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Preclinical studies of the combined effect of anti-MYCN PNA and Retinoic Acid as potential approach to treat Neuroblastoma
Get PDFNeuroblastoma (NB) is the deadliest cancer in early childhood. Around 25% of patients pre- sent MYCN-amplification (MNA) which is linked to poor prognosis, metastasis, and therapy- resistance. While retinoic acid (RA) is beneficial only for some NB patients, the cause of its resistance is still unknown. Thus, there remains a need for new therapies to treat NB.
I show that MYCN-specific inhibition by the antigene oligonucleotide BGA002 in combination with 13-cis RA (BGA002-RA) overcome resistance in MNA-NB cell lines, leading to potent MYCN mRNA expression and protein decrease. Moreover, BGA002-RA reactivated neuron differentiation or led to apoptosis in MNA-NB cell lines, and inhibited invasiveness capacity. Since NB and PI3K/mTOR pathway are strictly related MYCN down-regulation by BGA002 led to mTOR pathway inhibition in MNA-NB, that was strengthened by BGA002-RA. I further analyzed if MYCN silencing may induce autophagy reactivation, and indeed BGA002-RA caused a massive increase in lysosomes and macrovacuoles in MNA-NB cells.
In addition, while MYCN is known to induce angiogenesis, BGA002-RA in vivo treatment elim- inated the tumor vascularization in a MNA-NB mice model, and significantly increased the survival.
Overall, these results indicate that MYCN modulation mediates the therapeutic efficacy of RA and the development of RA resistance in MNA-NB. Furthermore, by targeting MYCN, we show a cancer-specific way of mTOR pathway inhibition only in MNA-NB, avoiding side effects of targeting mTOR in normal cells. These findings warrant clinical testing of BGA002-RA as a potential strategy to overcome RA resistance in MNA-NB
Modelling of ORC components and systems for low-medium temperature heat recovery applications with reduced environmental impact
Get PDFAlthough its great potential as low to medium temperature waste heat recovery (WHR) solution, the ORC technology presents open challenges that still prevent its diffusion in the market, which are different depending on the application and the size at stake. Focusing on the micro range power size and low temperature heat sources, the ORC technology is still not mature due to the lack of appropriate machines and working fluids. Considering instead the medium to large size, the technology is already available but the investment is still risky. The intention of this thesis is to address some of the topical themes in the ORC field, paying special attention in the development of reliable models based on realistic data and accounting for the off-design performance of the ORC system and of each of its components.
Concerning the “Micro-generation” application, this work: i) explores the modelling methodology, the performance and the optimal parameters of reciprocating piston expanders; ii) investigates the performance of such expander and of the whole micro-ORC system when using Hydrofluorocarbons as working fluid or their new low GWP alternatives and mixtures; iii) analyzes the innovative ORC reversible architecture (conceived for the energy storage), its optimal regulation strategy and its potential when inserted in typical small industrial frameworks.
Regarding the “Industrial WHR” sector, this thesis examines the WHR opportunity of ORCs, with a focus on the natural gas compressor stations application. This work provides information about all the possible parameters that can influence the optimal sizing, the performance and thus the feasibility of installing an ORC system. New WHR configurations are explored: i) a first one, relying on the replacement of a compressor prime mover with an ORC; ii) a second one, which consists in the use of a supercritical CO2 cycle as heat recovery system
Instrumental and sensory analyses for the characterization of food, phytotherapeutic or pharmaceutical hemp products
Get PDFTo address the request to develop rapid and easy methods for determining the cannabinoids, an HPLC-UV method (8 min) to separate and quantify the 10 main cannabinoids in hemp inflorescences was developed, and in-house validated. Moreover, the antioxidant activity of cannabidiol (CBD) in two oily matrices was investigated and compared to that of α-tocopherol, in relation to the growing market of oily solutions containing cannabidiol. Then, since no univocal legislation on the evaluation of quality and authenticity of hemp seed oil (HSO) exists, the composition and quality of cold-pressed HSOs were also explored, highlighting a great variability in terms of oxidative state minor compounds content. From the sensory point of view, a panel was trained, a specific sensory wheel and a profile sheet were developed. Due to the Covid-19 pandemic, the sensory evaluation was also performed at home. The panel showed a good performance both in the laboratory and remotely. Moreover, a focus group was used to investigate consumers’ attitudes, pointing out that a high-quality HSO has to be cold-pressed and green for them. Then, the evaluation of stability during the storage of HSOs was investigated. The results showed that photo-oxidation did not seem to significantly affect the quality of the oil during the first 3 months of storage. Finally, a study about the evolution of the volatile profile of 9 HSOs, under accelerated oxidation conditions, allowed identifying volatile markers of HSOs oxidation and freshness.
