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Sample records for bystander dose response

  1. A review: Development of a microdose model for analysis of adaptive response and bystander dose response behavior.

    Science.gov (United States)

    Leonard, Bobby E

    2008-02-27

    Prior work has provided incremental phases to a microdosimetry modeling program to describe the dose response behavior of the radio-protective adaptive response effect. We have here consolidated these prior works (Leonard 2000, 2005, 2007a, 2007b, 2007c) to provide a composite, comprehensive Microdose Model that is also herein modified to include the bystander effect. The nomenclature for the model is also standardized for the benefit of the experimental cellular radio-biologist. It extends the prior work to explicitly encompass separately the analysis of experimental data that is 1.) only dose dependent and reflecting only adaptive response radio-protection, 2.) both dose and dose-rate dependent data and reflecting only adaptive response radio-protection for spontaneous and challenge dose damage, 3.) only dose dependent data and reflecting both bystander deleterious damage and adaptive response radio-protection (AR-BE model). The Appendix cites the various applications of the model. Here we have used the Microdose Model to analyze the, much more human risk significant, Elmore et al (2006) data for the dose and dose rate influence on the adaptive response radio-protective behavior of HeLa x Skin cells for naturally occurring, spontaneous chromosome damage from a Brachytherapy type (125)I photon radiation source. We have also applied the AR-BE Microdose Model to the Chromosome inversion data of Hooker et al (2004) reflecting both low LET bystander and adaptive response effects. The micro-beam facility data of Miller et al (1999), Nagasawa and Little (1999) and Zhou et al (2003) is also examined. For the Zhou et al (2003) data, we use the AR-BE model to estimate the threshold for adaptive response reduction of the bystander effect. The mammogram and diagnostic X-ray induction of AR and protective BE are observed. We show that bystander damage is reduced in the similar manner as spontaneous and challenge dose damage as shown by the Azzam et al (1996) data. We cite

  2. Neoplastic transformation in vitro by low doses of ionizing radiation: Role of adaptive response and bystander effects

    International Nuclear Information System (INIS)

    Ko, M.; Lao, X.-Y.; Kapadia, R.; Elmore, E.; Redpath, J.L.

    2006-01-01

    The shape of the dose-response curve for cancer induction by low doses of ionizing radiation is of critical importance to the assessment of cancer risk at such doses. Epidemiologic analyses are limited by sensitivity to doses typically greater than 50-100 mGy for low LET radiation. Laboratory studies allow for the examination of lower doses using cancer-relevant endpoints. One such endpoint is neoplastic transformation in vitro. It is known that this endpoint is responsive to both adaptive response and bystander effects. The relative balance of these processes is likely to play an important role in determining the shape of the dose-response curve at low doses. A factor that may influence this balance is cell density at time of irradiation. The findings reported in this paper indicate that the transformation suppressive effect of low doses previously seen following irradiation of sub-confluent cultures, and attributed to an adaptive response, is reduced for irradiated confluent cultures. However, even under these conditions designed to optimize the role of bystander effects the data do not fit a linear no-threshold model and are still consistent with the notion of a threshold dose for neoplastic transformation in vitro by low LET radiation

  3. Mechanisms and biological importance of photon-induced bystander responses. Do they have an impact on low-dose radiation responses

    International Nuclear Information System (INIS)

    Tomita, Masanori; Maeda, Munetoshi

    2015-01-01

    Elucidating the biological effect of low linear energy transfer (LET), low-dose and/or low-dose-rate ionizing radiation is essential in ensuring radiation safety. Over the past two decades, non-targeted effects, which are not only a direct consequence of radiation-induced initial lesions produced in cellular DNA but also of intra- and inter-cellular communications involving both targeted and non-targeted cells, have been reported and are currently defining a new paradigm in radiation biology. These effects include radiation-induced adaptive response, low-dose hypersensitivity, genomic instability, and radiation-induced bystander response (RIBR). RIBR is generally defined as a cellular response that is induced in non-irradiated cells that receive bystander signals from directly irradiated cells. RIBR could thus play an important biological role in low-dose irradiation conditions. However, this suggestion was mainly based on findings obtained using high-LET charged-particle radiations. The human population (especially the Japanese, who are exposed to lower doses of radon than the world average) is more frequently exposed to low-LET photons (X-rays or γ-rays) than to high-LET charged-particle radiation on a daily basis. There are currently a growing number of reports describing a distinguishing feature between photon-induced bystander response and high-LET RIBR. In particular, photon-induced by-stander response is strongly influenced by irradiation dose, the irradiated region of the targeted cells, and p53 status. The present review focuses on the photon-induced bystander response, and discusses its impact on the low-dose radiation effect. (author)

  4. Implications of effects ''adaptive response'', ''low-dose hypersensitivity'' und ''bystander effect'' for cancer risk at low doses and low dose rates

    International Nuclear Information System (INIS)

    Jacob, P

    2006-01-01

    A model for carcinogenesis (the TSCE model) was applied in order to examine the effects of ''Low-dose hypersensitivity (LDH)'' and the ''Bystander effect (BE)'' on the derivation of radiation related cancer mortality risks. LDH has been discovered to occur in the inactivation of cells after acute exposure to low LET radiation. A corresponding version of the TSCE model was applied to the mortality data on the Abomb survivors from Hiroshima and Nagasaki. The BE has been mainly observed in cells after exposure to high LET radiation. A Version of the TSCE model which included the BE was applied to the data on lung cancer mortality from the workers at the Mayak nuclear facilities who were exposed to Plutonium. In general an equally good description of the A-bomb survivor mortality data (for all solid, stomach and lung tumours) was found for the TSCE model and the (conventional) empirical models but fewer parameters were necessary for the TSCE model. The TSCE model which included the effects of radiation induced cell killing resulted in non-linear dose response curves with excess relative risks after exposure at young ages that were generally lower than in the models without cell killing. The main results from TSCE models which included cell killing described by either conventional survival curves or LDH were very similar. A sub multiplicative effect from the interaction of smoking and exposure to plutonium was found to result from the analysis of the Mayak lung cancer mortality data. All models examined resulted in the predominant number of Mayak lung cancer deaths being ascribed to smoking. The interaction between smoking and plutonium exposures was found to be the second largest effect. The TSCE model resulted in lower estimates for the lung cancer excess relative risk per unit plutonium dose than the empirical risk model, but this difference was not found to be statistically significant. The excess relative risk dose responses were linear in the empirical model and

  5. Significance and nature of bystander responses induced by various agents.

    Science.gov (United States)

    Verma, Neha; Tiku, Ashu Bhan

    2017-07-01

    Bystander effects in a biological system are the responses shown by non-targeted neighbouring cells/tissues/organisms. These responses are triggered by factors released from targeted cells when exposed to a stress inducing agent. The biological response to stress inducing agents is complex, owing to the diversity of mechanisms and pathways activated in directly targeted and bystander cells. These responses are highly variable and can be either beneficial or hazardous depending on the cell lines tested, dose of agent used, experimental end points and time course selected. Recently non-targeted cells have even been reported to rescue the directly exposed cells by releasing protective signals that might be induced by non-targeted bystander responses. The nature of bystander signal/s is not yet clear. However, there are evidences suggesting involvement of ROS, RNS, protein factors and even DNA molecules leading to the activation of a number of signaling pathways. These can act independently or in a cascade, to induce events leading to changes in gene expression patterns that could elicit detrimental or beneficial effects. Many review articles on radiation induced bystander responses have been published. However, to the best of our knowledge, a comprehensive review on bystander responses induced by other genotoxic chemicals and stress inducing agents has not been published so far. Therefore, the aim of the present review is to give an overview of the literature on different aspects of bystander responses: agents that induce these responses, factors that can modulate bystander responses and the mechanisms involved. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    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

  7. Low-Dose Ionizing Radiation Affects Mesenchymal Stem Cells via Extracellular Oxidized Cell-Free DNA: A Possible Mediator of Bystander Effect and Adaptive Response

    Directory of Open Access Journals (Sweden)

    V. A. Sergeeva

    2017-01-01

    Full Text Available We have hypothesized that the adaptive response to low doses of ionizing radiation (IR is mediated by oxidized cell-free DNA (cfDNA fragments. Here, we summarize our experimental evidence for this model. Studies involving measurements of ROS, expression of the NOX (superoxide radical production, induction of apoptosis and DNA double-strand breaks, antiapoptotic gene expression and cell cycle inhibition confirm this hypothesis. We have demonstrated that treatment of mesenchymal stem cells (MSCs with low doses of IR (10 cGy leads to cell death of part of cell population and release of oxidized cfDNA. cfDNA has the ability to penetrate into the cytoplasm of other cells. Oxidized cfDNA, like low doses of IR, induces oxidative stress, ROS production, ROS-induced oxidative modifications of nuclear DNA, DNA breaks, arrest of the cell cycle, activation of DNA reparation and antioxidant response, and inhibition of apoptosis. The MSCs pretreated with low dose of irradiation or oxidized cfDNA were equally effective in induction of adaptive response to challenge further dose of radiation. Our studies suggest that oxidized cfDNA is a signaling molecule in the stress signaling that mediates radiation-induced bystander effects and that it is an important component of the development of radioadaptive responses to low doses of IR.

  8. SU-D-16A-03: A Radiation Pneumonitis Dose-Response Model Incorporating Non- Local Radiation-Induced Bystander Effect

    International Nuclear Information System (INIS)

    Gordon, J; Snyder, K; Zhong, H; Chetty, I

    2014-01-01

    Purpose: Dose-response models that can reliably predict radiation pneumonitis (RP) to guide radiation therapy (RT) for lung cancer presently do not exist. A model is proposed that incorporates non-local radiationinduced bystander effect (RIBE). Methods: A single sigmoid response function, derived from published data for whole lung irradiation, relates RP probability to cumulative lung damage, regardless of fractionation scheme. Lung damage is assumed to be caused by direct local radiation damage, quantified via the linear-quadratic (LQ) model, and RIBE. Based on published data, RIBE is assumed to be activated when per-fraction dose rises above ∼0.6 Gy, but is constant with dose above that threshold. Integral RIBE damage is assumed proportional to lung volume irradiated above ∼0.6 Gy per fraction. Key model parameters include LQ α and β, and two RIBE parameters: the single-fraction probability δ of damage, and a proportionality parameter κ that relates the potential for RIBE damage to irradiated lung volume. All parameters are tentatively fitted from published data, the RIBE parameters from published RP rates for conventionally fractionated RT (CFRT) and stereotactic body RT (SBRT). Results: The model predicts dose-response curves that are consistent with clinical experience. It provides a tentative explanation for why V20 (33 fractions), V13 (20 fractions) and V5 (<10 fractions) are observed to be correlated with RP. It also provides a plausible explanation for the success of SBRT — RIBE damage increases with the number of fractions, so penalizes CFRT relative to SBRT. Conclusion: The proposed model is relatively simple, extrapolates from published data, plausibly explains several clinical observations, and produces dose-response curves that are consistent with clinical experience. While capable of elaboration, its ability to explain doseresponse experience with different fractionation schemes using a small number of assumptions and parameters is an

  9. SU-D-16A-03: A Radiation Pneumonitis Dose-Response Model Incorporating Non- Local Radiation-Induced Bystander Effect

    Energy Technology Data Exchange (ETDEWEB)

    Gordon, J; Snyder, K; Zhong, H; Chetty, I [Henry Ford Health System, Dept. Radiation Oncology, Detroit, MI (United States)

    2014-06-01

    Purpose: Dose-response models that can reliably predict radiation pneumonitis (RP) to guide radiation therapy (RT) for lung cancer presently do not exist. A model is proposed that incorporates non-local radiationinduced bystander effect (RIBE). Methods: A single sigmoid response function, derived from published data for whole lung irradiation, relates RP probability to cumulative lung damage, regardless of fractionation scheme. Lung damage is assumed to be caused by direct local radiation damage, quantified via the linear-quadratic (LQ) model, and RIBE. Based on published data, RIBE is assumed to be activated when per-fraction dose rises above ∼0.6 Gy, but is constant with dose above that threshold. Integral RIBE damage is assumed proportional to lung volume irradiated above ∼0.6 Gy per fraction. Key model parameters include LQ α and β, and two RIBE parameters: the single-fraction probability δ of damage, and a proportionality parameter κ that relates the potential for RIBE damage to irradiated lung volume. All parameters are tentatively fitted from published data, the RIBE parameters from published RP rates for conventionally fractionated RT (CFRT) and stereotactic body RT (SBRT). Results: The model predicts dose-response curves that are consistent with clinical experience. It provides a tentative explanation for why V20 (33 fractions), V13 (20 fractions) and V5 (<10 fractions) are observed to be correlated with RP. It also provides a plausible explanation for the success of SBRT — RIBE damage increases with the number of fractions, so penalizes CFRT relative to SBRT. Conclusion: The proposed model is relatively simple, extrapolates from published data, plausibly explains several clinical observations, and produces dose-response curves that are consistent with clinical experience. While capable of elaboration, its ability to explain doseresponse experience with different fractionation schemes using a small number of assumptions and parameters is an

  10. X-ray-induced bystander response reduce spontaneous mutations in V79 cells

    International Nuclear Information System (INIS)

    Maeda, Munetoshi; Kobayashi, Katsumi; Matsumoto, Hideki; Usami, Noriko; Tomiya, Masanori

    2013-01-01

    The potential for carcinogenic risks is increased by radiation-induced bystander responses; these responses are the biological effects in unirradiated cells that receive signals from the neighboring irradiated cells. Bystander responses have attracted attention in modern radiobiology because they are characterized by non-linear responses to low-dose radiation. We used a synchrotron X-ray microbeam irradiation system developed at the Photon Factory, High Energy Accelerator Research Organization, KEK, and showed that nitric oxide (NO)-mediated bystander cell death increased biphasically in a dose-dependent manner. Here, we irradiated five cell nuclei using 10 × 10 µm 2 5.35 keV X-ray beams and then measured the mutation frequency at the hypoxanthine-guanosine phosphoribosyl transferase (HPRT) locus in bystander cells. The mutation frequency with the null radiation dose was 2.6 × 10 -5 (background level), and the frequency decreased to 5.3 × 10 -6 with a dose of approximately 1 Gy (absorbed dose in the nucleus of irradiated cells). At high doses, the mutation frequency returned to the background level. A similar biphasic dose-response effect was observed for bystander cell death. Furthermore, we found that incubation with 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), a specific scavenger of NO, suppressed not only the biphasic increase in bystander cell death but also the biphasic reduction in mutation frequency of bystander cells. These results indicate that the increase in bystander cell death involves mechanisms that suppress mutagenesis. This study has thus shown that radiation-induced bystander responses could affect processes that protect the cell against naturally occurring alterations such as mutations. (author)

  11. Radiation induced bystander effects: mechanisms and implication for low dose radiation risk assessment

    International Nuclear Information System (INIS)

    Hei, T.L.; Randers-Pehrson, G.; Zhou, H.

    2003-01-01

    Using a precision microbeam to target an exact fraction of cells in a population and irradiated their nuclei with exactly one alpha particle each, we found that the frequencies of induced mutations and chromosomal changes in populations where some known fractions of nuclei were hit are consistent with non-hit cells contributing significantly to the response. In fact, irradiation of 10% of a mammalian cell population with a single alpha particle per cell results in a mutant yield similar to that observed when all of the cells in the population are irradiated. Although the bystander observations have been well established, the underlying mechanism(s) remain largely unknown. There are indications that multiple pathways are involved in the bystander phenomenon and different cell types respond differently to the bystander signaling. In confluent monolayers, there is evident that gap junctional communication is crucial in mediating the bystander effect whereas reactive oxygen and reactive nitrogen species have been implicated as the mediating molecules in sub-confluent cultures. Although p53 is not necessary for the expression of bystander effect, there is evident that repair deficient cells may express a higher bystander response. Using cDNA microarrays, a number of cellular signaling genes have been shown to be differentially expressed among bystander cells. The functional roles of these genes in the bystander effect will be discussed. The bystander observations imply that the relevant target for various radiobiological endpoints is larger than an individual cell and suggest a need to reconsider the validity of the linear extrapolation in making risk estimate for low dose radiation exposure. (Work supported by NIH grants CA 49062 and CA-RR11623)

  12. Potential implications of the bystander effect on TCP and EUD when considering target volume dose heterogeneity.

    Science.gov (United States)

    Balderson, Michael J; Kirkby, Charles

    2015-01-01

    In light of in vitro evidence suggesting that radiation-induced bystander effects may enhance non-local cell killing, there is potential for impact on radiotherapy treatment planning paradigms such as the goal of delivering a uniform dose throughout the clinical target volume (CTV). This work applies a bystander effect model to calculate equivalent uniform dose (EUD) and tumor control probability (TCP) for external beam prostate treatment and compares the results with a more common model where local response is dictated exclusively by local absorbed dose. The broad assumptions applied in the bystander effect model are intended to place an upper limit on the extent of the results in a clinical context. EUD and TCP of a prostate cancer target volume under conditions of increasing dose heterogeneity were calculated using two models: One incorporating bystander effects derived from previously published in vitro bystander data ( McMahon et al. 2012 , 2013a); and one using a common linear-quadratic (LQ) response that relies exclusively on local absorbed dose. Dose through the CTV was modelled as a normal distribution, where the degree of heterogeneity was then dictated by changing the standard deviation (SD). Also, a representative clinical dose distribution was examined as cold (low dose) sub-volumes were systematically introduced. The bystander model suggests a moderate degree of dose heterogeneity throughout a target volume will yield as good or better outcome compared to a uniform dose in terms of EUD and TCP. For a typical intermediate risk prostate prescription of 78 Gy over 39 fractions maxima in EUD and TCP as a function of increasing SD occurred at SD ∼ 5 Gy. The plots only dropped below the uniform dose values for SD ∼ 10 Gy, almost 13% of the prescribed dose. Small, but potentially significant differences in the outcome metrics between the models were identified in the clinically-derived dose distribution as cold sub-volumes were introduced. In terms of

  13. Single cell low dose studies of bystander cell killing with targeted ultrasoft x-rays

    International Nuclear Information System (INIS)

    Schettino, G.; Prise, K.M.; Folkard, M.; Vojnovic, B.; Michael, B.D.; Wu, L.; Held, K.D.

    2003-01-01

    Full text: Bystander responses have attracted considerable interest in the recent years and several investigations have reported a binary behavior with the effect triggered by very small doses and immediately reaching a plateau. The Ultrasoft X-ray Microprobe in operation at the GCI is a facility designed to precisely assess the biological response of individual cells in vitro irradiated with a sub-micron size X-ray beam . Although recent improvements have upgrade the facility with AlK and TiK X-rays, most of the bystander studies have been performed using CK X-rays of 278 eV. The high sensitivity and the accurate irradiation and revisiting of the individual samples allowed us to investigate specific characteristics of the bystander phenomenon. In particular, evidences of a dose dependency of cell killing by bystander effect have been found at doses below 0.2 Gy where no differences is observed between all cell and single cell irradiation. Recent improvements have also allowed us to individually identify the phase of the cell cycle of all samples exposed. Although the G2-S phase have been found the most sensitive in responding to the bystander signal (a factor of 1.3), cells in the G1 phase also respond significantly while the phase of the irradiated cell doesn't seem to play a critical role. The time scale of the bystander effect has also been investigated by irradiating the same sample(s) twice with a few hours gap between exposures. Results indicate that the bystander signal is transmitted within a few minutes from the irradiation as replacing the medium immediately after irradiation does not influence the response, and it doesn't depend on the number of cells irradiated (up to 5). However, after a resting time of a few hours (3 h), the system seems to reset itself and a second irradiation has been shown to trigger a further bystander effect. Finally, by considering the total amount of energy deposited in to the sample population as critical parameter (instead

  14. Bystander effects of exposure to low-dose-rate 125I seeds on human lung cancers cells in vitro

    International Nuclear Information System (INIS)

    Jia Rongfei; Chen Honghong; Yu Lei; Zhao Meijia; Shao Chunlin; Cheng Wenying

    2007-01-01

    The bystander effects induced by continuous low-dose-rate (LDR) 125 I seeds radiation on damage of human lung cancer cells were investigated. Human adenocarcinoma cell line A549 and human small cell lung cancer cell line NCI-H446, which have different sensitivities to high-dose rate (HDR) external irradiation, were exposed directly to 125 I seeds in vitro and co-cultured with unirradiated cells for 24 h. Using cytokinesis-blocking micronucleus method and γ H2AX fluorescence immunoassay, bystander effects induced by 2Gy and 4Gy 125 I seed irradiation on micronucleus formation and DNA double-strand breaks (DSBs) of human lung cancer cells were detected and evaluated. The results showed that irradiation with 125 I seeds can induce medium-mediated bystander effects in A549 cells and NCI-H446 cells, exhibiting that both micronuclei formation and γ H2AX focus formation in bystander cells were increased significantly compared with non-irradiated cells. The extent of DNA damage induced by bystander effects was correlated with accumulated radiation dose and radiosensitive of tumor cells. NCI-H446 cells that were sensitive to HDR γ irradiation were more sensitive to continuous LDR irradiation and bystander effects than A549. However, a comparison between the bystander effects and direct effects elicits the intensity of bystander responses of A549 cells was higher than that of NCI-H446 cells. A dose-related reduction in bystander responses was observed both in A549 cells and NCI-H446 cells, suggesting that the signaling factors involved in the bystander signaling pathways may decrease with the increase of cell damages. (authors)

  15. An extracellular DNA mediated bystander effect produced from low dose irradiated endothelial cells

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    Ermakov, Aleksei V., E-mail: avePlato@mail.ru [Research Centre for Medical Genetics, Russian Academy of Medical Sciences, Moscow (Russian Federation); Konkova, Marina S.; Kostyuk, Svetlana V.; Smirnova, Tatiana D.; Malinovskaya, Elena M.; Efremova, Liudmila V.; Veiko, Natalya N. [Research Centre for Medical Genetics, Russian Academy of Medical Sciences, Moscow (Russian Federation)

    2011-07-01

    The human umbilical vein endothelial cells culture was exposed to X-ray radiation in a low dose of 10 cGy. The fragments of extracellular genomic DNA (ecDNA{sup R}) were isolated from the culture medium after the short-term incubation. A culture medium of unirradiated endothelial cells was then supplemented with ecDNA{sup R}, followed by analysing the cells along the series of parameters (bystander effect). The exposed cells and bystander endotheliocytes showed similar response to low doses: approximation of the 1q12 loci of chromosome 1 and their transposition into the cellular nucleus, change in shape of the endotheliocytic nucleus, activation of the nucleolus organizing regions (NORs), actin polymerization, and an elevated level of DNA double-stranded breaks. Following blockade of TLR9 receptors with oligonucleotide-inhibitor or chloroquine in the bystander cells these effects - except of activation of NORs - on exposure to ecDNA{sup R} disappeared, with no bystander response thus observed. The presence of the radiation-induced apoptosis in the bystander effect being studied suggests a possibility for radiation-modified ecDNA fragments (i.e., stress signaling factors) to be released into the culture medium, whereas inhibition of TLR9 suggests the binding these ligands to the recipient cells. A similar DNA-signaling pathway in the bystander effect we previously described for human lymphocytes. Integrity of data makes it possible to suppose that a similar signaling mechanism which we demonstrated for lymphocytes (humoral system) might also be mediated in a monolayer culture of cells (cellular tissue) after the development of the bystander effect in them and transfer of stress signaling factors (ecDNA{sup R}) through the culture medium.

  16. An extracellular DNA mediated bystander effect produced from low dose irradiated endothelial cells

    International Nuclear Information System (INIS)

    Ermakov, Aleksei V.; Konkova, Marina S.; Kostyuk, Svetlana V.; Smirnova, Tatiana D.; Malinovskaya, Elena M.; Efremova, Liudmila V.; Veiko, Natalya N.

    2011-01-01

    The human umbilical vein endothelial cells culture was exposed to X-ray radiation in a low dose of 10 cGy. The fragments of extracellular genomic DNA (ecDNA R ) were isolated from the culture medium after the short-term incubation. A culture medium of unirradiated endothelial cells was then supplemented with ecDNA R , followed by analysing the cells along the series of parameters (bystander effect). The exposed cells and bystander endotheliocytes showed similar response to low doses: approximation of the 1q12 loci of chromosome 1 and their transposition into the cellular nucleus, change in shape of the endotheliocytic nucleus, activation of the nucleolus organizing regions (NORs), actin polymerization, and an elevated level of DNA double-stranded breaks. Following blockade of TLR9 receptors with oligonucleotide-inhibitor or chloroquine in the bystander cells these effects - except of activation of NORs - on exposure to ecDNA R disappeared, with no bystander response thus observed. The presence of the radiation-induced apoptosis in the bystander effect being studied suggests a possibility for radiation-modified ecDNA fragments (i.e., stress signaling factors) to be released into the culture medium, whereas inhibition of TLR9 suggests the binding these ligands to the recipient cells. A similar DNA-signaling pathway in the bystander effect we previously described for human lymphocytes. Integrity of data makes it possible to suppose that a similar signaling mechanism which we demonstrated for lymphocytes (humoral system) might also be mediated in a monolayer culture of cells (cellular tissue) after the development of the bystander effect in them and transfer of stress signaling factors (ecDNA R ) through the culture medium.

  17. A review of the bystander effect and its implications for low-dose exposure

    International Nuclear Information System (INIS)

    Prise, K.M.; Folkard, M.; Michael, B.D.

    2003-01-01

    Current models for the interaction between ionising radiation and living cells or tissues are based on direct genetic damage produced by energy deposition in cellular DNA. An important observation which has questioned this basic assumption is radiation-induced bystander response, in which cells which have not been directly targeted respond if their neighbours have been exposed. This response predominates at low doses of relevance to radiation risk analysis (<0.2 Gy) and therefore needs to be fully characterised. The development of microbeams, which allow individual cells within populations to be targeted with precise doses of radiation, has provided a useful tool for quantifying this response. The authors' studies have targeted individual human and mouse cells with counted protons and helium ions and monitored neighbouring cells for the production of bystander responses. Bystander responses have been measured after exposures as low as a single proton or helium ion delivered to an individual cell. An important aspect is that these responses saturate with increasing dose to the single target cell, thus the relative roles of direct and indirect (non-targeted) responses change with dose. Studies with multicellular, tissue-based models are providing evidence that bystander responses may have a complex phenotype involving multiple pathways and the overall response may be a balance between multiple signalling processes and responses to radiation exposure. Current models for radiation risk assume a linear non-threshold response and have generally been extrapolated from high-dose exposures. The involvement of competing processes at low doses may have important consequences for understanding the effects of low-dose exposure. (author)

  18. DNA damage and the bystander response in tumor and normal cells exposed to X-rays.

    Science.gov (United States)

    Subhashree, M; Venkateswarlu, R; Karthik, K; Shangamithra, V; Venkatachalam, P

    2017-09-01

    Monolayer and suspension cultures of tumor (BMG-1, CCRF-CEM), normal (AG1522, HADF, lymphocytes) and ATM-mutant (GM4405) human cells were exposed to X-rays at doses used in radiotherapy (high dose and high dose-rate) or radiological imaging (low dose and low dose-rate). Radiation-induced DNA damage, its persistence, and possible bystander effects were evaluated, based on DNA damage markers (γ-H2AX, p53 ser15 ) and cell-cycle-specific cyclins (cyclin B1 and cyclin D1). Dose-dependent DNA damage and a dose-independent bystander response were seen after exposure to high dose and high dose-rate radiation. The level of induced damage (expression of p53 ser15 , γ-H2AX) depended on ATM status. However, low dose and dose-rate exposures neither increased expression of marker proteins nor induced a bystander response, except in the CCRF-CEM cells. Bystander effects after high-dose irradiation may contribute to stochastic and deterministic effects. Precautions to protect unexposed regions or to inhibit transmission of DNA damage signaling might reduce radiation risks. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Oxidative stress as a significant factor for development of an adaptive response in irradiated and nonirradiated human lymphocytes after inducing the bystander effect by low-dose X-radiation

    Energy Technology Data Exchange (ETDEWEB)

    Ermakov, Aleksei V., E-mail: avePlato@mail.ru [Research Centre for Medical Genetics, Russian Academy of Medical Science, ul. Moskvorechye, 1, Moscow 115478 (Russian Federation); Konkova, Marina S.; Kostyuk, Svetlana V.; Egolina, Natalya A.; Efremova, Liudmila V.; Veiko, Natalya N. [Research Centre for Medical Genetics, Russian Academy of Medical Science, ul. Moskvorechye, 1, Moscow 115478 (Russian Federation)

    2009-10-02

    X-radiation (10 cGy) was shown to induce in human lymphocytes transposition of homologous chromosomes loci from the membrane towards the centre of the nucleus and activation of the chromosomal nucleolus-forming regions (NFRs). These effects are transmitted by means of extracellular DNA (ecDNA) fragments to nonirradiated cells (the so-called bystander effect, BE). We demonstrated that in the development of the BE an important role is played by oxidative stress (which is brought about by low radiation doses and ecDNA fragments of the culture medium of the irradiated cells), by an enzyme of apoptosis called caspase-3, and by DNA-binding receptors of the bystander cells, presumably TLR9. Proposed herein is a scheme of the development of an adaptive response and the BE on exposure to radiation. Ionizing radiation induces apoptosis of the radiosensitive fraction of cells due to the development of the 'primary' oxidative stress (OS). DNA fragments of apoptotic cells are released into the intercellular space and interact with the DNA-binding receptors of the bystander cells. This interaction activates in lymphocytes signalling pathways associated with synthesis of the reactive oxygen species and nitrogen species, i.e., induces secondary oxidative stress accompanied by apoptosis of part of the cells, etc. Hence, single exposure to radiation may be followed by relatively long-lasting in the cellular population oxidative stress contributing to the development of an adaptive response. We thus believe that ecDNA of irradiated apoptotic lymphocytes is a significant factor of stress-signalling.

  20. Molecular pathways in the bystander response of cells exposed to very low fluences of alpha particles

    International Nuclear Information System (INIS)

    Little, J.B.

    2000-01-01

    Full text: We have examined biological effects in cell populations exposed to very low mean doses of alpha radiation by which only a small fraction of the cells are actually traversed by an alpha particle. We showed earlier that an enhanced frequency of sister chromatid exchanges and HPRT mutations occur in the non-irradiated, 'bystander' cells. The frequency of mutations induced by a single alpha particle traversing the nucleus of a cell was increased nearly fivefold at the lowest fluence studied, a result of mutations occurring in bystander cells. This was associated with a similar increase in the induction of micronuclei, indicating the induction of DNA damage in bystander cells. In order to gain information concerning molecular pathways, we studied changes in gene expression in bystander cells in confluent cultures of human diploid fibroblasts or mouse embryo-derived fibroblasts (MEFs) by western analysis and in-situ immunofluorescence. The expression levels of p53, p21 Waf1 and p34 cdc2 were significantly modulated in bystander cells. The upregulation of p53 and p21 Waf1 did not occur in cultures irradiated at low density, and was markedly reduced in the presence of the gap junction inhibitor lindane. The importance of gap-junction mediated intercellular communication was confirmed in connexin-43 knockout MEFs. Western blot analyses and electrophoretic mobility shift assays indicate that the bystander response is suppressed by incubation with superoxide dismutase as well as an inhibitor of NADPH oxidase, and is associated with the induction of NFKB, suggesting the effect is mediated by oxidative stress. The stress-activated protein kinase p38 and its downstream effector ATF2 are also induced in bystander cells independent of oxidative stress. These results will be discussed in terms of whether activation of the p53 damage response pathway is the direct result of signaling from irradiated cells, or rather is a consequence of DNA induced damage in the bystander

  1. Apoptosis is signalled early by low doses of ionising radiation in a radiation-induced bystander effect

    International Nuclear Information System (INIS)

    Furlong, Hayley; Mothersill, Carmel; Lyng, Fiona M.; Howe, Orla

    2013-01-01

    Highlights: ► Molecular mechanisms involved in the production of a radiation induced bystander effect are not well known. ► We investigate gene expression changes in apoptotic genes in both direct and bystander responses. ► We demonstrate initiation of the apoptotic cascade in a bystander response. ► Lower doses reveal a specific but differential response related to apoptosis compared to higher doses. - Abstract: It is known that ionising radiation (IR) induces a complex signalling apoptotic cascade post-exposure to low doses ultimately to remove damaged cells from a population, specifically via the intrinsic pathway. Therefore, it was hypothesised that bystander reporter cells may initiate a similar apoptotic response if exposed to low doses of IR (0.05 Gy and 0.5 Gy) and compared to directly irradiated cells. Key apoptotic genes were selected according to their role in the apoptotic cascade; tumour suppressor gene TP53, pro-apoptotic Bax and anti-apoptotic Bcl2, pro-apoptotic JNK and anti-apoptotic ERK, initiator caspase 2 and 9 and effector caspase 3, 6 and 7. The data generated consolidated the role of apoptosis following direct IR exposure for all doses and time points as pro-apoptotic genes such as Bax and JNK as well as initiator caspase 7 and effector caspase 3 and 9 were up-regulated. However, the gene expression profile for the bystander response was quite different and more complex in comparison to the direct response. The 0.05 Gy dose point had a more significant apoptosis gene expression profile compared to the 0.5 Gy dose point and genes were not always expressed within 1 h but were sometimes expressed 24 h later. The bystander data clearly demonstrates initiation of the apoptotic cascade by the up-regulation of TP53, Bax, Bcl-2, initiator caspase 2 and effector caspase 6. The effector caspases 3 and 7 of the bystander samples demonstrated down-regulation in their gene expression levels at 0.05 Gy and 0.5 Gy at both time points therefore not

  2. Apoptosis is signalled early by low doses of ionising radiation in a radiation-induced bystander effect

    Energy Technology Data Exchange (ETDEWEB)

    Furlong, Hayley, E-mail: hayley.furlong@dit.ie [DIT Centre for Radiation and Environmental Science, Focas Research Institute, Dublin Institute of Technology, Kevin St, Dublin 8 (Ireland); School of Biological Sciences, College of Sciences and Health, Dublin Institute of Technology, Kevin St, Dublin 8 (Ireland); Mothersill, Carmel [Medical Physics and Applied Radiation Sciences, Nuclear Research Building, 1280 Hamilton, Ontario L8S 4K1 (Canada); Lyng, Fiona M. [DIT Centre for Radiation and Environmental Science, Focas Research Institute, Dublin Institute of Technology, Kevin St, Dublin 8 (Ireland); Howe, Orla [DIT Centre for Radiation and Environmental Science, Focas Research Institute, Dublin Institute of Technology, Kevin St, Dublin 8 (Ireland); School of Biological Sciences, College of Sciences and Health, Dublin Institute of Technology, Kevin St, Dublin 8 (Ireland)

    2013-01-15

    Highlights: ► Molecular mechanisms involved in the production of a radiation induced bystander effect are not well known. ► We investigate gene expression changes in apoptotic genes in both direct and bystander responses. ► We demonstrate initiation of the apoptotic cascade in a bystander response. ► Lower doses reveal a specific but differential response related to apoptosis compared to higher doses. - Abstract: It is known that ionising radiation (IR) induces a complex signalling apoptotic cascade post-exposure to low doses ultimately to remove damaged cells from a population, specifically via the intrinsic pathway. Therefore, it was hypothesised that bystander reporter cells may initiate a similar apoptotic response if exposed to low doses of IR (0.05 Gy and 0.5 Gy) and compared to directly irradiated cells. Key apoptotic genes were selected according to their role in the apoptotic cascade; tumour suppressor gene TP53, pro-apoptotic Bax and anti-apoptotic Bcl2, pro-apoptotic JNK and anti-apoptotic ERK, initiator caspase 2 and 9 and effector caspase 3, 6 and 7. The data generated consolidated the role of apoptosis following direct IR exposure for all doses and time points as pro-apoptotic genes such as Bax and JNK as well as initiator caspase 7 and effector caspase 3 and 9 were up-regulated. However, the gene expression profile for the bystander response was quite different and more complex in comparison to the direct response. The 0.05 Gy dose point had a more significant apoptosis gene expression profile compared to the 0.5 Gy dose point and genes were not always expressed within 1 h but were sometimes expressed 24 h later. The bystander data clearly demonstrates initiation of the apoptotic cascade by the up-regulation of TP53, Bax, Bcl-2, initiator caspase 2 and effector caspase 6. The effector caspases 3 and 7 of the bystander samples demonstrated down-regulation in their gene expression levels at 0.05 Gy and 0.5 Gy at both time points therefore not

  3. The different radiation response and radiation-induced bystander effects in colorectal carcinoma cells differing in p53 status

    Energy Technology Data Exchange (ETDEWEB)

    Widel, Maria, E-mail: maria.widel@polsl.pl [Biosystems Group, Institute of Automatic Control, Silesian University of Technology, 16 Akademicka Street, 44-100 Gliwice (Poland); Lalik, Anna; Krzywon, Aleksandra [Biosystems Group, Institute of Automatic Control, Silesian University of Technology, 16 Akademicka Street, 44-100 Gliwice (Poland); Poleszczuk, Jan [College of Inter-faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, 93 Zwirki i Wigury Street, 02-089 Warsaw (Poland); Department of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida (United States); Fujarewicz, Krzysztof; Rzeszowska-Wolny, Joanna [Biosystems Group, Institute of Automatic Control, Silesian University of Technology, 16 Akademicka Street, 44-100 Gliwice (Poland)

    2015-08-15

    Highlights: • We tested radiation response and bystander effect on HCT116p53+/+ and p53−/− cells. • The p53+/+ cells developed premature senescence in exposed and bystander neighbors. • Directly exposed and bystander p53−/− cells died profoundly through apoptosis. • Interleukins 6 and 8 were differently generated by both cell lines. • NFκB path was activated mainly in p53+/+ hit cells, in p53 −/− in bystanders only. - Abstract: Radiation-induced bystander effect, appearing as different biological changes in cells that are not directly exposed to ionizing radiation but are under the influence of molecular signals secreted by irradiated neighbors, have recently attracted considerable interest due to their possible implication for radiotherapy. However, various cells present diverse radiosensitivity and bystander responses that depend, inter alia, on genetic status including TP53, the gene controlling the cell cycle, DNA repair and apoptosis. Here we compared the ionizing radiation and bystander responses of human colorectal carcinoma HCT116 cells with wild type or knockout TP53 using a transwell co-culture system. The viability of exposed to X-rays (0–8 Gy) and bystander cells of both lines showed a roughly comparable decline with increasing dose. The frequency of micronuclei was also comparable at lower doses but at higher increased considerably, especially in bystander TP53-/- cells. Moreover, the TP53-/- cells showed a significantly elevated frequency of apoptosis, while TP53+/+ counterparts expressed high level of senescence. The cross-matched experiments where irradiated cells of one line were co-cultured with non-irradiated cells of opposite line show that both cell lines were also able to induce bystander effects in their counterparts, however different endpoints revealed with different strength. Potential mediators of bystander effects, IL-6 and IL-8, were also generated differently in both lines. The knockout cells secreted IL-6 at

  4. The different radiation response and radiation-induced bystander effects in colorectal carcinoma cells differing in p53 status

    International Nuclear Information System (INIS)

    Widel, Maria; Lalik, Anna; Krzywon, Aleksandra; Poleszczuk, Jan; Fujarewicz, Krzysztof; Rzeszowska-Wolny, Joanna

    2015-01-01

    Highlights: • We tested radiation response and bystander effect on HCT116p53+/+ and p53−/− cells. • The p53+/+ cells developed premature senescence in exposed and bystander neighbors. • Directly exposed and bystander p53−/− cells died profoundly through apoptosis. • Interleukins 6 and 8 were differently generated by both cell lines. • NFκB path was activated mainly in p53+/+ hit cells, in p53 −/− in bystanders only. - Abstract: Radiation-induced bystander effect, appearing as different biological changes in cells that are not directly exposed to ionizing radiation but are under the influence of molecular signals secreted by irradiated neighbors, have recently attracted considerable interest due to their possible implication for radiotherapy. However, various cells present diverse radiosensitivity and bystander responses that depend, inter alia, on genetic status including TP53, the gene controlling the cell cycle, DNA repair and apoptosis. Here we compared the ionizing radiation and bystander responses of human colorectal carcinoma HCT116 cells with wild type or knockout TP53 using a transwell co-culture system. The viability of exposed to X-rays (0–8 Gy) and bystander cells of both lines showed a roughly comparable decline with increasing dose. The frequency of micronuclei was also comparable at lower doses but at higher increased considerably, especially in bystander TP53-/- cells. Moreover, the TP53-/- cells showed a significantly elevated frequency of apoptosis, while TP53+/+ counterparts expressed high level of senescence. The cross-matched experiments where irradiated cells of one line were co-cultured with non-irradiated cells of opposite line show that both cell lines were also able to induce bystander effects in their counterparts, however different endpoints revealed with different strength. Potential mediators of bystander effects, IL-6 and IL-8, were also generated differently in both lines. The knockout cells secreted IL-6 at

  5. The different radiation response and radiation-induced bystander effects in colorectal carcinoma cells differing in p53 status.

    Science.gov (United States)

    Widel, Maria; Lalik, Anna; Krzywon, Aleksandra; Poleszczuk, Jan; Fujarewicz, Krzysztof; Rzeszowska-Wolny, Joanna

    2015-08-01

    Radiation-induced bystander effect, appearing as different biological changes in cells that are not directly exposed to ionizing radiation but are under the influence of molecular signals secreted by irradiated neighbors, have recently attracted considerable interest due to their possible implication for radiotherapy. However, various cells present diverse radiosensitivity and bystander responses that depend, inter alia, on genetic status including TP53, the gene controlling the cell cycle, DNA repair and apoptosis. Here we compared the ionizing radiation and bystander responses of human colorectal carcinoma HCT116 cells with wild type or knockout TP53 using a transwell co-culture system. The viability of exposed to X-rays (0-8 Gy) and bystander cells of both lines showed a roughly comparable decline with increasing dose. The frequency of micronuclei was also comparable at lower doses but at higher increased considerably, especially in bystander TP53-/- cells. Moreover, the TP53-/- cells showed a significantly elevated frequency of apoptosis, while TP53+/+ counterparts expressed high level of senescence. The cross-matched experiments where irradiated cells of one line were co-cultured with non-irradiated cells of opposite line show that both cell lines were also able to induce bystander effects in their counterparts, however different endpoints revealed with different strength. Potential mediators of bystander effects, IL-6 and IL-8, were also generated differently in both lines. The knockout cells secreted IL-6 at lower doses whereas wild type cells only at higher doses. Secretion of IL-8 by TP53-/- control cells was many times lower than that by TP53+/+ but increased significantly after irradiation. Transcription of the NFκBIA was induced in irradiated TP53+/+ mainly, but in bystanders a higher level was observed in TP53-/- cells, suggesting that TP53 is required for induction of NFκB pathway after irradiation but another mechanism of activation must operate in

  6. Workplace mobbing: How the victim's coping behavior influences bystander responses.

    Science.gov (United States)

    Mulder, Roelie; Bos, Arjan E R; Pouwelse, Mieneke; van Dam, Karen

    2017-01-01

    Victims of workplace mobbing show diverse coping behavior. We investigated the impact of this behavior on bystander cognitions, emotions, and helping toward the victim, integrating coping literature with attribution theory. Adult part-time university students (N = 161) working at various organizations participated in a study with a 3(Coping: approach/avoidance/neutral) × 2(Gender Victim: male/female) × 2(Gender Bystander: male/female) design. Victims showing approach (vs. avoidance) coping were considered to be more self-reliant and less responsible for the continuation of the mobbing, and they elicited less anger. Continuation responsibility and self-reliance mediated the relationship between the victim's coping behavior and bystanders' helping intentions. Female (vs. male) participants reported more sympathy for the victim and greater willingness to help, and female (vs. male) victims elicited less anger. Theoretical and practical implications of the findings are discussed.

  7. Investigations into the bystander effect: signal versus response

    International Nuclear Information System (INIS)

    Vines, A.M.; Seymour, C.B.; Mothersill, C.E.

    2003-01-01

    The bystander effect is the general term used to describe the effects seen in cells or tissue that have never been directly irradiated, but display similar symptoms to those that have. Some of these symptoms include reduced cell survival, chromosomal aberrations, and increased apoptosis. This investigation aims to explore the signal produced by certain cell and tissue types, and the relationship this has with the subsequent response. The goal is to elucidate whether the reduction in cell survival frequently seen in response to the bystander effect is determined by the signal produced or the response of the cell type. Firstly, a matrix design experiment was set up using 3 cell lines. Each cell line was irradiated to produce ICCM (Irradiated Cell Conditioned Medium), which was in turn used to treat all cell lines in the study. Medium transfer is carried out within cell lines, (ICCM from CHO onto CHO cells) and between cell lines (ICCM from CHO onto HPV-G cells). In the second set of experiments, tissue samples from male Wister rats were used to generate ITCM (Irradiated Tissue Conditioned Medium). This medium was then tested on a cell line with an established response to the bystander effect. As an extension to these two experimental protocols, both ICCM and ITCM were used to investigate if there is calcium flux in the cells as a response to the bystander medium. This has recently been shown to be an early response to the bystander signal. Results indicate that it is the signal produced by the irradiated cells that determine the overall effect of the bystander signal, and not the response of the cells expose to it. CHO-K1 cells treated with autologous ICCM show a 16.2% drop in cell survival. However, when this cell line is treated with HPV-G ICCM, it shows a 36.5% drop in survival. HPV-G cells treated with autologous medium display a similar response to this, with a 41.1% drop in survival, though when treated with CHO-K1 ICCM, the drop in survival is 22.9%. This

  8. Bystanders' Supportive and Passive Responses to Cyberaggression

    Science.gov (United States)

    Machackova, Hana; Dedkova, Lenka; Sevcikova, Anna; Cerna, Alena

    2018-01-01

    Bystanders in cyberaggression can support the victim, join the aggressor, or remain passive. We examined how supportive and passive adolescent Czech cyberbystanders (N = 443, ages 12-18) differ in terms of individual characteristics, emotional responses, and contextual factors. The most substantial distinguishing factor between the two groups…

  9. What is the role of the bystander response in radionuclide therapies?

    Directory of Open Access Journals (Sweden)

    Darren eBrady

    2013-08-01

    Full Text Available Radionuclide therapy for cancer is undergoing a renaissance, with a wide range of radionuclide and clinical delivery systems currently under investigation. Dosimetry at the cellular and subcellular level is complex with inhomogeneity and incomplete targeting of all cells such that some tumour cells will receive little or no direct radiation energy. There is now sufficient preclinical evidence of a bystander response which can modulate the biology of these unirradiated cells with current research demonstrating both protective and inhibitory responses. Dependence upon fraction of irradiated cells has also been found has and the presence of functional gap junctions appears to be import for several bystander responses. The selection of either high or low LET radionuclides may be critical. While low LET radionuclides appear to have a bystander response proportional to dose, the dose-response from high LET radionuclides are more complex. In media transfer experiments a U shaped response curve has been demonstrated for high LET treatments. However this U shaped response has not been seen with co-culture experiments and its relevance remains uncertain. For high LET treatments there is a suggestion that dose rate effects may also be important with inhibitory effects noted with 125I labelling study and a stimulatory seen with 123I labelling in one study.

  10. Vanguards of paradigm shift in radiation biology. Radiation-induced adaptive and bystander responses

    International Nuclear Information System (INIS)

    Matsumoto, Hideki; Hamada, Nobuyuki; Kobayashi, Yasuhiko; Takahashi, Akihisa; Ohnishi, Takeo

    2007-01-01

    The risks of exposure to low dose ionizing radiation (below 100 mSv) are estimated by extrapolating from data obtained after exposure to high dose radiation, using a linear no-threshold model (LNT model). However, the validity of using this dose-response model is controversial because evidence accumulated over the past decade has indicated that living organisms, including humans, respond differently to low dose/low dose-rate radiation than they do to high dose/high dose-rate radiation. In other words, there are accumulated findings which cannot be explained by the classical ''target theory'' of radiation biology. The radioadaptive response, radiation-induced bystander effects, low-dose radio-hypersensitivity, and genomic instability are specifically observed in response to low dose/low dose-rate radiation, and the mechanisms underlying these responses often involve biochemical/molecular signals that respond to targeted and non-targeted events. Recently, correlations between the radioadaptive and bystander responses have been increasingly reported. The present review focuses on the latter two phenomena by summarizing observations supporting their existence, and discussing the linkage between them from the aspect of production of reactive oxygen and nitrogen species. (author)

  11. The bystander cell-killing effect mediated by nitric oxide in normal human fibroblasts varies with irradiation dose but not with radiation quality.

    Science.gov (United States)

    Yokota, Yuichiro; Funayama, Tomoo; Mutou-Yoshihara, Yasuko; Ikeda, Hiroko; Kobayashi, Yasuhiko

    2015-05-01

    To investigate the dependence of the bystander cell-killing effect on radiation dose and quality, and to elucidate related molecular mechanisms. Normal human fibroblast WI-38 cells were irradiated with 0.125 - 2 Gy of γ-rays or carbon ions and were co-cultured with non-irradiated cells. Survival rates of bystander cells were investigated using the colony formation assays, and nitrite concentrations in the medium were measured using the modified Saltzman method. Survival rates of bystander cells decreased with doses of γ-rays and carbon ions of ≤ 0.5 Gy. Treatment of the specific nitric oxide (NO) radical scavenger prevented reductions in survival rates of bystander cells. Moreover, nitrite concentrations increased with doses of less than 0.25 Gy (γ-rays) and 1 Gy (carbon ions). The dose responses of increased nitrite concentrations as well as survival reduction were similar between γ-rays and carbon ions. In addition, negative relationships were observed between survival rates and nitrite concentrations. The bystander cell-killing effect mediated by NO radicals in normal human fibroblasts depends on irradiation doses of up to 0.5 Gy, but not on radiation quality. NO radical production appears to be an important determinant of γ-ray- and carbon-ion-induced bystander effects.

  12. Bystander effects of radiation

    International Nuclear Information System (INIS)

    Umar, Neethu Fathima; Daniel, Nittu

    2013-01-01

    The Radiation-Induced Bystander Effect is the phenomenon in which unirradiated cells show irradiated effects due to the signals received from nearby irradiated cells. Evidence suggests that targeted cytoplasmic irradiation results in mutation in the nucleus of the hit cells. Cells that are not directly hit by an alpha particle, but are in the vicinity of one that is hit, also contribute to the genotoxic response of the cell population. When cells are irradiated, and the medium is transferred to unirradiated cells, these unirradiated cells show bystander responses when assayed for clonogenic survival and oncogenic transformation. The demonstration of a bystander effect in human tissues and, more recently, in whole organisms have clear implication of the potential relevance of the non-targeted response to human health. This effect may also contribute to the final biological consequences of exposure to low doses of radiation. The radiation-induced bystander effect represents a paradigm shift in our understanding of the radiobiological effects of ionizing radiation, in that extranuclear and extracellular events may also contribute to the final biological consequences of exposure to low doses of radiation. Multiple pathways are involved in the bystander phenomenon, and different cell types respond differently to bystander signalling. Using cDNA microarrays, a number of cellular signalling genes, including cyclooxygenase-2 (CQX-2), have been shown to be casually linked to the bystander phenomenon. The observation that inhibition of the phosphorylation of extracellular signal-related kinase (ERK) suppressed the bystander response further confirmed the important role of the mitogen-activated protein kinase (MAPK) signalling cascade in the bystander process. The cells deficient in mitochondrial DNA showed a significantly reduced response to bystander signalling, suggesting a functional role of mitochondria in the signalling process. (author)

  13. Elevated sodium chloride concentrations enhance the bystander effects induced by low dose alpha-particle irradiation

    International Nuclear Information System (INIS)

    Han Wei; Zhu Lingyan; Jiang Erkang; Wang Jun; Chen Shaopeng; Bao Linzhi; Zhao Ye; Xu An; Yu Zengliang; Wu Lijun

    2007-01-01

    Previous studies have shown that high NaCl can be genotoxic, either alone or combined with irradiation. However, little is known about the relationship between environmental NaCl at elevated conditions and radiation-induced bystander effects (RIBE). RIBE, which has been considered as non-targeted bystander responses, has been demonstrated to occur widely in various cell lines. In the present study, RIBE under the elevated NaCl culture condition was assessed in AG 1522 cells by both the induction of γ-H2AX, a reliable marker of DNA double-strand break (DSB) for the early process ( G -methyl-L-arginine, an inhibitor of nitric oxide synthase, the induced fraction of foci-positive cells was effectively inhibited both in 0.2 cGy α-particle irradiated and adjacent non-irradiated regions under either normal or elevated NaCl conditions. These results suggested that the cultures with elevated NaCl medium magnified the damage effects induced by the low dose α-particle irradiation and nitric oxide generated by irradiation was also very important in this process

  14. [Radiation-induced bystander effect: the important part of ionizing radiation response. Potential clinical implications].

    Science.gov (United States)

    Wideł, Maria; Przybyszewski, Waldemar; Rzeszowska-Wolny, Joanna

    2009-08-18

    It has long been a central radiobiological dogma that the damaging effects of ionizing radiation, such as cell death, cytogenetic changes, apoptosis, mutagenesis, and carcinogenesis, are the results of the direct ionization of cell structures, particularly DNA, or indirect damage via water radiolysis products. However, several years ago attention turned to a third mechanism of radiation, termed the "bystander effect" or "radiation-induced bystander effect" (RIBE). This is induced by agents and signals emitted by directly irradiated cells and manifests as a lowering of survival, cytogenetic damage, apoptosis enhancement, and biochemical changes in neighboring non-irradiated cells. The bystander effect is mainly observed in in vitro experiments using very low doses of alpha particles (range; mGy, cGy), but also after conventional irradiation (X-rays, gamma rays) at low as well as conventional doses. The mechanisms responsible for the bystander effect are complex and still poorly understood. It is believed that molecular signals released from irradiated cells induce different signaling ways in non-irradiated neighboring cells, leading to the observed events. The molecular signals may be transmitted through gap junction intercellular communication and through a medium transfer mechanism. The nature of these transmitted factors are diverse, and still not definitely established. It seems that RIBE may have important clinical implications for health risk associated with radiation exposure. Potentially, this effect may have important implications in the creation of whole-body or localized side effects in tissues beyond the irradiation field and also in low-dose radiological and radioisotope diagnostics. Factors emitted by irradiated cells may result in the risk of genetic instability, mutations, and second primary cancer induction. They might also have their own part in inducing and extending post-radiation side effects in normal tissue. The bystander effect may be a

  15. Radiation-induced bystander effect: The important part of ionizing radiation response. Potential clinical implications

    Directory of Open Access Journals (Sweden)

    Maria Wideł

    2009-08-01

    Full Text Available It has long been a central radiobiological dogma that the damaging effects of ionizing radiation, such as cell death, cytogenetic changes, apoptosis, mutagenesis, and carcinogenesis, are the results of the direct ionization of cell structures, particularly DNA, or indirect damage via water radiolysis products. However, several years ago attention turned to a third mechanism of radiation, termed the “bystander effect” or “radiation-induced bystander effect” (RIBE. This is induced by agents and signals emitted by directly irradiated cells and manifests as a lowering of survival, cytogenetic damage, apoptosis enhancement, and biochemical changes in neighboring non-irradiated cells. The bystander effect is mainly observed in in vitro experiments using very low doses of alpha particles (range; mGy, cGy, but also after conventional irradiation (X-rays, gamma rays at low as well as conventional doses. The mechanisms responsible for the bystander effect are complex and still poorly understood. It is believed that molecular signals released from irradiated cells induce different signaling ways in non-irradiated neighboring cells, leading to the observed events. The molecular signals may be transmitted through gap junction intercellular communication and through a medium transfer mechanism. The nature of these transmitted factors are diverse, and still not defi nitely established. It seems that RIBE may have important clinical implications for health risk associated with radiation exposure. Potentially, this effectmay have important implications in the creation of whole-body or localized side effects in tissues beyond the irradiation fi eld and also in low-dose radiological and radioisotope diagnostics. Factors emitted by irradiated cells may result in the risk of genetic instability, mutations, and second primary cancer induction. They might also have their own part in inducing and extending post-radiation side effects in normal tissue. The

  16. Membrane-Dependent Bystander Effect Contributes to Amplification of the Response to Alpha-Particle Irradiation in Targeted and Nontargeted Cells

    International Nuclear Information System (INIS)

    Hanot, Maite; Hoarau, Jim; Carriere, Marie; Angulo, Jaime F.; Khodja, Hicham

    2009-01-01

    Purpose: Free radicals are believed to play an active role in the bystander response. This study investigated their origin as well as their temporal and spatial impacts in the bystander effect. Methods and Materials: We employed a precise alpha-particle microbeam to target a small fraction of subconfluent osteoblastic cells (MC3T3-E1). γH2AX-53BP1 foci, oxidative metabolism changes, and micronuclei induction in targeted and bystander cells were assessed. Results: Cellular membranes and mitochondria were identified as two distinct reactive oxygen species producers. The global oxidative stress observed after irradiation was significantly attenuated after cells were treated with filipin, evidence for the primal role of membrane in the bystander effect. To determine the membrane's impact at a cellular level, micronuclei yield was measured when various fractions of the cell population were individually targeted while the dose per cell remained constant. Induction of micronuclei increased in bystander cells as well as in targeted cells and was attenuated by filipin treatment, demonstrating a role for bystander signals between irradiated cells in an autocrine/paracrine manner. Conclusions: A complex interaction of direct irradiation and bystander signals leads to a membrane-dependent amplification of cell responses that could influence therapeutic outcomes in tissues exposed to low doses or to environmental exposure.

  17. Response to Commentaries on Bystander Training as Leadership Training.

    Science.gov (United States)

    Katz, Jackson

    2018-03-01

    In this article, the author responds to three commentaries about his article "Bystander Training as Leadership Training: Notes on the Origins, Philosophy, and Pedagogy of the Mentors in Violence Prevention Model," published in this volume. Topics covered in the commentaries and response include questions about evaluation and evidence for program effectiveness; the necessity for gender violence prevention education to be gender transformative and part of a comprehensive, multilevel prevention approach, especially for adolescents; and the degree to which Mentors in Violence Prevention (MVP), as a "social justice"-oriented program, incorporates intersectional and anti-oppression frameworks and perspectives.

  18. Exposures involving perturbations of the EM field have non-linear effects on radiation response and can alter the expression of radiation induced bystander effects

    Science.gov (United States)

    Mothersill, Carmel; Seymour, Colin

    2012-07-01

    Our recent data suggest there is a physical component to the bystander signal induced by radiation exposure and that alternative medicine techniques such as Reiki and acupuncture or exposures to weak EM fields alter the response of cells to direct irradiation and either altered bystander signal production or altered the response of cells receiving bystander signals. Our proposed mechanism to explain these findings is that perturbation of electromagnetic (EM) fields is central to the induction of low radiation dose responses especially non-targeted bystander effects. In this presentation we review the alternative medicine data and other data sets from our laboratory which test our hypothesis that perturbation of bio-fields will modulate radiation response in the low dose region. The other data sets include exposure to MRI, shielding using lead and or Faraday cages, the use of physical barriers to bystander signal transmission and the use of membrane channel blockers. The data taken together strongly suggest that EM field perturbation can modulate low dose response and that in fact the EM field rather than the targeted deposition of ionizing energy in the DNA may be the key determinant of dose response in a cell or organism The results also lead us to suspect that at least when chemical transmission is blocked, bystander signals can be transmitted by other means. Our recent experiments suggest light signals and volatiles are not likely. We conclude that alternative medicine and other techniques involving electromagnetic perturbations can modify the response of cells to low doses of ionizing radiation and can induce bystander effects similar to those seen in medium transfer experiments. In addition to the obvious implications for mechanistic studies of low dose effects, this could perhaps provide a novel target to exploit in space radiation protection and in optimizing therapeutic gain during radiotherapy.

  19. Sci—Fri PM: Topics — 04: What if bystander effects influence cell kill within a target volume? Potential consequences of dose heterogeneity on TCP and EUD on intermediate risk prostate patients

    Energy Technology Data Exchange (ETDEWEB)

    Balderson, M.J.; Kirkby, C. [Department of Physics and Astronomy, University of Calgary, Calgary, Alberta (Canada); Department of Medical Physics, Tom Baker Cancer Centre, Calgary, Alberta (Canada); Department of Medical Physics, Jack Ady Cancer Centre, Lethbridge, Alberta (Canada)

    2014-08-15

    In vitro evidence has suggested that radiation induced bystander effects may enhance non-local cell killing which may influence radiotherapy treatment planning paradigms. This work applies a bystander effect model, which has been derived from published in vitro data, to calculate equivalent uniform dose (EUD) and tumour control probability (TCP) and compare them with predictions from standard linear quadratic (LQ) models that assume a response due only to local absorbed dose. Comparisons between the models were made under increasing dose heterogeneity scenarios. Dose throughout the CTV was modeled with normal distributions, where the degree of heterogeneity was then dictated by changing the standard deviation (SD). The broad assumptions applied in the bystander effect model are intended to place an upper limit on the extent of the results in a clinical context. The bystander model suggests a moderate degree of dose heterogeneity yields as good or better outcome compared to a uniform dose in terms of EUD and TCP. Intermediate risk prostate prescriptions of 78 Gy over 39 fractions had maximum EUD and TCP values at SD of around 5Gy. The plots only dropped below the uniform dose values for SD ∼ 10 Gy, almost 13% of the prescribed dose. The bystander model demonstrates the potential to deviate from the common local LQ model predictions as dose heterogeneity through a prostate CTV is varies. The results suggest the potential for allowing some degree of dose heterogeneity within a CTV, although further investigations of the assumptions of the bystander model are warranted.

  20. Sci—Fri PM: Topics — 04: What if bystander effects influence cell kill within a target volume? Potential consequences of dose heterogeneity on TCP and EUD on intermediate risk prostate patients

    International Nuclear Information System (INIS)

    Balderson, M.J.; Kirkby, C.

    2014-01-01

    In vitro evidence has suggested that radiation induced bystander effects may enhance non-local cell killing which may influence radiotherapy treatment planning paradigms. This work applies a bystander effect model, which has been derived from published in vitro data, to calculate equivalent uniform dose (EUD) and tumour control probability (TCP) and compare them with predictions from standard linear quadratic (LQ) models that assume a response due only to local absorbed dose. Comparisons between the models were made under increasing dose heterogeneity scenarios. Dose throughout the CTV was modeled with normal distributions, where the degree of heterogeneity was then dictated by changing the standard deviation (SD). The broad assumptions applied in the bystander effect model are intended to place an upper limit on the extent of the results in a clinical context. The bystander model suggests a moderate degree of dose heterogeneity yields as good or better outcome compared to a uniform dose in terms of EUD and TCP. Intermediate risk prostate prescriptions of 78 Gy over 39 fractions had maximum EUD and TCP values at SD of around 5Gy. The plots only dropped below the uniform dose values for SD ∼ 10 Gy, almost 13% of the prescribed dose. The bystander model demonstrates the potential to deviate from the common local LQ model predictions as dose heterogeneity through a prostate CTV is varies. The results suggest the potential for allowing some degree of dose heterogeneity within a CTV, although further investigations of the assumptions of the bystander model are warranted

  1. Bystander effects and radiotherapy.

    Science.gov (United States)

    Marín, Alicia; Martín, Margarita; Liñán, Olga; Alvarenga, Felipe; López, Mario; Fernández, Laura; Büchser, David; Cerezo, Laura

    2015-01-01

    Radiation-induced bystander effects are defined as biological effects expressed after irradiation by cells whose nuclei have not been directly irradiated. These effects include DNA damage, chromosomal instability, mutation, and apoptosis. There is considerable evidence that ionizing radiation affects cells located near the site of irradiation, which respond individually and collectively as part of a large interconnected web. These bystander signals can alter the dynamic equilibrium between proliferation, apoptosis, quiescence or differentiation. The aim of this review is to examine the most important biological effects of this phenomenon with regard to areas of major interest in radiotherapy. Such aspects include radiation-induced bystander effects during the cell cycle under hypoxic conditions when administering fractionated modalities or combined radio-chemotherapy. Other relevant aspects include individual variation and genetics in toxicity of bystander factors and normal tissue collateral damage. In advanced radiotherapy techniques, such as intensity-modulated radiation therapy (IMRT), the high degree of dose conformity to the target volume reduces the dose and, therefore, the risk of complications, to normal tissues. However, significant doses can accumulate out-of-field due to photon scattering and this may impact cellular response in these regions. Protons may offer a solution to reduce out-of-field doses. The bystander effect has numerous associated phenomena, including adaptive response, genomic instability, and abscopal effects. Also, the bystander effect can influence radiation protection and oxidative stress. It is essential that we understand the mechanisms underlying the bystander effect in order to more accurately assess radiation risk and to evaluate protocols for cancer radiotherapy.

  2. Radioadaptive response to the medium-mediated bystander induction of DNA strand breaks in HeLa cells

    International Nuclear Information System (INIS)

    Ikushima, T.; Okuyama, M.

    2003-01-01

    Full text: Numerous investigators have reported two cellular responses of importance at low doses that have a potential impact on the risk estimation of ionizing radiation. The radioadaptive response confers resistance to a subsequent dose by a low priming dose, while the bystander effect exaggerates the effect of small doses. The present study was conducted to examine the interaction of the radioadaptive response with the bystander effect in HeLa cells. The culture was irradiated with 0.5 to 8 Gy of 140 kVp X-rays and one hour later, the medium was taken, passed through a filter and transferred to the parallel culture of non-irradiated HeLa cells as non-targeted cells. After incubation for 30 min, the induced DNA damage was analyzed by the single cell gel-electrophoresis assay under alkaline or neutral conditions. The treatments resulted in a dose-dependent increase in tail moment under either conditions, indicating the induction of DNA single- and double-strand breaks. The clonogenic survival of non-irradiated cells was also reduced after they were cultured in the medium that was taken from irradiated cultures. Any change was not observed when the medium alone was irradiated. These results give the disputed evidence that certain genotoxic factor(s) released from irradiated cells into the culture medium can induce DNA strand breaks leading to cell death. It is also suggested that physical contact between irradiated and non-irradiated cells may not be required for the bystander effect. In adapted cells that were pre-exposed to 5 cGy of X-rays and cultured for 4 h beforehand, the yield of DNA strand breaks induced by X-rayed medium was reduced by about 50 %. The results, in conjunction with our early finding (Ikushima et al., 1996) suggest that the radioadaptive response resulting from such a low dose may diminish the bystander effect through an enhanced DNA repair function

  3. Temporally distinct response of irradiated normal human fibroblasts and their bystander cells to energetic heavy ions

    International Nuclear Information System (INIS)

    Hamada, Nobuyuki; Ni, Meinan; Funayama, Tomoo; Sakashita, Tetsuya; Kobayashi, Yasuhiko

    2008-01-01

    Ionizing radiation-induced bystander effects have been documented for a multitude of endpoints such as mutations, chromosome aberrations and cell death, which arise in nonirradiated bystander cells having received signals from directly irradiated cells; however, energetic heavy ion-induced bystander response is incompletely characterized. To address this, we employed precise microbeams of carbon and neon ions for targeting only a very small fraction of cells in confluent fibroblast cultures. Conventional broadfield irradiation was conducted in parallel to see the effects in irradiated cells. Exposure of 0.00026% of cells led to nearly 10% reductions in the clonogenic survival and twofold rises in the apoptotic incidence regardless of ion species. Whilst apoptotic frequency increased with time up to 72 h postirradiation in irradiated cells, its frequency escalated up to 24 h postirradiation but declined at 48 h postirradiation in bystander cells, indicating that bystander cells exhibit transient commitment to apoptosis. Carbon- and neon-ion microbeam irradiation similarly caused almost twofold increments in the levels of serine 15-phosphorylated p53 proteins, irrespective of whether 0.00026, 0.0013 or 0.0066% of cells were targeted. Whereas the levels of phosphorylated p53 were elevated and remained unchanged at 2 h and 6 h postirradiation in irradiated cells, its levels rose at 6 h postirradiation but not at 2 h postirradiation in bystander cells, suggesting that bystander cells manifest delayed p53 phosphorylation. Collectively, our results indicate that heavy ions inactivate clonogenic potential of bystander cells, and that the time course of the response to heavy ions differs between irradiated and bystander cells. These induced bystander responses could be a defensive mechanism that minimizes further expansion of aberrant cells

  4. Bystander effects, adaptive response and genomic instability induced by prenatal irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Streffer, Christian [Institute for Science and Ethics, University Duisburg-Essen, Auf dem Sutan 12, D-45239 Essen (Germany)]. E-mail: streffer.essen@t-online.de

    2004-12-02

    The developing human embryo and fetus undergo very radiosensitive stages during the prenatal development. It is likely that the induction of low dose related effects such as bystander effects, the adaptive response, and genomic instability would have profound effects on embryonic and fetal development. In this paper, I review what has been reported on the induction of these three phenomena in exposed embryos and fetuses. All three phenomena have been shown to occur in murine embryonic or fetal cells and structures, although the induction of an adaptive response (and also likely the induction of bystander effects) are limited in terms of when during development they can be induced and the dose or dose-rate used to treat animals in utero. In contrast, genomic instability can be induced throughout development, and the effects of radiation exposure on genome instability can be observed for long times after irradiation including through pre- and postnatal development and into the next generation of mice. There are clearly strain-specific differences in the induction of these phenomena and all three can lead to long-term detrimental effects. This is true for the adaptive response as well. While induction of an adaptive response can make fetuses more resistant to some gross developmental defects induced by a subsequent high dose challenge with ionizing radiation, the long-term effects of this low dose exposure are detrimental. The negative effects of all three phenomena reflect the complexity of fetal development, a process where even small changes in the timing of gene expression or suppression can have dramatic effects on the pattern of biological events and the subsequent development of the mammalian organism.

  5. What role for DNA damage and repair in the bystander response?

    International Nuclear Information System (INIS)

    Prise, Kevin M.; Folkard, Melvyn; Kuosaite, Virginija; Tartier, Laurence; Zyuzikov, Nikolai; Shao, Chunlin

    2006-01-01

    The radiation-induced bystander effect challenges the accepted paradigm of direct DNA damage in response to energy deposition driving the biological consequences of radiation exposure. With the bystander response, cells which have not been directly exposed to radiation respond to their neighbours being targeted. In our own studies we have used novel targeted microbeam approaches to specifically irradiate parts of individual cells within a population to quantify the bystander response and obtain mechanistic information. Using this approach it has become clear that energy deposited by radiation in nuclear DNA is not required to trigger the effect, with cytoplasmic irradiation required. Irradiated cells also trigger a bystander response regardless of whether they themselves live or die, suggesting that the phenotype of the targeted cell is not a determining factor. Despite this however, a range of evidence has shown that repair status is important for dealing with the consequences of a bystander signal. Importantly, repair processes involved in the processing of dsb appear to be involved suggesting that the bystander response involves the delayed or indirect production of dsb-type lesions in bystander cells. Whether these are infact true dsb or complexes of oxidised bases in combination with strand breaks and the mechanisms for their formation, remains to be elucidated

  6. BYSTANDER EFFECTS GENOMIC INSTABILITY, ADAPTIVE RESPONSE AND CANCER RISK ASSESSMENT FOR RADIAION AND CHEMICAL EXPOSURES

    Science.gov (United States)

    BYSTANDER EFFECTS, GENOMIC INSTABILITY, ADAPTIVE RESPONSE AND CANCER RISK ASSESSMENT FOR RADIATION AND CHEMICAL EXPOSURESR. Julian PrestonEnvironmental Carcinogenesis Division, U.S. Environmental Protection Agency, Research Triangle Park, N.C. 27711, USAThere ...

