupled with the capability of the constituent atoms to passivation are the main factors determining the magnitude of the radiation-induced effects in chalcogenide glasses.

  6. Radiation-induced mutation at minisatellite loci

    SciTech Connect

    Dubrova, Y.E. |; Nesterov, V.N.; Krouchinsky, N.G.

    1997-10-01

    We are studying the radiation-induced increase of mutation rate in minisatellite loci in mice and humans. Minisatellite mutations were scored by multilocus DNA fingerprint analysis in the progeny of {gamma}-irradiated and non-irradiated mice. The frequency of mutation in offspring of irradiated males was 1.7 higher that in the control group. Germline mutation at human minisatellite loci was studied among children born in heavily polluted areas of the Mogilev district of Belarus after the Chernobyl accident and in a control population. The frequency of mutation assayed both by DNA fingerprinting and by eight single locus probes was found to be two times higher in the exposed families than in the control group. Furthermore, mutation rate was correlated with the parental radiation dose for chronic exposure {sup 137}Cs, consistent with radiation-induction of germline mutation. The potential use of minisatellites in monitoring germline mutation in humans will be discussed.

  7. Radiation induced carcinoma of the larynx

    SciTech Connect

    Amendola, B.E.; Amendola, M.A.; McClatchey, K.D.

    1985-07-01

    A squamous cell carcinoma presented in a 20 year old female nonsmoker three years after receiving a high dosage of radiation therapy to the base of the skull, face and entire neuroaxis and intense combination chemotherapy for a parameningeal rhabdomyosarcoma of the paranasal sinuses is reported. The larynx received a dose of about 3,500 rads over an eight week period. This dosage in conjunction with the associated intense chemotherapy regimen given to the patient may explain the appearance of a radiation induced tumor in an unusually short latent period. This certainly represents a risk in young patients in whom an aggressive combined approach is taken and the physician should be aware of.

  8. Management of radiation-induced rectal bleeding.

    PubMed

    Laterza, Liboria; Cecinato, Paolo; Guido, Alessandra; Mussetto, Alessandro; Fuccio, Lorenzo

    2013-11-01

    Pelvic radiation disease is one of the major complication after radiotherapy for pelvic cancers. The most commonly reported symptom is rectal bleeding which affects patients' quality of life. Therapeutic strategies for rectal bleeding are generally ignored and include medical, endoscopic, and hyperbaric oxygen treatments. Most cases of radiation-induced bleeding are mild and self-limiting, and treatment is normally not indicated. In cases of clinically significant bleeding (i.e. anaemia), medical therapies, including stool softeners, sucralfate enemas, and metronidazole, should be considered as first-line treatment options. In cases of failure, endoscopic therapy, mainly represented by argon plasma coagulation and hyperbaric oxygen treatments, are valid and complementary second-line treatment strategies. Although current treatment options are not always supported by high-quality studies, patients should be reassured that treatment options exist and success is achieved in most cases if the patient is referred to a dedicated centre.

  9. Dietary Supplement Attenuates Radiation-Induced Osteoclastogenic and Oxidative Stress-Related Responses and Protects Adult Mice from Radiation-Induced Bone Loss

    NASA Technical Reports Server (NTRS)

    Globus, Ruth; Schreurs, Ann-Sofie; Tahimic, Candice; Shirazi-Fard, Yasaman; Alwood, Joshua; Shahnazari, Mohammed; Halloran, Bernard

    2015-01-01

    Our central hypothesis is that oxidative stress plays a key role in cell dysfunction and progressive bone loss caused by radiation exposure during spaceflight. In animal studies, excess free radical formation is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility. We previously reported that exposure to low or high-LET radiation rapidly increases expression levels of pro-osteoclastogenic and oxidative stress-related genes in bone and marrow, followed by pathological changes in skeletal structure. To screen various antioxidants for radioprotective effects on bone, 4 month old, male C57Bl6/J mice were treated with a dietary antioxidant cocktail, injectable alpha-lipoic acid, or a dried plum-enriched diet (DP). Mice were then exposed to 2Gy 137Cs total body radiation and one day later marrow cells were collected and the relevant genes analyzed for expression levels. Of the candidates tested, DP was most effective in reducing bone resorption-related gene expression. Microcomputed tomography revealed that DP also prevented the radiation-induced deterioration of skeletal microarchitecture, as indicated by percent bone volume, trabecular spacing and trabecular number. DP had similar protective effects on skeletal structure after sequential exposure to protons (0.5 Gy, 150MeV/n) and 56Fe 0.5Gy, 600 MeV/n). When cultured ex vivo under osteogenic conditions, bone marrow-derived cells from DP-fed animals exhibited increased colony numbers compared to control diet-fed animals. These findings suggest that DP exerted pro-osteogenic effects apart from previously identified anti-resorptive actions, which may contribute to radioprotection of skeletal tissue. In conclusion, a diet enriched in certain types of antioxidants and polyphenols such as DP may be useful as an intervention to protect tissues from degenerative effects of ionizing radiation.

  10. Pentoxifylline Regulates Plasminogen Activator Inhibitor-1 Expression and Protein Kinase A Phosphorylation in Radiation-Induced Lung Fibrosis.

    PubMed

    Lee, Jong-Geol; Shim, Sehwan; Kim, Min-Jung; Myung, Jae Kyung; Jang, Won-Suk; Bae, Chang-Hwan; Lee, Sun-Joo; Kim, Kyeong Min; Jin, Young-Woo; Lee, Seung-Sook; Park, Sunhoo

    2017-01-01

    Purpose. Radiation-induced lung fibrosis (RILF) is a serious late complication of radiotherapy. In vitro studies have demonstrated that pentoxifylline (PTX) has suppressing effects in extracellular matrix production in fibroblasts, while the antifibrotic action of PTX alone using clinical dose is yet unexplored. Materials and Methods. We used micro-computed tomography (micro-CT) and histopathological analysis to evaluate the antifibrotic effects of PTX in a rat model of RILF. Results. Micro-CT findings showed that lung density, volume loss, and mediastinal shift are significantly increased at 16 weeks after irradiation. Simultaneously, histological analysis demonstrated thickening of alveolar walls, destruction of alveolar structures, and excessive collagen deposition in the irradiated lung. PTX treatment effectively attenuated the fibrotic changes based on both micro-CT and histopathological analyses. Western analysis also revealed increased levels of plasminogen activator inhibitor- (PAI-) 1 and fibronectin (FN) and PTX treatment reduced expression of PAI-1 and FN by restoring protein kinase A (PKA) phosphorylation but not TGF-β/Smad in both irradiated lung tissues and epithelial cells. Conclusions. Our results demonstrate the antifibrotic effect of PTX on radiation-induced lung fibrosis and its effect on modulation of PKA and PAI-1 expression as possible antifibrotic mechanisms.

  11. Pentoxifylline Regulates Plasminogen Activator Inhibitor-1 Expression and Protein Kinase A Phosphorylation in Radiation-Induced Lung Fibrosis

    PubMed Central

    Bae, Chang-Hwan; Jin, Young-Woo; Lee, Seung-Sook

    2017-01-01

    Purpose. Radiation-induced lung fibrosis (RILF) is a serious late complication of radiotherapy. In vitro studies have demonstrated that pentoxifylline (PTX) has suppressing effects in extracellular matrix production in fibroblasts, while the antifibrotic action of PTX alone using clinical dose is yet unexplored. Materials and Methods. We used micro-computed tomography (micro-CT) and histopathological analysis to evaluate the antifibrotic effects of PTX in a rat model of RILF. Results. Micro-CT findings showed that lung density, volume loss, and mediastinal shift are significantly increased at 16 weeks after irradiation. Simultaneously, histological analysis demonstrated thickening of alveolar walls, destruction of alveolar structures, and excessive collagen deposition in the irradiated lung. PTX treatment effectively attenuated the fibrotic changes based on both micro-CT and histopathological analyses. Western analysis also revealed increased levels of plasminogen activator inhibitor- (PAI-) 1 and fibronectin (FN) and PTX treatment reduced expression of PAI-1 and FN by restoring protein kinase A (PKA) phosphorylation but not TGF-β/Smad in both irradiated lung tissues and epithelial cells. Conclusions. Our results demonstrate the antifibrotic effect of PTX on radiation-induced lung fibrosis and its effect on modulation of PKA and PAI-1 expression as possible antifibrotic mechanisms. PMID:28337441

  12. Study of radiation induced cancers in a breast screening programme.

    PubMed

    León, A; Verdú, G; Cuevas, M D; Salas, M D; Villaescusa, J I; Bueno, F

    2001-01-01

    It is demonstrated that screening mammography programmes reduce breast cancer mortality considerably. Nevertheless, radiology techniques have an intrinsic risk, the most important being the late somatic effect of the induction of cancer. This study was carried out in order to evaluate the risk to the population produced by the Comunidad Valenciana Breast Screening Programme. All the calculations are carried out for two risk models, UNSCEAR 94 and NRPB 93. On the one hand, screening series detriments are investigated as a function of doses delivered and other parameters related to population structure and X ray equipment. On the other hand the radiation induced cancer probability for a woman who starts at 45 years and remains in the programme until 65 years old is calculated as a function of mammography units' doses and average compression breast thickness. Finally, risk comparison between a screening programme starting at 45 years old and another one starting at 50 years old is made.

  13. Radiation-induced polymerization for the immobilization of penicillin acylase

    SciTech Connect

    Boccu, E.; Carenza, M.; Lora, S.; Palma, G.; Veronese, F.M.

    1987-06-01

    The immobilization of Escherichia coli penicillin acylase was investigated by radiation-induced polymerization of 2-hydroxyethyl methacrylate at low temperature. A leak-proof composite that does not swell in water was obtained by adding the cross-linking agent trimethylolpropane trimethacrylate to the monomer-aqueous enzyme mixture. Penicillin acylase, which was immobilized with greater than 70% yield, possessed a higher Km value toward the substrate 6-nitro-3-phenylacetamidobenzoic acid than the free enzyme form (Km = 1.7 X 10(-5) and 1 X 10(-5) M, respectively). The structural stability of immobilized penicillin acylase, as assessed by heat, guanidinium chloride, and pH denaturation profiles, was very similar to that of the free-enzyme form, thus suggesting that penicillin acylase was entrapped in its native state into aqueous free spaces of the polymer matrix.

  14. Probabilistic methodology for estimating radiation-induced cancer risk

    SciTech Connect

    Dunning, D.E. Jr.; Leggett, R.W.; Williams, L.R.

    1981-01-01

    The RICRAC computer code was developed at Oak Ridge National Laboratory to provide a versatile and convenient methodology for radiation risk assessment. The code allows as input essentially any dose pattern commonly encountered in risk assessments for either acute or chronic exposures, and it includes consideration of the age structure of the exposed population. Results produced by the analysis include the probability of one or more radiation-induced cancer deaths in a specified population, expected numbers of deaths, and expected years of life lost as a result of premature fatalities. These calculatons include consideration of competing risks of death from all other causes. The program also generates a probability frequency distribution of the expected number of cancers in any specified cohort resulting from a given radiation dose. The methods may be applied to any specified population and dose scenario.

  15. [Medical prevention and treatment of radiation-induced pulmonary complications].

    PubMed

    Vallard, A; Rancoule, C; Le Floch, H; Guy, J-B; Espenel, S; Le Péchoux, C; Deutsch, É; Magné, N; Chargari, C

    2017-08-01

    Radiation-induced lung injuries mainly include the (acute or sub-acute) radiation pneumonitis, the lung fibrosis and the bronchiolitis obliterans organizing pneumonia (BOOP). The present review aims at describing the diagnostic process, the current physiopathological knowledge, and the available (non dosimetric) preventive and curative treatments. Radiation-induced lung injury is a diagnosis of exclusion, since clinical, radiological, or biological pathognomonic evidences do not exist. Investigations should necessarily include a thoracic high resolution CT-scan and lung function tests with a diffusing capacity of the lung for carbon monoxide. No treatment ever really showed efficacy to prevent acute radiation-induced lung injury, or to treat radiation-induced lung fibrosis. The most promising drugs in order to prevent radiation-induced lung injury are amifostine, angiotensin-converting-enzyme inhibitors and pentoxifylline. Inhibitors of collagen synthesis are currently tested at a pre-clinical stage to limit the radiation-induced lung fibrosis. Regarding available treatments of radiation-induced pneumonitis, corticoids can be considered the cornerstone. However, no standardized program or guidelines concerning the initial dose and the gradual tapering have been scientifically established. Alternative treatments can be prescribed, based on clinical cases reporting on the efficacy of immunosuppressive drugs. Such data highlight the major role of the lung dosimetric protection in order to efficiently prevent radiation-induced lung injury. Copyright © 2017 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

  16. Radiation-induced osteosarcoma of the sphenoid bone

    SciTech Connect

    Tanaka, S.; Nishio, S.; Morioka, T.; Fukui, M.; Kitamura, K.; Hikita, K. )

    1989-10-01

    The case of a patient who developed osteosarcoma in the sphenoid bone 15 years after radiation therapy for a craniopharyngioma is reported. Radiation-induced osteosarcoma of the sphenoid bone has not been reported previously. Reported cases of radiation-induced osteosarcomas are reviewed.

  17. Radiation-induced blood-brain barrier changes: pathophysiological mechanisms and clinical implications.

    PubMed

    d'Avella, D; Cicciarello, R; Angileri, F F; Lucerna, S; La Torre, D; Tomasello, F

    1998-01-01

    The pathophysiology of whole-brain radiation (WBR) toxicity remains incompletely understood. The possibility of a primary change in blood-brain barrier (BBB) associated with microvascular damage was investigated. Rats were exposed to conventional fractionation in radiation (200 +/- cGy/d, 5d/wk; total dose, 4,000 cGy). BBB changes were assessed by means of the quantitative 14C-alpha-aminoisobutyric acid (AIB) technique coupled with standard electron microscopy (EM) and morphometric techniques as well as studies of the transcapillary passage of horseradish peroxidase (HRP). At 15 days after WBR, AIB transport across BBB increased significantly in cerebral cortex. EM disclosed vesicular transport of HRP across the intact endothelium without opening of the tight junctions. Ninety days after WBR, well-defined alterations of the microvasculature were observed. The main feature of cortical microvessels was their collapsed aspect, associated with perivascular edema containing cell debris. Data suggest a possible association between damage of the microvascular/glial unit of tissue injury and development of radiation-induced brain cerebral dysfunction. We hypothesize the following sequence of pathophysiological events: WBR causes an early increase in BBB permeability, which produces perivascular edema and microvascular collapse. The interference with microcirculation affects blood flow and energy supply to the tissue, resulting in structural damage on an ischemic/dysmetabolic basis.

  18. Deep Friction Massage in Treatment of Radiation-induced Fibrosis: Rehabilitative Care for Breast Cancer Survivors

    PubMed Central

    Warpenburg, Mary J.

    2014-01-01

    Treatment for invasive breast cancer usually involves some combination of surgery, radiation therapy, chemotherapy, hormone therapy, and/or targeted therapy. For approximately 50% of patients, radiation therapy is a component of the therapies used. As a result, radiation-induced fibrosis is becoming a common and crippling side effect, leading to muscle imbalance with a lessened range of motion as well as pain and dysfunction of the vascular and lymphatic systems. No good estimates are available for how many patients experience complications from radiation. Radiation-induced fibrosis can affect the underlying fascia, muscles, organs, and bones within the primary target field and the larger secondary field that is caused by the scatter effect of radioactive elements. For breast cancer patients, the total radiation field may include the neck, shoulder, axillary, and thoracic muscles and the ribs for both the ipsilateral (cancer-affected) and contralateral sides. This case study indicates that therapy using deep friction massage can affect radiation-induced fibrosis beneficially, particularly in the thoracic muscles and the intercostals (ie, the muscles between the ribs). When delivered in intensive sessions using deep friction techniques, massage has the potential to break down fibrotic tissues, releasing the inflammation and free radicals that are caused by radiation therapy. In the course of the massage, painful and debilitating spasms resulting from fibrosis can be relieved and the progressive nature of the radiation-induced fibrosis interrupted. PMID:26770116

  19. Deep Friction Massage in Treatment of Radiation-induced Fibrosis: Rehabilitative Care for Breast Cancer Survivors.

    PubMed

    Warpenburg, Mary J

    2014-10-01

    Treatment for invasive breast cancer usually involves some combination of surgery, radiation therapy, chemotherapy, hormone therapy, and/or targeted therapy. For approximately 50% of patients, radiation therapy is a component of the therapies used. As a result, radiation-induced fibrosis is becoming a common and crippling side effect, leading to muscle imbalance with a lessened range of motion as well as pain and dysfunction of the vascular and lymphatic systems. No good estimates are available for how many patients experience complications from radiation. Radiation-induced fibrosis can affect the underlying fascia, muscles, organs, and bones within the primary target field and the larger secondary field that is caused by the scatter effect of radioactive elements. For breast cancer patients, the total radiation field may include the neck, shoulder, axillary, and thoracic muscles and the ribs for both the ipsilateral (cancer-affected) and contralateral sides. This case study indicates that therapy using deep friction massage can affect radiation-induced fibrosis beneficially, particularly in the thoracic muscles and the intercostals (ie, the muscles between the ribs). When delivered in intensive sessions using deep friction techniques, massage has the potential to break down fibrotic tissues, releasing the inflammation and free radicals that are caused by radiation therapy. In the course of the massage, painful and debilitating spasms resulting from fibrosis can be relieved and the progressive nature of the radiation-induced fibrosis interrupted.

  20. 3D ultrasound Nakagami imaging for radiation-induced vaginal fibrosis

    NASA Astrophysics Data System (ADS)

    Yang, Xiaofeng; Rossi, Peter; Shelton, Joseph; Bruner, Debrorah; Tridandapani, Srini; Liu, Tian

    2014-03-01

    Radiation-induced vaginal fibrosis is a debilitating side-effect affecting up to 80% of women receiving radiotherapy for their gynecological (GYN) malignancies. Despite the significant incidence and severity, little research has been conducted to identify the pathophysiologic changes of vaginal toxicity. In a previous study, we have demonstrated that ultrasound Nakagami shape and PDF parameters can be used to quantify radiation-induced vaginal toxicity. These Nakagami parameters are derived from the statistics of ultrasound backscattered signals to capture the physical properties (e.g., arrangement and distribution) of the biological tissues. In this paper, we propose to expand this Nakagami imaging concept from 2D to 3D to fully characterize radiation-induced changes to the vaginal wall within the radiation treatment field. A pilot study with 5 post-radiotherapy GYN patients was conducted using a clinical ultrasound scanner (6 MHz) with a mechanical stepper. A serial of 2D ultrasound images, with radio-frequency (RF) signals, were acquired at 1 mm step size. The 2D Nakagami shape and PDF parameters were calculated from the RF signal envelope with a sliding window, and then 3D Nakagami parameter images were generated from the parallel 2D images. This imaging method may be useful as we try to monitor radiation-induced vaginal injury, and address vaginal toxicities and sexual dysfunction in women after radiotherapy for GYN malignancies.

  1. Prevention and management of radiation-induced dermatitis, mucositis, and xerostomia.

    PubMed

    Radvansky, Lauren J; Pace, Makala B; Siddiqui, Asif

    2013-06-15

    Current strategies for preventing and managing radiation-induced dermatitis, mucositis, and xerostomia are reviewed, with an emphasis on pharmacologic interventions. Nearly two thirds of all patients with cancer receive radiation therapy during the course of treatment, frequently resulting in acute skin and mucosal toxicities. The severity of radiotherapy-associated toxicities varies according to multiple treatment- and patient-related factors (e.g., total radiation dose and dose fractionation schedule, volume of organ or tissue irradiated, use of concurrent versus sequential chemotherapy, comorbid conditions, functional performance status). Three major radiation toxicities encountered in clinical practice are (1) radiation dermatitis, typically managed with a variety of topical agents such as water-based moisturizing creams or lotions, topical steroids, antiinflammatory emulsions, and wound dressings, (2) radiation-induced oral mucositis, which can be managed through proper basic oral care practices, appropriate pain management, and the use of medicated mouthwashes and oral rinses and gels, and (3) radiation-induced xerostomia, which can be alleviated with saliva substitutes, moistening agents, and sialagogues. Pharmacists involved in the care of patients receiving radiotherapy can play an important role in optimizing symptom control, educating patients on self-care strategies, and adverse effect monitoring and reporting. Radiation-induced dermatitis, mucositis, and xerostomia can cause significant morbidity and diminished quality of life. Pharmacologic interventions for the prevention and treatment of these toxicities include topical agents for dermatitis; oral products, analgesics, and palifermin for mucositis; and amifostine, saliva substitutes, and pilocarpine for xerostomia.

  2. Inactivation of Kupffer Cells by Gadolinium Chloride Protects Murine Liver From Radiation-Induced Apoptosis

    SciTech Connect

    Du Shisuo; Qiang Min; Zeng Zhaochong; Ke Aiwu; Ji Yuan; Zhang Zhengyu; Zeng Haiying; Liu Zhongshan

    2010-03-15

    Purpose: To determine whether the inhibition of Kupffer cells before radiotherapy (RT) would protect hepatocytes from radiation-induced apoptosis. Materials and Methods: A single 30-Gy fraction was administered to the upper abdomen of Sprague-Dawley rats. The Kupffer cell inhibitor gadolinium chloride (GdCl3; 10 mg/kg body weight) was intravenously injected 24 h before RT. The rats were divided into four groups: group 1, sham RT plus saline (control group); group 2, sham RT plus GdCl3; group 3, RT plus saline; and group 4, RT plus GdCl3. Liver tissue was collected for measurement of apoptotic cytokine expression and evaluation of radiation-induced liver toxicity by analysis of liver enzyme activities, hepatocyte micronucleus formation, apoptosis, and histologic staining. Results: The expression of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha was significantly attenuated in group 4 compared with group 3 at 2, 6, 24, and 48 h after injection (p <0.05). At early points after RT, the rats in group 4 exhibited significantly lower levels of liver enzyme activity, apoptotic response, and hepatocyte micronucleus formation compared with those in group 3. Conclusion: Selective inactivation of Kupffer cells with GdCl3 reduced radiation-induced cytokine production and protected the liver against acute radiation-induced damage.

  3. The Therapeutic Effect of Adipose-Derived Mesenchymal Stem Cells for Radiation-Induced Bladder Injury

    PubMed Central

    Qiu, Xuefeng; Zhang, Shiwei; Zhao, Xiaozhi; Fu, Kai; Guo, Hongqian

    2016-01-01

    This study was designed to investigate the protective effect of adipose derived mesenchymal stem cells (AdMSCs) against radiation-induced bladder injury (RIBI). Female rats were divided into 4 groups: (a) controls, consisting of nontreated rats; (b) radiation-treated rats; (c) radiation-treated rats receiving AdMSCs; and (d) radiation-treated rats receiving AdMSCs conditioned medium. AdMSCs or AdMSCs conditioned medium was injected into the muscular layer of bladder 24 h after radiation. Twelve weeks after radiation, urinary bladder tissue was collected for histological assessment and enzyme-linked immunosorbent assay (ELISA) after metabolic cage investigation. At the 1 w, 4 w, and 8 w time points following cells injection, 3 randomly selected rats in RC group and AdMSCs group were sacrificed to track injected AdMSCs. Metabolic cage investigation revealed that AdMSCs showed protective effect for radiation-induced bladder dysfunction. The histological and ELISA results indicated that the fibrosis and inflammation within the bladder were ameliorated by AdMSCs. AdMSCs conditioned medium showed similar effects in preventing radiation-induced bladder dysfunction. In addition, histological data indicated a time-dependent decrease in the number of AdMSCs in the bladder following injection. AdMSCs prevented radiation induced bladder dysfunction and histological changes. Paracrine effect might be involved in the protective effects of AdMSCs for RIBI. PMID:27051426

  4. Mechanisms of radiation-induced brain toxicity and implications for future clinical trials.

    PubMed

    Kim, Jae Ho; Brown, Stephen L; Jenrow, Kenneth A; Ryu, Samuel

    2008-05-01

    Radiation therapy is widely used in the treatment of primary malignant brain tumors and metastatic tumors of the brain with either curative or palliative intent. The limitation of cancer radiation therapy does not derive from the inability to ablate tumor, but rather to do so without excessively damaging the patient. Among the varieties of radiation-induced brain toxicities, it is the late delayed effects that lead to severe and irreversible neurological consequences. Following radiation exposure, late delayed effects within the CNS have been attributable to both parenchymal and vascular damage involving oligodendrocytes, neural progenitors, and endothelial cells. These reflect a dynamic process involving radiation-induced death of target cells and subsequent secondary reactive neuroinflammatory processes that are believed to lead to selective cell loss, tissue damage, and functional deficits. The progressive, late delayed damage to the brain after high-dose radiation is thought to be caused by radiation-induced long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines. Experimental studies suggest that radiation-induced brain injury can be successfully mitigated and treated with several well established drugs in wide clinical use which exert their effects by blocking pro-inflammatory cytokines and reactive oxygen species. This review highlights preclinical and early clinical data that are translatable for future clinical trials.

  5. A Prospective Cohort Study on Radiation-induced Hypothyroidism: Development of an NTCP Model

    SciTech Connect

    Boomsma, Marjolein J.; Bijl, Hendrik P.; Christianen, Miranda E.M.C.; Beetz, Ivo; Chouvalova, Olga; Steenbakkers, Roel J.H.M.; Laan, Bernard F.A.M. van der; Oosting, Sjoukje F.; Schilstra, Cornelis; Langendijk, Johannes A.

    2012-11-01

    Purpose: To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced hypothyroidism. Methods and Materials: The thyroid-stimulating hormone (TSH) level of 105 patients treated with (chemo-) radiation therapy for head-and-neck cancer was prospectively measured during a median follow-up of 2.5 years. Hypothyroidism was defined as elevated serum TSH with decreased or normal free thyroxin (T4). A multivariate logistic regression model with bootstrapping was used to determine the most important prognostic variables for radiation-induced hypothyroidism. Results: Thirty-five patients (33%) developed primary hypothyroidism within 2 years after radiation therapy. An NTCP model based on 2 variables, including the mean thyroid gland dose and the thyroid gland volume, was most predictive for radiation-induced hypothyroidism. NTCP values increased with higher mean thyroid gland dose (odds ratio [OR]: 1.064/Gy) and decreased with higher thyroid gland volume (OR: 0.826/cm{sup 3}). Model performance was good with an area under the curve (AUC) of 0.85. Conclusions: This is the first prospective study resulting in an NTCP model for radiation-induced hypothyroidism. The probability of hypothyroidism rises with increasing dose to the thyroid gland, whereas it reduces with increasing thyroid gland volume.

  6. Glycyrrhetinic acid alleviates radiation-induced lung injury in mice

    PubMed Central

    Chen, Jinmei; Zhang, Weijian; Zhang, Lurong; Zhang, Jiemin; Chen, Xiuying; Yang, Meichun; Chen, Ting; Hong, Jinsheng

    2017-01-01

    Radiation-induced lung injury (RILI) is a common complication of thoracic radiotherapy, but efficacious therapy for RILI is lacking. This study ascertained whether glycyrrhetinic acid (GA; a functional hydrolyzed product of glycyrrhizic acid, which is extracted from herb licorice) can protect against RILI and investigated its relationship to the transforming growth factor (TGF)-β1/Smads signaling pathway. C57BL/6 mice were divided into four groups: a control group, a GA group and two irradiation (IR) groups. IR groups were exposed to a single fraction of X-rays (12 Gy) to the thorax and administered normal saline (IR + NS group) or GA (IR + GA group). Two days and 17 days after irradiation, histologic analyses were performed to assess the degree of lung injury, and the expression of TGF-β1, Smad2, Smad3 and Smad7 was recorded. GA administration mitigated the histologic changes of lung injury 2 days and 17 days after irradiation. Protein and mRNA expression of TGF-β1, Smad2 and Smad3, and the mRNA level of Smad7, in lung tissue were significantly elevated after irradiation. GA decreased expression of TGF-β1, Smad2 and Smad3 in lung tissue, but did not increase Smad7 expression. GA can protect against early-stage RILI. This protective effect may be associated with inhibition of the TGF-β1/Smads signaling pathway. PMID:27672101

  7. Radiation-induced sarcomas of the head and neck

    PubMed Central

    Thiagarajan, Anuradha; Iyer, N Gopalakrishna

    2014-01-01

    With improved outcomes associated with radiotherapy, radiation-induced sarcomas (RIS) are increasingly seen in long-term survivors of head and neck cancers, with an estimated risk of up to 0.3%. They exhibit no subsite predilection within the head and neck and can arise in any irradiated tissue of mesenchymal origin. Common histologic subtypes of RIS parallel their de novo counterparts and include osteosarcoma, chondrosarcoma, malignant fibrous histiocytoma/sarcoma nitricoxide synthase, and fibrosarcoma. While imaging features of RIS are not pathognomonic, large size, extensive local invasion with bony destruction, marked enhancement within a prior radiotherapy field, and an appropriate latency period are suggestive of a diagnosis of RIS. RIS development may be influenced by factors such as radiation dose, age at initial exposure, exposure to chemotherapeutic agents and genetic tendency. Precise pathogenetic mechanisms of RIS are poorly understood and both directly mutagenizing effects of radiotherapy as well as changes in microenvironments are thought to play a role. Management of RIS is challenging, entailing surgery in irradiated tissue and a limited scope for further radiotherapy and chemotherapy. RIS is associated with significantly poorer outcomes than stage-matched sarcomas that arise independent of irradiation and surgical resection with clear margins seems to offer the best chance for cure. PMID:25493233

  8. Radiation-induced bystander effect: early process and rapid assessment.

    PubMed

    Wang, Hongzhi; Yu, K N; Hou, Jue; Liu, Qian; Han, Wei

    2015-01-01

    Radiation-induced bystander effect (RIBE) is a biological process that has received attention over the past two decades. RIBE refers to a plethora of biological effects in non-irradiated cells, including induction of genetic damages, gene expression, cell transformation, proliferation and cell death, which are initiated by receiving bystander signals released from irradiated cells. RIBE brings potential hazards to normal tissues in radiotherapy, and imparts a higher risk from low-dose radiation than we previously thought. Detection with proteins related to DNA damage and repair, cell cycle control, proliferation, etc. have enabled rapid assessment of RIBE in a number of research systems such as cultured cells, three-dimensional tissue models and animal models. Accumulated experimental data have suggested that RIBE may be initiated rapidly within a time frame as short as several minutes after radiation. These have led to the requirement of techniques capable of rapidly assessing RIBE itself as well as assessing the early processes involved. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  9. Grape seed extract Vitis vinifera protects against radiation-induced oxidative damage and metabolic disorders in rats.

    PubMed

    Saada, Helen N; Said, Ussama Z; Meky, Nefissa H; Abd El Azime, Afrag S

    2009-03-01

    Whole body exposure to ionizing radiation induces the formation of reactive oxygen species (ROS) in different tissues provoking oxidative damage, organ dysfunction and metabolic disturbances. The present study was designed to determine the possible protective effect of grape seed extract (GSE), rich in proanthocyanidins against gamma-radiation-induced oxidative stress in heart and pancreas tissues associated with serum metabolic disturbances. Irradiated rats were whole body exposed to 5 Gy gamma-radiation. GSE-treated irradiated rats received 100 mg GSE/kg/day, by gavage, for 14 days before irradiation. The animals were killed on days 1, 14 and 28 after irradiation. Significant decreases of SOD, CAT and GSH-Px activities associated with significant increases of TBARS levels were recorded in both tissues after irradiation. GSE administration pre-irradiation significantly attenuated the radiation-induced oxidative stress in heart tissues which was substantiated by a significant amelioration of serum LDH, CPK and AST activities. GSE treatment also attenuated the oxidative stress in pancreas tissues which was associated with a significant improvement in radiation-induced hyperglycemia and hyperinsulinemia. In conclusion, the present data demonstrate that GSE would protect the heart and pancreas tissues from oxidative damage induced by ionizing irradiation. (c) 2008 John Wiley & Sons, Ltd.

  10. Radiation-induced degradation of aqueous fluoranthene

    NASA Astrophysics Data System (ADS)

    Popov, Petar; Getoff, Nikola

    2005-01-01

    The radiation-induced degradation of fluoranthene (FA) in slightly alkaline aqueous solution was investigated in the presence of air as well as of N 2O. Depending on the starting FA-concentration the determined Gi(-FA) was 0.34 for 1×10 -5 mol/l FA upto 0.67 for 4.6×10 -5 mol/l FA. As major radiolytic products found by HPLC-analysis were: 9-fluorene carboxylic acid ( Gi =0.006), 9-fluorenone ( Gi=0.004) and fluorene ( Gi=0.002) in addition to a mixture of carboxylic acids and aldehydes. In the presence of N 2O (90% OH, 10% H) practically the same products were observed, however in this case the yield of the carboxylic acids was about 2-times higher than in solutions saturated with air, but 4-times less aldehydes, resp. For illustration of the rather complicated degradation process a probable reaction mechanism is presented.

  11. Feasibility of OCT to detect radiation-induced esophageal damage in small animal models (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Jelvehgaran, Pouya; Alderliesten, Tanja; Salguero, Javier; Borst, Gerben; Song, Ji-Ying; van Leeuwen, Ton G.; de Boer, Johannes F.; de Bruin, Daniel M.; van Herk, Marcel B.

    2016-03-01

    Lung cancer survival is poor and radiotherapy patients often suffer serious treatment side effects. The esophagus is particularly sensitive leading to reduced food intake or even fistula formation. Only few direct techniques exist to measure radiation-induced esophageal damage, for which knowledge is needed to improve the balance between risk of tumor recurrence and complications. Optical coherence tomography (OCT) is a minimally-invasive imaging technique that obtains cross-sectional, high-resolution (1-10µm) images and is capable of scanning the esophageal wall up to 2-3mm depth. In this study we investigated the feasibility of OCT to detect esophageal radiation damage in mice. In total 30 mice were included in 4 study groups (1 main and 3 control groups). Mice underwent cone-beam CT imaging for initial setup assessment and dose planning followed by single-fraction dose delivery of 4, 10, 16, and 20Gy on 5mm spots, spaced 10mm apart. Mice were repeatedly imaged using OCT: pre-irradiation and up to 3 months post-irradiation. The control groups received either OCT only, irradiation only, or were sham-operated. We used histopathology as gold standard for radiation-induced damage diagnosis. The study showed edema in both the main and OCT-only groups. Furthermore, radiation-induced damage was primarily found in the highest dose region (distal esophagus). Based on the histopathology reports we were able to identify the radiation-induced damage in the OCT images as a change in tissue scattering related to the type of induced damage. This finding indicates the feasibility and thereby the potentially promising role of OCT in radiation-induced esophageal damage assessment.

  12. Arachidonic acid metabolites mediate the radiation-induced increase in glomerular albumin permeability.

    PubMed

    Sharma, Mukut; McCarthy, Ellen T; Sharma, Ram; Fish, Brian L; Savin, Virginia J; Cohen, Eric P; Moulder, John E

    2006-01-01

    Radiation-induced renal injury is characterized by proteinuria, hypertension, and progressive decline in renal function. We have previously shown that in vivo or in vitro irradiation of glomeruli with a single dose of radiation (9.5 Gy) increases glomerular albumin permeability (P(alb)) within 1 hr. The current studies tested the hypothesis that this early radiation-induced increase in P(alb) is caused by the release of arachidonic acid and by the generation of specific arachidonic acid metabolites. Glomeruli obtained from WAG/Rij/MCW rats and cultured rat glomerular epithelial and mesangial cells were studied after irradiation (9.5 Gy, single dose). Arachidonic acid release and eicosanoid synthesis by glomeruli or cultured glomerular cells were measured after irradiation, and the effect of inhibitors of phospholipase A2 (PLA2) and cyclooxygenase (COX) on the irradiation-induced increase in P(alb) was assessed. Arachidonic acid release was demonstrated within 10 mins of irradiation of isolated glomeruli and monolayer cultures of glomerular epithelial and mesangial cells. Prostaglandin F(2alpha) (PGF(2alpha)) and PGE2 release was increased after irradiation of isolated glomeruli. Blocking arachidonic acid release or COX activity before irradiation completely prevented the increase in P(alb). COX inhibition immediately after irradiation also diminished the radiation-induced increase in P(alb). We conclude that arachidonic acid and its COX metabolites play an essential role in the early cellular changes that lead to the radiation-induced increase in P(alb). Understanding of the early epigenetic effects of irradiation may lead to new intervention strategies against radiation-induced injury of normal tissues.

  13. Standardized Herbal Formula PM014 Inhibits Radiation-Induced Pulmonary Inflammation in Mice

    PubMed Central

    Kim, Jee-Youn; Shin, Dasom; Lee, Gihyun; Kim, Jin-Mo; Kim, Dongwook; An, Yong-Min; Yoo, Byung Rok; Chang, Hanna; Kim, Miran; Cho, Jaeho; Bae, Hyunsu

    2017-01-01

    Radiation therapy is widely used for thoracic cancers. However, it occasionally causes radiation-induced lung injuries, including pneumonitis and fibrosis. Chung-Sang-Bo-Ha-Tang (CSBHT) has been traditionally used to treat chronic pulmonary disease in Korea. PM014, a modified herbal formula derived from CSBHT, contains medicinal herbs of seven species. In our previous studies, PM014 exhibited anti-inflammatory effects in a chronic obstructive pulmonary disease model. In this study, we have evaluated the effects of PM014 on radiation-induced lung inflammation. Mice in the treatment group were orally administered PM014 six times for 2 weeks. Effects of PM014 on radiation pneumonitis were evaluated based on histological findings and differential cell count in bronchoalveolar lavage fluid. PM014 treatment significantly inhibited immune cell recruitment and collagen deposition in lung tissue. Normal lung volume, evaluated by radiological analysis, in PM014-treated mice was higher compared to that in irradiated control mice. PM014-treated mice exhibited significant changes in inspiratory capacity, compliance and tissue damping and elastance. Additionally, PM014 treatment resulted in the downregulation of inflammatory cytokines, chemokines, and fibrosis-related genes and a reduction in the transforming growth factor-β1-positive cell population in lung tissue. Thus, PM014 is a potent therapeutic agent for radiation-induced lung fibrosis and inflammation. PMID:28322297

  14. Repeated Autologous Bone Marrow-Derived Mesenchymal Stem Cell Injections Improve Radiation-Induced Proctitis in Pigs

    PubMed Central

    Busson, Elodie; Holler, Valerie; Strup-Perrot, Carine; Lacave-Lapalun, Jean-Victor; Lhomme, Bruno; Prat, Marie; Devauchelle, Patrick; Sabourin, Jean-Christophe; Simon, Jean-Marc; Bonneau, Michel; Lataillade, Jean-Jacques; Benderitter, Marc

    2013-01-01

    The management of proctitis in patients who have undergone very-high-dose conformal radiotherapy is extremely challenging. The fibrosis-necrosis, fistulae, and hemorrhage induced by pelvic overirradiation have an impact on morbidity. Augmenting tissue repair by the use of mesenchymal stem cells (MSCs) may be an important advance in treating radiation-induced toxicity. Using a preclinical pig model, we investigated the effect of autologous bone marrow-derived MSCs on high-dose radiation-induced proctitis. Irradiated pigs received repeated intravenous administrations of autologous bone marrow-derived MSCs. Immunostaining and real-time polymerase chain reaction analysis were used to assess the MSCs' effect on inflammation, extracellular matrix remodeling, and angiogenesis, in radiation-induced anorectal and colon damages. In humans, as in pigs, rectal overexposure induces mucosal damage (crypt depletion, macrophage infiltration, and fibrosis). In a pig model, repeated administrations of MSCs controlled systemic inflammation, reduced in situ both expression of inflammatory cytokines and macrophage recruitment, and augmented interleukin-10 expression in rectal mucosa. MSC injections limited radiation-induced fibrosis by reducing collagen deposition and expression of col1a2/col3a1 and transforming growth factor-β/connective tissue growth factor, and by modifying the matrix metalloproteinase/TIMP balance. In a pig model of proctitis, repeated injections of MSCs effectively reduced inflammation and fibrosis. This treatment represents a promising therapy for radiation-induced severe rectal damage. PMID:24068742

  15. Repeated autologous bone marrow-derived mesenchymal stem cell injections improve radiation-induced proctitis in pigs.

    PubMed

    Linard, Christine; Busson, Elodie; Holler, Valerie; Strup-Perrot, Carine; Lacave-Lapalun, Jean-Victor; Lhomme, Bruno; Prat, Marie; Devauchelle, Patrick; Sabourin, Jean-Christophe; Simon, Jean-Marc; Bonneau, Michel; Lataillade, Jean-Jacques; Benderitter, Marc

    2013-11-01

    The management of proctitis in patients who have undergone very-high-dose conformal radiotherapy is extremely challenging. The fibrosis-necrosis, fistulae, and hemorrhage induced by pelvic overirradiation have an impact on morbidity. Augmenting tissue repair by the use of mesenchymal stem cells (MSCs) may be an important advance in treating radiation-induced toxicity. Using a preclinical pig model, we investigated the effect of autologous bone marrow-derived MSCs on high-dose radiation-induced proctitis. Irradiated pigs received repeated intravenous administrations of autologous bone marrow-derived MSCs. Immunostaining and real-time polymerase chain reaction analysis were used to assess the MSCs' effect on inflammation, extracellular matrix remodeling, and angiogenesis, in radiation-induced anorectal and colon damages. In humans, as in pigs, rectal overexposure induces mucosal damage (crypt depletion, macrophage infiltration, and fibrosis). In a pig model, repeated administrations of MSCs controlled systemic inflammation, reduced in situ both expression of inflammatory cytokines and macrophage recruitment, and augmented interleukin-10 expression in rectal mucosa. MSC injections limited radiation-induced fibrosis by reducing collagen deposition and expression of col1a2/col3a1 and transforming growth factor-β/connective tissue growth factor, and by modifying the matrix metalloproteinase/TIMP balance. In a pig model of proctitis, repeated injections of MSCs effectively reduced inflammation and fibrosis. This treatment represents a promising therapy for radiation-induced severe rectal damage.

