Orchestration of multiscale model for computational oncology

Cancer is a challenging disease that involves multiple types of biological interactions in different time and space scales. Often computational modelling has been facing problems that, in the current technology level, is impracticable to represent in a single space-time continuum. To handle this sort of problems, complex orchestrations of multiscale models is frequently done. PRIMAGE is a large EU project that aims to support personalized childhood cancer diagnosis and prognosis. The goal is to do so predicting the growth of the solid tumour using multiscale in-silico technologies. The project proposes an open cloud-based platform to support decision making in the clinical management of paediatric cancers. The orchestration of predictive models is in general complex and would require a software framework that support and facilitate such task. The present work, proposes the development of an updated framework, referred herein as the VPH-HFv3, as a part of the PRIMAGE project. This framework, a complete re-writing with respect to the previous versions, aims to orchestrate several models, which are in concurrent development, using an architecture as simple as possible, easy to maintain and with high reusability. This sort of problem generally requires unfeasible execution times. To overcome this problem was developed a strategy of particularisation, which maps the upper-scale model results into a smaller number and homogenisation which does the inverse way and analysed the accuracy of this approach.

Novel tools for conservation genetics in marine fish: population structure and evolution of the European hake (Merluccius merluccius) inferred by SNP variation and applications to traceability

The research presented in my PhD thesis is part of a wider European project, FishPopTrace, focused on traceability of fish populations and products. My work was aimed at developing and analyzing novel genetic tools for a widely distributed marine fish species, the European hake (Merluccius merluccius), in order to investigate population genetic structure and explore potential applications to traceability scenarios. A total of 395 SNPs (Single Nucleotide Polymorphisms) were discovered from a massive collection of Expressed Sequence Tags, obtained by high-throughput sequencing, and validated on 19 geographic samples from Atlantic and Mediterranean. Genome-scan approaches were applied to identify polymorphisms on genes potentially under divergent selection (outlier SNPs), showing higher genetic differentiation among populations respect to the average observed across loci. Comparative analysis on population structure were carried out on putative neutral and outlier loci at wide (Atlantic and Mediterranean samples) and regional (samples within each basin) spatial scales, to disentangle the effects of demographic and adaptive evolutionary forces on European hake populations genetic structure. Results demonstrated the potential of outlier loci to unveil fine scale genetic structure, possibly identifying locally adapted populations, despite the weak signal showed from putative neutral SNPs. The application of outlier SNPs within the framework of fishery resources management was also explored. A minimum panel of SNP markers showing maximum discriminatory power was selected and applied to a traceability scenario aiming at identifying the basin (and hence the stock) of origin, Atlantic or Mediterranean, of individual fish. This case study illustrates how molecular analytical technologies have operational potential in real-world contexts, and more specifically, potential to support fisheries control and enforcement and fish and fish product traceability.

Cannabinoid system combined to classic targets for a new MTDL strategy: design and synthesis of natural inspired molecules for Alzheimer's disease

In this thesis is described the design and synthesis of potential agents for the treatment of the multifactorial Alzheimer’s disease (AD). Our multi-target approach was to consider cannabinoid system involved in AD, together with classic targets. In the first project, designed modifications were performed on lead molecule in order to increase potency and obtain balanced activities on fatty acid amide hydrolase and cholinesterases. A small library of compounds was synthesized and biological results showed increased inhibitory activity (nanomolar range) related to selected target. The second project was focused on the benzofuran framework, a privileged structure being a common moiety found in many biologically active natural products and therapeutics. Hybrid molecules were designed and synthesized, focusing on the inhibition of cholinesterases, Aβ aggregation, FAAH and on the interaction with CB receptors. Preliminary results showed that several compounds are potent CB ligands, in particular the high affinity for CB2 receptors, could open new opportunities to modulate neuroinflammation. The third and the fourth project were carried out at the IMS, Aberdeen, under the supervision of Prof. Matteo Zanda. The role of the cannabinoid system in the brain is still largely unexplored and the relationship between the CB1 receptors functional modification, density and distribution and the onset of a pathological state is not well understood. For this reasons, Rimonabant analogues suitable as radioligands were synthesized. The latter, through PET, could provide reliable measurements of density and distribution of CB1 receptors in the brain. In the fifth project, in collaboration with CHyM of York, the goal was to develop arginine analogues that are target specific due to their exclusively location into NOS enzymes and could work as MRI contrasting agents. Synthesized analogues could be suitable substrate for the transfer of polarization by p-H2 molecules through SABRE technique transforming MRI a more sensitive and faster technique.

Dalla genesi alla liquidazione degli ELTIF. Un nuovo e "instabile" tassello nella composita disciplina della gestione collettiva del risparmio

La presente trattazione concerne gli European long-term investment fund, disciplinati dal regolamento UE 2015/760 del 29 aprile 2015, meglio noti come ELTIF, di cui si è inteso indagare i molteplici aspetti che attengono all’operatività degli stessi, dalla genesi sino alla fase della liquidazione. Trattandosi di uno dei più recenti tasselli della composita disciplina europea del risparmio gestito, si è ritenuto opportuno anzitutto prendere le mosse dall’evoluzione della regolamentazione, domestica e comunitaria, della gestione collettiva del risparmio, la quale rappresenta la “cornice” normativa di riferimento entro cui si colloca il veicolo in discorso. Definito il percorso evolutivo della disciplina de qua, si è posta quindi l’attenzione sulla regolamentazione degli ELTIF che, pur migliorabile sotto diversi profili, rappresenta un significativo passo in avanti nel senso della costruzione dell’Unione dei mercati di capitali e del rilancio dell’economia europea. In particolare, l’indagine ha riguardato anzitutto i connotati della nuova fattispecie (carattere europeo, orizzonte temporale di lungo periodo, illiquidità). L’analisi dei tratti fisiognomici è stata funzionale non solo a verificare se essi, nella loro peculiarità, siano o meno idonei a definire un tipo a sé stante di prodotto, ma altresì a valutare in che termini essi producano un effetto conformativo sulla disciplina del prodotto stesso, specie con riferimento alla fase dell’investimento e del disinvestimento. Con l’intento di vagliare l’opportunità di interventi sul dato normativo che mirino ad accrescere l’attrattività degli ELTIF, si è volta quindi l’attenzione alla fase finale della vita del fondo, in quanto l’esiguità della disciplina dettata con riferimento alla liquidazione si espone ad applicazioni dubbie che, in larga parte, lasciano spazio all’autonomia regolamentare del prodotto e, dunque, all’applicazione di discipline nazionali disomogenee; e ciò specie con riferimento a una peculiare ipotesi di liquidazione promossa dagli investitori in conseguenza del mancato soddisfacimento della richiesta di rimborso avanzata.