  7. New aspects of studies on stress response. Radiation-induced bystander effect

    International Nuclear Information System (INIS)

    Matsumoto, Hideki; Hayashi, Sachiko; Jin, Zhao-Hui; Hatashita, Masanori; Kano, Eiichi

    2001-01-01

    This review describes the bystander effect which is the secondary stress response induced by the primary target affected by radiation and other environmental factors. The bystander effect can be exerted from the primary target cells through the gap junction, through interaction between ligands and receptors, through interaction between secreted bystander factors and receptors and through secreted bystander factors. Through the first, the typical one firstly shown in AG1521 cells is that, despite the pass of only 2% of irradiated α-particles through the target cell nucleus, much more cells respond to express p53 and p21/WAF1. Through the second, the Fas/Fas ligand in the target induce apoptosis of the non-target cells. As for the third, participation of cytokines and growth factors is suggested. Many investigations concern the fourth of bystander effects by the bystander factors: e.g., authors have studied the effects of X-ray, carbon beam or hyperthermia on nitric oxide synthase induction in A-172 cells. Studies of bystander effects possibly extend the concept of radiation biology. (K.H.)

  8. Bystanders' responses to offline bullying and cyberbullying: The role of empathy and normative beliefs about aggression.

    Science.gov (United States)

    Machackova, Hana; Pfetsch, Jan

    2016-04-01

    Cyberbullying often takes place with the virtual presence or knowledge of bystanders. While we have some evidence about the determinants of bystanders' responses to offline bullying, we lack empirical studies concerning the variables that influence bystanders' responses to cyberbullying. The current study examines bystanders' responses to offline bullying and cyberbullying incidents. Two types of responses were captured: support toward the victims and the reinforcement of bullies' actions. Using data from 321 German adolescents (ages 12-18; M = 14.99; 44% girls), the association between bystanders' responses and normative beliefs about verbal aggression and cyberaggression, and affective and cognitive empathy, were tested in a path model. Both types of normative beliefs positively predicted the reinforcement of bullies, and normative belief about verbal aggression also predicted support for the victims of offline bullying. Both types of empathy predicted support in offline bullying, but only affective empathy predicted support in cyberbullying. There was no link between affective or cognitive empathy to the reinforcement of bullies. Moreover, bystanders' tendencies to respond supportively to the victim or to reinforce the bully were rather consistent in both cyber- and offline bullying, but there was no link between support and reinforcement. The findings are discussed with regard to implications for prevention and intervention efforts. © 2016 Scandinavian Psychological Associations and John Wiley & Sons Ltd.

  9. Elevated sodium chloride concentrations enhance the bystander effects induced by low dose alpha-particle irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Han Wei; Zhu Lingyan; Jiang Erkang; Wang Jun; Chen Shaopeng; Bao Linzhi; Zhao Ye; Xu An; Yu Zengliang [Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, Hefei 230031 (China); Wu Lijun [Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, Hefei 230031 (China)], E-mail: ljw@ipp.ac.cn

    2007-11-01

    Previous studies have shown that high NaCl can be genotoxic, either alone or combined with irradiation. However, little is known about the relationship between environmental NaCl at elevated conditions and radiation-induced bystander effects (RIBE). RIBE, which has been considered as non-targeted bystander responses, has been demonstrated to occur widely in various cell lines. In the present study, RIBE under the elevated NaCl culture condition was assessed in AG 1522 cells by both the induction of {gamma}-H2AX, a reliable marker of DNA double-strand break (DSB) for the early process (<1 h post irradiation), and the generation of micronuclei (MN), a sensitive marker for relative long process of RIBE. Our results showed that in the absence of irradiation, NaCl at elevated concentration such as 8.0, 9.0 and 10.0 g/L did not significantly increase the frequency of {gamma}-H2AX foci-positive cells and the number of foci per positive cell comparing with that NaCl at a normal concentration (6.8 g/L). However, with 0.2 cGy {alpha}-particle irradiation, the induced fraction of {gamma}-H2AX foci-positive cells and the number of induced {gamma}-H2AX foci per positive cell were significantly increased in both irradiated and adjacent non-irradiated regions. Similarly, the induction of MN by 0.2 cGy {alpha}-particle irradiation also increased with the elevated NaCl concentrations. With N{sup G}-methyl-L-arginine, an inhibitor of nitric oxide synthase, the induced fraction of foci-positive cells was effectively inhibited both in 0.2 cGy {alpha}-particle irradiated and adjacent non-irradiated regions under either normal or elevated NaCl conditions. These results suggested that the cultures with elevated NaCl medium magnified the damage effects induced by the low dose {alpha}-particle irradiation and nitric oxide generated by irradiation was also very important in this process.

  10. Genotoxicity in the eyes of bystander cells

    International Nuclear Information System (INIS)

    Hei, Tom K.; Persaud, Rudranath; Zhou, Hongning; Suzuki, Masao

    2004-01-01

    The controversial use of a linear, no threshold extrapolation model for low dose risk assessment has become even more so in light of the recent reports on the bystander phenomenon. The answer to the question as to which of the two phenomena, bystander versus adaptive response, is more important has practical implication in terms of low dose radiation risk assessment. In this review, genotoxicity is used as an endpoint to introduce the two phenomena, provide some insight into the mechanisms of bystander effect and to bridge the two low dose phenomena which operate in opposite directions: the bystander effect tends to exaggerate the effect at low doses, by communicating damage from hit to non-hit cells whereas the adaptive response confers resistance to a subsequent challenging dose by an initial low priming dose

  11. Space radiation-induced bystander effect: kinetics of biologic responses, mechanisms, and significance of secondary radiations

    International Nuclear Information System (INIS)

    Gonon, Geraldine

    2011-01-01

    Widespread evidence indicates that exposure of cell cultures to a particles results in significant biological changes in both the irradiated and non-irradiated bystander cells in the population. The induction of non-targeted biological responses in cell cultures exposed to low fluences of high charge (Z) and high energy (E) particles is relevant to estimates of the health risks of space radiation and to radiotherapy. Here, we investigated the mechanisms underlying the induction of stressful effects in confluent normal human fibroblast cultures exposed to low fluences of 1000 MeV/u iron ions (linear energy transfer (LET) 151 keV/μm), 600 MeV/u silicon ions (LET 50 keV/μm) or 290 MeV/u carbon ions (LET 13 keV/μm). We compared the results with those obtained in cell cultures exposed, in parallel, to low fluences of 0.92 MeV/u a particles (LET 109 keV/μm). Induction of DNA damage, changes in gene expression, protein carbonylation and lipid peroxidation during 24 h after exposure of confluent cultures to mean doses as low as 0.2 cGy of iron or silicon ions strongly supported the propagation of stressful effects from irradiated to bystander cells. At a mean dose of 0.2 cGy, only 1 and 3 % of the cells would be targeted through the nucleus by an iron or silicon ion, respectively. Within 24 h post-irradiation, immunoblot analyses revealed significant increases in the levels of phospho-TP53 (serine 15), p21Waf1 (also known as CDKN1A), HDM2, phospho-ERK1/2, protein carbonylation and lipid peroxidation. The magnitude of the responses suggested participation of non-targeted cells in the response. Furthermore, when the irradiated cell populations were subcultured in fresh medium shortly after irradiation, greater than expected increases in the levels of these markers were also observed during 24 h. Together, the results imply a rapidly propagated and persistent bystander effect. In situ analyses in confluent cultures showed 53BP1 foci formation, a marker of DNA damage, in

  12. Relationship between the adaptive response and bystander effect produced by single cell irradiation using a focused ultrasoft x-ray microbeam

    International Nuclear Information System (INIS)

    Wu, L.; Schettino, G.; Folkard, M.; Yu, Z.; Prise, K.; Michael, B.; Wang, Y.

    2003-01-01

    Full text: Using the cell killing method and our newly developed focused carbon-K ultrasoft X-rays, we tested for an interaction between bystander responses and adaptive responses by irradiating only one V79 cell in a population with a dose of 0.2 or 1Gy, combined with a conventional 240kVp X irradiation (0, 0.01, 0.05, 0.2 or 1Gy) 2 hours before or after bystander treatment. The clonogenic survival of V79 cells was precisely measured by a single cell revisiting assay after incubation for 3 days. Our results clearly showed that the cell killing by the bystander treatment could be reduced by about 5% if we treated the cells with a very low dose of conventional 240kVp X-rays of 0.01 or 0.05Gy (at which dose they only kill 1 or 2% cells in a population), whether the conventional dose was given before or after bystander irradiation. When the conventional dose was increased to 0.2 or 1Gy (at which dose they could kill about 10 or 25% V79 cells), no adaptive response was found if we treated the cells with conventional irradiation first and bystander irradiation afterwards. However, the adaptive responses observed when we irradiated a single cell within the whole cell population before 0.2 or 1Gy conventional irradiation was given. This showed that the bystander-mediated adaptive response could increase the cell survival by 5 or 8% respectively compared with the cell killing by conventional irradiation of 0.2 or 1Gy only. We also tested the distribution of dead clones in the microbeam dishes either for bystander irradiation only or combined with conventional X-rays. We did not find any distance relationship between the irradiated cell and non-irradiated cells, which was consistent with our previous bystander irradiation studies showing an equal probability of finding damaged clones any where in the scanned area of the dish

  13. RAD9 deficiency enhances radiation induced bystander DNA damage and transcriptomal response

    International Nuclear Information System (INIS)

    Ghandhi, Shanaz A; Ponnaiya, Brian; Panigrahi, Sunil K; Hopkins, Kevin M; Cui, Qingping; Hei, Tom K; Amundson, Sally A; Lieberman, Howard B

    2014-01-01

    Radiation induced bystander effects are an important component of the overall response of cells to irradiation and are associated with human health risks. The mechanism responsible includes intra-cellular and inter-cellular signaling by which the bystander response is propagated. However, details of the signaling mechanism are not well defined. We measured the bystander response of Mrad9 +/+ and Mrad9 −/− mouse embryonic stem cells, as well as human H1299 cells with inherent or RNA interference-mediated reduced RAD9 levels after exposure to 1 Gy α particles, by scoring chromosomal aberrations and micronuclei formation, respectively. In addition, we used microarray gene expression analyses to profile the transcriptome of directly irradiated and bystander H1299 cells. We demonstrated that Mrad9 null enhances chromatid aberration frequency induced by radiation in bystander mouse embryonic stem cells. In addition, we found that H1299 cells with reduced RAD9 protein levels showed a higher frequency of radiation induced bystander micronuclei formation, compared with parental cells containing inherent levels of RAD9. The enhanced bystander response in human cells was associated with a unique transcriptomic profile. In unirradiated cells, RAD9 reduction broadly affected stress response pathways at the mRNA level; there was reduction in transcript levels corresponding to genes encoding multiple members of the UVA-MAPK and p38MAPK families, such as STAT1 and PARP1, suggesting that these signaling mechanisms may not function optimally when RAD9 is reduced. Using network analysis, we found that differential activation of the SP1 and NUPR1 transcriptional regulators was predicted in directly irradiated and bystander H1299 cells. Transcription factor prediction analysis also implied that HIF1α (Hypoxia induced factor 1 alpha) activation by protein stabilization in irradiated cells could be a negative predictor of the bystander response, suggesting that local hypoxic stress

  14. Nitric oxide mediated bystander responses induced by microbeam targeted cells

    International Nuclear Information System (INIS)

    Shao, C.; Prise, K.M.; Folkard, M.; Michael, B.D.

    2003-01-01

    Considerable evidence has recently been accumulated in support of the existence of a 'bystander effect', which cells having received no irradiation show biological consequences from their vicinal irradiated cells. The application of microbeams is providing new insights into the radiation-induced bystander effect. The present study found that when a fraction of radioresistant human glioblastoma cells were individually targeted with a precise number of helium ions generated from the Gray Cancer Institute Charged Particle Microbeam, micronucleus (MN) induction significantly exceeded the expected value that was calculated from the number of MN observed when all of the cells were targeted assuming no bystander effect occurring. Even when only a single cell within a population was hit by one helium ion, the MN induction in the population could be increased by 16%. These results provide direct evidence of radiation-induced bystander effect. Moreover, MN was effectively induced in the unirradiated primary human fibroblasts and glioblastoma cells either co-cultured with irradiated cells or treated with the medium harvested from irradiated cells, indicating a signal molecule was produced from the irradiated cells. However, when c-PTIO, a nitric oxide (NO)-specific scavenger, was present in the medium during and after irradiation until MN analysis, the production of MN in all of the above cases was reduced to low levels. Consequently, NO plays an important role in the radiation-induced bystander effect

  15. “Protective Bystander Effects Simulated with the State-Vector Model”—HeLa x Skin Exposure to 137Cs Not Protective Bystander Response But Mammogram and Diagnostic X-Rays Are

    Science.gov (United States)

    Leonard, Bobby E.

    2008-01-01

    The recent Dose Response journal article “Protective Bystander Effects Simulated with the State-Vector Model” (Schollnberger and Eckl 2007) identified the suppressive (below natural occurring, zero primer dose, spontaneous level) dose response for HeLa x skin exposure to 137Cs gamma rays (Redpath et al 2001) as a protective Bystander Effect (BE) behavior. I had previously analyzed the Redpath et al (2001) data with a Microdose Model and conclusively showed that the suppressive response was from Adaptive Response (AR) radio-protection (Leonard 2005, 2007a). The significance of my microdose analysis has been that low LET radiation induced single (i.e. only one) charged particle traversals through a cell can initiate a Poisson distributed activation of AR radio-protection. The purpose of this correspondence is to clarify the distinctions relative to the BE and the AR behaviors for the Redpath groups 137Cs data, show conversely however that the Redpath group data for mammography (Ko et al 2004) and diagnostic (Redpath et al 2003) X-rays do conclusively reflect protective bystander behavior and also herein emphasize the need for radio-biologist to apply microdosimetry in planning and analyzing their experiments for BE and AR. Whether we are adamantly pro-LNT, adamantly anti-LNT or, like most of us, just simple scientists searching for the truth in radio-biology, it is important that we accurately identify our results, especially when related to the LNT hypothesis controversy. PMID:18846260

  16. Short and long term bystander effect induction by fathead minnows (Pimephales promelas, Rafinesque, 1820) injected with environmentally relevant whole body doses of 226Ra

    International Nuclear Information System (INIS)

    Smith, Richard W.; Seymour, Colin B.; Mothersill, Carmel E.

    2013-01-01

    Bystander effect induction by fathead minnows injected with environmentally relevant doses of 226 Ra was investigated. Twenty four h and 6 months after injection with a single dose of 21, 210 or 2100 μBq, fin tissue samples emitted a pro-apoptotic signal, which reduced the clonogenic survival of an apoptosis sensitive reporter cell line. Twenty four h and 10 weeks after injection explants from non-injected bystander fish, swum with the injected fish, also emitted a pro-apoptotic signal. However 6 months after injection the bystander fish to 21 and 210 μBq injected fish emitted an anti-apoptotic signal. This demonstrates that extremely low dose irradiation can have effects outside of the irradiated fish. This has implications for population and ecosystem responses to contamination. -- Highlights: • Non-injected fish, swum with injected fish, gave the same response for up to 10 weeks. • After 6 months this response by non-injected fish changed to an anti-apoptotic signal. • This shows that 226 Ra contamination can have effects outside of the irradiated fish

  17. Bystander responses in three-dimensional cultures containing radiolabelled and unlabelled human cells

    International Nuclear Information System (INIS)

    Pinto, M.; Azzam, E. I.; Howell, R. W.

    2006-01-01

    Research on the radiation-induced bystander effect has been carried out mainly in 2-D tissue culture systems. This study uses a 3-D model, wherein apparently normal human diploid fibroblasts (AG1522) are grown in a carbon scaffold, to investigate the induction of a G 1 checkpoint in bystander cells present alongside radiolabelled cells. Cultures were simultaneously pulse-labelled with 3 H-deoxycytidine ( 3 HdC) to selectively irradiate a minor fraction of cells, and bromodeoxyuridine (BrdU) to identify the radiolabelled cells. After thorough washing of cultures, iododeoxyuridine (IdU) was administered to detect proliferating bystander cells. The cultures were harvested at various times thereafter, and cells were reacted with two monoclonal antibodies specific to IdU/BrdU or BrdU, respectively, stained with propidium iodide, and subjected to multi-parameter flow cytometry. Cell-cycle progression was followed in radiolabelled cells (BrdU + ) that were chronically irradiated by low energy beta particles emitted by DNA-incorporated 3 H, and in unlabelled bystander cells (BrdU - ) by a flow cytometry based cumulative labelling index assay. As expected, radiolabelled cells were delayed, in a dose-dependent manner, in G 2 and subsequently G 1 . No delay occurred in progression of bystander cells through G 1 , when the labelled cells were irradiated at dose rates up to 0.32 Gy h -1 . (authors)

  18. Low Doses of Gamma-Irradiation Induce an Early Bystander Effect in Zebrafish Cells Which Is Sufficient to Radioprotect Cells

    Science.gov (United States)

    Pereira, Sandrine; Malard, Véronique; Ravanat, Jean-Luc; Davin, Anne-Hélène; Armengaud, Jean; Foray, Nicolas; Adam-Guillermin, Christelle

    2014-01-01

    The term “bystander effect” is used to describe an effect in which cells that have not been exposed to radiation are affected by irradiated cells though various intracellular signaling mechanisms. In this study we analyzed the kinetics and mechanisms of bystander effect and radioadaptation in embryonic zebrafish cells (ZF4) exposed to chronic low dose of gamma rays. ZF4 cells were irradiated for 4 hours with total doses of gamma irradiation ranging from 0.01–0.1 Gy. In two experimental conditions, the transfer of irradiated cells or culture medium from irradiated cells results in the occurrence of DNA double strand breaks in non-irradiated cells (assessed by the number of γ-H2AX foci) that are repaired at 24 hours post-irradiation whatever the dose. At low total irradiation doses the bystander effect observed does not affect DNA repair mechanisms in targeted and bystander cells. An increase in global methylation of ZF4 cells was observed in irradiated cells and bystander cells compared to control cells. We observed that pre-irradiated cells which are then irradiated for a second time with the same doses contained significantly less γ-H2AX foci than in 24 h gamma-irradiated control cells. We also showed that bystander cells that have been in contact with the pre-irradiated cells and then irradiated alone present less γ-H2AX foci compared to the control cells. This radioadaptation effect is significantly more pronounced at the highest doses. To determine the factors involved in the early events of the bystander effect, we performed an extensive comparative proteomic study of the ZF4 secretomes upon irradiation. In the experimental conditions assayed here, we showed that the early events of bystander effect are probably not due to the secretion of specific proteins neither the oxidation of these secreted proteins. These results suggest that early bystander effect may be due probably to a combination of multiple factors. PMID:24667817

  19. Mechanism of protection of bystander cells by exogenous carbon monoxide: Impaired response to damage signal of radiation-induced bystander effect

    International Nuclear Information System (INIS)

    Han, W.; Yu, K.N.; Wu, L.J.; Wu, Y.C.; Wang, H.Z.

    2011-01-01

    A protective effect of exogenous carbon monoxide (CO), generated by CO releasing molecule ticarbonyldichlororuthenium (II) dimer (CORM-2), on the bystander cells from the toxicity of radiation-induced bystander effect (RIBE) was revealed in our previous study. In the present work, a possible mechanism of this CO effect was investigated. The results from medium transfer experiments showed that α-particle irradiated Chinese hamster ovary (CHO) cells would release nitric oxide (NO), which was detected with specific NO fluorescence probe, to induce p53 binding protein 1 (BP1) formation in the cell population receiving the medium, and the release peak was found to be at 1 h post irradiation. Treating the irradiated or bystander cells separately with CO (CORM-2) demonstrated that CO was effective in the bystander cells but not the irradiated cells. Measurements of NO production and release with a specific NO fluorescence probe also showed that CO treatment did not affect the production and release of NO by irradiated cells. Protection of CO on cells to peroxynitrite, an oxidizing free radical from NO, suggested that CO might protect bystander cells via impaired response of bystander cells to NO, a RIBE signal in our research system.

  20. Mechanism of protection of bystander cells by exogenous carbon monoxide: Impaired response to damage signal of radiation-induced bystander effect

    Energy Technology Data Exchange (ETDEWEB)

    Han, W. [Department of Physics and Materials Science, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon Tong, Kowloon (Hong Kong); Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China); Yu, K.N., E-mail: peter.yu@cityu.edu.hk [Department of Physics and Materials Science, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon Tong, Kowloon (Hong Kong); Wu, L.J. [Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China); Wu, Y.C. [Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China); School of Nuclear Science and Technology, University of Science and Technology of China, Hefei 230029 (China); Wang, H.Z. [Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031 (China)

    2011-05-10

    A protective effect of exogenous carbon monoxide (CO), generated by CO releasing molecule ticarbonyldichlororuthenium (II) dimer (CORM-2), on the bystander cells from the toxicity of radiation-induced bystander effect (RIBE) was revealed in our previous study. In the present work, a possible mechanism of this CO effect was investigated. The results from medium transfer experiments showed that {alpha}-particle irradiated Chinese hamster ovary (CHO) cells would release nitric oxide (NO), which was detected with specific NO fluorescence probe, to induce p53 binding protein 1 (BP1) formation in the cell population receiving the medium, and the release peak was found to be at 1 h post irradiation. Treating the irradiated or bystander cells separately with CO (CORM-2) demonstrated that CO was effective in the bystander cells but not the irradiated cells. Measurements of NO production and release with a specific NO fluorescence probe also showed that CO treatment did not affect the production and release of NO by irradiated cells. Protection of CO on cells to peroxynitrite, an oxidizing free radical from NO, suggested that CO might protect bystander cells via impaired response of bystander cells to NO, a RIBE signal in our research system.

  1. Bystander effects and compartmental stress response to X-ray irradiation in L929 cells.

    Science.gov (United States)

    Temelie, Mihaela; Stroe, Daniela; Petcu, Ileana; Mustaciosu, Cosmin; Moisoi, Nicoleta; Savu, Diana

    2016-08-01

    Bystander effects are indirect consequences of radiation and many other stress factors. They occur in cells that are not directly exposed to these factors, but receive signals from affected cells either by gap junctions or by molecules released in the medium. Characterizing these effects and deciphering the underlying mechanisms involved in radiation-induced bystander effects are relevant for cancer radiotherapy and radioprotection. At doses of X-ray radiation 0.5 and 1 Gy, we detected bystander effects as increased numbers of micronuclei shortly after the treatment, through medium transfer and by co-cultures. Interestingly, bystander cells did not exhibit long-term adverse changes in viability. Evaluation of several compartmental stress markers (CHOP, BiP, mtHsp60, cytHsp70) by qRT-PCR did not reveal expression changes at transcriptional level. We investigated the involvement of ROS and NO in this process by addition of specific scavengers of these molecules, DMSO or c-PTIO in the transferred medium. This approach proved that ROS but not NO is involved in the induction of lesions in the acceptor cells. These results indicate that L929 cells are susceptible to stress effects of radiation-induced bystander signaling.

  2. Critical role of gap junction communication, calcium and nitric oxide signaling in bystander responses to focal photodynamic injury.

    Science.gov (United States)

    Calì, Bianca; Ceolin, Stefano; Ceriani, Federico; Bortolozzi, Mario; Agnellini, Andrielly H R; Zorzi, Veronica; Predonzani, Andrea; Bronte, Vincenzo; Molon, Barbara; Mammano, Fabio

    2015-04-30

    Ionizing and nonionizing radiation affect not only directly targeted cells but also surrounding "bystander" cells. The underlying mechanisms and therapeutic role of bystander responses remain incompletely defined. Here we show that photosentizer activation in a single cell triggers apoptosis in bystander cancer cells, which are electrically coupled by gap junction channels and support the propagation of a Ca2+ wave initiated in the irradiated cell. The latter also acts as source of nitric oxide (NO) that diffuses to bystander cells, in which NO levels are further increased by a mechanism compatible with Ca(2+)-dependent enzymatic production. We detected similar signals in tumors grown in dorsal skinfold chambers applied to live mice. Pharmacological blockade of connexin channels significantly reduced the extent of apoptosis in bystander cells, consistent with a critical role played by intercellular communication, Ca2+ and NO in the bystander effects triggered by photodynamic therapy.

  3. A Randomized Controlled Trial of a Multi-Dose Bystander Intervention Program Using Peer Education Theater

    Science.gov (United States)

    McMahon, Sarah; Winter, Samantha C.; Palmer, Jane E.; Postmus, Judy L.; Peterson, N. Andrew; Zucker, Sharon; Koenick, RuthAnne

    2015-01-01

    This article reports findings from a longitudinal, experimental evaluation of a peer education theater program, Students Challenging Realities and Educating Against Myths (SCREAM) Theater. This study examines the impact of SCREAM Theater on a range of bystander-related outcomes (i.e. bystander intentions, bystander efficacy, perception of friend…

  4. Dependence of the bystander effect for micronucleus formation on dose of heavy-ion radiation in normal human fibroblasts

    International Nuclear Information System (INIS)

    Matsumoto, Yoshitaka; Hamada, Nobuyuki; Aoki-Nakano, Mizuho; Furusawa, Yoshiya; Funayama, Tomoo; Sakashita, Tetsuya; Kobayashi, Yasuhiko; Wada, Seiichi; Kakizaki, Takehiko

    2015-01-01

    Ionising radiation-induced bystander effects are well recognised, but its dependence on dose or linear energy transfer (LET) is still a matter of debate. To test this, 49 sites in confluent cultures of AG01522D normal human fibroblasts were targeted with microbeams of carbon (103 keV μm -1 ), neon (375 keV μm -1 ) and argon ions (1260 keV μm -1 ) and evaluated for the bystander-induced formation of micronucleus that is a kind of a chromosome aberration. Targeted exposure to neon and argon ions significantly increased the micronucleus frequency in bystander cells to the similar extent irrespective of the particle numbers per site of 1- 6. In contrast, the bystander micronucleus frequency increased with increasing the number of carbon-ion particles in a range between 1 and 3 particles per site and was similar in a range between 3 and 8 particles per site. These results suggest that the bystander effect of heavy ions for micronucleus formation depends on dose. (authors)

  5. Bystander Helping Behavior in Response to Workplace Bullying

    OpenAIRE

    Hellemans, Catherine; Dal Cason, Davide; Casini, Annalisa

    2017-01-01

    This research examines the role of colleagues in workplace bullying. While colleagues could often intervene to support the victim or stop the situation, passive behaviors and non-intervention are more frequent. The bystander effect highlighted by Latané and Darley (1970) has been studied in the context of school bullying and sexual harassment, but only rarely in the context of workplace bullying. We tested the impact of the belief in a just world for others, self-efficacy, perceived severity,...

  6. Characteristics and mechanisms of the bystander response in monolayer cell cultures exposed to very low fluences of alpha particles

    International Nuclear Information System (INIS)

    Little, John B.; Azzam, Edouard I.; Toledo, Sonia M. de; Nagasawa, Hatsumi

    2005-01-01

    When confluent cultures of mammalian cells are irradiated with very low fluences of alpha particles whereby only occasional cells receive any radiation exposure, genetic changes are observed in the non-irradiated ('bystander') cells. Upregulation of the p53 damage-response pathway as well as activation of proteins in the MAPK family occurred in bystander cells; p53 was phosphorylated on the serine 15 residue suggesting that the upregulation of p53 was a consequence of DNA damage. Damage signals were transmitted to bystander cells through gap junctions, as confirmed by the use of genetically manipulated cells including connexin43 knockouts. Expression of connexin43 was markedly enhanced by irradiation. A moderate bystander effect was observed for specific gene mutations and chromosomal aberrations. This effect was markedly enhanced in cells defective in the non-homologous end joining DNA repair pathway. Finally, an upregulation of oxidative metabolism occurred in bystander cells; the increased levels of reactive oxygen species appeared to be derived from flavine-containing oxidase enzymes. We hypothesize that genetic effects observed in non-irradiated bystander cells are a consequence of oxidative base damage; >90% of mutations in bystander cells were point mutations. When bystander cells cannot repair DNA double strand breaks, they become much more sensitive to the induction of chromosomal aberrations and mutations, the latter consisting primarily of deletion mutants. While we propose that the genetic effects occurring in bystander cells are a consequence of oxidative stress, the nature of the signal that initiates this process remains to be determined

  7. Contribution of radiation-induced, nitric oxide-mediated bystander effect to radiation-induced adaptive response.

    Science.gov (United States)

    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

  8. Potential association of bystander-patient relationship with bystander response and patient survival in daytime out-of-hospital cardiac arrest.

    Science.gov (United States)

    Tanaka, Yoshio; Maeda, Tetsuo; Kamikura, Takahisa; Nishi, Taiki; Omi, Wataru; Hashimoto, Masaaki; Sakagami, Satoru; Inaba, Hideo

    2015-01-01

    To investigate whether the bystander-patient relationship affects bystander response to out-of-hospital cardiac arrest (OHCA) and patient outcomes depending on the time of day. This population-based observational study in Japan involving 139,265 bystander-witnessed OHCAs (90,426 family members, 10,479 friends/colleagues, and 38,360 others) without prehospital physician involvement was conducted from 2005 to 2009. Factors associated with better bystander response [early emergency call and bystander cardiopulmonary resuscitation (BCPR)] and 1-month neurologically favourable survival were assessed. The rates of dispatcher-assisted CPR during daytime (7:00-18:59) and nighttime (19:00-6:59) were highest in family members (45.6% and 46.1%, respectively, for family members; 28.7% and 29.2%, respectively, for friends/colleagues; and 28.1% and 25.3%, respectively, for others). However, the BCPR rates were lowest in family members (35.5% and 37.8%, respectively, for family members; 43.7% and 37.8%, respectively, for friends/colleagues; and 59.3% and 50.0%, respectively, for others). Large delays (≥ 5 min) in placing emergency calls and initiating BCPR were most frequent in family members. The overall survival rate was lowest (2.7%) for family members and highest (9.1%) for friends/colleagues during daytime. Logistic regression analysis revealed that the effect of bystander relationship on survival was significant only during daytime [adjusted odds ratios (95% CI) for survival from daytime OHCAs with family as reference were 1.51 (1.36-1.68) for friends/colleagues and 1.23 (1.13-1.34) for others]. Family members are least likely to perform BCPR and OHCAs witnessed by family members are least likely to survive during daytime. Different strategies are required for family-witnessed OHCAs. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  9. Sticks, Stones, and Stigma: Student Bystander Behavior in Response to Hearing the Word "Retard"

    Science.gov (United States)

    Albert, Avery B.; Jacobs, Holly E.; Siperstein, Gary N.

    2016-01-01

    The present study explored the prevalence of the r-word in schools and students' bystander behavior in response to hearing the word. In total, 2,297 students from 12 high schools across the country participated in this study. Results revealed the r-word was used frequently among high school students, most often toward individuals without…

  10. A biological-based model that links genomic instability, bystander effects, and adaptive response

    International Nuclear Information System (INIS)

    Scott, B.R.

    2004-01-01

    This paper links genomic instability, bystander effects, and adaptive response in mammalian cell communities via a novel biological-based, dose-response model called NEOTRANS 3 . The model is an extension of the NEOTRANS 2 model that addressed stochastic effects (genomic instability, mutations, and neoplastic transformation) associated with brief exposure to low radiation doses. With both models, ionizing radiation produces DNA damage in cells that can be associated with varying degrees of genomic instability. Cells with persistent problematic instability (PPI) are mutants that arise via misrepair of DNA damage. Progeny of PPI cells also have PPI and can undergo spontaneous neoplastic transformation. Unlike NEOTRANS 2 , with NEOTRANS 3 newly induced mutant PPI cells and their neoplastically transformed progeny can be suppressed via our previously introduced protective apoptosis-mediated (PAM) process, which can be activated by low linear energy transfer (LET) radiation. However, with NEOTRANS 3 (which like NEOTRANS 2 involves cross-talk between nongenomically compromised [e.g., nontransformed, nonmutants] and genomically compromised [e.g., mutants, transformants, etc.] cells), it is assumed that PAM is only activated over a relatively narrow, dose-rate-dependent interval (D PAM ,D off ); where D PAM is a small stochastic activation threshold, and D off is the stochastic dose above which PAM does not occur. PAM cooperates with activated normal DNA repair and with activated normal apoptosis in guarding against genomic instability. Normal repair involves both error-free repair and misrepair components. Normal apoptosis and the error-free component of normal repair protect mammals by preventing the occurrence of mutant cells. PAM selectively removes mutant cells arising via the misrepair component of normal repair, selectively removes existing neoplastically transformed cells, and probably selectively removes other genomically compromised cells when it is activated

  11. Association of Bystander Cardiopulmonary Resuscitation and Survival According to Ambulance Response Times After Out-of-Hospital Cardiac Arrest.

    Science.gov (United States)

    Rajan, Shahzleen; Wissenberg, Mads; Folke, Fredrik; Hansen, Steen Møller; Gerds, Thomas A; Kragholm, Kristian; Hansen, Carolina Malta; Karlsson, Lena; Lippert, Freddy K; Køber, Lars; Gislason, Gunnar H; Torp-Pedersen, Christian

    2016-12-20

    Bystander-initiated cardiopulmonary resuscitation (CPR) increases patient survival after out-of-hospital cardiac arrest, but it is unknown to what degree bystander CPR remains positively associated with survival with increasing time to potential defibrillation. The main objective was to examine the association of bystander CPR with survival as time to advanced treatment increases. We studied 7623 out-of-hospital cardiac arrest patients between 2005 and 2011, identified through the nationwide Danish Cardiac Arrest Registry. Multiple logistic regression analysis was used to examine the association between time from 911 call to emergency medical service arrival (response time) and survival according to whether bystander CPR was provided (yes or no). Reported are 30-day survival chances with 95% bootstrap confidence intervals. With increasing response times, adjusted 30-day survival chances decreased for both patients with bystander CPR and those without. However, the contrast between the survival chances of patients with versus without bystander CPR increased over time: within 5 minutes, 30-day survival was 14.5% (95% confidence interval [CI]: 12.8-16.4) versus 6.3% (95% CI: 5.1-7.6), corresponding to 2.3 times higher chances of survival associated with bystander CPR; within 10 minutes, 30-day survival chances were 6.7% (95% CI: 5.4-8.1) versus 2.2% (95% CI: 1.5-3.1), corresponding to 3.0 times higher chances of 30-day survival associated with bystander CPR. The contrast in 30-day survival became statistically insignificant when response time was >13 minutes (bystander CPR vs no bystander CPR: 3.7% [95% CI: 2.2-5.4] vs 1.5% [95% CI: 0.6-2.7]), but 30-day survival was still 2.5 times higher associated with bystander CPR. Based on the model and Danish out-of-hospital cardiac arrest statistics, an additional 233 patients could potentially be saved annually if response time was reduced from 10 to 5 minutes and 119 patients if response time was reduced from 7 (the median

  12. Distinction of the memory B cell response to cognate antigen versus bystander inflammatory signals.

    Science.gov (United States)

    Benson, Micah J; Elgueta, Raul; Schpero, William; Molloy, Michael; Zhang, Weijun; Usherwood, Edward; Noelle, Randolph J

    2009-08-31

    The hypothesis that bystander inflammatory signals promote memory B cell (B(MEM)) self-renewal and differentiation in an antigen-independent manner is critically evaluated herein. To comprehensively address this hypothesis, a detailed analysis is presented examining the response profiles of B-2 lineage B220(+)IgG(+) B(MEM) toward cognate protein antigen in comparison to bystander inflammatory signals. After in vivo antigen encounter, quiescent B(MEM) clonally expand. Surprisingly, proliferating B(MEM) do not acquire germinal center (GC) B cell markers before generating daughter B(MEM) and differentiating into plasma cells or form structurally identifiable GCs. In striking contrast to cognate antigen, inflammatory stimuli, including Toll-like receptor agonists or bystander T cell activation, fail to induce even low levels of B(MEM) proliferation or differentiation in vivo. Under the extreme conditions of adjuvanted protein vaccination or acute viral infection, no detectable bystander proliferation or differentiation of B(MEM) occurred. The absence of a B(MEM) response to nonspecific inflammatory signals clearly shows that B(MEM) proliferation and differentiation is a process tightly controlled by the availability of cognate antigen.

  13. Role of Reactive Oxygen Species and Nitric Oxide in Mediating Chemotherapeutic Drug Induced Bystander Response in Human Cancer Cells Exposed In-Vitro

    Science.gov (United States)

    Chinnadurai, Mani; Rao, Bhavna S; Deepika, Ramasamy; Paul, Solomon F.D.; Venkatachalam, Perumal

    2012-01-01

    Background The intention of cancer chemotherapy is to control the growth of cancer cells using chemical agents. However, the occurrence of second malignancies has raised concerns, leading to re-evaluation of the current strategy in use for chemotherapeutic agents. Although the mechanisms involved in second malignancy remain ambiguous, therapeutic-agent-induced non-DNA targeted effects like bystander response and genomic instability cannot be eliminated completely. Hence, Bleomycin (BLM) and Neocarzinostatin (NCS), chemotherapeutic drugs with a mode of action similar to ionizing radiation, were used to study the mechanism of bystander response in human cancer cells (A549, CCRF-CEM and HL-60) by employing co-culture methodology. Methods Bystander effect was quantified using micronucleus (MN) assay and in-situ immunofluorescence(γH2AX assay).The role of reactive oxygen species (ROS) and nitric oxide (NO) in mediating the bystander response was explored by pre-treating bystander cells with dimethylsulphoxide (DMSO) and C-PTIO respectively. Results Bystander response was observed only in CCRF-CEM and A549 cells (P bystander response on treatment with DMSO, suggests that ROS has a more significant role in mediating the bystander response.Since the possibility of the ROS and NO in mediating these bystander effect was confirmed, mechanistic control of these signaling molecules could either reduce radiation damage and potential carcinogenicity of normal tissues (by reducing bystander signaling) or maximize cell sterilization during chemotherapy (by amplifying bystander responses in tumors). PMID:29147282

  14. A composite microdose Adaptive Response (AR) and Bystander Effect (BE) model-application to low LET and high LET AR and BE data.

    Science.gov (United States)

    Leonard, Bobby E

    2008-08-01

    It has been suggested that Adaptive Response (AR) may reduce risk of adverse health effects due to ionizing radiation. But very low dose Bystander Effects (BE) may impose dominant deleterious human risks. These conflicting behaviors have stimulated controversy regarding the Linear No-Threshold human risk model. A dose and dose rate-dependent microdose model, to examine AR behavior, was developed in prior work. In the prior work a number of in vitro and in vivo dose response data were examined with the model. Recent new data show AR behavior with some evidence of very low dose BE. The purpose of this work is to supplement the microdose model to encompass the Brenner and colleagues BaD (Bystander and Direct Damage) model and apply this composite model to obtain new knowledge regarding AR and BE and illustrate the use of the model to plan radio-biology experiments. The biophysical composite AR and BE Microdose Model quantifies the accumulation of hits (Poisson distributed, microdose specific energy depositions) to cell nucleus volumes. This new composite AR and BE model provides predictions of dose response at very low dose BE levels, higher dose AR levels and even higher dose Direct (linear-quadratic) Damage radiation levels. We find good fits of the model to both BE data from the Columbia University microbeam facility and combined AR and BE data for low Linear Energy Transfer (LET) and high LET data. A Bystander Factor of about 27,000 and an AR protection factor of 0.61 are obtained for the low LET in vivo mouse spleen exposures. A Bystander Factor of 317 and an AR protection factor of 0.53 are obtained for high LET radon alpha particles in human lymphocytes. In both cases the AR is activated at most by one or two radiation induced charged particle traversals through the cell nucleus. The results of the model analysis is consistent with a premise that both Bystander damage and Adaptive Response radioprotection can occur in the same cell type, derived from the same

  15. DUOX 1 is induced in human thyroid cells submitted to X-Ray irradiation and is responsible for the bystander effect

    Energy Technology Data Exchange (ETDEWEB)

    Boufraqech, M.; Chevallier Lagente, O.; Weyemi, U.; Talbot, M.; Al Ghuzlan, A.; Courtin, F.; Bidart, J.M.; Schlumberger, M.; Dupuy, C. [UMR 8200 CNRS, Institut Gustave Roussy, Villejuit (France); Ameziane el Hassani, R. [UBRM, Centre National de l' Energie, des Sciences et des Techniques Nucleaires, Rabat (Morocco)

    2012-07-01

    Radiation-induced bystander effect is the mechanism by which cells that have not been directly exposed to ionizing radiation behave like exposed cells: they die or show chromosomal instability and other phenotypic abnormalities. Bystander cells may be either adjacent or at some distance from the exposed cells. Irradiated cells release soluble factors that can be transferred through cell culture medium to non-irradiated cells. These factors include cytokines and reactive oxygen species (ROS). The aim of this study was to identify the ROS generating system induced by X-ray irradiation of human thyroid cells that could be responsible for the bystander effect. Irradiation of human thyroid epithelial cells (HTori-3 cells) induced an extracellular production of H{sub 2}O{sub 2} after 4 days that was related to the radiation dose. Our study shows that radiation exposure increases DUOX-1 expression after several days, suggesting that this H{sub 2}O{sub 2} generating system could be responsible for the late bystander effect. This could have a potential importance for radiation risk assessment and for cancer radiotherapy

  16. Simulating Social Situations in Immersive Virtual Reality - A Study of Bystander Responses to Violent Emergencies

    OpenAIRE

    Rovira i Pérez, A.

    2016-01-01

    The goal of this research is to show how immersive virtual reality (IVR) can be used to study human responses to extreme emergencies in social situations. Participants interact realistically with animated virtual humans. We show this through experimental studies of bystander responses to a violent confrontation, and find that there are conditions under which people intervene to help virtual characters that are threatened. We go on to show that a reinforcement learning (RL) method can capture ...

  17. Association of bystander cardiopulmonary resuscitation and survival according to ambulance response-times after out-of-hospital cardiac arrest

    DEFF Research Database (Denmark)

    Rajan, Shahzleen; Wissenberg, Mads; Folke, Fredrik

    2016-01-01

    30-day survival chances decreased for both patients with bystander CPR and those without. However, the contrast between the survival chances of patients with versus without bystander CPR increased over time: within 5 minutes, 30-day survival was 14.5% (95% confidence interval [CI]: 12.8-16.4) versus...... 6.3% (95% CI: 5.1-7.6), corresponding to 2.3 times higher chances of survival associated with bystander CPR; within 10 minutes, 30-day survival chances were 6.7% (95% CI: 5.4-8.1) versus 2.2% (95% CI: 1.5-3.1), corresponding to 3.0 times higher chances of 30-day survival associated with bystander...... CPR. The contrast in 30-day survival became statistically insignificant when response time was >13 minutes (bystander CPR vs no bystander CPR: 3.7% [95% CI: 2.2-5.4] vs 1.5% [95% CI: 0.6-2.7]), but 30-day survival was still 2.5 times higher associated with bystander CPR. Based on the model and Danish...

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

    OpenAIRE

    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.

  19. Study of influence of catechins on bystander responses in alpha-particle radiobiological experiments using thin PADC films

    International Nuclear Information System (INIS)

    Law, Y.L.; Yu, K.N.

    2009-01-01

    In this study, Chinese hamster ovary (CHO) cells were cultured in custom-made petri dishes with thin PADC films as substrates. Alpha particles with energies of 5 MeV were then irradiated from the bottom of PADC films. The DNA strand breaks in the bystander cells induced by irradiation were quantified with the use of terminal dUTP transferase-mediated nick end-labeling (TUNEL) assay. To study the influence of catechins on the bystander responses, catechins were added into the medium before alpha-particle irradiation of the cells. Fewer DNA strand breaks in the bystander cells were observed. As catechins are ROS (reactive oxygen species)-scavengers, the studied bystander cells might have been protected from radiation through scavenging of ROS by catechins.

  20. Study of influence of catechins on bystander responses in alpha-particle radiobiological experiments using thin PADC films

    Energy Technology Data Exchange (ETDEWEB)

    Law, Y.L. [Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong (Hong Kong); Yu, K.N., E-mail: peter.yu@cityu.edu.h [Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong (Hong Kong)

    2009-10-15

    In this study, Chinese hamster ovary (CHO) cells were cultured in custom-made petri dishes with thin PADC films as substrates. Alpha particles with energies of 5 MeV were then irradiated from the bottom of PADC films. The DNA strand breaks in the bystander cells induced by irradiation were quantified with the use of terminal dUTP transferase-mediated nick end-labeling (TUNEL) assay. To study the influence of catechins on the bystander responses, catechins were added into the medium before alpha-particle irradiation of the cells. Fewer DNA strand breaks in the bystander cells were observed. As catechins are ROS (reactive oxygen species)-scavengers, the studied bystander cells might have been protected from radiation through scavenging of ROS by catechins.

  1. Relationship Between Emergency Medical Services Response Time and Bystander Intervention in Patients With Out-of-Hospital Cardiac Arrest.

    Science.gov (United States)

    Goto, Yoshikazu; Funada, Akira; Goto, Yumiko

    2018-04-27

    The response time of emergency medical services (EMS) is an important determinant of survival after out-of-hospital cardiac arrest. We sought to identify upper limits of EMS response times and bystander interventions associated with neurologically intact survival. We analyzed the records of 553 426 patients with out-of-hospital cardiac arrest in a Japanese registry between 2010 and 2014. The primary study end point was 1-month neurologically intact survival (Cerebral Performance Category scale 1 or 2). Increased EMS response time was associated with significantly decreased adjusted odds of 1-month neurologically intact survival (adjusted odds ratio [aOR] for each 1-minute increase, 0.89; 95% confidence interval [CI], 0.89-0.90), although this relationship was modified by bystander interventions. The bystander interventions and the ranges of EMS response times that were associated with increased adjusted 1-month neurologically intact survival were as follows: bystander defibrillation, from ≤2 minutes (aOR, 3.10 [95% CI, 1.25-7.31]) to 13 minutes (aOR, 5.55 [95% CI, 2.66-11.2]); bystander conventional cardiopulmonary resuscitation, from 3 minutes (aOR 1.48 [95% CI, 1.02-2.12]) to 11 minutes (aOR 2.41 [95% CI, 1.61-3.56]); and bystander chest-compression-only cardiopulmonary resuscitation, from ≤2 minutes (aOR 1.57 [95% CI, 1.01-2.25]) to 11 minutes (aOR 1.92 [95% CI, 1.45-2.56]). However, the increase in neurologically intact survival of those receiving bystander interventions became statistically insignificant compared with no bystander interventions when the EMS response time was outside these ranges. The upper limits of the EMS response times associated with improved 1-month neurologically intact survival were 13 minutes when bystanders provided defibrillation (typically with cardiopulmonary resuscitation) and 11 minutes when bystanders provided cardiopulmonary resuscitation without defibrillation. © 2018 The Authors. Published on behalf of the

  2. The key role of miR-21-regulated SOD2 in the medium-mediated bystander responses in human fibroblasts induced by α-irradiated keratinocytes

    International Nuclear Information System (INIS)

    Tian, Wenqian; Yin, Xiaoming; Wang, Longxiao; Wang, Jingdong; Zhu, Wei; Cao, Jianping; Yang, Hongying

    2015-01-01

    Highlights: • After co-culture with α-irradiated HaCaT cells, WS1 cells displayed oxidative stress and DNA damage. • Increased miR-21 expression in bystander cells was critical to the occurrence of RIBEs. • SOD2 of bystander cells played an important role in bystander responses. • miR-21 mediated bystander effects through its regulation on SOD2. - Abstract: Radiation-induced bystander effect (RIBE) is well accepted in the radiation research field by now, but the underlying molecular mechanisms for better understanding this phenomenon caused by intercellular communication and intracellular signal transduction are still incomplete. Although our previous study has demonstrated an important role of miR-21 of unirradiated bystander cells in RIBEs, the direct evidence for the hypothesis that RIBE is epigenetically regulated is still limited and how miR-21 mediates RIBEs is unknown. Reactive oxygen species (ROS) have been demonstrated to be involved in RIBEs, however, the roles of anti-oxidative stress system of cells in RIBEs are unclear. Using transwell insert co-culture system, we investigated medium-mediated bystander responses in WS1 human fibroblasts after co-culture with HaCaT keratinocytes traversed by α-particles. Results showed that the ROS levels in unirradiated bystander WS1 cells were significantly elevated after 30 min of co-culture, and 53BP1 foci, a surrogate marker of DNA damage, were obviously induced after 3 h of co-culture. This indicates the occurrence of oxidative stress and DNA damage in bystander WS1 cells after co-culture with irradiated keratinocytes. Furthermore, the expression of miR-21 was increased in bystander WS1 cells, downregulation of miR-21 eliminated the bystander responses, overexpression of miR-21 alone could induce bystander-like oxidative stress and DNA damage in WS1 cells. These data indicate an important mediating role of miR-21 in RIBEs. In addition, MnSOD or SOD2 in WS1 cells was involved in the bystander effects

  3. The key role of miR-21-regulated SOD2 in the medium-mediated bystander responses in human fibroblasts induced by α-irradiated keratinocytes

    Energy Technology Data Exchange (ETDEWEB)

    Tian, Wenqian; Yin, Xiaoming; Wang, Longxiao; Wang, Jingdong; Zhu, Wei; Cao, Jianping [School of Radiation Medicine and Protection, Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, 199 Renai Road, Suzhou Industrial Park, Suzhou, Jiangsu Province 215123 (China); Yang, Hongying, E-mail: yanghongying@suda.edu.cn [School of Radiation Medicine and Protection, Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, 199 Renai Road, Suzhou Industrial Park, Suzhou, Jiangsu Province 215123 (China); Institute of Radiotherapy & Oncology, Soochow University (China)

    2015-10-15

    Highlights: • After co-culture with α-irradiated HaCaT cells, WS1 cells displayed oxidative stress and DNA damage. • Increased miR-21 expression in bystander cells was critical to the occurrence of RIBEs. • SOD2 of bystander cells played an important role in bystander responses. • miR-21 mediated bystander effects through its regulation on SOD2. - Abstract: Radiation-induced bystander effect (RIBE) is well accepted in the radiation research field by now, but the underlying molecular mechanisms for better understanding this phenomenon caused by intercellular communication and intracellular signal transduction are still incomplete. Although our previous study has demonstrated an important role of miR-21 of unirradiated bystander cells in RIBEs, the direct evidence for the hypothesis that RIBE is epigenetically regulated is still limited and how miR-21 mediates RIBEs is unknown. Reactive oxygen species (ROS) have been demonstrated to be involved in RIBEs, however, the roles of anti-oxidative stress system of cells in RIBEs are unclear. Using transwell insert co-culture system, we investigated medium-mediated bystander responses in WS1 human fibroblasts after co-culture with HaCaT keratinocytes traversed by α-particles. Results showed that the ROS levels in unirradiated bystander WS1 cells were significantly elevated after 30 min of co-culture, and 53BP1 foci, a surrogate marker of DNA damage, were obviously induced after 3 h of co-culture. This indicates the occurrence of oxidative stress and DNA damage in bystander WS1 cells after co-culture with irradiated keratinocytes. Furthermore, the expression of miR-21 was increased in bystander WS1 cells, downregulation of miR-21 eliminated the bystander responses, overexpression of miR-21 alone could induce bystander-like oxidative stress and DNA damage in WS1 cells. These data indicate an important mediating role of miR-21 in RIBEs. In addition, MnSOD or SOD2 in WS1 cells was involved in the bystander effects

  4. Bystander responses to a violent incident in an immersive virtual environment.

    Science.gov (United States)

    Slater, Mel; Rovira, Aitor; Southern, Richard; Swapp, David; Zhang, Jian J; Campbell, Claire; Levine, Mark

    2013-01-01

    Under what conditions will a bystander intervene to try to stop a violent attack by one person on another? It is generally believed that the greater the size of the crowd of bystanders, the less the chance that any of them will intervene. A complementary model is that social identity is critical as an explanatory variable. For example, when the bystander shares common social identity with the victim the probability of intervention is enhanced, other things being equal. However, it is generally not possible to study such hypotheses experimentally for practical and ethical reasons. Here we show that an experiment that depicts a violent incident at life-size in immersive virtual reality lends support to the social identity explanation. 40 male supporters of Arsenal Football Club in England were recruited for a two-factor between-groups experiment: the victim was either an Arsenal supporter or not (in-group/out-group), and looked towards the participant for help or not during the confrontation. The response variables were the numbers of verbal and physical interventions by the participant during the violent argument. The number of physical interventions had a significantly greater mean in the in-group condition compared to the out-group. The more that participants perceived that the Victim was looking to them for help the greater the number of interventions in the in-group but not in the out-group. These results are supported by standard statistical analysis of variance, with more detailed findings obtained by a symbolic regression procedure based on genetic programming. Verbal interventions made during their experience, and analysis of post-experiment interview data suggest that in-group members were more prone to confrontational intervention compared to the out-group who were more prone to make statements to try to diffuse the situation.

  5. Bystander responses to a violent incident in an immersive virtual environment.

    Directory of Open Access Journals (Sweden)

    Mel Slater

    Full Text Available Under what conditions will a bystander intervene to try to stop a violent attack by one person on another? It is generally believed that the greater the size of the crowd of bystanders, the less the chance that any of them will intervene. A complementary model is that social identity is critical as an explanatory variable. For example, when the bystander shares common social identity with the victim the probability of intervention is enhanced, other things being equal. However, it is generally not possible to study such hypotheses experimentally for practical and ethical reasons. Here we show that an experiment that depicts a violent incident at life-size in immersive virtual reality lends support to the social identity explanation. 40 male supporters of Arsenal Football Club in England were recruited for a two-factor between-groups experiment: the victim was either an Arsenal supporter or not (in-group/out-group, and looked towards the participant for help or not during the confrontation. The response variables were the numbers of verbal and physical interventions by the participant during the violent argument. The number of physical interventions had a significantly greater mean in the in-group condition compared to the out-group. The more that participants perceived that the Victim was looking to them for help the greater the number of interventions in the in-group but not in the out-group. These results are supported by standard statistical analysis of variance, with more detailed findings obtained by a symbolic regression procedure based on genetic programming. Verbal interventions made during their experience, and analysis of post-experiment interview data suggest that in-group members were more prone to confrontational intervention compared to the out-group who were more prone to make statements to try to diffuse the situation.

  6. Mechanisms underlying cellular responses of cells from haemopoietic tissue to low dose/low LET radiation

    Energy Technology Data Exchange (ETDEWEB)

    Munira A Kadhim

    2010-03-05

    To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e., less than 0.1 Gy), including the lowest possible dose, that of a single electron track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these “non-targeted” responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry and risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate radiation-induced genomic instability and bystander responses in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/H and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition on two non-targeted radiation responses in these models; the bystander effect and genomic instability, which we believe are closely related. We will specifically focus on the effects of low doses of low LET radiation, down to doses approaching a single electron traversal. Using conventional X-ray and γ-ray sources, novel dish separation and targeted irradiation approaches, we will be able to assess the role of genetic variation under various bystander conditions at doses down to a few electron tracks. Irradiations will be carried out using facilities in routine operation for bystander targeted studies. Mechanistic studies of instability and the bystander response in different cell lineages will focus initially on the role of cytokines which have been shown to be involved in bystander signaling and the initiation of instability. These studies also aim

  7. HL60 human premyelocitic cell line as a model system for bystander response

    International Nuclear Information System (INIS)

    Dini, V.; Tabocchini, M.A.; Belli, M.; Simone, G.; Di Carlo, B.; Sapora, O.; Superiore di Sanita, Rome

    2007-01-01

    Complete text of publication follows. Objective: to evaluate HL60 human premyelocitic cell line as a model system to study bystander response. Methods: HL60 cell line, isolated from the blood of a patient affected by premyelocitic leukemia, has 45-46 chromosomes with abnormalities mainly on chromosomes 5, 8 and X and can undergo chemical-induced in vitro differentiation. Differentiation gives rise to granulocytes, monocytes or macrophages depending on the drug used. We define as proliferative (AP) cells those in log phase of growth with less than 10 passages from thawing and as differentiated (D) cells those treated with 10 nM TPA (phorbol ester) for 72 hours. Phorbol ester treatment induces differentiation to monocytes and macrophages. Differentiation has been evaluated through the expression of differentiation cluster membrane antigens (CD95, CD9 and CD14). Results: AP cells resulted positive for CD95 and negative for CD9 and CD14, while D cells resulted positive for CD9 and negative for CD95 and CD14. Our data on AP and D cells showed that: (i) the level of intracellular reactive oxygen and nitrogen species (ROS and RNS) is lower in D cells compared to AP cells; (ii) radiation induced DNA damage (single and double strand breaks, SSB and DSB, as measured with the comet assay technique) is lower in D cells than in AP cells. This different radiosensitivity can be related to the higher degree of compactness of nuclear structure in D cells. Radiation induced bystander effect (BE) was analyzed with the medium transfer technique. The medium from irradiated, with 0.5 Gy of γ-rays, AP cells was collected after 0, 2, 4 and 24 hours from irradiation and added to non irradiated log phase cells. The frequency of micronuclei formation in bystander cells was measured by using the cytokinesis block technique by adding cytochalasin B to the non irradiated culture together with the irradiated medium. Preliminary data indicate about 1.4-fold increase in micronuclei formation in

  8. Bystander Effects of Ionizing Radiation

    Energy Technology Data Exchange (ETDEWEB)

    Little, John B. [Harvard T.H. Chan School of Public Health, Boston, MA (United States). Dept. of Genetics and Complex Diseases

    2017-01-17

    The objectives of this grant renewal are to provide administrative support and travel funds to allow the continued participation of the principal investigator (Dr. John B. Little) as an advisor to research initiated by several research fellows from his laboratory. The actual research will be carried out under the direction of Dr. Hatsumi Nagasawa with the collaboration of Dr. Joel Bedford at the Colorado State University, and by Drs. Edouard Azzam and Sonia de Toledo at the University of Medicine and Dentistry of New Jersey. Dr. Little will advise on the planning of experiments and development of experimental protocols, the analysis of data, and the preparation of manuscripts for publication. The Specific Aims for several of the planned experiments include: 1) to extend studies of the role of recombinational repair in the bystander effect by examining other genes in this pathway and cell lines deficient in excision repair; 2) to continue studies to determine the nature of the damage signal transmitted to bystander cells including the expression of several connexins in the bystander response, and the extent to which the enhanced oxidative metabolism observed in bystander cells may relate to the nature of the transmitted bystander signal; 3) to utilize a genome-wide approach to examine the genetic basis for the hypersensitivity to ionization we have observed in unaffected parents of patients with hereditary retinoblastoma, as well as from a group of apparently normal individuals that show similar radiosensitivity; 4) to complete studies concerning the induction of high frequencies of cells with massive chromosome damage in clonal derivatives of p53 and p21 knockout mouse cell lines; in particular to examine the role of telomere changes in this phenomenon. Overall, the results of these studies should enhance our understanding of the risk of low-dose exposures to ionizing radiation, including human populations to residential radon as well as occupational exposures.

  9. Bystander Effects of Ionizing Radiation

    International Nuclear Information System (INIS)

    Little, John B.

    2017-01-01

    The objectives of this grant renewal are to provide administrative support and travel funds to allow the continued participation of the principal investigator (Dr. John B. Little) as an advisor to research initiated by several research fellows from his laboratory. The actual research will be carried out under the direction of Dr. Hatsumi Nagasawa with the collaboration of Dr. Joel Bedford at the Colorado State University, and by Drs. Edouard Azzam and Sonia de Toledo at the University of Medicine and Dentistry of New Jersey. Dr. Little will advise on the planning of experiments and development of experimental protocols, the analysis of data, and the preparation of manuscripts for publication. The Specific Aims for several of the planned experiments include: 1) to extend studies of the role of recombinational repair in the bystander effect by examining other genes in this pathway and cell lines deficient in excision repair; 2) to continue studies to determine the nature of the damage signal transmitted to bystander cells including the expression of several connexins in the bystander response, and the extent to which the enhanced oxidative metabolism observed in bystander cells may relate to the nature of the transmitted bystander signal; 3) to utilize a genome-wide approach to examine the genetic basis for the hypersensitivity to ionization we have observed in unaffected parents of patients with hereditary retinoblastoma, as well as from a group of apparently normal individuals that show similar radiosensitivity; 4) to complete studies concerning the induction of high frequencies of cells with massive chromosome damage in clonal derivatives of p53 and p21 knockout mouse cell lines; in particular to examine the role of telomere changes in this phenomenon. Overall, the results of these studies should enhance our understanding of the risk of low-dose exposures to ionizing radiation, including human populations to residential radon as well as occupational exposures.

  10. BRCA1, FANCD2 and Chk1 are potential molecular targets for the modulation of a radiation-induced DNA damage response in bystander cells.

    Science.gov (United States)

    Burdak-Rothkamm, Susanne; Rothkamm, Kai; McClelland, Keeva; Al Rashid, Shahnaz T; Prise, Kevin M

    2015-01-28

    Radiotherapy is an important treatment option for many human cancers. Current research is investigating the use of molecular targeted drugs in order to improve responses to radiotherapy in various cancers. The cellular response to irradiation is driven by both direct DNA damage in the targeted cell and intercellular signalling leading to a broad range of bystander effects. This study aims to elucidate radiation-induced DNA damage response signalling in bystander cells and to identify potential molecular targets to modulate the radiation induced bystander response in a therapeutic setting. Stalled replication forks in T98G bystander cells were visualised via bromodeoxyuridine (BrdU) nuclear foci detection at sites of single stranded DNA. γH2AX co-localised with these BrdU foci. BRCA1 and FANCD2 foci formed in T98G bystander cells. Using ATR mutant F02-98 hTERT and ATM deficient GM05849 fibroblasts it could be shown that ATR but not ATM was required for the recruitment of FANCD2 to sites of replication associated DNA damage in bystander cells whereas BRCA1 bystander foci were ATM-dependent. Phospho-Chk1 foci formation was observed in T98G bystander cells. Clonogenic survival assays showed moderate radiosensitisation of directly irradiated cells by the Chk1 inhibitor UCN-01 but increased radioresistance of bystander cells. This study identifies BRCA1, FANCD2 and Chk1 as potential targets for the modulation of radiation response in bystander cells. It adds to our understanding of the key molecular events propagating out-of-field effects of radiation and provides a rationale for the development of novel molecular targeted drugs for radiotherapy optimisation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Influence of catechins on bystander responses in CHO cells induced by alpha-particle irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Law, Y.L.; Wong, T.P.W. [Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong (Hong Kong); Yu, K.N. [Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong (Hong Kong)], E-mail: peter.yu@cityu.edu.hk

    2010-04-15

    In this work, we studied alpha-particle induced and medium-mediated bystander effects in Chinese hamster ovary (CHO) cells through micronucleus (MN) assay. We showed that signal transduction from irradiated cells to bystander cells occur within a short time after irradiation. We then studied the effects of ROS (reactive oxygen species)-scavenging catechins in the medium before irradiation. We observed decreases in the percentage of bystander cells with MN formation and thus proved the protection effect of catechins on bystander cells from radiation.

  12. Real-time Molecular Study of Bystander Effects of Low dose Low LET radiation Using Living Cell Imaging and Nanoparticale Optics

    Energy Technology Data Exchange (ETDEWEB)

    Natarajan, Mohan [UT Health Science Center at San Antonio; Xu, Nancy R [Old Dominion University; Mohan, Sumathy [UT Health Science Center at San Antonio

    2013-06-03

    In this study two novel approaches are proposed to investigate precisely the low dose low LET radiation damage and its effect on bystander cells in real time. First, a flow shear model system, which would provide us a near in vivo situation where endothelial cells in the presence of extra cellular matrix experiencing continuous flow shear stress, will be used. Endothelial cells on matri-gel (simulated extra cellular matrix) will be subjected to physiological flow shear (that occurs in normal blood vessels). Second, a unique tool (Single nano particle/single live cell/single molecule microscopy and spectroscopy; Figure A) will be used to track the molecular trafficking by single live cell imaging. Single molecule chemical microscopy allows one to single out and study rare events that otherwise might be lost in assembled average measurement, and monitor many target single molecules simultaneously in real-time. Multi color single novel metal nanoparticle probes allow one to prepare multicolor probes (Figure B) to monitor many single components (events) simultaneously and perform multi-complex analysis in real-time. These nano-particles resist to photo bleaching and hence serve as probes for unlimited timeframe of analysis. Single live cell microscopy allows one to image many single cells simultaneously in real-time. With the combination of these unique tools, we will be able to study under near-physiological conditions the cellular and sub-cellular responses (even subtle changes at one molecule level) to low and very low doses of low LET radiation in real time (milli-second or nano-second) at sub-10 nanometer spatial resolution. This would allow us to precisely identify, at least in part, the molecular mediators that are responsible of radiation damage in the irradiated cells and the mediators that are responsible for initiating the signaling in the neighboring cells. Endothelial cells subjected to flow shear (2 dynes/cm2 or 16 dynes/cm2) and exposed to 0.1, 1 and 10

  13. Radiation-induced bystander effects in vivo are sex specific

    International Nuclear Information System (INIS)

    Koturbash, Igor; Kutanzi, Kristy; Hendrickson, Karl; Rodriguez-Juarez, Rocio; Kogosov, Dmitry; Kovalchuk, Olga

    2008-01-01

    Ionizing radiation (IR) effects span beyond the area of direct exposure and can be observed in neighboring and distant naive cells and organs. This phenomenon is termed a 'bystander effect'. IR effects in directly exposed tissue in vivo are epigenetically mediated and distinct in males and females. Yet, IR-induced bystander effects have never been explored in a sex-specificity domain. We used an in vivo mouse model, whereby the bystander effects are studied in spleen of male and female animals subjected to head exposure when the rest of the body is protected by a medical-grade lead shield. We analyzed the induction of DNA damage and alterations in global DNA methylation. Molecular parameters were correlated with cellular proliferation and apoptosis levels. The changes observed in bystander organs are compared to the changes in unexposed animals and animals exposed to predicted and measured scatter doses. We have found the selective induction of DNA damage levels, global DNA methylation, cell proliferation and apoptosis in exposed and bystander spleen tissue of male and female mice. Sex differences were significantly diminished in animals subjected to a surgical removal of gonads. These data constitute the first evidence of sex differences in radiation-induced bystander effects in mouse spleen in vivo. We show the role of sex hormones in spleen bystander responses and discuss implications of the observed changes

  14. Radiation-induced bystander effects in vivo are sex specific

    Energy Technology Data Exchange (ETDEWEB)

    Koturbash, Igor; Kutanzi, Kristy; Hendrickson, Karl; Rodriguez-Juarez, Rocio; Kogosov, Dmitry [Department of Biological Sciences, University of Lethbridge, Alberta T1K 3M4 (Canada); Kovalchuk, Olga [Department of Biological Sciences, University of Lethbridge, Alberta T1K 3M4 (Canada)], E-mail: olga.kovalchuk@uleth.ca

    2008-07-03

    Ionizing radiation (IR) effects span beyond the area of direct exposure and can be observed in neighboring and distant naive cells and organs. This phenomenon is termed a 'bystander effect'. IR effects in directly exposed tissue in vivo are epigenetically mediated and distinct in males and females. Yet, IR-induced bystander effects have never been explored in a sex-specificity domain. We used an in vivo mouse model, whereby the bystander effects are studied in spleen of male and female animals subjected to head exposure when the rest of the body is protected by a medical-grade lead shield. We analyzed the induction of DNA damage and alterations in global DNA methylation. Molecular parameters were correlated with cellular proliferation and apoptosis levels. The changes observed in bystander organs are compared to the changes in unexposed animals and animals exposed to predicted and measured scatter doses. We have found the selective induction of DNA damage levels, global DNA methylation, cell proliferation and apoptosis in exposed and bystander spleen tissue of male and female mice. Sex differences were significantly diminished in animals subjected to a surgical removal of gonads. These data constitute the first evidence of sex differences in radiation-induced bystander effects in mouse spleen in vivo. We show the role of sex hormones in spleen bystander responses and discuss implications of the observed changes.

  15. Radiation-induced bystander effects in vivo are sex specific.

    Science.gov (United States)

    Koturbash, Igor; Kutanzi, Kristy; Hendrickson, Karl; Rodriguez-Juarez, Rocio; Kogosov, Dmitry; Kovalchuk, Olga

    2008-07-03

    Ionizing radiation (IR) effects span beyond the area of direct exposure and can be observed in neighboring and distant naïve cells and organs. This phenomenon is termed a 'bystander effect'. IR effects in directly exposed tissue in vivo are epigenetically mediated and distinct in males and females. Yet, IR-induced bystander effects have never been explored in a sex-specificity domain. We used an in vivo mouse model, whereby the bystander effects are studied in spleen of male and female animals subjected to head exposure when the rest of the body is protected by a medical-grade lead shield. We analyzed the induction of DNA damage and alterations in global DNA methylation. Molecular parameters were correlated with cellular proliferation and apoptosis levels. The changes observed in bystander organs are compared to the changes in unexposed animals and animals exposed to predicted and measured scatter doses. We have found the selective induction of DNA damage levels, global DNA methylation, cell proliferation and apoptosis in exposed and bystander spleen tissue of male and female mice. Sex differences were significantly diminished in animals subjected to a surgical removal of gonads. These data constitute the first evidence of sex differences in radiation-induced bystander effects in mouse spleen in vivo. We show the role of sex hormones in spleen bystander responses and discuss implications of the observed changes.

