STATE INSTITUTION «NATIONAL RESEARCH CENTER FOR RADIATION MEDICINE OF THE NATIONAL ACADEMY OF MEDICAL SCIENCES OF UKRAINE¼ - RESEARCH ACTIVITIES AND SCIENTIFIC ADVANCE IN 2019. / REZUL'TATY ROBOTY DU «NATsIONAL'NYI NAUKOVYI TsENTR RADIATsIINOÏ MEDYTsYNY AKADEMIÏ MEDYChNYKh NAUK UKRAÏNY¼ U 2019 ROTsI.

Research activities and scientific advance achieved in 2019 at the State Institution «National Research Center forRadiation Medicine of the National Academy of Medical Sciences of Ukraine¼ (NRCRM) concerning medical problemsof the Chornobyl disaster, radiation medicine, radiobiology, radiation hygiene and epidemiology in collaborationwith the WHO network of medical preparedness and assistance in radiation accidents are outlined in the annualreport. The report presents the results of fundamental and applied research works of the study of radiation effectsand health effects of the Chornobyl accident.The report also shows the results of scientific-organizational and health care work, staff training.The Scientific Council meeting of NAMS approved the NRCRM Annual Report.

The 20th Gray lecture 2019: health and heavy ions.

OBJECTIVE: Particle radiobiology has contributed new understanding of radiation safety and underlying mechanisms of action to radiation oncology for the treatment of cancer, and to planning of radiation protection for space travel. This manuscript will highlight the significance of precise physical and biologically effective dosimetry to this translational research for the benefit of human health.This review provides a brief snapshot of the evolving scientific basis for, and the complex current global status, and remaining challenges of hadron therapy for the treatment of cancer. The need for particle radiobiology for risk planning in return missions to the Moon, and exploratory deep-space missions to Mars and beyond are also discussed. METHODS: Key lessons learned are summarized from an impressive collective literature published by an international cadre of multidisciplinary experts in particle physics, radiation chemistry, medical physics of imaging and treatment planning, molecular, cellular, tissue radiobiology, biology of microgravity and other stressors, theoretical modeling of biophysical data, and clinical results with accelerator-produced particle beams. RESULTS: Research pioneers, many of whom were Nobel laureates, led the world in the discovery of ionizing radiations originating from the Earth and the Cosmos. Six radiation pioneers led the way to hadron therapy and the study of charged particles encountered in outer space travel. Worldwide about 250,000 patients have been treated for cancer, or other lesions such as arteriovenous malformations in the brain between 1954 and 2019 with charged particle radiotherapy, also known as hadron therapy. The majority of these patients (213,000) were treated with proton beams, but approximately 32,000 were treated with carbon ion radiotherapy. There are 3500 patients who have been treated with helium, pions, neon or other ions. There are currently 82 facilities operating to provide ion beam clinical treatments. Of these, only 13 facilities located in Asia and Europe are providing carbon ion beams for preclinical, clinical, and space research. There are also numerous particle physics accelerators worldwide capable of producing ion beams for research, but not currently focused on treating patients with ion beam therapy but are potentially available for preclinical and space research. Approximately, more than 550 individuals have traveled into Lower Earth Orbit (LEO) and beyond and returned to Earth. CONCLUSION: Charged particle therapy with controlled beams of protons and carbon ions have significantly impacted targeted cancer therapy, eradicated tumors while sparing normal tissue toxicities, and reduced human suffering. These modalities still require further optimization and technical refinements to reduce cost but should be made available to everyone in need worldwide. The exploration of our Universe in space travel poses the potential risk of exposure to uncontrolled charged particles. However, approaches to shield and provide countermeasures to these potential radiation hazards in LEO have allowed an amazing number of discoveries currently without significant life-threatening medical consequences. More basic research with components of the Galactic Cosmic Radiation field are still required to assure safety involving space radiations and combined stressors with microgravity for exploratory deep space travel. ADVANCES IN KNOWLEDGE: The collective knowledge garnered from the wealth of available published evidence obtained prior to particle radiation therapy, or to space flight, and the additional data gleaned from implementing both endeavors has provided many opportunities for heavy ions to promote human health.

