ALBERT

Description: ABSTRACT Ewing sarcoma (ES) is a highly aggressive bone and soft tissue cancer, representing the second most common primary malignant bone tumor in children and adolescents. Although the development of a multimodal therapy, including both local control (surgery and/or radiation) and systemic multidrug chemotherapy, has determined a significant improvement in survival, patients with metastatic and recurrent disease still face a poor prognosis. Moreover, considering that ES primarily affects young patients, there are concerns about long-term adverse effects of the therapy. Therefore, more rational strategies, targeting specific molecular alterations underlying ES, are required. Recent studies suggest that SRC family kinases (SFKs), which are aberrantly activated in most cancer types, could represent key therapeutic targets also for ES. Here, we challenged ES cell lines with a recently developed selective SFK inhibitor (a pyrazolo[3,4- d ]pyrimidine derivative, called SI221), which was previously shown to be a valuable proapoptotic agent in other tumor types while not affecting normal cells. We observed that SI221 significantly reduced ES cell viability and proved to be more effective than the well-known SFK inhibitor PP2. SI221 was able to induce apoptosis in ES cells and also reduced ES cell clonogenic potential. Furthermore, SI221 was also able to reduce ES cell migration. At the molecular level, our data suggest that SFK inhibition through SI221 could reduce ES cell viability at least in part by hindering an SFK-NOTCH1 receptor-p38 mitogen-activated protein kinase (MAPK) axis. Overall, our study suggests a potential application of specific SFK inhibition in ES therapy. This article is protected by copyright. All rights reserved

Description: The effect of grain size on mantle viscosity is comparable to that of temperature and pressure. The current 3-D distribution of grain size in the mantle is however unknown. To explore the possible variability of grain size, we use: geodynamic inferences of effective viscosity, vacancy diffusion rates in upper-mantle minerals and perovspkite in the lower mantle, lateral variations in temperature derived from seismic images, and different geotherms. An important outcome of this modeling is a new mapping of lateral viscosity variations throughout the mantle. The corresponding 3-D variations in grain size are characterized by two order of magnitude changes. We find a correlation between grain size variability in the mantle and absolute viscosity changes with depth. Our findings suggest that the traditional assumption of Arrhenius temperature dependence for vacancy diffusion in the lower mantle is not sufficient to constrain the deformation mechanisms that determine its effective bulk viscosity.

Description: Global Navigation Satellite System (GNSS) signals exhibit rapid fluctuations at high and low latitudes as a consequence of propagation through drifting ionospheric irregularities. We focus on the high latitude scintillation problem, taking advantage of a conjunction of EISCAT Incoherent Scatter Radar (ISR) observations and a GPS scintillation monitor viewing the same line-of-sight. Just after 20:00 UT on 17 October 2013, an auroral E-region ionization enhancement occurred with associated phase scintillations. This investigation uses the scintillation observations to estimate the ionospheric electron density distribution beyond the spatial resolution of the ISR (5 - 15 km along the line-of-sight in this case). Following the approach of Deshpande et al . [2014], signal propagation is modeled through a specified density distribution. A multiple phase screen propagation algorithm is applied to irregularities conforming to the description of Costa and Kelley [1977] and constrained to match the macroscopic conditions observed by the ISR. A 50-member ensemble of modeled outputs is approximately consistent with the observations according to the standard deviation of the phase (σ p ) . The observations have σ p  = 0.23 radians, while the ensemble of modeled realizations has σ p  = 0.23 + 0.04 -0.04. By comparison of the model output with the scintillation observations, we show that the density fluctuations cannot be a constant fraction of the mean density. The model indicates that E-region density fluctuations whose standard deviation varies temporally between 5 - 25% of the mean (ISR-observed) density are required to explain the observed phase scintillations.

Description: Osteosarcoma (OS), an aggressive highly invasive and metastatic bone-malignancy, shows therapy resistance and recurrence, two features that likely depend on cancer stem cells (CSCs), which hold both self-renewing and malignant potential. So, effective anticancer therapies against OS should specifically target and destroy CSCs. We previously found that the let-7d microRNA was downregulated in the 3AB-OS-CSCs, derived from the human OS-MG63 cells. Here, we aimed to assess whether let-7d modulation affected tumorigenic and stemness properties of these OS-CSCs. We found that let-7d-overexpression reduced cell proliferation, by decreasing CCND2 and E2F2 cell-cycle-activators and increasing p21 and p27 CDK-inhibitors. Let-7d also decreased sarcosphere-and-colony forming ability, two features associated with self-renewing, and it reduced the expression of stemness genes, including Oct3/4, Sox2, Nanog, Lin28B and HMGA2. Moreover, let-7d induced mesenchymal-to-epithelial-transition, as shown by both N-Cadherin-E-cadherin-switch and decrease in vimentin. Surprisingly, such switch was accompanied by enhanced migratory/invasive capacities, with a strong increase in MMP9, CXCR4 and VersicanV1. Let-7d- overexpression also reduced cell sensitivity to apoptosis induced by both serum-starvation and various chemotherapy drugs, concomitant with decrease in caspase-3 and increase in BCL2 expression. Our data suggest that let-7d in 3AB-OS-CSCs could induce plastic-transitions from CSCs-to-non-CSCs and vice-versa. To our knowledge this is the first study to comprehensively examine the expression and functions of let-7d in OS-CSCs. By showing that let-7d has both tumor suppressor and oncogenic functions in this context, our findings suggest that, before prospecting new therapeutic strategies based on let-7d modulation, it is urgent to better define its multiple functions. This article is protected by copyright. All rights reserved

