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TiMMing: developing an innovative suite of bioinformatic tools to harmonize and track the origin of copy number alterations in the evolutive history of multiple myeloma
Get PDFMultiple Myeloma (MM) is a hematologic cancer with heterogeneous and complex genomic landscape, where Copy Number Alterations (CNAs) play a key role in the disease's pathogenesis and prognosis. It is of biological and clinical interest to study the temporal occurrence of early alterations, as they play a disease "driver" function by deregulating key tumor pathways.
This study presents an innovative bioinformatic tools suite created for harmonizing and tracing the origin of CNAs throughout the evolutionary history of MM. To this aim, large cohorts of newly-diagnosed MM (NDMM, N=1582) and Smoldering-MM (SMM, N=282) were aggregated.
The tools developed in this study enable the harmonization of CNAs as obtained from different genomic platforms in such a way that a high statistical power can be obtained. By doing so, the high numerosity of those cohorts was harnessed for the identification of novel genes characterized as "driver" (NFKB2, NOTCH2, MAX, EVI5 and MYC-ME2-enhancer), and the generation of an innovative timing model, implemented with a statistical method to introduce confidence intervals in the CNAs-calls.
By applying this model on both NDMM and SMM cohorts, it was possible to identify specific CNAs (1q(CKS1B)amp, 13q(RB1)del, 11q(CCND1)amp and 14q(MAX)del) and categorize them as "early"/ "driver" events. A high level of precision was guaranteed by the narrow confidence intervals in the timing estimates. These CNAs were proposed as critical MM alterations, which play a foundational role in the evolutionary history of both SMM and NDMM. Finally, a multivariate survival model was able to identify the independent genomic alterations with the greatest effect on patients’ survival, including RB1-del, CKS1B-amp, MYC-amp, NOTCH2-amp and TRAF3-del/mut.
In conclusion, the alterations that were identified as both "early-drivers” and correlated with patients’ survival were proposed as biomarkers that, if included in wider survival models, could provide a better disease stratification and an improved prognosis definition
Big data and AI applications for health and research. Co-regulation mechanisms as a prosed solution for data protection law issues
Get PDFBig data and AI are paving the way to promising scenarios in clinical practice and research. However, the use of such technologies might clash with GDPR requirements. Today, two forces are driving the EU policies in this domain. The first is the necessity to protect individuals’ safety and fundamental rights. The second is to incentivize the deployment of innovative technologies. The first objective is pursued by legislative acts such as the GDPR or the AIA, the second is supported by the new data strategy recently launched by the European Commission.
Against this background, the thesis analyses the issue of GDPR compliance when big data and AI systems are implemented in the health domain. The thesis focuses on the use of co-regulatory tools for compliance with the GDPR. This work argues that there are two level of co-regulation in the EU legal system. The first, more general, is the approach pursued by the EU legislator when shaping legislative measures that deal with fast-evolving technologies. The GDPR can be deemed a co-regulatory solution since it mainly introduces general requirements, which implementation shall then be interpretated by the addressee of the law following a risk-based approach. This approach, although useful is costly and sometimes burdensome for organisations. The second co-regulatory level is represented by specific co-regulatory tools, such as code of conduct and certification mechanisms. These tools are meant to guide and support the interpretation effort of the addressee of the law.
The thesis argues that the lack of co-regulatory tools which are supposed to implement data protection law in specific situations could be an obstacle to the deployment of innovative solutions in complex scenario such as the health ecosystem. The thesis advances hypothesis on theoretical level about the reasons of such a lack of co-regulatory solutions
Composition of the water space and sea level rise. The case of the Basso Ferrarese area.
Get PDFLa tesi esplora il rapporto tra architettura e acqua, concentrandosi sulle nuove sfide poste dall'innalzamento del livello del mare per i territori marginali come il Basso Ferrarese nel Delta del Po. L'acqua è stata esplorata come elemento fluente e legato alla vita umana attraverso vari aspetti, dall'abitare ai giardini di Barragan, dalle opere di ingegneria romana alle architetture galleggianti. La ricerca ha portato alla creazione di un vocabolario progettuale che comprende relazioni spaziali, funzionali, formali e percettive per sviluppare nuovi scenari futuri.
La tesi considera le sfide del cambiamento climatico soprattutto in relazione all’innalzamento del mare, che richiede nuovi approcci progettuali. L'elaborazione di visioni e immaginari utopici, in cui l'acqua diventa materia del progetto, è considerata importante dalla letteratura legata all’ecological urbanism per creare nuovi territori che affrontino le sfide ambientali in modo sostenibile.
