1,721,061 research outputs found
Targeting Hedgehog pathway in medulloblastoma: identification of SALL4A as a new activator and isoflavone c22 as multitarget inhibitor
Full text linkHedgehog (Hh) pathway is essential for embryonal development and tissues homeostasis; its alteration causes several human cancers, including medulloblastoma (MB), the most common brain malignancy in childhood. Because of its crucial role in tumorigenesis, the regulation of the Hh pathway and the identification of new Hh modulators emerged as a field of great interest in tumor biology.
My Ph. D. project was focused on two main goals:
Aim 1 | Identification of new molecular mechanisms involved in Hh signalling pathway regulation and MB tumorigenesis. To address this aim, we focused on the identification of new interactors of the known Hh negative regulator and tumor suppressor RENKCTD11. Through mass spectrometry analysis, we identified the transcription factor SALL4A. SALL4A plays a key role in maintaining pluripotency and self-renewal of embryonic stem cells, regulating different signalling pathway. SALL4A expression is inhibited in the post-natal period in many adult tissues, but it is reactivated in different tumors and is often related to worse prognosis and lower survival rate. Our data demonstrate that SALL4A is a substrate of RENKCTD11, that induces its poly-ubiquitylation and its consequent proteasome-mediated degradation. In order to investigate its biological role in Hh signalling, we demonstrated that SALL4A enhances GLI1 activity working in complex with HDAC1, a well known Hh activator. Of note, we observed that the proliferation ability of human MB cell lines increases in presence of SALL4A, whereas their migration rate is reduced after its genetic depletion; in vivo, SALL4A genetic depletion leads to a reduction of Hh-dependent tumor growth. Our findings identify SALL4A as a previously unknown regulator of Hh pathway able to promote, in complex with HDAC1, GLI1 activity and to contribute to Hh-dependent tumorigenesis. Hence, SALL4A stands as a new molecular target involved in the onset and progression of Hh-dependent tumors and represents an interesting focus in cancer research.
Aim 2 | Pharmacological targeting of Hedgehog pathway. Given the primary role of Hh signalling in tumorigenesis and in the maintenance of cancer stem cell niches, this pathway is now considered an attractive therapeutic target in cancer. In recent years, many efforts have focused on the development of drugs that can block the activating effect of SMO receptor. However, several studies underlined some limitations of the inhibitors identified so far, linked in particular to the poor selectivity, the onset of drug resistance events and the activation of GLI1 mediated by other oncogenic pathways. These evidences raise the need to identify new and more effective Hh inhibitors able to overcome drug resistance and to counteract tumor growth. To this end, my research activity was aimed at identifying, characterizing and optimizing new molecules able to block the oncogenic potential of Hh. In particular, by combining the most profitable pharmacophores for targeting SMO and GLI1 by synthetic isoflavones, we designed and synthesized the isoflavone 22, a small molecule that acts as a multitarget Hh inhibitor blocking both SMO and GLI1 activity at the same time. Compound 22 is able to inhibit Hh-dependent tumor growth in human and murine MB cells at sub-micromolar concentration, as a consequence of the reduction in GLI1 expression levels. Isoflavone 22 remarkably shows a strong anti-tumor effect also in vivo by suppressing cell proliferation and promoting apoptosis. Molecular modeling further corroborated the multitarget mechanism of action of compound 22, showing that the drug is able to fit the ligand binding site in both SMO and GLI1. Overall, these results reveal a valuable form of targeted therapy to increase the efficacy and to decrease the toxicity of individual anticancer agents; our findings discover the first multitarget Hh inhibitor that impinges Hh-dependent tumor growth and stands as new potential weapons against Hh-driven tumors
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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