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NRF2 INHIBITION AS A NEW THERAPEUTIC APPROACH IN LYMPHOID NEOPLASMS SENSITIVE AND RESISTANT TO BORTEZOMIB PRELIMINARY STUDY
No full textDissertação de Mestrado em Química Medicinal apresentada à Faculdade de Ciências e TecnologiaDurante a hematopoiese, podem ocorrer alterações nas células percussoras ou no microambiente da medula óssea o que dá origem à proliferação e acumulação de células malignas, levando ao desenvolvimento de neoplasias hematológicas. As neoplasias da célula B madura, como o linfoma difuso das grandes células B (LDGC B) e o mieloma múltiplo (MM), são um grupo bastante heterógeno de neoplasias hematológicas que resultam da transformação neoplásica das células B, nas quais o stresse oxidativo (SO) pode ter um papel fundamental na sua patogénese bem como no desenvolvimento de resistência às terapêuticas anti-cancerígenas. Vários mecanismos estão implicados no desenvolvido de resistência a fármacos, como SO, o qual resulta do desequilíbrio entre a formação das espécies reativas de oxigénio (ROS) e as defesas antioxidantes da célula, como a glutationa reduzida (GSH), e desempenha um papel fundamental no desenvolvimento de neoplasias bem como na resistência fármacos anti-neoplásicos. O NRF2 (Nuclear factor erythroid2-related factor 2) é um fator de transcrição (FT) fundamental na resposta ao stresse oxidativo, sendo o principal mecanismo de resposta citoprotetora e de manutenção do estado redox. Se por um lado, o NRF2 previne a carcinogénese ao manter o equilíbrio celular em situações adversas por outro, esta capacidade protetora contribui para a progressão do cancro e desenvolvimento de resistência a terapêuticas. Além disso, este FT é regulado negativamente pelo KEAP-1, o qual é degradado na via da ubiquitina proteasoma, constituindo a inibição do proteasoma uma estratégia terapêutica já aprovada no tratamento do MM. No entanto, o desenvolvimento de resitência aos inibidores do proteasoma (IP) pode levar à falência da terapêutica. Posto isto, a inibição da atividade do NRF2 poderá constituir uma potencial estratégia terapêutica para tratar neoplasias linfoides, bem como para ultrapassar a resistência aos IP, em particular ao bortezomib, no MM. Assim, o objetivo deste estudo foi avaliar o potencial terapêutico do brusatol, um inibidor do NRF2, em modelos in vitro de neoplasias linfoides, nomeadamente de LDGC B e MM, bem como o seu papel na resistência ao bortezomib. Para tal, as linhas celulares de neoplasias linfoides, nomeadamente de LDGC B (as células Farage) e de MM (as células H929) e resistente ao bortezomib (as células H929 BTZ) foram incubadas, durante 72 horas, na ausência e na presença de concentrações crescentes de bortezomib e de brusatol, em monoterapia, e a atividade metabólica foi determinada pelo ensaio da resazurina. As doses de brusatol que demonstraram ter maior potencial terapêutico, às 72 horas, foram selecionadas para os restantes ensaios. O tipo de morte celular foi analisado por citometria de fluxo, através da dupla marcação com Anexina-V e 7-AAD, bem como por microscopia ótica, após coloração de May-Grünwald Giemsa O ciclo celular foi avaliado por citometria de fluxo, utilizando a solução de iodeto de propídeo/RNase. Para avaliar o potencial da membrana mitocondrial utilizou-se a sonda JC-1 e recorreu-se à técnica de citometria de fluxo. Verificaram-se, também, os níveis de peróxidos intracelulares, de anião superóxido e de glutationa reduzida pela técnica de citometria de fluxo, em que se utilizaram as sondas DCFH2-DA, DHE e MO, respetivamente. Os resultados foram analisados tendo em consideração um nível de significância de 95% (p<0,05). Os resultados obtidos mostraram que o bortezomib reduziu a atividade metabólica em todas as linhas celulares, sendo, a linha resistente a este IP, as células H929 BTZ, , as menos sensíveis, comprovando a resistência destas células ao bortezomib. Além disso, o brusatol reduziu a atividade metabólica de forma dependente da dose, do tempo e do tipo de linha celular. De facto, a linha celular Farage revelou ser a mais sensível ao brusatol, sendo o seu IC50, às 72 horas de incubação, de 5.6 nM. Comparando o efeito do inibidor do NRF2 nas células de MM, as H929 BTZ mostraram ter uma maior sensibilidade à ação do brusatol com IC50, às 72 horas, de 16.9 nM, menor do que o IC50 das células sensíveis (H929, 26.6 nM). A análise do tipo de morte e do ciclo celular, evidenciou que o brusatol tem efeito citotóxico e citostático. A marcação com Anexina V e 7-AAD demonstrou um aumento da percentagem de células em apoptose tardia/necrose de 25% nas células H929, 8% nas células H929 BTZ e 16% nas células Farage, para as doses de brusatol mais elevadas e em comparação com o controlo. Pela técnica de microscopia ótica, observaram-se características morfológicas típicas da apoptose técnica, tais como blebbings e fragmentação nuclear, o indica que o brusatol induz morte celular, preferencialmente, por apoptose, em todas as linhas celulares. Para além disso, este fármaco induz um bloqueio do ciclo celular na fase G0/G1, menos significativo no caso das células Farage. Para além disso, a exposição ao brusatol resultou, de uma forma