The Phosphoinositide 3-Kinase Pathway in Human Cancer: Genetic Alterations and Therapeutic Implications

The phosphoinositide 3-kinase (PI3K) pathway is frequently activated in human cancer and represents an attractive target for therapies based on small molecule inhibitors. PI3K isoforms play an essential role in the signal transduction events activated by cell surface receptors including receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs). There are eight known PI3K isoforms in humans, which have been subdivided into three classes (I-III). Therefore PI3Ks show considerable diversity and it remains unclear which kinases in this family should be targeted in cancer. The class IA of PI3K comprises the p110α, p110β and p110δ isoforms, which associate with activated RTKs. In human cancer, recent reports have described activating mutations in the PIK3CA gene encoding p110α, and inactivating mutations in the phosphatase and tensin homologue (PTEN) gene, a tumour suppressor and antagonist of the PI3K pathway. The PIK3CA mutations described in cancer constitutively activate p110α and, when expressed in cells drive oncogenic transformation. Moreover, these mutations cause the constitutive activation of downstream signaling molecules such as Akt/protein kinase B (PKB), mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (S6K) that is commonly observed in cancer cells. In addition to p110α, the other isoforms of the PI3K family may also play a role in human cancer, although their individual functions remain to be precisely identified. In this review we will discuss the evidence implicating individual PI3K isoforms in human cancer and their potential as drug targets in this context

Monitoring of the radio galaxy M 87 at Very High Energy with MAGIC during a low emission state between 2012 and 2015

AbstractWe present the preliminary results from observing the nearby radio galaxy M 87 for 156 hours (between the years 2012 and 2015) with the MAGIC telescopes, which lead to a significant very high energy (VHE, E > 100 GeV) detection of the source in quiescent states each year. Our VHE analysis combined with quasi-simultaneous data at other energies (from gamma-rays, X-rays, optical and radio) provides a unique opportunity to study the source variability and its broadband spectral energy distribution, which is found to disfavour a one-zone synchrotron/synchrotron self-Compton model. Therefore, other alternative scenarios for the photon emission are explored. We also find that the VHE emission is compatible with being produced close to the source radio core as previous data already indicated. A detailed paper presenting full results of the observing campaign is in preparation

Coherence and Consciousness: Study of Fronto-Parietal Gamma Synchrony in Patients with Disorders of Consciousness

Evaluation of consciousness needs to be supported by the evidence of brain activation during external stimulation in patients with unresponsive wakefulness syndrome (UWS). Assessment of patients should include techniques that do not depend on overt motor responses and allow an objective investigation of the spontaneous patterns of brain activity. In particular, electroencephalography (EEG) coherence allows to easily measure functional relationships between pairs of neocortical regions and seems to be closely correlated with cognitive or behavioral measures. Here, we show the contribution of higher order associative cortices of patients with disorder of consciousness (N\ua0=\ua026) in response to simple sensory stimuli, such as visual, auditory and noxious stimulation. In all stimulus modalities an increase of short-range parietal and long-range fronto-parietal coherences in gamma frequencies were seen in the controls and minimally conscious patients. By contrast, UWS patients showed no significant modifications in the EEG patterns after stimulation. Our results suggest that UWS patients can not activate associative cortical networks, suggesting a lack of information integration. In fact, fronto-parietal circuits result to be connectively disrupted, conversely to patients that exhibit some form of consciousness. In the light of this, EEG coherence can be considered a powerful tool to quantify the involvement of cognitive processing giving information about the integrity of fronto-parietal network. This measure can represent a new neurophysiological marker of unconsciousness and help in determining an accurate diagnosis and rehabilitative intervention in each patient

LZS/Al2O3 nanostructured composites obtained by colloidal processing and spark plasma sintering

