Decitabine immunosensitizes human gliomas to NY-ESO-1 specific T lymphocyte targeting through the Fas/Fas Ligand pathway

<p>Abstract</p> <p>Background</p> <p>The lack of effective treatments for gliomas makes them a significant health problem and highlights the need for the development of novel and innovative treatment approaches. Immunotherapy is an appealing strategy because of the potential ability for immune cells to traffic to and destroy infiltrating tumor cells. However, the absence of well-characterized, highly immunogenic tumor-rejection antigens (TRA) in gliomas has limited the implementation of targeted immune-based therapies.</p> <p>Methods</p> <p>We hypothesized that treatment with the demethylating agent, decitabine, would upregulate the expression of TRA on tumor cells, thereby facilitating enhanced surveillance by TRA-specific T cells.</p> <p>Results and Discussion</p> <p>Treatment of human glioma cells with decitabine increased the expression of NY-ESO-1 and other well characterized cancer testes antigens. The upregulation of NY-ESO-1 made these tumors susceptible to NY-ESO-1-specific T-cell recognition and lysis. Interestingly, decitabine treatment of T98 glioma cells also sensitized them to Fas-dependent apoptosis with an agonistic antibody, while a Fas blocking antibody could largely prevent the enhanced functional recognition by NY-ESO-1 specific T cells. Thus, decitabine treatment transformed a non-immunogenic glioma cell into an immunogenic target that was efficiently recognized by NY-ESO-1--specific T cells.</p> <p>Conclusions</p> <p>Such data supports the hypothesis that agents which alter epigenetic cellular processes may "immunosensitize" tumor cells to tumor-specific T cell-mediated lysis.</p

Destabilization of the Dystrophin-Glycoprotein Complex without Functional Deficits in α-Dystrobrevin Null Muscle

α-Dystrobrevin is a component of the dystrophin-glycoprotein complex (DGC) and is thought to have both structural and signaling roles in skeletal muscle. Mice deficient for α-dystrobrevin (adbn−/−) exhibit extensive myofiber degeneration and neuromuscular junction abnormalities. However, the biochemical stability of the DGC and the functional performance of adbn−/− muscle have not been characterized. Here we show that the biochemical association between dystrophin and β-dystroglycan is compromised in adbn−/− skeletal muscle, suggesting that α-dystrobrevin plays a structural role in stabilizing the DGC. However, despite muscle cell death and DGC destabilization, costamere organization and physiological performance is normal in adbn−/− skeletal muscle. Our results demonstrate that myofiber degeneration alone does not cause functional deficits and suggests that more complex pathological factors contribute to the development of muscle weakness in muscular dystrophy

Fasciola hepatica IN BOVINES IN BRAZIL: DATA AVAILABILITY AND SPATIAL DISTRIBUTION

Fasciolosis is a disease of importance for both veterinary and public health. For the first time, georeferenced prevalence data of Fasciola hepatica in bovines were collected and mapped for the Brazilian territory and data availability was discussed. Bovine fasciolosis in Brazil is monitored on a Federal, State and Municipal level, and to improve monitoring it is essential to combine the data collected on these three levels into one dataset. Data were collected for 1032 municipalities where livers were condemned by the Federal Inspection Service (MAPA/SIF) because of the presence of F. hepatica. The information was distributed over 11 states: Espírito Santo, Goiás, Minas Gerais, Mato Grosso do Sul, Mato Grosso, Pará, Paraná, Rio de Janeiro, Rio Grande do Sul, Santa Catarina and São Paulo. The highest prevalence of fasciolosis was observed in the southern states, with disease clusters along the coast of Paraná and Santa Catarina and in Rio Grande do Sul. Also, temporal variation of the prevalence was observed. The observed prevalence and the kriged prevalence maps presented in this paper can assist both animal and human health workers in estimating the risk of infection in their state or municipality

Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies

Cutaneous melanoma is a very aggressive neoplasia of melanocytic origin with constantly growing incidence and mortality rates world-wide. Epigenetic modifications (i.e., alterations of genomic DNA methylation patterns, of post-translational modifications of histones, and of microRNA profiles) have been recently identified as playing an important role in melanoma development and progression by affecting key cellular pathways such as cell cycle regulation, cell signalling, differentiation, DNA repair, apoptosis, invasion and immune recognition. In this scenario, pharmacologic inhibition of DNA methyltransferases and/or of histone deacetylases were demonstrated to efficiently restore the expression of aberrantly-silenced genes, thus re-establishing pathway functions. In light of the pleiotropic activities of epigenetic drugs, their use alone or in combination therapies is being strongly suggested, and a particular clinical benefit might be expected from their synergistic activities with chemo-, radio-, and immuno-therapeutic approaches in melanoma patients. On this path, an important improvement would possibly derive from the development of new generation epigenetic drugs characterized by much reduced systemic toxicities, higher bioavailability, and more specific epigenetic effects

First measurement of the |t|-dependence of coherent J/ψ photonuclear production

The first measurement of the cross section for coherent J/ψ photoproduction as a function of |t|, the square of the momentum transferred between the incoming and outgoing target nucleus, is presented. The data were measured with the ALICE detector in ultra-peripheral Pb–Pb collisions at a centre-of-mass energy per nucleon pair sNN=5.02TeV with the J/ψ produced in the central rapidity region |y|<0.8, which corresponds to the small Bjorken-x range (0.3−1.4)×10−3. The measured |t|-dependence is not described by computations based only on the Pb nuclear form factor, while the photonuclear cross section is better reproduced by models including shadowing according to the leading-twist approximation, or gluon-saturation effects from the impact-parameter dependent Balitsky–Kovchegov equation. These new results are therefore a valid tool to constrain the relevant model parameters and to investigate the transverse gluonic structure at very low Bjorken-x.publishedVersio

Distribuição Do Carbono Orgânico Nas Frações Do Solo Em Diferentes Ecossistemas Na Amazônia Central

Organic matter plays an important role in many soil properties, and for that reason it is necessary to identify management systems which maintain or increase its concentrations. The aim of the present study was to determine the quality and quantity of organic C in different compartments of the soil fraction in different Amazonian ecosystems. The soil organic matter (FSOM) was fractionated and soil C stocks were estimated in primary forest (PF), pasture (P), secondary succession (SS) and an agroforestry system (AFS). Samples were collected at the depths 0-5, 5-10, 10-20, 20-40, 40-60, 60-80, 80-100, 100-160, and 160-200 cm. Densimetric and particle size analysis methods were used for FSOM, obtaining the following fractions: FLF (free light fraction), IALF (intra-aggregate light fraction), F-sand (sand fraction), F-clay (clay fraction) and F-silt (silt fraction). The 0-5 cm layer contains 60% of soil C, which is associated with the FLF. The F-clay was responsible for 70% of C retained in the 0-200 cm depth. There was a 12.7 g kg-1 C gain in the FLF from PF to SS, and a 4.4 g kg-1 C gain from PF to AFS, showing that SS and AFS areas recover soil organic C, constituting feasible C-recovery alternatives for degraded and intensively farmed soils in Amazonia. The greatest total stocks of carbon in soil fractions were, in decreasing order: (101.3 Mg ha-1 of C - AFS) > (98.4 Mg ha-1 of C - FP) > (92.9 Mg ha-1 of C - SS) > (64.0 Mg ha-1 of C - P). The forms of land use in the Amazon influence C distribution in soil fractions, resulting in short- or long-term changes. © 2015, Revista Brasileira de Ciencia do Solo. All rights reserved