Peggy Louise Olive: A journey through the 'comet' and beyond.

Peggy Olive from the British Columbia Cancer Research Center in Canada is credited with the development of a method to measure DNA damage in individual cells based on the technique of microelectrophoresis that she named the 'comet assay'; a well-accepted method to measure DNA damage, hypoxia and apoptosis. A multifaceted person and an ardent campaigner of environmental issues, Peggy has contributed significantly to several areas of radiobiology related to the treatment of cancer, her expertise being tumor hypoxia and gamma H2AX foci as a biomarker in radiotherapy.

Sunlight radiation as a villain and hero: 60 years of illuminating research.

In the 60 years since the inaugural edition of the International Journal of Radiation Biology, much of our understanding of the biological effects of solar radiation has changed. Earlier in the century, sunlight played a 'hero's' role in reducing disabling rickets, while today debate still continues on the amount of sun required before exposure reveals the 'villainous' side of solar radiation. Although knowledge of the ultra violet (UV) component of sunlight as a carcinogen has become widespread, skin cancer rates are still rising yearly. Twentieth century attitudes have seen an about-face in the field of dermatological sun protection, with sunscreens changing from recipes designed to promote a 'healthy tan' to formulations proven to block both ultraviolet B (UVB) and more recently, ultraviolet A (UVA), to minimize premature sun-aging and skin cancer risk. In the early 1960s, DNA was first found to exist within mitochondria, while recently the connections between mitochondrial changes and UV radiation exposure have been expanded. Sixty years ago, understanding of the endocrine systems of mammals was enjoying its infancy. Early discoveries that light, particularly natural light, could have profound effects on functions such as sleep patterns and hormonal balance were made, while today more advanced knowledge has led to lighting improvements having pronounced effects on human wellbeing. Photosensitization 60 years ago was a health concern for both humans and their domestic animals, while today chemically engineered photosensitizing drugs can be administered along with highly directed light to pinpoint delivery targets for drug action. Life on earth is inextricably bound up with solar radiation. This article attempts to outline many of the ways in which our opinions about solar radiation have changed since the journal's inception.

Radiobiology at the forefront: Hanns Langendorff and two of his disciples.

Hanns Langendorff (1902-1974) was an eminent radiobiologist and a visionary, who not only helped found the field, but also made significant scientific contributions. He was a member of the first editorial board of IJRB and actually published a paper in its first issue about the radio-protector 5-hydroxytryptamine. Langendorff started working in the field of radiobiology in 1929 and became director of the 'Radiologisches Institut' of Freiburg University in 1936. His studies impressively show the development of radiobiology over decades in areas such as radiation-induced cell death at various stages of development, as well as radiosensitivity of sea urchin, yeast and mammals. Using mice, Langendorff made many early discoveries about spermatogenesis, hematopoiesis, prenatal development, chromosomal damage and metabolic pathways after exposures to X-rays and neutrons. He also investigated aspects of target theory and dosimetry and developed personal dosimeters using films. After the atomic bomb catastrophes in Japan, Langendorff and his collaborators soon began research in mice related to acute radiation sickness and stimulated the development of radioprotectors by studying their mechanisms of action associated with cell death, as well as cellular and metabolic changes involved. Langendorff also trained a cadre of young scientists who advanced the field and brought it to its golden age in the seventies and the eighties. Research activities of two of his disciples are reviewed: Ulrich Hagen and the author. Both made significant contributions: Hagen mainly studying DNA-damage and repair in vitro as well in cells and the author investigating metabolic processes, cellular and chromosomal damage, prenatal effects, genomic instability, individual radio-sensitivity and their connections to cancer therapy.

Big data in radiation biology and epidemiology; an overview of the historical and contemporary landscape of data and biomaterial archives.

