Glioblastoma and glioblastoma stem cells are dependent on functional MTH1

Glioblastoma multiforme (GBM) is an aggressive form of brain cancer with poor prognosis. Cancer cells are characterized by a specific redox environment that adjusts metabolism to its specific needs and allows the tumor to grow and metastasize. As a consequence, cancer cells and especially GBM cells suffer from elevated oxidative pressure which requires antioxidant-defense and other sanitation enzymes to be upregulated. MTH1, which degrades oxidized nucleotides, is one of these defense enzymes and represents a promising cancer target. We found MTH1 expression levels elevated and correlated with GBM aggressiveness and discovered that siRNA knock-down or inhibition of MTH1 with small molecules efficiently reduced viability of patient-derived GBM cultures. The effect of MTH1 loss on GBM viability was likely mediated through incorporation of oxidized nucleotides and subsequent DNA damage. We revealed that MTH1 inhibition targets GBM independent of aggressiveness as well as potently kills putative GBM stem cells in vitro. We used an orthotopic zebrafish model to confirm our results in vivo and light-sheet microscopy to follow the effect of MTH1 inhibition in GBM in real time. In conclusion, MTH1 represents a promising target for GBM therapy and MTH1 inhibitors may also be effective in patients that suffer from recurring disease

Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models

RASopathies, characterized by germline mutations in genes encoding proteins of the RAS-ERK signaling pathway, show overlapping phenotypes, which manifest themselves with a varying severity of intellectual disability. However, it is unclear to what extent they share the same downstream pathophysiology that underlies the cognitive deficits. Costello syndrome (CS) is a rare RASopathy caused by activating mutations in the HRAS gene. Here we investigated the mechanisms underlying the cognitive deficits of HRas G12V/G12V mice. HRas G12V/G12V mice showed robust upregulation of ERK signaling, neuronal hypertrophy, increased brain volume, spatial learning deficits, and impaired mGluR-dependent long-term depression (LTD). In contrast, long-term potentiation (LTP), which is affected in other RASopathy mouse models was unaffected. Treatment with lovastatin, a HMG-CoA-Reductase inhibitor which has been shown to rescue the behavioral phenotypes of mouse models of NF1 and Noonan syndrome, was unable to restore ERK signaling and the cognitive deficits of HRas G12V/G12V mice. Administration of a potent mitogen-activated protein kinase (MEK) inhibitor rescued the ERK upregulation and the mGluR-LTD deficit of HRas G12V/G12V mice, but failed to rescue the cognitive deficits. Taken together, this study indicates that the fundamental molecular and cellular mechanisms underlying the cognitive aspects of different RASopathies are remarkably distinct, and may require disease specific treatments

The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas.

Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inhibition of colony-stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that although overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas reestablish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment-driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor-1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors

International consensus model for comparative assessment of chemical emissions in LCA

Achieving consensus among scientists is often a challenge?particularly in model development. In this article we describe a recent scientific consensus-building process for Life Cycle Impact Assessment (LCIA) models applied to chemical emissions--including the strategy, execution, and results of a process that used model comparison to achieve parsimony. This process has succeeded in establishing a transparent LCIA consensus model. We present the lessons that may be adapted by similar consensus processes in other fields. LCIA characterizes potential impacts on human health and the environment attributable to chemical emissions over the life cycle of a product. LCIA relies on substance-specific characterization factors (CFs) that combine exposure potential and toxicity to represent the relative contribution of the substance to health and environmental impacts (1). LCIA focuses on comparative assessment, using approaches adapted from risk assessment. In 2003, in response to large variations in available methods, an international model comparison/consensus process was initiated. This process was under the umbrella of the Life Cycle Initiative, a joint effort of the United Nations Environment Program (UNEP) and the Society of Environmental Toxicology and Chemistry (SETAC) (2). The process encompassed an international group of model developers responsible for the most commonly-used worldwide LCIA characterization models and focused on characterization of human and ecosystem health impacts. It also involved disciplinary experts in fate and transport, exposure assessment, health risk assessment, and ecotoxicology. The comparison/consensus process fostered a common understanding among the participants of which model elements contribute most to the relative magnitude of LCIA characterization factors. It became clear that with a careful focus on the most influential model elements a consensus model could be established. Experience dictated that a more transparent model would be more likely to gain and retain acceptance and wide-spread use. The need for consistent documentation and transparency led the participants to create an entirely new model, building on contributions from the existing models. This required consensus on essential model elements, provided robust results consistent with existing models, and made parsimony a guiding principle. The tangible outcome is "USEtox", named in recognition of the UNEP-SETAC Life Cycle Initiative under which it was developed. The model is supported by all participating model teams as a basis for future global recommendations of LCIA characterization factors

