NSCLC as the Paradigm of Precision Medicine at Its Finest: The Rise of New Druggable Molecular Targets for Advanced Disease

Standard treatment for advanced non-small cell lung cancer (NSCLC) historically consisted of systemic cytotoxic chemotherapy until the early 2000s, when precision medicine led to a revolutionary change in the therapeutic scenario. The identification of oncogenic driver mutations in EGFR, ALK and ROS1 rearrangements identified a subset of patients who largely benefit from targeted agents. However, since the proportion of patients with druggable alterations represents a minority, the discovery of new potential driver mutations is still an urgent clinical need. We provide a comprehensive review of the emerging molecular targets in NSCLC and their applications in the advanced setting.     

Molecular Effects of Chronic Exposure to Palmitate in Intestinal Organoids: A New Model to Study Obesity and Diabetes

Intestinal cell dysfunctions involved in obesity and associated diabetes could be correlated with impaired intestinal cell development. To date, the molecular mechanisms underlying these dysfunctions have been poorly investigated because of the lack of a good model for studying obesity. The main aim of this study was to investigate the effects of lipotoxicity on intestinal cell differentiation in small intestinal organoid platforms, which are used to analyze the regulation of cell differentiation. Mouse intestinal organoids were grown in the presence/absence of high palmitate concentrations (0.5 mM) for 48 h to simulate lipotoxicity. Palmitate treatment altered the expression of markers involved in the differentiation of enterocytes and goblet cells in the early (Hes1) and late (Muc2) phases of their development, respectively, and it modified enterocytes and goblet cell numbers. Furthermore, the expression of enteroendocrine cell progenitors (Ngn3) and I cells (CCK) markers was also impaired, as well as CCK-positive cell numbers and CCK secretion. Our data indicate, for the first time, that lipotoxicity simultaneously influences the differentiation of specific intestinal cell types in the gut: enterocytes, goblet cells and CCK cells. Through this study, we identified novel targets associated with molecular mechanisms affected by lipotoxicity that could be important for obesity and diabetes therapy.     

NGF Modulates Cholesterol Metabolism and Stimulates ApoE Secretion in Glial Cells Conferring Neuroprotection against Oxidative Stress

Cholesterol plays a crucial role in the brain, where its metabolism is particularly regulated by astrocytic activity. Indeed, adult neurons suppress their own cholesterol biosynthesis and import this sterol through ApoE-rich particles secreted from astrocytes. Recent evidence suggests that nerve growth factor (NGF) may exert neurotrophic activity by influencing cell metabolism. Nevertheless, the effect of NGF on glial cholesterol homeostasis has still not been elucidated. Thus, the aim of this project is to assess whether NGF could influence cholesterol metabolism in glial cells. To reach this objective, the U373 astrocyte-derived cell line was used as an experimental model. Immunoblot and ELISA analysis showed that proteins and enzymes belonging to the cholesterol metabolism network were increased upon NGF treatment in glial cells. Furthermore, NGF significantly increased ApoE secretion and the amount of extracellular cholesterol in the culture medium. Co-culture and U373-conditioned medium experiments demonstrated that NGF treatment efficiently counteracted rotenone-mediated cytotoxicity in N1E-115 neuronal cells. Conversely, neuroprotection mediated by NGF treatment was suppressed when N1E-115 were co-cultured with ApoE-silenced U373 cells. Taken together, these data suggest that NGF controls cholesterol homeostasis in glial cells. More importantly, NGF exerts neuroprotection against oxidative stress, which is likely associated with the induction of glial ApoE secretion.     

Energy-aware lazy scheduling algorithm for energy-harvesting sensor nodes

The main problem in dealing with energy-harvesting (EH) sensor nodes is represented by the scarcity and non-stationarity of powering, due to the nature of the renewable energy sources. In this work, the authors address the problem of task scheduling in processors located in sensor nodes powered by EH sources. Some interesting solutions have appeared in the literature in the recent past, as the lazy scheduling algorithm (LSA), which represents a performing mix of scheduling effectiveness and ease of implementation. With the aim of achieving a more efficient and conservative management of energy resources, a new improved LSA solution is here proposed. Indeed, the automatic ability of foreseeing at run-time the task energy starving (i.e. the impossibility of finalizing a task due to the lack of power) is integrated within the original LSA approach. Moreover, some modifications have been applied in order to reduce the LSA computational complexity and thus maximizing the amount of energy available for task execution. The resulting technique, namely energy-aware LSA, has then been tested in comparison with the original one, and a relevant performance improvement has been registered both in terms of number of executable tasks and in terms of required computational burden.     

