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Background: The activation of Fas/Fas ligand (FasL) and DR4-DR5/tumor necrosis factor-related-apoptosis-inducing ligand (TRAIL) pathways in cancer cells triggers apoptosis. The objective of this study was to investigate the prognostic value of soluble FasL (sFasL) and soluble (sTRAIL) in the serum of patients with bladder cancer. Methods: The sFasL and sTRAIL levels in the sera of patients with bladder cancer or healthy donors were determined using the enzyme-linked immunosorbent assay. Micro-culture tetrazolium viability assay and Western blot were used to analyze cell cytotoxicity and death receptors protein expression respectively. Results: Whether no difference in sTRAIL levels was seen between patients and controls, the level of sFasL was higher in patients than that in healthy donors. According to, sFasL level was the highest in the serum of patients with superficial stage or low- and medium-grade cancer. Moreover, sFasL in patients with superficial noninvasive bladder tumors or low- and medium-grade cancers was higher than that in patients with invasive carcinomas and high-grade cancers. Patients with high levels of sFasL survive longer than those with low levels, probably related to the cytotoxic potential of FasL preserved in its soluble form. Conclusion: The data suggest that monitoring the level of sFasL and its cytotoxic activity could be a prognostic marker in the follow-up of patients with bladder cancer.

Gold phosphine complexes, such as auranofin, have been recognized for decades as antirheumatic agents. Clinical trials are now underway to validate their use in anticancer or anti-HIV treatments. However, their mechanisms of action remain unclear. A challenging question is whether the gold phosphine complex is a prodrug that is administered in an inactive precursor form or rather that the gold atom remains attached to the phosphine ligand during treatment. In this study, we present two novel gold complexes, which we compared to auranofin and to their phosphonium analogue. The chosen ligand is a phosphine-based smart probe, whose strong fluorescence depends on the presence of the gold atom. The in vitro biological action of the gold complexes and the phosphonium derivative were investigated, and a preliminary in vivo study in healthy zebrafish larvae allowed us to evaluate gold complex biodistribution and toxicity. The different analyses carried out showed that these gold complexes were stable and behaved differently from phosphonium and auranofin, both in vitro and in vivo. Two-photon microscopy experiments demonstrated that the cellular targets of these gold complexes are not the same as those of the phosphonium analogue. Moreover, despite similar IC50 values in some cancer cell lines, gold complexes displayed a low toxicity in vivo, in contrast to the phosphonium salt. They are therefore suitable for future in vivo investigations.

International audience; Various studies in western countries found Akt amplification to be a frequent event in human cancers, including bladder, but the correlation with clinicopathological features is controversial. Such studies have not been reported in African populations, including Tunisians. The purpose of this study was to assess expression of the phosphorylated/activated forms of Akt in tumors from Tunisian patients with bladder cancer and to correlate its expression with pathological and clinical parameters of the disease. The study included 72 patients of whom 34 were diagnosed as low- to medium-grade and 35 as high-grade; 30 were muscle stage and 39 non-muscle stage. Primary tumors from these patients, normal adjacent tissues, or bladder cancer cell-lines were analyzed for Ser473 phosphorylated Akt expression by Western blot. Seventy-two percent of primary tumors from patients with bladder cancer had increased levels of p-Akt. The p-Akt levels in patients with high-grade bladder cancer were significantly elevated compared to patients with low- or medium-grade bladder cancer. In invasive carcinoma, the p-Akt level was significantly higher than in superficial non-invasive bladder tumors. Concerning the influence of tobacco on Akt activation, no significant differences of p-Akt expression were found between non-smoker and smoker patients. Altogether, our results suggest that Akt activation can provide useful prognostic information and that tobacco represents a serious risk factor for recurrence in a cohort of Tunisian patients.

