Targeting focal adhesion assembly by ethoxyfagaronine prevents lymphoblastic cell adhesion to fibronectin

Background: Leukemic cell adhesion to proteins of the bone marrow microenvironment provides signals which control morphology, motility and cell survival. We described herein the ability of ethoxyfagaronine (etxfag), a soluble synthetic derivative of fagaronine, to prevent leukemic cell adhesion to fibronectin peptide (FN/V). Methods: Phosphorylation of fak and pyk2 were evaluated by immunoblotting. Labelled proteins were localized by confocal microscopy. PI 3-kinase activity was evaluated by in vitro kinase assay. Results: Subtoxic concentration of etxfag reduced L1210 cell adhesion to FN/V dependently of β1 integrin engagement. Etxfag impaired FN-dependent formation of β1 clustering without modifying β1 expression at the cell membrane. This was accompanied by a decrease of focal adhesion number, a diminution of fak and pyk2 phosphorylation at Tyr-576, Tyr-861 and Tyr-579, respectively leading to their dissociations from β1 integrin and inhibition of PI 3-kinase activity. Etxfag also induced a cell retraction accompanied by a redistribution of phosphorylated fak and pyk2 in the perinuclear region and lipid raft relocalization. Conclusion: Through its anti-adhesive potential, etxfag, combined with conventional cytotoxic drugs could be potentially designed as a new anti-leukemic drug

The anti-invasive activity of synthetic alkaloid ethoxyfagaronine on L1210 leukemia cells is mediated by down-regulation of plasminogen activators and MT1-MMP expression and activity

Quaternary benzo[c]phenanthridines such as fagaronine are natural substances which have been reported to exhibit anticancer and anti-leukemic properties. However, the therapeutic use of these molecules is limited due to the high dose required to exhibit anti-tumor activity and subsequent toxicity. In this study, we describe the therapeutic potential of a new derivative of fagaronine, Ethoxyfagaronine (N-methyl-12-ethoxy-2hydroxy-3, 8, 9-trimethoxybenzo[c]-phenanthridiniumchlorhydrate) as an anti-leukemic agent. Cytotoxic activity and cell growth inhibition of Ethoxyfagaronine (Etxfag) was tested on murine L1210 leukemia cells using trypan blue assay and MTT assay. At the concentration of 10−7 M, Etxfag induced less than 10% of cell death. Etxfag (10−7 M) was tested on L1210 cell invasiveness using matrigel™ precoated transwell chambers and efficiently reduces the invasive potential of L1210 cells by more than 50% as compared with untreated cells. Western blot and immunofluorescence experiments showed that Etxfag decreased both MT1-MMP expression and activation at the cell surface, decreased plasmin activity by down-regulating u-PAR and uPA expression at the cell surface and increasing PAI-1 secretion in conditioned media. The set of our findings underscore the therapeutic potential of ethoxyfagaronine as a new potential anticancer agent able to prevent leukemic cell dissemination

Understanding and simulating the material behavior during multi-particle irradiations

A number of studies have suggested that the irradiation behavior and damage processes occurring during sequential and simultaneous particle irradiations can significantly differ. Currently, there is no definite answer as to why and when such differences are seen. Additionally, the conventional multi-particle irradiation facilities cannot correctly reproduce the complex irradiation scenarios experienced in a number of environments like space and nuclear reactors. Therefore, a better understanding of multi-particle irradiation problems and possible alternatives are needed. This study shows ionization induced thermal spike and defect recovery during sequential and simultaneous ion irradiation of amorphous silica. The simultaneous irradiation scenario is shown to be equivalent to multiple small sequential irradiation scenarios containing latent damage formation and recovery mechanisms. The results highlight the absence of any new damage mechanism and time-space correlation between various damage events during simultaneous irradiation of amorphous silica. This offers a new and convenient way to simulate and understand complex multi-particle irradiation problems

Exfoliation and diffusion following helium ion implantation in fluorapatite: implicattions for radiochronology and radioactive waste disposal

The properties of fluorapatite, both a useful radiochronometer and a potential storage matrix specific for minor actinides produced by the reprocessing of spent nuclear fuel, have been investigated with emphasis to its response to alpha decay. Exfoliation, which occurs after implantation of high doses of 1.6-MeV He-ions (>1.4×1017 ions cm−2, corresponding to 5% atomic proportion), could set an upper limit to the concentration of imbedded actinides (about 2 atoms % corresponding to 20 wt. %) or storage age unless significant diffusion of radiogenic He intervenes. This process has been studied by combining He implantation, thermal treatments in the temperature range 124–250°C and measurement of the resulting He profile by an ion beam technique (ERDA) using 8.5-MeV C ions. The diffusion coefficient follows an Arrhenius' law with an activation energy of 120 (±2) KJ/mole and a frequency factor of 14.5 (±7)×10−3 cm2 sec−1 in agreement with literature data. The inferred closure temperature which validates the U,Th–He radiochronological method also fits previous values: 97 (±10)°C for grain size 165 μm. With respect to radwaste disposal. He volume diffusion is too small to exclude the occurrence of exfoliation unless diffusion at grain boundary is much higher and a fine-grain matrix is deliberately chosen

Security Analysis of IoT Systems Using Attack Trees

International audienc

Quantifying Risks to Data Assets Using Formal Metrics in Embedded System Design

This paper addresses quantifying security risks associated with data assets within design models of embedded systems. Attack and system behaviours are modelled as time-dependent stochastic processes. The presence of the time dimension allows accounting for dynamic aspects of potential attacks and a system: the probability of a success- ful attack changes as time progresses; and a system possesses different data assets as its execution unfolds. These models are used to quan- tify two important attributes of security: confidentiality and integrity. In particular, likelihood/consequence-based measures of confidentiality and integrity losses are proposed to characterise security risks to data assets. In our method, we consider attack and system behaviours as two sepa- rate models that are later elegantly combined for security analysis. This promotes knowledge reuse and avoids adding extra complexity in the system design process. We demonstrate the effectiveness of the proposed method and metrics on smart metering devices.