80 research outputs found
Epidermal growth factor receptor kinase domain mutations are rare in salivary gland carcinomas
Activating mutations within the epidermal growth factor (EGFR) tyrosine kinase domain identify non-small cell lung cancer patients with improved clinical response to tyrosine kinase inhibitor therapy. Recently, we identified two EGFR mutations in a cohort of 25 salivary gland carcinomas (SGCs) by screening the tumour samples for the both most common hotspot mutations in exons 19 and 21 by allele-specific PCR. Here, we present a comprehensive sequencing analysis of the entire critical EGFR tyrosine kinase domain in 65 SGC of the main histopathological types. We found EGFR mutations in the tyrosine kinase domain to be a rare event in SGCs. No additional mutations other than the two known exon 19 deletions (c.2235_2249del15) in a mucoepidermoid carcinoma and an adenoid cystic carcinoma have been detected. Other putative predictive markers for EGFR-targeted therapy in SGCs might be relevant and should be investigated
High-resolution analysis of individual Drosophila melanogaster larvae uncovers individual variability in locomotion and its neurogenetic modulation
Neuronally orchestrated muscular movement and locomotion are defining faculties of multicellular animals. Due to its simple brain and genetic accessibility, the larva of the fruit fly Drosophila melanogaster allows one to study these processes at tractable levels of complexity. However, although the faculty of locomotion clearly pertains to the individual, most studies of locomotion in larvae use measurements aggregated across animals, or animals tested one by one, an extravagance for larger-scale analyses. This prevents grasping the inter- and intra-individual variability in locomotion and its neurogenetic determinants. Here, we present the IMBA (individual maggot behaviour analyser) for analysing the behaviour of individual larvae within groups, reliably resolving individual identity across collisions. We use the IMBA to systematically describe the inter- and intra-individual variability in locomotion of wild-type animals, and how the variability is reduced by associative learning. We then report a novel locomotion phenotype of an adhesion GPCR mutant. We further investigated the modulation of locomotion across repeated activations of dopamine neurons in individual animals, and the transient backward locomotion induced by brief optogenetic activation of the brain-descending ‘mooncrawler’ neurons. In summary, the IMBA is an easy-to-use toolbox allowing an unprecedentedly rich view of the behaviour and its variability of individual larvae, with utility in multiple biomedical research contexts
Activation of the EGFR/ERK pathway in high-grade mucoepidermoid carcinomas of the salivary glands
Regulator of G-protein signaling 5 (RGS5) protein: a novel marker of cancer vasculature elicited and sustained by the tumor’s proangiogenic microenvironment
We previously identified regulator of G-protein signaling 5 (RGS5) among several genes expressed by tumor-derived endothelial cells (EC). In this study, we provide the first in vivo/ex vivo evidence of RGS5 protein in the vasculature of ovarian carcinoma clinical specimens and its absence in human ovaries. Consistent with this, we show higher amounts of Rgs5 transcript in EC isolated from human cancers (as opposed to normal tissues) and demonstrate that expression is sustained by a milieu of factors typical of the proangiogenic tumor environment, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2). Supporting these findings, we show elevated levels of Rgs5 mRNA in the stroma from strongly (as opposed to weakly) angiogenic ovarian carcinoma xenografts and accordingly, we also show more of the protein associated to the abnormal vasculature. RGS5 protein predominantly colocalizes with the endothelium expressing platelet/endothelial cell adhesion molecule-1 (PECAM-1/CD31) and to a much lesser extent with perivascular/mural cells expressing platelet-derived growth factor receptor-beta (PDGFR-β) or alpha smooth muscle actin (αSMA). To toughen the relevance of the findings, we demonstrate RGS5 in the blood vessels of other cancer models endowed with a proangiogenic environment, such as human melanoma and renal carcinoma xenografts; to the contrary, it was undetectable in the vasculature of normal mouse tissues. RGS5 expression by the cancer vasculature triggered and retained by the proangiogenic microenvironment supports its exploitation as a novel biomarker and opens the path to explore new possibilities of therapeutic intervention aimed at targeting tumor blood vessels
All-d-Enantiomer of β-Amyloid Peptide Forms Ion Channels in Lipid Bilayers
Alzheimer’s disease (AD) is the most common type
of senile
dementia in aging populations. Amyloid β (Aβ)-mediated
dysregulation of ionic homeostasis is the prevailing underlying mechanism
leading to synaptic degeneration and neuronal death. Aβ-dependent
ionic dysregulation most likely occurs either directly via unregulated
ionic transport through the membrane or indirectly via Aβ binding
to cell membrane receptors and subsequent opening of existing ion
channels or transporters. Receptor binding is expected to involve
a high degree of stereospecificity. Here, we investigated whether
an Aβ peptide enantiomer, whose entire sequence consists of d-amino acids, can form ion-conducting channels; these channels
can directly mediate Aβ effects even in the absence of receptor–peptide
interactions. Using complementary approaches of planar lipid bilayer
(PLB) electrophysiological recordings and molecular dynamics (MD)
simulations, we show that the d-Aβ isomer exhibits
ion conductance behavior in the bilayer indistinguishable from that
described earlier for the l-Aβ isomer. The d isomer forms channel-like pores with heterogeneous ionic conductance
similar to the l-Aβ isomer channels, and the d-isomer channel conductance is blocked by Zn2+, a known
blocker of l-Aβ isomer channels. MD simulations further
verify formation of β-barrel-like Aβ channels with d- and l-isomers, illustrating that both d- and l-Aβ barrels can conduct cations. The calculated
values of the single-channel conductance are approximately in the
range of the experimental values. These findings are in agreement
with amyloids forming Ca2+ leaking, unregulated channels
in AD, and suggest that Aβ toxicity is mediated through a receptor-independent,
nonstereoselective mechanism
Stress, ageing and their influence on functional, cellular and molecular aspects of the immune system
The immune response is essential for keeping an organism healthy and for defending it from different types of pathogens. It is a complex system that consists of a large number of components performing different functions. The adequate and controlled interaction between these components is necessary for a robust and strong immune response. There are, however, many factors that interfere with the way the immune response functions. Stress and ageing now consistently appear in the literature as factors that act upon the immune system in the way that is often damaging. This review focuses on the role of stress and ageing in altering the robustness of the immune response first separately, and then simultaneously, discussing the effects that emerge from their interplay. The special focus is on the psychological stress and the impact that it has at different levels, from the whole system to the individual molecules, resulting in consequences for physical health
Age-related macular degeneration associated polymorphism rs10490924 in ARMS2 results in deficiency of a complement activator
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