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Design, synthesis and biochemical characterization of Fingolimod analogs for targeting PP2A
Get PDFPP2A (Protein Phosphatase 2A) is a Ser/Thr phosphatase ubiquitously expressed and highly conserved among the species (especially eukariotes). It is involved in delicate signaling pathways, and overall it has the effect to enhance pro-apoptotic and anti-proliferative events; a decrease of its activity makes anti-apoptotic and proliferative signals prevail. Its activity, as the activity of any other phosphatase, is counterbalanced by protein kinases; while the latter have been widely studied through the years, the role of PP2A was taken into account much more recently, and together with that the possibility to consider it as a drug target has been exploited. Indeed, PP2A is demonstrated to be down-regulated in several forms of tumors, in particular leukemias with a peculiar focus on B-CLL (B cell chronic lymphocytic leukemia). To date, the main hypothesis to explain this is that PP2A is inactivated not directly, but because of the over-expression of the protein SET, its endogenous inhibitor. In these cases, the capability of the cell to die is strongly impaired, so trying to restore PP2A activity is nowadays being exploited as a new, possible anti-cancer therapy.
Fingolimod (IUPAC name 2-amino-2-[2-(4-octylphenyl)ethyl]propan-1,3-diol) has been approved in 2010 for the treatment of relapsing-remitting forms of multiple sclerosis. Its activity is due to the fact that, once internalized by the cell, it gets phosphorylated and reaches a structural similarity with sphingosine-1-phosphate (S1P), mimicking it on T cells: by overstimulating S1P receptors, indeed, Fingolimod can lead to their degradation, avoiding the possibility for T cells to egress secondary lymphoid organs and to keep on damaging neural axons. In more recent years, it has been shown that Fingolimod can restore PP2A activity in tumors as a side effect; the mechanism underlying this event is still not clear, but it is probably due to the interaction Fingolimod has with the PP2A/SET complex. Curiously, this activity needs Fingolimod not to be phosphorylated.
This thesis work presents the synthesis and characterization of a library of Fingolimod analogs which are meant to isolate the pro-apoptotic effect from the immunosuppressive one. Keeping in mind that Fingolimod acts on PP2A only if unphosphorylated, this means designing and synthesizing molecules with modulated structural characteristics, but with a peculiar focus on their phosphorylatability. This approach is meant to obtain new potential anti-cancer drug entities that could restore the capability of the involved cells to die for apoptosis. The compounds were assayed in the laboratory of Prof. Brunati (Department of Molecular Medicine, University of Padova) for their capability to restore PP2A activity in B-CLL cells. In this sense, some promising compounds were obtained and the results of the biochemical assays on the most performing compound have been here reported.
In addition to this, the aim of producing PP2A (catalytic subunit) and SET proteins through recombinant DNA technique was pursued in order to obtain more details about the structural features involved in the interactions between the proteins themselves, and also the eventual ones between the proteins and the synthesized compounds; this part of the project was performed at Diamond Light Source (UK). Combining all the pieces of information obtained from these aims will lead both to an enhanced knowledge about the structural interactions between PP2A and SET (which to date is lacking) and to the possibility of rationalize eventual structure-activity relationships between the proteins of interest and anti-cancer compounds; this will help in elucidating the structural characteristics which are needed for the molecules to be active, and as a consequence in designing more, improved, rationalized Fingolimod analogs.PP2A (Protein Fosfatasi 2A) è una serin/treonin fosfatasi espressa in maniera ubiquitaria e altamente conservata tra le specie (eucarioti in primis). Essa è coinvolta in delicati pathway di segnalazione cellulare, ed ha come effetto complessivo quello di promuovere eventi pro-apoptotici ed anti-proliferativi; una sua diminuita attività comporta un aumento di segnali anti-apoptotici e proliferativi. La sua attività, come quella di ogni fosfatasi, è controbilanciata dalle protein chinasi; mentre queste ultime sono state ampiamente indagate nel corso degli anni, il ruolo di PP2A è stato preso in considerazione solo molto più di recente, e insieme ad esso è stata esplorata la possibilità di considerare l’enzima un target per farmaci. Infatti, è stato dimostrato che l’attività di PP2A è ridotta in svariate forme tumorali, in particolare leucemie e ancor più nel dettaglio nei casi di B-CLL (leucemia linfatica cronica a cellule B). Al momento, la principale ipotesi per spiegare questo fenomeno è che PP2A sia inattivata non tanto in maniera diretta, quanto piuttosto per aumentata espressione della proteina SET, suo inibitore endogeno. In questi casi, la capacità della cellula di entrare in apoptosi è fortemente compromessa, quindi la possibilità di ripristino dell’attività di PP2A è attualmente presa in considerazione come nuova, possibile terapia anti tumorale.
