The rna-binding ubiquitin ligase mex3a affects glioblastoma tumorigenesis by inducing ubiquitylation and degradation of rig-i

Glioblastoma multiforme (GB) is the most malignant primary brain tumor in humans, with an overall survival of approximatively 15 months. The molecular heterogeneity of GB, as well as its rapid progression, invasiveness and the occurrence of drug-resistant cancer stem cells, limits the efficacy of the current treatments. In order to develop an innovative therapeutic strategy, it is mandatory to identify and characterize new molecular players responsible for the GB malignant phenotype. In this study, the RNA-binding ubiquitin ligase MEX3A was selected from a gene expression analysis performed on publicly available datasets, to assess its biological and still-unknown activity in GB tumorigenesis. We find that MEX3A is strongly up-regulated in GB specimens, and this correlates with very low protein levels of RIG-I, a tumor suppressor involved in differentiation, apoptosis and innate immune response. We demonstrate that MEX3A binds RIG-I and induces its ubiquitylation and proteasome-dependent degradation. Further, the genetic depletion of MEX3A leads to an increase of RIG-I protein levels and results in the suppression of GB cell growth. Our findings unveil a novel molecular mechanism involved in GB tumorigenesis and suggest MEX3A and RIG-I as promising therapeutic targets in GB

A Smo/Gli multitarget hedgehog pathway inhibitor impairs tumor growth

Pharmacological Hedgehog (Hh) pathway inhibition has emerged as a valuable anticancer strategy. A number of small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector glioma-associated oncogene 1 (Gli1) has been designed and developed. In a recent study, we exploited the high versatility of the natural isoflavone scaffold for targeting the Hh signaling pathway at multiple levels showing that the simultaneous targeting of Smo and Gli1 provided synergistic Hh pathway inhibition stronger than single administration. This approach seems to effectively overcome the drug resistance, particularly at the level of Smo. Here, we combined the pharmacophores targeting Smo and Gli1 into a single and individual isoflavone, compound 22, which inhibits the Hh pathway at both upstream and downstream level. We demonstrate that this multitarget agent suppresses medulloblastoma growth in vitro and in vivo through antagonism of Smo and Gli1, which is a novel mechanism of action in Hh inhibition

Left Atrial Ablation Versus Biatrial Ablation for Persistent and Permanent Atrial Fibrillation A Prospective and Randomized Study

ObjectivesThe aim of this study was to compare—in patients with persistent and permanent atrial fibrillation (AF)—the efficacy and safety of left atrial ablation with that of a biatrial approach.BackgroundLeft atrium-based catheter ablation of AF, although very effective in the paroxysmal form of the arrhythmia, has an insufficient efficacy in patients with persistent and permanent AF.MethodsEighty highly symptomatic patients (age, 58.6 ± 8.9 years) with persistent (n = 43) and permanent AF (n = 37), refractory to antiarrhythmic drugs, were randomized to two different ablation approaches guided by electroanatomical mapping. A procedure including circumferential pulmonary vein, mitral isthmus, and cavotricuspid isthmus ablation was performed in 41 cases (left atrial ablation group). In the remaining 39 patients (biatrial ablation group), the aforementioned approach was integrated by the following lesions in the right atrium: intercaval posterior line, intercaval septal line, and electrical disconnection of the superior vena cava.ResultsDuring follow-up (mean duration 14 ± 5 months), AF recurred in 39% of patients in the left atrial ablation group and in 15% of patients in the biatrial ablation group (p = 0.022). Multivariable Cox regression analysis showed that ablation technique was an independent predictor of AF recurrence during follow-up.ConclusionsIn patients with persistent and permanent AF, circumferential pulmonary vein ablation, combined with linear lesions in the right atrium, is feasible, safe, and has a significantly higher success rate than left atrial and cavotricuspid ablation alone

A smo/gli multitarget hedgehog pathway inhibitor impairs tumor growth

Pharmacological Hedgehog (Hh) pathway inhibition has emerged as a valuable anticancer strategy. A number of small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector glioma-associated oncogene 1 (Gli1) has been designed and developed. In a recent study, we exploited the high versatility of the natural isoflavone scaffold for targeting the Hh signaling pathway at multiple levels showing that the simultaneous targeting of Smo and Gli1 provided synergistic Hh pathway inhibition stronger than single administration. This approach seems to effectively overcome the drug resistance, particularly at the level of Smo. Here, we combined the pharmacophores targeting Smo and Gli1 into a single and individual isoflavone, compound 22, which inhibits the Hh pathway at both upstream and downstream level. We demonstrate that this multitarget agent suppresses medulloblastoma growth in vitro and in vivo through antagonism of Smo and Gli1, which is a novel mechanism of action in Hh inhibition

Design, Teoria Ator-rede e Artesanato: Estudo da inserção de designers em um contexto artesanal utilizando a Cartografia de Controvérsias.

