Diels-Alder thermoreversible polymer networks and their nanocomposites

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Ferroptosis and Iron Metabolism in Cancer Growth

Il ferro è un micronutriente essenziale per la vita, ma è anche necessario per sostenere il metabolismo accelerato delle cellule tumorali. Inoltre, l’aumento dei livelli di ferro causa stress ossidativo nelle cellule, promuovendo la perossidazione lipidica e causando morte cellulare per ferroptosi. Perciò, la doppia natura del ferro (essenziale e tossico allo stesso tempo) lo rende un promettente target terapeutico nella lotta al cancro. Considerato ciò, in questa tesi di dottorato abbiamo indagato gli effetti degli induttori di ferroptosi e della chelazione del ferro in due diversi tipi di tumore entrambi poco caratterizzati per il loro metabolismo del ferro e per il meccanismo di ferroptosi: il glioblastoma e il rabdomiosarcoma. Il glioblastoma è il tumore del sistema nervoso centrale più frequente negli adulti, ed è caratterizzato da un’estrema aggressività e da un elevato rischio di recidive, risultanti in una scarsa prognosi dei pazienti. Recentemente, cellule staminali di glioblastoma, note come glioblastoma cancer stem cells (GBM CSCs), sono state identificate come responsabili della ricaduta della malattia. Perciò, abbiamo investigato sull’efficacia degli induttori di ferroptosi nel ridurre la vitalità cellulare delle GBM CSCs. Abbiamo dimostrato che gli induttori di ferroptosi inibiscono potentemente la crescita di linee di GBM CSCs in vitro. Inoltre, abbiamo osservato che gli induttori di ferroptosi aumentano l’efficacia della temozolomide, incoraggiando ulteriori analisi sul meccanismo della ferroptosi nelle GBM CSCs. L’altra tipologia di tumore studiata nel presente lavoro di tesi, in collaborazione con il gruppo di ricerca del Prof. Fanzani (all’Università di Brescia) è il rabdomiosarcoma, un tumore dell’età pediatrica aggressivo e metastatico che si sviluppa da miociti non differenziati. Le terapie attuali contro il RMS includono l’asportazione chirurgica, seguita, dove necessario, da diverse strategie combinate di chemio- e radioterapia; ciononostante, questi trattamenti risultano spesso non curativi. Siccome i chelanti del ferro possono impedire efficacemente la crescita del RMS, abbiamo investigato gli effetti su linee cellulari di RMS del didox, inibitore della ribonucleotide reduttasi con proprietà di chelante del ferro. Abbiamo scoperto che il didox inibisce significativamente la crescita in vitro di linee cellulari di RMS rappresentative dei due sottotipi più frequenti, embrionale e alveolare, riducendo inoltre la loro motilità, la loro clonogenicità e alterando il loro metabolismo del ferro. Inoltre, abbiamo dimostrato che il didox contrasta la crescita in vivo di linee cellulari di RMS alveolare, suggerendo che l’uso di questo inibitore potrebbe essere efficace nel trattamento del rabdomiosarcoma. Inoltre, tra le varie alterazioni molecolari identificate nei RMS, l’overespressione di caveolina 1 (Cav 1) è stata correlata con un aumento della sensibilità di linee cellulari di RMS agli induttori di ferroptosi. Perciò, abbiamo investigato sul meccanismo della ferroptosi in linee cellulari di RMS embrionale overesprimenti Cav 1. Abbiamo dimostrato che queste cellule esprimono livelli alterati di geni e proteine correlati al metabolismo lipidico. Inoltre, abbiamo rilevato, nelle cellule overesprimenti Cav 1, un aumento dei livelli di espressione, sia genica sia proteica, di ACSL4, l’enzima responsabile dell’inserzione nelle membrane cellulari degli acidi grassi polinsaturi. Di conseguenza, abbiamo investigato sul ruolo di ACSL4 nella sensibilità alla ferroptosi di queste cellule. Inibendo sia la sua attività sia la sua espressione, abbiamo scoperto che ACSL4 non sembra direttamente coinvolto nell’aumentata sensibilità alla ferroptosi di queste cellule. In aggiunta, abbiamo dimostrato che la modulazione del contenuto lipidico delle cellule