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\"A chilling exposâe of the international effort to minimize the health and environmental consequences of nuclear radiation in the wake of Chernobyl. Governments and journalists tell us that though Chernobyl was \"the worst nuclear disaster in history,\" a reassuringly small number of people died (44), and nature recovered. Yet, drawing on a decade of fine-grained archival research and interviews in Ukraine, Russia, and Belarus, Kate Brown uncovers a much more disturbing story--one in which radioactive isotypes caused hundreds of thousands of casualties. Scores of Soviet scientists, bureaucrats, and civilians documented stunning increases in cases of birth defects, child mortality, cancers, and a multitude of prosaic diseases, which they linked to Chernobyl. Worried that this evidence would blow the lid on the effects of massive radiation release from weapons testing during the Cold War, international scientists and diplomats tried to bury or discredit it. A haunting revelation of how political exigencies shape responses to disaster, Manual for Survival makes clear the irreversible impact on every living thing not just from Chernobyl, but from eight decades of radiation from nuclear energy and weaponry.\"-- Provided by publisher.

BEIR VII develops the most up-to-date and comprehensive risk estimates for cancer and other health effects from exposure to low-level ionizing radiation. It is among the first reports of its kind to include detailed estimates for cancer incidence in addition to cancer mortality. In general, BEIR VII supports previously reported risk estimates for cancer and leukemia, but the availability of new and more extensive data have strengthened confidence in these estimates. A comprehensive review of available biological and biophysical data supports a \"linear-no-threshold\" (LNT) risk model-that the risk of cancer proceeds in a linear fashion at lower doses without a threshold and that the smallest dose has the potential to cause a small increase in risk to humans. The report is from the Board on Radiation Research Effects that is now part of the newly formed Nuclear and Radiation Studies Board.

Acute exposure to ionizing radiation induces massive cell death and severe damage to tissues containing actively proliferating cells, including bone marrow and the gastrointestinal tract. However, the cellular and molecular mechanisms underlying this pathology remain controversial. Here, we show that mice deficient in the double-stranded DNA sensor AIM2 are protected from both subtotal body irradiation-induced gastrointestinal syndrome and total body irradiation-induced hematopoietic failure. AIM2 mediates the caspase-1-dependent death of intestinal epithelial cells and bone marrow cells in response to double-strand DNA breaks caused by ionizing radiation and chemotherapeutic agents. Mechanistically, we found that AIM2 senses radiation-induced DNA damage in the nucleus to mediate inflammasome activation and cell death. Our results suggest that AIM2 may be a new therapeutic target for ionizing radiation exposure.

AbstractObjectiveTo evaluate the effect of protracted low dose, low dose rate exposure to ionising radiation on the risk of cancer.DesignMultinational cohort study.SettingCohorts of workers in the nuclear industry in France, the UK, and the US included in a major update to the International Nuclear Workers Study (INWORKS).Participants309 932 workers with individual monitoring data for external exposure to ionising radiation and a total follow-up of 10.7 million person years.Main outcome measuresEstimates of excess relative rate per gray (Gy) of radiation dose for mortality from cancer.ResultsThe study included 103 553 deaths, of which 28 089 were due to solid cancers. The estimated rate of mortality due to solid cancer increased with cumulative dose by 52% (90% confidence interval 27% to 77%) per Gy, lagged by 10 years. Restricting the analysis to the low cumulative dose range (0-100 mGy) approximately doubled the estimate of association (and increased the width of its confidence interval), as did restricting the analysis to workers hired in the more recent years of operations when estimates of occupational external penetrating radiation dose were recorded more accurately. Exclusion of deaths from lung cancer and pleural cancer had a modest effect on the estimated magnitude of association, providing indirect evidence that the association was not substantially confounded by smoking or occupational exposure to asbestos.ConclusionsThis major update to INWORKS provides a direct estimate of the association between protracted low dose exposure to ionising radiation and solid cancer mortality based on some of the world’s most informative cohorts of radiation workers. The summary estimate of excess relative rate solid cancer mortality per Gy is larger than estimates currently informing radiation protection, and some evidence suggests a steeper slope for the dose-response association in the low dose range than over the full dose range. These results can help to strengthen radiation protection, especially for low dose exposures that are of primary interest in contemporary medical, occupational, and environmental settings.

