Molecular Radiation Biology Research Articles

Computational modeling and a Geant4-DNA study of the rejoining of direct and indirect DNA damage induced by low energy electrons and carbon ions

Purpose DNA double-strand breaks (DSBs) created by ionizing radiations are considered as the most detrimental lesion, which could result in the cell death or sterilization. As the empirical evidence gathered from the cellular and molecular radiation biology has demonstrated significant correlations between the initial and lasting levels of DSBs, gaining knowledge into the DSB repair mechanisms proves vital. Much effort has been invested into understanding the mechanisms triggering the repair and processes engaged after irradiation of cells. Given a mechanistic model, we performed – to our knowledge – the first Monte Carlo study of the expected repair kinetics of carbon ions and electrons using on the one hand Geant4-DNA simulations of electrons for benchmarking purposes and on the other hand quantifying the influence of direct and indirect damage. Our objective was to calculate the DSB repair rates using a repair mechanism for G1 and early S phases of the cell cycle in conjunction with simulations of the DNA damage. Materials and Methods Based on Geant4-DNA simulations of DSB damage caused by electrons and carbon ions – using a B-DNA model and a water sphere of 3 μm radius resembling the mean size of human cells – we derived the kinetics of various biochemical repair processes. Results The overall repair times of carbon ions increased with the DSB complexity. Comparison of the DSB complexity (DSBc) and repair times as a function of carbon-ion energy suggested that the repair time of no specific fraction of DSBs could solely be explained as a function of DSB complexity. Conclusion Analysis of the carbon-ion repair kinetics indicated that, given a fraction of DSBs, decreasing the energy would result in an increase of the repair time. The disagreements of the calculated and experimental repair kinetics for electrons could, among others, be due to larger damage complexity predicted by simulations or created actually by electrons of comparable energies to x-rays. They are also due to the employed repair mechanisms, which introduce no inherent dependence on the radiation type but make direct use of the simulated DSBs.

Low Dose Ionising Radiation-Induced Hormesis: Therapeutic Implications to Human Health

The concept of radiation-induced hormesis, whereby a low dose is beneficial and a high dose is detrimental, has been gaining attention in the fields of molecular biology, environmental toxicology and radiation biology. There is a growing body of literature that recognises the importance of hormetic dose response not only in the radiation field, but also with molecular agents. However, there is continuing debate on the magnitude and mechanism of radiation hormetic dose response, which could make further contributions, as a research tool, to science and perhaps eventually to public health due to potential therapeutic benefits for society. The biological phenomena of low dose ionising radiation (LDIR) includes bystander effects, adaptive response, hypersensitivity, radioresistance and genomic instability. In this review, the beneficial and the detrimental effects of LDIR-induced hormesis are explored, together with an overview of its underlying cellular and molecular mechanisms that may potentially provide an insight to the therapeutic implications to human health in the future.

Insight into Five-Years Master of Science Program in Radiation Biology

The MSc course in radiation biology has been developed in early 2014 to educate young academics from many fields of medicine and life sciences in the highly interdisciplinary field at the interface of biology, physics, and medicine. The goal was to establish an internationally acknowledged program with diverse and heterogeneous student cohorts, who benefit from each other academically as well as culturally. Depending on the chosen focus within the MSc, i.e. translational radiobiology, radiation protection or molecular radiation biology, we expect the postgraduates to be experts with a strong ability to analyze data independently, advise politicians, companies or others seeking information in this field, or to pursue a career as a medical or clinician scientist. We evaluated the student cohort’s data from the last years regarding gender, age, and nationality as well as the highest degree before applying and career path after graduation. Most of the data come from the application database in the campus management system TUM online at the Technical University of Munich. Additional data has been collected during the years with evaluation surveys and interviews. From overall 162 applications and an average of 45 applications per year in the last three years, 35% of the students are from Africa and Asia each, 24% from Europe and 6% from North and South America. 54% of the applications are from female and 46% from male applicants. Most of the applicants were between 24-29 years old, the total range of age was 20-50 years. The most common degree before application was in medicine with 31% and biology with 28%, followed by a degree in physics with 16% and biotechnology with 12%. 4% of the 162 applicants had a degree health science and 3% in pharmacy, 6% had other degrees. In the first three years, we had student cohorts between 7-10 students with no dropouts. The newest class started in 2018 officially with 19 students, after a few dropouts, we are left with 15 students. So far the first two classes graduated the program. Ten out of those 18 graduates chose to do a PhD, preferably in a German research institute. Three students decided to go back to Medicine with the opportunity to use their degree to become a medical or clinician-scientist in the field of Radiation Oncology, and one student got hired for the training position to become medical physics expert. Another three students went to work in the economy for example in the pharmaceutical industry, and one student is working in a federal institution back in her home country. All over, we have a hiring rate of 67% in the expected fields, right after graduation. After five years of planning and establishing the program, our expectations regarding heterogeneity and diversity of applicants have been met exceedingly. All graduates had excellent career opportunities reflecting the necessity of this MSc and its topics. The future vision includes an expansion of the program as well as undergraduate education opportunities in this field.