Description: Restenosis is a complex pathophysiological disease whose causative mechanisms are not fully understood. Previous studies allowed us to demonstrate the efficacy of bone marrow mesenchymal stromal cells (MSCs) transplantation in limiting the pathophysiological remodeling in a model of arteriotomy-induced (re)stenosis. In the current research we studied the effectiveness of G-CSF treatment on male rate rats that were subjected carotid arteriotomy in order to evaluate a potentially effective non-invasive strategy that recapitulates the MSC-mediated recovery of injured vessels. WKY male rats were subjected carotid arteriotomy and given a nine day treatment (3 days pre- to 6 days post-arteriotomy) with G-CSF or saline. Carotids were harvested 7 and 30 days following arteriotomy (early- and late-phase, respectively). Although morphometrical analysis did not reveal differences in lumen narrowing between G-CSF- and PBS-carotids 30 days following arteriotomy, we detected a noticeable conservative effect of G-CSF treatment on vascular wall morphology. Histological and molecular analysis revealed an increase in cellularity within the tunica media with a concomitant increase of the VSMCs differentiation markers both at early- and late-phases of (re)stenotic response in G-CSF-treated carotids (Sm22-alpha, Myocd and Smtn). These findings were accompanied by the downregulation of oxidative stress-related genes in G-CSF-injured rats. The effect exerted by G-CSF in our model of arteriotomy-induced (re)stenosis seemed support the recovery of the architecture of the tunica media of injured vessels by: i) inducing VSMCs differentiation; and ii) limiting the oxidative-stress response induced by arteriotomy. This article is protected by copyright. All rights reserved

Description: Increased vascular smooth muscle cell (VSMC) proliferation is a factor in atherosclerosis and injury-induced arterial (re)stenosis. Inhibition of polyamine synthesis by α-difluoro-methylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, attenuates VSMC proliferation with high sensitivity and specificity. However, cells can escape polyamine synthesis blockade by importing polyamines from the environment. To address this issue, polyamine transport inhibitors (PTIs) have been developed. We investigated the effects of the novel trimer44NMe (PTI-1) alone and in combination with DFMO on VSMC polyamine uptake, proliferation and phenotype regulation. PTI-1 efficiently inhibited polyamine uptake in primary mouse aortic and human coronary VSMCs in the absence as well as in the presence of DFMO. Interestingly, culture with DFMO for 2 days substantially (〉95%) reduced putrescine (Put) and spermidine (Spd) contents without any effect on proliferation. Culture with PTI-1 alone had no effect on either polyamine levels or proliferation rate, but the combination of both treatments reduced Put and Spd levels below the detection limit and inhibited proliferation. Treatment with DFMO for a longer time period (4 days) reduced Put and Spd below their detection limits and reduced proliferation, showing that only a small pool of polyamines is needed to sustain VSMC proliferation. Inhibited proliferation by polyamine depletion was associated with maintained expression of contractile smooth marker genes. In cultured intact mouse aorta, PTI-1 potentiated the DFMO-induced inhibition of cell proliferation. The combination of endogenous polyamine synthesis inhibition with uptake blockade is thus a viable approach for targeting unwanted vascular cell proliferation in vivo , including vascular restenosis. This article is protected by copyright. All rights reserved

Description: Drifting structures characterized by inhomogeneities in the spatial electron density distribution at ionospheric heights cause the scintillation of radio waves propagating through. The fractional electron density fluctuations and the corresponding scintillation levels may reach extreme values at low latitudes during high solar activity. Different levels of scintillation were observed on experimental data collected in the Asian sector at low latitudes by means of a GPS dual frequency receiver under moderate solar activity (2005). The GPS receiver used in these campaigns was particularly modified in firmware in order to record power estimates on the C/A code as well as on the carriers L1 and L2. Strong scintillation activity was recorded in the post-sunset period (saturating S4 and SI as high as 20 dB). Spectral modifications and broadening was observed during high levels of scintillation possibly indicating refractive scattering taking place instead of diffractive scattering. A possible interpretation of those events was attempted on the basis of the refractive scattering theory developed by Uscinski (1968) and Booker and MajidiAhi (1981).

Description: Rapid fluctuations in the amplitude and phase of a transionospheric radio signal caused by small scale plasma density irregularities in the ionosphere are known as scintillation. Scintillation can seriously impair a GNSS (Global Navigation Satellite Systems) receiver tracking performance, thus affecting the required levels of availability, accuracy and integrity, and consequently the reliability of modern day GNSS based applications. This paper presents an analysis of correlation between scintillation levels and tracking performance of a GNSS receiver for GPS L1C/A, L2C and GLONASS L1, L2 signals. The analyses make use of data recorded over Presidente Prudente (22.1°S, 51.4°W, dip latitude ∼12.3°S) in Brazil, a location close to the Equatorial Ionisation Anomaly (EIA) crest in Latin America. The study presents for the first time this type of correlation analysis for GPS L2C and GLONASS L1, L2 signals. The scintillation levels are defined by the amplitude scintillation index, S4 and the receiver tracking performance is evaluated by the phase tracking jitter. Both S4 and the phase tracking jitter are estimated from the post correlation In-Phase (I) and Quadra-Phase (Q) components logged by the receiver at a high rate. Results reveal that the dependence of the phase tracking jitter on the scintillation levels can be represented by a quadratic fit for the signals. The results presented in this paper are of importance to GNSS users, especially in view of the forthcoming high phase of solar cycle 24 (predicted for 2013).