Orientador: Maria do Carmo Martins Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Educação Resumo: Este trabalho de pesquisa, desenvolvido com referenciais da história da educação, aborda a trajetória de vida da escritora e professora de Maria Firmina dos Reis (1825 a 1917) e analisa três de suas obras, Úrsula, A Escrava e Gupeva sob aspectos pertinentes à educação. O trabalho se desenvolve com fontes documentais do ensino maranhense (relatórios, leis e regimentos), obras da historiografia educacional tais como VIDAL (2013) e CASTRO (2013), que possibilitam um diálogo metodológico a respeito da instrução pública maranhense e, obras literárias de Maria Firmina dos Reis, procurando compreender sua trajetória docente, o contexto educacional do período em que trabalhou como professora, fundou a primeira escola mista de Guimarães na Província do Maranhão e produziu contos e novelas que se destacam sob aspectos educativos . Em que pese algumas de suas obras já serem estudadas em trabalhos voltados aos estudos literários, tais como Mendes (2006) e Oliveira (2007), nesta pesquisa é a professora de primeiras letras que é destacada, em seu ofício e suas missões. Para a análise e compreensão da problemática desta pesquisa, definimos um corpus conceitual de categorias da História Cultural na perspectiva de Chartier (1990; 2002) e de Le Goff (1990) e nos valemos do conceito de memória, em Martins & Rocha (2005). A metodologia de leitura das obras beneficiou-se da proposta de "configuração textual" em Mortatti (2000). A análise interpretativa dos textos estudados permitiu apreender que o discurso de suas obras tem a intencionalidade ensinar, criticar e/ou moralizar seus leitores. Fica demonstrado ainda que a escrita proposta por Maria Firmina dos Reis é relevante por seu caráter didático-pedagógico e moral para a educação no século XIX, e permite retirar do anonimato uma professora deste período Abstract: This research, developed with references of History of Education, aims to known the life history and the trajectory of a writer and a school teacher called Maria Firmina dos Reis (1825-1917), who lived, teached and wrote in Maranhão, Brazil, in the XIX century. We also analyzes three of his works, "Ursula", "A Slave" and "Gupeva" in some relevant aspects of Education. It is develops with documentary sources of Maranhão Education's (reports, laws and political regulations), works of brazilian educational history such as Vidal (2013) and Castro (2013), which enable a methodological dialogue about Public Instruction in the XIX century and Literary works of Reis, seeking understand teaching trajectory, the educational context of the period in which he was a school teacher, and she founded the first mixed school in Guimarães. She also produced short stories and novels that stand out educational aspects in the same period. Some of his works are already studied in work aimed to literary studies, such as Mendes (2006) and Oliveira (2007), but on this research, is a teacher of childrens and primary school what is highlighted in his craft and its missions. For the analysis and understanding of this problematic search, we defined a conceptual corpus of Cultural History in Perspective of Chartier (1990; 2002), Le Goff (1990), Martins & Rocha (2005) and Mortatti (2000). The interpretative analysis of texts studied allowed apprehend that speech his works have an intention to teach, criticize and / or moralizing your readers and the writer, as the same time, has a relevant didactic and pedagogical character Mestrado Educação Mestra em Educação CAPES

HTLV-1 is more pathogenic than HTLV-2 despite having a similar genome and closely related transactivating oncoproteins. Both Tax-1 protein from HTLV-1 and Tax-2 from HTLV-2 activate the NF-κB pathway. The mechanisms involved in Tax-1 deregulation of this signalling pathway have been thoroughly investigated, but little is known about regulation by Tax-2. We have compared the interaction of Tax-1 and Tax-2 with two key NF-κB signalling factors: TAK1-binding protein 2 (TAB2), an adaptor involved in the activation of TAK1 kinase, and RelA, the active subunit of the canonical RelA/p50 NF-κB transcription factor. Tax-2 formed stable complexes with both RelA and TAB2. These two NF-κB factors colocalized with Tax proteins in dotted cytoplasmic structures targeted by calreticulin, a multi-process calcium-buffering chaperone. Co-expression of RelA and/or TAB2 markedly increased Tax-mediated NF-κB activation. These findings provide new insights into the role of RelA, TAB2 and Tax in the deregulation of the NF-κB pathway.

The original global entrepreneurship monitor model predicts that the business activity at the national level varies with the general national framework conditions, while entrepreneurial activity varies with the entrepreneurial framework conditions (Reynolds et al., 2005). The aim of the national expert survey is to provide a general diagnostic approach to the entrepreneurship institutions that can be applied to any territorial level: as nation, region, city or others. It selects a representative sample of experts and asks them to make valuations on the target territory, using questionnaires. The global entrepreneurship monitor also provides the total early-stage entrepreneurship activity for the studied countries which is the percent of working age population both about to start an entrepreneurial activity, and that have started one from a maximum of three years and half. Therefore, this paper examines data collected from the Global Entrepreneurship Monitor 2011 National Expert Survey Global Individual Level Data in order to assess the impact of the environmental variables on entrepreneurship. Results show that the variables entrepreneurial level of education at vocational, professional, college and university, research and development level of transference, physical infrastructures and services access and cultural, social norms and society support, have more impact in the total early-stage entrepreneurship activity.

