Development of a robust DNA damage model including persistent telomere-associated damage with application to secondary cancer risk assessment

Mathematical modelling has been instrumental to understand kinetics of radiation-induced DNA damage repair and associated secondary cancer risk. The widely accepted two-lesion kinetic (TLK) model assumes two kinds of double strand breaks, simple and complex ones, with different repair rates. Recently, persistent DNA damage associated with telomeres was reported as a new kind of DNA damage. We therefore extended existing versions of the TLK model by new categories of DNA damage and re-evaluated those models using extensive data. We subjected different versions of the TLK model to a rigorous model discrimination approach. This enabled us to robustly select a best approximating parsimonious model that can both recapitulate and predict transient and persistent DNA damage after ionizing radiation. Models and data argue for i) nonlinear dose-damage relationships, and ii) negligible saturation of repair kinetics even for high doses. Additionally, we show that simulated radiation-induced persistent telomere-associated DNA damage foci (TAF) can be used to predict excess relative risk (ERR) of developing secondary leukemia after fractionated radiotherapy. We suggest that TAF may serve as an additional measure to predict cancer risk after radiotherapy using high dose rates. This may improve predicting risk-dose dependency of ionizing radiation especially for long-term therapies

FoCo: a simple and robust quantification algorithm of nuclear foci

BACKGROUND: The number of γH2AX foci per nucleus is an accepted measure of the number of DNA double-strand breaks in single cells. One of the experimental techniques for γH2AX detection in cultured cells is immunofluorescent labelling of γH2AX and nuclei followed by microscopy imaging and analysis. RESULTS: In this study, we present the algorithm FoCo for reliable and robust automatic nuclear foci counting in single cell images. FoCo has the following advantages with respect to other software packages: i) the ability to reliably quantify even densely distributed foci, e.g., on images of cells subjected to radiation doses up to 10 Gy, ii) robustness of foci quantification in the sense of suppressing out-of-focus background signal, and iii) its simplicity. FoCo requires only 5 parameters that have to be adjusted by the user. CONCLUSIONS: FoCo is an open-source user-friendly software with GUI for individual foci counting, which is able to produce reliable and robust foci quantifications even for low signal/noise ratios and densely distributed foci. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12859-015-0816-5) contains supplementary material, which is available to authorized users

ENANTIOSELECTIVE [2+2+2] CYCLOISOMERISATION OF ALKYNES IN THE SYNTHESIS OF HELICENES: THE SEARCH FOR EFFECTIVE CHIRAL LIGANDS

The enantioselective [2+2+2] cycloisomerisation of the aromatic triynes under nickel(0) catalysis to afford nonracemic [6]- and [7]helicene derivatives has been systematically studied. A collection of mono- and bidentate phosphines, phosphites, phosphinites and phosphinous amides possessing stereogenic units such as chiral centre, axis or plane (or their combinations) has been tested and axially chiral binaphthyl-derived monodentate MOP-type phosphine ligands were the optimal class of ligands. Nickel complexes of these ligands afforded nonracemic tetrahydro[6]helicene in up to 64% ee in a model reaction.</jats:p