This Ph.D. was developed in the context of the scholarship “Harmonized procedures of analysis of medical, herbal, food and industrial cannabis: development and validation of cannabinoids’ quality control methods, of extraction and preparation of derivatives from the plant raw material, according to the product destination” funded by Enecta S.r.l
The Oratory and the care. Assistance and medicine in Papal Rome (16th-17h centuries)
Get PDFLa tesi è incentrata sul rapporto tra una comunità religiosa maschile, la Congregazione dell'Oratorio di Roma dei secoli XVI e XVII, e il concetto di cura, mettendo in dialogo storia sociale, storia religiosa e storia della medicina.
La prima parte indaga il coinvolgimento degli Oratoriani nella rete caritativa urbana, sottolineando il loro contributo nello sviluppo e nell'amministrazione di una serie di ospedali, ma anche il loro impegno pratico nella cura spirituale e corporale dei malati. La seconda parte prende in esame i professionisti sanitari che frequentavano l'Oratorio, inquadrando il loro rapporto con i padri nel quadro di una più ampia rete di connessioni sociali e politiche nella Roma pontificia. Inoltre, mettendo in rilievo le specificità di speziali, barbieri-chirurghi e medici, l'indagine considera il loro coinvolgimento nella vita religiosa della comunità e la messa a frutto del loro sapere, in ambito umanistico e anatomico.
La terza parte studia il complesso rapporto dei sacerdoti con il proprio corpo e con la salute. Viene rilevato il peso delle condizioni sanitarie nell’accettazione di nuovi membri, i legami tra estetica, identità sociale e medicina, ma si prendono in considerazione anche l’ambigua funzione del cibo – inteso come strumento di ascesi che di cura – e il funzionamento concreto dell'organizzazione medica della comunità. Inoltre, un capitolo analizza la circolazione del sapere medico, evidenziando il ruolo della biblioteca, la raccolta e lo scambio di ricette mediche e l'importanza della spezieria comunitaria, mentre un altro capitolo si focalizza sui viaggi terapeutici e sulla pratica del termalismo. L'ultima parte è incentrata sulla peste romana del 1656-57, analizzando il modo in cui la Congregazione affrontò lo scoppio e lo sviluppo dell'epidemia, sia in casa che in città, per sottolineare il fragile e ambiguo equilibrio che definirono tra carità e tutela della salute.The thesis focuses on the relationship between a male religious community, the Congregation of the Oratory of Rome of the 16th and 17th centuries, and healthcare, connecting social history, religious history and history of medicine.
The first part centers on the involvement of the Oratorians in the urban charitable network, underlining their contribution in the development and the administration of a series of hospitals, but also their practical commitment in the spiritual and bodily care of the sick. The second part concentrates on the health professionals who attended the Oratory, framing their relationship with the fathers within a broader network of social and political connections in the Papal Rome. Also, stressing the differences between apothecaries, barber-surgeons and physicians, the analysis considers their involvement in the religious life of the community and the exploitation of their humanistic and anatomical expertise.