geral, numa diminuição do potencialDuring hematopoiesis, may occur alterations in the precursor cells or in the bone marrow microenvironment that give rise to the proliferation and accumulation of malignant cells which leads to the development of hematological neoplasms. Mature B cell neoplasms, such as diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM), are a very heterogeneous group of hematological neoplasms that result of the neoplastic transformation of B cells, in which the oxidative stress may have a key role in their pathogenesis as well as in the development of resistance to anticancer therapeutics. Several mechanisms are involved in the development of dug resistance, such as oxidative stress, which results from the disequilibrium between the production of reactive oxygen species (ROS) and antioxidant defenses, such as reduced glutathione (GSH), and plays a crucial role in the development of neoplasms as well as in antineoplastic drug resistence. The NRF2 (Nuclear factor erythroid2-related factor 2) is a transcription factor (TF) essential for the response to oxidative stress, being the main mechanism of cytoprotective response and responsable for the maintenance of the redox state. If on one hand, NRF2 can prevent carcinogenesis by maintaining the cellular equilibrium in adverse situations, on the other hand, this protective capacity contributes to cancer progression and the development of resistence to therapeutics. Furthermore, this TF is negatively regulated by KEAP-1, which is degradaded by the ubiquitin proteasome pathway, being the proteasome inhibition a therapeutic stratgey aproved for the treatment of MM. However, the development of resistance to proteasome inhibitors (PI) may lead to failure of the therapeutic. Therefore, the inhibition of the NRF2 activity may represent a potential therapeutic strategy for the treatment of lymphoid neoplasms, as well as to overcome the resistance to PI, in particular to bortezomib, in MM cases. Thus, the aim of this study was to evaluate the therapeutic potential of brusatol, a NRF2 inhibitor, in lymphoid neoplasms in vitro models, particularly of DLBCL and MM, as well its role in bortezomib resistance. To do so, the cell lines of lymphoid neoplasms, specifically of DLBCL (Farage cell line) and of MM sensitive (H929 cell line) and resistant to bortezomib (H929 BTZ cell line), were incubated in the absence and presence of increasing concentrations of bortezomib and brusatol, for 72 hours, in monotherapy, and the metabolic activity was determined by the resazurin assay. The concentrations of brusatol which showed to have the best therapeutic potential, at 72 hours, were selected for the remaining experiments. The type of cell death was analyzed by flow cytometry, using the Annexin-V and 7-AAD double staining, as well as by optical microscopy, after smear staining according to May-Grünwald Giemsa protocol. The cell cycle was evaluated by flow cytometry, using the propidium iodide/RNAse solution. The mitochondrial membrane potential was quantified by flow cytometry, using JC-1 probe. The levels of intracellular peroxides, superoxide anion and reduced glutathione levels were also verified by flow cytometry, using DCFH2-DA, DHE and MO probes, respectively. Results were analyzed statistically considering a 95% significance level (p<0,05). The results showed that bortezomib reduced the metabolic activity in all cell lines, being the MM cells resistant to this PI, H929 BTZ cells, the least sensitive ones, which confirms the resistance of these cells to bortezomib. Moreover, brusatol reduced the metabolic activity in dose, time, and cell line dependent manner. In fact, the DLBCL cells were the most sensitive ones to brusatol, being the IC50 value, at 72 hours of incubation, 5.6 nM. By comparing the effect of the NRF2 inhibitor in the MM cells, the resistant ones were more sensitive to brusatol, being the IC50, at 72 hours, 16.9 nM, which is lower than the IC50 of the sensitive cells (26.6 nM). The cell death and cycle analysis showed that brusatol has a cytotoxic and cytostatic effect. Anneix B and 7-AAD staining demonstrated an increase in the percentage of cells in late apoptosis/necrosis of 25% in H929 cells, 8% in H929 BTZ cells and 16% in Farage cells, for the higher doses of brusatol and comparing to control. By optical microscopy were observed morphological changes typical of apoptosis, such as blebblings and nuclear fragmentation, which indicates that brusatol induces cell death, mainly, by apoptosis, in all cell lines. Moreover, this drug induces cell cycle arrest in phase G0/G1, less significant in Farage cells. Moreover, the exposure to brusatol resulted, in general, in a decrease in the mitochondrial membrane potential and the evaluation of the ROS and GSH levels showed that this drug is capable of induce increase in ROS levels and decrease in GSH levels. These results suggest that brusatol induces apoptosis by the mitochondrial pathway, being its action associat
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
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
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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