Fingolimod (nome IUPAC 2-ammino-2-[2-(4-ottilfenil)etil]propan-1,3-diolo) è stato approvato nel 2010 per il trattamento della sclerosi multipla in forma recidivante-remitente. La sua attività è legata al fatto che, una volta internalizzato dalla cellula, esso viene fosforilato e diventa strutturalmente simile alla sfingosina-1-fosfato (S1P), mimandone l’azione sui linfociti T: sovrastimolando i recettori per S1P, infatti, Fingolimod può portare alla loro degradazione, evitando che i linfociti T possano uscire dai linfonodi e perpetrare il danneggiamento degli assoni neuronali. Più di recente, è stato dimostrato che Fingolimod può, come effetto collaterale, ristabilire nei tumori l’attività di PP2A; il meccanismo sottostante a questa attività non è stato ancora del tutto chiarito, ma sembra legato all’interazione tra Fingolimod e il complesso PP2A/SET. Curiosamente, questa funzione richiede che Fingolimod non sia fosforilato.
Questo lavoro di tesi presenta la sintesi e la caratterizzazione di una libreria di analoghi di Fingolimod che vogliono isolare l’effetto pro-apoptotico da quello immunosoppressivo. Tenendo a mente che Fingolimod agisce su PP2A solo se non fosforilato, ciò significa progettare e creare molecole con caratteristiche strutturali modulate rispetto al composto preso a modello, ma con un’attenzione particolare alla loro capacità di subire fosforilazione. Questo approccio ha lo scopo di ottenere nuove, potenziali drug entities anti-cancro che possano ripristinare la capacità delle cellule interessate di subire apoptosi. I composti sono stati testati nel laboratorio della Prof. Brunati (Dipartimento di Medicina Molecolare, Università di Padova) per valutare la loro attività verso PP2A in cellule di B-CLL. In questo senso, sono stati ottenuti alcuni composti meritevoli di interesse e vengono qui riportati i risultati dei saggi biologici sul composto più attivo.
Inoltre, è stato perseguito lo scopo di produrre le proteine PP2A (subunità catalitica) e SET tramite tecnica del DNA ricombinante al fine di ottenere dettagli strutturali sull’interazione tra proteine, e sulla eventuale modalità di legame tra queste e i composti sintetizzati; questa parte del progetto è stata svolta presso Diamond Light Source (UK). Il lavoro svolto getta le basi per un approfondito studio strutturale dell’interazione tra PP2A e SET (che, ad oggi, è piuttosto lacunosa), sia alla razionalizzazione delle relazioni struttura-attività tra le proteine di interesse e composti anti-neoplastici; questo potrà aiutare a chiarire le caratteristiche strutturali di cui necessitano le molecole per essere attive, e di conseguenza a progettare in modo razionalizzato analoghi di Fingolimod nuovi e migliorati
Niñez trans : experiencia de reconocimiento y derecho a la identidad
No full textFil: Pavan, Valeria. Comunidad Homosexual Argentina; Argentina.Este libro brinda testimonio sobre las experiencias y alternativas que acompañaron el inédito caso del reconocimiento legal de una niña trans de cinco años de edad llamada Luana. Presenta, por un lado, una mirada política e institucional para mostrar la importancia de reconocerse y darse a conocer como instrumento para alcanzar derechos y muestra que, en el recorrido que llevó a Luana a tener un documento de identidad con su nombre y su género, fueron fundamentales las políticas públicas y la actuación de los organismos del Estado responsables de su implementación. Por otro lado, es el relato de una experiencia que constituye un antecedente para que otras familias con situaciones asimilables puedan reconocerse y las ayude a elegir y construir sus propios recorridos. Y, especialmente, el conjunto de artículos compilados en este volumen sirve para que la sociedad revise y discuta algunas ideas, conceptos y construcciones alrededor de temas de género, identidad y sexualidad.This book bears witness to the experiences and alternatives that accompanied the unprecedented case of the legal recognition of a five-year-old trans girl named Luana. On the one hand, it presents a political and institutional perspective to demonstrate the importance of self-recognition and self-disclosure as a means to achieve rights, showing that public policies and the actions of the state agencies responsible for their implementation were fundamental to Luana's journey to obtaining an identity document reflecting her name and gender. On the other hand, it recounts an experience that serves as a precedent for other families in similar situations, helping them to recognize their own experiences and choose and build their own paths. And, especially, the collection of articles compiled in this volume serves as a platform for society to review and discuss certain ideas, concepts, and constructs surrounding issues of gender, identity, and sexuality.Este livro testemunha as experiências e alternativas que acompanharam o caso inédito do reconhecimento legal de Luana, uma menina trans de cinco anos. Por um lado, apresenta uma perspectiva política e institucional para demonstrar a importância do autorreconhecimento e da autodeclaração como meios de alcançar direitos, mostrando que as políticas públicas e as ações dos órgãos estatais responsáveis ??por sua implementação foram fundamentais na jornada de Luana para obter um documento de identidade que refletisse seu nome e gênero. Por outro lado, relata uma experiência que serve de precedente para outras famílias em situações semelhantes, ajudando-as a reconhecer suas próprias vivências e a escolher e construir seus próprios caminhos. E, sobretudo, a coletânea de artigos reunidos neste volume serve como plataforma para a sociedade revisar e debater certas ideias, conceitos e construções que envolvem questões de gênero, identidade e sexualidade
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
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
MOTOR IMPAIRMENT AND SOCIAL RESPONSIVENESS REDUCTION AFTER CB1 AGONIST ADMINISTRATION IN MICE
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