  16. Radiation-Induced Alopecia after Endovascular Embolization under Fluoroscopy

    PubMed Central

    Ounsakul, Vipawee; Iamsumang, Wimolsiri

    2016-01-01

    Radiation-induced alopecia after fluoroscopically guided procedures is becoming more common due to an increasing use of endovascular procedures. It is characterized by geometric shapes of nonscarring alopecia related to the area of radiation. We report a case of a 46-year-old man presenting with asymptomatic, sharply demarcated rectangular, nonscarring alopecic patch on the occipital scalp following cerebral angiography with fistula embolization under fluoroscopy. His presentations were compatible with radiation-induced alopecia. Herein, we also report a novel scalp dermoscopic finding of blue-grey dots in a target pattern around yellow dots and follicles, which we detected in the lesion of radiation-induced alopecia. PMID:28074164

  17. Rebamipide ameliorates radiation-induced intestinal injury in a mouse model.

    PubMed

    Shim, Sehwan; Jang, Hyo-Sun; Myung, Hyun-Wook; Myung, Jae Kyung; Kang, Jin-Kyu; Kim, Min-Jung; Lee, Seung Bum; Jang, Won-Suk; Lee, Sun-Joo; Jin, Young-Woo; Lee, Seung-Sook; Park, Sunhoo

    2017-08-15

    Radiation-induced enteritis is a major side effect in cancer patients undergoing abdominopelvic radiotherapy. Radiation exposure produces an uncontrolled inflammatory cascade and epithelial cell loss leading to impaired epithelial barrier function. The goal of this study was to determine the effect of rebamipide on regeneration of the intestinal epithelia after radiation injury. The abdomens of C57BL/6 mice were exposed to 13Gy of irradiation (IR) and then the mice were treated with rebamipide. Upon IR, intestinal epithelia were destroyed structurally at the microscopic level and bacterial translocation was increased. The intestinal damage reached a maximum level on day 6 post-IR and intestinal regeneration occurred thereafter. We found that rebamipide significantly ameliorated radiation-induced intestinal injury. In mice treated with rebamipide after IR, intestinal barrier function recovered and expression of the tight junction components of the intestinal barrier were upregulated. Rebamipide administration reduced radiation-induced intestinal mucosal injury. The levels of proinflammatory cytokines and matrix metallopeptidase 9 (MMP9) were significantly reduced upon rebamipide administration. Intestinal cell proliferation and β-catenin expression also increased upon rebamipide administration. These data demonstrate that rebamipide reverses impairment of the intestinal barrier by increasing intestinal cell proliferation and attenuating the inflammatory response by inhibiting MMP9 and proinflammatory cytokine expression in a murine model of radiation-induced enteritis. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Protective effects of selenocystine against γ-radiation-induced genotoxicity in Swiss albino mice.

    PubMed

    Kunwar, Amit; Jayakumar, S; Bhilwade, H N; Bag, P P; Bhatt, H; Chaubey, R C; Priyadarsini, K I

    2011-05-01

    Selenocystine (CysSeSeCys), a diselenide aminoacid exhibiting glutathione peroxidase-like activity and selective antitumor effects, was examined for in vivo antigenotoxic and antioxidant activity in Swiss albino mice after exposure to a sublethal dose (5 Gy) of γ-radiation. For this, CysSeSeCys was administered intraperitoneally (i.p.) to mice at a dosage of 0.5 mg/kg body weight for 5 consecutive days prior to whole-body γ-irradiation. When examined in the hepatic tissue, CysSeSeCys administration reduced the DNA damage at 30 min after radiation exposure by increasing the rate of DNA repair. Since antigenotoxic agents could alter the expression of genes involved in cell cycle arrest and DNA repair, the transcriptional changes in p53, p21 and GADD45α were monitored in the hepatic tissue by real-time PCR. The results show that CysSeSeCys alone causes moderate induction of these three genes. However, CysSeSeCys pretreatment resulted in a suppression of radiation-induced enhancement of p21 and GADD45α expression, but did not affect p53 expression. Further analysis of radiation-induced oxidative stress markers in the same tissue indicated that CysSeSeCys significantly inhibits lipid peroxidation and prevents the depletion of antioxidant enzymes and glutathione (GSH) levels. Additionally, it also prevents radiation-induced DNA damage in other radiation sensitive cellular systems like peripheral leukocytes and bone marrow, which was evident by a decrease in comet parameters and micronucleated polychromatic erythrocytes (mn-PCEs) frequency, respectively. Based on these observations, it is concluded that CysSeSeCys exhibits antigenotoxic effects, reduces radiation-induced oxidative stress, and is a promising candidate for future exploration as a radioprotector.

  19. Dried Plum Protects From Radiation-Induced Bone Loss by Attenuating Pro-Osteoclastic and Oxidative Stress Responses

    NASA Technical Reports Server (NTRS)

    Globus, Ruth

    2015-01-01

    Future space explorations beyond the earths magnetosphere will increase human exposure to space radiation and associated risks to skeletal health. We hypothesize that oxidative stress resulting from radiation exposure plays a major role in progressive bone loss and dysfunction in associated tissue. In animal studies, increased free radical formation is associated with pathological changes in bone structure, enhanced bone resorption, reduced bone formation and decreased bone mineral density, which can lead to skeletal fragility. Our long-term goals are to define the mechanisms and risk of bone loss in the spaceflight environment and to facilitate the development of effective countermeasures. We had previously reported that exposure to low or high-LET radiation correlates with an acute increase in the expression of pro-osteoclastic and oxidative stress genes in bone during the early response to radiation followed by pathological changes in skeletal structure. We then conducted systematic screening for potential countermeasures against bone loss where we tested the ability of various antioxidants to mitigate the radiation-induced increase in expression of these markers. For the screen, 16-week old C57Bl6J mice were treated with a dietary antioxidant cocktail, injectable DHLA or a dried plum-enriched diet (DP). Mice were then exposed to 2Gy 137Cs radiation and one day later, marrow cells were collected and the relevant genes analyzed for expression levels. Among the candidate countermeasures tested, DP was most effective in reducing the expression of genes associated with bone loss. Furthermore, analysis of skeletal structure by microcomputed tomography (microCT) revealed that DP also prevents the radiation-induced deterioration in skeletal microarchitecture as indicated by parameters such as percent bone volume (BVTV), trabecular spacing and trabecular number. We also found that DP has similar protective effects on skeletal structure in a follow-up study using 1 Gy of

  20. Molecular Mechanisms and Treatment of Radiation-Induced Lung Fibrosis

    PubMed Central

    Ding, Nian-Hua; Li, Jian Jian; Sun, Lun-Quan

    2014-01-01

    Radiation-induced lung fibrosis (RILF) is a severe side effect of radiotherapy in lung cancer patients that presents as a progressive pulmonary injury combined with chronic inflammation and exaggerated organ repair. RILF is a major barrier to improving the cure rate and well-being of lung cancer patients because it limits the radiation dose that is required to effectively kill tumor cells and diminishes normal lung function. Although the exact mechanism is unclear, accumulating evidence suggests that various cells, cytokines and regulatory molecules are involved in the tissue reorganization and immune response modulation that occur in RILF. In this review, we will summarize the general symptoms, diagnostics, and current understanding of the cells and molecular factors that are linked to the signaling networks implicated in RILF. Potential approaches for the treatment of RILF will also be discussed. Elucidating the key molecular mediators that initiate and control the extent of RILF in response to therapeutic radiation may reveal additional targets for RILF treatment to significantly improve the efficacy of radiotherapy for lung cancer patients. PMID:23909719

  1. Radiation-induced sarcomas of the chest wall

    SciTech Connect

    Souba, W.W.; McKenna, R.J. Jr.; Meis, J.; Benjamin, R.; Raymond, A.K.; Mountain, C.F.

    1986-02-01

    Sixteen patients are presented who had sarcomas of the chest wall at a site where a prior malignancy had been irradiated. The first malignancies included breast cancer (ten cases), Hodgkin's disease (four cases), and others (two cases). Radiation doses varied from 4200 to 5500 R (mean, 4900 R). The latency period ranged from 5 to 28 years (mean, 13 years). The histologic types of the radiation-induced sarcomas were as follows: malignant fibrous histiocytoma, nine cases; osteosarcoma, six cases; and malignant mesenchymoma, one case. The only long-term survivor is alive and well 12 years after resection of a clavicular chondroblastic osteosarcoma. Three cases were recently diagnosed. Despite aggressive multimodality treatment, the remaining 13 patients have all died from their sarcomas (mean survival, 13.5 months). All patients have apparently been cured of their first malignancies. Chemotherapy was ineffective. No treatment, including forequarter amputation, appeared to palliate the patients with supraclavicular soft tissue sarcomas. Major chest wall resection offered good palliation for seven of eight patients with sarcomas arising in the sternum or lateral chest wall. Close follow-up is needed to detect signs of these sarcomas in the ever-increasing number of patients receiving therapeutic irradiation.

  2. Interleukin-32 Positively Regulates Radiation-Induced Vascular Inflammation

    SciTech Connect

    Kobayashi, Hanako; Yazlovitskaya, Eugenia M.; Lin, P. Charles

    2009-08-01

    Purpose: To study the role of interleukin-32 (IL-32), a novel protein only detected in human tissues, in ionizing radiation (IR)-induced vascular inflammation. Methods and Materials: Irradiated (0-6 Gy) human umbilical vein endothelial cells treated with or without various agents-a cytosolic phospholipase A2 (cPLA2) inhibitor, a cyclooxygenase-2 (Cox-2) inhibitor, or lysophosphatidylcholines (LPCs)-were used to assess IL-32 expression by Northern blot analysis and quantitative reverse transcriptase-polymerase chain reaction. Expression of cell adhesion molecules and leukocyte adhesion to endothelial cells using human acute monocytic leukemia cell line (THP-1) cells was also analyzed. Results: Ionizing radiation dramatically increased IL-32 expression in vascular endothelial cells through multiple pathways. Ionizing radiation induced IL-32 expression through nuclear factor {kappa}B activation, through induction of cPLA2 and LPC, as well as induction of Cox-2 and subsequent conversion of arachidonic acid to prostacyclin. Conversely, blocking nuclear factor {kappa}B, cPLA2, and Cox-2 activity impaired IR-induced IL-32 expression. Importantly, IL-32 significantly enhanced IR-induced expression of vascular cell adhesion molecules and leukocyte adhesion on endothelial cells. Conclusion: This study identifies IL-32 as a positive regulator in IR-induced vascular inflammation, and neutralization of IL-32 may be beneficial in protecting from IR-induced inflammation.

  3. Hyperbaric Oxygen Therapy for Radiation-Induced Cystitis and Proctitis

    SciTech Connect

    Oliai, Caspian; Fisher, Brandon; Jani, Ashish; Wong, Michael; Poli, Jaganmohan; Brady, Luther W.; Komarnicky, Lydia T.

    2012-11-01

    Purpose: To provide a retrospective analysis of the efficacy of hyperbaric oxygen therapy (HBOT) for treating hemorrhagic cystitis (HC) and proctitis secondary to pelvic- and prostate-only radiotherapy. Methods and Materials: Nineteen patients were treated with HBOT for radiation-induced HC and proctitis. The median age at treatment was 66 years (range, 15-84 years). The range of external-beam radiation delivered was 50.0-75.6 Gy. Bleeding must have been refractory to other therapies. Patients received 100% oxygen at 2.0 atmospheres absolute pressure for 90-120 min per treatment in a monoplace chamber. Symptoms were retrospectively scored according to the Late Effects of Normal Tissues-Subjective, Objective, Management, Analytic (LENT-SOMA) scale to evaluate short-term efficacy. Recurrence of hematuria/hematochezia was used to assess long-term efficacy. Results: Four of the 19 patients were lost to follow-up. Fifteen patients were evaluated and received a mean of 29.8 dives: 11 developed HC and 4 proctitis. All patients experienced a reduction in their LENT-SOMA score. After completion of HBOT, the mean LENT-SOMA score was reduced from 0.78 to 0.20 in patients with HC and from 0.66 to 0.26 in patients with proctitis. Median follow-up was 39 months (range, 7-70 months). No cases of hematuria were refractory to HBOT. Complete resolution of hematuria was seen in 81% (n = 9) and partial response in 18% (n = 2). Recurrence of hematuria occurred in 36% (n = 4) after a median of 10 months. Complete resolution of hematochezia was seen in 50% (n = 2), partial response in 25% (n = 1), and refractory bleeding in 25% (n = 1). Conclusions: Hyperbaric oxygen therapy is appropriate for radiation-induced HC once less time-consuming therapies have failed to resolve the bleeding. In these conditions, HBOT is efficacious in the short and long term, with minimal side effects.

  4. Organotypic culture in three dimensions prevents radiation-induced transformation in human lung epithelial cells

    NASA Astrophysics Data System (ADS)

    El-Ashmawy, Mariam; Coquelin, Melissa; Luitel, Krishna; Batten, Kimberly; Shay, Jerry W.

    2016-08-01

    The effects of radiation in two-dimensional (2D) cell culture conditions may not recapitulate tissue responses as modeled in three-dimensional (3D) organotypic culture. In this study, we determined if the frequency of radiation-induced transformation and cancer progression differed in 3D compared to 2D culture. Telomerase immortalized human bronchial epithelial cells (HBECs) with shTP53 and mutant KRas expression were exposed to various types of radiation (gamma, +H, 56Fe) in either 2D or 3D culture. After irradiation, 3D structures were dissociated and passaged as a monolayer followed by measurement of transformation, cell growth and expression analysis. Cells irradiated in 3D produced significantly fewer and smaller colonies in soft agar than their 2D-irradiated counterparts (gamma P = 0.0004 +H P = 0.049 56Fe P < 0.0001). The cell culture conditions did not affect cell killing, the ability of cells to survive in a colony formation assay, and proliferation rates after radiation—implying there was no selection against cells in or dissociated from 3D conditions. However, DNA damage repair and apoptosis markers were increased in 2D cells compared to 3D cells after radiation. Ideally, expanding the utility of 3D culture will allow for a better understanding of the biological consequences of radiation exposure.

  5. Organotypic culture in three dimensions prevents radiation-induced transformation in human lung epithelial cells

    PubMed Central

    El-Ashmawy, Mariam; Coquelin, Melissa; Luitel, Krishna; Batten, Kimberly; Shay, Jerry W.

    2016-01-01

    The effects of radiation in two-dimensional (2D) cell culture conditions may not recapitulate tissue responses as modeled in three-dimensional (3D) organotypic culture. In this study, we determined if the frequency of radiation-induced transformation and cancer progression differed in 3D compared to 2D culture. Telomerase immortalized human bronchial epithelial cells (HBECs) with shTP53 and mutant KRas expression were exposed to various types of radiation (gamma, +H, 56Fe) in either 2D or 3D culture. After irradiation, 3D structures were dissociated and passaged as a monolayer followed by measurement of transformation, cell growth and expression analysis. Cells irradiated in 3D produced significantly fewer and smaller colonies in soft agar than their 2D-irradiated counterparts (gamma P = 0.0004; +H P = 0.049; 56Fe P < 0.0001). The cell culture conditions did not affect cell killing, the ability of cells to survive in a colony formation assay, and proliferation rates after radiation—implying there was no selection against cells in or dissociated from 3D conditions. However, DNA damage repair and apoptosis markers were increased in 2D cells compared to 3D cells after radiation. Ideally, expanding the utility of 3D culture will allow for a better understanding of the biological consequences of radiation exposure. PMID:27539227

  6. Radiation induced destruction of thebaine, papaverine and noscapine in methanol

    NASA Astrophysics Data System (ADS)

    Kantoğlu, Ömer; Ergun, Ece

    2016-07-01

    The presence of methanol decreases the efficiency of radiation-induced decomposition of alkaloids in wastewater. Intermediate products were observed before the complete degradation of irradiated alkaloids. In order to identify the structure of the by-products and the formation pathway, thebaine, papaverine and noscapine solutions were prepared in pure methanol and irradiated using a 60Co gamma cell at absorbed doses of 0, 1, 3, 5, 7, 10, 30, 50 and 80 kGy. The dose-dependent alkaloid degradation and by-product formation were monitored by ESI mass spectrometer. Molecular structures of the by-products and reaction pathways were proposed. Oxygenated and methoxy group containing organic compounds was observed in the mass spectra of irradiated alkaloids. At initial dose values oxygenated by-products were formed due to the presence of dissolved oxygen in solutions. After the consumption of dissolved oxygen with radicals, the main mechanism was addition of solvent radicals to alkaloid structure. However, it was determined that alkaloids and by-products were completely degraded at doses higher than 50 kGy. The G-value and degradation efficiency of alkaloids were also evaluated.

  7. Pathogenesis and Prevention of Radiation-induced Myocardial Fibrosis

    PubMed

    Liu, Li Kun; Ouyang, Weiwei; Zhao, Xing; Su, Sheng Fa; Yang, Yan; Ding, Wen Jin; Luo, Da Xian; He, Zhi Xu; Lu, Bing

    2017-03-01

    Radiation therapy is one of the most important methods for the treatment of malignant tumors. However, in radiotherapy for thoracic tumors such as breast cancer, lung cancer, esophageal cancer, and mediastinal lymphoma, the heart, located in the mediastinum, is inevitably affected by the irradiation, leading to pericardial disease, myocardial fibrosis, coronary artery disease, valvular lesions, and cardiac conduction system injury, which are considered radiation-induced heart diseases. Delayed cardiac injury especially myocardial fibrosis is more prominent, and its incidence is as high as 20–80%. Myocardial fibrosis is the final stage of radiation-induced heart diseases, and it increases the stiffness of the myocardium and decreases myocardial systolic and diastolic function, resulting in myocardial electrical physiological disorder, arrhythmia, incomplete heart function, or even sudden death. This article reviews the pathogenesis and prevention of radiation-induced myocardial fibrosis for providing references for the prevention and treatment of radiation-induced myocardial fibrosis. Creative Commons Attribution License

  8. Radiation-induced charge trapping in bipolar base oxides

    SciTech Connect

    Fleetwood, D.M.; Riewe, L.C.; Witczak, Schrimpf, R.D.

    1996-03-01

    Capacitance-voltage and thermally stimulated current methods are used to investigate radiation induced charge trapping in bipolar base oxides. Results are compared with models of oxide and interface trap charge buildup at low electric fields.

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

    NASA Astrophysics Data System (ADS)

    Kennedy, Ann

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

  10. Protective effect of esculentoside A on radiation-induced dermatitis and fibrosis

    SciTech Connect

    Xiao Zhenyu; Su Ying; Yang Shanmin; Yin Liangjie; Wang Wei; Yi Yanghua; Fenton, Bruce M.; Zhang Lurong; Okunieff, Paul . E-mail: paul_okunieff@urmc.rochester.edu

    2006-07-01

    Purpose: To investigate the effect of esculentoside A (EsA) on radiation-induced cutaneous and fibrovascular toxicity and its possible molecular mechanisms, both in vivo and in vitro. Methods and Materials: Mice received drug intervention 18 hours before 30 Gy to the right hind leg. Alterations in several cytokines expressed in skin tissue 2 days after irradiation were determined by ELISA. Early skin toxicity was evaluated 3 to 4 weeks after irradiation by skin scoring, and both tissue contraction and expression of TGF-{beta}1 were determined for soft-tissue fibrosis 3 months after irradiation. In vitro, the effect of EsA on radiation-induced nitric oxide (NO) and cytokine production in different cell types was measured by application of 2, 4, and 8 Gy. Results: In vivo, EsA reduced levels of IL-1{alpha}, MCP-1, VEGF, and TGF-{beta}1 in cutaneous tissue and reduced soft-tissue toxicity. In vitro, EsA inhibited the IL-1{alpha} ordinarily produced after 4 Gy in A431 cells. In Raw264.7 cells, EsA reduced levels of IL-1{alpha}, IL-1{beta}, and NO production costimulated by radiation and lipopolysaccharide (LPS). In L-929 cells, EsA inhibited VEGF, TNF, and MCP-1 production at 2, 4, and 8 Gy. Conclusions: Esculentoside A protects soft tissues against radiation toxicity through inhibiting the production of several proinflammatory cytokines and inflammatory mediators in epithelial cells, macrophages, fibroblasts, and skin tissue.

  11. NLRP3 inflammasome activation mediates radiation-induced pyroptosis in bone marrow-derived macrophages

    PubMed Central

    Liu, Yan-gang; Chen, Ji-kuai; Zhang, Zi-teng; Ma, Xiu-juan; Chen, Yong-chun; Du, Xiu-ming; Liu, Hong; Zong, Ying; Lu, Guo-cai

    2017-01-01

    A limit to the clinical benefit of radiotherapy is not an incapacity to eliminate tumor cells but rather a limit on its capacity to do so without destroying normal tissue and inducing inflammation. Recent evidence reveals that the inflammasome is essential for mediating radiation-induced cell and tissue damage. In this study, using primary cultured bone marrow-derived macrophages (BMDM) and a mouse radiation model, we explored the role of NLRP3 inflammasome activation and the secondary pyroptosis underlying radiation-induced immune cell death. We observed an increasing proportion of pyroptosis and elevating Caspase-1 activation in 10 and 20 Gy radiation groups. Nlrp3 knock out significantly diminished the quantity of cleaved-Caspase-1 (p10) and IL-1β as well as the proportion of pyroptosis. Additionally, in vivo research shows that 9.5 Gy of radiation promotes Caspase-1 activation in marginal zone cells and induces death in mice, both of which can be significantly inhibited by knocking out Nlrp3. Thus, based on these findings, we conclude that the NLRP3 inflammasome activation mediates radiation-induced pyroptosis in BMDMs. Targeting NLRP3 inflammasome and pyroptosis may serve as effective strategies to diminish injury caused by radiation. PMID:28151471

  12. Systematic review of hyperbaric oxygen therapy for the treatment of radiation-induced skin necrosis.

    PubMed

    Borab, Zachary; Mirmanesh, Michael D; Gantz, Madeleine; Cusano, Alessandro; Pu, Lee L Q

    2017-04-01

    Every year, 1.2 million cancer patients receive radiation therapy in the United States. Late radiation tissue injury occurs in an estimated 5-15% of these patients. Tissue injury can include skin necrosis, which can lead to chronic nonhealing wounds. Despite many treatments available to help heal skin necrosis such as hyperbaric oxygen therapy, no clinical guidelines exist and evidence is lacking. The purpose of this review is to identify and comprehensively summarize studies published to date to evaluate the effectiveness of hyperbaric oxygen therapy for the treatment of radiation-induced skin necrosis. Adhering to PRISMA guidelines, a systematic review of currently published articles was performed, evaluating the use of hyperbaric oxygen to treat skin necrosis. Eight articles were identified, including one observational cohort, five case series, and two case reports. The articles describe changes in symptoms and alteration in wound healing of radiation-induced skin necrosis after treatment with hyperbaric oxygen therapy. Hyperbaric oxygen therapy is a safe intervention with promising outcomes; however, additional evidence is needed to endorse its application as a relevant therapy in the treatment of radiation-induced skin necrosis.

  13. The potential influence of radiation-induced microenvironments in neoplastic progression

    NASA Technical Reports Server (NTRS)

    Barcellos-Hoff, M. H.; Chatterjee, A. (Principal Investigator)

    1998-01-01

    Ionizing radiation is a complete carcinogen, able both to initiate and promote neoplastic progression and is a known carcinogen of human and murine mammary gland. Tissue response to radiation is a composite of genetic damage, cell death and induction of new gene expression patterns. Although DNA damage is believed to initiate carcinogenesis, the contribution of these other aspects of radiation response are beginning to be explored. Our studies demonstrate that radiation elicits rapid and persistent global alterations in the mammary gland microenvironment. We postulate that radiation-induced microenvironments may affect epithelial cells neoplastic transformation by altering their number or susceptibility. Alternatively, radiation induced microenvironments may exert a selective force on initiated cells and/or be conducive to progression. A key impetus for these studies is the possibility that blocking these events could be a strategy to interrupt neoplastic progression.

  14. Epigenetic regulation of diacylglycerol kinase alpha promotes radiation-induced fibrosis.

    PubMed

    Weigel, Christoph; Veldwijk, Marlon R; Oakes, Christopher C; Seibold, Petra; Slynko, Alla; Liesenfeld, David B; Rabionet, Mariona; Hanke, Sabrina A; Wenz, Frederik; Sperk, Elena; Benner, Axel; Rösli, Christoph; Sandhoff, Roger; Assenov, Yassen; Plass, Christoph; Herskind, Carsten; Chang-Claude, Jenny; Schmezer, Peter; Popanda, Odilia

    2016-03-11

    Radiotherapy is a fundamental part of cancer treatment but its use is limited by the onset of late adverse effects in the normal tissue, especially radiation-induced fibrosis. Since the molecular causes for fibrosis are largely unknown, we analyse if epigenetic regulation might explain inter-individual differences in fibrosis risk. DNA methylation profiling of dermal fibroblasts obtained from breast cancer patients prior to irradiation identifies differences associated with fibrosis. One region is characterized as a differentially methylated enhancer of diacylglycerol kinase alpha (DGKA). Decreased DNA methylation at this enhancer enables recruitment of the profibrotic transcription factor early growth response 1 (EGR1) and facilitates radiation-induced DGKA transcription in cells from patients later developing fibrosis. Conversely, inhibition of DGKA has pronounced effects on diacylglycerol-mediated lipid homeostasis and reduces profibrotic fibroblast activation. Collectively, DGKA is an epigenetically deregulated kinase involved in radiation response and may serve as a marker and therapeutic target for personalized radiotherapy.

  15. Epigenetic regulation of diacylglycerol kinase alpha promotes radiation-induced fibrosis

    PubMed Central

    Weigel, Christoph; Veldwijk, Marlon R.; Oakes, Christopher C.; Seibold, Petra; Slynko, Alla; Liesenfeld, David B.; Rabionet, Mariona; Hanke, Sabrina A.; Wenz, Frederik; Sperk, Elena; Benner, Axel; Rösli, Christoph; Sandhoff, Roger; Assenov, Yassen; Plass, Christoph; Herskind, Carsten; Chang-Claude, Jenny; Schmezer, Peter; Popanda, Odilia

    2016-01-01

    Radiotherapy is a fundamental part of cancer treatment but its use is limited by the onset of late adverse effects in the normal tissue, especially radiation-induced fibrosis. Since the molecular causes for fibrosis are largely unknown, we analyse if epigenetic regulation might explain inter-individual differences in fibrosis risk. DNA methylation profiling of dermal fibroblasts obtained from breast cancer patients prior to irradiation identifies differences associated with fibrosis. One region is characterized as a differentially methylated enhancer of diacylglycerol kinase alpha (DGKA). Decreased DNA methylation at this enhancer enables recruitment of the profibrotic transcription factor early growth response 1 (EGR1) and facilitates radiation-induced DGKA transcription in cells from patients later developing fibrosis. Conversely, inhibition of DGKA has pronounced effects on diacylglycerol-mediated lipid homeostasis and reduces profibrotic fibroblast activation. Collectively, DGKA is an epigenetically deregulated kinase involved in radiation response and may serve as a marker and therapeutic target for personalized radiotherapy. PMID:26964756

  16. Anti-apoptotic peptides protect against radiation-induced cell death.

    PubMed

    McConnell, Kevin W; Muenzer, Jared T; Chang, Kathy C; Davis, Chris G; McDunn, Jonathan E; Coopersmith, Craig M; Hilliard, Carolyn A; Hotchkiss, Richard S; Grigsby, Perry W; Hunt, Clayton R

    2007-04-06

    The risk of terrorist attacks utilizing either nuclear or radiological weapons has raised concerns about the current lack of effective radioprotectants. Here it is demonstrated that the BH4 peptide domain of the anti-apoptotic protein Bcl-xL can be delivered to cells by covalent attachment to the TAT peptide transduction domain (TAT-BH4) and provide protection in vitro and in vivo from radiation-induced apoptotic cell death. Isolated human lymphocytes treated with TAT-BH4 were protected against apoptosis following exposure to 15Gy radiation. In mice exposed to 5Gy radiation, TAT-BH4 treatment protected splenocytes and thymocytes from radiation-induced apoptotic cell death. Most importantly, in vivo radiation protection was observed in mice whether TAT-BH4 treatment was given prior to or after irradiation. Thus, by targeting steps within the apoptosis signaling pathway it is possible to develop post-exposure treatments to protect radio-sensitive tissues.

  17. The potential influence of radiation-induced microenvironments in neoplastic progression

    NASA Technical Reports Server (NTRS)

    Barcellos-Hoff, M. H.; Chatterjee, A. (Principal Investigator)

    1998-01-01

    Ionizing radiation is a complete carcinogen, able both to initiate and promote neoplastic progression and is a known carcinogen of human and murine mammary gland. Tissue response to radiation is a composite of genetic damage, cell death and induction of new gene expression patterns. Although DNA damage is believed to initiate carcinogenesis, the contribution of these other aspects of radiation response are beginning to be explored. Our studies demonstrate that radiation elicits rapid and persistent global alterations in the mammary gland microenvironment. We postulate that radiation-induced microenvironments may affect epithelial cells neoplastic transformation by altering their number or susceptibility. Alternatively, radiation induced microenvironments may exert a selective force on initiated cells and/or be conducive to progression. A key impetus for these studies is the possibility that blocking these events could be a strategy to interrupt neoplastic progression.

  18. Radar detection of radiation-induced ionization in air

    DOEpatents

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

    2015-07-21

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

  19. Selenoprotein P Inhibits Radiation-Induced Late Reactive Oxygen Species Accumulation and Normal Cell Injury

    SciTech Connect

    Eckers, Jaimee C.; Kalen, Amanda L.; Xiao, Wusheng; Sarsour, Ehab H.; Goswami, Prabhat C.

    2013-11-01

    Purpose: Radiation is a common mode of cancer therapy whose outcome is often limited because of normal tissue toxicity. We have shown previously that the accumulation of radiation-induced late reactive oxygen species (ROS) precedes cell death, suggesting that metabolic oxidative stress could regulate cellular radiation response. The purpose of this study was to investigate whether selenoprotein P (SEPP1), a major supplier of selenium to tissues and an antioxidant, regulates late ROS accumulation and toxicity in irradiated normal human fibroblasts (NHFs). Methods and Materials: Flow cytometry analysis of cell viability, cell cycle phase distribution, and dihydroethidium oxidation, along with clonogenic assays, were used to measure oxidative stress and toxicity. Human antioxidant mechanisms array and quantitative real-time polymerase chain reaction assays were used to measure gene expression during late ROS accumulation in irradiated NHFs. Sodium selenite addition and SEPP1 overexpression were used to determine the causality of SEPP1 regulating late ROS accumulation and toxicity in irradiated NHFs. Results: Irradiated NHFs showed late ROS accumulation (4.5-fold increase from control; P<.05) that occurs after activation of the cell cycle checkpoint pathways and precedes cell death. The mRNA levels of CuZn- and Mn-superoxide dismutase, catalase, peroxiredoxin 3, and thioredoxin reductase 1 increased approximately 2- to 3-fold, whereas mRNA levels of cold shock domain containing E1 and SEPP1 increased more than 6-fold (P<.05). The addition of sodium selenite before the radiation treatment suppressed toxicity (45%; P<.05). SEPP1 overexpression suppressed radiation-induced late ROS accumulation (35%; P<.05) and protected NHFs from radiation-induced toxicity (58%; P<.05). Conclusion: SEPP1 mitigates radiation-induced late ROS accumulation and normal cell injury.

  20. Selenoprotein P inhibits radiation-induced late reactive oxygen species accumulation and normal cell injury.

    PubMed

    Eckers, Jaimee C; Kalen, Amanda L; Xiao, Wusheng; Sarsour, Ehab H; Goswami, Prabhat C

    2013-11-01

    Radiation is a common mode of cancer therapy whose outcome is often limited because of normal tissue toxicity. We have shown previously that the accumulation of radiation-induced late reactive oxygen species (ROS) precedes cell death, suggesting that metabolic oxidative stress could regulate cellular radiation response. The purpose of this study was to investigate whether selenoprotein P (SEPP1), a major supplier of selenium to tissues and an antioxidant, regulates late ROS accumulation and toxicity in irradiated normal human fibroblasts (NHFs). Flow cytometry analysis of cell viability, cell cycle phase distribution, and dihydroethidium oxidation, along with clonogenic assays, were used to measure oxidative stress and toxicity. Human antioxidant mechanisms array and quantitative real-time polymerase chain reaction assays were used to measure gene expression during late ROS accumulation in irradiated NHFs. Sodium selenite addition and SEPP1 overexpression were used to determine the causality of SEPP1 regulating late ROS accumulation and toxicity in irradiated NHFs. Irradiated NHFs showed late ROS accumulation (4.5-fold increase from control; P<.05) that occurs after activation of the cell cycle checkpoint pathways and precedes cell death. The mRNA levels of CuZn- and Mn-superoxide dismutase, catalase, peroxiredoxin 3, and thioredoxin reductase 1 increased approximately 2- to 3-fold, whereas mRNA levels of cold shock domain containing E1 and SEPP1 increased more than 6-fold (P<.05). The addition of sodium selenite before the radiation treatment suppressed toxicity (45%; P<.05). SEPP1 overexpression suppressed radiation-induced late ROS accumulation (35%; P<.05) and protected NHFs from radiation-induced toxicity (58%; P<.05). SEPP1 mitigates radiation-induced late ROS accumulation and normal cell injury. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. Hesperidin as Radioprotector against Radiation-induced Lung Damage in Rat: A Histopathological Study

    PubMed Central

    Haddadi, Gholam Hassan; Rezaeyan, Abolhasan; Mosleh-Shirazi, Mohammad Amin; Hosseinzadeh, Massood; Fardid, Reza; Najafi, Masoud; Salajegheh, Ashkan

    2017-01-01

    Reactive oxygen species (ROS) are generated by ionizing radiation, and one of the organs commonly affected by ROS is the lung. Radiation-induced lung injury including pneumonia and lung fibrosis is a dose-limiting factor in radiotherapy (RT) of patients with thorax irradiation. Administration of antioxidants has been proved to protect against ROS. The present study was aimed to assess the protective effect of hesperidin (HES) against radiation-induced lung injury of male rats. Fifty rats were divided into three groups. G1: Received no HES and radiation (sham). G2: Underwent γ-irradiation to the thorax. G3: Received HES and underwent γ-irradiation. The rats were exposed to a single dose of 18 Gy using cobalt-60 unit and were administered HES (100 mg/kg) for 7 days before irradiation. Histopathological analysis was performed 24 h and 8 weeks after RT. Histopathological results in 24 h showed radiation-induced inflammation and presence of more inflammatory cells as compared to G1 (P < 0.05). Administration of HES significantly decreased such an effect when compared to G2 (P < 0.05). Histopathological evaluation in 8 weeks showed a significant increase in mast cells, inflammation, inflammatory cells, alveolar thickness, vascular thickness, pulmonary edema, and fibrosis in G2 when compared to G1 (P < 0.05). HES significantly decreased inflammatory response, fibrosis, and mast cells when compared to G2 (P < 0.05). Administration of HES resulted in decreased radiation pneumonitis and radiation fibrosis in the lung tissue. Thus, the present study showed HES to be an efficient radioprotector against radiation-induced damage in the lung of tissue rats. PMID:28405105

  2. Epigenetic determinants of space radiation-induced cognitive dysfunction

    PubMed Central

    Acharya, Munjal M.; Baddour, Al Anoud D.; Kawashita, Takumi; Allen, Barrett D.; Syage, Amber R.; Nguyen, Thuan H.; Yoon, Nicole; Giedzinski, Erich; Yu, Liping; Parihar, Vipan K.; Baulch, Janet E.

    2017-01-01

    Among the dangers to astronauts engaging in deep space missions such as a Mars expedition is exposure to radiations that put them at risk for severe cognitive dysfunction. These radiation-induced cognitive impairments are accompanied by functional and structural changes including oxidative stress, neuroinflammation, and degradation of neuronal architecture. The molecular mechanisms that dictate CNS function are multifaceted and it is unclear how irradiation induces persistent alterations in the brain. Among those determinants of cognitive function are neuroepigenetic mechanisms that translate radiation responses into altered gene expression and cellular phenotype. In this study, we have demonstrated a correlation between epigenetic aberrations and adverse effects of space relevant irradiation on cognition. In cognitively impaired irradiated mice we observed increased 5-methylcytosine and 5-hydroxymethylcytosine levels in the hippocampus that coincided with increased levels of the DNA methylating enzymes DNMT3a, TET1 and TET3. By inhibiting methylation using 5-iodotubercidin, we demonstrated amelioration of the epigenetic effects of irradiation. In addition to protecting against those molecular effects of irradiation, 5-iodotubercidin restored behavioral performance to that of unirradiated animals. The findings of this study establish the possibility that neuroepigenetic mechanisms significantly contribute to the functional and structural changes that affect the irradiated brain and cognition. PMID:28220892

  3. Parathyroid hormone attenuates radiation-induced increases in collagen crosslink ratio at periosteal surfaces of mouse tibia.

    PubMed

    Oest, Megan E; Gong, Bo; Esmonde-White, Karen; Mann, Kenneth A; Zimmerman, Nicholas D; Damron, Timothy A; Morris, Michael D

    2016-05-01

    As part of our ongoing efforts to understand underlying mechanisms contributing to radiation-associated bone fragility and to identify possible treatments, we evaluated the longitudinal effects of parathyroid hormone (PTH) treatment on bone quality in a murine model of limited field irradiation. We hypothesized PTH would mitigate radiation-induced changes in the chemical composition and structure of bone, as measured by microscope-based Raman spectroscopy. We further hypothesized that collagen crosslinking would be especially responsive to PTH treatment. Raman spectroscopy was performed on retrieved tibiae (6-7/group/time point) to quantify metrics associated with bone quality, including: mineral-to-matrix ratio, carbonate-to-phosphate ratio, mineral crystallinity, collagen crosslink (trivalent:divalent) ratio, and the mineral and matrix depolarization ratios. Irradiation disrupted the molecular structure and orientation of bone collagen, as evidenced by a higher collagen crosslink ratio and lower matrix depolarization ratio (vs. non-irradiated control bones), persisting until 12weeks post-irradiation. Radiation transiently affected the mineral phase, as evidenced by increased mineral crystallinity and mineral-to-matrix ratio at 4weeks compared to controls. Radiation decreased bone mineral depolarization ratios through 12weeks, indicating increased mineral alignment. PTH treatment partially attenuated radiation-induced increases in collagen crosslink ratio, but did not restore collagen or mineral alignment. These post-radiation matrix changes are consistent with our previous studies of radiation damage to bone, and suggest that the initial radiation damage to bone matrix has extensive effects on the quality of tissue deposited thereafter. In addition to maintaining bone quality, preventing initial radiation damage to the bone matrix (i.e. crosslink ratio, matrix orientation) may be critical to preventing late-onset fragility fractures.

  4. Clinical and dosimetric factors of radiation-induced esophageal injury: Radiation-induced esophageal toxicity

    PubMed Central

    Qiao, Wen-Bo; Zhao, Yan-Hui; Zhao, Yan-Bin; Wang, Rui-Zhi

    2005-01-01

    AIM: To analyze the clinical and dosimetric predictive factors for radiation-induced esophageal injury in patients with non-small-cell lung cancer (NSCLC) during three-dimensional conformal radiotherapy (3D-CRT). METHODS: We retrospectively analyzed 208 consecutive patients (146 men and 62 women) with NSCLC treated with 3D-CRT. The median age of the patients was 64 years (range 35-87 years). The clinical and treatment parameters including gender, age, performance status, sequential chemotherapy, concurrent chemotherapy, presence of carinal or subcarinal lymph nodes, pretreatment weight loss, mean dose to the entire esophagus, maximal point dose to the esophagus, and percentage of volume of esophagus receiving >55 Gy were studied. Clinical and dosimetric factors for radiation-induced acute and late grade 3-5 esophageal injury were analyzed according to Radiation Therapy Oncology Group (RTOG) criteria. RESULTS: Twenty-five (12%) of the two hundred and eight patients developed acute or late grade 3-5 esophageal injury. Among them, nine patients had both acute and late grade 3-5 esophageal injury, two died of late esophageal perforation. Concurrent chemotherapy and maximal point dose to the esophagus ≥60 Gy were significantly associated with the risk of grade 3-5 esophageal injury. Fifty-four (26%) of the two hundred and eight patients received concurrent chemotherapy. Among them, 25 (46%) developed grade 3-5 esophageal injury (P = 0.0001<0.01). However, no grade 3-5 esophageal injury occurred in patients who received a maximal point dose to the esophagus <60 Gy (P = 0.0001<0.01). CONCLUSION: Concurrent chemotherapy and the maximal esophageal point dose ≥60 Gy are significantly associated with the risk of grade 3-5 esophageal injury in patients with NSCLC treated with 3D-CRT. PMID:15849822

  5. Optical-Based Analysis of Soft Tissue Structures

    PubMed Central

    Goth, Will; Lesicko, John; Sacks, Michael S.; Tunnell, James W.

    2017-01-01

    Fibrous structures are an integral and dynamic feature of soft biological tissues that are directly related to the tissues’ condition and function. A greater understanding of mechanical tissue behavior can be gained through quantitative analyses of structure alone, as well as its integration into computational models of soft tissue function. Histology and other nonoptical techniques have traditionally dominated the field of tissue imaging, but they are limited by their invasiveness, inability to provide resolution on the micrometer scale, and dynamic information. Recent advances in optical modalities can provide higher resolution, less invasive imaging capabilities, and more quantitative measurements. Here we describe contemporary optical imaging techniques with respect to their suitability in the imaging of tissue structure, with a focus on characterization and implementation into subsequent modeling efforts. We outline the applications and limitations of each modality and discuss the overall shortcomings and future directions for optical imaging of soft tissue structure. PMID:27420574

  6. Mechanistic micro-structural theory of soft tissues growth and remodeling: tissues with unidirectional fibers.

    PubMed

    Lanir, Yoram

    2015-04-01

    A new mechanistic theory was developed for soft tissues growth and remodeling (G&R). The theory considers tissues with unidirectional fibers. It is based on the loading-dependent local turnover events of each constituent and on the resulting evolution of the tissue micro-structure, the tissue dimensions and its mechanical properties. The theory incorporates the specific mechanical properties and turnover kinetics of each constituent, thereby establishing a general framework which can serve for future integration of additional mechanisms involved in G&R. The feasibility of the theory was examined by considering a specific realization of tissues with one fibrous constituent (collagen fibers), assuming a specific loading-dependent first-order fiber's turnover kinetics and the fiber's deposition characteristics. The tissue was subjected to a continuous constant rate growth. Model parameters were adopted from available data. The resulting predictions show qualitative agreement with a number of well-known features of tissues including the fibers' non-uniform recruitment density distribution, the associated tissue convex nonlinear stress-stretch relationship, and the development of tissue pre-stretch and pre-stress states. These results show that mechanistic micro-structural modeling of soft tissue G&R based on first principles can successfully capture the evolution of observed tissues' structure and size, and of their associated mechanical properties.

