Editor's Note: EGFR Activation and Signaling in Cancer Cells Are Enhanced by the Membrane-Bound Metalloprotease MT4-MMP.

peer reviewedThe editors are publishing this note to alert readers to concerns about this article (1). In Fig. 2, the actin loading control bands for cyclin D1 and cyclin D2 are identical-the authors clarified that the Western blots for cyclin D1 and cyclin D2 were performed on the same samples, however, this was not indicated in the figure legend. Additionally, in Fig. 6C, the p-EGFR bands in MDA-MB-231 cells showing stimulation by TGFa treatment are identical to the p-EGFR bands showing stimulation by EGF treatment. In the original submission of this manuscript, a correct version of this figure was used to show both TGFa and EGF could stimulate p-EGFR in control vector (CTR)- and MT4-MMP-expressing (MT4) MDA-MB-231 cells, but these panels were mistakenly duplicated in the revised and final versions of the manuscript

Tumor resistance to ferroptosis driven by Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells and Fatty Acid Biding Protein-4 (FABP4) in tumor microenvironment promote tumor recurrence.

PROBLEM: Tumor recurrence is a major clinical issue that represents the principal cause of cancer-related deaths, with few targetable common pathways. Mechanisms by which residual tumors persist and progress under a continuous shift between hypoxia-reoxygenation after neoadjuvent-therapy are unknown. In this study, we investigated the role of lipid metabolism and tumor redox balance in tumor recurrence. METHODS: Lipidomics, proteomics and mass spectrometry imaging approaches where applied to mouse tumor models of recurrence. Genetic and pharmacological inhibitions of lipid mediators in tumors were used in vivo and in functional assays in vitro. RESULTS: We found that stearoyl-CoA desaturase-1 (SCD1) expressed by cancer cells and fatty acid binding protein-4 (FABP4) produced by tumor endothelial cells (TECs) and adipocytes in the tumor microenvironment (TME) are essential for tumor relapse in response to tyrosine kinase inhibitors (TKI) and chemotherapy. SCD1 and FABP4 were also found upregulated in recurrent human breast cancer samples and correlated with worse prognosis of cancer patients with different types of tumors. Mechanistically, SCD1 leads to fatty acid (FA) desaturation and FABP4 derived from TEM enhances lipid droplet (LD) in cancer cells, which cooperatively protect from oxidative stress-induced ferroptosis. We revealed that lipid mobilization and desaturation elicit tumor intrinsic antioxidant and anti-ferroptotic resources for survival and regrowth in a harsh TME. Inhibition of lipid transport from TME by FABP4 inhibitor reduced tumor regrowth and by genetic - or by pharmacological - targeting SCD1 in vivo, tumor regrowth was abolished completely. CONCLUSION: This finding unveils that it is worth taking advantage of tumor lipid addiction, as a tumor vulnerability to design novel treatment strategy to prevent cancer recurrence

Observance des patients sous antivitamines K (connaissance des patients et gestion de leur traitement)

Un pour cent de la population bénéficie d'un traitement anticoagulant. Les anticoagulants sont responsables de 18000 hospitalisations par an, les accidents hémorragiques étant les motifs les plus fréquents. il s'agit là d'un véritable problème de santé publique, étant donné le caractère indispensable de ces médicaments dans certaines pathologies et la fréquence de sa prescription. Une bonne observance médicamenteuse est indispensable pour réduire le nombre d'accidents iatrogènes. La connaissance et la compréhension du traitement par le patient et sa capacité à le gérer sont des facteurs indispensables à une bonne observance. C'est à l'aide d'un questionnaire simple et adapté aux patients, relatif aux connaissances et à la gestion de leur traitement, que j ai tenté d'évaluer les facteurs favorisant la mauvaise observance thérapeutique. Ce questionnaire a été distribué dans des cabinets de médecine de ville ou à l hôpital, sur la Guadeloupe. Il était distribué aux patients sous AVK qui le remplissaient seul et le remettaient par la suite de manière anonyme dans une urne. Soixante-deux patients ont répondu à cette étude, permettant de souligner des lacunes dans la connaissance et la gestion du traitement et d'évoquer des causes à celles-ci. Des recommandations officielles récentes existent pour accompagner les patients et les aider à gérer leur traitement, montrant bien que ce problème est loin d'être résolu, mais que des solutions se présentent pour réduire le risque iatrogène des anticoagulants oraux : outils d'aide à l'observance, éducation thérapeutique, recherche sur de nouveaux médicaments.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

