1,721,043 research outputs found
Targeting the formyl peptide receptor 1 for treatment of glioblastoma
Get PDFBackground and Aims Gliomas account for over half of all primary brain
tumours and have a very poor prognosis, with a median survival of less than
two years. There is an urgent and unmet clinical need to develop new
therapies against glioma. Recent reports have indicated the overexpression of
FPR1 in gliomas particularly in high grade gliomas. The aim of this project was
to identify and synthesise small molecule FPR1 antagonists, and to
demonstrate a proof of principle in preclinical in vitro and in vivo models that
small molecule FPR1 antagonism can retard expansion of glioma.
Methods A number of small molecule FPR1 antagonists were identified by
in silico design, or from the literature and then were prepared using chemical
synthesis. FPR1 antagonists were evaluated in vitro for their ability to abrogate
FPR1-induced cellular responses in a range of models including calcium
mobilisation, cell migration, and invasion. The efficacy of FPR1 antagonist
ICT12035 in vivo was assessed in a U-87 MG subcutaneous xenograft model.
Results Virtual high throughput screening using a homology model of
FPR1 led to the identification of two small molecule FPR1 antagonists. At the
same time chemical synthesis of two other antagonists, ICT5100 and
ICT12035 as well as their analogues were carried out. The FPR1 antagonists
were assessed in calcium flux assay which gave an insight into their structure-activity
relationship. Further investigation of both ICT5100 and ICT12035
demonstrated that both small molecule FPR1 antagonists were effective at
abrogating FPR1-induced calcium mobilisation, migration, and invasion in U-
87 MG in vitro models in a dose-dependent manner. ICT12035 is a particularly
selective and potent inhibitor of FPR1 with an IC50 of 37.7 nM in calcium flux
assay. Additionally, it was shown that the FPR1 antagonist ICT12035 was able
to arrest the growth rate of U-87 MG xenografted tumours in mice.
Conclusion The results demonstrate that targeting FPR1 by a small
molecule antagonist such as ICT12035, could provide a potential new therapy
for the treatment of glioblastoma.Yorkshire Cancer Researc
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
Explorative studies to understand if aldehyde dehydrogenase (ALDH) expression in colon cancer can be exploited as a target for therapeutic intervention. Expression profiling of ALDH7A1 in colorectal cancer
No full textColorectal cancer (CRC) has been one of the leading causes of cancer related deaths worldwide. CRC patients with recurrent or metastatic disease remain difficult to treat with current treatment options.
Aldehyde dehydrogenases (ALDHs) are enzymes that play key roles in protecting cells against aldehyde-generated toxicity. Specific isoforms are also known to contribute to disease development. Emerging evidence suggests that specific ALDH isoforms might also be important for biomarker or drug discovery in CRC. The current thesis is focused on evaluating ALDH7A1 and other isoforms in patient samples while also investigating a novel library of naphthalimide-based compounds with potential to be used as hypoxia activated prodrugs (HAPs, and longer term as ALDH-targeting fluorescent probes. The current study is the first study to compare both Nigerian and UK patients with CRC disease. Interestingly, however, results showed ALDH7A1, and GLUT-1 were co-expressed in CRC xenografts and tissue microarrays (TMAs) revealing hypoxia also impacts on ALDH7A1 expression in clinical samples. Both ALDH1B1 and ALDH7A1 were shown to be highly expressed in all patient samples, however, in-depth mechanistic studies are required to fully elucidate the role of ALDHs in CRC.
Investigation of naphthalimide-based compounds including the anticancer agents amonafide and mitonafide (MITO) were carried out to understand the cytotoxic potency under both normoxic and hypoxic conditions. Only a few compounds were soluble in water and could undergo biological testing, which limited the structure-activity relationship studies. CD-10 was explored with MITO to develop a formulation to overcome the solubility issues. Studies presented in this thesis show for the first time that liposomes can be used to encapsulate naphthalimide compounds, providing an opportunity for investigating all compounds in the naphthalimide library in future studies.