Redução de proteína bruta com suplementação de aminoácidos, com base no conceito de proteína ideal, em rações para alevinos de tilápia-do-nilo Reduction of crude protein with amino acid supplementation, based on ideal protein concept, in diets for Nile tilapia fingerlings

Objetivou-se avaliar o efeito da redução da proteína bruta (PB) da ração com suplementação de aminoácidos, com base no conceito de proteína ideal, sobre o desempenho de alevinos de tilápia-do-nilo (Oreochromis niloticus). Utilizaram-se 396 alevinos, linhagem tailandesa, com 0,80 ± 0,17 g de peso vivo, distribuídos em delineamento de blocos ao acaso, composto de seis tratamentos (32, 31, 30, 29, 28 e 27% de PB), seis blocos por tratamento e 11 peixes por unidade experimental. As rações foram formuladas para serem isoenergéticas e isolisínicas digestíveis, mantendo-se constantes as relações mínimas dos aminoácidos com a lisina. Os peixes foram mantidos em 36 aquários de 130 L, dotados de abastecimento de água, temperatura controlada e aeração individual, e alimentados à vontade seis vezes ao dia durante 40 dias. A redução do teor de proteína bruta da ração não afetou o ganho de peso, a taxa de crescimento específico, o consumo de ração, o consumo de lisina digestível, o teor de proteína corporal, as taxas de deposição de gordura e de proteína e a eficiência de retenção de nitrogênio dos peixes. Os peixes alimentados com rações com 27% de PB apresentaram pior conversão alimentar, menor eficiência de utilização da lisina para ganho, menor consumo de nitrogênio e umidade corporal, maior eficiência protéica para ganho e mais alto teor de gordura corporal. O nível de proteína bruta da ração para alevinos de tilápia-do-nilo pode ser reduzido em quatro pontos percentuais (de 32 para 28%), pois essa redução não prejudica o desempenho dos animais, desde que as rações sejam suplementadas com aminoácidos essenciais limitantes.<br>The effect of decreasing dietary crude protein (CP) with supplementation of amino acids, based on the ideal protein concept on Nile tilapia (Oreochromis niloticus) fingerlings performance was evaluated. A total of 396 fingerlings from Thai strain, with 0.80 ± 0.17 g of BW, was allotted to a randomized block design, with six levels of CP (32, 31, 30, 29, 28 and 27% of CP) in the diets, six replications with 11 fish each. The diets were formulated to be isocaloric and digestible isolysine, remaining constant the amino acids to lysine minimum ratio. The fish were kept in 36 aquariums of 130 L, equipped with water supply, controlled temperature and individual aeration, and ad libitum fed six times a day for 40 days. The reduction of CP content of the diet did not affect weight gain, specific growth rate, feed intake, digestible lysine intake, body protein content, fat and protein deposition rates and nitrogen retention efficiency of fishes. The fish fed diets with 27% of CP lower feed: gain ratio, lysine efficiency for gain, nitrogen intake and body water and higher protein efficiency for gain and body fat content. The level of crude protein of the diet for Nile tilapia fingerlings can be reduced by four percentage points (from 32 to 28%), without negative effect on the performance of the animals, since the diets are supplemented with essential limiting amino acids