LONG/TERM GENETIC AND EPIGENETIC DISORDERS IN PERSONS EXPOSED TO IONIZING RADIATION AND THEIR DESCENDANTS (review). / VIDDALENI GENETYChNI TA EPIGENETYChNI PORUShENNIa U OPROMINENYKh OSIB TA ÏKhNIKh NAShchADKIV (ogliad).

The review is devoted to long-term genetic and epigenetic disorders in exposed individuals and their descendants,namely to cytogenetic effects in the Chornobyl NPP accident clean-up workers and their children, DNA methylation as an epigenetic modification of human genome. Data presented in review expand the understanding of risk of the prolonged exposure for the present and future generations, which is one of key problems posed by fundamental radiation genetics and human radiobiology.

MODIFICATION OF THE TUMOR/INDUCED BYSTANDER EFFECT BY IRRADIATION UNDER COCULTIVATION OF LYMPHOCYTES FROM PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA AND LYMPHOCYTES FROM HEALTHY DONORS. / MODYFIKATsIIa OPROMINENNIaM PUKhLYNNO/INDUKOVANOGO EFEKTU SVIDKA PRY SUMISNO/ROZDIL'NOMU KUL'TYVUVANNI LIMFOTsYTIV KhVORYKh NA KhRONIChNU LIMFOTsYTARNU LEIKEMIIu Z LIMFOTsYTAMY ZDOROVYKh DONORIV.

OBJECTIVE: Study the tumor-induced bystander effect of blood cells from chronic lymphocytic leukemia (CLL)patients on non-transformed bystander cells (peripheral blood lymphocytes (PBL) of conditionally healthy individ-uals) and the possibility of its modification after the impact of ionizing radiation. MATERIALS AND METHODS: We carried out cocultivation and separate cultivation of blood samples from conditionallyhealthy volunteers and patients with CLL according to our technique. Using the Comet assay, the relative level ofDNA damage was evaluated. RESULTS: A statistically significant increase (р < 0.001) in the level of DNA damage in PBL culture of conditionallyhealthy individuals after co-cultivation with malignant cells of CLL patients was observed. After irradiation, a drop in the level of cells with a high degree of DNA damage was noted, which was connected with an increase in the frequency of cells that were delayed in division at the S stage of the cell cycle. An increase in apoptotic activity in cultures of bystander cells was observed in all variants of the experiment (р < 0.001). CONCLUSION: The influence of irradiated blood cells of patients with CLL results in an enhancement of the tumor-induced bystander effect manifestation in the PBL of conditionally healthy individuals.

Gastrointestinal leiomyosarcoma demonstrate a predilection for distant recurrence and poor response to systemic treatments.

BACKGROUND: Primary leiomyosarcoma (LMS) of the gastrointestinal (GI) tract is rare. Limited literature exists regarding the clinical characteristics and outcome for patients with localised and metastatic disease. METHODS: A retrospective chart review was performed for patients greater than 18 years of age diagnosed with GI LMS at The Royal Marsden Hospital between 1 January 2000-1 May 2020. Descriptive statistics were performed. Patients were censored at data cut-off date of 27 June 2020. RESULTS: Forty-six patients with a median age at diagnosis of 54 years (range 25-85) were identified. Fifteen percent (n = 7) of patients previously received abdominal radiation for an unrelated cancer. All patients with localised disease (n = 36) had resection with oncological margins. For patients who underwent potentially curative surgery, median recurrence-free survival (mRFS) was 13 months (0.4-183 months), and half of these patients (n = 18) developed recurrent disease post resection (distant n = 16, local n = 2). Median overall survival (mOS) was 27 months for patients with distant recurrence. Twenty-one percent (n = 10) of patients presented with synchronous metastatic disease and their mOS was 19 months. Median progression-free survival (mPFS) for patients treated with conventional chemotherapy ranged from 2.0 to 8.0 months. CONCLUSION: The risk of recurrence is significant, and recurrence-free survival was short even with complete oncologic resection. The relationship of prior abdominal radiotherapy to the development of GI LMS warrants further investigation. Outcomes with systemic therapy for metastatic disease were poor and there is a need for the development of more effective systemic therapies.

Charged-Iron-Particles Found in Galactic Cosmic Rays are Potent Inducers of Epithelial Ovarian Tumors.