Over the past 60 years a great number of very large datasets have been generated from the experimental exposure of animals to external radiation and internal contamination. This accumulation of 'big data' has been matched by increasingly large epidemiological studies from accidental and occupational radiation exposure, and from plants, humans and other animals affected by environmental contamination. We review the creation, sustainability and reuse of this legacy data, and discuss the importance of Open data and biomaterial archives for contemporary radiobiological sciences, radioecology and epidemiology. We find evidence for the ongoing utility of legacy datasets and biological materials, but that the availability of these resources depends on uncoordinated, often institutional, initiatives to curate and archive them. The importance of open data from contemporary experiments and studies is also very clear, and yet there are few stable platforms for their preservation, sharing, and reuse. We discuss the development of the ERA and STORE data sharing platforms for the scientific community, and their contribution to FAIR sharing of data. The contribution of funding agency and journal policies to the support of data sharing is critical for the maximum utilisation and reproducibility of publicly funded research, but this needs to be matched by training in data management and cultural changes in the attitudes of investigators to ensure the sustainability of the data and biomaterial commons.

Radiation protection biology then and now.

Purpose: Radiation biology is a branch of the radiation research field which focuses on studying radiation effects in cells and organisms. Radiation can be used in biological investigations for two, mutually non-exclusive reasons: (1) to study biological processes by perturbing their functioning (qualitative approach) and (2) to assess consequences of radiation-induced damage (quantitative approach). While the former approach has a basic research character, the latter has an applied character that is driven by needs of medical applications and radiological protection. Radiation protection biology is defined in the sense of the second approach. The aim of the article is to provide a historical review of how radiation protection biology developed and how it influences radiological protection. Conclusions: While radiobiological investigations started immediately after the discovery of X-rays, the qualitative approach dominated until the end of World War II. After 1945, the nuclear weapons race and nuclear energy programs initiated quantitative radiobiological research. Radiation protection biology does not provide results from which radiation risks can be directly derived. Rather, it provides data that is necessary for understanding the nature of risks. Most recent years have seen, especially in Europe, a growing interest in coordinated studies on the effects of low radiation doses.

Exploring the legacy and impact of historical IJRB articles and contributions to ICRP publications and Radiation Research articles through graphical reference mapping.

The International Journal of Radiation Biology (IJRB) celebrates its 60th birthday this year. Ahead of this very special issue, we wanted to produce strong representations of the journal's publication history in order to celebrate the current status of the journal and to look forward to its future. This was accomplished using 'reference maps'. Reference data were used from 1959 onward from the highest-cited paper in IJRB, for each respective year, to create a figure displaying when those articles were cited in IJRB since their publication. This was done to show the relative impact of historical IJRB papers to future research. Common themes of research were also examined by decade. Additionally, to show the historical impact of the journal outside of its immediate area of research and its practical applications, information on IJRB articles cited by the International Commission on Radiological Protection (ICRP) was collected. It was in 1959 when IJRB published the first issue, and when ICRP also issued Publication 1. Among all Publications (1-139), 43 publications have thus far cited 320 IJRB papers and each of which have been cited 1-7 times. Most notably, Publications 90, 99, 118, and 131 cited more than 40 IJRB papers. Further research was done into references for IJRB's contemporary journal: Radiation Research. The most highly cited IJRB articles for each year together since its inception were cited 16,760 times since they were published and cited 1385 times in Radiation Research. Together, these three datasets and their representations show the diversity of historical IJRB publications, the impact of historical IJRB articles in both future research in the journal and outside of it, and articles which new prospective authors contributing to IJRB might find useful in their own research.

Early authors - R. H. Mole.

Purpose: To reflect on the contributions of R. H. Mole to radiobiology. Robin Mole was a very active radiobiologist when the IJRB was first established and had two papers in the first few issues of the journal in 1959. Conclusions: R. H. Mole made significant contributions to radiobiology and is particularly associated with studies of the effects of low dose exposures on the reproductive health of mammals. Many of his ideas are still debated and remain controversial.