  16. Regulation of early signaling and gene expression in the α-particle and bystander response of IMR-90 human fibroblasts

    Directory of Open Access Journals (Sweden)

    Hei Tom K

    2010-07-01

    Full Text Available Abstract Background The existence of a radiation bystander effect, in which non-irradiated cells respond to signals from irradiated cells, is well established. To understand early signaling and gene regulation in bystander cells, we used a bio-informatics approach, measuring global gene expression at 30 minutes and signaling pathways between 30 minutes and 4 hours after exposure to α-particles in IMR-90 fibroblasts. Methods We used whole human genome microarrays and real time quantitative PCR to measure and validate gene expression. Microarray analysis was done using BRB-Array Tools; pathway and ontology analyses were done using Ingenuity Pathway Analysis and PANTHER, respectively. We studied signaling in irradiated and bystander cells using immunoblotting and semi-quantitative image analysis. Results Gene ontology suggested signal transduction and transcriptional regulation responding 30 minutes after treatment affected cell structure, motility and adhesion, and interleukin synthesis. We measured time-dependent expression of genes controlled by the NF-κB pathway; matrix metalloproteinases 1 and 3; chemokine ligands 2, 3 and 5 and interleukins 1β, 6 and 33. There was an increased response of this set of genes 30 minutes after treatment and another wave of induction at 4 hours. We investigated AKT-GSK3β signaling and found both AKT and GSK3β are hyper-phosphorylated 30 minutes after irradiation and this effect is maintained through 4 hours. In bystander cells, a similar response was seen with a delay of 30 minutes. We proposed a network model where the observed decrease in phosphorylation of β-catenin protein after GSK3β dependent inactivation can trigger target gene expression at later times after radiation exposure Conclusions These results are the first to show that the radiation induced bystander signal induces a widespread gene expression response at 30 minutes after treatment and these changes are accompanied by modification of

  17. Bystander effects in unicellular organisms

    International Nuclear Information System (INIS)

    DeVeaux, Linda C.; Durtschi, Lynn S.; Case, Jonathan G.; Wells, Douglas P.

    2006-01-01

    Radiation-induced bystander effects have been seen in mammalian cells from diverse origins. These effects can be transmitted through the medium to cells not present at the time of irradiation. We have developed an assay for detecting bystander effects in the unicellular eukaryote, the fission yeast Schizosaccharomyces pombe. This assay allows maximal exposure of unirradiated cells to cells that have received electron beam irradiation. S. pombe cells were irradiated with 16-18 MeV electrons from a pulsed electron LINAC. When survival of the irradiated cells decreased to approximately 50%, forward-mutation to 2-deoxy-D-glucose resistance increased in the unirradiated bystander cells. Further increase in dose had no additional effect on this increase. In order to detect this response, it was necessary for the irradiated cell/unirradiated cell ratio to be high. Other cellular stresses, such as heat treatment, UV irradiation, and bleomycin exposure, also caused a detectable response in untreated cells grown with the treated cells. We discuss evolutionary implications of these results

  18. Bystander effects in unicellular organisms

    Energy Technology Data Exchange (ETDEWEB)

    DeVeaux, Linda C. [Idaho Accelerator Center, Campus Box 8263, Idaho State University, Pocatello, ID 83209 (United States) and Department of Biological Sciences, Campus Box 8007, Idaho State University, Pocatello, ID 83209 (United States)]. E-mail: develind@isu.edu; Durtschi, Lynn S. [Department of Biological Sciences, Campus Box 8007, Idaho State University, Pocatello, ID 83209 (United States); Case, Jonathan G. [Department of Physics, Campus Box 8106, Idaho State University, Pocatello, ID 83209 (United States); Wells, Douglas P. [Department of Physics, Campus Box 8106, Idaho State University, Pocatello, ID 83209 (United States)

    2006-05-11

    Radiation-induced bystander effects have been seen in mammalian cells from diverse origins. These effects can be transmitted through the medium to cells not present at the time of irradiation. We have developed an assay for detecting bystander effects in the unicellular eukaryote, the fission yeast Schizosaccharomyces pombe. This assay allows maximal exposure of unirradiated cells to cells that have received electron beam irradiation. S. pombe cells were irradiated with 16-18 MeV electrons from a pulsed electron LINAC. When survival of the irradiated cells decreased to approximately 50%, forward-mutation to 2-deoxy-D-glucose resistance increased in the unirradiated bystander cells. Further increase in dose had no additional effect on this increase. In order to detect this response, it was necessary for the irradiated cell/unirradiated cell ratio to be high. Other cellular stresses, such as heat treatment, UV irradiation, and bleomycin exposure, also caused a detectable response in untreated cells grown with the treated cells. We discuss evolutionary implications of these results.

  19. Bystander effects in unicellular organisms.

    Science.gov (United States)

    DeVeaux, Linda C; Durtschi, Lynn S; Case, Jonathan G; Wells, Douglas P

    2006-05-11

    Radiation-induced bystander effects have been seen in mammalian cells from diverse origins. These effects can be transmitted through the medium to cells not present at the time of irradiation. We have developed an assay for detecting bystander effects in the unicellular eukaryote, the fission yeast Schizosaccharomyces pombe. This assay allows maximal exposure of unirradiated cells to cells that have received electron beam irradiation. S. pombe cells were irradiated with 16-18 MeV electrons from a pulsed electron LINAC. When survival of the irradiated cells decreased to approximately 50%, forward-mutation to 2-deoxy-d-glucose resistance increased in the unirradiated bystander cells. Further increase in dose had no additional effect on this increase. In order to detect this response, it was necessary for the irradiated cell/unirradiated cell ratio to be high. Other cellular stresses, such as heat treatment, UV irradiation, and bleomycin exposure, also caused a detectable response in untreated cells grown with the treated cells. We discuss evolutionary implications of these results.

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

    Science.gov (United States)

    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.

  1. Expression profiles are different in carbon ion-irradiated normal human fibroblasts and their bystander cells

    International Nuclear Information System (INIS)

    Iwakawa, Mayumi; Hamada, Nobuyuki; Imadome, Kaori; Funayama, Tomoo; Sakashita, Testuya; Kobayashi, Yasuhiko; Imai, Takashi

    2008-01-01

    Evidence has accumulated that ionizing radiation induces biological effects in non-irradiated bystander cells having received signals from directly irradiated cells; however, energetic heavy ion-induced bystander response is incompletely characterized. Here we performed microarray analysis of irradiated and bystander fibroblasts in confluent cultures. To see the effects in bystander cells, each of 1, 5 and 25 sites was targeted with 10 particles of carbon ions (18.3 MeV/u, 103 keV/μm) using microbeams, where particles traversed 0.00026, 0.0013 and 0.0066% of cells, respectively. diated cells, cultures were exposed to 10% survival dose (D), 0.1D and 0.01D of corresponding broadbeams (108 keV/μm). Irrespective of the target numbers (1, 5 or 25 sites) and the time (2 or 6 h postirradiation), similar expression changes were observed in bystander cells. Among 874 probes that showed more than 1.5-fold changes in bystander cells, 25% were upregulated and the remainder downregulated. These included genes related to cell communication (PIK3C2A, GNA13, FN1, ANXA1 and IL1RAP), stress response (RAD23B, ATF4 and EIF2AK4) and cell cycle (MYCN, RBBP4 and NEUROG1). Pathway analysis revealed serial bystander activation of G protein/PI-3 kinase pathways. Instead, genes related to cell cycle or death (CDKN1A, GADD45A, NOTCH1 and BCL2L1), and cell communication (IL1B, TCF7 and ID1) were upregulated in irradiated cells, but not in bystander cells. Our results indicate different expression profiles in irradiated and bystander cells, and imply that intercellular signaling between irradiated and bystander cells activate intracellular signaling, leading to the transcriptional stress response in bystander cells

  2. Bystander Effects Induced by Continuous Low-Dose-Rate 125I Seeds Potentiate the Killing Action of Irradiation on Human Lung Cancer Cells In Vitro

    International Nuclear Information System (INIS)

    Chen, H.H.; Jia, R.F.; Yu, L.; Zhao, M.J.; Shao, C.L.; Cheng, W.Y.

    2008-01-01

    Purpose: To investigate bystander effects of low-dose-rate (LDR) 125 I seed irradiation on human lung cancer cells in vitro. Methods and Materials: A549 and NCI-H446 cell lines of differing radiosensitivity were directly exposed to LDR 125 I seeds irradiation for 2 or 4 Gy and then cocultured with nonirradiated cells for 24 hours. Induction of micronucleus (MN), γH2AX foci, and apoptosis were assayed. Results: After 2 and 4 Gy irradiation, micronucleus formation rate (MFR) and apoptotic rate of A549 and NCI-H446 cells were increased, and the MFR and apoptotic rate of NCI-H446 cells was 2.1-2.8 times higher than that of A549 cells. After coculturing nonirradiated bystander cells with 125 I seed irradiated cells for 24 hours, MFR and the mean number of γH2AX foci/cells of bystander A549 and NCI-H446 cells were similar and significantly higher than those of control (p 125 I seeds could induce bystander effects, which potentiate the killing action on tumor cells and compensate for the influence of nonuniform distribution of radiation dosage on therapeutic outcomes

  3. The key role of miR-21-regulated SOD2 in the medium-mediated bystander responses in human fibroblasts induced by α-irradiated keratinocytes.

    Science.gov (United States)

    Tian, Wenqian; Yin, Xiaoming; Wang, Longxiao; Wang, Jingdong; Zhu, Wei; Cao, Jianping; Yang, Hongying

    2015-10-01

    Radiation-induced bystander effect (RIBE) is well accepted in the radiation research field by now, but the underlying molecular mechanisms for better understanding this phenomenon caused by intercellular communication and intracellular signal transduction are still incomplete. Although our previous study has demonstrated an important role of miR-21 of unirradiated bystander cells in RIBEs, the direct evidence for the hypothesis that RIBE is epigenetically regulated is still limited and how miR-21 mediates RIBEs is unknown. Reactive oxygen species (ROS) have been demonstrated to be involved in RIBEs, however, the roles of anti-oxidative stress system of cells in RIBEs are unclear. Using transwell insert co-culture system, we investigated medium-mediated bystander responses in WS1 human fibroblasts after co-culture with HaCaT keratinocytes traversed by α-particles. Results showed that the ROS levels in unirradiated bystander WS1 cells were significantly elevated after 30min of co-culture, and 53BP1 foci, a surrogate marker of DNA damage, were obviously induced after 3h of co-culture. This indicates the occurrence of oxidative stress and DNA damage in bystander WS1 cells after co-culture with irradiated keratinocytes. Furthermore, the expression of miR-21 was increased in bystander WS1 cells, downregulation of miR-21 eliminated the bystander responses, overexpression of miR-21 alone could induce bystander-like oxidative stress and DNA damage in WS1 cells. These data indicate an important mediating role of miR-21 in RIBEs. In addition, MnSOD or SOD2 in WS1 cells was involved in the bystander effects, overexpression of SOD2 abolished the bystander oxidative stress and DNA damage, indicating that SOD2 was critical to the induction of RIBEs. Moreover, we found that miR-21 regulated SOD2, suggesting that miR-21 might mediate bystander responses through its regulation on SOD2. In conclusion, this study revealed a profound role of miR-21-regulated SOD2 of unirradiated WS1

  4. Bystander effect induced by radiotherapeutic doses in breast carcinoma cell line

    International Nuclear Information System (INIS)

    Zubiria, M.G.; Martinez, M.; Dodat, D.; Sanchez, G.; Casas, O.; Guerci, A.

    2008-01-01

    Full text: Bystander effect (BSE) refers to observed effects in cells that have not been directly crossed by radiation and which are near the radiated cells. It is suggested that different communication and signaling cellular pathways, such as gap junctions and the release of diverse clastogenics factors (reactive oxygen species and cytokines), take place in this phenomenon. Delayed Genomic Instability (GI) could be explained by means of BSE and it could be showed by the decrease of cloning efficiency, the increase of apoptosis, point mutations, and micronuclei frequency. The relevance of this phenomenon is discussed in the carcinogenic process. Besides, BSE is also important because of its impact on the present paradigm of the ionizing effect of radiation, essentially based on the Theory of the Target. The importance of this research in radiotherapy could be the optimization of the therapeutic effects of radiation. In the present study was evaluated the BSE in breast carcinoma cell line MCF-7 by the application of both techniques: Comet Assay (alkaline version) and Clonogenic Assay. Conclusions: ROS involvement in BSE was corroborated by Comet Assay in this cell line; ICM treatment decreased cloning efficiency, checked by Clonogenic Assay. This results are very important for the reconsideration of the current paradigm of Target Theory and its application in radiobiology. (author)

  5. Workplace mobbing and bystanders' helping behaviour towards victims: the role of gender, perceived responsibility and anticipated stigma by association.

    Science.gov (United States)

    Mulder, Roelie; Pouwelse, Mieneke; Lodewijkx, Hein; Bolman, Catherine

    2014-08-01

    We examined victims' perceived responsibility and bystanders' anticipated risk of being victimized themselves when others associate them with the victim (stigma by association, SBA) as possible antecedents of bystanders' helping behaviour towards a victim of workplace mobbing, and explored the effects of gender. Guided by the attribution model of social conduct (Weiner, 2006), a 2 × 2 vignette experiment was conducted. Participants were Dutch regional government employees (N = 161). Path analyses generally supported the hypotheses, but showed different results for women and men. In the strong (Vs. weak) responsibility condition, women reported less sympathy and more anger and men only more anger, which resulted in lower helping intention. Additionally, for men the results showed an unexpected direct positive effect of responsibility on helping intention. Furthermore, in the strong SBA condition, women and men reported more fear and men, unexpectedly, more anger. Consequently, helping intention decreased. The findings on gender are discussed in the context of social role theory, gender and emotion. Our findings suggest that to prevent and tackle mobbing, organizations and professionals should be aware of the attributional and emotional processes and gender differences in bystanders' helping behaviour. © 2013 International Union of Psychological Science.

  6. Bystander deixis

    DEFF Research Database (Denmark)

    Rijkhoff, Jan

    1998-01-01

    The purpose of this contribution is to discuss non-standard speech forms of Romani and other languages in the larger context of bystander deixis, a subcategory of social deixis. First I will propose a three-way classification of instances of bystander deixis and illustrate them with examples from...... Romani and several other languages across the globe. The second part is concerned with the contextual factors that must have a place in a discourse model that wants to be able to handle linguistic manifestations of bystander deixis. Due the fact that Romani has typically been used for in......-group communication, this language presents a particularly rich source of information in the area of secret languages and other forms of bystander deixis. Moreover, as is also made abundantly clear in this volume, many jargons, trade varieties, secret languages and other more or less non-standard speech varieties...

  7. Radiation-induced bystander effects in the Atlantic salmon (salmo salar L.) following mixed exposure to copper and aluminum combined with low-dose gamma radiation

    Energy Technology Data Exchange (ETDEWEB)

    Mothersill, Carmel; Seymour, Colin B. [McMaster University, Medical Physics and Applied Radiation Sciences Department, Hamilton, ON (Canada); Norwegian University of Life Sciences, Department of Plant and Environmental Sciences, Aas (Norway); Smith, Richard W. [McMaster University, Medical Physics and Applied Radiation Sciences Department, Hamilton, ON (Canada); Heier, Lene Soerlie; Teien, Hans-Christian; Land, Ole Christian; Oughton, Deborah; Salbu, Brit [Norwegian University of Life Sciences, Department of Plant and Environmental Sciences, Aas (Norway)

    2014-03-15

    Very little is known about the combined effects of low doses of heavy metals and radiation. However, such ''multiple stressor'' exposure is the reality in the environment. In the work reported in this paper, fish were exposed to cobalt 60 gamma irradiation with or without copper or aluminum in the water. Doses of radiation ranged from 4 to 75 mGy delivered over 48 or 6 h. Copper doses ranged from 10 to 80 μg/L for the same time period. The aluminum dose was 250 μg/L. Gills and skin were removed from the fish after exposure and explanted in tissue culture flasks for investigation of bystander effects of the exposures using a stress signal reporter assay, which has been demonstrated to be a sensitive indicator of homeostatic perturbations in cells. The results show complex synergistic interactions of radiation and copper. Gills on the whole produce more toxic bystander signals than skin, but the additivity scores show highly variable results which depend on dose and time of exposure. The impacts of low doses of copper and low doses of radiation are greater than additive, medium levels of copper alone have a similar level of effect of bystander signal toxicity to the low dose. The addition of radiation stress, however, produces clear protective effects in the reporters treated with skin-derived medium. Gill-derived medium from the same fish did not show protective effects. Radiation exposure in the presence of 80 μg/L led to highly variable results, which due to animal variation were not significantly different from the effect of copper alone. The results are stressor type, stressor concentration and time dependent. Clearly co-exposure to radiation and heavy metals does not always lead to simple additive effects. (orig.)

  8. Bystander effects: intercellular transmission of radiation damage signals

    Energy Technology Data Exchange (ETDEWEB)

    Little, J.B.; Azzam, E.I.; Toledo, S.M. de; Nagasawa, H

    2002-07-01

    Biological effects were examined in confluent cultures of fibroblasts and epithelial cells exposed to very low mean doses of alpha radiation, doses by which only 1-2% of the cells were actually traversed by an alpha particle. Enhanced frequencies of sister chromatid exchanges and HPRT mutations occurred in the non-irradiation, 'bystander' cells associated with a similar increase in the frequency of micronuclei, indicating the induction of DNA damage in these cells. In order to gain information concerning molecular pathways, changes in gene expression were examined in bystander cells by western analysis and in situ immunofluorescence staining. The expression levels of p53, p21 and MDM2 were significantly modulated in bystander cells: the damage signals leading to these changes were transmitted from irradiated to bystander cells by gap junction mediated intracellular communication. The bystander response was suppressed by incubation with superoxide dismutase as well as an inhibitor of NADPH oxidase, suggesting the effect may be mediated by oxidative stress. To examine other signalling pathways responsive to oxidative stress, the activation of stress-related kinases and their downstream transcription factors were analysed in bystander cells by western blotting and electrophoretic mobility shift assays: a 2-4 fold increase in the phosphorylation levels of JNK, EPK1/2, p90RSK, Elk-1 and ATF2 was observed. These changes were detected by 15 min after irradiation and persisted for at least 1 h. These findings indicate the activation of multiple signal transduction pathways in bystander cells, involving signals arising from the plasma membrane as well as from DNA damage. (author)

  9. Heavy-ion radiation induced bystander effect in mice

    Science.gov (United States)

    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.

  10. Evidence for induction of DNA double strand breaks in the bystander response to targeted soft X-rays in repair deficient CHO cells

    International Nuclear Information System (INIS)

    Kashino, Genro; Suzuki, Keiji; Prise, K.M.

    2005-01-01

    Evidence is accumulating that irradiated cells produce some signals which interact with non-exposed cells in the same population. Here, we analysed the mechanism of such a bystander effect from targeted cells to non-targeted cells. Firstly, in order to investigate the bystander effect in Chinese hamster ovary (CHO) cell lines we irradiated a single cell within a population and scored the formation of micronuclei. When a single nucleus in the population, of double strand break repair deficient xrs5 cells, was targeted with 1 Gy of Al-K soft X-rays, elevated numbers of micronuclei were induced in the neighbouring unirradiated cells. The induction of micronuclei was also observed when conditioned medium was transferred from irradiated to non-irradiated xrs5 cells. These results suggest that DNA double strand breaks are caused by factors secreted in the medium from irradiated cells. To clarify the involvements of radical species in the bystander response, cells were treated with 0.5%DMSO 1 hour before irradiation and then bystander effects were estimated in xrs5 cells. The results showed clearly that DMSO treatment during X-irradiation suppress the induction of micronuclei in bystander xrs5 cells, when conditioned medium was transferred from irradiated xrs5 cells. Therefore, it is suggested that radical species induced by ionizing radiation are important for producing bystander signals. (author)

  11. Moral Disengagement Among Bystanders to School Bullying

    DEFF Research Database (Denmark)

    Obermann, Marie-Louise

    2011-01-01

    This study examined the use of moral disengagement among children indirectly involved in bullying (bystanders). A sample of Danish adolescents (N = 660, M age 12.6 years) were divided into four groups depending on their bystander status: (a) outsiders, who did not experience bullying among...... their peers; (b) defenders, who were likely to help the victims in bullying episodes; (c) guilty bystanders, who did nothing to help bullied peers but felt guilty about it; and (d) unconcerned bystanders, who witnessed peers being bullied, without feeling responsible. Results indicated that, besides from...... active personal involvement in bullying others, being an unconcerned bystander to bullying also associates with moral disengagement. Unconcerned bystanders had significantly higher moral disengagement than guilty bystanders and defenders. Outsiders also showed significant higher disengagement than...

  12. Contribution of bystander effects in radiation induced genotoxicity

    International Nuclear Information System (INIS)

    Zhou, H.; Persaud, R.; Gillispie, J.; Randers-Pehrson, G.; Hei, T.K.; Suzuki, Masao

    2005-01-01

    The controversial use of a linear, no threshold extrapolation model for low dose risk assessment is based on the accepted dogma that the deleterious effects of ionizing radiation such as mutagenesis and carcinogenesis are attributable mainly to direct damage to DNA. However, this extrapolation was challenged by the recent reports on the bystander phenomenon. The bystander effect contributes to this debate by implying that the biological effects of low doses, where not all cells are traversed by a charged particle, are amplified by the transfer of factors to un-irradiated neighbors. This interested phenomenon implies that a linear extrapolation of risks from high to low doses may underestimate rather than over estimate low dose risks. Together with some radiation-induced phenomena such as adaptive response and genomic instability, the radiobiological response at low doses is likely to be a complex interplay among many factors. (author)

  13. Radiation Bystander Effects Mechanism

    Directory of Open Access Journals (Sweden)

    Shokohzaman Soleymanifard

    2009-06-01

    Full Text Available Introduction: Radiation Induced Bystander Effect (RIBE which cause radiation effects in non-irradiated cells, has challenged the principle according to which radiation traversal through the nucleus of a cell is necessary for producing biological responses. What is the mechanism of this phenomenon? To have a better understanding of this rather ambiguous concept substantial number of original and reviewed article were carefully examined. Results: Irradiated cells release molecules which can propagate in cell environment and/or transmit through gap junction intercellular communication. These molecules can reach to non-irradiated cells and transmit bystander signals. In many investigations, it has been confirmed that these molecules are growth factors, cytokines, nitric oxide and free radicals like reactive oxygen species (ROS. Transmission of by stander signal to neighboring cells persuades them to produce secondary growth factors which in their turn cause further cell injuries. Some investigators suggest, organelles other than nucleus (mitochondria and cell membrane are the origin of these signals.  There is another opinion which suggests double strand breaks (DSB are not directly generated in bystander cells, rather they are due to smaller damage like single strand breaks which accumulate and end up to DSB. Although bystander mechanisms have not been exactly known, it can be confirmed that multiple mechanisms and various pathways are responsible for this effect. Cell type, radiation type, experimental conditions and end points identify the dominant mechanism. Conclusion: Molecules and pathways which are responsible for RIBE, also cause systemic responses to other non-irradiation stresses. So RIBE is a kind of systemic stress or innate immune responses, which are performed by cell microenvironment. Irradiated cells and their signals are components of microenvironment for creating bystander effects.

  14. Spatially Fractionated Radiation Induces Cytotoxicity and Changes in Gene Expression in Bystander and Radiation Adjacent Murine Carcinoma Cells

    Science.gov (United States)

    Asur, Rajalakshmi S.; Sharma, Sunil; Chang, Ching-Wei; Penagaricano, Jose; Kommuru, Indira M.; Moros, Eduardo G.; Corry, Peter M.; Griffin, Robert J.

    2012-01-01

    Radiation-induced bystander effects have been extensively studied at low doses, since evidence of bystander induced cell killing and other effects on unirradiated cells were found to be predominant at doses up to 0.5 Gy. Therefore, few studies have examined bystander effects induced by exposure to higher doses of radiation, such as spatially fractionated radiation (GRID) treatment. In the present study, we evaluate the ability of GRID treatment to induce changes in GRID adjacent (bystander) regions, in two different murine carcinoma cell lines following exposure to a single irradiation dose of 10 Gy. Murine SCK mammary carcinoma cells and SCCVII squamous carcinoma cells were irradiated using a brass collimator to create a GRID pattern of nine circular fields 12 mm in diameter with a center-to-center distance of 18 mm. Similar to the typical clinical implementation of GRID, this is approximately a 50:50 ratio of direct and bystander exposure. We also performed experiments by irradiating separate cultures and transferring the medium to unirradiated bystander cultures. Clonogenic survival was evaluated in both cell lines to determine the occurrence of radiation-induced bystander effects. For the purpose of our study, we have defined bystander cells as GRID adjacent cells that received approximately 1 Gy scatter dose or unirradiated cells receiving conditioned medium from irradiated cells. We observed significant bystander killing of cells adjacent to the GRID irradiated regions compared to sham treated controls. We also observed bystander killing of SCK and SCCVII cells cultured in conditioned medium obtained from cells irradiated with 10 Gy. Therefore, our results confirm the occurrence of bystander effects following exposure to a high-dose of radiation and suggest that cell-to-cell contact is not required for these effects. In addition, the gene expression profile for DNA damage and cellular stress response signaling in SCCVII cells after GRID exposure was studied

  15. A Role for Bioelectric Effects in the Induction of Bystander Signals by Ionizing Radiation?

    Science.gov (United States)

    Mothersill, C.; Moran, G.; McNeill, F.; Gow, M.D.; Denbeigh, J.; Prestwich, W.; Seymour, C.B.

    2007-01-01

    The induction of “bystander effects” i.e. effects in cells which have not received an ionizing radiation track, is now accepted but the mechanisms are not completely clear. Bystander effects following high and low LET radiation exposure are accepted but mechanisms are still not understood. There is some evidence for a physical component to the signal. This paper tests the hypothesis that bioelectric or biomagnetic phenomena are involved. Human immortalized skin keratinocytes and primary explants of mouse bladder and fish skin, were exposed directly to ionizing radiation or treated in a variety of bystander protocols. Exposure of cells was conducted by shielding one group of flasks using lead, to reduce the dose below the threshold of 2mGy 60Cobalt gamma rays established for the bystander effect. The endpoint for the bystander effect in the reporter system used was reduction in cloning efficiency (RCE). The magnitude of the RCE was similar in shielded and unshielded flasks. When cells were placed in a Faraday cage the magnitude of the RCE was less but not eliminated. The results suggest that liquid media or cell-cell contact transmission of bystander factors may be only part of the bystander mechanism. Bioelectric or bio magnetic fields may have a role to play. To test this further, cells were placed in a Magnetic Resonance Imaging (MRI) machine for 10min using a typical head scan protocol. This treatment also induced a bystander response. Apart from the obvious clinical relevance, the MRI results further suggest that bystander effects may be produced by non-ionizing exposures. It is concluded that bioelectric or magnetic effects may be involved in producing bystander signaling cascades commonly seen following ionizing radiation exposure. PMID:18648606

  16. Differential Bystander Signaling Between Radioresistant Chondrosarcoma Cells and Fibroblasts After X-Ray, Proton, Iron Ion and Carbon Ion Exposures

    Energy Technology Data Exchange (ETDEWEB)

    Wakatsuki, Masaru, E-mail: wa@mbe.nifty.com [Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba (Japan); Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts (United States); Magpayo, Nicole; Kawamura, Hidemasa; Held, Kathryn D. [Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts (United States)

    2012-09-01

    Purpose: Chondrosarcoma is well known as a radioresistant tumor, but the mechanisms underlying that resistance are still unclear. The bystander effect is well documented in the field of radiation biology. We investigated the bystander response induced by X-rays, protons, carbon ions, and iron ions in chondrosarcoma cells using a transwell insert co-culture system that precludes physical contact between targeted and bystander cells. Methods and Materials: Human chondrosarcoma cells were irradiated with 0.1-, 0.5-, 1-, and 2-Gy X-rays, protons, carbon ions or iron ions using a transwell insert co-culture system. Formation of micronuclei and p53 binding protein 1 staining in bystander and irradiated cells were analyzed and bystander signaling between mixed cultures of chondrosarcoma cells, and normal human skin fibroblasts was investigated. Results: In this study, we show that the fraction of cells with DNA damages in irradiated chondrosarcoma cells showed dose-dependent increases with all beams. However, the fraction of cells with DNA damages in all bystander chondrosarcoma cells did not show any change from the levels in control cells. In the bystander signaling between mixed cultures of chondrosarcoma cells and fibroblasts, the amount of micronucleus formation in all bystander chondrosarcoma cells co-cultured with irradiated fibroblasts were the same as the levels for control cells. However, all bystander fibroblasts co-cultured with irradiated chondrosarcoma cells showed significant increases in the fraction of micronucleated cells compared to the rate of control cells. Conclusions: We conclude that chondrosarcoma cells in the transwell insert co-culture system could release bystander stimulations but could not develop bystander responses.

  17. Differential Bystander Signaling Between Radioresistant Chondrosarcoma Cells and Fibroblasts After X-Ray, Proton, Iron Ion and Carbon Ion Exposures

    International Nuclear Information System (INIS)

    Wakatsuki, Masaru; Magpayo, Nicole; Kawamura, Hidemasa; Held, Kathryn D.

    2012-01-01

    Purpose: Chondrosarcoma is well known as a radioresistant tumor, but the mechanisms underlying that resistance are still unclear. The bystander effect is well documented in the field of radiation biology. We investigated the bystander response induced by X-rays, protons, carbon ions, and iron ions in chondrosarcoma cells using a transwell insert co-culture system that precludes physical contact between targeted and bystander cells. Methods and Materials: Human chondrosarcoma cells were irradiated with 0.1-, 0.5-, 1-, and 2-Gy X-rays, protons, carbon ions or iron ions using a transwell insert co-culture system. Formation of micronuclei and p53 binding protein 1 staining in bystander and irradiated cells were analyzed and bystander signaling between mixed cultures of chondrosarcoma cells, and normal human skin fibroblasts was investigated. Results: In this study, we show that the fraction of cells with DNA damages in irradiated chondrosarcoma cells showed dose-dependent increases with all beams. However, the fraction of cells with DNA damages in all bystander chondrosarcoma cells did not show any change from the levels in control cells. In the bystander signaling between mixed cultures of chondrosarcoma cells and fibroblasts, the amount of micronucleus formation in all bystander chondrosarcoma cells co-cultured with irradiated fibroblasts were the same as the levels for control cells. However, all bystander fibroblasts co-cultured with irradiated chondrosarcoma cells showed significant increases in the fraction of micronucleated cells compared to the rate of control cells. Conclusions: We conclude that chondrosarcoma cells in the transwell insert co-culture system could release bystander stimulations but could not develop bystander responses.

  18. Experimental verification for in vitro technique confirmation of bystander effect induced by gamma radiation in CHO-K1 cell line

    International Nuclear Information System (INIS)

    Viana, P.H.L.; Goes, A.M.; Gomes, D.A.

    2013-01-01

    The bystander effect refers to biological responses detected in cells not directly irradiated but influenced, somehow, by signals transmitted from neighboring irradiated cells. These biological responses include sister chromatid exchange, mutations, micronucleus formation, chromosomal aberrations, carcinogenesis, apoptosis and necrosis. Although its existence is unquestionable, the mechanisms involved on triggering the bystander effect are not yet completely elucidated. Previous studies have shown that the bystander effect depends on a large variety of parameters including the radiation dose, the dose rate, the type of radiation and type of cells or tissue. This study aims to confirm the technique previously used in the literature in human cell lines for the bystander effect verification. The results suggest that the working conditions adopted by the group show technical efficiency and enables the reproduction of the bystander effect. (author)

  19. Detection of chromosomal instability in α-irradiated and bystander human fibroblasts

    International Nuclear Information System (INIS)

    Ponnaiya, Brian; Jenkins-Baker, Gloria; Bigelow, Alan; Marino, Stephen; Geard, Charles R.

    2004-01-01

    There is increasing evidence biological responses to ionizing radiation are not confined to those cells that are directly hit, but may be seen in the progeny at subsequent generations (genomic instability) and in non-irradiated neighbors of irradiated cells (bystander effects). These so called non-targeted phenomena would have significant contributions to radiation-induced carcinogenesis, especially at low doses where only a limited number of cells in a population are directed hit. Here we present data using a co-culturing protocol examining chromosomal instability in α-irradiated and bystander human fibroblasts BJ1-htert. At the first cell division following exposure to 0.1 and 1 Gy α-particles, irradiated populations demonstrated a dose dependent increase in chromosome-type aberrations. At this time bystander BJ1-htert populations demonstrated elevated chromatid-type aberrations when compared to controls. Irradiated and bystander populations were also analyzed for chromosomal aberrations as a function of time post-irradiation. When considered over 25 doublings, all irradiated and bystander populations had significantly higher frequencies of chromatid aberrations when compared to controls (2-3-fold over controls) and were not dependent on dose. The results presented here support the link between the radiation-induced phenomena of genomic instability and the bystander effect

  20. Nitric oxide mediated DNA double strand breaks induced in proliferating bystander cells after {alpha}-particle irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Han Wei [Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong (Hong Kong); Chen Shaopeng [Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong (Hong Kong); Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, Hefei 230031 (China); Yu, K.N., E-mail: peter.yu@cityu.edu.hk [Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong (Hong Kong); Wu Lijun [Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, Hefei 230031 (China)

    2010-02-03

    Low-dose {alpha}-particle exposures comprise 55% of the environmental dose to the human population and have been shown to induce bystander responses. Previous studies showed that bystander effect could induce stimulated cell growth or genotoxicity, such as excessive DNA double strand breaks (DSBs), micronuclei (MN), mutation and decreased cell viability, in the bystander cell population. In the present study, the stimulated cell growth, detected with flow cytometry (FCM), and the increased MN and DSB, detected with p53 binding protein 1 (53BP1) immunofluorescence, were observed simultaneously in the bystander cell population, which were co-cultured with cells irradiated by low-dose {alpha}-particles (1-10 cGy) in a mixed system. Further studies indicated that nitric oxide (NO) and transforming growth factor {beta}1 (TGF-{beta}1) played very important roles in mediating cell proliferation and inducing MN and DSB in the bystander population through treatments with NO scavenger and TGF-{beta}1 antibody. Low-concentrations of NO, generated by spermidine, were proved to induce cell proliferation, DSB and MN simultaneously. The proliferation or shortened cell cycle in bystander cells gave them insufficient time to repair DSBs. The increased cell division might increase the probability of carcinogenesis in bystander cells since cell proliferation increased the probability of mutation from the mis-repaired or un-repaired DSBs.

  1. Nitric oxide mediated DNA double strand breaks induced in proliferating bystander cells after α-particle irradiation

    International Nuclear Information System (INIS)

    Han Wei; Chen Shaopeng; Yu, K.N.; Wu Lijun

    2010-01-01

    Low-dose α-particle exposures comprise 55% of the environmental dose to the human population and have been shown to induce bystander responses. Previous studies showed that bystander effect could induce stimulated cell growth or genotoxicity, such as excessive DNA double strand breaks (DSBs), micronuclei (MN), mutation and decreased cell viability, in the bystander cell population. In the present study, the stimulated cell growth, detected with flow cytometry (FCM), and the increased MN and DSB, detected with p53 binding protein 1 (53BP1) immunofluorescence, were observed simultaneously in the bystander cell population, which were co-cultured with cells irradiated by low-dose α-particles (1-10 cGy) in a mixed system. Further studies indicated that nitric oxide (NO) and transforming growth factor β1 (TGF-β1) played very important roles in mediating cell proliferation and inducing MN and DSB in the bystander population through treatments with NO scavenger and TGF-β1 antibody. Low-concentrations of NO, generated by spermidine, were proved to induce cell proliferation, DSB and MN simultaneously. The proliferation or shortened cell cycle in bystander cells gave them insufficient time to repair DSBs. The increased cell division might increase the probability of carcinogenesis in bystander cells since cell proliferation increased the probability of mutation from the mis-repaired or un-repaired DSBs.

  2. Signaling factors and pathways of α-particle irradiation induced bilateral bystander responses between Beas-2B and U937 cells

    International Nuclear Information System (INIS)

    Fu, Jiamei; Wang, Juan; Wang, Xiangdong; Wang, Ping; Xu, Jinping; Zhou, Cuiping; Bai, Yang; Shao, Chunlin

    2016-01-01

    Highlights: • Radiation damage of Beas-2B cells was enhanced by macrophage-mediated bilateral bystander responses. • Expressions of TNF-α and IL-8 in the α-irradiated Beas-2B cells were dependent on ERK and p38 pathways. • The neighboring U937 cells further increased the generation of TNF-α and IL-8 in the α-irradiated Beas-2B cells. • NF-κB dependent upregulation of TNF-α and IL-8 was induced in the bystander U937 cells. - Abstract: Although radiation induced bystander effects (RIBE) have been investigated for decades for their potential health risk, the underlying gene regulation is still largely unclear, especially the roles of immune system and inflammatory response in RIBE. In the present study, macrophage U937 cells and epithelial Beas-2B cells were co-cultured to disclose the cascades of bystander signaling factors and intercellular communications. After α-particle irradiation, both ERK and p38 pathways were activated in Beas-2B cells and were associated with the autocrine and paracrine signaling of TNF-α and IL-8, resulting in direct damage to the irradiated cells. Similar upregulation of TNF-α and IL-8 was induced in the bystander U937 cells after co-culture with α-irradiated Beas-2B cells. This upregulation was dependent on the activation of NF-κB pathway and was responsible for the enhanced damage of α-irradiated Beas-2B cells. Interestingly, the increased expressions of TNF-α and IL-8 mRNAs in the bystander U937 cells were clearly relayed on the activated ERK and p38 pathways in the irradiated Beas-2B cells, and the upregulation of TNF-α and IL-8 mRNAs in co-cultured Beas-2B cells was also partly due to the activated NF-κB pathway in the bystander U937 cells. With the pretreatment of U0126 (MEK1/2 inhibitor), SB203580 (p38 inhibitor) or BAY 11-7082 (NF-κB inhibitor), the aggravated damage in the α-irradiated Beas-2B cells could be largely alleviated. Our results disclosed novel signaling cascades of macrophage-mediated bilateral

  3. Signaling factors and pathways of α-particle irradiation induced bilateral bystander responses between Beas-2B and U937 cells

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Jiamei; Wang, Juan; Wang, Xiangdong; Wang, Ping; Xu, Jinping; Zhou, Cuiping; Bai, Yang; Shao, Chunlin, E-mail: clshao@shmu.edu.cn

    2016-07-15

    Highlights: • Radiation damage of Beas-2B cells was enhanced by macrophage-mediated bilateral bystander responses. • Expressions of TNF-α and IL-8 in the α-irradiated Beas-2B cells were dependent on ERK and p38 pathways. • The neighboring U937 cells further increased the generation of TNF-α and IL-8 in the α-irradiated Beas-2B cells. • NF-κB dependent upregulation of TNF-α and IL-8 was induced in the bystander U937 cells. - Abstract: Although radiation induced bystander effects (RIBE) have been investigated for decades for their potential health risk, the underlying gene regulation is still largely unclear, especially the roles of immune system and inflammatory response in RIBE. In the present study, macrophage U937 cells and epithelial Beas-2B cells were co-cultured to disclose the cascades of bystander signaling factors and intercellular communications. After α-particle irradiation, both ERK and p38 pathways were activated in Beas-2B cells and were associated with the autocrine and paracrine signaling of TNF-α and IL-8, resulting in direct damage to the irradiated cells. Similar upregulation of TNF-α and IL-8 was induced in the bystander U937 cells after co-culture with α-irradiated Beas-2B cells. This upregulation was dependent on the activation of NF-κB pathway and was responsible for the enhanced damage of α-irradiated Beas-2B cells. Interestingly, the increased expressions of TNF-α and IL-8 mRNAs in the bystander U937 cells were clearly relayed on the activated ERK and p38 pathways in the irradiated Beas-2B cells, and the upregulation of TNF-α and IL-8 mRNAs in co-cultured Beas-2B cells was also partly due to the activated NF-κB pathway in the bystander U937 cells. With the pretreatment of U0126 (MEK1/2 inhibitor), SB203580 (p38 inhibitor) or BAY 11-7082 (NF-κB inhibitor), the aggravated damage in the α-irradiated Beas-2B cells could be largely alleviated. Our results disclosed novel signaling cascades of macrophage-mediated bilateral

  4. BYSTANDER EFFECTS, GENOMIC INSTABILITY, ADAPTIVE RESPONSE AND CANCER RISK ASSESSMENT FOR RADIATION AND CHEMICAL EXPOSURES

    Science.gov (United States)

    There is an increased interest in utilizing mechanistic data in support of the cancer risk assessment process for ionizing radiation and environmental chemical exposures. In this regard the use of biologically based dose-response models is particularly advocated. The aim is to pr...

  5. Experimental verification for in vitro technique confirmation of bystander effect induced by gamma radiation in CHO-K1 cell line; Verificacao experimental para confirmacao da tecnica in vitro do efeito bystander induzido por radiacao gama na linhagem celular CHO-K1

    Energy Technology Data Exchange (ETDEWEB)

    Viana, P.H.L.; Goes, A.M.; Gomes, D.A., E-mail: pedroleroybio@hotmail.com [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Departamento Bioquimica e Imunologia. Lab. de Imunologia Celular e Molecular; Grynberg, S.E., E-mail: seg@cdtn.br [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil)

    2013-08-15

    The bystander effect refers to biological responses detected in cells not directly irradiated but influenced, somehow, by signals transmitted from neighboring irradiated cells. These biological responses include sister chromatid exchange, mutations, micronucleus formation, chromosomal aberrations, carcinogenesis, apoptosis and necrosis. Although its existence is unquestionable, the mechanisms involved on triggering the bystander effect are not yet completely elucidated. Previous studies have shown that the bystander effect depends on a large variety of parameters including the radiation dose, the dose rate, the type of radiation and type of cells or tissue. This study aims to confirm the technique previously used in the literature in human cell lines for the bystander effect verification. The results suggest that the working conditions adopted by the group show technical efficiency and enables the reproduction of the bystander effect. (author)

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

    Science.gov (United States)

    Lorimore, S A; Wright, E G

    2003-01-01

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

  7. Genomic instability induced in distant progeny of bystander cells depends on the connexins expressed in the irradiated cells.

    Science.gov (United States)

    de Toledo, Sonia M; Buonanno, Manuela; Harris, Andrew L; Azzam, Edouard I

    2017-10-01

    damage. In response to moderate doses from either sparsely or densely ionizing radiations, toxic and protective effects are rapidly communicated to bystander cells through gap junctions. We infer that bystander cells damaged by the initial co-culture (expressing Cx26 or Cx43) die or undergo proliferative arrest, but that the bystander cells that were initially protected (expressing Cx32) express DNA damage upon sequential passaging. Together, the results inform the roles that intercellular communication play under stress conditions, and aid assessment of the health risks of exposure to ionizing radiation. Identification of the communicated molecules may enhance the efficacy of radiotherapy and help attenuate its debilitating side-effects.

  8. Bystander effect: Biological endpoints and microarray analysis

    Energy Technology Data Exchange (ETDEWEB)

    Chaudhry, M. Ahmad [Department of Medical Laboratory and Radiation Sciences, College of Nursing and Health Sciences, University of Vermont, 302 Rowell Building, Burlington, VT 05405 (United States) and DNA Microarray Facility, University of Vermont, Burlington, VT 05405 (United States)]. E-mail: mchaudhr@uvm.edu

    2006-05-11

    In cell populations exposed to ionizing radiation, the biological effects occur in a much larger proportion of cells than are estimated to be traversed by radiation. It has been suggested that irradiated cells are capable of providing signals to the neighboring unirradiated cells resulting in damage to these cells. This phenomenon is termed the bystander effect. The bystander effect induces persistent, long-term, transmissible changes that result in delayed death and neoplastic transformation. Because the bystander effect is relevant to carcinogenesis, it could have significant implications for risk estimation for radiation exposure. The nature of the bystander effect signal and how it impacts the unirradiated cells remains to be elucidated. Examination of the changes in gene expression could provide clues to understanding the bystander effect and could define the signaling pathways involved in sustaining damage to these cells. The microarray technology serves as a tool to gain insight into the molecular pathways leading to bystander effect. Using medium from irradiated normal human diploid lung fibroblasts as a model system we examined gene expression alterations in bystander cells. The microarray data revealed that the radiation-induced gene expression profile in irradiated cells is different from unirradiated bystander cells suggesting that the pathways leading to biological effects in the bystander cells are different from the directly irradiated cells. The genes known to be responsive to ionizing radiation were observed in irradiated cells. Several genes were upregulated in cells receiving media from irradiated cells. Surprisingly no genes were found to be downregulated in these cells. A number of genes belonging to extracellular signaling, growth factors and several receptors were identified in bystander cells. Interestingly 15 genes involved in the cell communication processes were found to be upregulated. The induction of receptors and the cell

  9. Bystander effect: Biological endpoints and microarray analysis

    International Nuclear Information System (INIS)

    Chaudhry, M. Ahmad

    2006-01-01

    In cell populations exposed to ionizing radiation, the biological effects occur in a much larger proportion of cells than are estimated to be traversed by radiation. It has been suggested that irradiated cells are capable of providing signals to the neighboring unirradiated cells resulting in damage to these cells. This phenomenon is termed the bystander effect. The bystander effect induces persistent, long-term, transmissible changes that result in delayed death and neoplastic transformation. Because the bystander effect is relevant to carcinogenesis, it could have significant implications for risk estimation for radiation exposure. The nature of the bystander effect signal and how it impacts the unirradiated cells remains to be elucidated. Examination of the changes in gene expression could provide clues to understanding the bystander effect and could define the signaling pathways involved in sustaining damage to these cells. The microarray technology serves as a tool to gain insight into the molecular pathways leading to bystander effect. Using medium from irradiated normal human diploid lung fibroblasts as a model system we examined gene expression alterations in bystander cells. The microarray data revealed that the radiation-induced gene expression profile in irradiated cells is different from unirradiated bystander cells suggesting that the pathways leading to biological effects in the bystander cells are different from the directly irradiated cells. The genes known to be responsive to ionizing radiation were observed in irradiated cells. Several genes were upregulated in cells receiving media from irradiated cells. Surprisingly no genes were found to be downregulated in these cells. A number of genes belonging to extracellular signaling, growth factors and several receptors were identified in bystander cells. Interestingly 15 genes involved in the cell communication processes were found to be upregulated. The induction of receptors and the cell

  10. Bystander-mediated genomic instability after high LET radiation in murine primary haemopoietic stem cells

    International Nuclear Information System (INIS)

    Bowler, Deborah A.; Moore, Stephen R.; Macdonald, Denise A.; Smyth, Sharon H.; Clapham, Peter; Kadhim, Munira A.

    2006-01-01

    Communication between irradiated and unirradiated (bystander) cells can result in responses in unirradiated cells that are similar to responses in their irradiated counterparts. The purpose of the current experiment was to test the hypothesis that bystander responses will be similarly induced in primary murine stem cells under different cell culture conditions. The experimental systems used here, co-culture and media transfer, are similar in that they both restrict communication between irradiated and bystander cells to media borne factors, but are distinct in that with the media transfer technique, cells can only communicate after irradiation, and with co-culture, cells can communication before, during and after irradiation. In this set of parallel experiments, cell type, biological endpoint, and radiation quality and dose, were kept constant. In both experimental systems, clonogenic survival was significantly decreased in all groups, whether irradiated or bystander, suggesting a substantial contribution of bystander effects (BE) to cell killing. Genomic instability (GI) was induced under all radiation and bystander conditions in both experiments, including a situation where unirradiated cells were incubated with media that had been conditioned for 24 h with irradiated cells. The appearance of delayed aberrations (genomic instability) 10-13 population doublings after irradiation was similar to the level of initial chromosomal damage, suggesting that the bystander factor is able to induce chromosomal alterations soon after irradiation. Whether these early alterations are related to those observed at later timepoints remains unknown. These results suggest that genomic instability may be significantly induced in a bystander cell population whether or not cells communicate during irradiation

  11. Bystander effects in radiotherapy of non-small cell lung cancer

    International Nuclear Information System (INIS)

    McKenzie, D.R.

    2011-01-01

    Full text: School of Physics, The University of Sydney, Australia Objectives The bystander effect causes a response in unirradiated cells that are in communication with cells that receive a radiation dose. In recent work we have shown that there are 3 types bystander effect and that the expression of these effects follows a Ii course. The aim of this work is to identify the conditions for the three types of bystander effects in radiotherapy of non-small cell II cancer. A human non small cell lung cancer cell line (NCI-H460) was irradiated with a 6 MV photon beam produced from a Varian I i near accelerator to doses of 2, 4, 6 and 8 Gy. These cells v termed donor cells. At selected time intervals after exposure (5,15 and 60 min), the medium was transferred to receiver cells of the cell line in separate flasks. The clonogenic survival fraction of the receiver cells was determined following 5 days of incubation comparing cells receiving transfer of medium from exposed cells to cell receiving transfer from sham exposed cells. The experimental design controlled for the density of cells in the donor flask, the e of irradiation on the medium alone and on the donor cell metabolites. The results show a strong time course for the bystander signal expression, which is dependent on the density of cells in the donor receiver flasks. Sub lethal doses of radiation resulted in a proliferative response at short time intervals after exposure [15 min] but a toxic response when medium transfer was carried out after 60 min. A higher cell density in the donor flasks produces an increased response in the receiver flasks for the same volume of medium transferred. The latter response corresponds to Bystander Effect type 1 in which a reduced survival is observed in cells receiving medium from cells that receive a high but not lethal dose. The proliferative response, corresponding to Bystander Effect type 3 is more general and is not strongly dependent on dose. Following a lethal dose of

  12. Relationship between P53 and bystander effect induced by radiated hepatoma cells

    International Nuclear Information System (INIS)

    Zhao Meijia; Shen Bo; Yuan Dexiao; Cheng Honghong; Shao Chunlin

    2009-01-01

    The role of p53 in bystander responses on normal liver cells were investigated by co-culturing irradiated hepatoma cells with non-irradiated bystander Chang liver cells. It was found that radiosensitivity of the hepatoma cells was relative to p53. HepG2 cells with wtp53 had the highest radiosensitivity followed by PLC/PRF/5 cells with mtp53 and Hep3B cells with null-p53. The induction of bystander micronucleus(MN) was observed only in the Chang liver cells that had been co-cultured with HepG2 cells but not co-cultured with PLC/PRF/5 or Hep3B. Also, this bystander MN was relative to the irradiation dose and the cell co-culture rime. When the hepatoma cells were treated with pifithrin-α, a p53 inhibitor, their radiosensitivities were reduced, and the bystander effect was diminished. The results indicate that p53 could regulate not only the radiosensitivity but also the bystander response. (authors)

  13. Advanced Computational Approaches for Characterizing Stochastic Cellular Responses to Low Dose, Low Dose Rate Exposures

    Energy Technology Data Exchange (ETDEWEB)

    Scott, Bobby, R., Ph.D.

    2003-06-27

    applications of NEOTRANS2, indicate that nonlinear threshold-type, dose-response relationships for excess stochastic effects (problematic nonlethal mutations, neoplastic transformation) should be expected after exposure to low linear energy transfer (LET) gamma rays or gamma rays in combination with high-LET alpha radiation. Similar thresholds are expected for low-dose-rate low-LET beta irradiation. We attribute the thresholds to low-dose, low-LET radiation induced protection against spontaneous mutations and neoplastic transformations. The protection is presumed mainly to involve selective elimination of problematic cells via apoptosis. Low-dose, low-LET radiation is presumed to trigger wide-area cell signaling, which in turn leads to problematic bystander cells (e.g., mutants, neoplastically transformed cells) selectively undergoing apoptosis. Thus, this protective bystander effect leads to selective elimination of problematic cells (a tissue cleansing process in vivo). However, this protective bystander effects is a different process from low-dose stimulation of the immune system. Low-dose, low-LET radiation stimulation of the immune system may explain why thresholds for inducing excess cancer appear much larger (possibly more than 100-fold larger) than thresholds for inducing excess mutations and neoplastic transformations, when the dose rate is low. For ionizing radiation, the current risk assessment paradigm is such that the relative risk (RR) is always ¡Ý 1, no matter how small the dose. Our research results indicate that for low-dose or low-dose-rate, low-LET irradiation, RR < 1 may be more the rule than the exception. Directly tied to the current RR paradigm are the billion-dollar cleanup costs for radionuclide-contaminated DOE sites. Our research results suggest that continued use of the current RR paradigm for which RR ¡Ý 1 could cause more harm than benefit to society (e.g., by spreading unwarranted fear about phantom excess risks associated with low-dose low

  14. Bystander effect in human hepatoma HepG2 cells caused by medium transfers at different times after high-LET carbon ion irradiation

    International Nuclear Information System (INIS)

    Wu Qingfeng; Li Qiang; Jin Xiaodong; Liu Xinguo; Dai Zhongying

    2011-01-01

    Although radiation-induced bystander effects have been well documented in a variety of biological systems, whether irradiated cells have the ability to generate bystander signaling persistently is still unclear and the clinical relevance of bystander effects in radiotherapy remains to be elucidated. This study examines tumor cellular bystander response to autologous medium from cell culture irradiated with high-linear energy transfer (LET) heavy ions at a therapeutically relevant dose in terms of clonogenic cell survival. In vitro experiments were performed using human hepatoma HepG2 cell line exposed to 100 keV/μm carbon ions at a dose of 2 Gy. Two different periods (2 and 12 h) after irradiation, irradiated cell conditioned medium (ICCM) and replenished fresh medium were harvested and then transferred to unirradiated bystander cells. Cellular bystander responses were measured with the different medium transfer protocols. Significant higher survival fractions of unirradiated cells receiving the media from the irradiated cultures at the different times post-irradiation than those of the control were observed. Even replenishing fresh medium for unirradiated cells which had been exposed to the ICCM for 12 h could not prevent the bystander cells from the increased survival fraction. These results suggest that the irradiated cells could release unidentified signal factor(s), which induced the increase in survival fraction for the unirradiated bystander cells, into the media sustainedly and the carbon ions triggered a cascade of signaling events in the irradiated cells rather than secreting the soluble signal factor(s) just at a short period after irradiation. Based on the observations in this study, the importance of bystander effect in clinical radiotherapy was discussed and incorporating the bystander effect into the current radiobiological models, which are applicable to heavy ion radiotherapy, is needed urgently.

  15. Model of avascular tumor growth and response to low dose exposure

    International Nuclear Information System (INIS)

    Rodriguez Aguirre, J M; Custidiano, E R

    2011-01-01

    A single level cellular automata model is described and used to simulate early tumor growth, and the response of the tumor cells under low dose radiation affects. In this model the cell cycle of the population of normal and cancer cells is followed. The invasion mechanism of the tumor is simulated by a local factor that takes into account the microenvironment hardness to cell development, in a picture similar to the AMTIH model. The response of normal and cancer cells to direct effects of radiation is tested for various models and a model of bystander response is implemented.

  16. An investigation of bystander effects in Schizosaccharomyces pombe

    International Nuclear Information System (INIS)

    DeVeaux, L.C.; Wells, D.P.; Durtschi, L.S.; Reda, M.; Frujinoiu, C.; Harmon, F.

    2003-01-01

    Full text: 'Bystander' effects have been documented in various mammalian cell types and appear to act by two distinct mechanisms. One response requires a functional gap-junction. A non gap-junction-mediated response has also been observed in human cell lines, indicating release of a signaling factor. No analogous response has been investigated in unicellular organisms. Given that DNA damage signaling pathways are present in simple eukaryotes, we investigated bystander signaling effects using a single-celled organism, the fission yeast Schizosaccharomyces pombe. This organism may provide a much simpler model system than higher eukaryotic cells for studying these effects. We measured survival and mutation rate in an unirradiated culture after exposure to an irradiated culture. These two cultures were mixed immediately after irradiation, and any signaling factor that was produced had direct and continuous access to the unirradiated cells during subsequent cell divisions. The irradiated culture was from a multiply auxotrophic strain, whereas the unirradiated culture was from a prototrophic strain. Surviving colonies of the unirradiated culture were thus easily distinguished from those arising from irradiated cells. Mutation rates were measured as forward mutation to 2-deoxyglucose resistance. We have investigated bystander effects with electron and gamma dose from 6 to 20 MeV electron linacs. We varied electron beam energies, dose rates and temporal distributions of dose. The importance of this research stems from the fundamental evolutionary significance of cell signaling of any kind in unicellular systems, representing a major step toward the evolution of multi-cellular states

  17. Statistical and low dose response

    International Nuclear Information System (INIS)

    Thorson, M.R.; Endres, G.W.R.

    1981-01-01

    The low dose response and the lower limit of detection of the Hanford dosimeter depend upon may factors, including the energy of the radiation, whether the exposure is to be a single radiation or mixed fields, annealing cycles, environmental factors, and how well various batches of TLD materials are matched in the system. A careful statistical study and sensitivity analysis were performed to determine how these factors influence the response of the dosimeter system. Estimates have been included in this study of the standard deviation of calculated dose for various mixed field exposures from 0 to 1000 mrem

  18. Dose response relationship and Alara

    International Nuclear Information System (INIS)

    Hubert, P.

    1986-09-01

    In this paper, it will be shown how dose-response relationships allow to give quantitative figures for the detriment of irradiation. At this stage, the detriment is expressed directly as a certain number of health effects, whose valuation is not dealt with here. The present tools for quantifying, their weaknesses and their strenghts, and their scientific basis will be developed

  19. Human Lung Cancer Risks from Radon – Part II – Influence from Combined Adaptive Response and Bystander Effects – A Microdose Analysis

    Science.gov (United States)

    Leonard, Bobby E.; Thompson, Richard E.; Beecher, Georgia C.

    2010-01-01

    In the prior Part I, the potential influence of the low level alpha radiation induced bystander effect (BE) on human lung cancer risks was examined. Recent analysis of adaptive response (AR) research results with a Microdose Model has shown that single low LET radiation induced charged particles traversals through the cell nucleus activates AR. We have here conducted an analysis based on what is presently known about adaptive response and the bystander effect (BE) and what new research is needed that can assist in the further evaluation human cancer risks from radon. We find that, at the UNSCEAR (2000) worldwide average human exposures from natural background and man-made radiations, the human lung receives about a 25% adaptive response protection against the radon alpha bystander damage. At the UNSCEAR (2000) minimum range of background exposure levels, the lung receives minimal AR protection but at higher background levels, in the high UNSCEAR (2000) range, the lung receives essentially 100% protection from both the radon alpha damage and also the endogenic, spontaneously occurring, potentially carcinogenic, lung cellular damage. PMID:22461760

  20. Human Lung Cancer Risks from Radon – Part III - Evidence of Influence of Combined Bystander and Adaptive Response Effects on Radon Case-Control Studies - A Microdose Analysis

    Science.gov (United States)

    Leonard, Bobby E.; Thompson, Richard E.; Beecher, Georgia C.

    2012-01-01

    Since the publication of the BEIR VI (1999) report on health risks from radon, a significant amount of new data has been published showing various mechanisms that may affect the ultimate assessment of radon as a carcinogen, in particular the potentially deleterious Bystander Effect (BE) and the potentially beneficial Adaptive Response radio-protection (AR). The case-control radon lung cancer risk data of the pooled 13 European countries radon study (Darby et al 2005, 2006) and the 8 North American pooled study (Krewski et al 2005, 2006) have been evaluated. The large variation in the odds ratios of lung cancer from radon risk is reconciled, based on the large variation in geological and ecological conditions and variation in the degree of adaptive response radio-protection against the bystander effect induced lung damage. The analysis clearly shows Bystander Effect radon lung cancer induction and Adaptive Response reduction in lung cancer in some geographical regions. It is estimated that for radon levels up to about 400 Bq m−3 there is about a 30% probability that no human lung cancer risk from radon will be experienced and a 20% probability that the risk is below the zero-radon, endogenic spontaneous or perhaps even genetically inheritable lung cancer risk rate. The BEIR VI (1999) and EPA (2003) estimates of human lung cancer deaths from radon are most likely significantly excessive. The assumption of linearity of risk, by the Linear No-Threshold Model, with increasing radon exposure is invalid. PMID:22942874

  1. Comparison of Radiation-Induced Bystander Effect in QU-DB Cells after Acute and Fractionated Irradiation: An In Vitro Study.

    Science.gov (United States)

    Soleymanifard, Shokouhozaman; Bahreyni Toossi, Mohammad Taghi; Kamran Samani, Roghayeh; Mohebbi, Shokoufeh

    2016-01-01

    Radiation effects induced in non-irradiated cells are termed radiation-induced bystander effects (RIBE). The present study intends to examine the RIBE response of QU-DB bystander cells to first, second and third radiation fractions and compare their cumulative outcome with an equal, single acute dose. This experimental study irradiated three groups of target cells for one, two and three times with(60)Co gamma rays. One hour after irradiation, we transferred their culture media to non-irradiated (bystander) cells. We used the cytokinesis block micronucleus assay to evaluate RIBE response in the bystander cells. The numbers of micronuclei generated in bystander cells were determined. RIBE response to single acute doses increased up to 4 Gy, then decreased, and finally at the 8 Gy dose disappeared. The second and third fractions induced RIBE in bystander cells, except when RIBE reached to the maximum level at the first fraction. We split the 4 Gy acute dose into two fractions, which decreased the RIBE response. However, fractionation of 6 Gy (into two fractions of 3 Gy or three fractions of 2 Gy) had no effect on RIBE response. When we split the 8 Gy acute dose into two fractions we observed RIBE, which had disappeared following the single 8 Gy dose. The impact of dose fractionation on RIBE induced in QU-DB cells de- pended on the RIBE dose-response relationship. Where RIBE increased proportion- ally with the dose, fractionation reduced the RIBE response. In contrast, at high dos- es where RIBE decreased proportionally with the dose, fractionation either did not change RIBE (at 6 Gy) or increased it (at 8 Gy).

  2. Signaling pathways underpinning the manifestations of ionizing radiation-induced bystander effects.

    Science.gov (United States)

    Hamada, Nobuyuki; Maeda, Munetoshi; Otsuka, Kensuke; Tomita, Masanori

    2011-06-01

    For nearly a century, ionizing radiation has been indispensable to medical diagnosis. Furthermore, various types of electromagnetic and particulate radiation have also been used in cancer therapy. However, the biological mechanism of radiation action remains incompletely understood. In this regard, a rapidly growing body of experimental evidence indicates that radiation exposure induces biological effects in cells whose nucleus has not been irradiated. This phenomenon termed the 'non-targeted effects' challenges the long-held tenet that radiation traversal through the cell nucleus is a prerequisite to elicit genetic damage and biological responses. The non-targeted effects include biological effects in cytoplasm-irradiated cells, bystander effects that arise in non-irradiated cells having received signals from irradiated cells, and genomic instability occurring in the progeny of irradiated cells. Such non-targeted responses are interrelated, and the bystander effect is further related with an adaptive response that manifests itself as the attenuated stressful biological effects of acute high-dose irradiation in cells that have been pre-exposed to low-dose or low-dose-rate radiation. This paper reviews the current body of knowledge about the bystander effect with emphasis on experimental approaches, in vitro and in vivo manifestations, radiation quality dependence, temporal and spatial dependence, proposed mechanisms, and clinical implications. Relations of bystander responses with the effects in cytoplasm-irradiated cells, genomic instability and adaptive response will also be briefly discussed.

  3. Evidence for induction of DNA double strand breaks in the bystander response to targeted soft X-rays in CHO cells

    International Nuclear Information System (INIS)

    Kashino, Genro; Prise, Kevin M.; Schettino, Giuseppe; Folkard, Melvyn; Vojnovic, Borivoj; Michael, Barry D.; Suzuki, Keiji; Kodama, Seiji; Watanabe, Masami

    2004-01-01

    This study investigated the role of DNA double strand breaks and DNA base damage in radiation-induced bystander responses in Chinese hamster ovary (CHO) cell lines. Two CHO repair-deficient clones, xrs5 (DNA double strand break repair-deficient) and EM9 (DNA base excision repair-deficient) were used in addition to the wild type (CHO). The Gray Cancer Institute ultrasoft X-ray microprobe is a powerful tool for investigating the bystander response, because it permits the irradiation of only a single nucleus of a cell, as reported previously. In order to investigate the bystander effect in each repair-deficient cell line, we irradiated a single cell within a population and scored the formation of micronuclei. When a single nucleus in the population was targeted with 1 Gy, elevated numbers of micronuclei were induced in the neighbouring unirradiated cells in the EM9 and xrs5 cell lines, whereas induction was not observed in CHO. The induction of micronuclei in xrs5 was significantly higher than that in EM9. Under these conditions, the surviving fraction in the neighbouring cells was significantly lower in xrs5 than in the other cell lines, showing a higher cell killing effect in xrs5. To confirm that bystander factors secreted from irradiated cells caused these effects, we carried out medium transfer experiments using conventional X-irradiation. Medium conditioned for 24 h with irradiated cells was transferred to unirradiated cells and elevated induction of micronuclei was observed in xrs5. These results suggest that DNA double strand breaks rather than base damage are caused by factors secreted in the medium from irradiated cells

  4. Homeostatic 'bystander' proliferation of human peripheral blood B cells in response to polyclonal T-cell stimulation in vitro.

    Science.gov (United States)

    Jasiulewicz, Aleksandra; Lisowska, Katarzyna A; Pietruczuk, Krzysztof; Frąckowiak, Joanna; Fulop, Tamas; Witkowski, Jacek M

    2015-11-01

    The mechanisms of maintenance of adequate numbers of B lymphocytes and of protective levels of immunoglobulins in the absence of antigenic (re)stimulation remain not fully understood. Meanwhile, our results presented here show that both peripheral blood naive and memory B cells can be activated strongly and non-specifically (in a mitogen-like fashion) in 5-day in vitro cultures of anti-CD3- or concanavalin A (Con A)-stimulated peripheral blood mononuclear cells of healthy people. This polyclonal, bystander activation of the B cells includes multiple divisions of most of them (assessed here by the flow cytometric technique of dividing cell tracking) and significant antibody [immunoglobulin M (IgM) and IgG] secretion. Observed proliferation of the CD19(+) B cells depends on contact with stimulated T helper (Th) cells (via CD40-CD40L interaction) and on the response of B cells to secreted interleukins IL-5, IL-10 and IL-4, and is correlated with the levels of these Th-derived molecules, while it does not involve the ligation of the BCR/CD19 complex. We suggest that the effect might reflect the situation occurring in vivo as the homeostatic proliferation of otherwise non-stimulated, peripheral B lymphocytes, providing an always ready pool for efficient antibody production to any new (or cognate) antigen challenge. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  5. Study on bystander effect and associated mechanism mediated through culture medium

    International Nuclear Information System (INIS)

    Tu Xumin; Lei Suwen; Zhang Zhixing; Lv Huimin

    2005-01-01

    Objective: To study the bystander effect and associated mechanism mediated through the irradiated cell culture medium. Methods: Splenic natural killer (NK) cells were obtained from healthy male ICR strain mice. Culture medium irradiated with different doses of 60 Co γ-rays was used for culturing Yac-I lymphoma cells. The degree of injury of the latter by activated NK cells was observed. A part of the culture media were pretreated with 1% DMSO, a scavenger of reactive oxygen species (ROS), in order to investigate the possible mechanism of a radiation-induced bystander response. Results: Severer injury was induced in Yac-I cells cultured in the media pre-irradiated with different doses of γ-rays than that in Yac-I cells cultured in unirradiated medium, as shown by increased sensitivity to murine splenic NK cells (P<0.01). Culturing Yac-I cells in DMSO-pretreated medium considerably reduced the activation of NK cells, especially in 0.25 Gy and 0.5 Gy γ-irradiated media. Therefore, it can be expected that DMSO can partly suppress ROS-induced bystander effect. Conclusion: The irradiated culture medium of Yac-I cells can trigger bystander effect. ROS likely plays an important role in radiation-induced bystander effect that can be partly suppressed by pretreatment with DMSO. (authors)

  6. Detection of genomic instability in α-irradiated and bystander human fibroblasts

    International Nuclear Information System (INIS)

    Ponnaiya, B.; Jenkins-Baker, G.; Bigelow, A.; Marino, S.; Geard, C.R.

    2003-01-01

    Full text: We have previously demonstrated a radiation induced bystander effect using novel co-culturing techniques where irradiated and bystander cells were cultured on two surfaces of mylar separated by media. Here we present data from experiments designed to investigate the induction of chromosomal aberrations in irradiated and bystander fibroblasts using these co-culturing techniques. Immortalized fibroblasts ((BJ1-tert) were cultured on both mylar surfaces and cells on one side were irradiated with 0.1 or 1 Gy -particles (an average of 1 and 10 particles per cell nucleus respectively), the two sides were separated 1 hour post irradiation and analyzed for chromosomal aberrations using standard Giemsa staining at either immediate or delayed time points. At 24-30 hours post irradiation, frequencies of chromosomal aberrations in irradiated populations were increased in a dose dependent manner as expected. Populations that received 0.1 and 1 Gy had 0.3 and 1.3 aberrations/cell; these aberrations were almost exclusively chromosome type aberrations. In contrast, at these times bystander populations had elevated yields of chromatid-type aberrations. When assayed at later times (15-20 population doublings post irradiation) both irradiated and bystander cells demonstrated elevated frequencies of chromatid-type aberrations. Frequencies in the irradiated populations ranged from 0.07 to 0.09 aberrations/ cell at 15 doublings, and 0.09-0.14/cell at 20 doublings, with no apparent dose response. Aberration frequencies in the bystander populations were between 0.08-0.14 per cell at the delayed time points assayed. Interestingly, the chromatid-type aberrations observed immediately post irradiation in the bystander cells, and at later times in both the irradiated and bystander populations were qualitatively similar to those previously observed at delayed times in neutron irradiated epithelial cells. Furthermore, there was a similar lack of a dose response in those studies as

  7. Dose response relationship at low doses

    International Nuclear Information System (INIS)

    Schull, W.J.

    1992-01-01

    The data that have accrued in Hiroshima and Nagasaki on the effects of ionizing radiation on the developing human brain are reviewed. Effects considered are severe mental retardation, lowered IQ scores, decline in school performance, seizures, other neuropsychological effects, and small head size. All these factors may be related to radiation doses received by the mother during pregnancy. (L.L.) 3 figs., tab., 7 refs

  8. Linear, no threshold response at low doses of ionizing radiation: ideology, prejudice and science

    International Nuclear Information System (INIS)

    Kesavan, P.C.

