Inhibitors of Apoptosis Proteins (IAPs) as Targets for Anti-Cancer Treatment

Smac mimetics (SMs) constitute a class of compounds that target the inhibitor of apoptosis proteins (IAPs) and enhance the cytotoxic activity of several drugs. In our work, we built and characterized a library of about 140 SMs and focused on SM83 due to its high affinity for the targets, cytotoxic activity and good pharmacokinetic profile. In vivo, SM83 reduced in monotherapy the primary tumor growth of two triple negative breast cancer xenografts. Furthermore, SM83 treatment, alone or in combinations with TRAIL-armed CD34+cell, resulted in the reduction of spontaneous lung metastasis formation. Mechanistically, by depleting cIAP1, SM83 affects the expression of the tumor genes and inhibits the metastasis-promoting gene Snai2, thus preventing cancer cell motility. Moreover, we tested SM83 as a standalone in ascites cancer models and described an in vivo anti-tumor effect against cancer cell lines that are intrinsically resistant to SM treatment in vitro. In the in vivo settings, SM83, in fact, triggered an inflammation event of the host, characterized by macrophage secretion of TNF, IL-1β and interferon-γ (IFNγ), and rapidly killed floating tumor cells within the ascites by a non-apoptotic mechanism. Of note, SM83 treatment caused the massive accumulation of neutrophils within the ascites and tumor nodules, which, however, was not responsible for cancer cell killing. Finally, we described the capability of SM83 to enhance the cytotoxic activity of camptothecin especially in human epithelial cells expressing oncogenic KRAS. The increased sensitivity of these premalignant cells is caused by an ERK2-dependent up-regulation of NOXA. Of note, oncogenic KRAS fails to sensitize a panel of isogenic cancer cell lines with wild type and mutated KRAS, and we demonstrated that this unresponsiveness could be reverted by concomitant inhibition of AKT. Therefore, our work suggests that the activation of AKT is capable of counterbalancing the potential pro-death stimulus triggered by oncogenic KRAS

Editor's Introduction

The issue is a result of the research programme about ‘The problem of indeterminacy. Meaning, knowledge, action’ (‘Il problema dell’indeterminatezza. Significato, conoscenza, azione’, PRIN 2015, national coordinator Luigi Perissinotto). The project was developed by a Cagliari research team that worked on the indeterminacy problem concerning the linguistic, conceptual and interpretative mechanisms actively involved in the construction of the images of the past. These concepts and other themes were the subject of a conference in May 2019. The outcomes are now mostly presented in this number. The great questions of representation, fancy, figurative languages, image (as a form shaping matter and not merely reproducing a given structure) and time (and the relationship amongst past, present and future) are preeminently but not exclusively linked to the past as it is investigated by historians (past human actions and resulting chains of events)..

Ruled Imagination

This paper aims to show how Paul Ricoeur’s inquiry on memory, trace, and testimony contributes to rebalancing a framework that, at the dialectical level between imagination and representation, would essentially present historians’ work as hermeneutical. In Ricoeur’s later writings, we find a differently balanced perspective by focusing the (neurobiological and psychological) substrate of representation behind trace and memory. Representation precedes interpretation. And neither memory’s fidelity nor history’s epistemic truth belong to a game that would be solely played within the communicative space of a plurality of cognitive agents who are exchanging, controlling and sharing their experiences. Consequently, the reality of the past itself emerges in the practice of memory’s background

Social impact assessment of wind power generation. An innovative method for decision making processes

This paper explores the social impact for population in the energy sector combining LCA and SIA (social impact assessment). As case study, a new 66 MW wind power plant under development in the countryside of Southern Sardinia has been considered. The innovative method, based on the analysis of the context, aims to empirically analyze some selected sustainability indicators. The proposed method starts from a detailed analysis of the wind power project, with particular reference to the plant site characteristics, technical features of the wind farm, opinions of the stakeholders, environmental and social impacts and expected economic benefits. The acquired data are validated with a Severity statistical method that identifies the KPIs. The indicators are classified into general categories of damage Human life, Safety guarantee, Social resources, Public participation and analyzed through a combined SIA-LCA method to identify indicators damage weights. This work shows the importance of putting together indicators already explored in the environmental field such as Human health, Ecosystem quality, Resource, Climate Change and as social indicators Renewable Energy with Noise, Visual Impact, Shadow Flichers, the perceptions of the local community