Astronauts traveling in deep space are exposed to high-charge and energy (HZE) particles from galactic cosmic rays. We have previously determined that irradiation of adult female mice with iron HZE particles induces DNA double-strand breaks, oxidative damage and apoptosis in ovarian follicles, causing premature ovarian failure. These effects occur at lower doses than with conventional photon irradiation. Ovarian failure with resultant loss of negative feedback and elevated levels of gonadotropin hormones is thought to play a role in the pathophysiology of ovarian cancer. Therefore, we hypothesized that charged-iron-particle irradiation induces ovarian tumorigenesis in mice. In this study, three-month-old female mice were exposed to 0 cGy (sham) or 50 cGy iron ions and aged to 18 months. The 50 cGy irradiated mice had increased weight gain with age and lack of estrous cycling, consistent with ovarian failure. A total of 47% and 7% of mice irradiated with 50 cGy had unilateral and bilateral ovarian tumors, respectively, whereas 14% of mice in the 0 cGy group had unilateral tumors. The tumors contained multiple tubular structures, which were lined with cells positive for the epithelial marker cytokeratin, and had few proliferating cells. In some tumors, packets of cells between the tubular structures were immunopositive for the granulosa cell marker FOXL2. Based on these findings, tumors were diagnosed as tubular adenomas or mixed tubular adenoma/granulosa cell tumors. In conclusion, charged-iron-particle-radiation induces ovarian tumors in mice, raising concerns about ovarian tumors as late sequelae of deep space travel in female astronauts.

The Birth of the Illegitimate Linear No-Threshold Model: An Invalid Paradigm for Estimating Risk Following Low-dose Radiation Exposure.

This paper examines the birthing process of the linear no-threshold model with respect to genetic effects and carcinogenesis. This model was conceived >70 years ago but still remains a foundational element within much of the scientific thought regarding exposure to low-dose ionizing radiation. This model is used today to provide risk estimates for cancer resulting from any exposure to ionizing radiation down to zero dose, risk estimates that are only theoretical and, as yet, have never been conclusively demonstrated by empirical evidence. We are literally bathed every second of every day in low-dose radiation exposure due to natural background radiation, exposures that vary annually from a few mGy to 260 mGy, depending upon where one lives on the planet. Irrespective of the level of background exposure to a given population, no associated health effects have been documented to date anywhere in the world. In fact, people in the United States are living longer today than ever before, likely due to always improving levels of medical care, including even more radiation exposure from diagnostic medical radiation (eg, x-ray and computed tomography imaging examinations) which are well within the background dose range across the globe. Yet, the persistent use of the linear no-threshold model for risk assessment by regulators and advisory bodies continues to drive an unfounded fear of any low-dose radiation exposure, as well as excessive expenditures on putative but unneeded and wasteful safety measures.

Age Modifies the Effect of 2-MeV Fast Neutrons on Rat Mammary Carcinogenesis.

The relative biological effectiveness (RBE) of neutrons depends on their physical nature (e.g., energy) and the biological context (e.g., end points, materials). From the perspective of radiological protection, age is an important biological context that influences radiation-related cancer risk, but very few studies have addressed its potential impact on neutron effects. We therefore investigated the influence of age on the effect of accelerator-generated fast neutrons (mean energy, ∼2 MeV) in an animal model of breast carcinogenesis. Female Sprague-Dawley rats at 1, 3 and 7 weeks of age were irradiated with fast neutrons at absorbed doses of 0.0485-0.97 Gy. All animals were kept under specific pathogen-free conditions and screened weekly for mammary tumors by palpation until they were 90 weeks old. Tumors were diagnosed based on histology. Mathematical modeling was used to analyze mammary cancer incidence, collectively using data from this study and a previously reported experiment on 137Cs gamma rays. The results indicate that neutron irradiation elevated the risk of palpable mammary carcinoma with a linear dose response, the slope of which depended on age at time of irradiation. The RBE of neutron radiation was 7.5 ± 3.4, 9.3 ± 3.5 and 26.1 ± 8.9 (mean ± SE) for animals exposed at 1, 3 and 7 weeks of age, respectively. Our results indicate that age of the animal is an important factor influencing the effect of fast neutrons on breast cancer risk.

NADPH Oxidase-1 Plays a Key Role in Keratinocyte Responses to UV Radiation and UVB-Induced Skin Carcinogenesis.

The nicotinamide adenine dinucleotide phosphate oxidase (NOX) family enzymes are involved in several physiological functions. However, their roles in keratinocyte responses to UV radiation have not been clearly elucidated. This study shows that, among other NOX family members, UVB irradiation results in a biphasic activation of NOX1 that plays a critical role in defining keratinocyte fate through the modulation of the DNA damage response network. Indeed, suppression of both bursts of UVB-induced NOX1 activation by using a specific peptide inhibitor of NOX1 (InhNOX1) is associated with increased nucleotide excision repair efficiency and reduction of apoptosis, which is finally translated into decreased photocarcinogenesis. On the contrary, when only the second peak of UVB-induced NOX1 activation is blocked, both nucleotide excision repair efficiency and apoptosis are decreased. Our results show that inhibition of NOX1 activation could be a promising target for the prevention and treatment of UVB-induced skin cancer in nucleotide excision repair-proficient and -deficient patients.

