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Bright-field multiplex immunohistochemistry for tumor. Microenvironment evaluation in mucosal melanoma of the head and neck region: technical aspects, results, and correlation with clinicopathologic features and molecular landscape
Get PDFMucosal melanoma of the head and neck region (MM-H&N) is a rare disease, characterized by a poor prognosis and limited therapeutic strategies, especially regarding targeted therapy (lower rate of targetable mutations compared to cutaneous melanoma) and immunotherapy (lack of diagnostic tools able to predict the response). Meanwhile, bright-field multiplex immunohistochemistry (BF-mIHC) is emerging as a promising tool for characterizing tumor microenvironment (TME) and predicting response to immunotherapy in several tumors, including melanoma. This PhD project aims to develop a BF-mIHC protocol to evaluate the TME in MM-H&N, analyze the correlation between immune markers/immune profiles and MM-H&N features (clinicopathologic and molecular), and find new biomarkers useful for prognostic-therapeutic stratification of these patients. Specific aims are: (I) describe the clinicopathological features of MM-H&N; (II) analyze
the molecular status of MM-H&N and correlate it with the clinicopathological features; (III) analyze the molecular status of multiple specimens from the same patient to verify whether molecular heterogeneity of MM-H&N could affect the results with relevant prognostic-therapeutic implications; (IV) develop a BF-mIHC protocol to study TME in MM-H&N; (V) analyze the correlation between immune markers/immune profiles and MM-H&N features (clinicopathologic and molecular) to test whether BF-mIHC could be a promising tool for prognostic-therapeutic characterization of these patients
Quantitative susceptibility mapping as biomarker of neurodegeneration: methodological models and clinical applications
Get PDFQuantitative Susceptibility Mapping (QSM) is an advanced magnetic resonance technique that can quantify in vivo biomarkers of pathology, such as alteration in iron and myelin concentration. It allows for the comparison of magnetic susceptibility properties within and between different subject groups. In this thesis, QSM acquisition and processing pipeline are discussed, together with clinical and methodological applications of QSM to neurodegeneration. In designing the studies, significant emphasis was placed on results reproducibility and interpretability.
The first project focuses on the investigation of cortical regions in amyotrophic lateral sclerosis. By examining various histogram susceptibility properties, a pattern of increased iron content was revealed in patients with amyotrophic lateral sclerosis compared to controls and other neurodegenerative disorders. Moreover, there was a correlation between susceptibility and upper motor neuron impairment, particularly in patients experiencing rapid disease progression.
Similarly, in the second application, QSM was used to examine cortical and sub-cortical areas in individuals with myotonic dystrophy type 1. The thalamus and brainstem were identified as structures of interest, with relevant correlations with clinical and laboratory data such as neurological evaluation and sleep records.
In the third project, a robust pipeline for assessing radiomic susceptibility-based features reliability was implemented within a cohort of patients with multiple sclerosis and healthy controls.
Lastly, a deep learning super-resolution model was applied to QSM images of healthy controls. The employed model demonstrated excellent generalization abilities and outperformed traditional up-sampling methods, without requiring a customized re-training.