    2014-01-01

    The linear, no threshold (LNT) response model assumes that there is no threshold dose for the radiation-induced genetic effects (heritable mutations and cancer), and it forms the current basis for radiation protection standards for radiation workers and the general public. The LNT model is, however, based more on ideology than valid radiobiological data. Further, phenomena such as 'radiation hormesis', 'radioadaptive response', 'bystander effects' and 'genomic instability' are now demonstrated to be radioprotective and beneficial. More importantly, the 'differential gene expression' reveals that qualitatively different proteins are induced by low and high doses. This finding negates the LNT model which assumes that qualitatively similar proteins are formed at all doses. Thus, all available scientific data challenge the LNT hypothesis. (author)

  9. Radionuclides in radiation-induced bystander effect; may it share in radionuclide therapy?

    Science.gov (United States)

    Widel, M

    2017-01-01

    For many years in radiobiology and radiotherapy predominated the conviction that cellular DNA is the main target for ionizing radiation, however, the view has changed in the past 20 years. Nowadays, it is assumed that not only directed (targeted) radiation effect, but also an indirect (non-targeted) effect may contribute to the result of radiation treatment. Non-targeted effect is relatively well recognized after external beam irradiation in vitro and in vivo, and comprises such phenomena like radiation-induced bystander effect (RIBE), genomic instability, adaptive response and abscopal (out of field) effect. These stress-induced and molecular signaling mediated phenomena appear in non-targeted cells as variety responses resembling that observed in directly hit cells. Bystander effects can be both detrimental and beneficial in dependence on dose, dose-rate, cell type, genetic status and experimental condition. Less is known about radionuclide-induced non-targeted effects in radionuclide therapy, although, based on characteristics of the radionuclide radiation, on experiments in vitro utilizing classical and 3-D cell cultures, and preclinical study on animals it seems obvious that exposure to radionuclide is accompanied by various bystander effects, mostly damaging, less often protective. This review summarizes existing data on radionuclide induced bystander effects comprising radionuclides emitting beta- and alpha-particles and Auger electrons used in tumor radiotherapy and diagnostics. So far, separation of the direct effect of radionuclide decay from crossfire and bystander effects in clinical targeted radionuclide therapy is impossible because of the lack of methods to assess whether, and to what extent bystander effect is involved in human organism. Considerations on this topic are also included.

  10. A reaction-diffusion model for radiation-induced bystander effects.

    Science.gov (United States)

    Olobatuyi, Oluwole; de Vries, Gerda; Hillen, Thomas

    2017-08-01

    We develop and analyze a reaction-diffusion model to investigate the dynamics of the lifespan of a bystander signal emitted when cells are exposed to radiation. Experimental studies by Mothersill and Seymour 1997, using malignant epithelial cell lines, found that an emitted bystander signal can still cause bystander effects in cells even 60 h after its emission. Several other experiments have also shown that the signal can persist for months and even years. Also, bystander effects have been hypothesized as one of the factors responsible for the phenomenon of low-dose hyper-radiosensitivity and increased radioresistance (HRS/IRR). Here, we confirm this hypothesis with a mathematical model, which we fit to Joiner's data on HRS/IRR in a T98G glioma cell line. Furthermore, we use phase plane analysis to understand the full dynamics of the signal's lifespan. We find that both single and multiple radiation exposure can lead to bystander signals that either persist temporarily or permanently. We also found that, in an heterogeneous environment, the size of the domain exposed to radiation and the number of radiation exposures can determine whether a signal will persist temporarily or permanently. Finally, we use sensitivity analysis to identify those cell parameters that affect the signal's lifespan and the signal-induced cell death the most.

  11. On the Inclusion of Short-distance Bystander Effects into a Logistic Tumor Control Probability Model.

    Science.gov (United States)

    Tempel, David G; Brodin, N Patrik; Tomé, Wolfgang A

    2018-01-01

    Currently, interactions between voxels are neglected in the tumor control probability (TCP) models used in biologically-driven intensity-modulated radiotherapy treatment planning. However, experimental data suggests that this may not always be justified when bystander effects are important. We propose a model inspired by the Ising model, a short-range interaction model, to investigate if and when it is important to include voxel to voxel interactions in biologically-driven treatment planning. This Ising-like model for TCP is derived by first showing that the logistic model of tumor control is mathematically equivalent to a non-interacting Ising model. Using this correspondence, the parameters of the logistic model are mapped to the parameters of an Ising-like model and bystander interactions are introduced as a short-range interaction as is the case for the Ising model. As an example, we apply the model to study the effect of bystander interactions in the case of radiation therapy for prostate cancer. The model shows that it is adequate to neglect bystander interactions for dose distributions that completely cover the treatment target and yield TCP estimates that lie in the shoulder of the dose response curve. However, for dose distributions that yield TCP estimates that lie on the steep part of the dose response curve or for inhomogeneous dose distributions having significant hot and/or cold regions, bystander effects may be important. Furthermore, the proposed model highlights a previously unexplored and potentially fruitful connection between the fields of statistical mechanics and tumor control probability/normal tissue complication probability modeling.

  12. The relative biological effectiveness of out-of-field dose

    International Nuclear Information System (INIS)

    Balderson, Michael; Koger, Brandon; Kirkby, Charles

    2016-01-01

    Purpose: using simulations and models derived from existing literature, this work investigates relative biological effectiveness (RBE) for out-of-field radiation and attempts to quantify the relative magnitudes of different contributing phenomena (spectral, bystander, and low dose hypersensitivity effects). Specific attention is paid to external beam radiotherapy treatments for prostate cancer. Materials and methods: using different biological models that account for spectral, bystander, and low dose hypersensitivity effects, the RBE was calculated for different points moving radially out from isocentre for a typical single arc VMAT prostate case. The RBE was found by taking the ratio of the equivalent dose with the physical dose. Equivalent doses were calculated by determining what physical dose would be necessary to produce the same overall biological effect as that predicted using the different biological models. Results: spectral effects changed the RBE out-of-field less than 2%, whereas response models incorporating low dose hypersensitivity and bystander effects resulted in a much more profound change of the RBE for out-of-field doses. The bystander effect had the largest RBE for points located just outside the edge of the primary radiation beam in the cranial caudal (z-direction) compared to low dose hypersensitivity and spectral effects. In the coplanar direction, bystander effect played the largest role in enhancing the RBE for points up to 8.75 cm from isocentre. Conclusions: spectral, bystander, and low dose hypersensitivity effects can all increase the RBE for out-of-field radiation doses. In most cases, bystander effects seem to play the largest role followed by low dose hypersensitivity. Spectral effects were unlikely to be of any clinical significance. Bystander, low dose hypersensitivity, and spectral effect increased the RBE much more in the cranial caudal direction (z-direction) compared with the coplanar directions. (paper)

  13. Intranasal delivery of cholera toxin induces th17-dominated T-cell response to bystander antigens.

    Directory of Open Access Journals (Sweden)

    Jee-Boong Lee

    Full Text Available Cholera toxin (CT is a potent vaccine adjuvant, which promotes mucosal immunity to protein antigen given by nasal route. It has been suggested that CT promotes T helper type 2 (Th2 response and suppresses Th1 response. We here report the induction of Th17-dominated responses in mice by intranasal delivery of CT. This dramatic Th17-driving effect of CT, which was dependent on the B subunit, was observed even in Th1 or Th2-favored conditions of respiratory virus infection. These dominating Th17 responses resulted in the significant neutrophil accumulation in the lungs of mice given CT. Both in vitro and in vivo treatment of CT induced strongly augmented IL-6 production, and Th17-driving ability of CT was completely abolished in IL-6 knockout mice, indicating a role of this cytokine in the Th17-dominated T-cell responses by CT. These data demonstrate a novel Th17-driving activity of CT, and help understand the mechanisms of CT adjuvanticity to demarcate T helper responses.

  14. Radiation-induced bystander effects enhanced by elevated sodium chloride through sensitizing cells to bystander factors

    International Nuclear Information System (INIS)

    Zhu Lingyan; Han Wei; Chen Shaopeng; Zhao Ye; Jiang Erkang; Bao Lingzhi; Pei Bei; Yang Gen; Zhao Guoping; Wang Jun; Xu An; Wu Lijun

    2008-01-01

    Radiation-induced bystander effects (RIBE) have been demonstrated to occur widely in various cell lines. However, very little data is available on the genotoxic effects of RIBE combined with other factor(s). We reported previously that with a low dose of α-particle irradiation, the fraction of γ-H2AX foci-positive cells in non-irradiated bystander cells was significantly increased under elevated NaCl culture conditions. In this study, we further investigated the functional role of NaCl in the enhancement of RIBE using a specially designed co-culture system and micronucleus (MN) test. It was shown that the MN frequency was not increased significantly by elevated NaCl (9.0 g/L) alone or by medium exposure. However, with 1.0 cGy α-particle irradiation, the induced MN frequency increased significantly in both irradiated and non-irradiated bystander regions. Additional studies showed that elevated NaCl made the non-irradiated bystander cells more vulnerable to bystander factors. Furthermore, it was found that the induced MN frequency in cells both in irradiated and non-irradiated bystander regions was weakened when the hypertonic medium was changed to normotonic medium for 2 h before irradiation. Such observations were quite similar to the co-effect of NaCl and hydrogen peroxide (H 2 O 2 ), indicating that elevated NaCl might sensitize non-irradiated cells to bystander factors-induced oxidative stress

  15. Novel features of radiation-induced bystander signaling in Arabidopsis thaliana demonstrated using root micro-grafting

    Science.gov (United States)

    Wang, Ting; Li, Fanghua; Xu, Wei; Bian, Po; Wu, Yuejin; Wu, Lijun

    2012-01-01

    Radiation-induced bystander effects (RIBE) have been well demonstrated in whole organisms, as well as in single-cell culture models in vitro and multi-cellular tissues models in vitro, however, the underlying mechanisms remain unclear, including the temporal and spatial course of bystander signaling. The RIBE in vivo has been shown to exist in the model plant Arabidopsis thaliana (A. thaliana). Importantly, the unique plant grafting provides a delicate approach for studying the temporal and spatial course of bystander signaling in the context of whole plants. In our previous study, the time course of bystander signaling in plants has been well demonstrated using the root micro-grafting technique. In this study, we further investigated the temporal cooperation pattern of multiple bystander signals, the directionality of bystander signaling, and the effect of bystander tissues on the bystander signaling. The results showed that the bystander response could also be induced efficiently when the asynchronously generated bystander signals reached the bystander tissues in the same period, but not when they entered into the bystander tissues in an inversed sequence. The absence of bystander response in root-inversed grafting indicated that the bystander signaling along roots might be of directionality. The bystander signaling was shown to be independent of the bystander tissues. PMID:23072991

  16. Vincristine-induced bystander effect in human lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Testi, Serena; Azzarà, Alessia; Giovannini, Caterina; Lombardi, Sara [Unità di Genetica, Dipartimento di Biologia, Pisa University, Via Derna 1, 56126 Pisa (Italy); Piaggi, Simona [Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Pisa University, Via Savi 10, 56126 Pisa (Italy); Facioni, Maria Sole [Unità di Genetica, Dipartimento di Biologia, Pisa University, Via Derna 1, 56126 Pisa (Italy); Scarpato, Roberto, E-mail: roberto.scarpato@unipi.it [Unità di Genetica, Dipartimento di Biologia, Pisa University, Via Derna 1, 56126 Pisa (Italy); Research Center of Nutraceuticals and Food for Health, University of Pisa, Pisa (Italy)

    2016-07-15

    Highlights: • We studied whether or not vincristine induced a bystander response in human lymphocytes. • Vincristine significantly increased MN frequencies in mononucleated recipient cells. • ROS or soluble proteins (IL-32 and TGF-β) may account for the observed response. - Abstract: Bystander effect is a known radiobiological effect, widely described using ionizing radiations and which, more recently, has also been related to chemical mutagens. In this study, we aimed to assess whether or not a bystander response can be induced in cultured human peripheral lymphocytes by vincristine, a chemotherapeutic mutagen acting as spindle poison, and by mitomycin-C, an alkylating agent already known to induce this response in human lymphoblastoid cells. Designing a modified ad hoc protocol for the cytokinesis blocked micronucleus (MN) assay, we detected the presence of a dose-dependent bystander response in untreated cultures receiving the conditioned medium (CM) from mitomycin-C (MMC) or vincristine (VCR) treated cultures. In the case of MMC, MN frequencies, expressed as micronucleated binucleates, were: 13.5 ± 1.41 at 6 μM, 22 ± 2.12 at 12 μM or 28.25 ± 5.13 at 15 μM vs. a control value of 4.75 ± 1.59. MN levels for VCR, expressed as micronucleated mononucleates were: 2.75 ± 0.88 at 0.0 μM, 27.25 ± 2.30 at 0.4 μM, 46.25 ± 1.94 at 0.8 μM, 98.25 ± 7.25 at 1.6 μM. To verify that no mutagen residual was transferred to recipient cultures together with the CM, we evaluated MN levels in cultures receiving the medium immediately after three washings following the chemical treatment (unconditioned medium). We further confirmed these results using a cell-mixing approach where untreated lymphocytes were co-cultured with donor cells treated with an effect-inducing dose of MMC or VCR. A distinct production pattern of both reactive oxygen species and soluble mediator proteins by treated cells may account for the differences observed in the manifestation of the

  17. Vincristine-induced bystander effect in human lymphocytes

    International Nuclear Information System (INIS)

    Testi, Serena; Azzarà, Alessia; Giovannini, Caterina; Lombardi, Sara; Piaggi, Simona; Facioni, Maria Sole; Scarpato, Roberto

    2016-01-01

    Highlights: • We studied whether or not vincristine induced a bystander response in human lymphocytes. • Vincristine significantly increased MN frequencies in mononucleated recipient cells. • ROS or soluble proteins (IL-32 and TGF-β) may account for the observed response. - Abstract: Bystander effect is a known radiobiological effect, widely described using ionizing radiations and which, more recently, has also been related to chemical mutagens. In this study, we aimed to assess whether or not a bystander response can be induced in cultured human peripheral lymphocytes by vincristine, a chemotherapeutic mutagen acting as spindle poison, and by mitomycin-C, an alkylating agent already known to induce this response in human lymphoblastoid cells. Designing a modified ad hoc protocol for the cytokinesis blocked micronucleus (MN) assay, we detected the presence of a dose-dependent bystander response in untreated cultures receiving the conditioned medium (CM) from mitomycin-C (MMC) or vincristine (VCR) treated cultures. In the case of MMC, MN frequencies, expressed as micronucleated binucleates, were: 13.5 ± 1.41 at 6 μM, 22 ± 2.12 at 12 μM or 28.25 ± 5.13 at 15 μM vs. a control value of 4.75 ± 1.59. MN levels for VCR, expressed as micronucleated mononucleates were: 2.75 ± 0.88 at 0.0 μM, 27.25 ± 2.30 at 0.4 μM, 46.25 ± 1.94 at 0.8 μM, 98.25 ± 7.25 at 1.6 μM. To verify that no mutagen residual was transferred to recipient cultures together with the CM, we evaluated MN levels in cultures receiving the medium immediately after three washings following the chemical treatment (unconditioned medium). We further confirmed these results using a cell-mixing approach where untreated lymphocytes were co-cultured with donor cells treated with an effect-inducing dose of MMC or VCR. A distinct production pattern of both reactive oxygen species and soluble mediator proteins by treated cells may account for the differences observed in the manifestation of the

  18. Indirect macrophage responses to ionizing radiation: implications for genotype-dependent bystander signaling.

    Science.gov (United States)

    Coates, Philip J; Rundle, Jana K; Lorimore, Sally A; Wright, Eric G

    2008-01-15

    In addition to the directly mutagenic effects of energy deposition in DNA, ionizing radiation is associated with a variety of untargeted and delayed effects that result in ongoing bone marrow damage. Delayed effects are genotype dependent with CBA/Ca mice, but not C57BL/6 mice, susceptible to the induction of damage and also radiation-induced acute myeloid leukemia. Because macrophages are a potential source of ongoing damaging signals, we have determined their gene expression profiles and we show that bone marrow-derived macrophages show widely different intrinsic expression patterns. The profiles classify macrophages derived from CBA/Ca mice as M1-like (pro-inflammatory) and those from C57BL/6 mice as M2-like (anti-inflammatory); measurements of NOS2 and arginase activity in normal bone marrow macrophages confirm these findings. After irradiation in vivo, but not in vitro, C57BL/6 macrophages show a reduction in NOS2 and an increase in arginase activities, indicating a further M2 response, whereas CBA/Ca macrophages retain an M1 phenotype. Activation of specific signal transducer and activator of transcription signaling pathways in irradiated hemopoietic tissues supports these observations. The data indicate that macrophage activation is not a direct effect of radiation but a tissue response, secondary to the initial radiation exposure, and have important implications for understanding genotype-dependent responses and the mechanisms of the hemotoxic and leukemogenic consequences of radiation exposure.

  19. Response effects due to bystander presence in CASI and paper-and-pencil surveys of drug use and alcohol use.

    Science.gov (United States)

    Aquilino, W S; Wright, D L; Supple, A J

    2000-01-01

    In this study we investigated the influence of bystanders on self-administered interviews asking about the use of alcohol and illicit drugs. Interview participants were adolescents and young adults living in urban and suburban areas of the United States. Participants were assigned randomly to either a computerized or a paper-and-pencil self-administered interview. Results show that the impact of bystanders during the interview varies according to the identity of the bystander, age of the person interviewed, and the mode of interview. When a parent was present during the interview, survey participants were less likely to report the use of alcohol and marijuana. The influence of parents was stronger for adolescents than for young adults. The use of computer-assisted self-administered interviewing, compared to interviews with paper-and-pencil forms, reduced the effects due to the presence of parents during the interview. The presence of siblings during the interview had a small, negative effect on reports of using alcohol or illicit drugs. Among married or cohabiting respondents, the presence of the husband, wife, or live-in partner had no influence on reports of alcohol use or drug use.

  20. Endothelial cells: From innocent bystanders to active participants in immune responses.

    Science.gov (United States)

    Al-Soudi, A; Kaaij, M H; Tas, S W

    2017-09-01

    The endothelium is crucially important for the delivery of oxygen and nutrients throughout the body under homeostatic conditions. However, it also contributes to pathology, including the initiation and perpetuation of inflammation. Understanding the function of endothelial cells (ECs) in inflammatory diseases and molecular mechanisms involved may lead to novel approaches to dampen inflammation and restore homeostasis. In this article, we discuss the various functions of ECs in inflammation with a focus on pathological angiogenesis, attraction of immune cells, antigen presentation, immunoregulatory properties and endothelial-to-mesenchymal transition (EndMT). We also review the current literature on approaches to target these processes in ECs to modulate immune responses and advance anti-inflammatory therapies. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  1. Beyond the Situational Model: Bystander Action Consequences to Intervening in Situations Involving Sexual Violence.

    Science.gov (United States)

    Moschella, Elizabeth A; Bennett, Sidney; Banyard, Victoria L

    2016-03-02

    Sexual violence is a widely reported problem in college communities. To date, research has largely focused on bystander intervention as one way to help prevent this problem. Although perceived consequences of bystander intervention, such as the weighting of costs and benefits, have been examined, little research has explored what happens after a bystander intervenes. The current study investigated what bystanders report as perceived outcomes and actual consequences of their bystander actions in response to risk for sexual assault. Of the 545 surveyed, 150 reported having taking bystander action in the past month and qualitatively described their bystander behavior and the responses of those parties involved. A range of behavioral responses and intervention methods were identified. The most frequent responses reported by participants were victims conveying positive and perpetrators conveying negative responses. Different types of helping were associated with bystanders reporting different types of responses to their actions. Future research should incorporate additional measures of consequences of bystander intervention. Implications for policy and bystander intervention programs are discussed, stressing the need for bystander intervention programs to address a range of bystander behaviors and explain the potential consequences and risks of intervening. © The Author(s) 2016.

  2. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders.

    Science.gov (United States)

    Caughey, Byron; Lansbury, Peter T

    2003-01-01

    Many neurodegenerative diseases, including Alzheimer's and Parkinson's and the transmissible spongiform encephalopathies (prion diseases), are characterized at autopsy by neuronal loss and protein aggregates that are typically fibrillar. A convergence of evidence strongly suggests that protein aggregation is neurotoxic and not a product of cell death. However, the identity of the neurotoxic aggregate and the mechanism by which it disables and eventually kills a neuron are unknown. Both biophysical studies aimed at elucidating the precise mechanism of in vitro aggregation and animal modeling studies support the emerging notion that an ordered prefibrillar oligomer, or protofibril, may be responsible for cell death and that the fibrillar form that is typically observed at autopsy may actually be neuroprotective. A subpopulation of protofibrils may function as pathogenic amyloid pores. An analogous mechanism may explain the neurotoxicity of the prion protein; recent data demonstrates that the disease-associated, infectious form of the prion protein differs from the neurotoxic species. This review focuses on recent experimental studies aimed at identification and characterization of the neurotoxic protein aggregates.

  3. Responses of epithelial cells to low and very low doses of low let radiation

    International Nuclear Information System (INIS)

    Mothersill, Carmel; Seymour, Colin

    2003-01-01

    Recent advances in our knowledge of the biological effects of low doses of ionizing radiation have shown unexpected phenomena. These vary in the endpoint used to detect them and in the dose range examined but all occur as high-frequency events in cell populations. They include: 1. a 'bystander effect' which can be demonstrated at low doses as a transferable.factor(s) causing radiobiological effects in unexposed cells, 2. an assortment of delayed effects' occurring in progeny of cells exposed to low doses, 3. Low-dose Hypersensitivity (HRS) and Increased radioresistance (IRR) which can collectively be demonstrated as a change in the dose-effect relationship, occurring around 0.5-1 Gy of low LET radiation and 4. adaptive responses where cells exposed to very low doses followed by higher doses, exhibit an induced relatively resistant response to the second dose. In all cases, the effect of very low doses is greater than would be predicted by extrapolation of high dose data and is inconsistent with conventional DNA break/repair-based radiobiology. In practical risk assessment terms, the relative importance of the effects are high at low doses where they dominate the response, and small at high doses. This paper reviews these assorted phenomena and in particular seeks to explore whether related or distinct mechanisms underlie these various effects Understanding the mechanistic basis of these phenomena may suggest new approaches to controlling death or survival sectoring at low radiation doses. The key question is whether these low dose phenomena necessitate a new approach to risk assessment. (author)

  4. Dose-response relationship in clinical oncology

    International Nuclear Information System (INIS)

    Gehan, E.A.

    1984-01-01

    The relationship of dose (and dose rate) to response and toxicity in clinical oncology is reviewed. The concepts expressed by some authors in dose-response studies in animal and human systems are reviewed briefly. Dose rate and tactics of conducting clinical studies are reviewed for both radiotherapy and various types of chemotherapeutic treatment. Examples are given from clinical studies in Hodgkin's disease, acute leukemia, and breast cancer that may prove useful in planning future clinical studies

  5. Protective and detrimental bystander effects induced by x-irradiation in the limb bud cell cultures of fetal mice

    International Nuclear Information System (INIS)

    Wang, B.; Ohyama, H.; Shang, Y.; Yukawa, O.; Aizawa, S.; Hayata, I.

    2003-01-01

    Full text: Radioadaptive response and bystander effect represent important phenomena in radiobiology with an impact on the novel bioresponse mechanisms and risk estimates. The micromass cultures of limb bud cells (LBCs) provide an in vitro cellular maturation system, in which progress of cellular proliferation and differentiation is comparably paralleled to that of in vivo. This paper reports for the first time the evidential correlation and interaction, which simultaneously exist in the micromass culture system, between radioadaptive response and bystander effect. A radioadaptive response was induced in LBCs of embryonic day 11 (E11) ICR mice. Conditioning irradiation of the E11 cells with 30 cGy resulted in a significant protective effect against the occurrence of apoptosis, inhibition of cellular proliferation and differentiation induced by a challenging dose of 5 Gy given next day. Both protective and detrimental bystander effects were observed, namely, irradiating 50% of the E11 cells with 30 cGy led to a successful induction of radioadaptive response, and irradiating 70% of the E12 cells with 5 Gy produced comparably the detrimental effect to that of when all the cells were irradiated. Further, the bystander effects were markedly vanished by pretreatment of the cells with inhibitors to block the gap junction-mediated intracellular communication. These results indicated that the bystander effect played an important role in both the induction of a protective effect by the conditioning dose and the detrimental effect by the challenging irradiation. Concerning the underlying mechanism, the gap junction-mediated intracellular communication was suggested being involved in the induction of the bystander effects

  6. Dose response of micronuclei induced by combination radiation of α-particles and γ-rays in human lymphoblast cells

    Energy Technology Data Exchange (ETDEWEB)

    Ren, Ruiping; He, Mingyuan; Dong, Chen; Xie, Yuexia; Ye, Shuang; Yuan, Dexiao [Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032 (China); Shao, Chunlin, E-mail: clshao@shmu.edu.cn [Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032 (China)

    2013-01-15

    Highlights: ► α-Particle induced MN had a biphasic dose–response followed by a bystander model. ► MN dose–response of α- and γ-combination IR was similar to that of α-particle. ► α-Particles followed by γ-rays yielded a synergistic effect on MN induction. ► Low dose γ-rays triggered antagonistic and adaptive responses against α-particle. - Abstract: Combination radiation is a real situation of both nuclear accident exposure and space radiation environment, but its biological dosimetry is still not established. This study investigated the dose–response of micronuclei (MN) induction in lymphocyte by irradiating HMy2.CIR lymphoblast cells with α-particles, γ-rays, and their combinations. Results showed that the dose–response of MN induced by γ-rays was well-fitted with the linear-quadratic model. But for α-particle irradiation, the MN induction had a biphasic phenomenon containing a low dose hypersensitivity characteristic and its dose response could be well-stimulated with a state vector model where radiation-induced bystander effect (RIBE) was involved. For the combination exposure, the dose response of MN was similar to that of α-irradiation. However, the yield of MN was closely related to the sequence of irradiations. When the cells were irradiated with α-particles at first and then γ-rays, a synergistic effect of MN induction was observed. But when the cells were irradiated with γ-rays followed by α-particles, an antagonistic effect of MN was observed in the low dose range although this combination radiation also yielded a synergistic effect at high doses. When the interval between two irradiations was extended to 4 h, a cross-adaptive response against the other irradiation was induced by a low dose of γ-rays but not α-particles.

  7. Experimental data and dose-response models

    International Nuclear Information System (INIS)

    Ullrich, R.L.

    1985-01-01

    Dose-response relationships for radiation carcinogenesis have been of interest to biologists, modelers, and statisticians for many years. Despite his interest there are few instances in which there are sufficient experimental data to allow the fitting of various dose-response models. In those experimental systems for which data are available the dose-response curves for tumor induction for the various systems cannot be described by a single model. Dose-response models which have been observed following acute exposures to gamma rays include threshold, quadratic, and linear models. Data on sex, age, and environmental influences of dose suggest a strong role of host factors on the dose response. With decreasing dose rate the effectiveness of gamma ray irradiation tends to decrease in essentially every instance. In those cases in which the high dose rate dose response could be described by a quadratic model, the effect of dose rate is consistent with predictions based on radiation effects on the induction of initial events. Whether the underlying reasons for the observed dose-rate effect is a result of effects on the induction of initial events or is due to effects on the subsequent steps in the carcinogenic process is unknown. Information on the dose response for tumor induction for high LET (linear energy transfer) radiations such as neutrons is even more limited. The observed dose and dose rate data for tumor induction following neutron exposure are complex and do not appear to be consistent with predictions based on models for the induction of initial events

  8. The Effect of Cognitive Behavioral Therapy and Cognitive Behavioral Therapy Plus Media on the Reduction of Bullying and Victimization and the Increase of Empathy and Bystander Response in a Bully Prevention Program for Urban Sixth-Grade Students

    Science.gov (United States)

    McLaughlin, Laura Pierce

    2009-01-01

    The purpose of this study was to investigate the effect of cognitive behavioral therapy and cognitive behavioral therapy plus media on the reduction of bullying and victimization and the increase in empathy and bystander response in a bully prevention program for urban sixth-graders. Sixty-eight students participated. Because one of the…

  9. Dose-response curves from incomplete data

    International Nuclear Information System (INIS)

    Groer, P.G.

    1978-01-01

    Frequently many different responses occur in populations (animal or human) exposed to ionizing radiation. To obtain a dose-response curve, the exposed population is first divided into sub-groups whose members received the same radiation dose. To estimate the response, the fraction of subjects in each sub-group that showed the particular response of interest is determined. These fractions are plotted against dose to give the dose-response curve. This procedure of plotting the fractions versus the radiation dose is not the correct way to estimate the time distribution for a particular response at the different dose levels. Other observed responses competed for the individuals in the exposed population and therefore prevented manifestation of the complete information on the response-time distribution for one specific response. Such data are called incomplete in the statistical literature. A procedure is described which uses the by now classical Kaplan-Meier estimator, to establish dose-response curves from incomplete data under the assumption that the different observed responses are statistically independent. It is demonstrated that there is insufficient information in the observed survival functions to estimate the time distribution for one particular response if the assumption of independence is dropped. In addition, it is not possible to determine from the data (i.e. type of response and when it occurred) whether or not the different response-time distributions are independent. However, it is possible to give sharp bounds between which the response has to lie. This implies that for incomplete data, only a 'dose-response band' can be established if independence of the competing responses cannot be assumed. Examples are given using actual data to illustrate the estimation procedures

  10. Development of a mathematical model to study the radiation-induced bystander effect

    Energy Technology Data Exchange (ETDEWEB)

    Meireles, Sincler P. de; Santos, Adriano M.; Grynberg, Suely Epsztein, E-mail: spm@cdtn.b, E-mail: amsantos@cdtn.b, E-mail: seg@cdtn.b [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil); Nunes, Maria Eugenia S., E-mail: mariaeugenia@iceb.ufop.b [Universidade Federal de Ouro Preto (UFOP), MG (Brazil)

    2011-07-01

    Living organisms are composed of millions of cells that together perform tasks of great complexity. Although every cell has an internal structure that obeys the laws of chemistry and biochemistry, it is the interactions between cells that generate a range of different phenomena. Until the 1990s it was believed that the DNA was the single molecule affected by radiation, the so-called theory of the single target. But some observations began to challenge this theory; in 1992 the bystander effect was described by Nagasawa and Little. This effect is responsible for a series of responses such as death, chromosomal instability or other abnormalities that occur in non-irradiated cells that came into contact with irradiated cells or medium from irradiated cells. Understanding the bystander effect may have important consequences for therapy and studies of low-dose risk. In this work, we have developed a computational model to study the bystander effect. This computational model is a two-dimensional cellular automata, consisting of two overlapping networks, where the first represents the cell culture, and the second one, the medium in which cells are embedded. The computational model allows the establishment of curves to describe the behavior of the effect for different levels of signals released in the irradiated medium by the irradiated cells or by the bystander cells when a second order effect is considered. The percentage of cell survival obtained from the mathematical model showed to be in good agreement with experimental data available in the literature. (author)

  11. Development of a mathematical model to study the radiation-induced bystander effect

    International Nuclear Information System (INIS)

    Meireles, Sincler P. de; Santos, Adriano M.; Grynberg, Suely Epsztein; Nunes, Maria Eugenia S.

    2011-01-01

    Living organisms are composed of millions of cells that together perform tasks of great complexity. Although every cell has an internal structure that obeys the laws of chemistry and biochemistry, it is the interactions between cells that generate a range of different phenomena. Until the 1990s it was believed that the DNA was the single molecule affected by radiation, the so-called theory of the single target. But some observations began to challenge this theory; in 1992 the bystander effect was described by Nagasawa and Little. This effect is responsible for a series of responses such as death, chromosomal instability or other abnormalities that occur in non-irradiated cells that came into contact with irradiated cells or medium from irradiated cells. Understanding the bystander effect may have important consequences for therapy and studies of low-dose risk. In this work, we have developed a computational model to study the bystander effect. This computational model is a two-dimensional cellular automata, consisting of two overlapping networks, where the first represents the cell culture, and the second one, the medium in which cells are embedded. The computational model allows the establishment of curves to describe the behavior of the effect for different levels of signals released in the irradiated medium by the irradiated cells or by the bystander cells when a second order effect is considered. The percentage of cell survival obtained from the mathematical model showed to be in good agreement with experimental data available in the literature. (author)

  12. Cell damage from radiation-induced bystander effects for different cell densities simulated by a mathematical model via cellular automata

    Energy Technology Data Exchange (ETDEWEB)

    Meireles, Sincler P. de; Santos, Adriano M.; Grynberg, Suely Epsztein, E-mail: spm@cdtn.b, E-mail: amsantos@cdtn.b, E-mail: seg@cdtn.b [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil); Nunes, Maria Eugenia S., E-mail: mariaeugenia@iceb.ufop.b [Universidade Federal de Ouro Preto (UFOP), MG (Brazil)

    2011-07-01

    During recent years, there has been a shift from an approach focused entirely on DNA as the main target of ionizing radiation to a vision that considers complex signaling pathways in cells and among cells within tissues. Several newly recognized responses were classified as the so-called non-target responses in which the biological effects are not directly related to the amount of energy deposited in the DNA of cells that were traversed by radiation. In 1992 the bystander effect was described referring to a series of responses such as death, chromosomal instability or other abnormalities that occur in non-irradiated cells that came into contact with irradiated cells or medium from irradiated cells. In this work, we have developed a mathematical model via cellular automata, to quantify cell death induced by the bystander effect. The model is based on experiments with irradiated cells conditioned medium which suggests that irradiated cells secrete molecules in the medium that are capable of damaging other cells. The computational model consists of two-dimensional cellular automata which is able to simulate the transmission of bystander signals via extrinsic route and via Gap junctions. The model has been validated by experimental results in the literature. The time evolution of the effect and the dose-response curves were obtained in good accordance to them. Simulations were conducted for different values of bystander and irradiated cell densities with constant dose. From this work, we have obtained a relationship between cell density and effect. (author)

  13. Cell damage from radiation-induced bystander effects for different cell densities simulated by a mathematical model via cellular automata

    International Nuclear Information System (INIS)

    Meireles, Sincler P. de; Santos, Adriano M.; Grynberg, Suely Epsztein; Nunes, Maria Eugenia S.

    2011-01-01

    During recent years, there has been a shift from an approach focused entirely on DNA as the main target of ionizing radiation to a vision that considers complex signaling pathways in cells and among cells within tissues. Several newly recognized responses were classified as the so-called non-target responses in which the biological effects are not directly related to the amount of energy deposited in the DNA of cells that were traversed by radiation. In 1992 the bystander effect was described referring to a series of responses such as death, chromosomal instability or other abnormalities that occur in non-irradiated cells that came into contact with irradiated cells or medium from irradiated cells. In this work, we have developed a mathematical model via cellular automata, to quantify cell death induced by the bystander effect. The model is based on experiments with irradiated cells conditioned medium which suggests that irradiated cells secrete molecules in the medium that are capable of damaging other cells. The computational model consists of two-dimensional cellular automata which is able to simulate the transmission of bystander signals via extrinsic route and via Gap junctions. The model has been validated by experimental results in the literature. The time evolution of the effect and the dose-response curves were obtained in good accordance to them. Simulations were conducted for different values of bystander and irradiated cell densities with constant dose. From this work, we have obtained a relationship between cell density and effect. (author)

  14. The importance of bystander effects in radiation therapy in melanoma skin-cancer cells and umbilical-cord stromal stem cells

    International Nuclear Information System (INIS)

    Gómez-Millán, Jaime; Katz, Iana Suly Santos; Farias, Virgínea de Araujo; Linares-Fernández, Jose-Luis; López-Peñalver, Jesús; Ortiz-Ferrón, Gustavo; Ruiz-Ruiz, Carmen; Oliver, Francisco Javier; Ruiz de Almodóvar, José Mariano

    2012-01-01

    Purpose: To examine direct and bystander radiation-induced effects in normal umbilical-cord stromal stem cell (HCSSC) lines and in human cancer cells. Materials and methods: The UCSSC lines used in this study were obtained in our laboratory. Two cell lines (UCSSC 35 and UCSSC 37) and two human melanoma skin-cancer cells (A375 and G361) were exposed to ionizing radiation to measure acute radiation-dosage cell-survival curves and radiation-induced bystander cell-death response. Normal cells, although extremely sensitive to ionizing radiation, were resistant to the bystander effect whilst tumor cells were sensitive to irradiated cell-conditioned media, showing a dose–response relationship that became saturated at relatively low doses. We applied a biophysical model to describe bystander cell-death through the binding of a ligand to the cells. This model allowed us to calculate the maximum cell death (χ max ) produced by the bystander effect together with its association constant (K By ) in terms of dose equivalence (Gy). The values obtained for K By in A375 and G361 cells were 0.23 and 0.29 Gy, respectively. Conclusion: Our findings help to understand how anticancer therapy could have an additional decisive effect in that the response of sub-lethally hit tumor cells to damage might be required for therapy to be successful because the survival of cells communicating with irradiated cells is reduced.

  15. Critical reevaluation of the dose-response relationships for carcinogenic effects of low-level ionizing radiation

    International Nuclear Information System (INIS)

    Upton, A.C.

    2003-01-01

    In recent decades, it has been customary, for radiation protection purposes, to assume that the overall risk of radiation-induced cancer increases as a linear-nonthreshold function of the dose. The existing data do not exclude the existence of a threshold, however, and the dose-response relationship is known to vary, depending on the type of cancer in queation, the dose, dose rate, and LET of the radiation, the age, sex, and physiological state of the exposed individuals, and other variables, including the potential influence of adaptive responses and bystander effects at low doses. In light of advncing knowledge, therefore, the dose-response relationship for carcinogenic effects of low-level radiation has been reevaluated periodically by the National Council on Radiation Protection and Measurements, the International Commission of Radiological Protection, the United Nations Scientific Committee on the Effects of Atomic Radiation, the U.S. National Academy of Sciences, and other organizations. The most recent such reviews have generally found the weight of evidence to suggest that lesions which are precursors to cancer (i.e., mutations and chromosome aberrations), and certain types of cancer as well, may increase in frequency linearly with the dose in the low-dose domain. On this basis, it is concluded that no alternative dose-response model for the carcinogenic effects of low-level radiation is more plausible than the linear-nonthreshold model, although other dose-response relationships cannot be excluded. (authors)

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

    Science.gov (United States)

    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

  17. Non-targeted bystander effects induced by ionizing radiation

    International Nuclear Information System (INIS)

    Morgan, William F.; Sowa, Marianne B.

    2007-01-01

    Radiation-induced bystander effects refer to those responses occurring in cells that were not subject to energy deposition events following ionizing radiation. These bystander cells may have been neighbors of irradiated cells, or physically separated but subject to soluble secreted signals from irradiated cells. Bystander effects have been observed in vitro and in vivo and for various radiation qualities. In tribute to an old friend and colleague, Anthony V. Carrano, who would have said 'well what are the critical questions that should be addressed, and so what?', we review the evidence for non-targeted radiation-induced bystander effects with emphasis on prevailing questions in this rapidly developing research field, and the potential significance of bystander effects in evaluating the detrimental health effects of radiation exposure

  18. Bystander cells enhance NK cytotoxic efficiency by reducing search time.

    Science.gov (United States)

    Zhou, Xiao; Zhao, Renping; Schwarz, Karsten; Mangeat, Matthieu; Schwarz, Eva C; Hamed, Mohamed; Bogeski, Ivan; Helms, Volkhard; Rieger, Heiko; Qu, Bin

    2017-03-13

    Natural killer (NK) cells play a central role during innate immune responses by eliminating pathogen-infected or tumorigenic cells. In the microenvironment, NK cells encounter not only target cells but also other cell types including non-target bystander cells. The impact of bystander cells on NK killing efficiency is, however, still elusive. In this study we show that the presence of bystander cells, such as P815, monocytes or HUVEC, enhances NK killing efficiency. With bystander cells present, the velocity and persistence of NK cells were increased, whereas the degranulation of lytic granules remained unchanged. Bystander cell-derived H 2 O 2 was found to mediate the acceleration of NK cell migration. Using mathematical diffusion models, we confirm that local acceleration of NK cells in the vicinity of bystander cells reduces their search time to locate target cells. In addition, we found that integrin β chains (β1, β2 and β7) on NK cells are required for bystander-enhanced NK migration persistence. In conclusion, we show that acceleration of NK cell migration in the vicinity of H 2 O 2 -producing bystander cells reduces target cell search time and enhances NK killing efficiency.

  19. Studies of Bystander Effects in 3-D Tissue Systems Using a Low-LET Microbeam

    International Nuclear Information System (INIS)

    Brenner, David J.

    2009-01-01

    It is now accepted that biological effects may occur in cells that were not themselves traversed by ionizing radiation but are close to those that were. Little is known about the mechanism underlying such a bystander effect, although cell-to-cell communication is thought to be important. Previous work demonstrated a significant bystander effect for clonogenic survival and oncogenic transformation in C3H 10T(1/2) cells. Additional studies were undertaken to assess the importance of the degree of cell-to-cell contact at the time of irradiation on the magnitude of this bystander effect by varying the cell density. When 10% of cells were exposed to a range of 2-12 alpha particles, a significantly greater number of cells were inactivated when cells were irradiated at high density than at low density. In addition, the oncogenic transformation frequency was significantly higher in high-density cultures. These results suggest that when a cell is hit by radiation, the transmission of the bystander signal through cell-to-cell contact is an important mediator of the effect, implicating the involvement of intracellular communication through gap junctions. Additional studies to address the relationship between the bystander effect and the adaptive response were undertaken. A novel apparatus, where targeted and non-targeted cells were grown in close proximity, was used to investigate these. It was further examined whether a bystander effect or an adaptive response could be induced by a factor(s) present in the supernatants of cells exposed to a high or low dose of X-rays, respectively. When non-hit cells were co-cultured for 24 h with cells irradiated with 5 Gy alpha-particles, a significant increase in both cell killing and oncogenic transformation frequency was observed. If these cells were treated with 2 cGy X-rays 5 h before co-culture with irradiated cells, approximately 95% of the bystander effect was cancelled out. A 2.5-fold decrease in the oncogenic transformation

  20. Repair and dose-response at low doses

    International Nuclear Information System (INIS)

    Totter, J.R.; Weinberg, A.M.

    1977-04-01

    The DNA of each individual is subject to formation of some 2-4 x 10 14 ion pairs during the first 30 years of life from background radiation. If a single hit is sufficient to cause cancer, as is implicit in the linear, no-threshold theories, it is unclear why all individuals do not succumb to cancer, unless repair mechanisms operate to remove the damage. We describe a simple model in which the exposed population displays a distribution of repair thresholds. The dose-response at low dose is shown to depend on the shape of the threshold distribution at low thresholds. If the probability of zero threshold is zero, the response at low dose is quadratic. The model is used to resolve a longstanding discrepancy between observed incidence of leukemia at Nagasaki and the predictions of the usual linear hypothesis

  1. Radiation-induced bystander effects in cultured human stem cells.

    Directory of Open Access Journals (Sweden)

    Mykyta V Sokolov

    2010-12-01

    Full Text Available The radiation-induced "bystander effect" (RIBE was shown to occur in a number of experimental systems both in vitro and in vivo as a result of exposure to ionizing radiation (IR. RIBE manifests itself by intercellular communication from irradiated cells to non-irradiated cells which may cause DNA damage and eventual death in these bystander cells. It is known that human stem cells (hSC are ultimately involved in numerous crucial biological processes such as embryologic development; maintenance of normal homeostasis; aging; and aging-related pathologies such as cancerogenesis and other diseases. However, very little is known about radiation-induced bystander effect in hSC. To mechanistically interrogate RIBE responses and to gain novel insights into RIBE specifically in hSC compartment, both medium transfer and cell co-culture bystander protocols were employed.Human bone-marrow mesenchymal stem cells (hMSC and embryonic stem cells (hESC were irradiated with doses 0.2 Gy, 2 Gy and 10 Gy of X-rays, allowed to recover either for 1 hr or 24 hr. Then conditioned medium was collected and transferred to non-irradiated hSC for time course studies. In addition, irradiated hMSC were labeled with a vital CMRA dye and co-cultured with non-irradiated bystander hMSC. The medium transfer data showed no evidence for RIBE either in hMSC and hESC by the criteria of induction of DNA damage and for apoptotic cell death compared to non-irradiated cells (p>0.05. A lack of robust RIBE was also demonstrated in hMSC co-cultured with irradiated cells (p>0.05.These data indicate that hSC might not be susceptible to damaging effects of RIBE signaling compared to differentiated adult human somatic cells as shown previously. This finding could have profound implications in a field of radiation biology/oncology, in evaluating radiation risk of IR exposures, and for the safety and efficacy of hSC regenerative-based therapies.

  2. An Investigation of the Effects of Raw Garlic on Radiation-induced Bystander Effects in MCF7 Cells

    Directory of Open Access Journals (Sweden)

    Shokouhozaman Soleymanifard

    2014-11-01

    Full Text Available Introduction Radiation-induced bystander effect (RIBE is a phenomenon in which radiation signals are transmitted from irradiated cells to non-irradiated ones, inducing radiation effects in these cells. RIBE plays an effective role in radiation response at environmentally relevant low doses and in radiotherapy, given its impact on adjacent normal tissues or those far from the irradiated tumor. Reactive oxygen species contribute to RIBE induction. Therefore, the present study was conducted to investigate the possible inhibitory effects of garlic, as an antioxidant-containing plant, on RIBE. Materials and Methods MCF7 cells, treated with raw garlic extracts, were irradiated by 60Co gamma rays, and their culture medium was transferred to non-irradiated autologous bystander cells. Percentage cell viability and micronucleus formation in both irradiated and bystander cells were examined and compared with corresponding cell groups, not treated with garlic. Results Treatment with garlic extract reduced the number of micronucleus-containing cells in both irradiated and bystander cells. However, it only increased the percentage cell viability in bystander cells, not the irradiated ones. Conclusion RIBE was effectively suppressed by raw garlic extracts. Inhibitory effects of raw garlic may be of particular importance for exposure to environmentally relevant low doses, where RIBE dominates direct radiation effects. They are also partially important for addressing the limited therapeutic gain of radiotherapy, as they may only increase the percentage cell viability of bystander cells, not the directly irradiated tumor cells. However, more comprehensive in-vivo research regarding garlic treatment duration is required to support the obtained results.

  3. Radiation-induced bystander effects enhanced by elevated sodium chloride through sensitizing cells to bystander factors

    Energy Technology Data Exchange (ETDEWEB)

    Zhu Lingyan; Han Wei; Chen Shaopeng; Zhao Ye; Jiang Erkang; Bao Lingzhi; Pei Bei; Yang Gen; Zhao Guoping; Wang Jun; Xu An [Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, P.O. Box 1126, Hefei 230031, Anhui (China); Wu Lijun [Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, P.O. Box 1126, Hefei 230031, Anhui (China)], E-mail: ljw@ipp.ac.cn

    2008-09-26

    Radiation-induced bystander effects (RIBE) have been demonstrated to occur widely in various cell lines. However, very little data is available on the genotoxic effects of RIBE combined with other factor(s). We reported previously that with a low dose of {alpha}-particle irradiation, the fraction of {gamma}-H2AX foci-positive cells in non-irradiated bystander cells was significantly increased under elevated NaCl culture conditions. In this study, we further investigated the functional role of NaCl in the enhancement of RIBE using a specially designed co-culture system and micronucleus (MN) test. It was shown that the MN frequency was not increased significantly by elevated NaCl (9.0 g/L) alone or by medium exposure. However, with 1.0 cGy {alpha}-particle irradiation, the induced MN frequency increased significantly in both irradiated and non-irradiated bystander regions. Additional studies showed that elevated NaCl made the non-irradiated bystander cells more vulnerable to bystander factors. Furthermore, it was found that the induced MN frequency in cells both in irradiated and non-irradiated bystander regions was weakened when the hypertonic medium was changed to normotonic medium for 2 h before irradiation. Such observations were quite similar to the co-effect of NaCl and hydrogen peroxide (H{sub 2}O{sub 2}), indicating that elevated NaCl might sensitize non-irradiated cells to bystander factors-induced oxidative stress.

  4. Dose/response relationships and policy formulation

    International Nuclear Information System (INIS)

    Robinson, P.D.

    1981-01-01

    The ICRP 26 cost/benefit approach to establishing operational radiation protection guidelines is discussed. The purpose is to aid the policy maker in the decision making process, using as a basis the dose-response curve

  5. Bystanders not so innocent after all.

    Science.gov (United States)

    Batten, Marcel; Ghilardi, Nico

    2012-06-29

    Interleukin 27 (IL-27) regulates immune responses, including T helper 17 (Th17) cell activity. In this issue of Immunity, Hirahara et al. (2012) demonstrate that IL-27 suppresses Th17 cells in trans through induction of the inhibitory ligand PD-L1 on bystander T cells. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Dose-response-a challenge for allelopathy?

    Science.gov (United States)

    Belz, Regina G; Hurle, Karl; Duke, Stephen O

    2005-04-01

    The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions.

  7. The Dose Response Relationship for Radiation Carcinogenesis

    Science.gov (United States)

    Hall, Eric

    2008-03-01

    Recent surveys show that the collective population radiation dose from medical procedures in the U.S. has increased by 750% in the past two decades. It would be impossible to imagine the practice of medicine today without diagnostic and therapeutic radiology, but nevertheless the widespread and rapidly increasing use of a modality which is a known human carcinogen is a cause for concern. To assess the magnitude of the problem it is necessary to establish the shape of the dose response relationship for radiation carcinogenesis. Information on radiation carcinogenesis comes from the A-bomb survivors, from occupationally exposed individuals and from radiotherapy patients. The A-bomb survivor data indicates a linear relationship between dose and the risk of solid cancers up to a dose of about 2.5 Sv. The lowest dose at which there is a significant excess cancer risk is debatable, but it would appear to be between 40 and 100 mSv. Data from the occupation exposure of nuclear workers shows an excess cancer risk at an average dose of 19.4 mSv. At the other end of the dose scale, data on second cancers in radiotherapy patients indicates that cancer risk does not continue to rise as a linear function of dose, but tends towards a plateau of 40 to 60 Gy, delivered in a fractionated regime. These data can be used to estimate the impact of diagnostic radiology at the low dose end of the dose response relationship, and the impact of new radiotherapy modalities at the high end of the dose response relationship. In the case of diagnostic radiology about 90% of the collective population dose comes from procedures (principally CT scans) which involve doses at which there is credible evidence of an excess cancer incidence. While the risk to the individual is small and justified in a symptomatic patient, the same is not true of some screening procedures is asymptomatic individuals, and in any case the huge number of procedures must add up to a potential public health problem. In the

  8. Ionizing radiation-induced bystander mutagenesis and adaptation: Quantitative and temporal aspects

    International Nuclear Information System (INIS)

    Zhang Ying; Zhou Junqing; Baldwin, Joseph; Held, Kathryn D.; Prise, Kevin M.; Redmond, Robert W.; Liber, Howard L.

    2009-01-01

    This work explores several quantitative aspects of radiation-induced bystander mutagenesis in WTK1 human lymphoblast cells. Gamma-irradiation of cells was used to generate conditioned medium containing bystander signals, and that medium was transferred onto naive recipient cells. Kinetic studies revealed that it required up to 1 h to generate sufficient signal to induce the maximal level of mutations at the thymidine kinase locus in the bystander cells receiving the conditioned medium. Furthermore, it required at least 1 h of exposure to the signal in the bystander cells to induce mutations. Bystander signal was fairly stable in the medium, requiring 12-24 h to diminish. Medium that contained bystander signal was rendered ineffective by a 4-fold dilution; in contrast a greater than 20-fold decrease in the cell number irradiated to generate a bystander signal was needed to eliminate bystander-induced mutagenesis. This suggested some sort of feedback inhibition by bystander signal that prevented the signaling cells from releasing more signal. Finally, an ionizing radiation-induced adaptive response was shown to be effective in reducing bystander mutagenesis; in addition, low levels of exposure to bystander signal in the transferred medium induced adaptation that was effective in reducing mutations induced by subsequent γ-ray exposures.

  9. Neutron induced bystander effect among zebrafish embryos

    Science.gov (United States)

    Ng, C. Y. P.; Kong, E. Y.; Kobayashi, A.; Suya, N.; Uchihori, Y.; Cheng, S. H.; Konishi, T.; Yu, K. N.

    2015-12-01

    The present paper reported the first-ever observation of neutron induced bystander effect (NIBE) using zebrafish (Danio rerio) embryos as the in vivo model. The neutron exposure in the present work was provided by the Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) facility at the National Institute of Radiological Sciences (NIRS), Chiba, Japan. Two different strategies were employed to induce NIBE, namely, through directly partnering and through medium transfer. Both results agreed with a neutron-dose window (20-50 mGy) which could induce NIBE. The lower dose limit corresponded to the threshold amount of neutron-induced damages to trigger significant bystander signals, while the upper limit corresponded to the onset of gamma-ray hormesis which could mitigate the neutron-induced damages and thereby suppress the bystander signals. Failures to observe NIBE in previous studies were due to using neutron doses outside the dose-window. Strategies to enhance the chance of observing NIBE included (1) use of a mono-energetic high-energy (e.g., between 100 keV and 2 MeV) neutron source, and (2) use of a neutron source with a small gamma-ray contamination. It appeared that the NASBEE facility used in the present study fulfilled both conditions, and was thus ideal for triggering NIBE.

  10. Predicting High-School Students' Bystander Behavior in Simulated Dating Violence Situations.

    Science.gov (United States)

    Jouriles, Ernest N; Rosenfield, David; Yule, Kristen; Sargent, Kelli S; McDonald, Renee

    2016-03-01

    Dating violence among adolescents is associated with a variety of negative health consequences for victims. Bystander programs are being developed and implemented with the intention of preventing such violence, but determinants of high-school students' responsive bystander behavior remain unclear. The present study examines hypothesized determinants of high-school students' bystander behavior in simulated situations of dating violence. Participants were 80 high-school students who completed self-reports of hypothesized determinants of bystander behavior (responsibility, efficacy, and perceived benefits for intervening) at a baseline assessment. A virtual-reality paradigm was used to observationally assess bystander behavior at 1-week and 6-month assessments after baseline. Efficacy for intervening was positively associated with observed bystander behavior at the 1-week and 6-month assessments. Moreover, efficacy predicted bystander behavior over and above feelings of responsibility and perceived benefits for intervening. Contrary to our predictions, neither responsibility nor perceived benefits for intervening were associated with observed bystander behavior. This research advances our understanding of determinants of bystander behavior for high-school students and can inform prevention programming for adolescents. The study also introduces an innovative way to assess high-school students' bystander behavior. Copyright © 2016 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

  11. Bystander response to 2.5 Gy of protons in a human 3-dimensional skin model in 16 h after exposure

    Data.gov (United States)

    National Aeronautics and Space Administration — Bystander mechanisms that originate in the areas surrounding a tissue damage presumably play an important role participating in wound healing and tissue remodeling....

  12. The Significance of the Bystander Effect: Modeling, Experiments, and More Modeling

    Energy Technology Data Exchange (ETDEWEB)

    Brenner, David J.

    2009-07-22

    Non-targeted (bystander) effects of ionizing radiation are caused by intercellular signaling; they include production of DNA damage and alterations in cell fate (i.e. apoptosis, differentiation, senescence or proliferation). Biophysical models capable of quantifying these effects may improve cancer risk estimation at radiation doses below the epidemiological detection threshold. Understanding the spatial patterns of bystander responses is important, because it provides estimates of how many bystander cells are affected per irradiated cell. In a first approach to modeling of bystander spatial effects in a three-dimensional artificial tissue, we assumed the following: (1) The bystander phenomenon results from signaling molecules (S) that rapidly propagate from irradiated cells and decrease in concentration (exponentially in the case of planar symmetry) as distance increases. (2) These signals can convert cells to a long-lived epigenetically activated state, e.g. a state of oxidative stress; cells in this state are more prone to DNA damage and behavior alterations than normal and therefore exhibit an increased response (R) for many end points (e.g. apoptosis, differentiation, micronucleation). These assumptions were implemented by a mathematical formalism and computational algorithms. The model adequately described data on bystander responses in the 3D system using a small number of adjustable parameters. Mathematical models of radiation carcinogenesis are important for understanding mechanisms and for interpreting or extrapolating risk. There are two classes of such models: (1) long-term formalisms that track pre-malignant cell numbers throughout an entire lifetime but treat initial radiation dose-response simplistically and (2) short-term formalisms that provide a detailed initial dose-response even for complicated radiation protocols, but address its modulation during the subsequent cancer latency period only indirectly. We argue that integrating short- and long

  13. Caffeine Markedly Enhanced Radiation-Induced Bystander Effects

    International Nuclear Information System (INIS)

    Jiang Erkang; Wu Lijun

    2009-01-01

    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). (ion beam bioengineering)

  14. Computer modelling of radiation-induced bystander effect

    International Nuclear Information System (INIS)

    Khvostunov, Igor K.; Nikjoo, Hooshang

    2002-01-01

    Radiation-induced genomic instability and bystander effects are now well established consequences of exposure of living cells to ionising radiation. It has been observed that cells not directly hit by radiation tracks may still exhibit radiation effects. We present a quantitative modelling of the radiation-induced bystander effect based on a diffusion model of spreading the bystander signal. The model assumes the bystander factor to be a protein of low molecular weight, given out by the hit cell, diffusing in the medium and reacting with non-hit cells. The model calculations successfully predict the results of cell survival in an irradiated conditioned medium. The model predicts the shape of dose-effect relationship for cell survival and oncogenic transformation induced by broad-beam and micro-beam irradiation by alpha-particles. (author)

  15. Genomic instability after targeted irradiation of human lymphocytes: Evidence for inter-individual differences under bystander conditions

    International Nuclear Information System (INIS)

    Kadhim, Munira A.; Lee, Ryonfa; Moore, Stephen R.; Macdonald, Denise A.; Chapman, Kim L.; Patel, Gaurang; Prise, Kevin M.

    2010-01-01

    Environmental 222 radon exposure is a human health concern, and many studies demonstrate that very low doses of high LET α-particle irradiation initiate deleterious genetic consequences in both irradiated and non-irradiated bystander cells. One consequence, radiation-induced genomic instability (RIGI), is a hallmark of tumorigenesis and is often assessed by measuring delayed chromosomal aberrations. We utilised a technique that facilitates transient immobilization of primary lymphocytes for targeted microbeam irradiation and have reported that environmentally relevant doses, e.g. a single 3 He 2+ particle traversal to a single cell, are sufficient to induce RIGI. Herein we sought to determine differences in radiation response in lymphocytes isolated from five healthy male donors. Primary lymphocytes were irradiated with a single particle per cell nucleus. We found evidence for inter-individual variation in radiation response (RIGI, measured as delayed chromosome aberrations). Although this was not highly significant, it was possibly masked by high levels of intra-individual variation. While there are many studies showing a link between genetic predisposition and RIGI, there are few studies linking genetic background with bystander effects in normal human lymphocytes. In an attempt to investigate inter-individual variation in the induction of bystander effects, primary lymphocytes were irradiated with a single particle under conditions where fractions of the population were traversed. We showed a marked genotype-dependent bystander response in one donor after exposure to 15% of the population. The findings may also be regarded as a radiation-induced genotype-dependent bystander effect triggering an instability phenotype.

  16. Genomic instability after targeted irradiation of human lymphocytes: Evidence for inter-individual differences under bystander conditions

    Energy Technology Data Exchange (ETDEWEB)

    Kadhim, Munira A., E-mail: mkadhim@brookes.ac.uk [School of Life Sciences, Oxford Brookes University, Oxford OX3 0BP (United Kingdom); Lee, Ryonfa [Biophysics, GSI Helmholtzzentrum fuer Schwerionenforschung GmbH, Planckstrasse 1, D-64291 Darmstadt (Germany); Moore, Stephen R.; Macdonald, Denise A. [Radiation and Genome Stability Unit, Medical Research Council, Harwell, Oxfordshire OX11 0RD (United Kingdom); Chapman, Kim L. [School of Life Sciences, Oxford Brookes University, Oxford OX3 0BP (United Kingdom); Patel, Gaurang; Prise, Kevin M. [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast BT9 7BL (United Kingdom)

    2010-06-01

    Environmental {sup 222}radon exposure is a human health concern, and many studies demonstrate that very low doses of high LET {alpha}-particle irradiation initiate deleterious genetic consequences in both irradiated and non-irradiated bystander cells. One consequence, radiation-induced genomic instability (RIGI), is a hallmark of tumorigenesis and is often assessed by measuring delayed chromosomal aberrations. We utilised a technique that facilitates transient immobilization of primary lymphocytes for targeted microbeam irradiation and have reported that environmentally relevant doses, e.g. a single {sup 3}He{sup 2+} particle traversal to a single cell, are sufficient to induce RIGI. Herein we sought to determine differences in radiation response in lymphocytes isolated from five healthy male donors. Primary lymphocytes were irradiated with a single particle per cell nucleus. We found evidence for inter-individual variation in radiation response (RIGI, measured as delayed chromosome aberrations). Although this was not highly significant, it was possibly masked by high levels of intra-individual variation. While there are many studies showing a link between genetic predisposition and RIGI, there are few studies linking genetic background with bystander effects in normal human lymphocytes. In an attempt to investigate inter-individual variation in the induction of bystander effects, primary lymphocytes were irradiated with a single particle under conditions where fractions of the population were traversed. We showed a marked genotype-dependent bystander response in one donor after exposure to 15% of the population. The findings may also be regarded as a radiation-induced genotype-dependent bystander effect triggering an instability phenotype.

  17. The crooked shall be made straight: dose response relationships for carcinogenesis

    International Nuclear Information System (INIS)

    Hall, E.J.

    2003-01-01

    Estimates of radiation-induced malignancies come principally from the A-bomb survivors and from medically exposed individuals, including second cancers in radiotherapy patients. The A-bomb survivors show an excess incidence of carcinomas which is linear with dose from about 10 cGy to 2.5 Gy. Above and below this dose range, there is considerable uncertainty concerning the shape of the dose response relationship. These two dose ranges will be discussed separately. Low dose extrapolations ICRP and NCRP suggest that cancer risks at doses lower than those at which direct epidemiological observations are possible should be obtained by a linear extrapolation from higher doses. This is labeled a 'prudent and conservative' assumption but is a subject of considerable controversy. Two factors, the existence of radiosensitive subgroups in the human population (such as AT heterozygotes), and the demonstration of a Bystander effect both exaggerate the consequences of small doses of radiation and imply that a linear extrapolation from high doses would underestimate low dose risks. High dose extrapolations In the context of radiotherapy, some normal tissues receive 70 Gy, while a larger volume receives a lower dose, but still far higher than the range for which data are available from the A-bomb survivors. The question is, what is the dose response for carcinogenesis in the range 10 to 70 Gy? At one extreme, it might be expected that the risk of inducing cancer would fall off rapidly at higher does due to cell killing. The other extreme possibility is that the risk of solid tumors levels off by about 10 Gy, but does not decline thereafter. For a few cancers, data are available from 2 Gy in A-bomb survivors to 70 Gy in radiotherapy patients, and it appears that the relative risk does not vary with dose. This implies that the volume of tissue irradiated is more important than the maximum dose. This result has far reaching implications for new technologies such as IMRT, which

  18. Alpha-particles microbeam irradiation: impact of reactive oxygen species in bystander effect

    International Nuclear Information System (INIS)

    Hanot, M.

    2008-11-01

    Ionizing radiation-induced bystander effects arise in bystander cells that receive signals from directly irradiated cells. To date, free radicals are believed to play an active role in the bystander response, but this is incompletely characterized. To mark temporal and spatial impacts of bystander effect, we employed a precise α-particle microbeam to target a small fraction of sub-confluent osteoblastic cell cultures (MC3T3-E1). We identified the cellular membrane and mitochondria like two distinct places generating reactive oxygen species. The global oxidative stress observed after irradiation was significantly attenuated after filipin treatment, evidencing the pivotal role of membrane in MC3T3-E1 cells bystander response. To determine impact of bystander effect at a cell level, cellular consequences of this membrane-dependant bystander effect were then investigated. A variable fraction of the cell population (10 to 100%) was individually targeted. In this case, mitotic death and micronuclei yield both increased in bystander cells as well as in targeted cells demonstrating a role of bystander signals between irradiated cells in an autocrine or paracrine manner. Our results indicate a complex interaction of direct irradiation and bystander signals that lead to a membrane-dependant amplification of cell responses. (author)

  19. Human Lung Cancer Risks from Radon – Part I - Influence from Bystander Effects - A Microdose Analysis

    Science.gov (United States)

    Leonard, Bobby E.; Thompson, Richard E.; Beecher, Georgia C.

    2010-01-01

    Since the publication of the BEIR VI report in 1999 on health risks from radon, a significant amount of new data has been published showing various mechanisms that may affect the ultimate assessment of radon as a carcinogen, at low domestic and workplace radon levels, in particular the Bystander Effect (BE) and the Adaptive Response radio-protection (AR). We analyzed the microbeam and broadbeam alpha particle data of Miller et al. (1995, 1999), Zhou et al. (2001, 2003, 2004), Nagasawa and Little (1999, 2002), Hei et al. (1999), Sawant et al. (2001a) and found that the shape of the cellular response to alphas is relatively independent of cell species and LET of the alphas. The same alpha particle traversal dose response behavior should be true for human lung tissue exposure to radon progeny alpha particles. In the Bystander Damage Region of the alpha particle response, there is a variation of RBE from about 10 to 35. There is a transition region between the Bystander Damage Region and Direct Damage Region of between one and two microdose alpha particle traversals indicating that perhaps two alpha particle “hits” are necessary to produce the direct damage. Extrapolation of underground miners lung cancer risks to human risks at domestic and workplace levels may not be valid. PMID:21731539

  20. Perspectives on the role of bystander effect and genomic instability on therapy-induced secondary malignancy

    International Nuclear Information System (INIS)

    Perumal, Venkatachalam; Raavi, Venkateswarlu; Kanagaraj, Karthik; Shangamithra, V.; Paul, Solomon F.D.; Chinnadurai, M.

    2017-01-01

    Deviation from the orchestra of regulated cell division into unregulated and then result into the formation of tumor, is known as carcinogenesis. While causes and hallmarks of many cancer types are well established, newer concepts on tumor cell response to treatment, challenges established therapeutic regime and drives into alternative toward the better management. The phenomena of therapeutics induced bystander response, and genomic instability on late effects of cancer therapy is emerging as a newer challenge. Bystander response is defined as the manifestation of radiation/chemotherapy drug signatures on the unexposed cells which are in the closer vicinity of the directly exposed; on the other hand, genomic instability is defined as the expression of radiation/chemotherapy drug signatures in the progeny of exposed cells. Unequivocally, existence of those phenomena has been demonstrated with many cell types (both in vitro and in vivo) followed by radiation and widely used chemotherapeutic drugs. Nevertheless, it is also revealed that the effects are variable and depend on dose, type of radiation/chemicals agents, experimental model, type of donor and recipient cells, and biomarkers adopted; moreover, to observe those effects, reactive oxygen species has been reported as leading mediators of those responses when compared to other molecules such as interleukins, cytokines, and inflammatory markers. Available data on those phenomena and our findings suggest that a role of therapeutic drugs induced bystander effects, and genomic instability on the development of secondary malignancy cannot be ruled out completely. (author)

  1. Bystander effects and their implications for clinical radiotherapy

    International Nuclear Information System (INIS)

    Munro, Alastair J

    2009-01-01

    Radiation-induced bystander effects are defined as those biological effects expressed, after irradiation, by cells whose nuclei have not been directly irradiated. Radiation oncologists are only gradually beginning to appreciate the clinical relevance of radiation-induced bystander effects and associated phenomena: adaptive responses, genomic instability and abscopal effects. Incorporating bystander effects into the science underpinning clinical radiotherapy will involve moving beyond simple mechanistic models and towards a more systems-based approach. It is, given the protean nature of bystander effects, difficult to devise a coherent research strategy to investigate the clinical impact and relevance of bystander phenomena. Epidemiological approaches will be required, the traditional research models based on randomised controlled trials are unlikely to be adequate for the task. Any consideration of bystander effects challenges not only clinicians' preconceptions concerning the effects of radiation on tumours and normal tissues but also their ingenuity. This review covers, from a clinical perspective, the issues and problems associated with radiation-induced bystander effects.

  2. Radiation-induced bystander effects and the DNA paradigm: An 'out of field' perspective

    International Nuclear Information System (INIS)

    Mothersill, Carmel; Seymour, C.B.

    2006-01-01

    Over the past 20 years there has been increasing evidence that cells and the progeny of cells surviving a very low dose of ionizing radiation [μ-mGy] can exhibit a wide range of non-monotonic effects such as adaptive responses, low dose hypersensitivity and other delayed effects. These effects are inconsistent with the expected dose-response, when based on extrapolation of high dose data and cast doubt on the reliability of extrapolating from high dose data to predict low dose effects. Recently the cause of many of these effects has been tentatively ascribed to so-called 'bystander effects'. These are effects that occur in cells not directly hit by an ionizing track but which are influenced by signals from irradiated cells and are thus highly relevant in situations where the dose is very low. Not all bystander effects may be deleterious although most endpoints measured involve cell damage or death. In this commentary, we consider how these effects impact the historical central dogma of radiobiology and radiation protection, which is that DNA double strand breaks are the primary radiation-induced lesion which can be quantifiably related to received dose and which determine the probability that a cancer will result from a radiation exposure. We explore the low dose issues and the evidence and conclude that in the very low dose region, the primary determinant of radiation exposure outcome is the genetic and epigenetic background of the individual and not solely the dose. What this does is to dissociate dose from effect as a quantitative relationship, but it does not necessarily mean that the effect is ultimately unrelated to DNA damage. The fundamental thesis we present is that at low doses fundamentally different mechanisms underlie radiation action and that at these doses, effect is not quantitatively related to dose

  3. The impact of ultra-brief chest compression-only CPR video training on responsiveness, compression rate, and hands-off time interval among bystanders in a shopping mall.

    Science.gov (United States)

    Panchal, Ashish R; Meziab, Omar; Stolz, Uwe; Anderson, Wes; Bartlett, Mitchell; Spaite, Daniel W; Bobrow, Bentley J; Kern, Karl B

    2014-09-01

    Recent studies have demonstrated higher-quality chest compressions (CCs) following a 60 s ultra-brief video (UBV) on compression-only CPR (CO-CPR). However, the effectiveness of UBVs as a CPR-teaching tool for lay bystanders in public venues remains unknown. Determine whether an UBV is effective in teaching laypersons CO-CPR in a public setting and if viewing leads to superior responsiveness and CPR skills. Adult lay bystanders were enrolled in a public shopping mall and randomized to: (1) Control (CTR): sat idle for 60 s; (2) UBV: watched a 60 s UBV on CO-CPR. Subjects were read a scenario detailing a sudden collapse in the mall and asked to do what they "thought was best" on a mannequin. Performance measures were recorded for 2 min: responsiveness (time to call 911 and first CCs) and CPR quality [CC depth, rate, hands-off interval (time without CC after first CC)]. One hundred subjects were enrolled. Demographics were similar between groups. UBV subjects called 911 more frequently (percent difference: 31%) and initiated CCs sooner in the arrest scenario (median difference (MD): 5 s). UBV cohort had increased CC rate (MD: 19 cpm) and decreased hands-off interval (MD: 27 s). There was no difference in CC depth. Bystanders with UBV training in a shopping mall had significantly improved responsiveness, CC rate, and decreased hands-off interval. Given the short length of training, UBV may have potential as a ubiquitous intervention for public venues to help improve bystander reaction to arrest and CO-CPR performance. Published by Elsevier Ireland Ltd.

