The role of interleuchin 6 (IL-6) in the promotion of an aggressive and stem cell-like phenotype in human breast cancer cells and in stem/progenitor cells expanded in vitro as mammospheres

High serum levels of Interleukin-6 (IL-6) correlate with poor outcome in breast cancer patients. However no data are available on the relationship between IL-6 and stem/progenitor cells which may fuel the genesis of breast cancer in vivo. Herein, we address this issue in mammospheres (MS), multi-cellular structures enriched in stem/progenitor cells of the mammary gland, and also in MCF-7 breast cancer cells. We show that MS from node invasive breast carcinoma tissues express IL-6 mRNA at higher levels than MS from matched non-neoplastic mammary glands. We find that IL-6 mRNA is detectable only in basal-like breast carcinoma tissues, an aggressive variant showing stem cell features. Our results reveal that IL-6 triggers a Notch-3-dependent up-regulation of the Notch ligand Jagged-1, whose interaction with Notch-3 promotes the growth of MS and MCF-7 derived spheroids. Moreover, IL-6 induces a Notch-3-dependent up-regulation of the carbonic anhydrase IX gene, which promotes a hypoxia-resistant/invasive phenotype in MCF-7 cells and MS. Finally, an autocrine IL-6 loop relies upon Notch-3 activity to sustain the aggressive features of MCF-7-derived hypoxia-selected cells. In conclusion, our data support the hypothesis that IL-6 induces malignant features in Notch-3 expressing, stem/progenitor cells from human ductal breast carcinoma and normal mammary gland.

Prevention of binge drinking in young adolescents through the promotion of a balanced level of psychological well-being: be-dry

This doctoral thesis presents a project carried out in secondary schools located in the city of Ferrara with the primary objective of demonstrating the effectiveness of an intervention based on Well-Being Therapy (Fava, 2016) in reducing alcohol use and improving lifestyles. In the first part (chapters 1-3), an introduction on risky behaviors and unhealthy lifestyle in adolescence is presented, followed by an examination of the phenomenon of binge drinking and of the concept of psychological well-being. In the second part (chapters 4-6), the experimental study is presented. A three-arm cluster randomized controlled trial including three test periods was implemented. The study involved eleven classes that were randomly assigned to receive well-being intervention (WBI), lifestyle intervention (LI) or not receive intervention (NI). Results were analyzed by linear mixed model and mixed-effects logistic regression with the aim to test the efficacy of WBI in comparison with LI and NI. AUDIT-C total score increased more in NI in comparison with WBI (p=0.008) and LI (p=0.003) at 6-month. The odds to be classified as at-risk drinker was lower in WBI (OR 0.01; 95%CI 0.01–0.14) and LI (OR 0.01; 95%CI 0.01–0.03) than NI at 6-month. The odds to use e-cigarettes at 6-month (OR 0.01; 95%CI 0.01–0.35) and cannabis at post-test (OR 0.01; 95%CI 0.01–0.18) were less in WBI than NI. Sleep hours at night decreased more in NI than in WBI (p = 0.029) and LI (p = 0.006) at 6-month. Internet addiction scores decreased more in WBI (p = 0.003) and LI (p = 0.004) at post-test in comparison with NI. Conclusions about the obtained results, limitations of the study, and future implications are discussed. In the seventh chapter, the data of the project collected during the pandemic are presented and compared with those from recent literature.

Reconciling the Irreconcilable? Sovereign Debt Restructuring and the Principles of International Law. A Law and Economics Perspective

This Thesis focuses on the principles of international law relevant to the resolution of legal disputes arising from sovereign insolvency conflicts. It attempts to contribute to the “incremental” approach literature by identifying principles, justifying their application in litigation and assessing whether they may help to reconcile the trade-offs prevalent in that context. For that purpose, this Thesis distinguishes between two different types of principles. First, it investigates the “Principles of Public International Law” (henceforth, “PIL principles”). Said category refers to norms of the law of nations which can be considered functionally and structurally similar to domestic constitutional principles (i.e., that can be regarded as “optimization” or “prima facie” requirements). This Thesis underscores the PIL principles protecting the interests of the creditors and citizens as well as the “public interest”, arguing that decision makers face a trade-off between these principles in the context of restructurings. Secondly, this Thesis inquires into the “general principles of domestic law” (henceforth, “GPDs”) which can be applied in sovereign debt restructuring. Two GPDs are identified: a “stay” on litigation and a “cram down” on dissenting creditors’ claims. Although both principles have been identified by the prior literature, this work advances a small but significant “twist” in the methodology used for that purpose: it relies exclusively on functional and comparative analysis. Moreover, this work justifies the application of said GPDs for two jurisdictions: New York and Germany. Finally, it posits that those GPDs can help to mitigate the trade-offs between PIL principles, thus reconciling the interests at stake.

The European External Action Service and the Implementation of the 'Union Method' in European Foreign Policy

The European External Action Service (EEAS or Service) is one of the most significant and most debated innovations introduced by the Lisbon Treaty. This analysis intends to explain the anomalous design of the EEAS in light of its function, which consists in the promotion of external action coherence. Coherence is a principle of the EU legal system, which requires synergy in the external actions of the Union and its Members. It can be enforced only through the coordination of European policy-makers' initiatives, by bridging the gap between the 'Communitarian' and intergovernmental approaches. This is the 'Union method' envisaged by A. Merkel: "coordinated action in a spirit of solidarity - each of us in the area for which we are responsible but all working towards the same goal". The EEAS embodies the 'Union method', since it is institutionally linked to both Union organs and Member States. It is also capable of enhancing synergy in policy management and promoting unity in international representation, since its field of action is delimited not by an abstract concern for institutional balance but by a pragmatic assessment of the need for coordination in each sector. The challenge is now to make sure that this pragmatic approach is applied with respect to all the activities of the Service, in order to reinforce its effectiveness. The coordination brought by the EEAS is in fact the only means through which a European foreign policy can come into being: the choice is not between the Community method and the intergovernmental method, but between a coordinated position and nothing at all.

Strategic decision making in international firms: effect of top management team internationalization on international strategic decision process

In this research project, I have integrated two research streams on international strategic decisions making in international firms: upper echelons or top management teams (TMT) internationalization research and international strategic decision making process research. Both research streams in international business literature have evolved independently, but there is a potential in combining these two streams of research. The first empirical paper “TMT internationalization and international strategic decision making process: a decision level analysis of rationality, speed, and performance” explores the influence of TMT internationalization on strategic decision rationality and speed and, subsequently, their effect on international strategic decision effectiveness (performance). The results show that the internationalization of TMT is positively related to decision effectiveness and this relationship is mediated by decision rationality while the hypotheses regarding the association between TMT internationalization and decision speed, and the mediating effect of speed were not supported. The second paper “TMT internationalization and international strategic decision rationality: the mediating role of international information” of my thesis is a simple but logical extension of first paper. The first paper showed that TMT Internationalization has a significant positive effect on international strategic decision rationality. The second paper explicitly showed that TMT internationalization affect on international strategic decision rationality comes from two sources: international experience (personal international knowledge and information) and international information collected from managerial international contacts. For this research project, I have collected data from international software firms in Pakistan. My research contributes to the literature on upper echelons theory and strategic decision making in context of international business and international firms by explicitly examining the link between TMT internationalization and characteristics of strategic decisions making process (i.e. rationality and speed) in international firms and their possible mediating effect on performance.