1,721,008 research outputs found
Leveraging technological opportunities in cancer genomics
No full textCancer genomics is a thriving field with constant methodological and technological advances. These developments enable personalized and targeted treatments for cancer patients based on the unique genomic profiles of tumors. In this thesis I leveraged novel technologies for the advancement of cancer research and care. In chapter 1 I introduced the different types of genomic variation, the genomic characteristics of cancer, the importance of genomic technology for personalized medicine and the potential of liquid biopsies for low-invasive cancer monitoring. I also introduced model systems used in cancer research, including patient-derived organoids (PDOs), detailing the potential for their use particularly in ovarian cancer (OC). Lastly, I introduced the role of somatic SV in cancer and the different sequencing technologies that are used to detect them, along with the challenges that this presents.
In the first part of this thesis, we used organoid technology to advance OC research. In chapter 2 we established and characterized a PDO biobank that faithfully represented the disease, and presented its applications. Next, we expanded the OC-PDO biobank and used those PDOs for extensive drug screening in chapter 3. We performed screening assays on 36 PDO lines derived from 23 patients and retrospectively compared their drug responses to clinical responses of the patients.
In the second part of the thesis I focused on somatic structural variation in cancer. Accurate detection of structural variants (SVs) is still challenging, and truth sets and standardized workflows are lacking. We tackled the challenge of accurate somatic SV detection in cancer genomes and generated a truth set of somatic SVs that can be used for method development and benchmarking, which I presented in chapter 4. Furthermore, we developed methods to utilize long-read sequencing and somatic structural variants (SVs) for cancer dynamics after treatment and minimal residual disease tracing. In chapter 5, we developed an assay that leveraged nanopore sequencing technology for rapid detection of somatic SVs from a tumor.We also developed an assay that leverages CRISPR-Cas9 based enrichment of genomic targets in pediatric leukemias from the lymphoid lineage. In chapter 6, we targeted loci recurrently involved in genomic rearrangements in these leukemias, such as the immunoglobulin (Ig) and T-cell receptor (TCR) loci, and the KMT2A and SIL-TAL1 fusion-gene loci.
Finally, in chapter 7 I discussed and reflected on the technological advances presented in the previous chapters. I explained the advantages of PDO technology in OC research, but also the challenges for its further clinical implementation in clinical care. Similarly, I identify current challenges and propose several solutions for enhancing the knowledge of the role of somatic SVs in cancer and implementation of long-read sequencing. In conclusion, this thesis proposes several cancer genomics technological opportunities to advance cancer research and develop personalized diagnostic assays to improve patients’ outcomes
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
Relating genomic and functional heterogeneity to clinical outcomes in epithelial ovarian cancer
No full textThe expression and function of microRNAs in vertebrate embryonic development
No full textMicroRNAs regulate gene expression at the posttranscriptional level by binding to the 3'UTR of mRNAs. These small RNA molecules (~22 bases in length) are processed from long primary transcripts (pri-miRNA). In animals, microRNAs bind with imperfect complementarity to their target mRNA. This leads to relocalization of the mRNA to cytoplasmic bodies, where the mRNA is degraded and translationally repressed. Although the mechanism of inhibition is still unclear, the work in this thesis introduces one important aspect of miRNA regulation, which is the recognition of the target mRNA. Using zebrafish embryos as an in vivo system, the activity of the let-7 miRNA was determined. Analysis of all possible point mutant derivatives of let-7 showed that the first 8 nucleotides are most important for its activity. This part of the microRNA is known as the microRNA seed. As a consensus, many mRNA that are targeted by microRNAs are regulated by perfect seed pairing. MicroRNA target prediction algorithms use the microRNA seed as the basis for computational target identification. Such predictions have shown that every microRNA may regulate hundreds of mRNAs. The regulation of these mRNAs is essential for embryonic development, since animals without microRNAs cannot live. To understand the role of individual microRNAs in vertebrate embryonic development, this thesis describes a method to visualize microRNAs in the embryo, based on Locked Nucleic Acid (LNA) probes. MicroRNA expression analysis was thus far limited to low resolution Northern blotting and micro-arrays. Determining the expression of 115 conserved microRNAs with LNA probes revealed striking tissue-specific expression patterns, suggesting that microRNAs play a role in tissue development or maintenance of tissue identity. The complete microRNA repertoire of an animal is estimated to run into the thousands. To extend the set of zebrafish microRNAs, this thesis describes a cloning approach combined with deep-sequencing to identify new microRNAs. This showed that the conserved and highly expressed microRNAs in zebrafish are now known. Also 66 novel microRNAs were discovered, but these are generally poorly conserved and expressed at low levels. Vertebrate embryonic development is most easily studied in zebrafish, but genetically disrupting miRNA genes to see which miRNA does what is technically challenging. In this thesis, a method is described to transiently interfere with miRNA function during the first few days of zebrafish embryonic development by introducing specific antisense morpholino oligonucleotides (morpholinos have been used previously to interfere with the synthesis of the much larger mRNAs). Morpholinos targeting the miRNA precursor can block processing of the pri-miRNA or directly inhibit the activity of the mature miRNA. Morpholino-mediated microRNA knockdown did not reveal gross developmental defects for many microRNAs. However, knockdown of zebrafish miR-375 showed that this microRNA is essential for formation of the insulin-secreting pancreatic islet. Loss of miR-375 results in dispersed islet cells by 36 hours postfertilization, representing one of the first vertebrate miRNA loss-of-function phenotypes. Morpholinos will be widely applied for studying microRNAs in embryonic development
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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