The objective of our study was to explore a possible molecular mechanism by which ultraviolet (UV) biophotons could elicit bystander responses in reporter cells and resolve the problem of seemingly ...mutually exclusive mechanisms of a physical UV signal & a soluble factor-mediated bystander signal.
The human colon carcinoma cell line, HCT116 p53 +/+, was directly irradiated with 0.5 Gy tritium beta particles to induce ultraviolet biophoton emission. Bystander cells were not directly irradiated but were exposed to the emitted UV biophotons. Medium was subsequently harvested from UV-exposed bystander cells. The exosomes extracted from this medium were incubated with reporter cell populations. These reporter cells were then assayed for clonogenic survival and mitochondrial membrane potential with and without prior treatment of the exosomes with RNase.
Clonogenic cell survival was significantly reduced in reporter cells incubated with exosomes extracted from cells exposed to secondarily-emitted UV. These exosomes also induced significant mitochondrial membrane depolarization in receiving reporter cells. Conversely, exosomes extracted from non-UV-exposed cells did not produce bystander effects in reporter cells. The treatment of exosomes with RNase prior to their incubation with reporter cells effectively abolished bystander effects in reporter cells and this suggests a role for RNA in mediating the bystander response elicited by UV biophotons and their produced exosomes.
This study supports a role for exosomes released from UV biophoton-exposed bystander cells in eliciting bystander responses and also indicates a reconciliation between the UV-mediated bystander effect and the bystander effect which has been suggested in the literature to be mediated by soluble factors.
This reflection aims to look at the evolution of thinking about radiation dose response relationships from the early years of the journal when target theory prevailed to the present day when dose ...response is seen as a more holistic process involving multiple levels of organization and communication. The review is structured to consider how the old ideas evolved leading to apparently abrupt paradigm shifts. The odd data leading to these conceptual shifts are reviewed. Topics, which are currently still not mainstream are considered with a view to how they may change the future of radiobiology. Finally some personal reflections on the insights gained during the writing of the review are presented. The major conclusion from this study is that ideas concerning survival curves and radiation dose responses evolved and (epi)mutated gradually, driven in a large part by the techniques available for studying radiobiological processes. The illusion of abrupt paradigm shifts is not really borne out by the history when primary references are studied rather than textbooks or reviews. The textbooks necessarily simplify and distil complex data to provide a 'take-home message' while reviews are usually very personal collations selected among the vast amount of scientific literature. Primary references reveal the context of the discussion and the caveats and uncertainties of the authors.
The field of low dose radiobiology has advanced considerably in the last 30 years from small indications in the 1980's that all was not simple, to a paradigm shift which occurred during the 1990's, ...which severely dented the dose-driven models and DNA centric theories which had dominated until then. However while the science has evolved, the application of that science in environmental health protection has not. A reason for this appears to be the uncertainties regarding the shape of the low dose response curve, which lead regulators to adopt a precautionary approach to radiation protection. Radiation protection models assume a linear relationship between dose (i.e. energy deposition) and effect (in this case probability of an adverse DNA interaction leading to a mutation). This model does not consider non-targeted effects (NTE) such as bystander effects or delayed effects, which occur in progeny cells or offspring not directly receiving energy deposition from the dose. There is huge controversy concerning the role of NTE with some saying they reflect “biology” and that repair and homeostatic mechanisms sort out the apparent damage while others consider them to be a class of damage which increases the size of the target. One thing which has recently become apparent is that NTE may be very critical for modelling long-term effects at the level of the population rather than the individual. The issue is that NTE resulting from an acute high dose such as occurred after the A-bomb or Chernobyl occur in parallel with chronic effects induced by the continuing residual effects due to radiation dose decay. This means that if ambient radiation doses are measured for example 25 years after the Chernobyl accident, they only represent a portion of the dose effect because the contribution of NTE is not included.
•This paper presents a new concept in Environmental Radiobiology, which could explain why effects are detected in Chernobyl and Fukushima wildlife at ambient doses which are very low.•We suggest that non-targeted effects such as genomic instability, lethal mutations and bystander signalling, contribute a persistent legacy dimension to the total measured effect.•This “historic dose” component needs to be incorporated into dose effect models in order to predict true levels of risk.
Purpose: A major issue in radiotherapy is the relative resistance of hypoxic cells to radiation. Historic approaches to this problem include the use of oxygen mimetic compounds to sensitize tumour ...cells, which were unsuccessful. This review looks at modern approaches aimed at increasing the efficacy of targeting and radiosensitizing hypoxic tumour microenvironments relative to normal tissues and asks the question of whether non-targeted effects in radiobiology may provide a new “target”. Novel techniques involve the integration of recent technological advancements such as nanotechnology, cell manipulation, and medical imaging. Particularly, the major areas of research discussed in this review include tumour hypoxia imaging through PET imaging to guide carbogen breathing, gold nanoparticles, macrophage-mediated drug delivery systems used for hypoxia-activate prodrugs, and autophagy inhibitors. Furthermore, this review outlines several features of these methods, including the mechanisms of action to induce radiosensitization, the increased accuracy in targeting hypoxic tumour microenvironments relative to normal tissue, preclinical/clinical trials, and future considerations. Conclusions: This review suggests that the four novel tumour hypoxia therapeutics demonstrate compelling evidence that these techniques can serve as powerful tools to increase targeting efficacy and radiosensitizing hypoxic tumour microenvironments relative to normal tissue. Each technique uses a different way to manipulate the therapeutic ratio, which we have labelled “oxygenate, target, use, and digest”. In addition, by focusing on emerging non-targeted and out-of-field effects, new umbrella targets are identified, which instead of sensitizing hypoxic cells, seek to reduce the radiosensitivity of normal tissues.