  7. Modification of polyethylene by radiation-induced graft polymerization of acrylic acid

    NASA Astrophysics Data System (ADS)

    Sidorova, L. P.; Aliev, A. D.; Zlobin, V. B.; Aliev, R. E.; Chalykh, A. E.; Kabanov, V. Ya.

    The kinetics investigation of the radiation-induced graft polymerization of acrylic acid onto low density polyethylene by direct method in aqueous solution in the presence of Mohr's salt, was performed. The technique of the contrasting of polyacrylic acid (PAA) graft layer was worked out by Ag +-ions. The structural and morphological peculiarities of grafted copolymers of PE with PAA were determined by the method of electron probe, and X-ray microanalysis by means of the electron microscopy.

  8. Radiation-induced thymine base damage in replicating chromatin

    SciTech Connect

    Warters, R.L.; Childers, T.J.

    1982-06-01

    The efficiency of radiation-induced production of 5',6'-dihydroxydihydrothymine (t/sup ..gamma../)-type damage was determined in nascent and mature chromatin DNA for the dose range of 50 to 150 krad. These large doses affected neither the total fraction of nuclear DNA in chromatin subunits nor the nucleosome subunit repeat length. The DNA in nascent chromatin, however, was found to be 3.3 times more sensitive than mature chromatin DNA to ..gamma..-ray (/sup 137/Cs)-induced t/sup ..gamma../-type damage, while thymine damage of this type was uniformly distributed in the nucleosomal DNA of mature chromatin (i.e., in the nucleosome core and spacer DNA). The half-time for the transition of nascent DNA sensitivity to mature chromatin DNA sensitivity levels was the same as the half-time at 37/sup 0/C for the maturation of nascent into mature chromatin structure. The rate at which nascent chromatin matured was unaffected by radiation doses as large as 150 krad. The most logical explanation for the greater sensitivity of nascent DNA to radiation is the decreased concentration of histone chromosomal proteins in nascent chromatin.

  9. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

    NASA Astrophysics Data System (ADS)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B.; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  10. Intraperitoneal administration of chitosan/DsiRNA nanoparticles targeting TNFα prevents radiation-induced fibrosis.

    PubMed

    Nawroth, Isabel; Alsner, Jan; Behlke, Mark A; Besenbacher, Flemming; Overgaard, Jens; Howard, Kenneth A; Kjems, Jørgen

    2010-10-01

    One of the most common and dose-limiting long-term adverse effects of radiation therapy is radiation-induced fibrosis (RIF), which is characterized by restricted tissue flexibility, reduced compliance or strictures, pain and in severe cases, ulceration and necrosis. Several strategies have been proposed to ameliorate RIF but presently no effective one is available. Recent studies have reported that tumor necrosis factor-α (TNFα) plays a role in fibrogenesis. Male CDF1 mice were radiated with a single dose of 45 Gy. Chitosan/DsiRNA nanoparticles targeting TNFα were intraperitoneal injected and late radiation-induced fibrosis (RIF) was assessed using a modification of the leg contracture model. Additionally, the effect of these nanoparticles on tumor growth and tumor control probability in the absence of radiation was examined in a C3H mammary carcinoma model. We show in this work, that targeting TNFα in macrophages by intraperitoneal administration of chitosan/DsiRNA nanoparticles completely prevented radiation-induced fibrosis in CDF1 mice without revealing any cytotoxic side-effects after a long-term administration. Furthermore, such TNFα targeting was selective without any significant influence on tumor growth or irradiation-related tumor control probability. This nanoparticle-based RNAi approach represents a novel approach to prevent RIF with potential application to improve clinical radiation therapeutic strategies. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  11. The chemokine, CCL3, and its receptor, CCR1, mediate thoracic radiation-induced pulmonary fibrosis.

    PubMed

    Yang, Xuebin; Walton, William; Cook, Donald N; Hua, Xiaoyang; Tilley, Stephen; Haskell, Christopher A; Horuk, Richard; Blackstock, A William; Kirby, Suzanne L

    2011-07-01

    Patients receiving thoracic radiation often develop pulmonary injury and fibrosis. Currently, there are no effective measures to prevent or treat these conditions. We tested whether blockade of the chemokine, CC chemokine ligand (CCL) 3, and its receptors, CC chemokine receptor (CCR) 1 and CCR5, can prevent radiation-induced lung inflammation and fibrosis. C57BL/6J mice received thoracic radiation, and the interaction of CCL3 with CCR1 or CCR5 was blocked using genetic techniques, or by pharmacologic intervention. Lung inflammation was assessed by histochemical staining of lung tissue and by flow cytometry. Fibrosis was measured by hydroxyproline assays and collagen staining, and lung function was studied by invasive procedures. Irradiated mice lacking CCL3 or its receptor, CCR1, did not develop the lung inflammation, fibrosis, and decline in lung function seen in irradiated wild-type mice. Pharmacologic treatment of wild-type mice with a small molecule inhibitor of CCR1 also prevented lung inflammation and fibrosis. By contrast, mice lacking CCR5 were not protected from radiation-induced injury and fibrosis. The selective interaction of CCL3 with its receptor, CCR1, is critical for radiation-induced lung inflammation and fibrosis, and these conditions can be largely prevented by a small molecule inhibitor of CCR1.

  12. The inflammasome accelerates radiation-induced lung inflammation and fibrosis in mice.

    PubMed

    Sohn, Sung-Hwa; Lee, Ji Min; Park, Soojin; Yoo, Hyun; Kang, Jeong Wook; Shin, Dasom; Jung, Kyung-Hwa; Lee, Yun-Sil; Cho, Jaeho; Bae, Hyunsu

    2015-03-01

    Although lung inflammation and fibrosis are well-documented dose-limiting side effects of lung irradiation, the mechanisms underlying these pathologies are unknown. An improved mechanistic understanding of radiation-induced pneumonitis is a prerequisite for the development of more effective radiotherapy; this was the rationale for the current study. Mouse lungs were focally irradiated with 75 Gy. The numbers of neutrophils, lymphocytes, macrophages, and total cells in the bronchoalveolar lavage fluid were counted, and pro-inflammatory cytokine levels were measured. Histological analysis and immunohistochemical staining for Tgf-β1 and Cd68 (a macrophage-specific protein) was also performed. After irradiation, mice developed pneumonitis, and exhibited higher numbers of neutrophils, lymphocytes, eosinophils, macrophages, and total cells compared to controls. In addition, inflammasome (Nlrp3, and caspase 1, Il1a, and Il1β), adhesion molecule (Vcam1), and cytokine (Il6) genes were significantly upregulated in the IR group. Cd68 and Tgfb1 proteins were significantly increased after irradiation. Upregulation of Cd68 and Tgfb1 correlates with the onset of radiation-induced pneumonitis and fibrosis. In addition, radiation-induced pneumonitis and fibrosis are accompanied by upregulation of phenotypic markers of inflammasome activity. Our findings have implications for the onset and exacerbation of damage in normal lung tissue. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Mitigation of whole-body gamma radiation-induced damages by Clerodendron infortunatum in mammalian organisms.

    PubMed

    Chacko, Tiju; Menon, Aditya; Majeed, Teeju; Nair, Sivaprabha V; John, Nithu Sara; Nair, Cherupally Krishnan Krishnan

    2016-11-17

    Several phytoceuticals and extracts of medicinal plants are reported to mitigate deleterious effects of ionizing radiation. The potential of hydro-alcoholic extract of Clerodendron infortunatum (CIE) for providing protection to mice exposed to gamma radiation was investigated. Oral administration of CIE bestowed a survival advantage to mice exposed to lethal doses of gamma radiation. Radiation-induced depletion of the total blood count and bone marrow cellularity were prevented by treatment with CIE. Damage to the cellular DNA (as was evident from the comet assay and the micronucleus index) was also found to be decreased upon CIE administration. Radiation-induced damages to intestinal crypt cells was also reduced by CIE. Studies on gene expression in intestinal cells revealed that there was a marked increase in the Bax/Bcl-2 ratio in mice exposed to whole-body 4 Gy gamma radiation, and that administration of CIE resulted in significant lowering of this ratio, suggestive of reduction of radiation-induced apoptosis. Also, in the intestinal tissue of irradiated animals, following CIE treatment, levels of expression of the DNA repair gene Atm were found to be elevated, and there was reduction in the expression of the inflammatory Cox-2 gene. Thus, our results suggest a beneficial use of Clerodendron infortunatum for mitigating radiation toxicity.

  14. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments.

    PubMed

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  15. The role of secretory granules in radiation-induced dysfunction of rat salivary glands

    SciTech Connect

    Peter, B.; Van Waarde, M.A.W.H.; Konings, A.W.T.; Vissink, A. |; `s-Gravenmade, E.J.

    1995-02-01

    To investigate the possible role of secretory granules in radiation-induced salivary gland dysfunction, rats were pretreated with isoproterenol (5 mg/kg intraperitoneally) to degranulate salivary gland acini. At maximal depletion, salivary glands were locally irradiated with a single dose of 15 Gy of X rays. Parotid and submandibular/sublingual saliva samples were collected before and 1-10 days after irradiation. The lag phase, flow rate, concentrations of potassium and sodium, and amylase secretion were determined. Sham-treated, isoproterenol-treated and irradiated animals provided reference data. In the parotid gland, but not in the submandibular gland, protection against radiation-induced changes in flow rate and composition of saliva occurred after pretreatment with isoproterenol. Combining morphological data from a previous study with data from the current study, it is suggested that improvement of parotid gland function is attributed predominantly to a proliferative stimulus on acinar cells by isoproterenol and not to its degranulation effect. After pretreatment with isoproterenol, an earlier expression of radiation-induced acinar cell damage leading to death was observed, followed by a faster tissue recovery. Thus the proliferative stimulus on acinar cells may accelerate the unmasking of latent lethal damage, resulting in the earlier replacement of dead cells by new, functionally intact cells. 33 refs., 2 figs.

  16. Effects of NOX1 on fibroblastic changes of endothelial cells in radiation-induced pulmonary fibrosis

    PubMed Central

    CHOI, SEO-HYUN; KIM, MISEON; LEE, HAE-JUNE; KIM, EUN-HO; KIM, CHUN-HO; LEE, YOON-JIN

    2016-01-01

    Lung fibrosis is a major complication in radiation-induced lung damage following thoracic radiotherapy, while the underlying mechanism has remained to be elucidated. The present study performed immunofluorescence and immunoblot assays on irradiated human pulmonary artery endothelial cells (HPAECs) with or without pre-treatment with VAS2870, a novel NADPH oxidase (NOX) inhibitor, or small hairpin (sh)RNA against NOX1, -2 or -4. VAS2870 reduced the cellular reactive oxygen species content induced by 5 Gy radiation in HPAECs and inhibited phenotypic changes in fibrotic cells, including increased alpha smooth muscle actin and vimentin, and decreased CD31 and vascular endothelial cadherin expression. These fibrotic changes were significantly inhibited by treatment with NOX1 shRNA, but not by NOX2 or NOX4 shRNA. Next, the role of NOX1 in pulmonary fibrosis development was assessed in the lung tissues of C57BL/6J mice following thoracic irradiation using trichrome staining. Administration of an NOX1-specific inhibitor suppressed radiation-induced collagen deposition and fibroblastic changes in the endothelial cells (ECs) of these mice. The results suggested that radiation-induced pulmonary fibrosis may be efficiently reduced by specific inhibition of NOX1, an effect mediated by reduction of fibrotic changes of ECs. PMID:27053172

  17. Radiation-induced trismus in the ARTSCAN head and neck trial.

    PubMed

    Lindblom, Ulrika; Gärskog, Ola; Kjellén, Elisabeth; Laurell, Göran; Levring Jäghagen, Eva; Wahlberg, Peter; Zackrisson, Björn; Nilsson, Per

    2014-05-01

    Trismus, a well-known sequelae after treatment of head and neck cancer, decreases a patient's oral function and quality of life. The main objectives of this study were to: 1) investigate the long-term prevalence of radiation-induced trismus in patients treated for head and neck cancer according to two different fractionation schedules; and 2) model a dose-response relationship for trismus. Patients were recruited from the Swedish ARTSCAN trial, a prospective randomised multicentre study comparing conventional and accelerated fractionation. A total of 124 patients agreed to a clinical ENT examination 21-127 months (median 66 months) after beginning radiation therapy. Trismus-related scores were assessed using the EORTC H&N35 Quality of Life questionnaire. The TheraBite(®) range of motion scale was used to measure maximal interincisal distance. The dose-response relationship for structures important for mastication and the temporomandibular joints was investigated by normal tissue complication probability modelling. No significant differences in patient-reported trismus or maximal interincisal distance were found between the two trial arms. Patient-reported moderate to high scores regarding trismus increased from 3% at the start of radiation therapy to 25% at the long-term follow-up. Maximal interincisal distance correlated significantly with patient-reported scores of trismus. The best dose-response fit to the endpoint data was found for the dose to the ipsilateral masseter. Trismus is a persistent complication after radiotherapy with 3D-conformal radiation therapy. We found no difference between the severity and prevalence of trismus between conventional and accelerated fractionation, but a significant correlation between the absorbed dose to the mastication structures and opening of the mouth. Further prospective studies may determine whether a reduced dose to structures important for mastication using intensity-modulated radiation therapy will reduce problems

  18. Vitamin D Deficiency Is Associated With the Severity of Radiation-Induced Proctitis in Cancer Patients

    SciTech Connect

    Ghorbanzadeh-Moghaddam, Amir; Gholamrezaei, Ali; Hemati, Simin

    2015-07-01

    Purpose: Radiation-induced injury to normal tissues is a common complication of radiation therapy in cancer patients. Considering the role of vitamin D in mucosal barrier hemostasis and inflammatory responses, we investigated whether vitamin D deficiency is associated with the severity of radiation-induced acute proctitis in cancer patients. Methods and Materials: This prospective observational study was conducted in cancer patients referred for pelvic radiation therapy. Serum concentration of 25-hydroxyvitamin D was measured before radiation therapy. Vitamin D deficiency was defined as 25-hydroxyvitamin D concentrations of <35 nmol/L and <40 nmol/L in male and female patients, respectively, based on available normative data. Acute proctitis was assessed after 5 weeks of radiation therapy (total received radiation dose of 50 Gy) and graded from 0 to 4 using Radiation Therapy Oncology Group (RTOG) criteria. Results: Ninety-eight patients (57.1% male) with a mean age of 62.8 ± 9.1 years were studied. Vitamin D deficiency was found in 57 patients (58.1%). Symptoms of acute proctitis occurred in 72 patients (73.4%) after radiation therapy. RTOG grade was significantly higher in patients with vitamin D deficiency than in normal cases (median [interquartile range] of 2 [0.5-3] vs 1 [0-2], P=.037). Vitamin D deficiency was associated with RTOG grade of ≥2, independent of possible confounding factors; odds ratio (95% confidence interval) = 3.07 (1.27-7.50), P=.013. Conclusions: Vitamin D deficiency is associated with increased severity of radiation-induced acute proctitis. Investigating the underlying mechanisms of this association and evaluating the effectiveness of vitamin D therapy in preventing radiation-induced acute proctitis is warranted.

  19. A selenocysteine derivative therapy affects radiation-induced pneumonitis in the mouse.

    PubMed

    Kunwar, Amit; Jain, V K; Priyadarsini, K I; Haston, Christina K

    2013-10-01

    The mechanism leading to the radiation-induced lung response of pneumonitis is largely unknown. Here we investigated whether treatment with 3,3'-diselenodipropionic acid (DSePA), which reduces radiation-induced oxidative stress in acute response models, decreases the lung response to irradiation. Mice of the C3H/HeJ (alveolitis/pneumonitis-responding) strain received 18 Gy whole-thorax irradiation, and a subset of these mice was treated with DSePA (2 mg/kg) three times per week, beginning at 2 hours after radiation treatment, and continuing in the postirradiation period until death because of respiratory distress symptoms. DSePA treatment increased the postirradiation survival time of mice by an average of 32 days (P = 0.0002). Radiation-treated and DSePA-treated mice presented lower levels of lipid peroxidation and augmented glutathione peroxidase in the lungs, compared with those levels measured in mice receiving radiation only, when mice receiving radiation only were killed because of distress symptoms, whereas catalase and superoxide dismutase levels did not show consistent differences among treatment groups. DSePA treatment decreased pneumonitis and the numbers of mast cells, neutrophils, and lymphocytes in the lungs and bronchoalveolar lavage, respectively, of irradiated mice relative to mice exposed to radiation alone. DSePA treatment also decreased the radiation-induced increase in granulocyte colony-stimulating factor levels in the bronchoalveolar lavage and lung-tissue expression of intercellular adhesion molecule-1 and E-selectin, while increasing the expression of glutathione peroxidase-4. We conclude that DSePA treatment reduces radiation-induced pneumonitis in mice by delaying oxidative damage and the inflammatory cell influx.

  20. Radiation-induced myeloid leukemia in murine models

    PubMed Central

    2014-01-01

    The use of radiation therapy is a cornerstone of modern cancer treatment. The number of patients that undergo radiation as a part of their therapy regimen is only increasing every year, but this does not come without cost. As this number increases, so too does the incidence of secondary, radiation-induced neoplasias, creating a need for therapeutic agents targeted specifically towards incidence reduction and treatment of these cancers. Development and efficacy testing of these agents requires not only extensive in vitro testing but also a set of reliable animal models to accurately recreate the complex situations of radiation-induced carcinogenesis. As radiation-induced leukemic progression often involves genomic changes such as rearrangements, deletions, and changes in methylation, the laboratory mouse Mus musculus, with its fully sequenced genome, is a powerful tool in cancer research. This fact, combined with the molecular and physiological similarities it shares with man and its small size and high rate of breeding in captivity, makes it the most relevant model to use in radiation-induced leukemia research. In this work, we review relevant M. musculus inbred and F1 hybrid animal models, as well as methods of induction of radiation-induced myeloid leukemia. Associated molecular pathologies are also included. PMID:25062865

  1. Radiation-induced myeloid leukemia in murine models.

    PubMed

    Rivina, Leena; Davoren, Michael; Schiestl, Robert H

    2014-07-25

    The use of radiation therapy is a cornerstone of modern cancer treatment. The number of patients that undergo radiation as a part of their therapy regimen is only increasing every year, but this does not come without cost. As this number increases, so too does the incidence of secondary, radiation-induced neoplasias, creating a need for therapeutic agents targeted specifically towards incidence reduction and treatment of these cancers. Development and efficacy testing of these agents requires not only extensive in vitro testing but also a set of reliable animal models to accurately recreate the complex situations of radiation-induced carcinogenesis. As radiation-induced leukemic progression often involves genomic changes such as rearrangements, deletions, and changes in methylation, the laboratory mouse Mus musculus, with its fully sequenced genome, is a powerful tool in cancer research. This fact, combined with the molecular and physiological similarities it shares with man and its small size and high rate of breeding in captivity, makes it the most relevant model to use in radiation-induced leukemia research. In this work, we review relevant M. musculus inbred and F1 hybrid animal models, as well as methods of induction of radiation-induced myeloid leukemia. Associated molecular pathologies are also included.

  2. Cell-Assisted Lipotransfer Improves Volume Retention in Irradiated Recipient Sites and Rescues Radiation-Induced Skin Changes

    PubMed Central

    Luan, Anna; Duscher, Dominik; Whittam, Alexander J.; Paik, Kevin J.; Zielins, Elizabeth R.; Brett, Elizabeth A.; Atashroo, David A.; Hu, Michael S.; Lee, Gordon K.; Gurtner, Geoffrey C.; Longaker, Michael T.; Wan, Derrick C.

    2016-01-01

    Radiation therapy is not only a mainstay in the treatment of many malignancies but also results in collateral obliteration of microvasculature and dermal/subcutaneous fibrosis. Soft tissue reconstruction of hypovascular, irradiated recipient sites through fat grafting remains challenging; however, a coincident improvement in surrounding skin quality has been noted. Cell-assisted lipotransfer (CAL), the enrichment of fat with additional adipose-derived stem cells (ASCs) from the stromal vascular fraction, has been shown to improve fat volume retention, and enhanced outcomes may also be achieved with CAL at irradiated sites. Supplementing fat grafts with additional ASCs may also augment the regenerative effect on radiation-damaged skin. In this study, we demonstrate the ability for CAL to enhance fat graft volume retention when placed beneath the irradiated scalps of immunocompromised mice. Histologic metrics of fat graft survival were also appreciated, with improved structural qualities and vascularity. Finally, rehabilitation of radiation-induced soft tissue changes were also noted, as enhanced amelioration of dermal thickness, collagen content, skin vascularity, and biomechanical measures were all observed with CAL compared to unsupplemented fat grafts. Supplementation of fat grafts with ASCs therefore shows promise for reconstruction of complex soft tissue defects following adjuvant radiotherapy. PMID:26661694

  3. Cardiac Tissue Structure, Properties, and Performance: A Materials Science Perspective

    PubMed Central

    Golob, Mark; Moss, Richard L.; Chesler, Naomi C.

    2014-01-01

    From an engineering perspective, many forms of heart disease can be thought of as a reduction in biomaterial performance, in which the biomaterial is the tissue comprising the ventricular wall. In materials science, the structure and properties of a material are recognized to be interconnected with performance. In addition, for most measurements of structure, properties, and performance, some processing is required. Here, we review the current state of knowledge regarding cardiac tissue structure, properties, and performance as well as the processing steps taken to acquire those measurements. Understanding the impact of these factors and their interactions may enhance our understanding of heart function and heart failure. We also review design considerations for cardiac tissue property and performance measurements because, to date, most data on cardiac tissue has been obtained under non-physiological loading conditions. Novel measurement systems that account for these design considerations may improve future experiments and lead to greater insight into cardiac tissue structure, properties, and ultimately performance. PMID:25081385

  4. Dosimetric Analysis of Radiation-Induced Gastric Bleeding

    PubMed Central

    Feng, Mary; Normolle, Daniel; Pan, Charlie C.; Dawson, Laura A.; Amarnath, Sudha; Ensminger, William D.; Lawrence, Theodore S.; Ten Haken, Randall K.

    2012-01-01

    Purpose Radiation-induced gastric bleeding has been poorly understood. In this study, we describe dosimetric predictors for gastric bleeding after fractionated radiotherapy and compare several predictive models. Materials & Methods The records of 139 sequential patients treated with 3-dimensional conformal radiotherapy (3D-CRT) for intrahepatic malignancies between January 1999 and April 2002 were reviewed. Median follow-up was 7.4 months. Logistic regression and Lyman normal tissue complication probability (NTCP) models for the occurrence of ≥ grade 3 gastric bleed were fit to the data. The principle of maximum likelihood was used to estimate parameters for all models. Results Sixteen of 116 evaluable patients (14%) developed gastric bleeds, at a median time of 4.0 months (mean 6.5 months, range 2.1–28.3 months) following completion of RT. The median and mean of the maximum doses to the stomach were 61 and 63 Gy (range 46 Gy–86 Gy), respectively, after bio-correction to equivalent 2 Gy daily fractions. The Lyman NTCP model with parameters adjusted for cirrhosis was most predictive of gastric bleed (AUROC=0.92). Best fit Lyman NTCP model parameters were n =0.10, and m =0.21, with TD50(normal) =56 Gy and TD50(cirrhosis) = 22 Gy. The low n value is consistent with the importance of maximum dose; a lower TD50 value for the cirrhosis patients points out their greater sensitivity. Conclusion This study demonstrates that the Lyman NTCP model has utility for predicting gastric bleeding, and that the presence of cirrhosis greatly increases this risk. These findings should facilitate the design of future clinical trials involving high-dose upper abdominal radiation. PMID:22541965

  5. Dosimetric Analysis of Radiation-induced Gastric Bleeding

    SciTech Connect

    Feng, Mary; Normolle, Daniel; Pan, Charlie C.; Dawson, Laura A.; Amarnath, Sudha; Ensminger, William D.; Lawrence, Theodore S.; Ten Haken, Randall K.

    2012-09-01

    Purpose: Radiation-induced gastric bleeding has been poorly understood. In this study, we described dosimetric predictors for gastric bleeding after fractionated radiation therapy. Methods and Materials: The records of 139 sequential patients treated with 3-dimensional conformal radiation therapy (3D-CRT) for intrahepatic malignancies were reviewed. Median follow-up was 7.4 months. The parameters of a Lyman normal tissue complication probability (NTCP) model for the occurrence of {>=}grade 3 gastric bleed, adjusted for cirrhosis, were fitted to the data. The principle of maximum likelihood was used to estimate parameters for NTCP models. Results: Sixteen of 116 evaluable patients (14%) developed gastric bleeds at a median time of 4.0 months (mean, 6.5 months; range, 2.1-28.3 months) following completion of RT. The median and mean maximum doses to the stomach were 61 and 63 Gy (range, 46-86 Gy), respectively, after biocorrection of each part of the 3D dose distributions to equivalent 2-Gy daily fractions. The Lyman NTCP model with parameters adjusted for cirrhosis predicted gastric bleed. Best-fit Lyman NTCP model parameters were n=0.10 and m=0.21 and with TD{sub 50} (normal) = 56 Gy and TD{sub 50} (cirrhosis) = 22 Gy. The low n value is consistent with the importance of maximum dose; a lower TD{sub 50} value for the cirrhosis patients points out their greater sensitivity. Conclusions: This study demonstrates that the Lyman NTCP model has utility for predicting gastric bleeding and that the presence of cirrhosis greatly increases this risk. These findings should facilitate the design of future clinical trials involving high-dose upper abdominal radiation.

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

    NASA Astrophysics Data System (ADS)

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

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

  7. Radiation-induced damage to DNA: mechanistic aspects and measurement of base lesions

    NASA Astrophysics Data System (ADS)

    Cadet, J.; Douki, T.; Gasparutto, D.; Gromova, M.; Pouget, J.-P.; Ravanat, J.-L.; Romieu, A.; Sauvaigo, S.

    1999-05-01

    Emphasis has been placed in the present survey on mechanistic aspects of the radiation-induced decomposition of the guanine moiety of DNA and model compounds. An almost complete description of the radical reactions induced by both rad OH radicals (indirect effects) and one-electron oxidation (direct effects) in aerated aqueous solution is now possible. This was inferred from both earliest investigations of the transient radicals of these reactions and detailed structural determination of the final decomposition products. Information is also provided on several tandem lesions whose formation results from one initial radical event involving either the sugar moiety or the base residue of nucleosides. It should be noted that there is a paucity of information on the radiation-induced formation of base damage within cellular DNA. A critical evaluation of the available methods aimed at monitoring the levels of oxidative base damage to cellular DNA is made in the second part of the review article.

  8. Effects of Pharmacological Inhibition and Genetic Deficiency of Plasminogen Activator Inhibitor-1 in Radiation-Induced Intestinal Injury

    SciTech Connect

    Abderrahmani, Rym; Francois, Agnes; Buard, Valerie; Benderitter, Marc; Sabourin, Jean-Christophe; Crandall, David L.; Milliat, Fabien

    2009-07-01

    Purpose: To investigate effects of plasminogen activator inhibitor 1 (PAI-1) genetic deficiency and pharmacological PAI-1 inhibition with PAI-039 in a mouse model of radiation-induced enteropathy. Methods and Materials: Wild-type (Wt) and PAI-1{sup -/-} knockout mice received a single dose of 19 Gy to an exteriorized localized intestinal segment. Sham and irradiated Wt mice were treated orally with 1 mg/g of PAI-039. Histological modifications were quantified using a radiation injury score. Moreover, intestinal gene expression was monitored by real-time PCR. Results: At 3 days after irradiation, PAI-039 abolished the radiation-induced increase in the plasma active form of PAI-1 and limited the radiation-induced gene expression of transforming growth factor {beta}1 (TGF-{beta}1), CTGF, PAI-1, and COL1A2. Moreover, PAI-039 conferred temporary protection against early lethality. PAI-039 treatment limited the radiation-induced increase of CTGF and PAI-1 at 2 weeks after irradiation but had no effect at 6 weeks. Radiation injuries were less severe in PAI-1{sup -/-} mice than in Wt mice, and despite the beneficial effect, 3 days after irradiation, PAI-039 had no effects on microscopic radiation injuries compared to untreated Wt mice. Conclusions: A genetic deficiency of PAI-1 is associated with amelioration of late radiation enteropathy. Pharmacological inhibition of PAI-1 by PAI-039 positively impacts the early, acute phase increase in plasma PAI-1 and the associated radiation-induced gene expression of inflammatory/extracellular matrix proteins. Since PAI-039 has been shown to inhibit the active form of PAI-1, as opposed to the complete loss of PAI-1 in the knockout animals, these data suggest that a PAI-1 inhibitor could be beneficial in treating radiation-induced tissue injury in acute settings where PAI-1 is elevated.

  9. Therapy with Multipotent Mesenchymal Stromal Cells Protects Lungs from Radiation-Induced Injury and Reduces the Risk of Lung Metastasis.

    PubMed

    Klein, Diana; Schmetter, Alexandra; Imsak, Roze; Wirsdörfer, Florian; Unger, Kristian; Jastrow, Holger; Stuschke, Martin; Jendrossek, Verena

    2016-01-10

    Previous thorax irradiation promotes metastatic spread of tumor cells to the lung. We hypothesized that vascular damage facilitates lung metastasis after thorax irradiation and that therapeutically applied multipotent mesenchymal stromal cells (MSCs) with reported repair activity may prevent these adverse effects of ionizing radiation by protecting lung endothelia from radiation-induced damage. Previous whole-thorax irradiation (WTI) with 15 Gy significantly enhanced seeding and metastatic growth of tumor cells in the lung. WTI was further associated with endothelial cell damage, senescence of lung epithelial cells, and upregulation of invasion- and inflammation-promoting soluble factors, for example, endothelial matrix metalloproteinase 2 (Mmp2), its activator Mmp14, the cofactor tissue inhibitor of metalloproteinases 2 (Timp2), chemokine (C-C motif) ligand 2 (Ccl2), and urokinase-type plasminogen activator (Plau/uPA), and recruitment of CD11b+CD11c- myelomonocytic cells. Inhibition of Mmp2 counteracted radiation-induced vascular dysfunction without preventing increased metastasis. In contrast, therapy with bone marrow or aorta-derived MSCs within 2 weeks postirradiation antagonized radiation-induced damage to resident cells as well as the resulting secretome changes and abrogated the metastasis-promoting effects of WTI. Therapy with MSCs protects lungs from radiation-induced injury and reduces the risk of lung metastasis. MSC-mediated inhibition of Mmp2 mediates their protective effects at the vasculature. Furthermore, local and systemic effects such as inhibition of radiation-induced senescence of bronchial epithelial cells and associated secretion of immunomodulatory factors may participate in the inhibitory effect of MSCs on lung metastasis. MSC therapy is a promising strategy to prevent radiation-induced lung injury and the resulting increased risk of metastasis.

  10. Hypopharyngeal carcinoma after radiation for tuberculosis: radiation-induced carcinoma.

    PubMed

    van der Putten, Lisa; de Bree, Remco; Kuik, Dirk J; Rietveld, Derek H F; Langendijk, Johannes A; Leemans, C René

    2010-09-01

    Radiation may cause radiation-induced cancers after a long latency period. In a group of 111 patients surgically treated for hypopharyngeal carcinoma, patients previously treated with radiotherapy for tuberculosis in the neck were compared to patients without previous radiotherapy. Seven patients (7.4%) underwent radiotherapy (median age 15 years) and developed a hypopharyngeal carcinoma (median age 70 years, median latency period 54.4 year). Considering this long latency period and the localisation in the previous radiation field these tumours can be classified as potentially radiation-induced carcinomas. Patients with potentially radiation-induced carcinomas were significantly older when the hypopharyngeal carcinoma was diagnosed (p=0.048), were more frequently females (p=0.05) and had a worse 5-year regional control rate (p=0.048). When radiotherapy is considered in young patients the risk of induction of tumours has to be kept in mind. Copyright 2010 Elsevier Ltd. All rights reserved.

  11. Development of a new minipig model to study radiation-induced gastrointestinal syndrome and its application in clinical research.

    PubMed

    Shim, Sehwan; Jang, Won-Suk; Lee, Sun-Joo; Jin, Sungho; Kim, Jin; Lee, Seung-Sook; Bang, Ho Yoon; Jeon, Byung Suk; Park, Sunhoo

    2014-04-01

    Because of insufficient clinical data regarding acute radiation damage after single high-dose radiation exposure, acute radiation-induced gastrointestinal (GI) syndrome remains difficult to treat. The goal of this study was to establish an appropriate and efficient minipig model to study high-dose radiation-induced GI syndrome after radiation exposure. For endoscopic access to the ileum, ileocutaneous anastomosis was performed 3 weeks before irradiation in six male Göttingen minipigs. Minipigs were locally irradiated at the abdominal area using a gamma source as follows: 1,000 cGy (n = 3) and 1,500 cGy (n = 3). Endoscopic evaluation for the terminal ileum was periodically performed via the ileocutaneous anastomosis tract. Pieces of tissue were serially taken for histological examination. The irradiated intestine presented characteristic morphological changes over time. The most obvious changes in the ileum were mucosal atrophy and telangiectasia from day 1 to day 17 after abdominal irradiation. Microscopic findings were characterized as architectural disorganization, loss of villi and chronic active inflammation. Increase in cyclooxygenase-2 (COX-2) expression was closely correlated with severity of tissue damage and inflammation. Particularly, the plasma citrulline level (PCL), a potential marker for radiation-induced intestinal damage, was significantly decreased the day after irradiation and recovered when irradiated mucosa was normalized. Our results also showed that PCL changes were positively correlated with microscopic changes and the endoscopic score in radiation-induced mucosal damage. In conclusion, the ileocutaneous anastomosis model using the minipig mimics human GI syndrome and allows the study of sequential changes in the ileum, the main target tissue of abdominal irradiation. In addition, PCL could be a simple biomarker for radiation-induced intestinal damage.

  12. Amifostine Reduces Radiation-Induced Complications in a Murine Model of Expander-Based Breast Reconstruction

    PubMed Central

    Felice, Peter A.; Nelson, Noah S.; Page, Erin E.; Deshpande, Sagar S.; Donneys, Alexis; Rodriguez, José; Buchman, Steven R.

    2014-01-01

    Background Immediate expander-based breast reconstruction after mastectomy is a prevalent option for many women with breast cancer. When coupled with adjuvant radiation, however, radiation-induced skin and soft tissue injury diminish the success of this reconstructive technique. We hypothesize that prophylactic administration of the cytoprotectant Amifostine will reduce soft tissue complications from irradiation, aiding expander-based reconstruction for women battling this disease. Methods Sprague Dawley rats were divided into two experimental groups, Operative Expander Placement (Expander) and Operative Sham (Sham). Expander specimens received a sub-latissimus tissue expander with a 15cc fill volume; Shams underwent identical procedures without expander placement. Experimental groups were further divided into Control specimens receiving no further intervention, XRT specimens receiving human-equivalent radiation, and AMF-XRT specimens receiving both Amifostine and human-equivalent radiation. Animals underwent a 45-day recovery period and were evaluated grossly and via ImageJ analysis for skin and soft tissue complications. Results None of the Control, XRT, or AMF-XRT Sham specimens showed skin and soft tissue complications. For Expander animals, significantly fewer AMF-XRT specimens (4 of 13, 30%) demonstrated skin and soft tissue complications compared to XRT specimens (9 of 13, 69%; p = 0.041). ImageJ evaluation of Expander specimens demonstrated a significant increase in skin and soft tissue necrosis for XRT specimens (12.94%), compared with AMF-XRT animals (6.96%, p = 0.019). Conclusions Amifostine pre-treatment significantly reduced skin and soft-tissue complications in both gross inspection and ImageJ analysis. These findings demonstrate that Amifostine prophylaxis provides protection against radiation-induced skin and soft tissue injury in a murine model of expander-based breast reconstruction. Level of Evidence Animal study, not gradable for level of

  13. Panretinal photocoagulation for radiation-induced ocular ischemia

    SciTech Connect

    Augsburger, J.J.; Roth, S.E.; Magargal, L.E.; Shields, J.A.

    1987-08-01

    We present preliminary findings on the effectiveness of panretinal photocoagulation in preventing neovascular glaucoma in eyes with radiation-induced ocular ischemia. Our study group consisted of 20 patients who developed radiation-induced ocular ischemia following cobalt-60 plaque radiotherapy for a choroidal or ciliary body melanoma. Eleven of the 20 patients were treated by panretinal photocoagulation shortly after the diagnosis of ocular ischemia, but nine patients were left untreated. In this non-randomized study, the rate of development of neovascular glaucoma was significantly lower (p = 0.024) for the 11 photocoagulated patients than for the nine who were left untreated.

  14. The Mechanisms of Radiation-Induced Bystander Effect

    PubMed Central

    Najafi, M; Fardid, R; Hadadi, Gh; Fardid, M

    2014-01-01

    The radiation-induced bystander effect is the phenomenon which non-irradiated cells exhibit effects along with their different levels as a result of signals received from nearby irradiated cells. Responses of non-irradiated cells may include changes in process of translation, gene expression, cell proliferation, apoptosis and cells death. These changes are confirmed by results of some In-Vivo studies. Most well-known important factors affecting radiation-induced bystander effect include free radicals, immune system factors, expression changes of some genes involved in inflammation pathway and epigenetic factors. PMID:25599062

  15. [Symptoms, diagnosis and treatment of radiation-induced enteritis].

    PubMed

    Sinkó, Dániel; Baranyai, Zsolt; Nemeskéri, Csaba; Teknos, Dániel; Jósa, Valéria; Hegedus, László; Mayer, Arpád

    2010-09-05

    The number of radiotherapy in the treatment of malignant diseases is increasing worldwide. During the radiotherapy of tumors in the minor pelvis and abdomen intestinal inflammation of different degree may occur even if special attention is paid. Irradiation to the minor pelvis causes in half of the cases radiation induced acute enteritis, whereas in 25% chronic enteritis and colitis will develop. Chronic enteritis following radiotherapy raises a number of diagnostic and therapeutic problems that can be solved only with cooperation of different specialties. Authors present a short review regarding therapeutical options of radiation induced enteritis.

  16. Quercetin liposomes protect against radiation-induced pulmonary injury in a murine model

    PubMed Central

    LIU, HAO; XUE, JIAN-XING; LI, XING; AO, RUI; LU, YOU

    2013-01-01

    In the present study, the hypothesis that quercetin liposomes are able to effectively protect against radiation-induced pulmonary injury in a murine model was tested. C57BL/6J mice receiving whole-thorax radiotherapy (16 Gy) were randomly divided into three groups: control, radiation therapy plus saline (RT+NS) and RT plus quercetin (RT+QU). At 1, 4, 8 and 24 weeks post-irradiation, lung injury was assessed by measuring oxidative damage and the extent of acute pneumonitis and late fibrosis. In the lung tissues from the RT+NS group, the malondialdehyde (MDA) levels were significantly elevated and superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities were significantly reduced; the total cell counts and inflammatory cell proportions in the bronchoalveolar lavage fluid (BALF), plasma tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β1 concentrations and the hydroxyproline (HP) content were significantly increased. Quercetin liposome administration significantly reduced the MDA content and increased SOD and GSH-PX activities in the lung tissues, and reduced the total cell counts and inflammatory cell proportions in the BALF, plasma TNF-α and TGF-β1 concentrations and the HP content in the lung tissues. A histological examination revealed suppression of the inflammatory response and reduced TGF-β1 expression and fibrosis scores. Radiation-induced oxidative damage ranged from pneumonitis to lung fibrosis. Quercetin liposomes were shown to protect against radiation-induced acute pneumonitis and late fibrosis, potentially by reducing oxidative damage. PMID:24137346

  17. Quercetin liposomes protect against radiation-induced pulmonary injury in a murine model.

    PubMed

    Liu, Hao; Xue, Jian-Xing; Li, Xing; Ao, Rui; Lu, You

    2013-08-01

    In the present study, the hypothesis that quercetin liposomes are able to effectively protect against radiation-induced pulmonary injury in a murine model was tested. C57BL/6J mice receiving whole-thorax radiotherapy (16 Gy) were randomly divided into three groups: control, radiation therapy plus saline (RT+NS) and RT plus quercetin (RT+QU). At 1, 4, 8 and 24 weeks post-irradiation, lung injury was assessed by measuring oxidative damage and the extent of acute pneumonitis and late fibrosis. In the lung tissues from the RT+NS group, the malondialdehyde (MDA) levels were significantly elevated and superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities were significantly reduced; the total cell counts and inflammatory cell proportions in the bronchoalveolar lavage fluid (BALF), plasma tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β1 concentrations and the hydroxyproline (HP) content were significantly increased. Quercetin liposome administration significantly reduced the MDA content and increased SOD and GSH-PX activities in the lung tissues, and reduced the total cell counts and inflammatory cell proportions in the BALF, plasma TNF-α and TGF-β1 concentrations and the HP content in the lung tissues. A histological examination revealed suppression of the inflammatory response and reduced TGF-β1 expression and fibrosis scores. Radiation-induced oxidative damage ranged from pneumonitis to lung fibrosis. Quercetin liposomes were shown to protect against radiation-induced acute pneumonitis and late fibrosis, potentially by reducing oxidative damage.

