Targeting the p53–MDM2 interaction by the small-molecule MDM2 antagonist Nutlin-3a: a new challenged target therapy in adult Philadelphia positive acute lymphoblastic leukemia patients

The human p53 tumor suppressor, known as the “guardian of the genome”, is one of the most important molecules in human cancers. One mechanism for suppressing p53 uses its negative regulator, MDM2, which modulates p53 by binding directly to and decreasing p53 stability. In testing novel therapeutic approaches activating p53, we investigated the preclinical activity of the MDM2 antagonist, Nutlin-3a, in Philadelphia positive (Ph+) and negative (Ph-) leukemic cell line models, and primary B-Acute lymphoblastic leukemia (ALL) patient samples. In this study we demonstrated that treatment with Nutlin-3a induced grow arrest and apoptosis mediated by p53 pathway in ALL cells with wild-type p53, in time and dose-dependent manner. Consequently, MDM2 inhibitor caused an increase of pro-apoptotic proteins and key regulators of cell cycle arrest. The dose-dependent reduction in cell viability was confirmed in primary blast cells from Ph+ ALL patients with the T315I Bcr-Abl kinase domain mutation. In order to better elucidate the implications of p53 activation and to identify biomarkers of clinical activity, gene expression profiling analysis in sensitive cell lines was performed. A total of 621 genes were differentially expressed (p < 0.05). We found a strong down-regulation of GAS41 (growth-arrest specific 1 gene) and BMI1 (a polycomb ring-finger oncogene) (fold-change -1.35 and -1.11, respectively; p-value 0.02 and 0.03, respectively) after in vitro treatment as compared to control cells. Both genes are repressors of INK4/ARF and p21. Given the importance of BMI in the control of apoptosis, we investigated its pattern in treated and untreated cells, confirming a marked decrease after exposure to MDM2 inhibitor in ALL cells. Noteworthy, the BMI-1 levels remained constant in resistant cells. Therefore, BMI-1 may be used as a biomarker of response. Our findings provide a strong rational for further clinical investigation of Nutlin-3a in Ph+ and Ph-ALL.

Effects of 2013 Cap reform on land market: regionalized farm payments and changes in farmers’ intended behaviour

The CAP reform process has been a central issue for agricultural economics research in recent years, and is gaining further attention in view of the post-2013 perspectives (Viaggi et al., 2010; Bartolini et al., 2011). Today the CAP is in the middle of a new reform process. Through the debate generated by the official proposals, published in October 2011 (COM(2011)625/3), the European Union (EU) engaged in a revision of the CAP ended on 26 June 2013 when a political agreement has been reached (IP/13/613, MEMO-13-621 and IP/13/864). In particular, in Italy the switch of the payment regime from historical to regional bases will take place. The underlying assumption is that the shift to regionalized payments changes the remuneration of inputs and has an impact on farmers’ allocation of fixed resources. In this context, farmers are expected to adjust their plans to the new policy environment as the regionalization of support is meant to create a change in incentives faced by farmers. The objective of this thesis is to provide an ex-ante analysis of the potential impact of the introduction of regionalized payments, within the post-2013 CAP reform, on the land market. Regionalized payments seem to produce differentiated effects and contribute to a general (slight) increase of land exchanges. The individual reaction to the new payments introduction would be different depending on location and specialization. These effects seem to be also strongly influenced by the difference in historical payments endowment and value, i.e. by the previous historical system of distribution of payments.