Characterisation of cytotoxicity and DNA damage induced by the topoisomerase II-directed bisdioxopiperazine anti-cancer agent ICRF-187 (dexrazoxane) in yeast and mammalian cells

BACKGROUND: Bisdioxopiperazine anti-cancer agents are inhibitors of eukaryotic DNA topoisomerase II, sequestering this protein as a non-covalent protein clamp on DNA. It has been suggested that such complexes on DNA represents a novel form of DNA damage to cells. In this report, we characterise the cytotoxicity and DNA damage induced by the bisdioxopiperazine ICRF-187 by a combination of genetic and molecular approaches. In addition, the well-established topoisomerase II poison m-AMSA is used for comparison. RESULTS: By utilizing a panel of Saccharomyces cerevisiae single-gene deletion strains, homologous recombination was identified as the most important DNA repair pathway determining the sensitivity towards ICRF-187. However, sensitivity towards m-AMSA depended much more on this pathway. In contrast, disrupting the post replication repair pathway only affected sensitivity towards m-AMSA. Homologous recombination (HR) defective irs1SF chinese hamster ovary (CHO) cells showed increased sensitivity towards ICRF-187, while their sensitivity towards m-AMSA was increased even more. Furthermore, complementation of the XRCC3 deficiency in irs1SF cells fully abrogated hypersensitivity towards both drugs. DNA-PK(cs )deficient V3-3 CHO cells having reduced levels of non-homologous end joining (NHEJ) showed slightly increased sensitivity to both drugs. While exposure of human small cell lung cancer (SCLC) OC-NYH cells to m-AMSA strongly induced γH2AX, exposure to ICRF-187 resulted in much less induction, showing that ICRF-187 generates fewer DNA double strand breaks than m-AMSA. Accordingly, when yeast cells were exposed to equitoxic concentrations of ICRF-187 and m-AMSA, the expression of DNA damage-inducible genes showed higher levels of induction after exposure to m-AMSA as compared to ICRF-187. Most importantly, ICRF-187 stimulated homologous recombination in SPD8 hamster lung fibroblast cells to lower levels than m-AMSA at all cytotoxicity levels tested, showing that the mechanism of action of bisdioxopiperazines differs from that of classical topoisomerase II poisons in mammalian cells. CONCLUSION: Our results point to important differences in the mechanism of cytotoxicity induced by bisdioxopiperazines and topoisomerase II poisons, and suggest that bisdioxopiperazines kill cells by a combination of DNA break-related and DNA break-unrelated mechanisms

A recursive kinematic random forest and alpha beta filter classifier for 2D radar tracks

In this work, we show that by using a recursive random forest together with an alpha beta filter classifier it is possible to classify radar tracks from the tracks’ kinematic data. The kinematic data is from a 2D scanning radar without Doppler or height information. We use random forest as this classifier implicit handles the uncertainty in the position measurements. As stationary targets can have an apparently high speed because of the measurement uncertainty, we use an alpha beta filter classifier to classify stationary targets from moving targets. We show an overall classification rate from simulated data at 82.6 % and from real world data 79.7 %. Additional to the confusion matrix we also show recordings of real world data

Self-Rated Health as a Predictor of Death after Two Years:The Importance of Physical and Mental Wellbeing Postintensive Care

Introduction. The objective of this study is, among half-year intensive care survivors, to determine whether self-assessment of health can predict two-year mortality. Methods. The study is a prospective cohort study based on the Procalcitonin and Survival Study trial. Half-year survivors from this 1200-patient multicenter intensive care trial were sent the SF-36 questionnaire. We used both a simple one-item question and multiple questions summarized as a Physical Component Summary (PCS) and a Mental Component Summary (MCS) score. The responders were followed for vital status 730 days after inclusion. Answers were dichotomized into a low-risk and a high-risk group and hazard ratios (HR) with 95% confidence interval (CI) were calculated by Cox proportional hazard analyses. Conclusion. We found that self-rated health measured by a single question was a strong independent predictor of two-year all-cause mortality (HR: 1.8; 95% CI: 1.1–3.0). The multi-item component scores of the SF-36 also predicted two-year mortality (PCS: HR: 2.9; 95% CI 1.7–5.0) (MCS: HR: 1.9; 95% CI 1.1–3.4). These results suggest that self-rated health questions could help in identifying patients at excess risk. Randomized controlled trials are needed to test whether our findings represent causality

Effective interactions and large-scale diagonalization for quantum dots

The widely used large-scale diagonalization method using harmonic oscillator basis functions (an instance of the Rayleigh-Ritz method, also called a spectral method, configuration-interaction method, or ``exact diagonalization'' method) is systematically analyzed using results for the convergence of Hermite function series. We apply this theory to a Hamiltonian for a one-dimensional model of a quantum dot. The method is shown to converge slowly, and the non-smooth character of the interaction potential is identified as the main problem with the chosen basis, while on the other hand its important advantages are pointed out. An effective interaction obtained by a similarity transformation is proposed for improving the convergence of the diagonalization scheme, and numerical experiments are performed to demonstrate the improvement. Generalizations to more particles and dimensions are discussed.Comment: 7 figures, submitted to Physical Review B Single reference error fixe