  18. Subcutaneous administration of bovine superoxide dismutase protects lungs from radiation-induced lung injury.

    PubMed

    Antonic, Vlado; Rabbani, Zahid N; Jackson, Isabel L; Vujaskovic, Zeljko

    2015-10-01

    The objective of the present study was to determine whether single administration of the antioxidant enzyme bovine superoxide dismutase (bSOD) after radiation therapy (RT) mitigates development of pulmonary toxicity in rats. Female F344 rats (n = 60) were divided among six experimental groups: (1) RT, single dose of 21 Gy to the right hemithorax; (2) RT + 5 mg/kg bSOD; (3) RT + 15 mg/kg bSOD; (4) No RT; (5) sham RT + 5 mg/kg bSOD; and (6) sham RT + 15 mg/kg bSOD. A single subcutaneous injection of bSOD (5 or 15 mg/kg) was administered 24 h post-radiation. The effects of bSOD on radiation-induced lung injury were assessed by measurement of body weight, breathing frequency, and histopathological changes. Immunohistochemistry was used to evaluate oxidative stress (8-OHdG(+), NOX4(+), nitrotyrosine(+), and 4HNE(+) cells), macrophage activation (ED1(+)), and expression of profibrotic transforming growth factor-β or TGF-β in irradiated tissue. Radiation led to an increase in all the evaluated parameters. Treatment with 15 mg/kg bSOD significantly decreased levels of all the evaluated parameters including tissue damage and breathing frequency starting 6 weeks post-radiation. Animals treated with 5 mg/kg bSOD trended toward a suppression of radiation-induced lung damage but did not reach statistical significance. The single application of bSOD (15 mg/kg) ameliorates radiation-induced lung injury through suppression of reactive oxygen species/reactive nitrogen species or ROS/RNS-dependent tissue damage.

  19. Radiation-Induced Phase Transformations in Ilmenite-Group Minerals

    SciTech Connect

    Mitchell, J. N.

    1997-12-31

    Transmission electron microscopy (TEM) is a powerful tool for characterizing and understanding radiation-induced structural changes in materials. We have irradiated single crystals of ilmenite (FeTiO{sub 3}) and geikielite (MgTiO{sub 3}) using ions and electrons to better understand the response of complex oxides to radiation. Ion irradiation experiments of bulk single crystals at 100 K show that ilmenite amorphized at doses of less than 1x10(exp15) Ar(2+)/sq cm and at a damage level in the peak damage region of 1 displacement per atom (dpa). Transmission electron microscopy and electron diffraction of a cross-sectioned portion of this crystal confirmed the formation of a 150 am thick amorphous layer. Geikielite proved to be more radiation resistant, requiring a flux of 2x10(exp 15) Xe(2+)/sq cm to induce amorphization at 100 K. This material did not amorphize at 470 K, despite a dose of 2.5 x10(exp 16) Xe(2+)/sq cm and a damage level as high as 25 dpa. Low temperature irradiations of electron- transparent crystals with 1 MeV Kr(+) also show that ilmenite amorphized after a damage level of 2.25 dpa at 175 K.Similar experiments on geikielite show that the microstructure is partially amorphous and partially crystalline after 10 dpa at 150 K. Concurrent ion and electron irradiation of both materials with 1 MeV Kr(+) and 0.9 MeV electrons produced dislocation loops in both materials, but no amorphous regions were formed. Differences in the radiation response of these isostructural oxides suggests that in systems with Mg-Fe solid solution, the Mg-rich compositions may be more resistant to structural changes.

  20. Radiation-induced inflammatory markers of brain injury are modulated by PPARdelta activation in vitro and in vivo

    NASA Astrophysics Data System (ADS)

    Schnegg, Caroline Isabel

    As a result of improvements in cancer therapy and health care, the population of long-term cancer survivors is growing. For these approximately 12 million long-term cancer survivors, brain metastases are a significant risk. Fractionated partial or whole-brain irradiation (fWBI) is often required to treat both primary and metastatic brain cancer. Radiation-induced normal tissue injury, including progressive cognitive impairment, however, can significantly affect the well-being of the approximately 200,000 patients who receive these treatments each year. Recent reports indicate that radiation-induced brain injury is associated with chronic inflammatory and oxidative stress responses, as well as increased microglial activation in the brain. Anti-inflammatory drugs may, therefore, be a beneficial therapy to mitigate radiation-induced brain injury. We hypothesized that activation of peroxisomal proliferator activated receptor delta (PPARō) would prevent or ameliorate radiation-induced brain injury, including cognitive impairment, in part, by alleviating inflammatory responses in microglia. For our in vitro studies, we hypothesized that PPARō activation would prevent the radiation-induced inflammatory response in microglia following irradiation. Incubating BV-2 murine microglial cells with the (PPAR)ō agonist, L-165041, prevented the radiation-induced increase in: i) intracellular ROS generation, ii) Cox-2 and MCP-1 expression, and iii) IL-1β and TNF-α message levels. This occured, in part, through PPARō-mediated modulation of stress activated kinases and proinflammatory transcription factors. PPARō inhibited NF-κB via transrepression by physically interacting with the p65 subunit, and prevented activation of the PKCα/MEK1/2/ERK1/2/AP-1 pathway by inhibiting the radiation-induced increase in intracellular ROS generation. These data support the hypothesis that PPARō activation can modulate the radiation-induced oxidative stress and inflammatory

  1. Collagen in Human Tissues: Structure, Function, and Biomedical Implications from a Tissue Engineering Perspective

    NASA Astrophysics Data System (ADS)

    Balasubramanian, Preethi; Prabhakaran, Molamma P.; Sireesha, Merum; Ramakrishna, Seeram

    The extracellular matrix is a complex biological structure encoded with various proteins, among which the collagen family is the most significant and abundant of all, contributing 30-35% of the whole-body protein. "Collagen" is a generic term for proteins that forms a triple-helical structure with three polypeptide chains, and around 29 types of collagen have been identified up to now. Although most of the members of the collagen family form such supramolecular structures, extensive diversity exists between each type of collagen. The diversity is not only based on the molecular assembly and supramolecular structures of collagen types but is also observed within its tissue distribution, function, and pathology. Collagens possess complex hierarchical structures and are present in various forms such as collagen fibrils (1.5-3.5 nm wide), collagen fibers (50-70 nm wide), and collagen bundles (150-250 nm wide), with distinct properties characteristic of each tissue providing elasticity to skin, softness of the cartilage, stiffness of the bone and tendon, transparency of the cornea, opaqueness of the sclera, etc. There exists an exclusive relation between the structural features of collagen in human tissues (such as the collagen composition, collagen fibril length and diameter, collagen distribution, and collagen fiber orientation) and its tissue-specific mechanical properties. In bone, a transverse collagen fiber orientation prevails in regions of higher compressive stress whereas longitudinally oriented collagen fibers correlate to higher tensile stress. The immense versatility of collagen compels a thorough understanding of the collagen types and this review discusses the major types of collagen found in different human tissues, highlighting their tissue-specific uniqueness based on their structure and mechanical function. The changes in collagen during a specific tissue damage or injury are discussed further, focusing on the many tissue engineering applications for

  2. Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis.

    PubMed

    Chandra, Abhishek; Wang, Luqiang; Young, Tiffany; Zhong, Leilei; Tseng, Wei-Ju; Levine, Michael A; Cengel, Keith; Liu, X Sherry; Zhang, Yejia; Pignolo, Robert J; Qin, Ling

    2017-08-31

    Bone atrophy and its related fragility fractures are frequent, late side effects of radiotherapy in cancer survivors and have a detrimental impact on their quality of life. In another study, we showed that parathyroid hormone 1-34 and anti-sclerostin antibody attenuates radiation-induced bone damage by accelerating DNA repair in osteoblasts. DNA damage responses are partially regulated by the ubiquitin proteasome pathway. In the current study, we examined whether proteasome inhibitors have similar bone-protective effects against radiation damage. MG132 treatment greatly reduced radiation-induced apoptosis in cultured osteoblastic cells. This survival effect was owing to accelerated DNA repair as revealed by γH2AX foci and comet assays and to the up-regulation of Ku70 and DNA-dependent protein kinase, catalytic subunit, essential DNA repair proteins in the nonhomologous end-joining pathway. Administration of bortezomib (Bzb) reversed the loss of trabecular bone structure and strength in mice at 4 wk after focal radiation. Histomorphometry revealed that Bzb significantly increased the number of osteoblasts and activity in the irradiated area and suppressed the number and activity of osteoclasts, regardless of irradiation. Two weeks of Bzb treatment accelerated DNA repair in bone-lining osteoblasts and thus promoted their survival. Meanwhile, it also inhibited bone marrow adiposity. Taken together, we demonstrate a novel role of proteasome inhibitors in treating radiation-induced osteoporosis.-Chandra, A., Wang, L., Young, T., Zhong, L., Tseng, W.-J., Levine, M. A., Cengel, K., Liu, X. S., Zhang, Y., Pignolo, R. J., Qin, L. Proteasome inhibitor bortezomib is a novel therapeutic agent for focal radiation-induced osteoporosis. © FASEB.

  3. Combined inhibition of TGFβ and PDGF signaling attenuates radiation-induced pulmonary fibrosis.

    PubMed

    Dadrich, Monika; Nicolay, Nils H; Flechsig, Paul; Bickelhaupt, Sebastian; Hoeltgen, Line; Roeder, Falk; Hauser, Kai; Tietz, Alexandra; Jenne, Jürgen; Lopez, Ramon; Roehrich, Manuel; Wirkner, Ute; Lahn, Michael; Huber, Peter E

    2016-05-01

    Background : Radiotherapy (RT) is a mainstay for the treatment of lung cancer, but the effective dose is often limited by the development of radiation-induced pneumonitis and pulmonary fibrosis. Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on pulmonary fibrosis development remain unclear. Methods : C57BL/6 mice were treated with 20 Gy to the thorax to induce pulmonary fibrosis. PDGF receptor inhibitors SU9518 and SU14816 (imatinib) and TGFβ receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results : Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and TGFβ inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and TGFβ-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and TGFβ pathways. Conclusion : Combined small-molecule inhibition of PDGF and TGFβ signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement : RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where TGFβ and PDGF play a key role. Here, we show that a combined inhibition of

  4. Combined inhibition of TGFβ and PDGF signaling attenuates radiation-induced pulmonary fibrosis

    PubMed Central

    Dadrich, Monika; Nicolay, Nils H.; Flechsig, Paul; Bickelhaupt, Sebastian; Hoeltgen, Line; Roeder, Falk; Hauser, Kai; Tietz, Alexandra; Jenne, Jürgen; Lopez, Ramon; Roehrich, Manuel; Wirkner, Ute; Lahn, Michael; Huber, Peter E.

    2016-01-01

    ABSTRACT Background: Radiotherapy (RT) is a mainstay for the treatment of lung cancer, but the effective dose is often limited by the development of radiation-induced pneumonitis and pulmonary fibrosis. Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on pulmonary fibrosis development remain unclear. Methods: C57BL/6 mice were treated with 20 Gy to the thorax to induce pulmonary fibrosis. PDGF receptor inhibitors SU9518 and SU14816 (imatinib) and TGFβ receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results: Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and TGFβ inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and TGFβ-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and TGFβ pathways. Conclusion: Combined small-molecule inhibition of PDGF and TGFβ signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement: RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where TGFβ and PDGF play a key role. Here, we show that a combined

  5. Endoglin haploinsufficiency reduces radiation-induced fibrosis and telangiectasia formation in mouse kidneys.

    PubMed

    Scharpfenecker, Marion; Floot, Ben; Russell, Nicola S; Ten Dijke, Peter; Stewart, Fiona A

    2009-09-01

    Endoglin is a transforming growth factor beta (TGF-beta) co-receptor mainly expressed in dividing endothelial cells. It regulates cell proliferation and survival and is upregulated at sites of vessel repair. Mutations in endoglin have been linked to the vascular disease hereditary hemorrhagic telangiectasia (HHT). HHT patients display dilated capillaries (telangiectasia) that are prone to rupture. Cancer patients receiving radiotherapy develop similar vascular damage in normal tissues lying in the irradiation field. If located in the mucosa, irradiation-induced telangiectasia can lead to severe bleeding. Therefore, this study was aimed at investigating the role of endoglin in radiation-induced telangiectasia formation. Kidneys of endoglin heterozygous (Eng(+/-)) or wild type mice were irradiated with 16 Gy. Mice were sacrificed after 20 weeks and changes in gene expression and protein levels were analysed. Expression of TGF-beta target genes involved in radiation-induced fibrosis and fibrosis development in the kidney decreased in Eng(+/-) compared to wild type mice. Unexpectedly, Eng(+/-) mice also displayed reduced telangiectasia formation in the irradiated kidney. Endoglin plays an important role in the development of irradiation-induced normal tissue damage. Future studies will show whether interfering with endoglin functions protects tissues from late radiation toxicity.

  6. Radiofrequency radiation-induced calcium ion efflux enhancement from human and other neuroblastoma cells in culture

    SciTech Connect

    Dutta, S.K.; Ghosh, B.; Blackman, C.F.

    1989-01-01

    To test the generality of radiofrequency radiation-induced changes in /sup 45/Ca2+ efflux from avian and feline brain tissues, human neuroblastoma cells were exposed to electromagnetic radiation at 147 MHz, amplitude-modulated (AM) at 16 Hz, at specific absorption rates (SAR) of 0.1, 0.05, 0.01, 0.005, 0.001, and 0.0005 W/kg. Significant /sup 45/Ca2+ efflux was obtained at SAR values of 0.05 and 0.005 W/kg. Enhanced efflux at 0.05 W/kg peaked at the 13-16 Hz and at the 57.5-60 Hz modulation ranges. A Chinese hamster-mouse hybrid neuroblastoma was also shown to exhibit enhanced radiation-induced /sup 45/Ca2+ efflux at an SAR of 0.05 W/kg, using 147 MHz, AM at 16 Hz. These results confirm that amplitude-modulated radiofrequency radiation can induce responses in cells of nervous tissue origin from widely different animal species, including humans. The results are also consistent with the reports of similar findings in avian and feline brain tissues and indicate the general nature of the phenomenon.

  7. Fluid-structure Interaction Simulations of Deformable Soft Tissue

    NASA Astrophysics Data System (ADS)

    Borazjani, Iman

    2011-11-01

    Soft tissue interacts with the surrounding fluid environment in many biological and biomedical applications. Simulating such an interaction is quite challenging due to the large non-linear deformations of tissue, flow pulsatility, transition to turbulence, and non-linear fluid-structure interaction. We have extended our previous three-dimensional fluid-structure interaction (FSI) framework for rigid bodies (Borazjani, Ge, and Sotiropoulos, Journal of Computational Physics, 2008) to deformable soft tissue by coupling our incompressible Navier-Stokes solver for fluids with a non-linear large deformation finite element method for soft tissue. We use Fung-type constitutive law for the soft tissue that can capture the stress-strain behavior of the tissue. The FSI solver adopts a strongly-coupled partitioned approach that is stabilized with under-relaxation and Aitken acceleration technique. We validate our solvers against the experimental data for tissue valves and elastic tubes. We show the capabilities of our solver by simulating the fluid-structure interaction of tissue valves implanted in the aortic positions and elastic collapsible tubes. This work was partly supported by the Center for Computational Research at the University at Buffalo.

  8. Poor outcome in radiation-induced constrictive pericarditis

    SciTech Connect

    Karram, T.; Rinkevitch, D.; Markiewicz, W. )

    1993-01-15

    The purpose was to compare the outcome of patients with radiation-induced constrictive pericarditis versus patients with constiction due to another etiology. Twenty patients with constrictive pericarditis were seen during 1975-1986 at a single medical center. Six had radiation-induced constrictive pericarditis (Group A). The etiology was idiopathic in ten subjects and secondary to carcinomatous encasement, chronic renal failure, purulent infection and tuberculosis in one patient each (Group B, N = 14). Meang age was 53.4 [+-] 15.5 years. Extensive pericardiectomy was performed in 3/6 Group A and 13/14 Group B patients. All Group A patients died, 4 weeks - 11 years post-diagnosis (median = 10 months). Two Group A patients died suddenly, one died post-operatively of respiratory failure, another of pneumonia and two of recurrent carcinoma. Thirteen Group B patients are alive (median follow-up = 72 months). The only death in this group was due to metastatic cancer. The poor outcome with radiation-induced constriction is probably multi-factorial. Poor surgical outcome is to be expected in patients with evidence of recurrent tumor, high-dose irradiation, pulmonary fibrosis or associated radiation-induced myocardinal, valvular or coronary damage.

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

    NASA Technical Reports Server (NTRS)

    Ullrich, R. L.; Ponnaiya, B.

    1998-01-01

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

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

    NASA Technical Reports Server (NTRS)

    Ullrich, R. L.; Ponnaiya, B.

    1998-01-01

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

  11. Radiation-induced augmentation of the immune response

    SciTech Connect

    Anderson, R.E.; Lefkovits, I.; Troup, G.M.

    1980-01-01

    Radiation-induced augmentation of the immune response has been shown to occur both in vivo and in vitro. Evidence is presented to implicate injury to an extremely radiosensitive T cell in the expression of this phenomenon. Experiments are outlined which could be employed to support or reflect this hypothesis.

  12. Use of probiotics for prevention of radiation-induced diarrhea

    PubMed Central

    Delia, P; Sansotta, G; Donato, V; Frosina, P; Messina, G; De Renzis, C; Famularo, G

    2007-01-01

    AIM: To investigate the efficacy of a high-potency probiotic preparation on prevention of radiation-induced diarrhea in cancer patients. METHODS: This was a double-blind, placebo-controlled trial. Four hundred and ninety patients who underwent adjuvant postoperative radiation therapy after surgery for sigmoid, rectal, or cervical cancer were assigned to either the high-potency probiotic preparation VSL#3 (one sachet t.i.d.,) or placebo starting from the first day of radiation therapy. Efficacy endpoints were incidence and severity of radiation-induced diarrhea, daily number of bowel movements, and the time from the start of the study to the use of loperamide as rescue medication. RESULTS: More placebo patients had radiation-induced diarrhea than VSL#3 patients (124 of 239 patients, 51.8%, and 77 of 243 patients, 31.6%; P < 0.001) and more patients given placebo suffered grade 3 or 4 diarrhea compared with VSL#3 recipients (55.4% and 1.4%, P < 0.001). Daily bowel movements were 14.7 ± 6 and 5.1 ± 3 among placebo and VSL#3 recipients (P < 0.05), and the mean time to the use of loperamide was 86 ± 6 h for placebo patients and 122 ± 8 h for VSL#3 patients (P < 0.001). CONCLUSION: Probiotic lactic acid-producing bacteria are an easy, safe, and feasible approach to protect cancer patients against the risk of radiation-induced diarrhea. PMID:17352022

  13. Radiation-induced cognitive impairment-from bench to bedside

    PubMed Central

    Greene-Schloesser, Dana; Robbins, Mike E.

    2012-01-01

    Approximately 100 000 patients per year in the United States with primary and metastatic brain tumor survive long enough (>6 months) to develop radiation-induced brain injury. Before 1970, the human brain was thought to be radioresistant; the acute central nervous system (CNS) syndrome occurs after single doses of ≥30 Gy, and white matter necrosis can occur at fractionated doses of ≥60 Gy. Although white matter necrosis is uncommon with modern radiation therapy techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become increasingly important, having profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenic mechanisms involved in radiation-induced cognitive impairment. Although reductions in hippocampal neurogenesis and hippocampal-dependent cognitive function have been observed in rodent models, it is important to recognize that other brain regions are affected; non–hippocampal-dependent reductions in cognitive function occur. Neuroinflammation is viewed as playing a major role in radiation-induced cognitive impairment. During the past 5 years, several preclinical studies have demonstrated that interventional therapies aimed at modulating neuroinflammation can prevent/ameliorate radiation-induced cognitive impairment independent of changes in neurogenesis. Translating these exciting preclinical findings to the clinic offers the promise of improving the quality of life in patients with brain tumors who receive radiation therapy. PMID:23095829

  14. SPHINX Measurements of Radiation Induced Conductivity of Foam

    SciTech Connect

    Ballard, W.P.; Beutler, D.E.; Burt, M.; Dudley, K.J.; Stringer, T.A.

    1998-12-14

    Experiments on the SPHINX accelerator studying radiation-induced conductivity (RIC) in foam indicate that a field-exclusion boundary layer model better describes foam than a Maxwell-Garnett model that treats the conducting gas bubbles in the foam as modifying the dielectric constant. In both cases, wall attachment effects could be important but were neglected.

  15. Obstructive jaundice due to radiation-induced hepatic duct stricture

    SciTech Connect

    Chandrasekhara, K.L.; Iyer, S.K.

    1984-10-01

    A case of obstructive jaundice due to radiation-induced hepatic duct stricture is reported. The patient received postoperative radiation for left adrenal carcinoma, seven years prior to this admission. The sequelae of hepatobiliary radiation and their management are discussed briefly.

  16. Radiation-Induced Immune Modulation in Prostate Cancer

    DTIC Science & Technology

    2007-01-01

    postulate that radiation-induced TNFR I probably acts as a “ brake ” on immunity. Because of the high risk of the proposed experiment and high...the rest of body shielded. Tumor diameters were measured in three mutually orthogonal dimensions at 2–3 day intervals with a vernier caliper and the

  17. Radiation-induced nonlinear optical response of quartz fibers

    NASA Astrophysics Data System (ADS)

    Plaksin, O. A.

    2006-10-01

    The intensity of radiation-induced luminescence and transient optical losses in KU-1 (Russia) and K-3 (Japan) quartz glass optical tibers irradiated in a fast pulsed fission reactor (a pulse duration of 80 μs and a neutron flux up to 7 × 1016 cm 2 s 2) has been measured in the visible range. The intensity of the fast luminescence component nonlinearly depends on the neutron flux. The luminescence intensity and the transient optical losses depend on the probe light intensity. Suppression of radiation-induced luminescence is observed at wavelengths that are longer or shorter than the probe light wavelength. Light probing leads to an increase in transient optical losses and a more rapid recovery of transparency. A model of two photon fluxes is proposed to analyze the relationship of the effects of suppression of radiation-induced luminescence and the increase in optical losses upon light probing. The effect of suppression of radiation-induced luminescence can be used to control the optical properties of fibers in radiation fields.

  18. Data acquisition system used in radiation induced electrical degradation experiments

    SciTech Connect

    White, D.P.

    1995-04-01

    Radiation induced electrical degradation (RIED) of ceramic materials has recently been reported and is the topic of much research at the present time. The object of this report is to describe the data acquisition system for an experiment designed to study RIED at the High Flux Beam Reactor (HFBR) at Brookhaven National Laboratory.

  19. Prevention of Radiation-Induced Breast Cancer by Amifostine

    DTIC Science & Technology

    2006-06-01

    acetylcysteine and captopril . 4 Task 2. To determine if post-irradiation amifostine treatment can reduce the frequency of radiation-induced ductal...similar to amifostine but more suited to oral administration such as WR- 3689, WR151327, N-acetylcysteine and captopril . The first task is to

  20. Prevention of Radiation-Induced Breast Cancer by Amifostine

    DTIC Science & Technology

    2009-01-01

    acetylcysteine and captopril . 4 Task 2. To determine if post-irradiation amifostine treatment can reduce the frequency of radiation-induced ductal...similar to amifostine but more suited to oral administration such as WR- 3689, WR151327, N-acetylcysteine and captopril . The first task is to

  1. Prevention of Radiation-Induced Breast Cancer by Amifostine

    DTIC Science & Technology

    2007-12-01

    and captopril . 4 Task 2. To determine if post-irradiation amifostine treatment can reduce the frequency of radiation-induced ductal dysplasia...amifostine but more suited to oral administration such as WR- 3689, WR151327, N-acetylcysteine and captopril . The first task is to determine if

  2. Radiation induces senescence and a bystander effect through metabolic alterations.

    PubMed

    Liao, E-C; Hsu, Y-T; Chuah, Q-Y; Lee, Y-J; Hu, J-Y; Huang, T-C; Yang, P-M; Chiu, S-J

    2014-05-22

    Cellular senescence is a state of irreversible growth arrest; however, the metabolic processes of senescent cells remain active. Our previous studies have shown that radiation induces senescence of human breast cancer cells that display low expression of securin, a protein involved in control of the metaphase-anaphase transition and anaphase onset. In this study, the protein expression profile of senescent cells was resolved by two-dimensional gel electrophoresis to investigate associated metabolic alterations. We found that radiation induced the expression and activation of glyceraldehyde-3-phosphate dehydrogenase that has an important role in glycolysis. The activity of lactate dehydrogenase A, which is involved in the conversion of pyruvate to lactate, the release of lactate and the acidification of the extracellular environment, was also induced. Inhibition of glycolysis by dichloroacetate attenuated radiation-induced senescence. In addition, radiation also induced activation of the 5'-adenosine monophosphate-activated protein kinase (AMPK) and nuclear factor kappa B (NF-κB) pathways to promote senescence. We also found that radiation increased the expression of monocarboxylate transporter 1 (MCT1) that facilitates the export of lactate into the extracellular environment. Inhibition of glycolysis or the AMPK/NF-κB signalling pathways reduced MCT1 expression and rescued the acidification of the extracellular environment. Interestingly, these metabolic-altering signalling pathways were also involved in radiation-induced invasion of the surrounding, non-irradiated breast cancer and normal endothelial cells. Taken together, radiation can induce the senescence of human breast cancer cells through metabolic alterations.

  3. The structure-mechanical relationship of palm vascular tissue.

    PubMed

    Wang, Ningling; Liu, Wangyu; Huang, Jiale; Ma, Ke

    2014-08-01

    The structure-mechanical relationship of palm sheath is studied with numerical and experimental methods. The cellular structure of the vascular tissue is rebuilt with an image-based reconstruction method and used to create finite element models. The validity of the models is firstly verified with the results from the tensile tests. Then, the cell walls inside each of the specific regions (fiber cap, vessel, xylem, etc.) are randomly removed to obtain virtually imperfect structures. By comparing the magnitudes of performance degradation in the different imperfect structures, the influences of each region on the overall mechanical performances of the vascular tissue are discussed. The longitudinal stiffness and yield strength are sensitive to the defects in the vessel regions. While in the transverse directions (including the radial and tangential directions), the parenchymatous tissue determines the mechanical properties of the vascular tissue. Moreover, the hydraulic, dynamic response and energy absorption behavior of the vascular tissue are numerically explored. The flexibility of natural palm tissue enhances its impact resistance. Under the quasi-static compression, the cell walls connecting the fiber cap and the vessel dissipate more energy. The dominant role of the fiber cap in the plastic energy dissipation under high-speed impact is observed. And the radially-arranged fiber cap also allows the palm tissue to improve its tangential mechanical performances under hydraulic pressure.

  4. Dietary Curcumin Increases Antioxidant Defenses in Lung, Ameliorates Radiation-Induced Pulmonary Fibrosis, and Improves Survival in Mice

    PubMed Central

    Lee, James C.; Kinniry, Paul A.; Arguiri, Evguenia; Serota, Matthew; Kanterakis, Stathis; Chatterjee, Shampa; Solomides, Charalambos C.; Javvadi, Prashanthi; Koumenis, Constantinos; Cengel, Keith A.; Christofidou-Solomidou, Melpo

    2010-01-01

    The effectiveness of lung radiotherapy is limited by radiation tolerance of normal tissues and by the intrinsic radiosensitivity of lung cancer cells. The chemopreventive agent curcumin has known antioxidant and tumor cell radiosensitizing properties. Its usefulness in preventing radiation-induced pneumonopathy has not been tested previously. We evaluated dietary curcumin in radiation-induced pneumonopathy and lung tumor regression in a murine model. Mice were given 1%or 5%(w/w) dietary curcumin or control diet prior to irradiation and for the duration of the experiment. Lungs were evaluated at 3 weeks after irradiation for acute lung injury and inflammation by evaluating bronchoalveolar lavage (BAL) fluid content for proteins, neutrophils and at 4 months for pulmonary fibrosis. In a separate series of experiments, an orthotopic model of lung cancer using intravenously injected Lewis lung carcinoma (LLC) cells was used to exclude possible tumor radioprotection by dietary curcumin. In vitro, curcumin boosted antioxidant defenses by increasing heme oxygenase 1 (HO-1) levels in primary lung endothelial and fibroblast cells and blocked radiation-induced generation of reactive oxygen species (ROS). Dietary curcumin significantly increased HO-1 in lungs as early as after 1 week of feeding, coinciding with a steady-state level of curcumin in plasma. Although both 1% and 5% w/w dietary curcumin exerted physiological changes in lung tissues by significantly decreasing LPS-induced TNF-α production in lungs, only 5%dietary curcumin significantly improved survival of mice after irradiation and decreased radiation-induced lung fibrosis. Importantly, dietary curcumin did not protect LLC pulmonary metastases from radiation killing. Thus dietary curcumin ameliorates radiation-induced pulmonary fibrosis and increases mouse survival while not impairing tumor cell killing by radiation. PMID:20426658

  5. Protein and miRNA profiling of radiation-induced skin injury in rats: the protective role of peroxiredoxin-6 against ionizing radiation.

    PubMed

    Zhang, Shuyu; Wang, Wenjie; Gu, Qing; Xue, Jiao; Cao, Han; Tang, Yiting; Xu, Xiaohui; Cao, Jianping; Zhou, Jundong; Wu, Jinchang; Ding, Wei-Qun

    2014-04-01

    Radiation-induced skin injury is a serious concern during radiotherapy. However, the molecular mechanism underlying the pathogenesis of radiation-induced skin injury has not been extensively reported. Most biological functions are performed and regulated by proteins and noncoding RNAs, including microRNAs (miRNAs). The interplay between mRNA and miRNA has been implicated in disease initiation and progression. Technical advances in genomics and proteomics have enabled the exploration of the etiology of diseases and have the potential to broaden our understanding of the molecular pathogenesis of radiation-induced skin injury. In this study, we compared the protein and miRNA expression in rat skin irradiated with a 45-Gy electron beam with expression from adjacent normal tissues. We found 24 preferentially expressed proteins and 12 dysregulated miRNAs in irradiated skin. By analyzing the protein and miRNA profiles using bioinformatics tools, we identified a possible interaction between miR-214 and peroxiredoxin-6 (PRDX-6). Next, we investigated the expression of PRDX-6 and the consequences of its dysregulation. PRDX-6 is suppressed by radiation-inducible miR-214 and is involved in the pathogenesis of radiation-induced skin injury. Overexpression of PRDX-6 conferred radioresistance on cells, decreased cell apoptosis, and preserved mitochondrial integrity after radiation exposure. In addition, in vivo transfection with PRDX-6 reduced radiation-induced reactive oxygen species and the malondialdehyde concentration and ameliorated radiation-induced skin damage in rats. Our present findings illustrate the molecular changes during radiation-induced skin injury and the important role of PRDX-6 in ameliorating this damage in rats. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Radiation-induced endometriosis in Macaca mulatta

    SciTech Connect

    Fanton, J.W.; Golden, J.G. )

    1991-05-01

    Female rhesus monkeys received whole-body doses of ionizing radiation in the form of single-energy protons, mixed-energy protons, X rays, and electrons. Endometriosis developed in 53% of the monkeys during a 17-year period after exposure. Incidence rates for endometriosis related to radiation type were: single-energy protons, 54%; mixed-energy protons, 73%; X rays, 71%; and electrons, 57%. The incidence of endometriosis in nonirradiated control monkeys was 26%. Monkeys exposed to single-energy protons, mixed-energy protons, and X rays developed endometriosis at a significantly higher rate than control monkeys (chi 2, P less than 0.05). Severity of endometriosis was staged as massive, moderate, and minimal. The incidence of these stages were 65, 16, and 19%, respectively. Observations of clinical disease included weight loss in 43% of the monkeys, anorexia in 35%, space-occupying masses detected by abdominal palpation in 55%, abnormal ovarian/uterine anatomy on rectal examination in 89%, and radiographic evidence of abdominal masses in 38%. Pathological lesions were endometrial cyst formation in 69% of the monkeys, adhesions of the colon in 66%, urinary bladder in 50%, ovaries in 86%, and ureters in 44%, focal nodules of endometrial tissue throughout the omentum in 59%, and metastasis in 9%. Clinical management of endometriosis consisted of debulking surgery and bilateral salpingo-oophorectomy combined in some cases with total abdominal hysterectomy. Postoperative survival rates at 1 and 5 years for monkeys recovering from surgery were 48 and 36%, respectively.

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

    SciTech Connect

    Yano, Hiroyuki; Hamanaka, Ryoji; Nakamura, Miki; Sumiyoshi, Hideaki; Matsuo, Noritaka; Yoshioka, Hidekatsu

    2012-02-17

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

  8. Multiphase poroelastic finite element models for soft tissue structure

    SciTech Connect

    Simon, B.R.

    1992-06-01

    During the last two decades. biological structures with soft tissue components have been modeled using poroelastic or mixture-based constitutive laws, i.e., the material is viewed as a deformable (porous) solid matrix that is saturated by mobile tissue fluid. These structures exhibit a highly nonlinear, history-dependent material behavior; undergo finite strains-, and may swell or shrink when tissue ionic concentrations are altered. Given the geometric and material complexity of soft tissue structures and that they are subjected to complicated initial and boundary conditions, finite element models (FEMs) have been very useful for quantitative structural analyses. This paper surveys recent applications of poroelastic and mixture-based theories and the associated FEMs for the study of the biomechanics of soft tissues, and indicates future directions for research in this area. Equivalent finite-strain poroelastic and mixture continuum biomechanical models are presented. Special attention is given to the identification of material properties using a porohyperelastic constitutive law and a total Lagrangian view for the formulation. The associated FEMS are then formulated to include this porohyperelastic material response and finite strains. Extensions of the theory are suggested in order to include inherent viscoelasticity, transport phenomena, and swelling in soft tissue structures. A number of biomechanical research areas are identified, and possible applications of the porohyperelastic and mixture-based FEMs are suggested.

  9. Multiphase poroelastic finite element models for soft tissue structures

    SciTech Connect

    Simon, B.R.

    1992-12-01

    During the last two decades, biological structures with soft tissue components have been modeled using poroelastic or mixture-based constitutive laws, i.e., the material is viewed as a deformable (porous) solid matrix that is saturated by mobile tissue fluid. These structures exhibit a highly nonlinear, history-dependent material behavior; undergo finite strains; and may swell or shrink when tissue ionic concentrations are altered. Give the geometric and material complexity of soft tissue structures and that they are subjected to complicated initial and boundary conditions, finite element models (FEMs) have been very useful for quantitative structural analyses. This paper surveys recent applications of poroelastic and mixture-based theories and the associated FEMs for the study of the biomechanics of soft tissues, and indicates future directions for research in this area. Equivalent finite-strain poroelastic and mixture continuum biomechanical models are presented. Special attention is given to the identification of material properties using a porohyperelastic constitutive law ans a total Lagrangian view for the formulation. The associated FEMs are then formulated to include this porohyperelastic material response and finite strains. Extensions of the theory are suggested in order to include inherent viscoelasticity, transport phenomena, and swelling in soft tissue structures. A number of biomechanical research areas are identified, and possible applications of the porohyperelastic and mixture-based FEMs are suggested. 62 refs., 11 figs., 3 tabs.

  10. Gamma radiation induced resistivity changes in Iron

    NASA Astrophysics Data System (ADS)

    Tundwal, Ambika; Kumar, V.; Datta, A.

    2017-03-01

    Monte Carlo Code JA-IPU is used for estimation of Frenkel pairs and their effect on change of resistivity of Iron on irradiation by gamma spectrum of Co60. The Code includes three cascade processes of incident gamma, produced electrons and recoiled atoms and simulation of the lattice structure of the target material. Change in experimentally measured resistivity of Iron is found to vary with number of Frenkel pairs as (x - 1) ln N d .

  11. Risk and survival outcomes of radiation-induced CNS tumors.

    PubMed

    Lee, Jessica W; Wernicke, A Gabriella

    2016-08-01

    Patients treated with cranial radiation are at risk of developing secondary CNS tumors. Understanding the incidence, treatment, and long-term outcomes of radiation-induced CNS tumors plays a role in clinical decision-making and patient education. Additionally, as meningiomas and pituitary tumors have been detected at increasing rates across all ages and may potentially be treated with radiation, it is important to know and communicate the risk of secondary tumors in children and adults. After conducting an extensive literature search, we identified publications that report incidence and long-term outcomes of radiation-induced CNS tumors. We reviewed 14 studies in children, which reported that radiation confers a 7- to 10-fold increase in subsequent CNS tumors, with a 20-year cumulative incidence ranging from 1.03 to 28.9 %. The latency period for secondary tumors ranged from 5.5 to 30 years, with gliomas developing in 5-10 years and meningiomas developing around 15 years after radiation. We also reviewed seven studies in adults, where the two strongest studies showed no increased risk while the remaining studies found a higher risk compared to the general population. The latency period for secondary CNS tumors in adults ranged from 5 to 34 years. Treatment and long-term outcomes of radiation-induced CNS tumors have been documented in four case series, which did not conclusively demonstrate that secondary CNS tumors fared worse than primary CNS tumors. Radiation-induced CNS tumors remain a rare occurrence that should not by itself impede radiation treatment. Additional investigation is needed on the risk of radiation-induced tumors in adults and the long-term outcomes of these tumors.

  12. Automatic segmentation of histological structures in mammary gland tissue sections

    SciTech Connect

    Fernandez-Gonzalez, Rodrigo; Deschamps, Thomas; Idica, Adam K.; Malladi, Ravikanth; Ortiz de Solorzano, Carlos

    2004-02-17

    Real-time three-dimensional (3D) reconstruction of epithelial structures in human mammary gland tissue blocks mapped with selected markers would be an extremely helpful tool for breast cancer diagnosis and treatment planning. Besides its clear clinical application, this tool could also shed a great deal of light on the molecular basis of breast cancer initiation and progression. In this paper we present a framework for real-time segmentation of epithelial structures in two-dimensional (2D) images of sections of normal and neoplastic mammary gland tissue blocks. Complete 3D rendering of the tissue can then be done by surface rendering of the structures detected in consecutive sections of the blocks. Paraffin embedded or frozen tissue blocks are first sliced, and sections are stained with Hematoxylin and Eosin. The sections are then imaged using conventional bright field microscopy and their background is corrected using a phantom image. We then use the Fast-Marching algorithm to roughly extract the contours of the different morphological structures in the images. The result is then refined with the Level-Set method which converges to an accurate (sub-pixel) solution for the segmentation problem. Finally, our system stacks together the 2D results obtained in order to reconstruct a 3D representation of the entire tissue block under study. Our method is illustrated with results from the segmentation of human and mouse mammary gland tissue samples.

  13. Clinical Experiences with Radiation Induced Thyroid Cancer after Chernobyl

    PubMed Central

    Reiners, Christoph

    2011-01-01

    The risk of developing thyroid cancer increases considerably after exposure to external or internal radiation, especially in children below the age of 10. After the Chernobyl reactor accident, the yearly incidence of childhood thyroid cancer in Belarus increased to approximately 40 per 1.000.000 in girls and to roughly 20 per 1.000.000 in boys compared to approximately 0.5 cases per 1.000.000 prior to the accident. Typically, young children with thyroid cancer after radiation exposure present in ≈95% of the cases as papillary cancers, in ≈50% as invasive tumors growing outside the thyroid capsule, in ≈65% with lymph node metastases and in ≈15% with distant metastases. A joint Belarusian-German project starting in April 1993 that combined treatment with surgery and radioiodine was organized in 237 selected children from Belarus who were exposed to the Chernobyl fallout and had advanced stages of thyroid cancer. The study group included 141 girls and 96 boys. Their median age at the time of the accident was 1.7 years; whereas the median age at the time of diagnosis was 12.4 years. With the exception of two cases with follicular histology, the majority of the patients had been diagnosed with papillary thyroid cancers. In 63%, the tumor had grown outside the thyroid capsule and invaded the tissue of the neck (pT4). Nearly all of the selected cases (96%) showed-up with lymph node metastases (pN1) and 43% of the patients with distant metastases mainly to the lungs (pM1). In 58% of the children, complete remissions of thyroid cancer could be achieved until December 31st 2010 and in 34% of the children, stable partial remissions; in the remaining 8% of the patients, partial remissions were observed. The risk of radiation-induced thyroid cancer increased considerably in children and adolescents who were affected by the Chernobyl reactor accident. In spite of the fact, that thyroid cancers in young children seem to behave more aggressively than in older patients, the

  14. X-ray phase contrast imaging of calcified tissue and biomaterial structure in bioreactor engineered tissues.

    PubMed

    Appel, Alyssa A; Larson, Jeffery C; Garson, Alfred B; Guan, Huifeng; Zhong, Zhong; Nguyen, Bao-Ngoc B; Fisher, John P; Anastasio, Mark A; Brey, Eric M

    2015-03-01

    Tissues engineered in bioreactor systems have been used clinically to replace damaged tissues and organs. In addition, these systems are under continued development for many tissue engineering applications. The ability to quantitatively assess material structure and tissue formation is critical for evaluating bioreactor efficacy and for preimplantation assessment of tissue quality. Techniques that allow for the nondestructive and longitudinal monitoring of large engineered tissues within the bioreactor systems will be essential for the translation of these strategies to viable clinical therapies. X-ray Phase Contrast (XPC) imaging techniques have shown tremendous promise for a number of biomedical applications owing to their ability to provide image contrast based on multiple X-ray properties, including absorption, refraction, and scatter. In this research, mesenchymal stem cell-seeded alginate hydrogels were prepared and cultured under osteogenic conditions in a perfusion bioreactor. The constructs were imaged at various time points using XPC microcomputed tomography (µCT). Imaging was performed with systems using both synchrotron- and tube-based X-ray sources. XPC µCT allowed for simultaneous three-dimensional (3D) quantification of hydrogel size and mineralization, as well as spatial information on hydrogel structure and mineralization. Samples were processed for histological evaluation and XPC showed similar features to histology and quantitative analysis consistent with the histomorphometry. These results provide evidence of the significant potential of techniques based on XPC for noninvasive 3D imaging engineered tissues grown in bioreactors. © 2014 Wiley Periodicals, Inc.

