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Exploratory analysis of the role of circulating microRNA in metastatic melanoma patients
Get PDFMicroRNAs act as oncogene or tumor suppressor gene regulators and are actively released from tumor cells in the circulation. Specific microRNAs can be isolated and quantified in the blood, usually in serum or plasma fractions, where they are uncommonly stable. Cell-free microRNAs serve many, and possibly yet unexplored, functional roles and microRNA levels reflect underlying conditions and have been associated with skin cancer presence, stage and evolution. However, the clinical potential of circulating miRNAs in metastatic melanoma remains largely undefined.
From May 2020 to September 2022, we conducted a spontaneous, monocentric, exploratory study on human tissues in vitro, which aimed to evaluate the prognostic and predictive role of circulating miRNAs in metastatic melanoma patients.
At the Medical Oncology Unit of Policlinico Sant’Orsola-Malpighi of Bologna, peripheral venous blood samples from patients with metastatic melanoma treated with checkpoint inhibitors (CPI) were collected before the start of CPI (baseline, T0) and longitudinally, approximately every 3 months (T1, T2, etc). Circulating miRNA quantification was performed by droplet digital PCR (Biorad) using an EvaGreen and LNA primer-based assays. QuantaSoft Program (Biorad) calculated the absolute quantifications of each miRNA, indicated as copies/µL.
After analysis of the literature, we chose to analyze miR-155-5p, miR-320a and miR-424-5p level. All miRNAs except miR-424-5p show a significantly higher level in plasma of patients who are alive after 1 year of follow-up. High/low levels of baseline miR-155-5p, miR-320a and miR-424-5p are significantly associated with overall survival and progression-free survival.
Furthermore, a preliminary analysis on the group of patients who received first-line with anti-PD-1 (N=7), baseline miR-155-5p shows higher levels in responder vs. non responder patients (p 0.06).
These data, though promising, are preliminary and need to be further investigated in a larger cohort of patients
New catalytic strategies for the manipulation of arenes
Get PDFThe aim of this Doctoral Thesis is the development of new catalytic synthetic methodologies in the context of the modern organic chemistry setting, with special focus on the use of cheap, sustainable catalytic materials. Specifically, during the course my PhD, I focused my research on two main distinct catalytic strategies, namely: the use of carbonaceous materials as catalysts (carbocatalysis) and nickel catalysis, also investigating a synergistic combination of the two. These methodologies were explored as means for the manipulation of (hetero)aromatic cores, representing ubiquitous, easily accessible and privileged scaffolds in medicinal or natural products chemistry. Both polar and radical reaction manifolds were engaged as complementary reactivities, capitalizing on metal- as well as organo-based activation modes. Particular attention has been devoted to addressing modern synthetic challenges or highly sought- after methodologies. Specifically, protocols for direct substitution of alcohols, dearomatization of arene nuclei, formation of C-S bonds, carbon dioxide fixation, C-C bond activation and fluoroalkylation were successfully achieved under carbo- or nickel catalyzed conditions
Role of Glutaredoxin-2 in tumor oncocytic transformation
Get PDFGli oncocitomi sono tumori epiteliali caratterizzati da un accumulo di mitocondri strutturalmente e funzionalmente compromessi, a prognosi generalmente benigna. Le cause genetiche della trasformazione oncocitaria sono tuttora sconosciute; pertanto, lo studio di oncocitomi in contesti familiari sindromici è utile nella ricerca dei determinanti genetici predisponenti il fenotipo. Diversi membri di una famiglia affetta da sindrome dell’iperparatiroidismo con tumore della mandibola (HPT-JT), dovuta ad un'ampia delezione in CDC73, hanno mostrato recidiva di tumori paratiroidei oncocitari. Il sequenziamento dell’esoma ha escluso mutazioni private della famiglia; all'interno della delezione ereditata, tuttavia, sono stati individuati elementi regolatori del gene glutaredossina 2 (GLRX2), codificante un'isoforma mitocondriale deputata alla deglutationilazione proteica reversibile -modificazione modulante l’attività di numerosi target- il cui ruolo nel cancro non è noto. La proteina è risultata assente in tutti i tumori e dimezzata nei tessuti sani dei soggetti. Per indagare se la sua assenza alteri la deglutationilazione