  4. Bystander effects and biota: implications of radiation-induced bystander effects for protection of the environment from ionising radiation

    International Nuclear Information System (INIS)

    Mothersill, C.E.; Seymour, C.B.

    2003-01-01

    Bystander effects are now known to be induced by both high and low LET in a variety of cells in culture. They have been proven to occur in vivo in mice following 0.5Gy total body irradiation and in blood from humans being treated for cancer by radiotherapy. Effects have also been detected in fish, crustacea and molluscs. The important questions now are not whether bystander effects occur but why and what implications they have, if any, for radiation protection. Different species and different genetic backgrounds within a species produce different types of bystander effect, different organs also produce different effects. This paper will review the data in this field and will discuss likely implications for protection of man and non-human biota. In particular it will look at the potential long-term outcomes for different organisational levels, from cell to ecosystem, of bystander mechanisms. In view of new concerns about the effects of low level radiation on non-human biota, emphasis will be placed on considering how bystander effects might operate at chronic low doses versus acute accidental low doses. Problems of radiation interaction with chemicals, whether chemicals can also induce 'bystander effects' , and how regulators might handle these situations which occur all the time in real environments, will be presented for discussion. Finally the paper will discuss likely implications of these mechanisms for evolutionary biology

  5. Preventing Interpersonal Violence on College Campuses: The Effect of One Act Training on Bystander Intervention.

    Science.gov (United States)

    Alegría-Flores, Kei; Raker, Kelli; Pleasants, Robert K; Weaver, Mark A; Weinberger, Morris

    2015-05-22

    Sexual assault, stalking, dating violence, and intimate partner violence, herein collectively termed interpersonal violence (IV), are public health problems affecting 20% to 25% of female college students. Currently, One Act is one of the few IV prevention training programs at universities that teach students bystander skills to intervene in low- and high-risk IV situations. The objectives of this study were 1) to evaluate One Act's effects on date rape attitudes and behaviors, and bystanders' confidence, willingness to help, and behavior, and 2) to compare the effects on bystander skills between One Act and Helping Advocates for Violence Ending Now (HAVEN), an IV response training program with similar participants. Data were collected over 2 years, before and after One Act and HAVEN trainings. We measured outcomes with four scales: College Date Rape Attitudes and Behaviors, Bystander Confidence, Willingness to Help, and Bystander Behavior. The analysis compared within- and between-group mean differences in scale scores pre- and post-trainings using linear mixed models. One Act showed improvements for date rape attitudes and behaviors (p trainings' effects on bystander willingness to help and behavior had similar patterns but were not statistically significant. We found a larger positive impact on bystander confidence among students who participated in the bystander prevention training compared with the response training. Further research is needed to improve the measures for bystander behavior and measure the bystander trainings' larger impact on the community. © The Author(s) 2015.

  6. Are nonparticipants in prosocial behavior merely innocent bystanders?

    Science.gov (United States)

    Anker, Ashley E; Feeley, Thomas Hugh

    2011-01-01

    Latané and Darley's (1970) bystander intervention theory was used to model individuals' participation in two prosocial behaviors (organ donation, green living). It is argued that nonparticipants in prosocial helping are innocent bystanders who likely fail to notice the need, do not interpret the cause as an emergency, do not accept responsibility for the need to help, and have little knowledge on how to help. Data in study 1 (n = 494) indicate support for the proposed innocent bystander path model (notice event → interpret event as emergency → accept responsibility → knowledge of how to help) in organ donation. Study 2 (n = 519) replicated the model in the context of green living and additionally found a direct path from noticing the event to knowledge of how to help. Implications of framing nonparticipation in prosocial behaviors as innocent bystander effects are discussed in context of campaign communication.

  7. Dose-response analysis using R

    DEFF Research Database (Denmark)

    Ritz, Christian; Baty, Florent; Streibig, Jens Carl

    2015-01-01

    Dose-response analysis can be carried out using multi-purpose commercial statistical software, but except for a few special cases the analysis easily becomes cumbersome as relevant, non-standard output requires manual programming. The extension package drc for the statistical environment R provides...

  8. Single toxin dose-response models revisited

    Energy Technology Data Exchange (ETDEWEB)

    Demidenko, Eugene, E-mail: eugened@dartmouth.edu [Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH03756 (United States); Glaholt, SP, E-mail: sglaholt@indiana.edu [Indiana University, School of Public & Environmental Affairs, Bloomington, IN47405 (United States); Department of Biological Sciences, Dartmouth College, Hanover, NH03755 (United States); Kyker-Snowman, E, E-mail: ek2002@wildcats.unh.edu [Department of Natural Resources and the Environment, University of New Hampshire, Durham, NH03824 (United States); Shaw, JR, E-mail: joeshaw@indiana.edu [Indiana University, School of Public & Environmental Affairs, Bloomington, IN47405 (United States); Chen, CY, E-mail: Celia.Y.Chen@dartmouth.edu [Department of Biological Sciences, Dartmouth College, Hanover, NH03755 (United States)

    2017-01-01

    The goal of this paper is to offer a rigorous analysis of the sigmoid shape single toxin dose-response relationship. The toxin efficacy function is introduced and four special points, including maximum toxin efficacy and inflection points, on the dose-response curve are defined. The special points define three phases of the toxin effect on mortality: (1) toxin concentrations smaller than the first inflection point or (2) larger then the second inflection point imply low mortality rate, and (3) concentrations between the first and the second inflection points imply high mortality rate. Probabilistic interpretation and mathematical analysis for each of the four models, Hill, logit, probit, and Weibull is provided. Two general model extensions are introduced: (1) the multi-target hit model that accounts for the existence of several vital receptors affected by the toxin, and (2) model with a nonzero mortality at zero concentration to account for natural mortality. Special attention is given to statistical estimation in the framework of the generalized linear model with the binomial dependent variable as the mortality count in each experiment, contrary to the widespread nonlinear regression treating the mortality rate as continuous variable. The models are illustrated using standard EPA Daphnia acute (48 h) toxicity tests with mortality as a function of NiCl or CuSO{sub 4} toxin. - Highlights: • The paper offers a rigorous study of a sigmoid dose-response relationship. • The concentration with highest mortality rate is rigorously defined. • A table with four special points for five morality curves is presented. • Two new sigmoid dose-response models have been introduced. • The generalized linear model is advocated for estimation of sigmoid dose-response relationship.

  9. Role of ROS-mediated autophagy in radiation-induced bystander effect of hepatoma cells.

    Science.gov (United States)

    Wang, Xiangdong; Zhang, Jianghong; Fu, Jiamei; Wang, Juan; Ye, Shuang; Liu, Weili; Shao, Chunlin

    2015-05-01

    Autophagy plays a crucial role in cellular response to ionizing radiation, but it is unclear whether autophagy can modulate radiation-induced bystander effect (RIBE). Here, we investigated the relationship between bystander damage and autophagy in human hepatoma cells of HepG2. HepG2 cells were treated with conditioned medium (CM) collected from 3 Gy γ-rays irradiated hepatoma HepG2 cells for 4, 12, or 24 h, followed by the measurement of micronuclei (MN), intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and protein expressions of microtubule-associated protein 1 light chain 3 (LC3) and Beclin-1 in the bystander HepG2 cells. In some experiments, the bystander HepG2 cells were respectively transfected with LC3 small interfering RNA (siRNA), Beclin-1 siRNA or treated with 1% dimethyl sulfoxide (DMSO). Additional MN and mitochondrial dysfunction coupled with ROS were induced in the bystander cells. The expressions of protein markers of autophagy, LC3-II/LC3-I and Beclin-1, increased in the bystander cells. The inductions of bystander MN and overexpressions of LC3 and Beclin-1 were significantly diminished by DMSO. However, when the bystander cells were transfected with LC3 siRNA or Beclin-1 siRNA, the yield of bystander MN was significantly enhanced. The elevated ROS have bi-functions in balancing the bystander effects. One is to cause MN and the other is to induce protective autophagy.

  10. Investigation of the bystander effect in MRC5 cells after acute and fractionated irradiation in vitro

    Directory of Open Access Journals (Sweden)

    Shokouhozaman Soleymanifard

    2014-01-01

    Full Text Available Radiation-induced bystander effect (RIBE has been defined as radiation responses observed in nonirradiated cells. It has been the focus of investigators worldwide due to the deleterious effects it induces in nonirradiated cells. The present study was performed to investigate whether acute or fractionated irradiation will evoke a differential bystander response in MRC5 cells. A normal human cell line (MRC5, and a human lung tumor cell line (QU-DB were exposed to 0, 1, 2, and 4Gy of single acute or fractionated irradiation of equal fractions with a gap of 6 h. The MRC5 cells were supplemented with the media of irradiated cells and their micronucleus frequency was determined. The micronucleus frequency after single and fractionated irradiation did not vary significantly in the MRC5 cells conditioned with autologous or QU-DB cell-irradiated media, except for 4Gy where the frequency of micronucleated cells was lower in those MRC5 cells cultured in the media of QU-DB-exposed with a single dose of 4Gy. Our study demonstrates that the radiation-induced bystander effect was almost similar after single acute and fractionated exposure in MRC5 cells.

  11. Investigation of the bystander effect in MRC5 cells after acute and fractionated irradiation in vitro

    International Nuclear Information System (INIS)

    Soleymanifard, Shokouhozaman; Toossi, Mohammad Taghi Bahreyni; Samani, Roghayeh Kamran; Mohebbi, Shokoufeh

    2014-01-01

    Radiation-induced bystander effect (RIBE) has been defined as radiation responses observed in nonirradiated cells. It has been the focus of investigators worldwide due to the deleterious effects it induces in nonirradiated cells. The present study was performed to investigate whether acute or fractionated irradiation will evoke a differential bystander response in MRC5 cells. A normal human cell line (MRC5), and a human lung tumor cell line (QU-DB) were exposed to 0, 1, 2, and 4Gy of single acute or fractionated irradiation of equal fractions with a gap of 6 h. The MRC5 cells were supplemented with the media of irradiated cells and their micronucleus frequency was determined. The micronucleus frequency after single and fractionated irradiation did not vary significantly in the MRC5 cells conditioned with autologous or QU-DB cell-irradiated media, except for 4Gy where the frequency of micronucleated cells was lower in those MRC5 cells cultured in the media of QU-DB-exposed with a single dose of 4Gy. Our study demonstrates that the radiation-induced bystander effect was almost similar after single acute and fractionated exposure in MRC5 cells. (author)

  12. Critical reevaluation of the dose-response relationships for carcinogenic effects of low-level ionizing radiation

    International Nuclear Information System (INIS)

    Upton, Arthur C.

    2002-01-01

    In recent decades, it has been customary, for radiation protection purposes, to assume that the overall risk of radiation- included cancer increases as a linear-nonthreshold function of the dose. The existing data do not exclude the existence of a threshold, however, and the dose-response relationship is known to vary depending on the type of cancer in question, the dose, dose rate and LET of the radiation, the age, sex and physiological state of the exposed individuals, and other variables, including the potential influence of adaptive responses and bystander effects at low doses. In light of advancing knowledge, therefore, the dose-response relationship for carcinogenic effects of low-level radiation has been reevaluated periodically by the National Council on Radiation Protection and Measurements, the International Commission of Radiological Protection, the United Nations Scientific Committee on the Effects of Atomic Radiation, the U.S. National Academy of Sciences Committee on the Effects of Atomic Radiation, the U.S. National Academy of Sciences, and other organizations. The most recent such reviews have generally found the weight of evidence to suggest that lesions which are precursors to cancer (i.e., mutations and chromosome aberrations), and certain types of cancer as well, may increase in frequency linearly aberrations), and certain types of cancer as well, may increase in frequency linearly with the dose in the low-dose domain. On this basis, it is concluded that no alternative dose-response model for the carcinogenic effects of low-level radiation is ore plausible than the linear-nonthreshold model, although other dose-response relationships cannot be excluded. (author)

  13. Bystander apoptosis in human cells mediated by irradiated blood plasma

    Energy Technology Data Exchange (ETDEWEB)

    Vinnikov, Volodymyr, E-mail: vlad.vinnikov@mail.ru [Grigoriev Institute for Medical Radiology of the National Academy of Medical Science of Ukraine (Ukraine); Lloyd, David; Finnon, Paul [Centre for Radiation, Chemical and Environmental Hazards of the Health Protection Agency of the United Kingdom (United Kingdom)

    2012-03-01

    Following exposure to high doses of ionizing radiation, due to an accident or during radiotherapy, bystander signalling poses a potential hazard to unirradiated cells and tissues. This process can be mediated by factors circulating in blood plasma. Thus, we assessed the ability of plasma taken from in vitro irradiated human blood to produce a direct cytotoxic effect, by inducing apoptosis in primary human peripheral blood mononuclear cells (PBM), which mainly comprised G{sub 0}-stage lymphocytes. Plasma was collected from healthy donors' blood irradiated in vitro to 0-40 Gy acute {gamma}-rays. Reporter PBM were separated from unirradiated blood with Histopaque and held in medium with the test plasma for 24 h at 37 Degree-Sign C. Additionally, plasma from in vitro irradiated and unirradiated blood was tested against PBM collected from blood given 4 Gy. Apoptosis in reporter PBM was measured by the Annexin V test using flow cytometry. Plasma collected from unirradiated and irradiated blood did not produce any apoptotic response above the control level in unirradiated reporter PBM. Surprisingly, plasma from irradiated blood caused a dose-dependent reduction of apoptosis in irradiated reporter PBM. The yields of radiation-induced cell death in irradiated reporter PBM (after subtracting the respective values in unirradiated reporter PBM) were 22.2 {+-} 1.8% in plasma-free cultures, 21.6 {+-} 1.1% in cultures treated with plasma from unirradiated blood, 20.2 {+-} 1.4% in cultures with plasma from blood given 2-4 Gy and 16.7 {+-} 3.2% in cultures with plasma from blood given 6-10 Gy. These results suggested that irradiated blood plasma did not cause a radiation-induced bystander cell-killing effect. Instead, a reduction of apoptosis in irradiated reporter cells cultured with irradiated blood plasma has implications concerning oncogenic risk from mutated cells surviving after high dose in vivo irradiation (e.g. radiotherapy) and requires further study.

  14. Bystander apoptosis in human cells mediated by irradiated blood plasma

    International Nuclear Information System (INIS)

    Vinnikov, Volodymyr; Lloyd, David; Finnon, Paul

    2012-01-01

    Following exposure to high doses of ionizing radiation, due to an accident or during radiotherapy, bystander signalling poses a potential hazard to unirradiated cells and tissues. This process can be mediated by factors circulating in blood plasma. Thus, we assessed the ability of plasma taken from in vitro irradiated human blood to produce a direct cytotoxic effect, by inducing apoptosis in primary human peripheral blood mononuclear cells (PBM), which mainly comprised G 0 -stage lymphocytes. Plasma was collected from healthy donors’ blood irradiated in vitro to 0–40 Gy acute γ-rays. Reporter PBM were separated from unirradiated blood with Histopaque and held in medium with the test plasma for 24 h at 37 °C. Additionally, plasma from in vitro irradiated and unirradiated blood was tested against PBM collected from blood given 4 Gy. Apoptosis in reporter PBM was measured by the Annexin V test using flow cytometry. Plasma collected from unirradiated and irradiated blood did not produce any apoptotic response above the control level in unirradiated reporter PBM. Surprisingly, plasma from irradiated blood caused a dose-dependent reduction of apoptosis in irradiated reporter PBM. The yields of radiation-induced cell death in irradiated reporter PBM (after subtracting the respective values in unirradiated reporter PBM) were 22.2 ± 1.8% in plasma-free cultures, 21.6 ± 1.1% in cultures treated with plasma from unirradiated blood, 20.2 ± 1.4% in cultures with plasma from blood given 2–4 Gy and 16.7 ± 3.2% in cultures with plasma from blood given 6–10 Gy. These results suggested that irradiated blood plasma did not cause a radiation-induced bystander cell-killing effect. Instead, a reduction of apoptosis in irradiated reporter cells cultured with irradiated blood plasma has implications concerning oncogenic risk from mutated cells surviving after high dose in vivo irradiation (e.g. radiotherapy) and requires further study.

  15. Bystanders Are the Key to Stopping Bullying

    Science.gov (United States)

    Padgett, Sharon; Notar, Charles E.

    2013-01-01

    Bullying is the dominance over another. Bullying occurs when there is an audience. Peer bystanders provide an audience 85% of instances of bullying. If you remove the audience bullying should stop. The article is a review of literature (2002-2013) on the role of bystanders; importance of bystanders; why bystanders behave as they do; resources to…

  16. Modulation of modeled microgravity on radiation-induced bystander effects in Arabidopsis thaliana

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ting [Key Laboratory of Ion Beam Bio-engineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences and Anhui Province, Hefei, Anhui 230031 (China); Sun, Qiao [Space Molecular Biological Lab, China Academy of Space Technology, Beijing 100086 (China); Xu, Wei; Li, Fanghua [Key Laboratory of Ion Beam Bio-engineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences and Anhui Province, Hefei, Anhui 230031 (China); Li, Huasheng; Lu, Jinying [Space Molecular Biological Lab, China Academy of Space Technology, Beijing 100086 (China); Wu, Lijun; Wu, Yuejin [Key Laboratory of Ion Beam Bio-engineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences and Anhui Province, Hefei, Anhui 230031 (China); Liu, Min [Space Molecular Biological Lab, China Academy of Space Technology, Beijing 100086 (China); Bian, Po [Key Laboratory of Ion Beam Bio-engineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences and Anhui Province, Hefei, Anhui 230031 (China)

    2015-03-15

    Highlights: • The effects of microgravity on the radiation-induced bystander effects (RIBE) were definitely demonstrated. • The effects of microgravity on RIBE might be divergent for different biological events. • The microgravity mainly modified the generation or transport of bystander signals at early stage. - Abstract: Both space radiation and microgravity have been demonstrated to have inevitable impact on living organisms during space flights and should be considered as important factors for estimating the potential health risk for astronauts. Therefore, the question whether radiation effects could be modulated by microgravity is an important aspect in such risk evaluation. Space particles at low dose and fluence rate, directly affect only a fraction of cells in the whole organism, which implement radiation-induced bystander effects (RIBE) in cellular response to space radiation exposure. The fact that all of the RIBE experiments are carried out in a normal gravity condition bring forward the need for evidence regarding the effect of microgravity on RIBE. In the present study, a two-dimensional rotation clinostat was adopted to demonstrate RIBE in microgravity conditions, in which the RIBE was assayed using an experimental system of root-localized irradiation of Arabidopsis thaliana (A. thaliana) plants. The results showed that the modeled microgravity inhibited significantly the RIBE-mediated up-regulation of expression of the AtRAD54 and AtRAD51 genes, generation of reactive oxygen species (ROS) and transcriptional activation of multicopy P35S:GUS, but made no difference to the induction of homologous recombination by RIBE, showing divergent responses of RIBE to the microgravity conditions. The time course of interaction between the modeled microgravity and RIBE was further investigated, and the results showed that the microgravity mainly modulated the processes of the generation or translocation of the bystander signal(s) in roots.

  17. Role of ATM in bystander signaling between human monocytes and lung adenocarcinoma cells.

    Science.gov (United States)

    Ghosh, Somnath; Ghosh, Anu; Krishna, Malini

    2015-12-01

    The response of a cell or tissue to ionizing radiation is mediated by direct damage to cellular components and indirect damage mediated by radiolysis of water. Radiation affects both irradiated cells and the surrounding cells and tissues. The radiation-induced bystander effect is defined by the presence of biological effects in cells that were not themselves in the field of irradiation. To establish the contribution of the bystander effect in the survival of the neighboring cells, lung carcinoma A549 cells were exposed to gamma-irradiation, 2Gy. The medium from the irradiated cells was transferred to non-irradiated A549 cells. Irradiated A549 cells as well as non-irradiated A549 cells cultured in the presence of medium from irradiated cells showed decrease in survival and increase in γ-H2AX and p-ATM foci, indicating a bystander effect. Bystander signaling was also observed between different cell types. Phorbol-12-myristate-13-acetate (PMA)-stimulated and gamma-irradiated U937 (human monocyte) cells induced a bystander response in non-irradiated A549 (lung carcinoma) cells as shown by decreased survival and increased γ-H2AX and p-ATM foci. Non-stimulated and/or irradiated U937 cells did not induce such effects in non-irradiated A549 cells. Since ATM protein was activated in irradiated cells as well as bystander cells, it was of interest to understand its role in bystander effect. Suppression of ATM with siRNA in A549 cells completely inhibited bystander effect in bystander A549 cells. On the other hand suppression of ATM with siRNA in PMA stimulated U937 cells caused only a partial inhibition of bystander effect in bystander A549 cells. These results indicate that apart from ATM, some additional factor may be involved in bystander effect between different cell types. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Significance of radiation-induced bystander effects in radiation therapy

    International Nuclear Information System (INIS)

    Suzuki, Masao

    2014-01-01

    Since 1994, a Phase I/II clinical study and radiotherapy have carried out using carbon-ion beams produced with the Heavy Ion Medical Accelerator in Chiba (HIMAC) at National Institute of Radiological Sciences. Now we constructed the new treatment facility for the advanced carbon-ion therapy at HIMAC applying a 3D fast spot scanning system with pencil beams. In the field of fundamental biological studies for high-LET heavy ions, there are some reports regarding bystander effects after exposure to alpha particles derived from 238 Pu or He-ion microbeams. However, only limited sets of studies have examined bystander effects after exposure to different ion species heavier than helium, such as carbon ions. We have been investigating bystander cellular responses in both normal human and human tumor cells irradiated with the HIMAC carbon ions. Bystander cell-killing effect was observed in the cells harboring wild-type P53 gene, but not in the P53-mutated cells. Moreover, observed bystander effect was suppressed by treating with a specific inhibitor of gap-junction mediated cell-cell communication. There is clear evidence that the carbon-ion irradiation enables the enhanced cell killing in cells with wild-type P53 gene via gap-junction mediated bystander effect. (author)

  19. MRC5 and QU-DB bystander cells can produce bystander factors and induce radiation bystander effect

    Directory of Open Access Journals (Sweden)

    Mohammad Taghi Bahreyni Toossi

    2014-01-01

    Full Text Available Radiation damages initiated by radiation-induced bystander effect (RIBE are not limited to the first or immediate neighbors of the irradiated cells, but the effects have been observed in the cells far from the irradiation site. It has been postulated that bystander cells, by producing bystander factors, are actively involved in the propagation of bystander effect in the regions beyond the initial irradiated site. Current study was planned to test the hypothesis. MRC5 and QU-DB cell lines were irradiated, and successive medium transfer technique was performed to induce bystander effects in two bystander cell groups. Conditioned medium extracted from the target cells was transferred to the bystander cells (first bystander cells. After one hour, conditioned medium was substituted by fresh medium. Two hours later, the fresh medium was transferred to a second group of non-irradiated cells (second bystander cells. Micronucleated cells (MC were counted to quantify damages induced in the first and second bystander cell groups. Radiation effect was observed in the second bystander cells as well as in the first ones. Statistical analyses revealed that the number of MC in second bystander subgroups was significantly more than the corresponding value observed in control groups, but in most cases it was equal to the number of MC observed in the first bystander cells. MRC5 and QU-DB bystander cells can produce and release bystander signals in the culture medium and affect non-irradiated cells. Therefore, they may contribute to the RIBE propagation.

  20. Studies of ionising radiation induced bystander effects in 3D artificial tissue system and applications for radiation protection

    International Nuclear Information System (INIS)

    Belyakov, Oleg V.; Kuopio Univ.

    2008-01-01

    The universality of the target theory of radiation-induced effects is challenged by observations on non-targeted effects such as bystander effects. Essential features of non-targeted effects are that they do not require direct nuclear exposure by radiation and they are particularly significant at low doses. This new evidence suggests a need for a new paradigm in radiation biology. The new paradigm should cover both the classical (targeted) and the non-targeted effects. The bystander effect cannot be comprehensively explained on the basis of a single cell reaction. It is well known that an organism is composed of different cell types that interact as functional units in a way to maintain normal tissue function. Therefore the radiation response is not simply the sum of cellular responses as assumed in classical radiobiology, predominantly from studies using cell cultures. Experimental models, which maintain tissue-like intercellular cell signalling and 3D structure, are essential for proper understanding of the bystander effect. Our work relates to experimentation with novel 3D artificial human tissue systems available from MatTek Corporation (Boston, USA). Air-liquid interface culture technique is used to grow artificial tissues, which allow to model conditions present in vivo. The Gray Cancer Institute (Northwood, UK) charged particle microbeam was used to irradiate tissue samples in a known pattern with a known number of 3 He 2+ particles or protons. After irradiation, the tissues models were incubated for 3 days, fixed in 10 % NBF, paraffin embedded and then sliced into 5 μm histological sections located at varying distances from the plane of the irradiated cells. We studied in situ apoptosis and markers of differentiation. Significantly elevated bystander induced apoptosis was observed with 3'-OH DNA end-labelling based technique in 3D artificial tissue systems. Our results also suggested an importance of proliferation and differentiation status for bystander

  1. MiR-21 is involved in radiation-induced bystander effects

    Science.gov (United States)

    Xu, Shuai; Ding, Nan; Pei, Hailong; Hu, Wentao; Wei, Wenjun; Zhang, Xurui; Zhou, Guangming; Wang, Jufang

    2014-01-01

    Radiation-induced bystander effects are well-established phenomena, in which DNA damage responses are induced not only in the directly irradiated cells but also in the non-irradiated bystander cells through intercellular signal transmission. Recent studies hint that bystander effects are possibly mediated via small non-coding RNAs, especially microRNAs. Thus, more details about the roles of microRNA in bystander effects are urgently needed to be elucidated. Here we demonstrated that bystander effects were induced in human fetal lung MRC-5 fibroblasts through medium-mediated way by different types of radiation. We identified a set of differentially expressed microRNAs in the cell culture medium after irradiation, among which the up-regulation of miR-21 was further verified with qRT-PCR. In addition, we found significant upregulation of miR-21 in both directly irradiated cells and bystander cells, which was confirmed by the expression of miR-21 precursor and its target genes. Transfection of miR-21 mimics into non-irradiated MRC-5 cells caused bystander-like effects. Taken together, our data reveals that miR-21 is involved in radiation-induced bystander effects. Elucidation of such a miRNA-mediated bystander effect is of utmost importance in understanding the biological processes related to ionizing radiation and cell-to-cell communication. PMID:25483031

  2. Design of radiation dose tumor response assays

    International Nuclear Information System (INIS)

    Suit, H.D.; Hwang, T.; Hsieh, C.; Thames, H.

    1985-01-01

    The efficient utilization of animals in a radiation dose response assay for tumor control requires a definition of the goal, e.g., TCD50 or slope. A series of computer modelled ''experiments'' have been performed for each of a number of allocations of dose levels (DL) and number of animals/DL. The authors stipulated that the assumed TCD50 was .85 of true value; assumed slope was correct. They stipulated a binominal distribution of observed tumor control results at each dose level. A pilot assay used 6 tumors at 7 DL (from TCD1-TCD97). The second assay used 30 tumors assigned to 2,3,5 or 9 DL and to selected tumor control probabilities (TCP derived from the pilot run. Results from 100 test runs were combined with the pilot run for each of the combination of DL and TCP values. Logit regression lines were fitted through these ''data'' and the 95% CL around the TCD50 and the TCD37 values and the variances of the slopes were computed. These experiments were repeated using the method suggested by Porter (1980). Results show that a different strategy is needed depending upon the goal, viz. TCD50 or TCD37 vs slope. The differences between the two approaches are discussed

  3. Bystander or No Bystander for Gene Directed Enzyme Prodrug Therapy

    Directory of Open Access Journals (Sweden)

    Adam V. Patterson

    2009-11-01

    Full Text Available Gene directed enzyme prodrug therapy (GDEPT of cancer aims to improve the selectivity of chemotherapy by gene transfer, thus enabling target cells to convert nontoxic prodrugs to cytotoxic drugs. A zone of cell kill around gene-modified cells due to transfer of toxic metabolites, known as the bystander effect, leads to tumour regression. Here we discuss the implications of either striving for a strong bystander effect to overcome poor gene transfer, or avoiding the bystander effect to reduce potential systemic effects, with the aid of three successful GDEPT systems. This review concentrates on bystander effects and drug development with regard to these enzyme prodrug combinations, namely herpes simplex virus thymidine kinase (HSV-TK with ganciclovir (GCV, cytosine deaminase (CD from bacteria or yeast with 5-fluorocytodine (5-FC, and bacterial nitroreductase (NfsB with 5-(azaridin-1-yl-2,4-dinitrobenzamide (CB1954, and their respective derivatives.

  4. MONTEC, an interactive fortran program to simulate radiation dose and dose-rate responses of populations

    International Nuclear Information System (INIS)

    Perry, K.A.; Szekely, J.G.

    1983-09-01

    The computer program MONTEC was written to simulate the distribution of responses in a population whose members are exposed to multiple radiation doses at variable dose rates. These doses and dose rates are randomly selected from lognormal distributions. The individual radiation responses are calculated from three equations, which include dose and dose-rate terms. Other response-dose/rate relationships or distributions can be incorporated by the user as the need arises. The purpose of this documentation is to provide a complete operating manual for the program. This version is written in FORTRAN-10 for the DEC system PDP-10

  5. Evidence for radiation-induced Bystander effects and relevance to radiotherapy and to radiation protection

    International Nuclear Information System (INIS)

    Georgieva, R.

    2006-01-01

    Full text: There are two major arms of radiation science in which Bystander effects (ByEff) could be of practical importance: radiotherapy and risk assessment. Basic biological principles, including dose-response relationships that have become dogma in the context of targeted effects of IR must now be reconsidered. The direct effects of radiation and the bystander components had to be reinvestigated to show the difference between them. It may be necessary to introduce a factor for ByEff's when calculating dose to both normal tissues and tumor. Presumably the relative effects on normal or tumor tissues could be different and that difference may not be always predictable. In relation to radiation protection, the existence of RIByEff's raises important questions for the way radiation dose is measured and modeled. The biological effect of exposure to low-doses radiation is likely to vary between individuals and between organs in one the same individual. Further studies on non-targeted effects should contribute to the establishment of adequate environmental and occupational radiation protection standards. This lecture looks at the history, the current data and controversies that are now beginning to resolve the questions concerning the mechanisms underlying the induction and transmission of ByEff. Especially, effects on radiotherapy and radiation protection are discussed

  6. Involvement of MAPK proteins in bystander effects induced by chemicals and ionizing radiation

    International Nuclear Information System (INIS)

    Asur, Rajalakshmi; Balasubramaniam, Mamtha; Marples, Brian; Thomas, Robert A.; Tucker, James D.

    2010-01-01

    Many studies have examined bystander effects induced by ionizing radiation, however few have evaluated the ability of chemicals to induce similar effects. We previously reported the ability of two chemicals, mitomycin C (MMC) and phleomycin (PHL) to induce bystander effects in normal human lymphoblastoid cell lines. The focus of the current study was to determine the involvement of the MAPK proteins in bystander effects induced by physical and chemical DNA damaging agents and to evaluate the effects of MAPK inhibition on bystander-induced caspase 3/7 activation. The phosphorylation levels of the MAPK proteins ERK1/2, JNK, and p38, were measured from 1 to 24 h following direct or bystander exposure to MMC, PHL or radiation. We observed transient phosphorylation, at early time points, of all 3 proteins in bystander cells. We also evaluated the effect of MAPK inhibition on bystander-induced caspase 3/7 activity to determine the role of MAPK proteins in bystander-induced apoptosis. We observed bystander-induced activation of caspase 3/7 in bystander cells. Inhibition of MAPK proteins resulted in a decrease in caspase 3/7 activity at the early time points, and the caspase activity increased (in the case of ERK inhibition) or returned to basal levels (in the case of JNK or p38 inhibition) between 12 and 24 h. PHL is considered to be a radiomimetic agent, however in the present study PHL behaved more like a chemical and not like radiation in terms of MAPK phosphorylation. These results point to the involvement of MAPK proteins in the bystander effect induced by radiation and chemicals and provide additional evidence that this response is not limited to radiation but is a generalized stress response in cells.

  7. What kind of prior low dose radiation does the adaptive response induce?

    International Nuclear Information System (INIS)

    Suzuki, Masao

    2009-01-01

    Described are the adaptive response (AR) and genetic instability (GI) induced by different kind of low dose radiation (LDR) and their relation with the bystander effect. For this, human normal cells were placed at 2.65 m distance from the target of National Institute of Radiological Sciences (NIRS) Heavy Ion Medical Accelerator in Chiba (HIMAC) to see the biological effect of LDR of mixed radiations (1-1.5 mGy/day; mixture of 94% gamma ray, 1.9% neutron (N) and particle ions mainly containing proton (P) in the rest). Cells were then irradiated with 1.5 Gy X-ray. No effect on the lethality was observed as compared with control cells without LDR. The mutation on hprt gene was found significantly elevated 2-30 days after LDR, suggesting that GI had been induced. To see the effect of each radiation on GI, gamma ray ( 137 Cs), N ( 241 Am-Be) and heavy ion (HIMAC He, C and Fe) as LDR were separately irradiated to cells with total 1 mGy/7-8 hr and then acutely with the X-ray. He and C ions were found to promote mutation 1.9 and 4.0 times higher on frequencies, respectively, and N, to reduce the mutation rate to 15% (AR). Results indicated that cell responses were quite different dependently on linear energy transfer. The probability of hit number of ions in the cell population was calculated to be 61, 15 and 2% for He, C and Fe, respectively, suggesting an existence of considerable number of cells not irradiated. Presence of a gap-junction specific inhibitor (GSI) at LDR resulted in normalization of mutation rate in all groups of cells, suggesting that the bystander effect through cell-cell signal transduction affected the cell response to X-irradiation. For AR induction by N, when 1.5% of cells in culture were irradiated by P in NIRS SPICE as LDR, AR in mutation was observed and was inhibited by GSI, suggesting that N completely destroyed the hit cell but concomitantly yielded recoil P substantially acted as LDR. Above findings indicated that the exact radiation risk can

  8. Equivalent dose determination in foraminifera: analytical description of the CO2--signal dose-response curve

    International Nuclear Information System (INIS)

    Hoffmann, D.; Woda, C.; Mangini, A.

    2003-01-01

    The dose-response of the CO 2 - signal (g=2.0006) in foraminifera with ages between 19 and 300 ka is investigated. The sum of two exponential saturation functions is an adequate function to describe the dose-response curve up to an additional dose of 8000 Gy. It yields excellent dating results but requires an artificial doses of at least 5000 Gy. For small additional doses of about 500 Gy the single exponential saturation function can be used to calculate a reliable equivalent dose D E , although it does not describ the dose-response for higher doses. The CO 2 - -signal dose-response indicates that the signal has two components of which one is less stable than the other

  9. Biological responses to low dose rate gamma radiation

    International Nuclear Information System (INIS)

    Magae, Junji; Ogata, Hiromitsu

    2003-01-01

    Linear non-threshold (LNT) theory is a basic theory for radioprotection. While LNT dose not consider irradiation time or dose-rate, biological responses to radiation are complex processes dependent on irradiation time as well as total dose. Moreover, experimental and epidemiological studies that can evaluate LNT at low dose/low dose-rate are not sufficiently accumulated. Here we analyzed quantitative relationship among dose, dose-rate and irradiation time using chromosomal breakage and proliferation inhibition of human cells as indicators of biological responses. We also acquired quantitative data at low doses that can evaluate adaptability of LNT with statistically sufficient accuracy. Our results demonstrate that biological responses at low dose-rate are remarkably affected by exposure time, and they are dependent on dose-rate rather than total dose in long-term irradiation. We also found that change of biological responses at low dose was not linearly correlated to dose. These results suggest that it is necessary for us to create a new model which sufficiently includes dose-rate effect and correctly fits of actual experimental and epidemiological results to evaluate risk of radiation at low dose/low dose-rate. (author)

  10. Theoretic simulation for CMOS device on total dose radiation response

    International Nuclear Information System (INIS)

    He Baoping; Zhou Heqin; Guo Hongxia; He Chaohui; Zhou Hui; Luo Yinhong; Zhang Fengqi

    2006-01-01

    Total dose effect is simulated for C4007B, CC4007RH and CC4011 devices at different absorbed dose rate by using linear system theory. When irradiation response and dose are linear, total dose radiation and post-irradiation annealing at room temperature are determined for one random by choosing absorbed dose rate, and total dose effect at other absorbed dose rate can be predicted by using linear system theory. The simulating results agree with the experimental results at different absorbed dose rate. (authors)

  11. Dose-rate dependence of thermoluminescence response

    International Nuclear Information System (INIS)

    McKeever, S.W.S.; Chen, R.; Groom, P.J.; Durrani, S.A.

    1980-01-01

    The previously observed dose-rate effect of thermoluminescence in quartz at high dose-rates is given at theoretical formulation. Computer calculations simulating the experimental conditions yield similar results to the experimental ones. (orig.)

  12. The effect of melanin on the bystander effect in human keratinocytes

    Energy Technology Data Exchange (ETDEWEB)

    Mosse, I. [Institute of Genetics and Cytology of the National Academy of Sciences, Academicheskaya Str. 27, Minsk (Belarus)]. E-mail: i.mosse@igc.bas-net.by; Marozik, P. [Institute of Genetics and Cytology of the National Academy of Sciences, Academicheskaya Str. 27, Minsk (Belarus); Radiation and Environmental Science Centre, DIT, Dublin 8 (Ireland); Seymour, C. [Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Ont. (Canada); Mothersill, C. [Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Ont. (Canada)

    2006-05-11

    The influence of melanin on radiation-induced bystander effects has been studied. Melanin is known to be a natural substance with proved radioprotective properties in different organisms and cell lines. It is non-toxic and is effective against acute and chronic irradiation. The lower the radiation dose, the higher the relative impact of melanin protection. In this study influence of melanin on human keratinocytes (HPV-G cells) has been studied using the colony-forming assay. We have shown that bystander donor medium from 0.5 Gy irradiated cells when transferred to unirradiated cells, caused almost the same effect as direct irradiation. Melanin increased the colony-forming ability of bystander recipient cells when it was added into culture medium before irradiation. The effect of melanin added after irradiation was to produce less protection in both the directly irradiated and bystander medium treated groups. The absorption spectrum of the filtered medium is identical to one of the intact culture medium showing that melanin was not present in filtered medium. Thus, it cannot protect recipient cells but reduces the amount of the bystander effect. It is concluded that melanin added before irradiation effectively decreased the radiation dose. The reduction of the impact of the bystander signal on recipient cells when melanin was added to the donor medium after harvest but before filtration, may mean that the bystander signal has a physical component as melanin can absorb all types of physical energy.

  13. The effect of melanin on the bystander effect in human keratinocytes

    International Nuclear Information System (INIS)

    Mosse, I.; Marozik, P.; Seymour, C.; Mothersill, C.

    2006-01-01

    The influence of melanin on radiation-induced bystander effects has been studied. Melanin is known to be a natural substance with proved radioprotective properties in different organisms and cell lines. It is non-toxic and is effective against acute and chronic irradiation. The lower the radiation dose, the higher the relative impact of melanin protection. In this study influence of melanin on human keratinocytes (HPV-G cells) has been studied using the colony-forming assay. We have shown that bystander donor medium from 0.5 Gy irradiated cells when transferred to unirradiated cells, caused almost the same effect as direct irradiation. Melanin increased the colony-forming ability of bystander recipient cells when it was added into culture medium before irradiation. The effect of melanin added after irradiation was to produce less protection in both the directly irradiated and bystander medium treated groups. The absorption spectrum of the filtered medium is identical to one of the intact culture medium showing that melanin was not present in filtered medium. Thus, it cannot protect recipient cells but reduces the amount of the bystander effect. It is concluded that melanin added before irradiation effectively decreased the radiation dose. The reduction of the impact of the bystander signal on recipient cells when melanin was added to the donor medium after harvest but before filtration, may mean that the bystander signal has a physical component as melanin can absorb all types of physical energy

  14. On the Actual Risk of Bystander Intervention

    DEFF Research Database (Denmark)

    Liebst, Lasse Suonperä; Heinskou, Marie Bruvik; Ejbye-Ernst, Peter

    2018-01-01

    Objectives: Bystander studies have rarely considered the victimization risk associated with intervention into violent, dangerous emergencies. To address this gap, we aim to identify factors that influence bystanders’ risk of being physically victimized. Methods: We observed bystander behavior fro...

  15. Bystander signaling via oxidative metabolism

    Directory of Open Access Journals (Sweden)

    Sawal HA

    2017-08-01

    Full Text Available Humaira Aziz Sawal,1 Kashif Asghar,2 Matthias Bureik,3 Nasir Jalal4 1Healthcare Biotechnology Department, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, 2Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan; 3Health Science Platform, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China; 4Health Science Platform, Department of Molecular and Cellular Pharmacology, Tianjin University, Tianjin, China Abstract: The radiation-induced bystander effect (RIBE is the initiation of biological end points in cells (bystander cells that are not directly traversed by an incident-radiation track, but are in close proximity to cells that are receiving the radiation. RIBE has been indicted of causing DNA damage via oxidative stress, besides causing direct damage, inducing tumorigenesis, producing micronuclei, and causing apoptosis. RIBE is regulated by signaling proteins that are either endogenous or secreted by cells as a means of communication between cells, and can activate intracellular or intercellular oxidative metabolism that can further trigger signaling pathways of inflammation. Bystander signals can pass through gap junctions in attached cell lines, while the suspended cell lines transmit these signals via hormones and soluble proteins. This review provides the background information on how reactive oxygen species (ROS act as bystander signals. Although ROS have a very short half-life and have a nanometer-scale sphere of influence, the wide variety of ROS produced via various sources can exert a cumulative effect, not only in forming DNA adducts but also setting up signaling pathways of inflammation, apoptosis, cell-cycle arrest, aging, and even tumorigenesis. This review outlines the sources of the bystander effect linked to ROS in a cell, and provides methods of investigation for researchers who would like to

  16. Role of iNOS in Bystander Signaling Between Macrophages and Lymphoma Cells

    International Nuclear Information System (INIS)

    Ghosh, Somnath; Maurya, Dharmendra Kumar; Krishna, Malini

    2008-01-01

    Purpose: The present report describes the bystander effects of radiation between similar and dissimilar cells and the role of iNOS in such communication. Materials and Methods: EL-4 and RAW 264.7 cells were exposed to 5 Gy γ-irradiation. The medium from irradiated cells was transferred to unirradiated cells. Results: Irradiated EL-4 cells as well as those cultured in the presence of medium from γ-irradiated EL-4 cells showed an upregulation of NF-κB, iNOS, p53, and p21/waf1 genes. The directly irradiated and the bystander EL-4 cells showed an increase in DNA damage, apoptosis, and NO production. Bystander signaling was also found to exist between RAW 264.7 (macrophage) and EL-4 (lymphoma) cells. Unstimulated or irradiated RAW 264.7 cells did not induce bystander effect in unirradiated EL-4 cells, but LPS stimulated and irradiated RAW 264.7 cells induced an upregulation of NF-κB and iNOS genes and increased the DNA damage in bystander EL-4 cells. Treatment of EL-4 or RAW 264.7 cells with L-NAME significantly reduced the induction of gene expression and DNA damage in the bystander EL-4 cells, whereas treatment with cPTIO only partially reduced the induction of gene expression and DNA damage in the bystander EL-4 cells. Conclusions: It was concluded that active iNOS in the irradiated cells was essential for bystander response

  17. Mahalanobis distance and variable selection to optimize dose response

    International Nuclear Information System (INIS)

    Moore, D.H. II; Bennett, D.E.; Wyrobek, A.J.; Kranzler, D.

    1979-01-01

    A battery of statistical techniques are combined to improve detection of low-level dose response. First, Mahalanobis distances are used to classify objects as normal or abnormal. Then the proportion classified abnormal is regressed on dose. Finally, a subset of regressor variables is selected which maximizes the slope of the dose response line. Use of the techniques is illustrated by application to mouse sperm damaged by low doses of x-rays

  18. Dose/dose-rate responses of shrimp larvae to UV-B radiation

    International Nuclear Information System (INIS)

    Damkaer, D.M.

    1981-01-01

    Previous work indicated dose-rate thresholds in the effects of UV-B on the near-surface larvae of three shrimp species. Additional observations suggest that the total dose response varies with dose-rate. Below 0.002 Wm -2 sub([DNA]) irradiance no significant effect is noted in activity, development, or survival. Beyond that dose-rate threshold, shrimp larvae are significantly affected if the total dose exceeds about 85 Jm -2 sub([DNA]). Predictions cannot be made without both the dose-rate and the dose. These dose/dose-rate thresholds are compared to four-year mean dose/dose-rate solar UV-B irradiances at the experimental site, measured at the surface and calculated for 1 m depth. The probability that the shrimp larvae would receive lethal irradiance is low for the first half of the season of surface occurrence, even with a 44% increase in damaging UV radiation. (orig.)

  19. Bystander signaling via oxidative metabolism.

    Science.gov (United States)

    Sawal, Humaira Aziz; Asghar, Kashif; Bureik, Matthias; Jalal, Nasir

    2017-01-01

    The radiation-induced bystander effect (RIBE) is the initiation of biological end points in cells (bystander cells) that are not directly traversed by an incident-radiation track, but are in close proximity to cells that are receiving the radiation. RIBE has been indicted of causing DNA damage via oxidative stress, besides causing direct damage, inducing tumorigenesis, producing micronuclei, and causing apoptosis. RIBE is regulated by signaling proteins that are either endogenous or secreted by cells as a means of communication between cells, and can activate intracellular or intercellular oxidative metabolism that can further trigger signaling pathways of inflammation. Bystander signals can pass through gap junctions in attached cell lines, while the suspended cell lines transmit these signals via hormones and soluble proteins. This review provides the background information on how reactive oxygen species (ROS) act as bystander signals. Although ROS have a very short half-life and have a nanometer-scale sphere of influence, the wide variety of ROS produced via various sources can exert a cumulative effect, not only in forming DNA adducts but also setting up signaling pathways of inflammation, apoptosis, cell-cycle arrest, aging, and even tumorigenesis. This review outlines the sources of the bystander effect linked to ROS in a cell, and provides methods of investigation for researchers who would like to pursue this field of science.

  20. Damaging and protective bystander cross-talk between human lung cancer and normal cells after proton microbeam irradiation

    International Nuclear Information System (INIS)

    Desai, Sejal; Kobayashi, Alisa; Konishi, Teruaki; Oikawa, Masakazu; Pandey, Badri N.

    2014-01-01

    Graphical abstract: - Highlights: • Proton-microbeam irradiated A549 cells send damaging signals to bystander A549 cells. • Irradiated A549–A549 bystander response is through gap junctional communication. • Bystander WI38 cells exert protective signalling in irradiated A549 cells. • Rescue of irradiated A549 cells by WI38 cells is independent of gap junctions. - Abstract: Most of the studies of radiation-induced bystander effects (RIBE) have been focused on understanding the radiobiological changes observed in bystander cells in response to the signals from irradiated cells in a normal cell population with implications to radiation risk assessment. However, reports on RIBE with relevance to cancer radiotherapy especially investigating the bidirectional and criss-cross bystander communications between cancer and normal cells are limited. Hence, in present study employing co-culture approach, we have investigated the bystander cross-talk between lung cancer (A549) and normal (WI38) cells after proton-microbeam irradiation using γ-H2AX foci fluorescence as a measure of DNA double-strand breaks (DSBs). We observed that in A549–A549 co-cultures, irradiated A549 cells exert damaging effects in bystander A549 cells, which were found to be mediated through gap junctional intercellular communication (GJIC). However, in A549–WI38 co-cultures, irradiated A549 did not affect bystander WI38 cells. Rather, bystander WI38 cells induced inverse protective signalling (rescue effect) in irradiated A549 cells, which was independent of GJIC. On the other hand, in response to irradiated WI38 cells neither of the bystander cells (A549 or WI38) showed significant increase in γ-H2AX foci. The observed bystander signalling between tumour and normal cells may have potential implications in therapeutic outcome of cancer radiotherapy

  1. Damaging and protective bystander cross-talk between human lung cancer and normal cells after proton microbeam irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Desai, Sejal [Radiation Signalling and Cancer Biology Section, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085 (India); Kobayashi, Alisa; Konishi, Teruaki; Oikawa, Masakazu [Radiation System and Engineering Section, Department of Technical Support and Development, Research, Development and Support Center, National Institute of Radiological Sciences, Chiba 263-8555 (Japan); Pandey, Badri N., E-mail: badrinarain@yahoo.co.in [Radiation Signalling and Cancer Biology Section, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085 (India)

    2014-05-15

    Graphical abstract: - Highlights: • Proton-microbeam irradiated A549 cells send damaging signals to bystander A549 cells. • Irradiated A549–A549 bystander response is through gap junctional communication. • Bystander WI38 cells exert protective signalling in irradiated A549 cells. • Rescue of irradiated A549 cells by WI38 cells is independent of gap junctions. - Abstract: Most of the studies of radiation-induced bystander effects (RIBE) have been focused on understanding the radiobiological changes observed in bystander cells in response to the signals from irradiated cells in a normal cell population with implications to radiation risk assessment. However, reports on RIBE with relevance to cancer radiotherapy especially investigating the bidirectional and criss-cross bystander communications between cancer and normal cells are limited. Hence, in present study employing co-culture approach, we have investigated the bystander cross-talk between lung cancer (A549) and normal (WI38) cells after proton-microbeam irradiation using γ-H2AX foci fluorescence as a measure of DNA double-strand breaks (DSBs). We observed that in A549–A549 co-cultures, irradiated A549 cells exert damaging effects in bystander A549 cells, which were found to be mediated through gap junctional intercellular communication (GJIC). However, in A549–WI38 co-cultures, irradiated A549 did not affect bystander WI38 cells. Rather, bystander WI38 cells induced inverse protective signalling (rescue effect) in irradiated A549 cells, which was independent of GJIC. On the other hand, in response to irradiated WI38 cells neither of the bystander cells (A549 or WI38) showed significant increase in γ-H2AX foci. The observed bystander signalling between tumour and normal cells may have potential implications in therapeutic outcome of cancer radiotherapy.

  2. Dose-response relationships for carcinogens: a review

    International Nuclear Information System (INIS)

    Zeise, L.; Wilson, R.; Crouch, E.A.C.

    1987-01-01

    The authors review the experimental evidence for various shapes of dose-response relationships for carcinogens and summarize those experiments that give the most information on relatively low doses. A brief review of some models is given to illustrate the shapes of dose-response curve expected from them. Their major interest is in the use of dose-response relationships to estimate risks to humans at low doses, and so they pay special attention to experimentally observed and theoretically expected nonlinearities. There are few experimental examples of nonlinear dose-response relations in humans, but this may simply be due to the limitations in the data. The several examples in rodents, even though for high dose data, suggest that nonlinearity is common. In some cases such nonlinearities may be rationalized on the basis of the pharmacokinetics of the test compound or its metabolites

  3. Application of microbeam in bio-science and life science. Biological effects induced in bystander cells by particle microbeams

    International Nuclear Information System (INIS)

    Suzuki, Masao

    2006-01-01

    Biological events occurring in cells directly hit by radiation appear in bystander cells nearby not hit directly, which is called the bystander effect. This review describes the events and mechanisms of biological bystander effect yielded by the low-dose radiation including the microbeam. Bystander effects, particularly by charged particle beams, have been studied by two representative approaches by α-ray from plutonium (stochastic irradiation) and by particle microbeams (targeted irradiation), where a bystander effect like chromosome aberrations is shown to occur by communication between irradiated and non-irradiated cells through gap junction. Bystander effects that do not require the cell contact also occur in the irradiated cell-conditioned medium (ICCM), where, not only the short-life radicals like reactive oxygen species and NO, but also more long-life factors participate. Authors have shown the presence of such bystander-inducing factors in ICCM, producing the aberrations even 48 hr after irradiation of either low or high linear energy transfer (LET) radiation. Bystander effects can be important from the aspect of risk assessments of radiation in the terrestrial/spatial environment involving aircraft as well as in cancer therapy by low-dose heavy particle beams. (T.I)

  4. Oligodendroglial response to ionizing radiation: Dose and dose-rate response

    International Nuclear Information System (INIS)

    Levy, R.P.

    1991-01-01

    An in vitro system using neuroglia from neonatal rat brain was developed to examining the morphologic, immunocytochemical and biochemical response of oligodendroglia to ionizing radiation. Following acute γ-radiation at day-in-culture (DIC) 8, oligodendrocyte counts at DIC 14 were 55% to 65% of control values after 2 Gy, and 29% to 36% after 5 Gy. Counts increased to near-normal levels at DIC 21 in the 2 Gy group and to 75% of normal in the 5 Gy group. Myelin basic protein levels (MBP) at DIC 14 were 60% of control values after 2 Gy, and 40% after 5 Gy. At DIC 21, MBP after 2 Gy was 45% greater than that observed at DIC 14, but MBP, as a fraction of age-matched control values, dropped from 60% to 50%. Following 5 Gy, absolute MBP changed little between DIC 14 and DIC 21, but decreased from 40% to 25% of control cultures. It was concluded that oligodendrocytes in irradiated cultures had significantly lower functional capacity than did unirradiated controls. The response to split-dose irradiation indicated that nearly all sublethal damage in the oligodendrocyte population (and its precursors) was repaired within 3 h to 4 h. At DIC 14, the group irradiated in a single fraction had significantly lower oligodendrocyte counts than any group given split doses; all irradiated cultures had marked depression of MBP synthesis, but to significant differences referable to time interval between doses. At DIC 21, cultures irradiated at intervals of 0 h to 2 h had similar oligodendrocyte counts to one another, but these counts were significantly lower than in cultures irradiated at intervals of 4 h to 6 h; MBP levels remained depressed at DIC 21 for all irradiated cultures. The oligodendrocyte response to dose rate (0.03 to 1.97 Gy/min) was evaluated at DIC 14 and DIC 21. Exposure at 0.03 Gy/min suppressed oligodendrocyte counts at DIC 21 less than did higher dose rates in 5-Gy irradiated cultures

  5. Dose-Response Calculator for ArcGIS

    Science.gov (United States)

    Hanser, Steven E.; Aldridge, Cameron L.; Leu, Matthias; Nielsen, Scott E.

    2011-01-01

    The Dose-Response Calculator for ArcGIS is a tool that extends the Environmental Systems Research Institute (ESRI) ArcGIS 10 Desktop application to aid with the visualization of relationships between two raster GIS datasets. A dose-response curve is a line graph commonly used in medical research to examine the effects of different dosage rates of a drug or chemical (for example, carcinogen) on an outcome of interest (for example, cell mutations) (Russell and others, 1982). Dose-response curves have recently been used in ecological studies to examine the influence of an explanatory dose variable (for example, percentage of habitat cover, distance to disturbance) on a predicted response (for example, survival, probability of occurrence, abundance) (Aldridge and others, 2008). These dose curves have been created by calculating the predicted response value from a statistical model at different levels of the explanatory dose variable while holding values of other explanatory variables constant. Curves (plots) developed using the Dose-Response Calculator overcome the need to hold variables constant by using values extracted from the predicted response surface of a spatially explicit statistical model fit in a GIS, which include the variation of all explanatory variables, to visualize the univariate response to the dose variable. Application of the Dose-Response Calculator can be extended beyond the assessment of statistical model predictions and may be used to visualize the relationship between any two raster GIS datasets (see example in tool instructions). This tool generates tabular data for use in further exploration of dose-response relationships and a graph of the dose-response curve.

  6. Nitric oxide-mediated bystander signal transduction induced by heavy-ion microbeam irradiation

    Science.gov (United States)

    Tomita, Masanori; Matsumoto, Hideki; Funayama, Tomoo; Yokota, Yuichiro; Otsuka, Kensuke; Maeda, Munetoshi; Kobayashi, Yasuhiko

    2015-07-01

    In general, a radiation-induced bystander response is known to be a cellular response induced in non-irradiated cells after receiving bystander signaling factors released from directly irradiated cells within a cell population. Bystander responses induced by high-linear energy transfer (LET) heavy ions at low fluence are an important health problem for astronauts in space. Bystander responses are mediated via physical cell-cell contact, such as gap-junction intercellular communication (GJIC) and/or diffusive factors released into the medium in cell culture conditions. Nitric oxide (NO) is a well-known major initiator/mediator of intercellular signaling within culture medium during bystander responses. In this study, we investigated the NO-mediated bystander signal transduction induced by high-LET argon (Ar)-ion microbeam irradiation of normal human fibroblasts. Foci formation by DNA double-strand break repair proteins was induced in non-irradiated cells, which were co-cultured with those irradiated by high-LET Ar-ion microbeams in the same culture plate. Foci formation was suppressed significantly by pretreatment with an NO scavenger. Furthermore, NO-mediated reproductive cell death was also induced in bystander cells. Phosphorylation of NF-κB and Akt were induced during NO-mediated bystander signaling in the irradiated and bystander cells. However, the activation of these proteins depended on the incubation time after irradiation. The accumulation of cyclooxygenase-2 (COX-2), a downstream target of NO and NF-κB, was observed in the bystander cells 6 h after irradiation but not in the directly irradiated cells. Our findings suggest that Akt- and NF-κB-dependent signaling pathways involving COX-2 play important roles in NO-mediated high-LET heavy-ion-induced bystander responses. In addition, COX-2 may be used as a molecular marker of high-LET heavy-ion-induced bystander cells to distinguish them from directly irradiated cells, although this may depend on the time

  7. TakeCARE, a Video to Promote Bystander Behavior on College Campuses: Replication and Extension.

    Science.gov (United States)

    Jouriles, Ernest N; Sargent, Kelli S; Salis, Katie Lee; Caiozzo, Christina; Rosenfield, David; Cascardi, Michele; Grych, John H; O'Leary, K Daniel; McDonald, Renee

    2017-08-01

    Previous research has demonstrated that college students who view TakeCARE, a video bystander program designed to encourage students to take action to prevent sexual and relationship violence (i.e., bystander behavior), display more bystander behavior relative to students who view a control video. The current study aimed to replicate and extend these findings by testing two different methods of administering TakeCARE and examining moderators of TakeCARE's effects on bystander behavior. Students at four universities ( n = 557) were randomly assigned to one of three conditions: (a) view TakeCARE in a monitored computer lab, (b) view TakeCARE at their own convenience after receiving an email link to the video, or (c) view a video about study skills (control group). Participants completed measures of bystander behavior at baseline and at a 1-month follow-up. Participants in both TakeCARE conditions reported more bystander behavior at follow-up assessments, compared with participants in the control condition. The beneficial effect of TakeCARE did not differ significantly across administration methods. However, the effects of TakeCARE on bystander behavior were moderated by students' perceptions of campus responsiveness to sexual violence, with more potent effects when students perceived their institution as responsive to reports of sexual violence.

  8. Intercellular and intracellular signaling pathways mediating ionizing radiation-induced bystander effects

    International Nuclear Information System (INIS)

    Hamada, Nobuyuki; Hara, Takamitsu; Kobayashi, Yasuhiko; Matsumoto, Hideki

    2007-01-01

    A rapidly growing body of experimental evidence indicates that ionizing radiation induces biological effects in non-irradiated bystander cells that have received signals from adjacent or distant irradiated cells. This phenomenon, which has been termed the ionizing radiation-induced bystander effect, challenges the long-standing paradigm that radiation traversal through the nucleus of a cell is a prerequisite to elicit genetic damage or a biological response. Bystander effects have been observed in a number of experimental systems, and cells whose nucleus or cytoplasm is irradiated exert bystander responses. Bystander cells manifest a multitude of biological consequences, such as genetic and epigenetic changes, alterations in gene expression, activation of signal transduction pathways, and delayed effects in their progeny. Several mediating mechanisms have been proposed. These involve gap junction-mediated intercellular communication, secreted soluble factors, oxidative metabolism, plasma membrane-bound lipid rafts, and calcium fluxes. This paper reviews briefly the current knowledge of the bystander effect with a focus on proposed mechanisms. The potential benefit of bystander effects to cancer radiotherapy will also be discussed. (author)

  9. Bystander Effect Induced by UV Radiation; why should we be interested? 

    Directory of Open Access Journals (Sweden)

    Maria Widel

    2012-11-01

    Full Text Available The bystander effect, whose essence is an interaction of cells directly subjected to radiation with adjacent non-subjected cells, via molecular signals, is an important component of ionizing radiation action. However, knowledge of the bystander effect in the case of ultraviolet (UV radiation is quite limited. Reactive oxygen and nitrogen species generated by UV in exposed cells induce bystander effects in non-exposed cells, such as reduction in clonogenic cell survival and delayed cell death, oxidative DNA damage and gene mutations, induction of micronuclei, lipid peroxidation and apoptosis. Although the bystander effect after UV radiation has been recognized in cell culture systems, its occurrence in vivo has not been studied. However, solar UV radiation, which is the main source of UV in the environment, may induce in human dermal tissue an inflammatory response and immune suppression, events which can be considered as bystander effects of UV radiation. The oxidative damage to DNA, genomic instability and the inflammatory response may lead to carcinogenesis. UV radiation is considered one of the important etiologic factors for skin cancers, basal- and squamous-cell carcinomas and malignant melanoma. Based on the mechanisms of actions it seems that the UV-induced bystander effect can have some impact on skin damage (carcinogenesis?, and probably on cells of other tissues. The paper reviews the existing data about the UV-induced bystander effect and discusses a possible implication of this phenomenon for health risk. 

  10. The application of microbeam in the research on radiation-induced bystander effects

    International Nuclear Information System (INIS)

    Xiong Jie; Han Ling

    2002-01-01

    There has been more and more attention to the phenomenon known as radiation-induced bystander effects, which will have a tremendous effect on the research in low -dose radiation biological effects. However, due to the stochastic nature of energy deposition and the random position of tracts, direct evidence for bystander effects and exact results of single particle interacts with a cell cannot be provided by using conventional broad-field irradiation. The availability of microbeam, especially the single particle microbeam in the world, whereby individual cells or precise location of cells can be irradiated with either a single or an exact number of particles provides a useful tool for the research on radiation-induced bystander effects. The author describes the radiation -induced bystander effect and the application of microbeam in the research on it

  11. Mechanisms of the Bystander Effect

    International Nuclear Information System (INIS)

    Hall, Eric J.

    2008-01-01

    Generations of students in radiation biology have been taught that heritable biological damage requires direct damage to DNA. We now know that this is not true. The Bystander Effect is the name given to the phenomenon whereby biological effects are observed in cells that are not themselves traversed by a charged particle, but are in close proximity to cells that are. Several research groups have convincingly demonstrated a bystander effect for alpha particle, which are heavy and high LET, because charged particles can be focused into a tiny beam that can be directed onto individual cells. The biological effects seen in adjacent non-hit cells clearly represents a bystander effect. It is not so easy to demonstrate a similar effect for x-rays or for the electrons set in motion by the absorption of x-rays. In this project we used two types of cell that could be recognized one from the other. One cell type was fed radioactive tritiated thymidine, which is incorporated into the DNA, . The tritium emits electrons which have a very short range so that they do not even get out of the cell. These cells were then mixed with a different type of cell which are routinely used to assess mutations. The mixed cells formed a cluster, where the two types of cells were in close contact, and left for some hours. Subsequently, the two types of cells were separated and studied. A substantial fraction of the cells that had incorporated the tritiated thymidine were killed by the radiation. The interesting finding is that the cells that had not incorporated tritiated thymidine, but had been in close contact with cells that had, exhibited a significant incidence of mutations. These experiments clearly demonstrated a bystander effect for low LET electrons. In further experiments, it was possible to show that the bystander effect was greatest when the two cell types were in gap junction communication.

  12. Dose-response relationship with radiotherapy: an evidence?

    International Nuclear Information System (INIS)

    Chauvet, B.; Rauglaudre, G. de; Mineur, L.; Alfonsi, M.; Reboul, F.

    2003-01-01

    The dose-response relationship is a fundamental basis of radiobiology. Despite many clinical data, difficulties remain to demonstrate a relation between dose and local control: relative role of treatment associated with radiation therapy (surgery, chemotherapy, hormonal therapy), tumor heterogeneity, few prospective randomized studies, uncertainty of local control assessment. Three different situations are discussed: tumors with high local control probabilities for which dose effect is demonstrated by randomized studies (breast cancer) or sound retrospective data (soft tissues sarcomas), tumors with intermediate local control probabilities for which dose effect seems to be important according to retrospective studies and ongoing or published phase III trials (prostate cancer), tumors with low local control probabilities for which dose effect appears to be modest beyond standard doses, and inferior to the benefit of concurrent chemotherapy (lung and oesophageal cancer). For head and neck tumors, the dose-response relationship has been explored through hyperfractionation and accelerated radiation therapy and a dose effect has been demonstrated but must be compared to the benefit of concurrent chemotherapy. Last but not least, the development of conformal radiotherapy allow the exploration of the dose response relationship for tumors such as hepatocellular carcinomas traditionally excluded from the field of conventional radiation therapy. In conclusion, the dose-response relationship remains a sound basis of radiation therapy for many tumors and is a parameter to take into account for further randomized studies. (author)

  13. Proteomic overview and perspectives of the radiation-induced bystander effects.

    Science.gov (United States)

    Chevalier, François; Hamdi, Dounia Houria; Saintigny, Yannick; Lefaix, Jean-Louis

    2015-01-01

    Radiation proteomics is a recent, promising and powerful tool to identify protein markers of direct and indirect consequences of ionizing radiation. The main challenges of modern radiobiology is to predict radio-sensitivity of patients and radio-resistance of tumor to be treated, but considerable evidences are now available regarding the significance of a bystander effect at low and high doses. This "radiation-induced bystander effect" (RIBE) is defined as the biological responses of non-irradiated cells that received signals from neighboring irradiated cells. Such intercellular signal is no more considered as a minor side-effect of radiotherapy in surrounding healthy tissue and its occurrence should be considered in adapting radiotherapy protocols, to limit the risk for radiation-induced secondary cancer. There is no consensus on a precise designation of RIBE, which involves a number of distinct signal-mediated effects within or outside the irradiated volume. Indeed, several cellular mechanisms were proposed, including the secretion of soluble factors by irradiated cells in the extracellular matrix, or the direct communication between irradiated and neighboring non-irradiated cells via gap junctions. This phenomenon is observed in a context of major local inflammation, linked with a global imbalance of oxidative metabolism which makes its analysis challenging using in vitro model systems. In this review article, the authors first define the radiation-induced bystander effect as a function of radiation type, in vitro analysis protocols, and cell type. In a second time, the authors present the current status of protein biomarkers and proteomic-based findings and discuss the capacities, limits and perspectives of such global approaches to explore these complex intercellular mechanisms. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Exosome-mediated microRNA transfer plays a role in radiation-induced bystander effect.

    Science.gov (United States)

    Xu, Shuai; Wang, Jufang; Ding, Nan; Hu, Wentao; Zhang, Xurui; Wang, Bing; Hua, Junrui; Wei, Wenjun; Zhu, Qiyun

    2015-01-01

    Bystander effects can be induced through cellular communication between irradiated cells and non-irradiated cells. The signals that mediate this cellular communication, such as cytokines, reactive oxygen species, nitric oxide and even microRNAs, can be transferred between cells via gap junctions or extracellular medium. We have previously reported that miR-21, a well described DDR (DNA damage response) microRNA, is involved in radiation-induced bystander effects through a medium-mediated way. However, the mechanisms of the microRNA transfer have not been elucidated in details. In the present study, it was found that exosomes isolated from irradiated conditioned medium could induce bystander effects. Furthermore, we demonstrated plenty of evidences that miR-21, which is up-regulated as a result of mimic transfection or irradiation, can be transferred from donor or irradiated cells into extracellular medium and subsequently get access to the recipient or bystander cells through exosomes to induce bystander effects. Inhibiting the miR-21 expression in advance can offset the bystander effects to some extent. From all of these results, it can be concluded that the exosome-mediated microRNA transfer plays an important role in the radiation-induced bystander effects. These findings provide new insights into the functions of microRNAs and the cellular communication between the directly irradiated cells and the non-irradiated cells.

  15. Multifraction dose response of growing and resting phase hair follicles

    International Nuclear Information System (INIS)

    Vegesna, V.; Withers, H.R.

    1987-01-01

    It has been established in both the clinic and the laboratory that there is a differentiation response to changes in dose per fraction in early and late responding tissues. To study one possible biological reason for differences in early and late responses. The authors selected one kind of cellular entity, the hair follicle, in two different phases of mitotic activity. The follicles are usually in a resting phase (7-12 wks), but mitotic activity can be initiated by plucking the club hairs. This was done on one half of the thorax and then exposing mice to doses of radiation (cesium gamma-ray). Dose responses for epilation between growing (early) and resting (late) follicles were compared for the same mouse. The fractionated response was studied by reducing the dose down to 2.5 Gy/fx. As the literature suggests, the total dose tolerated by a resting (late) follicle increased more than that for a growing (early) follicle

  16. Dose Response Model of Biological Reaction to Low Dose Rate Gamma Radiation

    International Nuclear Information System (INIS)

    Magae, J.; Furikawa, C.; Hoshi, Y.; Kawakami, Y.; Ogata, H.

