Subsequent and simultaneous electrophysiological investigation of the retina and the visual cortex in neurodegenerative and psychiatric diseases: what are the forecasts for the medicine of tomorrow?

Visual electrophysiological deficits have been reported in neurodegenerative disorders as well as in mental disorders. Such alterations have been mentioned in both the retina and the cortex, notably affecting the photoreceptors, retinal ganglion cells (RGCs) and the primary visual cortex. Interestingly, such impairments emphasize the functional role of the visual system. For this purpose, the present study reviews the existing literature with the aim of identifying key alterations in electroretinograms (ERGs) and visual evoked potentials electroencephalograms (VEP-EEGs) of subjects with neurodegenerative and psychiatric disorders. We focused on psychiatric and neurodegenerative diseases due to similarities in their neuropathophysiological mechanisms. Our research focuses on decoupled and coupled ERG/VEP-EEG results obtained with black-and-white checkerboards or low-level visual stimuli. A decoupled approach means recording first the ERG, then the VEP-EEG in the same subject with the same visual stimuli. The second method means recording both ERG and VEP-EEG simultaneously in the same participant with the same visual stimuli. Both coupled and decoupled results were found, indicating deficits mainly in the N95 ERG wave and the P100 VEP-EEG wave in Parkinson’s, Alzheimer’s, and major depressive disorder. Such results reinforce the link between the retina and the visual cortex for the diagnosis of psychiatric and neurodegenerative diseases. With that in mind, medical devices using coupled ERG/VEP-EEG measurements are being developed in order to further investigate the relationship between the retina and the visual cortex. These new techniques outline future challenges in mental health and the use of machine learning for the diagnosis of mental disorders, which would be a crucial step toward precision psychiatry

The translation initiation complex eIF4F is involved in resistance to MAPK inhibitors

Le mélanome métastatique est un des cancers les plus agressifs avec une croissance constante du nombre de nouveaux cas par an dans le monde.Deux mutations sont principalement à l’origine de ce cancer : BRAF(V600) et NRAS(Q61). Les principaux traitements sont des thérapies ciblant BRAF lui-même ou MEK, prescrites en monothérapie ou en combinaison. La moitié des patients répondent à ce traitement mais malheureusement rechutent dans les 6 mois à 1 an après le début du traitement. Les mécanismes de résistance décrits passent par une réactivation de la voie des MAPK, de la voie PI3K/Akt/mTOR ou par une dérégulation de l’apoptose.Les deux premières voies de signalisation permettent la régulation d’un complexe : le complexe d’initiation de la traduction eIF4F. Ce complexe est composé de 3 protéines : eIF4E, une protéine qui s’associe à la coiffe 7-methyl-guanosine, eIF4A une hélicase et eIF4G une protéine échafaudage dont un des rôles est de maintenir la cohésion de ce complexe.Le complexe eIF4F étant en aval de deux voies dérégulées dans le mélanome, le but de ma thèse a été de mettre en évidence une potentielle implication de ce complexe dans la résistance aux thérapies ciblant BRAF et MEK.Pour cela, dans un premier temps, nous avons traiter des lignées cellulaires de mélanome BRAF(V600) sensibles et résistantes aux anti-BRAF et anti-MEK. Nous avons ensuite quantifié les interactions eIF4E-eIF4G, synonymes d’activation du complexe eIF4F, et les interactions eIF4E-4EBP1, synonymes d’inhibition de la traduction par une technique de Proximity Ligation Assay (PLA). Ces expériences ont permis de conclure que les inhibiteurs de BRAF et de MEK induisaient une dissociation du complexe dans les lignées sensibles, alors qu’il reste maintenu dans les lignées résistantes. Ces résultats ont été confirmés sur des tumeurs de patients répondeurs et non répondeurs à ces mêmes traitements. Par la suite, nous avons reproduits ces expériences avec un panel de lignées cellulaires mutées en NRAS(Q61) et avons observé les mêmes résultats.Nous avons donc pu mettre en évidence l’implication du complexe eIF4F dans la résistance aux thérapies ciblant la voie des MAPK dans les mélanomes mutés en BRAF et en NRAS, mais également découvert une nouvelle cible thérapeutique potentielle.La seconde partie de cette thèse a consisté au test de plusieurs inhibiteurs connus et spécifiques d’eIF4A (silvestrol, flavaglines, hippuristanol, patéamine A) ou de l’interaction eIF4E-eIF4G (4EGI1). Tous ces inhibiteurs ont sensibilisé les lignées résistantes aux thérapies ciblées mais aucun ne pouvait être potentiellement utilisable en clinique.L’utilisation d’un vecteur bicistronique dans le cadre d’un criblage de drogue a permis d’identifier 4 flavaglines qui inhibent significativement le complexe d’initiation de la traduction. L’une d’entre elles (FL3) a été testé in vivo dans un modèle de xénogreffes issues de lignées cellulaires de mélanomes résistantes. Les résultats ont montré un effet synergique de cette drogue en combinaison avec le vemurafenib (anti-BRAF) ainsi qu’une inhibition de la croissance tumorale. En conclusion, nous avons identifié une nouvelle cible thérapeutique et un nouveau biomarqueur de résistance aux thérapies ciblées dans deux contextes mutationnels de mélanome différents : BRAF et NRAS.In BRAF(V600) or NRAS(Q61)-mutant tumours, most mechanisms of resistance to drugs that target the BRAF and/or MEK kinases rely on reactivation of the RAS–RAF–MEK–ERK mitogen-activated protein kinase (MAPK) signal transduction pathway or on activation of the alternative PI(3)K–AKT–mTOR pathway (which is ERK independent). These two pathways converge to regulate the formation of the eIF4F eukaryotic translation initiation complex. By using an in situ method to detect the eIF4E-eIF4G and eIF4E-4EBP1 interactions, we recently showed that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, is associated with resistance to anti-BRAF and/or anti-MEK in BRAF(V600)-mutant cancer cell lines. We next focused on NRAS-mutant cancer cell lines and found that this complex is also involved in the resistance to anti-MEK compounds. Strikingly, inhibiting the eIF4F complex in BRAF or NRAS-mutated cell lines is able to overcome resistance and to synergize with drugs targeting BRAF or MEK kinases. As a result, eIF4F appears to be a promising therapeutic target in a BRAF or NRAS-mutation context

