Multicentric myxoid liposarcoma: report of two cases

<p>Abstract</p> <p>Background</p> <p>Multicentric myxoid liposarcoma is a rather infrequent tumour that tends to behave aggressively.</p> <p>Case presentation</p> <p>We herein report two further cases of this tumour that have been managed in our Hospital. Both were young men with multiple sites of involvement at the moment of diagnosis and both have shown a bad prognosis with frequent recurrences after treatment and rapid death in one case.</p> <p>Conclusion</p> <p>We comment on the diagnosis of this entity and on the therapeutic options available for these patients.</p

Suppressing Electroweak Precision Observables in 5D Warped Models

We elaborate on a recently proposed mechanism to suppress large contributions to the electroweak precision observables in five dimensional (5D) warped models, without the need for an extended 5D gauge sector. The main ingredient is a modification of the AdS metric in the vicinity of the infrared (IR) brane corresponding to a strong deviation from conformality in the IR of the 4D holographic dual. We compute the general low energy effective theory of the 5D warped Standard Model, emphasizing additional IR contributions to the wave function renormalization of the light Higgs mode. We also derive expressions for the S and T parameters as a function of a generic 5D metric and zero-mode wave functions. We give an approximate formula for the mass of the radion that works even for strong deviation from the AdS background. We proceed to work out the details of an explicit model and derive bounds for the first KK masses of the various bulk fields. The radion is the lightest new particle although its mass is already at about 1/3 of the mass of the lightest resonances, the KK states of the gauge bosons. We examine carefully various issues that can arise for extreme choices of parameters such as the possible reintroduction of the hierarchy problem, the onset of nonperturbative physics due to strong IR curvature or the creation of new hierarchies near the Planck scale. We conclude that a KK scale of 1 TeV is compatible with all these constraints.Comment: 44 pages, 11 figures, references adde

Sialic Acid Glycobiology Unveils Trypanosoma cruzi Trypomastigote Membrane Physiology.

Trypanosoma cruzi, the flagellate protozoan agent of Chagas disease or American trypanosomiasis, is unable to synthesize sialic acids de novo. Mucins and trans-sialidase (TS) are substrate and enzyme, respectively, of the glycobiological system that scavenges sialic acid from the host in a crucial interplay for T. cruzi life cycle. The acquisition of the sialyl residue allows the parasite to avoid lysis by serum factors and to interact with the host cell. A major drawback to studying the sialylation kinetics and turnover of the trypomastigote glycoconjugates is the difficulty to identify and follow the recently acquired sialyl residues. To tackle this issue, we followed an unnatural sugar approach as bioorthogonal chemical reporters, where the use of azidosialyl residues allowed identifying the acquired sugar. Advanced microscopy techniques, together with biochemical methods, were used to study the trypomastigote membrane from its glycobiological perspective. Main sialyl acceptors were identified as mucins by biochemical procedures and protein markers. Together with determining their shedding and turnover rates, we also report that several membrane proteins, including TS and its substrates, both glycosylphosphatidylinositol-anchored proteins, are separately distributed on parasite surface and contained in different and highly stable membrane microdomains. Notably, labeling for α(1,3)Galactosyl residues only partially colocalize with sialylated mucins, indicating that two species of glycosylated mucins do exist, which are segregated at the parasite surface. Moreover, sialylated mucins were included in lipid-raft-domains, whereas TS molecules are not. The location of the surface-anchored TS resulted too far off as to be capable to sialylate mucins, a role played by the shed TS instead. Phosphatidylinositol-phospholipase-C activity is actually not present in trypomastigotes. Therefore, shedding of TS occurs via microvesicles instead of as a fully soluble form

Human SOD2 Modification by Dopamine Quinones Affects Enzymatic Activity by Promoting Its Aggregation: Possible Implications for Parkinson’s Disease

Mitochondrial dysfunction and oxidative stress are considered central in dopaminergic neurodegeneration in Parkinson’s disease (PD). Oxidative stress occurs when the endogenous antioxidant systems are overcome by the generation of reactive oxygen species (ROS). A plausible source of oxidative stress, which could account for the selective degeneration of dopaminergic neurons, is the redox chemistry of dopamine (DA) and leads to the formation of ROS and reactive dopamine-quinones (DAQs). Superoxide dismutase 2 (SOD2) is a mitochondrial enzyme that converts superoxide radicals to molecular oxygen and hydrogen peroxide, providing a first line of defense against ROS. We investigated the possible interplay between DA and SOD2 in the pathogenesis of PD using enzymatic essays, site-specific mutagenesis, and optical and high-field-cw-EPR spectroscopies. Using radioactive DA, we demonstrated that SOD2 is a target of DAQs. Exposure to micromolar DAQ concentrations induces a loss of up to 50% of SOD2 enzymatic activity in a dose-dependent manner, which is correlated to the concomitant formation of protein aggregates, while the coordination geometry of the active site appears unaffected by DAQ modifications. Our findings support a model in which DAQ-mediated SOD2 inactivation increases mitochondrial ROS production, suggesting a link between oxidative stress and mitochondrial dysfunction

Understanding the behaviour of hackers while performing attack tasks in a professional setting and in a public challenge

