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Background Metabolic adaptations can sustain the pro-neoplastic functions exerted by macrophages in the tumor microenvironment. Malignant peripheral nerve sheath tumors (MPNSTs), aggressive and incurable sarcomas that develop either sporadically or in the context of the genetic syndrome Neurofibromatosis type 1, are highly infiltrated by macrophages, whose contribution to MPNST growth remains poorly characterized. Here, we analyze the role played by the molecular chaperone TRAP1, a regulator of mitochondrial metabolic pathways, in shaping the pro-tumoral activity of macrophages associated to MPNST cells. Methods We have studied the phenotypic changes elicited by a MPNST cell-conditioned medium in macrophages with or without TRAP1, and their subsequent ability to support MPNST cell growth and migration and endothelial cell angiogenesis. Results The presence of TRAP1 is required in both naive and M2-like macrophages for eliciting phenotypic changes that lead to the acquisition of pro-neoplastic features. TRAP1-expressing macrophages become able to sustain MPNST cell growth and migration and to exert pro-angiogenic properties on endothelial cells through accumulation of the metabolite succinate and the ensuing activation of a HIF-1α-dependent transcriptional program. Conclusions Our data provide evidence of a molecular crosstalk between MPNST cellular components, in which soluble factors released by cancer cells drive phenotypic changes in macrophages that in turn enhance pro-tumoral biological routines in both MPNST and endothelial cells. TRAP1-dependent metabolic rewiring in macrophages is mandatory for sustaining this interplay, as a TRAP1-succinate-HIF-1α signaling axis orchestrates their acquisition of tumor-promoting features. Graphical abstract

Neurofibromin loss drives neoplastic growth and a rewiring of mitochondrial metabolism. Here we report that neurofibromin ablation dampens expression and activity of NADH dehydrogenase, the respiratory chain complex I, in an ERK-dependent fashion, decreasing both respiration and intracellular NAD+. Expression of the alternative NADH dehydrogenase NDI1 raises NAD+/NADH ratio, enhances the activity of the NAD+-dependent deacetylase SIRT3 and interferes with tumorigenicity in neurofibromin-deficient cells. The antineoplastic effect of NDI1 is mimicked by administration of NAD+ precursors or by rising expression of the NAD+ deacetylase SIRT3 and is synergistic with ablation of the mitochondrial chaperone TRAP1, which augments succinate dehydrogenase activity further contributing to block pro-neoplastic metabolic changes. These findings shed light on bioenergetic adaptations of tumors lacking neurofibromin, linking complex I inhibition to mitochondrial NAD+/NADH unbalance and SIRT3 inhibition, as well as to down-regulation of succinate dehydrogenase. This metabolic rewiring could unveil attractive therapeutic targets for neoplasms related to neurofibromin loss.

Artificial Intelligence (AI) has become a driving force in modern research, industry and public administration and the European Union (EU) is embracing this technology with a view to creating societal, as well as economic, value. This effort has been shared by EU Member States which were all encouraged to develop their own national AI strategies outlining policies and investment levels. This study focuses on how EU Member States are approaching the promise to develop and use AI for the good of society through the lens of their national AI strategies. In particular, we aim to investigate how European countries are investing in AI and to what extent the stated plans contribute to the good of people and society as a whole. Our contribution consists of three parts: (i) a conceptualization of AI for social good highlighting the role of AI policy, in particular, the one put forward by the European Commission (EC); (ii) a qualitative analysis of 15 European national strategies mapping investment plans and suggesting their relation to the social good (iii) a reflection on the current status of investments in socially good AI and possible steps to move forward. Our study suggests that while European national strategies incorporate money allocations in the sphere of AI for social good (e.g. education), there is a broader variety of underestimated actions (e.g. multidisciplinary approach in STEM curricula and dialogue among stakeholders) that can boost the European commitment to sustainable and responsible AI innovation.

This paper presents the results of an extensive study investigating the opinions on Artificial Intelligence (AI) of a sample of 4,006 European citizens from eight distinct countries (France, Germany, Italy, Netherlands, Poland, Romania, Spain, and Sweden). The aim of the study is to gain a better understanding of people's views and perceptions within the European context, which is already marked by important policy actions and regulatory processes. To survey the perceptions of the citizens of Europe we design and validate a new questionnaire (PAICE) structured around three dimensions: people's awareness, attitude, and trust. We observe that while awareness is characterized by a low level of self-assessed competency, the attitude toward AI is very positive for more than half of the population. Reflecting upon the collected results, we highlight implicit contradictions and identify trends that may interfere with the creation of an ecosystem of trust and the development of inclusive AI policies. The introduction of rules that ensure legal and ethical standards, along with the activity of high-level educational entities, and the promotion of AI literacy are identified as key factors in supporting a trustworthy AI ecosystem. We make some recommendations for AI governance focused on the European context and conclude with suggestions for future work.

Artificial intelligence (AI) is already part of our daily lives and is playing a key role in defining the economic and social shape of the future. In 2018, the European Commission introduced its AI strategy able to compete in the next years with world powers such as China and US, but relying on the respect of European values and fundamental rights. As a result, most of the Member States have published their own National Strategy with the aim to work on a coordinated plan for Europe. In this paper, we present an ongoing study on how European countries are approaching the field of Artificial Intelligence, with its promises and risks, through the lens of their national AI strategies. In particular, we aim to investigate how European countries are investing in AI and to what extent the stated plans can contribute to the benefit of the whole society. This paper reports the main findings of a qualitative analysis of the investment plans reported in 15 European National Strategies