Combined therapies of antithrombotics and antioxidants delay in silico brain tumor progression

Glioblastoma multiforme, the most frequent type of primary brain tumor, is a rapidly evolving and spatially heterogeneous high-grade astrocytoma that presents areas of necrosis, hypercellularity and microvascular hyperplasia. The aberrant vasculature leads to hypoxic areas and results in an increase of the oxidative stress selecting for more invasive tumor cell phenotypes. In our study we assay in silico different therapeutic approaches which combine antithrombotics, antioxidants and standard radiotherapy. To do so, we have developed a biocomputational model of glioblastoma multiforme that incorporates the spatio-temporal interplay among two glioma cell phenotypes corresponding to oxygenated and hypoxic cells, a necrotic core and the local vasculature whose response evolves with tumor progression. Our numerical simulations predict that suitable combinations of antithrombotics and antioxidants may diminish, in a synergetic way, oxidative stress and the subsequent hypoxic response. This novel therapeutical strategy, with potentially low or no toxicity, might reduce tumor invasion and further sensitize glioblastoma multiforme to conventional radiotherapy or other cytotoxic agents, hopefully increasing median patient overall survival time.Comment: 8 figure

CTCF orchestrates the germinal centre transcriptional program and prevents premature plasma cell differentiation

In germinal centres (GC) mature B cells undergo intense proliferation and immunoglobulin gene modification before they differentiate into memory B cells or long-lived plasma cells (PC). GC B-cell-to-PC transition involves a major transcriptional switch that promotes a halt in cell proliferation and the production of secreted immunoglobulins. Here we show that the CCCTC-binding factor (CTCF) is required for the GC reaction in vivo, whereas in vitro the requirement for CTCF is not universal and instead depends on the pathways used for B-cell activation. CTCF maintains the GC transcriptional programme, allows a high proliferation rate, and represses the expression of Blimp-1, the master regulator of PC differentiation. Restoration of Blimp-1 levels partially rescues the proliferation defect of CTCF-deficient B cells. Thus, our data reveal an essential function of CTCF in maintaining the GC transcriptional programme and preventing premature PC differentiation

Effect of lamellar orientation and width on the strength and operating deformation mechanisms of fully lamellar TiAl alloys determined by micropillar compression

Titanium aluminide alloys are of interest for the aerospace industry due to their low density(3.9-4.2g/cm3), good high-temperature strength retention, high modulus and creep strength, as well as high resistance to oxidation. The TiAl alloys of commercial interest typically contain two phases: γ TiAl and a2 Ti3Al, but their microstructure can substantially vary depending on composition and thermomechanical history. They can be classified as fully lamellar, near lamellar, duplex or near gamma. Fully lamellar microstructures formed by colonies of lamellar γ and a2 phases are typically obtained after heat treatment at temperatures above the a-transus, with the soaking temperature and cooling rate [1] being critical variables to determine the microstructural parameters, such as colony size, volume fraction and lamellar width. They present the best high temperature strength [1-2]; However, they lack room temperature ductility, which has limited their application so far. In this context, several compositional families have been developed in the last years, especially as a function of alloying elements, such as, niobium, tantalum, tungsten or molybdenum, which stabilize the β phase affecting the volume fraction and size of lamellar colonies. Two of the most important families are TNB alloys, with high niobium concentration and small additions of boron and carbon, where solidification takes place through the phase and TNM alloys, with even larger additions of niobium and molybdenum. Solidification of TNM alloys takes place through the β phase inducing further grain refinement due to β→a transformation [3] during cooling. The lack of ductility of fully lamellar TiAl alloys is associated with the anisotropic deformation of individual colonies, as a function of lamellar orientation () with respect to the loading axis. In this regard, micropillar compression is a powerful technique to determine the different deformation modes of TiAl colonies as a function of lamellar orientation. This has been shown in previous studies for TNB alloys (Ti45Al2Nb2MnXB), where the outcomes of micropillar compression were compared with results obtained from macroscopic tests using polysynthetically twinned crystals (PTS) [4]. Three different deformation modes where found: a soft deformation mode (=45º) and two hard modes (=0º and =90º), due to the activation of different slip systems in each case. However, the role of lamellar width has not been studied in detail before. This work focuses on an alloy belonging to the TNM family, with the objective of studying the role of lamellar orientation and lamellar width on the anisotropic mechanical response of individual colonies. For this, a Ti43.5Al4Nb1MoXB alloy was subjected to different thermal treatments with the objective of refining the lamellar width. In particular, after heating up and soaking at 1260ºC (above the a-transus), three cooling rates were selected to cool down to 800ºC (a2 + β + γ region): 40ºC/min, 400ºC/min and 4000ºC/min. The cooling rate was reduced to 40ºC/min from 800ºC in all cases to avoid cracking. As a result, the average lamellar width was varied within a range of two orders of magnitude (from a few nanometers to more than 200nm) for the same alloy composition. The anisotropy of individual colonies and their deformation modes as a function of lamellar orientation were studied by micropillar compression. For this, square micropillars were milled by means of FIB with dimensions of 5 x 5 x 15m3. Uniaxial compression was carried out using a flat-punch diamond tip with a diameter of 10m under displacement control mode at a strain rate of 10-3 s-1 up to a maximum engineering strain of 10%. Deformed micropillars were analyzed to relate the orientation of lamellar interfaces with the activation of different deformation modes. The results are compared with those obtained in TNB alloys as well as a function of the average lamellar width. [1] F. Appel, J. Paul, M. Oehring, Gamma Titanium Aluminide Alloys: Science and Technology. Wiley, 2011. [2] M.E. Kassner, M.T. Pérez-Prado. Fundamentals of Creep in Metals and Alloys, Elsevier, 2004. [3] H. Clemens, S. Mayer, Adv. Eng. Mater. 15 (2013) 191–215. [4] A.J. Palomares-García, M.T. Pérez Prado, J.M. Molina-Aldareguia Acta Mater. 123 (2017) 102-114

