1,720,980 research outputs found
Investigating HK2 as a potential therapeutic target in glioblastoma
Get PDFA thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy.Glioblastoma is the most common high-grade primary brain tumour in adults. Current treatments have limited success with average survival comprehensively low. Effective drug treatments are hindered predominantly by the complex genetic background of glioblastoma heterogeneity, as such there is a compelling need for the development of effective therapeutics. An approach is to target abnormal metabolic pathways that are universally dysregulated in glioblastoma. The identification of potential targets and the development of therapeutic agents is crucial for the advancement of treatment. Hexokinase 2 (HK2) has a prominent role in glycolysis, acting as the rate-limiting step in the pathway. HK2 is highly expressed in many cancers and its role as the rate-limiting step of glycolysis may potentially contribute to tumour growth. Overexpression of HK2 has also been associated with drug resistant phenotypes, in parallel, its inhibition has improved the effectiveness of anticancer agents, suggesting HK2 as a potential therapeutic target. The role of methylation and its association with expression levels of HK2 was determined in glioblastoma fresh frozen biopsies and patient-derived cultures, through pyrosequencing and quantitative PCR. CRISPR knockout was utilised to investigate the effect of inhibiting HK2 on proliferation and to determine the role of HK2 in chemoresistance. The anti-proliferative effects of HK2 inhibitors 3-bromopyruvic-acid (3-BPA) and metformin were investigated via cytotoxic assays and FACS analysis was used to determine their mechanism of action. Additionally, downstream expression changes were investigated via expression profiler arrays, across 84 key genes involved in the regulation and enzymatic pathways of glucose metabolism. Hypomethylation was demonstrated in all biopsies (n=100) and cultures (n=15) compared to normal brain tissue; with average methylation of 4.6% compared to 26% respectively (p1000- fold change in all biopsies and cultures compared to normal brain tissue and a strong correlation between hypomethylation and increased level of expression (p50% genes demonstrated reduced levels of expression compared to the corresponding parent/non-treated cultures. This study demonstrates the predominant role of HK2 within the glycolytic pathway, with overexpression potentially key in driving the genetic alterations downstream. This study also verifies a strong correlation between increased expression of HK2 and hypomethylation, additionally highlighting the impact HK2 has on inferior patient prognosis. HK2-KO revealed considerable ubiquitous reductions in downstream gene expression compared to glioblastoma biopsy tissue and parent cultures. Additionally, an increase in drug sensitivity was depicted with the loss of HK2 signifying the potential of targeting HK2 as a novel therapy in a significant subset of glioblastoma
MiRNA influences in mesenchymal stem cell commitment to neuroblast lineage development
Get PDFA thesis submitted in partial fulfilment of the requirements of the University of Wolverhampton for the degree of Professional Doctorate in Biomedical Science.Mesenchymal Stem Cells (MSCs) are multipotent stromal
cells that can self-renew and differentiate into cells from the
mesodermal cell lineage. Under specific conditions, MSCs
are known to transdifferentiate into the neuronal cell
lineage. The aim of this study was to investigate if specific
microRNAs (miRNAs) are responsible for neural induction,
differentiation and fate specification and if they can induce
MSCs to commit to a neuroblast and/or mature neuron cell
lineage. The selected miRNAs were miR-107, miR-124 and
miR-381, which respectively are known to promote
neurogenesis, neural differentiation and neural proliferation.
Targeting protein expression by transiently destroying the
messenger RNA using miRNAs is an alternative to destroying
the gene permanently and, being a transient process, the
cells being differentiated should not retain any permanent
evidence of this process. The objectives of this study were
to culture MSCs from the Wharton’s Jelly, transform these
MSCs into neural-like cells using the spent medium from the
neuroblastoma cell line SH-SY5Y, and further treat these conditioned cells with retinoic acid to induce further
maturation. MSCs were characterised by trilineage
differentiation and all three cell types were tested for a
series of CD and neural markers. Once characterised, the
three cell types were transfected with one of the three
selected miRNAs and a target gene for each miRNA was
analysed but results were sub-optimal. The MSCs and
neural-like derivatives were then tested for a selection of
neural markers. Once again results provided limited
information, however it was observed that miR-107 and
miR-124 have the potential to induce MSCs to differentiate
into neural-like cells and that these miRNAs may also induce
intermediate neural progenitors and immature neuron cell
types to differentiate further.Malta Government Scholarship Scheme
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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