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Coming dissertations at MedFak

  • Immunologic Markers in the Tumor Microenvironment of Classical Hodgkin Lymphoma Author: Alex R. Gholiha Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-455817 Publication date: 2021-11-09 13:25

    In classical Hodgkin lymphoma (cHL), cytokine regulation and cellular composition of the tumor microenvironment (TME) is crucial for tumor cell survival. In paper I, we examined the presence of CD138+ plasma cells and IgG4+ plasma cells in diagnostic cHL biopsies with immunohistochemistry (IHC). We found that increasing proportions of CD138+ plasma cells in the TME were associated with B-symptoms and inferior survival. IgG4+ plasma cells in the TME were a rare finding. In paper II, we investigated IL-6+ leukocytes and IL-6+ Hodgkin-Reed-Sternberg (HRS) cells in the TME of primary cHL. We observed that an IL-6+ leukocyte proportion of ≤ 1% in the TME was an independent adverse prognostic marker for event-free and overall survival. Further, the presence of IL-6+ leukocytes correlated with an increased proportion of CD138+ plasma cells and CD68+macrophages in the TME. IL-6+ HRS cells correlated with increased proportions of CD68+macrophages, PD-L1+ leukocytes, and PD-L1+HRS cells. In paper III, we investigated CD47 surface glycoprotein expression on HRS cells in the TME. CD47 is mainly known to promote antiphagocytic signaling via interaction with the SIRPa protein on phagocytic cells. IHC for CD47 was performed on diagnostic cHL biopsies. Cases with high CD47 expression on HRS cells had an inferior survival in univariate and multivariate analyses, adjusting for established prognostic factors compared with patients with low CD47 expression on HRS cells. In paper IV, using the Proximity Extension Assay (PEA) method, we identified 17 distinguishing immunologic proteins in cHL when comparing cHL diagnostic tissue lysates with reactive lymph node lysates from controls. In addition, 8 of these 17 proteins were elevated in cHL plasma compared with plasma from controls. Several of the identified proteins have established evidence in cHL as PD-L1, IL-6, CCL17, LAG3, and several proteins were introduced as new potential targets. In conclusion, our findings increase our knowledge regarding several immunological elements within the TME of cHL introducing clinicopathological associations of prognostic and potential therapeutic future implications. 

     

  • The effect of intermittent theta-burst stimulation over the dorsomedial prefrontal cortext on brain activity in depression Author: Wiebke Struckmann Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-452406 Publication date: 2021-11-09 09:19

    Repetitive transcranial magnetic stimulation is an emerging alternative for treatment-resistant depression, with ongoing developments in stimulation protocols and treatment targets. As such, intermittent theta-burst stimulation (iTBS) delivered over the dorsomedial prefrontal cortex (dmPFC) has shown promise, however establishing a need for neuroimaging studies to further understand the treatment mechanisms. 

    This thesis aims to explore the effects of dmPFC-iTBS on brain activity in depression, using data from a randomized controlled trial and two add-on brain imaging studies with shared methodology. Study I investigated the prefrontal blood oxygenation (oxy-Hb) response during, as well as before and after iTBS sessions at the first, fifth, and final day of treatment. Oxy-Hb was assessed using functional near-infrared spectroscopy (fNIRS). Study II examined patients’ cognitive performance and concurrent prefrontal oxy-Hb before and after a full iTBS treatment course, again using fNIRS. The patient data were also compared to a sample of healthy controls. Study III assessed whether iTBS modulates functional brain activity during an emotional picture anticipation paradigm, using functional magnetic resonance imaging (fMRI). Study IV investigated the functional connectivity of the brain network behind the oxy-Hb response observed in study I. This was done by using the fNIRS optode locations as seeds in a resting-state fMRI analysis before and after a full iTBS treatment course. 

    In summary, brain activity was modulated by iTBS both in an acute and delayed matter. Patients receiving active iTBS had increased prefrontal oxy-Hb levels during the fifth and final iTBS session, suggesting that this modulation was being built up during the treatment course (study I). Resting-state functional connectivity of this prefrontal cortex region to the insula or, when adding oxy-Hb change as a regressor, the posterior parietal cortex was modulated after active, but not sham, iTBS (study IV). Likewise, amygdala activation during exposure to picture stimuli of negative valence was reduced after active, but not sham, iTBS (study III). While patients displayed cognitive deficits compared to healthy controls before treatment start, active iTBS did not alter their cognitive performance or concurrent prefrontal oxy-Hb (study II).

  • Obesity in obstetric care : Consequences and risk prediction Author: Heiðrún Pétursdóttir Maack Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-455583 Publication date: 2021-11-03 12:16

    The incidence of obesity is increasing at an alarming rate worldwide and the epidemic has reached the pregnant population of developed countries. Obesity is associated with several obstetric complications for both the mother, the fetus and the new-born. Today, obesity risk assessment is based on body mass index (BMI). However, the majority of women considered obese based on BMI will have an event-free pregnancy and delivery. Obesity is one of the greatest challenges for obstetricians and improving prediction of risk among obese women is essential.

    The overall aim of this thesis was to increase the capacity for early pregnancy prediction of obesity-related late adverse pregnancy outcomes in women with overweight and obesity. 

    The thesis encompassed four population-based cohort studies. The first showed that obesity in early pregnancy modulated the association between depression and infant birthweight. Women with obesity and depression gave birth to infants with higher birthweight than non-depressive obese women. The opposite pattern was seen in normal-weight women, where depressed women gave birth to infants with lower birthweight than non-depressive women. About one-third of pregnant women with obesity are metabolically unhealthy, which was the focus of the second study. Almost half of those women developed at least one obesity-related complication and the risk was higher than in women with obesity who were metabolically healthy. The difference seemed to have little clinical relevance. Further, women with metabolically unhealthy obesity have numerous risk factors for development of cardiovascular disease later in life, including altered levels of cardiovascular markers in blood samples. The third and fourth studies explored if estimation of fat distribution in the first half of pregnancy predicted preeclampsia development. It was found that waist circumference (WC) measured in the first trimester was associated with increased risk of developing preeclampsia. However, first-trimester WC was highly correlated with BMI and adding WC to a prediction model already including BMI did not improve its prediction performance. The research team also measured abdominal adipose tissue with ultrasound in the second trimester. Both subcutaneous adipose tissue (SAT) thickness and visceral adipose tissue (VAT) thickness were associated with preeclampsia development, but only SAT thickness had an association that remained after adjustment for BMI.

    In conclusion, assessment of obese women in early pregnancy for detection of high risk for obesity-related complications is essential. Comorbidity of other diseases, such as depression, should be taken into account. Metabolically unhealthy obesity during pregnancy has little impact in the short term, but might be an opportunity for prevention of long-term consequences in obese women. Central obesity, measured as WC or SAT/VAT thickness, was associated with preeclampsia, but only SAT thickness seemed to improve prediction of preeclampsia in models already addressing obesity as BMI.

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