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Targeting Endo180 with an antibody-drug conjugate for cancer treatment
No full textAntibody-drug conjugates (ADCs) are formed of an antibody attached to a cytotoxic drug via a linker which is cleaved upon internalisation of the ADC into the cell. This allows very toxic drugs to be directed to specific cells in the body. Endo180 is a constitutively recycling transmembrane receptor and therefore an ideal target for an antibody-drug conjugate. Endo180 is highly expressed on many tumours of mesenchymal origin, including a large proportion of sarcomas. Endo180 is also upregulated on cancer-associated fibroblasts (CAFs) in the stroma of breast and other epithelial cancers. Previous work by our laboratory has demonstrated a tumour promoting and immune restrictive role of Endo180 CAFs.
The aim of this PhD was to assess the utility of targeting Endo180 with an ADC and the efficacy of an Endo180-ADC in both tumour cell-targeting and CAF-targeting contexts. In vitro characterisation established that an anti-Endo180 monoclonal antibody conjugated to the anti-mitotic agent, MMAE, via a cleavable linker, is rapidly internalised into target cells, causing cell death specifically in Endo180-expressing sarcoma cell lines. In a sarcoma tumour xenograft model, the Endo180-vc-MMAE ADC drove on target cytotoxicity resulting in tumour regression and a significant impairment of metastatic colonisation of the lungs, liver and lymph nodes. Investigation of this Endo180-vc-MMAE ADC in fibroblasts determined that whilst the fibroblasts were not as sensitive to the ADC, they were able to process the ADC and release free drug, killing surrounding tumours cells in a bystander effect.
This thesis proposes that an Endo180-ADC is a potential candidate for targeted therapy of solid mesenchymal tumours. Further studies are required to develop an antibody recognising mouse Endo180, which was unsuccessful during this PhD, in order to assess of off-tumour toxicities of an Endo180-ADC and to gain a better understanding of the efficacy of an Endo180-ADC targeting CAFs in animal models
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
Identifying actionable pathways in breast cancer serosal metastasis
No full textMetastasis to the peritoneal and pleural cavities, also termed the serous cavities, is a common occurrence in advanced breast cancer. The serous cavities are lined by the mesothelium, an epithelial monolayer which provides a hospitable environment for the serosal spread of intra-abdominal cancers. Despite breast cancer being the most common extra-abdominal cancer spreading to the serosal cavities and the leading cause of pleural effusion and ascites in women, patients with breast cancer serosal metastasis face limited therapeutic options. The aim of this project was to uncover the mechanisms of crosstalk between mesothelial cells and breast cancer cells and to reveal therapeutic vulnerabilities that impair serosal colonisation.Using a novel ultrasound-guided intrapleural injection model and an intraperitoneal injection model, I showed that breast cancer cells co-localise with mesothelial cells and rapidly expand along the sub-mesothelial basal lamina when inoculated in the serous cavities. Furthermore, breast cancer cells co-cultured with mesothelial cells as 3D spheroids show increased viability compared to tumour cells alone, and loss of E-cadherin in tumour cells potentiates this interaction. Transcriptomic analysis and cell-cell communication inference of the co-cultured spheroids pinpointed basement membrane components as top predicted mesothelial-derived ligands binding to tumour cell receptors. In parallel, mesothelial cells acquired a cancer-associated mesothelial cell signature upon co-culture with tumour cells, displaying increased extracellular matrix (ECM) deposition and remodelling. Validation of top communication inference candidate genes by RNA interference identified mesothelial-derived fibronectin and laminin α5 as ECM components involved in the regulation of tumour cell viability. Targeting tumour cell binding of the mesothelial basement membrane via FAK inhibition is being tested as a strategy to limit serosal spread of breast cancer in vivo. Together these results demonstrate that mesothelial cells provide a supportive niche for breast cancer serosal colonisation and that mesothelial-tumour cell interaction is an actionable target against advanced metastatic disease
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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