Education and training for radiation scientists: radiation research program and American Society of Therapeutic Radiology and Oncology Workshop, Bethesda, Maryland, May 12-14, 2003

Current and potential shortfalls in the number of radiation scientists stand in sharp contrast to the emerging scientific opportunities and the need for new knowledge to address issues of cancer survivorship and radiological and nuclear terrorism. In response to these challenges, workshops organized by the Radiation Research Program (RRP), National Cancer Institute (NCI) (Radiat. Res. 157, 204-223, 2002; Radiat. Res. 159, 812-834, 2003), and National Institute of Allergy and Infectious Diseases (NIAID) (Nature, 421, 787, 2003) have engaged experts from a range of federal agencies, academia and industry. This workshop, Education and Training for Radiation Scientists, addressed the need to establish a sustainable pool of expertise and talent for a wide range of activities and careers related to radiation biology, oncology and epidemiology. Although fundamental radiation chemistry and physics are also critical to radiation sciences, this workshop did not address workforce needs in these areas. The recommendations include: (1) Establish a National Council of Radiation Sciences to develop a strategy for increasing the number of radiation scientists. The strategy includes NIH training grants, interagency cooperation, interinstitutional collaboration among universities, and active involvement of all stakeholders. (2) Create new and expanded training programs with sustained funding. These may take the form of regional Centers of Excellence for Radiation Sciences. (3) Continue and broaden educational efforts of the American Society for Therapeutic Radiology and Oncology (ASTRO), the American Association for Cancer Research (AACR), the Radiological Society of North America (RSNA), and the Radiation Research Society (RRS). (4) Foster education and training in the radiation sciences for the range of career opportunities including radiation oncology, radiation biology, radiation epidemiology, radiation safety, health/government policy, and industrial research. (5) Educate other scientists and the general public on the quantitative, basic, molecular, translational and applied aspects of radiation sciences.     

Report on an interagency workshop on the radiobiology of nuclear terrorism. Molecular and cellular biology dose (1-10 Sv) radiation and potential mechanisms of radiation protection (Bethesda,Maryland, December 17-18, 2001)

The events of September 11, 2001 have focused attention on the possibility of nuclear terrorism, and 1-10 Sv is arguably the dose range of biological interest, since doses in this range both pose a risk of acute effects and are potentially survivable. Because of this interest, a coalition of U.S. government agencies (NCI, DOD, DOE) and the Radiation Research Society convened a workshop in December 2001 "to focus on molecular, cellular and tissue changes that occur [at doses of 1-10 Sv] and potential mechanisms of radioprotection". A draft report of this workshop was posted on the NCI website in February 2002. According to the draft, the workshop was also intended to "determine the research opportunities and resources required [and] develop a research-action plan for further discussion and implementation." Injuries after exposure to ionizing radiation are important to patients with cancer and to populations potentially subject to accidental or intentional exposure. In these populations, partial- or whole-body exposures in the range of 1-10 Sv are possible. The consequences of exposure of limited tissue volumes to doses above 10 Sv have been researched because of their applicability to cancer therapy, while exposure to doses below 1 Sv has been researched because of nuclear fallout and space exploration issues. Except for research aimed at protection of members of the armed forces, the intervening dose range has received relatively little attention. The workshop participants concluded that although we currently have only a limited ability to deal with the consequences of radiation exposures in this range, focused research would have the potential of rapidly expanding such capabilities.     