Across the three disorders investigated, it was evident that QSM is capable of distinguishing between patient groups and healthy controls while establishing correlations between imaging measurements and clinical data. These studies lay the foundation for future research, with the ultimate goal of achieving earlier and less invasive diagnoses of neurodegenerative disorders within the context of personalized medicine
The european citizens' initiative: an analysis of its effectiveness as a tool for participatory democracy
Get PDFFin dalla sua attuazione nel 2012, l'Iniziativa dei cittadini europei (ICE) ha catturato l'attenzione di accademici e politici per il suo apparente potenziale come strumento di democrazia partecipativa in grado di promuovere il coinvolgimento diretto dei cittadini nel processo decisionale dell'UE. Tuttavia, dopo il suo lancio, questo strumento sembra aver deluso le speranze e le aspettative riposte in esso e, invece di fungere da ponte tra i cittadini e le istituzioni dell'UE, sembra essere diventato una chiara prova della leadership burocratica dell'UE a Bruxelles. Con la riforma della sua legislazione di attuazione, le istituzioni europee hanno voluto dare all'ICE un'altra possibilità di raggiungere il suo pieno potenziale di democratizzazione. A tre anni dall'entrata in vigore del nuovo Regolamento 2019/788 e a più di dieci anni dal suo inserimento nell'ordinamento giuridico europeo, riteniamo che sia il momento giusto per valutare il reale impatto dell'ICE nella promozione della democrazia partecipativa nell'UE. Per raggiungere questo obiettivo, la presente tesi di dottorato intraprende un'analisi completa di questa struttura di opportunità per la partecipazione dei cittadini, esplorando le sue origini, il suo quadro normativo, la sua applicazione pratica e le sue implicazioni per la democrazia europea attraverso un approccio interdisciplinare che combina l'uso di metodi sia qualitativi che quantitativi. Questa ricerca mira a fornire una comprensione più profonda e critica dell'ICE e del suo ruolo nella costruzione di un'Europa più partecipativa e più vicina ai cittadini.Since its implementation in 2012, the European Citizens' Initiative (ECI) has captured the attention of academics and politicians for its apparent potential as a participatory democracy tool that can promote direct citizen involvement in EU decision-making. However, since its launch, this tool seems to have dashed the hopes and expectations placed in it, and instead of serving as a bridge between citizens and EU institutions, it seems to have become a clear evidence of the EU's bureaucratic leadership in Brussels. By reforming its implementing legislation, the EU institutions wanted to give the ECI another chance to reach its full democratization potential. Three years after the entry into force of the new Regulation 2019/788 and more than a decade after its inclusion in the European legal system, we believe it is the right time to assess the real impact of the ECI in promoting participatory democracy in the EU. To achieve this goal, this dissertation undertakes a comprehensive analysis of this opportunity structure for citizen participation, exploring its origins, its regulatory framework, its practical application, and its implications for European democracy through an interdisciplinary approach that combines the use of both qualitative and quantitative methods. This research aims to provide a deeper and more critical understanding of the ECI and its role in building a more participatory and citizen-friendly Europe
Addressing challenges in heterogeneous embedded systems programming: security and performance
Get PDFEmbedded systems are increasingly integral to daily life, improving and facilitating the efficiency of modern Cyber-Physical Systems which provide access to sensor data, and actuators. As modern architectures become increasingly complex and heterogeneous, their optimization becomes a challenging task. Additionally, ensuring platform security is important to avoid harm to individuals and assets. This study primarily addresses challenges in contemporary Embedded Systems, focusing on platform optimization and security enforcement.
The initial section of this study delves into the application of machine learning methods to efficiently determine the optimal number of cores for a parallel RISC-V cluster to minimize energy consumption using static source code analysis.
Results demonstrate that automated platform configuration is not only viable but also that there is a moderate performance trade-off when relying solely on static features.
The second part focuses on addressing the problem of heterogeneous device mapping, which involves assigning tasks to the most suitable computational device in a heterogeneous platform for optimal runtime.
The contribution of this section lies in the introduction of novel pre-processing techniques, along with a training framework called Siamese Networks, that enhances the classification performance of DeepLLVM, an advanced approach for task mapping.
Importantly, these proposed approaches are independent from the specific deep-learning model used.
Finally, this research work focuses on addressing issues concerning the binary exploitation of software running in modern Embedded Systems.
It proposes an architecture to implement Control-Flow Integrity in embedded platforms with a Root-of-Trust, aiming to enhance security guarantees with limited hardware modifications.
The approach involves enhancing the architecture of a modern RISC-V platform for autonomous vehicles by implementing a side-channel communication mechanism that relays control-flow changes executed by the process running on the host core to the Root-of-Trust.
