Caveolin-1 is a risk factor for postsurgery metastasis in preclinical melanoma models

Melanomas are highly lethal skin tumours that are frequently treated by surgical resection. However, the efficacy of such procedures is often limited by tumour recurrence and metastasis. Caveolin-1 (CAV1) has been attributed roles as a tumour suppressor, although in late-stage tumours, its presence is associated with enhanced metastasis. The expression of this protein in human melanoma development and particularly how the presence of CAV1 affects metastasis after surgery has not been defined. CAV1 expression in human melanocytes and melanomas increases with disease progression and is highest in metastatic melanomas. The effect of increased CAV1 expression can then be evaluated using B16F10 murine melanoma cells injected into syngenic immunocompetent C57BL/6 mice or human A375 melanoma cells injected into immunodeficient B6Rag1−/− mice. Augmented CAV1 expression suppresses tumour formation upon a subcutaneous injection, but enhances lung metastasis of cells injected into the tail vein in both models. A procedure was initially developed using B16F10 melanoma cells in C57BL/6 mice to mimic better the situation in patients undergoing surgery. Subcutaneous tumours of a defined size were removed surgically and local tumour recurrence and lung metastasis were evaluated after another 14 days. In this postsurgery setting, CAV1 presence in B16F10 melanomas favoured metastasis to the lung, although tumour suppression at the initial site was still evident. Similar results were obtained when evaluating A375 cells in B6Rag1−/− mice. These results implicate CAV1 expression in melanomas as a marker of poor prognosis for patients undergoing surgery as CAV1 expression promotes experimental lung metastasis in two different preclinical models

Encapsulation of gold nanostructures and oil-in-water nanocarriers in microgels with biomedical potential

Indexación: Scopus.Funding: This research was funded by FONDECYT 1161450, 1150744, 11130494 and 1170929, FONDEQUIP EQM160157, EQM170111, CONICYT-FONDAP 15130011, and CONICYT PhD Scholarship 21141137.Here we report the incorporation of gold nanostructures (nanospheres or nanorods, functionalized with carboxylate-end PEG) and curcumin oil-in-water (O/W) nanoemulsions (CurNem) into alginate microgels using the dripping technique. While gold nanostructures are promising nanomaterials for photothermal therapy applications, CurNem possess important pharmacological activities as reported here. In this sense, we evaluated the effect of CurNem on cell viability of both cancerous and non-cancerous cell lines (AGS and HEK293T, respectively), demonstrating preferential toxicity in cancer cells and safety for the non-cancerous cells. After incorporating gold nanostructures and CurNem together into the microgels, microstructures with diameters of 220 and 540 µm were obtained. When stimulating microgels with a laser, the plasmon effect promoted a significant rise in the temperature of the medium; the temperature increase was higher for those containing gold nanorods (11–12 ◦ C) than nanospheres (1–2 ◦ C). Interestingly, the incorporation of both nanosystems in the microgels maintains the photothermal properties of the gold nanostructures unmodified and retains with high efficiency the curcumin nanocarriers. We conclude that these results will be of interest to design hydrogel formulations with therapeutic applications. © 2018 by the authors.https://www.mdpi.com/1420-3049/23/5/120

Analytic solution for nonlinear shock acceleration in the Bohm limit

The selfconsistent steady state solution for a strong shock, significantly modified by accelerated particles is obtained on the level of a kinetic description, assuming Bohm-type diffusion. The original problem that is commonly formulated in terms of the diffusion-convection equation for the distribution function of energetic particles, coupled with the thermal plasma through the momentum flux continuity equation, is reduced to a nonlinear integral equation in one variable. Its solution provides selfconsistently both the particle spectrum and the structure of the hydrodynamic flow. A critical system parameter governing the acceleration process is found to be $\Lambda = M^{-3/4}\Lambda_1$, where $\Lambda_1 =\eta p_1/mc$, with a suitably normalized injection rate $\eta$, the Mach number M >> 1, and the cut-off momentum $p_1$. We particularly focus on an efficient solution, in which almost all the energy of the flow is converted into a few energetic particles. It was found that (i) for this efficient solution (or, equivalently, for multiple solutions) to exist, the parameter $\zeta =\eta\sqrt{p_0 p_1}/mc$ must exceed a critical value $\zeta_{cr} \sim 1$ ($p_0$ is the injection momentum), (ii) the total shock compression ratio r increases with M and saturates at a level that scales as $ r \propto \Lambda_1 (iii) the downstream power-law spectrum has the universal index q=3.5 over a broad momentum range. (iv) completely smooth shock transitions do not appear in the steady state kinetic description.Comment: 39 pages, 3 PostScript figures, uses aasms4.sty, to appear in Aug. 20, 1997 issue ApJ, vol. 48