When critical assets or functionalities are included in a piece of software accessible to the end users, code protections are used to hinder or delay the extraction or manipulation of such critical assets. The process and strategy followed by hackers to understand and tamper with protected software might differ from program understanding for benign purposes. Knowledge of the actual hacker behaviours while performing real attack tasks can inform better ways to protect the software and can provide more realistic assumptions to the developers, evaluators, and users of software protections. Within Aspire, a software protection research project funded by the EU under framework programme FP7, we have conducted three industrial case studies with the involvement of professional penetration testers and a public challenge consisting of eight attack tasks with open participation. We have applied a systematic qualitative analysis methodology to the hackers’ reports relative to the industrial case studies and the public challenge. The qualitative analysis resulted in 459 and 265 annotations added respectively to the industrial and to the public challenge reports. Based on these annotations we built a taxonomy consisting of 169 concepts. They address the hacker activities related to (i) understanding code; (ii) defining the attack strategy; (iii) selecting and customizing the tools; and (iv) defeating the protections. While there are many commonalities between professional hackers and practitioners, we could spot many fundamental differences. For instance, while industrial professional hackers aim at elaborating automated and reproducible deterministic attacks, practitioners prefer to minimize the effort and try many different manual tasks. This analysis allowed us to distill a number of new research directions and potential improvements for protection techniques. In particular, considering the critical role of analysis tools, protection techniques should explicitly attack them, by exploiting analysis problems and complexity aspects that available automated techniques are bad at addressing

High Quality Long-Term CD4+ and CD8+ Effector Memory Populations Stimulated by DNA-LACK/MVA-LACK Regimen in Leishmania major BALB/c Model of Infection

Heterologous vaccination based on priming with a plasmid DNA vector and boosting with an attenuated vaccinia virus MVA recombinant, with both vectors expressing the Leishmania infantum LACK antigen (DNA-LACK and MVA-LACK), has shown efficacy conferring protection in murine and canine models against cutaneus and visceral leishmaniasis, but the immune parameters of protection remain ill defined. Here we performed by flow cytometry an in depth analysis of the T cell populations induced in BALB/c mice during the vaccination protocol DNA-LACK/MVA-LACK, as well as after challenge with L. major parasites. In the adaptive response, there is a polyfunctional CD4+ and CD8+ T cell activation against LACK antigen. At the memory phase the heterologous vaccination induces high quality LACK-specific long-term CD4+ and CD8+ effector memory cells. After parasite challenge, there is a moderate boosting of LACK-specific CD4+ and CD8+ T cells. Anti-vector responses were largely CD8+-mediated. The immune parameters induced against LACK and triggered by the combined vaccination DNA/MVA protocol, like polyfunctionality of CD4+ and CD8+ T cells with an effector phenotype, could be relevant in protection against leishmaniasis

How Morphological Constraints Affect Axonal Polarity in Mouse Neurons

Neuronal differentiation is under the tight control of both biochemical and physical information arising from neighboring cells and micro-environment. Here we wished to assay how external geometrical constraints applied to the cell body and/or the neurites of hippocampal neurons may modulate axonal polarization in vitro. Through the use of a panel of non-specific poly-L-lysine micropatterns, we manipulated the neuronal shape. By applying geometrical constraints on the cell body we provided evidence that centrosome location was not predictive of axonal polarization but rather follows axonal fate. When the geometrical constraints were applied to the neurites trajectories we demonstrated that axonal specification was inhibited by curved lines. Altogether these results indicated that intrinsic mechanical tensions occur during neuritic growth and that maximal tension was developed by the axon and expressed on straight trajectories. The strong inhibitory effect of curved lines on axon specification was further demonstrated by their ability to prevent formation of multiple axons normally induced by cytochalasin or taxol treatments. Finally we provided evidence that microtubules were involved in the tension-mediated axonal polarization, acting as curvature sensors during neuronal differentiation. Thus, biomechanics coupled to physical constraints might be the first level of regulation during neuronal development, primary to biochemical and guidance regulations

T-Cell Immune Responses Against Env from CRF12_BF and Subtype B HIV-1 Show High Clade-Specificity that Can Be Overridden by Multiclade Immunizations

BACKGROUND: The extreme genetic diversity of the human immunodeficiency virus type 1 (HIV-1) poses a daunting challenge to the generation of an effective AIDS vaccine. In Argentina, the epidemic is characterized by the high prevalence of infections caused by subtype B and BF variants. The aim of this study was to characterize in mice the immunogenic and antigenic properties of the Env protein from CRF12_BF in comparison with clade B, employing prime-boost schemes with the combination of recombinant DNA and vaccinia virus (VV) vectors. METHODOLOGY/PRINCIPAL FINDINGS: As determined by ELISPOT from splenocytes of animals immunized with either EnvBF or EnvB antigens, the majority of the cellular responses to Env were found to be clade-specific. A detailed peptide mapping of the responses reveal that when there is cross-reactivity, there are no amino acid changes in the peptide sequence or were minimal and located at the peptide ends. In those cases, analysis of T cell polifunctionality and affinity indicated no differences with respect to the cellular responses found against the original homologous sequence. Significantly, application of a mixed immunization combining both clades (B and BF) induced a broader cellular response, in which the majority of the peptides targeted after the single clade vaccinations generated a positive response. In this group we could also find significant cellular and humoral responses against the whole gp120 protein from subtype B. CONCLUSIONS/SIGNIFICANCE: This work has characterized for the first time the immunogenic peptides of certain EnvBF regions, involved in T cell responses. It provides evidence that to improve immune responses to HIV there is a need to combine Env antigens from different clades, highlighting the convenience of the inclusion of BF antigens in future vaccines for geographic regions where these HIV variants circulate