overesprimenti Cav 1 può alterare la loro sensibilità all’induttore di ferroptosi RSL3.Iron is an essential micronutrient for life, but it is also required to sustain the accelerated metabolism of cancer cells. On the other hand, the increased amount of this metal causes cellular oxidative stress, promoting lipid peroxidation and causing ferroptotic cell death. Thus, the double face of iron (essential and toxic at the same time) makes it a promising target to counteract tumor growth. Therefore, in this PhD thesis we investigated the effects of ferroptosis inducers and iron modulation in two different tumor types, poorly characterized for iron metabolism and ferroptosis mechanism: glioblastoma and rhabdomyosarcoma. Glioblastoma (GBM) is the most common tumor of the central nervous system in adults and is characterized by extreme aggressiveness and elevated risk of tumor recurrence, resulting in poor patient prognosis. Recently, stem like GBM cells, named glioblastoma cancer stem cells (GBM CSCs), have been identified responsible for the resistance to current therapies and tumor relapse; therefore, new therapeutic approaches are required. In this context, we investigated whether ferroptosis inducing agents could affect the viability of GBM CSCs. We demonstrated that ferroptosis inducers can potently inhibit the growth of GBM CSC lines. Moreover, we observed that, ferroptosis inducers could increase the efficacy of temozolomide, encouraging further studies for unravelling the mechanism of ferroptosis in GBM CSCs. The other type of tumor studied in the present PhD thesis, in collaboration with Prof. Fanzani’s group (University of Brescia), is rhabdomyosarcoma (RMS), an aggressive and metastatic pediatric cancer that develops from undifferentiated myocytes. Current therapies for RMS include surgical resection followed, when required, by different strategies of aggressive chemotherapy and radiotherapy; these treatments, however, are often not curative thus requiring new therapeutic tools. Recently, since we demonstrated that iron chelators can efficiently impair RMS tumor growth, we investigated the effects on RMS cells of didox, a synthetic inhibitor of the regulatory subunit of ribonucleotide reductase RRM2 with iron chelating properties. We found that didox can effectively inhibit the in vitro growth of RMS cell lines representative of the most frequent subtypes, embryonal (ERMS) and alveolar (ARMS), also altering their motility, their clonogenic capability, and their iron status. Moreover, we demonstrated that didox was able to impair the in vivo growth of ARMS cells, suggesting that the use of this inhibitor could be effective in the treatment of RMS. Additionally, among the many molecular alterations identified in RMS, the overexpression of caveolin 1 (Cav 1) has been demonstrated to correlate with an increased sensitivity of RMS cells to ferroptosis inducers. Therefore, we investigated the mechanism of ferroptosis in Cav 1 overexpressing ERMS cells, with a particular focus on the alterations on lipid metabolism in these cells. We demonstrated that RMS cells that overexpressed Cav 1 are characterized by an altered expression of various lipid metabolism related genes and proteins. Interestingly, we found that Cav 1 overexpressing cells showed increased expression of both mRNA and protein level of long chain fatty acid CoA ligase 4 (ACSL4), the enzyme responsible for the insertion in the cell membrane of polyunsaturated fatty acids (PUFAs). Thus, we investigated the role of ACSL4 in the ferroptosis sensitivity of these cells, finding that ACSL4 seems not directly involved in the increased susceptibility to ferroptosis of these cells. Moreover, we found that the modulation of lipid content of Cav 1 overexpressing cells can alter their sensitivity to ferroptosis inducer RSL3: the treatment in combination with PUFAs further decrease the cell sensitivity to RSL3, whereas the combination with MUFAs protected the cells to RSL3-induced ferroptosis

