Ruolo dell'Enantiomero (R)-9-HSA nel controllo della proliferazione in una linea di Adenocarcinoma del Colon umano

9-hydroxystearic acid (9-HSA) is an endogenous lipoperoxidation product and its administration to HT29, a colon adenocarcinoma cell line, induced a proliferative arrest in G0/G1 phase mediated by a direct activation of the p21WAF1 gene, bypassing p53. We have previously shown that 9-HSA controls cell growth and differentiation by inhibiting histone deacetylase 1 (HDAC1) activity, showing interesting features as a new anticancer drug. The interaction of 9-HSA with the catalytic site of the 3D model has been tested with a docking procedure: noticeably, when interacting with the site, the (R)-9-enantiomer is more stable than the (S) one. Thus, in this study, (R)- and (S)-9-HSA were synthesized and their biological activity tested in HT29 cells. At the concentration of 50 M (R)-9-HSA showed a stronger antiproliferative effect than the (S) isomer, as indicated by the growth arrest in G0/G1. The inhibitory effect of (S)-9-HSA on HDAC1, HDAC2 and HDAC3 activity was less effective than that of the (R)-9-HSA in vitro, and the inhibitory activity of both the (R)- and the (S)-9-HSA isomer, was higher on HDAC1 compared to HDAC2 and HDAC3, thus demonstrating the stereospecific and selective interaction of 9-HSA with HDAC1. In addition, histone hyperacetylation caused by 9-HSA treatment was examined by an innovative HPLC/ESI/MS method. Analysis on histones isolated from control and treated HT29 confirmed the higher potency of (R)-9-HSA compared to (S)-9-HSA, severely affecting H2A-2 and H4 acetylation. On the other side, it seemed of interest to determine whether the G0/G1 arrest of HT29 cell proliferation could be bypassed by the stimulation with the growth factor EGF. Our results showed that 9-HSA-treated cells were not only prevented from proliferating, but also showed a decreased [3H]thymidine incorporation after EGF stimulation. In this condition, HT29 cells expressed very low levels of cyclin D1, that didn’t colocalize with HDAC1. These results suggested that the cyclin D1/HDAC1 complex is required for proliferation. Furthermore, in the effort of understanding the possible mechanisms of this effect, we have analyzed the degree of internalization of the EGF/EGFR complex and its interactions with HDAC1. EGF/EGFR/HDAC1 complex quantitatively increases in 9-HSA-treated cells but not in serum starved cells after EGF stimulation. Our data suggested that 9-HSA interaction with the catalytic site of the HDAC1 disrupts the HDAC1/cyclin D1 complex and favors EGF/EGFR recruitment by HDAC1, thus enhancing 9-HSA antiproliferative effects. In conclusion 9-HSA is a promising HDAC inhibitor with high selectivity and specificity, capable of inducing cell cycle arrest and histone hyperacetylation, but also able to modulate HDAC1 protein interaction. All these aspects may contribute to the potency of this new antitumor agent.

Biomeccanica del servizio e del diritto nel tennis: confronto fra atleti di livello di gioco differente

Il tennis è uno sport molto diffuso che negli ultimi trent’anni ha subito molti cambiamenti. Con l’avvento di nuovi materiali più leggeri e maneggevoli la velocità della palla è aumentata notevolmente, rendendo così necessario una modifica a livello tecnico dei colpi fondamentali. Dalla ricerca bibliografica sono emerse interessanti indicazioni su angoli e posizioni corporee ideali da mantenere durante le varie fasi dei colpi, confrontando i giocatori di altissimo livello. Non vi sono invece indicazioni per i maestri di tennis su quali siano i parametri più importanti da allenare a seconda del livello di gioco del proprio atleta. Lo scopo di questa tesi è quello di individuare quali siano le variabili tecniche che influenzano i colpi del diritto e del servizio confrontando atleti di genere differente, giocatori di livello di gioco diverso (esperti, intermedi, principianti) e dopo un anno di attività programmata. Confrontando giocatori adulti di genere diverso, è emerso che le principali differenze sono legate alle variabili di prestazione (velocità della palla e della racchetta) per entrambi i colpi. Questi dati sono simili a quelli riscontrati nel test del lancio della palla, un gesto non influenzato dalla tecnica del colpo. Le differenze tecniche di genere sono poco rilevanti ed attribuibili alla diversa interpretazione dei soggetti. Nel confronto di atleti di vario livello di gioco le variabili di prestazione presentano evidenti differenze, che possono essere messe in relazione con alcune differenze tecniche rilevate nei gesti specifici. Nel servizio i principianti tendono a direzionare l’arto superiore dominante verso la zona bersaglio, abducendo maggiormente la spalla ed avendo il centro della racchetta più a destra rispetto al polso. Inoltre, effettuano un caricamento minore degli arti inferiori, del tronco e del gomito. Per quanto riguarda il diritto si possono evidenziare queste differenze: l’arto superiore è sempre maggiormente esteso per il gruppo dei principianti; il tronco, nei giocatori più abili viene utilizzato in maniera più marcata, durante la fase di caricamento, in movimenti di torsione e di inclinazione laterale. Gli altri due gruppi hanno maggior difficoltà nell’eseguire queste azioni preparatorie, in particolare gli atleti principianti. Dopo un anno di attività programmata sono stati evidenziati miglioramenti prestativi. Anche dal punto di vista tecnico sono state notate delle differenze che possono spiegare il miglioramento della performance nei colpi. Nel servizio l’arto superiore si estende maggiormente per colpire la palla più in alto possibile. Nel diritto sono da sottolineare soprattutto i miglioramenti dei movimenti del tronco in torsione ed in inclinazione laterale. Quindi l’atleta si avvicina progressivamente ad un’esecuzione tecnica corretta. In conclusione, dal punto di vista tecnico non sono state rilevate grosse differenze tra i due generi che possano spiegare le differenze di performance. Perciò questa è legata più ad un fattore di forza che dovrà essere allenata con un programma specifico. Nel confronto fra i vari livelli di gioco e gli effetti di un anno di pratica si possono individuare variabili tecniche che mostrano differenze significative tra i gruppi sperimentali. Gli evoluti utilizzano tutto il corpo per effettuare dei colpi più potenti, utilizzando in maniera tecnicamente più valida gli arti inferiori, il tronco e l’arto superiore. I principianti utilizzano prevalentemente l’arto superiore con contributi meno evidenti degli altri segmenti. Dopo un anno di attività i soggetti esaminati hanno dimostrato di saper utilizzare meglio il tronco e l’arto superiore e ciò può spiegare il miglioramento della performance. Si può ipotizzare che, per il corretto utilizzo degli arti inferiori, sia necessario un tempo più lungo di apprendimento oppure un allenamento più specifico.

