Targeting Hsp27/eIF4E interaction with phenazine compound: A promising alternative for castration-resistant prostate cancer treatment

The actual strategy to improve current therapies in advanced prostate cancer involves targeting genes activated by androgen withdrawal, either to delay or prevent the emergence of the castration-refractory phenotype. However, these genes are often implicated in several physiological processes, and long-term inhibition of survival proteins might be accompanied with cytotoxic effects. To avoid this problem, an alternative therapeutic strategy relies on the identification and use of compounds that disrupt specific protein-protein interactions involved in androgen withdrawal. Specifically, the interaction of the chaperone protein Hsp27 with the initiation factor eIF4E leads to the protection of protein synthesis initiation process and enhances cell survival during cell stress induced by castration or chemotherapy. Thus, in this work we aimed at i) identifying the interaction site of the Hsp27/eIF4E complex and ii) interfere with the relevant protein/protein association mechanism involved in castration-resistant progression of prostate cancer. By a combination of experimental and modeling techniques, we proved that eIF4E interacts with the C-terminal part of Hsp27, preferentially when Hsp27 is phosphorylated. We also observed that the loss of this interaction increased cell chemo-and hormone-sensitivity. In order to find a potential inhibitor of Hsp27/eIF4E interaction, BRET assays in combination with molecular simulations identified the phenazine derivative 14 as the compound able to efficiently interfere with this protein/protein interaction, thereby inhibiting cell viability and increasing cell death in chemo- and castration-resistant prostate cancer models in vitro and in vivo

Study and optimization of freeze-drying cycles of a model probiotic strain

[EN] This work is based on the experimental study of the freeze-drying process to understand the impact of numerous factors on the survival rates of a model probiotic strain of Lactobacillus casei type. With the aim to find out if cell density in the matrix and survival rates are linked, we have studied the location of the cells after freeze drying inside a porous matrix composed of a lactose basis with a polymer, the polyvinylpyrrolidone (PVP) in various amounts. The best survival rate were obtained at slow freezing rate for a formulation containing 5% (m/V) of lactose and 5% (m/V) of PVP.Verlhac, P.; Vessot-Crastes, S.; Degobert, G.; Cogné, C.; Andrieu, J.; Beney, L.; Gervais, P. (2018). Study and optimization of freeze-drying cycles of a model probiotic strain. En IDS 2018. 21st International Drying Symposium Proceedings. Editorial Universitat Politècnica de València. 635-642. https://doi.org/10.4995/IDS2018.2018.7400OCS63564

Financial fragmentation and SMEs’ access to finance

This paper focuses on the impact of financial fragmentation on small and medium enterprises (SMEs)’ access to finance. We combine country-level data on financial fragmentation and the ECB’s SAFE (Survey on the Access to Finance of Enterprises) data for 12 European Union (EU) countries over 2009-2016. Our findings indicate that an increase in financial fragmentation not only raises the probability of all firms to be rationed but also to be charged higher loan rates; in addition, it increases the likelihood of borrower discouragement and it impairs firms’ perceptions of the future availability of bank funds. Less creditworthy firms are even more likely to become credit rationed, suggesting a flight to quality effect in lending. However, our study also documents a potential adverse effect of increasing bank market power resulting from greater integration. This suggests that financial integration could impair firms’ financing, if not accompanied by policy initiatives aimed at maintaining an optimal level of competition in the banking sector

World-Wide FINGERS Network: A global approach to risk reduction and prevention of dementia

© 2020 The Authors. Alzheimer\u27s & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer\u27s Association Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer\u27s disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline—from at-risk asymptomatic states to early symptomatic stages—in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies

Etude des mécanismes d'action d'Hsp 27 responsables de l'évolution androgéno-indépendante des cancers de la prostate : mise en évidence de nouvelles stratégies thérapeutiques.

