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

Persistent expression of BMP-4 in embryonic chick adrenal cortical cells and its role in chromaffin cell development

Background: Adrenal chromaffin cells and sympathetic neurons both originate from the neural crest, yet signals that trigger chromaffin development remain elusive. Bone morphogenetic proteins (BMPs) emanating from the dorsal aorta are important signals for the induction of a sympathoadrenal catecholaminergic cell fate. Results: We report here that BMP-4 is also expressed by adrenal cortical cells throughout chick embryonic development, suggesting a putative role in chromaffin cell development. Moreover, bone morphogenetic protein receptor IA is expressed by both cortical and chromaffin cells. Inhibiting BMP-4 with noggin prevents the increase in the number of tyrosine hydroxylase positive cells in adrenal explants without affecting cell proliferation. Hence, adrenal BMP-4 is likely to induce tyrosine hydroxylase in sympathoadrenal progenitors. To investigate whether persistent BMP-4 exposure is able to induce chromaffin traits in sympathetic ganglia, we locally grafted BMP-4 overexpressing cells next to sympathetic ganglia. Embryonic day 8 chick sympathetic ganglia, in addition to principal neurons, contain about 25% chromaffin-like cells. Ectopic BMP-4 did not increase this proportion, yet numbers and sizes of "chromaffin" granules were significantly increased. Conclusions: BMP-4 may serve to promote specific chromaffin traits, but is not sufficient to convert sympathetic neurons into a chromaffin phenotype

Visualizing Ultrafast Kinetic Instabilities in Laser-Driven Solids using X-ray Scattering

Ultra-intense lasers that ionize and accelerate electrons in solids to near the speed of light can lead to kinetic instabilities that alter the laser absorption and subsequent electron transport, isochoric heating, and ion acceleration. These instabilities can be difficult to characterize, but a novel approach using X-ray scattering at keV energies allows for their visualization with femtosecond temporal resolution on the few nanometer mesoscale. Our experiments on laser-driven flat silicon membranes show the development of structure with a dominant scale of ~60\unit{nm} in the plane of the laser axis and laser polarization, and ~95\unit{nm} in the vertical direction with a growth rate faster than $0.1/\mathrm{fs}$. Combining the XFEL experiments with simulations provides a complete picture of the structural evolution of ultra-fast laser-induced instability development, indicating the excitation of surface plasmons and the growth of a new type of filamentation instability. These findings provide new insight into the ultra-fast instability processes in solids under extreme conditions at the nanometer level with important implications for inertial confinement fusion and laboratory astrophysics

The potential impact of biochemical mediators on telomere attrition in major depressive disorder and implications for future study designs: A narrative review

BACKGROUND: Major depressive disorder (MDD) has been proposed to represent a "disease of premature aging", which is associated with certain biomarkers of cellular ageing and numerous other age-related diseases. Over the last decade, telomere length (TL) arose as a surrogate for cellular aging. Recent data suggests that TL might be reduced in patients with MDD, however, results are still inconclusive. This might be explained by the lack of assessment of potential biochemical mediators that are directly associated with telomere shortening and frequently observed in patients with MDD. METHODS: A narrative review was performed. The PubMed database was searched for relevant studies. RESULTS: We identified four major mediators, which are recurrently reported in patients with MDD and are associated with reduced TL: inflammation/oxidative stress, dysregulation of the hypothalamic-pituitary-adrenal axis, metabolic dysbalance including insulin resistance, and decreased brain-derived neurotrophic factor. These mediators are also mutually associated and were not systematically assessed in current studies investigating TL and MDD, which might explain inconclusive findings across current literature. Finally, we discuss possible ways to assess those mediators and potential implications of such approaches for future research. LIMITATIONS: The majority of identified studies had cross-sectional designs and used heterogeneous methods to assess TL and associated relevant biochemical mediators. CONCLUSIONS: A better understanding of the complex interactions between biochemical mediators, somatic comorbidities and shortened telomeres in patients with MDD might further specify the pathophysiology-based conceptualization and, based on that, personalized treatment of MDD

Killing Me Softly—Future Challenges in Apoptosis Research

The induction of apoptosis, a highly regulated and clearly defined mode of cell dying, is a vital tenet of modern cancer therapy. In this review we focus on three aspects of apoptosis research which we believe are the most crucial and most exciting areas currently investigated and that will need to be better understood in order to enhance the efficacy of therapeutic measures. First, we discuss which target to select for cancer therapy and argue that not the cancer cell as such, but its interaction with the microenvironment is a more promising and genetically stable site of attack. Second, the complexity of combination therapy is elucidated using the PI3-K-mediated signaling network as a specific example. Here we show that the current clinical approach to sensitize malignancies to apoptosis by maximal, prolonged inhibition of so-called survival pathways can actually be counter productive. Third, we propose that under certain conditions which will need to be clearly defined in future, chronification of a tumor might be preferable to the attempt at a cure. Finally, we discuss further problems with utilizing apoptosis induction in cancer therapy and propose a novel potential therapeutic approach that combines the previously discussed features

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

Transcription of sialic acid catabolism genes in Corynebacterium glutamicum is subject to catabolite repression and control by the transcriptional repressor NanR

Uhde A, Brühl N, Goldbeck O, et al. Transcription of sialic acid catabolism genes in Corynebacterium glutamicum is subject to catabolite repression and control by the transcriptional repressor NanR. J Bacteriol. 2016;198(16):2204-2218