Unpacking the innovation toolbox for design research and practice

The terms design and innovation are intuitively related, but the relationship between these two concepts is more complex and subtle than it appears at first sight. Few authors have made rigorous attempts to explore this relationship in depth, and the contributions present in the literature generally suffer the specialist backgrounds on which they are grounded. Consequently, this paper provides a high-level synthesis of the innovation management domain and defines an original framework that allows the positioning of the concepts from Innovation Management that are most relevant for scholars and practitioners operating in the Design domain. Specifically, this framework provides a concise representation of the typologies of innovation activities along the technology lifecycle, and associates them to their business implications and to technical and organizational implications on the design process. This framework allows scholars and practitioners from both fields to identify the typical design challenges that are inherent to each type of innovation activity, and to evaluate the suitability of specific support methods and tools

Tackling the Design of Platform-Based Service Systems, Integrating Data and Cultures: The Case of Urban Markets

Different design traditions address the design of services. When adopted alone, they can limit design, especially if services systems are complex. Some combinations among service design traditions are theorized in the literature and a cultural synthesis is considered a priority. This paper discusses a practical application of that synthesis: systematic/data-driven methods from engineering and service innovation are applied within a participatory and transformative environment. Intangible versus material and functional versus experience service elements are considered. The case study on urban markets shows that economics and the transactional/functional mechanics of a service system must be understood for proper design actions, and that overcoming separations between strands of literature is necessary to achieve this aim. Moreover, since urban markets are two-sided platforms in a physical setting, the study allows easier investigation than in modern digital platforms regarding how platform economics affect the design of a service system, providing insights for digital services as well. Originality is due to generally scant contributions on urban market design, since markets are often regulated, rather than designed, beyond the rare practical attempts of cultural synthesis

CHRONOBIOLOGY IN DIVERGENT THINKING: HOW DESIGNERS ARE AFFECTED BY TIME OF DAY

Chronobiology is the science that studies the role of time in biology. The study of time in human bodies revealed the presence of internal rhythms related to the time of day. Considering divergent thinking as one of the essential cognitive activities of conceptual design, this paper presents the results of investigating the effect of time of day on designers’ brain activity while performing divergent thinking tasks. An experiment was run with a revised Alternative Uses Task, measuring brain activity with an electroencephalogram (EEG) device. Students with different educational backgrounds were recruited for this experiment, including engineering and industrial design students, to determine if the time of day affected them differently. The brain waves and related power results show significant differences with respect to the time of day and educational background. The differences are particularly evident considering the interaction of these factors. Further studies are required to understand the relationship between the differences detected and the designers’ behavioral performance and to identify which time of day is most effective for idea-generation activities for designers

Phytodepuration of Pyroligneous Liquor: A Case Study

Wastewaters generated by the pyrolytic process require treatments to reduce the risks of contamination in rivers, lakes, and coastal waters. Utilizing constructed wetlands is one of the possible approaches according to a Circular Economy System. Plant Growth-Promoting Bacteria (PGPB) and Arbuscular Mycorrhizal Fungi (AMF) can improve plant growth and enhance the bioremediation of wastewater. Two experiments were set up: in the first, a pilot mesocosm was designed to evaluate the effects of a consortium of AM fungi and a PGPB strain on Phragmites australis. After 60 days, the highest plant growth was obtained after inoculation with the combination of microorganisms. In the second experiment, a constructed wetland was built to remediate wastewaters from gasification plant. The plants were efficient in scavenging biological oxygen demand (BOD5), chemical oxygen demand (COD), total fat and oils, hydrocarbons, phenols, aldehydes, surfactants, fluorides, sulfites, sulfates, nitrate, and phosphorus. These data suggest that inoculation of P. australis with AMF and PGPB strains significantly improve the depuration process of wastewaters from gasification plants via constructed wetlands

Star-shaped furoate-PCL: An effective compound for the development of graphite nanoplatelets-based films

