H2AX phosphorylation screen of cells from radiosensitive cancer patients reveals a novel DNA double-strand break repair cellular phenotype

BACKGROUND: About 1-5% of cancer patients suffer from significant normal tissue reactions as a result of radiotherapy (RT). It is not possible at this time to predict how most patients' normal tissues will respond to RT. DNA repair dysfunction is implicated in sensitivity to RT particularly in genes that mediate the repair of DNA double-strand breaks (DSBs). Phosphorylation of histone H2AX (phosphorylated molecules are known as gammaH2AX) occurs rapidly in response to DNA DSBs, and, among its other roles, contributes to repair protein recruitment to these damaged sites. Mammalian cell lines have also been crucial in facilitating the successful cloning of many DNA DSB repair genes; yet, very few mutant cell lines exist for non-syndromic clinical radiosensitivity (RS).\ud \ud METHODS: Here, we survey DNA DSB induction and repair in whole cells from RS patients, as revealed by gammaH2AX foci assays, as potential predictive markers of clinical radiation response.\ud \ud RESULTS: With one exception, both DNA focus induction and repair in cell lines from RS patients were comparable with controls. Using gammaH2AX foci assays, we identified a RS cancer patient cell line with a novel ionising radiation-induced DNA DSB repair defect; these data were confirmed by an independent DNA DSB repair assay.\ud \ud CONCLUSION: gammaH2AX focus measurement has limited scope as a pre-RT predictive assay in lymphoblast cell lines from RT patients; however, the assay can successfully identify novel DNA DSB repair-defective patient cell lines, thus potentially facilitating the discovery of novel constitutional contributions to clinical RS

Chromosomal radiosensitivity and acute radiation side effects after radiotherapy in tumour patients - a follow-up study

Radiotherapists are highly interested in optimizing doses especially for patients who tend to suffer from side effects of radiotherapy (RT). It seems to be helpful to identify radiosensitive individuals before RT. Thus we examined aberrations in FISH painted chromosomes in in vitro irradiated blood samples of a group of patients suffering from breast cancer. In parallel, a follow-up of side effects in these patients was registered and compared to detected chromosome aberrations. METHODS: Blood samples (taken before radiotherapy) were irradiated in vitro with 3 Gy X-rays and analysed by FISH-painting to obtain aberration frequencies of first cycle metaphases for each patient. Aberration frequencies were analysed statistically to identify individuals with an elevated or reduced radiation response. Clinical data of patients have been recorded in parallel to gain knowledge on acute side effects of radiotherapy. RESULTS: Eight patients with a significantly elevated or reduced aberration yield were identified by use of a t-test criterion. A comparison with clinical side effects revealed that among patients with elevated aberration yields one exhibited a higher degree of acute toxicity and two patients a premature onset of skin reaction already after a cumulative dose of only 10 Gy. A significant relationship existed between translocations in vitro and the time dependent occurrence of side effects of the skin during the therapy period. CONCLUSIONS: The results suggest that translocations can be used as a test to identify individuals with a potentially elevated radiosensitivity

Accelerating ocean species discovery and laying the foundations for the future of marine biodiversity research and monitoring

This is the final version. Available from Frontiers Media via the DOI in this record. Ocean Census is a new Large-Scale Strategic Science Mission aimed at accelerating the discovery and description of marine species. This mission addresses the knowledge gap of the diversity and distribution of marine life whereby of an estimated 1 million to 2 million species of marine life between 75% to 90% remain undescribed to date. Without improved knowledge of marine biodiversity, tackling the decline and eventual extinction of many marine species will not be possible. The marine biota has evolved over 4 billion years and includes many branches of the tree of life that do not exist on land or in freshwater. Understanding what is in the ocean and where it lives is fundamental science, which is required to understand how the ocean works, the direct and indirect benefits it provides to society and how human impacts can be reduced and managed to ensure marine ecosystems remain healthy. We describe a strategy to accelerate the rate of ocean species discovery by: 1) employing consistent standards for digitisation of species data to broaden access to biodiversity knowledge and enabling cybertaxonomy; 2) establishing new working practices and adopting advanced technologies to accelerate taxonomy; 3) building the capacity of stakeholders to undertake taxonomic and biodiversity research and capacity development, especially targeted at low- and middle-income countries (LMICs) so they can better assess and manage life in their waters and contribute to global biodiversity knowledge; and 4) increasing observational coverage on dedicated expeditions. Ocean Census, is conceived as a global open network of scientists anchored by Biodiversity Centres in developed countries and LMICs. Through a collaborative approach, including co-production of science with LMICs, and by working with funding partners, Ocean Census will focus and grow current efforts to discover ocean life globally, and permanently transform our ability to document, describe and safeguard marine species.Nippon Foundatio

Genetic contributions to two special factors of neuroticism are associated with affluence, higher intelligence, better health, and longer life

Higher scores on the personality trait of neuroticism, the tendency to experience negative emotions, are associated with worse mental and physical health. Studies examining links between neuroticism and health typically operationalize neuroticism by summing the items from a neuroticism scale. However, neuroticism is made up of multiple heterogeneous facets, each contributing to the effect of neuroticism as a whole. A recent study showed that a 12-item neuroticism scale described one broad trait of general neuroticism and two special factors, one characterizing the extent to which people worry and feel vulnerable, and the other characterizing the extent to which people are anxious and tense. This study also found that, although individuals who were higher on general neuroticism lived shorter lives, individuals whose neuroticism was characterized by worry and vulnerability lived longer lives. Here, we examine the genetic contributions to the two special factors of neuroticism—anxiety/tension and worry/vulnerability—and how they contrast with that of general neuroticism. First, we show that, whereas the polygenic load for neuroticism is associated with the genetic risk of coronary artery disease, lower intelligence, lower socioeconomic status (SES), and poorer self-rated health, the genetic variants associated with high levels of anxiety/tension, and high levels of worry/vulnerability are associated with genetic variants linked to higher SES, higher intelligence, better self-rated health, and longer life. Second, we identify genetic variants that are uniquely associated with these protective aspects of neuroticism. Finally, we show that different neurological pathways are linked to each of these neuroticism phenotypes.</p