Mitochondrial DNA double-strand breaks (mtDSBs) are toxic lesions that compromise the integrity of mitochondrial DNA (mtDNA) and alter mitochondrial function 1 . Communication between mitochondria and the nucleus is essential to maintain cellular homeostasis; however, the nuclear response to mtDSBs remains unknown 2 . Here, using mitochondrial-targeted transcription activator-like effector nucleases (TALENs) 1 , 3 , 4 , we show that mtDSBs activate a type-I interferon response that involves the phosphorylation of STAT1 and activation of interferon-stimulated genes. After the formation of breaks in the mtDNA, herniation 5 mediated by BAX and BAK releases mitochondrial RNA into the cytoplasm and triggers a RIG-I–MAVS-dependent immune response. We further investigated the effect of mtDSBs on interferon signalling after treatment with ionizing radiation and found a reduction in the activation of interferon-stimulated genes when cells that lack mtDNA are exposed to gamma irradiation. We also show that mtDNA breaks synergize with nuclear DNA damage to mount a robust cellular immune response. Taken together, we conclude that cytoplasmic accumulation of mitochondrial RNA is an intrinsic immune surveillance mechanism for cells to cope with mtDSBs, including breaks produced by genotoxic agents. Breaks in mitochondrial DNA cause leakage of mitochondrial RNA into the cytoplasm, enhancing immune surveillance and synergizing with nuclear DNA damage to mount a robust type-I interferon immune response.

Charged-particle radiotherapy (CPRT) utilizing low and high linear energy transfer (low-/high-LET) ionizing radiation (IR) is a promising cancer treatment modality having unique physical energy deposition properties. CPRT enables focused delivery of a desired dose to the tumor, thus achieving a better tumor control and reduced normal tissue toxicity. It increases the overall radiation tolerance and the chances of survival for the patient. Further improvements in CPRT are expected from a better understanding of the mechanisms governing the biological effects of IR and their dependence on LET. There is increasing evidence that high-LET IR induces more complex and even clustered DNA double-strand breaks (DSBs) that are extremely consequential to cellular homeostasis, and which represent a considerable threat to genomic integrity. However, from the perspective of cancer management, the same DSB characteristics underpin the expected therapeutic benefit and are central to the rationale guiding current efforts for increased implementation of heavy ions (HI) in radiotherapy. Here, we review the specific cellular DNA damage responses (DDR) elicited by high-LET IR and compare them to those of low-LET IR. We emphasize differences in the forms of DSBs induced and their impact on DDR. Moreover, we analyze how the distinct initial forms of DSBs modulate the interplay between DSB repair pathways through the activation of DNA end resection. We postulate that at complex DSBs and DSB clusters, increased DNA end resection orchestrates an increased engagement of resection-dependent repair pathways. Furthermore, we summarize evidence that after exposure to high-LET IR, error-prone processes outcompete high fidelity homologous recombination (HR) through mechanisms that remain to be elucidated. Finally, we review the high-LET dependence of specific DDR-related post-translational modifications and the induction of apoptosis in cancer cells. We believe that in-depth characterization of the biological effects that are specific to high-LET IR will help to establish predictive and prognostic signatures for use in future individualized therapeutic strategies, and will enhance the prospects for the development of effective countermeasures for improved radiation protection during space travel.

The endothelium, a tissue that forms a single layer of cells lining various organs and cavities of the body, especially the heart and blood as well as lymphatic vessels, plays a complex role in vascular biology. It contributes to key aspects of vascular homeostasis and is also involved in pathophysiological processes, such as thrombosis, inflammation, and hypertension. Epidemiological data show that high doses of ionizing radiation lead to cardiovascular disease over time. The aim of this review is to summarize the current knowledge on endothelial cell activation and dysfunction after ionizing radiation exposure as a central feature preceding the development of cardiovascular diseases.

