1,720,958 research outputs found
c-Myc oncoprotein is stabilized by FGFR activation: therapeutic potential of FGF/FGFR inhibitors in c-Myc-driven B-cell non-Hodgkin Lymphoma
No full textI linfomi non Hodgkin a cellule B (B-NHL) sono un gruppo eterogeneo di tumori ematologici che originano dai linfociti B periferici. Tra questi, un sottogruppo di linfomi diffusi a grandi cellule B (DLBCL) e tutti i linfomi di Burkitt (BL) sono B-NHL aggressivi guidati dall’oncoproteina c-Myc. Sebbene i trattamenti attuali spesso forniscano una remissione completa, circa la metà dei pazienti presenta una recidiva. Pertanto, gli approcci mirati a inibire c-Myc possono rappresentare una nuova strategia terapeutica per i B-NHL aggressivi. Recentemente abbiamo dimostrato che l'attivazione del segnale indotta dai fattori di crescita dei fibroblasti (FGF) è coinvolta nella stabilizzazione della proteina c-Myc in diversi tipi di tumore; infatti l'inibizione di FGF o dei recettori per FGF (FGFR) porta alla degradazione proteasomale della proteina c-Myc. Su questa base, ipotizziamo che il blocco di FGF/FGFR possa avere un forte impatto sulla crescita e sulla diffusione dei B-NHL aggressivi guidati da c-Myc. Lo scopo di questa tesi è quindi volto a studiare gli effetti dell'inibizione della segnalazione di FGF nei B-NHL aggressivi guidati da c-Myc utilizzando due diversi approcci: (i) una strategia di intrappolamento di FGF a livello extracellulare (utilizzando la small molecule FGF trap NSC12) e (ii) un approccio di inibizione dei recettori per FGF (utilizzando l’inibitore tirosino-chinasico Erdafitinib, approvato dalla FDA).
I dati riportati in questa tesi mostrano che i campioni derivati da pazienti DLBCL e BL positivi per c-Myc esprimono alti livelli di (p)FGFR attivato/fosforilato. È interessante notare che la fosforilazione di FGFR non è stata osservata nei campioni DLBCL negativi per c-Myc, suggerendo una forte correlazione tra l'attivazione di FGFR e l'espressione della proteina c-Myc. Per valutare il ruolo del sistema FGF/FGFR nei B-NHL guidati da c-Myc, abbiamo testato l’attività antitumorale di NSC12 ed Erdafitinib in linee cellulari c-Myc positive di DLBCL (RI -1, U2932, SU-DHL-6 e SU-DHL-10) e di BL (RAJI, DAUDI). Tutte le linee cellulari esprimono diversi FGFR e FGF e alti livelli di pFGFR in assenza di stimoli esogeni, indicando la presenza di una stimolazione autocrina mediata da FGF. I trattamenti in vitro con NSC12 o Erdafitinib hanno fortemente inibito l’attivazione di FGFR e hanno indotto la rapida degradazione proteosomale della proteina c-Myc. Ciò è stato confermato dal co-trattamento con l'inibitore del proteosoma MG132 che ha impedito la degradazione di c-Myc. Meccanicisticamente, il blocco di FGF/FGFR influisce sulla stabilità della proteina c-Myc riducendo la fosforilazione di c-Myc in Ser62 e aumentando la fosforilazione di c-Myc in Thr58 necessaria per la degradazione della proteina c-Myc. Ciò si ottiene attraverso l'inibizione della chinasi ERK1/2 (che fosforila c-Myc in Ser62) e l'attivazione della chinasi BRD4 (che fosforila c-Myc in Thr58). La diminuzione dei livelli di proteina c-Myc è stata accompagnata da una ridotta proliferazione delle cellule tumorali e da un aumento dell'apoptosi mediata dai ROS. È importante sottolineare che il trattamento in vivo con NSC12 o Erdafitinib ha ridotto significativamente la crescita di xenotrapianti tumorali sia DLBCL che BL. Da notare che NSC12 o Erdafitinib in combinazione con la terapia standard R-CHOP hanno potenziato gli effetti anti-linfoma sulle linee cellulari DLBCL e sulle cellule purificate da pazienti DLBCL.B-cell non-Hodgkin lymphomas (B-NHL) are a heterogeneous group of blood malignancies arising from peripheral B lymphocytes. Among them, a subset of Diffuse Large B-cell Lymphomas (DLBCL) and all Burkitt’s lymphomas (BL) are c-Myc-driven aggressive B-NHL. Although current treatments often provide complete remission, approximately half of the patient’s relapse. Thus, approaches targeting c-Myc may represent a novel therapeutic strategy for aggressive B-NHL. Recently we have demonstrated that activation of the fibroblast growth factor (FGF) signaling is involved in the stabilization of c-Myc protein in different tumor types, FGF or FGF receptor (FGFR) inhibition leading to the proteasomal degradation of c-Myc protein. On this basis, FGF/FGFR blockade may represent a promising strategy to inhibit c-Myc.