Life Cycle Assessment of an Integrated PV-ACAES System

The aim of this paper is to evaluate the overall life cycle environmental impact of an adiabatic compressed air energy storage (ACAES) system, which is designed to achieve the best match between the power production of a photovoltaic (PV) power plant and the power demand from the final user. The electrical energy demand of a small town, with a maximum power load of about 10 MW, is considered a case study. The ACAES system is designed with a compressor-rated power of about 10 MW and charging and discharging times of 10 and 24 h, respectively. Different sizes of the PV plant, ranging from 20 to 40 MWp, and two different solutions for the compressed air storage, an underground cavern, and a gas pipeline, are analyzed. The aim of this analysis is to compare the impacts on human health, ecosystem quality, climate change, and resource consumption of the PV power generation plant and the integrated PV-ACAES system with those of a reference scenario in which the end user demand is met entirely by the grid. The best results in terms of a reduction in environmental impact in comparison to the reference scenario are obtained for a small PV plant (20 MW) without the ACAES section, with reductions of about 85–95% depending on the category of impact. The integration of the ACAES system improves energy self-consumption but worsens the environmental impact, especially for air storage in gas pipelines. The best configuration in terms of environmental impact is based on a 30 MW PV plant integrated with an ACAES section using an underground cavern for air storage and allows for improvements in the energy self-consumption of between 38% and 61%, with a reduction in the environmental impact compared to the reference scenario of about 80–91% depending on the impact categor

Texturizzazione laser della lega di magnesio AZ31 per migliorare l’adesione nelle applicazioni biomedicali

"Laser surface texturing of AZ31 Magnesium Alloy to improve adhesion in biomedical application Cardiovascular stent have assumed a primary role to solve heart problems related to constraints that lead to the malfunctioning of a hollow organ. The research is shifting more and more towards the creations of less invasive stent having biocompatibility and biodegradability as primary requirements. Metal that best meets both these requirements and also the structural ones is Magnesium and its alloys. The greatest limit to the use of this material comes from its low corrosion resistance that it is manifested at the body pH. The idea at the basis of this work is to cover the Magnesium stent with a biodegradable polymer to increase its resistance to corrosion. The following paper focuses the study on the texturing surface treatments, achievable by a laser beam, in order to optimize the adhesion between the substrate and the polymer. The Magnesium alloy used is AZ31. Studies of surface modification through the mechanisms of the remelting and microdrilling by laser have been performed on the AZ31 surface. The characterization of the selected surfaces in terms of roughness variations, changes in wettability, oxides formation and geometry of the obtained structures, led to the identification of a limited number of conditions that will be further investigated.

Unchangeability of the past: human and natural sciences in comparison

The issue is a result of the research programme about ‘The problem of indeterminacy. Meaning, knowledge, action’ (‘Il problema dell’indeterminatezza. Significato, conoscenza, azione’, PRIN 2015, national coordinator Luigi Perissinotto). The project was developed by a Cagliari research team that worked on the indeterminacy problem concerning the linguistic, conceptual and interpretative mechanisms actively involved in the construction of the images of the past. These concepts and other themes were the subject of a conference in May 2019

Life Cycle Analysis of a Hydrogen Valley with multiple end-users

This paper aims to evaluate the environmental impact along the overall life cycle of the various components of a Hydrogen Valley with multiple end-users fed by green hydrogen. As case study, a hydrogen valley including a MW-scale electrolyser powered by different percentages of energy supplied by a wind farm and/or a photovoltaic plant, and an H2 storage section is considered. The H2 produced is used to feed a fleet of fuel cell electric vehicles and a stationary fuel cell, while the residue H2 is injected in a natural gas pipeline considering a maximum safety limit of 5%vol. When the safety limit is reached, the H2 overproduction can be used to produce biomethane through a biological hydrogen methanation process. With the aim of analysing the actual contribution of these hydrogen-based ecosystems towards more sustainable energy systems, a Life Cycle Analysis of the hydrogen valley is carried out. The results show that the final use of hydrogen for fuel cell electric vehicles produces the most valuable environmental benefits. Moreover, Hydrogen Valley solutions integrated with photovoltaic plants allows to maximize the use of H2 in fuel cell electric vehicles and therefore are the most valuable choice from an environmental point of view

Sintering behaviour of 3D-printed 18K 5N gold alloy by binder jetting: a preliminary study

Binder jetting is a versatile additive manufacturing technique suitable to produce alloys that are difficult to obtain by powder bed fusion techniques, such as precious metals, due to their high reflectivity and thermal conductivity. In this study, a 18K 5N gold alloy powder was employed in the printing process. Different heat treatments and densification processes were employed to achieve final-stage sintering and remove residual porosity, whilst controlling the evolution of copper oxides by reduction with hydrogen and graphite. Powder, green and sintered samples were characterised at the microstructural level by X-ray diffraction, microscopy and energy dispersive X-ray spectroscopy to assess phase transitions and secondary-phase formation. Oxide-free components with a final relative density above 90% were achieved by densification at 830 °C combined with carbon- and CO-induced reduction of tenorite and cuprite. The optimal manufacturing route was chosen to produce a bezel, as a case study for the adoption of this technique in the jewellery industry