A novel Nodal enhancer dependent on pluripotency factors and Smad2/3 signaling conditions a regulatory switch during epiblast maturation

During early development, modulations in the expression of Nodal, a TGFβ family member, determine the specification of embryonic and extra-embryonic cell identities. Nodal has been extensively studied in the mouse, but aspects of its early expression remain unaccounted for. We identified a conserved hotspot for the binding of pluripotency factors at the Nodal locus and called this sequence “highly bound element” (HBE). Luciferase-based assays, the analysis of fluorescent HBE reporter transgenes, and a conditional mutation of HBE allowed us to establish that HBE behaves as an enhancer, is activated ahead of other Nodal enhancers in the epiblast, and is essential to Nodal expression in embryonic stem cells (ESCs) and in the mouse embryo. We also showed that HBE enhancer activity is critically dependent on its interaction with the pluripotency factor Oct4 and on Activin/Nodal signaling. Use of an in vitro model of epiblast maturation, relying on the differentiation of ESCs into epiblast stem cells (EpiSCs), revealed that this process entails a shift in the regulation of Nodal expression from an HBE-driven phase to an ASE-driven phase, ASE being another autoregulatory Nodal enhancer. Deletion of HBE in ESCs or in EpiSCs allowed us to show that HBE, although not necessary for Nodal expression in EpiSCs, is required in differentiating ESCs to activate the differentiation-promoting ASE and therefore controls this regulatory shift. Our findings clarify how early Nodal expression is regulated and suggest how this regulation can promote the specification of extra-embryonic precusors without inducing premature differentiation of epiblast cells. More generally, they open new perspectives on how pluripotency factors achieve their function

Exploring the neural basis of phonological representations from sounds and vision

Speech is a multisensory signal that we can decipher from the voice and/or the lips. If the successive computational steps necessary to transform the auditory signal into meaningful language representations have been extensively explored, little is known on how the visual input of speech is processed in the brain; and how auditory and visual speech information are combined to converge onto a unified linguistic percept. In this study, we aim to identify brain regions that are involved in auditory (phonemes) and visual (visemes) phonology and explore whether some brain regions can be considered as multisensory abstract phonological regions supporting both auditory and visual phonological representations. We rely on functional magnetic resonance imaging (fMRI) in healthy adults to classify brain activity patterns evoked by phonemes and visemes. Preliminary results suggest that a network of visual, motor, auditory and frontal regions are involved in viseme recognition. Interestingly, auditorily defined phonological regions (in superior temporal gyrus - STG) seem to be involved in visual phonological representations as well. Moreover, overlap between auditory and visual decoding in mid- and posterior STG and in motor cortex indicate that these regions could be involved in the integration of auditory and visual speech phonology

Aligned motion-direction information for touch and vision in the human brain

Motion directions can be perceived through vision and touch. Do motion directions align across the senses somewhere in the brain, and if so, using which frame of reference? This is a non-trivial computational problem because vision and touch are initially coded using different spatial frames of reference, and because our limbs move constantly to adopt different postures. In the first experiment, we used fMRI to identify motion-selective regions in vision and touch. In addition to sensory specific motion selective regions, we observed that the middle occipito-temporal region (hMT+/V5) is motion selective across the senses. In another experiment, we delivered directional visual and tactile motion stimuli across different hand postures. Multivariate Pattern Analysis (MVPA) revealed that motion directions can be decoded in both vision and touch. Interestingly, tactile motion directions could be decoded in both body-centered and externally-centered coordinate systems. However, crossmodal decoding revealed that visual motion directions align with tactile directions only using an externally-centred coordinate system. Our results show that motion directions in vision and touch are aligned in hMT+/V5 relying on a common external frame of reference