Despite decades of research to understand the biological effects of ionising radiation, there is still much uncertainty over the role of dose rate. Motivated by a virtual workshop on the “Effects of spatial and temporal variation in dose delivery” organised in November 2020 by the Multidisciplinary Low Dose Initiative (MELODI), here, we review studies to date exploring dose rate effects, highlighting significant findings, recent advances and to provide perspective and recommendations for requirements and direction of future work. A comprehensive range of studies is considered, including molecular, cellular, animal, and human studies, with a focus on low linear-energy-transfer radiation exposure. Limits and advantages of each type of study are discussed, and a focus is made on future research needs.

Resistance to ionizing radiation, a first-line therapy for many cancers, is a major clinical challenge. Personalized prediction of tumor radiosensitivity is not currently implemented clinically due to insufficient accuracy of existing machine learning classifiers. Despite the acknowledged role of tumor metabolism in radiation response, metabolomics data is rarely collected in large multi-omics initiatives such as The Cancer Genome Atlas (TCGA) and consequently omitted from algorithm development. In this study, we circumvent the paucity of personalized metabolomics information by characterizing 915 TCGA patient tumors with genome-scale metabolic Flux Balance Analysis models generated from transcriptomic and genomic datasets. Metabolic biomarkers differentiating radiation-sensitive and -resistant tumors are predicted and experimentally validated, enabling integration of metabolic features with other multi-omics datasets into ensemble-based machine learning classifiers for radiation response. These multi-omics classifiers show improved classification accuracy, identify clinical patient subgroups, and demonstrate the utility of personalized blood-based metabolic biomarkers for radiation sensitivity. The integration of machine learning with genome-scale metabolic modeling represents a significant methodological advancement for identifying prognostic metabolite biomarkers and predicting radiosensitivity for individual patients. Personalized prediction of tumor radiosensitivity would facilitate development of precision medicine workflows for cancer treatment. Here, the authors integrate machine learning and genome-scale metabolic modeling approaches to identify multi-omics biomarkers predictive of radiation response.

Background There is still uncertainty on whether ionizing radiation from CT scans can increase the risks of cancer. This study aimed to identify the association of cumulative ionizing radiation from CT scans with pertaining cancer risks in adults. Methods Five databases were searched from their inception to November 15, 2020. Observational studies reporting cancer risks from CT scans in adults were included. The main outcome included quantified cancer risks as cancer case numbers in exposed/unexposed adult participants with unified converted measures to odds ratio (OR) for relative risk, hazard ratio. Global background radiation (2.4 mSv per year) was used as control for lifetime attribution risk (LAR), with the same period from incubation after exposure until survival to 100 years. Results 25 studies were included with a sum of 111,649,943 participants (mean age: 45.37 years, 83.4% women), comprising 2,049,943 actual participants from 6 studies with an average follow-up period as 30.1 years (range, 5 to 80 years); 109,600,000 participants from 19 studies using LAR. The cancer risks for adults following CT scans were inordinately increased (LAR adults, OR, 10.00 [95% CI, 5.87 to 17.05]; actual adults, OR, 1.17 [95%CI, 0.89 to 1.55]; combined, OR, 5.89 [95%CI, 3.46 to 10.35]). Moreover, cancer risks elevated with increase of radiation dose (OR, 33.31 [95% CI, 21.33 to 52.02]), and multiple CT scan sites (OR, 14.08 [95% CI, 6.60 to 30.05]). The risk of solid malignancy was higher than leukemia. Notably, there were no significant differences for age, gender, country, continent, study quality and studying time phrases. Conclusions Based on 111.6 million adult participants from 3 continents (Asia, Europe and America), this meta-analysis identifies an inordinately increase in cancer risks from CT scans for adults. Moreover, the cancer risks were positively correlated with radiation dose and CT sites. The meta-analysis highlights the awareness of potential cancer risks of CT scans as well as more reasonable methodology to quantify cancer risks in terms of life expectancy as 100 years for LAR. Prospero trial registration number CRD42019133487.