Overall survival analyses of female malignancies in Southern Brazil during 2008–2017: A closer look at breast, cervical and ovarian cancer

Background: The aim of this study was to report the overall survival and baseline factors associated with OS for breast, cervical and ovarian cancer in Florianópolis, Southern Brazil, a region with quality-of-life indicators comparable to high-income countries. Methods: Cohort study was performed from probabilistic record linkage of the Mortality Information System and the Population-based cancer registry of Florianópolis. It was included breasts, cervical and ovarian cancer diagnosis during the period of 2008–2012 with a follow up of 60 months. Cox regression and Kaplan-Meier method were used for associations with overall survival and risk factors. Findings: 1857 cases of the three malignancies were included in the analysis. We identified 202 deaths in breast cancer subjects, 53 for cervical cancer and 51 for ovarian cancer. Metastatic disease at diagnosis was present in 31%, 9.6%, and 55% of the cases, respectively. Overall survival was statistically correlated with age, educational level and stage for breast cancer; age and stage for cervical cancer; age and stage for ovarian cancer. Interpretation: Metastatic disease and age are the main prognostic factors for the malignancies studied, as they were associated with both overall survival and risk of death. Better screening and preventive tests for early diagnosis are needed. Funding: Support of Research and Innovation in the State of Santa Catarina, Research Program for the Unified Health System (FAPESC/MS-DECIT/CNPQ/SES-SC-PPSUS); the Brazilian National Research Council (CNPq); and the Coordination for the Improvement of Higher Education Personnel (CAPES)

A ‘higher order' of telomere regulation: telomere heterochromatin and telomeric RNAs

Protection of chromosome ends from DNA repair and degradation activities is mediated by specialized protein complexes bound to telomere repeats. Recently, it has become apparent that epigenetic regulation of the telomric chromatin template critically impacts on telomere function and telomere-length homeostasis from yeast to man. Across all species, telomeric repeats as well as the adjacent subtelomeric regions carry features of repressive chromatin. Disruption of this silent chromatin environment results in loss of telomere-length control and increased telomere recombination. In turn, progressive telomere loss reduces chromatin compaction at telomeric and subtelomeric domains. The recent discoveries of telomere chromatin regulation during early mammalian development, as well as during nuclear reprogramming, further highlights a central role of telomere chromatin changes in ontogenesis. In addition, telomeres were recently shown to generate long, non-coding RNAs that remain associated to telomeric chromatin and will provide new insights into the regulation of telomere length and telomere chromatin. In this review, we will discuss the epigenetic regulation of telomeres across species, with special emphasis on mammalian telomeres. We will also discuss the links between epigenetic alterations at mammalian telomeres and telomere-associated diseases

The emergency department arrival mode and its relations to ED management and 30-day mortality in acute heart failure: an ancillary analysis from the EURODEM study

Background Acute heart failure patients are often encountered in emergency departments (ED) from 11% to 57% using emergency medical services (EMS). Our aim was to evaluate the association of EMS use with acute heart failure patients' ED management and short-term outcomes. Methods This was a sub-analysis of a European EURODEM study. Data on patients presenting with dyspnoea were collected prospectively from European EDs. Patients with ED diagnosis of acute heart failure were categorized into two groups: those using EMS and those self-presenting (non- EMS). The independent association between EMS use and 30-day mortality was evaluated with logistic regression. Results Of the 500 acute heart failure patients, with information about the arrival mode to the ED, 309 (61.8%) arrived by EMS. These patients were older (median age 80 vs. 75 years, p 30/min in 17.1% patients vs. 7.5%, p = 0.005). The only difference in ED management appeared in the use of ventilatory support: 78.3% of EMS patients vs. 67.5% of non- EMS patients received supplementary oxygen (p = 0.007), and non-invasive ventilation was administered to 12.5% of EMS patients vs. 4.2% non- EMS patients (p = 0.002). EMS patients were more often hospitalized (82.4% vs. 65.9%, p < 0.001), had higher in-hospital mortality (8.7% vs. 3.1%, p = 0.014) and 30-day mortality (14.3% vs. 4.9%, p < 0.001). The use of EMS was an independent predictor of 30-day mortality (OR = 2.54, 95% CI 1.11-5.81, p = 0.027). Conclusion Most acute heart failure patients arrive at ED by EMS. These patients suffer from more severe respiratory distress and receive more often ventilatory support. EMS use is an independent predictor of 30-day mortality