The aim of this study was to improve the dispersibility of graphite nanoplatelets (GNP) in films based on poly(ε-caprolactone) (PCL). To this end, a star-shaped PCL with furoate-like end groups (PCL-Fur), potentially capable of interacting/reacting with the surface of the graphene layers through Diels-Alder reactions, was synthesized by enzymatic catalysis. PCL-Fur was applied for film development by blending it with a commercial high molecular weight PCL (PCL-L) and GNP. The reactivity of GNP with respect to furoate groups was demonstrated by studying the thermal behavior of the GNP/methyl 2-furoate system, while the dispersibility of graphite in the solution containing PCL-Fur was studied by UV–Vis measurements. GNP proved to be well dispersed and adhered to the polymer matrix in the PCL-L/PCL-Fur/GNP composite films prepared by casting, in contrast to the films based on the neat PCL-L. This fine GNP dispersion resulted in films characterized by high electrical conductivity

Phytoremediation of a highly arsenic polluted site, using pteris vittata L. And arbuscular mycorrhizal fungi

Phytoremediation is a promising green technique for the restoration of a polluted environment, but there is often a gap between lab and field experiments. The fern, Pteris vittata L., can tolerate a high soil arsenic concentration and rapidly accumulate the metalloid in its fronds. Arbuscular mycorrhizal fungi (AMF) are mutualistic fungi that form a symbiosis with most land plants\u2019 roots, improve their growth, and induce stress tolerance. This paper reports the results obtained using P. vittata inoculated with AMF, to extract Arsenic (As) from an industrial site highly contaminated also by other pollutants. Two experiments have been performed. In the first one, AMF colonized ferns were grown for two years under controlled conditions in soil coming from the metallurgic site. Positive effects on plant health and As phytoextraction and accumulation were detected. Then, considering these results, we performed a three year in situ experiment in the industrial site, to assess the remediation of As at two different depths. Our results show that the colonization of P. vittata with AMF improved the remediation process of As with a significant impact on the depth 0\u20130.2 m

Sensitivity analysis of dynamic cell formation problem through meta-heuristic

In spite of many researches in literature investigating dynamic of cell formation (CF) problem, further research needs to be elaborated to assay hidden aspects of cellular manufacturing system (CMS), due to inherent complexity and uncertainty on optimizing this problem. In this paper, sensitivity analysis of modified self-adaptive differential evolution (MSDE) algorithm is proposed for basic parameters of CF problem, considering to the graphical representation supported by statistical analysis. Hence, a dynamic integer model of CF problem is first presented as the NP-hard problem. Then, the two basic test CF problems are introduced thereby the performance of MSDE algorithm assessed by diverse problems sizes through 140 runs from aspects of the average runtime of algorithm and the best local optimum objective function. Finally, statistical analysis is implemented on behavior of objective function values in order to validate our computational results graphically as well as statistically, giving some insights related to importance of CF parameters on designing CMS

Data-driven design: the new challenges of digitalization on product design and development

Abstract Digitalization and the momentous role being assumed by data are commonly viewed as pervasive phenomena whose impact is felt in all aspects of society and the economy. Design activity is by no means immune from this trend, and the relationship between digitalization and design is decades old. However, what is the current impact of this 'data revolution' on design? How will the design activity change? What are the resulting research questions of interest to academics? What are the main challenges for firms and for educational institutions having to cope with this change? The paper provides a comprehensive conceptual framework, based on recent literature and anecdotal evidence from the industry. It identifies three main streams: namely the consequences on designers, the consequences on design processes and the role of methods for data analytics. In turn, these three streams lead to implications at individual, organizational and managerial level, and several questions arise worthy of defining future research agendas. Moreover, the paper introduces relational diagrams depicting the interactions between the objects and the actors involved in the design process and suggests that what is occurring is by no means a simple evolution but a paradigmatic shift in the way artefacts are designed