Medulloblastoma Exome Sequencing Uncovers Subtype-Specific Somatic Mutations

Medulloblastomas are the most common malignant brain tumors in children1. Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles2–5. Here, we utilized whole exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas exhibit low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR, and LDB1, novel findings in medulloblastoma. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant but not wild type beta-catenin. Together, our study reveals the alteration of Wnt, Hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma

Conservação de energia em fornos de cozimento de anodo Energy saving in anode baking furnaces

A tendência por unidades de produção mais sustentáveis vem obrigando a indústria de alumínio a adotar estratégias para reduzir o consumo de energia e minimizar a geração de resíduos. Procedimentos nesta direção têm sido implementados em fornos de cozimento de anodo, onde alguns aprimoramentos têm permitido a redução no consumo de energia. Entretanto, sabe-se que durante a etapa de queima do anodo, elevada quantidade de calor é ainda dissipada para o ambiente, aumentando os custos com energia. Desta forma, o presente trabalho tem por objetivo apresentar alternativas de redução do consumo de combustível do forno de cozimento de anodo considerando, para isto, o transporte de calor das câmaras de combustão desde as paredes refratárias até o bloco de carbono, passando pelo coque fluido. Os resultados aqui obtidos indicam que uma possível mudança da distribuição do tamanho de partículas do coque, bem como, a adição de uma manta isolante no topo do forno pode aperfeiçoar o desempenho do sistema quando o foco é sustentabilidade e otimização do processo.<br>The trend for sustainable production units induced the aluminum industry to adopt strategies of reducing the energy consumption and waste generation. In this sense, several procedures have been carried out in the anode baking furnace, reducing its energy consumption. However, during the carbon block thermal treatment, a great amount of heat is still released to the environment, increasing the energy cost. Therefore, the present work aims to show alternatives of reducing the anode furnace energy consumption considering the heat flow from the combustion chamber, via the flue wall and the fluid coke, till the anode. The results point out that a change in the fluid coke particle size distribution as well as placing an insulating blanket on the top of the furnace can optimize the anode furnace performance when the focus is sustainability and the process optimization

Aplicação da ferramenta SWOT para avaliação das técnicas de dano ao choque térmico em materiais refratários SWOT as a tool to evaluate the thermal shock damage technique of refractory materials

A literatura indica diversos tipos de ensaios e diferentes métodos de avaliação de dano por choque térmico. Adicionalmente sabe-se que, em determinadas aplicações, esse tipo de dano é um dos principais responsáveis pela degradação do revestimento refratário. Neste contexto e buscando a melhor forma de reproduzir as condições em serviço do revestimento refratário, o presente trabalho foi realizado visando analisar qual tipo de ensaio de choque térmico e método de avaliação do dano são os mais adequados para avaliar o desempenho destes materiais. Essa análise foi baseada em uma revisão bibliográfica e resultados obtidos em laboratório, em que se comparou e avaliou as vantagens e desvantagens dos métodos mais relevantes encontrados na literatura. Por fim, com o auxilio da ferramenta SWOT foi possível verificar se o método adotado pelos autores desse trabalho é adequado para auxiliar na seleção do refratário para aplicação em calcinadores de leito fluidizado.<br>The literature shows different tests and techniques for evaluating the thermal shock damage. Additionally, it is known that, for certain applications, this type of wear mechanism is one of the main causes of fluid flash calciner refractory degradation. Within this context and in order to find the best way to reproduce the refractory lining service conditions, this work was carried out to point out which thermal shock test and damage assessment method are more suitable to evaluate these materials. This analysis was based on a literature review and laboratory experiments, comparing and evaluating the advantages and disadvantages of the most important methods available. Finally, with the support of the SWOT tool it was possible to evaluate whether the method adopted by the authors of this work is appropriated for helping the selection of the refractories for calciners application

Seleção de refratários para fornos de cozimento de anodo Refractories selection for anode baking furnace

Nos últimos anos a produção mundial de alumínio tem aumentado e para as empresas continuarem competitivas torna-se necessário que a média do custo de produção do metal seja reduzida. Uma das alternativas é aumentar a vida útil dos refratários usados em fornos de cozimento de anodo, bem como a sua capacidade de produção. Ambas estratégias podem resultar em maior qualidade do anodo e redução no custode manutenção do forno. O presente trabalho tem por objetivo apresentara caracterização termo-mecânica dos tijolos refratários utilizados em fornos de cozimento de anodo e a resistência destes materiais ao ataque químico. Os resultados indicam que a escolha da composição mais adequada depende de uma análise sistêmica das propriedades a alta temperatura, da resistência química e das práticas operacionais do forno.<br>In the latest years the worldwide production of aluminum is increasing and for the companies to keep their competitiveness it is necessary to reduce the average cost of the metal production. One of the alternatives is to increase the refractories working life used in anode baking furnaces and their production capacity. Both strategies may result in a higher anode quality and reduction of the furnace maintenance costs. This paper aims to present the thermo-mechanical characterization of the refractory bricks used in anode baking furnaces and their resistance to chemical attack. The results indicated that the selection of the most suitable composition depends on a systemic analysis involving the high temperature properties, chemical resistance and the operational practices of the furnace