The third part studies the complex relationship of the priests with their own bodies and healthcare. It highlights the weight of bodily conditions for the acceptance of new members in the Oratory, and the links between aesthetics, social identity and medicine, but it takes into account also the ambiguous functions of food – intended as a tool both for asceticism and healthcare – and the concrete functioning of the medical organization of the community. Moreover, a chapter analyses the circulation of medical knowledge, highlighting the role of the library, the collection and exchange of medical recipes and the importance of the Oratorian apothecary shop, while another chapter concentrates upon the therapeutic voyages and the practice of thermalism. The last part, focusing on the Roman plague of 1656-57, analyses how the Congregation coped with the epidemic outbreak and development, both in the house and in the city, in order to underline their fragile and ambiguous balance between charity and health protection
Modelling and Uncertainty Quantification application to SA simulation codes in advanced SMR
Get PDFIn the framework of a global transition to a low-carbon energy mix, the interest in advanced nuclear Small Modular Reactors (SMRs) has been growing at the international level. Due to the high level of maturity reached by Severe Accident Codes for currently operating rectors, their applicability to advanced SMRs is starting to be studied. Within the present work of thesis and in the framework of a collaboration between ENEA, UNIBO and IRSN, an ASTEC code model of a generic IRIS reactor has been developed. The simulation of a DBA sequence involving the operation of all the passive safety systems of the generic IRIS has been carried out to investigate the code model capability in the prediction of the thermal-hydraulics characterizing an integral SMR adopting a passive mitigation strategy. The following simulation of 4 BDBAs sequences explores the applicability of Severe Accident Codes to advance SMRs in beyond-design and core-degradation conditions.
The uncertainty affecting a code simulation can be estimated by using the method of Input Uncertainty Propagation, whose application has been realized through the RAVEN-ASTEC coupling and implementation on an HPC platform. This probabilistic methodology has been employed in a study of the uncertainty affecting the passive safety system operation in the DBA simulation of ASTEC, providing a further characterization of the thermal-hydraulics of this sequence. The application of the Uncertainty Quantification method to early core-melt phenomena has been investigated in the framework of a BEPU analysis of the ASTEC simulation of the QUENCH test-6 experiment. A possible solution to the encountered challenges has been proposed through the application of a Limit Surface search algorithm
Cerebral protection in aortic arch surgery
Get PDFNegli ultimi decenni, l’outcome dei pazienti sottoposti a chirurgia dell’aorta toracica è migliorato grazie ai progressi ottenuti nella gestione della circolazione
extracorporea, della protezione miocardica e cerebrale e del monitoraggio intra- e postoperatorio dei pazienti. Malgrado questo però, la chirurgia dell’arco aortico è ancora gravata da una significativa mortalità e morbilità dovute principalmente alle complicanze neurologiche conseguenti all’interruzione temporanea della
circolazione cerebrale.
Nel presente studio sono stati analizzati 364 pazienti trattati per sostituzione dell’arco aortico con l’ausilio della perfusione cerebrale selettiva anterograda,
presso l’Unità Operativa di Cardiochirurgia dell’Ospedale di Sant’Orsola di Bologna dal 1° gennaio 2015 al 31 maggio 2020.Le disfunzioni neurologiche permanenti sono state diagnosticate in 33 dei 364 pazienti (9.1%) operati, utilizzando la perfusione cerebrale selettiva anterograda
come tecnica di perfusione cerebrale. Pertanto abbiamo confrontato due gruppi di pazienti: un gruppo di 33 pazienti con deficit permanenti con il resto dei pazienti (331) che non aveva alcun deficit.
Tra le variabili intraoperatorie, i tipi di cannulazione arteriosa, in particolare la cannulazione dell’arteria femorale (109 [32.9%] vs 17 [51.5%], p-value=0.032) e
dell’aorta ascendente (56 [16.9%] vs 0, p-value=0.010), presentano delle differenze statisticamente significative tra i due gruppi.
Per quanto riguarda la perfusione cerebrale selettiva anterograda, i valori del flusso medio (899.63 ± 214.12 vs 952.52 ± 160.72, p-value=0.051) presentano una
differenza statisticamente significativa tra i due campioni.