  15. X-ray Phase Contrast Imaging of Calcified Tissue and Biomaterial Structure in Bioreactor Engineered Tissues

    SciTech Connect

    Appel, Alyssa A.; Larson, Jeffery C.; Garson, III, Alfred B.; Guan, Huifeng; Zhong, Zhong; Nguyen, Bao-Ngoc; Fisher, John P.; Anastasio, Mark A.; Brey, Eric M.

    2014-11-04

    Tissues engineered in bioreactor systems have been used clinically to replace damaged tissues and organs. In addition, these systems are under continued development for many tissue engineering applications. The ability to quantitatively assess material structure and tissue formation is critical for evaluating bioreactor efficacy and for preimplantation assessment of tissue quality. These techniques allow for the nondestructive and longitudinal monitoring of large engineered tissues within the bioreactor systems and will be essential for the translation of these strategies to viable clinical therapies. X-ray Phase Contrast (XPC) imaging techniques have shown tremendous promise for a number of biomedical applications owing to their ability to provide image contrast based on multiple X-ray properties, including absorption, refraction, and scatter. In this research, mesenchymal stem cell-seeded alginate hydrogels were prepared and cultured under osteogenic conditions in a perfusion bioreactor. The constructs were imaged at various time points using XPC microcomputed tomography (µCT). Imaging was performed with systems using both synchrotron- and tube-based X-ray sources. XPC µCT allowed for simultaneous three-dimensional (3D) quantification of hydrogel size and mineralization, as well as spatial information on hydrogel structure and mineralization. Samples were processed for histological evaluation and XPC showed similar features to histology and quantitative analysis consistent with the histomorphometry. Furthermore, these results provide evidence of the significant potential of techniques based on XPC for noninvasive 3D imaging engineered tissues grown in bioreactors.

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

    PubMed

    Yano, Hiroyuki; Hamanaka, Ryoji; Nakamura, Miki; Sumiyoshi, Hideaki; Matsuo, Noritaka; Yoshioka, Hidekatsu

    2012-02-17

    Radiation induced fibrosis occurs following a therapeutic or accidental radiation exposure in normal tissues. Tissue fibrosis is the excessive accumulation of collagen and other extracellular matrix components. This study investigated how ionizing radiation affects the expression level and signal pathway of type I collagen. Real time RT-RCR showed that both α1 and α2 chain of type I collagen mRNA were elevated from 48 h after irradiation with 10 Gy in NIH3T3 cells. The relative luciferase activities of both genes and type I collagen marker were elevated at 72 h. TGF-β1 mRNA was elevated earlier than those of type I collagen genes. A Western blot analysis showed the elevation of Smad phosphorylation at 72 h. Conversely, treatment with TGF-β receptor inhibitor inhibited the mRNA and relative luciferase activity of type I collagen. The phosphorylation of Smad was repressed with the inhibitor, and the luciferase activity was cancelled using a mutant construct of Smad binding site of α2(I) collagen gene. However, the MAPK pathways, p38, ERK1/2 and JNK, were not affected with specific inhibitors or siRNA. The data showed that the Smad pathway mediated the expression of type I collagen in radiation induced fibrosis. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Radiation-Induced Testicular Injury and Its Amelioration by Tinospora cordifolia (An Indian Medicinal Plant) Extract

    PubMed Central

    Sharma, Priyanka; Parmar, Jyoti; Sharma, Priyanka; Verma, Preeti; Goyal, P. K.

    2011-01-01

    The primary objective of this investigation is to determine the deleterious effects of sub lethal gamma radiation on testes and their possible inhibition by Tinospora cordifolia extract (TCE). For this purpose, one group of male Swiss albino mice was exposed to 7.5 Gy gamma radiation to serve as the irradiated control, while the other group received TCE (75 mg/kg b. wt./day) orally for 5 consecutive days half an hr before irradiation to serve as experimental. Exposure of animals to 7.5 Gy gamma radiation resulted into significant decrease in body weight, tissue weight, testes- body weight ratio and tubular diameter up to 15 days of irradiation. Cent percent mortality was recorded by day 17th in irradiated control, whereas all animals survived in experimental group. TCE pretreatment rendered significant increase in body weight, tissue weight, testes- body weight ratio and tubular diameter at various intervals as compared to irradiated group. Radiation induced histological lesions in testicular architecture were observed more severe in irradiated control then the experimental. TCE administration before irradiation significantly ameliorated radiation induced elevation in lipid peroxidation and decline in glutathione concentration in testes. These observations indicate the radio- protective potential of Tinospora cordifolia root extract in testicular constituents against gamma irradiation in mice. PMID:21350610

  18. Protective effects of Nigella sativa on gamma radiation-induced jejunal mucosal damage in rats.

    PubMed

    Orhon, Zeynep Nur; Uzal, Cem; Kanter, Mehmet; Erboga, Mustafa; Demiroglu, Murat

    2016-05-01

    The aim of this study was to compare the efficacy of Nigella sativa in protection of jejunal mucosa against harmful effects of gamma radiation. Radiotherapy group received abdominal gamma radiation of 15Gy in addition to physiological saline. Radiotherapy+Nigella sativa treatment group received abdominal gamma radiation of 15Gy in addition to Nigella sativa treatment in the amount of 400mg/kg. Radiotherapy and treatment groups were sacrificed 3 days after the exposure to irradiation. Then, jejunum samples were harvested for biochemical and histological assessment of mucosal injury. Nigella sativa treatment was found to significantly lower elevated tissue malondialdehyde (MDA) levels and, to raise reduced glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activity in intestinal tissues samples. Single dose 15Gy gamma-irradiation was noted to result in a marked jejunal mucosal injury. Three days after exposure to irradiation, the villi and Lieberkühn crypts were observed as denuded, and villous height diminished. Concomitantly with inflammatory cell invasion, capillary congestion and ulceration were observed in the atrophic mucosa. Nigella sativa treatment significantly attenuated the radiation induced morphological changes in the irradiated rat jejunal mucosa. Nigella sativa has protective effects against radiation-induced damage, suggesting that clinical transfer is feasible. Copyright © 2016 Elsevier GmbH. All rights reserved.

  19. Regulatory T Cells Promote β-Catenin–Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis

    SciTech Connect

    Xiong, Shanshan; Pan, Xiujie; Xu, Long; Yang, Zhihua; Guo, Renfeng; Gu, Yongqing; Li, Ruoxi; Wang, Qianjun; Xiao, Fengjun; Du, Li; Zhou, Pingkun; Zhu, Maoxiang

    2015-10-01

    Purpose: Radiation-induced pulmonary fibrosis results from thoracic radiation therapy and severely limits radiation therapy approaches. CD4{sup +}CD25{sup +}FoxP3{sup +} regulatory T cells (Tregs) as well as epithelium-to-mesenchyme transition (EMT) cells are involved in pulmonary fibrosis induced by multiple factors. However, the mechanisms of Tregs and EMT cells in irradiation-induced pulmonary fibrosis remain unclear. In the present study, we investigated the influence of Tregs on EMT in radiation-induced pulmonary fibrosis. Methods and Materials: Mice thoraxes were irradiated (20 Gy), and Tregs were depleted by intraperitoneal injection of a monoclonal anti-CD25 antibody 2 hours after irradiation and every 7 days thereafter. Mice were treated on days 3, 7, and 14 and 1, 3, and 6 months post irradiation. The effectiveness of Treg depletion was assayed via flow cytometry. EMT and β-catenin in lung tissues were detected by immunohistochemistry. Tregs isolated from murine spleens were cultured with mouse lung epithelial (MLE) 12 cells, and short interfering RNA (siRNA) knockdown of β-catenin in MLE 12 cells was used to explore the effects of Tregs on EMT and β-catenin via flow cytometry and Western blotting. Results: Anti-CD25 antibody treatment depleted Tregs efficiently, attenuated the process of radiation-induced pulmonary fibrosis, hindered EMT, and reduced β-catenin accumulation in lung epithelial cells in vivo. The coculture of Tregs with irradiated MLE 12 cells showed that Tregs could promote EMT in MLE 12 cells and that the effect of Tregs on EMT was partially abrogated by β-catenin knockdown in vitro. Conclusions: Tregs can promote EMT in accelerating radiation-induced pulmonary fibrosis. This process is partially mediated through β-catenin. Our study suggests a new mechanism for EMT, promoted by Tregs, that accelerates radiation-induced pulmonary fibrosis.

  20. Regulatory T Cells Promote β-Catenin--Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis.

    PubMed

    Xiong, Shanshan; Pan, Xiujie; Xu, Long; Yang, Zhihua; Guo, Renfeng; Gu, Yongqing; Li, Ruoxi; Wang, Qianjun; Xiao, Fengjun; Du, Li; Zhou, Pingkun; Zhu, Maoxiang

    2015-10-01

    Radiation-induced pulmonary fibrosis results from thoracic radiation therapy and severely limits radiation therapy approaches. CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) as well as epithelium-to-mesenchyme transition (EMT) cells are involved in pulmonary fibrosis induced by multiple factors. However, the mechanisms of Tregs and EMT cells in irradiation-induced pulmonary fibrosis remain unclear. In the present study, we investigated the influence of Tregs on EMT in radiation-induced pulmonary fibrosis. Mice thoraxes were irradiated (20 Gy), and Tregs were depleted by intraperitoneal injection of a monoclonal anti-CD25 antibody 2 hours after irradiation and every 7 days thereafter. Mice were treated on days 3, 7, and 14 and 1, 3, and 6 months post irradiation. The effectiveness of Treg depletion was assayed via flow cytometry. EMT and β-catenin in lung tissues were detected by immunohistochemistry. Tregs isolated from murine spleens were cultured with mouse lung epithelial (MLE) 12 cells, and short interfering RNA (siRNA) knockdown of β-catenin in MLE 12 cells was used to explore the effects of Tregs on EMT and β-catenin via flow cytometry and Western blotting. Anti-CD25 antibody treatment depleted Tregs efficiently, attenuated the process of radiation-induced pulmonary fibrosis, hindered EMT, and reduced β-catenin accumulation in lung epithelial cells in vivo. The coculture of Tregs with irradiated MLE 12 cells showed that Tregs could promote EMT in MLE 12 cells and that the effect of Tregs on EMT was partially abrogated by β-catenin knockdown in vitro. Tregs can promote EMT in accelerating radiation-induced pulmonary fibrosis. This process is partially mediated through β-catenin. Our study suggests a new mechanism for EMT, promoted by Tregs, that accelerates radiation-induced pulmonary fibrosis. Copyright © 2015. Published by Elsevier Inc.

  1. Amelioration of radiation-induced skin injury by HIV-TAT-mediated protein transduction of RP-1 from Rana pleurade.

    PubMed

    Zhang, Shuyu; Wang, Wenjie; Peng, Ying; Gu, Qing; Luo, Judong; Zhou, Jundong; Wu, Jinchang; Hou, Yinglong; Cao, Jianping

    2014-01-01

    Radiation-induced reactive oxygen species (ROS) can damage DNA and most other biological macromolecules in skin and radiation-induced skin injury is a serious concern for radiation therapy. Skin possesses an extremely efficient antioxidant system, which is conferred by two systems: antioxidant enzymes and small molecules that can scavenge ROS by donating electrons. Amphibian skin is a multifunctional organ, which protects against dangers of various oxidative stresses. Recently, a small peptide called RP-1 was isolated from the skin secretions of Rana pleurade, which shows strong antioxidant activity. However, this RP-1 peptide is limited because its inability to across the cell membrane. Protein transduction domains (PTDs) have demonstrated high efficiency for facilitating the internalization of both homologous and heterogeneous proteins into cells. This study aims to elucidate the protective effects of a HIV-TAT (TAT) PTD-coupled RP-1 fusion protein (TAT-RP1) on radiation-induced skin injury in vitro and in vivo. The synthesized fusion TAT-RP1 peptide can be incorporated into human keratinocyte HaCaT cells in a dose- and time-dependent manner without cytotoxicity. We then evaluated the protective role of TAT-RP1 against ionizing radiation. TAT-RP1 supplementation increased anti-superoxide anion ability of HaCaT cells and decreased HaCaT cell radiosensitivity to irradiation. Moreover, TAT-RP1 was able to penetrate the skin of rats, entering epidermis as well as the dermis of the subcutaneous layer in skin tissue. Topical spread of TAT-RP1 promoted the amelioration of radiation-induced skin damage in rats. These results suggest that TAT-RP1 has potential as a protein therapy for radiation-induced skin injury.

  2. Amelioration of Radiation-induced Skin Injury by HIV-TAT-Mediated Protein Transduction of RP-1 from Rana pleurade

    PubMed Central

    Zhang, Shuyu; Wang, Wenjie; Peng, Ying; Gu, Qing; Luo, Judong; Zhou, Jundong; Wu, Jinchang; Hou, Yinglong; Cao, Jianping

    2014-01-01

    Radiation-induced reactive oxygen species (ROS) can damage DNA and most other biological macromolecules in skin and radiation-induced skin injury is a serious concern for radiation therapy. Skin possesses an extremely efficient antioxidant system, which is conferred by two systems: antioxidant enzymes and small molecules that can scavenge ROS by donating electrons. Amphibian skin is a multifunctional organ, which protects against dangers of various oxidative stresses. Recently, a small peptide called RP-1 was isolated from the skin secretions of Rana pleurade, which shows strong antioxidant activity. However, this RP-1 peptide is limited because its inability to across the cell membrane. Protein transduction domains (PTDs) have demonstrated high efficiency for facilitating the internalization of both homologous and heterogeneous proteins into cells. This study aims to elucidate the protective effects of a HIV-TAT (TAT) PTD-coupled RP-1 fusion protein (TAT-RP1) on radiation-induced skin injury in vitro and in vivo. The synthesized fusion TAT-RP1 peptide can be incorporated into human keratinocyte HaCaT cells in a dose- and time-dependent manner without cytotoxicity. We then evaluated the protective role of TAT-RP1 against ionizing radiation. TAT-RP1 supplementation increased anti-superoxide anion ability of HaCaT cells and decreased HaCaT cell radiosensitivity to irradiation. Moreover, TAT-RP1 was able to penetrate the skin of rats, entering epidermis as well as the dermis of the subcutaneous layer in skin tissue. Topical spread of TAT-RP1 promoted the amelioration of radiation-induced skin damage in rats. These results suggest that TAT-RP1 has potential as a protein therapy for radiation-induced skin injury. PMID:24396285

  3. Plasma-Radiation-Induced Interface States in Metal-Nitride-Oxide-Silicon Structure of Charge-Coupled Device Image Sensor and Their Reduction Using Pulse-Time-Modulated Plasma

    NASA Astrophysics Data System (ADS)

    Okigawa, Mitsuru; Ishikawa, Yasushi; Samukawa, Seiji

    2003-04-01

    We found that ultraviolet (UV) light from helium discharge plasma and a halogen lamp clearly induce SiO2-Si interface states in a metal-silicon-nitride-oxide-silicon (MNOS) structure. A dark current originating in the interface states of charge-coupled-device (CCD) image sensors also increases by this UV irradiation. Pulse-time-modulated (TM) plasma suppresses the interface states, resulting in the CCD dark current, by decreasing the UV light. On the other hand, results of Capacitance-Voltage (CV) measurement did not show the difference between UV irradiation and no irradiation. This indicates that fixed charges in the SiO2 cannot be generated by the UV lights. Using optical filters, we revealed that a photon energy of 3.90 eV (318 nm) to 4.96 eV (250 nm) causes an increase in the interface states.

  4. [Protective effect of Liuweidihuang Pills against cellphone electromagnetic radiation-induced histomorphological abnormality, oxidative injury, and cell apoptosis in rat testes].

    PubMed

    Ma, Hui-rong; Cao, Xiao-hui; Ma, Xue-lian; Chen, Jin-jin; Chen, Jing-wei; Yang, Hui; Liu, Yun-xiao

    2015-08-01

    To observe the effect of Liuweidihuang Pills in relieving cellphone electromagnetic radiation-induced histomorphological abnormality, oxidative injury, and cell apoptosis in the rat testis. Thirty adult male SD rats were equally randomized into a normal, a radiated, and a Liuweidihuang group, the animals in the latter two groups exposed to electromagnetic radiation of 900 MHz cellphone frequency 4 hours a day for 18 days. Meanwhile, the rats in the Liuweidihuang group were treated with the suspension of Liuweidihuang Pills at 1 ml/100 g body weight and the other rats intragastrically with the equal volume of purified water. Then all the rats were killed for observation of testicular histomorphology by routine HE staining, measurement of testicular malondialdehyde (MDA) and glutathione (GSH) levels by colorimetry, and determination of the expressions of bax and bcl-2 proteins in the testis tissue by immunohistochemistry. Compared with the normal controls, the radiated rats showed obviously loose structure, reduced layers of spermatocytes, and cavitation in the seminiferous tubules. Significant increases were observed in the MDA level (P < 0.01) and bax expression (P < 0.01) but decreases in the GSH level (P < 0.01) and bcl-2 expression (P < 0.01) in the testis issue of the radiated rats. In comparison with the radiated rats, those of the Liuweidihuang group exhibited nearly normal testicular structure, significantly lower MDA level (P < 0.05), bax expression (P < 0.01), and bcl-2 expression (P < 0.01). Liuweidihuang Pills can improve cellphone electromagnetic radiation-induced histomorphological abnormality of the testis tissue and reduce its oxidative damage and cell apoptosis.

  5. FTIR protein secondary structure analysis of human ascending aortic tissues.

    PubMed

    Bonnier, Franck; Rubin, Sylvain; Debelle, Laurent; Ventéo, Lydie; Pluot, Michel; Baehrel, Bernard; Manfait, Michel; Sockalingum, Ganesh D

    2008-08-01

    The advent of moderate dilatations in ascending aortas is often accompanied by structural modifications of the main components of the aortic tissue, elastin and collagen. In this study, we have undertaken an approach based on FTIR microscopy coupled to a curve-fitting procedure to analyze secondary structure modifications in these proteins in human normal and pathological aortic tissues. We found that the outcome of the aortic pathology is strongly influenced by these proteins, which are abundant in the media of the aortic wall, and that the advent of an aortic dilatation is generally accompanied by a decrease of parallel beta-sheet structures. Elastin, essentially composed of beta-sheet structures, seems to be directly related to these changes and therefore indicative of the elastic alteration of the aortic wall. Conventional microscopy and confocal fluorescence microscopy were used to compare FTIR microscopy results with the organization of the elastic fibers present in the tissues. This in-vitro study on 6 patients (three normal and three pathologic), suggests that such a spectroscopic marker, specific to aneurismal tissue characterization, could be important information for surgeons who face the dilemma of moderate aortic tissue dilatation of the ascending aortas.

  6. Involvement of intracellular expression of FGF12 in radiation-induced apoptosis in mast cells.

    PubMed

    Nakayama, Fumiaki; Müller, Kerstin; Hagiwara, Akiko; Ridi, Roland; Akashi, Makoto; Meineke, Viktor

    2008-09-01

    Several fibroblast growth factors (FGFs) are able to reduce and improve radiation-induced tissue damage through the activation of surface fibroblast growth factor receptors (FGFRs). In contrast, some FGFs lack classical signal sequences, which play roles in the release of FGFs, and the intracellular function of these FGFs is not well clarified. In this study, we evaluated the transcript levels of 22 FGFs in a human mast cell line, HMC-1, using quantitative RT-PCR and found that FGF2 and FGF12 were expressed in HMC-1 cells. FGF12 not only lacks classical signal sequences but also fails to activate FGFRs. HMC-1 cells were transfected with an expression vector of FGF12 to clarify the intracellular function of FGF12 after irradiation. The overexpression of FGF12 in HMC-1 cells decreased ionizing radiation-induced apoptosis, and siRNA-mediated repression of FGF12 expression augmented apoptosis in HMC-1 cells. The overexpression of FGF12 strongly suppressed the marked augmentation of apoptosis induced by inhibition of the MEK/ERK pathway with PD98059. In contrast, the mitogen-activated protein kinase (MAPK) scaffold protein islet brain 2 (IB2), which was reported to bind to FGF12, did not interfere with the anti-apoptotic effect of FGF12. The expression of FGF12 transcripts was also detected in murine cultured mast cells derived from bone marrow or fetal skin. These findings suggest that FGF12 intracellularly suppresses radiation-induced apoptosis in mast cells independently of IB2.

  7. Oligomer formation in the radiation-induced polymerization of styrene

    NASA Astrophysics Data System (ADS)

    Harayma, Hiroshi; Al-Sheikhly, Mohamad; Silverman, Joseph

    2003-12-01

    Analyses of the oligomers formed in radiation-induced polymerization of purified styrene were performed. The principal dimeric products were cis- and trans-diphenyl-cyclobutane with a relatively small amount of 1-phenyltetralin; the trimeric products were the optical isomers of 1-phenyl-4-[1'-phenylethyl-(1')]-tetralin in gamma-ray and 60 MeV proton irradiation. Oligomer formation increased with increasing dose, but more gradually than the linear formation of high polymer with dose. The yield was 0.25-3.1 μmol/J at low doses and decreased to an asymptotic value of 0.15 at higher doses. It appears that oligomers act as chain transfer agents during the polymerization reaction which would account for the observed decrease in molecular weight of the high polymer with increase in dose. Although the thermal and radiation-induced polymerization of styrene have different initiation steps, the oligomers produced by both reactions are similar in composition.

  8. Faecal microbiota transplantation protects against radiation-induced toxicity.

    PubMed

    Cui, Ming; Xiao, Huiwen; Li, Yuan; Zhou, Lixin; Zhao, Shuyi; Luo, Dan; Zheng, Qisheng; Dong, Jiali; Zhao, Yu; Zhang, Xin; Zhang, Junling; Lu, Lu; Wang, Haichao; Fan, Saijun

    2017-04-01

    Severe radiation exposure may cause acute radiation syndrome, a possibly fatal condition requiring effective therapy. Gut microbiota can be manipulated to fight against many diseases. We explored whether intestinal microbe transplantation could alleviate radiation-induced toxicity. High-throughput sequencing showed that gastrointestinal bacterial community composition differed between male and female mice and was associated with susceptibility to radiation toxicity. Faecal microbiota transplantation (FMT) increased the survival rate of irradiated animals, elevated peripheral white blood cell counts and improved gastrointestinal tract function and intestinal epithelial integrity in irradiated male and female mice. FMT preserved the intestinal bacterial composition and retained mRNA and long non-coding RNA expression profiles of host small intestines in a sex-specific fashion. Despite promoting angiogenesis, sex-matched FMT did not accelerate the proliferation of cancer cells in vivo FMT might serve as a therapeutic to mitigate radiation-induced toxicity and improve the prognosis of tumour patients after radiotherapy.

  9. Radiation-induced decomposition of explosives under extreme conditions

    SciTech Connect

    Giefers, Hubertus; Pravica, Michael; Yang, Wenge; Liermann, Peter

    2008-11-03

    We present high-pressure and high temperature studies of the synchrotron radiation-induced decomposition of powder secondary high explosives pentaerythritol tetranitrate (PETN) and 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) using white beam synchrotron radiation at the 16 BM-B and 16 BM-D sectors of the HP-CAT beamline at the Advanced Photon Source. The radiation-induced decomposition rate TATB showed dramatic slowing with pressure up to 26.6 GPa (the highest pressure studied), implying a positive activation volume of the activated complex. The decomposition rate of PETN varied little with pressure up to 15.7 GPa (the highest pressure studied). Diffraction line intensities were measured as a function of time using energy-dispersive methods. By measuring the decomposition rate as a function of pressure and temperature, kinetic and other constants associated with the decomposition reactions were extracted.

  10. Caffeine Markedly Enhanced Radiation-Induced Bystander Effects

    NASA Astrophysics Data System (ADS)

    Jiang, Erkang; Wu, Lijun

    2009-04-01

    In this paper it is shown that incubation with 2 mM caffeine enhanced significantly the MN (micronucleus) formation in both the 1 cGy α-particle irradiated and non-irradiated bystander regions. Moreover, caffeine treatment made the non-irradiated bystander cells more sensitive to damage signals. Treated by c-PTIO(2-(4-carboxy-phenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide), a nitric oxide (NO) scavenger, the MN frequencies were effectively inhibited, showing that nitric oxide might be very important in mediating the enhanced damage. These results indicated that caffeine enhanced the low dose α-particle radiation-induced damage in irradiated and non-irradiated bystander regions, and therefore it is important to investigate the relationship between the radiosensitizer and radiation-induced bystander effects (RIBE).

  11. Radioadaptive response for protection against radiation-induced teratogenesis.

    PubMed

    Okazaki, Ryuji; Ootsuyama, Akira; Norimura, Toshiyuki

    2005-03-01

    To clarify the characteristics of the radioadaptive response in mice, we compared the incidence of radiation-induced malformations in ICR mice. Pregnant ICR mice were exposed to a priming dose of 2 cGy (667 muGy/min) on day 9.5 of gestation and to a challenging dose of 2 Gy (1.04 Gy/min) 4 h later and were killed on day 18.5 of gestation. The incidence of malformations and prenatal death and fetal body weights were studied. The incidence of external malformations was significantly lower (by approximately 10%) in the primed (2 cGy + 2 Gy) mice compared to the unprimed (2 Gy alone) mice. However, there were no differences in the incidence of prenatal death or the skeletal malformations or the body weights between primed and unprimed mice. These results suggest that primary conditioning with low doses of radiation suppresses radiation-induced teratogenesis.

  12. Radiation induced viscous flow in amorphous thin films

    NASA Astrophysics Data System (ADS)

    Mayr, S. G.; Ashkenazy, Y.; Averback, R. S.

    2003-03-01

    We investigate surface roughness and stress relaxation in amorphous thin films during ion beam irradiation by a combination of experiments and molecular dynamics simulations. These experiments show, that smoothing occurs by a viscous mechanism. With computer simulations we investigate the model system CuTi, and find that radiation induced viscous flow is independent of the recoil energy between 100 and 15keV, when compared on the basis of defect production. Additionally we can identify a threshold recoil energy for flow of approximately 10eV. We show, that point defects can mediate the flow, by injection of interstitial and vacancy-like defects, which induce the same amount of flow as recoil events. The results are compared with the thermal spike model of radiation induced viscous flow.

  13. Dose and volume impact on radiation-induced xerostomia.

    PubMed

    Marmiroli, Luca; Salvi, Giovanna; Caiazza, Adolfo; Di Rienzo, Luigi; Massaccesi, Mariangela; Murino, Paola; Macchia, Gabriella

    2005-01-01

    Radiation-induced xerostomia consists in the chronic dryness of the mouth caused by parotid gland irradiation. Parotid glands produce approximately 60% of saliva while the rest is secreted by submandibular and accessory salivary glands. Methods of measuring the salivary output are essentially represented by 99mTc-pertechnate scintigraphy or simpler albeit less accurate methods in stimulated or unstimulated saliva. There are subjective and objective criteria of classification and grading of the secretion of saliva. Radiation-induced xerostomia, namely the residual salivary gland function is evidently associated with the mean dose absorbed. The salivary output tends to decrease after the end of radiotherapy. The partial dose-volume is substantially correlated with the mean dose to the whole gland. As for ipsilateral irradiation for head and neck cancer, conformal RT or IMRT allow to spare the contralateral parotid gland without increasing the risk of contralateral nodal recurrences. The monitoring system of late toxicity used by the authors is presented.

  14. Radiation-induced transient darkening of optically transparent polymers

    SciTech Connect

    Downey, S.W.; Builta, L.A.; Carlson, R.L.; Czuchlewski, S.J.; Moir, D.C.

    1986-11-15

    Results are presented for the radiation-induced transient darkening of thin organic polymer films normally used as Cerenkov light emissions sources. The radiation source is a 27-MeV, 10-..mu..C, 200-ns electron beam generated by the PHERMEX accelerator. The typical dose for a single pulse is 5 Mrad. At this dose, the broadband time-resolved percent transmission above 520 nm was measured for four common polymers: polyimide (Kapton-H), polyethylene terephthalate (Mylar), cellulose acetate, and high-density polyethylene. Kapton was found to darken the most and polyethylene darkened the least. The recovery time to normal transmission for Kapton was found to be greater than 10--20 ..mu..s. The radiation-induced attenuation coefficient is shown to depend on electronic band energy separation. The results show that Kapton is not the material of choice for a Cerenkov light source.

  15. Three-dimensional structure of brain tissue at submicrometer resolution

    NASA Astrophysics Data System (ADS)

    Saiga, Rino; Mizutani, Ryuta; Inomoto, Chie; Takekoshi, Susumu; Nakamura, Naoya; Tsuboi, Akio; Osawa, Motoki; Arai, Makoto; Oshima, Kenichi; Itokawa, Masanari; Uesugi, Kentaro; Takeuchi, Akihisa; Terada, Yasuko; Suzuki, Yoshio

    2016-01-01

    Biological objects are composed of submicrometer structures such as cells and organelles that are essential for their functions. Here, we report on three-dimensional X-ray visualization of cells and organelles at resolutions up to 100 nm by imaging microtomography (micro-CT) equipped with Fresnel zone plate optics. Human cerebral tissue, fruit fly cephalic ganglia, and Escherichia coli bacteria labeled with high atomic-number elements were embedded in epoxy resin and subjected to X-ray microtomography at the BL37XU and BL47XU beamlines of the SPring-8 synchrotron radiation facility. The obtained results indicated that soft tissue structures can be visualized with the imaging microtomography.

  16. Structured illumination microscopy of autofluorescent aggregations in human tissue.

    PubMed

    Best, Gerrit; Amberger, Roman; Baddeley, David; Ach, Thomas; Dithmar, Stefan; Heintzmann, Rainer; Cremer, Christoph

    2011-06-01

    Sections from human eye tissue were analyzed with Structured Illumination Microscopy (SIM) using a specially designed microscope setup. In this microscope the structured illumination was generated with a Twyman-Green Interferometer. This SIM technique allowed us to acquire light-optical images of autofluorophore distributions in the tissue with previously unmatched optical resolution. In this work the unique setup of the microscope made possible the application of SIM with three different excitation wavelengths (488, 568 and 647 nm), thus enabling us to gather spectral information about the autofluorescence signal.

  17. Modulation of Radiation-Induced Apoptosis by Thiolamines

    NASA Technical Reports Server (NTRS)

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

    1997-01-01

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

  18. Modulation of Radiation-Induced Apoptosis by Thiolamines

    NASA Technical Reports Server (NTRS)

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

    1997-01-01

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

  19. Torin2 Suppresses Ionizing Radiation-Induced DNA Damage Repair.

    PubMed

    Udayakumar, Durga; Pandita, Raj K; Horikoshi, Nobuo; Liu, Yan; Liu, Qingsong; Wong, Kwok-Kin; Hunt, Clayton R; Gray, Nathanael S; Minna, John D; Pandita, Tej K; Westover, Kenneth D

    2016-05-01

    Several classes of inhibitors of the mammalian target of rapamycin (mTOR) have been developed based on its central role in sensing growth factor and nutrient levels to regulate cellular metabolism. However, its ATP-binding site closely resembles other phosphatidylinositol 3-kinase-related kinase (PIKK) family members, resulting in reactivity with these targets that may also be therapeutically useful. The ATP-competitive mTOR inhibitor, Torin2, shows biochemical activity against the DNA repair-associated proteins ATM, ATR and DNA-PK, which raises the possibility that Torin2 and related compounds might radiosensitize cancerous tumors. In this study Torin2 was also found to enhance ionizing radiation-induced cell killing in conditions where ATM was dispensable, confirming the requirement for multiple PIKK targets. Moreover, Torin2 did not influence the initial appearance of γ-H2AX foci after irradiation but significantly delayed the disappearance of radiation-induced γ-H2AX foci, indicating a DNA repair defect. Torin2 increased the number of radiation-induced S-phase specific chromosome aberrations and reduced the frequency of radiation-induced CtIP and Rad51 foci formation, suggesting that Torin2 works by blocking homologous recombination (HR)-mediated DNA repair resulting in an S-phase specific DNA repair defect. Accordingly, Torin2 reduced HR-mediated repair of I-Sce1-induced DNA damage and contributed to replication fork stalling. We conclude that radiosensitization of tumor cells by Torin2 is associated with disrupting ATR- and ATM-dependent DNA damage responses. Our findings support the concept of developing combination cancer therapies that incorporate ionizing radiation therapy and Torin2 or compounds with similar properties.

  20. Thermodynamic models of radiation-induced processes in solids

    NASA Astrophysics Data System (ADS)

    Yurov, V. M.; Eremin, E. N.; Kasymov, S. S.; Laurinas, V. CH; Chernyavskii, A. V.

    2017-01-01

    A thermodynamic model is proposed to qualitatively describe the radiation-induced processes in solids: temperature dependence of the X-ray radio luminescence output, dependence of these processes on the excitation density, energy accumulating in a solid under exposure to ionizing radiation and its temperature dependence. The proposed model and the formula derived can be used to develop radiation-resistant and radiation-sensitive materials.

  1. Process and Radiation Induced Defects in Electronic Materials and Devices

    NASA Technical Reports Server (NTRS)

    Washington, Kenneth; Fogarty, T. N.

    1997-01-01

    Process and radiation induced defects are characterized by a variety of electrical techniques, including capacitance-voltage measurements and charge pumping. Separation of defect type into stacking faults, displacement damage, oxide traps, interface states, etc. and their related causes are discussed. The defects are then related to effects on device parameters. Silicon MOS technology is emphasized. Several reviews of radiation effects and silicon processing exist.

  2. Dynamics of radiation-induced amorphization in intermetallic compounds

    SciTech Connect

    Lam, N.Q.; Okamoto, P.R. ); Devanathan, R. Northwestern Univ., Evanston, IL . Dept. of Materials Science and Engineering); Meshii, M. . Dept. of Materials Science and Engineering)

    1992-06-01

    Recent progress in molecular-dynamics simulations of radiation-induced crystalline-to-amorphous transition in intermetallic compounds and the relationship between amorphization and melting are discussed. By focusing on the mean-square static displacement, which provides a generic measure of energy stored in the lattice in the forms of chemical and topological disorder, a unified description of solid-state amorphization as a disorder-induced, isothermal melting process can be developed within the framework of a generalized Lindemann criterion.

  3. Process and Radiation Induced Defects in Electronic Materials and Devices

    NASA Technical Reports Server (NTRS)

    Washington, Kenneth; Fogarty, T. N.

    1997-01-01

    Process and radiation induced defects are characterized by a variety of electrical techniques, including capacitance-voltage measurements and charge pumping. Separation of defect type into stacking faults, displacement damage, oxide traps, interface states, etc. and their related causes are discussed. The defects are then related to effects on device parameters. Silicon MOS technology is emphasized. Several reviews of radiation effects and silicon processing exist.

  4. Modeling radiation induced segregation in Iron-Chromium alloys

    SciTech Connect

    Senninger, Oriane; Soisson, Frederic; Martinez Saez, Enrique; Nastar, Maylise; Fu, Chu-Chun; Brechet, Yves

    2015-10-16

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

  5. Modeling radiation induced segregation in Iron-Chromium alloys

    DOE PAGES

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

    2015-10-16

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

  6. Radiation-induced cataract in astronauts and cosmonauts.

    PubMed

    Rastegar, Noushin; Eckart, Peter; Mertz, Manfred

    2002-07-01

    Opacification of the ocular lens is an important effect of exposure to ionizing radiation. Astronauts and cosmonauts are exposed to relatively high doses of all types of radiation in space, including high-energy particle radiation. A study was initiated to examine the lenses of the eyes of astronauts/cosmonauts to detect signs of radiation-induced cataracts. The aim of this study was to take a first step towards gaining improved, quantitative insight into the risk of radiation-induced cataract associated with long space missions. The lenses of 21 former astronauts and cosmonauts were examined, using an upgraded Topcon SL-45 B Scheimpflug camera system. The degrees of opacification in this group of astronauts and cosmonauts were compared with the measurements in a reference group. This reference group was established by examining a cohort of 395 persons using the same Scheimpflug system. Initial results indicated that opacity values in most of the astronauts and cosmonauts were slightly to strongly increased in regions IV (posterior cortex) and V (posterior capsule), compared with the average opacity values for the respective age-group of the reference cohort. The aim of this study - to conduct first examinations of astronauts' and cosmonauts' ocular lenses with regard to signs of radiation-induced cataract - was successfully achieved in a total of 21 astronauts and cosmonauts using a Scheimpflug camera system. It is planned to examine a larger group of astronauts and cosmonauts in the future.

  7. Radiation-induced grain boundary segregation in austenitic stainless steels

    SciTech Connect

    Bruemmer, S.M.; Charlot, L.A.; Vetrano, J.S.; Simonen, E.P.

    1994-11-01

    Radiation-induced segregation (RIS) to grain boundaries in Fe-Ni-Cr-Si stainless alloys has been measured as a function of irradiation temperature and dose. Heavy-ion irradiation was used to produce damage levels from 1 to 20 displacements per atom (dpa) at temperatures from 175 to 550{degrees}C. Measured Fe, Ni, and Cr segregation increased sharply with irradiation dose (from G to 5 dpa) and temperature (from 175 to about 350{degrees}C). However, grain boundary concentrations did not change significantly as dose or temperatures were further increased. Although interfacial compositions were similar, the width of radiation-induced enrichment or depletion profiles increased consistently with increasing dose or temperature. Impurity segregation (Si and P) was also measured, but only Si enrichment appeared to be radiation-induced. Grain boundary Si peaked at levels approaching 10 at% after irradiation doses to 10 dpa at an intermediate temperature of 325{degrees}C. No evidence of grain boundary silicide precipitation was detected after irradiation at any temperature. Equilibrium segregation of P was measured in the high-P alloys, but interfacial concentration did not increase with irradiation exposure. Comparisons to reported RIS in neutron-irradiated stainless steels revealed similar grain boundary compositional changes for both major alloying and impurity elements.

  8. Microfibril Structure Masks Fibrillin-2 in Postnatal Tissues*

    PubMed Central

    Charbonneau, Noe L.; Jordan, C. Diana; Keene, Douglas R.; Lee-Arteaga, Sui; Dietz, Harry C.; Rifkin, Daniel B.; Ramirez, Francesco; Sakai, Lynn Y.

    2010-01-01

    Fibrillin microfibrils are polymeric structures present in connective tissues. The importance of fibrillin microfibrils to connective tissue function has been demonstrated by the multiple genetic disorders caused by mutations in fibrillins and in microfibril-associated molecules. However, knowledge of microfibril structure is limited, largely due to their insolubility. Most previous studies have focused on how fibrillin-1 is organized within microfibril polymers. In this study, an immunochemical approach was used to circumvent the insolubility of microfibrils to determine the role of fibrillin-2 in postnatal microfibril structure. Results obtained from studies of wild type and fibrillin-1 null tissues, using monoclonal and polyclonal antibodies with defined epitopes, demonstrated that N-terminal fibrillin-2 epitopes are masked in postnatal microfibrils and can be revealed by enzymatic digestion or by genetic ablation of Fbn1. From these studies, we conclude that fetal fibrillin polymers form an inner core within postnatal microfibrils and that microfibril structure evolves as growth and development proceed into the postnatal period. Furthermore, documentation of a novel cryptic site present in EGF4 in fibrillin-1 underscores the molecular complexity and tissue-specific differences in microfibril structure. PMID:20404337

  9. Nanofibrous structured biomimetic strategies for skin tissue regeneration.

    PubMed

    Jayarama Reddy, Venugopal; Radhakrishnan, Sridhar; Ravichandran, Rajeswari; Mukherjee, Shayanti; Balamurugan, Ramalingam; Sundarrajan, Subramanian; Ramakrishna, Seeram

    2013-01-01

    Mimicking porous topography of natural extracellular matrix is advantageous for successful regeneration of damaged tissues or organs. Nanotechnology being one of the most promising and growing technology today shows an extremely huge potential in the field of tissue engineering. Nanofibrous structures that mimic the native extracellular matrix and promote the adhesion of various cells are being developed as tissue-engineered scaffolds for skin, bone, vasculature, heart, cornea, nervous system, and other tissues. A range of novel biocomposite materials has been developed to enhance the bioactive or therapeutic properties of these nanofibrous scaffolds via surface modifications, including the immobilization of functional cell-adhesive ligands and bioactive molecules such as drugs, enzymes, and cytokines. In skin tissue engineering, usage of allogeneic skin is avoided to reestablish physiological continuity and also to address the challenge of curing acute and chronic wounds, which remains as the area of exploration with various biomimetic approaches. Two-dimensional, three-dimensional scaffolds and stem cells are presently used as dermal regeneration templates for the treatment of full-thickness skin defects resulting from injuries and severe burns. The present review elaborates specifically on the fabrication of nanofibrous structured strategies for wound dressings, wound healing, and controlled release of growth factors for skin tissue regeneration.

  10. Challenges in engineering osteochondral tissue grafts with hierarchical structures.

    PubMed

    Gadjanski, Ivana; Vunjak-Novakovic, Gordana

    2015-01-01

    A major hurdle in treating osteochondral (OC) defects is the different healing abilities of two types of tissues involved - articular cartilage and subchondral bone. Biomimetic approaches to OC-construct engineering, based on recapitulation of biological principles of tissue development and regeneration, have potential for providing new treatments and advancing fundamental studies of OC tissue repair. This review on state of the art in hierarchical OC tissue graft engineering is focused on tissue engineering approaches designed to recapitulate the native milieu of cartilage and bone development. These biomimetic systems are discussed with relevance to bioreactor cultivation of clinically sized, anatomically shaped human cartilage/bone constructs with physiologic stratification and mechanical properties. The utility of engineered OC tissue constructs is evaluated for their use as grafts in regenerative medicine, and as high-fidelity models in biological research. A major challenge in engineering OC tissues is to generate a functionally integrated stratified cartilage-bone structure starting from one single population of mesenchymal cells, while incorporating perfusable vasculature into the bone, and in bone-cartilage interface. To this end, new generations of advanced scaffolds and bioreactors, implementation of mechanical loading regimens and harnessing of inflammatory responses of the host will likely drive the further progress.

