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Coming dissertations at MedFak

  • Peripheral immunity in patients with autoimmune endocrine diseases and the influence of physiological adaptions during pregnancy Author: Louise Magnusson Link: Publication date: 2021-04-16 08:59

    Type 1 diabetes (T1D), Hashimoto’s thyroiditis (HT), Graves’ disease (GD), and autoimmune Addison’s disease (AD) appear to share immunogenetic mechanisms. This idea is not novel, as “autoimmune tautology” is an established concept. An issue with previous studies is that no or few simultaneous comparisons between these autoimmune endocrine diseases have been made. Due to methodological limitations, immune deviations associated with these diseases have also been examined for a limited number of immune cell lineages and analytes. High-dimensional single-cell mass cytometry was thus employed to phenotypically characterise all peripheral CD45+ cell lineages, whilst immune-related proteins in plasma and cell supernatants were analysed by proximity extension assay. Patients with new-onset T1D, HT, and AD had altered frequencies of distinct clusters within antigen-presenting and cytotoxic cell lineages. Importantly, previously unreported alterations of rare cell subsets from patients with HT and AD were identified. The systemic immunoprofile of patients with autoimmune endocrine diseases was in general similar. However, an increased abundance of CDCP1 and SLAMF1 in plasma from patients with T1D, HT, and GD might reflect a higher degree of inflammation and lymphocyte activation.

    Pregnancy in healthy women entails two important features: 1) an increase in fractional β-cell area and 2) peripheral immunomodulation. The effects of pregnancy on T1D remain nevertheless equivocal, as there are conflicting results on β-cell function and longitudinal analyses on peripheral immunity are lacking. β-cell function and the plasma proteome in pregnant women with long-standing T1D (L-T1D) were therefore examined during three occasions: 1) first trimester, 2) third trimester, and 3) two months postpartum. An oral glucose tolerance test was performed to measure both fasting and stimulated C-peptide concentrations in plasma. Plasma proteins related to cell regulatory and immunological processes were analysed by proximity extension assay. Glucose-induced insulin secretion was regained in pregnant women with L-T1D, which decreased slowly after parturition. The plasma proteome was dynamic during gestation, although few analytes were functionally linked. A recovered β-cell function might be related to elevated plasma levels of prolactin, prokineticin-1, or glucagon. Moreover, reduced plasma levels of proteins related to leukocyte migration, T cell activation, and antigen-presentation might have further protected an improved β-cell function.

  • Preclinical PET imaging and therapy of Alzheimer's disease Author: Silvio R. Meier Link: Publication date: 2021-04-15 14:43

    The main histopathological hallmarks of Alzheimer’s disease are extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles, containing tau protein. Because of misfolded and aggregated proteins, activated microglia and astroglia react with a neuroinflammatory response, which may contribute to disease progression and severity. To date, there is no treatment available that stops the underlying mechanisms of the disease, but several new drug candidates entered clinical trials every year during the last decade. New treatments, aiming to clear Aβ from the brain parenchyma or to reduce Aβ production, are dependent on diagnostic tools to follow changes in brain Aβ pathology in vivo. The presence of brain amyloid, verified with positron emission tomography (PET), is a regularly used criterion for enrolling patients in clinical trials. However, current amyloid radioligands such as [11C]Pittsburgh Compound B ([11C]PiB) have some disadvantages, e.g. early saturation during disease progression and reduced binding to diffuse Aβ pathology. Currently available radioligands for imaging of neuroinflammation are also suboptimal. 

    In this thesis, we investigated the potential of a brain-penetrating, bispecific Aβ antibody as a PET ligand to detect effects of treatment. In paper I and II, we demonstrated that this ligand can follow Aβ disease progression and that Aβ reduction due to treatment with a BACE-1 inhibitor can be quantified in a mouse model of AD. In paper II we also compared antibody-PET with [11C]PiB-PET and showed that the two ligands provided differing read-outs.

    In paper III we created and investigated an antibody-based radioligand against the triggering receptor expressed on myeloid cells 2. Compared to wild type mice, transgenic animals displayed higher total in vivo exposure, calculated as the area under the concentration curve based on PET at 24 h, 48 h and 72 h post injection. However, differences were not evident in single time point PET images.

    In paper IV we investigated brain delivery of a nanobody against GFAP with and without active transcytosis over the blood-brain barrier in vivo. Brain uptake with active transcytosis was two times higher. However, brain retention after 8 h, 24 h or 48 h did not differ between transgenic and wild type mice. 

    In paper V we studied the potential of a hexavalent and bispecific antibody construct against soluble Aβ aggregates for PET or immunotherapy in vivo. Its brain retention increased with age when applied at tracer doses in genetically modified mice. However, when applied at therapeutic dose, it had no or very low impact on Aβ levels measured in brain homogenates. 

  • Promoting physical activity during and after curative cancer treatment : Assessment, experiences and effect of behaviour change support Author: Anne-Sophie Mazzoni Link: Publication date: 2021-04-14 10:43

    Aims:The overall aim of this thesis was to increase knowledge about the promotion of physical activity (PA) in patients during and after curative cancer treatment. Methods: Study I investigated agreement between a 7-day diary and the SenseWear Armband mini (SWA) when assessing PA and sedentary time in 65 participants with breast cancer. Agreement was examined with Bland-Altman plots. Studies II-IV used data from an RCT, where participants about to start curative treatment for breast, prostate or colorectal cancer, were randomised to six months of high or low-to-moderate intensity exercise (supervised group-based resistance- and home-based endurance training), with or without self-regulatory behaviour change techniques (BCTs; e.g. goal-setting and action planning). In study II, participants randomised to the groups with self-regulatory BCTs answered a questionnaire (n=229) and took part in semi-structured interviews (n=18) after exercise programme completion. The interviews were analysed with thematic analysis. In Study III, all participants (n=577) randomised were included. Exercise adherence during the intervention was assessed with attendance records, training logs and heart rate monitors. Regression analyses were performed to determine the effect of self-regulatory BCTs on exercise adherence. In Study IV, participants (n=301) who provided data about their PA level at 12-month follow-up were included. Regression analyses were performed to determine the effect of self-regulatory BCTs on PA maintenance and potential baseline predictors. Results: There were mean differences and wide limits of agreement between the 7-day diary and the SWA when assessing PA and sedentary time. Participants described different incentives to exercise, which fostered feelings of autonomy, competence and relatedness and helped them find motivation to exercise during cancer treatment. Social support from coaches, feedback, self-registration of exercise and scheduled sessions at a public gym were useful for exercising. There was no effect of the self-regulatory BCTs on exercise adherence during the intervention; however, a positive effect was found on PA maintenance at 12-month follow-up. Baseline predictors of PA maintenance at 12-month follow-up were health-related quality of life, exercise motivation, expectations of exercise and being a former or current smoker/snus user. Conclusions: A 7-day diary and the SWA have limited agreement and cannot be used interchangeably in patients with breast cancer. Individual incentives and a positive and supportive environment are crucial to increase exercise motivation in patients undergoing curative cancer treatment, and can be promoted using specific support (i.e. social support, feedback, self-registration of exercise and scheduled exercise sessions). The addition of self-regulatory BCTs is not likely to improve exercise adherence in patients undergoing curative treatment for breast, prostate or colorectal cancer and participating in structured, well-controlled exercise interventions, but may improve long-term PA maintenance in this population. Patients with low health-related quality of life, low exercise motivation, high expectations of exercise or with a history of tobacco use at the start of their cancer treatment may be those most in need of such support to maintain PA.