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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Prevalence, Risk Factors and Predictors of Adverse Outcomes of Febrile Neutropenia in Oncology Patients on Chemotherapy at the Red Cross War Memorial Children's Hospital: A Three Year Retrospective Study

Adekunle, Motunrayo 08 June 2022 (has links)
Background: Febrile neutropenia (FN) is the commonest fatal acute complication of cancer treatment in children. The need for regional clinical decision rules allowing for home-based care in those at low risk for adverse outcomes has been identified. Aims: To evaluate the prevalence and potential risk factors for FN, identify adverse outcomes and validate a tool to identify risk for adverse outcomes in a cohort of children treated for cancer at the Red Cross War Memorial Children's Hospital, Cape-Town, South Africa. Methodology: A retrospective cohort study from 1st January 2017 to 31st December 2019. Results: In all, 179 patients had chemotherapy and 267 FN episodes occurred. Independent predictors of FN were AML (p = 0.039), ALL (p = 0.020) and intensive chemotherapy (p = < 0.001). Mucositis (p = 0.001), CVAD (p = 0.004, haematologic malignancies (p = 0.040), blood transfusion during FN episode (p = 0.001) and severe neutropenia (white cell counts< 0.3 x 109 cells/L) (p = < 0.001) were risk factors for adverse outcomes. The mortality rate from FN was 3.57%. Independent predictors of adverse outcomes were AML (p = 0.001), CVAD in-situ (p = 0.019) and severe neutropenia (p = 0.005). Validation of risk stratification for adverse outcomes using the Swiss Paediatric Oncology Group (SPOG) index with a cut-off value of nine demonstrated a sensitivity and specificity of 52.3% and 62.0%, respectively. Positive and negative predictive values were 56.3% and 58.2%, respectively, with an overall accuracy of 57.4%. In our cohort, coordinates of the curve are best able to predict adverse outcomes with a cut-off value of 7.5. Conclusion: Adverse outcomes from treatment are likely in children with AML, severe neutropenia and those with CVADs in-situ. A lower cut-off of 7.5 using the SPOG FN risk index best predicted adverse outcomes in our cohort.
2

Establishment and maintenance of the DNA methylation pattern in the human alpha-globin cluster

Gaentzsch, Ricarda E. G. January 2013 (has links)
DNA methylation is an epigenetic modification that plays an important role in development and differentiation. The patterns of DNA methylation are largely established in early embryogenesis and maintained during development. Abnormal DNA methylation patterns have been associated with many human diseases, including cancer. Despite its importance, little is currently known about the mechanisms that determine DNA methylation patterns throughout the genome. To shed light on the molecular mechanisms that regulate DNA methylation, this study investigates whether DNA methylation patterns are established and maintained normally when human DNA is placed into a heterologous murine environment as opposed to its natural, endogenous chromosomal environment. Here, a previously generated transgenic mouse model, containing 117 kb of human DNA bearing the human &alpha;-globin cluster and all of its known regulatory elements, was analysed. The pattern of DNA methylation of the endogenous human &alpha;-globin cluster was compared with that of the transgenic cluster in the background of mouse embryonic stem cells (ESCs) and tissues. It was found that, although the normal human DNA methylation pattern was largely established and maintained in a mouse background, the region immediately around the human &alpha;-globin genes themselves is generally less methylated in mouse compared to human ESCs. It was found that regions adjacent and up to 2kb from the CpG islands (CGIs), so-called CGI shores, were unusually hypomethylated: this seems to be the result of an extension of CGIs in humanised mouse (hm) ESCs compared to human (h) ESCs. Furthermore, this hypomethylation appeared to increase during development in both erythroid and non-erythoid cells. To identify any cis-regulatory sequences responsible for the hypomethylated state of human CGI shores in the mouse, 2-4 kb human test sequences containing the CGI associated with the human &alpha;-globin 2 (α2) gene and its adjacent hypomethylated shore were re-integrated into the mouse &alpha;-globin locus via recombination-mediated cassette exchange (RMCE). Human CGI shores became hypomethylated in the context of the re-integrated test sequences, indicating that the appearance of hypomethylation is determined by the underlying human DNA sequence in the test fragments. In summary, the data presented here reveal that human CGIs become extended when placed in a mouse background leading to hypomethylation of human CGI shores in the mouse compared to the pattern of methylation at the normal endogenous human locus. These findings suggest that species-specific factors determine DNA methylation near CGIs. The transgenic mouse model provides an excellent system to dissect out species-specific regulation of CGI shore methylation. Furthermore, this study lays the foundation for future experiments addressing the role of DNA methylation in regulating human gene expression in the murine context, and examining the validity of transgenic mouse models for the study of human gene regulation.

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