Models for evaluating agents intended for the prophylaxis, mitigation and treatment of radiation injuries. Report of an NCI Workshop, December 3-4, 2003

To develop approaches to prophylaxis/protection, mitigation and treatment of radiation injuries, appropriate models are needed that integrate the complex events that occur in the radiation-exposed organism. While the spectrum of agents in clinical use or preclinical development is limited, new research findings promise improvements in survival after whole-body irradiation and reductions in the risk of adverse effects of radiotherapy. Approaches include agents that act on the initial radiochemical events, agents that prevent or reduce progression of radiation damage, and agents that facilitate recovery from radiation injuries. While the mechanisms of action for most of the agents with known efficacy are yet to be fully determined, many seem to be operating at the tissue, organ or whole animal level as well as the cellular level. Thus research on prophylaxis/protection, mitigation and treatment of radiation injuries will require studies in whole animal models. Discovery, development and delivery of effective radiation modulators will also require collaboration among researchers in diverse fields such as radiation biology, inflammation, physiology, toxicology, immunology, tissue injury, drug development and radiation oncology. Additional investment in training more scientists in radiation biology and in the research portfolio addressing radiological and nuclear terrorism would benefit the general population in case of a radiological terrorism event or a large-scale accidental event as well as benefit patients treated with radiation.     

Medical countermeasures for radiation combined injury: radiation with burn, blast, trauma and/or sepsis. report of an NIAID Workshop, March 26-27, 2007

Non-clinical human radiation exposure events such as the Hiroshima and Nagasaki bombings or the Chernobyl accident are often coupled with other forms of injury, such as wounds, burns, blunt trauma, and infection. Radiation combined injury would also be expected after a radiological or nuclear attack. Few animal models of radiation combined injury exist, and mechanisms underlying the high mortality associated with complex radiation injuries are poorly understood. Medical countermeasures are currently available for management of the non-radiation components of radiation combined injury, but it is not known whether treatments for other insults will be effective when the injury is combined with radiation exposure. Further research is needed to elucidate mechanisms behind the synergistic lethality of radiation combined injury and to identify targets for medical countermeasures. To address these issues, the National Institute of Allergy and Infectious Diseases convened a workshop to make recommendations on the development of animal models of radiation combined injury, possible mechanisms of radiation combined injury, and future directions for countermeasure research, including target identification and end points to evaluate treatment efficacy.     

Introduction to the special issue on molecular imaging in radiation biology

Molecular imaging is an evolving science that is concerned with the development of novel imaging probes and biomarkers that can be used to non-invasively image molecular and cellular processes. This special issue approaches molecular imaging in the context of radiation research, focusing on biomarkers and imaging methods that provide measurable signals that can assist in the quantification of radiation-induced effects of living systems at the physical, chemical and biological levels. The potential to image molecular changes in response to a radiation insult opens new and exciting opportunities for a more profound understanding of radiation biology, with the possibility of translation of these techniques to radiotherapy practice. This special issue brings together 14 reviews dedicated to the use of molecular imaging in the field of radiation research. The initial three reviews are introductory overviews of the key molecular imaging modalities: magnetic resonance, nuclear and optical. This is followed by 11 reviews each focusing on a specialist area within the field of radiation research. These include: hypoxia and perfusion, tissue metabolism, normal tissue injury, cell death and viability, receptor targeting and nanotechnology, reporter genes, reactive oxygen species (ROS), and biological dosimetry. Over the preceding decade, molecular imaging brought significant new advances to our understanding of every area of radiation biology. This special issue shows us these advances and points to the vibrant future of our field armed with these new capabilities.     

Priority list of research areas for radiological nuclear threat countermeasures

To help the nation prepare for the possibility of a terrorist attack using radiological and nuclear devices, the Office of Science and Technology Policy and the Homeland Security Council established an interagency working group. The working group deliberated on the research needs for radiological/ nuclear threat countermeasures and identified and prioritized 18 areas for further attention. The highest priorities were given to research on (1) radioprotectors for use prior to exposure; (2) therapeutic agents for postexposure treatment; (3) antimicrobial therapy for infections associated with radiation exposure; (4) cytokines and growth factors; (5) mechanisms of radiation injury at the molecular, cellular, tissue and organism levels; and (6) automation of biodosimetric assays. High priority was given to (1) developing biomarkers for biodosimetry; (2) enhancing training in the radiation sciences; (3) exploring the consequences of combined injury; (4) establishing a repository of information regarding investigational countermeasures; and (5) following the health of an exposed population to better prepare for subsequent events. The research areas that the committee felt required the attention of the radiation research community are described in this report in an effort to inform this community about the needs of the nation and to encourage researchers to address these critical issues.     

