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Coming dissertations at MedFak

  • Image-based multi-omics data integration : Exploring whole-body PET/MRI, -omics data and body composition Author: Robin Visvanathar Link: Publication date: 2022-05-19 14:11

    Advanced body composition analysis with whole-body imaging could uncover novel associations between regional tissue composition and metabolic disease. Imiomics is an automated image analysis framework that enables large-scale integration of magnetic resonance imaging (MRI) data and orthogonal technologies such as metabolomics and genomics for the detailed study of body composition. The Imiomics method is based on spatial normalisation to attain voxel-to-voxel correspondence in large cohorts of volumetric MR images. The spatially normalised data is then further used to generate voxel-wise statistical inference volumes for analysis. In this thesis, Imiomics was integrated with metabolomics for the first time, providing a detailed map of the relationship between the metabolome and regional body composition in T2D. Furthermore, Imiomics was integrated with genomics for the first time, exposing detailed associations between single nucleotide polymorphisms (SNPs) and sex-stratified body composition. A rapid and intuitive visual framework was developed for the analysis of volumetric Imiomics maps, and further applied to study the relationship between body composition and clinical variables in T2D. Whole-body positron emission tomography (PET)/MR was used to study detailed insulin-stimulated glucose metabolism and its associations with tissue volume and tissue fat fraction. This thesis has contributed to the field of advanced body composition research, primarily through the integration of Imiomics with additional -omics platforms.

  • CD93 in regulation of vascular function and tumour progression Author: Kalyani Vemuri Link: Publication date: 2022-05-19 08:50

    To achieve successful vascular targeting in cancer, a better understanding of the molecular mechanisms that lead to tumour vascular abnormalities is required.  The transmembrane protein CD93 is highly expressed in the vasculature of several tumours including glioblastoma and has emerged as a potential anti-angiogenic target. This thesis work explores the mechanisms through which CD93 contributes to vascular function and facilitates tumour progression. In paper I, we identify that CD93 interacts with the extracellular matrix (ECM) glycoprotein multimerin-2, which stabilizes CD93 at the cell surface and anchors it to the ECM protein fibronectin. CD93 binds to integrinα5β1 and regulates the activity of integrinβ1 and fibronectin fibrillogenesis in vitro. Consistent with this, the tumor vessels of CD93-/- mice bearing gliomas displayed an impaired integrinβ1 activity and fibronectin fibrillogenesis, suggesting that CD93-multimerin-2-fibronectin axis has an important role in tumour angiogenesis. In paper II, we explored the co-regulation of CD93 with other genes associated with glioblastoma vascular abnormalities. Using the publicly available Gliovis database for distinguished gene correlation analysis, we identified multimerin-2, fibronectin and angiopoietin-2 as candidate genes which are likely to be expressed with CD93 in glioblastoma vasculature. The expression of CD93, fibronectin and angiopoietin-2 was associated with high microvascular proliferation. Moreover, the presence of CD93 in a high proportion of the tumor vessels correlated with poor survival, suggesting that targeting CD93 can be beneficial for glioblastoma patients. In paper III, we explored the role of CD93 in the blood brain barrier (BBB) integrity. We demonstrate that CD93 regulates the activity of Rho-GTPases, thus stabilizing the endothelial junction molecules VE-cadherin and claudin-5 and preventing the internalization of VE-cadherin. Consistent with this, CD93-/- mice displayed a compromised BBB and exhibited an increased vascular permeability. In paper IV, we further explored the consequences of endothelial barrier disruption upon CD93-deficiency in cancer. We demonstrate that CD93 binds to VEGFR2 and that the absence of CD93 enhances VEGF-induced VEGFR2 phosphorylation in vitro. Consistent with this, melanoma-bearing CD93-/- mice displayed impaired vascular integrity and an enhanced MMP9 expression, leading to increased intravasation of tumour cells and increased metastatic spread. This phenotype was reversed to the wild-type level by inhibiting the VEGF-VEGFR2 signalling in CD93-/- mice. Taken together, this thesis work reveals a key role of CD93 in regulating vascular maturation and stabilization in health and cancer, and unveils its contribution to tumour progression and metastasis.

  • Effects of lung-protective ventilation on microbial growth and inflammatory biomarkers in experimental sepsis Author: Axel Nyberg Link: Publication date: 2022-05-18 08:57

    Sepsis is a severe disease state characterised by a dysregulated host response to infection. The need for mechanical ventilation is common in the sepsis population, for primarily pulmonary reasons or as a result of other organ dysfunction. Mechanical ventilation can be harmful to both the lungs and to extrapulmonary organs, particularly in association with an inflammatory insult. Great efforts has been made over the years in finding less injurious ventilator strategies aiming to reduce ventilator induced lung injury where focus has been on modulating tidal volume and positive end-expiratory pressure. A clear trend towards increased clinical use of this lung-protective ventilation has emerged. Consequently, investigation of the effects of mechanical ventilation on organs outside the lungs has earned growing scientific interest. We have used porcine experimental models to study the effects of different ventilator strategies. In an experimental Pseudomonas Aeruginosa pneumonia model the ventilatory differences on bacterial growth and lung injury were studied. Using an endotoxin challenge we aimed to study the effect of different ventilator regimens on systemic and organ-specific plasma levels of inflammatory cytokines and cell-free DNA. The effect of tidal volume on cerebral inflammation, metabolism and brain injury was studied during endotoxemia. Myostatin levels was studied in relation to anaesthesia, surgery, endotoxemia, pneumonia, inflammatory cytokines and different tidal volumes. The experiments were carried out for six hours or, to identify more long-term effects, for thirty hours.

    We found that ventilation with lower tidal volume and higher positive end-expiratory pressure reduce the bacterial burden and the development of lung injury in early pneumonia. Lung-protective ventilation suppresses systemic levels of cell free DNA and the liver is a significant contributor to systemic levels of cell free DNA, an effect that is attenuated by protective ventilation. Lower tidal volumes do not affect cerebral levels of cytokines but increase the cerebral perfusion, the cerebral metabolism and markers of brain injury in plasma and cerebral microdialysate. Plasma myostatin levels decrease in relation to surgery and anaesthesia where the decrease is decelerated by endotoxin. Myostatin levels in plasma were not affected by pneumonia or different tidal volumes.

    We conclude that lung-protective ventilation reduces pulmonary bacterial burden and lung injury in pneumonia and affects systemic and organ-specific levels of inflammatory markers in experimental sepsis with a potentially harmful effect on the brain.