  11. Multiview hyperspectral topography of tissue structural and functional characteristics

    NASA Astrophysics Data System (ADS)

    Zhang, Shiwu; Liu, Peng; Huang, Jiwei; Xu, Ronald

    2012-12-01

    Accurate and in vivo characterization of structural, functional, and molecular characteristics of biological tissue will facilitate quantitative diagnosis, therapeutic guidance, and outcome assessment in many clinical applications, such as wound healing, cancer surgery, and organ transplantation. However, many clinical imaging systems have limitations and fail to provide noninvasive, real time, and quantitative assessment of biological tissue in an operation room. To overcome these limitations, we developed and tested a multiview hyperspectral imaging system. The multiview hyperspectral imaging system integrated the multiview and the hyperspectral imaging techniques in a single portable unit. Four plane mirrors are cohered together as a multiview reflective mirror set with a rectangular cross section. The multiview reflective mirror set was placed between a hyperspectral camera and the measured biological tissue. For a single image acquisition task, a hyperspectral data cube with five views was obtained. The five-view hyperspectral image consisted of a main objective image and four reflective images. Three-dimensional topography of the scene was achieved by correlating the matching pixels between the objective image and the reflective images. Three-dimensional mapping of tissue oxygenation was achieved using a hyperspectral oxygenation algorithm. The multiview hyperspectral imaging technique is currently under quantitative validation in a wound model, a tissue-simulating blood phantom, and an in vivo biological tissue model. The preliminary results have demonstrated the technical feasibility of using multiview hyperspectral imaging for three-dimensional topography of tissue functional properties.

  12. Oxidative stress and gamma radiation-induced cancellous bone loss with musculoskeletal disuse

    PubMed Central

    Kondo, Hisataka; Yumoto, Kenji; Alwood, Joshua S.; Mojarrab, Rose; Wang, Angela; Almeida, Eduardo A. C.; Searby, Nancy D.; Limoli, Charles L.

    2010-01-01

    Exposure of astronauts in space to radiation during weightlessness may contribute to subsequent bone loss. Gamma irradiation of postpubertal mice rapidly increases the number of bone-resorbing osteoclasts and causes bone loss in cancellous tissue; similar changes occur in skeletal diseases associated with oxidative stress. Therefore, we hypothesized that increased oxidative stress mediates radiation-induced bone loss and that musculoskeletal disuse changes the sensitivity of cancellous tissue to radiation exposure. Musculoskeletal disuse by hindlimb unloading (1 or 2 wk) or total body gamma irradiation (1 or 2 Gy of 137Cs) of 4-mo-old, male C57BL/6 mice each decreased cancellous bone volume fraction in the proximal tibiae and lumbar vertebrae. The extent of radiation-induced acute cancellous bone loss in tibiae and lumbar vertebrae was similar in normally loaded and hindlimb-unloaded mice. Similarly, osteoclast surface in the tibiae increased 46% as a result of irradiation, 47% as a result of hindlimb unloading, and 64% as a result of irradiation + hindlimb unloading compared with normally loaded mice. Irradiation, but not hindlimb unloading, reduced viability and increased apoptosis of marrow cells and caused oxidative damage to lipids within mineralized tissue. Irradiation also stimulated generation of reactive oxygen species in marrow cells. Furthermore, injection of α-lipoic acid, an antioxidant, mitigated the acute bone loss caused by irradiation. Together, these results showed that disuse and gamma irradiation, alone or in combination, caused a similar degree of acute cancellous bone loss and shared a common cellular mechanism of increased bone resorption. Furthermore, irradiation, but not disuse, may increase the number of osteoclasts and the extent of acute bone loss via increased reactive oxygen species production and ensuing oxidative damage, implying different molecular mechanisms. The finding that α-lipoic acid protected cancellous tissue from the

  13. Protective effects of ulinastatin and methylprednisolone against radiation-induced lung injury in mice.

    PubMed

    Sun, Yu; Du, Yu-Jun; Zhao, Hui; Zhang, Guo-Xing; Sun, Ni; Li, Xiu-Jiang

    2016-09-01

    The effectiveness of ulinastatin and methylprednisolone in treating pathological changes in mice with radiation-induced lung injury (RILI) was evaluated. Forty C57BL/6 female mice received whole-chest radiation (1.5 Gy/min for 12 min) and were randomly allocated into Group R (single radiation, n = 10), Group U (ulinastatin treatment, n = 10), Group M (methylprednisolone treatment, n = 10), or Group UM (ulinastatin and methylprednisolone treatment, n = 10). Another 10 untreated mice served as controls (Group C). Pathological changes in lung tissue, pulmonary interstitial area density (PIAD) and expression levels of transforming growth factor β1 (TGF-β1) and tumor necrosis factor α (TNF-α) in lung tissue, serum and bronchoalveolar lavage fluid were determined. Alleviation of pathological changes in lung tissue was observed in Groups U, M and UM. Treatment with ulinastatin, methylprednisolone or both effectively delayed the development of fibrosis at 12 weeks after radiation. Ulinastatin, methylprednisolone or both could alleviate the radiation-induced increase in the PIAD (P < 0.05 or P < 0.01). Treatment with ulinastatin, methylprednisolone or both significantly reduced the expression of TNF-α, but not TGF-β1, at 9 weeks after radiation compared with Group R (P < 0.01). Ulinastatin and /: or methylprednisolone effectively decreased the level of TNF-α in lung tissue after RILI and inhibited both the inflammatory response and the development of fibrosis. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

  14. Detection of lobular structures in normal breast tissue.

    PubMed

    Apou, Grégory; Schaadt, Nadine S; Naegel, Benoît; Forestier, Germain; Schönmeyer, Ralf; Feuerhake, Friedrich; Wemmert, Cédric; Grote, Anne

    2016-07-01

    Ongoing research into inflammatory conditions raises an increasing need to evaluate immune cells in histological sections in biologically relevant regions of interest (ROIs). Herein, we compare different approaches to automatically detect lobular structures in human normal breast tissue in digitized whole slide images (WSIs). This automation is required to perform objective and consistent quantitative studies on large data sets. In normal breast tissue from nine healthy patients immunohistochemically stained for different markers, we evaluated and compared three different image analysis methods to automatically detect lobular structures in WSIs: (1) a bottom-up approach using the cell-based data for subsequent tissue level classification, (2) a top-down method starting with texture classification at tissue level analysis of cell densities in specific ROIs, and (3) a direct texture classification using deep learning technology. All three methods result in comparable overall quality allowing automated detection of lobular structures with minor advantage in sensitivity (approach 3), specificity (approach 2), or processing time (approach 1). Combining the outputs of the approaches further improved the precision. Different approaches of automated ROI detection are feasible and should be selected according to the individual needs of biomarker research. Additionally, detected ROIs could be used as a basis for quantification of immune infiltration in lobular structures. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Induction of Excess Centrosomes in Neural Progenitor Cells during the Development of Radiation-Induced Microcephaly

    PubMed Central

    Shimada, Mikio; Matsuzaki, Fumio; Kato, Akihiro; Kobayashi, Junya; Matsumoto, Tomohiro; Komatsu, Kenshi

    2016-01-01

    The embryonic brain is one of the tissues most vulnerable to ionizing radiation. In this study, we showed that ionizing radiation induces apoptosis in the neural progenitors of the mouse cerebral cortex, and that the surviving progenitor cells subsequently develop a considerable amount of supernumerary centrosomes. When mouse embryos at Day 13.5 were exposed to γ-rays, brains sizes were reduced markedly in a dose-dependent manner, and these size reductions persisted until birth. Immunostaining with caspase-3 antibodies showed that apoptosis occurred in 35% and 40% of neural progenitor cells at 4 h after exposure to 1 and 2 Gy, respectively, and this was accompanied by a disruption of the apical layer in which mitotic spindles were positioned in unirradiated mice. At 24 h after 1 Gy irradiation, the apoptotic cells were completely eliminated and proliferation was restored to a level similar to that of unirradiated cells, but numerous spindles were localized outside the apical layer. Similarly, abnormal cytokinesis, which included multipolar division and centrosome clustering, was observed in 19% and 24% of the surviving neural progenitor cells at 48 h after irradiation with 1 and 2 Gy, respectively. Because these cytokinesis aberrations derived from excess centrosomes result in growth delay and mitotic catastrophe-mediated cell elimination, our findings suggest that, in addition to apoptosis at an early stage of radiation exposure, radiation-induced centrosome overduplication could contribute to the depletion of neural progenitors and thereby lead to microcephaly. PMID:27367050

  16. Radiation-induced complications in prostate cancer patients treated with radiotherapy

    SciTech Connect

    Azuddin, A. Yusof; Rahman, I. Abdul; Mohamed, F.; Siah, N. J.; Saadc, M.; Ismail, F.

    2014-09-03

    The purpose of the study is to determine the relationship between radiation-induced complications with dosimetric and radiobiological parameters for prostate cancer patients that underwent the conformal radiotherapy treatment. 17 prostate cancer patients that have been treated with conformal radiotherapy were retrospectively analysed. The dosimetric data was retrieved in the form of dose-volume histogram (DVH) from Radiotherapy Treatment Planning System. The DVH was utilised to derived Normal Tissue Complication Probability (NTCP) in radiobiological data. Follow-up data from medical records were used to grade the occurrence of acute gastrointestinal (GI) and genitourinary (GU) complications using Radiation Therapy Oncology Group (RTOG) scoring system. The chi-square test was used to determine the relationship between radiation-induced complication with dosimetric and radiobiological parameters. 8 (47%) and 7 (41%) patients were having acute GI and GU complications respectively. The acute GI complication can be associated with V60{sub rectum}, rectal mean dose and NTCP{sub rectum} with p-value of 0.016, 0.038 and 0.049 respectively. There are no significant relationships of acute GU complication with dosimetric and radiobiological variables. Further study can be done by increase the sample size and follow up duration for deeper understanding of the factors that effecting the GU and GI complication in prostate cancer radiotherapy.

  17. A non-human primate model of radiation-induced cachexia

    PubMed Central

    Cui, Wanchang; Bennett, Alexander W.; Zhang, Pei; Barrow, Kory R.; Kearney, Sean R.; Hankey, Kim G.; Taylor-Howell, Cheryl; Gibbs, Allison M.; Smith, Cassandra P.; MacVittie, Thomas J.

    2016-01-01

    Cachexia, or muscle wasting, is a serious health threat to victims of radiological accidents or patients receiving radiotherapy. Here, we propose a non-human primate (NHP) radiation-induced cachexia model based on clinical and molecular pathology findings. NHP exposed to potentially lethal partial-body irradiation developed symptoms of cachexia such as body weight loss in a time- and dose-dependent manner. Severe body weight loss as high as 20–25% was observed which was refractory to nutritional intervention. Radiographic imaging indicated that cachectic NHP lost as much as 50% of skeletal muscle. Histological analysis of muscle tissues showed abnormalities such as presence of central nuclei, inflammation, fatty replacement of skeletal muscle, and muscle fiber degeneration. Biochemical parameters such as hemoglobin and albumin levels decreased after radiation exposure. Levels of FBXO32 (Atrogin-1), ActRIIB and myostatin were significantly changed in the irradiated cachectic NHP compared to the non-irradiated NHP. Our data suggest NHP that have been exposed to high dose radiation manifest cachexia-like symptoms in a time- and dose-dependent manner. This model provides a unique opportunity to study the mechanism of radiation-induced cachexia and will aid in efficacy studies of mitigators of this disease. PMID:27029502

  18. A non-human primate model of radiation-induced cachexia.

    PubMed

    Cui, Wanchang; Bennett, Alexander W; Zhang, Pei; Barrow, Kory R; Kearney, Sean R; Hankey, Kim G; Taylor-Howell, Cheryl; Gibbs, Allison M; Smith, Cassandra P; MacVittie, Thomas J

    2016-03-31

    Cachexia, or muscle wasting, is a serious health threat to victims of radiological accidents or patients receiving radiotherapy. Here, we propose a non-human primate (NHP) radiation-induced cachexia model based on clinical and molecular pathology findings. NHP exposed to potentially lethal partial-body irradiation developed symptoms of cachexia such as body weight loss in a time- and dose-dependent manner. Severe body weight loss as high as 20-25% was observed which was refractory to nutritional intervention. Radiographic imaging indicated that cachectic NHP lost as much as 50% of skeletal muscle. Histological analysis of muscle tissues showed abnormalities such as presence of central nuclei, inflammation, fatty replacement of skeletal muscle, and muscle fiber degeneration. Biochemical parameters such as hemoglobin and albumin levels decreased after radiation exposure. Levels of FBXO32 (Atrogin-1), ActRIIB and myostatin were significantly changed in the irradiated cachectic NHP compared to the non-irradiated NHP. Our data suggest NHP that have been exposed to high dose radiation manifest cachexia-like symptoms in a time- and dose-dependent manner. This model provides a unique opportunity to study the mechanism of radiation-induced cachexia and will aid in efficacy studies of mitigators of this disease.

  19. Consequences of ionizing radiation-induced damage in human neural stem cells.

    PubMed

    Acharya, Munjal M; Lan, Mary L; Kan, Vickie H; Patel, Neal H; Giedzinski, Erich; Tseng, Bertrand P; Limoli, Charles L

    2010-12-15

    Cranial irradiation remains a frontline treatment for brain cancer, but also leads to normal tissue damage. Although low-dose irradiation (≤10 Gy) causes minimal histopathologic change, it can elicit variable degrees of cognitive dysfunction that are associated with the depletion of neural stem cells. To decipher the mechanisms underlying radiation-induced stem cell dysfunction, human neural stem cells (hNSCs) subjected to clinically relevant irradiation (0-5 Gy) were analyzed for survival parameters, cell-cycle alterations, DNA damage and repair, and oxidative stress. hNSCs showed a marked sensitivity to low-dose irradiation that was in part due to elevated apoptosis and the inhibition of cell-cycle progression that manifested as a G2/M checkpoint delay. Efficient removal of DNA double-strand breaks was indicated by the disappearance of γ-H2AX nuclear foci. A dose-responsive and persistent increase in oxidative and nitrosative stress was found in irradiated hNSCs, possibly the result of a higher metabolic activity in the fraction of surviving cells. These data highlight the marked sensitivity of hNSCs to low-dose irradiation and suggest that long-lasting perturbations in the CNS microenvironment due to radiation-induced oxidative stress can compromise the functionality of neural stem cells.

  20. Preclinical evaluation of erythropoietin administration in a model of radiation-induced kidney dysfunction

    SciTech Connect

    Andratschke, Nicolaus; Schnaitera, Andrea; Weber, Wolfgang A.; Caia, Lu; Schill, Sabine; Wiedenmann, Nicole; Schwaiger, Markus; Molls, Michael; Nieder, Carsten . E-mail: cnied@hotmail.com

    2006-04-01

    Purpose: To test whether the clinically available growth factor erythropoietin (EPO) influences radiation-induced normal-tissue damage in a model of kidney dysfunction. Methods: Animal experiments were conducted to test the role of EPO administration in a C3H mouse model of unilateral kidney irradiation with 6, 8, and 10 Gy and to assess the effects of 2 different dose levels of EPO. The kidney function was assessed before radiotherapy, as well as 19, 25, 31, and 37 weeks thereafter by means of {sup 99m}Tc-dimercaptosuccinat scans (static scintigraphy). Results: Concomitant EPO administration significantly increased the degree of radiation-induced kidney dysfunction. A dose of 2,000 IU/kg body weight per injection tended to cause more damage than the lower dose of 500 IU/kg. Conclusion: Administration of growth factors concomitant to radiotherapy might modify the development of kidney dysfunction. Although insulin-like growth factor-1 has previously been shown to protect the kidney, such an effect could not be demonstrated for EPO. The latter agent even increased the development of nephropathy.

  1. Radiation-induced complications in prostate cancer patients treated with radiotherapy

    NASA Astrophysics Data System (ADS)

    Azuddin, A. Yusof; Rahman, I. Abdul; Siah, N. J.; Mohamed, F.; Saadc, M.; Ismail, F.

    2014-09-01

    The purpose of the study is to determine the relationship between radiation-induced complications with dosimetric and radiobiological parameters for prostate cancer patients that underwent the conformal radiotherapy treatment. 17 prostate cancer patients that have been treated with conformal radiotherapy were retrospectively analysed. The dosimetric data was retrieved in the form of dose-volume histogram (DVH) from Radiotherapy Treatment Planning System. The DVH was utilised to derived Normal Tissue Complication Probability (NTCP) in radiobiological data. Follow-up data from medical records were used to grade the occurrence of acute gastrointestinal (GI) and genitourinary (GU) complications using Radiation Therapy Oncology Group (RTOG) scoring system. The chi-square test was used to determine the relationship between radiation-induced complication with dosimetric and radiobiological parameters. 8 (47%) and 7 (41%) patients were having acute GI and GU complications respectively. The acute GI complication can be associated with V60rectum, rectal mean dose and NTCPrectum with p-value of 0.016, 0.038 and 0.049 respectively. There are no significant relationships of acute GU complication with dosimetric and radiobiological variables. Further study can be done by increase the sample size and follow up duration for deeper understanding of the factors that effecting the GU and GI complication in prostate cancer radiotherapy.

  2. Gene-modified Mesenchymal Stem Cells Protect Against Radiation-induced Lung Injury

    PubMed Central

    Xue, Jianxin; Li, Xin; Lu, You; Gan, Lu; Zhou, Lin; Wang, Yongsheng; Lan, Jie; Liu, Shurui; Sun, Lan; Jia, Li; Mo, Xianming; Li, Jian

    2013-01-01

    Radiation-induced lung injury (RILI) presents a common and major obstacle in the radiotherapy of thoracic cancers. The aim of this study was to examine whether RILI could be alleviated by mesenchymal stem cells (MSCs) expressing soluble transforming growth factor-β (TGF-β) type II receptor via an adenovirus (Ad-sTβR). Here, we systemically administered male MSCs into female mice challenged with thoracic irradiation. The data showed that either MSCs or Ad-sTβR transduced MSCs (Ad-sTβR-MSCs) specifically migrated into radiation-injured lung. Ad-sTβR-MSCs obviously alleviated lung injury, as reflected by survival and histopathology data, as well as the assays of malondialdehyde (MDA), hydroxyproline, plasma cytokines, and the expression of connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA). Furthermore, MSCs and Ad-sTβR-MSCs could adopt the characteristics of alveolar type II (ATII) cells. However, the MSCs levels in the lungs were relatively low to account for the noted therapeutic effects, suggesting the presence of other mechanisms. In vivo, MSCs-conditioned medium (MSCs CM) significantly attenuated RILI. In vitro, MSCs CM protected ATII cells against radiation-induced apoptosis and DNA damage, and modulated the inflammatory response, indicating the beneficial effects of MSCs are largely due to its paracrine activity. Our results provide a novel insight for RILI therapy that currently lack efficient treatments. PMID:23299797

  3. Dose-dependency and reversibility of radiation-induced injury in cardiac explant-derived cells of mice

    PubMed Central

    Luo, Lan; Yan, Chen; Urata, Yoshishige; Hasan, Al Shaimaa; Goto, Shinji; Guo, Chang-Ying; Zhang, Shouhua; Li, Tao-Sheng

    2017-01-01

    We evaluated the dose-dependency and reversibility of radiation-induced injury in cardiac explant-derived cells (CDCs), a mixed cell population grown from heart tissues. Adult C57BL/6 mice were exposed to 0, 10, 50 and 250 mGy γ-rays for 7 days and atrial tissues were collected for experiments 24 hours after last exposure. The number of CDCs was significantly decreased by daily exposure to over 250 mGy. Interestingly, daily exposure to over 50 mGy significantly decreased the c-kit expression and telomerase activity, increased 53BP1 foci in the nuclei of CDCs. However, CD90 expression and growth factors production in CDCs were not significantly changed even after daily exposure to 250 mGy. We further evaluated the reversibility of radiation-induced injury in CDCs at 1 week and 3 weeks after a single exposure to 3 Gy γ-rays. The number and growth factors production of CDCs were soon recovered at 1 week. However, the increased expression of CD90 were retained at 1 week, but recovered at 3 weeks. Moreover, the decreased expression of c-kit, impaired telomerase activity, and increased 53BP1 foci were poorly recovered even at 3 weeks. These data may help us to find the most sensitive and reliable bio-parameter(s) for evaluating radiation-induced injury in CDCs. PMID:28098222

  4. cAMP signaling inhibits radiation-induced ATM phosphorylation leading to the augmentation of apoptosis in human lung cancer cells.

    PubMed

    Cho, Eun-Ah; Kim, Eui-Jun; Kwak, Sahng-June; Juhnn, Yong-Sung

    2014-02-24

    The ataxia-telangiectasia mutated (ATM) protein kinase plays a central role in coordinating the cellular response to radiation-induced DNA damage. cAMP signaling regulates various cellular responses including metabolism and gene expression. This study aimed to investigate the mechanism through which cAMP signaling regulates ATM activation and cellular responses to ionizing radiation in lung cancer cells. Lung cancer cells were transfected with constitutively active stimulatory G protein (GαsQL), and irradiated with γ-rays. The phosphorylation of ATM and protein phosphatase 2A was analyzed by western blotting, and apoptosis was assessed by western blotting, flow cytometry, and TUNNEL staining. The promoter activity of NF-κB was determined by dual luciferase reporter assay. BALB/c mice were treated with forskolin to assess the effect in the lung tissue. Transient expression of GαsQL significantly inhibited radiation-induced ATM phosphorylation in H1299 human lung cancer cells. Treatment with okadaic acid or knock down of PP2A B56δ subunit abolished the inhibitory effect of Gαs on radiation-induced ATM phosphorylation. Expression of GαsQL increased phosphorylation of the B56δ and PP2A activity, and inhibition of PKA blocked Gαs-induced PP2A activation. GαsQL enhanced radiation-induced cleavage of caspase-3 and PARP and increased the number of early apoptotic cells. The radiation-induced apoptosis was increased by inhibition of NF-κB using PDTC or inhibition of ATM using KU55933 or siRNA against ATM. Pretreatment of BALB/c mice with forskolin stimulated phosphorylation of PP2A B56δ, inhibited the activation of ATM and NF-κB, and augmented radiation-induced apoptosis in the lung tissue. GαsQL expression decreased the nuclear levels of the p50 and p65 subunits and NF-κB-dependent activity after γ-ray irradiation in H1299 cells. Pretreatment with prostaglandin E2 or isoproterenol increased B56δ phosphorylation, decreased radiation-induced ATM

  5. Radiation-induced DNA damage and chromatin structure

    NASA Technical Reports Server (NTRS)

    Rydberg, B.; Chatterjee, A. (Principal Investigator)

    2001-01-01

    DNA lesions induced by ionizing radiation in cells are clustered and not randomly distributed. For low linear energy transfer (LET) radiation this clustering occurs mainly on the small scales of DNA molecules and nucleosomes. For example, experimental evidence suggests that both strands of DNA on the nucleosomal surface can be damaged in single events and that this damage occurs with a 10-bp modulation because of protection by histones. For high LET radiation, clustering also occurs on a larger scale and depends on chromatin organization. A particularly significant clustering occurs when an ionizing particle traverses the 30 nm chromatin fiber with generation of heavily damaged DNA regions with an average size of about 2 kbp. On an even larger scale, high LET radiation can produce several DNA double-strand breaks in closer proximity than expected from randomness. It is suggested that this increases the probability of misrejoining of DNA ends and generation of lethal chromosome aberrations.

  6. Radiation-induced DNA damage and chromatin structure

    NASA Technical Reports Server (NTRS)

    Rydberg, B.; Chatterjee, A. (Principal Investigator)

    2001-01-01

    DNA lesions induced by ionizing radiation in cells are clustered and not randomly distributed. For low linear energy transfer (LET) radiation this clustering occurs mainly on the small scales of DNA molecules and nucleosomes. For example, experimental evidence suggests that both strands of DNA on the nucleosomal surface can be damaged in single events and that this damage occurs with a 10-bp modulation because of protection by histones. For high LET radiation, clustering also occurs on a larger scale and depends on chromatin organization. A particularly significant clustering occurs when an ionizing particle traverses the 30 nm chromatin fiber with generation of heavily damaged DNA regions with an average size of about 2 kbp. On an even larger scale, high LET radiation can produce several DNA double-strand breaks in closer proximity than expected from randomness. It is suggested that this increases the probability of misrejoining of DNA ends and generation of lethal chromosome aberrations.

  7. Multiview hyperspectral topography of tissue structural and functional characteristics

    NASA Astrophysics Data System (ADS)

    Liu, Peng; Huang, Jiwei; Zhang, Shiwu; Xu, Ronald X.

    2016-01-01

    Accurate and in vivo characterization of structural, functional, and molecular characteristics of biological tissue will facilitate quantitative diagnosis, therapeutic guidance, and outcome assessment in many clinical applications, such as wound healing, cancer surgery, and organ transplantation. We introduced and tested a multiview hyperspectral imaging technique for noninvasive topographic imaging of cutaneous wound oxygenation. The technique integrated a multiview module and a hyperspectral module in a single portable unit. Four plane mirrors were cohered to form a multiview reflective mirror set with a rectangular cross section. The mirror set was placed between a hyperspectral camera and the target biological tissue. For a single image acquisition task, a hyperspectral data cube with five views was obtained. The five-view hyperspectral image consisted of a main objective image and four reflective images. Three-dimensional (3-D) topography of the scene was achieved by correlating the matching pixels between the objective image and the reflective images. 3-D mapping of tissue oxygenation was achieved using a hyperspectral oxygenation algorithm. The multiview hyperspectral imaging technique was validated in a wound model, a tissue-simulating blood phantom, and in vivo biological tissue. The experimental results demonstrated the technical feasibility of using multiview hyperspectral imaging for 3-D topography of tissue functional properties.

  8. Polarized front-face fluorescence for muscle tissue structure evaluation

    NASA Astrophysics Data System (ADS)

    Luc, C.; Clerjon, S.; Peyrin, F.; Lepetit, J.

    2008-05-01

    The fluorescence anisotropy of a rigid medium is a consequence of photoselection of fluorophores and their orientations. This makes it possible to use polarized front-face fluorescence to provide structural information on biological tissues like muscle. Tryptophan is the major intrinsic fluorophore in muscle. It is embedded in proteins which act as building blocks for muscle structuration because of their preferential alignment. Our working hypothesis is that when the arrangement of the proteins changes, there are concomitant changes in fluorescence anisotropy parameters. Our research is directed toward evaluating muscle structure and its evolution post mortem. We report a theoretical simple model of tryptophan fluorescence and an experimental method to measure the fluorescence anisotropy of biological opaque tissues. Instrumental and optical considerations have to be taken into account in experiments on front-face polarization to make certain of measurement accuracy. Therefore, we present a detailed report on the adjustments and corrections made on a conventional L-spectrofluorimeter to adapt it to fluorescence anisotropy measurements on biological tissues. Data from several experiments demonstrate how the method is able to show muscle structure modifications. We show how it is possible to fit experimental data with the model developed in order to obtain structural information.

  9. Synchrotron-Radiation Induced X-Ray Emission (SRIXE)

    SciTech Connect

    Jones, Keith W.

    1999-09-01

    and increase in scientific use can be maintained for the synchrotron x-ray source. A short summary of the present state of the synchrotron radiation-induced x-ray emission (SRIXE) method is presented here. Basically, SRIXE experiments can include any that depend on the detection. of characteristic x-rays produced by the incident x-ray beam born the synchrotron source as they interact with a sample. Thus, experiments done to measure elemental composition, chemical state, crystal, structure, and other sample parameters can be considered in a discussion of SRIXE. It is also clear that the experimentalist may well wish to use a variety of complementary techniques for study of a given sample. For this reason, discussion of computed microtomography (CMT) and x-ray diffraction is included here. It is hoped that this present discussion will serve as a succinct introduction to the basic ideas of SRIXE for those not working in the field and possibly help to stimulate new types of work by those starting in the field as well as by experienced practitioners of the art. The topics covered include short descriptions of (1) the properties of synchrotron radiation, (2) a description of facilities used for its production, (3) collimated microprobe, (4) focused microprobes, (5) continuum and monoenergetic excitation, (6) detection limits, (7) quantitation, (8) applications of SRIXE, (9) computed microtomography (CMT), and (10)chemical speciation using x-ray absorption near-edge structure (XANES) and extended x-ray absorption fine structure (EXAFS). An effort has been made to cite a wide variety of work from different laboratories to show the vital nature of the field.

  10. Effects of ozone oxidative preconditioning on radiation-induced organ damage in rats

    PubMed Central

    Gultekin, Fatma Ayca; Bakkal, Bekir Hakan; Guven, Berrak; Tasdoven, Ilhan; Bektas, Sibel; Can, Murat; Comert, Mustafa

    2013-01-01

    Because radiation-induced cellular damage is attributed primarily to harmful effects of free radicals, molecules with direct free radical scavenging properties are particularly promising as radioprotectors. It has been demonstrated that controlled ozone administration may promote an adaptation to oxidative stress, preventing the damage induced by reactive oxygen species. Thus, we hypothesized that ozone would ameliorate oxidative damage caused by total body irradiation (TBI) with a single dose of 6 Gy in rat liver and ileum tissues. Rats were randomly divided into groups as follows: control group; saline-treated and irradiated (IR) groups; and ozone oxidative preconditioning (OOP) and IR groups. Animals were exposed to TBI after a 5-day intraperitoneal pretreatment with either saline or ozone (1 mg/kg/day). They were decapitated at either 6 h or 72 h after TBI. Plasma, liver and ileum samples were obtained. Serum AST, ALT and TNF-α levels were elevated in the IR groups compared with the control group and were decreased after treatment with OOP. TBI resulted in a significant increase in the levels of MDA in the liver and ileal tissues and a decrease of SOD activities. The results demonstrated that the levels of MDA liver and ileal tissues in irradiated rats that were pretreated with ozone were significantly decreased, while SOD activities were significantly increased. OOP reversed all histopathological alterations induced by irradiation. In conclusion, data obtained from this study indicated that ozone could increase the endogenous antioxidant defense mechanism in rats and there by protect the animals from radiation-induced organ toxicity. PMID:22915786

  11. Protective effect of N-acetylcysteine against radiation induced DNA damage and hepatic toxicity in rats.

    PubMed

    Mansour, Heba H; Hafez, Hafez F; Fahmy, Nadia M; Hanafi, Nemat

    2008-02-01

    The present study was designed to evaluate the radioprotective effect of N- acetylcysteine (NAC) on gamma-radiation induced toxicity in hepatic tissue in rat. The cellular changes were estimated using malondialdehyde (MDA, an index of lipid peroxidation), superoxide dismutase (SOD), glutathione peroxidase (GSHPx), reduced glutathione (GSH), and total nitrate/nitrite (NO(x)) as markers of hepatic oxidative stress in rats following gamma-irradiation. The DNA damage was determined by agarose gel electrophoresis. To achieve the ultimate goal of this study, 40 adult rats were randomly divided into 4 groups of 10 animals each. Group I was injected intraperitoneally with saline solution for 7 consecutive days and served as control group. Group II was irradiated with a single dose of 6Gy gamma-radiation. Group III was daily injected with NAC (1g/kg, i.p.) for 7 consecutive days. Group IV received a daily i.p. injection of NAC (1g/kg, i.p.) for 7 consecutive days and 1h after the last dose, rats were irradiated with a single dose (6Gy) gamma-radiation. The animals were sacrificed after 24h. DNA damage was observed in tissue after total body irradiation with a single dose of 6Gy. Malondialdehyde and total nitrate/nitrite were increased significantly whereas the levels of GSH and antioxidant enzymes were significantly decreased in gamma-irradiated group. Pretreatment with NAC showed a significant decrease in the levels of MDA, NO(x) and DNA damage. The antioxidant enzymes increased significantly along with the levels of GSH. Moreover, histopathological examination of liver tissues confirmed the biochemical data. Thus, our results show that pretreatment with N-acetylcysteine offers protection against gamma-radiation induced cellular damage.

  12. Modification of collagen and noncollagenous proteins in radiation-induced muscular fibrosis

    SciTech Connect

    Wegrowski, J.; Lafuma, C.; Lefaix, J.L.; Daburon, F.; Robert, L.

    1988-06-01

    Six months after acute local gamma irradiation of the pig skin and adjacent muscle, the muscular tissue is replaced by a large mutilating and proliferative fibrosis deliminated by a perifibrotic inflammatory zone. The content and biosynthesis of collagen and noncollagenous proteins were studied in both fibrotic and perifibrotic zones after incubation of the biopsies with (/sup 14/C)proline or (/sup 35/S)methionine for 24 hr. Cells of perifibrotic and fibrotic regions synthesize about 10 times more proteins than those in the nonirradiated muscle. When compared to normal muscle tissue, our results indicate an important increase in collagen content and biosynthesis in fibrotic tissue. The increase in collagen biosynthesis in the irradiated tissue is more pronounced for type III collagen than for type I collagen. Biosynthesis of type III and type I collagens increases 20- and 10-fold, respectively, compared to the normal muscle. Type I to III collagen ratio in irradiated tissue decreases from 2.3 in normal tissue to 1.1 in fibrotic tissue. Histological examination of the biopsies as well as the protein pattern by polyacrylamide gel electrophoresis show striking differences in the perifibrotic and fibrotic areas as compared to the normal muscular tissue with a progressive disappearance of the myotubes replaced by a dense sclerotic tissue. The results indicate that the perifibrotic inflammatory area is engaged in a remodeling process and that the fibrotic tissue remains active in the neosynthesis of the extracellular matrix macromolecules with a high proportion of type III collagen. This high biosynthetic activity of the irradiated tissue may explain the pseudosarcomatous character of the radiation-induced lesions.

  13. Radiation-induced destruction of hydroxyl-containing amino acids and dipeptides

    NASA Astrophysics Data System (ADS)

    Sladkova, А. А.; Sosnovskaya, А. А.; Edimecheva, I. P.; Shadyro, О. I.

    2012-12-01

    The yields of molecular products resulting from radiolysis of hydroxyl-containing amino acids and dipeptides under various conditions were determined. The possibility of a new radiation-induced destruction pathway has been shown for serine and threonine, as well as for the dipeptides having residues of these amino acids at the N-terminal part of the respective molecule. This process includes formation of N-centered radicals from the starting molecules followed by their decomposition with elimination of side substituents. On radiolysis, serine and threonine were also shown to undergo free-radical destruction to form acetaldehyde and acetone, respectively. A mechanism has been proposed including consecutive stages of fragmentation of α-hydroxyl-containing carbon-centered radicals with elimination of ammonia and decomposition of the secondary radicals with elimination of CO2. The yields of CO2 obtained on radiolysis of serine and threonine were significantly higher (except for solutions at pH 12) than those for alanine and valine, which have no hydroxyl groups in their structures. The obtained data indicate that the hydroxyl-containing amino acids occupy a special place among other amino acids as regards the variety of radiation-induced reactions which they may undergo due to their structural features.

  14. Extracellular matrix hydrogels from decellularized tissues: Structure and function.

    PubMed

    Saldin, Lindsey T; Cramer, Madeline C; Velankar, Sachin S; White, Lisa J; Badylak, Stephen F

    2017-02-01

    Extracellular matrix (ECM) bioscaffolds prepared from decellularized tissues have been used to facilitate constructive and functional tissue remodeling in a variety of clinical applications. The discovery that these ECM materials could be solubilized and subsequently manipulated to form hydrogels expanded their potential in vitro and in vivo utility; i.e. as culture substrates comparable to collagen or Matrigel, and as injectable materials that fill irregularly-shaped defects. The mechanisms by which ECM hydrogels direct cell behavior and influence remodeling outcomes are only partially understood, but likely include structural and biological signals retained from the native source tissue. The present review describes the utility, formation, and physical and biological characterization of ECM hydrogels. Two examples of clinical application are presented to demonstrate in vivo utility of ECM hydrogels in different organ systems. Finally, new research directions and clinical translation of ECM hydrogels are discussed.

  15. Extracellular matrix, mechanotransduction and structural hierarchies in heart tissue engineering.

    PubMed

    Parker, Kevin K; Ingber, Donald E

    2007-08-29

    The spatial and temporal scales of cardiac organogenesis and pathogenesis make engineering of artificial heart tissue a daunting challenge. The temporal scales range from nanosecond conformational changes responsible for ion channel opening to fibrillation which occurs over seconds and can lead to death. Spatial scales range from nanometre pore sizes in membrane channels and gap junctions to the metre length scale of the whole cardiovascular system in a living patient. Synchrony over these scales requires a hierarchy of control mechanisms that are governed by a single common principle: integration of structure and function. To ensure that the function of ion channels and contraction of muscle cells lead to changes in heart chamber volume, an elegant choreography of metabolic, electrical and mechanical events are executed by protein networks composed of extracellular matrix, transmembrane integrin receptors and cytoskeleton which are functionally connected across all size scales. These structural control networks are mechanoresponsive, and they process mechanical and chemical signals in a massively parallel fashion, while also serving as a bidirectional circuit for information flow. This review explores how these hierarchical structural networks regulate the form and function of living cells and tissues, as well as how microfabrication techniques can be used to probe this structural control mechanism that maintains metabolic supply, electrical activation and mechanical pumping of heart muscle. Through this process, we delineate various design principles that may be useful for engineering artificial heart tissue in the future.

  16. Inhibition of radiation-induced skin fibrosis with imatinib.

    PubMed

    Horton, Jason A; Chung, Eun Joo; Hudak, Kathryn E; Sowers, Anastasia; Thetford, Angela; White, Ayla O; Mitchell, James B; Citrin, Deborah E

    2013-03-01

    Dermal fibrosis is a disabling late toxicity of radiotherapy. Several lines of evidence suggest that overactive signaling via the Platelet-derived growth factor receptor-beta (PDGFR-β) and V-abl Abelson murine leukemia viral oncogene homolog 1 (cAbl) may be etiologic factors in the development of radiation-induced fibrosis. We tested the hypothesis that imatinib, a clinically available inhibitor of PDGFR-β, Mast/stem cell growth factor receptor (c-kit) and cAbl, would reduce the severity of dermal fibrosis in a murine model. The right hind legs of female C3H/HeN mice were exposed to 35 Gy of X-rays. Cohorts of mice were maintained on chow formulated with imatinib 0.5 mg/g or control chow for the duration of the experiment. Bilateral hind limb extension was measured serially to assess fibrotic contracture. Immunohistochemistry and biochemical assays were used to evaluate the levels of collagen and cytokines implicated in radiation-induced fibrosis. Imatinib treatment significantly reduced hind limb contracture and dermal thickness after irradiation. Immunohistochemical studies demonstrated a substantial reduction in PDGFR-β phosphorylation. We also observed reduced Transforming Growth factor-β (TGF-β) and collagen expression in irradiated skin of imatinib-treated mice, suggesting that imatinib may suppress the fibrotic process by interrupting cross-talk between these pathways. Taken together, these results support that imatinib may be a useful agent in the prevention and treatment of radiation-induced dermal fibrosis.

  17. Measurements of prompt radiation induced conductivity of Kapton.

    SciTech Connect

    Preston, Eric F.; Zarick, Thomas Andrew; Sheridan, Timothy J.; Hartman, E. Frederick; Stringer, Thomas Arthur

    2010-10-01

    We performed measurements of the prompt radiation induced conductivity in thin samples of Kapton (polyimide) at the Little Mountain Medusa LINAC facility in Ogden, UT. Three mil samples were irradiated with a 0.5 {mu}s pulse of 20 MeV electrons, yielding dose rates of 1E9 to 1E10 rad/s. We applied variable potentials up to 2 kV across the samples and measured the prompt conduction current. Analysis rendered prompt conductivity coefficients between 6E-17 and 2E-16 mhos/m per rad/s, depending on the dose rate and the pulse width.

  18. Radiation-Induced Premelting of Ice at Silica Interfaces

    SciTech Connect

    Schoeder, S.; Reichert, H.; Schroeder, H.; Mezger, M.; Okasinski, J. S.; Dosch, H.; Honkimaeki, V.; Bilgram, J.

    2009-08-28

    The existence of surface and interfacial melting of ice below 0 deg. C has been confirmed by many different experimental techniques. Here we present a high-energy x-ray reflectivity study of the interfacial melting of ice as a function of both temperature and x-ray irradiation dose. We found a clear increase of the thickness of the quasiliquid layer with the irradiation dose. By a systematic x-ray study, we have been able to unambiguously disentangle thermal and radiation-induced premelting phenomena. We also confirm the previously announced very high water density (1.25 g/cm{sup 3}) within the emerging quasiliquid layer.

  19. A model of radiatively induced quark and lepton mass model

    NASA Astrophysics Data System (ADS)

    Nomura, Takaaki

    2017-07-01

    We discuss a radiatively induced quark and lepton mass model in the rst and second generation introducing extra U(1) gauge symmetry, discrete Z 2 symmetry, vector-like fermions and exotic scalar elds. Then we analyze the allowed parameter regions which simultaneously satisfy the constraints of FCNCs for the quark sector and of LFVs including μ - e conversion, observed quark mass and mixing, and the lepton mass and mixing. In addition, the typical value for the (g - 2) μ in our model is presented. We also show extension of the model in which Majorana type neutrino masses are generated at the two loop level.

  20. Mechanisms of Radiation Induced Effects in Carbon Nanotubes

    DTIC Science & Technology

    2016-10-01

    kilogram ( C kg –1 ) rad [absorbed dose] 1 × 10 –2 joule per kilogram (J kg –1 ) [gray (Gy)] rem [equivalent and effective dose] 1 × 10–2 joule per...8725 John J. Kingman Road, MS 6201 Fort Belvoir, VA 22060-6201 T E C H N IC A L R E P O R T DTRA-TR-17-5 Mechanisms of Radiation-Induced...CLASSIFICATION OF: a. REPORT b. ABSTRACT c . THIS PAGE 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 00-10-2016 Final Oct 5, 2010 - Dec 31, 2015 Mechanisms of

  1. Radiation-induced malignant and atypical peripheral nerve sheath tumors

    SciTech Connect

    Foley, K.M.; Woodruff, J.M.; Ellis, F.T.; Posner, J.B.