Workshop summary. Biomedical and Space-Related Research with Heavy Ions at the BEVALAC

The authors provide an overview of papers presented at a workshop on Biomedical and Space-Related Research with Heavy Ions at the BEVALAC at Lawrence Berkeley Laboratory. Goals of the meeting were to determine the critical experiments using heavy ions as probes in radiation physics, radiation chemistry, macromolecular and cellular biology, evolution science, basic neurophysiology, and medical therapies; how beam lines and facilities at Lawrence Berkeley Laboratory can be improved for these experiments; and implications in priorities and funding for national policy. Workshop topics included physics and facilities, cellular and molecular biology, tissue radiobiology, and the future of heavy ion research.     

Current imaging paradigms in radiation oncology

The technological revolution in imaging during recent decades has transformed the way image-guided radiation therapy is performed. Anatomical imaging (plain radiography, computed tomography, magnetic resonance imaging) greatly improved the accuracy of delineating target structures and has formed the foundation of 3D-based radiation treatment. However, the treatment planning paradigm in radiation oncology is beginning to shift toward a more biological and molecular approach as advances in biochemistry, molecular biology, and technology have made functional imaging (positron emission tomography, nuclear magnetic resonance spectroscopy, optical imaging) of physiological processes in tumors more feasible and practical. This review provides an overview of the role of current imaging strategies in radiation oncology, with a focus on functional imaging modalities, as it relates to staging and molecular profiling (cellular proliferation, apoptosis, angiogenesis, hypoxia, receptor status) of tumors, defining radiation target volumes, and assessing therapeutic response. In addition, obstacles such as imaging-pathological validation, optimal timing of post-therapy scans, spatial and temporal evolution of tumors, and lack of clinical outcome studies are discussed that must be overcome before a new era of functional imaging-guided therapy becomes a clinical reality.     

Changes in gene expression by 193- and 248-nm excimer laser radiation in cultured human fibroblasts.

Tissue ablation by ultraviolet excimer lasers results in exposure of viable cells to subablative doses of radiation. To understand the potential biological consequences better, we have studied changes in gene expression in cultured human skin fibroblasts exposed to either 193- or 248-nm laser light. Northern blot analyses revealed that both treatments up-regulate a common set of genes, including interstitial collagenase, tissue inhibitor of metalloprotease, metallothionein, and the proto-oncogene c-fos. Dose-response and kinetic studies of collagenase induction by 193-nm radiation showed a maximal effect with 60 J/m2 and at approximately 24 h. The induction was still persistent 96 h later. In addition to the commonly affected genes, known to be activated also by conventional UV light (254 nm) and tumor-promoting phorbol esters, other genes were found to be selectively induced by the 193-nm radiation. The heat-shock hsp70 mRNA, undetectable in controls and in cultures irradiated at 248 nm, was transiently induced 8 h after exposure to 193-nm radiation. Furthermore, a selective up-regulation of collagen type I expression was observed. The results indicate that the 193- and 248-nm radiations by excimer lasers elicit specific and different cellular responses, in addition to an overlapping pathway of gene activation common also to UV radiation by germicidal lamps. The laser-induced genes could serve as molecular markers in evaluating cell injury in situ.     