A historical reflection on our understanding of radiation-induced DNA double strand break repair in somatic mammalian cells; interfacing the past with the present.

Purpose: The International Journal of Radiation Biology (IJRB) is celebrating 60 years of publishing in 2019. IJRB has made an enormous contribution to publishing papers that have enhanced our understanding of the DNA damage response (DDR) activated following exposure to ionizing radiation (IR). The IR-induced DDR field has a rich history but many outstanding papers pass unread by young scientists overwhelmed by the current literature. We provide a historical reflection on key advances in the DDR field and interface them with current knowledge. Conclusions: DNA double strand breaks (DSBs) were identified as the major biological lesion induced by IR. But early studies on cells from IR-sensitive ataxia telangiectasia patients showed that DSB repair was not sufficient to prevent IR hypersensitivity. Subsequently, the ATM-dependent signal transduction process was revealed, with the breadth of the response being slowly unearthed. Early studies demonstrated at least two processes of DSB repair and revealed that mis-repair causes translocation formation. Recent studies, however, are unraveling more complexity in the repair process, including the specific processing of DSBs within transcriptionally active regions, and the significance of the chromatin environment. Despite the quality of these early and current studies, many questions remain to be addressed.

Neutrons are forever! Historical perspectives.

Purpose: Neutrons were an active field of radiobiology at the time of publication of the first issues of the International Journal of Radiation Biology in 1959. Three back-to-back papers published by Neary and his colleagues contain key elements of interest at the time. The present article aims to put these papers into context with the discovery of the neutron 27 years previously and then give a feel for how the field has progressed to the present day. It does not intend to provide a comprehensive review of this enormous field, but rather to provide selective summaries of main driving forces and developments. Conclusions: Neutron radiobiology has continued as a vigorous field of study throughout the past 84 years. Main driving forces have included concern for protection from the harmful effects of neutrons, exploitation and optimization for cancer therapy (fast beam therapy, brachytherapy and boron capture therapy), and scientific curiosity about the mechanisms of radiation action. Effort has fluctuated as the emphasis has shifted from time to time, but all three areas remain active today. Whatever the future holds for the various types of neutron therapy, the health protection aspects will remain with us permanently because of natural environmental exposure to neutrons as well as increased additional exposures from a variety of human activities.

Commemoration of Jack Fowler's life, work, impact and legacy.

Jack Fowler [formally Professor John Francis Fowler PhD, DSc, MD (Hon), FInstP, FRCR, FBIR, FAAPM, FASTRO, FACRO] was a remarkable scientist, known to many in the field of clinical radiation biology as at the forefront of applying linear-quadratic dose-fractionation-time modelling to help improve a wide range of cancer treatments using radiotherapy. His death on 1st December 2016 after a long career of 60 years was marked by Obituaries in six scientific journals in his field e.g.1-4 Jack is remembered for his quantification of biologically effective dose in a wide variety of radiotherapy practices and modified protocols (supported by experimental-system studies), his extensive publications, his didactic lecturing and teaching abilities, and his warm personality.

Cancer immunology and radiobiology: Oliver Scott's struggle for the perfect tumour model in translational research.

Oliver Scott is best known for his research into the role of tumour hypoxia in radiation oncology. Yet no less important were Oliver's activities in the development of concepts and methods for performing translational research on the effect of ionising radiation on tumour in experimental animals, stressing the importance of using strictly inbred animals for transplantation of tumours which had arisen in exactly the identical mouse strain. Otherwise residual immunity would lead to uncontrollable bias in the results of cure experiments, invalidating conclusions. These pioneering views are no less valid in today's cancer research.