Impact of the Circadian Clock on UV-Induced DNA Damage Response and Photocarcinogenesis.

The skin is in constant exposure to various external environmental stressors, including solar ultraviolet (UV) radiation. Various wavelengths of UV light are absorbed by the DNA and other molecules in the skin to cause DNA damage and induce oxidative stress. The exposure to excessive ultraviolet (UV) radiation and/or accumulation of damage over time can lead to photocarcinogenesis and photoaging. The nucleotide excision repair (NER) system is the sole mechanism for removing UV photoproduct damage from DNA, and genetic disruption of this repair pathway leads to the photosensitive disorder xeroderma pigmentosum (XP). Interestingly, recent work has shown that NER is controlled by the circadian clock, the body's natural time-keeping mechanism, through regulation of the rate-limiting repair factor xeroderma pigmentosum group A (XPA). Studies have shown reduced UV-induced skin cancer after UV exposure in the evening compared to the morning, which corresponds with times of high and low repair capacities, respectively. However, most studies of the circadian clock-NER connection have utilized murine models, and it is therefore important to translate these findings to humans to improve skin cancer prevention and chronotherapy.

DNA Methylation Patterns in Rat Mammary Carcinomas Induced by Pre- and Post-Pubertal Irradiation.

Several lines of evidence indicate one's age at exposure to radiation strongly modifies the risk of radiation-induced breast cancer. We previously reported that rat mammary carcinomas induced by pre- and post-pubertal irradiation have distinct gene expression patterns, but the changes underlying these differences have not yet been characterized. The aim of this investigation was to see if differences in CpG DNA methylation were responsible for the differences in gene expression between age at exposure groups observed in our previous study. DNA was obtained from the mammary carcinomas arising in female Sprague-Dawley rats that were either untreated or irradiated (γ-rays, 2 Gy) during the pre- or post-pubertal period (3 or 7 weeks old). The DNA methylation was analyzed using CpG island microarrays and the results compared to the gene expression data from the original study. Global DNA hypomethylation in tumors was accompanied by gene-specific hypermethylation, and occasionally, by unique tumor-specific patterns. We identified methylation-regulated gene expression candidates that distinguished the pre- and post-pubertal irradiation tumors, but these represented only 2 percent of the differentially expressed genes, suggesting that methylation is not a major or primary mechanism underlying the phenotypes. Functional analysis revealed that the candidate methylation-regulated genes were enriched for stem cell differentiation roles, which may be important in mammary cancer development and worth further investigation. However, the heterogeneity of human breast cancer means that the interpretation of molecular and phenotypic differences should be cautious, and take into account the co-variates such as hormone receptor status and cell-of-origin that may influence the associations.

Environmental risk factors for pancreatic cancer: an update.

Pancreatic cancer (PC) is one of the most aggressive diseases. Only 10 % of all PC cases are thought to be due to genetic factors. Here, we analyzed the most recently published case-control association studies, meta-analyses, and cohort studies with the aim to summarize the main environmental factors that could have a role in PC. Among the most dangerous agents involved in the initiation phase, there are the inhalation of cigarette smoke, and the exposure to mutagenic nitrosamines, organ-chlorinated compounds, heavy metals, and ionizing radiations. Moreover, pancreatitis, high doses of alcohol drinking, the body microbial infections, obesity, diabetes, gallstones and/or cholecystectomy, and the accumulation of asbestos fibers seem to play a crucial role in the progression of the disease. However, some of these agents act both as initiators and promoters in pancreatic acinar cells. Protective agents include dietary flavonoids, marine omega-3, vitamin D, fruit, vegetables, and the habit of regular physical activity. The identification of the factors involved in PC initiation and progression could be of help in establishing novel therapeutic approaches by targeting the molecular signaling pathways responsive to these stimuli. Moreover, the identification of these factors could facilitate the development of strategies for an early diagnosis or measures of risk reduction for high-risk people.

Mechanisms of Melanoma Promotion by Ultraviolet Radiation.

The mutagenic properties of ultraviolet radiation drive the initiation of melanoma. Induction of matrix metalloproteinases in melanoma cells by longwave UVA radiation, possibly via a Warburg-like effect, promotes melanoma invasiveness. This is one of several mechanisms by which ultraviolet radiation also promotes further growth of previously established melanomas.