核辐射对大深度快速上浮脱险致减压病大鼠相关指标的影响*

目的: 探讨不同剂量核暴露后不同时间对大深度快速上浮脱险致减压病大鼠模型的发病率、死亡率及损伤指标的影响。方法: 80只SD雄性大鼠,随机分成空白对照组、脱险对照组和6个干预组(4 Gy辐射后4 h脱险、6 Gy辐射后4 h脱险、12 Gy辐射后4 h脱险、4 Gy辐射后8 h脱险、6 Gy辐射后8 h脱险、12 Gy辐射8 h后脱险),每组10只。干预组动物先采用不同剂量γ射线外照射(4、6、12 Gy),再进行大深度快速上浮脱险实验(最大加压深度150 m),分析大鼠肺W/D、脾指数及血浆IL-1β的变化。结果: 与脱险对照组比较,核辐射后脱险大鼠的减压病发病率及死亡率明显上升。4 Gy、6 Gy照射4 h后上浮脱险的大鼠发病率和死亡率较照射8 h后高。12 Gy辐射后4 h及8 h脱险大鼠的减压病的发病率及死亡率均比低剂量照射组明显增高,死亡率尤其明显。和发病率及死亡率的变化相一致,肺组织湿/干比、肺组织病理损伤程度、脾指数下降也表现同样的变化趋势:较低剂量(4 Gy、6 Gy)辐射后4 h改变明显,8 h改变不明显,而高剂量(12 Gy)辐射后4、8 h均变化明显。和空白对照组及脱险对照组相比较,各辐射后脱险组的血浆IL-1β浓度均显著上升。结论: 核辐射引起放射性肺损伤、免疫功能下降及血浆炎症因子浓度升高,会增加大鼠快速上浮脱险致减压病的风险。     

Overview of the spaceflight radiation environment and its impact on cell biology experiments

Variables studied in typical cellular radiation biology experiments are cell killing, mutagenesis, transformation to malignancy, heritable damage, and DNA damage and repair. Dose response curves for cells exposed to low-LET radiations and some high LET radiations are well known. The low-LET dose rate in low earth orbit is roughly 1.0 mSv/day, the heavy-ion (Z>2) flux is about 1.0 particle/cm2-s corresponding to about 0.3 mSv/day, and the integrated neutron flux is roughly 2 neutrons/cm2-s corresponding to 0.012 mGy/d or, assuming a QF of 10, 0.12 mSv/d. Published dose-response curves were used to estimate the probability that a mammalian cell will be affected by each of the above types of damage. As a general approximation the exposure of an experimental cell population to the space radiation environment for 100 days will result in the following probabilities of damage per cell: cell killing based on clonogenicity 0.02, mutagenesis per locus based on phenotype analysis 1 x 10(-6), point mutation induction 2 x 10(-8) per locus, malignant transformation in vitro based on colony morphology 1.2 x 10(-5), heritable damage based on colony size 0.02, and induced DNA double-strand breaks based on fragment analysis by electrophoresis 3.5/cell or 0.26/cell after repair. Most of these figures are accurate to within a factor of 2. Thus the spaceflight radiation environment has essentially undetectable impact on typical cell biology experiments unless experimental goals involve the precise measurement of one of the above end-points. Other in vitro end-points, such as tissue morphogenesis and cell differentiation, are expected to be similarly unaffected by the spaceflight radiation environment.     

Individual response of humans to ionising radiation: governing factors and importance for radiological protection

Tissue reactions and stochastic effects after exposure to ionising radiation are variable between individuals but the factors and mechanisms governing individual responses are not well understood. Individual responses can be measured at different levels of biological organization and using different endpoints following varying doses of radiation, including: cancers, non-cancer diseases and mortality in the whole organism; normal tissue reactions after exposures; and, cellular endpoints such as chromosomal damage and molecular alterations. There is no doubt that many factors influence the responses of people to radiation to different degrees. In addition to the obvious general factors of radiation quality, dose, dose rate and the tissue (sub)volume irradiated, recognized and potential determining factors include age, sex, life style (e.g., smoking, diet, possibly body mass index), environmental factors, genetics and epigenetics, stochastic distribution of cellular events, and systemic comorbidities such as diabetes or viral infections. Genetic factors are commonly thought to be a substantial contributor to individual response to radiation. Apart from a small number of rare monogenic diseases such as ataxia telangiectasia, the inheritance of an abnormally responsive phenotype among a population of healthy individuals does not follow a classical Mendelian inheritance pattern. Rather it is considered to be a multi-factorial, complex trait.     

