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Coming dissertations at MedFak

  • Studies of the Role of the Gastrointestinal Tract in Children with Juvenile Idiopathic Arthritis (JIA) Author: Anders Öman Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-427157 Publication date: 2021-01-21 12:46

    Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children, but its cause is not fully established. Changes in the intestinal canal and an unfavourable composition of gut bacteria have been suggested as factors that can increase the risk of developing JIA and influence the disease course.

    This thesis investigated the possible association between JIA and changes in the intestinal canal.

    In a population-based study, 213 children diagnosed with JIA were screened for coeliac disease using immunoglobulin antibodies against tissue transglutaminase 2. Three children had a diagnosis of coeliac disease prior to screening and three previously undiagnosed cases were found through screening. The point prevalence for coeliac disease among children with JIA was 2.8%.

    In order to investigate if the composition of gut microbiotas in children with JIA differed from in healthy children and healthy siblings, 75 children with JIA were compared with 24 healthy controls, and eight children with JIA were compared pairwise with healthy siblings. Comparisons of microbiotas revealed trends towards altered relative abundances of taxa in children with JIA, but these were not significant when corrected for multiple comparisons.

    To examine the effects on gut microbiotas of treatment with methotrexate (MTX) or etanercept (ETN), faecal samples from 46 treatment-naïve children with JIA were compared with samples from children during treatment with MTX (n=29) or ETN (n=12). Paired comparisons were also made of children sampled both as treatment-naïve and during treatment with MTX (n=15) or ETN (n=7), including analyses of levels of faecal short-chain fatty acids. No significant differences were found after correction for multiple analyses.

    A pilot study investigated if improved clinical symptoms after interventions with exclusive enteral nutrition (EEN; n=6) or specific carbohydrate diet (SCD; n=10) in children with JIA were linked to changes in the gut microbiota. Faecal samples collected before the interventions were compared pairwise with samples collected after 3–5 weeks on the interventions. Both interventions altered microbiota composition, with a significant decrease in alpha-diversity and relative abundance of Actinobacteria during SCD.

    In conclusion, children with JIA most likely have an increased risk of coeliac disease and screening should be recommended. Faecal microbiota in children with JIA do not seem to differ compared with in healthy children or siblings. Treatment with MTX or ETN has no, or very limited, effect on the microbiota in faecal samples, but dietary interventions with EEN or SCD showed some changes in a pilot study.

  • Cancer Immunotherapy : Oncolytic viruses and CAR-T cells Author: Jing Ma Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-425970 Publication date: 2021-01-21 12:28

    Various forms of cancer immunotherapy have developed rapidly with improved survival and quality of life for cancer patients. Cancer immunotherapy aims to educate the patient’s immune system to eliminate cancer cells, including immune checkpoint inhibitors (ICIs), adoptive cell transfer (mostly T cells), oncolytic viruses (OVs) and cancer vaccines. Especially ICIs have induced durable responses in patients with many different types of cancers. Chimeric antigen receptor (CAR)-T cell therapy has shown good efficacy in treating hematologic malignancies. However, there is still a significant number of patients that do not benefit from these treatments due to immune evasion. Strategies to modify cancer immunotherapies with immunomodulating agent needs to be investigated to maximize the effect of immunotherapy. Helicobacter pylori Neutrophil Activating Protein (HP-NAP) could be used as an immunomodulating agent to recruit, activate and mature immune cells, such as dendritic cells (DCs), monocytes and neutrophils, and also induce T helper type 1 (Th1)-polarized response. In this thesis, we examined to arm oncolytic virus or CAR-T cells with HP-NAP.

