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101	Cell type-dependent differential activation of ERK by oncogenic KRAS or BRAF in the mouse intestinal epithelium Brandt, Raphael 10 March 2023 (has links) Kolorektale Karzinome (CRC) zeigen eine heterogene Ätiologie. Die Progression prämaligner Vorläufer zu CRC unterscheidet (U) sich in Morphologie, molekularen Veränderungen und Interaktion mit der Tumorumgebung. CRC weisen oft onkogene Mutationen in KRAS und BRAF auf. Diese steigern die MAPK Signalwegaktivität (Mpa). Obwohl sie im selben Signalweg wirken, sind KRAS und BRAF auf die CRC-Entitäten U verteilt. Dabei ist KRAS häufiger im sogenannten konventionellen und BRAF im serratierten Weg zu CRC mutiert. In dieser Studie nutzte ich murine intestinale Organoide (iO), die induzierbare (Ind) KRAS oder BRAF Onkogene exprimieren. Große U zwischen KRAS und BRAF zeigten sich sowohl in Signaltransduktion (ST) als auch im Phänotyp. Phosphoprotein-, ERK-Reporter-, scRNA-Seq und EM-Analysen ergaben eine starke Mpa durch BRAF, die zu hoher Expression von MAPK-Zielgenen und Verlust der epithelialen Integrität führte. iO nach KRAS-Ind blieben intakt, korrelierend mit moderater, zelltypspezifischer (ZS) Mpa in sekretorischen und undifferenzierten Zellen. Die meisten Enterozyten waren Mpa-negativ. ERK-Reporter zeigten: Das ZS Muster der Mpa ist nicht nur gegenüber KRAS, sondern auch dem Entzug von Wachstumsfaktoren stabil. Dies spricht für eine intrinsische, robuste Regulierung der Mpa. BRAF-Ind Mpa setzte die ZS Regulierung der MAPK außer Kraft und schädigte das Gewebe, im Einklang mit einer oberen Grenze tolerabler Mpa. Die ZS Mpa wurde in CRC-Zelllinien bestätigt, deren Mpa durch KRAS aber nicht BRAF U ausfiel. Ferner, nutzte ich iO mit bCatenin+KRAS-Ind, um den konventionellen Weg zu CRC zu modellieren. Die Kombination führte zu synergistischen Effekten, die sich in EGFR-unabhängigem Wachstum und der Aufhebung der ZS Mpa-Blockade äußerten, die durch eine Verschiebung der Differenzierung zu mehr Progenitorzellen bewirkt wurde. Zusammenfassend konnte ich U in der Mpa durch KRAS oder BRAF im Darmepithel feststellen, was dazu beiträgt, deren Rollen in der CRC-Genese zu bestimmen. / Colorectal cancer (CRC) is a disease with heterogeneous etiology. Premalignant lesions follow distinct routes of progression to carcinoma reflected by differences in morphology, molecular alterations and the tumor environment. Mutant KRAS and BRAF are frequent, leading to MAPK pathway activation (Mpa), which is relevant for CRC therapy. Despite acting in the same pathway, mutant KRAS and BRAF segregate to different entities, as KRAS is more frequent in the conventional- and BRAF being specific for the serrated route to CRC. I used murine intestinal organoids (iO) expressing inducible oncogenic KRAS or BRAF to study the impact of oncogenes in primary cells. I found marked differences in signal transduction and phenotype. Phospho-protein, ERK-reporter, scRNA-seq and EM data showed strong Mpa upon BRAF induction followed by ERK-target gene expression leading to tissue disruption. In contrast, KRAS left the tissue intact resulting in less and cell type-dependent Mpa limited to secretory cells, a subset of late-stage enterocytes and undifferentiated crypt cells. Most enterocytes were irresponsive to KRAS. The pattern of Mpa was robust towards KRAS or growth factor depletion arguing in favor of intrinsic, resilient MAPK regulation. In iO, BRAF-induced Mpa could break this cell type-specific regulation, indicating an upper limit of tolerable Mpa. I validated these findings in CRC cell lines that differed in Mpa in response to oncogenic KRAS but not BRAF. Finally, I used iO expressing an inducible form of stabilized bCatenin in combination with KRAS to mimic events frequently found in the conventional pathway to CRC. Expression of KRAS and bCatenin synergized in driving EGFR independent growth and breaking the villus-specific block of Mpa by altering differentiation towards progenitor cell types. In summary, this study emphasizes differences between Mpa induced by oncogenic KRAS or BRAF which helps clarifying their nature in different etiological routes to CRC genesis. KRAS KRASG12V BRAF BRAFV600E EGFR EGF MAPK ERK FIRE Reporter MEK MAPKK MAPKKK beta-Catenin intestinale Organoidkultur intestinale Organoide Mausmodelle von Tumoren kolorektales Karzinom kolorektale Karzionome CRC Primärzellen Tumormodelle Onkogene oncogenes KRAS oncogenes BRAF onkogene Signaltransduktion 3D Modell matrigel R-spondin RSPO Noggin KRAS KRASG12V BRAF BRAFV600E EGFR EGF MAPK ERK FIRE reporter MEK MAPKK MAPKKK beta-Catenin intestinal organoid intestinal organoids intestinal organoid culture murine model of cancer colorectal carcinoma CRC primary tumor model oncogenes oncogenic KRAS oncogenic BRAF 3D model matrigel R-spondin RSPO Noggin 610 Medizin und Gesundheit ddc:610