In summary, the data in this thesis support the need for further studies to explore aldehyde dehydrogenase (ALDH) and its expression in CRC and whether it can be exploited as target for biomarker or drug discovery.Petroleum Technology Development Fund (PTDF) Nigeri
Explorative studies to understand if aldehyde dehydrogenase (ALDH) expression in colon cancer can be exploited as a target for therapeutic intervention. Expression profiling of ALDH7A1 in colorectal cancer
No full textPetroleum Technology Development Fund (PTDF) NigeriaThe full text will be available at the end of the embargo period: 21st March 202
Investigation of mechanisms of drug resistance in colorectal cancer: a proteomic and pharmacological study using newly developed drug-resistant human cell line subclones
Get PDFDespite therapeutic advances, colorectal cancer still has a 45% mortality rate, and one of the most crucial problems is the development of acquired resistance to treatment with anticancer drugs.
Thus the aims of this project are to develop drug-resistant colon cancer cell lines in order to identify mechanisms of resistance for the most commonly drugs used in colorectal cancer: 5-fluorouracil, oxaliplatin, and irinotecan.
Following evaluation of drug sensitivity to these agents in an initial panel of eight colorectal cancer cell lines, 3 lines (DLD-1, KM-12 and HT-29) were selected for the development of 5-FU (3 lines), oxaliplatin (2) and irinotecan (1) resistant sublines by continuous drug exposure, with resistance confirmed using the MTT assay. Consistently resistant sublines were subject to a „stable isotope labelling with amino acids in cell culture‟ (SILAC) approach and a MudPIT proteomics strategy, employing 2D LC and Orbitrap Fusion mass spectrometric analysis, to identify novel predictive biomarkers for resistance. An average of 3622 proteins was quantified for each resistant and parent cell line pair, with on average 60-70 proteins up-regulated and 60-70 down-regulated in the drug resistant sublines. The validity of this approach was further confirmed using immunodetection techniques.
These studies have provided candidate proteins which can be assessed for their value as predictive biomarkers, or as therapeutic targets for the modulation of acquired drug resistance in colorectal cancer
Investigation of inhibitors of polysialyltransferase as novel therapeutics for neuroblastoma. Development of in vitro assays to assess the functionality and selectivity of novel small-molecule inhibitors of polysialyltransferases for use in neuroblastoma therapy
Get PDFPolysialic acid is aunique carbohydrate that decorates the surface of the neural cell adhesion molecule. Polysialic acidis an onco-developmental antigen, expressed in tumours principally of neuroendocrine origin, notably neuroblastoma,strongly correlating with invasion and metastasis. Polysialylation is regulated by two polysialyltransferase enzymes, PST(ST8SiaIV)and STX(ST8SiaII),withSTX dominant in cancer. Post-development polysialic acid expression is only found at low levels in the brain, thus this could be a novel target for cancer therapy. It is hypothesized that inhibition of polysialyltransferasecould lead to control of tumour dissemination and metastasis.The aims of this thesis were to develop tools and in vitro assays to screen novel polysialyltransferaseinhibitors. A panel of tumour cell lines were characterised in terms of growth parameters (using the MTT assay) and polysialic acid expression. This includes a pair of isogenic C6 rat glioma cells (C6-STX and C6-WT) and naturally polysialic acid expressing neuroblastoma cells(SH-SY5Y). Following this, an in vitro assay was validated to screen modulation of polysialic acid expression by removing pre-existing polysialic acid expression using endoneuraminidase N and evaluated the amount of re-expression of polysialic acid using immunocytochemistry. Then, a functional assay was developed and validated for invasion, the matrigel invasion assay. Cytidine monophosphate (tool compound) significantly reduced polysialic acidsurface expression and invasion. A panel of six novel polysialyltransferase inhibitors was screened for cytotoxicity, polysialic acidsurface expression and invasion. Of the potential polysialyltransferase inhibitorsevaluated, ICT3176 and ICT3172 were identified from virtual screening of Maybridge library and were emerged as the most promising inhibitors, demonstrating significant (p<0.05)reduction in cell-surface polysialic acidre-expression and invasion in polysialic acid expressing cells.Furthermore, the specificity of compounds for polysialyltransferase (α-2,8-sialyltransferase) over othermembers of the wider sialyltransferase family (α-2,3-and α-2,6-sialyltransferases) was confirmed using differential lectin staining. These results demonstrated that small molecule inhibitors as STX is possible and provides suitable in vitrocell based assays to discovery more potent derivatives
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
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