Frédéric Collin

Oxidative stress and the amyloid beta peptide in Alzheimer’s disease

Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer’s disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level.

Evaluation of response after neoadjuvant treatment in soft tissue sarcomas; the European Organization for Research and Treatment of Cancer–Soft Tissue and Bone Sarcoma Group (EORTC–STBSG) recommendations for pathological examination and reporting

At present, there is not a commonly used and generally accepted standardized approach for the pathologic evaluation of pretreated soft tissue sarcomas. Also, it is still unclear whether the cut-off for prognostic relevance is similar in the many different histological subtypes of STS. This manuscript, produced by a European Organization for Research and Treatment of Cancer - Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) endorsed task force, aims to propose standardization of the pathological examination process and the reporting of STS resection specimens after neoadjuvant radio- and/or chemotherapy.

A phase IIb multicentre study comparing the efficacy of trabectedin to doxorubicin in patients with advanced or metastatic untreated soft tissue sarcoma: The TRUSTS trial

PURPOSE To evaluate whether trabectedin as first-line chemotherapy for advanced/metastatic soft tissue sarcoma prolongs progression-free survival (PFS), compared to doxorubicin and, in the phase IIb part here, to select the most appropriate trabectedin treatment schedule (3-hour or 24-hour infusion) in terms of safety, convenience and efficacy. PATIENTS AND METHODS In this randomised multicentre prospective dose-selection phase IIb superiority trial, 133 patients were randomised between doxorubicin (n=43), trabectedin (3-hour infusion, T3h) (n=47) and trabectedin (24-hour infusion, T24h) (n=43). PFS was defined as time from random assignment until objective progression by response evaluation criteria in solid tumours (RECIST 1.1), a global deterioration of the health status requiring discontinuation of the treatment, or death from any cause. RESULTS The study was terminated due to lack of superiority in both trabectedin treatment arms as compared to the doxorubicin control arm. Median PFS was 2.8months in the T3h arm, 3.1months in the T24h arm and 5.5months in the doxorubicin arm. No significant improvements in PFS were observed in the trabectedin arms as compared to the doxorubicin arm (T24h versus doxorubicin: hazard ratio (HR) 1.13, 95% confidence interval (CI) 0.67-1.90, P=.675; T3h versus doxorubicin: HR 1.50, 95% CI 0.91-2.48, P=.944). Only one toxic death occurred in the T3h arm, but treatment had to be stopped due to toxicity in 7 (15.2%) (T3h), 8 (19.5%) (T24h) and 1 (2.5%) doxorubicin patients. CONCLUSION Doxorubicin continues to be the standard treatment in eligible patients with advanced/metastatic soft-tissue sarcoma (STS). Trabectedin 1.5mg/m(2)/24-hour infusion is the overall proven approach to delivering this agent in the second-line setting for patients with advanced or metastatic STS.

Numerical modelling of coupled transient phenomena

ABSTRACT The basic phenomena involved in thermo-hydro-mechanical processes in geomaterials have been described in the 1st chapter. The equations describing these phenomena are non-linear differential equations. Their solution can generally only be approximated thanks to numerical methods. This is the main subject of the present chapter. First the type of problems and the set of equations to be solved will be shortly recalled. Emphasis will be given on the non-linear contributions. In a second section, the mostly developed numerical method, i.e. the finite difference and the finite element methods will be discussed under the light of the problems to be treated. The iterative techniques allowing the solution of non linear equations will be described. A third section will be dedicated to the coupling terms and to their modelling. The question that rises then is How to model efficiently problems, which may differ highly from, the point of view of the time and length scales?

Using Local Second Gradient Model and Shear Strain Localisation to Model the Excavation Damaged Zone in Unsaturated Claystone

AbstractThe drilling of galleries induces damage propagation in the surrounding medium and creates, around them, the excavation damaged zone (EDZ). The prediction of the extension and fracture structure of this zone remains a major issue, especially in the context of underground nuclear waste storage. Experimental studies on geomaterials indicate that localised deformation in shear band mode usually appears prior to fractures. Thus, the excavation damaged zone can be modelled by considering the development of shear strain localisation bands. In the classical finite element framework, strain localisation suffers a mesh-dependency problem. Therefore, an enhanced model with a regularisation method is required to correctly model the strain localisation behaviour. Among the existing methods, we choose the coupled local second gradient model. We extend it to unsaturated conditions and we include the solid grain compressibility. Furthermore, air ventilation inside underground galleries engenders a rock–atmosphere interaction that could influence the damaged zone. This interaction has to be investigated in order to predict the damaged zone behaviour. Finally, a hydro-mechanical modelling of a gallery excavation in claystone is presented and leads to a fairly good representation of the EDZ. The main objectives of this study are to model the fractures by considering shear strain localisation bands, and to investigate if an isotropic model accurately reproduces the in situ measurements. The numerical results provide information about the damaged zone extension, structure and behaviour that are in very good agreement with in situ measurements and observations. For instance, the strain localisation bands that develop in chevron pattern during the excavation and rock desaturation, due to air ventilation, are observed close to the gallery.