    1980-04-01

    The reported peripheral nerve complications of therapeutic irradiation in humans include brachial and lumbar plexus fibrosis and cranial and peripheral nerve atrophy. We have encountered 9 patients with malignant (7) and atypical (2) peripheral nerve tumors occurring in an irradiated site suggesting that such tumors represent another delayed effect of radiation treatment on peripheral nerve. In all instances the radio-theray was within an acceptable radiation dosage, yet 3 patients developed local radiation-induced skin and bony abnormalities. The malignant peripheral nerve sheath tumors developed only in the radiation port. Animal studies support the clinical observation that malignant peripheral nerve sheath tumors can occur as a delayed effect of irradiation.

  2. Measurements of prompt radiation induced conductivity in Teflon (PTFE).

    SciTech Connect

    Hartman, E. Frederick; Zarick, Thomas Andrew; Sheridan, Timothy J.; Preston, E.

    2013-05-01

    We performed measurements of the prompt radiation induced conductivity (RIC) in thin samples of Teflon (PTFE) at the Little Mountain Medusa LINAC facility in Ogden, UT. Three mil (76.2 microns) samples were irradiated with a 0.5 %CE%BCs pulse of 20 MeV electrons, yielding dose rates of 1E9 to 1E11 rad/s. We applied variable potentials up to 2 kV across the samples and measured the prompt conduction current. Details of the experimental apparatus and analysis are reported in this report on prompt RIC in Teflon.

  3. Exaggerated radiation-induced fibrosis in patients with systemic sclerosis

    SciTech Connect

    Varga, J.; Haustein, U.F.; Creech, R.H.; Dwyer, J.P.; Jimenez, S.A. )

    1991-06-26

    Four patients with stable systemic sclerosis and limited skin involvement received radiation for the treatment of solid malignant neoplasms. Following localized irradiation, each patient developed an exaggerated cutaneous and internal fibrotic reaction in the irradiated areas. The surface area of fibrosis extended beyond the radiation portals employed, and the fibrotic process was poorly responsive to antifibrotic therapy. Three of the patients died of complications caused by fibrous encasement of internal organs. The extent and severity of postradiation fibrosis in these patients was distinctly unusual. These observations suggest that patients with systemic sclerosis are particularly susceptible to developing excessive radiation-induced fibrosis.

  4. Radiation-Induced Premelting of Ice at Silica Interfaces

    NASA Astrophysics Data System (ADS)

    Schöder, S.; Reichert, H.; Schröder, H.; Mezger, M.; Okasinski, J. S.; Honkimäki, V.; Bilgram, J.; Dosch, H.

    2009-08-01

    The existence of surface and interfacial melting of ice below 0°C has been confirmed by many different experimental techniques. Here we present a high-energy x-ray reflectivity study of the interfacial melting of ice as a function of both temperature and x-ray irradiation dose. We found a clear increase of the thickness of the quasiliquid layer with the irradiation dose. By a systematic x-ray study, we have been able to unambiguously disentangle thermal and radiation-induced premelting phenomena. We also confirm the previously announced very high water density (1.25g/cm3) within the emerging quasiliquid layer.

  5. Challenges and Opportunities in Radiation-induced Hemorrhagic Cystitis

    PubMed Central

    Zwaans, Bernadette M.M.; Nicolai, Heinz G.; Chancellor, Michael B.; Lamb, Laura E.

    2016-01-01

    As diagnosis and treatment of cancer is improving, medical and social issues related to cancer survivorship are becoming more prevalent. Hemorrhagic cystitis (HC), a rare but serious disease that may affect patients after pelvic radiation or systemic chemotherapy, has significant unmet medical needs. Although no definitive treatment is currently available, various interventions are employed for HC. Effects of nonsurgical treatments for HC are of modest success and studies aiming to control radiation-induced bladder symptoms are lacking. In this review, we present current and advanced therapeutic strategies for HC to help cancer survivors deal with long-term urologic health issues. PMID:27601964

  6. Radiation-induced breast angiosarcoma: a case report

    PubMed Central

    Tato-Varela, Sara; Albalat-Fernández, Rosa; Pabón-Fernández, Sara; Núñez-García, Diego; Calle-Marcos, Manolo La

    2016-01-01

    Radiation-induced breast angiosarcoma is a severe but rare late complication in the breast-preserving management of breast cancer through surgery and radiotherapy [1]. Often the initial diagnosis of this entity is complex given its relatively anodyne nature and usually being present in the form of typically multifocal reddish-purple papular skin lesions [2]. Because of the low incidence of this tumour, there is a limited number of studies regarding its optimal therapeutic management [3]. The preferred treatment is aggressive surgical removal and the prognosis is poor with an overall survival rate of 12–20% at five years [4]. PMID:28101140

  7. Regional structure-function relationships in mouse aortic valve tissue

    PubMed Central

    Krishnamurthy, Varun K.; Guilak, Farshid; Narmoneva, Daria A.; Hinton, Robert B.

    2010-01-01

    Site-specific biomechanical properties of the aortic valve play an important role in native valve function, and alterations in these properties may reflect mechanisms of degeneration and disease. Small animals such as targeted mutagenesis mice provide a powerful approach to model human valve disease pathogenesis; however, physical mechanical testing in small animals is limited by valve tissue size. Aortic valves are comprised of highly organized extracellular matrix compartmentalized in cusp and annulus regions, which have different functions. The objective of this study was to measure regional mechanical properties of mouse aortic valve tissue using a modified micropipette aspiration technique. Aortic valves were isolated from juvenile, adult and aged adult C57BL/6 wild type mice. Tissue tensile stiffness was determined for annulus and cusp regions using a half-space punch model. Stiffness for the annulus region was significantly higher compared to the cusp region at all stages. Further, aged adult valve tissue had decreased stiffness in both the cusp and annulus. Quantitative histochemical analysis revealed a collagen-rich annulus and a proteoglycan-rich cusp at all stages. In aged adult valves, there was proteoglycan infiltration of the annulus hinge, consistent with observed mechanical differences over time. These findings indicate that valve tissue biomechanical properties vary in wild type mice in a region-specific and age-related manner. The micropipette aspiration technique provides a promising approach for studies of valve structure and function in small animal models, such as transgenic mouse models of valve disease. PMID:20863504

  8. Experimental investigation on light propagation through apple tissue structures

    NASA Astrophysics Data System (ADS)

    Askoura, Mohamed Lamine; Piron, Vianney; Vaudelle, Fabrice; L'Huillier, Jean-Pierre; Madieta, Emmanuel; Mehinagic, Emira

    2015-07-01

    The interaction of light with biological materials, such as fruits and vegetables, is a complex process which involves both absorption, and scattering events at different scales. Measuring the optical properties of a fruit allows understanding the physical and chemical characteristics. In this paper, an optical bench based on the use of a continuous laser source and a CCD camera was developed to study the light diffusion inside apple tissue structures. The method refers to the well-known steady-state spatially resolved method. First, the optoelectronics system was tested with a tissue phantom in order to show the optimal sensing range required to obtain the best estimated optical properties. Second, experimental results were obtained using peeled and unpeeled apples as interrogated tissues. The data were confronted with a diffusion model in order to extract the optical properties at two wavelengths of 633, and 852 nm. To better understand the effect of the apple tissue structures, investigations into the propagation of light through a half cut apple were also performed.

  9. Three-dimensional structure of brain tissue at submicrometer resolution

    SciTech Connect

    Saiga, Rino; Mizutani, Ryuta; Inomoto, Chie; Takekoshi, Susumu; Nakamura, Naoya; Tsuboi, Akio; Osawa, Motoki; Arai, Makoto; Oshima, Kenichi; Itokawa, Masanari; Uesugi, Kentaro; Takeuchi, Akihisa; Terada, Yasuko; Suzuki, Yoshio

    2016-01-28

    Biological objects are composed of submicrometer structures such as cells and organelles that are essential for their functions. Here, we report on three-dimensional X-ray visualization of cells and organelles at resolutions up to 100 nm by imaging microtomography (micro-CT) equipped with Fresnel zone plate optics. Human cerebral tissue, fruit fly cephalic ganglia, and Escherichia coli bacteria labeled with high atomic-number elements were embedded in epoxy resin and subjected to X-ray microtomography at the BL37XU and BL47XU beamlines of the SPring-8 synchrotron radiation facility. The obtained results indicated that soft tissue structures can be visualized with the imaging microtomography.

  10. Multiscale mechanics of hierarchical structure/property relationships in calcified tissues and tissue/material interfaces

    PubMed Central

    Katz, J. Lawrence; Misra, Anil; Spencer, Paulette; Wang, Yong; Bumrerraj, Sauwanan; Nomura, Tsutomu; Eppell, Steven J.; Tabib-Azar, Massood

    2007-01-01

    This paper presents a review plus new data that describes the role hierarchical nanostructural properties play in developing an understanding of the effect of scale on the material properties (chemical, elastic and electrical) of calcified tissues as well as the interfaces that form between such tissues and biomaterials. Both nanostructural and microstructural properties will be considered starting with the size and shape of the apatitic mineralites in both young and mature bovine bone. Microstructural properties for human dentin and cortical and trabecular bone will be considered. These separate sets of data will be combined mathematically to advance the effects of scale on the modeling of these tissues and the tissue/biomaterial interfaces as hierarchical material/structural composites. Interfacial structure and properties to be considered in greatest detail will be that of the dentin/adhesive (d/a) interface, which presents a clear example of examining all three material properties, (chemical, elastic and electrical). In this case, finite element modeling (FEA) was based on the actual measured values of the structure and elastic properties of the materials comprising the d/a interface; this combination provides insight into factors and mechanisms that contribute to premature failure of dental composite fillings. At present, there are more elastic property data obtained by microstructural measurements, especially high frequency ultrasonic wave propagation (UWP) and scanning acoustic microscopy (SAM) techniques. However, atomic force microscopy (AFM) and nanoindentation (NI) of cortical and trabecular bone and the dentin–enamel junction (DEJ) among others have become available allowing correlation of the nanostructural level measurements with those made on the microstructural level. PMID:18270549

  11. Radiation-induced amorphization of intermetallic compounds: A molecular-dynamics study of CuTi and Cu sub 4 Ti sub 3

    SciTech Connect

    Lam, N.Q.; Okamoto, P.R. ); Sabochick, M.J. . Dept. of Engineering Physics)

    1991-06-01

    In the present paper, important results of our recent computer simulation of radiation-induced amorphization in the ordered compounds CuTi and Cu{sub 4}Ti{sub 3} are summarized. The energetic, structural, thermodynamic and mechanical responses of these intermetallics during chemical disordering, point-defect production and heating were simulated, using molecular dynamics and embedded-atom potentials. From the atomistic details obtained, the critical role of radiation-induced structural disorder in driving the crystalline-to-amorphous phase transformation is discussed. 25 refs., 4 figs.

  12. New era of radiotherapy: an update in radiation-induced lung disease

    PubMed Central

    Benveniste, M. F. K.; Welsh, J.; Godoy, M. C. B.; Betancourt, S. L.; Mawlawi, O. R; Munden, R. F.

    2014-01-01

    Over the last few decades, advances in radiotherapy (RT) technology have improved delivery of radiation therapy dramatically. Advances in treatment planning with the development of image-guided radiotherapy and in techniques such as proton therapy, allows the radiation therapist to direct high doses of radiation to the tumour. These advancements result in improved local regional control while reducing potentially damaging dosage to surrounding normal tissues. It is important for radiologists to be aware of the radiological findings from these advances in order to differentiate expected radiation-induced lung injury (RILD) from recurrence, infection, and other lung diseases. In order to understand these changes and correlate them with imaging, the radiologist should have access to the radiation therapy treatment plans. PMID:23473474

  13. Modeling of radiation-induced bystander effect using Monte Carlo methods

    NASA Astrophysics Data System (ADS)

    Xia, Junchao; Liu, Liteng; Xue, Jianming; Wang, Yugang; Wu, Lijun

    2009-03-01

    Experiments showed that the radiation-induced bystander effect exists in cells, or tissues, or even biological organisms when irradiated with energetic ions or X-rays. In this paper, a Monte Carlo model is developed to study the mechanisms of bystander effect under the cells sparsely populated conditions. This model, based on our previous experiment which made the cells sparsely located in a round dish, focuses mainly on the spatial characteristics. The simulation results successfully reach the agreement with the experimental data. Moreover, other bystander effect experiment is also computed by this model and finally the model succeeds in predicting the results. The comparison of simulations with the experimental results indicates the feasibility of the model and the validity of some vital mechanisms assumed.

  14. Radiation-induced cognitive dysfunction and cerebellar oxidative stress in mice: protective effect of alpha-lipoic acid.

    PubMed

    Manda, Kailash; Ueno, Megumi; Moritake, Takashi; Anzai, Kazunori

    2007-02-12

    Reactive oxygen species are implicated in neurodegeneration and cognitive disorders due to higher vulnerability of neuronal tissues. The cerebellum is recently reported to be involved in cognitive function. Therefore, present study aimed at investigating the role alpha-lipoic acid against radiation-induced oxidative stress and antioxidant status in cerebellum and its correlation with cognitive dysfunction. We observed spontaneous motor activities and spatial memory task of mice using pyroelectric infrared sensor and programmed video tracking system, respectively. Whole body X-irradiation (6 Gy) of mice substantially impaired the reference memory and motor activities of mice. However, acute intraperitoneal treatment of mice with alpha-lipoic acid prior to irradiation significantly attenuated such cognitive dysfunction. Alpha-lipoic acid pretreatment exerted a very high magnitude of protection against radiation-induced augmentation of protein carbonyls and thiobarbituric acid reactive substance (TBARS) in mice cerebellum. Further, radiation-induced deficit of total, nonprotein and protein-bound sulfhydryl (T-SH, NP-SH, PB-SH) contents of cerebellum and plasma ferric reducing power (FRAP) was also inhibited by alpha-lipoic acid pre-treatment. Moreover, alpha-lipoic acid treated mice showed an intact cytoarchitecture of cerebellum, higher counts of intact Purkinje cells and granular cells in comparison to untreated irradiated mice. Results clearly indicate that alpha-lipoic acid is potent neuroprotective antioxidant.

  15. Transgenerational inheritance of enhanced susceptibility to radiation-induced medulloblastoma in newborn Ptch1+/− mice after paternal irradiation

    PubMed Central

    Tanno, Barbara; Meschini, Roberta; Cordelli, Eugenia; Benassi, Barbara; Longobardi, Maria Grazia; Izzotti, Alberto; Pulliero, Alessandra; Mancuso, Mariateresa; Pacchierotti, Francesca

    2015-01-01

    The hypothesis of transgenerational induction of increased cancer susceptibility after paternal radiation exposure has long been controversial because of inconsistent results and the lack of a mechanistic interpretation. Here, exploiting Ptch1 heterozygous knockout mice, susceptible to spontaneous and radiation-induced medulloblastoma, we show that exposure of paternal germ cells to 1 Gy X-rays, at the spermatogonial stage, increased by a considerable 1.4-fold the offspring susceptibility to medulloblastoma induced by neonatal irradiation. This effect gained further biological significance thanks to a number of supporting data on the immunohistochemical characterization of the target tissue and preneoplastic lesions (PNLs). These results altogether pointed to increased proliferation of cerebellar granule cell precursors and PNLs cells, which favoured the development of frank tumours. The LOH analysis of tumor DNA showed Ptch1 biallelic loss in all tumor samples, suggesting that mechanisms other than interstitial deletions, typical of radiation-induced medulloblastoma, did not account for the observed increased cancer risk. This data was supported by comet analysis showing no differences in DNA damage induction and repair in cerebellar cells as a function of paternal irradiation. Finally, we provide biological plausibility to our results offering evidence of a possible epigenetic mechanism of inheritance based on radiation-induced changes of the microRNA profile of paternal sperm. PMID:26452034

  16. Radiation-induced transmissable chromosomal instability in haemopoietic stem cells

    NASA Astrophysics Data System (ADS)

    Kadhim, M. A.; Wright, E. G.

    Heritable radiation-induced genetic alterations have long been assumed to be ``fixed'' within the first cell division. However, there is a growing body of evidence that a considerable fraction of cells surviving radiation exposure appear normal, but a variety of mutational changes arise in their progeny due to a transmissible genomic instability. In our investigations of G-banded metaphases, non-clonal cytogenetic aberrations, predominantly chromatid-type aberrations, have been observed in the clonal descendants of murine and human haemopoietic stem cells surviving low doses (~1 track per cell) of alpha-particle irradiations. The data are consistent with a transmissible genetic instability induced in a stem cell resulting in a diversity of chromosomal aberrations in its clonal progeny many cell divisions later. Recent studies have demonstrated that the instability phenotype persists in vivo and that the expression of chromosomal instability has a strong dependence on the genetic characteristics of the irradiated cell. At the time when cytogenetic aberrations are detected, an increased incidence of hprt mutations and apoptotic cells have been observed in the clonal descendants of alpha-irradiated murine haemopoietic stem cells. Thus, delayed chromosomal abnormalities, delayed cell death by apoptosis and late-arising specific gene mutations may reflect diverse consequences of radiation-induced genomic instability. The relationship, if any, between these effects is not established. Current studies suggest that expression of these delayed heritable effects is determined by the type of radiation exposure, type of cell and a variety of genetic factors.

  17. Radiation-induced dural fibrosarcoma with unusually short latent period

    SciTech Connect

    Ghatak, N.R.; Aydin, F.; Leshner, R.T. Tulane Univ., New Orleans, LA )

    1993-05-01

    Although rare, the occurrence of radiation-induced intracranial neoplasms of various types is well known. Among these tumors, fibrosarcomas, especially in the region of seila turcica, seem to be the most common type. These tumors characteristically occur after a long latent period, usually several years, following radiation therapy. The authors now report a case of apparently radiation-induced fibrosarcoma with some unusual features in a 10-year-old boy who was treated with radiation for medulloblastoma. He received a total dose of 53.2 Gy radiation delivered at 1.8 per fraction with 6 MV acceleration using the standard craniospinal technique. An MRI at 15 months after the completion of radiotherapy showed a mass over the cerebral convexity, which increased two-fold in size within a period of 4 months. A well circumscribed tumor was removed from the fronto-parietal convexity. The tumor measured 5x4.5x1.5 cm and was attached to the dura with invasion of the overlying bone. Histologically, it displayed the characteristic features of a low-grade fibrosarcoma. The patient remains free of tumor 18 months after the surgery. This case emphasizes the potential risk for the development of a second neoplasm following therapeutic radiation and also documents, to the authors' knowledge, the shortest latent period reported so far between administration of radiotherapy and development of an intracranial tumor.

  18. Sestrin2 protects the myocardium against radiation-induced damage.

    PubMed

    Zeng, Yue-Can; Chi, Feng; Xing, Rui; Zeng, Jing; Gao, Song; Chen, Jia-Jia; Wang, Hong-Mei; Duan, Qiong-Yu; Sun, Yu-Nan; Niu, Nan; Tang, Mei-Yue; Wu, Rong

    2016-05-01

    The purpose of this study was to investigate the role of Sestrin2 in response to radiation-induced injury to the heart and on the cardiomyopathy development in the mouse. Mice with genetic deletion of the Sestrin2 (Sestrin2 knockout mice [Sestrin2 KO]) and treatment with irradiation (22 or 15 Gy) were used as independent approaches to determine the role of Sestrin2. Echocardiography (before and after isoproterenol challenge) and left ventricular (LV) catheterization were performed to evaluate changes in LV dimensions and function. Masson's trichrome was used to assess myocardial fibrosis. Immunohistochemistry and Western blot were used to detect the capillary density. After 22 or 15 Gy irradiation, the LV ejection fraction (EF) was impaired in wt mice at 1 week and 4 months after irradiation when compared with sham irradiation. Compared to wt mice, Sestrin2 KO mice had significant reduction in reduced LVEF at 1 week and 4 months after irradiation. A significant increase in LV end-diastolic pressure and myocardial fibrosis and a significant decrease in capillary density were observed in irradiation-wt mice, as well as in irradiation-Sestrin2 KO mice. Sestrin2 involved in the regulation of cardiomyopathy (such as myocardial fibrosis) after irradiation. Overexpression of Sestrin2 might be useful in limiting radiation-induced myocardial injury.

  19. Radiation-induced recurrent intestinal pseudo-obstruction

    SciTech Connect

    Conklin, J.L.; Anuras, S.

    1981-06-01

    The syndrome of intestinal pseudo-obstruction is a complex of signs and symptoms of intestinal obstruction without evidence of mechanical obstruction of the intestinal lumen. A patient with radiation-induced intestinal pseudoobstruction is described. The patient is a 74-year old woman with a history of chronic diarrhea, recurrent episodes of crampy abdominal pain, nausea and vomiting since receiving a 13,000 rad radiation dose to the pelvis in 1954. She has been hospitalized on many occasions for symptoms and signs of bowel obstruction. Upper gastrointestinal contrast roentgenograms with small bowel follow-through done during these episodes revealed multiple dilated loops of small bowel with no obstructing lesion. Barium enemas revealed no obstructing lesion. Each episode resolved with conservative therapy. Other secondary causes for intestinal pseudo-obstruction were ruled out in our patient. She gave no history of familial gastrointestinal disorders. Although postirradiation motility abnormalities have been demonstrated experimentally this is the first report of radiation induced intestinal pseudo-obstruction.

  20. Inhibition of radiation-induced polyuria by histamine receptor antagonists

    SciTech Connect

    Donlon, M.A.; Melia, J.A.; Helgeson, E.A.; Wolfe, W.W.

    1986-03-01

    In previous studies the authors have demonstrated that gamma radiation results in polyuria, which is preceded by polydypsia. This suggests that the increased thirst elicited by radiation causes increased urinary volume (UV). Histamine, which is released following radiation exposure, also elicits drinking by nonirradiated rats when administered exogenously. In this study the authors have investigated both the role of water deprivation and the effect of histamine receptor antagonists (HRA) on radiation-induced polyuria. Sprague-Dawley rats were housed individually in metabolic cages. Water was allowed ad libitum except in deprivation experiments where water was removed for 24 hr immediately following radiation. Cimetidine (CIM), an H2 HRA, and dexbromopheniramine (DXB), an H1 HRA, were administered i.p. (16 and 1 mg/kg, respectively) 30 min prior to irradiation (950 rads from a cobalt source). UV was determined at 24-hr intervals for 3 days preceding irradiation and 24 hr postirradiation. UV in DXB treated rats was significantly reduced 24 hr postirradiation (CON = 427 +/- 54%; DXB = 247 +/- 39% of preirradiated CON) compared to postirradiation control values. CIM did not affect postirradiation UV. These data suggest that radiation-induced polyuria is caused by polydypsia which is, in part, mediated by histamine induced by an H1 receptor.

  1. Genetic variation in radiation-induced cell death.

    PubMed

    Smirnov, Denis A; Brady, Lauren; Halasa, Krzysztof; Morley, Michael; Solomon, Sonia; Cheung, Vivian G

    2012-02-01

    Radiation exposure through environmental, medical, and occupational settings is increasingly common. While radiation has harmful effects, it has utility in many applications such as radiotherapy for cancer. To increase the efficacy of radiation treatment and minimize its risks, a better understanding of the individual differences in radiosensitivity and the molecular basis of radiation response is needed. Here, we integrated human genetic and functional genomic approaches to study the response of human cells to radiation. We measured radiation-induced changes in gene expression and cell death in B cells from normal individuals. We found extensive individual variation in gene expression and cellular responses. To understand the genetic basis of this variation, we mapped the DNA sequence variants that influence expression response to radiation. We also identified radiation-responsive genes that regulate cell death; silencing of these genes by small interfering RNA led to an increase in radiation-induced cell death in human B cells, colorectal and prostate cancer cells. Together these results uncovered DNA variants that contribute to radiosensitivity and identified genes that can be targeted to increase the sensitivity of tumors to radiation.

  2. Radiation-induced genomic instability in Caenorhabditis elegans.

    PubMed

    Huumonen, Katriina; Immonen, Hanna-Kaisa; Baverstock, Keith; Hiltunen, Mikko; Korkalainen, Merja; Lahtinen, Tapani; Parviainen, Juha; Viluksela, Matti; Wong, Garry; Naarala, Jonne; Juutilainen, Jukka

    2012-10-09

    Radiation-induced genomic instability has been well documented, particularly in vitro. However, the understanding of its mechanisms and their consequences in vivo is still limited. In this study, Caenorhabditis elegans (C. elegans; strain CB665) nematodes were exposed to X-rays at doses of 0.1, 1, 3 or 10Gy. The endpoints were measured several generations after exposure and included mutations in the movement-related gene unc-58, alterations in gene expression analysed with oligoarrays containing the entire C. elegans genome, and micro-satellite mutations measured by capillary electrophoresis. The progeny of the irradiated nematodes showed an increased mutation frequency in the unc-58 gene, with a maximum response observed at 1Gy. Significant differences were also found in gene expression between the irradiated (1Gy) and non-irradiated nematode lines. Differences in gene expression did not show clear clustering into certain gene categories, suggesting that the instability might be a chaotic process rather than a result of changes in the function of few specific genes such as, e.g., those responsible for DNA repair. Increased heterogeneity in gene expression, which has previously been described in irradiated cultured human lymphocytes, was also observed in the present study in C. elegans, the coefficient of variation of gene expression being higher in the progeny of irradiated nematodes than in control nematodes. To the best of our knowledge, this is the first publication reporting radiation-induced genomic instability in C. elegans.

  3. Radiation-induced skin carcinomas of the head and neck

    SciTech Connect

    Ron, E.; Modan, B.; Preston, D.; Alfandary, E.; Stovall, M.; Boice, J.D. Jr. )

    1991-03-01

    Radiation exposures to the scalp during childhood for tinea capitis were associated with a fourfold increase in skin cancer, primarily basal cell carcinomas, and a threefold increase in benign skin tumors. Malignant melanoma, however, was not significantly elevated. Overall, 80 neoplasms were identified from an extensive search of the pathology logs of all major hospitals in Israel and computer linkage with the national cancer registry. Radiation dose to the scalp was computed for over 10,000 persons irradiated for ringworm (mean 7 Gy), and incidence rates were contrasted with those observed in 16,000 matched comparison subjects. The relative risk of radiogenic skin cancer did not differ significantly between men or women or by time since exposure; however, risk was greatest following exposures in early childhood. After adjusting for sex, ethnic origin, and attained age, the estimated excess relative risk was 0.7 per Gy and the average excess risk over the current follow-up was 0.31/10(4) PY-Gy. The risk per Gy of radiation-induced skin cancer was intermediate between the high risk found among whites and no risk found among blacks in a similar study conducted in New York City. This finding suggests the role that subsequent exposure to uv radiation likely plays in the expression of a potential radiation-induced skin malignancy.

  4. The thermal stability of radiation-induced defects in illite

    NASA Astrophysics Data System (ADS)

    Riegler, T.; Allard, T.; Beaufort, D.; Cantin, J.-L.; von Bardeleben, H. J.

    2016-01-01

    High-purity illite specimens from the Mesoproterozoic unconformity-related uranium deposits of Kiggavik, Thelon basin, Nunavut (Canada), and Shea Creek (Athabasca basin, Saskatchewan, Canada) have been studied using electron paramagnetic resonance spectroscopy to determine the thermal stability of the main radiation-induced defects and question the potential of using illite as a natural dosimeter. The observed spectra are complex as they can show in the same region several contributions: (1) an unstable native defect, (2) the main stable defect named Ai by reference to a previous study (Morichon et al. in Phys Chem Minerals 35:339-346, 2008), (3) a signal at g = 2.063 assigned to a new defect, not yet fully characterized, named Ai2 center and (4) impurities such as vanadyl complex or divalent manganese. Isochronal heating shows that the new signal corresponds to a stable species. Isothermal heating experiments at 400 and 450 °C provide values of half-life extrapolated at room temperature and activation energy of 1.9-29,109 years and 1.3-1.4 eV, respectively, corresponding to the Ai center. These parameters allow the use of stable radiation-induced defects as a record of radioactivity down to the Paleoproterozoic period.

  5. Characterization of radiation-induced emesis in the ferret

    SciTech Connect

    King, G.L.

    1988-01-01

    Forty-eight ferrets (Mustela putorius furo) were individually head-shielded and radiated with bilateral cobalt 60 gamma radiation at 100 cGy min at doses ranging between 49 and 601 cGy. The emetic threshold was observed at 69 cGy, the ED 50 was calculated as 77 cGy, and 100% incidence of emesis occurred at 201 cGy. With increasing doses of radiation, the latency to first emesis after radiation decreased dramatically, whereas the duration of the prodromal period increased. Two other sets of experiments suggest that dopaminergic mechanisms play a minor role in radiation-induced emesis in the ferret. Twenty-two animals were injected either intravenously or subcutaneously with 30 to 300 micrograms /kg of apomorphine. Fewer than 50% of the animals vomited to 300 micrograms/kg apomorphine; central dopaminergic receptor activation was apparent at all doses. Another eight animals received 1 mg/kg domperidone prior to either 201 (n=4) or 401 (n=4) cGy radiation and their emetic responses were compared with NaCi-injected-irradiated controls (n=8). At 201 cGy, domperidone significantly reduced only the total time in emetic behavior. At 401 cGy, domperidone had no salutary effect on radiation-induced emesis. The emetic responses of the ferret to radiation and apomorphine are compared with these responses in other vomiting species.

  6. Characterization of radiation-induced emesis in the ferret

    SciTech Connect

    King, G.L.

    1988-06-01

    Forty-eight ferrets (Mustela putorius furo) were individually head-shielded and radiated with bilateral /sup 60/Co gamma radiation at 100 cGy min-1 at doses ranging between 49 and 601 cGy. The emetic threshold was observed at 69 cGy, the ED50 was calculated at 77 cGy, and 100% incidence of emesis occurred at 201 cGy. With increasing doses of radiation, the latency to first emesis after radiation decreased dramatically, whereas the duration of the prodromal period increased. Two other sets of experiments suggest that dopaminergic mechanisms play a minor role in radiation-induced emesis in the ferret. Twenty-two animals were injected either intravenously or subcutaneously with 30 to 300 micrograms/kg of apomorphine. Fewer than 50% of the animals vomited to 300 micrograms/kg apomorphine; central dopaminergic receptor activation was apparent at all doses. Another eight animals received 1 mg/kg domperidone prior to either 201 (n = 4) or 401 (n = 4) cGy radiation and their emetic responses were compared with NaCl-injected-irradiated controls (n = 8). At 201 cGy, domperidone significantly reduced only the total time in emetic behavior. At 401 cGy, domperidone had no salutary effect on radiation-induced emesis. The emetic responses of the ferret to radiation and apomorphine are compared with these responses in other vomiting species.

  7. [Radiation-induced genomic instability: phenomenon, molecular mechanisms, pathogenetic significance].

    PubMed

    Mazurik, V K; Mikhaĭlov, V F

    2001-01-01

    The recent data on the radiation-induced genome instability as a special state of progeny of cells irradiated in vitro as well as after a whole body exposure to ionizing radiation, that make these cells considerably different from normal, unirradiated cells, were considered. This state presents a number of cytogenetical, molecular-biological, cytological and biochemical manifestations untypical for normal cells. The state is controlled by the mechanisms of regulation of checkpoints of cell cycle, and apoptosis, that is under gene p53 control. The proof has been found that this state transfers from irradiated maternal cells to their surviving progeny by the epigenetical mechanisms and would exist until the cells restore the original state of response on the DNA damage. From the point of view of the genome instability conception, that considers the chromatine rearrangement as the adaptive-evolution mechanism of adaptation of the species to changeable environmental conditions, the radiation-induced genome instability may be considered as transition of irradiated progeny to the state of read these to adaptation changes with two alternative pathways. The first leads to adaptation to enviromental conditions and restoring of normal cell functions. The second presents the cell transition into the transformed state with remain genome instability and with increase of tumour growth probability.

  8. Mensenchymal stem cells can delay radiation-induced crypt death: impact on intestinal CD44(+) fragments.

    PubMed

    Chang, Peng-Yu; Jin, Xing; Jiang, Yi-Yao; Wang, Li-Xian; Liu, Yong-Jun; Wang, Jin

    2016-05-01

    Intestinal stem cells are primitive cells found within the intestinal epithelium that play a central role in maintaining epithelial homeostasis through self-renewal and commitment into functional epithelial cells. Several markers are available to identify intestinal stem cells, such as Lgr5, CD24 and EphB2, which can be used to sort intestinal stem cells from mammalian gut. Here, we identify and isolate intestinal stem cells from C57BL/6 mice by using a cell surface antigen, CD44. In vitro, some CD44(+) crypt cells are capable of forming "villus-crypt"-like structures (organoids). A subset strongly positive for CD44 expresses high levels of intestinal stem-cell-related genes, including Lgr5, Bmi1, Hopx, Lrig1, Ascl2, Smoc2 and Rnf43. Cells from this subset are more capable of developing into organoids in vitro, compared with the subset weakly positive for CD44. However, the organoids are sensitive to ionizing irradiation. We investigate the specific roles of mesenchymal stem cells in protecting organoids against radiation-induced crypt death. When co-cultured with mesenchymal stem cells, the crypt domains of irradiated organoids possess more proliferative cells and fewer apoptotic cells than those not co-cultured with mesenchymal stem cells. Cd44v6 continues to be expressed in the crypt domains of irradiated organoids co-cultured with mesenchymal stem cells. Our results indicate specific roles of mesenchymal stem cells in delaying radiation-induced crypt death in vitro.

  9. Radiation-induced cardiovascular diseases: Is the epidemiologic evidence compatible with the radiobiologic data?

    SciTech Connect

    Schultz-Hector, Susanne . E-mail: susanne.schultz-hector@helmholtz.de; Trott, Klaus-Ruediger Prof.

    2007-01-01

    The Life Span Study of Japanese atomic bomb survivors demonstrates that radiation exposure significantly increased the risk of developing ischemic heart disease, in particular myocardial infarction. Similarly, epidemiologic investigations in very large populations of patients who had received postoperative radiotherapy for breast cancer or for peptic ulcer demonstrate that radiation exposure of the heart with an average equivalent single dose of approximately 2 Gy significantly increased the risk of developing ischemic heart disease more than 10 years after irradiation. These epidemiologic findings are compatible with radiobiologic data on the pathogenesis of radiation-induced heart disease in experimental animals. The critical target structure appears to be the endothelial lining of blood vessels, in particular arteries, leading to early functional alterations such as pro-inflammatory responses and other changes, which are slowly progressive. Research should concentrate on the interaction of these radiation-induced endothelial changes with the early stages of age-related atherosclerosis to develop criteria for optimizing treatment plans in radiotherapy and also potential interventional strategies.

  10. Whole Brain Radiation-Induced Cognitive Impairment: Pathophysiological Mechanisms and Therapeutic Targets

    PubMed Central

    Lee, Yong Woo; Cho, Hyung Joon; Lee, Won Hee; Sonntag, William E.

    2012-01-01

    Radiation therapy, the most commonly used for the treatment of brain tumors, has been shown to be of major significance in tu-mor control and survival rate of brain tumor patients. About 200,000 patients with brain tumor are treated with either partial large field or whole brain radiation every year in the United States. The use of radiation therapy for treatment of brain tumors, however, may lead to devastating functional deficits in brain several months to years after treatment. In particular, whole brain radiation therapy results in a significant reduction in learning and memory in brain tumor patients as long-term consequences of treatment. Although a number of in vitro and in vivo studies have demonstrated the pathogenesis of radiation-mediated brain injury, the cel-lular and molecular mechanisms by which radiation induces damage to normal tissue in brain remain largely unknown. Therefore, this review focuses on the pathophysiological mechanisms of whole brain radiation-induced cognitive impairment and the iden-tification of novel therapeutic targets. Specifically, we review the current knowledge about the effects of whole brain radiation on pro-oxidative and pro-inflammatory pathways, matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) system and extracellular matrix (ECM), and physiological angiogenesis in brain. These studies may provide a foundation for defin-ing a new cellular and molecular basis related to the etiology of cognitive impairment that occurs among patients in response to whole brain radiation therapy. It may also lead to new opportunities for therapeutic interventions for brain tumor patients who are undergoing whole brain radiation therapy. PMID:24009822

  11. Modulation of ionizing radiation induced oxidative imbalance by semi-fractionated extract of Piper betle

    PubMed Central

    Verma, Savita; Dutta, Ajaswrata; Sankhwar, Sanghmitra; Shukla, Sandeep Kumar

    2010-01-01

    The study was planned to evaluate modulatory effect of aqueous extract of Piper betle leaf (PBL) on ionizing radiation mediated oxidative stress leading to normal tissues damage during radiotherapy and other radiation exposures. The total polyphenols and flavonoids known as free radical scavenger (chelators) were measured in the extract. To ascertain antioxidant potential of PBL extract, we studied free radical scavenging, metal chelation, reducing power, lipid peroxidation inhibition and ferric reducing antioxidant properties (FRAP ) using in vitro assays. Mice were exposed to varied radiation doses administered with the same extract prior to irradiation to confirm its oxidative stress minimizing efficacy by evaluating ferric reducing ability of plasma, reduced glutathione, lipid peroxidation and micro-nuclei frequency. PBL extract was effective in scavenging DPPH (up to 92% at 100 µg/ml) and superoxide radicals (up to 95% at 80 µg/ml), chelated metal ions (up to 83% at 50 µg/ml) and inhibited lipid peroxidation (up to 45.65% at 500 µg/ml) in a dose dependant manner using in vitro model. Oral administration of PBL extract (225 mg/kg body weight) 1 hr before irradiation in mice significantly enhanced (p < 0.01) radiation abated antioxidant potential of plasma and GSH level in all the observed organs. The treatment with extract effectively lowered the radiation induced lipid peroxidation at 24 hrs in all the selected organs with maximum inhibition in thymus (p < 0.01). After 48 hrs, lipid peroxidation was maximally inhibited in the group treated with the extract. Frequency of radiation induced micronucleated cells declined significantly (34.78%, p < 0.01) at 24 hrs post-irradiation interval by PBL extract administration. The results suggest that PBL extract has high antioxidant potential and relatively non-toxic and thus could be assertively used to mitigate radiotherapy inflicted normal tissues damage and also injuries caused by moderate doses of radiation

  12. Acute adaptive immune response correlates with late radiation-induced pulmonary fibrosis in mice.

    PubMed

    Paun, Alexandra; Kunwar, Amit; Haston, Christina K

    2015-02-20

    The lung response to radiation exposure can involve an immediate or early reaction to the radiation challenge, including cell death and an initial immune reaction, and can be followed by a tissue injury response, of pneumonitis or fibrosis, to this acute reaction. Herein, we aimed to determine whether markers of the initial immune response, measured within days of radiation exposure, are correlated with the lung tissue injury responses occurring weeks later. Inbred strains of mice known to be susceptible (KK/HIJ, C57BL/6J, 129S1/SvImJ) or resistant (C3H/HeJ, A/J, AKR/J) to radiation-induced pulmonary fibrosis and to vary in time to onset of respiratory distress post thoracic irradiation (from 10-23 weeks) were studied. Mice were untreated (controls) or received 18 Gy whole thorax irradiation and were euthanized at 6 h, 1d or 7 d after radiation treatment. Pulmonary CD4+ lymphocytes, bronchoalveolar cell profile & cytokine level, and serum cytokine levels were assayed. Thoracic irradiation and inbred strain background significantly affected the numbers of CD4+ cells in the lungs and the bronchoalveolar lavage cell differential of exposed mice. At the 7 day timepoint greater numbers of pulmonary Th1 and Th17 lymphocytes and reduced lavage interleukin17 and interferonγ levels were significant predictors of late stage fibrosis. Lavage levels of interleukin-10, measured at the 7 day timepoint, were inversely correlated with fibrosis score (R=-0.80, p=0.05), while serum levels of interleukin-17 in control mice significantly correlated with post irradiation survival time (R=0.81, p=0.04). Lavage macrophage, lymphocyte or neutrophil counts were not significantly correlated with either of fibrosis score or time to respiratory distress in the six mouse strains. Specific cytokine and lymphocyte levels, but not strain dependent lavage cell profiles, were predictive of later radiation-induced lung injury in this panel of inbred strains.

  13. Whole brain radiation-induced cognitive impairment: pathophysiological mechanisms and therapeutic targets.

    PubMed

    Lee, Yong Woo; Cho, Hyung Joon; Lee, Won Hee; Sonntag, William E

    2012-07-01

    Radiation therapy, the most commonly used for the treatment of brain tumors, has been shown to be of major significance in tu-mor control and survival rate of brain tumor patients. About 200,000 patients with brain tumor are treated with either partial large field or whole brain radiation every year in the United States. The use of radiation therapy for treatment of brain tumors, however, may lead to devastating functional deficits in brain several months to years after treatment. In particular, whole brain radiation therapy results in a significant reduction in learning and memory in brain tumor patients as long-term consequences of treatment. Although a number of in vitro and in vivo studies have demonstrated the pathogenesis of radiation-mediated brain injury, the cel-lular and molecular mechanisms by which radiation induces damage to normal tissue in brain remain largely unknown. Therefore, this review focuses on the pathophysiological mechanisms of whole brain radiation-induced cognitive impairment and the iden-tification of novel therapeutic targets. Specifically, we review the current knowledge about the effects of whole brain radiation on pro-oxidative and pro-inflammatory pathways, matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) system and extracellular matrix (ECM), and physiological angiogenesis in brain. These studies may provide a foundation for defin-ing a new cellular and molecular basis related to the etiology of cognitive impairment that occurs among patients in response to whole brain radiation therapy. It may also lead to new opportunities for therapeutic interventions for brain tumor patients who are undergoing whole brain radiation therapy.

  14. The effect of synbiotics on acute radiation-induced diarrhea and its association with mucosal inflammatory and adaptive responses in rats.