    2004-01-01

    It is necessary to use reproducible and stable indicators to evaluate biological responses to long term irradiation at low dose-rate. They should be simple and quantitative enough to produce the results statistically accurate, because we have to analyze the subtle changes of biological responses around background level at low dose. For these purposes we chose micronucleus formation of U2OS, a human osteosarcoma cell line, as indicators of biological responses. Cells were exposed to gamma ray in irradiation rom bearing 50,000 Ci 60Co. After irradiation, they were cultured for 24 h in the presence of cytochalasin B to block cytokinesis, and cytoplasm and nucleus were stained with DAPI and prospidium iodide, respectively. the number of binuclear cells bearing micronuclei was counted under a fluorescence microscope. Dose rate in the irradiation room was measured with PLD. Dose response of PLD is linear between 1 mGy to 10 Gy, and standard deviation of triplicate count was several percent of mean value. We fitted statistically dose response curves to the data, and they were plotted on the coordinate of linearly scale response and dose. The results followed to the straight line passing through the origin of the coordinate axes between 0.1-5 Gy, and dose and does rate effectiveness factor (DDREF) was less than 2 when cells were irradiated for 1-10 min. Difference of the percent binuclear cells bearing micronucleus between irradiated cells and control cells was not statistically significant at the dose above 0.1 Gy when 5,000 binuclear cells were analyzed. In contrast, dose response curves never followed LNT, when cells were irradiated for 7 to 124 days. Difference of the percent binuclear cells bearing micronucleus between irradiated cells and control cells was not statistically significant at the dose below 6 Gy, when cells were continuously irradiated for 124 days. These results suggest that dose response curve of biological reaction is remarkably affected by exposure

  17. Timely bystander CPR improves outcomes despite longer EMS times.

    Science.gov (United States)

    Park, Gwan Jin; Song, Kyoung Jun; Shin, Sang Do; Lee, Kyung Won; Ahn, Ki Ok; Lee, Eui Jung; Hong, Ki Jeong; Ro, Young Sun

    2017-08-01

    This study aimed to determine the impact of bystander CPR on clinical outcomes in patients with increasing response time from collapse to EMS response. A population-based observational study was conducted in patients with witnessed out-of-hospital cardiac arrest (OHCA) of presumed cardiac etiology from 2012 to 2014. The time interval from collapse to CPR by EMS providers was categorized into quartile groups: fastest group (bystander CPR and the time interval from collapse to CPR by EMS providers. A total of 15,354 OHCAs were analyzed. Bystander CPR was performed in 8591 (56.0%). Survival to hospital discharge occurred in 1632 (10.6%) and favorable neurological outcome in 996 (6.5%). In an interaction model of bystander CPR, compared to the fastest group, adjusted odds ratios (AORs) (95% CIs) for survival to discharge were 0.89 (0.66-1.20) in the fast group, 0.76 (0.57-1.02) in the late group, and 0.52 (0.37-0.73) in the latest group. For favorable neurological outcome, AORs were 1.12 (0.77-1.62) in the fast group, 0.90 (0.62-1.30) in the late group, 0.59 (0.38-0.91) in the latest group. The survival from OHCA decreases as the ambulance response time increases. The increase in mortality and worsening neurologic outcomes appear to be mitigated in those patients who receive bystander CPR. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Dose response relationship in local radiotherapy for hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Park, Hee Chul; Seong, Jin Sil; Han, Kwang Hyub; Chon, Chae Yoon; Moon, Young Myoung; Song, Jae Seok; Suh, Chang Ok

    2001-01-01

    In this study, it was investigated whether dose response relation existed or not in local radiotherapy for primary hepatocellular carcinoma. From January 1992 to March 2000, 158 patients were included in present study. Exclusion criteria included the presence of extrahepatic metastasis, liver cirrhosis of Child's class C, tumors occupying more than two thirds of the entire liver, and performance status on the ECOG scale of more than 3. Radiotherapy was given to the field including tumor with generous margin using 6, 10-MV X-ray. Mean tumor dose was 48.2±7.9 Gy in daily 1.8 Gy fractions. Tumor response was based on diagnostic radiologic examinations such as CT scan, MR imaging, hepatic artery angiography at 4-8 weeks following completion of treatment. Statistical analysis was done to investigate the existence of dose response relationship of local radiotherapy when it was applied to the treatment of primary hepatocellular carcinoma. An objective response was observed in 106 of 158 patients, giving a response rate of 67. 1%. Statistical analysis revealed that total dose was the most significant factor in relation to tumor response when local radiotherapy was applied to the treatment of primary hepatocellular carcinoma. Only 29.2% showed objective response in patients treated with dose less than 40 Gy, while 68.6% and 77.1 % showed major response in patients with 40-50 Gy and more than 50 Gy, respectively. Child-Pugh classification was significant factor in the development of ascites, overt radiation induced liver disease and gastroenteritis. Radiation dose was an important factor for development of radiation induced gastroduodenal ulcer. Present study showed the existence of dose response relationship in local radiotherapy for primary hepatocellular carcinoma. Only radiotherapy dose was a significant factor to predict the objective response. Further study is required to predict the maximal tolerance dose in consideration of liver function and non-irradiated liver

  19. Oligodendroglial response to ionizing radiation: Dose and dose-rate response

    International Nuclear Information System (INIS)

    Levy, R.P.

    1991-12-01

    An in vitro system using neuroglia from neonatal rat brain was developed to examine the morphologic, immunocytochemical and biochemical response of oligodendroglia to ionizing radiation. Following acute γ-irradiation at day-in-culture (DIC) 8, oligodendrocyte counts at DIC 14 were 55% to 65% of control values after 2 Gy, and 29% to 36% after 5 Gy. Counts increased to near-normal levels at DIC 21 in the 2 Gy group and to 75% of normal in the 5 Gy group. Myelin basic protein levels (MBP) at DIC 14 were 60% of control values after 2 Gy, and 40% after 5 Gy. At DIC 21, MBP after 2 Gy was 45% greater than that observed at DIC 14, but MBP, as a fraction of age-matched control values, dropped from 60% to 50%. Following 5 Gy, absolute MBP changed little between DIC 14 and DIC 21, but decreased from 40% to 25% of control cultures. The response to split-dose irradiation indicated that nearly all sublethal damage in the oligodendrocyte population (and its precursors) was repaired within 3 h to 4 h. A new compartmental cell model for radiation response in vitro of the oligodendrocyte population is proposed and examined in relation to the potential reaction to radiation injury in the brain

  20. Oligodendroglial response to ionizing radiation: Dose and dose-rate response

    Energy Technology Data Exchange (ETDEWEB)

    Levy, Richard P. [Univ. of California, Berkeley, CA (United States)

    1991-12-01

    An in vitro system using neuroglia from neonatal rat brain was developed to examine the morphologic, immunocytochemical and biochemical response of oligodendroglia to ionizing radiation. Following acute γ-irradiation at day-in-culture (DIC) 8, oligodendrocyte counts at DIC 14 were 55% to 65% of control values after 2 Gy, and 29% to 36% after 5 Gy. Counts increased to near-normal levels at DIC 21 in the 2 Gy group and to 75% of normal in the 5 Gy group. Myelin basic protein levels (MBP) at DIC 14 were 60% of control values after 2 Gy, and 40% after 5 Gy. At DIC 21, MBP after 2 Gy was 45% greater than that observed at DIC 14, but MBP, as a fraction of age-matched control values, dropped from 60% to 50%. Following 5 Gy, absolute MBP changed little between DIC 14 and DIC 21, but decreased from 40% to 25% of control cultures. The response to split-dose irradiation indicated that nearly all sublethal damage in the oligodendrocyte population (and its precursors) was repaired within 3 h to 4 h. A new compartmental cell model for radiation response in vitro of the oligodendrocyte population is proposed and examined in relation to the potential reaction to radiation injury in the brain.

  1. Oligodendroglial response to ionizing radiation: Dose and dose-rate response

    Energy Technology Data Exchange (ETDEWEB)

    Levy, R.P.

    1991-12-01

    An in vitro system using neuroglia from neonatal rat brain was developed to examine the morphologic, immunocytochemical and biochemical response of oligodendroglia to ionizing radiation. Following acute {gamma}-irradiation at day-in-culture (DIC) 8, oligodendrocyte counts at DIC 14 were 55% to 65% of control values after 2 Gy, and 29% to 36% after 5 Gy. Counts increased to near-normal levels at DIC 21 in the 2 Gy group and to 75% of normal in the 5 Gy group. Myelin basic protein levels (MBP) at DIC 14 were 60% of control values after 2 Gy, and 40% after 5 Gy. At DIC 21, MBP after 2 Gy was 45% greater than that observed at DIC 14, but MBP, as a fraction of age-matched control values, dropped from 60% to 50%. Following 5 Gy, absolute MBP changed little between DIC 14 and DIC 21, but decreased from 40% to 25% of control cultures. The response to split-dose irradiation indicated that nearly all sublethal damage in the oligodendrocyte population (and its precursors) was repaired within 3 h to 4 h. A new compartmental cell model for radiation response in vitro of the oligodendrocyte population is proposed and examined in relation to the potential reaction to radiation injury in the brain.

  2. Non-targeted effects of ionising radiation—Implications for low dose risk

    DEFF Research Database (Denmark)

    Kadhim, Munira; Salomaa, Sisko; Wright, Eric

    2013-01-01

    and adaptive responses are powered by fundamental, but not clearly understood systems that maintain tissue homeostasis. Despite excellent research in this field by various groups, there are still gaps in our understanding of the likely mechanisms associated with non-DNA targeted effects, particularly......Non-DNA targeted effects of ionising radiation, which include genomic instability, and a variety of bystander effects including abscopal effects and bystander mediated adaptive response, have raised concerns about the magnitude of low-dose radiation risk. Genomic instability, bystander effects....... Furthermore, it is still not known what the initial target and early interactions in cells are that give rise to non-targeted responses in neighbouring or descendant cells. This paper provides a commentary on the current state of the field as a result of the non-targeted effects of ionising radiation (NOTE...

  3. Friends, strangers, and bystanders: Informal practices of sexual assault intervention.

    Science.gov (United States)

    Wamboldt, Alexander; Khan, Shamus R; Mellins, Claude Ann; Hirsch, Jennifer S

    2018-05-07

    Sexual assault is a part of many students' experiences in higher education. In U.S. universities, one in four women and one in ten men report being sexually assaulted before graduation. Bystander training programmes have been shown to modestly reduce campus sexual assault. Like all public health interventions, however, they have unintended social consequences; this research examines how undergraduate men on one campus understand bystander interventions and how those understandings shape their actual practices. We draw on ethnographic data collected between August 2015 and January 2017 at Columbia University and Barnard College. Our findings show that university training and an earnest desire to be responsible lead many men to intervene in possible sexual assaults. However, students' gendered methods target more socially vulnerable and socially distant men while protecting popular men and those to whom they are socially connected. Students' actual bystander practices thus reproduce social hierarchies in which low prestige may or may not be connected to actual risks of sexual assault. These results suggest that understanding intragroup dynamics and social hierarchies is essential to assault prevention in universities and that students' actions as bystanders may be effective at preventing assaults in some circumstances but may lead to new risks of sexual assault.

  4. Dispatcher-assisted bystander cardiopulmonary resuscitation and survival in out-of-hospital cardiac arrest.

    Science.gov (United States)

    Hagihara, Akihito; Onozuka, Daisuke; Shibuta, Hidetoshi; Hasegawa, Manabu; Nagata, Takashi

    2018-04-19

    Bystander cardiopulmonary resuscitation (CPR) is critical to the survival of patients with out-of-hospital cardiac arrest (OHCA). However, it is unknown whether bystander CPR with or without dispatcher assistance is more effective or why. Thus, we evaluated the association between dispatcher-assisted bystander CPR (vs. bystander CPR without dispatcher assistance) and survival of patients with OHCA. This is a retrospective, nonrandomized, observational study using national registry data for all OHCAs. We performed a propensity analysis. Patients with OHCA of cardiac origin were 18-100 years of age and received bystander chest compression in Japan between 2005 and 2014. Outcome measures were bystander rescue breathing, return of spontaneous circulation (ROSC) before hospital arrival, and survival and Cerebral Performance Category (CPC) 1 or 2 at 1 month after the event. During the study period, 1,176,351 OHCAs occurred, and 87,400 cases met the inclusion criteria. Among propensity-matched patients, a negative association was observed between dispatcher-assisted bystander CPR and outcome measures in a fully-adjusted model [odds ratio (OR) (95% CI) for ROSC = 0.87 (0.78-0.97), P < 0.05; OR (95% CI) for 1-month survival = 0.81 (0.65-1.00), P < 0.05; OR (95% CI) for CPC 1 or 2 = 0.64 (0.43-0.93), P < 0.05]. OR of survival for dispatcher-assisted bystander CPR tended to decrease as the emergency medical services response time increased. Survival benefit was less for dispatcher-assisted bystander CPR with dispatcher assistance than without dispatcher assistance. Low quality is hypothesized to be the cause of the reduced benefit. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Cytogenetics dosimetry: dose-response curve for low doses of X-ray

    International Nuclear Information System (INIS)

    Lara, Virginia E. Noval; Pineda Bolivar, William R.; Riano, Victor M. Pabon; Ureana, Cecilia Crane

    2013-01-01

    The purpose of this study was to conduct a preliminary study for the standardization in the future, the dose-response curve for low doses of X-rays, through the analysis of in vitro cultures of peripheral blood samples of 3 men and 3 women occupationally not exposed to artificial sources of ionizing radiation, age 18-40 years, where possible nonsmokers

  6. Dose-response of photographic emulsions under gamma irradiation

    International Nuclear Information System (INIS)

    Tran Dai Nghiep; Do Thi Nguyet Minh; Le Van Vinh

    2003-01-01

    Photographic emulsion is irradiated under gamma rays irradiation of 137 Cs in the IAEA/WHO secondary standard dosimetry laboratory. Dose-response of the film is established. The sensitivity of the film is determined. The dose-rate effect is studied. (author)

  7. Dose/dose-rate responses of shrimp larvae to UV-B radiation

    Energy Technology Data Exchange (ETDEWEB)

    Damkaer, D.M.; Dey, D.B.; Heron, G.A.

    1981-01-01

    Previous work indicated dose-rate thresholds in the effects of UV-B on the near-surface larvae of three shrimp species. Additional observations suggest that the total dose response varies with dose-rate. Below 0.002 Wm/sup -2/sub((DNA)) irradiance no significant effect is noted in activity, development, or survival. Beyond that dose-rate threshold, shrimp larvae are significantly affected if the total dose exceeds about 85 Jm/sup -2/sub((DNA)). Predictions cannot be made without both the dose-rate and the dose. These dose/dose-rate thresholds are compared to four-year mean dose/dose-rate solar UV-B irradiances at the experimental site, measured at the surface and calculated for 1 m depth. The probability that the shrimp larvae would receive lethal irradiance is low for the first half of the season of surface occurrence, even with a 44% increase in damaging UV radiation.

  8. Assembled cross-species perchlorate dose-response data

    Data.gov (United States)

    U.S. Environmental Protection Agency — This data set contains dose-response data for perchlorate exposure in multiple species. These data were assembled from peer-reviewed studies. Species included in...

  9. Model for dose-response with alternative change of sign

    International Nuclear Information System (INIS)

    Osovets, S.V.

    1998-01-01

    A new mathematical model of dose-response relationships is proposed, suitable for calculating stochastic effects of low level exposure. The corresponding differential equations are presented as well as their solution. (A.K.)

  10. The influence of dose fractionation and dose rate on normal tissue responses

    International Nuclear Information System (INIS)

    Barendsen, G.W.

    1982-01-01

    An analysis of responses of a variety of normal tissues in animals to fractionated irradiations has been made with the aim of developing a formalism for the prediction of tolerance doses as a function of the dose per fraction and the overall treatment time. An important feature of the formalism is that it is directly based on radiological insights and therefore provides a logical concept to account for the diversity of tissue responses. (Auth.)

  11. Radiation-induced bystander effects. Mechanisms, biological implications, and current investigations at the Leipzig LIPSION facility

    International Nuclear Information System (INIS)

    Oesterreicher, J.; Prise, K.M.; Michael, B.D.; Vogt, J.; Butz, T.; Tanner, J.M.

    2003-01-01

    Background: The bystander effect is a relatively new area of radiobiological research, which is aimed at studying post-radiation changes in neighboring non-hit cells or tissues. The bystander effect of ionizing irradiation is important after low-dose irradiation in the range of up to 0.2 Gy, where a higher incidence of stochastic damage was observed than was expected from a linear-quadratic model. It is also important when the irradiation of a cell population is highly non-uniform. Objective: This review summarizes most of the important results and proposed bystander effect mechanisms as well as their impact on theory and clinical practice. The literature, in parts contradictory, is collected, the main topics are outlined, and some basic papers are described in more detail. In order to illustrate the microbeam technique, which is considered relevant for the bystander effect research, the state of the Leipzig LIPSION nanoprobe facility is described. Results: The existence of a radiation-induced bystander effect is now generally accepted. The current state of knowledge on it is summarized here. Several groups worldwide are working on understanding its different aspects and its impact on radiobiology and radiation protection. Conclusion: The observation of a bystander effect has posed many questions, and answering them is a challenging topic for radiobiology in the future. (orig.)

  12. Radiation-induced bystander effects. Mechanisms, biological implications, and current investigations at the Leipzig LIPSION facility

    Energy Technology Data Exchange (ETDEWEB)

    Oesterreicher, J. [Dept. of Nuclear Solid State Physics, Univ. of Leipzig (Germany); Dept. of Radiobiology and Immunology, Purkyne Military Medical Academy, Hradec Kralove (Czech Republic); Prise, K.M.; Michael, B.D. [Gray Cancer Inst., Mount Vernon Hospital, Northwood, Middlesex (United Kingdom); Vogt, J.; Butz, T. [Dept. of Nuclear Solid State Physics, Univ. of Leipzig (Germany); Tanner, J.M. [Clinic and Polyclinic of Radiation Oncology, Martin Luther Univ. Halle-Wittenberg (Germany)

    2003-02-01

    Background: The bystander effect is a relatively new area of radiobiological research, which is aimed at studying post-radiation changes in neighboring non-hit cells or tissues. The bystander effect of ionizing irradiation is important after low-dose irradiation in the range of up to 0.2 Gy, where a higher incidence of stochastic damage was observed than was expected from a linear-quadratic model. It is also important when the irradiation of a cell population is highly non-uniform. Objective: This review summarizes most of the important results and proposed bystander effect mechanisms as well as their impact on theory and clinical practice. The literature, in parts contradictory, is collected, the main topics are outlined, and some basic papers are described in more detail. In order to illustrate the microbeam technique, which is considered relevant for the bystander effect research, the state of the Leipzig LIPSION nanoprobe facility is described. Results: The existence of a radiation-induced bystander effect is now generally accepted. The current state of knowledge on it is summarized here. Several groups worldwide are working on understanding its different aspects and its impact on radiobiology and radiation protection. Conclusion: The observation of a bystander effect has posed many questions, and answering them is a challenging topic for radiobiology in the future. (orig.)

  13. Radiation induced bystander effect on hepatoma HepG2 cells under hypoxia condition

    International Nuclear Information System (INIS)

    Zhang Jianghong; Jin Yizun; Shao Chunlin; Prise KM

    2009-01-01

    Objective: To investigate radiation induced bystander effect and its mechanism on hepatoma HepG2 cells under hypoxia condition. Methods: Non-irradiated bystander hepatoma cells were co-cultured with irradiated cells or treated with the conditioned medium (CM) from irradiated cells, then micronuclei (MN) were measured for both irradiated cells and bystander cells. Results: The MN yield of irradiated HepG2 cells under hypoxic condition was significantly lower than that under normoxia, the oxygen enhancement ratio of HepG2 cells of MN was 1.6. For both hypoxic and normoxic condition, the MN yield of bystander cells were obviously enhanced to a similar high level after co-culturing with irradiated cells or with CM treatment, and it also correlated with the irradiation dose. When the hypoxic HepG2 cells were treated with either DMSO, a scavenger of reactive oxygen species (ROS), or aminoguanidine, an iNOS inhibitor, the yield of bystander MN was partly diminished, and the reducing rate of DMSO was 42.2%-46.7%, the reducing rate of aminoguanidine was 42% . Conclusion: ROS, NO and their downstream signal factors are involved in the radiation induced bystander effect of hypoxic HepG2 cells. (authors)

  14. Updating Dosimetry for Emergency Response Dose Projections.

    Science.gov (United States)

    DeCair, Sara

    2016-02-01

    In 2013, the U.S. Environmental Protection Agency (EPA) proposed an update to the 1992 Protective Action Guides (PAG) Manual. The PAG Manual provides guidance to state and local officials planning for radiological emergencies. EPA requested public comment on the proposed revisions, while making them available for interim use by officials faced with an emergency situation. Developed with interagency partners, EPA's proposal incorporates newer dosimetric methods, identifies tools and guidelines developed since the current document was issued, and extends the scope of the PAGs to all significant radiological incidents, including radiological dispersal devices or improvised nuclear devices. In order to best serve the emergency management community, scientific policy direction had to be set on how to use International Commission on Radiological Protection Publication 60 age groups in dose assessment when implementing emergency guidelines. Certain guidelines that lend themselves to different PAGs for different subpopulations are the PAGs for potassium iodide (KI), food, and water. These guidelines provide age-specific recommendations because of the radiosensitivity of the thyroid and young children with respect to ingestion and inhalation doses in particular. Taking protective actions like using KI, avoiding certain foods or using alternative sources of drinking water can be relatively simple to implement by the parents of young children. Clear public messages can convey which age groups should take which action, unlike how an evacuation or relocation order should apply to entire households or neighborhoods. New in the PAG Manual is planning guidance for the late phase of an incident, after the situation is stabilized and efforts turn toward recovery. Because the late phase can take years to complete, decision makers are faced with managing public exposures in areas not fully remediated. The proposal includes quick-reference operational guidelines to inform re-entry to

  15. Biological effects of low-dose ionizing radiation exposure

    International Nuclear Information System (INIS)

    Reinoehl-Kompa, Sabine; Baldauf, Daniela; Heller, Horst

    2009-01-01

    The report on the meeting of the Strahlenschutzkommission 2007 concerning biological effects of low-dose ionizing radiation exposure includes the following contributions: Adaptive response. The importance of DNA damage mechanisms for the biological efficiency of low-energy photons. Radiation effects in mammography: the relative biological radiation effects of low-energy photons. Radiation-induced cataracts. Carcinomas following prenatal radiation exposure. Intercellular apoptosis induction and low-dose irradiation: possible consequences for the oncogenesis control. Mechanistic models for the carcinogenesis with radiation-induced cell inactivation: application to all solid tumors in the Japanese atomic bomb survivors. Microarrays at low radiation doses. Mouse models for the analysis of biological effects of low-dose ionizing radiation. The bystander effect: observations, mechanisms and implications. Lung carcinoma risk of Majak workers - modeling of carcinogenesis and the bystander effect. Microbeam studies in radiation biology - an overview. Carcinogenesis models with radiation-induced genomic instability. Application to two epidemiological cohorts.

  16. Radiation Dose-Response Relationships and Risk Assessment

    International Nuclear Information System (INIS)

    Strom, Daniel J.

    2005-01-01

    The notion of a dose-response relationship was probably invented shortly after the discovery of poisons, the invention of alcoholic beverages, and the bringing of fire into a confined space in the forgotten depths of ancient prehistory. The amount of poison or medicine ingested can easily be observed to affect the behavior, health, or sickness outcome. Threshold effects, such as death, could be easily understood for intoxicants, medicine, and poisons. As Paracelsus (1493-1541), the 'father' of modern toxicology said, 'It is the dose that makes the poison.' Perhaps less obvious is the fact that implicit in such dose-response relationships is also the notion of dose rate. Usually, the dose is administered fairly acutely, in a single injection, pill, or swallow; a few puffs on a pipe; or a meal of eating or drinking. The same amount of intoxicants, medicine, or poisons administered over a week or month might have little or no observable effect. Thus, before the discovery of ionizing radiation in the late 19th century, toxicology ('the science of poisons') and pharmacology had deeply ingrained notions of dose-response relationships. This chapter demonstrates that the notion of a dose-response relationship for ionizing radiation is hopelessly simplistic from a scientific standpoint. While useful from a policy or regulatory standpoint, dose-response relationships cannot possibly convey enough information to describe the problem from a quantitative view of radiation biology, nor can they address societal values. Three sections of this chapter address the concepts, observations, and theories that contribute to the scientific input to the practice of managing risks from exposure to ionizing radiation. The presentation begins with irradiation regimes, followed by responses to high and low doses of ionizing radiation, and a discussion of how all of this can inform radiation risk management. The knowledge that is really needed for prediction of individual risk is presented

  17. Dose-response characteristics of an amorphous silicon EPID

    International Nuclear Information System (INIS)

    Winkler, Peter; Hefner, Alfred; Georg, Dietmar

    2005-01-01

    Electronic portal imaging devices (EPIDs) were originally developed for the purpose of patient setup verification. Nowadays, they are increasingly used as dosimeters (e.g., for IMRT verification and linac-specific QA). A prerequisite for any clinical dosimetric application is a detailed understanding of the detector's dose-response behavior. The aim of this study is to investigate the dosimetric properties of an amorphous silicon EPID (Elekta IVIEWGT) with respect to three photon beam qualities: 6, 10, and 25 MV. The EPID showed an excellent temporal stability on short term as well as on long term scales. The stability throughout the day was strongly influenced by warming up, which took several hours and affected EPID response by 2.5%. Ghosting effects increased the sensitivity of the EPID. They became more pronounced with decreasing time intervals between two exposures as well as with increasing dose. Due to ghosting, changes in pixel sensitivity amounted up to 16% (locally) for the 25 MV photon beam. It was observed that the response characteristics of our EPID depended on dose as well as on dose rate. Doubling the dose rate increased the EPID sensitivity by 1.5%. This behavior was successfully attributed to a dose per frame effect, i.e., a nonlinear relationship between the EPID signal and the dose which was delivered to the panel between two successive readouts. The sensitivity was found to vary up to 10% in the range of 1 to 1000 monitor units. This variation was governed by two independent effects. For low doses, the EPID signal was reduced due to the linac's changing dose rate during startup. Furthermore, the detector reading was influenced by intrabeam variations of EPID sensitivity, namely, an increase of detector response during uniform exposure. For the beam qualities which were used, the response characteristics of the EPID did not depend on energy. Differences in relative dose-response curves resulted from energy dependent temporal output

  18. RADIOIODINE TREATMENT OF GRAVES’ DISEASE – DOSE/RESPONSE ANALYSIS

    Directory of Open Access Journals (Sweden)

    Jitka Čepková

    2014-01-01

    Full Text Available The clinical outcome of 153 Graves’ disease patients treated with a wide dose range of radioactive iodine-131 (RAI was analyzed retrospectively. Six to nine months after the first dose of RAI 60 patients (39% were hypothyroid (or rather thyroxine-substituted and 26 (17% were euthyroid, while 67 patients (44% did not respond properly: in 32 (21% their antithyroid drug (ATD dose could be reduced but not withdrawn (partial response and 35 (23% remained hyperthyroid or the same dose of ATD was necessary (no response. The outcome did not correspond significantly to the administered activity of RAI (medians 259, 259, 222, and 259 MBq for hypothyroid, euthyroid, partial, and no response subgroups, respectively, or the activity retained in the gland at 24 h (medians 127, 105, 143, and 152 MBq. The effect was, however, clearly, and in a stepwise pattern, dependent on initial thyroid volume (17, 26, 33 and 35 ml, P  6 MBq/g, cure rate 80% and lower (≤ 6 MBq/g, cure rate 46% doses gave highly significant difference (P < 0.001. With our dosing range we found a dose-dependent clinical outcome that suggests an optimum delivered dose near 6.5 MBq/g, resulting in successful treatment of ca 80% patients.

  19. TESS-based dose-response using pediatric clonidine exposures

    International Nuclear Information System (INIS)

    Benson, Blaine E.; Spyker, Daniel A.; Troutman, William G.; Watson, William A.

    2006-01-01

    Objective: The toxic and lethal doses of clonidine in children are unclear. This study was designed to determine whether data from the American Association of Poison Control Centers Toxic Exposure Surveillance System (TESS) could be utilized to determine a dose-response relationship for pediatric clonidine exposure. Methods: 3458 single-substance clonidine exposures in children <6 years of age reported to TESS from January 2000 through December 2003 were examined. Dose ingested, age, and medical outcome were available for 1550 cases. Respiratory arrest cases (n = 8) were classified as the most severe of the medical outcome categories (Arrest, Major, Moderate, Mild, and No effect). Exposures reported as a 'taste or lick' (n = 51) were included as a dose of 1/10 of the dosage form involved. Dose ranged from 0.4 to 1980 (median 13) μg/kg. Weight was imputed based on a quadratic estimate of weight for age. Dose certainty was coded as exact (26% of cases) or not exact (74%). Medical outcome (response) was examined via logistic regression using SAS JMP (release 5.1). Results: The logistic model describing medical outcome (P < 0.0001) included Log dose/kg (P 0.0000) and Certainty (P = 0.045). Conclusion: TESS data can provide the basis for a statistically sound description of dose-response for pediatric clonidine poisoning exposures

  20. Neutron Exposures in Human Cells: Bystander Effect and Relative Biological Effectiveness

    Science.gov (United States)

    Seth, Isheeta; Schwartz, Jeffrey L.; Stewart, Robert D.; Emery, Robert; Joiner, Michael C.; Tucker, James D.

    2014-01-01

    Bystander effects have been observed repeatedly in mammalian cells following photon and alpha particle irradiation. However, few studies have been performed to investigate bystander effects arising from neutron irradiation. Here we asked whether neutrons also induce a bystander effect in two normal human lymphoblastoid cell lines. These cells were exposed to fast neutrons produced by targeting a near-monoenergetic 50.5 MeV proton beam at a Be target (17 MeV average neutron energy), and irradiated-cell conditioned media (ICCM) was transferred to unirradiated cells. The cytokinesis-block micronucleus assay was used to quantify genetic damage in radiation-naïve cells exposed to ICCM from cultures that received 0 (control), 0.5, 1, 1.5, 2, 3 or 4 Gy neutrons. Cells grown in ICCM from irradiated cells showed no significant increase in the frequencies of micronuclei or nucleoplasmic bridges compared to cells grown in ICCM from sham irradiated cells for either cell line. However, the neutron beam has a photon dose-contamination of 5%, which may modulate a neutron-induced bystander effect. To determine whether these low doses of contaminating photons can induce a bystander effect, cells were irradiated with cobalt-60 at doses equivalent to the percent contamination for each neutron dose. No significant increase in the frequencies of micronuclei or bridges was observed at these doses of photons for either cell line when cultured in ICCM. As expected, high doses of photons induced a clear bystander effect in both cell lines for micronuclei and bridges (pbystander effect in these cells. Finally, neutrons had a relative biological effectiveness of 2.0±0.13 for micronuclei and 5.8±2.9 for bridges compared to cobalt-60. These results may be relevant to radiation therapy with fast neutrons and for regulatory agencies setting standards for neutron radiation protection and safety. PMID:24896095

  1. Dose Response of Alanine Detectors Irradiated with Carbon Ion Beams

    DEFF Research Database (Denmark)

    Herrmann, Rochus; Jäkel, Oliver; Palmans, Hugo

    2011-01-01

    Purpose: The dose response of the alanine detector shows a dependence on particle energy and type, when irradiated with ion beams. The purpose of this study is to investigate the response behaviour of the alanine detector in clinical carbon ion beams and compare the results with model predictions......-dose curves deviate from predictions in the peak region, most pronounced at the distal edge of the peak. Conclusions: The used model and its implementation show a good overall agreement for quasi mono energetic measurements. Deviations in depth-dose measurements are mainly attributed to uncertainties...

  2. Confidence bounds for nonlinear dose-response relationships

    DEFF Research Database (Denmark)

    Baayen, C; Hougaard, P

    2015-01-01

    An important aim of drug trials is to characterize the dose-response relationship of a new compound. Such a relationship can often be described by a parametric (nonlinear) function that is monotone in dose. If such a model is fitted, it is useful to know the uncertainty of the fitted curve...... intervals for the dose-response curve. These confidence bounds have better coverage than Wald intervals and are more precise and generally faster than bootstrap methods. Moreover, if monotonicity is assumed, the profile likelihood approach takes this automatically into account. The approach is illustrated...

  3. Effects of dose fractionation on the response of alanine dosimetry

    International Nuclear Information System (INIS)

    Lundahl, Brad; Logar, John; Desrosiers, Marc; Puhl, James

    2014-01-01

    Alanine dosimetry is well established as a transfer standard and is becoming more prevalently used in routine dosimetry systems for radiation processing. Many routine measurement applications in radiation processing involve absorbed dose measurements resulting from fractioned exposures to ionizing radiation. Fractioning of absorbed dose is identified as an influence quantity (ISO/ASTM, 2013). This paper reports on study results of absorbed dose fractioning characteristics of alanine for gamma and high energy electron beam radiation sources. The results of this study indicate a radiation response difference due to absorbed dose fractioning in response can be observed after four fractionations for high-energy electron beams and no difference up to seven fractions for gamma rays using an ANOVA evaluation method. - Highlights: • Fractioning effects signaled in electron beam using an ANOVA at 6 equal increments. • Fractioning effects not signaled in gamma using an ANOVA up to 7 equal increments. • Insensitivity of alanine to dose fractioning indicates nominal impact on calibration

  4. Bystander chronic infection negatively impacts development of CD8+ T cell memory

    Science.gov (United States)

    Stelekati, Erietta; Shin, Haina; Doering, Travis A.; Dolfi, Douglas V.; Ziegler, Carly G.; Beiting, Daniel P.; Dawson, Lucas; Liboon, Jennifer; Wolski, David; Ali, Mohammed-Alkhatim A.; Katsikis, Peter D.; Shen, Hao; Roos, David S.; Haining, W. Nicholas; Lauer, Georg M.; Wherry, E. John

    2014-01-01

    Summary Epidemiological evidence suggests that chronic infections impair immune responses to unrelated pathogens and vaccines. The underlying mechanisms, however, are unclear and distinguishing effects on priming versus development of immunological memory has been challenging. We investigated whether bystander chronic infections impact differentiation of memory CD8+ T cells, the hallmark of protective immunity against intracellular pathogens. Chronic bystander infections impaired development of memory CD8+ T cells in several mouse models and humans. These effects were independent of initial priming and were associated with chronic inflammatory signatures. Chronic inflammation negatively impacted the number of bystander CD8+ T cells and their memory development. Distinct underlying mechanisms of altered survival and differentiation were revealed with the latter regulated by the transcription factors T-bet and Blimp-1. Thus, exposure to prolonged bystander inflammation impairs the effector to memory transition. These data have relevance for immunity and vaccination during persisting infections and chronic inflammation. PMID:24837104

  5. Thymocyte apoptosis in response to low-dose radiation

    International Nuclear Information System (INIS)

    Shu-Zheng, Liu; Ying-Chun, Zhang; Ying, Mu; Xu, Su; Jian-Xiang, Liu

    1996-01-01

    Thymocyte apoptosis was assessed by counting apoptotic bodies with flow cytometry (FCM) and measuring DNA fragmentation with fluorescence spectrophotometry (FSP). J-shaped dose-response curves were obtained after both whole-body irradiation (WBI) of mice and in vitro irradiation of EL4 cells with doses ranging from 0.025 to 4 Gy X-rays. There was a significant reduction of apoptosis rate to below control level with doses within 0.2 Gy, and a dose-dependent increase in apoptosis with doses above 0.5 Gy. When thymocytes were cultured 24 h after WBI with 75 mGy X-rays in complete RPMI 1640 medium, a reduction in apoptosis was observed in the course of incubation for 72 h, and the presence of Con A in the medium accentuated this reduction in a dose- and time-dependent manner. The implications of these observations and the possible molecular mechanisms for future studies are proposed

  6. The bystander effect in experimental systems and compatibility with radon-induced lung cancer in humans

    International Nuclear Information System (INIS)

    Little, M.P.; Wakeford, R.

    2002-01-01

    Bystander effects following exposure to α-particles have been observed in C3H 10T 1/2 cells and in other experimental systems, and imply that linearly extrapolating low-dose risks from high-dose data might materially underestimate risk. The ratio of lung cancer risk among persons exposed to low and high doses of radon daughters is 2.4-4.0, with an upper 95% confidence limit (CL) of about 14. Assuming that the bystander effect observed in the C3H 10T 1/2 data applies to human lung cells in vivo, the epidemiological data imply that the number of neighbouring cells that can contribute to the bystander effect is between 0 and 1, with an upper 95% CL of about 7. As a consequence, the bystander effect observed in the C3H 10T 1/2 system probably does not play a large part in the process of radon-induced lung carcinogenesis in humans. Other experimental data relating to the bystander effect after α-particle exposure are surveyed; some of these data are more compatible with the epidemiological data. (author)

  7. Radiation induced bystander signals are independent of DNA damage and DNA repair capacity of the irradiated cells

    Energy Technology Data Exchange (ETDEWEB)

    Kashino, Genro [Gray Cancer Institute, P.O. Box 100, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR (United Kingdom); Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, 2-1010 Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494 (Japan); Suzuki, Keiji [Division of Radiation Biology, Department of Radiology and Radiation Biology, Course of Life Sciences and Radiation Research, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521 (Japan); Matsuda, Naoki [Division of Radiation Biology and Protection, Center for Frontier Life Sciences, Nagasaki University, Nagasaki 852-8102 (Japan); Kodama, Seiji [Radiation Biology Laboratory, Radiation Research Center, Frontier Science Innovation Center, Organization for University-Industry-Government Cooperation, Osaka Prefecture University, 1-2 Gakuen-cho, Sakai, Osaka 599-8570 (Japan); Ono, Koji [Particle Radiation Oncology Research Center, Research Reactor Institute, Kyoto University, 2-1010 Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494 (Japan); Watanabe, Masami [Laboratory of Radiation Biology, Division of Radiation Life Science, Department of Radiation Life Science and Radiation Medical Science, Kyoto University Research Reactor Institute, 2-1010 Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka 590-0494 (Japan); Prise, Kevin M [Gray Cancer Institute, P.O. Box 100, Mount Vernon Hospital, Northwood, Middlesex HA6 2JR (United Kingdom) and Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Lisburn Road, Belfast BT9 7AB (United Kingdom)]. E-mail: prise@gci.ac.uk

    2007-06-01

    Evidence is accumulating that irradiated cells produce signals, which interact with non-exposed cells in the same population. Here, we analysed the mechanism for bystander signal arising in wild-type CHO cells and repair deficient varients, focussing on the relationship between DNA repair capacity and bystander signal arising in irradiated cells. In order to investigate the bystander effect, we carried out medium transfer experiments after X-irradiation where micronuclei were scored in non-targeted DSB repair deficient xrs5 cells. When conditioned medium from irradiated cells was transferred to unirradiated xrs5 cells, the level of induction was independent of whether the medium came from irradiated wild-type, ssb or dsb repair deficient cells. This result suggests that the activation of a bystander signal is independent of the DNA repair capacity of the irradiated cells. Also, pre-treatment of the irradiated cells with 0.5% DMSO, which suppresses micronuclei induction in CHO but not in xrs5 cells, suppressed bystander effects completely in both conditioned media, suggesting that DMSO is effective for suppression of bystander signal arising independently of DNA damage in irradiated cells. Overall the work presented here adds to the understanding that it is the repair phenotype of the cells receiving bystander signals, which determines overall response rather than that of the cell producing the bystander signal.

  8. The role of TGF-β1–miR-21–ROS pathway in bystander responses induced by irradiated non-small-cell lung cancer cells

    Science.gov (United States)

    Jiang, Y; Chen, X; Tian, W; Yin, X; Wang, J; Yang, H

    2014-01-01

    Background: Many studies have indicated an important implication of radiation-induced bystander effects (RIBEs) in cancer radiotherapy, but the detailed signalling remains unclear. Methods: The roles of tumour growth factor-beta1 (TGF-β1) and miR-21 in medium-mediated RIBEs in H1299 non-small-cell lung cancer cells were investigated using DNA damage, changes in proliferation and levels of reactive oxygen species (ROS) as end points. SB431542, a specific inhibitor of TGF-β type 1 receptor kinases, was used to inhibit TGF-β1 pathways in irradiated and bystander cells. Exogenous miR-21 regulation was achieved through inhibitor or mimic transfection. Results: Compared with relative sham-radiation-conditioned medium, radiation-conditioned medium (RCM) from irradiated cells 1 h post radiation (1-h RCM) caused an increase in ROS levels and DNA damage in bystander cells, while 18-h RCM induced cell cycle delay and proliferation inhibition. All these effects were eliminated by TGF-βR1 inhibition. One-hour RCM upregulated miR-21 expression in bystander cells, and miR-21 inhibitor abolished bystander oxidative stress and DNA damage. Eighteen-hour RCM downregulated miR-21 of bystander cells, and miR-21 mimic eliminated bystander proliferation inhibition. Furthermore, the dysregulation of miR-21 was attenuated by TGF-βR1 inhibition. Conclusions: The TGF-β1–miR-21–ROS pathway of bystander cells has an important mediating role in RIBEs in H1299 cells. PMID:24992582

  9. A Computational Model of Cellular Response to Modulated Radiation Fields

    Energy Technology Data Exchange (ETDEWEB)

    McMahon, Stephen J., E-mail: stephen.mcmahon@qub.ac.uk [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast, Northern Ireland (United Kingdom); Butterworth, Karl T. [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast, Northern Ireland (United Kingdom); McGarry, Conor K. [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast, Northern Ireland (United Kingdom); Radiotherapy Physics, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Northern Ireland (United Kingdom); Trainor, Colman [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast, Northern Ireland (United Kingdom); O' Sullivan, Joe M. [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast, Northern Ireland (United Kingdom); Clinical Oncology, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, Northern Ireland (United Kingdom); Hounsell, Alan R. [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast, Northern Ireland (United Kingdom); Radiotherapy Physics, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Northern Ireland (United Kingdom); Prise, Kevin M. [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast, Northern Ireland (United Kingdom)

    2012-09-01

    Purpose: To develop a model to describe the response of cell populations to spatially modulated radiation exposures of relevance to advanced radiotherapies. Materials and Methods: A Monte Carlo model of cellular radiation response was developed. This model incorporated damage from both direct radiation and intercellular communication including bystander signaling. The predictions of this model were compared to previously measured survival curves for a normal human fibroblast line (AGO1522) and prostate tumor cells (DU145) exposed to spatially modulated fields. Results: The model was found to be able to accurately reproduce cell survival both in populations which were directly exposed to radiation and those which were outside the primary treatment field. The model predicts that the bystander effect makes a significant contribution to cell killing even in uniformly irradiated cells. The bystander effect contribution varies strongly with dose, falling from a high of 80% at low doses to 25% and 50% at 4 Gy for AGO1522 and DU145 cells, respectively. This was verified using the inducible nitric oxide synthase inhibitor aminoguanidine to inhibit the bystander effect in cells exposed to different doses, which showed significantly larger reductions in cell killing at lower doses. Conclusions: The model presented in this work accurately reproduces cell survival following modulated radiation exposures, both in and out of the primary treatment field, by incorporating a bystander component. In addition, the model suggests that the bystander effect is responsible for a significant portion of cell killing in uniformly irradiated cells, 50% and 70% at doses of 2 Gy in AGO1522 and DU145 cells, respectively. This description is a significant departure from accepted radiobiological models and may have a significant impact on optimization of treatment planning approaches if proven to be applicable in vivo.

  10. A Computational Model of Cellular Response to Modulated Radiation Fields

    International Nuclear Information System (INIS)

    McMahon, Stephen J.; Butterworth, Karl T.; McGarry, Conor K.; Trainor, Colman; O’Sullivan, Joe M.; Hounsell, Alan R.; Prise, Kevin M.

    2012-01-01

    Purpose: To develop a model to describe the response of cell populations to spatially modulated radiation exposures of relevance to advanced radiotherapies. Materials and Methods: A Monte Carlo model of cellular radiation response was developed. This model incorporated damage from both direct radiation and intercellular communication including bystander signaling. The predictions of this model were compared to previously measured survival curves for a normal human fibroblast line (AGO1522) and prostate tumor cells (DU145) exposed to spatially modulated fields. Results: The model was found to be able to accurately reproduce cell survival both in populations which were directly exposed to radiation and those which were outside the primary treatment field. The model predicts that the bystander effect makes a significant contribution to cell killing even in uniformly irradiated cells. The bystander effect contribution varies strongly with dose, falling from a high of 80% at low doses to 25% and 50% at 4 Gy for AGO1522 and DU145 cells, respectively. This was verified using the inducible nitric oxide synthase inhibitor aminoguanidine to inhibit the bystander effect in cells exposed to different doses, which showed significantly larger reductions in cell killing at lower doses. Conclusions: The model presented in this work accurately reproduces cell survival following modulated radiation exposures, both in and out of the primary treatment field, by incorporating a bystander component. In addition, the model suggests that the bystander effect is responsible for a significant portion of cell killing in uniformly irradiated cells, 50% and 70% at doses of 2 Gy in AGO1522 and DU145 cells, respectively. This description is a significant departure from accepted radiobiological models and may have a significant impact on optimization of treatment planning approaches if proven to be applicable in vivo.

  11. Shared dosimetry error in epidemiological dose-response analyses

    International Nuclear Information System (INIS)

    Stram, Daniel O.; Preston, Dale L.; Sokolnikov, Mikhail; Napier, Bruce; Kopecky, Kenneth J.; Boice, John; Beck, Harold; Till, John; Bouville, Andre; Zeeb, Hajo

    2015-01-01

    Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of 'possible' dose history to workers given dose determinants. This paper takes up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope β is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of β) is biased for β≠0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. The use of these methods in the context of several studies including, the Mayak Worker Cohort, and the U.S. Atomic Veterans Study, is discussed

  12. TESS-based dose-response using pediatric clonidine exposures.

    Science.gov (United States)

    Benson, Blaine E; Spyker, Daniel A; Troutman, William G; Watson, William A

    2006-06-01

    The toxic and lethal doses of clonidine in children are unclear. This study was designed to determine whether data from the American Association of Poison Control Centers Toxic Exposure Surveillance System (TESS) could be utilized to determine a dose-response relationship for pediatric clonidine exposure. 3,458 single-substance clonidine exposures in children TESS from January 2000 through December 2003 were examined. Dose ingested, age, and medical outcome were available for 1550 cases. Respiratory arrest cases (n = 8) were classified as the most severe of the medical outcome categories (Arrest, Major, Moderate, Mild, and No effect). Exposures reported as a "taste or lick" (n = 51) were included as a dose of 1/10 of the dosage form involved. Dose ranged from 0.4 to 1980 (median 13) microg/kg. Weight was imputed based on a quadratic estimate of weight for age. Dose certainty was coded as exact (26% of cases) or not exact (74%). Medical outcome (response) was examined via logistic regression using SAS JMP (release 5.1). The logistic model describing medical outcome (P TESS data can provide the basis for a statistically sound description of dose-response for pediatric clonidine poisoning exposures.

  13. A Bully's Bystanders Are Never Innocent

    Science.gov (United States)

    Coloroso, Barbara

    2005-01-01

    Though they play the least active role, bystanders are a critical element in bullying. With peers looking on and providing at least tacit support, the bully is no longer acting alone. The bystanders have become allies to the point of magnifying the supposed negative attributes of the target. If the bullying cycle is to be broken, the role of the…

  14. Epidemiological methods for assessing dose-response and dose-effect relationships

    DEFF Research Database (Denmark)

    Kjellström, Tord; Grandjean, Philippe

    2007-01-01

    Selected Molecular Mechanisms of Metal Toxicity and Carcinogenicity General Considerations of Dose-Effect and Dose-Response Relationships Interactions in Metal Toxicology Epidemiological Methods for Assessing Dose-Response and Dose-Effect Relationships Essential Metals: Assessing Risks from Deficiency......Description Handbook of the Toxicology of Metals is the standard reference work for physicians, toxicologists and engineers in the field of environmental and occupational health. This new edition is a comprehensive review of the effects on biological systems from metallic elements...... access to a broad range of basic toxicological data and also gives a general introduction to the toxicology of metallic compounds. Audience Toxicologists, physicians, and engineers in the fields of environmental and occupational health as well as libraries in these disciplines. Will also be a useful...

  15. Dose-response meta-analysis of differences in means

    Directory of Open Access Journals (Sweden)

    Alessio Crippa

    2016-08-01

    Full Text Available Abstract Background Meta-analytical methods are frequently used to combine dose-response findings expressed in terms of relative risks. However, no methodology has been established when results are summarized in terms of differences in means of quantitative outcomes. Methods We proposed a two-stage approach. A flexible dose-response model is estimated within each study (first stage taking into account the covariance of the data points (mean differences, standardized mean differences. Parameters describing the study-specific curves are then combined using a multivariate random-effects model (second stage to address heterogeneity across studies. Results The method is fairly general and can accommodate a variety of parametric functions. Compared to traditional non-linear models (e.g. E max, logistic, spline models do not assume any pre-specified dose-response curve. Spline models allow inclusion of studies with a small number of dose levels, and almost any shape, even non monotonic ones, can be estimated using only two parameters. We illustrated the method using dose-response data arising from five clinical trials on an antipsychotic drug, aripiprazole, and improvement in symptoms in shizoaffective patients. Using the Positive and Negative Syndrome Scale (PANSS, pooled results indicated a non-linear association with the maximum change in mean PANSS score equal to 10.40 (95 % confidence interval 7.48, 13.30 observed for 19.32 mg/day of aripiprazole. No substantial change in PANSS score was observed above this value. An estimated dose of 10.43 mg/day was found to produce 80 % of the maximum predicted response. Conclusion The described approach should be adopted to combine correlated differences in means of quantitative outcomes arising from multiple studies. Sensitivity analysis can be a useful tool to assess the robustness of the overall dose-response curve to different modelling strategies. A user-friendly R package has been developed to facilitate

  16. A Generalized QMRA Beta-Poisson Dose-Response Model.

    Science.gov (United States)

    Xie, Gang; Roiko, Anne; Stratton, Helen; Lemckert, Charles; Dunn, Peter K; Mengersen, Kerrie

    2016-10-01

    Quantitative microbial risk assessment (QMRA) is widely accepted for characterizing the microbial risks associated with food, water, and wastewater. Single-hit dose-response models are the most commonly used dose-response models in QMRA. Denoting PI(d) as the probability of infection at a given mean dose d, a three-parameter generalized QMRA beta-Poisson dose-response model, PI(d|α,β,r*), is proposed in which the minimum number of organisms required for causing infection, K min , is not fixed, but a random variable following a geometric distribution with parameter 0Poisson model, PI(d|α,β), is a special case of the generalized model with K min = 1 (which implies r*=1). The generalized beta-Poisson model is based on a conceptual model with greater detail in the dose-response mechanism. Since a maximum likelihood solution is not easily available, a likelihood-free approximate Bayesian computation (ABC) algorithm is employed for parameter estimation. By fitting the generalized model to four experimental data sets from the literature, this study reveals that the posterior median r* estimates produced fall short of meeting the required condition of r* = 1 for single-hit assumption. However, three out of four data sets fitted by the generalized models could not achieve an improvement in goodness of fit. These combined results imply that, at least in some cases, a single-hit assumption for characterizing the dose-response process may not be appropriate, but that the more complex models may be difficult to support especially if the sample size is small. The three-parameter generalized model provides a possibility to investigate the mechanism of a dose-response process in greater detail than is possible under a single-hit model. © 2016 Society for Risk Analysis.

  17. Skull base chordomas: analysis of dose-response characteristics

    International Nuclear Information System (INIS)

    Niemierko, Andrzej; Terahara, Atsuro; Goitein, Michael

    1997-01-01

    Objective: To extract dose-response characteristics from dose-volume histograms and corresponding actuarial survival statistics for 115 patients with skull base chordomas. Materials and Methods: We analyzed data for 115 patients with skull base chordoma treated with combined photon and proton conformal radiotherapy to doses in the range 66.6Gy - 79.2Gy. Data set for each patient included gender, histology, age, tumor volume, prescribed dose, overall treatment time, time to recurrence or time to last observation, target dose-volume histogram, and several dosimetric parameters (minimum/mean/median/maximum target dose, percent of the target volume receiving the prescribed dose, dose to 90% of the target volume, and the Equivalent Uniform Dose (EUD). Data were analyzed using the Kaplan-Meier survivor function estimate, the proportional hazards (Cox) model, and parametric modeling of the actuarial probability of recurrence. Parameters of dose-response characteristics were obtained using the maximum likelihood method. Results: Local failure developed in 42 (36%) of patients, with actuarial local control rates at 5 years of 59.2%. The proportional hazards model revealed significant dependence of gender on the probability of recurrence, with female patients having significantly poorer prognosis (hazard ratio of 2.3 with the p value of 0.008). The Wilcoxon and the log-rank tests of the corresponding Kaplan-Meier recurrence-free survival curves confirmed statistical significance of this effect. The Cox model with stratification by gender showed significance of tumor volume (p=0.01), the minimum target dose (p=0.02), and the EUD (p=0.02). Other parameters were not significant at the α level of significance of 0.05, including the prescribed dose (p=0.21). Parametric analysis using a combined model of tumor control probability (to account for non-uniformity of target dose distribution) and the Weibull failure time model (to account for censoring) allowed us to estimate

  18. Determination of tolerance dose uncertainties and optimal design of dose response experiments with small animal numbers

    International Nuclear Information System (INIS)

    Karger, C.P.; Hartmann, G.H.

    2001-01-01

    Background: Dose response experiments aim to determine the complication probability as a function of dose. Adjusting the parameters of the frequently used dose response model P(D)=1/[1+(D 50 /D) k ] to the experimental data, 2 intuitive quantities are obtained: The tolerance dose D 50 and the slope parameter k. For mathematical reasons, however, standard statistic software uses a different set of parameters. Therefore, the resulting fit parameters of the statistic software as well as their standard errors have to be transformed to obtain D 50 and k as well as their standard errors. Material and Methods: The influence of the number of dose levels on the uncertainty of the fit parameters is studied by a simulation for a fixed number of animals. For experiments with small animal numbers, statistical artifacts may prevent the determination of the standard errors of the fit parameters. Consequences on the design of dose response experiments are investigated. Results: Explicit formulas are presented, which allow to calculate the parameters D 50 and k as well as their standard errors from the output of standard statistic software. The simulation shows, that the standard errors of the resulting parameters are independent of the number of dose levels, as long as the total number of animals involved in the experiment, remains constant. Conclusion: Statistical artifacts in experiments containing small animal numbers may be prevented by an adequate design of the experiment. For this, it is suggested to select a higher number of dose levels, rather than using a higher number of animals per dose level. (orig.) [de

  19. Proposal of a probabilistic dose-response model

    International Nuclear Information System (INIS)

    Barrachina, M.

    1997-01-01

    A biologically updated dose-response model is presented as an alternative to the linear-quadratic model currently in use for cancer risk assessment. The new model is based on the probability functions for misrepair and/or unrepair of DNA lesions, in terms of the radiation damage production rate in the cell (supposedly, a stem cell) and its repair-rate constant. The model makes use, interpreting it on the basis of misrepair probabilities, of the ''dose and dose-rate effectiveness factor'' of ICRP, and provides the way for a continuous extrapolation between the high and low dose-rate regions, ratifying the ''linear non-threshold hypothesis'' as the main option. Anyhow, the model throws some doubts about the additive property of the dose. (author)

  20. Response of cellulose nitrate track detectors to electron doses

    CERN Document Server

    Segovia, N; Moreno, A; Vazquez-Polo, G; Santamaría, T; Aranda, P; Hernández, A

    1999-01-01

    In order to study alternative dose determination methods, the bulk etching velocity and the latent track annealing of LR 115 track detectors was studied during electron irradiation runs from a Pelletron accelerator. For this purpose alpha irradiated and blank detectors were exposed to increasing electron doses from 10.5 to 317.5 kGy. After the irradiation with electrons the detectors were etched under routine conditions, except for the etching time, that was varied for each electron dose in order to reach a fixed residual thickness. The variation of the bulk etching velocity as a function of each one of the electron doses supplied, was interpolated in order to obtain dosimetric response curves. The observed annealing effect on the latent tracks is discussed as a function of the total electron doses supplied and the temperature.

  1. Theory of thermoluminescence gamma dose response: The unified interaction model

    International Nuclear Information System (INIS)

    Horowitz, Y.S.

    2001-01-01

    We describe the development of a comprehensive theory of thermoluminescence (TL) dose response, the unified interaction model (UNIM). The UNIM is based on both radiation absorption stage and recombination stage mechanisms and can describe dose response for heavy charged particles (in the framework of the extended track interaction model - ETIM) as well as for isotropically ionising gamma rays and electrons (in the framework of the TC/LC geminate recombination model) in a unified and self-consistent conceptual and mathematical formalism. A theory of optical absorption dose response is also incorporated in the UNIM to describe the radiation absorption stage. The UNIM is applied to the dose response supralinearity characteristics of LiF:Mg,Ti and is especially and uniquely successful in explaining the ionisation density dependence of the supralinearity of composite peak 5 in TLD-100. The UNIM is demonstrated to be capable of explaining either qualitatively or quantitatively all of the major features of TL dose response with many of the variable parameters of the model strongly constrained by ancilliary optical absorption and sensitisation measurements

  2. Bystander motivation in bullying incidents: to intervene or not to intervene?

    Science.gov (United States)

    Thornberg, Robert; Tenenbaum, Laura; Varjas, Kris; Meyers, Joel; Jungert, Tomas; Vanegas, Gina

    2012-08-01

    This research sought to extend knowledge about bystanders in bullying situations with a focus on the motivations that lead them to different responses. The 2 primary goals of this study were to investigate the reasons for children's decisions to help or not to help a victim when witnessing bullying, and to generate a grounded theory (or conceptual framework) of bystander motivation in bullying situations. Thirty students ranging in age from 9 to 15 years (M = 11.9; SD = 1.7) from an elementary and middle school in the southeastern United States participated in this study. Open- ended, semi-structured interviews were used, and sessions ranged from 30 to 45 minutes. We conducted qualitative methodology and analyses to gain an in-depth understanding of children's perspectives and concerns when witnessing bullying. A key finding was a conceptual framework of bystander motivation to intervene in bullying situations suggesting that deciding whether to help or not help the victim in a bullying situation depends on how bystanders define and evaluate the situation, the social context, and their own agency. Qualitative analysis revealed 5 themes related to bystander motives and included: interpretation of harm in the bullying situation, emotional reactions, social evaluating, moral evaluating, and intervention self-efficacy. Given the themes that emerged surrounding bystanders' motives to intervene or abstain from intervening, respondents reported 3 key elements that need to be confirmed in future research and that may have implications for future work on bullying prevention. These included: first, the potential importance of clear communication to children that adults expect bystanders to intervene when witnessing bullying; second, the potential of direct education about how bystanders can intervene to increase children's self-efficacy as defenders of those who are victims of bullying; and third, the assumption that it may be effective to encourage children's belief that

  3. Bystander effect of alpha-particle irradiation on mutagenicity and its associated mechanism

    International Nuclear Information System (INIS)

    Lu Ying; Yang Zhihua; Cao Zhenshan; Fan Feiyue; Zhu Maoxiang

    2004-01-01

    The work is to investigate α-particle irradiation-induced bystander effects on the mutagenicity in human chromosome 11 in the human-hamster hybrid (A L cells) and its possible mechanism. A L cells were used for assaying mutation rates of human chromosome 11 through screening mutants in the presence of anti-CD59 surface antigen antibody (S1) and complement. A grid was interposed between α-particle source and the cells being irradiated, so as to fix proportion of the irradiated cells (15%) and the bystander effects on the mutagenicity were detected. Free radical scavenger DMSO and intercellular communication inhibitor Lindane were selected to investigate the potential mechanism of α-particle induced bystander effect. There was clear dose-dependent relationship between mutation rate and the dose of alpha particle radiation. However, the mutant fractions of cell population shielded by the grid in α-particle irradiation system were much higher than the expected levels of irradiated cells. Lindane, but not DMSO, could obviously decrease this bystander effect induced by α-particle irradiation. Alpha-particle irradiation can induce bystander effect on the mutagenicity, in which intercellular communication may play important roles

  4. Maximum likelihood estimation for cytogenetic dose-response curves

    International Nuclear Information System (INIS)

    Frome, E.L.; DuFrain, R.J.

    1986-01-01

    In vitro dose-response curves are used to describe the relation between chromosome aberrations and radiation dose for human lymphocytes. The lymphocytes are exposed to low-LET radiation, and the resulting dicentric chromosome aberrations follow the Poisson distribution. The expected yield depends on both the magnitude and the temporal distribution of the dose. A general dose-response model that describes this relation has been presented by Kellerer and Rossi (1972, Current Topics on Radiation Research Quarterly 8, 85-158; 1978, Radiation Research 75, 471-488) using the theory of dual radiation action. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting dose-time-response models are intrinsically nonlinear in the parameters. A general-purpose maximum likelihood estimation procedure is described, and estimation for the nonlinear models is illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure

  5. Methodology for Estimating Ingestion Dose for Emergency Response at SRS

    CERN Document Server

    Simpkins, A A

    2002-01-01

    At the Savannah River Site (SRS), emergency response models estimate dose for inhalation and ground shine pathways. A methodology has been developed to incorporate ingestion doses into the emergency response models. The methodology follows a two-phase approach. The first phase estimates site-specific derived response levels (DRLs) which can be compared with predicted ground-level concentrations to determine if intervention is needed to protect the public. This phase uses accepted methods with little deviation from recommended guidance. The second phase uses site-specific data to estimate a 'best estimate' dose to offsite individuals from ingestion of foodstuffs. While this method deviates from recommended guidance, it is technically defensibly and more realistic. As guidance is updated, these methods also will need to be updated.

  6. Dose-response relationship in local radiotherapy for hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Park, Hee Chul; Seong, Jinsil; Han, Kwang Hyub; Chon, Chae Yoon; Moon, Young Myoung; Suh, Chang Ok

    2002-01-01

    Purpose: Dose escalation using three-dimensional conformal radiotherapy (3D-CRT) is based on the hypothesis that increasing the dose can enhance tumor control. This study aimed to determine whether a dose-response relationship exists in local radiotherapy for primary hepatocellular carcinoma (HCC). Methods and Materials: One hundred fifty-eight patients were enrolled in the present study between January 1992 and March 2000. The exclusion criteria included the presence of an extrahepatic metastasis, liver cirrhosis of Child class C, tumors occupying more than two-thirds of the entire liver, and a performance status on the Eastern Cooperative Oncology Group scale of more than 3. Radiotherapy was given to the field, including the tumor, with generous margin using 6- or 10-MV X-rays. The mean radiation dose was 48.2 ± 7.9 Gy in daily 1.8-Gy fractions. The tumor response was assessed based on diagnostic radiologic examinations, including a computed tomography scan, magnetic resonance imaging, and hepatic artery angiography 4-8 weeks after the completion of treatment. Liver toxicity and gastrointestinal complications were evaluated. Results: An objective response was observed in 106 of 158 (67.1%) patients. Statistical analysis revealed that the total dose was the most significant factor associated with the tumor response. The response rates in patients treated with doses 50 Gy were 29.2%, 68.6%, and 77.1%, respectively. Survivals at 1 and 2 years after radiotherapy were 41.8% and 19.9%, respectively, with a median survival time of 10 months. The rate of liver toxicity according to the doses 50 Gy was 4.2%, 5.9%, and 8.4%, respectively, and the rate of gastrointestinal complications was 4.2%, 9.9%, and 13.2%, respectively. Conclusions: The present study showed the existence of a dose-response relationship in local radiotherapy for primary HCC. Only the radiation dose was a significant factor for predicting an objective response. The results of this study showed that 3D

  7. The Radiation Dose-Response of the Human Spinal Cord

    International Nuclear Information System (INIS)

    Schultheiss, Timothy E.

    2008-01-01

    Purpose: To characterize the radiation dose-response of the human spinal cord. Methods and Materials: Because no single institution has sufficient data to establish a dose-response function for the human spinal cord, published reports were combined. Requisite data were dose and fractionation, number of patients at risk, number of myelopathy cases, and survival experience of the population. Eight data points for cervical myelopathy were obtained from five reports. Using maximum likelihood estimation correcting for the survival experience of the population, estimates were obtained for the median tolerance dose, slope parameter, and α/β ratio in a logistic dose-response function. An adequate fit to thoracic data was not possible. Hyperbaric oxygen treatments involving the cervical cord were also analyzed. Results: The estimate of the median tolerance dose (cervical cord) was 69.4 Gy (95% confidence interval, 66.4-72.6). The α/β = 0.87 Gy. At 45 Gy, the (extrapolated) probability of myelopathy is 0.03%; and at 50 Gy, 0.2%. The dose for a 5% myelopathy rate is 59.3 Gy. Graphical analysis indicates that the sensitivity of the thoracic cord is less than that of the cervical cord. There appears to be a sensitizing effect from hyperbaric oxygen treatment. Conclusions: The estimate of α/β is smaller than usually quoted, but values this small were found in some studies. Using α/β = 0.87 Gy, one would expect a considerable advantage by decreasing the dose/fraction to less than 2 Gy. These results were obtained from only single fractions/day and should not be applied uncritically to hyperfractionation

  8. Dose-response relationship in the treatment of gastrointestinal disorders.

    Science.gov (United States)

    Weihrauch, T R; Demol, P

    1989-08-01

    Numerous clinical studies have been performed to establish efficacy and safety of drugs in gastroenterological disorders. Only in a few if any of these studies, however, the rationale for the optimal dose and the dose regimens, respectively, have been addressed. Adequate and well-controlled dose finding studies play a key role in the clinical assessment of new drugs and in the evaluation of new indications. Hereby the range from the minimal effective dose to the maximal effective and well tolerated dose can be assessed and thus the optimal dose-range and dosage regimen be determined. Meaningful pharmacodynamic studies can be performed in the gastrointestinal tract also in healthy volunteers provided that a method with a high predictability for the desired therapeutic effect is available such as measurement of gastric acid secretion and its inhibition by a drug. Dose finding studies in gastroenterology can be carried out under two main aspects: First, to assess the pharmacodynamic and therapeutic effect of a compound on the gastrointestinal tract (e.g. anti-ulcer drug). Second, to evaluate the side effects of a drug on the gastrointestinal tract (e.g. gastric mucosal damage by non-steroidal anti-inflammatory drugs). For the evaluation of new drugs in gastrointestinal therapy a number of methods are available which yield accurate and reproducible data. While careful clinical-pharmacological dose-response studies using these methods have been carried out already more than a decade ago, it is surprising that therapeutic dose finding studies have become available only during the past few years. For scientific as well as for ethical reasons more trials which determine the optimal therapeutic dose are warranted.

  9. Maximum likelihood estimation for cytogenetic dose-response curves

    International Nuclear Information System (INIS)

    Frome, E.L; DuFrain, R.J.

    1983-10-01

    In vitro dose-response curves are used to describe the relation between the yield of dicentric chromosome aberrations and radiation dose for human lymphocytes. The dicentric yields follow the Poisson distribution, and the expected yield depends on both the magnitude and the temporal distribution of the dose for low LET radiation. A general dose-response model that describes this relation has been obtained by Kellerer and Rossi using the theory of dual radiation action. The yield of elementary lesions is kappa[γd + g(t, tau)d 2 ], where t is the time and d is dose. The coefficient of the d 2 term is determined by the recovery function and the temporal mode of irradiation. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting models are intrinsically nonlinear in the parameters. A general purpose maximum likelihood estimation procedure is described and illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure

  10. Some hybrid models applicable to dose-response relationships

    International Nuclear Information System (INIS)

    Kumazawa, Shigeru

    1992-01-01

    A new type of models of dose-response relationships has been studied as an initial stage to explore a reliable extrapolation of the relationships decided by high dose data to the range of low dose covered by radiation protection. The approach is to use a 'hybrid scale' of linear and logarithmic scales; the first model is that the normalized surviving fraction (ρ S > 0) in a hybrid scale decreases linearly with dose in a linear scale, and the second is that the induction in a log scale increases linearly with the normalized dose (τ D > 0) in a hybrid scale. The hybrid scale may reflect an overall effectiveness of a complex system against adverse events caused by various agents. Some data of leukemia in the atomic bomb survivors and of rodent experiments were used to show the applicability of hybrid scale models. The results proved that proposed models fit these data not less than the popular linear-quadratic models, providing the possible interpretation of shapes of dose-response curves, e.g. shouldered survival curves varied by recovery time. (author)

  11. Maximum likelihood estimation for cytogenetic dose-response curves

    Energy Technology Data Exchange (ETDEWEB)

    Frome, E.L; DuFrain, R.J.

    1983-10-01

    In vitro dose-response curves are used to describe the relation between the yield of dicentric chromosome aberrations and radiation dose for human lymphocytes. The dicentric yields follow the Poisson distribution, and the expected yield depends on both the magnitude and the temporal distribution of the dose for low LET radiation. A general dose-response model that describes this relation has been obtained by Kellerer and Rossi using the theory of dual radiation action. The yield of elementary lesions is kappa(..gamma..d + g(t, tau)d/sup 2/), where t is the time and d is dose. The coefficient of the d/sup 2/ term is determined by the recovery function and the temporal mode of irradiation. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting models are intrinsically nonlinear in the parameters. A general purpose maximum likelihood estimation procedure is described and illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure.

  12. X-ray radiation induced bystander effects of human glioblastoma T98G cells under hypoxia condition

    International Nuclear Information System (INIS)

    Zhang Jianghong; Jin Yizun; Shao Chunlin; Prise, K.M.

    2008-01-01

    Non-irradiated bystander human glioblastoma T98G cells were co-cultured (CC) with irradiated cells or treated with conditioned medium (CM) from irradiated cells under hypoxic condition, then micronucleus (MN) of both irradiated cells and bystander cells were measured for the investigation of radiation induced bystander effect and its mechanism. It has been found that the MN yield (Y MN ) of non-irradiated bystander T98G cells is obviously enhanced after the cell co-culture, or CM treatment, but this increment is diminished by free radical scavenger, dimethyl sulfoxide (DMSO). When hypoxic or normoxic T98G cells are treated with CM obtained from irradiated cells under either hypoxic or normoxic condition, the biggest bystander response has been observed in the group of hypoxic by- stander cells treated with CM from irradiated normoxic cells. However, all of these increments of bystander Y MN could be eliminated by aminoguanidine, an iNOS inhibitor. Therefore, under hypoxic condition, free radicals, especially reactive oxygen species and nitric oxide, are involved in the bystander response induced by irradiated T98G cells. (authors)

  13. Studying effects of Magnolol on alpha-particle induced bystander effects using PADC-film based dishes

    International Nuclear Information System (INIS)

    Wong, T.P.W.; Tse, A.K.W.; Fong, W.F.; Yu, K.N.

    2009-01-01

    Radiation-induced bystander effect refers to the biological response found in cells (called bystander cells) which are not irradiated directly by ionizing radiation but are next to cells irradiated directly by ionizing radiation. In the present paper, the effects of Magnolol, an extract from the bark of Magnolia officinalis which is used as a traditional Chinese medicine, were studied on alpha-particle induced bystander effects. In our experiments, Chinese hamster ovary (CHO) cells were cultured in PADC-film based dishes and were irradiated with low fluences of alpha particles passing through the PADC films. The precise number of cells traversed or missed by alpha particles could be determined by studying the alpha-particle tracks developed on the PADC films upon subsequent chemical etching. TdT-mediated dUTP Nick-End Labeling (TUNEL) assay was employed to analyze the biological response of bystander cells in terms of DNA strand breaks. With the pretreatment of Magnolol, the DNA strand breaks in bystander cells were reduced, which showed that the alpha-particle induced bystander effects were suppressed with the presence of Magnolol. Since Magnolol is an antioxidant which can scavenge reactive oxygen species (ROS), our results give support to that ROS play a role in the bystander signal transmission in our experiments.