Data reported in this thesis show that c-Myc positive DLBCL and BL patient-derived samples express high levels of activated/phosphorylated (p)FGFR. Interestingly, FGFR phosphorylation was not observed in c-Myc negative DLBCL samples, suggesting a strong correlation between FGFR activation and c-Myc protein expression. To assess the role of the FGF/FGFR system in c-Myc-driven B-NHL, we tested the effect on lymphoma fitness of the FGF trap molecule NSC12 and the FDA-approved FGFR TK inhibitor Erdafitinib in c-Myc positive DLBCL (RI-1, U2932, SU-DHL--6 and SU-DHL-10) and BL (RAJI, DAUDI) cell lines. All cell lines express several FGFRs and FGF ligands and high levels of pFGFR in the absence of exogenous stimuli, indicating the presence of an autocrine FGF stimulation. In vitro NSC12 or Erdafitinib treatments strongly inhibited FGFR activation and induced the rapid proteasomal degradation of c-Myc protein. This was confirmed by co-treatment with the proteosome inhibitor MG132 that prevented c-Myc degradation. The decrease of c-Myc protein levels was paralleled by reduced tumor cell proliferation and increased ROS-mediated apoptosis in all cell lines tested. By going deeper into the molecular mechanisms involved in c-Myc protein degradation upon FGF/FGFR blockade, we shew that NSC12 affects c-Myc protein stability by reducing c-Myc Ser62 phosphorylation and by increasing the c-Myc Thr58 phosphorylation necessary for c-Myc protein degradation. Moreover, we demonstrated that ERK1/2 is the kinase stabilizing c-Myc while BRD4 is the kinase that phosphorylates c-Myc protein at Thr58 in aggressive B-NHL since its inhibition causes a rescue of c-Myc protein levels.
In vivo treatment with NSC12 or Erdafitinib significantly reduced the growth of both DLBCL and BL tumor xenografts. In keeping with in vitro data, immunohistochemical analyses revealed a strong reduction of pFGFR and c-Myc protein levels in treated tumors compared to controls. To note, NSC12 or Erdafitinib in combination with the standard therapy R-CHOP exerted synergistic anti-lymphoma effects on DLBCL cell lines.
Altogether, these findings open new therapeutic hints for the treatment of c-MYC-driven aggressive B-NHL
Ten Years of CRISPRing Cancers In Vitro
Full text linkCell lines have always constituted a good investigation tool for cancer research, allowing scientists to understand the basic mechanisms underlying the complex network of phenomena peculiar to the transforming path from a healthy to cancerous cell. The introduction of CRISPR in everyday laboratory activity and its relative affordability greatly expanded the bench lab weaponry in the daily attempt to better understand tumor biology with the final aim to mitigate cancer’s impact in our lives. In this review, we aim to report how this genome editing technique affected in the in vitro modeling of different aspects of tumor biology, its several declinations, and analyze the advantages and drawbacks of each of them
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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