Phosphoinositide 3-kinase (PI3K) participates in extracellular signal-regulated kinase 1 and 2 (ERK1-2) activation according to signal strength, through unknown mechanisms. We report herein that Gab1/Shp2 constitutes a PI3K-dependent checkpoint of ERK1-2 activation regulated according to signal intensity. Indeed, by up- and down-regulation of signal strength in different cell lines and through different methods, we observed that Gab1/Shp2 and Ras/ERK1-2 in concert become independent of PI3K upon strong epidermal growth factor receptor (EGFR) stimulation and dependent on PI3K upon limited EGFR activation. Using Gab1 mutants, we observed that this conditional role of PI3K is dictated by the EGFR capability of recruiting Gab1 through Grb2 or through the PI3K lipid product PIP(3), according to a high or weak level of receptor stimulation, respectively. In agreement, Grb2 siRNA generates, in cells with maximal EGFR stimulation, a strong dependence on PI3K for both Gab1/Shp2 and ERK1-2 activation. Therefore, Ras/ERK1-2 depends on PI3K only when PIP(3) is required to recruit Gab1/Shp2, which occurs only under weak EGFR mobilization. Finally, we show that, in glioblastoma cells displaying residual EGFR activation, this compensatory mechanism becomes necessary to efficiently activate ERK1-2, which could probably contribute to tumor resistance to EGFR inhibitors.

As a part of environmental health surveillance programs related to Portuguese solid waste incinerators (SWI), two biomonitoring projects have been established to investigate additional exposure to lead in children under the age of 6 years living in the vicinity of those facilities. The above-mentioned programs, being the only ones in the country that integrate systematic observations on human exposure to heavy metals, have to provide systematic data from Portuguese regions on the extent and pattern of human exposure to heavy metals, namely to lead. The present paper is the third of a series of papers prepared to accomplish that objective in regards to lead exposure as evaluated by measuring lead levels in children under the age of 6 years. Altogether, 250 children from Lisbon and 247 from Madeira Island have already been involved in the investigation. The present study evaluates spatial and temporal trends of lead exposure, based on comparisons of children's blood lead levels, either stratified by living area (exposed and control groups), or by time of exposure (T0, the baseline time, and T1, after approximately 2 years of regular operation of the facilities). The results obtained correspond to a relatively reduced number of individuals. Possibly for this reason, they are not fully conclusive in relation to whether living in the vicinity of SWI represents an additional risk of higher exposure to lead. Time trends of lead exposure as evaluated by blood lead levels in children also do not show any clear pattern. These conclusions and the fact that altogether around 3% of children from the whole group have blood lead levels >or=10 microg/dl warrant further investigation in order to clarify the contribution of incinerator emissions to the levels of lead in children and to identify alternative sources for preventive purposes, taking into consideration the relevance of even low lead exposure from a public health perspective, mainly in relation to children.

Transformation by the Tax oncoprotein of the human T cell leukemia virus type 1 (HTLV-1) is governed by actions on cellular regulatory signals, including modulation of specific cellular gene expression via activation of signaling pathways, acceleration of cell cycle progression via stimulation of cyclin-dependent kinase activity leading to retinoblastoma protein (pRb) hyperphosphorylation and perturbation of survival signals. These actions control early steps in T cell transformation and development of Adult T cell leukemia (ATL), an aggressive malignancy of HTLV-1 infected T lymphocytes. Post-translational modifications of Tax by phosphorylation, ubiquitination, sumoylation and acetylation have been implicated in Tax-mediated activation of the NF-κB pathway, a key function associated with Tax transforming potential., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