The role of dose rate in radiation cancer risk: evaluating the effect of dose rate at the molecular, cellular and tissue levels using key events in critical pathways following exposure to low LET radiation.

PURPOSE: This review evaluates the role of dose rate on cell and molecular responses. It focuses on the influence of dose rate on key events in critical pathways in the development of cancer. This approach is similar to that used by the U.S. EPA and others to evaluate risk from chemicals. It provides a mechanistic method to account for the influence of the dose rate from low-LET radiation, especially in the low-dose region on cancer risk assessment. Molecular, cellular, and tissues changes are observed in many key events and change as a function of dose rate. The magnitude and direction of change can be used to help establish an appropriate dose rate effectiveness factor (DREF). CONCLUSIONS: Extensive data on key events suggest that exposure to low dose-rates are less effective in producing changes than high dose rates. Most of these data at the molecular and cellular level support a large (2-30) DREF. In addition, some evidence suggests that doses delivered at a low dose rate decrease damage to levels below that observed in the controls. However, there are some data human and mechanistic data that support a dose-rate effectiveness factor of 1. In summary, a review of the available molecular, cellular and tissue data indicates that not only is dose rate an important variable in understanding radiation risk but it also supports the selection of a DREF greater than one as currently recommended by ICRP ( 2007 ) and BEIR VII (NRC/NAS 2006 ).

Life-span exposure to sinusoidal-50 Hz magnetic field and acute low-dose γ radiation induce carcinogenic effects in Sprague-Dawley rats.

Background In 2002 the International Agency for Research on Cancer classified extremely low frequency magnetic fields (ELFMF) as a possible carcinogen on the basis of epidemiological evidence. Experimental bioassays on rats and mice performed up to now on ELFMF alone or in association with known carcinogens have failed to provide conclusive confirmation. Objectives To study the carcinogenic effects of combined exposure to sinusoidal-50 Hz (S-50 Hz) magnetic fields and acute γ radiation in Sprague-Dawley rats. Methods We studied groups of male and female Sprague-Dawley rats exposed from prenatal life until natural death to 20 or 1000 µT S-50 Hz MF and also to 0.1 Gy γ radiation delivered as a single acute exposure at 6 weeks of age. Results The results of the study showed significant carcinogenic effects for the mammary gland in males and females and a significant increased incidence of malignant schwannomas of the heart as well as increased incidence of lymphomas/leukemias in males. Conclusions These results call for a re-evaluation of the safety of non-ionizing radiation.

The Integration of LNT and Hormesis for Cancer Risk Assessment Optimizes Public Health Protection.

This paper proposes a new cancer risk assessment strategy and methodology that optimizes population-based responses by yielding the lowest disease/tumor incidence across the entire dose continuum. The authors argue that the optimization can be achieved by integrating two seemingly conflicting models; i.e., the linear no-threshold (LNT) and hormetic dose-response models. The integration would yield the optimized response at a risk of 10 with the LNT model. The integrative functionality of the LNT and hormetic dose response models provides an improved estimation of tumor incidence through model uncertainty analysis and major reductions in cancer incidence via hormetic model estimates. This novel approach to cancer risk assessment offers significant improvements over current risk assessment approaches by revealing a regulatory sweet spot that maximizes public health benefits while incorporating practical approaches for model validation.

[Chernobyl Awareness].

The essay contains the author's memories of the events related to the accident at the Chernobyl nuclear power plant and the thoughts about the short and long-term consequences of this disaster for society, human and biota. Awareness of the Chernobyl disaster as a multifaceted great incident which is significant for the whole world came slowly through a series of mistakes and errors. Currently it is essential to give a deeper insight into the lessons of Chernobyl for the sake of the future.

Effects of artificial light at night on human health: A literature review of observational and experimental studies applied to exposure assessment.

It has frequently been reported that exposure to artificial light at night (ALAN) may cause negative health effects, such as breast cancer, circadian phase disruption and sleep disorders. Here, we reviewed the literature assessing the effects of human exposure to ALAN in order to list the health effects of various aspects of ALAN. Several electronic databases were searched for articles, published through August 2014, related to assessing the effects of exposure to ALAN on human health; these also included the details of experiments on such exposure. A total of 85 articles were included in the review. Several observational studies showed that outdoor ALAN levels are a risk factor for breast cancer and reported that indoor light intensity and individual lighting habits were relevant to this risk. Exposure to artificial bright light during the nighttime suppresses melatonin secretion, increases sleep onset latency (SOL) and increases alertness. Circadian misalignment caused by chronic ALAN exposure may have negative effects on the psychological, cardiovascular and/or metabolic functions. ALAN also causes circadian phase disruption, which increases with longer duration of exposure and with exposure later in the evening. It has also been reported that shorter wavelengths of light preferentially disturb melatonin secretion and cause circadian phase shifts, even if the light is not bright. This literature review may be helpful to understand the health effects of ALAN exposure and suggests that it is necessary to consider various characteristics of artificial light, beyond mere intensity.