    PubMed

    Spyropoulos, Basileios G; Theodoropoulos, George; Misiakos, Evangelos P; Stoidis, Christos N; Zapatis, Haralambos; Diamantopoulou, Kalliopi; Gialeli, Chrisostomi; Karamanos, Nikos K; Karatzas, Gabriel; Machairas, Anastasios; Fotiadis, Constantinos; Zografos, George C; Kelekis, Nikolaos; Kouloulias, Vasileios

    2013-09-01

    Previous clinical studies advocated that probiotics beneficially affect acute radiation-induced diarrhea. These encouraging results were attributed to the restoration of the intestinal flora; however, there is lack of evidence if and how probiotics influence the underlying pathophysiological mechanisms. The present study was conducted to investigate the potential supporting role of a synbiotic preparation (combination of pro- and pre-biotics) on experimentally-induced acute radiation diarrhea from the perspective of mucosal inflammation and histological injury. Ninety adult Wistar rats were randomly assigned into six groups. Group A (non-irradiated), group B (non-irradiated/synbiotic supplemented), group C (irradiated), and group D (irradiated/synbiotic supplemented) were followed up to a week after the beginning of the experiment. Group E (irradiated) and group F (irradiated/synbiotic supplemented) were followed up for four days. On the last day of the experiments tissues were harvested for structural and molecular assessments. Synbiotic administration could not avert the occurrence of diarrhea, but significantly attenuated its severity. This effect was associated with the significant downregulation of neutrophil accumulation and lipid peroxidation during the acute phase. During the subacute phase, synbiotic treatment significantly improved both the histological profile and radiation mucositis. These mechanisms significantly contributed to the rehabilitation of the intestinal absorptive function as further indicated from the significantly reduced weight loss. Given the optimization of the intestinal flora exerted by synbiotics, the resolution of diarrhea relies on the suppression of the "reactive" and the augmentation of "regenerative" components of acute radiation-induced intestinal response.

  15. Structurally caused freezing point depression of biological tissues.

    PubMed

    BLOCH, R; WALTERS, D H; KUHN, W

    1963-01-01

    When investigating the freezing behaviour (by thermal analysis) of the glycerol-extracted adductor muscle of Mytilus edulis it was observed that the temperature of ice formation in the muscular tissue was up to 1.5 degrees C lower than the freezing point of the embedding liquid, a 0.25 N KCl solution with pH = 4.9 with which the tissue had been equilibrated prior to the freezing experiment. A smaller freezing point depression was observed if the pH values of the embedding 0.25 N KCl solution were above or below pH = 4.9. Reasoning from results obtained previously in analogous experiments with artificial gels, the anomalous freezing depression is explained by the impossibility of growing at the normal freezing temperature regular macroscopic crystals inside the gel, due to the presence of the gel network. The freezing temperature is here determined by the size of the microprisms penetrating the meshes of the network at the lowered freezing temperature. This process leads finally to an ice block of more or less regular structure in which the filaments are embedded. Prerequisite for this hindrance of ideal ice growth is a sufficient tensile strength of the filamental network. The existence of structurally caused freezing point depression in biological tissue is likely to invalidate many conclusions reported in the literature, in which hypertonicity was deduced from cryoscopic data.

  16. Homology modeling and structural validation of tissue factor pathway inhibitor

    PubMed Central

    Agrawal, Piyush; Thakur, Zoozeal; Kulharia, Mahesh

    2013-01-01

    Blood coagulation is a cascade of complex enzymatic reactions which involves specific proteins and cellular components to interact and prevent blood loss. The coagulation process begins by either “Tissue Dependent Pathway” (also known as extrinsic pathway) or by “contact activation pathway” (also known as intrinsic pathway). TFPI is an endogenous multivalent Kunitz type protease inhibitor which inhibits Tissue factor dependent pathway by inhibiting Tissue Factor:Factor VIIa (TF:FVIIa) complex and Factor Xa. TFPI is one of the most studied coagulation pathway inhibitor which has various clinical and potential therapeutic applications, however, its exact mechanism of inhibition is still unknown. Structure based mechanism elucidation is commonly employed technique in such cases. Therefore, in the current study the generated a complete TFPI structural model so as to understand the mechanistic details of it's functioning. The model was checked for stereochemical quality by PROCHECK-NMR, WHATIF, ProSA, and QMEAN servers. The model was selected, energy minimized and simulated for 1.5ns. The result of the study may be a guiding point for further investigations on TFPI and its role in coagulation mechanism. PMID:24143050

  17. A spin dependent recombination study of radiation induced defects at and near the Si/SiO sub 2 interface

    SciTech Connect

    Jupina, M.A.; Lenahan, P.M. )

    1989-12-01

    A new electron spin resonance technique, spin dependent recombination (SDR) permits extremely rapid, high signal to noise ratio electron spin resonance (ESR) measurements of electrically active radiation damage centers in (relatively) hard MOS transistors in integrated circuits. Using SDR the authors observe the radiation induced buildup of Pbo and E' centers at relatively low concentration in individual MOSFETs in integrated circuits with (100) silicon surface orientation. Earlier ESR studies of extremely large ({approximately}1 cm{sup 2}) capacitor structures have identified Pb and E' centers as the dominant radiation induced defects in MOS devices. The authors discuss how their results extend and confirm these earlier results and at least qualitatively answer objections to the earlier work related to the relevance of large capacitor studies to transistors in an integrated circuit.

  18. Contribution of radiation-induced, nitric oxide-mediated bystander effect to radiation-induced adaptive response.

    NASA Astrophysics Data System (ADS)

    Matsumoto, H.; Ohnishi, T.

    There has been a recent upsurge of interest in radiation-induced adaptive response and bystander effect which are specific modes in stress response to low-dose low-dose rate radiation Recently we found that the accumulation of inducible nitric oxide NO synthase iNOS in wt p53 cells was induced by chronic irradiation with gamma rays followed by acute irradiation with X-rays but not by each one resulting in an increase in nitrite concentrations of medium It is suggested that the accumulation of iNOS may be due to the depression of acute irradiation-induced p53 functions by pre-chronic irradiation In addition we found that the radiosensitivity of wt p53 cells against acute irradiation with X-rays was reduced after chronic irradiation with gamma rays This reduction of radiosensitivity of wt p53 cells was nearly completely suppressed by the addition of NO scavenger carboxy-PTIO to the medium This reduction of radiosensitivity of wt p53 cells is just radiation-induced adaptive response suggesting that NO-mediated bystander effect may considerably contribute to adaptive response induced by radiation

  19. ATM Mutations and the Development of Severe Radiation-Induced Morbidity Following Radiotherapy for Breast Cancer

    DTIC Science & Technology

    2005-07-01

    repair of radiation-induced damage. Furthermore, cells possessing a mutated copy of this gene are more radiosensitive than cells from individuals with...AD Award Number: DAMD17-02-1-0503 TITLE: ATM Mutations and the Development of Severe Radiation-Induced Morbidity Following Radiotherapy for Breast...2005 Annual 1 Jul 2004 - 30 Jun 2005 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER ATM Mutations and the Development of Severe Radiation-Induced Morbidity

  20. Hydrogen Protects Mice from Radiation Induced Thymic Lymphoma in BALB/c Mice

    PubMed Central

    Zhao, Luqian; Zhou, Chuanfeng; Zhang, Jian; Gao, Fu; Li, Bailong; Chuai, Yunhai; Liu, Cong; Cai, Jianming

    2011-01-01

    Ionizing radiation (IR) is a well-known carcinogen, however the mechanism of radiation induced thymic lymphoma is not well known. Moreover, an easy and effective method to protect mice from radiation induced thymic lymphoma is still unknown. Hydrogen, or H2, is seldom regarded as an important agent in medical usage, especially as a therapeutic gas. Here in this study, we found that H2 protects mice from radiation induced thymic lymphoma in BALB/c mice. PMID:21448340

  1. MiR-21 plays an Important Role in Radiation Induced Carcinogenesis in BALB/c Mice by Directly Targeting the Tumor Suppressor Gene Big-h3

    PubMed Central

    Liu, Cong; Li, Bailong; Cheng, Ying; Lin, Jing; Hao, Jun; Zhang, Shuyu; Mitchel, R.E.J.; Sun, Ding; Ni, Jin; Zhao, Luqian; Gao, Fu; Cai, Jianming

    2011-01-01

    Dysregulation of certain microRNAs (miRNAs) in cancer can promote tumorigenesis, metastasis and invasion. However, the functions and targets of only a few mammalian miRNAs are known. In particular, the miRNAs that participates in radiation induced carcinogenesis and the miRNAs that target the tumor suppressor gene Big-h3 remain undefined. Here in this study, using a radiation induced thymic lymphoma model in BALB/c mice, we found that the tumor suppressor gene Big-h3 is down-regulated and miR-21 is up-regulated in radiation induced thymic lymphoma tissue samples. We also found inverse correlations between Big-h3 protein and miR-21 expression level among different tissue samples. Furthermore, our data indicated that miR-21 could directly target Big-h3 in a 3′UTR dependent manner. Finally, we found that miR-21 could be induced by TGFβ, and miR-21 has both positive and negative effects in regulating TGFβ signaling. We conclude that miR-21 participates in radiation induced carcinogenesis and it regulates TGFβ signaling. PMID:21494432

  2. Radiation induced genome instability: multiscale modelling and data analysis

    NASA Astrophysics Data System (ADS)

    Andreev, Sergey; Eidelman, Yuri

    2012-07-01

    Genome instability (GI) is thought to be an important step in cancer induction and progression. Radiation induced GI is usually defined as genome alterations in the progeny of irradiated cells. The aim of this report is to demonstrate an opportunity for integrative analysis of radiation induced GI on the basis of multiscale modelling. Integrative, systems level modelling is necessary to assess different pathways resulting in GI in which a variety of genetic and epigenetic processes are involved. The multilevel modelling includes the Monte Carlo based simulation of several key processes involved in GI: DNA double strand breaks (DSBs) generation in cells initially irradiated as well as in descendants of irradiated cells, damage transmission through mitosis. Taking the cell-cycle-dependent generation of DNA/chromosome breakage into account ensures an advantage in estimating the contribution of different DNA damage response pathways to GI, as to nonhomologous vs homologous recombination repair mechanisms, the role of DSBs at telomeres or interstitial chromosomal sites, etc. The preliminary estimates show that both telomeric and non-telomeric DSB interactions are involved in delayed effects of radiation although differentially for different cell types. The computational experiments provide the data on the wide spectrum of GI endpoints (dicentrics, micronuclei, nonclonal translocations, chromatid exchanges, chromosome fragments) similar to those obtained experimentally for various cell lines under various experimental conditions. The modelling based analysis of experimental data demonstrates that radiation induced GI may be viewed as processes of delayed DSB induction/interaction/transmission being a key for quantification of GI. On the other hand, this conclusion is not sufficient to understand GI as a whole because factors of DNA non-damaging origin can also induce GI. Additionally, new data on induced pluripotent stem cells reveal that GI is acquired in normal mature

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

    PubMed

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

    2017-03-01

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

  4. Radiation-induced second cancers: the impact of 3D-CRT and IMRT

    NASA Technical Reports Server (NTRS)

    Hall, Eric J.; Wuu, Cheng-Shie

    2003-01-01

    Information concerning radiation-induced malignancies comes from the A-bomb survivors and from medically exposed individuals, including second cancers in radiation therapy patients. The A-bomb survivors show an excess incidence of carcinomas in tissues such as the gastrointestinal tract, breast, thyroid, and bladder, which is linear with dose up to about 2.5 Sv. There is great uncertainty concerning the dose-response relationship for radiation-induced carcinogenesis at higher doses. Some animal and human data suggest a decrease at higher doses, usually attributed to cell killing; other data suggest a plateau in dose. Radiotherapy patients also show an excess incidence of carcinomas, often in sites remote from the treatment fields; in addition there is an excess incidence of sarcomas in the heavily irradiated in-field tissues. The transition from conventional radiotherapy to three-dimensional conformal radiation therapy (3D-CRT) involves a reduction in the volume of normal tissues receiving a high dose, with an increase in dose to the target volume that includes the tumor and a limited amount of normal tissue. One might expect a decrease in the number of sarcomas induced and also (less certain) a small decrease in the number of carcinomas. All around, a good thing. By contrast, the move from 3D-CRT to intensity-modulated radiation therapy (IMRT) involves more fields, and the dose-volume histograms show that, as a consequence, a larger volume of normal tissue is exposed to lower doses. In addition, the number of monitor units is increased by a factor of 2 to 3, increasing the total body exposure, due to leakage radiation. Both factors will tend to increase the risk of second cancers. Altogether, IMRT is likely to almost double the incidence of second malignancies compared with conventional radiotherapy from about 1% to 1.75% for patients surviving 10 years. The numbers may be larger for longer survival (or for younger patients), but the ratio should remain the same.

  5. Radiation-induced second cancers: the impact of 3D-CRT and IMRT

    NASA Technical Reports Server (NTRS)

    Hall, Eric J.; Wuu, Cheng-Shie

    2003-01-01

    Information concerning radiation-induced malignancies comes from the A-bomb survivors and from medically exposed individuals, including second cancers in radiation therapy patients. The A-bomb survivors show an excess incidence of carcinomas in tissues such as the gastrointestinal tract, breast, thyroid, and bladder, which is linear with dose up to about 2.5 Sv. There is great uncertainty concerning the dose-response relationship for radiation-induced carcinogenesis at higher doses. Some animal and human data suggest a decrease at higher doses, usually attributed to cell killing; other data suggest a plateau in dose. Radiotherapy patients also show an excess incidence of carcinomas, often in sites remote from the treatment fields; in addition there is an excess incidence of sarcomas in the heavily irradiated in-field tissues. The transition from conventional radiotherapy to three-dimensional conformal radiation therapy (3D-CRT) involves a reduction in the volume of normal tissues receiving a high dose, with an increase in dose to the target volume that includes the tumor and a limited amount of normal tissue. One might expect a decrease in the number of sarcomas induced and also (less certain) a small decrease in the number of carcinomas. All around, a good thing. By contrast, the move from 3D-CRT to intensity-modulated radiation therapy (IMRT) involves more fields, and the dose-volume histograms show that, as a consequence, a larger volume of normal tissue is exposed to lower doses. In addition, the number of monitor units is increased by a factor of 2 to 3, increasing the total body exposure, due to leakage radiation. Both factors will tend to increase the risk of second cancers. Altogether, IMRT is likely to almost double the incidence of second malignancies compared with conventional radiotherapy from about 1% to 1.75% for patients surviving 10 years. The numbers may be larger for longer survival (or for younger patients), but the ratio should remain the same.

  6. The Role of DNA Methylation Changes in Radiation-Induced Bystander Effects in cranial irradiated Mice

    NASA Astrophysics Data System (ADS)

    Zhang, Meng; Sun, Yeqing; Xue, Bei; Wang, Xinwen; Wang, Jiawen

    2016-07-01

    Heavy-ion radiation could lead to bystander effect in neighboring non-hit cells by signals released from directly-irradiated cells. The exact mechanisms of radiation-induced bystander effect in distant organ remain obscure, yet accumulating evidence points to the role of DNA methylation changes in bystander effect. To identify the molecular mechanism that underlies bystander effects of heavy-ion radiation, the male Balb/c and C57BL mice were cranial exposed to 40, 200, 2000mGy dose of carbon heavy-ion radiation, while the rest of the animal body was shielded. The γH2AX foci as the DNA damage biomarker in directly irradiation organ ear and the distant organ liver were detected on 0, 1, 2, 6, 12 and 24h after radiation, respectively. Methylation-sensitive amplifcation polymorphism (MSAP) was used to monitor the level of polymorphic genomic DNA methylation changed with dose and time effects. The results show that cranial irradiated mice could induce the γH2AX foci and genomic DNA methylation changes significantly in both the directly irradiation organ ear and the distant organ liver. The percent of DNA methylation changes were time-dependent and tissue-specific. Demethylation polymorphism rate were highest separately at 1 h in 200 mGy and 6 h in 2000 mGy after irradiation in ear. The global DNA methylation changes tended to occur in the CG sites. We also found that the numbers of γH2AX foci and the genomic methylation changes of heavy-ion radiation-induced bystander effect in liver could be obvious 1 h after radiation and achieved the maximum at 6 h, while the changes could recover gradually at 12 h. The results suggest that mice head exposed to heavy-ion radiation can induce damage and methylation pattern changed in both directly radiation organ ear and distant organ liver. Moreover, our findings are important to understand the molecular mechanism of radiation induced bystander effects in vivo. Keywords: Heavy-ion radiation; Bystander effect; DNA methylation; γH2

  7. Alpha Lipoic Acid Attenuates Radiation-Induced Thyroid Injury in Rats

    PubMed Central

    Jung, Jung Hwa; Jung, Jaehoon; Kim, Soo Kyoung; Woo, Seung Hoon; Kang, Ki Mun; Jeong, Bae-Kwon; Jung, Myeong Hee; Kim, Jin Hyun; Hahm, Jong Ryeal

    2014-01-01

    Exposure of the thyroid to radiation during radiotherapy of the head and neck is often unavoidable. The present study aimed to investigate the protective effect of α-lipoic acid (ALA) on radiation-induced thyroid injury in rats. Rats were randomly assigned to four groups: healthy controls (CTL), irradiated (RT), received ALA before irradiation (ALA + RT), and received ALA only (ALA, 100 mg/kg, i.p.). ALA was treated at 24 h and 30 minutes prior to irradiation. The neck area including the thyroid gland was evenly irradiated with 2 Gy per minute (total dose of 18 Gy) using a photon 6-MV linear accelerator. Greater numbers of abnormal and unusually small follicles in the irradiated thyroid tissues were observed compared to the controls and the ALA group on days 4 and 7 after irradiation. However, all pathologies were decreased by ALA pretreatment. The quantity of small follicles in the irradiated rats was greater on day 7 than day 4 after irradiation. However, in the ALA-treated irradiated rats, the numbers of small and medium follicles were significantly decreased to a similar degree as in the control and ALA-only groups. The PAS-positive density of the colloid in RT group was decreased significantly compared with all other groups and reversed by ALA pretreatment. The high activity index in the irradiated rats was lowered by ALA treatment. TGF-ß1 immunoreactivity was enhanced in irradiated rats and was more severe on the day 7 after radiation exposure than on day 4. Expression of TGF-ß1 was reduced in the thyroid that had undergone ALA pretreatment. Levels of serum pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6) did not differ significantly between the all groups. This study provides that pretreatment with ALA decreased the severity of radiation-induced thyroid injury by reducing inflammation and fibrotic infiltration and lowering the activity index. Thus, ALA could be used to ameliorate radiation-induced thyroid injury. PMID:25401725

  8. Selective inhibition of microglia-mediated neuroinflammation mitigates radiation-induced cognitive impairment.

    PubMed

    Jenrow, Kenneth A; Brown, Stephen L; Lapanowski, Karen; Naei, Hoda; Kolozsvary, Andrew; Kim, Jae Ho

    2013-05-01

    Cognitive impairment precipitated by irradiation of normal brain tissue is commonly associated with radiation therapy for treatment of brain cancer, and typically manifests more than 6 months after radiation exposure. The risks of cognitive impairment are of particular concern for an increasing number of long-term cancer survivors. There is presently no effective means of preventing or mitigating this debilitating condition. Neuroinflammation mediated by activated microglial cytokines has been implicated in the pathogenesis of radiation-induced cognitive impairment in animal models, including the disruption of neurogenesis and activity-induced gene expression in the hippocampus. These pathologies evolve rapidly and are associated with relatively subtle cognitive impairment at 2 months postirradiation. However, recent reports suggest that more profound cognitive impairment develops at later post-irradiation time points, perhaps reflecting a gradual loss of responsiveness within the hippocampus by the disruption of neurogenesis. We hypothesized that inhibiting neuroinflammation using MW01-2-151SRM (MW-151), a selective inhibitor of proinflammatory cytokine production, might mitigate these deleterious radiation effects by preserving/restoring hippocampal neurogenesis. MW-151 therapy was initiated 24 h after 10 Gy whole-brain irradiation (WBI) administered as a single fraction and maintained for 28 days thereafter. Proinflammatory activated microglia in the dentate gyrus were assayed at 2 and 9 months post-WBI. Cell proliferation and neurogenesis in the dentate gyrus were assayed at 2 months post-WBI, whereas novel object recognition and long-term potentiation were assayed at 6 and 9 months post-WBI, respectively. MW-151 mitigated radiation-induced neuroinflammation at both early and late time points post-WBI, selectively mitigated the deleterious effects of irradiation on hippocampal neurogenesis, and potently mitigated radiation-induced deficits of novel object

  9. Calculation of radiation-induced creep and stress relaxation

    NASA Astrophysics Data System (ADS)

    Nagakawa, Johsei

    1995-08-01

    Numerical calculation based on a computer simulation of point defect kinetics under stress was performed to predict radiation-induced deformation in an Inconel X-750 bolt in a LWR core and for a 316 stainless steel blanket in experimental fusion reactors with the water-coolant scenario. Although the displacement rate is rather low, modest irradiation creep with nearly linear stress dependence was predicted below 200 MPa at 300°C in the LWR core. This low stress dependence causes significant stress relaxation, which coincides with the experimental data to 2 dpa. An almost equal amount of enhanced irradiation creep strain was predicted at 60°C in both solution annealed and cold worker 316 stainless steel in the water-cooled blanket. The stress relaxation is practically not expected without irradiation in both the cases, but the calculation predicts that it is definitely expected under irradiation.

  10. Measurements of prompt radiation induced conductivity of alumina and sapphire

    SciTech Connect

    Hartman, E. Frederick; Zarick, Thomas Andrew; Sheridan, Timothy J.; Preston, Eric F.

    2011-04-01

    We performed measurements of the prompt radiation induced conductivity in thin samples of Alumina and Sapphire at the Little Mountain Medusa LINAC facility in Ogden, UT. Five mil thick samples were irradiated with pulses of 20 MeV electrons, yielding dose rates of 1E7 to 1E9 rad/s. We applied variable potentials up to 1 kV across the samples and measured the prompt conduction current. Analysis rendered prompt conductivity coefficients between 1E10 and 1E9 mho/m/(rad/s), depending on the dose rate and the pulse width for Alumina and 1E7 to 6E7 mho/m/(rad/s) for Sapphire.

  11. Radiation Induced Cystitis and Proctitis - Prediction, Assessment and Management.

    PubMed

    Mallick, Supriya; Madan, Renu; Julka, Pramod K; Rath, Goura K

    2015-01-01

    Cystitis and proctitis are defined as inflammation of bladder and rectum respectively. Haemorrhagic cystitis is the most severe clinical manifestation of radiation and chemical cystitis. Radiation proctitis and cystitis are major complications following radiotherapy. Prevention of radiation-induced haemorrhagic cystitis has been investigated using various oral agents with minimal benefit. Bladder irrigation remains the most frequently adopted modality followed by intra-vesical instillation of alum or formalin. In intractable cases, surgical intervention is required in the form of diversion ureterostomy or cystectomy. Proctitis is more common in even low dose ranges but is self-limiting and improves on treatment interruption. However, treatment of radiation proctitis is broadly non-invasive or invasive. Non-invasive treatment consists of non-steroid anti-inflammatory drugs (NSAIDs), anti-oxidants, sucralfate, short chain fatty acids and hyperbaric oxygen. Invasive treatment consists of ablative procedures like formalin application, endoscopic YAG laser coagulation or argon plasma coagulation and surgery as a last resort.

  12. Radiatively induced breaking of conformal symmetry in a superpotential

    NASA Astrophysics Data System (ADS)

    Arbuzov, A. B.; Cirilo-Lombardo, D. J.

    2016-07-01

    Radiatively induced symmetry breaking is considered for a toy model with one scalar and one fermion field unified in a superfield. It is shown that the classical quartic self-interaction of the superfield possesses a quantum infrared singularity. Application of the Coleman-Weinberg mechanism for effective potential leads to the appearance of condensates and masses for both scalar and fermion components. That induces a spontaneous breaking of the initial classical symmetries: the supersymmetry and the conformal one. The energy scales for the scalar and fermion condensates appear to be of the same order, while the renormalization scale is many orders of magnitude higher. A possibility to relate the considered toy model to conformal symmetry breaking in the Standard Model is discussed.

  13. Dose-dependent radiation-induced hypotension in the canine

    SciTech Connect

    Cockerham, L.G.; Hampton, J.D.; Doyle, T.F.

    1986-01-01

    Radiation-induced early transient incapacitation (ETI) is often accompanied by severe systemic hypotension. However, postradiation hypotension does not occur with equal frequency in all species and is not reported with consistency in the canine. In an attempt to clarify the differences in reported canine post-radiation blood pressures, canine systemic blood pressures were determined both before and after exposure to gamma radiation of either 80 or 100 Gy. Data obtained from six sham-radiated beagles and 12 radiated beagles indicated that 100-Gy, whole-body, gamma radiation produced a decrease in systemic mean blood pressure while 80-Gy, whole-body, gamma radiation did not. Analysis of this data could be consistent with a quantal response to a gamma radiation dose between 80 Gy and 100 Gy.

  14. Radiation-induced cerebral meningioma: a recognizable entity.

    PubMed

    Rubinstein, A B; Shalit, M N; Cohen, M L; Zandbank, U; Reichenthal, E

    1984-11-01

    The authors retrospectively analyzed the clinical and histopathological findings in 201 patients with intracranial meningiomas operated on in the period 1978 to 1982. Forty-three of the patients (21.4%) had at some previous time received radiation treatment to their scalp, the majority for tinea capitis. The findings in these 43 irradiated patients were compared with those in the 158 non-irradiated patients. Several distinctive clinical and histological features were identified in the irradiated group, which suggest that radiation-induced meningiomas can be defined as a separate nosological subgroup. The use of irradiation in large numbers of children with tinea capitis in the era prior to the availability of griseofulvin may be responsible for a significantly increased incidence of intracranial meningiomas.

  15. [Radiation-induced and therapy-related AML/MDS].

    PubMed

    Inaba, Toshiya

    2009-10-01

    Radiation induced acute myeloid leukemia (AML) was recognized a century ago, soon after mankind found radiation. Atomic bomb survivors developed de novo AML with relatively short latency with very high frequency. By contrast, excess occurrence of myelodysplastic syndrome (MDS) as well as solid tumors was found decades late. This difference may be due to etiology that many de novo AML patients harbor chimeric leukemogenic genes caused by chromosomal translocations, while MDS patients rarely carry chimeras. In addition, epigenetic change would play important roles. Therapy related leukemia is mainly caused by topoisomerase II inhibitors that cause de novo AML with an 11q23 translocation or by alkyrating agents that induce MDS/AML with an AML1 point mutation and monosomy 7.

  16. Modification of microcrystalline cellulose by gamma radiation-induced grafting

    NASA Astrophysics Data System (ADS)

    Madrid, Jordan F.; Abad, Lucille V.

    2015-10-01

    Modified microcrystalline cellulose (MCC) was prepared through gamma radiation-induced graft polymerization of glycidyl methacrylate (GMA). Simultaneous grafting was employed wherein MCC with GMA in methanol was irradiated with gamma radiation in nitrogen atmosphere. The effects of different experimental factors such as monomer concentration, type of solvent and absorbed dose on the degree of grafting, Dg, were studied. The amount of grafted GMA, expressed as Dg, was determined gravimetrically. Information from grafted samples subjected to Fourier transformed infrared spectroscopy (FTIR) in attenuated total reflectance (ATR) mode showed peaks corresponding to GMA which indicates successful grafting. The X-ray diffraction (XRD) analysis revealed that the crystalline region of MCC was not adversely affected after grafting with GMA. The thermogravimetric analysis (TGA) data showed that the decomposition of grafted MCC occurred at higher temperature compared to the base MCC polymer.

  17. Invertase immobilization onto radiation-induced graft copolymerized polyethylene pellets

    NASA Astrophysics Data System (ADS)

    de Queiroz, Alvaro Antonio Alencar; Vitolo, Michele; de Oliveira, Rômulo Cesar; Higa, Olga Zazuco

    1996-06-01

    The graft copolymer poly(ethylene-g-acrylic acid) (LDPE-g-AA) was prepared by radiation-induced graft copolymerization of acrylic acid onto low density polyethylene (LDPE) pellets, and characterized by infrared photoacoustic spectroscopy and scanning electron microscopy (SEM). The presence of the grafted poly(acrylic acid) (PAA) was established. Invertase was immobilized onto the graft polymer and the thermodynamic parameters of the soluble and immobilized enzyme were determined. The Michaelis constant, Km, and the maximum reaction velocity, Vmax, were determined for the free and the immobilized invertase. The Michaelis constant, Km was larger for the immobilized invertase than for the free enzyme, whereas Vmax was smaller for the immobilized invertase. The thermal stability of the immobilized invertase was higher than that of the free enzyme.

  18. Pulsed radiation-induced attenuation in certain optical fibers

    SciTech Connect

    Weiss, J.D. )

    1992-05-01

    Using the X-ray pulse from the HERMES II simulation machine at Sandia National Laboratories, the pulsed radiation-induced attenuation was measured in two optical fibers considered to be 'nonrad-hard': the 50-micron-core, graded-index fiber from Corning and the plastic (PMMA) fiber from the Mitsubishi Rayon Company. These fibers were exposed to radiation up to doses of 19.5 and 28 krad(Si), respectively. In addition, fits of their post-radiation recovery were made to the geminate recombination model, from which the recombination-rate and generation constants, characteristic of this theory, were determined. These parameters should be useful in determining the response of the fibers to radiation conditions other than those encountered here. 18 refs.

  19. Potential targets for intervention in radiation-induced heart disease.

    PubMed

    Boerma, M; Hauer-Jensen, M

    2010-11-01

    Radiotherapy of thoracic and chest wall tumors, if all or part of the heart was included in the radiation field, can lead to radiation-induced heart disease (RIHD), a late and potentially severe side effect. RIHD presents clinically several years after irradiation and manifestations include accelerated atherosclerosis, pericardial and myocardial fibrosis, conduction abnormalities, and injury to cardiac valves. The pathogenesis of RIHD is largely unknown, and a treatment is not available. Hence, ongoing pre-clinical studies aim to elucidate molecular and cellular mechanisms of RIHD. Here, an overview of recent pre-clinical studies is given, and based on the results of these studies, potential targets for intervention in RIHD are discussed.

  20. Radiation-induced degradation of 4-chloroaniline in aqueous solution

    NASA Astrophysics Data System (ADS)

    Sánchez, M.; Wolfger, H.; Getoff, N.

    2002-12-01

    The radiation-induced decomposition of 4-chloroaniline (4-ClA) was studied under steady-state conditions using aqueous solutions saturated with air, pure oxygen, N 2O, argon and argon in the presence of t-Butanol. Using HPLC-method, the initial G-values of the substrate degradation as well as of a number of radiolytic products were determined. The formation of aminophenols, chlorophenols, aniline and phenol in addition to chloride, ammonia, formaldehyde and mixture of aldehydes as well as carboxylic acids was studied as a function of absorbed dose. Based on the experimental data, probable reaction mechanisms for the degradation of 4-ClA by γ-rays and the formation of the identified products are presented.

  1. Modulation of radiation-induced hemopoietic suppression by acute thrombocytopenia

    SciTech Connect

    Ebbe, S.; Phalen, E.; Threatte, G.; Londe, H.

    1985-01-01

    Modifications of radiation-induced hemopoietic suppression by acute thrombocytopenia were evaluated. Immediately before or after exposure to sublethal irradiation, mice were given a single injection of anti-mouse platelet serum (APS), normal heterologous serum, neuraminidase (N'ase), or saline, or no further treatment was provided. Hemopoiesis was evaluated by blood cell counts, hematocrits, and incorporation of (75Se)selenomethionine into platelets. APS and N'ase induced an acute thrombocytopenia from which there was partial recovery before the platelet count started to fall from the radiation. During the second post-treatment week, both thrombocytopoiesis and erythropoiesis were greater in mice that received APS or N'ase in addition to radiation than in control irradiated mice. Differences in leukopoiesis were not apparent. Therefore, both thrombocytopoiesis and erythropoiesis appeared to be responsive to a stimulus generated by acute thrombocytopenia in sublethally irradiated mice.

  2. [Nonsurgical treatment of chronic radiation-induced hemorrhagic proctitis].

    PubMed

    de Parades, Vincent; Bauer, Pierre; Marteau, Philippe; Chauveinc, Laurent; Bouillet, Thierry; Atienza, Patrick

    2008-01-01

    The incidence of radiation-induced chronic hemorrhagic proctitis is less than 10 to 20%. The onset of this proctitis is delayed relative to the radiation therapy and generally develops from 6 to 24 months later. There are numerous predisposing factors, the most important of which is the radiation therapy dose: risk increases exponentially above 40-45 Gy. Its pathophysiology involves progressive obliterating endarteritis and transmural interstitial fibrosis, which induce chronic ischemia that is irreversible and progressive during the years after radiation therapy. Its diagnosis depends most often on the combination of clinical history and typical endoscopic appearance (congestive mucosa and/or telangiectases). Topical administrative of sucralfate or corticosteroids as well as argon plasma coagulation, with formalin treatment if necessary, provides relief for most patients.

  3. Radiation-induced cationic polymerization of. beta. -pinene

    SciTech Connect

    Adur, A.M.; Williams, F.

    1981-03-01

    The radiation-induced polymerization of ..beta..-pinene carried out in bulk at ca.25/sup 0/ has been studied for different methods of monomer drying. It has been confirmed that the polymerization is sensitive to adventitious moisture and that substantial polymer yields (ca. 10% conversion per Mrad) can only be obtained under extremely dry conditions. Complete inhibition of the reaction by added tripropylamine corroborates the view that the polymerization is cationic. About half of the polymer formed is insoluble in the monomer. The number-average molecular weights for the soluble poly(..beta..-pinene) fraction have been measured by vapor pressure osmometry and are in the narrow range from 1700 to 2400 with little or no dependence on the degree of monomer conversion to polymer, at least up to 80%. The results are compared with literature reports on the polymerization of ..beta..-pinene by catalytic initiators.

  4. Bystander effects in radiation-induced genomic instability

    NASA Technical Reports Server (NTRS)

    Morgan, William F.; Hartmann, Andreas; Limoli, Charles L.; Nagar, Shruti; Ponnaiya, Brian

    2002-01-01

    Exposure of GM10115 hamster-human hybrid cells to X-rays can result in the induction of chromosomal instability in the progeny of surviving cells. This instability manifests as the dynamic production of novel sub-populations of cells with unique cytogenetic rearrangements involving the "marker" human chromosome. We have used the comet assay to investigate whether there was an elevated level of endogenous DNA breaks in chromosomally unstable clones that could provide a source for the chromosomal rearrangements and thus account for the persistent instability observed. Our results indicate no significant difference in comet tail measurement between non-irradiated and radiation-induced chromosomally unstable clones. Using two-color fluorescence in situ hybridization we also investigated whether recombinational events involving the interstitial telomere repeat-like sequences in GM10115 cells were involved at frequencies higher than random processes would otherwise predict. Nine of 11 clones demonstrated a significantly higher than expected involvement of these interstitial telomere repeat-like sequences at the recombination junction between the human and hamster chromosomes. Since elevated levels of endogenous breaks were not detected in unstable clones we propose that epigenetic or bystander effects (BSEs) lead to the activation of recombinational pathways that perpetuate the unstable phenotype. Specifically, we expand upon the hypothesis that radiation induces conditions and/or factors that stimulate the production of reactive oxygen species (ROS). These reactive intermediates then contribute to a chronic pro-oxidant environment that cycles over multiple generations, promoting chromosomal recombination and other phenotypes associated with genomic instability.

  5. Intercellular Adhesion Molecule 1 Knockout Abrogates Radiation Induced Pulmonary Inflammation

    NASA Astrophysics Data System (ADS)

    Hallahan, Dennis E.; Virudachalam, Subbulakshmi

    1997-06-01

    Increased expression of intercellular adhesion molecule 1 (ICAM-1; CD54) is induced by exposure to ionizing radiation. The lung was used as a model to study the role of ICAM-1 in the pathogenesis of the radiation-induced inflammation-like response. ICAM-1 expression increased in the pulmonary microvascular endothelium and not in the endothelium of larger pulmonary vessels following treatment of mice with thoracic irradiation. To quantify radiation-induced ICAM-1 expression, we utilized fluorescence-activated cell sorting analysis of anti-ICAM-1 antibody labeling of pulmonary microvascular endothelial cells from human cadaver donors (HMVEC-L cells). Fluorochrome conjugates and UV microscopy were used to quantify the fluorescence intensity of ICAM in the irradiated lung. These studies showed a dose- and time-dependent increase in ICAM-1 expression in the pulmonary microvascular endothelium. Peak expression occurred at 24 h, while threshold dose was as low as 2 Gy. To determine whether ICAM-1 is required for inflammatory cell infiltration into the irradiated lung, the anti-ICAM-1 blocking antibody was administered by tail vein injection to mice following thoracic irradiation. Inflammatory cells were quantified by immunofluorescence for leukocyte common antigen (CD45). Mice treated with the anti-ICAM-1 blocking antibody showed attenuation of inflammatory cell infiltration into the lung in response to ionizing radiation exposure. To verify the requirement of ICAM-1 in the inflammation-like radiation response, we utilized the ICAM-1 knockout mouse. ICAM-1 was not expressed in the lungs of ICAM-1-deficient mice following treatment with thoracic irradiation. ICAM-1 knockout mice had no increase in the inflammatory cell infiltration into the lung in response to thoracic irradiation. These studies demonstrate a radiation dose-dependent increase in ICAM-1 expression in the pulmonary microvascular endothelium, and show that ICAM-1 is required for inflammatory cell infiltration

  6. Radiation-induced leukemia: Comparative studies in mouse and man

    SciTech Connect

    Haas, M.

    1991-01-01

    We now have a clear understanding of the mechanism by which radiation-induced (T-cell) leukemia occurs. In irradiated mice (radiation-induced thymic leukemia) and in man (acute lymphoblastic T-cell leukemia, T-ALL) the mechanism of leukemogenesis is surprisingly similar. Expressed in the most elementary terms, T-cell leukemia occurs when T-cell differentiation is inhibited by a mutation, and pre-T cells attempt but fail to differentiate in the thymus. Instead of leaving the thymus for the periphery as functional T-cells they continue to proliferate in the thymus. The proliferating pre- (pro-) T-cells constitute the (early) acute T-cell leukemia (A-TCL). This model for the mechanism of T-cell leukemogenesis accounts for all the properties of both murine and human A-TCL. Important support for the model has recently come from work by Ilan Kirsch and others, who have shown that mutations/deletions in the genes SCL (TAL), SIL, and LCK constitute primary events in the development of T-ALL, by inhibiting differentiation of thymic pre- (pro-) T-cells. This mechanism of T-cell leukemogenesis brings several specific questions into focus: How do early A-TCL cells progress to become potently tumorigenic and poorly treatable Is it feasible to genetically suppress early and/or progressed A-TCL cells What is the mechanism by which the differentiation-inhibited (leukemic) pre-T cells proliferate During the first grant year we have worked on aspects of all three questions.

  7. Radiation-induced fibrosis: mechanisms and implications for therapy

    PubMed Central

    Straub, Jeffrey M.; New, Jacob; Hamilton, Chase D.; Lominska, Chris; Shnayder, Yelizaveta

    2015-01-01

    Purpose Radiation-induced fibrosis (RIF) is a long-term side effect of external beam radiation therapy for the treatment of cancer. It results in a multitude of symptoms that significantly impact quality of life. Understanding the mechanisms of RIF-induced changes is essential to developing effective strategies to prevent long-term disability and discomfort following radiation therapy. In this review, we describe the current understanding of the etiology, clinical presentation, pathogenesis, treatment, and directions of future therapy for this condition. Methods A literature review of publications describing mechanisms or treatments of RIF was performed. Specific databases utilized included PubMed and clinicaltrials.gov, using keywords “Radiation-Induced Fibrosis,” “Radiotherapy Complications,” “Fibrosis Therapy,” and other closely related terms. Results RIF is the result of a misguided wound healing response. In addition to causing direct DNA damage, ionizing radiation generates reactive oxygen and nitrogen species that lead to localized inflammation. This inflammatory process ultimately evolves into a fibrotic one characterized by increased collagen deposition, poor vascularity, and scarring. Tumor growth factor beta serves as the primary mediator in this response along with a host of other cytokines and growth factors. Current therapies have largely been directed toward these molecular targets and their associated signaling pathways. Conclusion Although RIF is widely prevalent among patients undergoing radiation therapy and significantly impacts quality of life, there is still much to learn about its pathogenesis and mechanisms. Current treatments have stemmed from this understanding, and it is anticipated that further elucidation will be essential for the development of more effective therapies. PMID:25910988

  8. Bystander effects in radiation-induced genomic instability

    NASA Technical Reports Server (NTRS)

    Morgan, William F.; Hartmann, Andreas; Limoli, Charles L.; Nagar, Shruti; Ponnaiya, Brian

    2002-01-01

    Exposure of GM10115 hamster-human hybrid cells to X-rays can result in the induction of chromosomal instability in the progeny of surviving cells. This instability manifests as the dynamic production of novel sub-populations of cells with unique cytogenetic rearrangements involving the "marker" human chromosome. We have used the comet assay to investigate whether there was an elevated level of endogenous DNA breaks in chromosomally unstable clones that could provide a source for the chromosomal rearrangements and thus account for the persistent instability observed. Our results indicate no significant difference in comet tail measurement between non-irradiated and radiation-induced chromosomally unstable clones. Using two-color fluorescence in situ hybridization we also investigated whether recombinational events involving the interstitial telomere repeat-like sequences in GM10115 cells were involved at frequencies higher than random processes would otherwise predict. Nine of 11 clones demonstrated a significantly higher than expected involvement of these interstitial telomere repeat-like sequences at the recombination junction between the human and hamster chromosomes. Since elevated levels of endogenous breaks were not detected in unstable clones we propose that epigenetic or bystander effects (BSEs) lead to the activation of recombinational pathways that perpetuate the unstable phenotype. Specifically, we expand upon the hypothesis that radiation induces conditions and/or factors that stimulate the production of reactive oxygen species (ROS). These reactive intermediates then contribute to a chronic pro-oxidant environment that cycles over multiple generations, promoting chromosomal recombination and other phenotypes associated with genomic instability.

  9. Radiation-induced fibrosis: mechanisms and implications for therapy.

    PubMed

    Straub, J