The Tax oncoprotein of HTLV-1 initiates T-cell transformation by dysregulating cell cycle progression and inhibiting DNA damage responses. The subsequent genomic instability might result in constitutive activation of the NF-κB pathway observed in HTLV-1-transformed T lymphocytes. Our previous results indicated that differential modifications of Tax by ubiquitination or sumoylation controlled its retention either in the cytoplasm or in the nucleus, respectively. Here we show that Tax is targeted to pre-existing punctate cytoplasmic structures which contain the TNF-receptor associated protein 2 (TAB2). Colocalization of Tax with TAB2 in these cytoplasmic structures induced the recruitment of additional components involved in the NF-κB activation cascade, including the regulatory subunit of the IKK complex, IKKgamma/NEMO, the RelA subunit of NF-κB and TAX1-BP1, which are Tax interacting partners. Overexpression of TAB2 strongly stimulated Tax-mediated activation of the NF-κB pathway indicating that the concentration of these NF-κB factors in Tax-containing cytoplasmic punctate structures is a step important for activation of the NF-κB pathway by Tax. Interestingly, calreticulin, a multifunctional calcium buffering chaperone previously involved in the nucleocytoplasmic transport of nuclear receptors such as glucocorticoid and thyroid receptors, was also recruited by Tax in these cytoplasmic structures. The fact that overexpressed IKKgamma concentrated in nuclear foci that included calreticulin and that co-expression of Tax and IKKgamma led to the redistribution of both IKKgamma and calreticulin from the nucleus to the cytoplasm suggested that calreticulin might be involved in the nuclear export of these factors and their recruitment in TAB2-containing cytoplasmic punctate structures. The possibility that Tax activates the NF-κB pathway via initiation of events in the nucleus leading to the transport of IKKgamma from the nucleus to the cytoplasm will be discussed.

As part of environmental health surveillance programs related to solid waste incinerators located near Lisbon and on Madeira Island, human biomonitoring projects have been implemented in Portugal, some of them focused on cross-sectional surveys of heavy metals in blood. One of the general aims of these programs is to provide Portuguese data on the extent and pattern of human exposure to the pollutants potentially released in the stack gases from the incinerators, namely heavy metals. The present investigation reports information specifically on blood lead levels of newborn-mother pairs living in the vicinity of the incinerators under study, as well as of statistically similar participants living outside the exposed area. For Lisbon, lead levels determined at the baseline period (T0), as well as three subsequent evaluations of potential specific impacts of the incinerator (T1, T2 and T3) are described in order to investigate spatial and temporal trends of human exposure to lead. Available data for Madeira, namely lead levels in blood from the study population before the incinerator started operation, is also described. For Lisbon, analyses showed a statistically significant decrease of lead concentrations in maternal (p

Human exposure to heavy metals makes it necessary to monitor these elements in the human body if the objective is to relate heavy metal exposure to adverse health effects. In Portugal, biomonitoring projects on heavy metals are being carried out on people living in the vicinity of solid waste incinerators. The projects are being developed in the ambit of two environmental health surveillance programs related to solid waste incineration facilities, one near Lisbon and the other on Madeira Island, that have the main objective of guaranteeing the safeguard of public health in relation to the potential negative impact of incineration processes on human health. These programs are the only ones in the country that integrate a systematic observation of human exposure to heavy metals as determined by the respective body burden in several population groups. Therefore, they are the only ones that are currently able to provide systematic data from Portuguese regions on the extent and pattern of human exposure to this type of pollutants. The present paper is the first of a series of three prepared papers with the objective of presenting and discussing available data. It addresses exposure to lead, cadmium and mercury as determined by their levels in blood of general population adults. Results suggest the effectiveness of source control measures in relation to both incinerators under study, similarly to what has been concluded from previous studies addressing exposure to dioxins. They also show, in relation to the baseline situation, a general significant trend for reduction of exposure to all studied heavy metals. Individuals from Lisbon seem to have a significantly higher body burden of the studied metals than those living in Madeira and, in general, metal exposure in men is significantly higher than in women, with the most relevant exception being the case of higher mercury levels in women, at the baseline and for both communities. Compared with published reference values for similar conditions, blood levels of cadmium, lead, and mercury of the present investigation seem to be relatively higher, in median terms and for extreme values, mainly in the case of cadmium and mercury. In the case of lead the differences are not so marked.