THE COMPLEXITY OF QUANTITIES IN RADIATION DOSIMETRY: THE ISSUE OF RADIATION QUALITY.

When Harald Rossi developed a new radiation measurement instrument more than 60 years ago-the tissue equivalent low-pressure proportional counter, also called Rossi Counter-his initial intention was to provide a technique to measure LET. He realized soon that the measurements provided insight into the stochastic nature of the interactions of ionizing radiation with matter and that the measured results represented an alternative to characterize radiation quality in terms of stochastic or microdosimetric quantities. Progress in cellular and molecular radiation biology and in simulating charged particle tracks in biological entities are now essential features and have extended the original delineation of the field of microdosimetry. This general field of microdosimetry, as part of an interdisciplinary approach for the study of molecular mechanisms and cellular radiation effects, continues to be an important area of radiation research, documented by 13 previous Microdosimetry Symposia and, again, at this Symposium. However, the quantification of radiation quality remains a subject of practical importance. In fact, the issue has gained in importance due to the application of ions for therapy and due to the need for protection from exposures to complex and high-energy radiation fields, for example, to cosmic radiation in civil aviation and space missions. In practice pragmatic, empirical approaches are being used which has led to a complex set of dosimetric quantities and terms.

Molecular radiation biology/oncology and its impact on preclinical and clinical research in radiotherapy

Scientists from 21 different countries worldwide participated in the 15th International Wolfsberg Meeting on Molecular Radiation Biology/Oncology, which was held from June 17 to 19, 2017 at Wolfsberg Castle, Switzerland. Thus, funded in 1997 by the first and the last author of this editorial the Wolfsberg Meeting Series could celebrate its 20st anniversary this year. According to comments from many participants the Wolfsberg Meeting Series is regarded as one of the top meetings in the field of molecular radiation biology/oncology. Right from the beginning this meeting series attracted international leading scientists to discuss cutting-edge research in molecular tumor and radiation biology as well as translational radiation oncology. The development of this meeting series to one of the world leading ones is interesting in that it was organized without support from of a major international scientific society. Nevertheless, however, in 2005 ESTRO became a strategic partner and has since supported the Wolfsberg Meeting Series by mainly two issues. First, by establishing the ESTRO-VARIAN-Juliana Denekamp Award for young scientists showing leadership for a specific research topic. This award has since 2005 been presented at the International Wolfsberg Meeting. Second, by supporting young ESTRO members with the prestigious ESTRO-Wolfsberg-Travel Award. This support reflects the basic idea of the organizers to arrange a high-profile international meeting where also young scientists can present their results and discuss many aspects of their scientific work with international leading experts. The special atmosphere of the Wolfsberg Meeting Series is created by the scientific structure, which provides detailed insights into international top research activities, by the friendly interaction of the participants both scientifically in the various sessions and socially at the Wolfsberg Barbecue and Dinner, and, especially, during and after the Wolfsberg Cup (a fun sports event). Last but not least the splendid location of the Wolfsberg Conference Center is certainly unique and is a guarantee for relaxed to the point coming discussions and the participants have always been eager to come back to the next Wolfsberg Meeting.