Molecular Pathways: The eIF4F Translation Initiation Complex—New Opportunities for Cancer Treatment

The eIF4F complex regulates the cap-dependent mRNA translation process. It is becoming increasingly evident that aberrant activity of this complex is observed in many cancers, leading to the selective synthesis of proteins involved in tumor growth and metastasis. The selective translation of cellular mRNAs controlled by this complex also contributes to resistance to cancer treatments, and downregulation of the eIF4F complex components can restore sensitivity to various cancer therapies. Here, we review the contribution of the eIF4F complex to tumorigenesis, with a focus on its role in chemoresistance as well as the promising use of new small-molecule inhibitors of the complex, including flavaglines/rocaglates, hippuristanol, and pateamine A. Clin Cancer Res; 23(1); 21-25. ©2016 AACR

Control of ellipticity in high-order harmonic generation driven by two linearly polarized fields

International audienceWe demonstrate experimentally the control of the polarization (ellipticity and polarization axis) of femtosecond high-order harmonics. The method relies on a two-color (omega - 2 omega) configuration, where both omega and 2 omega generating fields have linear polarizations with a variable crossing angle. We correlate our measurements with the conservation rules of energy and linear momentum accounting for harmonic generation in a two-color field. We evidence that the generation process, and especially the number of omega and 2 omega photons absorbed for generating a given harmonic, strongly depends on the crossing angle. Finally, relying on a simple formalism, we derive analytical formulae for calculating both polarization axis and ellipticity of the separate harmonics. The model corroborates our results and represents a base for future investigations

Synergistic effects of eIF4A and MEK inhibitors on proliferation of NRAS-mutant melanoma cell lines

Activating mutations of the NRAS (neuroblastoma rat sarcoma viral oncogene) protein kinase, present in many cancers, induce a constitutive activation of both the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signal transduction pathway and the PI(3)K-AKT-mTOR, pathway. This in turn regulates the formation of the eIF4F eukaryotic translation initiation complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, which binds to the 7-methylguanylate cap (m(7)G) at the 5' end of messenger RNAs. Small molecules targeting MEK (MEKi: MEK inhibitors) have demonstrated activity in NRAS-mutant cell lines and tumors, but resistance sets in most cases within months of treatment. Using proximity ligation assays, that allows visualization of the binding of eIF4E to the scaffold protein eIF4G, generating the active eIF4F complex, we have found that resistance to MEKi is associated with the persistent formation of the eIF4F complex in MEKi-treated NRAS-mutant cell lines. Furthermore, inhibiting the eIF4A component of the eIF4F complex, with a small molecule of the flavagline/rocaglate family, synergizes with inhibiting MEK to kill NRAS-mutant cancer cell lines

High-Brilliance Betatron γ\gamma-Ray Source Powered by Laser-Accelerated Electrons

International audienceRecent progress in laser-driven plasma acceleration now enables the acceleration of electrons to several gigaelectronvolts. Taking advantage of these novel accelerators, ultrashort, compact, and spatially coherent x-ray sources called betatron radiation have been developed and applied to high-resolution imaging. However, the scope of the betatron sources is limited by a low energy efficiency and a photon energy in the 10 s of kiloelectronvolt range, which for example prohibits the use of these sources for probing dense matter. Here, based on three-dimensional particle-in-cell simulations, we propose an original hybrid scheme that combines a low-density laser-driven plasma accelerator with a high-density beam-driven plasma radiator, thereby considerably increasing the photon energy and the radiated energy of the betatron source. The energy efficiency is also greatly improved, with about 1% of the laser energy transferred to the radiation, and the γ-ray photon energy exceeds the megaelectronvolt range when using a 15 J laser pulse. This high-brilliance hybrid betatron source opens the way to a wide range of applications requiring MeV photons, such as the production of medical isotopes with photonuclear reactions, radiography of dense objects in the defense or industrial domains, and imaging in nuclear physics