All’analisi multivariata, la dissezione aortica di tipo A (p = 0.010), la cannulazione femorale (p = 0.033) e l’arresto di circolo totale (p = 0.046) si confermano dei fattori
di rischio statisticamente significativi per l’insorgenza di disfunzioni neurologiche permanentiIn recent decades, the outcome of patients after thoracic aortic surgery has improved considerably. However, surgery of the thoracic aorta and, in particular, of the aortic arch is still associated with significant high mortality and morbidity caused by neurological complications resulting from temporary suspension of cerebral circulation. Cerebrovascular injuries in thoracic aortic surgery can be caused by inadequate cerebral protection, cerebral embolism and, in case of acute type A aortic dissection, cerebral malperfusion. The neurological outcome of these patients depends on the quality of central nervous system protection during the critical period of interruption of cerebral circulation. Various techniques have been proposed as a means of protecting the brain from ischemic injury, such as deep hypothermic circulatory arrest, retrograde cerebral perfusion, and antegrade selective cerebral perfusion.
Here we report our experience with the antegrade cerebral perfusion as preferred cerebral protection techniqu
Linear and nonlinear thermal instability of Newtonian and non-Newtonian fluid saturated porous media
Get PDFThe present work aims to investigate the influence of different aspects, such as non-standard steady solutions, complex fluid rheologies and non-standard porous-channel geometries, on the stability of a Darcy-Bénard system. In order to do so, both linear and nonlinear stability theories are considered. A linear analysis focuses on studying the dynamics of the single disturbance wave present in the system, while its nonlinear counterpart takes into consideration the interactions among the single modes. The scope of the stability analysis is to obtain information regarding the transition from an equilibrium solution to another one, and also information regarding the transition nature and the emergent solution after the transition. The disturbance governing equations are solved analytically, whenever possible, and numerical by considering different approaches. Among other important results, it is found that a cylinder cross-section does not affect the thermal instability threshold, but just the linear pattern selection for dilatant and pseudoplastic fluid saturated porous media. A new rheological model is proposed as a solution for singular issues involving the power-law model. Also, a generalised class of one parameter basic solutions is proposed as an alternative description of the isoflux Darcy--Bénard problem. Its stability is investigated
State aid control and the new frontiers of EU tax policy
Get PDFla tesi esamina l’applicazione del controllo sugli aiuti di Stato in materia fiscale tramite la disamina della giurisprudenza della Corte di giustizia. Il lavoro intende fornire una nuova prospettiva di analisi, valorizzando l’interazione tra la nozione di ‘aiuto fiscale’ ex art. 107(1) TFUE e le categorie tributarie nazionali, sottese all’applicazione del “test in tre fasi” coniato dalla Corte per identificare la presenza di un ‘vantaggio selettivo’. Facendo applicazione di tale prospettiva di analisi, la ricerca propone una nuova categorizzazione della ‘selettività fiscale’, tramite la quale vengono affrontate le tematiche più controverse legate all’applicazione dell’istituto. Infine, considerando i numerosi progetti di riforma della fiscalità diretta attualmente al vaglio delle Istituzioni europee, la tesi si confronta con il “futuro” del controllo sugli aiuti di Stato, identificato nella necessaria interazione con una cornice normativa armonizzata.The thesis examines the application of State aid control in fiscal matters through the case law of the Court of Justice. The work aims to provide a new perspective of analysis, enhancing the interaction between the notion of 'fiscal aid' under Article 107(1) TFEU and national tax categories. In doing so, the work focuses on the application of the "three-step test" coined by the Court to identify the presence of a 'selective advantage'. The research proposes a new categorization of 'fiscal selectivity', through which the most controversial issues related to the application of the institution are addressed. Finally, considering the numerous projects of reform of direct taxation currently under consideration by the European institutions, the thesis deals with the "future" of State aid control, identified in the necessary interaction with a harmonized regulatory framework
