Messa a punto di procedure per la semi-sintesi di composti ad attività antitumorale partendo da prodotti naturali. Studi di struttura-attività

Camptothecin, (CPT) is a pentacyclic alkaloid isolated for the first time from the Chinese tree Camptotheca acuminata, and which has soon attracted the attention of medicinal chemists and pharmacologists due to its promising anti-cancer activity against the most aggressive histo-types. So far, most of the synthesized camptothecin analogues are A and B ring modified compounds, which have been prepared via synthetic or semi-synthetic routes. To the best of our knowledge, a very limited number of C, D, or E ring modified analogues of CPT have been reported; moreover, the few derivatives known from the literature showed a reduced or no biological activity. This dissertation presents synthetic studies on camptothecin new derivatives along with the development of a new and general semi-synthetic methodology to obtain a large variety of analogues. We report here the semi-synthesis of a new family of 5-substituted CPT's, along with their biological activity evaluation, which will be compared with reference compounds. The use of carrier-linked prodrugs has emerged as a useful strategy to overcome some of the drawbacks related with the use of the parent drug, such as low solubility, membrane permeability properties, low oral absorption, instability, toxicity, and nontargeting. Herein we report CPT-prodrugs synthesized via ring opening of the lactone moiety as 17-O-acyl camptothecin tripartate conjugates, which bear a polyamine side chain with different architectures, as the carriers. Moreover, we found that the replacement of the oxygen atom with sulphur on the piridone D-ring, dramatically improves the potency of the novel 16a-thio-camptothecin derivatives, opening new possibilities in the modelling of this class of compounds.

Metodi di ottimizzazione morfologica nel progetto preliminare di propulsori aeronautici avanzati

The aim of this Doctoral Thesis is to develop a genetic algorithm based optimization methods to find the best conceptual design architecture of an aero-piston-engine, for given design specifications. Nowadays, the conceptual design of turbine airplanes starts with the aircraft specifications, then the most suited turbofan or turbo propeller for the specific application is chosen. In the aeronautical piston engines field, which has been dormant for several decades, as interest shifted towards turboaircraft, new materials with increased performance and properties have opened new possibilities for development. Moreover, the engine’s modularity given by the cylinder unit, makes it possible to design a specific engine for a given application. In many real engineering problems the amount of design variables may be very high, characterized by several non-linearities needed to describe the behaviour of the phenomena. In this case the objective function has many local extremes, but the designer is usually interested in the global one. The stochastic and the evolutionary optimization techniques, such as the genetic algorithms method, may offer reliable solutions to the design problems, within acceptable computational time. The optimization algorithm developed here can be employed in the first phase of the preliminary project of an aeronautical piston engine design. It’s a mono-objective genetic algorithm, which, starting from the given design specifications, finds the engine propulsive system configuration which possesses minimum mass while satisfying the geometrical, structural and performance constraints. The algorithm reads the project specifications as input data, namely the maximum values of crankshaft and propeller shaft speed and the maximal pressure value in the combustion chamber. The design variables bounds, that describe the solution domain from the geometrical point of view, are introduced too. In the Matlab® Optimization environment the objective function to be minimized is defined as the sum of the masses of the engine propulsive components. Each individual that is generated by the genetic algorithm is the assembly of the flywheel, the vibration damper and so many pistons, connecting rods, cranks, as the number of the cylinders. The fitness is evaluated for each individual of the population, then the rules of the genetic operators are applied, such as reproduction, mutation, selection, crossover. In the reproduction step the elitist method is applied, in order to save the fittest individuals from a contingent mutation and recombination disruption, making it undamaged survive until the next generation. Finally, as the best individual is found, the optimal dimensions values of the components are saved to an Excel® file, in order to build a CAD-automatic-3D-model for each component of the propulsive system, having a direct pre-visualization of the final product, still in the engine’s preliminary project design phase. With the purpose of showing the performance of the algorithm and validating this optimization method, an actual engine is taken, as a case study: it’s the 1900 JTD Fiat Avio, 4 cylinders, 4T, Diesel. Many verifications are made on the mechanical components of the engine, in order to test their feasibility and to decide their survival through generations. A system of inequalities is used to describe the non-linear relations between the design variables, and is used for components checking for static and dynamic loads configurations. The design variables geometrical boundaries are taken from actual engines data and similar design cases. Among the many simulations run for algorithm testing, twelve of them have been chosen as representative of the distribution of the individuals. Then, as an example, for each simulation, the corresponding 3D models of the crankshaft and the connecting rod, have been automatically built. In spite of morphological differences among the component the mass is almost the same. The results show a significant mass reduction (almost 20% for the crankshaft) in comparison to the original configuration, and an acceptable robustness of the method have been shown. The algorithm here developed is shown to be a valid method for an aeronautical-piston-engine preliminary project design optimization. In particular the procedure is able to analyze quite a wide range of design solutions, rejecting the ones that cannot fulfill the feasibility design specifications. This optimization algorithm could increase the aeronautical-piston-engine development, speeding up the production rate and joining modern computation performances and technological awareness to the long lasting traditional design experiences.