A geopolimerização como técnica para a aplicação do resíduo de bauxita Geopolymerization as a technique for bauxite residue applications

Encontrar aplicações sustentáveis para o resíduo de bauxita tem se mostrado um dos principais desafios da indústria do alumínio na atualidade. Com esse propósito, a geopolimerização pode se tornar uma solução interessante, uma vez que essa técnica seria capaz de tirar proveito de algumas das características mais típicas desse resíduo, como sua elevada alcalinidade e o seu significativo teor de compostos de silício e alumínio, produzindo materiais sólidos semelhantes em propriedades às cerâmicas tradicionais. Neste trabalho, o processamento, as propriedades e as possíveis aplicações dos geopolímeros compostos por resíduo de bauxita foram analisados. Além dos ensaios de porosidade aparente e resistência mecânica, as amostras preparadas também foram submetidas a um ensaio de lixiviação, de modo a já realizar uma avaliação prévia dos potenciais riscos ambientais decorrentes da utilização de um possível produto, e de quais procedimentos favoreceriam a sua passivação. Entre os principais resultados obtidos, verificou-se que a queima a 800 °C permitiu a algumas das composições desenvolvidas alcançarem valores de resistência à compressão da ordem de até 30 MPa, além de uma resistência à lixiviação muito próxima à de um tijolo de argila prensado comum, o que já permite considerar a construção civil como um dos setores mais favoráveis para a aplicação dos geopolímeros com resíduo de bauxita, principalmente pela enorme capacidade de consumo desse setor e da sua crescente demanda por produtos mais sustentáveis.<br>Finding sustainable applications for the bauxite residue is one of the leading challenges in the aluminium industry. For this purpose, the geopolymerization could become an interesting alternative, because this technique could make use of some of the typical characteristics of the bauxite residue, such as its alkalinity and expressive silicates and aluminates contents, resulting in solid materials with similar properties to usual traditional ceramics. In this work, the properties, processing and possible applications of such materials were analyzed. Besides the apparent porosity and the mechanical resistance tests, the obtained samples were also submitted to a leaching test, aiming to a preliminary evaluation of the potential environmental risks of application that a supposed product would represent, and which procedures could favour its passivation. As the main results, it was possible to verify that firing at 800 °C allowed some compositions to reach compression resistance values up to 30 MPa, and a leaching resistance closer to a common pressed clay brick, which makes the building materials a potential area of application for the bauxite residue geopolymers, based on the enormous consumption capacity of this area and its increasing demand for more sustainable products

α5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth

Neural tumors often express neurotransmitter receptors as markers of their developmental lineage. Although these receptors have been well characterized in electrophysiological, developmental and pharmacological settings, their importance in the maintenance and progression of brain tumors and, importantly, the effect of their targeting in brain cancers remains obscure. Here, we demonstrate high levels of GABRA5, which encodes the α5-subunit of the GABAA receptor complex, in aggressive MYC-driven, "Group 3" medulloblastomas. We hypothesized that modulation of α5-GABAA receptors alters medulloblastoma cell survival and monitored biological and electrophysiological responses of GABRA5-expressing medulloblastoma cells upon pharmacological targeting of the GABAA receptor. While antagonists, inverse agonists and non-specific positive allosteric modulators had limited effects on medulloblastoma cells, a highly specific and potent α5-GABAA receptor agonist, QHii066, resulted in marked membrane depolarization and a significant decrease in cell survival. This effect was GABRA5 dependent and mediated through the induction of apoptosis as well as accumulation of cells in S and G2 phases of the cell cycle. Chemical genomic profiling of QHii066-treated medulloblastoma cells confirmed inhibition of MYC-related transcriptional activity and revealed an enrichment of HOXA5 target gene expression. siRNA-mediated knockdown of HOXA5 markedly blunted the response of medulloblastoma cells to QHii066. Furthermore, QHii066 sensitized GABRA5 positive medulloblastoma cells to radiation and chemotherapy consistent with the role of HOXA5 in directly regulating p53 expression and inducing apoptosis. Thus, our results provide novel insights into the synthetic lethal nature of α5-GABAA receptor activation in MYC-driven/Group 3 medulloblastomas and propose its targeting as a novel strategy for the management of this highly aggressive tumor

Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.

Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, β-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic β-catenin signalling in medulloblastoma