    Papers I and II investigate oncolytic viruses. In paper I, we investigated wild-type Adenovirus (Ad), Semliki forest virus (SFV) and Vaccinia virus (VV), for their ability to mediate lysis of tumor cells, which was found to be associated with the release of danger-associated molecular patterns (DAMPs) and subsequently triggered phagocytosis and maturation of DCs. However, only SFV-infected tumor cells triggered significant Th1-cytokine release by DCs and induced antigen-specific T cell activation, while VV induced immunosuppressive responses. In Paper II, we armed VV and SFV with the tumor-associated antigen GD2 and HP-NAP. We found that arming these OVs with HP-NAP resulted in distinct anti-tumor immune response and therapeutic benefit. VV-GD2m-NAP showed significantly increased therapeutic efficacy compared to VV-GD2m, associated with elevated antiGD2 antibody production. In contrast, there was no additive antitumor effect for SFV-GD2m-NAP compared with SFV-GD2m. Due to intrinsic properties of OVs, engineering OVs with immunomodulating agents needs careful consideration. Engineering SFV or similar viruses, which is very immunogenic, should focus on improving oncolysis, de-bulking tumor and release of tumor-associated antigens, while for VV or similar viruses, with immunosuppressive properties, the focus can be on arming the virus with immune modulators to improve anti-tumor immune response. Papers III and IV investigate CAR-T cells. In paper III, CAR-T cells were engineered to inducible secrete HP-NAP upon antigen recognition (CAR(NAP)-Ts). CAR(NAP)-Ts successfully reduced tumor growth and prolonged survival of mice in several solid tumor models with epitope spreading and initiated endogenous anti-tumor immune responses. Secreted HP-NAP created an immunologically hot tumor microenvironment with enhanced infiltration of immune cells (DCs, neutrophils, macrophages, and cytotoxic natural killer cells). In paper IV, we developed CAR T cells targeting CD20 (rituCD20CAR T cells). We found that rituCD20CAR T cells could efficiently kill CD20-positive lymphoma cell lines (U2932, Karpas422, DB, U698, Raji, Daudi) as well as primary mantle cell CD20-positive lymphoma (CD20+ MCL) cells accompanying with IFNγ secretion. Both rituCD20CAR and NAP-armed rituCD20CAR(NAP) T-cell treatment delayed tumor growth and prolonged mice survival in the murine lymphoma A20-hCD20 model. In summary, combing OVs and CAR-T cells with the immunomodulating agent HP-NAP is a promising way of maximizing the benefit of immunotherapy to combat cancers.

  • Quality of life aspects of being diagnosed and living with prostate cancer Author: Oskar Bergengren Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-427317 Publication date: 2021-01-19 13:40

    Prostate cancer is largely a heterogenous disease, ranging from almost harmless to highly aggressive. Most men are diagnosed with favorable-risk disease with a long life expectancy even without treatment. The risk of overdiagnosing and overtreating these men is substantial, with reduced quality of life as a result. In this thesis, we study the diagnostics of, and the quality of life for men with prostate cancer. 

    In paper I, we studied satisfaction with care among men with low-risk prostate cancer in a nationwide, population-based setting and found a high overall satisfaction with care. Information and participation in decision-making were of great importance for satisfaction. However, men on active surveillance reported lower overall satisfaction with care, suggesting that they need more information and to be more participatory in their care.

    In paper II, we investigated choice and adherence to active surveillance and found that a doctor’s recommendation was the most important factor for choosing active surveillance as the primary treatment strategy. A rising PSA was the most common cause for diverting from active surveillance to curative treatment, even though PSA alone is a poor marker for disease progression.

    In paper III, we explored lifestyle changes after a prostate cancer diagnosis and a possible association between lifestyle changes and quality of life. We found that a considerable proportion of men change their lifestyle after a prostate cancer diagnosis and that a positive lifestyle change was associated with a higher quality of life. However, men with poorer functional outcomes after treatment were less likely to make lifestyle changes, suggesting that these men need better support and rehabilitation.

    In paper IV, we used a new simulation model to evaluate the benefit and harm of the increased PSA-driven diagnostic activity that has occurred over the last 30 years. We found that the increased diagnostic activity has resulted in a modest decrease in prostate cancer specific mortality but at the cost of substantial overdiagnosis and overtreatment.

    To conclude, this thesis provides information on factors to improve satisfaction with care, increase adherence to active surveillance, and to engage in positive lifestyle changes, possibly contributing to a higher quality of life.

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