[EN] Li2O-SiO2-ZrO2 (LZS) glass-ceramics have high mechanical strength, hardness, resistance to abrasion and chemical attack, but also a high coefficient of thermal expansion (CTE), which can be reduced adding alumina nanoparticles. The conventional glass-ceramic production is relatively complex and energy consuming, since it requires the melting of the raw materials to form a glass frit and a two-step milling process to obtain particle sizes adequate for compaction. This study describes the preparation of LZS glass-ceramics through a colloidal processing approach from mixtures of SiO2 and ZrO2 nanopowders and a Li precursor (lithium acetate obtained by reaction of the carbonate with acetic acid). Concentrated suspensions were freeze-dried to obtain homogeneous mixtures of powders that were pressed (100 MPa) and sintered conventionally and by spark plasma sintering. The effect of the alumina nanoparticles additions on suspensions rheology, sintering behavior and properties such as thermal expansion, thermal conductivity, hardness and Young's modulus were evaluated. (C) 2017 Elsevier Ltd. All rights reserved.This work has been supported by Ministerio de Economia y Competitividad (MINECO) and FEDER Funds under grant No MAT2016-67586-C3-R. Authors greatly acknowledge the financial Support of CAPES in the frame of the International Cooperation Program Science without Borders for Special Visiting Researcher PVE (MEC/MCTI/CAPES/CNPQ/FAPs/No 71/2013), Project no. A011/2013. A. Borrell acknowledges the MINECO for her Juan de la Cierva-Incorporacion contract (IJCI-2014-19839).Arcaro, S.; Novaes De Oliveira, A.; Gutierrez-Gonzalez, C.; Salvador Moya, MD.; Borrell Tomás, MA.; Moreno, R. (2017). LZS/Al2O3 nanostructured composites obtained by colloidal processing and spark plasma sintering. Journal of the European Ceramic Society. 37(16):5139-5148. https://doi.org/10.1016/j.jeurceramsoc.2017.03.023S51395148371

Properties of LZS/nanoAl2O3 glass-ceramic composites

[EN] The LZS glass-ceramic (19.58 Li2O center dot 11.10ZrO(2)center dot 69.32SiO(2)) have a high coefficient thermal expansion (CTE) which can be a limitation in some applications. The addition of alumina in a LZS glass-ceramic matrix is able to reduce the CTE significantly. This happens because of the alumina affinity with respect to lithium silicates to form beta-spodumene (LiAlSi2O6), a crystalline phase having a CTE nearly zero (0.9 x 10(-6) degrees C-1).In this work, (1-5 vol%) Al2O3 nanoparticles (13 nm) were added to a LZS (3.5 mu m) glass-ceramic matrix to prepare composites with the main goal of evaluation the influence of Al2O3 on their mechanical, thermal and electrical properties. Each composition was wet homogenized and then dried at 110 degrees C for 48 h for disaggregation. The composites, sintered at 900 degrees C for 30 min, with relative densities between 92% and 98%, showed zircon and beta-spodumene as main crystalline phases. The incorporation of increasing additions of nanosized alumina progressively decreases the final density. This makes the properties to slightly decrease, also. The Young's modulus significantly decreases from 111 to 78 GPa of hardness due to the exponential variation with porosity, but the changes of toughness and hardness are much lower. The electrical conductivity was maintained within +/- 10-7 S. cm(-1), and the dielectric constant ranged from 5 to 6 for all compositions. Thermal conductivity ranged around 4.2 to 3.5 W/mK. (C) 2017 Elsevier B.V. All rights reserved.This work has been supported by CAPES in the frame of the International Cooperation Program Science without Borders for Special Visiting Researcher PVE (MEC/MCTI/CAPES/CNPq/FAPs/ No 71/2013), Project No A011/2013 (Brazil) and CNPq (National Council for Scientific and Technological Development, Brazil). This work has been also supported by Ministerio de Economia y Cornpetitividad and FEDER Funds under grant No MAT2016-67586-C3-R and grant ENE2013-49111-C2-1-R. A. Borrell acknowledges the MINECO for her Juan de la Cierva-Incorporacion contract (IJCI-2014-19839).Arcaro, S.; Moreno, B.; Chinarro, E.; Salvador Moya, MD.; Borrell Tomás, MA.; Nieto, M.; Moreno, R.... (2017). Properties of LZS/nanoAl2O3 glass-ceramic composites. Journal of Alloys and Compounds. 710:567-574. https://doi.org/10.1016/j.jallcom.2017.03.299S56757471

PRNP P39L variant is a rare cause of frontotemporal dementia in Iialian population

The missense P39L variant in the prion protein gene (PRNP) has recently been associated with frontotemporal dementia (FTD). Here, we analyzed the presence of the P39L variant in 761 patients with FTD and 719 controls and found a single carrier among patients. The patient was a 67-year-old male, with a positive family history for dementia, who developed apathy, short term memory deficit, and postural instability at 66. Clinical and instrumental workup excluded prion disease. At MRI, bilateral frontal lobe atrophy was present. A diagnosis of FTD was made, with a mainly apathetic phenotype. The PRNP P39L mutation may be an extremely rare cause of FTD (0.13%)