Current concept of photocarcinogenesis.

There is ample evidence demonstrating that solar ultraviolet light (UV) induces human skin cancers. First, epidemiological studies have demonstrated a negative correlation between the latitude of residence and incidence and mortality rates of both melanoma and non-melanoma skin cancers in homogeneous populations. Second, skin cancer can be produced in mice by UV irradiation; the action spectrum of photocarcinogenesis falls into UVB (280-320 nm). Third, patients with genetic disorders that lead to deficiencies in repairing UV-induced DNA damage are prone to develop cancers in sun-exposed areas of the skin. Photocarcinogenesis is a multistage process that involves initiation, promotion, and progression. In addition UV induced immunosuppression is closely involved in photocarcinogenesis. Accumulation of DNA lesions caused by UV in several cancer related genes plays a crucial role in carcinogenesis. Indeed, even in actinic keratosis, precancerous lesions, genetic alterations can be observed. A conventional knowledge demonstrated that UVB induced DNA lesion causes genetic mutation (initiation) and UVB-inflammation (sunburn) induces promotion. However recent findings revealed that the photocarcinogenesis pathway is more complex consequences where each of these processes, mediated by various cellular, biochemical, and molecular changes, are closely related to each other. The pyrimidine photoproducts that result from direct DNA damage induced by UV are involved in developing skin cancer through mutations that lead to the upregulation or downregulation of signal transduction pathways, cell cycle dysregulation, and depletion of antioxidant defenses. In addition pyrimidine dimers have been shown to trigger UV induced immunosuppression, which also plays an important role in photocarcinogenesis, partly by upregulation of IL-10, an immunosuppressive cytokine. UV also produces oxidative stress and oxidative DNA damage in skin cells, which cause alteration of the genes involved in the cell cycle, apoptosis and modification of cell signaling by redox regulation, resulting in inflammation. It has been shown that in Ogg1 knockout mice which are deficient in repairing 8-oxo-7, 8-dihydroguanine (8-oxoG), UVB irradiation up-regulates the inflammatory gene, implying that 8-oxoG is involved in triggering inflammation. In this review I summarize the state of the art knowledge regarding photocarcinogenesis including experimental data and implication for clinical viewpoints.

The postirradiation incidence of cavernous angioma is higher in patients with childhood pineoblastoma or primitive neuroectodermal tumors than medulloblastoma.

PURPOSE: The purpose of this study is to investigate the incidence of cavernous angioma (CVA) in long-term survivors of childhood embryonal tumors treated by cranial irradiation. MATERIALS AND METHODS: Between 1990 and 2012, we treated 25 patients (13 males, 12 females) with embryonal tumors (17 medulloblastomas, 5 primitive neuroectodermal tumors (PNET), 3 pineoblastomas) with craniospinal irradiation. Follow-up ranged from 15.5 to 289.9 months, the irradiation dose to the whole neural axis from 18 to 36 Gy, and the total local dose from 49.6 to 60 Gy. All patients underwent follow-up magnetic resonance imaging (MRI) studies at least once a year, and the diagnosis of posttreatment CVA was based solely on MRI findings. RESULTS: At the time of this writing, 18 were alive and free of the recurrence of the original disease or the development of secondary neoplasms other than CVA; another 2 were alive with medulloblastoma or diffuse astrocytoma. Posttreatment, 14 patients developed CVAs in the course of a median of 56.7 months; 13 of these presented with multiple CVAs. Patients who underwent radiation therapy (RT) at an age younger than 6 years developed multiple CVAs significantly earlier than those treated at a later age (p = 0.0110). Patients with PNET or pineoblastoma developed Zabramski type 1 and 2 CVA significantly earlier than did medulloblastoma patients (p = 0.0042). CONCLUSION: We attribute the high rate of post-RT CVA in our long-term follow-up study of pediatric patients to the delivery of cranial irradiation for embryonal tumors, especially PNET and pineoblastoma, and recommend the regular, long-term follow-up of patients whose embryonal tumors were treated by cranial irradiation.