Valutazione dell'efficacia delle procedure di Pushover convenzionali, modali ed adattive applicate a telai piani in c.a. regolari ed irregolari in elevazione.

The research performed during the PhD and presented in this thesis, allowed to make judgments on pushover analysis method about its application in evaluating the correct structural seismic response. In this sense, the extensive critical review of existing pushover procedures (illustrated in chapter 1) outlined their major issues related to assumptions and to hypothesis made in the application of the method. Therefore, with the purpose of evaluate the effectiveness of pushover procedures, a wide numerical investigation have been performed. In particular the attention has been focused on the structural irregularity on elevation, on the choice of the load vector and on its updating criteria. In the study eight pushover procedures have been considered, of which four are conventional type, one is multi-modal, and three are adaptive. The evaluation of their effectiveness in the identification of the correct dynamic structural response, has been done by performing several dynamic and static non-linear analysis on eight RC frames, characterized by different proprieties in terms of regularity in elevation. The comparisons of static and dynamic results have then permitted to evaluate the examined pushover procedures and to identify the expected margin of error by using each of them. Both on base shear-top displacement curves and on considered storey parameters, the best agreement with the dynamic response has been noticed on Multi-Modal Pushover procedure. Therefore the attention has been focused on Displacement-based Adative Pushover, coming to define for it an improvement strategy, and on modal combination rules, advancing an innovative method based on a quadratic combination of the modal shapes (QMC). This latter has been implemented in a conventional pushover procedure, whose results have been compared with those obtained by other multi-modal procedures. The development of research on pushover analysis is very important because the objective is to come to the definition of a simple, effective and reliable analysis method, indispensable tool in the seismic evaluation of new or existing structures.

The potential of the 3-UPU translational parallel manipulator and a procedure to select the best architecture

The 3-UPU three degrees of freedom fully parallel manipulator, where U and P are for universal and prismatic pair respectively, is a very well known manipulator that can provide the platform with three degrees of freedom of pure translation, pure rotation or mixed translation and rotation with respect to the base, according to the relative directions of the revolute pair axes (each universal pair comprises two revolute pairs with intersecting and perpendicular axes). In particular, pure translational parallel 3-UPU manipulators (3-UPU TPMs) received great attention. Many studies have been reported in the literature on singularities, workspace, and joint clearance influence on the platform accuracy of this manipulator. However, much work has still to be done to reveal all the features this topology can offer to the designer when different architecture, i.e. different geometry are considered. Therefore, this dissertation will focus on this type of the 3-UPU manipulators. The first part of the dissertation presents six new architectures of the 3-UPU TPMs which offer interesting features to the designer. In the second part, a procedure is presented which is based on some indexes, in order to allows the designer to select the best architecture of the 3-UPU TPMs for a given task. Four indexes are proposed as stiffness, clearance, singularity and size of the manipulator in order to apply the procedure.