Hematopoietic cell renewal systems: mechanisms of coping and failing after chronic exposure to ionizing radiation

On the occasion of the first international workshop on systems radiation biology we review the role of cell renewal systems in maintaining the integrity of the mammalian organism after irradiation. First, 11 radiation emergencies characterized by chronic or protracted exposure of the human beings to ionizing irradiation were “revisited”. The data provide evidence to suggest that at a daily exposure of about 10–100 mSv, humans are capable of coping with the excess cell loss for weeks or even many months without hematopoietic organ failure. Below 10 mSv/day, the organisms show some cellular or subcellular indicators of response. At dose rates above 100 mSv/day, a progressive shortening of the life span of the irradiated organism is observed. To elucidate the mechanisms relevant to tolerance or failure, the Megakaryocyte–thrombocyte cell renewal system was investigated. A biomathematical model of this system was developed to simulate the development of thrombocyte concentration as a function of time after onset of chronic radiation exposure. The hematological data were taken from experimental chronic irradiation studies with dogs at the Argonne National Laboratory, USA. The results of thrombocyte response patterns are compatible with the notion of an “excess cell loss” (compared to the steady-state) in all proliferative cell compartments, including the stem cell pool. The “excess cell loss” is a function of the daily irradiation dose rate. Once the stem cell pool is approaching an exhaustion level, a “turbulence region” is reached. Then it takes a very little additional stress for the system to fail. We conclude that in mammalian radiation biology (including radiation medicine), it is important to understand the physiology and pathophysiology of cell renewal systems in order to allow predicting the development of radiation induced lesions.     

Ionizing radiation biomarkers for potential use in epidemiological studies

Ionizing radiation is a known human carcinogen that can induce a variety of biological effects depending on the physical nature, duration, doses and dose-rates of exposure. However, the magnitude of health risks at low doses and dose-rates (below 100mSv and/or 0.1mSvmin(-1)) remains controversial due to a lack of direct human evidence. It is anticipated that significant insights will emerge from the integration of epidemiological and biological research, made possible by molecular epidemiology studies incorporating biomarkers and bioassays. A number of these have been used to investigate exposure, effects and susceptibility to ionizing radiation, albeit often at higher doses and dose rates, with each reflecting time-limited cellular or physiological alterations. This review summarises the multidisciplinary work undertaken in the framework of the European project DoReMi (Low Dose Research towards Multidisciplinary Integration) to identify the most appropriate biomarkers for use in population studies. In addition to logistical and ethical considerations for conducting large-scale epidemiological studies, we discuss the relevance of their use for assessing the effects of low dose ionizing radiation exposure at the cellular and physiological level. We also propose a temporal classification of biomarkers that may be relevant for molecular epidemiology studies which need to take into account the time elapsed since exposure. Finally, the integration of biology with epidemiology requires careful planning and enhanced discussions between the epidemiology, biology and dosimetry communities in order to determine the most important questions to be addressed in light of pragmatic considerations including the appropriate population to be investigated (occupationally, environmentally or medically exposed), and study design. The consideration of the logistics of biological sample collection, processing and storing and the choice of biomarker or bioassay, as well as awareness of potential confounding factors, are also essential.     