Full particle simulation of a perpendicular collisionless shock: A shock-rest-frame model

The full kinetic dynamics of a perpendicular collisionless shock is studied by means of a one-dimensional electromagnetic full particle simulation. The present simulation domain is taken in the shock rest frame in contrast to the previous full particle simulations of shocks. Preliminary results show that the downstream state falls into a unique cyclic reformation state for a given set of upstream parameters through the self-consistent kinetic processes.Comment: 4 pages, 2 figures, published in "Earth, Planets and Space" (EPS), the paper with full resolution images is http://theo.phys.sci.hiroshima-u.ac.jp/~ryo/papers/shock_rest.pd

Integrin-mediated transactivation of P2X7R via hemichannel-dependent ATP release stimulates astrocyte migration.

Our previous reports indicate that ligand-induced αVβ3 integrin and Syndecan-4 engagement increases focal adhesion formation and migration of astrocytes. Additionally, ligated integrins trigger ATP release through unknown mechanisms, activating P2X7 receptors (P2X7R), and the uptake of Ca(2+) to promote cell adhesion. However, whether the activation of P2X7R and ATP release are required for astrocyte migration and whether αVβ3 integrin and Syndecan-4 receptors communicate with P2X7R via ATP remains unknown. Here, cells were stimulated with Thy-1, a reported αVβ3 integrin and Syndecan-4 ligand. Results obtained indicate that ATP was released by Thy-1 upon integrin engagement and required the participation of phosphatidylinositol-3-kinase (PI3K), phospholipase-C gamma (PLCγ) and inositol trisphosphate (IP3) receptors (IP3R). IP3R activation leads to increased intracellular Ca(2+), hemichannel (Connexin-43 and Pannexin-1) opening, and ATP release. Moreover, silencing of the P2X7R or addition of hemichannel blockers precluded Thy-1-induced astrocyte migration. Finally, Thy-1 lacking the integrin-binding site did not stimulate ATP release, whereas Thy-1 mutated in the Syndecan-4-binding domain increased ATP release, albeit to a lesser extent and with delayed kinetics compared to wild-type Thy-1. Thus, hemichannels activated downstream of an αVβ3 integrin-PI3K-PLCγ-IP3R pathway are responsible for Thy-1-induced, hemichannel-mediated and Syndecan-4-modulated ATP release that transactivates P2X7Rs to induce Ca(2+) entry. These findings uncover a hitherto unrecognized role for hemichannels in the regulation of astrocyte migration via P2X7R transactivation induced by integrin-mediated ATP release

Diamagnetic Suppression of Component Magnetic Reconnection at the Magnetopause

We present particle-in-cell simulations of collisionless magnetic reconnection in a system (like the magnetopause) with a large density asymmetry across the current layer. In the presence of an ambient component of the magnetic field perpendicular to the reconnection plane the gradient creates a diamagnetic drift that advects the X-line with the electron diamagnetic velocity. When the relative drift between the ions and electrons is of the order the Alfven speed the large scale outflows from the X-line necessary for fast reconnection cannot develop and the reconnection is suppressed. We discuss how these effects vary with both the plasma beta and the shear angle of the reconnecting field and discuss observational evidence for diamagnetic stabilization at the magnetopause.Comment: 10 pages, 10 figures; accepted by JGR; agu2001.cls and agu.bst include