Terapie sistemiche dell'epatocarcinoma (HCC): dalla preclinica alla clinica

Introduzione Attualmente i principali punti critici del trattamento dell’HCC avanzato sono: 1) la mancanza di predittori di risposta alla terapia con sorafenib, 2) lo sviluppo resistenze al sorafenib, 3) la mancanza di terapie di seconda linea codificate. Scopo della tesi 1) ricerca di predittori clinico-laboratoristici di risposta al sorafenib in pazienti ambulatoriali con HCC; 2) valutazione dell’impatto della sospensione temporanea-definitiva del sorafenib in un modello murino di HCC mediante tecniche ecografiche; 3) valutazione dell’efficacia della capecitabina metronomica come seconda linea dell’HCC non responsivo a sorafenib. Risultati Studio-1: 94 pazienti con HCC trattato con sorafenib: a presenza di metastasi e PVT-neoplastica non sembra inficiare l’efficacia del sorafenib. AFP basale <19 ng/ml è risultata predittrice di maggiore sopravvivenza, mentre lo sviluppo di nausea di una peggiore sopravvivenza. Studio -2: 14 topi con xenografts di HCC: gruppo-1 trattato con placebo, gruppo-2 trattato con sorafenib con interruzione temporanea del farmaco e gruppo-3 trattato con sorafenib con sospensione definitiva del sorafenib. La CEUS targettata per il VEGFR2 ha mostrato al giorno 13 valori maggiori di dTE nel gruppo-3 confermato da un aumento del VEGFR2 al Western-Blot. I tumori del gruppo-2 dopo 2 giorni di ritrattamento, hanno mostrato un aumento dell’elasticità tissutale all’elastonografia. Studio-3:19 pazienti trattati con capecitabina metronomica dopo sorafenib. Il TTP è stato di 5 mesi (95% CI 0-10), la PFS di 3,6 mesi (95% CI 2,8-4,3) ed la OS di 6,3 mesi (95% CI 4-8,6). Conclusioni Lo sviluppo di nausea ed astenia ed AFP basale >19, sono risultati predittivi di una minore risposta al sorafenib. La sospensione temporanea del sorafenib in un modello murino di HCC non impedisce il ripristino della risposta tumorale, mentre una interruzione definitiva tende a stimolare un “effetto rebound” dell’angiogenesi. La capecitabina metronomica dopo sorafenib ha mostrato una discreta attività anti-neoplastica ed una sicurezza accettabile.

Histone deacetylase inhibitors in adult patients with diffuse large b-cell lymphoma relapsed/refractory: a phase II study with Panobinostat

Backgrounds:Treatment of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not eligible to high dose therapy represents an unmet medical need. Panobinostat showed encouraging therapeutic activity in studies conducted in lymphoma cell lines and in vivo in patients with advanced hematologic malignancies.Purpose:FIL-PanAL10 (NCT01523834) is a phase II, prospective multicenter trial of the Fondazione Italiana Linfomi (FIL) to evaluate safety and efficacy of single agent Panobinostat as salvage therapy for R/R DLBCL patients and to evaluate a possible relationships between response and any biological features. Patients and Methods:Patients with R/R DLBCL were included. The treatment plan included 6 induction courses with Panobinostat monotherapy followed by other 6 courses of consolidation. The primary objective was to evaluate Panobinostat activity in terms of overall response (OR); secondary objectives were: CR rate, time to response (TTR), progression-free survival (PFS), safety and feasibility of Panobinostat. We included evaluation of the impact of pharmacogenetics, immunohistochemical patterns and patient’s specific gene expression and mutations as potential predictors of response to Panobinostat as explorative objectives. To this aim a pre-enrollment new tissue biopsy was mandatory. ResultsThirty-five patients, 21 males (60%), were enrolled between June 2011 and March 2014. At the end of induction phase, 7 responses (20%) were observed, including 4 CR (11%), while 28 patients (80%) discontinued treatment due to progressive disease (PD) in 21 (60%) or adverse events in 7 (20%). Median TTR in 9 responders was 2.6 months (range 1.8-12). With a median follow up of 6 months (range 1-34), the estimated 12 months PFS and OS were 27% and 30.5%, respectively. Grade 3-4 thrombocytopenia and neutropenia were the most common toxicities (in 29 (83%) and 12 (34%) patients, respectively. Conclusions The results of this study indicate that Panobinostat might be remarkably active in some patients with R/R DLBCL, showing durable CR

