1,720,975 research outputs found
Studio e caratterizzazione di nuovi farmaci molecolari nel trattamento dei tumori dipendenti dalla via oncogenica di Hedgehog.
Full text linkLa via di trasduzione del segnale di Hedgehog (Hh) gioca un ruolo cruciale nello sviluppo e nella tumorigenesi, nonchè nella proliferazione e mantenimento delle cellule staminali tumorali (CSCs). L’attivazione di questa via del segnale avviene in seguito al legame del ligando Hh con il recettore inibitorio Patched1 (Ptch1). Tale interazione rimuove l’effetto inibitorio che Ptch1 esercita su un altro recettore, Smoothened (Smo), che rappresenta il regolatore positivo chiave nella trasduzione del segnale. Questo evento consente il rilascio dei fattori trascrizionali zinc-finger della famiglia Gli (Gli1, Gli2 e Gli3), permettendone la traslocazione nucleare e la conseguente attività trascrizionale.
Un'aberrante attivazione del signaling è responsabile dell'insorgenza di diversi tipi di tumore tra i quali il medulloblastoma, il rabdomiosarcoma, il carcinoma a cellule basali e molti altri. La carcinogenesi Hh dipendente è legata ad alterazioni genetiche e/o molecolari a carico dei componenti più importanti della via, quali ad esempio mutazioni attivanti del recettore Smo, inattivanti il recettore Ptch1 o il regolatore SuFu, traslocazioni di Gli1 o amplificazioni di Gli1 o Gli2, iperattivazione di Gli1 attraverso meccanismi non canonici.
Dato il ruolo fondamentale nella tumorigenesi e nel mantenimento delle nicchie di cellule staminali tumorali, la via del segnale di Hh rappresenta oggi un attraente bersaglio terapeutico nel cancro. Negli ultimi anni la maggior parte delle ricerche sono state focalizzate sullo sviluppo di farmaci in grado di bloccare l’effetto attivatorio di Smo. Tra questi, il vismodegib (GDC-0449/Eridevige®) è stato il primo inibitore di Hh approvato dalla FDA nel 2012 per il trattamento del carcinoma a cellule basali. Tuttavia, diversi studi hanno portato alla luce alcuni limiti degli inibitori sin qui individuati, legati in particolare alla scarsa selettività, allo sviluppo di farmaco resistenza e all’attivazione dell’effettore finale della pathway, Gli1, mediata da altre vie oncogeniche. Queste evidenze sollevano la necessità di identificare nuovi e più efficaci inibitori di Hh in grado di vincere la farmaco resistenza e contrastare la crescita del tumore.
Al fine di raggiungere questo obiettivo, abbiamo condotto uno studio innovativo di tipo computazionale finalizzato all’individuazione, caratterizzazione e ottimizzazione di nuove molecole in grado di bloccare il potenziale oncogenico di Hh. Attraverso uno screening in silico di una libreria di piccole molecole di origine naturale, sintetica o semi-sintetica e sfruttando la struttura cristallografica dei componenti chiave di nostro interesse, il recettore Smo e il fattore di trascrizione Gli1, abbiamo identificato nuovi efficaci inibitori della via di Hh. In particolare, abbiamo individuato la prima molecola in grado di impedire l’attività trascrizionale di Gli1, grazie alla sua capacità di legare direttamente questo fattore di trascrizione ed inibirne il legame con il DNA. L’efficacia di tali molecole nel bloccare la proliferazione cellulare e quindi la crescita del tumore, è stata comprovata da test effettuati, in vitro ed in vivo, su modelli tumorali caratterizzati da un’aberrante attivazione del signaling di Hh. I nostri risultati svelano il potenziale di queste molecole come nuovi e promettenti approcci terapeutici per la cura dei tumori associati alla via di Hh
Insights into gli factors ubiquitylation methods
No full textThe Hedgehog (Hh) signaling pathway governs cell growth and tissue development. Malfunctioning of several Hh pathway components, including the key transcriptional effector Gli proteins, is responsible for the onset of several tumors. Gli proteins activity is finely controlled by multilayered regulatory mechanisms, the most prominent of which is their proteasome-dependent proteolytic cleavage or massive ubiquitin-mediated proteolysis. Here, we described multiple procedures to determine whether a Gli protein is ubiquitylated both in a cellular context and in vitro, in basal conditions or by different E3 ubiquitin ligases and whether these processes are associated to Gli proteasome degradation
Targeting GLI factors to inhibit the Hedgehog pathway
Full text linkHedgehog (Hh) signaling has emerged in recent years as an attractive target for anticancer therapy because its aberrant activation is implicated in several cancers. Major progress has been made in the development of SMOOTHENED (SMO) antagonists, although they have shown several limitations due to downstream SMO pathway activation or the occurrence of drug-resistant SMO mutations. Recently, particular interest has been elicited by the identification of molecules able to hit glioma-associated oncogene (GLI) factors, the final effectors of the Hh pathway, which provide a valid tool to overcome anti-SMO resistance. Here, we review results achieved in developing GLI antagonists, explaining their mechanisms of action and highlighting their therapeutic potential. We also underline the relevance of structural details in their discovery and optimization
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
Full text linkWe 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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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