Letteratura e realia. Le espressioni culturo-specifiche nelle traduzioni italiane della Wendeliteratur

Il presente lavoro affronta il problema della traduzione dei termini culturo-specifici nella letteratura contemporanea di lingua tedesca ambientata nella DDR. L’analisi della produzione narrativa della Wendeliteratur consente di osservare come il lessico e le espressioni tipiche della DDR vengano utilizzati nelle opere letterarie in funzione citazionale per denotare e connotare la realtà della Germania dell’Est. Attraverso un approccio integrato che coniuga i contributi teorici degli studi sulla traduzione con gli aspetti della pratica traduttiva il lavoro indaga il tema dei realia attraverso una presentazione delle ricerche esistenti, propone una classificazione specifica per i realia della DDR e procede a una ricognizione delle strategie e dei procedimenti traduttivi concreti, che consente di evidenziare le diverse scelte adottate dai traduttori. Attraverso un’analisi ermeneutica dei testi e lo strumento dell’isotopia come indicatore di coerenza le traduzioni italiane delle opere della Wendeliteratur sono oggetto di un’analisi critica. I risultati dell’analisi vengono infine utilizzati come riferimento per la traduzione dei realia nel racconto di F.C. Delius, Die Birnen von Ribbeck.

Evaluation and management of demersal stocks in the Adriatic: the case of common sole (Solea solea, L.) in the northern and central Adriatic Sea

This PhD thesis aimed to assess the status of common sole, one of the main commercial stocks in the Adriatic Sea, using a mix of conventional and innovative techniques to provide more reliable estimates of stock status compared to past advice. First, a meta-analysis was carried out using data-poor assessment model to analyze the whole catch assemblage of rapido fishery. The outcomes were used to estimate rebuilding time and forecast catches under different harvest control rule scenarios, with a reduction of 20% of fishing effort being suggested as a way to allow most of the species to recover to sustainable levels. Secondly, an ensemble of data-rich assessment models was developed to better incorporate uncertainty by using alternative hypotheses of main parameters. This was the first time an ensemble of models has been used in the Mediterranean to provide management advice. Consistent with data-poor analysis results, the ensemble outcomes indicated that the common sole stock was showing a recovering trend probably due to the effective management actions underway in the area rather than the moderate effort reduction according to the actual management plan. Moreover, back-calculation measurements were used to fit and compare monophasic and biphasic growth curves through the use of non-linear mixed effects models. The analyses revealed that the fitting of the biphasic curve was superior, confirming the theory that growth in size would decrease as a consequence of reproductive effort. A stock assessment simulation showed how the use of the monophasic pattern would result in a critical overestimation of biomass that could lead to a greater risk of overfishing. As a final step, a simulation-testing procedure was applied to determine the best performing reference points using stock-specific characteristic. The procedure could be routinely adopted to increase transparency in reference points calculation enhancing the credibility of scientific advice.

New Synthetic Polyamines as Multi-Target-Directed Ligands for the Treatment of Alzheimer's Disease and Cancer: Design, Synthesis and Biological Evaluation

Alzheimer's disease (AD) and cancer represent two of the main causes of death worldwide. They are complex multifactorial diseases and several biochemical targets have been recognized to play a fundamental role in their development. Basing on their complex nature, a promising therapeutical approach could be represented by the so-called "Multi-Target-Directed Ligand" approach. This new strategy is based on the assumption that a single molecule could hit several targets responsible for the onset and/or progression of the pathology. In particular in AD, most currently prescribed drugs aim to increase the level of acetylcholine in the brain by inhibiting the enzyme acetylcholinesterase (AChE). However, clinical experience shows that AChE inhibition is a palliative treatment, and the simple modulation of a single target does not address AD aetiology. Research into newer and more potent anti-AD agents is thus focused on compounds whose properties go beyond AChE inhibition (such as inhibition of the enzyme β-secretase and inhibition of the aggregation of beta-amyloid). Therefore, the MTDL strategy seems a more appropriate approach for addressing the complexity of AD and may provide new drugs for tackling its multifactorial nature. In this thesis, it is described the design of new MTDLs able to tackle the multifactorial nature of AD. Such new MTDLs designed are less flexible analogues of Caproctamine, one of the first MTDL owing biological properties useful for the AD treatment. These new compounds are able to inhibit the enzymes AChE, beta-secretase and to inhibit both AChE-induced and self-induced beta-amyloid aggregation. In particular, the most potent compound of the series is able to inhibit AChE in subnanomolar range, to inhibit β-secretase in micromolar concentration and to inhibit both AChE-induced and self-induced beta-amyloid aggregation in micromolar concentration. Cancer, as AD, is a very complex pathology and many different therapeutical approaches are currently use for the treatment of such pathology. However, due to its multifactorial nature the MTDL approach could be, in principle, apply also to this pathology. Aim of this thesis has been the development of new molecules owing different structural motifs able to simultaneously interact with some of the multitude of targets responsible for the pathology. The designed compounds displayed cytotoxic activity in different cancer cell lines. In particular, the most potent compounds of the series have been further evaluated and they were able to bind DNA resulting 100-fold more potent than the reference compound Mitonafide. Furthermore, these compounds were able to trigger apoptosis through caspases activation and to inhibit PIN1 (preliminary result). This last protein is a very promising target because it is overexpressed in many human cancers, it functions as critical catalyst for multiple oncogenic pathways and in several cancer cell lines depletion of PIN1 determines arrest of mitosis followed by apoptosis induction. In conclusion, this study may represent a promising starting pint for the development of new MTDLs hopefully useful for cancer and AD treatment.