A novel map-matching procedure for low-sampling GPS data with applications to traffic flow analysis

An extensive sample (2%) of private vehicles in Italy are equipped with a GPS device that periodically measures their position and dynamical state for insurance purposes. Having access to this type of data allows to develop theoretical and practical applications of great interest: the real-time reconstruction of traffic state in a certain region, the development of accurate models of vehicle dynamics, the study of the cognitive dynamics of drivers. In order for these applications to be possible, we first need to develop the ability to reconstruct the paths taken by vehicles on the road network from the raw GPS data. In fact, these data are affected by positioning errors and they are often very distanced from each other (~2 Km). For these reasons, the task of path identification is not straightforward. This thesis describes the approach we followed to reliably identify vehicle paths from this kind of low-sampling data. The problem of matching data with roads is solved with a bayesian approach of maximum likelihood. While the identification of the path taken between two consecutive GPS measures is performed with a specifically developed optimal routing algorithm, based on A* algorithm. The procedure was applied on an off-line urban data sample and proved to be robust and accurate. Future developments will extend the procedure to real-time execution and nation-wide coverage.

Oltre il limite invalicabile. Procedure, piani, progetti sostenibili per le aree militari dismissibili di Piacenza

The research project concerns the restoration of military real estate, starting from the procedures in progress in Italy related to dismission, with particular emphasis for Piacenza and the case study of Caserme Bixio and Nicolai (Comparto Nord/San Sisto-Cittadella). The work is aimed at defining the relationship between urban planning and rehabilitation of dismissed military areas, in order to create a synergic effort capable to face the transformation of these sites and their integration into the urban tissue. The results obtained from the various recordings performed in Italy and in USA during the preparation of this thesis may help to find a new possible scenario for the Comparto Nord and its historic buildings.

Procedure e strumenti innovativi per lo sfruttamento sostenibile delle risorse minerarie

L'approvvigionamento di risorse minerali e la tutela dell'ambiente sono spesso considerate attività contrapposte ed inconciliabili, ma in realtà rappresentano due necessità imprescindibili per le società moderne. Le georisorse, in quanto non rinnovabili, devono essere valorizzate in maniera efficiente, adoperando strumenti che garantiscano la sostenibilità ambientale, sociale ed economica degli interventi estrattivi. La necessità di tutelare il territorio e migliorare la qualità della vita delle comunità locali impone alla Pubblica Amministrazione di implementare misure per la riqualificazione di aree degradate, ma fino ai primi anni '90 la normativa di settore non prevedeva strumenti a tal proposito, e ciò ha portato alla proliferazione di siti estrattivi dismessi e abbandonati senza interventi di recupero ambientale. Il presente lavoro di ricerca fornisce contributi innovativi alla pianificazione e progettazione sostenibile delle attività estrattive, attraverso l'adozione di un approccio multidisciplinare alla trattazione del tema e l'utilizzo esperto dei Sistemi Informativi Geografici, in particolare GRASS GIS. A seguito di una approfondita analisi in merito agli strumenti e le procedure adottate nella pianificazione delle Attività Estrattive in Italia, sono stati sviluppati un metodo di indagine ed un sistema esperto per la previsione ed il controllo delle vibrazioni indotte nel terreno da volate in cava a cielo aperto, che consentono di ottimizzare la progettazione della volata e del sistema di monitoraggio delle vibrazioni grazie a specifici strumenti operativi implementati in GRASS GIS. A supporto di una più efficace programmazione di interventi di riqualificazione territoriale, è stata messa a punto una procedura per la selezione di siti dismessi e di potenziali interventi di riqualificazione, che ottimizza le attività di pianificazione individuando interventi caratterizzati da elevata sostenibilità ambientale, economica e sociale. I risultati ottenuti dimostrano la necessità di un approccio esperto alla pianificazione ed alla progettazione delle attività estrattive, incrementandone la sostenibilità attraverso l'adozione di strumenti operativi più efficienti.