102	Offentliga arkiv och barns rättigheter : Svenska arkivinstitutioners syn på barnkonventionen, tillgänglighet och delaktighet Ahlerup, Emma January 2021 (has links) The study examines the perception of the UN Convention on the Rights of the Child, children's participation and the accessibility for children, within public archival institutions. The notion of participation is linked to the Convention’s Article 12: respect for the views of the child, whilst accessibility is associated with Article 31: the right to leisure, play and culture. Furthermore, the study explores the preconditions for children’s participation in accordance with Harry Shier's model Pathways to participation. The method used are web-based surveys. A total of 318 Swedish public archival institutions were invited to participate in two online questionnaires which generated 187 and 153 responses respectively. The study shows that 78 percent of the respondents know that the Convention on the Rights of the Child is Swedish law and 90 percent are aware of the obligation to impose it. Nevertheless, only 43 percent believe that their own institution takes the Convention into account. The respondents report a lack of resources and competence as the main obstacles. About 65 percent of the respondents state that their institution welcome children and young people as visitors. 85 percent believe that it is important that Swedish archive institutions and archives are accessible, but only 27 percent feel that their own institution is in fact accessible to children and young people. Many respondents cite a lack of resources as the main reason. The part of the survey that is based on Harry Shier's participation model shows that the preconditions for children's participation in the activities of the public archives are low. But it is also clear that the respondents' personal inclinations for children's participation exceeds the preconditions and requirements of the institution. The major obstacles to children's participation thus seem to exist at a structural level. / Uppsatsen syftar till att kartlägga inställningen till barnkonventionen, barns delaktighet och arkivens tillgänglighet för barn inom svenska offentliga arkivinstitutioner. Tillgänglighet och delaktighet kopplas till barnkonventionens artikel 12 – respekt för barns åsikter och artikel 31 – rätt till fritid, lek och kultur. Studien undersöker också förutsättningar för delaktighet utifrån Harry Shiers delaktighetsmodell Pathways to participation. Svaren har inhämtats genom två webbaserade enkätundersökningar. Studien visar att 78 procent av respondenterna känner till att barnkonventionen är svensk lag och 90 procent att det ingår i deras uppdrag att följa den. Men bara 43 procent anser att den egna arbetsplatsen tar hänsyn till barnkonventionen och det största hindret uppges vara bristande resurser och kompetens. 65 procent uppger att de tar emot besök av barn och ungdomar. 85 procent anser att det är viktigt att svenska arkivinstitutioner och arkiv är tillgängliga för barn, men bara 27 procent upplever att det egna arkivet är tillgängligt för barn. Även här uppger många bristande resurser som främsta orsak. Den del av undersökningen som är baserad på Harry Shiers delaktighetsmodell visar att förutsättningarna för barns delaktighet i de offentliga arkivens verksamhet är låg. Men det är också tydligt att respondenternas personliga vilja och intresse överstiger arbetsplatsens organisatoriska förutsättningar och krav för barns delaktighet. De främsta hindren för barns delaktighet verkar således finnas på en strukturell nivå. Public archives Swedish archives the CRC accessibility participation Offentliga arkiv svenska arkiv barnkonventionen tillgänglighet delaktighet Harry Shiers delaktighetsmodell. Information Systems, Social aspects