Le cancer de la prostate (CaP) est devenu un véritable problème de santé publique dans les pays industrialisés. L'hormonothérapie reste le traitement de première ligne le plus efficace dans les cancers avancés mais il n'empêche pas la progression vers un stade androgéno-indépendant (AI), pour lequel la chimiothérapie s'avère peu efficace. Une des stratégies pour améliorer les thérapies actuelles consiste à cibler des gènes de survie surexprimés dans les CaPs AI afin de restaurer la sensibilité aux traitements du CaPs. Hsp27, protéine surexprimée dans ces cancers, à un effet cytoprotecteur qui engendre une résistance aux traitements. Elle est maintenant reconnue comme une cible thérapeutique importante. Rocchi et al. ont développé un oligonucléotide antisense (ASO) de deuxième génération (OGX-427) qui cible l'ARNm d'Hsp27. OGX-427 est actuellement en essai clinique phase II chez des patients atteints de CaPs au Canada et aux Etats-Unis. Mon projet de thèse a porté sur l'étude des mécanismes d'action d'Hsp27 impliqués dans l'évolution AI du CaP. Cette étude a pour but d'améliorer la sureté pharmacologique d'OGX-427, mais aussi d'identifier de nouvelles cibles thérapeutiques visant spécifiquement les cellules tumorales. Mes travaux de thèse ont montré que lors d'un stress cellulaire induit par hormonothérapie et/ou chimiothérapie, Hsp27 interagit avec le facteur eucaryotique d'initiation de la traduction eIF4E et le protège de sa dégradation par la voie ubiquitine/protéasome. Ceci maintient la synthèse protéique et engendre une survie cellulaire impliquée en partie dans l'effet cytoprotecteur médié par Hsp27.Prostate cancer (PC) has become a real public health issue in industrialized countries, mainly due to patients' relapse by castration-resistant (CR) disease after androgen ablation. One strategy to improve current therapies in advanced PC involves targeting genes that are activated by androgen withdrawal, either to delay or prevent the emergence of the CR phenotype. Hsp27 is over-expressed in this cancer and has been shown to play a cytoprotective role leading to treatments resistance. This protein is now considered as promising therapeutic target. Rocchi, P. et al. developed and patented a second generation antisens oligonucleotides (ASO) targeting Hsp27 that has been licensed (OGX-427) and phase II clinical trials are currently in process in PC in Canada and USA. My PhD project focused on the study of Hsp27 action mechanisms involved in CRPC progression. The present study aims to improve pharmacological safety of OGX-427 and to identify new therapeutic targets specific of CRPC cells. The results of my PhD have shown that during cell stress induced by hormone- and/or chemotherapy, Hsp27 interacts with eukaryotic translation initiation factor eIF4E and protects it from degradation by the ubiquitin/proteasome pathway. This maintains protein synthesis and leads to cell survival, partly involved in the cytoprotection mediated by Hsp27. Our work therefore concerned the characterization of the interaction site between Hsp27 and eIF4E in order to identify potential inhibitors of this interaction that could delay CRPC progression

Experimental data and modelling of thermal properties of ice creams

International audienc

Thermodynamic Properties and Water States in Ternary PVP/Lactose/Water Frozen Systems

International audienc

Crisis y cambios en el Clásico Tardío: los retos económicos de una ciudad entre Tierras Altas y Tierras Bajas mayas

International audienc

Study and optimization of freeze-drying cycles of model probiotic: Morphology characterization of Lyophilisates by SEM

International audienceThese experimental data are concerning the optimization of freeze-dryingcycles of a model type Casei probiotic bacteria with water based formulationsusing lactose and polymer polyvinylpyrolidone (PVP) as cry/lyo protectants.After a previous study devoted to the influence of the main freeze-dryingparameters (freezing rates; shelf temperature; total gas pressure) on thebacteria survival ratios, this paper reports some morphological data obtainedby scanning electron microscopy (SEM) with the final lyophilisates.The numerous and original SEM images realized with different formulationsof water binary or ternary mixtures with fixed operating conditions proved tobe very useful to explain and to understand the different bacteria survivalratios observed.,Thus, with bacteria or micro-organisms systems, this powerful investigationmethod of characterization of lyophilisates morphology should be morelargely used in the future for setting up the optimal formulations parameters(composition) and the connected operating physical parameters of freezedrying steps (freezing rate, shelf temperature, total gas pressure)