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Coming dissertations at Uppsala university

  • Role of MYCN in retinoblastoma : From carcinogenesis to tumor progression Author: Hanzhao Zhang Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-523595 Publication date: 2024-03-19 08:37

    Retinoblastoma, a pediatric malignancy of the retina, is primarily driven by the bi-allelic inactivation of the RB1gene. However, a subset of cases are characterized by proficient RB1 functions but with MYCN copy number mutations, suggesting an alternative oncogenic mechanism in the absence of RB1 mutations. The aim of this thesis is to investigate the intricate molecular and cellular pathways implicated in retinoblastoma, with a particular focus on the role of MYCN expression and its interplay with the cell cycle and apoptotic pathways.

    In Paper I, we explored the regulatory mechanisms underpinning MYCN-induced retinoblastoma using aRB1-proficient MYCN-overexpressing in vivo model in embryonic chicken retina and MYCN-transformed cells in culture. Our findings revealed that MYCN overexpression led to a significant upregulation of E2F levels, thereby dysregulating the cell cycle and mimicking the mechanistic phenotype of RB1-deficient tumors. Inhibition on E2f DNA-binding activity efficiently normalized growth and apoptosis in MYCN-transformed cells in culture. Despite RB1 proficiency, the elevated E2F levels induced a neoplastic behavior in retinal cells, indicating a novel mechanism of retinoblastoma carcinogenesis independent of RB1 inactivation.

    Paper II employed single-cell RNA sequencing to dissect the cellular composition of MYCN-driven retinoblastoma in chicken in vivo model, revealing a predominant origin in cone photoreceptor progenitors. This finding suggested a cell-type-specific vulnerability to MYCN-induced transformation. The research further identifies a notable heterogeneity within the MYCN-transformed cells, with a subset of cells exhibiting non-cone photoreceptor features but features of other neurons like ganglion cells. A cluster was also identified withelevated expression of genes related to malignancy and tumor progression, including UBE2C and TOP2A. This suggested a link between MYCN overexpression and tumor development, potentially mediated through the E2F pathway.

    In Paper III, the focus shifted to the interplay between MYCN expression, E2f activity, and the p53 pathway in human retinoblastoma cell lines exhibiting both RB1 deficiency and MYCN amplification. By modulating E2f and p53 pathway activities using chemical inhibitors, we demonstrated the essential role of MYCN expression level in mediating p53-driven growth inhibition and highlighted the independent effects of E2f inhibition and p53 activation by a Mdm2 inhibitor.

    Together, these studies illuminate the intricate molecular pathways involved in MYCN-amplified retinoblastoma, emphasizing the pivotal role of MYCN in disrupting cell cycle regulation and promoting tumorigenesis. These insights not only advance our understanding of retinoblastoma pathogenesis but also provide potential therapeutic targets within the MYCN-E2F axis, offering novel treatment strategies in MYCN-amplified retinoblastoma.

  • Patients’ Access to Their Mental Health Records : Understanding Policy, Access, and Patient Experiences Author: Annika Bärkås Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-522720 Publication date: 2024-03-15 14:21

    ORA is the concept of patients' access to clinical information, which has become more widespread worldwide. When patients are provided online record access (ORA) to their health records, concerns have been raised by healthcare professionals, especially when it comes to patients with mental health diagnoses. In the general population, positive aspects appear to outweigh the negative, yet limited research has so far explored the impact of ORA in mental healthcare. 

    The overall aim of this thesis was to explore how patients experience ORA in mental healthcare through four studies: 1) a literature review aimed to explore the current literature on the experiences of ORA among mental healthcare patients, care partners, and healthcare professionals, 2) a document analysis combined with key stakeholder email interviews that aimed to explore to what extent ORA in mental healthcare has been implemented in Sweden including national and local policy regulations, 3) an online patient survey study aimed to understand mental healthcare patients' experiences with ORA in Sweden, Estonia, Finland, and Norway, and 4) an online patient survey study aimed to understand if and how patients with mental health conditions experiences of ORA differs from patients in other healthcare settings. 

    More patients reported positive experiences with ORA in mental healthcare than negative experiences. Common benefits of ORA included, among others, a greater sense of control over their care, improved understanding of their mental health diagnosis, and better adherence to appointments. Despite patients' predominant positive experiences, only 17 out of 21 regions in Sweden offered ORA in mental healthcare in 2021. Additionally, many patients experienced errors and omissions and felt offended by the content of their health records. Mental healthcare patients experienced this at a higher rate than patients in other healthcare settings.

    In conclusion, mental healthcare patients have higher rates of negative experiences of ORA compared to patients in other healthcare settings. However, patients' experiences of ORA are still predominantly positive among both patient groups. Yet, in 2021, only 17 regions offered patients ORA in mental healthcare. Denying mental healthcare patients ORA to protect them from negative experiences could instead increase stigma in this patient group.

  • Miniaturized fluid system for high-pressure analytics Author: Simon Södergren Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-523408 Publication date: 2024-03-13 14:53

    High-pressure chemistry can be used to determine the contents of blood or water samples and to discover new chemistries. However, working with chemistry at pressures of many tens, or even hundreds, of bars often requires expensive and stationary equipment, such as autoclaves or chromatographic systems like high-performance liquid chromatography (HPLC).

    Since the introduction of microfluidics in the '90s, researchers have attempted to develop microfluidic chips as microreactors to speed up synthesis with faster mass and heat transfer. Other researchers have made efforts to create microfluidic chip-based HPLC to reduce the cost, increase the separation quality, speed up the analysis, and even enable portable systems for on-site medical or environmental analysis. Still, fully integrated systems have not yet been realized due to a lack of fluidic control components.

    This thesis presents novel methods for on-chip regulation and monitoring of pressure, flow, and temperature. Papers I and II specifically suggest a method for regulating backpressure and stabilizing pressure and flows using thermally controlled restrictors. Furthermore, a collaboration was made where a pressure-regulating chip was connected to an on-chip HPLC. The purpose of this was to activate sample plugs and therefore reduce the requirement for expensive surrounding equipment and enable portability, Paper III. Paper IV explores the use of a pressurized capsule to generate high-pressure flows that are coupled to a pressure-regulating chip to stabilize and regulate the pressure. Finally, an approach for integrating pressure sensors into high-pressure tolerant microchannels has been proposed, Paper V.

    The work conducted has provided new insights into fluid dynamics. The regulating method employed in Paper I-IV utilizes a restrictor that alters the pressure drop as temperature changes, hence changing the viscosity of the fluid. Although this technology has been known since before, new understandings have emerged regarding how the compressibility of incompressible fluids must be considered at higher pressures. Additionally, the concept of buffer capacitance is presented, which is central when working with high-pressure microfluidics.

    Through this thesis, discoveries of high-pressure microfluidics have been accomplished, which enable micro-total-analysis systems that could serve as portable HPLC equipment.

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