Molecular mechanisms involved in tumor repopulation after radiotherapy.

Radiotherapy remains one of most important treatment modalities for solid tumors. Current radiotherapy is mostly based on a set of concepts called the 4"R"s, which were established when there was lack of understanding of the underlying molecular mechanisms. However, progress made in the past two decades are beginning to allow us to see some of the molecular details involved in tumor response to radiation therapy. In this review, we will attempt to summarize some of the key discoveries in molecular radiation biology that have direct relevance to radiotherapy. We will focus our discussion on areas such as radiation induced tumor vasculogenesis, stem cell mobilization, and cellular repopulation. We hope our discussion will stimulate further studies in this important area of cancer research.

A review of stereotactic body radiation therapy (SBRT) from the molecular radiobiology perspective

Stereotactic body radiation therapy (SBRT) is a relatively new therapy being used to treat patients with many types of extracranial tumors and some metastases. Clinically, SBRT is well documented and research continues to grow and demonstrate the promising effects of SBRT on patients. Much advancement has been made technically as well, including better techniques for immobilizing patients and tumors. In this paper, emphasis is placed on reviewing the advancements and discoveries of SBRT which are related to molecular radiation biology. These studies include molecular comparisons of high- and low-dose radiation tactics, and molecular methods for improving the outcome of SBRT, including advancements in tumor cell tracking, strategies for increasing the speed of SBRT, and mechanisms behind normal tissue responses after high-dose radiation. Overall, there is still a relatively large amount of basic molecular unknowns involved in SBRT, and continued research is greatly anticipated.

Molecular radiotherapy — the radionuclide raffle?

Molecular radiotherapy — the radionuclide raffle?

A systems biology approach to radiation therapy optimization

During the last 20 years, the field of cellular and not least molecular radiation biology has been developed substantially and can today describe the response of heterogeneous tumors and organized normal tissues to radiation therapy quite well. An increased understanding of the sub-cellular and molecular response is leading to a more general systems biological approach to radiation therapy and treatment optimization. It is interesting that most of the characteristics of the tissue infrastructure, such as the vascular system and the degree of hypoxia, have to be considered to get an accurate description of tumor and normal tissue responses to ionizing radiation. In the limited space available, only a brief description of some of the most important concepts and processes is possible, starting from the key functional genomics pathways of the cell that are not only responsible for tumor development but also responsible for the response of the cells to radiation therapy. The key mechanisms for cellular damage and damage repair are described. It is further more discussed how these processes can be brought to inactivate the tumor without severely damaging surrounding normal tissues using suitable radiation modalities like intensity-modulated radiation therapy (IMRT) or light ions. The use of such methods may lead to a truly scientific approach to radiation therapy optimization, particularly when invivo predictive assays of radiation responsiveness becomes clinically available at a larger scale. Brief examples of the efficiency of IMRT are also given showing how sensitive normal tissues can be spared at the same time as highly curative doses are delivered to a tumor that is often radiation resistant and located near organs at risk. This new approach maximizes the probability to eradicate the tumor, while at the same time, adverse reactions in sensitive normal tissues are as far as possible minimized using IMRT with photons and light ions.

Can Monte Carlo track structure codes reveal reaction mechanism in DNA damage and improve radiation therapy?

Microdosimetry and track structure have been applied to scrutinize and understand aspects of radiation damage in biological molecules from a theoretical approach based on fundamental physical and chemical principles to provide hypothesis which are testable experimentally. To this end, track structure has provided a basis for understanding the mechanism(s) that shape dose–effect relationships. There is a wealth of information and data accumulated from chemical, cellular and molecular radiation biology that need to be placed in the framework of a general descriptive theory. While there are many classical radiobiology questions remain unanswered, new ideas and challenging questions are emerging. Among many, simulation of radiation track at molecular level is an emerging tool in radiobiology and theoretical radiotherapy. How can we update track structure codes to include and test current reaction mechanism(s) in DNA damage? How realistic can we simulate radiation tracks in well-defined DNA model systems as well as DNA in a tissue environment? To what extent can we probe DNA damage induced by electron and ion tracks through the cell? Can we predict the frequency and complexity of biological lesions? How can models of track structure be improved to provide more accurate information for therapy and risk estimation? In this paper, we present recent progress in development of low-energy electron tracks in condensed media and high-energy proton tracks and discuss progress in characterizing DNA damage in terms of types and complexity.

