1,720,983 research outputs found
Targeting BMI-1 as an innovative approach to overcome cancer multi drug resistance
No full textAging is among the major risk factors for the development of cancer and the main cause of cancer relapse and therapeutic failure is due to the onset of chemoresistance. Since many anticancer therapies cause cell death by inducing oxidative stress, one of the mechanisms activated by cancer cells to adapt and survive to the cytotoxic effect of therapeutic agents, is to stimulate the antioxidant defense.
In this regard, previous studies from the research group of my PhD tutor, showed that chronic exposure of cancer cells (HTLA-230) to the chemotherapeutic drug etoposide, at a dose comparable to that used in clinic, leads to the selection of a resistant cell line (HTLA-ER). Interestingly, resistant cells are characterized by efficient oxidative metabolism, display high amounts of glutathione (GSH) and overexpress the oncogenic protein BMI-1, which is capable of regulating GSH levels and is associated with cancer stemness, epithelial-mesenchymal transition (EMT), tumor invasion, metastasis and poor prognosis. Notably, both cell lines exhibit the same p53 mutation and no changes in the expression of MDM2, the endogenous inhibitor of p53.
Based on this background, the aim of this thesis is to investigate new strategies that can circumvent cancer chemoresistance, mainly by reducing intracellular GSH content and reactivating mutated p53.
Therefore, the effects of sulfasalazine, an xCT inhibitor, of PRIMA-1MET, a compound able to reactivate p53 functions, and of PTC596, a novel BMI-1 inhibitor, were investigated.
Firstly, it has been confirmed that HTLA-ER cells are multidrug-resistant, being unaffected by the cytotoxic effects of different chemotherapeutic drugs, and not only by etoposide.
Then, it has been found that PRIMA-1MET promotes apoptosis only in parental cells, whereas PTC596 does not trigger apoptosis in both cell populations. In addition, PRIMA-1MET and PTC596 inhibited the clonogenic potential of parental and resistant cells. Since sulfasalazine alone or combined was not effective on resistant cells it was excluded from the subsequent experiments. The evaluation of the expression of p53 and BMI-1, target proteins of the two tested drugs, showed that PRIMA-1MET does not modulate p53 protein levels, while PTC596 is able to significantly reduce the expression of BMI-1. Furthermore, given that EMT is involved in chemoresistance, EMT-related proteins were evaluated. In detail, PRIMA-1MET and, most importantly, PTC596 reduced the expression of n-cadherin, b-catenin and SNAIL, demonstrating an inhibition of EMT process. In addition, both compounds prevented the formation of cancer stem cells. Analysis of cellular redox state showed that treatments with PRIMA-1MET of parental cells and with PTC596 of both cell lines induced overproduction of reactive oxygen species and increased membrane lipid peroxidation. With regard to antioxidant response, it has been observed that i) resistant cells expressed a double GSH amount compared to that of parental cells and ii) PRIMA-1MET and, more markedly, PTC596 were able to deplete the thiol antioxidant content.
These promising findings certainly demonstrate the involvement of cellular redox state in chemoresistance, and suggest that PTC596, the most effective compound in resistant cells, can induce ferroptosis, a cell death characterized by membrane lipid peroxidation and reduction of GSH levels.
In fact, the co-treatment of PTC596 with compounds capable of inducing or inhibiting ferroptosis, confirmed the induction of this type of cell death. Therefore, an approach targeting BMI-1 and its related pathways could be a winning strategy to overcome cancer resistance to therapy
Le pensioni e la transizione verde: nuove disuguaglianze e ulteriori sfide per l’adeguatezza e la sostenibilità della previdenza
No full textPensions policy in Europe has gone through a long reform process in the last decades. Reforms have mainly addressed the consequences of population aging. Yet in the last years, policymakers have started to focus on new socio-economic challenges, for example those related to the so-called Green Transition – the transition to a neutral economic system with low carbon emissions. The same challenges are expected to be at the core of pension reforms in the future because of the projected impact on pension systems’ sustainability and adequacy. The present article proposes – through a forward-looking approach – the review of the expected impact of the Green Transition on pension policy. The article has a three-fold goal. The first is to review the main effects of the ecological transition on economic growth, labor markets and financial markets. Second, the article sheds light on the expected effects on the long-term viability of pensions and the
future reform strategies to address them. Third, the article proposes the reflection on future reform strategies.seful passpartout to give new communicative polish to a segmented archipelago of local and short-term micro-projects. The essay discusses some conditions that would allow interventions to combat juvenile educational poverty to be a real opportunity to rethink welfare strategies in an innovative way
Pensions and the green transition: policy and political issues at stake
No full textPension policy has gone through an intense period of reform over the past few decades. However, further changes are likely to take place in the near future. Major global trends, not only population ageing but also globalisation, technological innovation and climate change, are going to shape socio-economic and labour organisation and influence macroeconomic trends and will thus have an impact on the adequacy and long-term sustainability of pension policy. This paper focuses on the challenges of the green transition for pensions. We first examine its possible effects on economic growth and productivity, labour markets and the financial sector. We then investigate the potential consequences of the future ecological transition on the financing of old-age protection, future benefits and their adequacy, and the changing role of trade unions in approaching the complex dilemma of supporting the green transition on the one hand, while defending the short-term interests of their rank and file (in terms of tax, labour market and social policies) on the other
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Antimicrobial Peptides and Cationic Nanoparticles: A Broad-Spectrum Weapon to Fight Multi-Drug Resistance Not Only in Bacteria
No full textIn the last few years, antibiotic resistance and, analogously, anticancer drug resistance have increased considerably, becoming one of the main public health problems. For this reason, it is crucial to find therapeutic strategies able to counteract the onset of multi-drug resistance (MDR). In this review, a critical overview of the innovative tools available today to fight MDR is reported. In this direction, the use of membrane-disruptive peptides/peptidomimetics (MDPs), such as antimicrobial peptides (AMPs), has received particular attention, due to their high selectivity and to their limited side effects. Moreover, similarities between bacteria and cancer cells are herein reported and the hypothesis of the possible use of AMPs also in anticancer therapies is discussed. However, it is important to take into account the limitations that could negatively impact clinical application and, in particular, the need for an efficient delivery system. In this regard, the use of nanoparticles (NPs) is proposed as a potential strategy to improve therapy; moreover, among polymeric NPs, cationic ones are emerging as promising tools able to fight the onset of MDR both in bacteria and in cancer cells
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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