Designing to Facilitate Browsing: A Look Back at the Hyperties Workstation Browser

Since browsing hypertext can present a formidable cognitive challenge, user interface design plays a major role in determining acceptability. In the Unix workstation version of Hyperties, a research-oriented prototype, we focussed on design features that facilitate browsing. We first give a general overview of Hyperties and its markup language. Customizable documents can be generated by the conditional text feature that enables dynamic and selective display of text and graphics. In addition we present: — an innovative solution to link identification: pop-out graphical buttons of arbitrary shape.

— application of pie menus to permit low cognitive load actions that reduce the distraction of common actions, such as page turning or window selection.

— multiple window selection strategies that reduce clutter and housekeeping effort. We preferred piles-of-tiles, in which standard-sized windows were arranged in a consistent pattern on the display and actions could be done rapidly, allowing users to concentrate on the contents.

     

Flexible electronics: Prediction of substrate deformation during different steps of the lithography process

A numerical model was developed to simulate the micro-deformations of a polymeric substrate due to lithographic processing of different layers of a transistor-like structure. The results of the model were validated with the results from experiments. The model, a mechanical-thermal-hygroscopic model, takes into account the dimensional effects of temperature, moisture and stresses. It also includes the temperature dependent visco-elastic behaviour of the polymer substrate. The model can be used to predict overlay accuracies between different functional layers introduced by the lithographic process. It can also be used to understand the underlying processes such that it provides a tool to improve the overlay accuracy during actual processing.     

Mix design and performance analysis of asphalt concretes with electric arc furnace slag

The paper presents the results of a laboratory study, aimed at verifying the possibility to use two particular typologies of electric arc furnace (EAF) steel slags, in substitution of the natural aggregates, in the composition of wearing course asphalt concrete for flexible pavements. The experimental research has been articulated in a preliminary study of the chemical, leaching, physical, and mechanical properties of the EAF steel slag, and in the following mix design and performance characterisation of the bituminous conglomerates, through gyratory compaction tests, permanent deformations tests, Stiffness Modulus tests at various temperatures, fatigue tests and indirect tensile strength tests. All the mixtures with EAF slag have satisfied the requisites for acceptance in the road sector technical standards, thus resulting as suitable for use in the construction of road infrastructures, moreover presenting higher mechanical characteristics than those of the corresponding asphalts with full natural aggregate.     

Post-cracking behaviour of steel and macro-synthetic fibre-reinforced concretes

The present paper describes the results of an experimental investigation on the performances of concrete specimens reinforced with either steel or macro-synthetic fibres under three-point bending. Steel fibres are often used to improve the flexural toughness of concrete and are used in various structural applications while synthetic fibres are more often used to reduce crack opening due to shrinkage. Macro-synthetic fibres have been proposed more recently with the aim of creating an alternative to steel fibres in structural applications but their use is still limited.In the tests performed, specimens cast with the same concrete mix, but containing different dosages of either steel or macro-synthetic fibres, were used and compared. In general steel fibres were more efficient in increasing the toughness of concrete than macro-synthetic fibres, even though their results were significantly more scattered.Test results were used to calculate the parameters of stress-crack opening relations via inverse analysis using a cracked hinge model. This numerical model provided results, in terms of force-Crack Mouth Opening Displacement (CMOD) curves, in very good agreement with the experimental data.     

Molds and Resists Studies for Nanoimprint Lithography of Electrodes in Low-Voltage Polymer Thin-Film Transistors

A low-cost patterning of electrodes was investigated looking forward to replacing conventional photolithography for the processing of low-operating voltage polymeric thin-film transistors. Hard silicon, etched by sulfur hexafluoride and oxygen gas mixture, and flexible polydimethylsiloxane imprinting molds were studied through atomic force microscopy (AFM) and field emission gun scanning electron microscopy. The higher the concentration of oxygen in reactive ion etching, the lower the etch rate, sidewall angle, and surface roughness. A concentration around 30 % at 100 mTorr, 65 W and 70 sccm was demonstrated as adequate for submicrometric channels, presenting a reduced etch rate of 176 nm/min. Imprinting with positive photoresist AZ1518 was compared to negative SU-8 2002 by optical microscopy and AFM. Conformal results were obtained only with the last resist by hot embossing at 120 °C and 1 kgf/cm² for 2 min, followed by a 10 min post-baking at 100 °C. The patterning procedure was applied to define gold source and drain electrodes on oxide-covered substrates to produce bottom-gate bottom-contact transistors. Poly(3-hexylthiophene) (P3HT) devices were processed on high-κ titanium oxynitride (TiO _x N _y ) deposited by radiofrequency magnetron sputtering over indium tin oxide-covered glass to achieve low-voltage operation. Hole mobility on micrometric imprinted channels may approach amorphous silicon (～0.01 cm²/V s) and, since these devices operated at less than 5 V, they are not only suitable for electronic applications but also as sensors in aqueous media.