proteica predisponendo al fenotipo oncocitario, sono stati generati modelli cellulari TPC1 e HCT116 GLRX2 KO in cui sono stati riscontrati un ridotto tasso proliferativo ed un'alterata glutationilazione proteica, particolarmente in seguito a stress ossidativo. Un esperimento pilota in vivo ha mostrato cellule KO oncocitoidi, con mitocondri morfologicamente alterati, suggerendo che l’alterazione redox innescata dall’assenza di GLRX2 possa indurre una disfunzione metabolica mitocondriale tale da mimare quelle osservate negli oncocitomi. L’analisi proteomica ha individuato diversi target di glutationilazione nei campioni KO identificando proteine del ciclo di Krebs e della catena respiratoria mitocondriale. In particolare, una marcata glutationilazione del complesso della piruvato deidrogenasi (PDHc) è stata correlata ad una ridotta sintesi di ATP dipendente da piruvato. Considerando l'importanza dello stress ossidativo nella fisiopatologia del cancro ed il ruolo del glutatione nella risposta antiossidante, GLRX2 rappresenta un potenziale candidato nella regolazione del metabolismo ossidativo nelle cellule tumorali esposte allo stress e nella modulazione del fenotipo tumorale.Oncocytomas are epithelial tumors characterized by an accumulation of structurally and functionally compromised mitochondria, with a generally benign prognosis. The genetic causes behind oncocytic transformation are still unknown; therefore, the study of oncocytomas in syndromic familial contexts is particularly useful in the search for the genetic determinants of this phenotype. Several members of a family affected by hyperparathyroidism-jaw tumor syndrome (HPT-JT), due to a large deletion in CDC73, had recurrence of oncocytic parathyroid tumors. Exome sequencing ruled out private family mutations; however, within the inherited deletion, regulatory elements of the glutaredoxin 2 (GLRX2) gene have been identified. This gene encodes a mitochondrial isoform responsible for reversible protein deglutathionylation –a modification that modulates the activity of various targets- whose role in cancer is still unknown. The protein was absent in all tumors and halved in the healthy tissues of the subjects. To investigate whether its absence alters protein deglutathionylation predisposing to the oncocytic phenotype, TPC1 and HCT116 GLRX2 KO cell models were generated in which a reduced proliferative rate and altered glutathionylation of the proteome were found, particularly following oxidative stress. A pilot in vivo experiment showed oncocytic-like KO cells, with numerous altered mitochondria, consolidating the hypothesis that the redox alteration triggered by the absence of GLRX2 may induce a mitochondrial metabolic dysfunction mimicking those observed in oncocytomas. Proteomic analysis identified different glutathionylation targets in the KO samples such as proteins of the Krebs cycle and mitochondrial respiratory chain. Marked glutathionylation of the pyruvate dehydrogenase complex (PDHc) was correlated with a reduction in pyruvate-dependent ATP synthesis rate. Given the importance of oxidative stress in cancer pathophysiology and the role of glutathione in antioxidant response and protein function, GLRX2 represents a potential candidate in the regulation of oxidative metabolism in cancer cells exposed to stress and in the modulation of tumor phenotype
Performance assessment of vehicular connectivity in hybrid electric vehicles for fuel and emissions reduction
Get PDFNowadays, the spreading of the air pollution crisis enhanced by greenhouse gases emission is leading to the worsening of global warming. Recently, several metropolitan cities introduced Zero-Emissions Zones where the use of the Internal Combustion Engine is forbidden to reduce localized pollutants emissions. This is particularly problematic for Plug-in Hybrid Electric Vehicles, which usually work in depleting mode. In order to address these issues, the present thesis presents a viable solution by exploiting vehicular connectivity to retrieve navigation data of the urban event along a selected route. The battery energy needed, in the form of a minimum State of Charge (SoC), is calculated by a Speed Profile Prediction algorithm and a Backward Vehicle Model. That value is then fed to both a Rule-Based Strategy, developed specifically for this application, and an Adaptive Equivalent Consumption Minimization Strategy (A-ECMS). The effectiveness of this approach has been tested with a Connected Hardware-in-the-Loop (C-HiL) on a driving cycle measured on-road, stimulating the predictions with multiple re-routings.
