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Coming dissertations at MedFak

  • Magnetic Resonance Imaging of Human Brown Adipose Tissue : Methodological Development and Application Author: Elin Lundström Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-381766 Publication date: 2019-05-17 09:11

    Brown adipose tissue (BAT) is a thermogenic organ with the main human depot located in the cervical-supraclavicular (sBAT) region. BAT is proposed as a potential therapeutic target for obesity and diabetes. This thesis aims to contribute to the development of magnetic resonance imaging (MRI)-based methods and to the application of these in studies of human BAT. Water-fat MRI enables separation of water and fat, the dominant contributors to the MR signal, and the quantification of fat fraction (FF) and effective transverse relaxation rate (R2*). FF and R2* are often used in studies of human BAT, e.g. for characterizing the tissue and distinguishing it from white adipose tissue. A Cooling-reheating protocol was introduced for studying changes in sBAT, related to lipid content and perfusion. sBAT FF decreased after cold exposure. The sustained low FF after reheating suggested lipid consumption as the primary cause. This conclusion was based on the assumption of a normalized perfusion after reheating. An automated method for segmentation of sBAT was developed. The method compared well with a semi-automated reference method with respect to segmentation overlap and estimated mean sBAT FF and R2*. A modified version of the automated method was applied to a large-scale study where an association between sBAT FF and glucose tolerance indicated a role for BAT in glucose metabolism, potentially linked to the risk of developing diabetes.  A Cooling-reheating protocol was evaluated with positron emission tomography measurements of perfusion and cold-stimulated BAT activity. Inverse correlations between sBAT FF and BAT activity suggested sBAT FF to predict cold-induced BAT activity. After reheating, the cold-induced increase in perfusion normalized and the cold-induced decrease in FF partially normalized. This suggested potential decreases in FF after reheating to mainly be due to lipid consumption and decreases in FF after cold exposure to possibly be influenced by perfusion.

  • The Epigenome of Multiple Myeloma : From genome-wide analysis to pharmacological manipulation Author: Alba Atienza Párraga Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-377438 Publication date: 2019-05-16 11:34

    Nowadays epigenetic dysregulation is known to play a crucial role in virtually all cancers. In multiple myeloma (MM), an extensively heterogeneous malignancy, the key common feature among patients is the gene silencing imposed by the PRC2 complex through the addition of H3K27me3. This thesis focuses on the exploration of the MM epigenomic landscape, with an emphasis on both the interplay between H3K27me3 and other epigenetic tags, and on the effects of a series of inhibitors altering this profile.

    In paper I we provide the genome-wide H3K27me3 distribution unique to MM and demonstrate that the silencing of genes in the profile correlates with an advanced and poor-outcome disease. Reduction of H3K27me3 using the EZH2 inhibitor UNC1999 reactivates genes with anti-tumor activity and induces apoptosis in vitro.

    EZH2 inhibition also leads to downregulation of the MM oncogenes IRF-4, BLIMP-1, XBP-1 and c-MYC. Paper II identifies miR-125a-3p and miR-320c, predicted to target these oncogenes, as part of the PRC2 targets induced upon treatment.

    In addition, H3K27me3 can be recognized and bound by the PRC1 complex. In paper III we show that inhibition of PRC1 using PTC-209 induces apoptosis and this is further enhanced when PTC-209 is combined with UNC1999. Moreover, PTC-209 has been previously shown to reduce the expression of c-MYC. Combined treatment using PTC-209 and JQ1, demonstrated to downregulate c-MYC, results in additive and synergistic effects in reducing MM cell viability.

    In paper IV we present the first catalogue of genomic regulatory regions in normal plasma cells, as predicted by their combinations of histone marks. Using this, we demonstrate that in MM a subset of TSSs and enhancers become targeted by H3K27me3 and display high DNA methylation, pointing towards a possible silencing. Conversely, poised TSSs lose H3K27me3 and seemingly become de novo activated. Furthermore, we show that EZH2 physically interacts with the DNA methyltransferase DNMT1 and that combined inhibition using UNC1999 and the DNA hypomethylating agent AZA blocks the G2/M arrest triggered by AZA and induces apoptosis.

    In summary, this thesis highlights the complex interconnectivity of epigenetic mechanisms in MM and provides proof-of-principle of the anti-MM effects derived from inhibiting epigenetic components in single or combinatorial regimens.

  • Intellectual Disability and coexisting Autism and ADHD in Down syndrome - a population-based study Author: Ulrika Wester Oxelgren Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-381779 Publication date: 2019-05-16 08:29

    The thesis investigated associated neurodevelopmental/neuropsychiatric aspects in a population-based cohort of 60 children and adolescents (5–17 years) with Down syndrome (DS).

    Forty-one subjects were comprehensively assessed by a clinical research team; 17 (41%) and 14 (34%) met DSM criteria for autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), respectively.

    Forty-nine subjects had a formal cognitive test and 11 had clinical assessments due to profound intellectual disability (ID). Mild ID (IQ 50–70) was found in 9% of the teenagers (13–18 years) and in 35% of the younger (5–12 years) children. Corresponding figures for severe ID (IQ <50) were 91% and 65%, respectively. The ID was more severe in individuals with coexisting ASD.

    Levels and profiles of autistic symptoms, according to ADOS Module-1, were analysed. Children with DS and ASD, with different levels of ID, had significantly more symptoms within all autism domains, than those with DS only – a difference which remained when subgroups with severe ID were compared. A considerable proportion of subjects with DS had ASD in addition to ID, but there was a group with DS and severe ID without ASD. The autism profiles of children with DS and ASD were similar to those of children with idiopathic autism. The commonly used investigation tools used to diagnose ASD in the study, seemed to be appropriate in this patient group.

    An intervention programme, including education for parents and school staff, adapted to the specific needs of schoolchildren with DS and ASD was performed and evaluated. Although the studied group comprised older children and adolescents, most of whom with severe or profound ID, they could achieve goals and skills previously not managed. In addition, the parents’ views on the intervention were encouraging.

    In conclusion, there is a need of awareness of the increased prevalence of ASD and ADHD in children with DS. We suggest that screening for ASD and ADHD should be implemented for children with DS at the age of 3–5 years and at early school years, respectively. We also suggest that children with DS should be re-evaluated regarding level of ID before entering secondary school.

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