  14. Studying effects of Magnolol on alpha-particle induced bystander effects using PADC-film based dishes

    Energy Technology Data Exchange (ETDEWEB)

    Wong, T.P.W. [Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong (Hong Kong); Tse, A.K.W.; Fong, W.F. [Research and Development Division, School of Chinese Medicine, Hong Kong Baptist University, Baptist University Road, Kowloon Tong (Hong Kong); Yu, K.N., E-mail: peter.yu@cityu.edu.h [Department of Physics and Materials Science, City University of Hong Kong, Tat Chee Avenue, Kowloon Tong (Hong Kong)

    2009-10-15

    Radiation-induced bystander effect refers to the biological response found in cells (called bystander cells) which are not irradiated directly by ionizing radiation but are next to cells irradiated directly by ionizing radiation. In the present paper, the effects of Magnolol, an extract from the bark of Magnolia officinalis which is used as a traditional Chinese medicine, were studied on alpha-particle induced bystander effects. In our experiments, Chinese hamster ovary (CHO) cells were cultured in PADC-film based dishes and were irradiated with low fluences of alpha particles passing through the PADC films. The precise number of cells traversed or missed by alpha particles could be determined by studying the alpha-particle tracks developed on the PADC films upon subsequent chemical etching. TdT-mediated dUTP Nick-End Labeling (TUNEL) assay was employed to analyze the biological response of bystander cells in terms of DNA strand breaks. With the pretreatment of Magnolol, the DNA strand breaks in bystander cells were reduced, which showed that the alpha-particle induced bystander effects were suppressed with the presence of Magnolol. Since Magnolol is an antioxidant which can scavenge reactive oxygen species (ROS), our results give support to that ROS play a role in the bystander signal transmission in our experiments.

  15. Mathematical model for evaluation of dose-rate effect on biological responses to low dose γ-radiation

    International Nuclear Information System (INIS)

    Ogata, H.; Kawakami, Y.; Magae, J.

    2003-01-01

    Full text: To evaluate quantitative dose-response relationship on the biological response to radiation, it is necessary to consider a model including cumulative dose, dose-rate and irradiation time. In this study, we measured micronucleus formation and [ 3 H] thymidine uptake in human cells as indices of biological response to gamma radiation, and analyzed mathematically and statistically the data for quantitative evaluation of radiation risk at low dose/low dose-rate. Effective dose (ED x ) was mathematically estimated by fitting a general function of logistic model to the dose-response relationship. Assuming that biological response depends on not only cumulative dose but also dose-rate and irradiation time, a multiple logistic function was applied to express the relationship of the three variables. Moreover, to estimate the effect of radiation at very low dose, we proposed a modified exponential model. From the results of fitting curves to the inhibition of [ 3 H] thymidine uptake and micronucleus formation, it was obvious that ED 50 in proportion of inhibition of [ 3 H] thymidine uptake increased with longer irradiation time. As for the micronuclei, ED 30 also increased with longer irradiation times. These results suggest that the biological response depends on not only total dose but also irradiation time. The estimated response surface using the three variables showed that the biological response declined sharply when the dose-rate was less than 0.01 Gy/h. These results suggest that the response does not depend on total cumulative dose at very low dose-rates. Further, to investigate the effect of dose-rate within a wider range, we analyzed the relationship between ED x and dose-rate. Fitted curves indicated that ED x increased sharply when dose-rate was less than 10 -2 Gy/h. The increase of ED x signifies the decline of the response or the risk and suggests that the risk approaches to 0 at infinitely low dose-rate

  16. Harderian Gland Tumorigenesis: Low-Dose and LET Response

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Polly Y. [SRI International, Menlo Park, CA (United States). Biosciences Div.; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Cucinotta, Francis A. [Univ. of Nevada, Las Vegas, NV (United States). Dept. of Health Physics and Diagnostic Sciences; Bjornstad, Kathleen A. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Bakke, James [SRI International, Menlo Park, CA (United States). Biosciences Div.; Rosen, Chris J. [SRI International, Menlo Park, CA (United States). Biosciences Div.; Du, Nicholas [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Fairchild, David G. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.; Cacao, Eliedonna [Univ. of Nevada, Las Vegas, NV (United States). Dept. of Health Physics and Diagnostic Sciences; Blakely, Eleanor A. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Div.

    2016-04-19

    Increased cancer risk remains a primary concern for travel into deep space and may preclude manned missions to Mars due to large uncertainties that currently exist in estimating cancer risk from the spectrum of radiations found in space with the very limited available human epidemiological radiation-induced cancer data. Existing data on human risk of cancer from X-ray and gamma-ray exposure must be scaled to the many types and fluences of radiations found in space using radiation quality factors and dose-rate modification factors, and assuming linearity of response since the shapes of the dose responses at low doses below 100 mSv are unknown. The goal of this work was to reduce uncertainties in the relative biological effect (RBE) and linear energy transfer (LET) relationship for space-relevant doses of charged-particle radiation-induced carcinogenesis. The historical data from the studies of Fry et al. and Alpen et al. for Harderian gland (HG) tumors in the female CB6F1 strain of mouse represent the most complete set of experimental observations, including dose dependence, available on a specific radiation-induced tumor in an experimental animal using heavy ion beams that are found in the cosmic radiation spectrum. However, these data lack complete information on low-dose responses below 0.1 Gy, and for chronic low-dose-rate exposures, and there are gaps in the LET region between 25 and 190 keV/μm. In this study, we used the historical HG tumorigenesis data as reference, and obtained HG tumor data for 260 MeV/u silicon (LET ~70 keV/μm) and 1,000 MeV/u titanium (LET ~100 keV/μm) to fill existing gaps of data in this LET range to improve our understanding of the dose-response curve at low doses, to test for deviations from linearity and to provide RBE estimates. Animals were also exposed to five daily fractions of 0.026 or 0.052 Gy of 1,000 MeV/u titanium ions to simulate chronic exposure, and HG tumorigenesis from this fractionated study were compared to the

  17. Optimal dose-response relationships in voice therapy.

    Science.gov (United States)

    Roy, Nelson

    2012-10-01

    Like other areas of speech-language pathology, the behavioural management of voice disorders lacks precision regarding optimal dose-response relationships. In voice therapy, dosing can presumably vary from no measurable effect (i.e., no observable benefit or adverse effect), to ideal dose (maximum benefit with no adverse effects), to doses that produce toxic or harmful effects on voice production. Practicing specific vocal exercises will inevitably increase vocal load. At ideal doses, these exercises may be non-toxic and beneficial, while at intermediate or high doses, the same exercises may actually be toxic or damaging to vocal fold tissues. In pharmacology, toxicity is a critical concept, yet it is rarely considered in voice therapy, with little known regarding "effective" concentrations of specific voice therapies vs "toxic" concentrations. The potential for vocal fold tissue damage related to overdosing on specific vocal exercises has been under-studied. In this commentary, the issue of dosing will be explored within the context of voice therapy, with particular emphasis placed on possible "overdosing".

  18. Response of human fibroblasts to low dose rate gamma irradiation

    International Nuclear Information System (INIS)

    Dritschilo, A.; Brennan, T.; Weichselbaum, R.R.; Mossman, K.L.

    1984-01-01

    Cells from 11 human strains, including fibroblasts from patients with the genetic diseases of ataxia telangiectasia (AT), xeroderma pigmentosum (XP), and Fanconi's anemia (FA), were exposed to γ radiation at high (1.6-2.2 Gy/min) and at low (0.03-0.07 Gy/min) dose rates. Survival curves reveal an increase inthe terminal slope (D 0 ) when cells are irradiated at low dose rates compared to high dose rates. This was true for all cell lines tested, although the AT, FA, and XP cells are reported or postulated to have radiation repair deficiencies. From the response of these cells, it is apparent that radiation sensitivities differ; however, at low dose rate, all tested human cells are able to repair injury

  19. Target irradiation induced bystander effects between stem-like and non stem-like cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yu [State Key Laboratory of Nuclear Physics and Technology, School of Physics, Peking University, Beijing 100871 (China); Space Radiation Research Unit, International Open Laboratory, National Institute of Radiological Sciences, 4-9-1 Inage-ku, Chiba 263-8555 (Japan); Kobayashi, Alisa [Space Radiation Research Unit, International Open Laboratory, National Institute of Radiological Sciences, 4-9-1 Inage-ku, Chiba 263-8555 (Japan); Department of Technical Support and Development, National Institute of Radiological Sciences, 4-9-1 Inage-ku, Chiba 263-8555 (Japan); Maeda, Takeshi [Department of Technical Support and Development, National Institute of Radiological Sciences, 4-9-1 Inage-ku, Chiba 263-8555 (Japan); Fu, Qibin [State Key Laboratory of Nuclear Physics and Technology, School of Physics, Peking University, Beijing 100871 (China); Oikawa, Masakazu [Department of Technical Support and Development, National Institute of Radiological Sciences, 4-9-1 Inage-ku, Chiba 263-8555 (Japan); Yang, Gen, E-mail: gen.yang@pku.edu.cn [State Key Laboratory of Nuclear Physics and Technology, School of Physics, Peking University, Beijing 100871 (China); Space Radiation Research Unit, International Open Laboratory, National Institute of Radiological Sciences, 4-9-1 Inage-ku, Chiba 263-8555 (Japan); Konishi, Teruaki, E-mail: tkonishi@nirs.go.jp [Space Radiation Research Unit, International Open Laboratory, National Institute of Radiological Sciences, 4-9-1 Inage-ku, Chiba 263-8555 (Japan); Department of Technical Support and Development, National Institute of Radiological Sciences, 4-9-1 Inage-ku, Chiba 263-8555 (Japan); Uchihori, Yukio [Space Radiation Research Unit, International Open Laboratory, National Institute of Radiological Sciences, 4-9-1 Inage-ku, Chiba 263-8555 (Japan); Department of Technical Support and Development, National Institute of Radiological Sciences, 4-9-1 Inage-ku, Chiba 263-8555 (Japan); and others

    2015-03-15

    Highlights: • Existence of radiation induced bystander effects (RIBE) between cancer stem-like cells (CSCs) and non stem-like cancer cells (NSCCs) in human fibrosarcoma HT1080 cells. • Existence of significant difference in generation and response of bystander signals between CSCs and NSCCs. • CSCs are significantly less sensitive to NO scavenger than that of NSCCs in terms of DNA double strand breaks induced by RIBE. - Abstract: Tumors are heterogeneous in nature and consist of multiple cell types. Among them, cancer stem-like cells (CSCs) are suggested to be the principal cause of tumor metastasis, resistance and recurrence. Therefore, understanding the behavior of CSCs in direct and indirect irradiations is crucial for clinical radiotherapy. Here, the CSCs and their counterpart non stem-like cancer cells (NSCCs) in human HT1080 fibrosarcoma cell line were sorted and labeled, then the two cell subtypes were mixed together and chosen separately to be irradiated via a proton microbeam. The radiation-induced bystander effect (RIBE) between the CSCs and NSCCs was measured by imaging 53BP1 foci, a widely used indicator for DNA double strand break (DSB). CSCs were found to be less active than NSCCs in both the generation and the response of bystander signals. Moreover, the nitric oxide (NO) scavenger c-PTIO can effectively alleviate the bystander effect in bystander NSCCs but not in bystander CSCs, indicating a difference of the two cell subtypes in NO signal response. To our knowledge, this is the first report shedding light on the RIBE between CSCs and NSCCs, which might contribute to a further understanding of the out-of-field effect in cancer radiotherapy.

  20. Target irradiation induced bystander effects between stem-like and non stem-like cancer cells

    International Nuclear Information System (INIS)

    Liu, Yu; Kobayashi, Alisa; Maeda, Takeshi; Fu, Qibin; Oikawa, Masakazu; Yang, Gen; Konishi, Teruaki; Uchihori, Yukio

    2015-01-01

    Highlights: • Existence of radiation induced bystander effects (RIBE) between cancer stem-like cells (CSCs) and non stem-like cancer cells (NSCCs) in human fibrosarcoma HT1080 cells. • Existence of significant difference in generation and response of bystander signals between CSCs and NSCCs. • CSCs are significantly less sensitive to NO scavenger than that of NSCCs in terms of DNA double strand breaks induced by RIBE. - Abstract: Tumors are heterogeneous in nature and consist of multiple cell types. Among them, cancer stem-like cells (CSCs) are suggested to be the principal cause of tumor metastasis, resistance and recurrence. Therefore, understanding the behavior of CSCs in direct and indirect irradiations is crucial for clinical radiotherapy. Here, the CSCs and their counterpart non stem-like cancer cells (NSCCs) in human HT1080 fibrosarcoma cell line were sorted and labeled, then the two cell subtypes were mixed together and chosen separately to be irradiated via a proton microbeam. The radiation-induced bystander effect (RIBE) between the CSCs and NSCCs was measured by imaging 53BP1 foci, a widely used indicator for DNA double strand break (DSB). CSCs were found to be less active than NSCCs in both the generation and the response of bystander signals. Moreover, the nitric oxide (NO) scavenger c-PTIO can effectively alleviate the bystander effect in bystander NSCCs but not in bystander CSCs, indicating a difference of the two cell subtypes in NO signal response. To our knowledge, this is the first report shedding light on the RIBE between CSCs and NSCCs, which might contribute to a further understanding of the out-of-field effect in cancer radiotherapy

  1. Dose-response relation between physical activity and sick leave

    NARCIS (Netherlands)

    Proper, K.I.; Heuvel, S.G. van den; Vroome, E.M. de; Hildebrandt, V.H.; Beek, A.J. van der

    2006-01-01

    Objective: To investigate the dose-response relation between moderate and vigorous physical activity and sick leave in a working population. Methods: Data were used from three large Dutch databases: two continuous, cross sectional surveys among a representative sample of the Dutch population and one

  2. Global DNA methylation responses to low dose radiation exposure

    International Nuclear Information System (INIS)

    Newman, M.R.; Ormsby, R.J.; Blyth, B.J.; Sykes, P.J.; Bezak, E.

    2011-01-01

    Full text: High radiation doses cause breaks in the DNA which are considered the critical lesions in initiation of radiation-induced cancer. However, at very low radiation doses relevant for the general public, the induction of such breaks will be rare, and other changes to the DNA such as DNA methylation which affects gene expression may playa role in radiation responses. We are studying global DNA methylation after low dose radiation exposure to determine if low dose radiation has short- and/or long-term effects on chromatin structure. We developed a sensitive high resolution melt assay to measure the levels of DNA methylation across the mouse genome by analysing a stretch of DNA sequence within Long Interspersed Nuclear Elements-I (LINE I) that comprise a very large proportion of the mouse and human genomes. Our initial results suggest no significant short-term or longterm) changes in global NA methylation after low dose whole-body X-radiation of 10 J1Gyor 10 mGy, with a significant transient increase in NA methylation observed I day after a high dose of I Gy. If the low radiation doses tested are inducing changes in bal DNA methylation, these would appear to be smaller than the variation observed between the sexes and following the general stress of the sham-irradiation procedure itself. This research was funded by the Low Dose Radiation Research Program, Biological and Environmental Research, US DOE, Grant DE-FG02-05ER64104 and MN is the recipient of the FMCF/BHP Dose Radiation Research Scholarship.

  3. Dose escalation with 3-D CRT in prostate cancer: five year dose responses and optimal treatment

    International Nuclear Information System (INIS)

    Hanks, Gerald; Hanlon, Alexandra; Pinover, Wayne; Hunt, Margie; Movsas, Benjamin; Schultheiss, Timothy

    1997-01-01

    Purpose: To report 5 yr dose responses in prostate cancer patients treated with 3D-CRT and describe optimal treatment based on dose response. Methods: Dose escalation was studied in 233 consecutive patients treated with 3D-CRT between 3/89 and 10/92. All surviving patients have >32 mo follow-up, the median follow-up is 55 mo. Estimated logistic cumulative distribution functions (logit response models) fit to 5 yr actuarial bNED outcome are reported for 3 dose groups in each of 3 pretreatment PSA groupings (10-19.9 ng/ml and 20+ ng/ml); no dose response is observed for patients with pretreatment PSA <10 ng/ml. Logit response models fit to 5 yr actuarial late morbidity rates (grade 2 GI, grade 2 GU, grade 3,4 GI) are also reported for 4 dose groups. Patients are treated with CT planned 4-field conformal technique where the PTV encompasses the CTV by 1.0 cm in all directions including the anterior rectal wall margin. Patients are followed at 6 mo intervals with PSA and DRE, and bNED failure is defined as PSA ≥1.5 ng/ml and rising on two consecutive measures. The Fox Chase modification of the LENT morbidity scale is used for GI morbidity including any blood transfusion and/or more than 2 coagulations as a grade 3 event. GU morbidity follows the RTOG scale. Results: The logit response models based on 5 yr bNED results have slopes of 27% and 18% for pretreatment PSA grouping 10-19.9 ng/ml and 20+ ng/ml, respectively. The 50% bNED response is observed at 71 Gy and 80 Gy respectively, while the 80% bNED response is observed at 76 Gy for the 10-19.9 ng/ml group and estimated at 88 Gy for the 20+ ng/ml group. Logit dose response models for grade 2 GI and grade 2 GU morbidity show markedly different slopes, 23% versus 4%, respectively. The slope for grade 3,4 GI is 12%. The dose response model indicates grade 3,4 GI complication rates at 5 yrs are 8% at 76 Gy and 12% at 80 Gy. Conclusion: Based on 5 yr results, we can draw some conclusions about appropriate dose from these

  4. Effects of Low-Dose Alpha-Particle Irradiation in Human Cells: The Role of Induced Genes and the Bystander Effect. Final Technical Report (9/15/1998-5/31/2005)

    Energy Technology Data Exchange (ETDEWEB)

    Little, John B.

    2013-09-17

    This grant was designed to examine the cellular and molecular mechanisms for the bystander effect of radiation (initially described in this laboratory) whereby damage signals are passed from irradiated to non-irradiated cells in a population. These signals induce genetic effects including DNA damage, mutations and chromosomal aberrations in the nonirradiated cells. Experiments were carried out in cultured mammalian cells, primarily human diploid cells, irradiated with alpha particles. This research resulted in 17 publications in the refereed literature and is described in the Progress Report where it is keyed to the publication list. This project was initiated at the Harvard School of Public Health (HSPH) and continued in collaboration with students/fellows at Colorado State University (CSU) and the New Jersey Medical School (NJMS).

  5. Linear dose response curves in fungi and tradescantia

    International Nuclear Information System (INIS)

    Unrau, P.

    1999-07-01

    Tradescantia Clone 02 data suggests that linear non-threshold dose responses are expected to the lowest doses and dose rates of low linear energy transfer (LET) radiation. This is likely to be true for other living organisms even though Clone 02 is radiation sensitive. It is concluded that Clone 02 is partially defective in the RAD 6 pathway for the repair of DNA interstrand cross-links (ISCL) and other loss of coding damage (LCD), based on its cross sensitivities to EMS and ionizing radiation. Tradescantia Clone 02 data showing linear non-threshold induction of somatic genetic events in part reflects the repair deficiency of this Clone. More DNA damage is repaired by recombinational mechanisms in Clone 02 than would occur in a wild-type strain. Two important classes of DNA lesions are induced by ionizing radiation in DNA - double strand breaks (DSB) which are repaired by recombination mechanisms, and loss of coding information damage (LCD), which is repaired by error prone mechanisms but may also be a substrate for recombinational repair. Based on data from yeast, there are two different repair pathways which deal with these differing lesions with different somatic genetic consequences. From yeast, yield cross sections can be derived and applied to DNA damage and repair in Tradescantia. For Clone 02, per lesion, more visible genetic events are scored than in wild-type strains. In a radiation-derived sub-clone, Clone 0106, which is more variable than Clone 02, even more events occur per lesion. This derivative clone, plus breeding experiments, indicate that Clone 02 is heterozygous, or a 'carrier' for a mutant version of a gene in the Tradescantia RAD 6 repair pathway. Clone 02 is, therefore, much like a Fanconi's anemia carrier in a human population, while the Clone 0106 derivative is much like a homozygous Fanconi's anemia patient, with respect to its response to ionizing radiation damage. Two anomalies in its dose response curves for 'pink' loss of

  6. TL response of citrine samples for high-dose dosimetry

    International Nuclear Information System (INIS)

    Teixeira, Maria Ines; Caldas, Linda V.E.

    2011-01-01

    The possibility of using samples of Brazilian stones as quartz, amethyst, topaz, etc. for high-dose dosimetry has been studied in recent years at IPEN, using the thermoluminescence technique (TL). In this work, the TL properties of citrine samples were studied. They were exposed to different doses of gamma radiation ( 60 Co). The natural citrine stone was extracted from a mine in Minas Gerais state, Brazil; it is a tectosilicate ranked as one of three-dimensional structure, showing clear yellow to golden brown color. The natural citrine stone is classified as quartz (SiO 2 ), and it has a lower symmetry and more compact reticulum. The citrine stone samples were powdered, and the selected grains were mixed with Teflon in the proportion 2 (Teflon):1 (Citrine). The mixture was pressed and sintered for production of Citrine -Teflon pellets of 50 mg. The TL emission curve showed two peaks at 160 deg C and 220 deg C. To remove the TL peak (160 deg C) of the sintered citrine pellet glow curves, different thermal treatments were tested during several time intervals. The TL dose-response curve between 50 Gy and 100 kGy, the reproducibility of TL response and the lower detection dose were obtained. The preliminary results show that citrine may be useful for high-dose dosimetry. (author)

  7. Diabetogenic action of streptozotocin: relationship of dose to metabolic response

    Science.gov (United States)

    Junod, Alain; Lambert, André E.; Stauffacher, Werner; Renold, Albert E.

    1969-01-01

    The relationship between the dose of intravenously administered streptozotocin (a N-nitroso derivative of glucosamine) and the diabetogenic response has been explored by use of the following indices of diabetogenic action: serum glucose, urine volume, and glycosuria, ketonuria, serum immunoreactive insulin (IRI), and pancreatic IRI content. Diabetogenic activity could be demonstrated between the doses of 25 and 100 mg/kg, all indices used showing some degree of correlation with the dose administered. Ketonuria was only seen with the largest dose, 100 mg/kg. The most striking and precise correlation was that between the dose and the pancreatic IRI content 24 hr after administration of the drug, and it is suggested that this represents a convenient test system either for both related and unrelated beta cytotoxic compounds or for screening for modifying agents or antidiabetic substances of a novel type. Ability to produce graded depletion of pancreatic IRI storage capacity led to an analysis of the relationship between pancreatic IRI content and deranged carbohydrate metabolism. Abnormal glucose tolerance and insulin response were seen when pancreatic IRI was depleted by about one-third, while fasting hyperglycemia and gross glycosuria occurred when the depletion had reached two-thirds and three-quarters, respectively. The mild yet persistent anomaly produced by the lowest effective streptozotocin dose, 25 mg/kg, exhibits characteristics resembling the state of chemical diabetes in humans and might thus warrant further study as a possible model. Finally, the loss of the diabetogenic action of streptozotocin by pretreatment with nicotinamide was confirmed and was shown to be a function of the relative doses of nicotinamide and streptozotocin and of the interval between injections. PMID:4241908

  8. Radiation dose response of strand breaks in SINPV-DNA

    International Nuclear Information System (INIS)

    Zhang Chunxiang; Luo Daling; Li Mianfeng; Liu Xiaowei; Zeng Rong; Wang Xunzhang

    1995-01-01

    The Spodoplera litura Nuclear Polyhedrosis Viruses (SINPV) is a kind of insectile virus with a simple structure, in which a double helix DNA is encapsulated in a protein coat and there is no function of enzymatic repair. The SINPV samples in dry powdered form held in sealed plastic tube were irradiated by 1-100 kGy gamma rays. The single strand breaks (SSB) and double strand breaks (DSB) induced in SINPV after irradiation were measured by neutral and alkaline agarose gel electrophoresis. A dose-response function combining the responses of one-hit and two-hit events was used to describe the SSB and DSB dose-response curves. It is shown that the SSB are one-hit events and the DSB are the combination of both one-hit, and two-hit events, and two-hit events are predominant in the DSB process

  9. Cellular response to low Gamma-ray doses

    Energy Technology Data Exchange (ETDEWEB)

    Manzanares A, E; Vega C, H R; Leon, L.C. de . [Unidades Academicas de Estudios Nucleares, Universidad Autonoma de Zacatecas, A.P. 336, 98000 Zacatecas (Mexico); Rebolledo D, O; Radillo J, F [Facultad de Ciencias Biologicas y Agropecuarias de la Universidad de Colima, Colima (Mexico)

    2002-07-01

    Lymphocytes, obtained from healthy donors, were exposed to a low strength gamma-ray field to determine heat shock protein expression in function of radiation dose. Protein identification was carried out using mAb raised against Hsp70 and Hsc70.Hsp70 protein was detected after lymphocyte irradiation. In all cases, an increasing trend of relative amounts of Hsp70 in function to irradiation time was observed. After 1.25 c Gy gamma-ray dose, lymphocytes expressed Hsp70 protein, indicating a threshold response to gamma rays. (Author)

  10. Cellular response to low Gamma-ray doses

    International Nuclear Information System (INIS)

    Manzanares A, E.; Vega C, H.R.; Leon, L.C. de; Rebolledo D, O.; Radillo J, F.

    2002-01-01

    Lymphocytes, obtained from healthy donors, were exposed to a low strength gamma-ray field to determine heat shock protein expression in function of radiation dose. Protein identification was carried out using mAb raised against Hsp70 and Hsc70.Hsp70 protein was detected after lymphocyte irradiation. In all cases, an increasing trend of relative amounts of Hsp70 in function to irradiation time was observed. After 1.25 c Gy gamma-ray dose, lymphocytes expressed Hsp70 protein, indicating a threshold response to gamma rays. (Author)

  11. Dose response of rat retinal microvessels to proton dose schedules used clinically: a pilot study

    International Nuclear Information System (INIS)

    Archambeau, John O.; Mao, Xiao W.; McMillan, Paul J.; Gouloumet, Vanessa L.; Oeinck, Steven C.; Grove, Roger; Yonemoto, Leslie T.; Slater, Jerry D.; Slater, James M.

    2000-01-01

    Purpose: This preclinical rat pilot study quantifies retinal microvessel, endothelial, and pericyte population changes produced by proton irradiation Methods and Materials: The left eyes of rats were irradiated with single doses of 8, 14, 20, and 28 Gy protons; right eyes, with two fractions. Animals were euthanized, and eyes were removed; elastase digests were prepared, and cell populations were counted in sample fields. Results were compared with unirradiated controls. Results: Progressive time- and dose-dependent endothelial cell loss occurred following all schedules. Cell loss was significantly different from control values (p 0 phase of the mitotic cycle. 28 Gy produced photoreceptor cell loss. Conclusion: The retinal digest is an elegant bioassay to quantify the microvessel population response. Single- and split-dose schedules appear to yield similar outcomes, in terms of endothelial cell density

  12. Dose-response relationship for breast cancer induction at radiotherapy dose

    Directory of Open Access Journals (Sweden)

    Gruber Günther

    2011-06-01

    Full Text Available Abstract Purpose Cancer induction after radiation therapy is known as a severe side effect. It is therefore of interest to predict the probability of second cancer appearance for the patient to be treated including breast cancer. Materials and methods In this work a dose-response relationship for breast cancer is derived based on (i the analysis of breast cancer induction after Hodgkin's disease, (ii a cancer risk model developed for high doses including fractionation based on the linear quadratic model, and (iii the reconstruction of treatment plans for Hodgkin's patients treated with radiotherapy, (iv the breast cancer induction of the A-bomb survivor data. Results The fitted model parameters for an α/β = 3 Gy were α = 0.067Gy-1 and R = 0.62. The risk for breast cancer is according to this model for small doses consistent with the finding of the A-bomb survivors, has a maximum at doses of around 20 Gy and drops off only slightly at larger doses. The predicted EAR for breast cancer after radiotherapy of Hodgkin's disease is 11.7/10000PY which can be compared to the findings of several epidemiological studies where EAR for breast cancer varies between 10.5 and 29.4/10000PY. The model was used to predict the impact of the reduction of radiation volume on breast cancer risk. It was estimated that mantle field irradiation is associated with a 3.2-fold increased risk compared with mediastinal irradiation alone, which is in agreement with a published value of 2.7. It was also shown that the modelled age dependency of breast cancer risk is in satisfying agreement with published data. Conclusions The dose-response relationship obtained in this report can be used for the prediction of radiation induced secondary breast cancer of radiotherapy patients.

  13. Kinetics of the early adaptive response and adaptation threshold dose

    International Nuclear Information System (INIS)

    Mendiola C, M.T.; Morales R, P.

    2003-01-01

    The expression kinetics of the adaptive response (RA) in mouse leukocytes in vivo and the minimum dose of gamma radiation that induces it was determined. The mice were exposed 0.005 or 0.02 Gy of 137 Cs like adaptation and 1h later to the challenge dose (1.0 Gy), another group was only exposed at 1.0 Gy and the damage is evaluated in the DNA with the rehearsal it makes. The treatment with 0. 005 Gy didn't induce RA and 0. 02 Gy causes a similar effect to the one obtained with 0.01 Gy. The RA was show from an interval of 0.5 h being obtained the maximum expression with 5.0 h. The threshold dose to induce the RA is 0.01 Gy and in 5.0 h the biggest quantity in molecules is presented presumably that are related with the protection of the DNA. (Author)

  14. Dose response curves for effects of low-level radiation

    International Nuclear Information System (INIS)

    Myers, D.K.

    1980-01-01

    The linear dose-response model used by international committees to assess the genetic and carcinogenic hazards of low-level radiation appears to be the most reasonable interpretation of the available scientific data that are relevant to this topic. There are, of course, reasons to believe that this model may overestimate radiation hazards in certain instances, a fact acknowledged in recent reports of these committees. The linear model is now also being utilized to estimate the potential carcinogenic hazards of other agents such as asbestos and polycyclic aromatic hydrocarbons. This model implies that there is no safe dose for any of these agents and that potential health hazards will increase in direct proportion to total accumulated dose. The practical implication is the recommendation that all exposures should be kept 'as low as reasonably achievable, economic and social factors being taken into account'. (auth)

  15. The dose-response relationship for UV-tumorigenesis

    International Nuclear Information System (INIS)

    Gruijl, F.R. de.

    1982-01-01

    The main objective of the investigations was to extend the knowledge on experimental UV-carcinogenesis and to use the experimental results as guidelines for developing a dose-response model for UV-carcinogenesis. The animal experiments carried out were all long-term ones. It was decided that - in anticipation of the data to be obtained - a model for such an assessment should be developed using the experimental results available at the start of the present study (1977). This initial study is presented. The results of two animal experiments are presented, which show that UV radiation is capable of inducing a systemic effect that enhances the de novo formation of UV induced tumors. The results of the main experiment are presented. In this experiment groups of mice were subjected to daily exposure to a certain dose of UV radiation in order to find the dose-response relationship. The relation between the daily dose and the duration of the treatment till the appearance of tumors (for instance, as measured by the yield) was ascertained for tumors of different sizes. It appears that the growth of a tumor is dose-independent, and, therefore, only the initiation of a tumor is dose-dependent. Finally an experiment is presented in which it was measured that, if a mouse is subjected to daily UV exposure, the transmission of the epidermis in the shortwave UV region decreases continuously. This decrease is due to hyperplasia of the epidermis, i.e., thickening of the epidermis by an increase in the number of cells per unit surface area. (Auth.)

  16. Bystander first aid in trauma - prevalence and quality: a prospective observational study.

    Science.gov (United States)

    Bakke, H K; Steinvik, T; Eidissen, S-I; Gilbert, M; Wisborg, T

    2015-10-01

    Bystander first aid and basic life support can likely improve victim survival in trauma. In contrast to bystander first aid and out-of-hospital cardiac arrest, little is known about the role of bystanders in trauma response. Our aim was to determine how frequently first aid is given to trauma victims by bystanders, the quality of this aid, the professional background of first-aid providers, and whether previous first-aid training affects aid quality. We conducted a prospective 18-month study in two mixed urban-rural Norwegian counties. The personnel on the first ambulance responding to trauma calls assessed and documented first aid performed by bystanders using a standard form. A total of 330 trauma calls were included, with bystanders present in 97% of cases. Securing an open airway was correctly performed for 76% of the 43 patients in need of this first-aid measure. Bleeding control was provided correctly for 81% of 63 patients for whom this measure was indicated, and prevention of hypothermia for 62% of 204 patients. Among the first-aid providers studied, 35% had some training in first aid. Bystanders with documented first-aid training gave better first aid than those where first-aid training status was unknown. A majority of the trauma patients studied received correct pre-hospital first aid, but still there is need for considerable improvement, particularly hypothermia prevention. Previous first-aid training seems to improve the quality of first aid provided. The effect on patient survival needs to be investigated. © 2015 The Authors. The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  17. Biological effects of low-dose ionizing radiation exposure; Biologische Wirkungen niedriger Dosen ionisierender Strahlung

    Energy Technology Data Exchange (ETDEWEB)

    Reinoehl-Kompa, Sabine; Baldauf, Daniela; Heller, Horst (comps.)

    2009-07-01

    The report on the meeting of the Strahlenschutzkommission 2007 concerning biological effects of low-dose ionizing radiation exposure includes the following contributions: Adaptive response. The importance of DNA damage mechanisms for the biological efficiency of low-energy photons. Radiation effects in mammography: the relative biological radiation effects of low-energy photons. Radiation-induced cataracts. Carcinomas following prenatal radiation exposure. Intercellular apoptosis induction and low-dose irradiation: possible consequences for the oncogenesis control. Mechanistic models for the carcinogenesis with radiation-induced cell inactivation: application to all solid tumors in the Japanese atomic bomb survivors. Microarrays at low radiation doses. Mouse models for the analysis of biological effects of low-dose ionizing radiation. The bystander effect: observations, mechanisms and implications. Lung carcinoma risk of Majak workers - modeling of carcinogenesis and the bystander effect. Microbeam studies in radiation biology - an overview. Carcinogenesis models with radiation-induced genomic instability. Application to two epidemiological cohorts.

  18. Are Victims Truly Worse Off in the Presence of Bystanders? Revisiting the Bystander Effect

    NARCIS (Netherlands)

    Fromell, Hanna; Nosenzo, Daniele; Owens, Trudy; Tufano, Fabio

    2017-01-01

    Previous studies have shown that individuals are less likely to help a person in need when there are “bystanders” present who can also offer help. We designed an experiment to re-examine this “bystander effect” using modified dictator games. We find lower giving rates in the presence of bystanders,

  19. Analysis of thermal-dose response to heat

    International Nuclear Information System (INIS)

    Storm, F.; Roe, D.; Drury, B.

    1987-01-01

    The authors reasoned that if hyperthermia alone has a clinical anti-tumor effect, response should have a thermal dose relationship. The authors analyzed 100 patients with advanced cancer treated with magnetic-induction. Three methods of determining thermal dose were used: (A) t1x10, the lowest temperature sustained throughout the tumor for 30-60min during the first of ten daily treatments, which represents one usual course of ten hourly sessions; (B) t43 (equivalent minutes at 43C) which accounts for non-linear tumor heating by combining serially measured temperatures during the first treatment with a mathematical description of the time-temperature relationship for thermal inactivation or damage; (C) Ct43 (cumulative t43), which represents the t43 value multiplied by the actual number of subsequent daily treatments received. Response was defined as CR+PR+MR. The results show a statistically significant effect of heat alone for t1x10, t43, and Ct43. These analyses demonstrate a thermal-dose relationship between hyperthermia therapy and tumor response as a sole independent variable, which indicates that heat therapy has clinical anti-cancer activity

  20. Bystander Effects During Synchrotron Imaging Procedures?

    International Nuclear Information System (INIS)

    Schueltke, Elisabeth; Nikkhah, Guido; Bewer, Brian; Wysokinski, Tomasz; Chapman, Dean

    2010-01-01

    Using monochromatic beam and synchrotron phase-contrast technique at the biomedical beamline of the Italian synchrotron facility Elettra (SYRMEP), we have shown in a small animal model of malignant brain tumor that it is possible to obtain high-resolution images of very small tumors when they have developed from implanted tumor cells loaded with colloidal gold nanoparticles (GNP). All previous experiments were conducted in post-mortem samples. We have now designed a cell culture experiment to investigate the effects of synchrotron radiation with an energy and dose profile similar to that expected in our first in vivo imaging studies according to the protocol developed at SYRMEP.Materials and Methods: Culture flasks containing either gold-loaded or naieve C6 glioma cells were exposed to a dose of 0.5 Gy at 24 keV. The irradiated medium was aspirated and replaced with fresh growth medium. Twenty-four hours later this non-irradiated medium exposed to irradiated cells was aspirated, then added to non-irradiated C6 cells in order to investigate whether bystander effects are seen under the conditions of our image acquisition protocol. The irradiated medium was added to a number of other non-irradiated cell cultures. Cell counts were followed until 72 hrs after irradiation. Western blots were conducted with H2AX antibodies. This experiment was one of the first biomedical experiments conducted at BMIT, the new biomedical imaging and therapy beamline of the Canadian Light Source.Results: No significant differences in proliferation were seen between cells that were directly irradiated, exposed to irradiated medium or exposed to the non-irradiated 24-hr-medium from the irradiated cells. However, there was a tendency towards a higher number of double strand breaks in previously irradiated cells when they were exposed to non-irradiated medium that had been in contact with irradiated cells for 24 hrs.

  1. Linear dose response curves in fungi and tradescantia

    Energy Technology Data Exchange (ETDEWEB)

    Unrau, P. [Atomic Energy of Canada Ltd., Chalk River, Ontario (Canada)

    1999-07-15

    Tradescantia Clone 02 data suggests that linear non-threshold dose responses are expected to the lowest doses and dose rates of low linear energy transfer (LET) radiation. This is likely to be true for other living organisms even though Clone 02 is radiation sensitive. It is concluded that Clone 02 is partially defective in the RAD 6 pathway for the repair of DNA interstrand cross-links (ISCL) and other loss of coding damage (LCD), based on its cross sensitivities to EMS and ionizing radiation. Tradescantia Clone 02 data showing linear non-threshold induction of somatic genetic events in part reflects the repair deficiency of this Clone. More DNA damage is repaired by recombinational mechanisms in Clone 02 than would occur in a wild-type strain. Two important classes of DNA lesions are induced by ionizing radiation in DNA - double strand breaks (DSB) which are repaired by recombination mechanisms, and loss of coding information damage (LCD), which is repaired by error prone mechanisms but may also be a substrate for recombinational repair. Based on data from yeast, there are two different repair pathways which deal with these differing lesions with different somatic genetic consequences. From yeast, yield cross sections can be derived and applied to DNA damage and repair in Tradescantia. For Clone 02, per lesion, more visible genetic events are scored than in wild-type strains. In a radiation-derived sub-clone, Clone 0106, which is more variable than Clone 02, even more events occur per lesion. This derivative clone, plus breeding experiments, indicate that Clone 02 is heterozygous, or a 'carrier' for a mutant version of a gene in the Tradescantia RAD 6 repair pathway. Clone 02 is, therefore, much like a Fanconi's anemia carrier in a human population, while the Clone 0106 derivative is much like a homozygous Fanconi's anemia patient, with respect to its response to ionizing radiation damage. Two anomalies in its dose response curves for &apos

  2. No significant level of inheritable interchromosomal aberrations in the progeny of bystander primary human fibroblasts after alpha particle irradiation

    Science.gov (United States)

    Hu, Burong; Zhu, Jiayun; Zhou, Hongning; Hei, Tom K.

    2013-02-01

    A major concern for bystander effects is the probability that normal healthy cells adjacent to the irradiated cells become genomically unstable and undergo further carcinogenesis after therapeutic irradiation or space mission where astronauts are exposed to low dose of heavy ions. Genomic instability is a hallmark of cancer cells. In the present study, two irradiation protocols were performed in order to ensure pure populations of bystander cells and the genomic instability in their progeny were investigated. After irradiation, chromosomal aberrations of cells were analyzed at designated time points using G2 phase premature chromosome condensation (G2-PCC) coupled with Giemsa staining and with multiplex fluorescent in situ hybridization (mFISH). Our Giemsa staining assay demonstrated that elevated yields of chromatid breaks were induced in the progeny of pure bystander primary fibroblasts up to 20 days after irradiation. mFISH assay showed no significant level of inheritable interchromosomal aberrations were induced in the progeny of the bystander cell groups, while the fractions of gross aberrations (chromatid breaks or chromosomal breaks) significantly increased in some bystander cell groups. These results suggest that genomic instability occurred in the progeny of the irradiation associated bystander normal fibroblasts exclude the inheritable interchromosomal aberration.

  3. Bayesian Dose-Response Modeling in Sparse Data

    Science.gov (United States)

    Kim, Steven B.

    This book discusses Bayesian dose-response modeling in small samples applied to two different settings. The first setting is early phase clinical trials, and the second setting is toxicology studies in cancer risk assessment. In early phase clinical trials, experimental units are humans who are actual patients. Prior to a clinical trial, opinions from multiple subject area experts are generally more informative than the opinion of a single expert, but we may face a dilemma when they have disagreeing prior opinions. In this regard, we consider compromising the disagreement and compare two different approaches for making a decision. In addition to combining multiple opinions, we also address balancing two levels of ethics in early phase clinical trials. The first level is individual-level ethics which reflects the perspective of trial participants. The second level is population-level ethics which reflects the perspective of future patients. We extensively compare two existing statistical methods which focus on each perspective and propose a new method which balances the two conflicting perspectives. In toxicology studies, experimental units are living animals. Here we focus on a potential non-monotonic dose-response relationship which is known as hormesis. Briefly, hormesis is a phenomenon which can be characterized by a beneficial effect at low doses and a harmful effect at high doses. In cancer risk assessments, the estimation of a parameter, which is known as a benchmark dose, can be highly sensitive to a class of assumptions, monotonicity or hormesis. In this regard, we propose a robust approach which considers both monotonicity and hormesis as a possibility. In addition, We discuss statistical hypothesis testing for hormesis and consider various experimental designs for detecting hormesis based on Bayesian decision theory. Past experiments have not been optimally designed for testing for hormesis, and some Bayesian optimal designs may not be optimal under a

  4. Role of nitric oxide in targeted-subcellular organelles induced bystander effect

    International Nuclear Information System (INIS)

    Shao Chunlin; Folkard, M.; Prise, K.M.

    2007-01-01

    The work is to investigate the bystander effect and related signaling factor induced by targeted irradiation on tumor cells. Human glioblastoma T98G cells were irradiated with a precise number of helium microbeam ions, which targeted to either nuclear or cytoplasm. Chromosome damage and intracellular NO level were assayed. Influence of a NO free radical scavenger on these radiation responses was measured. Using DEANO, the cellular effect of NO was also studied. It was found that even only one cell with a population was targeted with one particle through either nuclear or cytoplasm, additional cellular damage was induced in other 10s cells through a signaling amplification pathway and related bystander response. Although cell damage induced directly by nuclear irradiation was greater than that induced by cytoplasmic irradiation, bystander responses induced by these two kinds of irradiation were similar. When a fraction of cells were individually irradiated by helium ions, the yield of micronuclei was obviously higher than that assuming no bystander effect. However, these targeted irradiation induced bystander response were inhibited by c-PTIO, a scavenger of nitric oxide (NO) free radical. Detected with a NO molecular probe DAF-AM, it was observed that when only 1% of cells were irradiated either through nuclear or cytoplasm, the percentage of NO-positive cells increased by about 30% so that the NO-related fluorescence intensity increased by 15%. Moreover, micronuclei were induced indeed in T98G cells treated with a NO donor. These indicate that NO is a bystander signaling factor for both nuclear irradiation and cytoplasmic irradiation. (authors)

  5. Cytogenetic dose-response and adaptive response in cells of ungulate species exposed to ionizing radiation

    International Nuclear Information System (INIS)

    Ulsh, B.A.; Miller, S.M.; Mallory, F.F.; Mitchel, R.E.J.; Morrison, D.P.; Boreham, D.R.

    2004-01-01

    In the studies reported here, the micronucleus assay, a common cytogenetic technique, was used to examine the dose-responses in fibroblasts from three ungulate species (white-tailed deer, woodland caribou, and Indian muntjac) exposed to high doses of ionizing radiation (1-4 Gy of 60 Co gamma radiation). This assay was also used to examine the effects of exposure to low doses (1-100 mGy) typical of what these species experience in a year from natural and anthropogenic environmental sources. An adaptive response, defined as the induction of resistance to a stressor by a prior exposure to a small 'adapting' stress, was observed after exposure to low doses. This work indicates that very small doses are protective for the endpoint examined. The same level of protection was seen at all adapting doses, including 1 radiation track per cell, the lowest possible cellular dose. These results are consistent with other studies in a wide variety of organisms that demonstrate a protective effect of low doses at both cellular and whole-organism levels. This implies that environmental regulations predicated on the idea that even the smallest dose of radiation carries a quantifiable risk of direct adverse consequences to the exposed organism require further examination. Cytogenetic assays provide affordable and feasible biological effects-based alternatives that are more biologically relevant than traditional contaminant concentration-based radioecological risk assessment

  6. Dose response relationship in anti-stress gene regulatory networks.

    Science.gov (United States)

    Zhang, Qiang; Andersen, Melvin E

    2007-03-02

    To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products) in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear) depends on changes in the specific values of local response coefficients (gains) distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear, and depending on

  7. Dose response relationship in anti-stress gene regulatory networks.

    Directory of Open Access Journals (Sweden)

    Qiang Zhang

    2007-03-01

    Full Text Available To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear depends on changes in the specific values of local response coefficients (gains distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear

  8. Role of nitric oxide in the radiation-induced bystander effect.

    Science.gov (United States)

    Yakovlev, Vasily A

    2015-12-01

    Cells that are not irradiated but are affected by "stress signal factors" released from irradiated cells are called bystander cells. These cells, as well as directly irradiated ones, express DNA damage-related proteins and display excess DNA damage, chromosome aberrations, mutations, and malignant transformation. This phenomenon has been studied widely in the past 20 years, since its first description by Nagasawa and Little in 1992, and is known as the radiation-induced bystander effect (RIBE). Several factors have been identified as playing a role in the bystander response. This review will focus on one of them, nitric oxide (NO), and its role in the stimulation and propagation of RIBE. The hydrophobic properties of NO, which permit its diffusion through the cytoplasm and plasma membranes, allow this signaling molecule to easily spread from irradiated cells to bystander cells without the involvement of gap junction intercellular communication. NO produced in irradiated tissues mediates cellular regulation through posttranslational modification of a number of regulatory proteins. The best studied of these modifications are S-nitrosylation (reversible oxidation of cysteine) and tyrosine nitration. These modifications can up- or down-regulate the functions of many proteins modulating different NO-dependent effects. These NO-dependent effects include the stimulation of genomic instability (GI) and the accumulation of DNA errors in bystander cells without direct DNA damage. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  9. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework

    International Nuclear Information System (INIS)

    Calabrese, Edward J.; Bachmann, Kenneth A.; Bailer, A. John; Bolger, P. Michael; Borak, Jonathan; Cai, Lu; Cedergreen, Nina; Cherian, M. George; Chiueh, Chuang C.; Clarkson, Thomas W.; Cook, Ralph R.; Diamond, David M.; Doolittle, David J.; Dorato, Michael A.; Duke, Stephen O.; Feinendegen, Ludwig; Gardner, Donald E.; Hart, Ronald W.; Hastings, Kenneth L.; Hayes, A. Wallace; Hoffmann, George R.; Ives, John A.; Jaworowski, Zbigniew; Johnson, Thomas E.; Jonas, Wayne B.; Kaminski, Norbert E.; Keller, John G.; Klaunig, James E.; Knudsen, Thomas B.; Kozumbo, Walter J.; Lettieri, Teresa; Liu, Shu-Zheng; Maisseu, Andre; Maynard, Kenneth I.; Masoro, Edward J.; McClellan, Roger O.; Mehendale, Harihara M.; Mothersill, Carmel; Newlin, David B.; Nigg, Herbert N.; Oehme, Frederick W.; Phalen, Robert F.; Philbert, Martin A.; Rattan, Suresh I.S.; Riviere, Jim E.; Rodricks, Joseph; Sapolsky, Robert M.; Scott, Bobby R.; Seymour, Colin; Sinclair, David A.; Smith-Sonneborn, Joan; Snow, Elizabeth T.; Spear, Linda; Stevenson, Donald E.; Thomas, Yolene; Tubiana, Maurice; Williams, Gary M.; Mattson, Mark P.

    2007-01-01

    Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines

  10. Response of pig skin to fractionated radiation doses

    International Nuclear Information System (INIS)

    Wiernik, G.; Hopewell, J.W.; Patterson, T.J.S.; Young, C.M.A.; Foster, J.L.

    1977-01-01

    The individual components of a fractionated course of irradiation treatment have been considered separately. Methods of accurate measurement of individual parameters has brought to light different interpretations of the observations. Reasons are given for the necessity of having a radiobiological model which has a direct relevance to the clinical situation. Results are reported for fractionated regimes of irradiation in which the dose has been varied above and below normal tissue tolerance which has been equated with clinical skin necrosis. The components of the acute skin reaction, erythema, pigmentation and desquamation have been analysed separately and their contribution as a method of measurement assessed. Initially, the range of numerical scores attributed to erythema did not reach the scores attributed to necrosis but we now believe that radiation damage expressed as erythema can move directly into necrosis without passing through desquamation. Desquamation, on the other hand, only became a useful parameter at higher dose levels; it has also been shown to be a component associated with skin breakdown. Pigmentation showed no dose response at the dose levels employed in our experiments and it is our belief that this is due to this system being fully saturated under these circumstances. Measurement of the late radiation reaction in the skin has been considered in detail and our results have been expressed by comparing the relative lengths of irradiated and control fields in the same pig. From these findings iso-effect graphs have been constructed and time and fractionation factors have been derived. (author)

  11. Low dose effects and non-monotonic dose responses for endocrine active chemicals: Science to practice workshop: Workshop summary

    DEFF Research Database (Denmark)

    Beausoleil, Claire; Ormsby, Jean-Nicolas; Gies, Andreas

    2013-01-01

    A workshop was held in Berlin September 12–14th 2012 to assess the state of the science of the data supporting low dose effects and non-monotonic dose responses (“low dose hypothesis”) for chemicals with endocrine activity (endocrine disrupting chemicals or EDCs). This workshop consisted of lectu...

  12. Radiation and chemotherapy bystander effects induce early genomic instability events: telomere shortening and bridge formation coupled with mitochondrial dysfunction.

    LENUS (Irish Health Repository)

    Gorman, Sheeona

    2012-02-01

    The bridge breakage fusion cycle is a chromosomal instability mechanism responsible for genomic changes. Radiation bystander effects induce genomic instability; however, the mechanism driving this instability is unknown. We examined if radiation and chemotherapy bystander effects induce early genomic instability events such as telomere shortening and bridge formation using a human colon cancer explant model. We assessed telomere lengths, bridge formations, mitochondrial membrane potential and levels of reactive oxygen species in bystander cells exposed to medium from irradiated and chemotherapy-treated explant tissues. Bystander cells exposed to media from 2Gy, 5Gy, FOLFOX treated tumor and matching normal tissue showed a significant reduction in telomere lengths (all p values <0.018) and an increase in bridge formations (all p values <0.017) compared to bystander cells treated with media from unirradiated tissue (0Gy) at 24h. There was no significant difference between 2Gy and 5Gy treatments, or between effects elicited by tumor versus matched normal tissue. Bystander cells exposed to media from 2Gy irradiated tumor tissue showed significant depolarisation of the mitochondrial membrane potential (p=0.012) and an increase in reactive oxygen species levels. We also used bystander cells overexpressing a mitochondrial antioxidant manganese superoxide dismutase (MnSOD) to examine if this antioxidant could rescue the mitochondrial changes and subsequently influence nuclear instability events. In MnSOD cells, ROS levels were reduced (p=0.02) and mitochondrial membrane potential increased (p=0.04). These events were coupled with a decrease in percentage of cells with anaphase bridges and a decrease in the number of cells undergoing telomere length shortening (p values 0.01 and 0.028 respectively). We demonstrate that radiation and chemotherapy bystander responses induce early genomic instability coupled with defects in mitochondrial function. Restoring mitochondrial

  13. The involvement of calcium and MAP kinase signaling pathways in the production of radiation-induced bystander effects.

    LENUS (Irish Health Repository)

    Lyng, F M

    2006-04-01

    Much evidence now exists regarding radiation-induced bystander effects, but the mechanisms involved in the transduction of the signal are still unclear. The mitogen-activated protein kinase (MAPK) pathways have been linked to growth factor-mediated regulation of cellular events such as proliferation, senescence, differentiation and apoptosis. Activation of multiple MAPK pathways such as the ERK, JNK and p38 pathways have been shown to occur after exposure of cells to radiation and a variety of other toxic stresses. Previous studies have shown oxidative stress and calcium signaling to be important in radiation-induced bystander effects. The aim of the present study was to investigate MAPK signaling pathways in bystander cells exposed to irradiated cell conditioned medium (ICCM) and the role of oxidative metabolism and calcium signaling in the induction of bystander responses. Human keratinocytes (HPV-G cell line) were irradiated (0.005-5 Gy) using a cobalt-60 teletherapy unit. The medium was harvested 1 h postirradiation and transferred to recipient HPV-G cells. Phosphorylated forms of p38, JNK and ERK were studied by immunofluorescence 30 min-24 h after exposure to ICCM. Inhibitors of the ERK pathway (PD98059 and U0126), the JNK pathway (SP600125), and the p38 pathway (SB203580) were used to investigate whether bystander-induced cell death could be blocked. Cells were also incubated with ICCM in the presence of superoxide dismutase, catalase, EGTA, verapamil, nifedipine and thapsigargin to investigate whether bystander effects could be inhibited because of the known effects on calcium homeostasis. Activated forms of JNK and ERK proteins were observed after exposure to ICCM. Inhibition of the ERK pathway appeared to increase bystander-induced apoptosis, while inhibition of the JNK pathway appeared to decrease apoptosis. In addition, reactive oxygen species, such as superoxide and hydrogen peroxide, and calcium signaling were found to be important modulators of

  14. Is There a Dose-Response Relationship for Heart Disease With Low-Dose Radiation Therapy?

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Eugene [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Corbett, James R. [Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States); Moran, Jean M. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Griffith, Kent A. [Department of Biostatistics, University of Michigan, Ann Arbor, Michigan (United States); Marsh, Robin B.; Feng, Mary; Jagsi, Reshma; Kessler, Marc L. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Ficaro, Edward C. [Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States); Pierce, Lori J., E-mail: ljpierce@umich.edu [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States)

    2013-03-15

    Purpose: To quantify cardiac radiation therapy (RT) exposure using sensitive measures of cardiac dysfunction; and to correlate dysfunction with heart doses, in the setting of adjuvant RT for left-sided breast cancer. Methods and Materials: On a randomized trial, 32 women with node-positive left-sided breast cancer underwent pre-RT stress single photon emission computed tomography (SPECT-CT) myocardial perfusion scans. Patients received RT to the breast/chest wall and regional lymph nodes to doses of 50 to 52.2 Gy. Repeat SPECT-CT scans were performed 1 year after RT. Perfusion defects (PD), summed stress defects scores (SSS), and ejection fractions (EF) were evaluated. Doses to the heart and coronary arteries were quantified. Results: The mean difference in pre- and post-RT PD was −0.38% ± 3.20% (P=.68), with no clinically significant defects. To assess for subclinical effects, PD were also examined using a 1.5-SD below the normal mean threshold, with a mean difference of 2.53% ± 12.57% (P=.38). The mean differences in SSS and EF before and after RT were 0.78% ± 2.50% (P=.08) and 1.75% ± 7.29% (P=.39), respectively. The average heart Dmean and D95 were 2.82 Gy (range, 1.11-6.06 Gy) and 0.90 Gy (range, 0.13-2.17 Gy), respectively. The average Dmean and D95 to the left anterior descending artery were 7.22 Gy (range, 2.58-18.05 Gy) and 3.22 Gy (range, 1.23-6.86 Gy), respectively. No correlations were found between cardiac doses and changes in PD, SSS, and EF. Conclusions: Using sensitive measures of cardiac function, no clinically significant defects were found after RT, with the average heart Dmean <5 Gy. Although a dose response may exist for measures of cardiac dysfunction at higher doses, no correlation was found in the present study for low doses delivered to cardiac structures and perfusion, SSS, or EF.

  15. Damage of chromosoms under irradiation of human blood lymphocytes and development of bystander effect.

    Science.gov (United States)

    Shemetun, O V

    2016-12-01

    the research the distribution of radiation induced damages among chromosomes and their bands in irra diated in vitro human blood lymphocytes and in unirradiated bystander cells.Material and methods of research: cultivation of human peripheral blood lymphocytes by semi micromethod D.A. Hungerford, modeling of radiation induced bystander effect in mixed cultures consisting of irradiated in vitro and non irradiated blood lymphocytes from persons of different gender, GTG staining of metaphase chromosomes and their cytogenetic analysis. Break points in chromosomes under the formation of aberrations were identified in exposed in vitro human peripheral blood lymphocytes in doses 0.25 Gy (95 breaks in 1248 cells) and 1.0 Gy (227 breaks in 726 cells) and in non irradiated bystander cells under their joint cultivation with irradiated in vitro human lymphocytes (51 breaks in 1137 cells at irradiation of adjacent populations of lymphocytes in dose 0.25 Gy and 75 breaks in 1321 cells at irradiation of adjacent population of lymphocytes in a dose 1.0 Gy). The distribution of injuries among the chromo somes and their bands was investigated. in radiation exposed in vitro human peripheral blood lymphocytes as well as in bystander cells the fre quency of damaged bands and number of breaks which localized in them exceeded the control value (p chromosomes were damaged according to their relative length. Location of bands with increasing number of breaks coincided with the «hot spots» of chromosome damage following irradiation and fragile sites. More sensitive to damage were G negative euchromatin chromosome bands, in which were localized 82 88 % breaks. Damageability of telomeric regions in the irradiated cells had no significant difference from the control, while in bystander cells was lower than control value (p < 0.05). O. V. Shemetun.

  16. Bystander Programs: Accommodating or Derailing Sexism?

    Directory of Open Access Journals (Sweden)

    Adam Reid

    2017-09-01

    Full Text Available Bystander programs implemented to meet federal requirements to reduce sexual assaults on college campuses in the United States must include primary prevention. Survey data (n = 280 and interview data (n = 20 presented in this paper explore students’ hypothetical and actual willingness to intervene as bystanders. Although most students surveyed (57% claim they would be very likely to intervene, fewer than half would be very suspicious of someone leading away an intoxicated individual at a party (45% of women and 28% of men: p < 0.01. Interview data reveal how students perceive risk factors at college parties and what types of bystander measures they attempt, including “distractions”, a nonconfrontational tactic in which bystanders avoid more direct but socially risky interventions. Subsumed in many current bystander programs is an invisible element of valorizing harmony. Condoning bystanders’ unwillingness to directly confront seemingly predatory individuals could make change seem out of reach and could also embolden offenders whose behavior is observed and only temporarily thwarted.

  17. Effect of heterogeneity of human population in cell radiosensitivity on the extrapolation of dose-response relationships to low doses

    International Nuclear Information System (INIS)

    Filyushkin, I.V.; Bragin, Yu.N.; Khandogina, E.K.

    1989-01-01

    Presented are the results of an investigation of the dose-response relationship for the yield of chromosome aberrations in peripheral blood lymphocytes of persons with some hereditary diseases which represent the high risk group with respect to the increased incidence of malignant tumors and decreased life span. Despite substantially different absolute radiosensitivities of chromosomes, the variations of the alpha/beta ratio determining the extrapolation of experimental dose-response relationships to low doses did not prove to be too high, the mean deviation from the control being 15%. This points to the possible practical use of the dose-response relationships averaged over the human population as a whole

  18. Studies on adaptive response of lymphocyte transformation induced by low-dose irradiation

    International Nuclear Information System (INIS)

    Du Zeji; Su Liaoyuan; Tian Hailin; Zou Huawei

    1995-10-01

    Human peripheral blood lymphocytes stimulated by mitogen in vitro for 24 h were exposed to low-dose γ-ray irradiation (0.5∼4.0 cGy, adaptive dose). They showed an adaptive response to the inhibition of 3 H-TdR incorporation by subsequent higher acute doses of γ-ray (challenge dose). At the interval of 24 h between adaptive dose and challenge dose, the strongest adaptive response induced by low-dose irradiation was found. It is also found that the response induced by 1.0 cGy of adaptive dose was more obvious than that by other doses and that 3.0 Gy of challenge dose produced the strongest adaptive response. As the challenge doses increased, the adaptive response reduced. (2 figs., 2 tabs.)

  19. Establishment and verification of dose-response curve of chromosomal aberrations after exposure to very high dose γ-ray

    International Nuclear Information System (INIS)

    Chen Ying; Luo Yisheng; Cao Zhenshan; Liu Xiulin

    2006-01-01

    To estimate accurately biological dose of the victims exposed to high dose, the dose-response curves of chromosome aberration induced by 6-22 Gy 60 Co γ-ray were established. Human peripheral blood in vitro was irradiated, then lymphocytes were concentrated, cultured 52h, 68h and 72h and harvested. The frequencies of dicentrics (multi-centrics) and rings were counted and compared between different culture times. The dose-response curves and equations were established, as well as verified with high dose exposure accidents. The experiment showed that the culture time should be prolonged properly after high dose exposure, and no significant differences were observed between 52-72h culture. The dose-response curve of 6-22 Gy fitted to linear-square model Y=-2.269 + 0.776D - 7.868 x 10 -3 D 2 and is reliable through verification of the accident dose estimations. In this study, the dose-response curve and equation of chromosome dic + r after 6-22 Gy high dose irradiation were established firstly, and exact dose estimation can be achieved according to it. (authors)

  20. Response of radiation monitors for ambient dose equivalent, H*(10)

    International Nuclear Information System (INIS)

    Grecco, Claudio Henrique dos Santos

    2001-01-01

    Radiation monitors are used all over the world to evaluate if places with presence of ionising radiation present safe conditions for people. Radiation monitors should be tested according to international or national standards in order to be qualified for use. This work describes a methodology and procedures to evaluate the energy and angular responses of any radiation monitor for ambient dose equivalent, H*(10), according to the recommendations of ISO and IEC standards. The methodology and the procedures were applied to the Monitor Inteligente de Radiacao MIR 7026, developed by the Instituto em Engenharia Nuclear (IEN), to evaluate and to adjust its response for H*(10), characterizing it as an ambient dose equivalent meter. The tests were performed at the Laboratorio Nacional de Metrologia das Radiacoes Ionizantes (LNMRI), at Instituto de Radioprotecao e Dosimetria (IRD), and results showed that the Monitor Inteligente de Radiacao MIR 7026 can be used as an EI*(10) meter, in accordance to the IEC 60846 standard requirements. The overall estimated uncertainty for the determination of the MIR 7026 response, in all radiation qualities used in this work, was 4,5 % to a 95 % confidence limit. (author)

  1. Studies of Bystander Effect and Intercellular Communication in Human Epithelial Cell Cultures Irradiated with X-rays

    International Nuclear Information System (INIS)

    Romppanen, E.; Trott, K. R.; Musatonen, R.; Leszcznski, D.; Belyakov, O.

    2004-01-01

    The bystander effect is a phenomenon whereby biological consequences of irradiation are expressed in nonexposed cells in the vicinity of exposed cells. Two main pathways have been proposed to mediate the bystander effect: Gap Junction Intercellular Communication (GJIC) and medium borne soluble factors dependent mechanisms. The present study was designed to evaluate the relative contributions of gap junction intercellular communication and of soluble extracellular factors on the bystander effects of low dose X-ray irradiation. HaCaT human epithelial cell monolayers were exposed to X-ray using specially constructed shield, which cover 95% or 56% or 0% of the cells from the radiation. To evaluate whether the GJIC is involved in transmission of the bystander signal from irradiated to nonirradiated cells, irradiations were performed in presence or absence of GJIC inhibitor lindane. The cytochalasin B block technique was used to quantify fractions of micronucleated cells 48 hours after the irradiation. Our results suggest that more micronucleated cells are induced in partially shielded monolayers than expected according to back extrapolation of the data from open field irradiation. Treatment with lindane considerably reduced amount of the bystander damage. We demonstrated that fraction of micronucleated cells after X-rays irradiation of 5% of cells with 1 Gy was 0.07±0.08 (without lindane) and 0.05±0.004 (in presence of lindane). Irradiation of 100% of cells with the same dose resulted in 0.023±0.04 /without lindane) and 0.013±0.02 (in presence of lindane) fractions of micronucleated cells. Comparison with open field data showed that the fraction of micronucleated cells after irradiation of 5% of the cell culture was 5-10 times greater than the estimated fraction assuming no bystander effect. Irradiation of 44% of cells ded not demonstrate a pronounced bystander effect. (Author) 20 refs

  2. Estimating adolescent sleep need using dose-response modeling.

    Science.gov (United States)

    Short, Michelle A; Weber, Nathan; Reynolds, Chelsea; Coussens, Scott; Carskadon, Mary A

    2018-04-01

    This study will (1) estimate the nightly sleep need of human adolescents, (2) determine the time course and severity of sleep-related deficits when sleep is reduced below this optimal quantity, and (3) determine whether sleep restriction perturbs the circadian system as well as the sleep homeostat. Thirty-four adolescents aged 15 to 17 years spent 10 days and nine nights in the sleep laboratory. Between two baseline nights and two recovery nights with 10 hours' time in bed (TIB) per night, participants experienced either severe sleep restriction (5-hour TIB), moderate sleep restriction (7.5-hour TIB), or no sleep restriction (10-hour TIB) for five nights. A 10-minute psychomotor vigilance task (PVT; lapse = response after 500 ms) and the Karolinska Sleepiness Scale were administered every 3 hours during wake. Salivary dim-light melatonin onset was calculated at baseline and after four nights of each sleep dose to estimate circadian phase. Dose-dependent deficits to sleep duration, circadian phase timing, lapses of attention, and subjective sleepiness occurred. Less TIB resulted in less sleep, more lapses of attention, greater subjective sleepiness, and larger circadian phase delays. Sleep need estimated from 10-hour TIB sleep opportunities was approximately 9 hours, while modeling PVT lapse data suggested that 9.35 hours of sleep is needed to maintain optimal sustained attention performance. Sleep restriction perturbs homeostatic and circadian systems, leading to dose-dependent deficits to sustained attention and sleepiness. Adolescents require more sleep for optimal functioning than typically obtained.

  3. Impact of Bystander Automated External Defibrillator Use on Survival and Functional Outcomes in Shockable Observed Public Cardiac Arrests.

    Science.gov (United States)

    Pollack, Ross A; Brown, Siobhan P; Rea, Thomas; Aufderheide, Tom; Barbic, David; Buick, Jason E; Christenson, James; Idris, Ahamed H; Jasti, Jamie; Kampp, Michael; Kudenchuk, Peter; May, Susanne; Muhr, Marc; Nichol, Graham; Ornato, Joseph P; Sopko, George; Vaillancourt, Christian; Morrison, Laurie; Weisfeldt, Myron

    2018-02-26

    Background - Survival following out-of-hospital cardiac arrest (OHCA) with shockable rhythms can be improved with early defibrillation. Although shockable OHCA accounts for only ≈25% of overall arrests, ≈60% of public OHCAs are shockable, offering the possibility of restoring thousands of individuals to full recovery with early defibrillation by bystanders. We sought to determine the association of bystander automated external defibrillator use with survival and functional outcomes in shockable observed public OHCA. Methods - From 2011 to 2015, the Resuscitation Outcomes Consortium prospectively collected detailed information on all cardiac arrests at 9 regional centers. The exposures were shock administration by a bystander-applied automated external defibrillator in comparison with initial defibrillation by emergency medical services. The primary outcome measure was discharge with normal or near-normal (favorable) functional status defined as a modified Rankin Score ≤2. Survival to hospital discharge was the secondary outcome measure. Results -Among 49 555 OHCAs, 4115 (8.3%) observed public OHCAs were analyzed, of which 2500 (60.8%) were shockable. A bystander shock was applied in 18.8% of the shockable arrests. Patients shocked by a bystander were significantly more likely to survive to discharge (66.5% versus 43.0%) and be discharged with favorable functional outcome (57.1% versus 32.7%) than patients initially shocked by emergency medical services. After adjusting for known predictors of outcome, the odds ratio associated with a bystander shock was 2.62 (95% confidence interval, 2.07-3.31) for survival to hospital discharge and 2.73 (95% confidence interval, 2.17-3.44) for discharge with favorable functional outcome. The benefit of bystander shock increased progressively as emergency medical services response time became longer. Conclusions - Bystander automated external defibrillator use before emergency medical services arrival in shockable observed

  4. The bystander effect of cancer gene therapy

    International Nuclear Information System (INIS)

    Lumniczky, K.; Safrany, G.

    2008-01-01

    Cancer gene therapy is a new, promising therapeutic agent. In the clinic, it should be used in combination with existing modalities, such as tumour irradiation. First, we summarise the most important fields of cancer gene therapy: gene directed enzyme pro-drug therapy; the activation of an anti-tumour immune attack; restoration of the wild type p53 status; the application of new, replication competent and oncolytic viral vectors; tumour specific, as well as radiation- and hypoxia-induced gene expression. Special emphasizes are put on the combined effect of these modalities with local tumour irradiation. Using the available vector systems, only a small portion of the cancer cells will contain the therapeutic genes under therapeutic situations. Bystander cell killing might contribute to the success of various gene therapy protocols. We summarise the evidences that lethal bystander effects may occur during cancer gene therapy. Bystander effects are especially important in the gene directed enzyme pro-drug therapy. There, bystander cell killing might have different routes: cell communication through gap junction intercellular contacts; release of toxic metabolites into the neighbourhood or to larger distances; phagocytosis of apoptotic bodies; and the activation of the immune system. Bystander cell killing can be enhanced by the introduction of gap junction proteins into the cells, by further activating the immune system with immune-stimulatory molecules, or by introducing genes into the cells that help the transfer of cytotoxic genes and / or metabolites into the bystander cells. In conclusion, there should be additional improvements in cancer gene therapy for the more efficient clinical application. (orig.)