However, even if hybrid electric vehicles have been recognized as a valid solution in response to increasingly tight regulations, the reduced engine load and the repeated engine starts and stops may reduce substantially the temperature of the exhaust after-treatment system (EATS), leading to relevant issues related to pollutant emission control. In this context, electrically heated catalysts (EHCs) represent a promising solution to ensure high pollutant conversion efficiency without affecting engine efficiency and performance. This work aims at studying the advantages provided by the introduction of a predictive EHC control function for a light-duty Diesel plug-in hybrid electric vehicle (PHEV) equipped with a Euro 7-oriented EATS. Based on the knowledge of future driving scenarios provided by vehicular connectivity, engine first start can be predicted and therefore an EATS pre-heating phase can be planned
Toward an understanding of the atmospheric forcing uncertainties in the Mediterranean Sea
Get PDFThe thesis has extensively investigated for the first time the statistical distributions of atmospheric
surface variables and heat fluxes for the Mediterranean Sea. After retrieving a 30-year atmospheric analysis dataset, we have captured the spatial patterns of the probability
distribution of the relevant atmospheric variables for ocean atmospheric forcing: wind components (U,V), wind amplitude, air temperature (T2M), dewpoint temperature (D2M) and mean sea-level pressure (MSL-P). The study reveals that a two-parameter PDF is not a good fit for T2M, D2M, MSL-P and wind components (U,V) and a three parameter skew-normal PDF is better suited. Such distribution captures properly the
data asymmetric tails (skewness). After removing the large seasonal cycle, we show the quality of the fit and the geographic structure of the PDF parameters. It is found that
the PDF parameters vary between different regions, in particular the shape (connected to the asymmetric tails) and the scale (connected to the spread of the distribution) parameters cluster around two or more values, probably connected to the different dynamics that produces the surface atmospheric fields in the Mediterranean basin. Moreover, using the atmospheric variables, we have computed the air-sea heat fluxes for a 20-years period and estimated the net heat budget over the Mediterranean Sea. Interestingly, the higher resolution analysis dataset provides a negative heat budget
of –3 W/m2 which is within the acceptable range for the Mediterranean Sea heat
budget closure. The lower resolution atmospheric reanalysis dataset(ERA5) does not satisfy the heat budget closure problem pointing out that a minimal resolution of the atmospheric forcing is crucial for the Mediterranean Sea dynamics.
The PDF framework developed in this thesis will be the basis for a future ensemble forecasting system that will use the statistical distributions to create perturbations of
the atmospheric ocean forcing
Democracy, empathy, literature. Encountering, discovering, listening to the other in formal education contexts
Get PDFLa riflessione sulle competenze democratiche è viva negli ultimi anni (Consiglio d’Europa, 2018; Legge 92/2019; Unesco, 2015) e il ruolo dell’educazione nel promuoverle è considerato cruciale. Lo studio qui presentato si è proposto di indagare empiricamente se e come una specifica competenza democratica – quella empatica – possa essere promossa nei contesti educativi formali grazie a esperienze di lettura di narrativa letteraria.
A partire dalla lettura in chiave fenomenologica del concetto di empatia (Boella, 2006, 2018; Stein 1917/2014; Zahavi, 2011, 2014) e dalle evidenze della ricerca – che mettono in evidenza alcuni elementi della lettura di narrativa letteraria in grado di sostenere il processo empatico (Cohen, 2001; Hakemulder, 2000, 2004; Keen, 2006; Kidd & Castano, 2013, 2017) – è stato elaborato un disegno di ricerca empirica avente l’obiettivo di comprendere se le esperienze di lettura in ambito scolastico possano configurarsi come “palestre di empatia” e se vi siano fattori in grado di facilitare (oppure ostacolare) tale processo.