Contribution of microscopy for understanding the mechanism of action against trypanosomatids

Transmission electron microscopy (TEM) has proved to be a useful tool to study the ultrastructural alterations and the target organelles of new antitrypanosomatid drugs. Thus, it has been observed that sesquiterpene lactones induce diverse ultrastructural alterations in both T. cruzi and Leishmania spp., such as cytoplasmic vacuolization, appearance of multilamellar structures, condensation of nuclear DNA, and, in some cases, an important accumulation of lipid vacuoles. This accumulation could be related to apoptotic events. Some of the sesquiterpene lactones (e.g., psilostachyin) have also been demonstrated to cause an intense mitochondrial swelling accompanied by a visible kinetoplast deformation as well as the appearance of multivesicular bodies. This mitochondrial swelling could be related to the generation of oxidative stress and associated to alterations in the ergosterol metabolism. The appearance of multilamellar structures and multiple kinetoplasts and flagella induced by the sesquiterpene lactone psilostachyin C indicates that this compound would act at the parasite cell cycle level, in an intermediate stage between kinetoplast segregation and nuclear division. In turn, the diterpene lactone icetexane has proved to induce the external membrane budding on T. cruzi together with an apparent disorganization of the pericellar cytoskeleton. Thus, ultrastructural TEM studies allow elucidating the possible mechanisms and the subsequent identification of molecular targets for the action of natural compounds on trypanosomatids.Fil: Lozano, Esteban Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Spina Zapata, Renata María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Barrera, Patricia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Tonn, Carlos Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; ArgentinaFil: Sosa Escudero, Miguel Angel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

Holographic Brownian Motion in Magnetic Environments

Using the gauge/gravity correspondence, we study the dynamics of a heavy quark in two strongly-coupled systems at finite temperature: Super-Yang-Mills in the presence of a magnetic field and non-commutative Super-Yang-Mills. In the former, our results agree qualitatively with the expected behavior from weakly-coupled theories. In the latter, we propose a Langevin equation that accounts for the effects of non-commutativity and we find new interesting features. The equation resembles the structure of Brownian motion in the presence of a magnetic field and implies that the fluctuations along non-commutative directions are correlated. Moreover, our results show that the viscosity is smaller than the commutative case and that the diffusion properties of the quark are unaffected by non-commutativity. Finally, we compute the random force autocorrelator and verify that the fluctuation-dissipation theorem holds in the presence of non-commutativity.Comment: 34 pages. v2: typos corrected. v3: title and abstract slightly modified in order to better reflect the contents of the paper; footnote 3 and one reference were also added; version accepted for publication in JHE

Electrostatic Effects in the Folding of the SH3 Domain of the c-Src Tyrosine Kinase: pH-Dependence in 3D-Domain Swapping and Amyloid Formation