Essa pesquisa discutiu a inserção do designer no contexto artesanal. Ocorreu entre 2014 e 2015 em uma associação artesã na cidade de Maria da Fé/MG. Teve como base teórica o uso da Teoria Ator-Rede e da Cartografia de Controvérsias para visualizar as movimentações dentro da rede estudada. Elaborou-se uma ferramenta para análise e visualização dos dados denominada Oligopticon-Maps, que permitiu uma visualização oligóptica dos vários momentos da rede. Com o objetivo de estudar essa inserção do designer, discutiu-se conceitos e visões sobre Design e Artesanato, realizando uma pesquisa de campo e posterior oficina sobre Criatividade em Artesanato dentro da associação estudada, para que assim se observasse as mudanças ocasionadas por essa interferência. Depois de mais de um ano de inserção, notou-se que a interferência de um designer pode ocasionar mudanças em relação ao processo projetual das artesãs, à maneira como elas enxergam o design e artesanato, ocorrendo, no entanto, uma desconstrução do discurso competente do profissional designer, principalmente ao se entrar no campo valorizando o conhecimento do pesquisado e se permitindo ser modificado pelos atores na rede. A pesquisa abriu caminho para pensar novas possibilidades de compreender o papel e atuação do designer nesses contextos e abrir espaço para discussões futuras concernindo as fronteiras entre design e artesanato e as visões desses profissionais

Estresse, ansiedade, crenças de autoeficácia e o desempenho dos bacharéis em Direito

Stress, anxiety and the self-efficacy beliefs levels were evaluated in 237 Law bachelors in preparation phase to be admitted at Ordem dos Advogados do Brasil - OAB. The purpose of this research was to evaluate the relationships between stress, anxiety, and self- efficacy beliefs related to the performance on both phases of the OAB. The subjects who answered this research were students of preparatory courses to the OAB exam. The Shait-Trait Anxiety Inventory of Spielberger, Inventário de Sintomas de Stress de Lipp - ISSL and Self-Efficacy were employed. Positive correlations were found between levels of stress, anxiety and self-efficacy beliefs. The correlations between the parameters obtained in these inventories and examinations performance were positive for the stress index and trait anxiety. The results of this study showed that candidates without stress symptoms have a twofold chance to be approved on the test than the candidates with stress symptomsForam avaliados os níveis de estresse, ansiedade e as crenças de autoeficácia de 237 bacharéis em Direito, em fase de preparação para ingresso na Ordem dos Advogados do Brasil - OAB. O objetivo desta pesquisa foi avaliar as relações entre estresse, ansiedade e crenças de autoeficácia com o desempenho, nas duas fases do exame da Ordem. Os participantes responderam aos inventários de Ansiedade Traço-Estado do Spielberger - IDATE, ao Inventário de Stress de Lipp - ISSL e a um Inventário de Autoeficácia. Foram encontradas correlações positivas entre os níveis de estresse, ansiedade e crenças de autoeficácia. As correlações entre os parâmetros obtidos nesses inventários e o desempenho nos exames foram positivas para os graus de estresse e de ansiedade-traço. Os resultados deste estudo demonstraram que candidatos sem sintomas de estresse têm duas vezes mais chance de serem aprovados em relação a candidatos com estresse.Fueron evaluados los niveles de estrés, ansiedad y las creencias de autoeficacia de 237 licenciados en Derecho, en fase de preparación para ingreso en la Ordem dos Advogados do Brasil (OAB). El objetivo de esta pesquisa fue evaluar las relaciones entre estrés, ansiedad y creencias de autoeficacia con el desempeño, en las dos fases del examen de la OAB. Los participantes respondieron a los inventarios de Ansiedad Trazo-Estado del Spielberger - IDATE, al Inventario de estrés de Lipp - ISSL y a un Inventario de Autoeficacia. Fueron encontradas correlaciones positivas entre los niveles de estrés, ansiedad y creencias de autoeficacia. Las correlaciones entre los parámetros obtenidos en esos inventarios y el desempeño en los exámenes fueron positivas para los grados de estrés y de ansiedad-trazo. Los resultados de este estudio demostraron que candidatos sin síntomas de estrés tienen dos veces más chances de seren aprobados en relación a candidatos con estrés