1,720,957 research outputs found
Clinical and biological implications of genomic lesions in Chronic Lymphocytic Leukaemia
No full textThe aim of this thesis was to interrogate the application of targeted genomics in the clinical management of Chronic Lymphocytic Leukaemia (CLL), and to explore inhibitory compounds of recurrently mutated genes in CLL. The genomic landscape of the LRF CLL4 clinical trial (n=500) was conducted using a custom 25 gene targeted re-sequencing NGS panel, identifying 903 variants (1.8/patient). SF3B1 was identified as the most recurrently mutated gene in the cohort (26%), with the mutation landscape and subclonal architecture assessed for all 25 genes, identifying previously observed and novel associations. Clinical statistical survival analysis of the CLL4 TruSeq mutation data was undertaken for overall and progression-free survival, using traditional techniques and supervised machine learning tools. SF3B1 was identified to associate with OS independently of multiple CLL biomarkers in a multivariate model, and as an important feature by machine learning approaches. In addition, subclonal TP53 mutations predicted poor OS and PFS in cases treated with chlorambucil, and co-mutated/deleted del(11q) and BIRC3 were found to independently predict for a poor PFS. Since SF3B1 was found to be the most recurrently mutated gene in CLL4, and it associated with poor OS, it was selected for in vitro targeting using splicing inhibitors (Spliceostatin A and Meayamycin B) in CLL cells. Splicing inhibitors elicited substantial apoptosis, with Spliceostatin A inducing downregulation of Mcl-1 at the protein and RNA level, as well as acting synergistically with venetoclax in the context of micro-environmental support. Therefore, direct inhibition of Mcl-1 in CLL cells was undertaken using the Mcl-1 specific inhibitor UMI-77, eliciting apoptosis at micro molar concentrations. However, UMI-77 did induce resensitisation to the level of SSA in the context of CLL microenvironment support, suggesting that inhibition of Mcl-1 alone may not be sufficient to overcome BCL-2 inhibitor resistance in CLL. This work has demonstrated that the application of targeted genomic screening can offer added value to CLL patient management where the monitoring of SF3B1 mutations can identify additional adverse disease events. In relation to targeting drugs to the spliceosome pathway in CLL, where SF3B1 is a major component, the current work demonstrated effective re-sensitisation of CLL cells to combination inhibitor exposure. Together, this research has provided a greater understanding of the clinical utility of gene mutation screening and challenges surrounding development of the next generation of therapies to circumvent molecular pathways that CLL cells use to proliferate and drive disease progression
The association between deaths from infection and mutations of the BRAF, FBXW7, NRAS and XPO1 genes: a report from the LRF CLL4 trial
No full textCauses of death, in particular deaths due to infection, have not been widely studied in randomised trials in chronic lymphocytic leukaemia. With long-term follow-up (median 13 years) we examined the cause of death in 600/777 patients in the LRF CLL4 trial. Blood samples, taken at randomisation from 499 patients, were available for identifying gene mutations. Infection was a cause of death in 258 patients (43%). Patients dying of infection were more likely than those who died of other causes to have received ≥2 lines of treatment (194/258 [75%] versus 231/342 [68%], P = 0.04) and to have died in the winter months (149/258 [58%] versus 166/342 [49%], P = 0.03), respectively. In patients with mutation data, the factors significantly associated with death from infection versus all other deaths were 11q deletion (47/162 [29%] versus 40/209 [19%], P = 0.03) and mutations of the BRAF, FBXW7, NRAS and XPO1 genes. Death was caused by an infection in 46/67 assessable patients (69%) who had a mutation of one or more of these four genes versus only 129/333 patients (39%) without any of these mutations (odds ratio: 3.46 [95% CI 1.98-6.07] P < 0.0001). Careful management of infection risk, including prophylaxis against infection, may be important in patients who carry these mutations.</p
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
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