4,554 research outputs found

    Orai1 Ca2+ channel modulators as therapeutic tools for treating cancer: Emerging evidence!

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    International audienceIn non-excitable cells, Orai proteins represent the main channel for Store-Operated Calcium Entry (SOCE), and also mediate various store-independent Calcium Entry (SICE) pathways. Deregulation of these pathways contribute to increased tumor cell proliferation, migration, metastasis, and angiogenesis. Among Orais, Orai1 is an attractive therapeutic target explaining the development of specific modulators. Therapeutic trials using Orai1 channel inhibitors have been evaluated for treating diverse diseases such as psoriasis and acute pancreatitis, and emerging data suggest that Orai1 channel modulators may be beneficial for cancer treatment. This review discusses herein the importance of Orai1 channel modulators as potential therapeutic tools and the added value of these modulators for treating cancer

    Squamous Cell Carcinoma of the Lung With Microsatellite Instability in a Patient With Lynch Syndrome: A Case Report

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    Lynch syndrome is the most common autosomal dominant inherited cancer predisposing syndrome, due to mutations in DNA mismatch repair genes. The key feature of cancers in Lynch syndrome is microsatellite instability and a high risk of developing mainly colorectal and uterine cancers. However, cancers with microsatellite instability outside this spectrum, for example, lung cancer, are extremely rare. Here, we report a case of squamous cell carcinoma of the lung with microsatellite instability in a patient with Lynch syndrome

    Branched pegylated linker-auristatin to control hydrophobicity for the production of homogeneous minibody-drug conjugate against HER2-positive breast cancer

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    International audienceTrastuzumab emtansine (KadcylaÂź) was the first antibody-drug conjugate (ADC) approved by the Food and DrugAdministration in 2013 against a solid tumor, and the first ADC to treat human epidermal growth factor receptor2 positive (HER2+) breast cancer. However, this second generation ADC is burden by several limitationsincluded heterogeneity, limited activity against heterogeneous tumor (regarding antigen expression) and suboptimaltumor penetration. To address this, different development strategies are oriented towards homogeneousconjugation, new drugs, optimized linkers and/or smaller antibody formats. To reach better developed nextgeneration ADCs, a key parameter to consider is the management of the hydrophobicity associated with thelinker-drug, increasing with and limiting the drug-to-antibody ratio (DAR) of the ADC. Here, an innovativebranched pegylated linker was developed, to control the hydrophobicity of the monomethyl auristatin E (MMAE)and its cathepsin B-sensitive trigger. This branched pegylated linker-MMAE was then used for the efficientgeneration of internalizing homogeneous ADC of DAR 8 and minibody-drug conjugate of DAR 4, targeting HER2.Both immunoconjugates were then evaluated in vitro and in vivo on breast cancer models. Interestingly, this studyhighlighted that the minibody-MMAE conjugate of DAR 4 was the best immunoconjugate regarding in vitrocellular internalization and cytotoxicity, gamma imaging, ex vivo biodistribution profile in mice and efficientreduction of tumor size in vivo. These results are very promising and encourage us to explore further fragmentdrugconjugate development

    Genetic Mapping of the Root Mycobiota in Rice and its Role in Drought Tolerance

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    International audienceRice is the second most produced crop worldwide, but is highly susceptible to drought. Micro-organisms can potentially alleviate the effects of drought. The aim of the present study was to unravel the genetic factors involved in the rice-microbe interaction, and whether genetics play a role in rice drought tolerance. For this purpose, the composition of the root mycobiota was characterized in 296 rice accessions (Oryza sativa L. subsp. indica) under control and drought conditions. Genome wide association mapping (GWAS) resulted in the identification of ten significant (LOD > 4) single nucleotide polymorphisms (SNPs) associated with six root-associated fungi: Ceratosphaeria spp., Cladosporium spp., Boudiera spp., Chaetomium spp., and with a few fungi from the Rhizophydiales order. Four SNPs associated with fungi-mediated drought tolerance were also found. Genes located around those SNPs, such as a DEFENSIN-LIKE (DEFL) protein, EXOCYST TETHERING COMPLEX (EXO70), RAPID ALKALINIZATION FACTOR-LIKE (RALFL) protein, peroxidase and xylosyltransferase, have been shown to be involved in pathogen defense, abiotic stress responses and cell wall remodeling processes. Our study shows that rice genetics affects the recruitment of fungi, and that some fungi affect yield under drought. We identified candidate target genes for breeding to improve rice-fungal interactions and hence drought tolerance

    Modeling clod evolution under rainfall according to clod size.

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    International audienceDeterming soil spatial variability is a key point in soil sciences either for soil preparation in precision agriculture, or because of influence on overland flow and erosion. Soil Surface Roughness (SSR) represents the undulation of the surface at small scale, due to the presence of small elevations and depressions. It results from tillage operations and changes over time due to weathering. SSR can be related to clod-size distribution. So, many research has been conducted on monitoring the size and number of clods using photogrammetry method. Nowadays, it is possible to acquire high resolution Digital Elevation Models (DEMs). This study seeks to model the evolution of clod size under rainfall impact with modeling and data processing tools.Seedbed-like soil surface was made in the laboratory by filling a tray with loose soil of silt loam and setting upon pre-sieved clods. It was eroded by controlled laboratory rainfalls. A millimeter DEM was recorded at each stage of the surface with laser-scanner. Wavelet-based clod segmentation leaded to measurement of the volume of individual clods. Clod subsets were formed according to clod size. Normalized mean volume decrease was modelled by exponential function.Greater clods showed swelling (volume increase) and erosion (volume decrease), with cumulated rainfall. These two phenomena being size dependent. Amplitude and slope parameters of the exponential decrease of clod volume could be modelled as a function of mean volume of the clod subset at initial stage. Results obtained with this surface strengthen those previously obtained with less data and basic segmentation. A power law is confirmed for amplitude parameter and a sigmoĂŻd function is highlighted for slope parameter.Modelling and data processing tools are efficient to differentiate and estimate the dynamics of clods depending on their size. Usually, clod size distribution is addressed with statistics of clod diameters obtained by real or numerical sieving. Working on 2.5 D DEMs gives also an acces to the vertical dimension of clods, which is included in their volume. This technique completes the usual roughness description and is promissing for use in precision agriculture or numerical surface generation