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) and Cancer-Related Fatigue (CRF) are syndromes with considerable overlap with respect to symptoms. There have been many studies that have ...compared the two conditions, and some of this research suggests that the etiologies of the conditions are linked in some cases. In this narrative review, CFS/ME and cancer are introduced, along with their known and putative mechanistic connections to multiple stressors including ionizing radiation. Next, we summarize findings from the literature that suggest the involvement of HPA-axis dysfunction, the serotonergic system, cytokines and inflammation, metabolic insufficiency and mitochondrial dysfunction, and genetic changes in CRF and CFS/ME. We further suspect that the manifestation of fatigue in both diseases and its causes could indicate that CRF and CFS/ME lie on a continuum of potential biological effects which occur in response to stress. The response to this stress likely varies depending on predisposing factors such as genetic background. Finally, future research ideas are suggested with a focus on determining if common biomarkers exist in CFS/ME patients and those afflicted with CRF. Both CFS/ME and CRF are relatively heterogenous syndromes, however, it is our hope that this review assists in future research attempting to elucidate the commonalities between CRF and CFS/ME.
Purpose: This review, which arose from a Radiation Research Society History symposium, traces the history of 'bystander effects' or 'indirect effects'(also known as 'abscopal effects', 'clastogenic ...effects' and more recently 'the secretosome'). In 1905, Murphy first drew attention to effects caused by the injection of irradiated cells into animals. In the present day, bystander effects are seen as part of the secretosome, where they coordinate responses to stressors at the tissue, organism, and population level. The review considers the history and also the reasons why this process of information exchange/communication appears to have been discovered and forgotten several times. The review then considers the evolution of our understanding of the mechanisms and what relevance these effects may have in radiation protection and radiotherapy.
Conclusions: The authors conclude that the phenomenon currently described as a 'bystander effect' has been described under a variety of different names since 1905. However recent advances in biology have made it possible to investigate mechanisms and potential impacts more fully. This has led to the current upsurge in research into this effect of radiation.
Objective
To determine whether the width of the shoulder and the size of the bystander effect are correlated using clonal lineages derived from a cultured cell line.
Methods
HCT 116 (p53 wildtype) ...cells were grown at cloning density and individual viable colonies were picked off and grown to establish a series of cell lines from both unirradiated and irradiated progenitors. These cell lines were then irradiated to generate full survival curves. Highly variant clones were then tested to determine the level of the bystander effect using a medium transfer protocol.
Results
The multi-target model gave the best fit in these experiments and size of the shoulder n is assessed in terms of radiosensitivity. The parent cell line has an n value of 1.1 while the most variant clones have n values of 0.88 (Clone G) and 5.5 (Clone A). Clonal lines subject to irradiation prior to isolation differed in bystander signal strength in comparison to clonal lines which were not initially irradiated (P = .055).
Conclusions
Based on these experiments we suggest there may be a link between shoulder size of a mammalian cell line and the strength of a bystander effect produced in vitro. This may have implications for radiotherapy related to out-of-field effects.
Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) is considered to be a multidimensional illness whose etiology is unknown. However, reports from Chernobyl, as well as those from the United ...States, have revealed an association between radiation exposure and the development of CFIDS. As such, we present an expanded model using a systems biology approach to explain the etiology of CFIDS as it relates to this cohort of patients. This paper proposes an integrated model with ionizing radiation as a suggested trigger for CFIDS mediated through UVA induction and biophoton generation inside the body resulting from radiation-induced bystander effects (RIBE). Evidence in support of this approach has been organized into a systems view linking CFIDS illness markers with the initiating events, in this case, low-dose radiation exposure. This results in the formation of reactive oxygen species (ROS) as well as important immunologic and other downstream effects. Furthermore, the model implicates melanoma and subsequent hematopoietic dysregulation in this underlying process. Through the identification of this association with melanoma, clinical medicine, including dermatology, hematology, and oncology, can now begin to apply its expansive knowledge base to provide new treatment options for an illness that has had few effective treatments.
The role of signalling in initiating and perpetuating effects triggered by deposition of ionising radiation energy in parts of a system is very clear. Less clear are the very early steps involved in ...converting energy to chemical and biological effects in non-targeted parts of the system. The paper aims to present a new model, which could aid our understanding of the role of low dose effects in determining ultimate disease outcomes. We propose a key role for electromagnetic signals resulting from physico-chemical processes such as excitation decay, and acoustic waves. These lead to the initiation of damage response pathways such as elevation of reactive oxygen species and membrane associated changes in key ion channels. Critically, these signalling pathways allow coordination of responses across system levels. For example, depending on how these perturbations are transduced, adverse or beneficial outcomes may predominate. We suggest that by appreciating the importance of signalling and communication between multiple levels of organisation, a unified theory could emerge. This would allow the development of models incorporating time, space and system level to position data in appropriate areas of a multidimensional domain. We propose the use of the term “infosome” to capture the nature of radiation-induced communication systems which include physical as well as chemical signals. We have named our model “the variable response model” or “VRM” which allows for multiple outcomes following exposure to low doses or to signals from low dose irradiated cells, tissues or organisms. We suggest that the use of both dose and infosome in radiation protection might open up new conceptual avenues that could allow intrinsic uncertainty to be embraced within a holistic protection framework.
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