Efficacy of radiation countermeasures depends on radiation quality

The detonation of a nuclear weapon or a nuclear accident represent possible events with significant exposure to mixed neutron/γ-radiation fields. Although radiation countermeasures generally have been studied in subjects exposed to pure photons (γ or X rays), the mechanisms of injury of these low linear energy transfer (LET) radiations are different from those of high-LET radiation such as neutrons, and these differences may affect countermeasure efficacy. We compared 30-day survival in mice after varying doses of pure γ and mixed neutron/γ (mixed field) radiation (MF, Dn/Dt = 0.65), and also examined peripheral blood cells, bone marrow cell reconstitution, and cytokine expression. Mixed-field-irradiated mice displayed prolonged defects in T-cell populations compared to mice irradiated with pure γ photons. In mouse survival assays, the growth factor granulocyte colony-stimulating factor (G-CSF) was effective as a (post-irradiation) mitigator against both γ-photons and mixed-field radiation, while the thrombopoietin (TPO) mimetic ALXN4100TPO was effective only against γ irradiation. The results indicate that radiation countermeasures should be tested against radiation qualities appropriate for specific scenarios before inclusion in response plans.     

Estimation value of plasma amino acid target analysis to the acute radiation injury early triage in the rat model

Rapid radiation injury early triage for large-scale people after radiation exposure is vital for limited medical resources allocation and early treatment of a large number of wounded after a nuclear accident. Owing to the high-throughput analysis and minimally invasive of collection sample, radiation metabolomics has been recently applied to radiation damage researches. Here, exploration the feasibility of estimating the acute radiation injury early triage by means of plasma amino acid target analysis was attempted using high performance liquid chromatography–electrospray tandem mass spectrometry (HPLC–ESI–MS/MS) technique. The nonlinear kernel partial least squares (KPLS) model was used to classify the radiation damage levels. The classification accuracy of without radiation exposure was 92.3 % at 5 h after exposure. At 24 h after exposure, the triage accuracies were all above 83 % in the different doses of irradiated groups, the correct classification rates of moderate and severe radiation injury were 91.7 and 92.3 % respectively. At 72 h after exposure, the classification accuracies of all levels of radiation injury were more than 90 %, the correct classification rates of moderate and severe groups were up to 100 %. This approach is useful for early predicting different levels of radiation exposure and for developing metabolomics strategies for radiation biodosimetry in humans, but need more data to consummate.     

Rapid proteomic remodeling of cardiac tissue caused by total body ionizing radiation

Accidental nuclear scenarios lead to environmental contamination of unknown level. Immediate radiation‐induced biological responses that trigger processes leading to adverse health effects decades later are not well understood. A comprehensive proteomic analysis provides a promising means to identify and quantify the initial damage after radiation exposure. Early changes in the cardiac tissue of C57BL/6 mice exposed to total body irradiation were studied, using a dose relevant to both intentional and accidental exposure (3 Gy gamma ray). Heart tissue protein lysates were analyzed 5 and 24 h after the exposure using isotope‐coded protein labeling (ICPL) and 2‐dimensional difference‐in‐gel‐electrophoresis (2‐D DIGE) proteomics approaches. The differentially expressed proteins were identified by LC‐ESI‐MS‐MS. Both techniques showed similar functional groups of proteins to be involved in the initial injury. Pathway analyses indicated that total body irradiation immediately induced biological responses such as inflammation, antioxidative defense, and reorganization of structural proteins. Mitochondrial proteins represented the protein class most sensitive to ionizing radiation. The proteins involved in the initial damage processes map to several functional categories involving cardiotoxicity. This prompts us to propose that these early changes are indicative of the processes that lead to an increased risk of cardiovascular disease after radiation exposure.     

Proteomics in radiation research: present status and future perspectives

Rapidly developing postgenome research has made proteins an attractive target for biological analysis. The well-established term of proteome is defined as the complete set of proteins expressed in a given cell, tissue or organism. Unlike the genome, a proteome is rapidly changing as it tends to adapt to microenvironmental signals. The systematic analysis of the proteome at a given time and state is referred to as proteomics. This technique provides information on the molecular and cellular mechanisms that regulate physiology and pathophysiology of the cell. Applications of proteome profiling in radiation research are increasing. However, the large-scale proteomics data sets generated need to be integrated into other fields of radiation biology to facilitate the interpretation of radiation-induced cellular and tissue effects. The aim of this review is to introduce the most recent developments in the field of radiation proteomics.