The new Beam Halo Monitor for the CMS experiment at the LHC

In the context of increasing beam energy and luminosity of the LHC accelerator at CERN, it will be important to accurately measure the Machine Induced Background. A new monitoring system will be installed in the CMS cavern for measuring the beam background at high radius. This detector, called the Beam Halo Monitor, will provide an online, bunch-by-bunch measurement of background induced by beam halo interactions, separately for each beam. The detector is composed of synthetic quartz Cherenkov radiators, coupled to fast UV sensitive photomultiplier tubes. The directional and fast response of the system allows the discrimination of the background particles from the dominant flux in the cavern induced by pp collision debris, produced within the 25 ns bunch spacing. The readout electronics of this detector will make use of many components developed for the upgrade of the CMS Hadron Calorimeter electronics, with a dedicated firmware and readout adapted to the beam monitoring requirements. The PMT signal will be digitized by a charge integrating ASIC, providing both the signal rise time and the charge integrated over one bunch crossing. The backend electronics will record bunch-by-bunch histograms, which will be published to CMS and the LHC using the newly designed CMS beam instrumentation specific DAQ. A calibration and monitoring system has been designed to generate triggered pulses of UV light to monitor the efficiency of the system. The experimental results validating the design of the detector, the calibration system and the electronics will be presented.

Discalculia e calcolo mentale: l'esperienza didattica in una scuola secondaria di primo grado

Nella tesi si illustra la discalculia, cioè un disturbo che interessa la sfera del calcolo e delle abilità matematiche. Segue una parte di ricerca in classe sul calcolo mentale, in cui è stato programmato un intervento didattico al fine di favorire il ragionamento e poi, tramite l’esercizio, consentire l’automatizzazione delle procedure risolutive.

Flipped classroom. Illustrazione del modello di insegnamento e resoconto di un'esperienza didattica

Questa tesi illustra approfonditamente il modello Flipped Classroom esponendo i nuovi ruoli rivestiti da insegnante e studente durante la prima inversione didattica, oltre che le numerose strategie attuabili nel corso del secondo momento pratico in aula, e le trasformazioni apportate dal metodo nell'ambito della valutazione scolastica. Infine, è presente un resoconto dettagliato della sperimentazione del modello Flipped Classroom che ho attuato personalmente presso una scuola secondaria di secondo grado, riportando inoltre le opinioni degli studenti delle due classi che ne hanno preso parte.

A Law and Economics Analysis of Trade Secrets: Optimal Scope of Law, Misappropriation and Alternative Damages Regimes

This thesis is primarily based on three core chapters, focused on the fundamental issues of trade secrets law. The goal of this thesis is to come up with policy recommendations to improve legal structure governing trade secrets. The focal points of this research are the following. What is the optimal scope of trade secrets law? How does it depend on the market characteristics such as degree of product differentiation between competing products? What factors need to be considered to balance the contradicting objectives of promoting innovation and knowledge diffusion? The second strand of this research focuses on the desirability of lost profits or unjust enrichment damage regimes in case of misappropriation of a trade secret. A comparison between these regimes is made and simple policy implications are extracted from the analysis. The last part of this research is an empirical analysis of a possible relationship between trade secrets sharing and misappropriation instances faced by firms.

