Cytotoxicity and DNA damage in the neutrophils of patients with sickle cell anaemia treated with hydroxyurea

Hydroxyurea (HU) is the most important advance in the treatment of sickle cell anaemia (SCA) for preventing complications and improving quality of life for patients. However, some aspects of treatment with HU remain unclear, including their effect on and potential toxicity to other blood cells such as neutrophils. This study used the measurement of Lactate Dehydrogenase (LDH) and Methyl ThiazolTetrazolium (MTT) and the comet assay to investigate the cytotoxicity and damage index (DI) of the DNA in the neutrophils of patients with SCA using HU.In the LDH and MTT assays, a cytoprotective effect was observed in the group of patients treated, as well as an absence of toxicity. When compared to patients without the treatment, the SS group (n=20, 13 women and 07 men, aged 18-69 years), and the group of healthy individuals (AA) used as a control group (n=52, 28 women and 24 men, aged 19-60 years), The SSHU group (n=21, 11 women and 10 men, aged 19-63 years) showed a significant reduction (p20 months), demonstrating that despite the cytoprotective effects in terms of cell viability, the use of HU can induce DNA damage in neutrophils

The impact of heavy reflectors on power distribution perturbations in large PWR reactor cores

International audienceThe paper is intended to provide a simple – but general – overview of the question of neutronics coupling in large PWR cores. As an example, we have investigated the sensitivity of the radial power distribution in the core to the nature of the reflector (conventional vs. a “heavy” stainless-steel one). This was done by applying a perturbation to some peripheral assemblies of the UAM GEN-III benchmark with a fresh fuel core. The perturbation was selected to simulate possible assembly bowing effects, causing a variation of the inter-assembly water gap, which can generate an azimuthal asymmetry in the power distribution. This is conventionally referred to as a ‘power tilt’. The amplification effect of the reflector on the power tilt for fresh fuel has been addressed in two steps. Firstly, we have compared the power tilt, computed with the deterministic code CRONOS2 (the neutronics diffusion module of the HEMERA chain) to that found with the probabilistic transport code MCNP, so as to validate the CRONOS2 response against a Monte Carlo reference and also obtain a quantification of the amplification effect at zero power. Then the thermal feedback and burn-up effects have been accounted for in the diffusion calculations so as to evaluate the sensitivity of the power tilt to the reactor operating conditions. The difference in the behavior of the cores with a conventional and a heavy reflector has been investigated through the examination of the power distributions and the dominance ratio of the systems, as well as of the assembly-wise infinite multiplication factors. Whilst the results help to explain the higher sensitivity to a peripheral perturbation of a fresh fuel heavy-reflected core compared to a conventionally-reflected one, they do not enable fully comprehensive conclusions to be drawn, especially towards End Of Cycle, due to the model assumptions and the limitation in the eigenvalue expansion. © 2016 Elsevier Lt

An extension of the generalized perturbation theory for spatial and energy collapsing

In this paper an extension of the Classical and Generalized Perturbation Theory is proposed which enables evaluating, at the 1st order, the contribution of any single spatial mesh to the variation of reactivity and reaction-rate ratios when an energy, spatial or energy/spatial collapsing is performed. An important achievement of the method is that it allows evaluating the individual asymptotic contribution of each spatial mesh to the variation, which enables investigating its spatial origin, very easily. Together with 1st order formulation, a simplified version is provided, which allows saving computation time while keeping an acceptable quality of the results. Some simple examples are provided, aimed at highlighting that the results obtained adopting the proposed formulation have a physical meaning and could be used to analyze the usual spatial/energy collapsing process in a convenient way. This formulation enlarges to the energy and spatial meshing the Classical and Generalized Perturbation Theory approaches to evaluate reactivity and reaction-rate ratio sensitivity to parameter variations. © 2010 Elsevier Ltd. All rights reserved

Advanced Numerical Simulation and Safety Demonstration of Generation IV Concepts

This paper, after stressing the current safety analysis practice for commercial reactors, investigates and discusses the new challenges facing the nuclear community in the field of advanced numerical simulation for the safety demonstration of the most attractive concepts among those selected by the Generation IV International Forum in 2002, i.e.: the High Temperature / Very High Temperature Reactors, HTR/VHTR, the Sodium Fast Reactors, SFR, and the Gas Fast Reactors, GFR. The paper widely emphasizes the new needs in terms of computation, validation and experimental qualification of computer codes and chains which show-up as a consequence of a new design and an advanced operation. All those needs engender new and quite challenging requests for well fitted experimental programs and connected R&D activities

Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance

PARP inhibitors (PARPi) induce synthetic lethality in homologous recombination repair (HRR)-deficient tumors and are used to treat breast, ovarian, pancreatic, and prostate cancers. Multiple PARPi resistance mechanisms exist, most resulting in restoration of HRR and protection of stalled replication forks. ATR inhibition was highlighted as a unique approach to reverse both aspects of resistance. Recently, however, a PARPi/WEE1 inhibitor (WEE1i) combination demonstrated enhanced antitumor activity associated with the induction of replication stress, suggesting another approach to tackling PARPi resistance. We analyzed breast and ovarian patientderived xenoimplant models resistant to PARPi to quantify WEE1i and ATR inhibitor (ATRi) responses as single agents and in combination with PARPi. Biomarker analysis was conducted at the genetic and protein level. Metabolite analysis by mass spectrometry and nucleoside rescue experiments ex vivo were also conducted in patient-derived models. Although WEE1i response was linked to markers of replication stress, including STK11/RB1 and phospho-RPA, ATRi response associated with ATM mutation. When combined with olaparib, WEE1i could be differentiated from the ATRi/olaparib combination, providing distinct therapeutic strategies to overcome PARPi resistance by targeting the replication stress response. Mechanistically, WEE1i sensitivity was associated with shortage of the dNTP pool and a concomitant increase in replication stress. Targeting the replication stress response is a valid therapeutic option to overcome PARPi resistance including tumors without an underlying HRR deficiency. These preclinical insights are now being tested in several clinical trials where the PARPi is administered with either the WEE1i or the ATRi