I sensi spirituali nel Liber di Angela da Foligno. La metafora del "gusto" nel Liber di Angela da Foligno e nella mistica femminile francescana tra XIII e XIV secolo.

Angela da Foligno’s Liber is a fundamental text for the scholar of Women Mystics between the XIIIth and the XIVth century in Italy and all over Europe, and it has been chosen in my research because of its originality, with refer of its feminine and franciscan essence. Angela teaches to the italian hagiographic tradition the internal point of view of the holy woman, who becomes the teller of her both ordinary and extraordinary experiences. After giving references about the religious and social historical universe in evolution during the XIIth century, my research proceeds with a linguistic and rhetorical analysis based upon the Liber. I have been searching in Angela’s text and in contemporary italian feminine hagiography the sensory metaphor of “tasting”. That kind of metaphor has an ancient memory and, thanks to the Origene’s studies - the Christian Father of the IIIrd century - we can easily recognize it already in the Bible; Origene identifies the sensory metaphor as a rhetoric system, able to exemplify the God learning process of soul. Theory of “spiritual senses”, theory of vision and rhetoric, evolving from the IIIrd to the XIIIth century, are the theological and linguistic heritage of our feminine and franciscan literature. Inside of that, the metaphor of “tasting” moves and changes, therefore becoming the favourite way of mystics to represent the contact of their souls with God.

Scienza, Tecnica, Politica: Il Problema del Metodo nel Pensiero di Jacopo Aconcio

