1,725,447 research outputs found
Recommended from our members
Abstract 4067: Combination venetoclax and selinexor effective in relapsed refractory multiple myeloma with translocation t(11;14)
No full textAbstract
Translocation t(11;14) positive multiple myeloma (MM) is sensitive to venetoclax, yet the drug lacks FDA approval in MM. Selinexor is an inhibitor of nuclear exporter XPO1 and is approved in relapsed refractory MM. We recently analyzed RNA-seq from 859 MM patient samples (MMRF CoMMpass study) and compared them to healthy bone marrow samples (GSE114922). After correcting for batch effects, differential gene expression analysis found apoptosis and cell cycle regulation amongst the top upregulated gene pathways in MM. We therefore hypothesized that MM would be sensitive to the combination of the pro-apoptotic drug, venetoclax, and selinexor, which causes cell cycle arrest.
Using a panel of 8 MM cell lines (U266-B1, KMS12BM, SKMM2, RPMI-8226, LP1, OPM2, KMS12PE, and NCIH929), we performed cell viability assays in increasing concentrations of selinexor, venetoclax, and a combination of the two drugs at 72 hours. Overall, the combination showed synergy in MM cell lines but strikingly, cell lines that possessed t(11;14) were more sensitive to the drug combination and showed enhanced synergy compared to the non-t(11;14). Average Bliss model synergy score were 0.5 in non-t(11;14) and 10.2 in t(11;14) MM cells (>10 indicates synergistic effects and <-10 indicates antagonistic drug effects).
To better understand molecular mechanisms underlying the observed synergistic effect in t(11;14), we performed western blot analysis in these cell lines treated with selinexor, venetoclax, the combination, or DMSO control for 24 hours. We measured protein levels of Cyclin D1, which is overexpressed in t(11;14) and a cargo of XPO1. We confirmed Cyclin D1 overexpression in t(11;14) cells lines but not in non-t(11;14) cells. Cyclin D1 levels decreased with selinexor, and the reduction was enhanced by adding venetoclax. Additionally, we measured levels of XPO1, p53, MCL-1, and p65, which we have previously shown to be altered by selinexor treatment. While venetoclax monotherapy caused increased MCL-1 expression, this was abrogated by combining with selinexor and the effects were statistically more significant in t(11;14) cell lines.
Concurrently, two patients with relapsed, refractory t(11;14) MM and disease progression after multiple lines of therapy were treated with venetoclax; however, after initial response, they developed resistance and progressive disease. Based off our preclinical results, selinexor was added to venetoclax and recaptured responses (VGPR and MR, respectively) suggesting a beneficial effect of the combination over single agent venetoclax. To our knowledge, this is the first report of patients with MM treated with the combination of selinexor and venetoclax. Further clinical evaluation of this combination in t(11;14) MM is planned and samples will be collected to better understand the mechanistic correlation between XPO1, BCL2/MCL-1, and Cyclin D1 levels and response.
Citation Format: Sana Chaudhry, Nina Nguyen, Rimpi Khurana, Tulasigeri M. Totiger, Skye Montoya, Jumana Afaghani, Terrence Bradley, Francesco Maura, Dickran Kazandjian, Jennifer Chapman, Stephan Schürer, Ola Landgren, James Hoffman, Justin Taylor. Combination venetoclax and selinexor effective in relapsed refractory multiple myeloma with translocation t(11;14) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4067
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe 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
No full text“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
No full textWe 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
No full textWe 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
- …