Fenomeni di transizione degli organismi edilizi, criteri operativi di inserimento ambientale e procedure di intervento

La presente tesi indaga le potenzialità, in termini di criteri operativi di inserimento ambientale e procedure di intervento, che possono derivare dall’analisi dei fenomeni insediativi facendo riferimento ai concetti di ‘transizione’ e ‘resilienza’. L’attuale periodo di crisi sembra scaturire dal disequilibrio di due fattori: le esigenze umane e l’ambiente. La contestualizzazione degli interventi, il graduale adattamento alle risorse ambientali locali e la valorizzazione dei processi “dal basso” sembrano consentire di riappropriarsi sia del valore identitario dei luoghi, dando risposta ai problemi di natura sociale evidenziati, sia della eco-compatibilità delle trasformazioni, del corretto utilizzo delle risorse energetiche e della gestione delle dinamiche economiche, in risposta ai problemi ambientali analizzati. Il prefigurare applicazioni pratiche del modello di trasformazione indagato alla scala edilizia, utilizzando tavole parametriche di analisi del costruito, viste d’insieme planivolumetriche ed elaborazioni di dati e immagini, può consentire la gestione di eventuali fasi di programmazione e di pianificazione da parte delle amministrazioni finalizzate a favorire e non ostacolare i presenti e futuri fenomeni di transizione. Particolarmente significativa appare l’analisi delle diverse tendenze di ricerca progettuale in atto, con riferimento a contributi caratterizzati da un’impostazione fenomenologica e tipo-morfologica, che dimostra l’attualità degli argomenti affrontati. La ricerca di Dottorato si conclude con l’applicazione dei criteri operativi di inserimento ambientale e delle procedure di intervento individuati ad uno specifico caso di studio.

Efficacia e complicanze durante la curva di apprendimento della Thulep: risultati a breve e medio termine delle prime 48 procedure

MATERIALI E METODI: Tra il 2012 e il 2013, abbiamo analizzato in uno studio prospettico i dati di 48 pazienti sottoposti a ThuLEP con approccio autodidatta. I pazienti sono stati rivalutati a 3, 6, 12 e 24 mesi con la valutazione del PSA, il residuo post-minzionale (RPM), l'uroflussometria (Qmax), l'ecografia transrettale e questionari validati (IPSS: international prostate symptom score e QoL: quality of life) RISULTATI: Il volume medio della prostata è di 63 ± 5,3 ml. Il tempo operatorio medio è stato di 127,58 ± 28.50 minuti. Il peso medio del tessuto asportato è stato di 30,40 ± 13,90 gr. A 6 mesi dopo l'intervento l'RPM medio è diminuito da 165,13 ± 80,15 ml a 7,78 ± 29.19 ml, mentre il Qmax medio è aumentato da 5.75 ± 1.67ml / s a 18.1 ± 5.27 ml / s. I valori medi dei IPSS e QoL hanno dimostrato un progressivo miglioramento: da 19.15 (IQR: 2-31) e 4 (IQR: 1-6) nel preoperatorio a 6.04 (IQR: 1-20) e 1.13 (IQR: 1-4), rispettivamente. Durante la curva di apprendimento si è assistito ad un progressivo aumento del peso del tessuto enucleato e ad una progressiva riduzione del tempo di ospedalizzazione e di cateterismo. Tra le principali complicanze ricordiamo un tasso di incontinenza transitoria del 12,5% a 3 mesi e del 2.1% a 12 mesi. CONCLUSIONI: ThuLEP rappresenta una tecnica chirurgica efficace, sicura e riproducibile indipendentemente dalle dimensioni della prostata. I nostri dati suggeriscono che la ThuLEP offre un miglioramento significativo dei parametri funzionali comparabili con le tecniche tradizionali, nonostante una lunga curva di apprendimento.