È stato utilizzato un approccio qualitativo fenomenologico. Sono stati analizzati (con l’ausilio di un code-book) i testi scritti di studenti (N=356), raccolti in 3 scuole (secondarie di I e II grado) del Nord/Centro Italia, durante gli anni scolastici 20-21 e 21-22. I testi riguardano la relazione instaurata con i personaggi narrativi.
I dati mostrano che le esperienze di lettura di narrativa letteraria possono essere occasioni di allenamento delle competenze empatiche, ma sottolineano anche come ciò non sia scontato, lineare o automatico. Il manifestarsi dell’empatia narrativa richiede impegno, tempo, testi capaci di far incontrare la ricchezza e la complessità dell’esperienza umana e spazi di confronto (intimo e con gli altri) critico e riflessivo. La mediazione dell’insegnante è chiamata in causa a più riprese ed emerge l’importanza di specifiche competenze disciplinari, pedagogiche e riflessive, da sviluppare e coltivare incessantemente.Competences for a democratic citizenship have been a topic of debate in recent years (Council of Europe, 2018; Italian Law 92/2019; Unesco, 2015) and the role of education in promoting them is considered crucial. This research aims to investigate whether and how a specific democratic competence – empathy – can be fostered in formal educational contexts, thanks to literary fiction reading experiences.
Starting from the phenomenological interpretation of empathy (Boella, 2006, 2018; Stein 1917/2014; Zahavi, 2011, 2014) and the scientific evidence – which highlights elements of literary fiction reading able to support the empathic process (Cohen, 2001; Hakemulder, 2000, 2004; Keen, 2006; Kidd & Castano, 2013, 2017) – an empirical research was designed, to understand whether reading experiences in schools can be training grounds for empathy and whether there are factors facilitating (or hindering) this process.
A qualitative phenomenological approach was employed. Written texts of students (N=356) – looking at the relationship they established with fictional characters – were collected in 3 different schools (lower and upper secondary schools) in North/Central Italy, during the academic years 2020-21 and 2021-22, and were analysed with the use of a code-book.
The data showed that literary fiction reading experiences can be opportunities for empathic competence training, but they also point out that this is not predictable, linear or automatic. “Narrative empathy” (Keen, 2006) requires effort, time, spaces for critical and reflective discussion (both intimate and with others) and texts capable of portraying the richness and complexity of human experiences. The mediation of the teacher is called into question repeatedly and the importance of specific disciplinary, pedagogical and reflexive competences – that are to be developed and unceasingly nurtured – emerges
Jewish eschatological literature between the 11th and 13th centuries: messianic and redemptive expectations in the light of the persecutions in the period of the Crusades
Get PDFQuesto lavoro prende in analisi le aspettative messianiche e di redenzione ebraiche nel periodo delle crociate, ossia tra l’XI e il XIII secolo. Fu, questa, un’epoca di importanti persecuzioni nei confronti delle comunità ebraiche – stanziate soprattutto in Germania –, sottoposte ad attacchi e a conversioni forzate da parte dei crociati diretti a Gerusalemme. In quel periodo venne copiato e rielaborato un gran numero di testi di carattere apocalittico-escatologico, il cui scopo, secondo la mia ricostruzione, era quello di infondere speranza negli ebrei oppressi e di consolarli in merito all’imminente liberazione dal giogo straniero che l’era messianica avrebbe comportato. Nella prima parte del lavoro ricostruisco il quadro storico in cui tali testi circolavano, mentre nella seconda propongo un’edizione e una traduzione italiana degli scritti più rilevanti per la discussione.This work examines Jewish messianic and redemptive expectations in the period of the crusades, i.e. between the 11th and 13th centuries. This was a time of significant persecution of Jewish communities - mainly settled in Germany - who were subjected to attacks and forced conversions by crusaders on their way to Jerusalem. At that time, a large number of apocalyptic-eschatological texts were copied and reworked. Their purpose, according to my reconstruction, was to instil hope in the oppressed Jews and to console them about the imminent liberation from the foreign yoke that the Messianic era would bring. In the first part of my work I reconstruct the historical framework in which these texts circulated, while in the second part I propose an Italian edition and translation of the most relevant writings for discussion
Digital 3D reconstruction as a research environment in art and architecture history: uncertainty classification and visualisation
Get PDFThe dissertation addresses the still not solved challenges concerned with the source-based digital 3D reconstruction, visualisation and documentation in the domain of archaeology, art and architecture history.
