Targeting the DNA damage response to overcome cancer drug resistance in glioblastoma

Glioblastoma multiforme (GBM) is one of the most recalcitrant brain tumors characterized by a tumor microenvironment (TME) that strongly supports GBM growth, aggressiveness, invasiveness, and resistance to therapy. Importantly, a common feature of GBM is the aberrant activation of receptor tyrosine kinases (RTKs) and of their downstream signaling cascade, including the non-receptor tyrosine kinase SRC. SRC is a central downstream intermediate of many RTKs, which triggers the phosphorylation of many substrates, therefore, promoting the regulation of a wide range of different pathways involved in cell survival, adhesion, proliferation, motility, and angiogenesis. In addition to the aforementioned pathways, SRC constitutive activity promotes and sustains inflammation and metabolic reprogramming concurring with TME development, therefore, actively sustaining tumor growth. Here, we aim to provide an updated picture of the molecular pathways that link SRC to these events in GBM. In addition, SRC targeting strategies are discussed in order to highlight strengths and weaknesses of SRC inhibitors in GBM management, focusing our attention on their potentialities in combination with conventional therapeutic approaches (i.e., temozolomide) to ameliorate therapy effectiveness

Targeting the DNA damage response to overcome cancer drug resistance in glioblastoma

Glioblastoma multiforme (GBM) is one of the most recalcitrant brain tumors characterized by a tumor microenvironment (TME) that strongly supports GBM growth, aggressiveness, invasiveness, and resistance to therapy. Importantly, a common feature of GBM is the aberrant activation of receptor tyrosine kinases (RTKs) and of their downstream signaling cascade, including the non-receptor tyrosine kinase SRC. SRC is a central downstream intermediate of many RTKs, which triggers the phosphorylation of many substrates, therefore, promoting the regulation of a wide range of different pathways involved in cell survival, adhesion, proliferation, motility, and angiogenesis. In addition to the aforementioned pathways, SRC constitutive activity promotes and sustains inflammation and metabolic reprogramming concurring with TME development, therefore, actively sustaining tumor growth. Here, we aim to provide an updated picture of the molecular pathways that link SRC to these events in GBM. In addition, SRC targeting strategies are discussed in order to highlight strengths and weaknesses of SRC inhibitors in GBM management, focusing our attention on their potentialities in combination with conventional therapeutic approaches (i.e., temozolomide) to ameliorate therapy effectiveness

The role of thermophoretic effect in the formation of soot from liquid fuels

In order to rationalize soot formation in two-phase combustion, the related dynamics can be conveniently studied in simpler systems. In the latest twenty years, experimental activity in drop towers and in the outer space have allowed to investigate the combustion of isolated droplets in microgravity conditions, i.e. spherically symmetric systems where buoyancy effects and slip velocity are absent, yet still containing the major phenomena affecting real combustion (unsteady evolution, convection, gas and soot radiation, heterogeneous properties and so on). In such conditions, it had been speculated [1] that a key role in soot formation is played by thermophoretic effect, because of which solid particles are transported towards the droplet surface, thus increasing their residence times in the fuel-rich area, where soot growth is kinetically favoured. The spherical symmetry also allows to numerically study these systems with a relatively low computational weight. The importance of thermophoresis in the dynamics of soot formation can thus be investigated in a variety of operating conditions (droplet size, pressure, composition, etc.), which is the subject of this work. Starting from a description of the constitutive parts of the isolated-droplet model, the transient dynamics of soot formation in n-heptane droplets is analysed. The impact of the submodel describing thermophoresis is considered in detail, and indications about its possible refinements are provided

H2 from biofuels and carriers: A concerted homo-heterogeneous kinetic model of ethanol partial oxidation and steam reforming on Rh/Al2O3

Investigating bioethanol as a renewable energy source is crucial in the context of H2-based economy. Ethanol partial oxidation and steam reforming on Rh/Al2O3 represent promising processes that have already proved to be highly tangled reacting systems. In this work, a significant step forward has been done towards the development of an engineering tool that can capture all the relevant features of the process; a combined homo-heterogeneous kinetic scheme was developed and validated against experimental data, informative of the catalytic and thermal activation of the C2-alcohol. In particular, a 36-species reduced homogeneous scheme was developed, able to cap -ture observed trends with a limited computational load. On the other side, a macro-kinetic heterogeneous scheme with six molecular reactions (ethanol oxidative dehydrogenation, total oxidation, decomposition, dehydrogenation, steam reforming and acetaldehyde post -reforming) was tuned to accurately describe ethanol/O2 and ethanol/H2O reacting systems.& COPY; 2023 Hydrogen Energy Publications LLC. Published by Elsevier Ltd. All rights reserved