Controllo molecolare del differenziamento osteoblestico per applicazioni nel campo della rigenerazione del tessuto osseo

The aim of the study was to identify expression signatures unique for specific stages of osteoblast differentiation in order to improve our knowledge of the molecular mechanisms underlying bone repair and regeneration. We performed a microarray analysis on the whole transcriptome of human mesenchymal stem cells (hMSCs) obtained from the femoral canal of patients undergoing hip replacement. By defining different time-points within the differentiation and mineralization phases of hMSCs, temporal gene expression changes were visualised. Importantly, the gene expression of adherent bone marrow mononuclear cells, being the undifferentiated progenitors of bone cells, was used as reference. In addition, only the cultures able to form mineral nodules at the final time-point were considered for the gene expression analyses. To obtain the genes of our interest, we only focused on genes: i) whose expression was significantly upregulated; ii) which are involved in pathways or biological processes relevant to proliferation, differentiation and functions of bone cells; iii) which changed considerably during the different steps of differentiation and/or mineralization. Among the 213 genes identified as differentially expressed by microarray analysis, we selected 65 molecular markers related to specific steps of osteogenic differentiation. These markers are grouped into various gene clusters according to their involvement in processes which play a key role in bone cell biology such as angiogenesis, ossification, cell communication, development and in pathways like TGF beta and Wnt signaling pathways. Taken together, these results allow us to monitor hMSC cultures and to distinguish between different stages of differentiation and mineralization. The signatures represent a useful tool to analyse a broad spectrum of functions of hMSCs cultured on scaffolds, especially when the constructs are conceived for releasing growth factors or other signals to promote bone regeneration. Morover, this work will enhance our understanding of bone development and will enable us to recognize molecular defects that compromise normal bone function as occurs in pathological conditions.

“Clinical and biological role of adjuvant dendritic cells vaccination in newly glioblastoma patients”

Background. Glioblastoma (GBM) is the most common primary tumor of central nervous system and it has a poor prognosis. Standard first line treatment, which includes surgery followed by adjuvant radio-chemotherapy,produces only modest benefits to survival. The interest for immunotherapy in this field derives from the development of new drugs and effective therapies as immune-check points inhibitors, adoptive T-cell approaches or dendritic cell (DC) based vaccines or a combinations of these. GBM is described as a typical “immune-deserted” cancer exhibiting a number of systemic and environmental immunosuppressive factors. Considering the role of microenvironment, and above all the lower tumor load and depletion of immunosuppressive cells in GBM, our hypothesis is that DC vaccine may induce an immune response. Main aims and study design. The main aim of this project is to study the role of immune system in GBM, including identification of potential prognostic and predictive markers of outcome and response to dendritic cell vaccine. Firstly, we performed a retrospective analysis on blood samples. Then, we analyzed the immuno-component in tissues samples of enrolled patients; and compared that with blood results. Then, the last part of the project is based on a prospective clinical trial on patients enrolled in DC-based vaccination produced at IRST Cell Factory and actually used for patients with melanoma and other tumors. The enrollment is still ongoing. Expected results. The project will i) develop an immune-panel of prognostic and predictive markers to help clinicians to improve the therapeutic strategy for GBM patients; ii) provide preliminary results on the effectiveness of immunotherapy on GBM patients.