1,720,995 research outputs found
Endometrial Cancer and Copy Number Variation
No full textEndometrial cancer is the most common gynaecological cancer in New Zealand and the incidence is increasing as the population ages. Genetic predictors of endometrial cancer risk that allow early detection of the disease are important for prevention and improved management strategies. Mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS1 and PMS2 are known to confer increased risk in a proportion of endometrial cancer cases, and the mutation spectrum includes copy number variants (CNVs). There are several other genes encoding proteins that act in the MMR pathways, but to date the evidence for their involvement in endometrial cancer predisposition is limited. This study aims to 1) To identify genes in the MMR pathway that are overlapped by CNVs in endometrial cancer cases, 2) To compare the CNV frequency of common and rare CNVs between endometrial cancer cases and controls, 3) To identify regions in the genome that are associated with endometrial cancer risk, and 4) To identify biological pathways that are enriched for genes overlapped by CNVs in cases and controls. Genome-wide scanning of CNVs was performed using Illumina610k single nucleotide polymorphism data from a large cohort of ~1300 endometrioid endometrial cancer cases and ~600 population-based female controls. Up to four CNV calling algorithms (CNVPartition, QuantiSNP, PennCNV and GNOSIS) were used to identify CNVs, and where possible, novel CNVs were validated by quantitative PCR.
This study has identified and confirmed deletions that disrupted known endometrial cancer susceptibility genes, MSH2 and MSH6. We also identified novel variants in several other mismatch repair pathway genes, including duplications overlapping TGFBR3 and MUTYH, and a deletion in RPA3, that are predicted to disrupt the coding sequence of TGFBR3 and RPA3. These results suggest that other genes within MMR pathway may be disrupted by mutations in a proportion of endometrial cancer cases and warrant further investigation. Three approaches were carried out to assess CNV load in cases and controls that defined CNV regions based on overlap with CNVs in the Database of Genomic Variants, overlap with discrete CNV clusters, and overlap with known coding genes. Results suggested that although there was no difference in the number of total CNVs between cases and controls, rare CNVs were shown to be more frequent in cases. For example, cases were found to have twice as many rare deletions as controls (p-value=2.2x10-16). Pathways analysis of genes overlapping these rare CNVs did not identify major gene networks in the endometrial cancer cases that were distinct from those found in the controls. However, some genes affected in the cases were found to form a network with genes, such as VEGF and FSH, which are known to play an important role in endometrial cancer development. Results from a genome-wide association study, identified several genes, including NF-κB, FSH and TK1 that were differentially affected by CNVs in cases and controls, but the relationship between these genes and endometrial cancer is unclear. Future studies will focus on confirming CNV load, genome wide association and pathway results in a larger cohort with age matched controls and characterising the contribution of individual variants with lymphablastoid cell line transcriptome analysis.
In conclusion, this study has identified areas for further investigation that have the potential to provide new insights into roles of CNVs in endometrial cancer susceptibility. These include three genes, RPA3, TGFBR3, and MUTYH, that have not previously been associated with endometrial cancer, and genomic features such as CpG islands, G4 quadruplexes and miRNAs that may have contributed to the development of endometrial cancer in this cohort. This thesis also highlights a number of limitations associated with studies of this kind, such as cohort size and cohort design, which must be overcome in order to successfully elucidate genetic contributors to this disease
Endometrial Cancer and Copy Number Variation
No full textEndometrial cancer is the most common gynaecological cancer in New Zealand and the incidence is increasing as the population ages. Genetic predictors of endometrial cancer risk that allow early detection of the disease are important for prevention and improved management strategies. Mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS1 and PMS2 are known to confer increased risk in a proportion of endometrial cancer cases, and the mutation spectrum includes copy number variants (CNVs). There are several other genes encoding proteins that act in the MMR pathways, but to date the evidence for their involvement in endometrial cancer predisposition is limited. This study aims to 1) To identify genes in the MMR pathway that are overlapped by CNVs in endometrial cancer cases, 2) To compare the CNV frequency of common and rare CNVs between endometrial cancer cases and controls, 3) To identify regions in the genome that are associated with endometrial cancer risk, and 4) To identify biological pathways that are enriched for genes overlapped by CNVs in cases and controls. Genome-wide scanning of CNVs was performed using Illumina610k single nucleotide polymorphism data from a large cohort of ~1300 endometrioid endometrial cancer cases and ~600 population-based female controls. Up to four CNV calling algorithms (CNVPartition, QuantiSNP, PennCNV and GNOSIS) were used to identify CNVs, and where possible, novel CNVs were validated by quantitative PCR.
This study has identified and confirmed deletions that disrupted known endometrial cancer susceptibility genes, MSH2 and MSH6. We also identified novel variants in several other mismatch repair pathway genes, including duplications overlapping TGFBR3 and MUTYH, and a deletion in RPA3, that are predicted to disrupt the coding sequence of TGFBR3 and RPA3. These results suggest that other genes within MMR pathway may be disrupted by mutations in a proportion of endometrial cancer cases and warrant further investigation. Three approaches were carried out to assess CNV load in cases and controls that defined CNV regions based on overlap with CNVs in the Database of Genomic Variants, overlap with discrete CNV clusters, and overlap with known coding genes. Results suggested that although there was no difference in the number of total CNVs between cases and controls, rare CNVs were shown to be more frequent in cases. For example, cases were found to have twice as many rare deletions as controls (p-value=2.2x10-16). Pathways analysis of genes overlapping these rare CNVs did not identify major gene networks in the endometrial cancer cases that were distinct from those found in the controls. However, some genes affected in the cases were found to form a network with genes, such as VEGF and FSH, which are known to play an important role in endometrial cancer development. Results from a genome-wide association study, identified several genes, including NF-κB, FSH and TK1 that were differentially affected by CNVs in cases and controls, but the relationship between these genes and endometrial cancer is unclear. Future studies will focus on confirming CNV load, genome wide association and pathway results in a larger cohort with age matched controls and characterising the contribution of individual variants with lymphablastoid cell line transcriptome analysis.
In conclusion, this study has identified areas for further investigation that have the potential to provide new insights into roles of CNVs in endometrial cancer susceptibility. These include three genes, RPA3, TGFBR3, and MUTYH, that have not previously been associated with endometrial cancer, and genomic features such as CpG islands, G4 quadruplexes and miRNAs that may have contributed to the development of endometrial cancer in this cohort. This thesis also highlights a number of limitations associated with studies of this kind, such as cohort size and cohort design, which must be overcome in order to successfully elucidate genetic contributors to this disease
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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