This approach has limited impact on performance and it is effective in enhancing the security of embedded platforms
Congested optimal transport in the Heisenberg group
Get PDFIn this thesis we adapted the problem of continuous congested optimal transport to the Heisenberg group, equipped with a sub-Riemannian metric: we restricted the set of admissible paths to the horizontal curves. We obtained the existence of equilibrium configurations, known as Wardrop Equilibria, through the minimization of a convex functional, over a suitable set of measures on the horizontal curves. Moreover, such equilibria induce transport plans that solve a Monge-Kantorovich problem associated with a cost, depending on the congestion itself, which we rigorously defined. We also proved the equivalence between this problem and a minimization problem defined over the set of p-summable horizontal vector fields with prescribed divergence. We showed that this new problem admits a dual formulation as a classical minimization problem of Calculus of Variations. In addition, even the Monge-Kantorovich problem associated with the sub-Riemannian distance turns out to be equivalent to a minimization problem over measures on horizontal curves. Passing through the notion of horizontal transport density, we proved that the Monge-Kantorovich problem can also be formulated as a minimization problem with a divergence-type constraint. Its dual formulation is the well-known Kantorovich duality theorem. In the end, we treated the continuous congested optimal transport problem with orthotropic cost function: we proved the Lipschitz regularity for solutions to a pseudo q-Laplacian-type equation arising from it
Entangling artificial intelligence with eXtended reality paradigms for human activity support
Get PDFDespite the ``Metaverse'' being a fairly recent inclusion in scholars' vocabulary, technologies needed to allow its creation and enable its use cases are now approaching their maturity.
In the Metaverse, eXtended Reality (XR) covers the fundamental role of providing natural and ergonomic ways to visualize and manipulate the elements in such a digital layer.
However, the rapid development of Metaverse use cases is also driven by advancements in other disciplines, such as Artificial Intelligence (AI), blockchains, and the Internet of Things.
In particular, XR and AI are jointly defining a new body of research at their intersection, here named ``Extended Artificial Intelligence'', that has potentially far-reaching effects on sectors like industrial production, health care, fitness, archival, creativity, and cultural heritage.
With the ``Extended Artificial Intelligence'', we could envision an entire digital world, that could define new ways of living, by supporting humans in their everyday activities.
Hence, it becomes fundamental to study how XR and AI should be orchestrated and composed, from both an academic and industrial perspective, to support humans in every aspect of their lives.
In such a research space, this thesis focuses on studying those dynamics in different use cases regarding three fields of study: Cultural Heritage, Creative industries, and Industrial production
Deciphering digital dreams: a critical study of blockchain and green finance
Get PDFThis dissertation explores the role of blockchain technology in the landscape of contemporary capitalism, with a particular focus on KlimaDAO, a Decentralized Autonomous Organization (DAO) that wanted to scale carbon markets. The initial enthusiasm surrounding this initiative followed a series of accusations and scandals that, however, didn’t shut down the project.
The study is situated at the intersection of economic anthropology and technology, offering a critical examination of how digital innovations like blockchain intersect with financial practices and society.
This research investigates the symbolic and practical implications of technologies and carbon markets, challenging orthodox notions of finance and environmentalism, providing an anthropological lens on the complexities and paradoxes generated by the convergence of technology, finance, and environmental initiatives. Furthermore, currents gaps in socio-anthropological literature surrounding carbon markets and blockchain are identified and addressed.
The methodology integrates a multidisciplinary approach, combining qualitative research methods such as participant observation and interviews with stakeholders, complemented by a comprehensive review of relevant literature spanning economic anthropology, technology studies, and environmental finance. The research presents a nuanced yet critical understanding of the motivations and aspirations of cryptocurrencies’ enthusiasts and experts.
What emerges is how these actors embody and repeat many orthodox standpoints and ideas, even if they are seen and see themselves as the carriers of new socio- economic forms, thus helping the reproduction of current capitalism as we know it. From this point of view, carbon markets and cryptocurrencies resemble each other: they are both praised and adopted by a growing quantity of economic players despite their numerous drawbacks.
My findings suggest that behind their success don’t lay mere monetary reasons, crypto are not only “get-rich-quick” schemes nor green finance is just greenwashing, but there’s a more profound connection with the symbolical, mythological and epistemological orders governing everyday life of capitalism
Clinical efficacy of high dose brachytherapy with non-sealed 188Re (rhenium) resin in patients with "difficult to treat" basal cell carcinoma unfit for dermatologic surgery
No full textIl carcinoma basocellulare(BCC) è il Non Melanoma Skin Cancers (NMSC) più frequente. I BCC considerando i criteri proposti dall’Associazione Europea di Dermato-Oncologia possono essere classificati in “easy-to-treat” e “difficult-to-treat”. La definizione di “difficult-to-treat” considera: (i)la difficoltà chirurgica a preservare la funzionalitá anatomica/estetica;(ii)i margini scarsamente definiti come nel sottotipo sclerodermiforme;(iii)area cutanea precedentemente sottoposta a radioterapia;(iv) multiple comorbidità del paziente.
