Parameters affecting cellular invasion and escape from the parasitophorous vacuole by different infective forms of Trypanosoma cruzi

In this study we have examined certain aspects of the process of cell invasion and parasitophorous vacuole escape by metacyclic trypomastigotes and extracellular amastigote forms of Trypanosoma cruzi (G strain). Using Vero (and HeLa) cells as targets, we detected differences in the kinetics of vacuole escape by the two forms. Alcalinization of intercellular pH influenced both invasion as well as the escape from the parasitophorous vacuole by metacyclic trypomastigotes, but not the escape kinetics of extracellular amastigotes. We used sialic acid mutants as target cells and observed that the deficiency of this molecule facilitated the escape of both infective forms. Hemolysin activity was only detected in extracellular amastigotes and neither form presented detectable transialidase activity. Invasion of extracellular amastigotes and trypomastigotes in Vero cells was affected in different ways by drugs that interfere with host cell Ca2+ mobilization. These results are in line with previous results that indicate that metacyclic trypomastigotes and extracellular amastigote forms utilize mechanisms with particular features to invade host cells and to escape from their parasitophorous vacuoles.

Role of Immune Escape Mechanisms in Hodgkin's Lymphoma Development and Progression: A Whole New World with Therapeutic Implications.

Hodgkin's lymphoma represents one of the most frequent lymphoproliferative syndromes, especially in young population. Although HL is considered one of the most curable tumors, a sizeable fraction of patients recur after successful upfront treatment or, less commonly, are primarily resistant. This work tries to summarize the data on clinical, histological, pathological, and biological factors in HL, with special emphasis on the improvement of prognosis and their impact on therapeutical strategies. The recent advances in our understanding of HL biology and immunology show that infiltrated immune cells and cytokines in the tumoral microenvironment may play different functions that seem tightly related with clinical outcomes. Strategies aimed at interfering with the crosstalk between tumoral Reed-Sternberg cells and their cellular partners have been taken into account in the development of new immunotherapies that target different cell components of HL microenvironment. This new knowledge will probably translate into a change in the antineoplastic treatments in HL in the next future and hopefully will increase the curability rates of this disease.

Role of immune escape mechanisms in Hodgkin's lymphoma development and progression: a whole new world with therapeutic implications.

Hodgkin's lymphoma represents one of the most frequent lymphoproliferative syndromes, especially in young population. Although HL is considered one of the most curable tumors, a sizeable fraction of patients recur after successful upfront treatment or, less commonly, are primarily resistant. This work tries to summarize the data on clinical, histological, pathological, and biological factors in HL, with special emphasis on the improvement of prognosis and their impact on therapeutical strategies. The recent advances in our understanding of HL biology and immunology show that infiltrated immune cells and cytokines in the tumoral microenvironment may play different functions that seem tightly related with clinical outcomes. Strategies aimed at interfering with the crosstalk between tumoral Reed-Sternberg cells and their cellular partners have been taken into account in the development of new immunotherapies that target different cell components of HL microenvironment. This new knowledge will probably translate into a change in the antineoplastic treatments in HL in the next future and hopefully will increase the curability rates of this disease.

Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape.

Malignant melanoma accounts for most of the increasing mortality from skin cancer. Melanoma cells were found to express Fas (also called Apo-1 or CD95) ligand (FasL). In metastatic lesions, Fas-expressing T cell infiltrates were proximal to FasL+ tumor cells. In vitro, apoptosis of Fas-sensitive target cells occurred upon incubation with melanoma tumor cells; and in vivo, injection of FasL+ mouse melanoma cells in mice led to rapid tumor formation. In contrast, tumorigenesis was delayed in Fas-deficient lpr mutant mice in which immune effector cells cannot be killed by FasL. Thus, FasL may contribute to the immune privilege of tumors.

Escape over a potential barrier driven by colored noise: Large but finite correlation times

The recent theory of Tsironis and Grigolini for the mean first-passage time from one metastable state to another of a bistable potential for long correlation times of the noise is extended to large but finite correlation times.

Modelling the evolution and spread of HIV immune escape mutants.

During infection with human immunodeficiency virus (HIV), immune pressure from cytotoxic T-lymphocytes (CTLs) selects for viral mutants that confer escape from CTL recognition. These escape variants can be transmitted between individuals where, depending upon their cost to viral fitness and the CTL responses made by the recipient, they may revert. The rates of within-host evolution and their concordant impact upon the rate of spread of escape mutants at the population level are uncertain. Here we present a mathematical model of within-host evolution of escape mutants, transmission of these variants between hosts and subsequent reversion in new hosts. The model is an extension of the well-known SI model of disease transmission and includes three further parameters that describe host immunogenetic heterogeneity and rates of within host viral evolution. We use the model to explain why some escape mutants appear to have stable prevalence whilst others are spreading through the population. Further, we use it to compare diverse datasets on CTL escape, highlighting where different sources agree or disagree on within-host evolutionary rates. The several dozen CTL epitopes we survey from HIV-1 gag, RT and nef reveal a relatively sedate rate of evolution with average rates of escape measured in years and reversion in decades. For many epitopes in HIV, occasional rapid within-host evolution is not reflected in fast evolution at the population level.

Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice.

Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastasis was not caused by excessive primary tumor growth but depended on endothelium-derived EETs at the site of metastasis. Administration of synthetic EETs recapitulated these results, while EET antagonists suppressed tumor growth and metastasis, demonstrating in vivo that pharmacological modulation of EETs can affect cancer growth. Furthermore, inhibitors of soluble epoxide hydrolase (sEH), the enzyme that metabolizes EETs, elevated endogenous EET levels and promoted primary tumor growth and metastasis. Thus, our data indicate a central role for EETs in tumorigenesis, offering a mechanistic link between lipid signaling and cancer and emphasizing the critical importance of considering possible effects of EET-modulating drugs on cancer.

First-passage and escape problems in the Feller process

The Feller process is an one-dimensional diffusion process with linear drift and state-dependent diffusion coefficient vanishing at the origin. The process is positive definite and it is this property along with its linear character that have made Feller process a convenient candidate for the modeling of a number of phenomena ranging from single-neuron firing to volatility of financial assets. While general properties of the process have long been well known, less known are properties related to level crossing such as the first-passage and the escape problems. In this work we thoroughly address these questions.

Upward influence tactics in virtual work settings

The globalization of work within organizations has generated a greater need for all type of workers to exert interpersonal influence through technology-mediated communication tools. This paper contributes to the analysis of interpersonal relations in virtual environments from a specific perspective: the choice of upward influence tactics. We propose that virtualwork settings may impact the upward influence tactic selected, as well as thecommunication medium used to enact it. In particular, we study whether the types of upward influence strategies found in presence environments, are relevant in a virtual work context. This research also analyzes the link between communication media and influence tactics used. Preliminary results suggest that there is an influence tactic that is specific of virtual work relations, which may be called intermediation and consists of finding an intermediary that is well connected with the target and can help in defining the best approach by the agent.

First-passage and escape problems in the Feller process

The Feller process is an one-dimensional diffusion process with linear drift and state-dependent diffusion coefficient vanishing at the origin. The process is positive definite and it is this property along with its linear character that have made Feller process a convenient candidate for the modeling of a number of phenomena ranging from single-neuron firing to volatility of financial assets. While general properties of the process have long been well known, less known are properties related to level crossing such as the first-passage and the escape problems. In this work we thoroughly address these questions.

Modelling the Evolution and Spread of HIV Immune Escape Mutants.

During infection with human immunodeficiency virus (HIV), immune pressure from cytotoxic T-lymphocytes (CTLs) selects for viral mutants that confer escape from CTL recognition. These escape variants can be transmitted between individuals where, depending upon their cost to viral fitness and the CTL responses made by the recipient, they may revert. The rates of within-host evolution and their concordant impact upon the rate of spread of escape mutants at the population level are uncertain. Here we present a mathematical model of within-host evolution of escape mutants, transmission of these variants between hosts and subsequent reversion in new hosts. The model is an extension of the well-known SI model of disease transmission and includes three further parameters that describe host immunogenetic heterogeneity and rates of within host viral evolution. We use the model to explain why some escape mutants appear to have stable prevalence whilst others are spreading through the population. Further, we use it to compare diverse datasets on CTL escape, highlighting where different sources agree or disagree on within-host evolutionary rates. The several dozen CTL epitopes we survey from HIV-1 gag, RT and nef reveal a relatively sedate rate of evolution with average rates of escape measured in years and reversion in decades. For many epitopes in HIV, occasional rapid within-host evolution is not reflected in fast evolution at the population level.

Is Self-employment a Way to Escape from Skill Mismatches?

During the last two decades, skill mismatches have become one of the most important issues of policy concern in the EU (European Commission, 2008). Hence, the literature has stressed the necessity to reduce skill mismatches. We contribute to this literature by analyzing the impact of the transition from salaried employment to self-employment on self-reported skill mismatches. To do so, we resort to the European Community Household Panel (ECHP) covering the period 1994–2001. Using panel data, we track individuals over time and measure their self-reported skill mismatch before and after the transition. Our empirical findings indicate not only that the average self-employee is less likely to declare being skill-mismatched but also that those individuals who transit from salaried employment to self-employment reduce their probability of skill mismatches after the transition. Keywords: Self-employment, skill mismatches, salaried employment. JEL Classification: L26, J24, B23 __________________________