Optimization and development of low environmental impact propulsion systems
Get PDFThe aim of the Ph.D. research project was to explore Dual Fuel combustion and hybridization. Natural gas-diesel Dual Fuel combustion was experimentally investigated on a 4-Stroke, 2.8 L, turbocharged, light-duty Diesel engine, considering four operating points in the range between low to medium-high loads at 3000 rpm. Then, a numerical analysis was carried out using a customized version of the KIVA-3V code, in order to optimize the diesel injection strategy of the highest investigated load. A second KIVA-3V model was used to analyse the interchangeability between natural gas and biogas on an intermediate operating point. Since natural gas-diesel Dual Fuel combustion suffers from poor combustion efficiency at low loads, the effects of hydrogen enriched natural gas on Dual Fuel combustion were investigated using a validated Ansys Forte model, followed by an optimization of the diesel injection strategy and a sensitivity analysis to the swirl ratio, on the lowest investigated load. Since one of the main issues of Low Temperature Combustion engines is the low power density, 2-Stroke engines, thanks to the double frequency compared to 4-Stroke engines, may be more suitable to operate in Dual Fuel mode. Therefore, the application of gasoline-diesel Dual Fuel combustion to a modern 2-Stroke Diesel engine was analysed, starting from the investigation of gasoline injection and mixture formation. As far as hybridization is concerned, a MATLAB-Simulink model was built to compare a conventional (combustion) and a parallel-hybrid powertrain applied to a Formula SAE race car
Environmental criminal law between individual liability and corporate compliance. Restorative Justice perspectives
Get PDFLo sviluppo della tesi intende analizzare tre tematiche che si ritengono essere cruciali nel ruolo che il diritto penale può avere per tutelare l’ambiente: in primo luogo la focalizzazione delle responsabilità in materia ambientale, tanto della persona fisica quanto della persona giuridica/ente in cui è maturata la violazione, sia essa meramente contravvenzionale, quanto delittuosa, di pericolo o di danno.
In secondo luogo la prevenzione: strutturare sistemi organizzati per cogliere allerte e strutturare metodi organizzati di gestione del rischio-reato è la risposta cui l’ordinamento tende per anticipare la commissione di fattispecie dotate di potenzialità dannose a diffusività esponenziale, anche per il tramite di ipotesi di reati presupposto “sentinella”, idonei a far eventualmente scattare strumenti di prevenzione di reati più gravi, cui le stesse sono, nella prassi, prodromiche.
Da ultimo, la riparazione: l’analisi delle tendenze legislative e, conseguentemente, dottrinali e giurisprudenziali di spazi per percorsi condivisi di riparazione del danno cagionato all’ambiente da parte tanto di persone fisiche quanto (e soprattutto, nell’intendimento del presente lavoro) da parte degli enti, strutture collettive che, ove organizzate, costituiscono le prime realtà a presidio tanto della prevenzione, quanto della riparazione dell’eventuale danno cagionato all’ambiente e spesso verificatosi nell’ambito della propria attività produttiva, ove lo scopo della massimizzazione del profitto deve necessariamente fare i conti, al giorno d’oggi, con la sostenibilità ambientale.The development of the thesis intends to analyze three issues that are crucial in the role that criminal law can issue in protecting the environment: first of all, the work is focused on environmental criminal liabilities, the individual and the corporate one, in which the crime has been produced, in order to check the limits of the Italian system of environmental criminal law related to the Legislative Decree n. 231/2001.
Then, the work focuses on the role of corporate compliance: structuring organized systems to detect alerts and ways to manage the crime-risk is the way in which law tries to anticipate the commission of environmental offenses that are known to have an exponential diffusivity.
The third part of the work focuses on the analysis of the role played by Restorative Justice in environmental crime law: a shared paths of reparation of the damage caused to the environment by both individuals and corporations could be a way to efficiently predict (and prevent) future damages and restore victims that suffered because of that crime