The tyrosine phosphatase Shp2 interacts with NPM-ALK and regulates anaplastic lymphoma cell growth and migration

Anaplastic large cell lymphomas (ALCL) are mainly characterized by the reciprocal translocation t(2;5)(p23;q35) that involves the anaplastic lymphoma kinase (ALK) gene and generates the fusion protein NPM-ALK with intrinsic tyrosine kinase activity. NPM-ALK triggers several signaling cascades, leading to increased cell growth, resistance to apoptosis, and changes in morphology and migration of transformed cells. To search for new NPM-ALK interacting molecules, we developed a mass spectrometry-based proteomic approach in HEK293 cells expressing an inducible NPM-ALK and identified the tyrosine phosphatase Shp2 as a candidate substrate. We found that NPM-ALK was able to bind Shp2 in coprecipitation experiments and to induce its phosphorylation in the tyrosine residues Y542 and Y580 both in HEK293 cells and ALCL cell lines. In primary lymphomas, antibodies against the phosphorylated tyrosine Y542 of Shp2 mainly stained ALK-positive cells. In ALCL cell lines, Shp2-constitutive phosphorylation was dependent on NPM-ALK, as it significantly decreased after short hairpin RNA (shRNA)-mediated NPM-ALK knock down. In addition, only the constitutively active NPM-ALK, but not the kinase dead NPM-ALK(K210R), formed a complex with Shp2, Gab2, and growth factor receptor binding protein 2 (Grb2), where Grb2 bound to the phosphorylated Shp2 through its SH2 domain. Shp2 knock down by specific shRNA decreased the phosphorylation of extracellular signal-regulated kinase 1/2 and of the tyrosine residue Y416 in the activation loop of Src, resulting in impaired ALCL cell proliferation and growth disadvantage. Finally, migration of ALCL cells was reduced by Shp2 shRNA. These findings show a direct involvement of Shp2 in NPM-ALK lymphomagenesis, highlighting its critical role in lymphoma cell proliferation and migration

LKB1 Down-Modulation by miR-17 Identifies Patients With NSCLC Having Worse Prognosis Eligible for Energy-Stress–Based Treatments

Abstract Introduction Preclinical models recently unveiled the vulnerability of LKB1/KRAS comutated NSCLC to metabolic stress-based treatments. Because miR-17 is a potential epigenetic regulator of LKB1, we hypothesized that wild-type LKB1 (LKB1WT) NSCLC with high miR-17 expression may be sensitive to an energetic stress condition, and eligible for metabolic frailties-based therapeutic intervention. Methods We took advantage of NSCLC cell lines with different combinations of KRAS mutation and LKB1 deletion and of patient-derived xenografts (PDXs) with high (LKB1WT/miR-17 high) or low (LKB1WT/miR-17 low) miR-17 expression. We evaluated LKB1 pathway impairment and apoptotic response to metformin. We retrospectively evaluated LKB1 and miR-17 expression levels in tissue specimens of patients with NSCLC and PDXs. In addition, a lung cancer series from The Cancer Genome Atlas data set was analyzed for miR-17 expression and potential correlation with clinical features. Results We identified miR-17 as an epigenetic regulator of LKB1 in NSCLC and confirmed targeting of miR-17 to LKB1 3′ untranslated region by luciferase reporter assay. We found that miR-17 overexpression functionally impairs the LKB1/AMPK pathway. Metformin treatment prompted apoptosis on miR-17 overexpression only in LKB1WT cell lines, and in LKB1WT/miR-17 high PDXs. A retrospective analysis in patients with NSCLC revealed an inverse correlation between miR-17 and LKB1 expression and highlighted a prognostic role of miR-17 expression in LKB1WT patients, which was further confirmed by The Cancer Genome Atlas data analysis. Conclusions We identified miR-17 as a mediator of LKB1 expression in NSCLC tumors. This study proposes a miR-17 expression score potentially exploitable to discriminate LKB1WT patients with NSCLC with impaired LKB1 expression and poor outcome, eligible for energy-stress-based treatments