La ricerca si è concentrata sul Delta del Po e sulla costa adriatica italiana come una delle aree più estese a rischio in Europa. La tesi propone un'immaginario per la composizione futura dello spazio d'acqua che consenta alla persistenza e all'elemento naturale di convivere in armonia. Attraverso esercitazioni progettuali, la ricerca ha esplorato le possibilità compositive dell'area e ha cercato di capire se il sistema di relazioni identificato nella prima fase di ricerca può essere utilizzato per definire nuove possibilità dell'area.
In sintesi, la tesi propone nuove riflessioni sul rapporto tra architettura e acqua e suggerisce l'importanza di un approccio sostenibile alle sfide ambientali che devono essere affrontate nei territori marginali. L'immaginario proposto per la composizione futura dello spazio d'acqua si basa su un sistema di relazioni che incoraggia la convivenza dell'uomo con la natura.This thesis explores the relationship between architecture and water, focusing on the new challenges posed by rising sea levels for marginal territories such as the Basso Ferrarese in the Po Delta. Water is explored as a flowing element, connected to human life through various aspects, from housing to Barragan's gardens, from Roman engineering works to floating architecture. The research has led to the creation of a design vocabulary that includes spatial, functional, formal, and perceptual relationships to develop new future scenarios.
The thesis considers the challenges of climate change, particularly in relation to sea level rise, which requires new design approaches. The development of utopian visions and imaginaries, in which water becomes a material for the project, is considered important by literature related to ecological urbanism to create new territories that address environmental challenges sustainably.
The research focused on the Po Delta and the Italian Adriatic coast as one of the largest at-risk areas in Europe. The thesis proposes an imaginary for the future composition of the water space that allows for the persistence and natural element to coexist in harmony. Through design exercises, the research explored the compositional possibilities of the area and sought to understand if the system of relationships identified in the first phase of research can be used to define new possibilities for the area.
In summary, the thesis proposes new reflections on the relationship between architecture and water and suggests the importance of a sustainable approach to environmental challenges that must be addressed in marginal territories. The proposed imaginary for the future composition of the water space is based on a system of relationships that encourages coexistence between humans and nature
Radiation characteristics enhancement of planar structures using metasurfaces
Get PDFIn this thesis, the focus is on utilizing metasurfaces to improve radiation characteristics of planar structures. The study encompasses various aspects of metasurface applications, including enhancing antenna radiation characteristics and manipulating electromagnetic (EM) waves, such as polarization conversion and anomalous reflection.
The thesis introduces the design of a single-port antenna with dual-mode operation, integrating metasurfaces. This antenna serves as the front-end for a next-generation tag, functioning as a position sensor with identification and energy harvesting capabilities. It operates in the lower European Ultra-Wideband (UWB) frequency range for communication/localization and the UHF band for wireless energy reception. The design aims for a low-profile stack-up that remains unaffected by background materials. Researchers worldwide are drawn to metasurfaces due to their EM wave manipulation capabilities. The thesis also demonstrates how a High-Impedance Surface (HIS) can enhance the antenna's versatility through metasurface application, including conformal design using 3D-printing technology, ensuring adaptability for various deformation and tracking/powering scenarios.
Additionally, the thesis explores two distinct metasurface applications. One involves designing an angularly stable super-wideband Circular Polarization Converter (CPC) operating from 11 to 35GHz with an impressive relative impedance bandwidth of 104.3%. The CPC shows a stable response even at oblique incidences up to 40 degrees, with a Peak Cross-Polarization Ratio (PCR) exceeding 62% across the entire band.
The second application focuses on an Intelligent Reflective Surface (IRS) capable of redirecting incoming waves in unconventional directions. Tunability is achieved through an artificially developed ferroelectric material (HfZrO) and distributed capacitive elements (IDC) to fine-tune impedance and phase responses at the meta-atom level. The IRS demonstrates anomalous reflection for normal incident waves.
These innovative applications of metasurfaces offer promising advancements in antenna design, EM wave manipulation, and versatile wireless communication systems
Circulating Hsa-mir-5096-5p predicts 18F-FDG PET/CT and modulates Somatostatin Receptor-2 expression: a candidate biomarker for pancreatic neuroendocrine tumors.