Hollow Cylinder Tests on Boom Clay: Modelling of Strain Localization in the Anisotropic Excavation Damaged Zone

Boom Clay is extensively studied as a potential candidate to host underground nuclear waste disposal in Belgium. To guarantee the safety of such a disposal, the mechanical behaviour of the clay during gallery excavation must be properly predicted. In that purpose, a hollow cylinder experiment on Boom Clay has been designed to reproduce, in a small-scale test, the Excavation Damaged Zone (EDZ) as experienced during the excavation of a disposal gallery in the underground. In this article, the focus is made on the hydro-mechanical constitutive interpretation of the displacement (experimentally obtained by medium resolution X-ray tomography scanning). The coupled hydro-mechanical response of Boom Clay in this experiment is addressed through finite element computations with a constitutive model including strain hardening/softening, elastic and plastic cross-anisotropy and a regularization method for the modelling of strain localization processes. The obtained results evidence the directional dependency of the mechanical response of the clay. The softening behaviour induces transient strain localization processes, addressed through a hydro-mechanical second grade model. The shape of the obtained damaged zone is clearly affected by the anisotropy of the materials, evidencing an eye-shaped EDZ. The modelling results agree with experiments not only qualitatively (in terms of the shape of the induced damaged zone), but also quantitatively (for the obtained displacement in three particular radial directions).

Numerical post failure methods in multiphysical problems

La rupture dans les geomateriaux est souvent precedee par la formation de fines bandes de localisation des deformations. La formation de ces bandes de localisation est un processus non negligeable, etudie a la fois sur le plan experimental et sur le plan theorique. Cet article resume les principaux phenomenes observes sur les processus localises et propose quelques outils theoriques et numeriques necessaires a la caracterisation de ces processus de localisation. Afin de tenir compte des interactions entre les differentes phases des milieux poreux, une technique de regularisation basee sur des modeles de type second gradient est etendue aux couplages mutiphysiques.

Local Second Gradient Models and Damage Mechanics: 1D Post-Localization Studies in Concrete Specimens

Continuum damage mechanics is often used as a framework for describing the variations of the elastic properties of due to micro-structural degradations. Experimentally, concrete specimens exhibit a network of microscopic cracks that nucleate sub-parallel to the axis of loading. Due to the presence of heterogeneities in the material (aggregates surrounded by a cement matrix), tensile transverse strains generate a self-equilibrated stress field orthogonal to the loading direction, a pure mode I (extension) is thus considered to describe the behaviour even in compression. This rupture mode must be reproduced numerically. This is the reason why the failure criterion of the chosen constitutive law is expressed in terms of the principal extensions and that a tension test is modelled at the end of this paper. The influence of micro-cracking due to the external loads is introduced via damage variables, ranging from 0 for the undamaged material to 1 for a completely damaged material.

On micromechanical damage modeling in geomechanics: Influence of numerical integration scheme

Tunnel excavations in deep rocks provide stress perturbations which initiate diffuse and/or localized damage propagation in the material. This damage phenomenon can lead to significant irreversible deformations and changes in rock properties. In this paper, we propose to model such behavior by considering a micromechanically-based damage approach. The resulting micromechanical model, which also accounts for initial stress, is described and assessed through the numerical analysis of a synthetic tunnel drilling in Opalinus Clay. A particular emphasis is put on the numerical integration of the model. In particular, an appropriate choice of the latter is required to ensure the numerical stability and a confident prediction of excavation damaged zone around tunnels.

Cyclic and Fatigue Behaviour of Rock Materials: Review, Interpretation and Research Perspectives

The purpose of this paper is to provide a comprehensive state of the art of fatigue and cyclic loading of natural rock materials. Papers published in the literature are classified and listed in order to ease bibliographical review, to gather data (sometimes contradictory) on classical experimental results and to analyse the main interpretation concepts. Their advantages and limitations are discussed, and perspectives for further work are highlighted. The first section summarises and defines the different experimental set-ups (type of loading, type of experiment) already applied to cyclic/fatigue investigation of rock materials. The papers are then listed based on these different definitions. Typical results are highlighted in next section. Fatigue/cyclic loading mainly results in accumulation of plastic deformation and/or damage cycle after cycle. A sample cyclically loaded at constant amplitude finally leads to failure even if the peak load is lower than its monotonic strength. This subcritical crack is due to a diffuse microfracturing and decohesion of the rock structure. The third section reviews and comments the concepts used to interpret the results. The fatigue limit and S–N curves are the most common concepts used to describe fatigue experiments. Results published from all papers are gathered into a single figure to highlight the tendency. Predicting the monotonic peak strength of a sample is found to be critical in order to compute accurate S–N curves. Finally, open questions are listed to provide a state of the art of grey areas in the understanding of fatigue mechanisms and challenges for the future.