Lo scopo di questo studio retrospettivo é quello di valutare l’efficacia terapeutica della brachiterapia con la resina con 188renio nei pazienti affetti da BCC “difficult-to-treat” considerando i seguenti parametri: il tipo istologico, la sede anatomica trattata, la dimensione del BCC e i BCC naive o versus i pluritrattati.
Sono stati inclusi nello studio i pazienti affetti da BCC “difficult-to-treat” e con spessore di infiltrazione inferiore ai 3 mm.
Tra ottobre 2017 e dicembre 2022, sono stati arruolati 64 pazienti con etá media di 81 anni affetti da 82 BCC “difficult-to-treat”: 60 erano BCC nodulari, 9 sclerodermiformi e 13 superficiali.
Il follow-up medio é risultato di 22 mesi. Tutte le lesioni che al follow-up con videodermatoscopia post trattamento con188renio risultavano sospette per recidiva di BCC sono state analizzate con biopsie multiple.
La brachiterapia con l’applicazione della resina al 188Renio si é dimostrata una metodica estremamente efficace con una risoluzione del 93% dei BCC “difficult to treat” con un tempo medio alla recidiva di 23 mesi.
Non sono state riscontrate differenze statisticamente significative di risposta alla brachiterapia considerando: (i)l’area anatomica trattata, (ii)la dimensione del tumore, (iii)i BCC precedentemente trattati versus i naive. Al contrario l’istotipo sclerodermiforme é risultato correlato a un rischio di recidiva piú alto rispetto al nodulare(p=0,03).
L’analisi multivariata ha confermato che il BCC sclerodermiforme ha un rischio di recidiva 7 volte superiore rispetto al BCC nodulare(modello di Cox HR 7,2) e la recidiva si verifica circa 12 settimane prima.Basal cell carcinoma (BCC) is the most frequent non-melanoma skin cancer. The European Association of Dermato-Oncology (EADO) classification divides BCCs into 2 categories, “easy-to-treat” (common) and “difficult-to- treat”. The definition of "difficult-to-treat" considers: (i)the surgical difficulty in preserving the anatomical/aesthetic functionality; (ii) poorly defined margins as in the sclerodermiform subtype; (iii) prior radiotherapy; (iv) patient’s comorbidities interfering with surgery.
The aim of this retrospective study is to evaluate the clinical efficacy of a single application of high-dose standardized brachytherapy using an unsealed 188Re in the management of “difficult to treat” BCC and to evalute the risk factors of recurrences considering the histological type, the anatomical site treated, the size of the BCC and naïve BCC or versus multi-treated BCC.
Patients with "difficult-to-treat" BCC and with infiltration thickness less than 3 mm were included in the study.
Between October 2017 and December 2022, 64 consecutive patients, affected by 82 histologically proven high-risk BCCs, were enrolled: 60 were nodular, 9 sclerodermiform and 13 superficial BCCs.
The average follow-up was 22 months. All lesions that at follow-up with videodermoscopy were found to be suspicious for BCC recurrence were subjected to multiple skin biopsies.
Brachytherapy with the application of 188 Rhenium resin has proven to be an extremely effective method with a resolution of 93% of "difficult to treat" BCCs with an average time to recurrence of 23 months.
No statistically significant differences in response to brachytherapy were found considering: (i) the anatomical area treated, (ii) the size of the tumor, (iii) previously treated versus naive BCCs. On the contrary, the scleroderma histotype was correlated with a higher risk of recurrence compared to the nodular one (p=0.03).
Multivariable analysis confirmed that sclerodermiform BCC has a 7-fold higher risk of recurrence than nodular BCC (Cox model HR 7.2) and recurrence occurs approximately 12 weeks earlier
Effect of sarcopenia and dynapenia on patient candidate to total knee arthroplasty: evaluation with segmentation on magnetic resonance imaging compared to healthy population
Get PDFIntroduction
The manuscript initially provides an overview of sarcopenia and its potential implications in traumatology and orthopaedic surgery. With advancements in medicine and personal care leading to increased life expectancy, the relevance of frailty, of which sarcopenia is a key factor, has grown. Sarcopenia, characterized by loss of muscle mass and/or function, has gained progressively increasing interest, necessitating early diagnosis, multidisciplinary assessment, and targeted interventions to mitigate its adverse effects on patient outcomes. However, challenges remain in standardizing diagnostic thresholds, particularly due to diverse ethnic backgrounds and recent growth in the field. Therefore, research efforts should concentrate on establishing standardized imaging thresholds for sarcopenia diagnosis to enable less invasive, quicker, and more certain diagnostic methods.