The SH3 domain of the c-Src tyrosine kinase (c-Src-SH3) aggregates to form intertwined dimers and amyloid fibrils at mild acid pHs. In this work, we show that a single mutation of residue Gln128 of this SH3 domain has a significant effect on: (i) its thermal stability; and (ii) its propensity to form amyloid fibrils. The Gln128Glu mutant forms amyloid fibrils at neutral pH but not at mild acid pH, while Gln128Lys and Gln128Arg mutants do not form these aggregates under any of the conditions assayed. We have also solved the crystallographic structures of the wild-type (WT) and Gln128Glu, Gln128Lys and Gln128Arg mutants from crystals obtained at different pHs. At pH 5.0, crystals belong to the hexagonal space group P6522 and the asymmetric unit is formed by one chain of the protomer of the c-Src-SH3 domain in an open conformation. At pH 7.0, crystals belong to the orthorhombic space group P212121, with two molecules at the asymmetric unit showing the characteristic fold of the SH3 domain. Analysis of these crystallographic structures shows that the residue at position 128 is connected to Glu106 at the diverging β-turn through a cluster of water molecules. Changes in this hydrogen-bond network lead to the displacement of the c-Src-SH3 distal loop, resulting also in conformational changes of Leu100 that might be related to the binding of proline rich motifs. Our findings show that electrostatic interactions and solvation of residues close to the folding nucleation site of the c-Src-SH3 domain might play an important role during the folding reaction and the amyloid fibril formation.This research was funded by the Spanish Ministry of Science and Innovation and Ministry of Economy and Competitiveness and FEDER (EU): BIO2009-13261-C02-01/02 (ACA); BIO2012-39922-C02-01/02 (ACA); CTQ2013-4493 (JLN) and CSD2008-00005 (JLN); Andalusian Regional Government (Spain) and FEDER (EU): P09-CVI-5063 (ACA); and Valentian Regional Government (Spain) and FEDER (EU): Prometeo 2013/018 (JLN). Data collection was supported by European Synchrotron Radiation Facility (ESRF), Grenoble, France: BAG proposals MX-1406 (ACA) and MX-1541 (ACA); and ALBA (Barcelona, Spain) proposals 2012010072 (ACA) and 2012100378 (ACA)

THG113.31, a specific PGF2alpha receptor antagonist, induces human myometrial relaxation and BKCa channel activation

BACKGROUND: PGF2alpha exerts a significant contractile effect on myometrium and is central to human labour. THG113.31, a specific non-competitive PGF2alpha receptor (FP) antagonist, exerts an inhibitory effect on myometrial contractility. The BKCa channel is ubiquitously encountered in human uterine tissue and plays a significant role in modulating myometrial cell membrane potential and excitability. The objective of this study was to investigate potential BKCa channel involvement in the response of human myometrium to THG113.31. METHODS: Single and whole-cell electrophysiological BKCa channel recordings from freshly dispersed myocytes, were investigated in the presence and absence of THG113.31. Functional studies investigated the effects of THG113.31 on isolated spontaneous myometrial contractions, in the presence and absence of the BKCa channel blocker, iberiotoxin. RESULTS: Single channel recordings identified the BKCa channel as a target of THG113.31. THG113.31 significantly increased the open state probability of these channels [control 0.023+/-0.006; 10 microM THG113.31 0.087+/-0.012 (P = 0.009); and 50 microM THG113.31 0.1356+/-0.018 (P = 0.001)]. In addition, THG113.31 increased whole-cell BKCa currents over a range of membrane potentials, and this effect was reversed by 100 nanoM IbTX. Isometric tension studies demonstrated that THG113.31 exerted a significant concentration-dependent relaxant effect on human myometrial tissue and pre-incubation of strips with IbTX abolished this effect on spontaneously occurring contractions. CONCLUSION: These data suggests that activation of the BKCa channel may contribute, at least partially, to the uterorelaxant effect of THG113.31

Alternative Oxidase Mediates Pathogen Resistance in Paracoccidioides brasiliensis Infection

Thermally dimorphic pathogenic fungi are responsible for potentially life-threatening diseases of immunocompetent and immunocompromised individuals. These microorganisms grow as conidia-producing mycelia in the environment, which when inhaled by the host convert to the pathogenic yeast form at 37°C. During adaptation and growth, fungi interact with host immune cells and must cope with defense mechanisms such as imposed-oxidative stress (e.g., reactive oxygen species; ROS). Alternative oxidase (AOX) is an enzyme recently implicated in the reduction of ROS production by the mitochondria when triggered by external stimuli, such as temperature and ROS. During this work we have evaluated the relevance of AOX during infection with Paracoccidioides brasiliensis, the etiological agent of one of the most prevalent mycoses in Latin America, paracoccidioidomycosis. We show that PbAOX gene expression is stimulated after interaction with alveolar macrophages or in the presence of H2O2 and is essential for survival against fungicidal activity of both the immune cells and the ROS compound. Moreover, decreasing PbAOX gene expression in P. brasiliensis led to increased survival of infected mice. Altogether, our data supports a relevant role for AOX in the virulence of P. brasiliensis