Get PDFGastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) are rare diseases encompassing pancreatic (PanNETs) and ileal NETs (SINETs), characterized by heterogeneous somatostatin receptors (SSTRs) expression. Treatments for inoperable GEP-NETs are limited, and SSTR-targeted Peptide Receptor Radionuclide Therapy (PRRT) achieves variable responses. Prognostic biomarkers for the management of GEP-NET patients are required. 18F-FDG uptake is a prognostic indicator of tumor aggressiveness This study aims to identify circulating prognostic miRNAs associated with 18F-FDG-PET/CT status, higher risk and lower response to PRRT. Whole miRNOme NGS was conducted on plasma samples from well-differentiated advanced, metastatic, inoperable G1, G2 and G3 GEP-NET patients enrolled in the non-randomized LUX (NCT02736500) and LUNET (NCT02489604) clinical trials prior to PRRT. Differential expression analysis was performed between 18F-FDG positive and negative patients. Validation was conducted by RT/qPCR in two distinct GEP-NET validation cohorts, considering PanNETs and SINETs, separately. The Cox regression assessed independent clinical parameters and imaging for progression-free survival (PFS) in PanNETs. In situ RNA hybridization combined with immunohistochemistry was performed to detect miR and protein expression in the same tissue specimens. This novel semi-automated miR-protein protocol was applied in PanNET FFPE specimens (n=9). In vitro functional experiments were performed in PanNET models. Hsa-miR-5096, hsa-let-7i-3p and hsa-miR-4311 were found to correlate with 18F-FDG-PET/CT in PanNETs (p-value:<0.005). Statistical analysis has shown that, hsa-miR-5096 can predict 6-month PFS (p-value:<0.001) and 12-month Overall Survival upon PRRT treatment (p-value:<0.05), as well as identify 18F-FDG-PET/CT positive PanNETs with worse prognosis after PRRT (p-value:<0.005). In addition, hsa-miR-5096 inversely correlated with both SSTR2 expression in PanNET tissue and with the 68Gallium-DOTATOC captation values (p-value:<0.05), and accordingly it was able to decrease SSTR2 when ectopically expressed in PanNET cells (p-value:<0.01). Hsa-miR-5096 well performs as a biomarker for 18F-FDG-PET/CT and as independent predictor of PFS. Moreover, exosome-mediated delivery of hsa-miR-5096 may promote SSTR2 heterogeneity and thus resistance to PRRT
Incentives, Sustainability, and Law: The relationship between executive pay regulation and corporate social responsibility
Get PDFWhat is the relationship between executive pay regulation and corporate social responsibility
(CSR)? Currently, CSR is neither sufficiently included in economic research on executive pay,
nor is pay regulation considered as a potential instrument in the growing body of CSR
legislation. The successful proliferation of CSR in business practice and the attention
policymakers and legislators now pay to it, however, have raised the importance of answering
these questions. Thus, this blind spot in corporate governance—the relationship between
compensation, CSR, and law—is the topic of this thesis.
The dissertation approaches these issues in two subsequent research question: first, the role of
executive pay regulation as an institutional determinant of CSR engagement is identified. From
the results of this, the second research question arises: should legislators promote CSR
engagement and—if so—how? Lastly, a case study is conducted to map how the influence of
index funds as an important driver of CSR in corporate governance should be accommodated
in the design of CSR legislation.
The research project shows that pay regulation is part of the institutional determinants of CSR
and, depending on its design, can incentivise or discourage different forms of CSR engagement.
As a form of private self-regulation, CSR is closely interconnected with legal rules and the
result of complex underlying drivers inside and outside the firm. The study develops a
differentiation of CSR activities to accommodate this complexity, which is applied in an
analysis of pay regulation. Together, these inquiries form a comprehensive picture of the ways
in which pay regulation sets incentives for CSR engagement. Finally, the thesis shows how
CSR-oriented pay regulation is consistent with the conventional goals of corporate governance
and eventually provides a prospect for the integration of CSR and corporate law in general
An analysis of the regulatory chill hypothesis: environmental protection in international investment law
Get PDFThe goal of this thesis has been to find out whether ISDS and international investment law exert a chilling effect on more stringent environmental standards at the domestic level. Due to the lack of consistent empirical and statistical evidence uncovered during the analysis, this thesis largely dismisses the regulatory chill hypothesis. However, two exceptions are identified: first, there is evidence of the efforts made by domestic industrial groups and trade unions to prevent the implementation of stricter environmental standards; second, it has become apparent that unfounded beliefs, e.g. about ISDS, held by lawmakers and regulators can play an important role in chilling stricter environmental standards.
For these reasons, a new and narrower definition of the regulatory chill phenomenon has been proposed, one that only encompasses those instances in which lawmakers, governments and government agencies refrain from adopting the laws and regulations that they deem the most appropriate because they believe that doing so would lead to adverse consequences at the international trade and investment level, despite a lack of consistent and robust evidence supporting their concerns.
