1,721,090 research outputs found
Functional assessment of germline variants of unknown clinical significance by mRNA analysis in patients at high risk of hereditary cancers
No full textGenetske različice lahko povzročijo nepravilno prepoznavo spojitvenih mest med procesom izrezovanja intronov in spajanja eksonov, ki ga izvrši izrezovalno-povezovalni kompleks med formiranjem zrele mRNA. Posledica tega je spremenjena mRNA molekula, kar je lahko vzrok za nastanek genetskih sindromov. Eden od načinov, da odkrijemo različice, ki povzročijo napačno prepoznavo spojitvenih mest je, da določimo neposreden vpliv različice na molekuli mRNA nosilca različice. Za namen te doktorske naloge smo razvili in validirali nov pristop sekvenciranja cDNA za določanje alternativnih transkriptov in zarodnih okvar na molekuli mRNA nastalih med procesom izrezovanja intronov in spajanja eksonov. Z novim pristopom sekvenciranja cDNA smo odkrili nove alternativne transkripte v genih STK11, NBN in BRIP1. V genu STK11 smo odkrili 18, v genu NBN 49 in v genu BRIP1 7 novih alternativnih transkriptov. Vse odkrite alternativne transkripte smo anotirali in objavili prvi obsežen katalog alternativnih transkriptov v navedenih genih. V drugem delu raziskave smo izvedli bioinformatsko oceno vpliva različic na izrezovanje intronov in spajanje eksonov. Funkcijsko smo opredelili 32 različic neznanega kliničnega pomena (VUS) v genih povezanimi z dednimi oblikami raka. S pomočjo novega pristopa sekvenciranja cDNA smo uspešno reklasificirali 65,6 % vseh VUS-ov (46,9 % v verjetno benigno različico in 18,8 % v verjetno patogeno različico). Od 2808 preiskovancev smo pri 2 % odkrili VUS s potencialnim vplivom na izrezovanje intronov in spajanje eksonov. Od analize mRNA je imelo korist 1,4 % pacientov, pri katerih smo VUS reklasificirali. Vzročno različico smo z analizo mRNA opredelili pri 0,2 % preiskovancih.During RNA splicing, genetic variants can alter the identification of splice sites recognized by the spliceosome. Altered recognition of splice sites can cause aberrant mRNA molecule, which can be the underlying cause of genetic syndrome development. One of the approaches to detect variants that cause misrecognition of splice sites is to determine the effect of the variant directly on the patient’s mRNA molecule. In this doctoral thesis, we developed and validated a new cDNA sequencing approach to identify splicing aberrations resulting from germline variants. By using new approach, we discovered 18, 49, and 7 new alternative transcripts in the STK11, NBN, and BRIP1 genes, respectively. We annotated all the discovered alternative transcripts and published the first comprehensive catalog of annotated alternative transcripts for these genes. In the second part of the study, we performed a bioinformatics assessment of variants\u27 impact on splicing. We functionally assessed 32 variants of unknown clinical significance (VUS) in genes associated with hereditary cancer syndromes. Using the novel cDNA sequencing approach, we successfully reclassified 65.6 % of all VUSs (46.9 % were reclassified as a likely benign variant and 18.8 % as a likely pathogenic variant). Among 2808 patients included in the study, we found that 2 % of them carried a VUS with a potential impact on splicing. We were able to successfully reclassify VUS in 1.4 % of patients through mRNA analysis. The causative variant was identified through mRNA analysis in 0.2 % of patients
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
Kratek pregled trenutnega stanja na področju tumorskih vakcin in povzetek našega dela na tem področju
Get PDFTumorske vakcine predstavljajo obliko biološkega (imunskega) zdravljenja, s katerim skušamo sprožiti učinkovit sistemski imunski odziv proti tumorskim antigenom, s tem pa tudi proti tumorskim celicam v celoti. Učinek tumorskih vakcin je tako odvisen od: 1) prisotnosti/odsotnosti prepoznavnih tumorskih antigenov, 2) prisotnosti kostimulatornih molekul, ki sodelujejo pri aktivaciji efektorskih celic, 3) učinkovitosti predstavljanja antigenov in kostimulatornih molekul efektorskim celicam, 4) razvoja specifične protitumorske imunosti in 5) razvoja procesov, s katerimi se tumorske celice izognejo imunskemu nadzoru. Glede na osnovne metode oblikovanja tumorskih vakcin in glede na njihovo pričakovano učinkovitost jih razdelimo v dve skupini: 1) vakcine prve generacije, ki temeljijo na načelih klasične imunologije – t. i. klasične tumorske vakcine, in 2) vakcine druge generacije, ki temeljijo na načelih molekularne imunologije – gensko spremenjene in rekombinantne tumorske vakcine. V tem članku želim predstaviti kratek pregled glavnih pristopov k oblikovanju tumorskih vakcin in raziskave s tega področja, ki potekajo na Onkološkem inštitutu
Pregled pomembnejših tumorskih označevalcev v klinični onkologiji
Get PDFV knjigi so predstavljeni nekateri najbolj znani tumorski označevalci, ki se določajo v serumih bolnikov za potrebe klinične onkologije. Poleg pomena posameznih tumorskih označevalcev so v knjigi opisane tudi referenčne vrednosti, indikacije in načini spremljanja bolnika
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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