103	Educational opportunities for the girl child in Africa : a necessary revisit of the discrimination factor with reference to Egypt, South Africa and Cameroon Chofor Che, Christian-Aime January 2003 (has links) "This paper is therefore inspired to look at education with respect to girl children in Africa. This paper, by drawing inspriation from other settings, is also motivated by the need to find solutions on how best the rights of the girl child can be protected in conjuction with the educational policy of African countries. ... The study is divided into six chapters. Chapter one provides the context in which the study is set, the objectives of the study and its importance. Chapter two examines the importance of the right to education and in education and takes note of the issue of discrimination with respect to girl child education in Africa. In chapter three various international treaties that concern provisions on education and the discrimination factor as to gender are identified. Also in the international milieu, the role of international bodies in the effective and efficient insurance of girl child education is included. Chapter four examines on a regional level, the extent to which the African Commission has effectively monitored the provision of the African Chater. The African Children's Charter and the Draft Protocol to the African Charter on Human and Peoples' Rights on the Rights of Women (the Draft Women's Protocol) in Africa are also discussed in relation to provisions in the African Charter and work done on girl child education by the African Commission. In this chapter, a comparative study is also done of instruments and the implementation mechanisms offered by the Inter-American and European systems to the African human rights system in terms of the girl child education. This is so because in terms of experience, jurisprudence and institutions, these systems are considered to be more advanced than the African human rights sytem. Finally chapter five discusses girl child education on a national level in Africa. This chapter focuses on the experiences of South Africa, Egypt and Cameroon. Educational policy and other national legislative instruments such as the constitutions of these countries are included. In the conclusion, the paper puts forward recommendations to assist new and old African democracies in advancing an administrative and political approach to the issue of discrimination with respect to girl child education." -- Chapter 1. / Prepared under the supervision of Dr. Enid Hill at the Department of Political Sciences, School of Humanities and Social Sciences, The American University in Cairo, Egypt / http://www.chr.up.ac.za/academic_pro/llm1/dissertations.html / Centre for Human Rights / LLM UCTD Right to education Education Human rights Socio-economic rights Girl child Girls Children's rights Gender discrimination Egypt South Africa (SA) Cameroon Africa Children's Charter Draft Women's Protocol
104	Weighted gene co-expression network analysis of colorectal patients to identify right drug-right target for potent efficacy of targeted therapy Tripathi, Anamika 10 December 2017 (has links) Indiana University-Purdue University Indianapolis (IUPUI) / Colon rectal cancer (CRC) is one of the most common cancers worldwide. It is characterized by the successive accumulation of mutations in genes controlling epithelial cell growth and differentiation leading to genomic in-stability. This results in the activation of proto-oncogene(K-ras), loss of tumor suppressor gene activity and ab-normality in DNA repair genes. Targeted therapy is a new generation of cancer treatment in which drugs attack targets which are specific for the cancer cell and are critical for its survival or for its malignant behavior. Survival of metastatic CRC patients has approximately doubled due to the development of new combinations of stan-dard chemotherapy, and the innovative targeted therapies, such as monoclonal antibodies against epidermal growth factor receptor (EGFR) or monoclonal antibodies against vascular endothelial growth factor (VEGFR).The study is to exhibit the need for right drug-right target and provides a proof of principle for potent efficacy of molecular targeted therapy for CRC. We have performed the weighted gene co-expression network analysis for three different patient cohort treated with different targeted therapy drugs. The results demonstrates the variation across different treatment regime in context of transcription factor networks. New significant tran-scription factors have been identified as potential biomarker for CRC cancer including EP300, STAT6, ATF3, ELK1, HNF4A, JUN, TAF1, IRF1, TP53, ELF1 and YY1. The results provides guidance for future omic study on CRC and additional validation work for potent biomarker for CRC. Colorectal Cancer(CRC) molecular targeted therapy co-expression network cetuximab treated patient weighted gene co-expression differentially expressed gene co-expression module module preservation patient cohort pathway analysis epidermal growth factor receptor vascular endothelial growth factor transcription factor transcriptional mi regulation gene expression chemotherapy

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