Altered metabolic landscape in IDH‐mutant gliomas affects phospholipid, energy, and oxidative stress pathways

Heterozygous mutations in NADP‐dependent isocitrate dehydrogenases (IDH) define the large majority of diffuse gliomas and are associated with hypermethylation of DNA and chromatin. The metabolic dysregulations imposed by these mutations, whether dependent or not on the oncometabolite D‐2‐hydroxyglutarate (D2HG), are less well understood. Here, we applied mass spectrometry imaging on intracranial patient‐derived xenografts of IDH‐mutant versus IDH wild‐type glioma to profile the distribution of metabolites at high anatomical resolution in situ. This approach was complemented by in vivo tracing of labeled nutrients followed by liquid chromatography–mass spectrometry (LC‐MS) analysis. Selected metabolites were verified on clinical specimen. Our data identify remarkable differences in the phospholipid composition of gliomas harboring the IDH1 mutation. Moreover, we show that these tumors are characterized by reduced glucose turnover and a lower energy potential, correlating with their reduced aggressivity. Despite these differences, our data also show that D2HG overproduction does not result in a global aberration of the central carbon metabolism, indicating strong adaptive mechanisms at hand. Intriguingly, D2HG shows no quantitatively important glucose‐derived label in IDH‐mutant tumors, which suggests that the synthesis of this oncometabolite may rely on alternative carbon sources. Despite a reduction in NADPH, glutathione levels are maintained. We found that genes coding for key enzymes in de novo glutathione synthesis are highly expressed in IDH‐mutant gliomas and the expression of cystathionine‐β‐synthase (CBS) correlates with patient survival in the oligodendroglial subtype. This study provides a detailed and clinically relevant insight into the in vivo metabolism of IDH1‐mutant gliomas and points to novel metabolic vulnerabilities in these tumors

De l'authenticite des annales et des histoires de iacite.

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Low Molecular Weight and Unfractionated Heparins Induce a down Regulation of Inflammation: Decreased Levels of Pro-Inflammatory Cytokines and Nuclear Factor-kB in LPS-Stimulated Human Monocytes.

Abstract Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are highly sulphated proteoglycans widely applied as anticoagulant drugs. They represent pivotal agents for the prevention and treatment of thromboembolic disorders, pulmonary embolism, disseminated intravascular coagulation and unstable angina. Several different studies have suggested that aside from their anticoagulant capacity, heparins possess anti-inflammatory properties, however reports have been conflicting. UFH and sulfated heparin derivatives have been shown to inhibit pro-inflammatory cytokine gene expression in lipopolysaccharide (LPS)-stimulated human mononuclear cells and to inhibit the nuclear factor-kB (NF-κB) activation in a tumor necrosis factor alpha (TNF-α) stimulated human endothelial cell line. However, other studies indicate that heparin in fact amplifies the inflammatory cytokine release in monocytes. Nevertheless, heparin appeared in several clinical trials to have the potential to treat inflammatory bowel disease, arthritis, rhinitis, and human asthma, with an anti-inflammatory effect dissociable from its anticoagulant activity. In the present study, we assessed the effect of LPS stimulation on heparin pre-treated and untreated pure human monocytes. Cells were isolated from whole blood and resuspended in RPMI supplemented with 10% platelet free autologous serum, before addition of unfractionated and low molecular weight heparins (1IU=10μg/ml and 0.1IU=1μg/ml per million cells) 15 minutes before LPS stimulation (1ng per million cells). Pro-inflammatory cytokine levels produced were measured by ELISA and NF-κB translocation using the TransAM Chemi Transcription Factor Assay. The production of TNF-α, interleukin (IL)-8, IL-6 and IL-1β was upregulated by LPS, and their levels significantly reduced when the cells were exposed to heparin, up to 3 fold with 0.1IU UFH. LPS-induced NF-κB translocation from the cytoplasm to the nucleus was also significantly reduced in heparin pre-treated cells; even at low heparin doses, as shown by a 1.5-fold reduction induced with 0.1IU UFH. NF-κB activation, a critical phenomenon in host inflammatory response, is implicated in a wide range of inflammatory diseases and therefore represents an ideal and novel molecular target. Here we report that both unfractionated and low molecular weight heparins possess the equal ability to significantly reduce the monocytic inflammatory reaction through inhibition of NF-κB activation. This indicates a potential mechanism responsible, in part, for the protective effect of the drug in inflammatory disorders. In clinical practice, heparin use as an anti-inflammatory agent is restricted by its potential to induce bleeding complications. Further investigations are required to elucidate the precise mechanism of action of the drug at the cellular level, and optimise the development of non-anticoagulant variants.</jats:p

Modelling of the DIADEMO Experiment with the CATHARE Code for ASTRID Gas Power Conversion System Studies

International audienceThe Advanced Sodium Technological Reactor for Industrial Demonstration (ASTRID) is a French Sodiumcooled Fast Reactor developed by the CEA and its partners. For safety reasons, a gas Power Conversion System based on a nitrogen Brayton cycle is investigated for the tertiary circuit. One of the key issue is the design of an innovative Sodium Gas Heat Exchanger (SGHE) that transfers heat from the sodium secondary loops to the nitrogen Brayton cycle. The safety demonstration of this new option will require the thermohydraulic calculation of a wide range of normal and accidental situations that will be performed using the CATHARE-3 code. The first qualification step of the SGHE is to validate the thermo-hydraulic performances of the component and is carried out at low scale (40kW) on the DIADEMO loop currently in operation in Cadarache. This paper presents in details the modelling of the whole DIADEMO experiment with the CATHARE-3 code. The focus is made on the modelling of the SGHE but the modelling of the sodium and nitrogen loops and their components is also presented. The comparison between the experimental data and the CATHARE calculations is performed on a Loss Of Flow Accident (LOFA). For this LOFA, the blower's rotational speed is reduced and a bypass line is open in the nitrogen loop. Thisstudy extends the validation of the CATHARE code and justifies the modelling choices of the SGHE used for ASTRID transient studies