Materials and Methods
The study recruited 20 healthy adult volunteers (HA) and patients candidate to total knee arthroplasty (TKA) meeting specific inclusion and exclusion criteria. All subjects underwent MRI scans, dynamometric testing, and surface electromyography for muscle assessment. Muscle measurements, including maximum cross-sectional area (CSA) and volume, were obtained from MRI scans using specialized software.
Results
MRI-scan segmentation allowed for evaluation of total lower limb muscle volume and side-to-side differences. Analyses focused on four muscle groups of interest: knee flexors, knee extensors, iliopsoas, and gluteal muscles, revealing statistically significant mean volume differences between TKA and HA subjects. TKA subjects exhibited overall volumetric reduction, particularly in muscles groups like knee extensors, and greater variability between right and left sides compared to HA subjects.
Discussion and Conclusion
The study highlights the impact of arthritic disease on muscle morphology. TKA patients demonstrated clear imbalances towards the healthy side, indicating deconditioning. These findings underscore the importance of early diagnosis and targeted interventions for sarcopenia management. Standard diagnostic criteria, more accessible tools and therapeutic protocols are essential to limit the adverse effects of sarcopenia on elderly patient and improve outcomes
Contribution to the study of access to Court of Cassation in the Italian and Spanish tradition
Get PDFNel corso degli ultimi decenni l’attenzione del legislatore e degli interpreti si è progressivamente indirizzata verso l’individuazione di meccanismi in grado di garantire alle Corti supreme di svolgere appieno le funzioni loro assegnate.
Nonostante le plurime riforme e la previsione di meccanismi di screening per la selezione dei ricorsi in cassazione, la Suprema corte italiana, divenuta ormai la propaggine delle centinaia di migliaia di ricorsi che inondano i piani bassi, si trova ad operare da diverso tempo in una situazione rasente lo stallo.
Il presente lavoro di ricerca si propone, quindi, di analizzare il «filtro» dinanzi la Corte suprema, un istituto che giova di una consolidata esperienza comparata, teso ad una cernita dei ricorsi “cassazionalmente rilevanti” e ideato per porre rimedio ai rischi connessi all’overload.
Alla luce di una certa vocazione trasnazionale del tema, che induce a ricercare le ragioni di una simile disfunzione anche ben oltre i confini strettamente nazionali, verrà condotta, al contempo, un’indagine comparata con l’esperienza giuridica del filtro in Spagna, configurante un vaglio latu sensu selettivo di rilievo nomofilattico, ancorato al criterio dell’«interés casacional», come novellato dall’ultima riforma intervenuta ad opera del Real decreto ley, 28 giugno 2023, n. 5.
Ricostruiti i tratti salienti del filtro in Italia, nella sua attuale formulazione, nonché la sua natura tipicamente procedimentale, verranno suggeriti una serie di spunti per una rimeditazione del filtro italiano, non solo previa modifica costituzionale, ma anche a costituzione invariata, stante la vigenza della garanzia costituzionale del ricorso per cassazione per violazione di legge.Over the last few decades, the legislator’s and practitioners’ attention has been progressively directed towards identifying mechanisms capable of ensuring that Supreme courts can fully perform their functions.
The purpose of this research is to analyse the “filter” before the Supreme court, an institute that aims to select “relevant” appeals.
A comparative study will be carried out with the legal tradition of the filter in Spain, configuring a selective screening of nomophylactic relevance, anchored to the criterion of the, so called, “interés casacional”, as reformed by the latest reform introduced by the Decree Law, 28 June 2023, no. 5.
Lastly, a series of ideas will be suggested for a rethinking of the Italian filter, not only with a hypothetical constitutional reform but also, with the unchanged constitution, because of the existence of constitutional guarantee of cassation appeal for violation of the law