Biomonitoring of dioxin body burden, as evaluated by PCDD/F levels in blood, has been carried out in a total of 138 adults from general population living in the vicinity of solid waste incinerators in Portugal. Measurements were performed included in cross-sectional surveys within two Environmental Health Surveillance Programs launched in response to ecotoxicological concern in relation to solid waste incinerators near Lisbon and in Madeira Island. Overall conclusion from first published results is indicative that dioxin exposure of global populations cannot be related to the emissions of these facilities, meaning that dioxin sources control seems to be effective in relation to both incinerators. Main objective of present work was to investigate potential determinants of dioxin levels in the studied populations. Findings from this investigation also suggest that incineration does not impact on dioxin blood levels of nearby residents. Follow-up of a small group of individuals (22) from Lisbon gives preliminary indication on temporal control effectiveness of the Lisbon facility. Regarding comparison between PCDD/F levels from Lisbon and Madeira communities, individuals from Lisbon show higher median PCDD/F levels, likely to be better explained by more highly polluted areas in Lisbon than by eventual differences in dietary habits of the studied groups. In fact, analysis performed on the diet of both groups (not detailed in the present study) does not show a statistically significant difference in relation to any of the most relevant foodstuffs in the context of dioxin exposure. Comparison between Lisbon and Madeira in relation to pattern of the single congeners for PCDD/Fs shows a very similar profile. The highest contributions to the PCDD/Fs toxicity came from 12378-PCDD, 23478-PCDF, Hexa-CDD, 2378-TCDD and Hexa-CDF.

In the context of two Environmental Health Surveillance Programs, launched in response to public and scientific concern in relation to waste incinerators located near Lisbon and in Madeira Island, two human biomonitoring projects have been started in Portugal, focussed in dioxins and dioxin-like compounds in human milk. Results from the undertaken studies have already provided data on the extent and pattern of dioxin body burden of both studied groups as well as a preliminary temporal trend of dioxin levels for the population residing near Lisbon incinerator. The present paper investigates difference between exposed and non-exposed subjects under study and, from a preventive perspective, possible covariates of the dioxin levels in human milk. Emissions from both incinerators appear to be well controlled as there is no increase of human body burden of dioxins as measured in human milk of individuals living near these facilities. Concerning other determinants of dioxin levels, results suggest confirmation of previously found significant age-dependent trend towards higher levels of dioxins in aged subjects. On the contrary, association between mother’s levels of dioxins and parity lost significance. Apart from the issue of incineration, the general conclusion for the general population is that living in Lisbon as compared to Madeira results in higher milk dioxin levels and possible health risks. The profile of the single congeners for PCDD/Fs in human milk from Madeira and Lisbon shows similar contributions for 12378-PCDD, 23478-PCDF, 123678-HCDD and 2378-TCDD, that account altogether for about 84% of the total identified dioxin body burden in the studied groups.

Background: Retroviruses HTLV-1 and HTLV-2 have homologous genomic structures but differ significantly in pathogenicity. HTLV-1 is associated with Adult T cell Leukemia (ATL), whereas infection by HTLV-2 has no association with neoplasia. Transformation of T lymphocytes by HTLV-1 is linked to the capacity of its oncoprotein Tax-1 to alter cell survival and cell cycle control mechanisms. Among these functions, Tax-1-mediated activation of cellular gene expression via the NF-κB pathway depends on Tax-1 post-translational modifications by ubiquitination and sumoylation. The Tax-2 protein of HTLV-2B (Tax-2B) is also modified by ubiquitination and sumoylation and activates the NF-κB pathway to a level similar to that of Tax-1. The present study aims to understand whether ubiquitination and sumoylation modifications are involved in Tax-2B-mediated activation of the NF-κB pathway.Results: The comparison of Tax-1 and Tax-2B lysine to arginine substitution mutants revealed conserved patterns and levels of ubiquitination with notable difference in the lysine usage for sumoylation. Neither Tax-1 nor Tax-2B ubiquitination and sumoylation deficient mutants could activate the NF-κB pathway and fusion of ubiquitin or SUMO-1 to the C-terminus of the ubiquitination and sumoylation deficient Tax-2B mutant strikingly restored transcriptional activity. In addition, ubiquitinated forms of Tax-2B colocalized with RelA and IKKγ in prominent cytoplasmic structures associated with the Golgi apparatus, whereas colocalization of Tax-2B with the RelA subunit of NF-κB and the transcriptional coactivator p300 in punctate nuclear structures was dependent on Tax-2B sumoylation, as previously observed for Tax-1.Conclusions: Both Tax-1 and Tax-2 activate the NF-κB pathway via similar mechanisms involving ubiquitination and sumoylation. Therefore, the different transforming potential of HTLV-1 and HTLV-2 is unlikely to be related to different modes of activation of the canonical NF-κB pathway. © 2012 Turci et al. licensee BioMed Central Ltd., SCOPUS: ar.j, info:eu-repo/semantics/published