1,720,959 research outputs found
SVILUPPO E CARATTERIZZAZIONE DI MODELLI PRECLINICI IN VIVO PER L'IDENTIFICAZIONE DI NUOVI APPROCCI TERAPEUTICI PER LA LEUCEMIA MIELOIDE ACUTA PEDIATRICA
No full textIn pediatric acute myeloid leukemia (AML) chemotherapy is the standard of care, but more than 25% of patients still relapse and after a disease recurrence the survival probability is extremely low (<50%). There is an urgent need to discover new treatments to ameliorate patients’ outcome. However, pediatric drug development is extremely reduced by the need of a better understanding of the adverse event profile of adult cancer indications in children, by the lack of pediatric-specific formulations, and by the reduced number of pediatric AML patients that can be included in clinical trials. Therefore, robust preclinical AML models to faithfully predict new drug efficacy is urgently needed to advance new drugs in clinical setting.
This PhD thesis aims at the development of more reliable preclinical models to improve treatments for children suffering from life threatening AML.
During my PhD I established patient derived xenograft models (PDX) of pediatric AML. Primary AML samples have been inoculated in NSG mice and, when engrafted, in 3 consequent mice recipients (namely P0, P1 and P2-PDXs). These models have been characterized for AML immunophenotypic profile and by RNA and whole-exome sequencing (WES). According to somatic mutations we determined AML clonal composition. These characterization allowed to select new drugs to be screened in vitro and in vivo. We finally generated 22 AML-PDXs mostly representing high-risk AML genetic markers such as t(5;11)NUP98-NSD1, t(3;5)NPM1-MLF1, t(16;16)CBFA2T3-GLIS2, t(16;21)FUS-ERG, KMT2A somatic translocations, or FLT3ITD mutation. We monitored the AML associated immunophenotype in PDXs finding it similar to that of the original AML. By WES we detected a consistent number of variants in each patient’s AML (ranging from 28 to 69), confirming a high intra-tumoral AML heterogeneity. Furthermore, we did not find any mutation recurrence among models, underlining a high inter-tumoral heterogeneity. In all models we tracked clonal evolution from patients’ AML to P2-PDXs highlighting that most variants were maintained, with very few variants acquired or lost during model development. Monitoring clonal dynamics we recognized a specific "founder" clone characterized by an average of 30 variants which are maintained up to P2 at the same allelic frequency, other small clones with an average of 10 variants increasing the allelic frequencies in P2 and, in a restricted number of models some lost clones. By WES and transcriptome analysis we highlighted druggable mutations and pathways allowing the selection of novel targeted drugs. We screened their efficacy in vitro alone or combined with Venetoclax, using AML ex vivo cells and mesenchymal stromal cells in a 3D co-culture system for exploring their synergy in reducing AML proliferation. This refinement permitted to select two drugs currently under evaluation in AML-PDX models.
Overall, in this work we created a large series of paired AML and xenograft models for advancing pediatric AML therapeutics. Our models represent a concrete perspective for both the identification of new variants and pathways involved in AML progression to deepen into AML biology, as well as the possibility to perform novel drug screenings that will be further used to increase AML drug portfolio, with the final aim to translate new drugs into human clinical trials, contributing to cure pediatric AML.In pediatric acute myeloid leukemia (AML) chemotherapy is the standard of care, but more than 25% of patients still relapse and after a disease recurrence the survival probability is extremely low (<50%). There is an urgent need to discover new treatments to ameliorate patients’ outcome. However, pediatric drug development is extremely reduced by the need of a better understanding of the adverse event profile of adult cancer indications in children, by the lack of pediatric-specific formulations, and by the reduced number of pediatric AML patients that can be included in clinical trials. Therefore, robust preclinical AML models to faithfully predict new drug efficacy is urgently needed to advance new drugs in clinical setting.
This PhD thesis aims at the development of more reliable preclinical models to improve treatments for children suffering from life threatening AML.
During my PhD I established patient derived xenograft models (PDX) of pediatric AML. Primary AML samples have been inoculated in NSG mice and, when engrafted, in 3 consequent mice recipients (namely P0, P1 and P2-PDXs). These models have been characterized for AML immunophenotypic profile and by RNA and whole-exome sequencing (WES). According to somatic mutations we determined AML clonal composition. These characterization allowed to select new drugs to be screened in vitro and in vivo. We finally generated 22 AML-PDXs mostly representing high-risk AML genetic markers such as t(5;11)NUP98-NSD1, t(3;5)NPM1-MLF1, t(16;16)CBFA2T3-GLIS2, t(16;21)FUS-ERG, KMT2A somatic translocations, or FLT3ITD mutation. We monitored the AML associated immunophenotype in PDXs finding it similar to that of the original AML. By WES we detected a consistent number of variants in each patient’s AML (ranging from 28 to 69), confirming a high intra-tumoral AML heterogeneity. Furthermore, we did not find any mutation recurrence among models, underlining a high inter-tumoral heterogeneity. In all models we tracked clonal evolution from patients’ AML to P2-PDXs highlighting that most variants were maintained, with very few variants acquired or lost during model development. Monitoring clonal dynamics we recognized a specific "founder" clone characterized by an average of 30 variants which are maintained up to P2 at the same allelic frequency, other small clones with an average of 10 variants increasing the allelic frequencies in P2 and, in a restricted number of models some lost clones. By WES and transcriptome analysis we highlighted druggable mutations and pathways allowing the selection of novel targeted drugs. We screened their efficacy in vitro alone or combined with Venetoclax, using AML ex vivo cells and mesenchymal stromal cells in a 3D co-culture system for exploring their synergy in reducing AML proliferation. This refinement permitted to select two drugs currently under evaluation in AML-PDX models.
Overall, in this work we created a large series of paired AML and xenograft models for advancing pediatric AML therapeutics. Our models represent a concrete perspective for both the identification of new variants and pathways involved in AML progression to deepen into AML biology, as well as the possibility to perform novel drug screenings that will be further used to increase AML drug portfolio, with the final aim to translate new drugs into human clinical trials, contributing to cure pediatric AML
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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