Evaluation of Early and Late Toxicities in Chemoradiation Trials

Combined chemoradiotherapy is increasingly becoming a standard of care for the nonoperative management of a variety of solid malignancies. A string of randomized controlled phase III trials have shown statistically significant and clinically relevant improvements in outcome, ostensibly without any apparent increase in late toxicity. However, the reliability and the sensitivity of toxicity reporting in most trials are questionable. Audits and phase IV studies suggest that the chemoradiotherapy success comes at a price in terms of late toxicity. This review presents some of the challenges in recording, analyzing, and reporting toxicity data. METHODS for summarizing toxicity are reviewed, and a new investigational metric, the TAME reporting system, is discussed. The need for special vigilance in the era of molecular-targeted agents is emphasized because of the possibility that unexpected serious adverse events with a low incidence may occur. Finally, we discuss how progress in molecular pathology and radiation biology may provide novel opportunities for stratifying patients according to risk of adverse effects, interventional targets for reducing or treating adverse effects, and surrogate markers of normal-tissue injury.

Molecular radiation biology/oncology

Molecular biology approaches in radiobiology and radiation oncology have improved our understanding of cellular radiation responses of both tumor and normal cells. These involve a variety of intracellular and intercellular signaling cascades regulating both radiation sensitivity and radiation resistance. Consequently, progress in molecular radiation biology will provide tools to develop new strategies in modern radiation oncology, which eventually will result in the improvement of tumor responses and decrease of normal tissue complications.

The European Masters of Science Course in Radiation Biology

The European Master of Science Course in Radiation Biology is jointly organized and taught by leading radiobiologists from five universities in five different European countries. The course is generously supported by the European Commission. Since 2000, the course has been organized by the Gray Cancer Institute in association with University College London. The other partner universities are Leiden (Netherlands), UCL Louvain (Belgium), München (Germany) and Salzburg (Austria). The overall aim of the European Master of Science Course in Radiation Biology is to maintain and expand the expertise within Europe in the radiobiological basis of radiation protection and of radiation oncology and to produce experts with a sufficient breadth of knowledge in all areas of “classical” and molecular radiation biology. Currently, in Europe, no single institution has the necessary expertise and resources to run an extensive and broad-ranging course. Therefore, a cooperative action of several universities from different EU member states has been developed for this purpose.

Organizational response of normal tissues to irradiation

A central tenet in the treatment of cancer patients with radiation has been that normal tissue complications were related to the volume of the tissue irradiated, although the mechanisms underlying this phenomenon were poorly understood. The advent of new treatment techniques, such as three-dimensional (3-D) conformal treatments, drove the developers of models to evaluate the resultant complex dose distribution plans, particularly in terms of predicting normal tissue complications. However, a lack of experimental data on the effects of changing volume on normal tissue responses made it difficult to substantiate these models. Consequently, radiobiology research on normal tissue dose volume effects in experimental animal models was initiated, providing considerable insight into the effect of changing volume on normal tissue response for a large number of tissues. This paper summarizes these data and the potential impact of new concepts and data in molecular radiation biology on dose volume effects in normal tissues.

At the birth of molecular radiation biology.

Rational thinking builds on feelings, too. This article starts with a tribute to Richard Setlow, an eminent scientist; it retraces as well some studies in molecular genetics that helped to understand basic questions of radiation biology. In the mid-1950s, the induction of a dormant virus (prophage) by irradiation of its host was an intriguing phenomenon. Soon, it was found that prophage induction results from the inactivation of the prophage repressor. Similarly, a score of induced cellular SOS functions were found to be induced when the LexA repressor is inactivated. Repressor inactivation involves the formation of a newly formed distinctive structure: a RecA-polymer wrapped around single-stranded DNA left by the arrest of replication at damaged sites. By touching this RecA nucleofilament, the LexA repressor is inactivated, triggering the sequential expression of SOS functions. The RecA nucleofilament acts as a chaperone, allowing recombinational repair to occur after nucleotide excision repair is over. The UmuD'C complex, synthesized slowly and parsimoniously, peaks at the end of recombinational repair, ready to be positioned at the tip of a RecA nucleofilament, placing the UmuD'C complex right at a lesion. At this location, UmuD'C prevents recombinational repair, and now acts as an error-prone paucimerase that fills the discontinuity opposite the damaged DNA. Finally, the elimination of lesions from the path of DNA polymerase, allows the resumption of DNA replication, and the SOS repair cycle switches to a normal cell cycle.