Preclinical development of anti-cancer strategies against human HER-2

HER-2 is a 185 kDa transmembrane receptor tyrosine kinase that belongs to the EGFR family. HER-2 is overexpressed in nearly 25% of human breast cancers and women with this subtype of breast cancer have a worse prognosis and frequently develop metastases. The progressive high number of HER-2-positive breast cancer patients with metastatic spread in the brain (up to half of women) has been attributed to the reduction in mortality, the effectiveness of Trastuzumab in killing metastatic cells in other organs and to its incapability to cross the blood-brain barrier. Apart from full-length-HER-2, a splice variant of HER-2 lacking exon 16 (here referred to as D16) was identified in human HER-2-positive breast cancers. Here, the contribution of HER-2 and D16 to mammary carcinogenesis was investigated in a model transgenic for both genes (F1 model). A dominant role of D16, especially in early stages of tumorigenesis, was suggested and the coexistence of heterogeneous levels of HER-2 and D16 in F1 tumors revealed the undeniable value of F1 strain as preclinical model of HER-2-positive breast cancer, closer resembling the human situation in respect to previous models. The therapeutical efficacy of anti-HER-2 agents, targeting HER-2 receptor (Trastuzumab, Lapatinib, R-LM249) or signaling effectors (Dasatinib, UO126, NVP-BKM120), was investigated in models of local or advanced HER-2-positive breast cancer. In contrast with early studies, data herein collected suggested that the presence of D16 can predict a better response to Trastuzumab and other agents targeting HER-2 receptor or Src activity. Using a multiorgan HER-2-positive metastatic model, the efficacy of NVP-BKM120 (PI3K inhibitor) in blocking the growth of brain metastases and the oncolytic ability of R-LM249 (HER-2-retargeted HSV) to reach and destroy metastatic HER-2-positive cancer cells were shown. Finally, exploiting the definition of “oncoantigen” given to HER-2, the immunopreventive activity of two vaccines on HER-2-positive mammary tumorigenesis was demonstrated.

Scene Reconstruction And Understanding By RGB-D Sensors

This thesis investigates interactive scene reconstruction and understanding using RGB-D data only. Indeed, we believe that depth cameras will still be in the near future a cheap and low-power 3D sensing alternative suitable for mobile devices too. Therefore, our contributions build on top of state-of-the-art approaches to achieve advances in three main challenging scenarios, namely mobile mapping, large scale surface reconstruction and semantic modeling. First, we will describe an effective approach dealing with Simultaneous Localization And Mapping (SLAM) on platforms with limited resources, such as a tablet device. Unlike previous methods, dense reconstruction is achieved by reprojection of RGB-D frames, while local consistency is maintained by deploying relative bundle adjustment principles. We will show quantitative results comparing our technique to the state-of-the-art as well as detailed reconstruction of various environments ranging from rooms to small apartments. Then, we will address large scale surface modeling from depth maps exploiting parallel GPU computing. We will develop a real-time camera tracking method based on the popular KinectFusion system and an online surface alignment technique capable of counteracting drift errors and closing small loops. We will show very high quality meshes outperforming existing methods on publicly available datasets as well as on data recorded with our RGB-D camera even in complete darkness. Finally, we will move to our Semantic Bundle Adjustment framework to effectively combine object detection and SLAM in a unified system. Though the mathematical framework we will describe does not restrict to a particular sensing technology, in the experimental section we will refer, again, only to RGB-D sensing. We will discuss successful implementations of our algorithm showing the benefit of a joint object detection, camera tracking and environment mapping.

Architettura e suolo

Questa tesi di laurea curriculare si propone come una lettura critica del percorso personale formativo universitario, attraverso l’analisi di due specifiche e diverse esperienze progettuali che affrontano il tema del rapporto “Architettura e Suolo”. Nella prima parte della tesi viene introdotto il concetto di locus e delle relazioni tra architettura e luogo. Il secondo capitolo affronta il pensiero di Francesco Venezia e Luigi Coccia che insegna come l’architettura debba mantenere vivo il valore della memoria, raccontare il luogo nella quale si inserisce e rapportarsi con esso. Non è possibile intervenire in un territorio senza prima averlo analizzato, aver capito la sua morfologia e conosciuto la sua storia. Il progetto del suolo risulta inscindibile rispetto al progetto architettonico ed assume pari valore: esso rappresenta un elemento fondativo che si pone in dialogo diretto, continuo e soprattutto reciproco con l’architettura. Il terzo capitolo si propone come un’analisi sul rapporto architettura suolo realizzata mettendo a confronto il lavoro svolto all’interno del Laboratorio di Progettazione Architettonica IV e quello del Laboratorio di Sintesi Finale. La lettura dei contributi di Francesco Venezia e Luigi Coccia è stata fondamentale per definire gli strumenti da utilizzare nell’analisi critica dei progetti selezionati e per capire come il rapporto tra architettura e suolo rappresenti un aspetto inprescindibile nel progetto.

Ricostruzione 3d da immagini rgb-d su piattaforma mobile

Viene proposto un porting su piattaforma mobile Android di un sistema SLAM (Simultaneous Localization And Mapping) chiamato SlamDunk. Il porting affronta problematiche di prestazioni e qualità delle ricostruzioni 3D ottenute, proponendo poi la soluzione ritenuta ottimale.

