mTor inhibitor GDC-0349 improves ASO induced SAMMSON knock down resulting in enhanced anti-tumor efficacy in uveal melanoma

Uveal melanoma (UM) is the most common intraocular malignancy in adults. The lack of an effective treatment results in a median survival time of less than one year for patients with metastatic disease and shows the high unmet need for the development of effective treatments. Recently, the melanoma-specific lncRNA SAMMSON was shown to be essential for skin melanoma survival. Analysis of a PAN cancer RNA-sequencing dataset revealed consistent expression of SAMMSON in uveal melanoma tumors. Targeting SAMMSON by means of antisense oligonucleotides (ASOs) results in a strong reduction in cell viability with induction of apoptosis of UM cells and slows down tumor growth in multiple UM PDX models. These effects were driven by impaired mitochondrial function and protein translation, resulting in cell death. To identify potential synergistic combinations, we combined SAMMSON knockdown with a library of 2911 FDA-approved drugs and quantified cell viability in a uveal melanoma cell line. The strongest synergy was obtained with the mTOR inhibitor GDC-0349. Combining SAMMSON knockdown with mTOR inhibition resulted in enhanced impairment of mitochondrial function and protein synthesis. Interestingly, we observed a more pronounced knockdown of SAMMSON when combining SAMMSON targeting ASOs with GDC-0349, suggesting mTOR inhibition facilitates ASO uptake in uveal melanoma cells. Further experiments are ongoing to confirm this mechanism. Taken together, these results demonstrate that SAMMSON inhibition in combination with mTOR inhibition could be a novel treatment option for uveal melanoma patients

Assessment of Translocator Protein Density, as Marker of Neuroinflammation, in Major Depressive Disorder: A Pilot, Multicenter, Comparative, Controlled, Brain PET Study (INFLADEP Study)

Background: Major depressive disorder (MDD) is a serious public health problem with high lifetime prevalence (4.4–20%) in the general population. The monoamine hypothesis is the most widespread etiological theory of MDD. Also, recent scientific data has emphasized the importance of immuno-inflammatory pathways in the pathophysiology of MDD. The lack of data on the magnitude of brain neuroinflammation in MDD is the main limitation of this inflammatory hypothesis. Our team has previously demonstrated the relevance of [18F] DPA-714 as a neuroinflammation biomarker in humans. We formulated the following hypotheses for the current study: (i) Neuroinflammation in MDD can be measured by [18F] DPA-714; (ii) its levels are associated with clinical severity; (iii) it is accompanied by anatomical and functional alterations within the frontal-subcortical circuits; (iv) it is a marker of treatment resistance.Methods: Depressed patients will be recruited throughout 4 centers (Bordeaux, Montpellier, Tours, and Toulouse) of the French network from 13 expert centers for resistant depression. The patient population will be divided into 3 groups: (i) experimental group—patients with current MDD (n = 20), (ii) remitted depressed group—patients in remission but still being treated (n = 20); and, (iii) control group without any history of MDD (n = 20). The primary objective will be to compare PET data (i.e., distribution pattern of neuroinflammation) between the currently depressed group and the control group. Secondary objectives will be to: (i) compare neuroinflammation across groups (currently depressed group vs. remitted depressed group vs. control group); (ii) correlate neuroinflammation with clinical severity across groups; (iii) correlate neuroinflammation with MRI parameters for structural and functional integrity across groups; (iv) correlate neuroinflammation and peripheral markers of inflammation across groups.Discussion: This study will assess the effects of antidepressants on neuroinflammation as well as its role in the treatment response. It will contribute to clarify the putative relationships between neuroinflammation quantified by brain neuroimaging techniques and peripheral markers of inflammation. Lastly, it is expected to open innovative and promising therapeutic perspectives based on anti-inflammatory strategies for the management of treatment-resistant forms of MDD commonly seen in clinical practice.Clinical trial registration (reference: NCT03314155): https://www.clinicaltrials.gov/ct2/show/NCT03314155?term=neuroinflammation&cond=depression&cntry=FR&rank=

Cycle sédimentaire et vertébrés d'une formation peu connue du Bassin de Paris, l'unité des Sables de Bourguillemont (Oise, France) (Paléocène supérieur)

Dutheil, Didier B., Moreau, Fabrice, Delhaye-Prat, Vincent (2002): Cycle sédimentaire et vertébrés d'une formation peu connue du Bassin de Paris, l'unité des Sables de Bourguillemont (Oise, France) (Paléocène supérieur). Geodiversitas 24 (4): 753-764, DOI: http://doi.org/10.5281/zenodo.537753

Triple noncontiguous thoracic spine fractures treated with hybrid 3D intraoperative CT-navigated minimal invasive fixation technique: a case report.

peer reviewe

Role of Interfacial Mg Atoms on the Electronic and Structural Properties of MgO Films on Ag(001)

International audienc

Tuning the Electronic Properties of MgO/metal Buried Interfaces by Mg Atom Intercalation

International audienc