1,721,034 research outputs found
Validation of lymphoma-associated antigens identified using autoantibody profiling and protein arrays
Get PDFDiffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma subtype with heterogeneous clinical outcome and a significant number of patients still die of their disease. Characterising lymphoma patients’ autoantibody repertoires represent one approach to improve the understanding of their disease biology. Our hypothesis was that characterisation of antigens eliciting humoural immune responses in lymphoma patients may provide insights into mechanisms of lymphomagenesis and identify novel diagnostic/therapeutic targets.HIP1R was validated as a novel B-NHL autoantigen by immunoblotting with patients’ sera. No response was identified to the related HIP1 protein. Consistent with this finding, more widespread expression of HIP1R, compared to HIP1, was observed in lymphoma cell lines. Expression studies, at both transcript (qRT-PCR and analysis of microarray datasets) and protein levels (blotting and immunolabelling), identified abundant HIP1R in normal B cells and low level expression in a poor prognosis activated B-cell (ABC)-like DLBCL subtype. Upregulation of HIP1R expression was observed in activated non-malignant B cells at both transcript and protein levels, suggesting that downregulation of HIP1R expression in ABC-DLBCL might be a disease-related process. Despite its potential for DLBCL subtyping, HIP1R protein expression was not statistically significantly associated with patients’ survival in a series of 256 DLBCL. Short FOXP1 isoforms were identified as one mechanism repressing HIP1R transcription in an ABC-DLBCL cell line. Phenotypic analysis of HIP1R-depleted B-cell lymphoma cells indicated that HIP1R silencing could increase the surface levels of B-cell receptor (BCR) components such as IgM and CD79b.HIP1R represents a novel lymphoma autoantigen and cell-of-origin marker for distinguishing germinal centre- versus ABC-DLBCL subtypes. As ABC-DLBCL survival is dependent on chronic BCR signalling, future studies will address whether HIP1R silencing plays a fundamental role in disease pathogenesis by promoting BCR signalling
The biology of ADGRL4/ELTD1 in angiogenesis and tumour development
Get PDFADGRL4/ELTD1 is an orphan adhesion G protein-coupled receptor that is expressed in both endothelial cells and vascular smooth muscle cells. ELTD1 expression was significantly upregulated in the tumour vasculature and previous studies in our laboratories identified ELTD1 as a novel regulator of tumour angiogenesis. The aims of this project were to further investigate ELTD1’s in vivo role in the normal and tumour vasculature. In this project, both constitutive and inducible endothelial cell-specific Eltd1 knockout mouse models were generated using Tie2-Cre and Pdgfb-Cre lines respectively. Both models exhibited no significant differences in body and organ weights, or other welfare parameters such as behaviour and movement. There were no observed immunohistochemical differences (CD31 and H&E) in the vital organs namely, brain, heart, lung, liver, kidney and spleen. Interestingly, inducible endothelial cell-specific Eltd1 knockout aortic rings showed inhibition in endothelial cell sprouting that was not observed in the constitutive knockout, suggesting a functional compensatory mechanism in the constitutive model. In both E0771 and MC38 syngeneic tumour models, despite no significant differences in tumour growth curves and survival outcomes, there were observed immunohistochemical differences with generally higher necrosis and hypoxia, and reduction in microvessel density and pericyte coverage in the Eltd1 knockout tumours. Both genetic and drug induced endothelial-Eltd1 deletion gave similar results which affirmed the effects of endothelial-Eltd1 on the tumour vasculature in vivo. Single cell sequencing of acute Eltd1-depleted lung endothelial cells revealed heterogeneity in Eltd1-expressing endothelial cells and showed that lung capillary endothelial cells had higher Eltd1 expression compared to lung arterial endothelial cells. Interestingly, their differential gene expression profiles were distinct. But in both endothelial cell subsets, there were differentially regulated genes whose functions have been associated with endothelial biology, angiogenesis, tumour development and immunology. In summary, endothelial-Eltd1 depletion did not cause toxicity but altered the tumour microenvironment. Therefore, ELTD1 could be considered as a potential target for cancer therapy in combination with other therapies targeting hypoxia and angiogenesis
Developing anti-p53/HLA-A*0201 T-cell receptor mimic antibodies for cancer immunotherapy
Get PDFT-cell receptor mimic (TCRm) antibodies target a dual antigen epitope consisting of a peptide derived from an intracellular protein, and the major histocompatibility complex class I (MHC-I) molecule that presents the peptide at the cell surface. As traditional antibodies typically target cell surface or secreted antigens, TCRm antibodies advantageously expand the range of targetable antigens to include peptides derived from intracellular proteins. This thesis describes the development of TCRm antibodies targeting peptides that are derived from the wild type p53 protein and are presented by human leukocyte antigen (HLA)-A2. We further characterised the specificity and safety of the T1-116C TCRm antibody, which was the most extensively studied TCRm antibody in the laboratory prior to the start of this DPhil project. We showed that T1-116C labels primary AML and myeloma cells. We investigated the specificity of the T1-116C TCRm antibody for the p5365-73 peptide, RMPEAAPPV, by substituting each amino acid within the peptide individually, and showed that T1-116C recognises multiple tumour antigens. Using in silico analysis we identified 271 potentially cross-reactive peptides. We tested a panel of 25 peptides that are conserved in mice in vitro, showing that T1-116C binds peptides derived from a broad range of normal tissues. Despite these findings, in vivo testing of T1-116C cross-reactivity in human HLA-A2 transgenic mice demonstrated that T1-116C does not cause toxicity to normal mouse tissues. We also generated chimeric antigen receptors (CARs) for T-cell therapy using the single chain variable fragment of p53-targeting TCRm antibodies to provide the CAR specificity. We found that the CAR derived from T2-2A, a TCRm antibody that targets the p53187-197 peptide, GLAPPQHLIRV, demonstrated superior specificity for target peptide-HLA-A2 tetramers and cell lines to the T1-116C CAR. Through these studies, the T2-2A TCRm antibody has emerged as a potential therapeutic agent when used in the CAR format
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
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