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Coming dissertations at MedFak

  • Epidemiology of Physical Activity and Fragility Fractures Author: Karl Stattin Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-402747 Publication date: 2020-02-19 12:45

    Fragility fractures mainly affect elderly individuals and often cause long term pain, loss of function and higher mortality rates. Physical activity improves balance, increases muscle strength and bone mineral density, and may reduce the risk of fragility fractures. The aim of this thesis is to investigate the association between physical activity and fragility fractures.

    In Paper I the risk of hip and any fracture was investigated across levels of habitual walking/bicycling and exercise in participants from the population-based Cohort of Swedish Men (COSM) and Swedish Mammography Cohort (SMC). Individuals walking/bicycling a maximum of 20 minutes per day had a lower risk of hip and any fracture than individuals who did not walk or bicycle. The risk of hip and any fracture was gradually lower with increasing levels of exercise. In Paper II participants in the cross-country skiing race Vasaloppet were compared to non-participants from the general population, and were found to have a higher risk of any and forearm fracture but a lower risk of hip, proximal humerus and lower leg fracture. There was no difference in the risk of vertebral fracture. In Paper III, the association between physical activity and cardiovascular candidate plasma protein concentrations were analyzed in participants from the EpiHealth cohort and the Swedish Mammography Cohort Clinical. Of 184 assayed proteins, 75 associations with physical activity were discovered and 28 subsequently replicated in multivariable adjusted models. In Paper IV the COSM, SMC and the Vasaloppet cohort were combined to achieve as wide a range of physical activity as possible and a common measure of physical activity was created using generalized structural equation modeling (GSEM). Low levels of physical activity were associated with higher risk of any and hip fracture but lower risk of wrist fracture. Individuals with physical activity close to the median of the combined cohort had the lowest risk of fracture, and higher levels of physical activity was associated with a higher risk of any fracture.

    In conclusion, physical activity is associated with a lower risk of major fractures such as hip fractures, but may in large quantities increase the risk of wrist and any fracture. Physical activity is associated with more beneficial concentrations of 28 cardiovascular plasma proteins.

  • New targeted therapies for malignant neural tumors : From systematic discovery to zebrafish models Author: Elin Almstedt Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-402542 Publication date: 2020-02-14 09:40

    Cancers in the neural system presents a major health challenge. The most aggressive brain tumor in adults, glioblastoma, has a median survival of 15 months and few therapeutic options. High-risk neuroblastoma, a childhood tumor originating in the sympathetic nervous system, has a 5-year survival under 50%, despite extensive therapy. Molecular characterization of these tumors has had some, but so far limited, clinical impact. In neuroblastoma, patients with ALK mutated tumors can benefit from treatment with ALK inhibitors. In glioblastoma, molecular subgroups have not yet revealed any subgroup-specific gene dependencies due to tumor heterogeneity and plasticity. In this thesis, we identify novel treatment candidates for neuroblastoma and glioblastoma. 

    In paper I, we discover novel drug targets for high-risk neuroblastoma by integrating patient data, large-scale pharmacogenomic profiles, and drug-protein interaction maps. Using a novel algorithm, TargetTranslator, we identify more than 80 targets for this patient group. Activation of cannabinoid receptor 2 (CNR2) or inhibition of mitogen-activated protein kinase 8 (MAPK8) reduces tumor growth in zebrafish and mice models of neuroblastoma, establishing TargetTranslator as a useful tool for target discovery in cancer. 

    In paper II, we screen approximately 1500 compounds across 100 molecularly characterized cell lines from patients to uncover heterogeneous responses to drugs in glioblastoma. We identify several connections between pathway activities and drug response. Sensitivity to proteasome inhibition is linked to oxidative stress response and p53 activity in cells, and can be predicted using a gene signature. We also discover sigma receptors as novel drug targets for glioblastoma and find a synergistic vulnerability in targeting cholesterol homeostasis.

    In paper III, we systematically explore novel targets for glioblastoma using an siRNA screen. Downregulation of ZBTB16 decreases cell cycle-related proteins and transcripts in patient-derived glioblastoma cells. Using a zebrafish assay, we find that ZBTB16 promotes glioblastoma invasion in vivo

    In paper IV, we characterized the growth of seven patient-derived glioblastoma cell lines in orthotopic zebrafish xenografts. Using automated longitudinal imaging, we find that tumor engraftment strongly correlates with tumor initiation capacity in mice xenografts and that the heterogeneous response to proteasome inhibitors is maintained in vivo

    In summary, this thesis identifies novel targets for glioblastoma and neuroblastoma using systematic approaches. Treatment candidates are evaluated in novel zebrafish xenograft models that are developed for high-throughput glioblastoma and neuroblastoma drug evaluation. Together, this thesis provides promising evidence of new therapeutic options for malignant neural tumors.

  • Challenges in Islet Transplantation and Strategies to Improve Beta-Cell Function Author: Hanna Liljebäck Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-402501 Publication date: 2020-02-14 08:49

    The incidence of type 1 diabetes is increasing worldwide and therapies of islet transplantation and potential cell-based therapies are rapidly evolving. Choosing the optimal site for such therapies is crucial for safety and for obtaining the best possible outcome. The liver is currently the site of choice, but is unfortunately associated with disadvantages for graft survival.

    In paper I, intraportally transplanted human islets were evaluated for hypoxia, apoptosis, and beta-cell survival. This revealed a substantial graft loss of approximately 50 % of transplanted islet mass at one month posttransplantation. At the same time, revascularization was increased, yet still lower than that of native islets. The highest rate of apoptosis was associated with prolonged time in culture prior transplantation.

    Due to progressive loss of graft function, repeated islet transplantation is often performed. A mouse model, used in paper II, demonstrated an increased survival rate of islets transplanted one week after a first transplant. This finding may reflect an improved engraftment environment “primed” by the first islet injection. No difference in islet vascular density could be ascribed to it.   

    As stem cell-based therapies improve, graft monitoring possibilities and retrieval are of importance for safely introducing these techniques into the clinic. Islet grafts to omentum and muscle cured diabetic mice in paper III. Gene expression was unaltered or increased for genes important for beta-cell function.

    Decidual stromal cells (DSCs) have immunomodulatory properties that could prove useful for treatments of autoimmune or inflammatory conditions. In paper IV, DSCs were found to be easily isolated from human placenta. The cells were characterized by surface markers, differentiation capacity and gene expression during culture. Co-culture with human pancreatic islets was also conducted. DSCs were observed to be very similar to other types of mesenchymal stromal cells. Greatest change in gene expression was seen between passage 2 and 5. The effect on human islet function may depend on islet viability prior to co-culture.

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