Exploring host-pathogen interactions through protein microarray. Large-scale protein microarray analysis revealed novel human receptors for the staphylococcal immune evasion protein FLIPr and for the neisserial adhesin NadA

Adhesion, immune evasion and invasion are key determinants during bacterial pathogenesis. Pathogenic bacteria possess a wide variety of surface exposed and secreted proteins which allow them to adhere to tissues, escape the immune system and spread throughout the human body. Therefore, extensive contacts between the human and the bacterial extracellular proteomes take place at the host-pathogen interface at the protein level. Recent researches emphasized the importance of a global and deeper understanding of the molecular mechanisms which underlie bacterial immune evasion and pathogenesis. Through the use of a large-scale, unbiased, protein microarray-based approach and of wide libraries of human and bacterial purified proteins, novel host-pathogen interactions were identified. This approach was first applied to Staphylococcus aureus, cause of a wide variety of diseases ranging from skin infections to endocarditis and sepsis. The screening led to the identification of several novel interactions between the human and the S. aureus extracellular proteomes. The interaction between the S. aureus immune evasion protein FLIPr (formyl-peptide receptor like-1 inhibitory protein) and the human complement component C1q, key players of the offense-defense fighting, was characterized using label-free techniques and functional assays. The same approach was also applied to Neisseria meningitidis, major cause of bacterial meningitis and fulminant sepsis worldwide. The screening led to the identification of several potential human receptors for the neisserial adhesin A (NadA), an important adhesion protein and key determinant of meningococcal interactions with the human host at various stages. The interaction between NadA and human LOX-1 (low-density oxidized lipoprotein receptor) was confirmed using label-free technologies and cell binding experiments in vitro. Taken together, these two examples provided concrete insights into S. aureus and N. meningitidis pathogenesis, and identified protein microarray coupled with appropriate validation methodologies as a powerful large scale tool for host-pathogen interactions studies.

New Application of Piezoelectric Ultrasounds in Maxillo-facial bone surgery

Background: Piezoelectric instrumentation seems to offer 3 important advantages for cutting bone structures. Be more precise because it is produced by micro-vibrations from the cutting insert. Be safer because the ultrasonic frequency used does not affect soft tissue. Thirdly, the less invasive cutting action produces minor tissue damage and consequently probably a better healing Aim of the Study: The aim of this study is to evaluate the effectiveness of piezoelectric device capability in maxillo-facial surgery, in order to take advantage of these favourable capacity. Material and Methods: Considering the several potential application of the piezoelectric technology in Orthognathic, Oncologic and Extractive surgery, we would like to design protocols in order to verify how this new device can modify the surgical technique, the surgical time, the patients healing and its quality of life. Results: Due to the precise Piezosurgery cut, we can manage the Cad-Cam-Custom Made plates protocol in Oncologic Surgery and in Orthognatic Surgery increasing our percentage of comparison between the 3D preoperative plan and the surgical execution. We also found a better quality of life impaction in Patient who underwent and extractive surgery Conclusion: Piezosurgery device seems to be a strong surgical aid were safe and precise cut are needed and its capability to reduce the discomfort Patients need to be study in deep also in major surgery like Orthognatic and Oncologic surgery.

La scrittura dell'interpretazione: Teoria e pratica della trascrizione musicale durante gli ‘anni veneziani’ di Bruno Maderna (1946-1952)

La definizione di «scrittura dell’interpretazione» comprime in una sola locuzione la descrizione dell’oggetto principale del nostro studio, ovvero il problema della trascrizione musicale, descritta, non tanto come un determinato genere musicale, quanto come una ragione di osmosi e interferenze tra il fatto compositivo e quello interpretativo. Ad una traversata di quel territorio ci si appresta incentrando la trattazione intorno alla figura e all’opera del giovane compositore e direttore Bruno Maderna, autore di diverse trascrizioni della cosiddetta musica antica (dall’Odhecaton A, Monteverdi, Viadana, Frescobaldi, Legrenzi, ed altri ancora). Attraverso gli esempi presentati si intende mostrare come l’approccio maderniano alla trascrizione musicale si giustifichi a partire dalla sua stessa teoria e pratica dell’interpretazione musicale, più che in base a concetti forti definiti sul versante della scrittura, quali ad esempio quelli di analisi e parodia. Pari attenzione si offre al contesto storico degli anni in cui egli gravita, opera e si afferma come musicista (1946-1952 circa), dedicando ampio spazio alle figure di Gian Francesco Malipiero, Angelo Ephrikian e Luigi Nono, autori a loro volta di trascrizioni e revisioni di opere del Cinquecento, del Seicento e del Settecento. Intorno ai loro rapporti viene fornita una documentazione significativa, in buona parte inedita o poco conosciuta dagli studiosi, resa disponibile grazie alle ricerche d’archivio di cui si avvantaggia la nostra trattazione.

