A critical evaluation of PI3K inhibition in Glioblastoma and Neuroblastoma therapy

Members of the PI3K/Akt/mTor signaling cascade are among the most frequently altered proteins in cancer, yet the therapeutic application of pharmacological inhibitors of this signaling network, either as monotherapy or in combination therapy (CT) has so far not been particularly successful. In this review we will focus on the role of PI3K/Akt/mTOR in two distinct tumors, Glioblastoma multiforme (GBM), an adult brain tumor which frequently exhibits PTEN inactivation, and Neuroblastoma (NB), a childhood malignancy that affects the central nervous system and does not harbor any classic alterations in PI3K/Akt signaling. We will argue that inhibitors of PI3K/Akt signaling can be components for potentially promising new CTs in both tumor entities, but further understanding of the signal cascade’s complexity is essential for successful implementation of these CTs. Importantly, failure to do this might lead to severe adverse effects, such as treatment failure and enhanced therapy resistance

Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells

The regulation of acetylation is central for the epigenetic control of lineage-specific gene expression and determines cell fate decisions. We provide evidence that the inhibition of histone deacetylases (HDACs) blocks the endothelial differentiation of adult progenitor cells. To define the mechanisms by which HDAC inhibition prevents endothelial differentiation, we determined the expression of homeobox transcription factors and demonstrated that HoxA9 expression is down-regulated by HDAC inhibitors. The causal involvement of HoxA9 in the endothelial differentiation of adult progenitor cells is supported by the finding that HoxA9 overexpression partially rescued the endothelial differentiation blockade induced by HDAC inhibitors. Knockdown and overexpression studies revealed that HoxA9 acts as a master switch to regulate the expression of prototypical endothelial-committed genes such as endothelial nitric oxide synthase, VEGF-R2, and VE-cadherin, and mediates the shear stress–induced maturation of endothelial cells. Consistently, HoxA9-deficient mice exhibited lower numbers of endothelial progenitor cells and showed an impaired postnatal neovascularization capacity after the induction of ischemia. Thus, HoxA9 is regulated by HDACs and is critical for postnatal neovascularization

Stratospheric aerosol - Observations, processes, and impact on climate

Interest in stratospheric aerosol and its role in climate have increased over the last decade due to the observed increase in stratospheric aerosol since 2000 and the potential for changes in the sulfur cycle induced by climate change. This review provides an overview about the advances in stratospheric aerosol research since the last comprehensive assessment of stratospheric aerosol was published in 2006. A crucial development since 2006 is the substantial improvement in the agreement between in situ and space-based inferences of stratospheric aerosol properties during volcanically quiescent periods. Furthermore, new measurement systems and techniques, both in situ and space based, have been developed for measuring physical aerosol properties with greater accuracy and for characterizing aerosol composition. However, these changes induce challenges to constructing a long-term stratospheric aerosol climatology. Currently, changes in stratospheric aerosol levels less than 20% cannot be confidently quantified. The volcanic signals tend to mask any nonvolcanically driven change, making them difficult to understand. While the role of carbonyl sulfide as a substantial and relatively constant source of stratospheric sulfur has been confirmed by new observations and model simulations, large uncertainties remain with respect to the contribution from anthropogenic sulfur dioxide emissions. New evidence has been provided that stratospheric aerosol can also contain small amounts of nonsulfate matter such as black carbon and organics. Chemistry-climate models have substantially increased in quantity and sophistication. In many models the implementation of stratospheric aerosol processes is coupled to radiation and/or stratospheric chemistry modules to account for relevant feedback processes

Environmental and socioeconomic effects of mosquito control in Europe using the biocide Bacillus thuringiensis subsp. israelensis (Bti)

International audienceBacillus thuringiensis subsp. israelensis (Bti) has been used in mosquito control programs to reduce nuisance in Europe for decades and is generally considered an environmentally-safe, effective and target-specific biocide. However, the use of Bti is not uncontroversial. Target mosquitoes and affected midges represent an important food source for many aquatic and terrestrial predators and reduction of their populations is likely to result in food-web effects at higher trophic levels. In the context of global biodiversity loss, this appears particularly critical since treated wetlands are often representing conservation areas. In this review, we address the current large-scale use of Bti for mosquito nuisance control in Europe, provide a description of its regulation followed by an overview of the available evidence on the parameters that are essential to evaluate Bti use in mosquito control. Bti accumulation and toxin persistence could result in a chronic expose of mosquito populations ultimately affecting their susceptibility, although observed increase in resistance to Bti in mosquito populations is low due to the four toxins involved. A careful independent monitoring of mosquito susceptibility, using sensitive bioassays, is mandatory to detect resistance development timely. Direct Bti effects were documented for non-target chironomids and other invertebrate groups and are discussed for amphibians. Field studies revealed contrasting results on possible impacts on chironomid abundances. Indirect, food-web effects were rarely studied in the environment. Depending on study design and duration, Bti effects on higher trophic levels were demonstrated or not. Further long-term field studies are needed, especially with observations of bird declines in Bti-treated wetland areas. Socio-economic relevance of mosquito control requires considering nuisance, vector-borne diseases and environmental effects jointly. Existing studies indicate that a majority of the population is concerned regarding potential environmental effects of Bti mosquito control and that they are willing to pay for alternative, more environment-friendly techniques

Potenzial der RELEASE-Datenbank für die Analyse der Therapiewirksamkeit bei Aphasie nach Schlaganfall

Jaecks P, Breitenstein C, Brühl S, et al. Potenzial der RELEASE-Datenbank für die Analyse der Therapiewirksamkeit bei Aphasie nach Schlaganfall. Sprachtherapie aktuell. Forschung-Wissen-Transfer. 2021: e2021-22