A reversible carnitine palmitoyltransferase 1 (CPT1) inhibitor offsets chronic lymphocytic leukaemia cell proliferation

Crucial for chronic lymphocytic leukaemia (CLL) development and progression are the iterative cycles of cell re-activation and proliferation that take place in lymphoid tissues. These iterative cycles are fundamental for the development and the progression of the disease. Since cellular fatty acid (FA) import and oxidation (FAO) were recently reported to be upregulated in CLL, compared to normal B lymphocytes, we explored the in vitro effects of ST1326, a reversible inhibitor of carnitine-palmitoyl transferase 1A (CPT1A), on leukaemic cells subject to activating microenvironment-mimicking stimuli. ST1326 induced dose-dependent mitochondrial dysfunction and cell death, which were remarkably higher in activated/proliferating than quiescent CLL cells. Drug sensitivity was observed irrespective of the presence of TP53 alterations or chromosomal abnormalities, which are known to cause chemoresistance in CLL patients. The treatment of normal B lymphocytes with ST1326, at doses lethal to CLL cells, causes only a slight inhibition of cell activation/proliferation, indicating a modest cytostatic, not cytotoxic, effect. ST1326 cytotoxicity in CLL was associated with decreased levels of intracellular Acetyl-CoA and down-regulation of signalling pathways that are crucial for leukaemic cell survival, activation and proliferation. In particular, environment-induced activation of STAT3 and STAT6 transcription factors, known to upregulate anti-apoptotic Bcl-2 family members Mcl-1 and Bcl-xL, was impaired by ST1326. As a consequence, drug combination experiments with the BH3-mimetic ABT-199/Venetoclax, whose effects are counteracted by Mcl-1/Bcl-xL and cell proliferation, showed strong ST1326-mediated potentiation of ABT-199 cytotoxicity in activated/proliferating CLL cells. We also observed that ST1326 showed a synergic effect with Fludarabine in activated/proliferating CLL cells. The data indicate that CLL cells turning to an activated/proliferating state become more dependent on FAO and more sensitive to FAO-antagonists, and pave the way for ST1326 as an adjuvant tool in anti-CLL drug-combination regimens with drugs that lose efficacy on proliferating leukaemic cells

Hypergeometric functions and new mirrors of Fano varieties

In this thesis we outline a strategy to write the hypergeometric function of a Fano weighted complete intersection X of dimension n as a period of a pencil of (n-1)-dimensional varieties. Conjecturally this function is a specialisation of the quantum period of X, thus the ideas in this thesis can be viewed as the basis of a new method to find Landau--Ginzburg mirrors for all Fano weighted complete intersections. Our strategy builds upon the work of Beukers, Cohen, and Mellit on finite hypergeometric functions, suggesting that the hypergeometric variation attached to X is linked to the variation of intermediate cohomology of a pencil of (n-1+2c)-dimensional varieties, where c is the codimension of X. This pencil can be viewed as a mirror of X of the wrong dimension. We focus on anticanonical del Pezzo weighted complete intersections. The feature which makes these surfaces especially interesting is that, if the ambient space has all weights greater than 1, they have empty anticanonical linear system, and therefore fall out of the range of the known mirror constructions. For each positive integer k we exhibit the hypergeometric function of the family of surfaces of degree 8k+4 in P(2,2k+1,2k+1,4k+1) as a period of a pencil of curves of genus 3k+1. This series is the main piece of the Johnson-Kollár classification of anticanonical del Pezzo weighted hypersurfaces. For all k our pencil is a mirror of the family. We build a candidate mirror for the family of surfaces of degree 15 in P(3,3,5,5) by identifying the variation of H^3 of its wrong dimension mirror with a quotient of the variation of H^1 of a pencil of genus-six curves. We also provide evidence that our constructions are compatible with the work of Hori-Vafa. We conclude by discussing our ideas to prove the conjectural Hodge--theoretic translation of the work of Beukers, Cohen, and Mellit.Open Acces

Hypergeometric local systems over Q\mathbb{Q} with Hodge vector (1,1,1,1)(1,1,1,1)

We consider all irreducible rank-4 hypergeometric local systems defined over $\mathbb{Q}$ that support a rational one-dimensional variation of Hodge structures of weight 3 and Hodge vector $(1,1,1,1)$. Up to a natural equivalence there are only 47 cases. The first 14 cases have maximally unipotent monodromy at one point and have been extensively studied in the literature. We show that all 47 local systems are associated to families of generically smooth threefolds and we analyze the geometry and arithmetic at their conifold point.Comment: 16 pages. Comments are welcom

Do Collective Action Clauses Influence Bond Yields? New Evidence from Emerging Markets

This paper provides new empirical evidence relevant to the debate over the desirability of reforms to the way that financial markets and the international community deal with sovereign debt crises. In particular, given the ongoing opposition of investors and some sovereigns to greater use of collective action clauses (CACs) in emerging market bonds, we present new evidence on the way that financial markets have priced the use or non-use of CACs. We supplement existing evidence that the use of CACs in Euromarket issues has not affected yields on new bond issues through an event study that shows that decisions by issuers to change away from, or to, the use of CACs has also not affected the pricing of issuers’ existing stock of debt in the secondary market. We also provide new evidence on the pricing of a large sample of bonds in the secondary market on 31 January 2003. The data show that even after the intense debate about sovereign debt restructuring through 2002, the inclusion or absence of CACs still had no economically or statistically significant impact on yields as of early 2003. Hence we conclude that investors still had not focused on which bonds have CACs, or that they believe that the inclusion of CACs is not relevant to the pricing of debt. The empirical evidence therefore suggests there is no good reason why there cannot be greater use of CACs, including in bonds sold into the US market. A strong case can be made that investors will benefit from well-targeted reforms to the way that sovereign debt crises are handled. Indeed, Mexico’s successful sale of global bonds with CACs on 26 February 2003 – the first placement of bonds with CACs by an emerging market sovereign into the US market – suggests that the long-held opposition to CACs in some quarters may be easing.bond yields; collective action clauses; debt restructuring; emerging markets; sovereign debt crises

La struttura e le attività del SSN

Il capitolo fornisce una visione d’insieme del Servizio Sanitario Nazionale (SSN) italiano, della sua organizzazione e delle sue attività, con un’attenzione particolare ai cambiamenti che ne hanno caratterizzato l’evoluzione negli ultimi anni

La struttura e le attività del SSN

Il capitolo dipinge un quadro complessivo del Servizio Sanitario Nazionale (SSN) italiano, della sua organizzazione e delle sue attività, con un’attenzione particolare ai cambiamenti che ne hanno caratterizzato l’evoluzione negli ultimi anni

Le metriche di monitoraggio e valutazione dell’implementazione del PNRR

Il capitolo approfondisce la governance e gli strumenti di monitoraggio del PNRR in Sanità, con riferimento specifico alla Missione 6. Lo studio presenta un'analisi delle dimensioni oggetto di attenzione e degli indicatori forniti a supporto dell'implementazione dei progetti PNRR che riguardano le aziende sanitarie italiane