La promozione dell'inclusione nei sistemi scolastici attraverso l'intervento di cooperazione internazionale: l'esperienza di El Salvador

La ricerca si colloca all’interno di un complesso intervento di cooperazione internazionale realizzato in El Salvador tra il 2009 e il 2014. Il Progetto di cooperazione è stato promosso dal Dipartimento di Scienze dell’Educazione dell’Università di Bologna e finanziato dalla Cooperazione Italiana. L’esperienza studiata rappresenta un esempio di promozione dell’inclusione nei sistemi scolastici di Paesi del Sud del mondo e si propone due obiettivi: 1) analizzare il processo di cambiamento della prospettiva di intervento promossa dalla cooperazione internazionale, evidenziando la dimensione educativa che sostiene processi di empowerment e ownership delle istituzioni locali; 2) contribuire al dibattito sull’ “inclusive education”, sostenendo processi di inclusione scolastica e sociale rivolti a tutti coloro che si trovano in situazione di svantaggio psico-fisico e/o socio-culturale. Le politiche locali del Ministero dell’Educazione dal 2009 hanno promosso un modello educativo con l’obiettivo di garantire il diritto all’educazione per tutti nella scuola pubblica. Lo studio costituisce un'indagine di tipo valutativo sul processo di sviluppo della scuola inclusiva in El Salvador, supportato dall’intervento di cooperazione internazionale. La ricerca utilizza in modo integrato strumenti di natura quantitativa (questionari) e qualitativa (interviste). Dai dati raccolti emerge come il processo di cooperazione sia stato caratterizzato dal principio della pari dignità tra esperti internazionali e autorità politiche e tecniche locali. Inoltre, la ricerca ha consentito di verificare come la cultura dell'inclusione si sia radicata in modo diffuso nella percezione della missione della scuola e il suo ruolo tra i protagonisti del sistema scolastico. Alla luce dei risultati, appare fondamentale continuare a investire sulla formazione tecnica delle figure chiave del sistema educativo; facilitare il processo di inclusione dei disabili nelle scuole regolari con una parallela trasformazione delle scuole speciali in centri di supporto all’integrazione; promuovere una sinergia di azione formativa tra il ministero, mondo accademico e della formazione professionale.

Electric techniques for the assessment of quality parameters of foodstuffs

In food industry, quality assurance requires low cost methods for the rapid assessment of the parameters that affect product stability. Foodstuffs are complex in their structure, mainly composed by gaseous, liquid and solid phases which often coexist in the same product. Special attention is given to water, concerned as natural component of the major food product or as added ingredient of a production process. Particularly water is structurally present in the matrix and not completely available. In this way, water can be present in foodstuff in many different states: as water of crystallization, bound to protein or starch molecules, entrapped in biopolymer networks or adsorbed on solid surfaces of porous food particles. The traditional technique for the assessment of food quality give reliable information but are destructive, time consuming and unsuitable for on line application. The techniques proposed answer to the limited disposition of time and could be able to characterize the main compositional parameters. Dielectric interaction response is mainly related to water and could be useful not only to provide information on the total content but also on the degree of mobility of this ubiquitous molecule in different complex food matrix. In this way the proposal of this thesis is to answer at this need. Dielectric and electric tool can be used for the scope and led us to describe the complex food matrix and predict food characteristic. The thesis is structured in three main part, in the first one some theoretical tools are recalled to well assess the food parameter involved in the quality definition and the techniques able to reply at the problem emerged. The second part explains the research conducted and the experimental plans are illustrated in detail. Finally the last section is left for rapid method easily implementable in an industrial process.