The second part of this thesis focusses on what could be done in international economic law to promote environmentally friendly FDI, while preventing the few instances in which regulatory chill may take place due to ill-founded beliefs held by lawmakers and regulators. Following an analysis that highlights the paramount role played by public participation and responsive institutions to achieve an appropriate level of environmental protection, this study ends with a proposal that recommends the adoption of a clause within IIAs that makes pre-investment environmental screening mandatory and free from ISDS oversight
New methodologies in organocatalysis: from discovery to application and mechanistic
Get PDFThis PhD thesis deals with three different topics: i) sulfoxonium ylides, ii) donor-acceptor cyclopropanes, and iii) desymmetrization reactions. Catalysis, and in more detail organocatalysis, is the fil rouge linking the three subjects of study.
The main focus treated during this doctorate period is the reactivity of sulfoxonium ylides, and in particular stabilized sulfoxonium ylides. Special attention has been dedicated to the behavior of these particular substrates under asymmetric and non-asymmetric reaction conditions. Moreover, also similarities and differences with the related, less stable, sulfonium ylides were fully analyzed, both experimentally and from a theoretical point of view. Two different reactions were developed in full. One conducted under acidic reaction conditions and the second one exploiting the asymmetric aminocatalysis.
Subsequently, the reactivity of donor-acceptor cyclopropanes was studied. After different attempts in the development of a new catalytic methodology based on these substrates, a non-conventional reactivity conducted under phase transfer catalysis was discovered and optimized. In particular, a chemodivergent reaction depending on the reaction conditions was developed.
Finally, during the period spent abroad, a preliminary study of a desymmetrization reaction was carried out. The studied reaction is based on an asymmetric elimination reaction conducted under asymmetric phosphoric acid catalysis.
In summary, this PhD thesis shows the versatility of different organocatalytic methodologies when applied to different reactions and substrates
Ship performance modelling for least-CO2 emission routes
Get PDFDecarbonization of maritime transport requires immediate action. In the short term, ship weather routing can provide greenhouse gas emission reductions, even for existing ships and without retrofitting them. Weather routing is based on making optimal use of both envi- ronmental information and knowledge about vessel seakeeping and performance. Combining them at a state-of-the-art level and making use of path planning in realistic conditions can be challenging.
To address these topics in an open-source framework, this thesis led to the development of a new module called bateau , and to its combination with the ship routing model VISIR. bateau includes both hull geometry and propulsion modelling for various vessel types. It has two objectives: to predict the sustained speed in a seaway and to estimate the CO2 emission rate during the voyage. Various semi-empirical approaches were used in bateau to predict the ship hydro- and aerodynamical resistance in both head and oblique seas. Assuming that the ship sails at a constant engine load, the involuntary speed loss due to waves was estimated. This thesis also attempted to clarify the role played by the actual representation of the sea state. In particular, the influence of the wave steepness parameter was assessed. For dealing with ships with a greater superstructure, the wind added resistance was also estimated. Numerical experiments via bateau were conducted for both a medium and a large-size container ships, a bulk-carrier, and a tanker. The simulations of optimal routes were carried out for a feeder containership during voyages in the North Indian Ocean and in the South China Sea. Least-CO2 routes were compared to the least-distance ones, assessing the relative CO2 savings. Analysis fields from the Copernicus Marine Service were used in the numerical experiments
Dynamic food systems and climate-induced risks transmission for food and nutritional security
Get PDFAgriculture market instability impedes achieving the global goal of sustainable and resilient food systems. Currently, the support to producers reaches the mammoth USD 540 billion a year and is projected to reach USD 1.8 trillion by 2030. This gigantic increase requires a repurposing agricultural support strategy (RASS), considering the market country-specific circumstances. These circumstances may vary with geographic locations, marketing structures, and product value chains. The fruit production system is crucial for health-conscious consumers and profit-oriented producers for food and nutritional security. Export is one of the main driving forces behind the expansion of the fruit sector, and during the year 2010-2018, trade significantly outpaced production increases. The previous literature states that irregular and unpredictable behaviour — Chaos — can arise from entirely rational economic decision-making within markets. Different markets' direct/indirect linkages through trade create trade hubs, and uncertainty may function as an avenue to transmit adverse shocks and increase vulnerability rather than contribute to resilience. Therefore, distinguishing Chaos into an endogenous and exogenous pattern of behaviour is cradled to formulate an effective RASS for resilient food systems and to understand global food crises.
The present research is aimed at studying the market dynamics of three regional trade hubs, i.e., Brazil (South America), Italy (Europe), and Pakistan (Asia), each representing advanced to traditional value chains to control uncertainty (risks). The present research encompasses 1) a systematic review to highlight the research dynamism and identify grey-areas of research. Based on the findings, we have investigated the 2) nonlinear impacts of climate-induced price responsiveness in monopsony markets. Once we highlighted the importance of marketing structures/arrangements, 3) we developed a risk transmission framework to address the co-evolving impacts in complex dynamic interactions