    ASPECTS evolution after endovascular successful reperfusion in the early and extended time window

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    International audienceBackground: The Alberta Stroke Program Early CT scan Score (ASPECTS) is a reliable imaging biomarker of infarct extent on admission but the value of 24-hour ASPECTS evolution in day-to-day practice is not well studied, especially after successful reperfusion. We aimed to assess the association between ASPECTS evolution after successful reperfusion with functional and safety outcomes, as well as to identify the predictors of ASPECTS evolution. Methods: We used data from an ongoing prospective multicenter registry. Stroke patients with anterior circulation large vessel occlusion treated with endovascular therapy (EVT) and achieved successful reperfusion (modified thrombolysis in cerebral ischemia (mTICI) 2b-3) were included. ASPECTS evolution was defined as one or more point decrease in ASPECTS at 24 hours. Results: A total of 2366 patients were enrolled. In a fully adjusted model, ASPECTS evolution was associated with lower odds of favorable outcome (modified Rankin Scale (mRS) score 0-2) at 90 days (adjusted odds ratio (aOR) = 0.46; 95% confidence interval (CI) = 0.37–0.57). In addition, ASPECTS evolution was a predictor of excellent outcome (90-day mRS 0-1) (aOR = 0.52; 95% CI = 0.49–0.57), early neurological improvement (aOR = 0.42; 95% CI = 0.35–0.51), and parenchymal hemorrhage (aOR = 2.64; 95% CI, 2.03–3.44). Stroke severity, admission ASPECTS, total number of passes, complete reperfusion (mTICI 3 vs. mTICI 2b-2c) and good collaterals emerged as predictors of ASPECTS evolution. Conclusion: ASPECTS evolution is a strong predictor of functional and safety outcomes after successful endovascular therapy. Higher number of EVT attempts and incomplete reperfusion are associated with ASPECTS evolution at day 1

    Euclid Preparation. TBD. Galaxy colour selections with Euclid and ground photometry for cluster weak-lensing analyses

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    International audienceWe derive galaxy colour selections from Euclid and ground-based photometry, aiming to accurately define background galaxy samples in cluster weak-lensing analyses. These selections are implemented in the Euclid data analysis pipelines for galaxy clusters. Given any set of photometric bands, we develop a method for the calibration of optimal galaxy colour selections that maximises the selection completeness, given a threshold on purity. Such colour selections are expressed as a function of the lens redshift. We calibrate galaxy selections using ground-based grizgriz and Euclid YEJEHEY_{\rm E}J_{\rm E}H_{\rm E} bands. Both selections produce a purity higher than 97%. The grizgriz selection completeness ranges from 30% to 84% in the lens redshift range zl∈[0.2,0.8]z_{\rm l}\in[0.2,0.8]. With the full grizYEJEHEgrizY_{\rm E}J_{\rm E}H_{\rm E} selection, the completeness improves by up to 2525 percentage points, and the zlz_{\rm l} range extends up to zl=1.5z_{\rm l}=1.5. The calibrated colour selections are stable to changes in the sample limiting magnitudes and redshift, and the selection based on grizgriz bands provides excellent results on real and simulated external data sets. Furthermore, the calibrated selections provide stable results using alternative photometric aperture definitions obtained from different ground-based telescopes. The grizgriz selection is also purer at high redshift and more complete at low redshift compared to colour selections found in the literature. We show that the calibrated colour selections provide robust results even when observations from a single band are missing from the ground-based data. Finally, we show that colour selections imply variations within the 1σ\sigma uncertainty in the mean multiplicative shear bias, mm, for stage III surveys. The first Euclid data releases will provide further insights into the impact of background selections on mm

    Metagenomic analyses of a microbial assemblage in a subglacial lake beneath the Vatnajökull ice cap, Iceland

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    Skaftårkatlar are two subglacial lakes located beneath the Vatnajökull ice cap in Iceland associated with geothermal and volcanic activity. Previous studies of these lakes with ribosomal gene (16S rDNA) tag sequencing revealed a limited diversity of bacteria adapted to cold, dark, and nutrient-poor waters. In this study, we present analyses of metagenomes from the lake which give new insights into its microbial ecology. Analyses of the 16S rDNA genes in the metagenomes confirmed the existence of a low-diversity core microbial assemblage in the lake and insights into the potential metabolisms of the dominant members. Seven taxonomic genera, Sulfuricurvum, Sulfurospirillum, Acetobacterium, Pelobacter/Geobacter, Saccharibacteria, Caldisericum, and an unclassified member of Prolixibacteraceae, comprised more than 98% of the rDNA reads in the library. Functional characterisation of the lake metagenomes revealed complete metabolic pathways for sulphur cycling, nitrogen metabolism, carbon fixation via the reverse Krebs cycle, and acetogenesis. These results show that chemolithoautotrophy constitutes the main metabolism in this subglacial ecosystem. This assemblage and its metabolisms are not reflected in enrichment cultures, demonstrating the importance of in situ investigations of this environment