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Coming dissertations at MedFak

  • Spatial immune analyses in clinical cancer tissue Author: Max Backman Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-477860 Publication date: 2022-08-23 14:47

    Cancer is a leading cause of premature death and lung cancer is the deadliest cancer type, with non-small cell lung cancer (NSCLC) representing 85% of lung cancer cases. Despite promising development in cancer treatment in recent decades, overall prognosis is poor. The aim of this thesis was to explore novel techniques in protein visualization in clinical cancer tissue to better our understanding of cancer immunity and to discover new biomarkers for improved cancer diagnostics.

    In Paper I traditional immunohistochemistry (IHC) was compared to the in-situ proximity ligation assay (isPLA). Both techniques were applied to stain 12 proteins in 39 cell lines and 37 tissue types. Two different antibodies were used in the IHC assay and in the isPLA, where binding by both antibodies is required to generate detection signals. The comparison of staining patterns showed that the isPLA presents a valuable alternative to traditional IHC.

    In Paper II cancer tissue from 357 NSCLC patients was immunophenotyped through IHC annotations of 11 different immune markers. A distinct group of cases with a signature of NK cells and/or plasma cells had favorable prognosis despite significantly lower T-cell activation signatures. This study provides a detailed description of the immune landscape in NSCLC, extending previous concepts, and highlights plasma and NK-cells as potential biomarkers for further validation.

    In Paper III a multiplex-multispectral pipeline was established to explore three immune marker panels in a NSCLC cohort, spatially quantifying 13 immune cell types. The immune composition of NSCLC was analyzed for the prognostic relevance of immune cell coordination. Cell densities and distances were found to contribute independently to prognosis, indicating that spatial information on local immune cell infiltration is crucial for understanding tumor immunity.

    In Paper IV an extensive characterization of the immune cell landscape of colon cancer identified a prognostic signature based on the ratio of CD8+ lymphocytes to CD68+CD163+ macrophages. This signature was superior to the state-of-the-art ‘Immunoscore’, and was also associated with longer survival when analyzed in other common cancer types. This presents a promising immunological biomarker that warrants further validation as a prognostic and predictive signature in common cancers.

    In summary, this thesis presents an in-depth study of immune cell infiltration in several cancer types to better understand cancer immunity. Through novel techniques and spatial metrics, we describe immunophenotypes that might contribute to cancer classification and prognostication. The identified immune phenomena may also present alternative treatment targets to overcome resistance to immunotherapy.

  • Neoehrlichia mikurensis in Sweden : An emerging tick-borne human pathogen Author: Lisa Labbé Sandelin Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-463314 Publication date: 2022-08-23 10:25

    Neoehrlichia mikurensis is an emerging tick-borne human pathogen, causing neoehrlichiosis in immunosuppressed and immunocompetent individuals. It targets the vascular endothelium, leading to thromboembolic and vascular events, but can also pass without symptoms. As symptoms easily are misinterpreted, immunosuppressive treatment or chemotherapy is often incorrectly initiated. Diagnostic delay can be considerable.

    The overall aim of this thesis was to gain a better understanding on N. mikurensis in Sweden, focusing on human infections and public health aspects. The prevalence of N. mikurensis in different populations was examined. The symptomatology of neoehrlichiosis and the risk of transfusion-mediated transmission was studied. 

    N. mikurensis was observed in low prevalences in ticks collected from migratory birds, in tick-bitten individuals, in patients with persistent symptoms attributed to presumed tick-bite exposure, and in blood donors. Fourteen N. mikurensis-positive individuals were identified. The majority were immunocompetent and asymptomatic. Both spontaneous clearance and persistence was observed. Two of 102 tick-bitten individuals were N. mikurensis-positive. Both presented with erythema migrans, but borreliosis was a more probable cause in both. The findings do not support a change in practice regarding first-line treatment of erythema migrans, but further studies are warranted.

    Persistence of N. mikurensis in blood raises questions regarding the possibility of transmission by transfusion and the risk of activating the infection if immune status is altered. N. mikurensis was identified in seven out of 1 006 blood donors. Look-back and tracing identified 12 recipients who were transfused with blood components from N. mikurensis-positive donors. Several recipients had multiple risk factors for severe neoehrlichiosis, but transfusion-transmitted neoehrlichiosis was not detected. Nevertheless, the possibility that N. mikurensis can be transmitted by transfusion cannot be excluded.

    Isolates from birds and blood donors were identical to previously reported Swedish human isolates. Migrating birds can act as dispersal vectors of N. mikurensis, but their role as transmission hosts is still unclear.

    The disease burden and public health impact of neoehrlichiosis is probably small, but information is lacking in several areas. Suspicion of neoehrlichiosis is warranted in immunocompromised and/or splenectomised patients with persistent fever, with or without thromboembolic and vascular events. Furthermore, neoehrlichiosis should be included in the differential diagnosis of anaplasmosis. Besides raised awareness, a possible mandatory notification is proposed as well as a comprehensive surveillance system for transfusion-transmitted infections. One of the priority issues is the possible need for screening of patients living in N. mikurensis-endemic areas before and during immunosuppressive treatment. 

  • Enabling disability rights in practise : Understanding how the governance of state-funded personal assistance is fulfilling the Swedish LSS Act Author: Heléne von Granitz Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-478735 Publication date: 2022-08-19 10:29

    Personal assistance (PA) is stated in Article 19 of the UNCRPD as an internationally recognised disability right and is operationalised as a measure in the Swedish Act concerning Support and Service for Persons with Certain Functional Impairments (the LSS Act). The Act’s overall policy goal is to promote good living conditions for the eligible persons by enabling participation in society on equal terms with others. The governance of PA is a divided responsibility between the municipality and the Swedish Social Insurance Agency (SSIA), which assesses and grants PA-allowance if the PA applicant exceed 20 hours of certain needs per week. The overall aim of the thesis was to explore how the governance of PA-allowance enables to fulfil the LSS Act policy goals. The main findings of the thesis demonstrate a tilt in PA towards a medical model of disability, marked by a domination and an increase of healthcare activities over time. Less activities representing participation in society were found and unequal access to PA activities across age, gender and groups of persons with disabilities. The findings imply an increased risk to social and financial exclusion of PA users. Further, the LSS Act’s rationale and policy goals were shown to have a weakened impact on the SSIA instruction, the refined policy tool which outlines the PA-allowance granting process. A development towards a medicalised application of PA-allowance was found, characterised by healthcare measures to support medical conditions and a shift towards PA users with less ability to partake in the PA-allowance granting process. Factors shown to have influenced the governance of PA-allowance include: case law, changed policy priorities, weakened PA collaboration structures, inadequate monitoring of PA outcomes, strained working conditions at the SSIA and extensive complexities of the PA-allowance application. This thesis illustrates that the SSIA regime logic has thoroughly influenced the LSS policy outcome with time and emphasises the need for social reform policy tools to be continuously calibrated towards the original policy goals to uphold policy compliance. The regression of PA, by gradually resigning to a medical model of disability, demonstrates weakened conditions for Swedish disability policy through the LSS Act to fulfil Article 19 of the UNCRPD.

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