  5. Neuromuscular dose-response studies: determining sample size.

    Science.gov (United States)

    Kopman, A F; Lien, C A; Naguib, M

    2011-02-01

    Investigators planning dose-response studies of neuromuscular blockers have rarely used a priori power analysis to determine the minimal sample size their protocols require. Institutional Review Boards and peer-reviewed journals now generally ask for this information. This study outlines a proposed method for meeting these requirements. The slopes of the dose-response relationships of eight neuromuscular blocking agents were determined using regression analysis. These values were substituted for γ in the Hill equation. When this is done, the coefficient of variation (COV) around the mean value of the ED₅₀ for each drug is easily calculated. Using these values, we performed an a priori one-sample two-tailed t-test of the means to determine the required sample size when the allowable error in the ED₅₀ was varied from ±10-20%. The COV averaged 22% (range 15-27%). We used a COV value of 25% in determining the sample size. If the allowable error in finding the mean ED₅₀ is ±15%, a sample size of 24 is needed to achieve a power of 80%. Increasing 'accuracy' beyond this point requires increasing greater sample sizes (e.g. an 'n' of 37 for a ±12% error). On the basis of the results of this retrospective analysis, a total sample size of not less than 24 subjects should be adequate for determining a neuromuscular blocking drug's clinical potency with a reasonable degree of assurance.

  6. The Association of IFI27 Expression and Fatigue Intensification during Localized Radiation Therapy: Implication of a Para-Inflammatory Bystander Response

    Directory of Open Access Journals (Sweden)

    Leorey N. Saligan

    2013-08-01

    Full Text Available The mechanisms behind fatigue intensification during cancer therapy remain elusive. The interferon alpha-inducible protein 27 (IFI27 was the most up-regulated gene based on our previous microarray data in fatigued men with non-metastatic prostate cancer receiving localized external beam radiation therapy (EBRT. The purpose of this study was to confirm the IFI27 up-regulation and determine its association with fatigue intensification during EBRT. Peripheral blood samples and fatigue scores were collected at three time points—prior to EBRT, at midpoint, and at completion of EBRT. Confirmatory quantitative real time polymerase chain reaction (qPCR and enzyme-linked immunosorbent assay (ELISA were utilized to verify the microarray results. Subjects were a total of 40 Caucasian men with prostate cancer; 20 scheduled for EBRT (65.6 ± 7.5 years old, and 20 on active surveillance as controls (62.8 ± 6.1 years old. Significant IFI27 expression overtime during EBRT was confirmed by qPCR (p < 0.5, which correlated with fatigue scores during EBRT (R = −0.90, p = 0.006. Alterations in mechanisms associated with immune response and mitochondrial function that explain the up-regulation of IFI27 may provide an understanding of the pathways related to the intensification of fatigue during localized radiation therapy.

  7. Rethinking the bystander role in school violence prevention.

    Science.gov (United States)

    Stueve, Ann; Dash, Kimberly; O'Donnell, Lydia; Tehranifar, Parisa; Wilson-Simmons, Renée; Slaby, Ronald G; Link, Bruce G

    2006-01-01

    Public concerns about school shootings and safety draw attention to the role bystanders can play in preventing school violence. Although school violence prevention plans are often required, there is little guidance about whether these should address the roles of bystanders and what actions bystanders should take in different circumstances, from more common instances of bullying and fighting to rare, but potentially lethal, threats and use of weapons. Literature pertaining to bystanders is reviewed and applied to the school setting. The definition of bystander is expanded, including parents, teachers, and other school staff as well as youths and those who have information about potential violence as well as those who witness its occurrence. Barriers preventing bystanders from taking positive actions are discussed. The authors call on health promotion researchers and practitioners to work with school communities to identify norms, attitudes, and outcome expectancies that shape bystander behaviors to inform prevention efforts.

  8. Bystander effects of ionizing radiation can be modulated by signaling amines

    International Nuclear Information System (INIS)

    Poon, R.C.C.; Agnihotri, N.; Seymour, C.; Mothersill, C.

    2007-01-01

    Actual risk and risk management of exposure to ionizing radiation are among the most controversial areas in environmental health protection. Recent developments in radiobiology especially characterization of bystander effects have called into question established dogmas and are thought to cast doubt on the scientific basis of the risk assessment framework, leading to uncertainty for regulators and concern among affected populations. In this paper we test the hypothesis that small signaling molecules widely used throughout the animal kingdom for signaling stress or environmental change, such as 5-Hydroxytryptamine (5-HT, serotonin), L-DOPA, glycine or nicotine are involved in bystander signaling processes following ionizing radiation exposure. We report data which suggest that nano to micromolar concentrations of these agents can modulate bystander-induced cell death. Depletion of 5-HT present in tissue culture medium, occurred following irradiation of cells. This suggested that 5-HT might be bound by membrane receptors after irradiation. Expression of 5-HT type 3 receptors which are Ca 2+ ion channels was confirmed in the cells using immunocytochemistry and receptor expression could be increased using radiation or 5-HT exposure. Zofran and Kitryl, inhibitors of 5-HT type 3 receptors, and reserpine a generic serotonin antagonist block the bystander effect induced by radiation or by serotonin. The results may be important for the mechanistic understanding of how low doses of radiation interact with cells to produce biological effects

  9. Relationship of dose rate and total dose to responses of continuously irradiated beagles

    International Nuclear Information System (INIS)

    Fritz, T.E.; Norris, W.P.; Tolle, D.V.; Seed, T.M.; Poole, C.M.; Lombard, L.S.; Doyle, D.E.

    1978-01-01

    Young-adult beagles were exposed continuously (22 hours/day) to 60 Co γ rays in a specially constructed facility. The exposure rates were either 5, 10, 17, or 35 R/day, and the exposures were terminated at either 600, 1400, 2000, or 4000 R. A total of 354 dogs were irradiated; 221 are still alive as long-term survivors, some after more than 2000 days. The data on survival of these dogs, coupled with data from similar preliminary experiments, allow an estimate of the LD 50 for γ-ray exposures given at a number of exposure rates. They also allow comparison of the relative importance of dose rate and total dose, and the interaction of these two variables, in the early and late effects after protracted irradiation. The LD 50 for the beagle increases from 258 rad delivered at 15 R/minute to approximately 3000 rad at 10 R/day. Over this entire range, the LD 50 is dependent upon hematopoietic damage. At 5 R/day and less, no meaningful LD 50 can be determined; there is nearly normal continued hematopoietic function, survival is prolonged, and the dogs manifest varied individual responses in other organ systems. Although the experiment is not complete, interim data allow several important conclusions. Terminated exposures, while not as effective as radiation continued until death, can produce myelogenous leukemia at the same exposure rate, 10 R/day. More importantly, at the same total accumulated dose, lower exposure rates are more damaging than higher rates on the basis of the rate and degree of hematological recovery that occurs after termination of irradiation. Thus, the rate of hematologic depression, the nadir of the depression, and the rate of recovery are dependent upon exposure rate; the latter is inversely related and the former two are directly related to exposure rate

  10. Relationship of dose rate and total dose to responses of continuously irradiated beagles

    International Nuclear Information System (INIS)

    Fritz, T.E.; Norris, W.P.; Tolle, D.V.; Seed, T.M.; Poole, C.M.; Lombard, L.S.; Doyle, D.E.

    1978-01-01

    Young-adult beagles were exposed continuously (22 hours/day) to 60 Co gamma rays in a specially constructed facility. The exposure rates were 5, 19, 17 or 35 R/day, and the exposures were terminated at 600, 1400, 2000 or 4000 R. A total of 354 dogs were irradiated; 221 are still alive as long-term survivors, some after more than 2000 days. The data on survival of these dogs, coupled with data from similar preliminary experiments, allow an estimate of the LD 50 for gamma-ray exposures given at a number of exposure rates. They also allow comparison of the relativeimportance of dose rate and total dose, and the interaction of these two variables, in the early and late effects after protracted irradiation. The LD 50 for the beagle increases from 344 R (258 rads) delivered at 15 R/minute to approximately 4000 R (approximately 3000 rads) at 10 R/day. Over this entire range, the LD 50 is dependent upon haematopoietic damage. At 5 R/day and less, no definitive LD 50 can be determined; there is nearly normal continued haematopoietic function, survival is prolonged, and the dogs manifest varied individual responses in the organ systems. Although the experiment is not complete, interim data allow serveral important conclusions. Terminated exposures, while not as effective as irradiation continued until death, can produce myelogenous leukaemia at the same exposure rate, 10 R/day. More importantly, at the same total accumulated dose, lower exposure rates appear more damaging than higher rates on the basis of the rate and degree of haematological recovery that occurs after termination of irradiation. Thus, the rate of haematologic depression, the nadir of the depression and the rate of recovery are dependent upon exposure rate; the latter is inversely related and the first two are directly related to exposure rate. ( author)

  11. Biophysical Monitoring and dose response characteristics of irradiated hemoglobin

    International Nuclear Information System (INIS)

    Elshemey, W.M; Selim, N.S.; Desouky, O.

    2003-01-01

    The present work aims to move a step forward towards a deeper understanding of the scattering of x-ray, from lyophilized biological samples. Comparative study has been performed using LAXS and UV-visible spectrophotometry for monitoring the dose response characteristics of the hemoglobin molecule of irradiated blood. Blood samples were irradiated at doses ranging from 5 up to 100 Gy. Diluted hemoglobin solution was scanned in the UV- visible range (200-700 nm), and lyophilized hemoglobin was prepared for LAXS measurement. The radiation-induced changes in the hemoglobin structure have been evaluated. The LAXS profile of hemoglobin molecule is characterized by the presence of two peaks in the forward direction of scattering. These peaks were found to be sensitive to the variations in the molecular structure of a given sample. The obtained results suggest that the 1 s t peak, recorded at 4.65 o , is sensitive to the tertiary and quaternary structure of the globin part, while the major peak, recorded at 10.5 o , appeared to be related to its primary and secondary structure

  12. Biological profiling and dose-response modeling tools ...

    Science.gov (United States)

    Through its ToxCast project, the U.S. EPA has developed a battery of in vitro high throughput screening (HTS) assays designed to assess the potential toxicity of environmental chemicals. At present, over 1800 chemicals have been tested in up to 600 assays, yielding a large number of concentration-response data sets. Standard processing of these data sets involves finding a best fitting mathematical model and set of model parameters that specify this model. The model parameters include quantities such as the half-maximal activity concentration (or “AC50”) that have biological significance and can be used to inform the efficacy or potency of a given chemical with respect to a given assay. All of this data is processed and stored in an online-accessible database and website: http://actor.epa.gov/dashboard2. Results from these in vitro assays are used in a multitude of ways. New pathways and targets can be identified and incorporated into new or existing adverse outcome pathways (AOPs). Pharmacokinetic models such as those implemented EPA’s HTTK R package can be used to translate an in vitro concentration into an in vivo dose; i.e., one can predict the oral equivalent dose that might be expected to activate a specific biological pathway. Such predicted values can then be compared with estimated actual human exposures prioritize chemicals for further testing.Any quantitative examination should be accompanied by estimation of uncertainty. We are developing met

  13. A new paradigm in radioadaptive response developing from microbeam research

    International Nuclear Information System (INIS)

    Matsumoto, Hideki; Tomita, Masanori; Otsuka, Kensuke; Hatashita, Masanori

    2009-01-01

    A classic paradigm in radiation biology asserts that all radiation effects on cells, tissues and organisms are due to the direct action of radiation on living tissue. Using this model, possible risks from exposure to low dose ionizing radiation (below 100 mSv) are estimated by extrapolating from data obtained after exposure to higher doses of radiation, using a linear non-threshold model (LNT model). However, the validity of using this dose-response model is controversial because evidence accumulated over the past decade has indicated that living organisms, including humans, respond differently to low dose/low dose-rate radiation than they do to high dose/high dose-rate radiation. These important responses to low dose/low dose-rate radiation are the radiation-induced adaptive response, the bystander response, low-dose hypersensitivity, and genomic instability. The mechanisms underlying these responses often involve bio-chemical and molecular signals generated in response to targeted and non-targeted events. In order to define and understand the bystander response to provide a basis for the understanding of non-targeted events and to elucidate the mechanisms involved, recent sophisticated research has been conducted with X-ray microbeams and charged heavy particle microbeams, and these studies have produced many new observations. Based on these observations, associations have been suggested to exist between the radio-adaptive and bystander responses. The present review focuses on these two phenomena, and summarizes observations supporting their existence, and discusses the linkage between them in light of recent results obtained from experiments utilizing microbeams. (author)

  14. Patch test dose-response study of p-phenylenediamine

    DEFF Research Database (Denmark)

    Sosted, Heidi; Menné, Torkil; Johansen, Jeanne Duus

    2006-01-01

    The elicitation response in allergic contact dermatitis for the hair dye substance p-phenylenediamine (PPD) is dose dependent, but threshold concentrations have not previously been investigated. 15 PPD-sensitive patients participated in a serial dilution 48-hr patch test with PPD using 8...... concentrations of PPD ranging from 1 to 10 000 on the upper back. Petrolatum was applied as control. Three concentrations (50, 100 and 500 p.p.m. PPD) were also applied to the retroauricular area and on the lateral aspects of the upper arms. 14 of the 15 participants reacted to one or more of the test samples....... The threshold value for 10% of the tested persons (ED10) based on+or stronger reactions for PPD on the back was 38 p.p.m. (CI: 4.3-100). There were no statistically significant differences in the sensitivity of the three anatomical regions. The upper back is a suitable region for patch testing patients...

  15. Alcohol and cirrhosis: dose--response or threshold effect?

    DEFF Research Database (Denmark)

    Kamper-Jørgensen, Mads; Grønbaek, Morten; Tolstrup, Janne

    2004-01-01

    BACKGROUND/AIMS: General population studies have shown a strong association between alcohol intake and death from alcoholic cirrhosis, but whether this is a dose-response or a threshold effect remains unknown, and the relation among alcohol misusers has not been studied. METHODS: A cohort of 6152...... alcohol misusing men and women aged 15-83 were interviewed about drinking pattern and social issues and followed for 84,257 person-years. Outcome was alcoholic cirrhosis mortality. Data was analyzed by means of Cox-regression models. RESULTS: In this large prospective cohort study of alcohol misusers...... there was a 27 fold increased mortality from alcoholic cirrhosis in men and a 35 fold increased mortality from alcoholic cirrhosis in women compared to the Danish population. Number of drinks per day was not significantly associated with death from alcoholic cirrhosis, since there was no additional risk of death...

  16. Dose-response curve estimation: a semiparametric mixture approach.

    Science.gov (United States)

    Yuan, Ying; Yin, Guosheng

    2011-12-01

    In the estimation of a dose-response curve, parametric models are straightforward and efficient but subject to model misspecifications; nonparametric methods are robust but less efficient. As a compromise, we propose a semiparametric approach that combines the advantages of parametric and nonparametric curve estimates. In a mixture form, our estimator takes a weighted average of the parametric and nonparametric curve estimates, in which a higher weight is assigned to the estimate with a better model fit. When the parametric model assumption holds, the semiparametric curve estimate converges to the parametric estimate and thus achieves high efficiency; when the parametric model is misspecified, the semiparametric estimate converges to the nonparametric estimate and remains consistent. We also consider an adaptive weighting scheme to allow the weight to vary according to the local fit of the models. We conduct extensive simulation studies to investigate the performance of the proposed methods and illustrate them with two real examples. © 2011, The International Biometric Society.

  17. Photon hormesis deactivates alpha-particle induced bystander effects between zebrafish embryos

    International Nuclear Information System (INIS)

    Ng, C.Y.P.; Cheng, S.H.; Yu, K.N.

    2017-01-01

    In the present work, we studied the effects of low-dose X-ray photons on the alpha-particle induced bystander effects between embryos of the zebrafish, Danio rerio. The effects on the naive whole embryos were studied through quantification of apoptotic signals (amounts of cells undergoing apoptosis) at 24 h post fertilization (hpf) using vital dye acridine orange staining, followed by counting the stained cells under a fluorescent microscope. We report data showing that embryos at 5 hpf subjected to a 4.4 mGy alpha-particle irradiation could release a stress signal into the medium, which could induce bystander effect in partnered naive embryos sharing the same medium. We also report that the bystander effect was deactivated when the irradiated embryos were subjected to a concomitant irradiation of 10 or 14 mGy of X-rays, but no such deactivation was achieved if the concomitant X-ray dose dropped to 2.5 or 5 mGy. In the present study, the significant drop in the amount of apoptotic signals on the embryos having received 4.4 mGy alpha particles together X-rays irradiation from 2.5 or 5 mGy to 10 or 14 mGy, together with the deactivation of RIBE with concomitant irradiation of 10 or 14 mGy of X-rays supported the participation of photon hormesis with an onset dose between 5 and 10 mGy, which might lead to removal of aberrant cells through early apoptosis or induction of high-fidelity DNA repair. As we found that photons and alpha particles could have opposite biological effects when these were simultaneously irradiated onto living organisms, these ionizing radiations could be viewed as two different environmental stressors, and the resultant effects could be regarded as multiple stressor effects. The present work presented the first study on a multiple stressor effect which occurred on bystander organisms. In other words, this was a non-targeted multiple stressor effect. The photon hormesis could also explain some failed attempts to observe neutron-induced bystander

  18. Dose-response relationships for radium-induced bone sarcomas

    International Nuclear Information System (INIS)

    Rowland, R.E.; Stehney, A.F.; Lucas, H.F. Jr.

    1981-01-01

    The incidence of bone sarcomas among 3055 female radium-dial workers who entered the dial industry before 1950 was used to determine dose-response relationships for the induction of bone sarcomas by radium. Two subpopulations were analyzed: all measured cases who survived at last five years after the start of employment and all cases who survived at least two years after first measurement. The first constituted a group based on year of entry; it contained 1468 women who experienced 42 bone sarcomas; the expected number was 0.4. The second comprised a group based on first measurement; it contained 1257 women who experienced 13 bone sarcomas; the expected number was 0.2. The dose-response function, I = (C + αD + #betta#D 2 )e/sup -#betta#D/, and simplifications of this general form, were fit to each data set. Two functions, I = (C + αD + #betta#D 2 )e/sup -#betta#D/ and I = (C + #betta#D 2 )e/sup -#betta#D/, fit the data for year of entry (p greater than or equal to 0.05); both these functions and I = (C + αD) fit the data for first measurement. The function I = (C + #betta#D 2 )e/sup -#betta#D/ was used to predict the number of bone sarcomas in all other pre-1950 radium cases (medical, laboratory, and other exposure); fewer were actually observed than the fit of this function to the female dial workers predicted

  19. Low-dose radiation-induced adaptive response in bone marrow cells of mice

    International Nuclear Information System (INIS)

    Farooqi, Zeba; Kesavan, P.C.

    1993-01-01

    Using bone marrow cells of whole body irradiated mice, the cytogenetic adaptive response induced by low conditioning doses of gamma-rays was investigated. The conditioning doses (0.025 and 0.05 Gy) were given at a dose-rate of 1.67 Gy/min. The challenging dose of 1 Gy was given at a dose-rate of 0.045 Gy/s. The challenging dose was given at different time intervals after the conditioning dose. The time intervals between the conditioning dose and challenging dose were 2, 7.5, 13, 18.5 and 24 h. When the time interval between the conditioning dose and the challenging dose was 2 h, both conditioning doses (0.025 and 0.05 Gy) reduced the frequency of MNPCEs and chromosomal aberrations in the bone marrow cells. The data collected at different time intervals (7.5, 13, 18.5 h) reveal that the radioadaptive response persisted for a longer time when the lower conditioning dose (0.025 Gy) was given. With the higher conditioning dose (0.05 Gy), the radioadaptive response disappeared after a time interval of 13 h. When the time interval between the conditioning dose and the challenging doses was 18.5 or 24 h, only the lower conditioning dose appeared effective in inducing the radioadaptive response

  20. Quantitative analysis of biological responses to low dose-rate γ-radiation, including dose, irradiation time, and dose-rate

    International Nuclear Information System (INIS)

    Magae, J.; Furukawa, C.; Kawakami, Y.; Hoshi, Y.; Ogata, H.

    2003-01-01

    Full text: Because biological responses to radiation are complex processes dependent on irradiation time as well as total dose, it is necessary to include dose, dose-rate and irradiation time simultaneously to predict the risk of low dose-rate irradiation. In this study, we analyzed quantitative relationship among dose, irradiation time and dose-rate, using chromosomal breakage and proliferation inhibition of human cells. For evaluation of chromosome breakage we assessed micronuclei induced by radiation. U2OS cells, a human osteosarcoma cell line, were exposed to gamma-ray in irradiation room bearing 50,000 Ci 60 Co. After the irradiation, they were cultured for 24 h in the presence of cytochalasin B to block cytokinesis, cytoplasm and nucleus were stained with DAPI and propidium iodide, and the number of binuclear cells bearing micronuclei was determined by fluorescent microscopy. For proliferation inhibition, cells were cultured for 48 h after the irradiation and [3H] thymidine was pulsed for 4 h before harvesting. Dose-rate in the irradiation room was measured with photoluminescence dosimeter. While irradiation time less than 24 h did not affect dose-response curves for both biological responses, they were remarkably attenuated as exposure time increased to more than 7 days. These biological responses were dependent on dose-rate rather than dose when cells were irradiated for 30 days. Moreover, percentage of micronucleus-forming cells cultured continuously for more than 60 days at the constant dose-rate, was gradually decreased in spite of the total dose accumulation. These results suggest that biological responses at low dose-rate, are remarkably affected by exposure time, that they are dependent on dose-rate rather than total dose in the case of long-term irradiation, and that cells are getting resistant to radiation after the continuous irradiation for 2 months. It is necessary to include effect of irradiation time and dose-rate sufficiently to evaluate risk

  1. Dependence of total dose response of bipolar linear microcircuits on applied dose rate

    International Nuclear Information System (INIS)

    McClure, S.; Will, W.; Perry, G.; Pease, R.L.

    1994-01-01

    The effect of dose rate on the total dose radiation hardness of three commercial bipolar linear microcircuits is investigated. Total dose tests of linear bipolar microcircuits show larger degradation at 0.167 rad/s than at 90 rad/s even after the high dose rate test is followed by a room temperature plus a 100 C anneal. No systematic correlation could be found for degradation at low dose rate versus high dose rate and anneal. Comparison of the low dose rate with the high dose rate anneal data indicates that MIL-STD-883, method 1019.4 is not a worst-case test method when applied to bipolar microcircuits for low dose rate space applications

  2. The differential role of human macrophage in triggering secondary bystander effects after either gamma-ray or carbon beam irradiation.

    Science.gov (United States)

    Dong, Chen; He, Mingyuan; Tu, Wenzhi; Konishi, Teruaki; Liu, Weili; Xie, Yuexia; Dang, Bingrong; Li, Wenjian; Uchihori, Yukio; Hei, Tom K; Shao, Chunlin

    2015-07-10

    The abscopal effect could be an underlying factor in evaluating prognosis of radiotherapy. This study established an in vitro system to examine whether tumor-generated bystander signals could be transmitted by macrophages to further trigger secondary cellular responses after different irradiations, where human lung cancer NCI-H446 cells were irradiated with either γ-rays or carbon ions and co-cultured with human macrophage U937 cells, then these U937 cells were used as a bystander signal transmitter and co-cultured with human bronchial epithelial cells BEAS-2B. Results showed that U937 cells were only activated by γ-irradiated NCI-H446 cells so that the secondary injuries in BEAS-2B cells under carbon ion irradiation were weaker than γ-rays. Both TNF-α and IL-1α were involved in the γ-irradiation induced secondary bystander effect but only TNF-α contributed to the carbon ion induced response. Further assay disclosed that IL-1α but not TNF-α was largely responsible for the activation of macrophages and the formation of micronucleus in BEAS-2B cells. These data suggest that macrophages could transfer secondary bystander signals and play a key role in the secondary bystander effect of photon irradiation, while carbon ion irradiation has conspicuous advantage due to its reduced secondary injury. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  3. The effect of bystander medium on the apoptotic process in HPV-G cells

    International Nuclear Information System (INIS)

    Maguire, P.; Lyng, F.; Seymour, C.; Mothersill, C.

    2003-01-01

    Full text: It has been shown in recent years that in both in vivo and in vitro situations irradiated cells cause what is known as the bystander effect. This presently unknown factor causes chromosomal aberrations, initiation of apoptosis and reduced clonogenic survival. Using the medium transfer method to study the bystander effect, this study investigated early events in the apoptotic cascade, which leads to cell death in cells receiving medium from irradiated cells but which were not themselves irradiated. Medium from irradiated ( 0.005Gy to 5Gy) human HPV G keratinocytes was harvested one hour after irradiation, sterile filtered and transferred on to unirradiated HPV-G cells. The appearance of apoptotic markers in the apoptotic cascade was monitored over a period of 48 hours following medium transfer. These apoptotic markers include loss of mitochondrial membrane potential, cytochrome c release and the activity of the death inducing caspase 3. Clonogenic survival of HPV-G cells over a nine day period was also monitored to assess the final survival of the cells. A TUNEL assay, which indicated the level of apoptosis over a 72 hour period after exposure to bystander medium was also performed. Data collected in this study indicates that for very low doses (0.005Gy) the appearance of well-characterised early 'apoptotic' markers such as changes in mitochondrial membrane potential doesn't mean the cell has committed to the apoptotic cascade leading to cell death. This has been illustrated for bystander medium from 0.005Gy irradiated cells, which causes mitochondrial membrane potential depolarisation after six-hour exposure but little difference has been noted for clonogenic survival for exposure to 0.005Gy bystander medium from that of the control. The results may help clarify how cells sector to death or survival following receipt of a signal from a radiation event

  4. Gamma Low-Dose-Rate Ionizing Radiation Stimulates Adaptive Functional and Molecular Response in Human Aortic Endothelial Cells in a Threshold-, Dose-, and Dose Rate-Dependent Manner.

    Science.gov (United States)

    Vieira Dias, Juliana; Gloaguen, Celine; Kereselidze, Dimitri; Manens, Line; Tack, Karine; Ebrahimian, Teni G

    2018-01-01

    A central question in radiation protection research is whether low-dose and low-dose-rate (LDR) exposures to ionizing radiation play a role in progression of cardiovascular disease. The response of endothelial cells to different LDR exposures may help estimate risk of cardiovascular disease by providing the biological mechanism involved. We investigated the effect of chronic LDR radiation on functional and molecular responses of human aorta endothelial cells (HAoECs). Human aorta endothelial cells were continuously irradiated at LDR (6 mGy/h) for 15 days and analyzed at time points when the cumulative dose reached 0.05, 0.5, 1.0, and 2.0 Gy. The same doses were administered acutely at high-dose rate (HDR; 1 Gy/min). The threshold for the loss of angiogenic capacity for both LDR and HDR radiations was between 0.5 and 1.0 Gy. At 2.0 Gy, angiogenic capacity returned to normal only for HAoEC exposed to LDR radiation, associated with increased expression of antioxidant and anti-inflammatory genes. Pre-LDR, but not pre-HDR, radiation, followed by a single acute 2.0 Gy challenge dose sustained the expression of antioxidant and anti-inflammatory genes and stimulated angiogenesis. Our results suggest that dose rate is important in cellular response and that a radioadaptive response is involved for a 2.0 Gy dose at LDR.

  5. Gamma Low-Dose-Rate Ionizing Radiation Stimulates Adaptive Functional and Molecular Response in Human Aortic Endothelial Cells in a Threshold-, Dose-, and Dose Rate–Dependent Manner

    Science.gov (United States)

    Vieira Dias, Juliana; Gloaguen, Celine; Kereselidze, Dimitri; Manens, Line; Tack, Karine; Ebrahimian, Teni G

    2018-01-01

    A central question in radiation protection research is whether low-dose and low-dose-rate (LDR) exposures to ionizing radiation play a role in progression of cardiovascular disease. The response of endothelial cells to different LDR exposures may help estimate risk of cardiovascular disease by providing the biological mechanism involved. We investigated the effect of chronic LDR radiation on functional and molecular responses of human aorta endothelial cells (HAoECs). Human aorta endothelial cells were continuously irradiated at LDR (6 mGy/h) for 15 days and analyzed at time points when the cumulative dose reached 0.05, 0.5, 1.0, and 2.0 Gy. The same doses were administered acutely at high-dose rate (HDR; 1 Gy/min). The threshold for the loss of angiogenic capacity for both LDR and HDR radiations was between 0.5 and 1.0 Gy. At 2.0 Gy, angiogenic capacity returned to normal only for HAoEC exposed to LDR radiation, associated with increased expression of antioxidant and anti-inflammatory genes. Pre-LDR, but not pre-HDR, radiation, followed by a single acute 2.0 Gy challenge dose sustained the expression of antioxidant and anti-inflammatory genes and stimulated angiogenesis. Our results suggest that dose rate is important in cellular response and that a radioadaptive response is involved for a 2.0 Gy dose at LDR. PMID:29531508

  6. Rescue Effects: Irradiated Cells Helped by Unirradiated Bystander Cells

    Science.gov (United States)

    Lam, R. K. K.; Fung, Y. K.; Han, W.; Yu, K. N.

    2015-01-01

    The rescue effect describes the phenomenon where irradiated cells or organisms derive benefits from the feedback signals sent from the bystander unirradiated cells or organisms. An example of the benefit is the mitigation of radiation-induced DNA damages in the irradiated cells. The rescue effect can compromise the efficacy of radioimmunotherapy (RIT) (and actually all radiotherapy). In this paper, the discovery and subsequent confirmation studies on the rescue effect were reviewed. The mechanisms and the chemical messengers responsible for the rescue effect studied to date were summarized. The rescue effect between irradiated and bystander unirradiated zebrafish embryos in vivo sharing the same medium was also described. In the discussion section, the mechanism proposed for the rescue effect involving activation of the nuclear factor κB (NF-κB) pathway was scrutinized. This mechanism could explain the promotion of cellular survival and correct repair of DNA damage, dependence on cyclic adenosine monophosphate (cAMP) and modulation of intracellular reactive oxygen species (ROS) level in irradiated cells. Exploitation of the NF-κB pathway to improve the effectiveness of RIT was proposed. Finally, the possibility of using zebrafish embryos as the model to study the efficacy of RIT in treating solid tumors was also discussed. PMID:25625514

  7. Critical target and dose and dose-rate responses for the induction of chromosomal instability by ionizing radiation

    Science.gov (United States)

    Limoli, C. L.; Corcoran, J. J.; Milligan, J. R.; Ward, J. F.; Morgan, W. F.

    1999-01-01

    To investigate the critical target, dose response and dose-rate response for the induction of chromosomal instability by ionizing radiation, bromodeoxyuridine (BrdU)-substituted and unsubstituted GM10115 cells were exposed to a range of doses (0.1-10 Gy) and different dose rates (0.092-17.45 Gy min(-1)). The status of chromosomal stability was determined by fluorescence in situ hybridization approximately 20 generations after irradiation in clonal populations derived from single progenitor cells surviving acute exposure. Overall, nearly 700 individual clones representing over 140,000 metaphases were analyzed. In cells unsubstituted with BrdU, a dose response was found, where the probability of observing delayed chromosomal instability in any given clone was 3% per gray of X rays. For cells substituted with 25-66% BrdU, however, a dose response was observed only at low doses (1.0 Gy), the incidence of chromosomal instability leveled off. There was an increase in the frequency and complexity of chromosomal instability per unit dose compared to cells unsubstituted with BrdU. The frequency of chromosomal instability appeared to saturate around approximately 30%, an effect which occurred at much lower doses in the presence of BrdU. Changing the gamma-ray dose rate by a factor of 190 (0.092 to 17.45 Gy min(-1)) produced no significant differences in the frequency of chromosomal instability. The enhancement of chromosomal instability promoted by the presence of the BrdU argues that DNA comprises at least one of the critical targets important for the induction of this end point of genomic instability.

  8. Immune response and anamnestic immune response in children after a 3-dose primary hepatitis b vaccination

    International Nuclear Information System (INIS)

    Afzal, M.F.; Sultan, M.A.; Saleemi, A.I.

    2017-01-01

    Diseases caused by Hepatitis B virus (HBV) have a worldwide distribution. Pakistan adopted the recommendations of World Health Organization (WHO) for routine universal infant vaccination against hepatitis B in 2002, currently being administered at 6, 10, and 14 weeks of age in a combination vaccine. This study was conducted to determine the immune response and anamnestic immune response in children, 9 months-10 years of age, after a 3-dose primary Hepatitis B vaccination. Methods: This cross sectional study was conducted in the Department of Paediatrics, King Edward Medical University/Mayo Hospital, Lahore, Pakistan, from January to June, 2014. A total of 200 children of either sex between the ages of 9 months to 10 years, docu mented to have received 3 doses of hepatitis B vaccines according to Expanded Program of Immunization (6,10,14 weeks) schedule in infancy, were recruited by consecutive sampling. The level of serum anti-HBsAb by ELIZA was measured. Children with anti-HBs titers =10 mIU/mL were considered to be immune. Those with anti-HBsAb levels <10 mIU/mL were offered a booster dose of infant recombinant hepatitis B vaccine. The second serum sample was obtained 21-28 days following the administration of the booster dose and the anamnestic immune response was measured. Data was analysed using SPSS 17 to determine the relation between time interval since last vaccination and antibody titer. Chi square test was applied. Results: Of the 200 children, protective antibody response was found in 58 percent. Median serological response was 18.60 (range 2.82-65.15). Antibody levels were found to have a statistically significant (p-value 0.019) negative correlation with the time since last administration of vaccine. A booster dose of Hepatitis B vaccine was administered to all non-responders, with each registering a statistically significant (p-value 0.00) anamnestic response. Conclusion: The vaccination schedule with short dosage interval was unable to provide

  9. Gamma-H2AX as a biomarker of DNA damage induced by ionizing radiation in targeted and bystander human artificial skin models and peripheral blood lymphocytes

    Science.gov (United States)

    Redon, Christophe; Dickey, Jennifer; Bonner, William; Sedelnikova, Olga

    30 min after irradiation and then declined at a relatively steady pace as the cell repaired the DNA damage. Radiation effects were still detectable after 48 hrs for doses greater than 1 Gy and remained linear to initial dose. Activated bystander lymphocytes cultured with media from irradiated lymphocytes exhibited a two-fold increased damage response as seen by gamma- H2AX formation. The effect reached a maximum 3 hrs post-exposure and was retained for over 24 hrs. Thus, detection of gamma-H2AX formation to determine DNA damage in a minimally invasive skin test and a non-invasive blood test could be useful and promising tools to analyze direct and indirect effects of radiation exposure.

  10. Protective effect of mild endoplasmic reticulum stress on radiation-induced bystander effects in hepatocyte cells

    Science.gov (United States)

    Xie, Yuexia; Ye, Shuang; Zhang, Jianghong; He, Mingyuan; Dong, Chen; Tu, Wenzhi; Liu, Peifeng; Shao, Chunlin

    2016-01-01

    Radiation-induced bystander effect (RIBE) has important implications for secondary cancer risk assessment during cancer radiotherapy, but the defense and self-protective mechanisms of bystander normal cells are still largely unclear. The present study found that micronuclei (MN) formation could be induced in the non-irradiated HL-7702 hepatocyte cells after being treated with the conditioned medium from irradiated hepatoma HepG2 cells under either normoxia or hypoxia, where the ratio of the yield of bystander MN induction to the yield of radiation-induced MN formation under hypoxia was much higher than that of normoxia. Nonetheless, thapsigargin induced endoplasmic reticulum (ER) stress and dramatically suppressed this bystander response manifested as the decrease of MN and apoptosis inductions. Meanwhile, the interference of BiP gene, a major ER chaperone, amplified the detrimental RIBE. More precisely, thapsigargin provoked ER sensor of PERK to initiate an instantaneous and moderate ER stress thus defensed the hazard form RIBE, while BiP depletion lead to persistently destroyed homeostasis of ER and exacerbated cell injury. These findings provide new insights that the mild ER stress through BiP-PERK-p-eIF2α signaling pathway has a profound role in protecting cellular damage from RIBE and hence may decrease the potential secondary cancer risk after cancer radiotherapy. PMID:27958308

  11. Differential effects of p53 on bystander phenotypes induced by gamma ray and high LET heavy ion radiation

    Science.gov (United States)

    He, Mingyuan; Dong, Chen; Konishi, Teruaki; Tu, Wenzhi; Liu, Weili; Shiomi, Naoko; Kobayashi, Alisa; Uchihori, Yukio; Furusawa, Yoshiya; Hei, Tom K.; Dang, Bingrong; Shao, Chunlin

    2014-04-01

    High LET particle irradiation has several potential advantages over γ-rays such as p53-independent response. The purpose of this work is to disclose the effect of p53 on the bystander effect induced by different LET irradiations and underlying mechanism. Lymphocyte cells of TK6 (wild type p53) and HMy2.CIR (mutated p53) were exposed to either low or high LET irradiation, then their mitochondrial dysfunction and ROS generation were detected. The micronuclei (MN) induction in HL-7702 hepatocytes co-cultured with irradiated lymphocytes was also measured. It was found that the mitochondrial dysfunction, p66Shc activation, and intracellular ROS were enhanced in TK6 but not in HMy2.CIR cells after γ-ray irradiation, but all of them were increased in both cell lines after carbon and iron irradiation. Consistently, the bystander effect of MN formation in HL-7702 cells was only triggered by γ-irradiated TK6 cells but not by γ-irradiated HMy2.CIR cells. But this bystander effect was induced by both lymphocyte cell lines after heavy ion irradiation. PFT-μ, an inhibitor of p53, only partly inhibited ROS generation and bystander effect induced by 30 keV/μm carbon-irradiated TK6 cells but failed to suppress the bystander effect induced by the TK6 cells irradiated with either 70 keV/μm carbon or 180 keV/μm iron. The mitochondrial inhibitors of rotenone and oligomycin eliminated heavy ion induced ROS generation in TK6 and HMy2.CIR cells and hence diminished the bystander effect on HL-7702 cells. These results clearly demonstrate that the bystander effect is p53-dependent for low LET irradiation, but it is p53-independent for high LET irradiation which may be because of p53-independent ROS generation due to mitochondrial dysfunction.

  12. Radiobiological responses for two cell lines following continuous low dose-rate (CLDR) and pulsed dose rate (PDR) brachytherapy

    International Nuclear Information System (INIS)

    Hanisch, Per Henrik; Furre, Torbjoern; Olsen, Dag Rune; Pettersen, Erik O.

    2007-01-01

    The iso-effective irradiation of continuous low-dose-rate (CLDR) irradiation was compared with that of various schedules of pulsed dose rate (PDR) irradiation for cells of two established human lines, T-47D and NHIK 3025. Complete single-dose response curves were obtained for determination of parameters α and β by fitting of the linear quadratic formula. Sublethal damage repair constants μ and T 1/2 were determined by split-dose recovery experiments. On basis of the acquired parameters of each cell type the relative effectiveness of the two regimens of irradiation (CLDR and PDR) was calculated by use of Fowler's radiobiological model for iso-effect irradiation for repeated fractions of dose delivered at medium dose rates. For both cell types the predicted and observed relative effectiveness was compared at low and high iso-effect levels. The results indicate that the effect of PDR irradiation predicted by Fowler's model is equal to that of CLDR irradiation for both small and large doses with T-47D cells. With NHIK 3025 cells PDR irradiation induces a larger effect than predicted by the model for small doses, while it induces the predicted effect for high doses. The underlying cause of this difference is unclear, but cell-cycle parameters, like G2-accumulation is tested and found to be the same for the two cell lines

  13. Effect of radiation doses rate on SOS response induction in irradiated Escherichia coli Cells

    International Nuclear Information System (INIS)

    Cuetara Lugo, Elizabeth B.; Fuentes Lorenzo, Jorge L.; Almeida Varela, Eliseo; Prieto Miranda, Enrique F.; Sanchez Lamar, Angel; Llagostera Casal, Montserrat

    2005-01-01

    The present work is aimed to study the effect of radiation dose rate on the induction of SOS response in Escherichia coli cells. We measured the induction of sul A reporter gene in PQ-37 (SOS Chromotest) cells. Lead devises were built with different diameter and these were used for diminishing the dose rate of PX- -30M irradiator. Our results show that radiation doses rate significantly modifies the induction of SOS response. Induction factor increases proportionally to doses rate in Escherichia coli cells defective to nucleotide excision repair (uvrA), but not in wild type cells. We conclude that the dose rate affects the level of induction of SOS response

  14. Population variability in biological adaptive responses to DNA damage and the shapes of carcinogen dose-response curves

    International Nuclear Information System (INIS)

    Conolly, Rory B.; Gaylor, David W.; Lutz, Werner K.

    2005-01-01

    Carcinogen dose-response curves for both ionizing radiation and chemicals are typically assumed to be linear at environmentally relevant doses. This assumption is used to ensure protection of the public health in the absence of relevant dose-response data. A theoretical justification for the assumption has been provided by the argument that low dose linearity is expected when an exogenous agent adds to an ongoing endogenous process. Here, we use computational modeling to evaluate (1) how two biological adaptive processes, induction of DNA repair and cell cycle checkpoint control, may affect the shapes of dose-response curves for DNA-damaging carcinogens and (2) how the resulting dose-response behaviors may vary within a population. Each model incorporating an adaptive process was capable of generating not only monotonic dose-responses but also nonmonotonic (J-shaped) and threshold responses. Monte Carlo analysis suggested that all these dose-response behaviors could coexist within a population, as the spectrum of qualitative differences arose from quantitative changes in parameter values. While this analysis is largely theoretical, it suggests that (a) accurate prediction of the qualitative form of the dose-response requires a quantitative understanding of the mechanism (b) significant uncertainty is associated with human health risk prediction in the absence of such quantitative understanding and (c) a stronger experimental and regulatory focus on biological mechanisms and interindividual variability would allow flexibility in regulatory treatment of environmental carcinogens without compromising human health

  15. Bystander Tactics: Life on Turf in Karachi

    Directory of Open Access Journals (Sweden)

    Tania Ahmad

    2012-03-01

    Full Text Available This article posits an analytic of the bystander, as a supplement to studies of perpetrators and victims, in relation to political affiliation, mobilization and violence in Karachi. In particular, I use ethnographic findings to elucidate the tactics of anticipation used by Karachi residents of neighborhoods widely considered the turf of the Muttahida Qaumi Movement (MQM. The examples of students’ and teachers’ reactions to a college rumble between rival groups, parents’ attempts to keep their sons from being recruited into party politics, and young people confident in their ability to navigate an economy of affiliation demonstrate a range of bystander tactics, in which subjection and subversion are aligned. Although metanarratives of democratization frequently elide the everyday activity of standing by, it constitutes a pervasive mode of participation in Karachi’s political landscape.

  16. Active Defending and Passive Bystanding Behavior in Bullying: The Role of Personal Characteristics and Perceived Peer Pressure

    Science.gov (United States)

    Pozzoli, Tiziana; Gini, Gianluca

    2010-01-01

    This study examined the role of pro-victim attitudes, personal responsibility, coping responses to observations of bullying, and perceived peer normative pressure in explaining defending the victim and passive bystanding behavior in bullying. A total of 462 Italian early adolescents (mean age = 13.4 years, SD = 9 months) participated in the study.…

  17. Bystander Motivation in Bullying Incidents: To Intervene or Not to Intervene?

    Directory of Open Access Journals (Sweden)

    Robert Thornberg

    2012-08-01

    Full Text Available Introduction: This research sought to extend knowledge about bystanders in bullying situations with a focus on the motivations that lead them to different responses. The 2 primary goals of this study were to investigate the reasons for children’s decisions to help or not to help a victim when witnessing bullying, and to generate a grounded theory (or conceptual framework of bystander motivation in bullying situations.Methods: Thirty students ranging in age from 9 to 15 years (M=11.9; SD=1.7 from an elementary and middle school in the southeastern United States participated in this study. Open- ended, semistructured interviews were used, and sessions ranged from 30 to 45 minutes. We conducted qualitative methodology and analyses to gain an in-depth understanding of children’s perspectives and concerns when witnessing bullying.Results: A key finding was a conceptual framework of bystander motivation to intervene in bullying situations suggesting that deciding whether to help or not help the victim in a bullying situation depends on how bystanders define and evaluate the situation, the social context, and their own agency. Qualitative analysis revealed 5 themes related to bystander motives and included: interpretation of harm in the bullying situation, emotional reactions, social evaluating, moral evaluating, and intervention self-efficacy.Conclusion: Given the themes that emerged surrounding bystanders’ motives to intervene or abstain from intervening, respondents reported 3 key elements that need to be confirmed in future research and that may have implications for future work on bullying prevention. These included: first, the potential importance of clear communication to children that adults expect bystanders to intervene when witnessing bullying; second, the potential of direct education about how bystanders can interveneto increase children’s self-efficacy as defenders of those who are victims of bullying; and third, the assumption

  18. Fertility of Tall Girls Treated with High-Dose Estrogen, a Dose-Response Relationship

    NARCIS (Netherlands)

    Hendriks, A. E. J.; Drop, S. L. S.; Laven, J. S. E.; Boot, A. M.

    Context: High-dose estrogen treatment to reduce final height of tall girls increases their risk for infertility in later life. Objective: The aim was to study the effect of estrogen dose on fertility outcome of these women. Design/Setting: We conducted a retrospective cohort study of university

  19. High-Dose Atomoxetine Treatment of ADHD in Youths with Limited Response to Standard Doses

    Science.gov (United States)

    Kratochvil, Christopher J.; Michelson, David; Newcorn, Jeffrey H.; Weiss, Margaret D.; Busner, Joan; Moore, Rodney J.; Ruff, Dustin D.; Ramsey, Janet; Dickson, Ruth; Turgay, Atilla; Saylor, Keith E.; Luber, Stephen; Vaughan, Brigette; Allen, Albert J.

    2007-01-01

    Objective: To assess the utility and tolerability of higher than standard atomoxetine doses to treat attention-deficit/hyperactivity disorder (ADHD). Method: Two randomized, double-blind trials of atomoxetine nonresponders ages 6 to 16 years were conducted comparing continued treatment with same-dose atomoxetine to treatment using greater than…

  20. Study on cellular survival adaptive response induced by low dose irradiation of 153Sm

    International Nuclear Information System (INIS)

    Zhu Shoupeng; Xiao Dong

    1999-01-01

    The present study engages in determining whether low dose irradiation of 153 Sm could cut down the responsiveness of cellular survival to subsequent high dose exposure of 153 Sm so as to make an inquiry into approach the protective action of adaptive response by second irradiation of 153 Sm. Experimental results indicate that for inductive low dose of radionuclide 153 Sm 3.7 kBq/ml irradiated beforehand to cells has obvious resistant effect in succession after high dose irradiation of 153 Sm 3.7 x 10 2 kBq/ml was observed. Cells exposed to low dose irradiation of 153 Sm become adapted and therefore the subsequent cellular survival rate induced by high dose of 153 Sm is sufficiently higher than high dose of 153 Sm merely. It is evident that cellular survival adaptive response could be induced by pure low dose irradiation of 153 Sm only

  1. The crosstalk between α-irradiated Beas-2B cells and its bystander U937 cells through MAPK and NF-κB signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Jiamei; Yuan, Dexiao; Xiao, Linlin; Tu, Wenzhi; Dong, Chen; Liu, Weili; Shao, Chunlin, E-mail: clshao@shmu.edu.cn

    2016-01-15

    Highlights: • α-irradiated Beas-2B cells induced bystander effects in macrophage U937 cells. • The neighboring macrophages enhanced the damage of α-irradiated Beas-2B cells. • MAPK and NF-κB pathways were activated in U937 cells after cell co-culture. • NF-κB and MAPK pathways participated in the bilateral bystander responses. - Abstract: Although accumulated evidence suggests that α-particle irradiation induced bystander effect may relevant to lung injury and cancer risk assessment, the exact mechanisms are not yet elucidated. In the present study, a cell co-culture system was used to investigate the interaction between α-particle irradiated human bronchial epithelial cells (Beas-2B) and its bystander macrophage U937 cells. It was found that the cell co-culture amplified the detrimental effects of α-irradiation including cell viability decrease and apoptosis promotion on both irradiated cells and bystander cells in a feedback loop which was closely relevant to the activation of MAPK and NF-κB pathways in the bystander U937 cells. When these two pathways in U937 cells were disturbed by special pharmacological inhibitors before cell co-culture, it was found that a NF-κB inhibitor of BAY 11-7082 further enhanced the proliferation inhibition and apoptosis induction in bystander U937 cells, but MAPK inhibitors of SP600125 and SB203580 protected cells from viability loss and apoptosis and U0126 presented more beneficial effect on cell protection. For α-irradiated epithelial cells, the activation of NF-κB and MAPK pathways in U937 cells participated in detrimental cellular responses since the above inhibitors could largely attenuate cell viability loss and apoptosis of irradiated cells. Our results demonstrated that there are bilateral bystander responses between irradiated lung epithelial cells and macrophages through MAPK and NF-κB signaling pathways, which accounts for the enhancement of α-irradiation induced damage.

  2. The crosstalk between α-irradiated Beas-2B cells and its bystander U937 cells through MAPK and NF-κB signaling pathways

    International Nuclear Information System (INIS)

    Fu, Jiamei; Yuan, Dexiao; Xiao, Linlin; Tu, Wenzhi; Dong, Chen; Liu, Weili; Shao, Chunlin

    2016-01-01

    Highlights: • α-irradiated Beas-2B cells induced bystander effects in macrophage U937 cells. • The neighboring macrophages enhanced the damage of α-irradiated Beas-2B cells. • MAPK and NF-κB pathways were activated in U937 cells after cell co-culture. • NF-κB and MAPK pathways participated in the bilateral bystander responses. - Abstract: Although accumulated evidence suggests that α-particle irradiation induced bystander effect may relevant to lung injury and cancer risk assessment, the exact mechanisms are not yet elucidated. In the present study, a cell co-culture system was used to investigate the interaction between α-particle irradiated human bronchial epithelial cells (Beas-2B) and its bystander macrophage U937 cells. It was found that the cell co-culture amplified the detrimental effects of α-irradiation including cell viability decrease and apoptosis promotion on both irradiated cells and bystander cells in a feedback loop which was closely relevant to the activation of MAPK and NF-κB pathways in the bystander U937 cells. When these two pathways in U937 cells were disturbed by special pharmacological inhibitors before cell co-culture, it was found that a NF-κB inhibitor of BAY 11-7082 further enhanced the proliferation inhibition and apoptosis induction in bystander U937 cells, but MAPK inhibitors of SP600125 and SB203580 protected cells from viability loss and apoptosis and U0126 presented more beneficial effect on cell protection. For α-irradiated epithelial cells, the activation of NF-κB and MAPK pathways in U937 cells participated in detrimental cellular responses since the above inhibitors could largely attenuate cell viability loss and apoptosis of irradiated cells. Our results demonstrated that there are bilateral bystander responses between irradiated lung epithelial cells and macrophages through MAPK and NF-κB signaling pathways, which accounts for the enhancement of α-irradiation induced damage.

  3. Development and Psychometrics of Instruments to Assess School Personnel's Bystander Action in Situations of Teen Relationship Abuse and Sexual Assault.

    Science.gov (United States)

    Edwards, Katie M; Sessarego, Stephanie N; Stanley, Linda R; Mitchell, Kimberly J; Eckstein, Robert P; Rodenhizer, Kara Anne E; Leyva, P Caroline; Banyard, Victoria L

    2017-12-01

    This article describes recently developed instruments that assess school personnel's bystander barriers and intentions in situations of teen relationship abuse, sexual assault, and sexual harassment, as well as perceptions of school readiness specific to relationship abuse, sexual assault, and sexual harassment prevention and response. Participants were 1,150 high school personnel from 25 schools in New Hampshire, Massachusetts, and Maine. Specific instruments focused on bystander intentions, bystander action, barriers to bystander action, and perceptions of school readiness. Participants were randomly divided into two groups for analysis-the exploratory sample (ES; n = 575) and the confirmatory sample (CS; n = 575). Overall, the measures demonstrated acceptable fit indices. Results suggested that most measures and subscales had adequate reliability, but a few subscales had less than ideal internal consistency, which can likely be attributed to the small number of items. More work is needed, but these measures act as a starting point by which the role of school personnel in prevention initiatives and bystander intervention can be evaluated.

  4. Chronic periodontitis and smoking. Prevalence and dose-response relationship.

    Science.gov (United States)

    Khan, Shahrukh; Khalid, Taimur; Awan, Kamran H

    2016-08-01

    To determine the prevalence and dose-response relationship of chronic periodontitis among smokers in Pakistan.   This is a cross-sectional study among participants seeking dental care in Karachi Medical and Dental College, Karachi, Pakistan. A total of 443 participants with a mean age of 44.3 (±6.5) participated in the study from April 2011 to December 2011. Males comprised 64.7%, and females comprised 35.2%. Participants were interviewed on social demographics and oral habits. Participants with shallow pockets (3.5-5.5 mm) and deep pockets (greater than 5.5 mm) were considered suffering from chronic periodontitis. The characteristics of participants were assessed using frequency distribution for categorical variables and mean (standard deviation) for continuous variables.  Among 443 participants, smokers were distributed as 55.1% and non-smokers as 44.9%. Smoking was found to be significantly related to young adults (p less than 0.007), male gender (p less than 0.001), and lower education level (p less than 0.01). Overall prevalence of chronic periodontitis among smokers was estimated at 81.6%. Heavy smoking was found to have significantly high prevalence (p less than 0.001) and severity (p less than 0.001) of periodontitis as compared with moderate and light smokers. The multivariate unadjusted model depicted 3.5 times higher risk of chronic periodontitis among smokers (p less than 0.001). Chronic periodontitis had a high prevalence among smokers. Heavy smoking was found to have a higher risk for having periodontitis.

  5. Dose-response relationship of autonomic nervous system responses to individualized training impulse in marathon runners.

    Science.gov (United States)

    Manzi, Vincenzo; Castagna, Carlo; Padua, Elvira; Lombardo, Mauro; D'Ottavio, Stefano; Massaro, Michele; Volterrani, Maurizio; Iellamo, Ferdinando

    2009-06-01

    In athletes, exercise training induces autonomic nervous system (ANS) adaptations that could be used to monitor training status. However, the relationship between training and ANS in athletes has been investigated without regard for individual training loads. We tested the hypothesis that in long-distance athletes, changes in ANS parameters are dose-response related to individual volume/intensity training load and could predict athletic performance. A spectral analysis of heart rate (HR), systolic arterial pressure variability, and baroreflex sensitivity by the sequences technique was investigated in eight recreational athletes during a 6-mo training period culminating with a marathon. Individualized training load responses were monitored by a modified training impulse (TRIMP(i)) method, which was determined in each athlete using the individual HR and lactate profiling determined during a treadmill test. Monthly TRIMP(i) steadily increased during the training period. All the ANS parameters were significantly and very highly correlated to the dose of exercise with a second-order regression model (r(2) ranged from 0.90 to 0.99; P marathon. These results suggest that in recreational athletes, ANS adaptations to exercise training are dose related on an individual basis, showing a progressive shift toward a sympathetic predominance, and that LF oscillations in HRV at peak training load could predict athletic achievement in this athlete population.

  6. Dose-Response of Sodium Bicarbonate Ingestion Highlights Individuality in Time Course of Blood Analyte Responses.

    Science.gov (United States)

    Jones, Rebecca Louise; Stellingwerff, Trent; Artioli, Guilherme Giannini; Saunders, Bryan; Cooper, Simon; Sale, Craig

    2016-10-01

    To defend against hydrogen cation accumulation and muscle fatigue during exercise, sodium bicarbonate (NaHCO 3 ) ingestion is commonplace. The individualized dose-response relationship between NaHCO 3 ingestion and blood biochemistry is unclear. The present study investigated the bicarbonate, pH, base excess and sodium responses to NaHCO 3 ingestion. Sixteen healthy males (23 ± 2 years; 78.6 ± 15.1 kg) attended three randomized order-balanced, nonblinded sessions, ingesting a single dose of either 0.1, 0.2 or 0.3 g·kg -1 BM of NaHCO 3 (Intralabs, UK). Fingertip capillary blood was obtained at baseline and every 10 min for 1 hr, then every 15 min for a further 2 hr. There was a significant main effect of both time and condition for all assessed blood analytes (p ≤ .001). Blood analyte responses were significantly lower following 0.1 g·kg -1 BM compared with 0.2 g·kg -1 BM; bicarbonate concentrations and base excess were highest following ingestion of 0.3 g·kg -1 BM (p ≤ .01). Bicarbonate concentrations and pH significantly increased from baseline following all doses; the higher the dose the greater the increase. Large interindividual variability was shown in the magnitude of the increase in bicarbonate concentrations following each dose (+2.0-5; +5.1-8.1; and +6.0-12.3 mmol·L -1 for 0.1, 0.2 and 0.3 g·kg -1 BM) and in the range of time to peak concentrations (30-150; 40-165; and 75-180 min for 0.1, 0.2 and 0.3 g·kg -1 BM). The variability in bicarbonate responses was not affected by normalization to body mass. These results challenge current practices relating to NaHCO 3 supplementation and clearly show the need for athletes to individualize their ingestion protocol and trial varying dosages before competition.

  7. Biochemical and immunological responses to low doses of ionizing radiation

    International Nuclear Information System (INIS)

    Shabon, M.H.; Sayed, Z.S.; Mahdy, E.M.; El-Gawish, M.A.; Shosha, W.

    2006-01-01

    Malondialdehyde, lactate dehydrogenase, iron concentration, IL-6 and IL-1b concentration, hemoglobin content, red cells, white cells and platelet counts were determined in seventy-two male albino rats divided into two main groups. The first one was subdivided into 7 subgroups; control and 6 irradiated subgroups with 0.1, 0.2, 0.3, 0.5, 0.7 and 1 Gy single dose of gamma radiation. The other was subdivided into 4 subgroups irradiated with fractionated doses of gamma radiation; three groups were irradiated with 0.3, 0.7 and 1 Gy (0.1 Gy/day) and the last subgroup with 1 Gy (0.2 Gy/day). All animals were sacrificed after three days of the last irradiation dose. The results revealed that all biochemical parameters were increased in rats exposed to fractionated doses more than the single doses. Hematological parameters were decreased in rats exposed to single doses more than the fractionated ones. In conclusion, the data of this study highlights the stimulatory effect of low ionizing radiation doses (= 1 Gy), whether single or fractionated, on some biochemical and immunological parameters

  8. Dose-response effects in an outbreak of Salmonella enteritidis.

    OpenAIRE

    Mintz, E. D.; Cartter, M. L.; Hadler, J. L.; Wassell, J. T.; Zingeser, J. A.; Tauxe, R. V.

    1994-01-01

    The effects of ingested Salmonella enteritidis (SE) dose on incubation period and on the severity and duration of illness were estimated in a cohort of 169 persons who developed gastroenteritis after eating hollandaise sauce made from grade-A shell eggs. The cohort was divided into three groups based on self-reported dose of sauce ingested. As dose increased, median incubation period decreased (37 h in the low exposure group v. 21 h in the medium exposure group v. 17.5 h in the high exposure ...

  9. Tumor and normal tissue responses to fractioned non-uniform dose delivery

    Energy Technology Data Exchange (ETDEWEB)

    Kaellman, P; Aegren, A; Brahme, A [Karolinska Inst., Stockholm (Sweden). Dept. of Radiation Physics

    1996-08-01

    The volume dependence of the radiation response of a tumor is straight forward to quantify because it depends primarily on the eradication of all its clonogenic cells. A tumor therefore has a parallel organization as any surviving clonogen in principle can repopulate the tumor. The difficulty with the response of the tumor is instead to know the density and sensitivity distribution of the most resistant clonogenic cells. The increase in the 50% tumor control dose and the decrease in the maximum normalized slope of the dose response relation, {gamma}, in presence of small compartments of resistant tumor cells have therefore been quantified to describe their influence on the dose response relation. Injury to normal tissue is a much more complex and gradual process. It depends on earlier effects induced long before depletion of the differentiated and clonogenic cells that in addition may have a complex structural and functional organization. The volume dependence of the dose response relation of normal tissues is therefore described here by the relative seriality, s, of the infrastructure of the organ. The model can also be generalized to describe the response of heterogeneous tissues to non uniform dose distributions. The new model is compared with clinical and experimental data on normal tissue response, and shows good agreement both with regard to the shape of dose response relation and the volume dependence of the isoeffect dose. The response of tumors and normal tissues are quantified for arbitrary dose fractionations using the linear quadratic cell survival parameters {alpha} and {beta}. The parameters of the dose response relation are derived both for a constant dose per fraction and a constant number of dose fractions, thus in the latter case accounting also for non uniform dose delivery. (author). 26 refs, 4 figs.

  10. Hybrid model of the radiation-induced bystander effect

    International Nuclear Information System (INIS)

    Braga, Viviane V.B.; Faria, Fernando Pereira de; Grynberg, Suely Epsztein

    2013-01-01

    The radiation-induced bystander effect (RIBE) refer to biological alterations in non-irradiated cells that occupy the same medium (culture or tissue) of irradiated cells. The biochemical mechanisms of the RIBE are not completely elucidated. However, several experiments indicate its existence. The objective of this work is to quantify the effect via stochastic and deterministic approaches. The hypotheses of the model are: a) one non-irradiated healthy cell interacts with signals that propagate through the medium. These signals are released by irradiated cells. At the time of interaction cell-signal, the cell can become damaged and signaling or damage and not signaling; b) Both types of damage cells repair with certain rate becoming health cells; c) The diffusion of signals obey the discrete diffusion equation with decay in two dimensions. d) The signal concentration released by irradiated cells depends on the dose in the low dose range (< 0.3 Gy) and saturates for higher dose values. As expected, the temporal analysis of the model as a function of the repair rate shows that the survival fraction decreases as the repair rate is reduced. The analysis of the extent of damage triggered by a signal concentration released by a single irradiated cell at time zero show that the damage grows with the maximum simulation time. The results show good agreement with the experimental data. The stochastic and deterministic methods used are in qualitative agreement, as expected. (author)

  11. Hybrid model of the radiation-induced bystander effect

    Energy Technology Data Exchange (ETDEWEB)

    Braga, Viviane V.B.; Faria, Fernando Pereira de; Grynberg, Suely Epsztein, E-mail: vitoriabraga06@gmail.com, E-mail: fernandopereirabh@gmail.com, E-mail: seg@cdtn.br [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil)

    2013-07-01

    The radiation-induced bystander effect (RIBE) refer to biological alterations in non-irradiated cells that occupy the same medium (culture or tissue) of irradiated cells. The biochemical mechanisms of the RIBE are not completely elucidated. However, several experiments indicate its existence. The objective of this work is to quantify the effect via stochastic and deterministic approaches. The hypotheses of the model are: a) one non-irradiated healthy cell interacts with signals that propagate through the medium. These signals are released by irradiated cells. At the time of interaction cell-signal, the cell can become damaged and signaling or damage and not signaling; b) Both types of damage cells repair with certain rate becoming health cells; c) The diffusion of signals obey the discrete diffusion equation with decay in two dimensions. d) The signal concentration released by irradiated cells depends on the dose in the low dose range (< 0.3 Gy) and saturates for higher dose values. As expected, the temporal analysis of the model as a function of the repair rate shows that the survival fraction decreases as the repair rate is reduced. The analysis of the extent of damage triggered by a signal concentration released by a single irradiated cell at time zero show that the damage grows with the maximum simulation time. The results show good agreement with the experimental data. The stochastic and deterministic methods used are in qualitative agreement, as expected. (author)

  12. Low dose response analysis through a cytogenetic end-point

    International Nuclear Information System (INIS)

    Bojtor, I.; Koeteles, G.J.

    1998-01-01

    The effects of low doses were studied on human lymphocytes of various individuals. The frequency of micronuclei in cytokinesis-blocked cultured lymphocytes was taken as end-point. The probability distribution of radiation-induced increment was statistically proved and identified as to be asymmetric when the blood samples had been irradiated with doses of 0.01-0.05 Gy of X-rays, similarly to that in unirradiated control population. On the contrary, at or above 1 Gy the corresponding normal curve could be accepted only reflecting an approximately symmetrical scatter of the increments about their mean value. It was found that the slope as well as the closeness of correlation of the variables considerably changed when lower and lower dose ranges had been selected. Below approximately 0.2 Gy even an unrelatedness was found betwen the absorbed dose and the increment

  13. The dependence of radiation response on the dose per fraction

    International Nuclear Information System (INIS)

    Joiner, M.C.

    1989-01-01

    The linear-quadratic (LQ) model explains the dependence of total dose in a fractionated course on the dose per fraction, in a very wide range of tumour and normal tissue studies, providing the dose per fraction remains above 2 Gy. In the range 2-1 Gy per fraction, some experimental studies show less increase in total dose than predicted by LQ; a probable explanation is incomplete repair between fractions given 2 seen between 1 and 0.1 Gy per fraction. This cannot be explained by incomplete repair; a modified LQ model where α decreases sharply with increasing dose per fraction in the range 0-1 Gy fits these data. The basic LQ model describes data from neutron fractionation studies, so the relationship between relative biological effectiveness (RBE) and X-ray dose per fraction can be expressed in terms of LQ parameters and fitted directly to RBE data. Results from different experiments, different assays and both top-up and full-course fractionation techniques, can all be included in one analysis. (author)

  14. Use of synchrotron medical microbeam irradiation to investigate radiation-induced bystander and abscopal effects in vivo.

    Science.gov (United States)

    Fernandez-Palomo, Cristian; Bräuer-Krisch, Elke; Laissue, Jean; Vukmirovic, Dusan; Blattmann, Hans; Seymour, Colin; Schültke, Elisabeth; Mothersill, Carmel

    2015-09-01

    The question of whether bystander and abscopal effects are the same is unclear. Our experimental system enables us to address this question by allowing irradiated organisms to partner with unexposed individuals. Organs from both animals and appropriate sham and scatter dose controls are tested for expression of several endpoints such as calcium flux, role of 5HT, reporter assay cell death and proteomic profile. The results show that membrane related functions of calcium and 5HT are critical for true bystander effect expression. Our original inter-animal experiments used fish species whole body irradiated with low doses of X-rays, which prevented us from addressing the abscopal effect question. Data which are much more relevant in radiotherapy are now available for rats which received high dose local irradiation to the implanted right brain glioma. The data were generated using quasi-parallel microbeams at the biomedical beamline at the European Synchrotron Radiation Facility in Grenoble France. This means we can directly compare abscopal and "true" bystander effects in a rodent tumour model. Analysis of right brain hemisphere, left brain and urinary bladder in the directly irradiated animals and their unirradiated partners strongly suggests that bystander effects (in partner animals) are not the same as abscopal effects (in the irradiated animal). Furthermore, the presence of a tumour in the right brain alters the magnitude of both abscopal and bystander effects in the tissues from the directly irradiated animal and in the unirradiated partners which did not contain tumours, meaning the type of signal was different. Copyright © 2015. Published by Elsevier Ltd.

  15. The evolutionary reserve cell concept and model of cellular response induced by low doses of radiation

    International Nuclear Information System (INIS)

    Spitkovsky, D.M.; Talyzina, T.A.

    1995-01-01

    The model is based on the concept of programmed initiation of genetic damage in sub-populations of specific evolutionary reserve cells (ERC). The model quantitatively predicts a dose response of genetic lesions at low dose range and furnishes an explanation of the minimum observed in the dose-response curve at doses corresponding to one (on the average) event of energy deposition per ERC. The complex shape of the dose-response curve is demonstrated to result from superposition of processes in different sub-populations within the exposed cell population (at low doses mainly in ERC). Programmed initiation of genetic lesions in ERC requires two hits to cell membrane and probably, at the same time, to the cell nucleus. The equation for dicentric yield in human lymphocytes as a function of dose describes the experimental observations rather well. (Author)

  16. Mechanisms of Low Dose Radio-Suppression of Genomic Instability

    Energy Technology Data Exchange (ETDEWEB)

    Engelward, Bevin P. [Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)

    2009-09-16

    The major goal of this project is to contribute toward the elucidation of the impact of long term low dose radiation on genomic stability. We have created and characterized novel technologies for delivering long term low dose radiation to animals, and we have studied genomic stability by applying cutting edge molecular analysis technologies. Remarkably, we have found that a dose rate that is 300X higher than background radiation does not lead to any detectable genomic damage, nor is there any significant change in gene expression for genes pertinent to the DNA damage response. These results point to the critical importance of dose rate, rather than just total dose, when evaluating public health risks and when creating regulatory guidelines. In addition to these studies, we have also further developed a mouse model for quantifying cells that have undergone a large scale DNA sequence rearrangement via homologous recombination, and we have applied these mice in studies of both low dose radiation and space radiation. In addition to more traditional approaches for assessing genomic stability, we have also explored radiation and possible beneficial effects (adaptive response), long term effects (persistent effects) and effects on communication among cells (bystander effects), both in vitro and in vivo. In terms of the adaptive response, we have not observed any significant induction of an adaptive response following long term low dose radiation in vivo, delivered at 300X background. In terms of persistent and bystander effects, we have revealed evidence of a bystander effect in vivo and with researchers at and demonstrated for the first time the molecular mechanism by which cells “remember” radiation exposure. Understanding the underlying molecular mechanisms by which radiation can induce genomic instability is fundamental to our ability to assess the biological impact of low dose radiation. Finally, in a parallel set of studies we have explored the effects of heavy

  17. Bystander-witnessed cardiac arrest is associated with reported agonal breathing and leads to less frequent bystander CPR.

    Science.gov (United States)

    Brinkrolf, P; Metelmann, B; Scharte, C; Zarbock, A; Hahnenkamp, K; Bohn, A

    2018-04-18

    Although the importance of bystander cardiopulmonary resuscitation has been shown in multiple studies, the rate of bystander cardiopulmonary resuscitation is still relatively low in many countries. Little is known on bystanders' perceptions influencing the decision to start cardiopulmonary resuscitation. Our study aims to determine such factors. Semi-structured telephone interviews with bystanders of out-of-hospital cardiac arrests between December 2014 and April 2016 were performed in a prospective manner. This single-center survey was conducted in the city of Münster, Germany. The bystander's sex and age, the perception of the victim's breathing and initial condition were correlated with the share of bystander cardiopulmonary resuscitation in the corresponding group. 101 telephone interviews were performed with 57 male and 44 female participants showing a mean age of 52.7 (SD ± 16.3). In case of apnoea 38 out of 46 bystanders (82.6%) started cardiopulmonary resuscitation; while in case of descriptions indicating agonal breathing 19 out of 35 bystanders (54.3%) started cardiopulmonary resuscitation (p = .007). If the patient was found unconscious 47 out of 63 bystanders (74.7%) performed cardiopulmonary resuscitation, while in cases of witnessed cardiac arrest 19 out of 38 bystanders (50%) attempted cardiopulmonary resuscitation (p = .012). Witnessed change of consciousness is an independent factor significantly lowering the probability of starting cardiopulmonary resuscitation (regression coefficient -1.489, p bystander-CPR was started. These data reinforce the importance of teaching the recognition of early cardiac arrest. Copyright © 2018 Elsevier B.V. All rights reserved.