The aim of this PhD thesis is to study accurately and in depth the figure and the literary production of the intellectual Jacopo Aconcio. This minor author of the 16th century has long been considered a sort of “enigmatic character”, a profile which results from the work of those who, for many centuries, have left his writing to its fate: a story of constant re-readings and equally incessant oversights. This is why it is necessary to re-read Aconcio’s production in its entirety and to devote to it a monographic study. Previous scholars’ interpretations will obviously be considered, but at the same time an effort will be made to go beyond them through the analysis of both published and manuscript sources, in the attempt to attain a deeper understanding of the figure of this man, who was a Christian, a military and hydraulic engineer and a political philosopher,. The title of the thesis was chosen to emphasise how, throughout the three years of the doctorate, my research concentrated in equal measure and with the same degree of importance on all the reflections and activities of Jacopo Aconcio. My object, in fact, was to establish how and to what extent the methodological thinking of the intellectual found application in, and at the same time guided, his theoretical and practical production. I did not mention in the title the author’s religious thinking, which has always been considered by everyone the most original and interesting element of his production, because religion, from the Reformation onwards, was primarily a political question and thus it was treated by almost all the authors involved in the Protestant movement - Aconcio in the first place. Even the remarks concerning the private, intimate sphere of faith have therefore been analysed in this light: only by acknowledging the centrality of the “problem of politics” in Aconcio’s theories, in fact, is it possible to interpret them correctly. This approach proves the truth of the theoretical premise to my research, that is to say the unity and orderliness of the author’s thought: in every field of knowledge, Aconcio applies the rules of the methodus resolutiva, as a means to achieve knowledge and elaborate models of pacific cohabitation in society. Aconcio’s continuous references to method can make his writing pedant and rather complex, but at the same time they allow for a consistent and valid analysis of different disciplines. I have not considered the fact that most of his reflections appear to our eyes as strongly conditioned by the time in which he lived as a limit. To see in him, as some have done, the forerunner of Descartes’ methodological discourse or, conversely, to judge his religious theories as not very modern, is to force the thought of an author who was first and foremost a Christian man of his own time. Aconcio repeats this himself several times in his writings: he wants to provide individuals with the necessary tools to reach a full-fledged scientific knowledge in the various fields, and also to enable them to seek truth incessantly in the religious domain, which is the duty of every human being. The will to find rules, instruments, effective solutions characterizes the whole of the author’s corpus: Aconcio feels he must look for truth in all the arts, aware as he is that anything can become science as long as it is analysed with method. Nevertheless, he remains a man of his own time, a Christian convinced of the existence of God, creator and governor of the world, to whom people must account for their own actions. To neglect this fact in order to construct a “character”, a generic forerunner, but not participant, of whatever philosophical current, is a dangerous and sidetracking operation. In this study, I have highlighted how Aconcio’s arguments only reveal their full meaning when read in the context in which they were born, without depriving them of their originality but also without charging them with meanings they do not possess. Through a historical-doctrinal approach, I have tried to analyse the complex web of theories and events which constitute the substratum of Aconcio’s reflection, in order to trace the correct relations between texts and contexts. The thesis is therefore organised in six chapters, dedicated respectively to Aconcio’s biography, to the methodological question, to the author’s engineering activity, to his historical knowledge and to his religious thinking, followed by a last section concerning his fortune throughout the centuries. The above-mentioned complexity is determined by the special historical moment in which the author lived. On the one hand, thanks to the new union between science and technique, the 16th century produces discoveries and inventions which make available a previously unthinkable number of notions and lead to a “revolution” in the way of studying and teaching the different subjects, which, by producing a new form of intellectual, involved in politics but also aware of scientific-technological issues, will contribute to the subsequent birth of modern science. On the other, the 16th century is ravaged by religious conflicts, which shatter the unity of the Christian world and generate theological-political disputes which will inform the history of European states for many decades. My aim is to show how Aconcio’s multifarious activity is the conscious fruit of this historical and religious situation, as well as the attempt of an answer to the request of a new kind of engagement on the intellectual’s behalf. Plunged in the discussions around methodus, employed in the most important European courts, involved in the abrupt acceleration of technical-scientific activities, and especially concerned by the radical religious reformation brought on by the Protestant movement, Jacopo Aconcio reflects this complex conjunction in his writings, without lacking in order and consistency, differently from what many scholars assume. The object of this work, therefore, is to highlight the unity of the author’s thought, in which science, technique, faith and politics are woven into a combination which, although it may appear illogical and confused, is actually tidy and methodical, and therefore in agreement with Aconcio’s own intentions and with the specific characters of European culture in the Renaissance. This theory is confirmed by the reading of the Ars muniendorum oppidorum, Aconcio’s only work which had been up till now unavailable. I am persuaded that only a methodical reading of Aconcio’s works, without forgetting nor glorifying any single one, respects the author’s will. From De methodo (1558) onwards, all his writings are summae, guides for the reader who wishes to approach the study of the various disciplines. Undoubtedly, Satan’s Stratagems (1565) is something more, not only because of its length, but because it deals with the author’s main interest: the celebration of doubt and debate as bases on which to build religious tolerance, which is the best method for pacific cohabitation in society. This, however, does not justify the total centrality which the Stratagems have enjoyed for centuries, at the expense of a proper understanding of the author’s will to offer examples of methodological rigour in all sciences. Maybe it is precisely because of the reforming power of Aconcio’s thought that, albeit often forgotten throughout the centuries, he has never ceased to reappear and continues to draw attention, both as a man and as an author. His ideas never stop stimulating the reader’s curiosity and this may ultimately be the best demonstration of their worth, independently from the historical moment in which they come back to the surface.

Chortheater. Genesi di un modello Tipologie corali nel Novecento

In the Nineties year in the German Studies’ area appears a new reflection around the theatrical chorus thank to the activity of theatrical personalities as Heiner Müller, Einar Schleef, Elfriede Jelinek or Christoph Marthaler. So Hans Thies Lehmann, in his compendium about the Postdramatic Theater (Hans-Thies Lehmann, Postdramatisches Theater, Verlag der Autoren, Frankfurt am Main 1999) advances the new category of the Chortheater (Chor Theatre) to explain e new form of drama and performative event; again in 1999 appear the important essay of Detlev Baur (Detlev Baur, Der Chor im Theater des 20. Jahrhunderts. Typologie des theatralen Mittels Chor, Niemeyer, Tübingen 1999), that gives an important device about this instrument but without giving the reasons of the its modifications in such different historical times. Then in 2004, Erika Fischer-Lichte, (Theatre, Sacrifice, Ritual. Exploring Forms of Political Theatre, Routledge, London-New York 2005), reflects about the connection between ritual and theatre in the 20th Century. Thank to this studies the search aim was to give a new story of the chorus as theatrical and performative tool, in his liminal essence in creating immersive or alienating theatrical relation with the audience and to give specific features to distinguish it from general categories such as choral theatre o ensemble theatre.