The emerging BIM methodology and the exchange data format IFC are changing the way of collaboration, visualisation and documentation in the planning, construction and facility management process. The introduction and development of the Semantic Web (Web 3.0), spreading the idea of structured, formalised and linked data, offers semantically enriched human- and machine-readable data.
In contrast to civil engineering and cultural heritage, academic object-oriented disciplines, like archaeology, art and architecture history, are acting as outside spectators.
Since the 1990s, it has been argued that a 3D model is not likely to be considered a scientific reconstruction unless it is grounded on accurate documentation and visualisation. However, these standards are still missing and the validation of the outcomes is not fulfilled. Meanwhile, the digital research data remain ephemeral and continue to fill the growing digital cemeteries.
This study focuses, therefore, on the evaluation of the source-based digital 3D reconstructions and, especially, on uncertainty assessment in the case of hypothetical reconstructions of destroyed or never built artefacts according to scientific principles, making the models shareable and reusable by a potentially wide audience.
The work initially focuses on terminology and on the definition of a workflow especially related to the classification and visualisation of uncertainty. The workflow is then applied to specific cases of 3D models uploaded to the DFG repository of the AI Mainz. In this way, the available methods of documenting, visualising and communicating uncertainty are analysed.
In the end, this process will lead to a validation or a correction of the workflow and the initial assumptions, but also (dealing with different hypotheses) to a better definition of the levels of uncertainty
Influenza della modalità di applicazione degli adesivi universali sulla forza di adesione e attività enzimatica a livello della dentina coronale e radicolare
Get PDFObjective:
The aims of this thesis were to analyze the application mode of the universal adhesives (UA) and to give instructions for clinical procedures. The etching mode of UA on the bond strength to dentin and on the risk of retention, marginal discoloration, marginal adaptation and post-operative sensitivity (POS) was analyzed by two systematic reviews. Three in vitro studies were conducted: 1) evaporation mode of a UA on coronal dentin; 2) cementation approach on radicular dentin; 3) adhesion of metal brackets to enamel.
Materials and methods:
Two systematic review were conducted firstly, then in vitro study to investigate the evaporation mode in presence or not of pulpal pressure by means of μTBS, and the enzymatic activity using in situ zymography, at T0 and T6.
The cementation of a fiber into radicular dentin with different resin-cements was studied, by push-out bond strength evaluation.
Orthodontic brackets were cemented according to 4 adhesive protocols and shear bond strength test was conducted. Two adhesive removal techniques were evaluated, and spectrophotometry was used.
Results:
The probability of POS occurrence was less in SE. SEE approach seems to perform better than SE.
Air-drying resulted in higher μTBS. Suction-evaporation, aging and ER mode increased MMPs activity.
Differences in NL expression were present at T0 for fiber post study, and the aging produced an increase in marginal infiltration.
Brackets cemented with new universal cement with previous etchant application showed good μTBS values.
Conclusion:
SEE performed better than SE and TE with UA in terms of uTBS.
Evaporating with air-drying is better for UA in terms of uTBS and enzymatic activity.
Aging and choice of resin cement for cementation of fiber posts influenced the PBS.