NL mind-best: aweb server for ligands and proteins discovery; theoretic experimental study of proteins of giardia lamblia

Comunicaciones a congreso

Effect of implantoplasty on the elastic limit of dental implants of different diameters

Background Implantoplasty reduces both implant diameter and the thickness of its walls, subsequently reducing the ability of the implant to resist fracture in response to functional load. In combination with an increase in the crown-implant ratio due to bone loss, this could increase the lever effect, which in presence of high masticatory forces or parafunctional habits, could lead to complications such as fracture of the implant or loosening of the prosthetic screw. Objectives To determine the elastic limits of internal connection, dental implants of different designs and diameters after an implantoplasty. Materials and methods This in vitro study included 315 tapered internal connection titanium dental implants, the threads of which were removed with an industrial milling machine-for standardized implantoplasty (IMP1; n = 105)-or with the conventional approach-manually, using high-speed burs (IMP2; n = 105). The remaining 105 implants were used as controls. The final implant diameters were recorded. The quality of the newly polished surfaces was assessed by scanning electron microscopy. All implants were subjected to a mechanical pressure resistance test. A Tukey''s test for multiple comparisons was used to detect differences in the elastic limit and final implant diameters between the implant groups. Results There were statistically significant differences in the elastic limit between the IMP1, IMP2, and control groups (p < 0.05). Furthermore, the implant diameter was significantly smaller in the IMP1 and IMP2 groups (p < 0.05). Scanning electron microscopy revealed smooth implant surfaces in the IMP1 and IMP2 groups, with some titanium particles visible in the IMP1 group. Conclusions Implantoplasty significantly decreased the elastic limit of internal connection titanium dental implants, especially in those with a smaller diameter (3-3.5 mm)

On the robustness of scale invariance in SOC models

A random neighbor extremal stick-slip model is introduced. In the thermodynamic limit, the distribution of states has a simple analytical form and the mean avalanche size, as a function of the coupling parameter, is exactly calculable. The system is critical only at a special point Jc in the coupling parameter space. However, the critical region around this point, where approximate scale invariance holds, is very large, suggesting a mechanism for explaining the ubiquity of scale invariance in Nature.Comment: 6 pages, 4 figures; submitted to Physical Review E; http://link.aps.org/doi/10.1103/PhysRevE.59.496

Gold Nanosystems Covered with Doxorubicin/DNA Complexes: A Therapeutic Target for Prostate and Liver Cancer

Different gold nanosystems covered with DNA and doxorubicin (Doxo) were designed and synthesized for cancer therapy, starting from Au@16-Ph-16 cationic nanoparticles and DNA–Doxo complexes prepared under saturation conditions. For the preparation of stable, biocompatible, and small-sized compacted Au@16-Ph-16/DNA–Doxo nanotransporters, the conditions for the DNA–Doxo compaction process induced by gold nanoparticles were first explored using fluorescence spectroscopy, circular dichroism and atomic force microscopy techniques. The reverse process, which is fundamental for Doxo liberation at the site of action, was found to occur at higher CAu@16-Ph-16 concentrations using these techniques. Zeta potential, dynamic light scattering and UV–visible spectroscopy reveal that the prepared compacted nanosystems are stable, highly charged and of adequate size for the effective delivery of Doxo to the cell. This fact is verified by in vitro biocompatibility and internalization studies using two prostate cancer-derived cell lines (LNCaP and DU145) and one hepatocellular carcinoma-derived cell line (SNU-387), as well as a non-tumor prostate (PNT2) cell line and a non-hepatocarcinoma hepatoblastoma cell line (Hep-G2) model used as a control in liver cells. However, the most outstanding results of this work are derived from the use of the CI+NI combined treatments which present strong action in cancer-derived cell lines, while a protective effect is observed in non-tumor cell lines. Hence, novel therapeutic targets based on gold nanoparticles denote high selectivity compared to conventional treatment based on free Doxo at the same concentration. The results obtained show the viability of both the proposed methodology for internalization of compacted nanocomplexes inside the cell and the effectiveness of the possible treatment and minimization of side effects in prostate and liver cancer