Differences in telomere length between sporadic and familial cutaneous melanoma

BACKGROUND: Several pieces of evidence indicate that a complex relationship exists between constitutional telomere length (TL) and the risk of cutaneous melanoma. Although the general perception is that longer telomeres increase melanoma risk, some studies do not support this association. We hypothesise that discordant data are due to the characteristics of the studied populations. OBJECTIVES: To evaluate the association of telomere length with familial and sporadic melanoma. METHODS: TL was measured by multiplex quantitative PCR in leukocytes from 310 melanoma patients according to familial/sporadic and single/multiple cancers and 216 age-matched controls. RESULTS: Patients with sporadic melanoma were found to have shorter telomeres as compared to those with familial melanoma. In addition, shorter telomeres, while tending to reduce the risk of familial melanoma regardless of single or multiple tumors, nearly trebled the risk of single sporadic melanoma. CONCLUSIONS: This is the first time that TL has been correlated to opposite effects on melanoma risk according to the presence or absence of familial predisposition. Individual susceptibility to melanoma should be taken into account when assessing the role of TL as a risk factor. This article is protected by copyright. All rights reserved

Methodological factors affecting joint moments estimation in clinical gait analysis: A systematic review

Quantitative gait analysis can provide a description of joint kinematics and dynamics, and it is recognized as a clinically useful tool for functional assessment, diagnosis and intervention planning. Clinically interpretable parameters are estimated from quantitative measures (i.e. ground reaction forces, skin marker trajectories, etc.) through biomechanical modelling. In particular, the estimation of joint moments during motion is grounded on several modelling assumptions: (1) body segmental and joint kinematics is derived from the trajectories of markers and by modelling the human body as a kinematic chain; (2) joint resultant (net) loads are, usually, derived from force plate measurements through a model of segmental dynamics. Therefore, both measurement errors and modelling assumptions can affect the results, to an extent that also depends on the characteristics of the motor task analysed (i.e. gait speed). Errors affecting the trajectories of joint centres, the orientation of joint functional axes, the joint angular velocities, the accuracy of inertial parameters and force measurements (concurring to the definition of the dynamic model), can weigh differently in the estimation of clinically interpretable joint moments. Numerous studies addressed all these methodological aspects separately, but a critical analysis of how these aspects may affect the clinical interpretation of joint dynamics is still missing. This article aims at filling this gap through a systematic review of the literature, conducted on Web of Science, Scopus and PubMed. The final objective is hence to provide clear take-home messages to guide laboratories in the estimation of joint moments for the clinical practice

The ESPERIA satellite project for detecting seismo-associated effects in the topside ionosphere. First instrumental tests in space

In recent times, ionospheric and magnetospheric perturbations constituted by radiation belt particle precipitations, variations of temperature and density of ionic and electronic components of ionospheric plasma as well as electric and magnetic field fluctuations have been detected on board of the LEO satellites and associated with earthquake preparation and occurrence. Several mechanisms have been suggested as justifying the seismoelectromagnetic phenomena observed in the upper lithosphere and in the topside ionosphere before, during and after an earthquake. Their propagation in these media has also been investigated, but physical knowledge of such processes is below standard. Consequently, coordinated space and ground-based observations based on data gathered simultaneously in space and at the Earth's surface are needed to investigate seismo-associated phenomena. To this end, the ESPERIA space mission project has been designed for the Italian Space Agency (ASI). To date, a few instruments of its payload have been built and tested in space. This paper reports on the justification, science background, and characteristics of the ESPERIA mission project as well as the description and testing of ESPERIA Instruments (ARINA and LAZIO-EGLE) in space

Fully Ir(iii) tetrazolate soft salts: the road to white-emitting ion pairs

The first examples of anionic Ir(iii) bis-tetrazolate complexes and their combination with a cationic Ir(iii)tetrazole derivative forming "fully tetrazolate" Ir(iii) based soft salts as O2-sensitive white emitters are described herein

Theory-based scaling laws of near and far scrape-off layer widths in single-null L-mode discharges

Theory-based scaling laws of the near and far scrape-off layer (SOL) widths are analytically derived for L-mode diverted tokamak discharges by using a two-fluid model. The near SOL pressure and density decay lengths are obtained by leveraging a balance among the power source, perpendicular turbulent transport across the separatrix, and parallel losses at the vessel wall, while the far SOL pressure and density decay lengths are derived by using a model of intermittent transport mediated by filaments. The analytical estimates of the pressure decay length in the near SOL is then compared to the results of three-dimensional, flux-driven, global, two-fluid turbulence simulations of L-mode diverted tokamak plasmas, and validated against experimental measurements taken from an experimental multi-machine database of divertor heat flux profiles, showing in both cases a very good agreement. Analogously, the theoretical scaling law for the pressure decay length in the far SOL is compared to simulation results and to experimental measurements in TCV L-mode discharges, pointing out the need of a large multi-machine database for the far SOL decay lengths