Brackets cementation with a new resin- cement seems to offer the highest bond strength and leaves more cement remnants after the bracket removal
Moving toward "justice" on digital platforms? A contribution to the study of alternative dispute resolution in digital markets
Get PDFDa alcuni decenni l'UE sta promuovendo l'uso di sistemi di risoluzione alternativa delle controversie (ADR) per favorire l'accesso alla giustizia dei consumatori. La presente tesi fornisce una panoramica completa della "prima generazione" di regole in tema di ADR, con l'obiettivo di indagare le ragioni strutturali del fallimento di tale cornice normativa nel colmare il divario con la pratica commerciale nella risoluzione delle controversie osservabile nei mercati digitali.
L'emergere del modello organizzativo della piattaforma nei mercati digitali ha evidenziato l’urgenza di una nuova ondata di regolamentazione. In particolare, le piattaforme digitali di grandi dimensioni (VLOPs) si pongono nell’ottica di esercitare funzioni simili a quelle di aggiudicazione delle controversie precedentemente svolte, in maniera esclusiva, dai sistemi giuridici nazionali o dalle istituzioni ADR. La seconda parte della tesi si basa sull'analisi del fenomeno delle piattaforme digitali da una prospettiva di diritto civile, considerando l'evoluzione del diritto dell'UE in questo settore e il dibattito dottrinale sulle relazioni contrattuali nell’economia delle piattaforme.
L'analisi si concentrerà sui sistemi interni di gestione dei reclami utilizzati dalle VLOPs per risolvere i propri conflitti con gli utenti o per giudicare controversie tra utenti. Questi sistemi saranno inquadrati come online dispute resolution (ODR) delle piattaforme. Per sostenere l'analisi del fenomeno, la tesi presenterà quattro casi studio di sistemi di ODR attualmente offerti da VLOPs di diverse categorie.
Complessivamente, la tesi mira a fornire una nuova dimensione alla nozione di ODR, offrendo un dettagliato quadro del ruolo delle piattaforme digitali nella risoluzione delle controversie, anche alla luce del Regolamento Platform-to-business (UE 1150/2019) e del Digital Service Act (UE 2065/2022). Dall’indagine emerge la necessità per gli studiosi del diritto processuale civile di prestare attenzione a questo fenomeno emergente, anche al fine di evitare che la risoluzione delle controversie operata dalle piattaforme digitali diventi un ostacolo sostanziale all'accesso alla giustizia dei cittadini.For decades, the EU has been advocating for the use of ADR systems to promote consumers' access to justice in transnational disputes. The dissertation gives a comprehensive overview of the "first generation" of ADR rules, with the aim of investigating the structural reasons for the failure in bridging the gap between the commercial practice in dispute resolution observed in digital markets and the envisaged development consumers’ ADR in Europe.
The raise of the platform model in digital markets has highlighted the pre-existent need for additional regulation. In particular, VLOPs exercise functions reminiscent of the adjudication of disputes, which were previously carried out exclusively by national legal systems or ADR institutions. The second part of the dissertation builds on the analysis of the phenomenon of digital platforms from a civil law perspective, considering the relevant evolutions of EU law in this area and the doctrinal debate on contractual relationships in the platform economy.
The analysis will finally focus on the internal complaint-handling systems adopted by VLOPs for resolving conflicts between the user and the platform or for adjudicating disputes between users. These systems will be framed as platforms’ online dispute resolution mechanisms (ODR). To support the analysis of the phenomenon, the dissertation will present four case studies of ODR systems currently offered by VLOPs of different categories.
Overall, the dissertation aims to provide a new dimension to the notion of ODR, offering a detailed framework of the role of digital platforms in conflict resolution, also in the light of the Platform-to-business Regulation (UE 1150/2019) and Digital Service Act (UE 2065/2022). It highlights the need for procedural law scholars to focus on this phenomenon to scrutinize dispute resolution operated by digital platforms, also preventing it from becoming a substantial obstacle to citizens' access to justice