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

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

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

Translational regulation of the mRNA encoding the ubiquitin peptidase USP1 involved in the DNA damage response as a determinant of Cisplatin resistance

<p>Cisplatin (cis-diaminedichloroplatin (II), CDDP) is part of the standard therapy for a number of solid tumors including Non-Small-Cell Lung Cancer (NSCLC). The initial response observed is in most cases only transient and tumors quickly become refractory to the drug. Tumor cell resistance to CDDP relies on multiple mechanisms, some of which still remain unknown. In search for such mechanisms, we examined the impact of CDDP on mRNA translation in a sensitive and in a matched resistant NSCLC cell line. We identified a set of genes whose mRNAs are differentially translated in CDDP resistant vs. sensitive cells. The translation of the mRNA encoding the Ubiquitin-Specific Peptidase 1 (USP1), a Ubiquitin peptidase with important function in multiple DNA repair pathways, is inhibited by CDDP exposure in the sensitive cells, but not in the resistant cells. This lack of down-regulation of USP1 expression at the translational level plays a primary role in CDDP resistance since inhibition of USP1 expression or activity by siRNA or the small molecule inhibitor ML323, respectively is sufficient to re-sensitize resistant cells to CDDP. We involved the USP1 mRNA translation as a major mechanism of CDDP resistance in NSCLC cells and suggest that USP1 could be evaluated as a candidate predictive marker and as a therapeutic target to overcome CDDP resistance. More generally, our results indicate that analysis of gene expression at the level of mRNA translation is a useful approach to identify new determinants of CDDP resistance.</p

An epitranscriptomic mechanism underlies selective mRNA translation remodelling in melanoma persister cells

International audienceCancer persister cells tolerate anticancer drugs and serve as the founders of acquired resistance and cancer relapse. Here we show that a subpopulation of BRAFV600 mutant melanoma cells that tolerates exposure to BRAF and MEK inhibitors undergoes a reversible remodelling of mRNA translation that evolves in parallel with drug sensitivity. Although this process is associated with a global reduction in protein synthesis, a subset of mRNAs undergoes an increased efficiency in translation. Inhibiting the eIF4A RNA helicase, a component of the eIF4F translation initiation complex, abrogates this selectively increased translation and is lethal to persister cells. Translation remodelling in persister cells coincides with an increased N6-methyladenosine modification in the 5'-untranslated region of some highly translated mRNAs. Combination of eIF4A inhibitor with BRAF and MEK inhibitors effectively inhibits the emergence of persister cells and may represent a new therapeutic strategy to prevent acquired drug resistance