Novel molecular targets for tumor radiosensitization Molecular radiation biology and oncology workshop: Translation of molecular mechanisms into clinical radiotherapy

Novel molecular targets for tumor radiosensitization Molecular radiation biology and oncology workshop: Translation of molecular mechanisms into clinical radiotherapy

Postgraduate studies in radiation biology in Europe.

The present system of radiobiological research in universities and research centres is no longer able to train radiobiologists who have a comprehensive understanding of the entire field of radiation biology including both 'classical' and molecular radiation biology. However, such experts are needed in view of the role radiation protection plays in our societies. No single institution in Europe could now run a 1-year, full-time course which covers all aspects of the radiobiological basis of radiation protection. Therefore, a cooperative action of several universities from different EU member states has been developed and is described herein.

304 - Molecular radiation biology at the clinical interface

304 - Molecular radiation biology at the clinical interface

Mechanisms underlying cellular radiosensitivity and R.B.E.: Introductory remarks

A general outline of the symposium titled “Mechanisms underlying cellular radiosensitivity and R.B.E.” will be given in the introduction. The essential topics of molecular radiation biology are described with respect to the damage, repair and mutagenesis caused by high-LET irradiation to cellular DNA. The importance of clustered DNA lesions (locally multiply damaged sites) formed in vivo is discussed. This symposium is devoted to the mechanisms of the biological effects of radiation with high LET, especially with regard to the effects of heavy ions and neutrons which may cause possible risks in space flight, (e.g. carcinogenesis and mutagenesis). Detailed understanding of these risks, however, demands knowledge of the molecular mechanisms involved in the biological effects of high-LET radiations. Thus, it was the organizers' idea to hold a symposium dealing with primary physical and chemical events caused in cellular deoxyribonucleoproteins by densely-ionizing radiations and to relate them to track structures and energy transfer processes. The mechanisms of DNA damage were regarded from different points of view including those considering DNA repair and mutagenesis. Problems associated with cell survival and radiation protection were discussed as well. Our knowledge of the molecular mechanisms of high-LET radiation actions, however, is limited compared to what we know about low-LET radiation effects (e.g. from gamma-rays or X-rays). To emphasize this statement, I would like to summarize briefly the open questions in molecular radiation biology, what we know already about low-LET effects and what is lacking describing the effect of high-LET radiation.

γ線と紫外線を照射した農産物腐敗性藻菌類の生存曲線の数量的解析

It is expected that gamma (γ) and ultraviolet (UV) rays are applicable to sterilize agricultural products for reducing storage losses. In practical application, D10-and D99.9-value in γ and UV irradiation have been used as sterilization indices. However, our preliminary results showed that these survival curves were exponential having a shoulder at a beginning in many strains of molds. This suggests the difficulty in assessing a sterilization level accurately using these indices.The survival curves of several molds infecting agricultural products for γ irradiation were simulated with a multi hit theory in molecular radiation biology. On the other hand, the effect of UV irradiation on the survival curves was simulated by multi hit theory, taking into account the decrease in UV-intensity in liquid suspensions due to Lambert's law. It was found that the models based on a multi hit theory well simulated the effects of γ and UV irradiation. Among molds tried in this study, the four hits model best fit to the observed data in cases of Phycomycetes.These results demonstrated that D10-and L-values, instead of conventional indices based on D10-and D99.9-values, should be used to assess the sterilization level accurately. To obtain more reliable measurement, a target area and a hit number, a parameter of penetration in UV-sterilization should be taken into considerations.