Percepire

In un contesto di consapevolezza rispetto all’importanza che l’ambiente riveste nei processi educativi, rientra anche l’interesse verso il ruolo del colore e i benefici legati alla presenza del colore all’interno degli ambienti scolastici. Accanto ad un inquadramento teorico, il contributo presenta le ipotesi progettuali sviluppate per la scuola primaria Cadorna

Carbon Neutral Lifestyles and NDCs: Advice and Policy Perspectives

Climate change is one of the most important challenges for the present generation, which is living in decades characterized by a drastic increase in greenhouse gas emissions, especially in the most developed countries: not only the production realities – for which policies already largely provide for mitigation measures – contribute to emissions; but also, individual citizens to whom only a small part of the envisaged measures are addressed. Among the policies in which the demand side is little addressed are the Nationally Determined Contributions, which embody the efforts of each country to reduce national emissions and adapt to the impacts of climate change, as stated in the Paris Agreement signed in 2015 between the Member States of the United Nations Framework Convention on Climate Change (UNFCCC). Integrating advice on carbon neutral lifestyles in NDCs and long-term strategies could have positive implications in both social, economic, and environmental terms, paving the way for more holistic and inclusive policies, fundamental elements to pursue a development that is sustainable in the short and above all in the medium-long term. Taking this into account, the present work, which forms an integral part of the studies of WP 7 within the Horizon 2020 Project CAMPAIGNers- Citizens Acting on Mitigation Pathways through Active Implementation of a Goal-setting Network1, aims to understand what the consequences deriving from the inclusion of carbon neutral lifestyle advice in the Nationally Determined Contributions and national climate strategies would be, and to operationally implement practical examples and ways to include behavioural aspects of the carbon neutral lifestyle in the sectors studied, based on national data and statistics from the countries participating in the Project2. The innovative aspect of the Project lies in integrating the quantitative aspects deriving from the scientific evidence of official statistics with qualitative aspects generated by the collaboration between partners and stakeholders, in the form of surveys and focus groups: in this way it is possible to effectively overlap the spheres of economic and environmental analysis with that of policy making, providing a tool capable of directing strategies and international agendas

Smart Governance: urban regeneration and integration policies in Europe. Turin and Malmö case studies

Integration policies point out not only the objective of social cohesion but also the need to strengthen foreign community leadership, so that they can actively contribute to local socio - economic development. This implies a considerable degree of coordination between the public bodies, the communities, the social and economic operators. Local governments find it more and more difficult to manage the substantial immigration phenomena by efficient integration policies. The topic of integration of the foreign community, though part of Europe 2020 Strategy as concerns an inclusive growth, is not widely treated by smart cities, more inclined to work on smart and sustainable growth. The paper proposes some examples that can provide local authorities insights for the adoption of integration policies within an integrated development process and it illustrates the case studies of “Barriera di Milano” regeneration program in Turin (Italy) and of some neighbourhood regenerations in Malmö (Sweden). In particular, the paper discusses some tools of smart governance applied to urban regeneration interventions, such as community empowerment actions within a strategic planning process and community involvement methods through the practise of living labs and urban farming. The smart aspect of the operations consists of the adoption of integration policies functional not only to promote social cohesion but also to promote local economic development through immigrant community empowerment

Smart Governance: Strategic Planning and Urban Regeneration. Manchester and Turin Case Studies

The paper discusses some governance tools applied by local public bodies to urban regeneration interventions, assuming that traditional models of governance and programming are inadequat

La montagna sull’Isola: la rotta verso la sostenibilità, PNRR e oltre

Si propone un’analisi ed interpretazione dell’evento organizzato il 18 ottobre 2022 dalla Fondazione Eni Enrico Mattei e dal Dipartimento di Scienze Economiche dell’Università degli Studi di Verona. L’evento, in continuità con gli incontri organizzati nel corso del Festival ASviS 2020 e 2021, si colloca all’interno di un innovativo percorso di ricerca-azione dal titolo “Quale sostenibilità per le aree montane in Italia?” che i due enti stanno portando avanti con l’obiettivo di contribuire a far sì che lo sviluppo sostenibile, nelle sue diverse dimensioni e specificità territoriali, diventi prospettiva condivisa