STATE INSTITUTION NATIONAL RESEARCH CENTER FOR RADIATION MEDICINE OF THE NATIONAL ACADEMY OF MEDICAL SCIENCES OF UKRAINE - RESEARCH ACTIVITIES AND SCIENTIFIC ADVANCE IN 2017. / REZUL'TATY ROBOTY DU NATsIONAL'NYI NAUKOVYI TsENTR RADIATsIINOÏ MEDYTsYNY NATsIONAL'NOÏ AKADEMIÏ MEDYChNYKh NAUK UKRAÏNY U 2017 ROTsI.

Research activities and scientific advance achieved in 2017 at the State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine¼ (NRCRM) concerning medical problems of the Chornobyl disaster, radiation medicine, radiobiology, radiation hygiene and epidemiology in collaboration with the WHO network of medical preparedness and assistance in radiation accidents are outlined in the annual report. The report presents the results of fundamental and applied research works of the study of radiation effects and health effects of the Chornobyl accident; fulfillment of tasks of «State social program for improving safety, occupational health and working environment in 2014-2018 years¼.The report also shows the results of scientific-organizational and health care work, staff training.The NRCRM Annual Report was approved at the Scientific Council meeting of NAMS on March 23, 2018.

Focus small to find big - the microbeam story.

PURPOSE: Even though the first ultraviolet microbeam was described by S. Tschachotin back in 1912, the development of sophisticated micro-irradiation facilities only began to flourish in the late 1980s. In this article, we highlight significant microbeam experiments, describe the latest microbeam irradiator configurations and critical discoveries made by using the microbeam apparatus. MATERIALS AND METHODS: Modern radiological microbeams facilities are capable of producing a beam size of a few micrometers, or even tens of nanometers in size, and can deposit radiation with high precision within a cellular target. In the past three decades, a variety of microbeams has been developed to deliver a range of radiations including charged particles, X-rays, and electrons. Despite the original intention for their development to measure the effects of a single radiation track, the ability to target radiation with microbeams at sub-cellular targets has been extensively used to investigate radiation-induced biological responses within cells. RESULTS: Studies conducted using microbeams to target specific cells in a tissue have elucidated bystander responses, and further studies have shown reactive oxygen species (ROS) and reactive nitrogen species (RNS) play critical roles in the process. The radiation-induced abscopal effect, which has a profound impact on cancer radiotherapy, further reaffirmed the importance of bystander effects. Finally, by targeting sub-cellular compartments with a microbeam, we have reported cytoplasmic-specific biological responses. Despite the common dogma that nuclear DNA is the primary target for radiation-induced cell death and carcinogenesis, studies conducted using microbeam suggested that targeted cytoplasmic irradiation induces mitochondrial dysfunction, cellular stress, and genomic instability. A more recent development in microbeam technology includes application of mouse models to visualize in vivo DNA double-strand breaks. CONCLUSIONS: Microbeams are making important contributions towards our understanding of radiation responses in cells and tissue models.

Radiation fractionation: the search for isoeffect relationships and mechanisms.

PURPOSE: Review the historical basis for the use of fractionated radiation in radiation oncology. CONCLUSION: The history of dose fractionation in radiation oncology is long and tortuous, and the radiobiologist's understanding of why fractionation worked came decades after radiation oncologists had adopted multi-week daily-dose fractionation as 'standard'. Central to the history is the search for 'isoeffective' formulas that would allow different radiation schedules to be compared. Initially, this meant dealing with different lengths of treatment, leading to the 1944 Strandqvist formulation that dominated thinking for decades. Concerns about the number of fractions, not just the total time, led to the 1967 Ellis NSD formulation that held sway through the 1980s. The development of experimental radiotherapy in 1970s (e.g. Fowler's work at the Gray Laboratory, and Fischer's work at Yale) led to biologically-based approaches that culminated with the Biologically Effective Dose (BED) concept. BED is the current dogma for treatment optimization, but it must be used with caution, as there are multiple formulations, and some parameters have debatable values. There is also a controversy about whether BED is biologically-based or a 'curve-fitting' exercise. These latter issues are beyond the scope of this article, but the history of fractionation models suggests that our current concepts are probably wrong, although when used with caution they are clearly useful.