Coming theses from other universities
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Exploring Disease Patterns in the Long-Term Follow-Up of Juvenile Idiopathic Arthritis : Focus on Psoriasis, HLA-B27, and Temporomandibular Involvement
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-539872
Juvenile idiopathic arthritis (JIA) is an umbrella term encompassing a heterogeneous group of chronic arthritis in children. Many of these have significant differences from adult arthritis, while others possibly represent similar diseases in children and adults. Classification aims to enhance the understanding of the disease’s pathogenesis, patterns of phenotypes, disease trajectories, and treatment responses.
Patient-reported outcome measures (PROMs) are invaluable for assessing disease burden and play an important role in co-producing optimal health care for the child with JIA.
This thesis has its origin in the Nordic JIA study, a population-based, prospective study of 510 children with newly diagnosed JIA who were included between 1997 and 1999. In the 8-year follow-up, we found that features associated with psoriasis were linked to more severe disease progression over time. A significant proportion of children with both psoriasis and arthritis were not classified as having juvenile psoriatic arthritis (JPsA). To ensure that these children receive early, personalized treatment, future classifications should include psoriasis and psoriasis-related characteristics as criteria.
In the 18-year follow-up, we studied temporomandibular joint (TMJ) arthritis. Orofacial symptoms and dysfunctions were common, and two-thirds of participants showed condylar deformities or erosions on cone-beam computed tomography (CBCT). An interdisciplinary approach is recommended to optimize management throughout the course of the disease.
The presence of HLA-B27 was associated with an increased risk of not being in remission off medication after 18 years of disease duration in males but not in females. Uveitis in HLA-B27 positive individuals is not always symptomatic, which clinicians need to be aware of.
The Juvenile Arthritis Multidimensional Assessment Report, JAMAR, was translated into Swedish and validated in a clinical setting. The Swedish JAMAR proved to be a reliable tool that can be used in both routine clinical practice and research. The responses from the questionnaire can also serve as a basis for discussions between patients and caregivers.
In conclusion, JIA is a complex disease requiring attention to multiple aspects. Our results highlight the need for better classification of psoriasis in JIA, the importance of careful and multidisciplinary follow-up for TMJ arthritis, and an association between HLA-B27 positivity and more severe disease. The Swedish version of JAMAR serves as a valuable complement to existing PROMs and has the potential to enhance health care for children with JIA.
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Elucidation of mechanisms in modulation of signaling by transforming growth factor-β (TGF-β) in breast cancer
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-540435
The cytokine transforming growth factor-β (TGF-β) is overexpressed in most advanced solid cancers, and it has a biphasic role in tumor progres-sion. Initially, TGF-β acts as a tumor suppressor since it inhibits the prolif-eration and promotes apoptosis of most cell types. However, in advanced cancers, TGF-β acts as a tumor promoter, which includes effects on the tumor cells, e.g. promotion of epithelial-mesenchymal transition (EMT), which is connected with increased invasiveness and metastasis, as well as effects on non-tumor cells.
Breast cancer, the most commonly diagnosed cancer in women. Given the importance of TGF-β in regulating both tumor suppression and promotion, understanding its precise role in breast cancer could offer new opportunities for therapeutic intervention, particularly in developing treatments that can selectively block the tumor-promoting effects of TGF-β without disrupting its normal physiological functions.
In this study, we explored the mechanisms by which the transcription factor ΔNp63, the epigenetic regulator chromodomain helicase DNA binding protein 4 (CHD4), the Rho-associated coiled-coil-containing protein kinases (ROCK1 and ROCK2), and integrin-αvβ5, influence TGF-β signaling and how these factors contribute to breast cancer progression.
Paper I demonstrated that TGF-β, through the activation of SMAD2/3, leads to the dissociation of ΔNp63 from the NURD or NCOR/SMRT histone deacetylation complexes. while promoting the formation of ΔNp63-p300 complexes, which alters histone acetylation levels and affects ΔNp63-dependent transcriptional outcomes.
Paper II showed that ROCK1 and ROCK2 have opposing effects on TGF-β-SMAD3/4 transcriptional activity. ROCK1 inhibits, while ROCK2 stimulates this activity, both in a kinase-dependent manner. Consistent with these findings, depletion of ROCK1 enhances TGF-β-induced invasion in breast cancer cells, whereas ROCK2 depletion reduces invasion.
Paper III revealed that CHD4 knock-out significantly increases CAGA12-GFP activity in MDA-MB-231 cells, with similar results observed in other breast cancer subtypes, underscoring the broad relevance of this finding. CHD4 is primarily localized in the nucleus and interacted with SMAD3, to a lesser extent with SMAD2, but not with SMAD4, in a ligand-dependent manner.
Paper IV demonstrated that integrin-αvβ5 facilitates the activation of the MEK-ERK MAPK pathway, which in turn promotes the expression of AP-1 components, particularly FOS family members. This enhances the expression of a subset of TGF-β-inducible genes associated with migration and invasion, including LAMB3, WNT7B, MMP9, and IL-11.
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Immune response in a human endotoxin model and critical COVID-19
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-540368
Background: Sepsis arises, by definition, from a dysregulated immune response to infection, leading to organ dysfunction and high mortality. Despite advances in antimicrobial treatments and organ support, pharmacological breakthroughs remain limited. The human endotoxin model serves as a bridge between animal models and human trials, simulating systemic inflammatory response syndrome (SIRS) and sepsis for evaluating potential therapies.
The COVID-19 pandemic, driven by SARS-CoV-2, caused widespread morbidity and mortality. Patients with severe disease exhibited immune dysregulation, characterized by hyperinflammation and immune suppression. Given the similarity in immune dysregulation, insights from previous SARS outbreaks and sepsis research were applied to the SARS-CoV-2, emphasizing the need to balance immune suppression and infection-fighting capacity in both conditions.
Methods: Part one involved a human endotoxemia model, where endotoxin was administered to healthy volunteers, to simulate systemic inflammatory response syndrome (SIRS). Inhaled nitric oxide (iNO) and glucocorticoid (GC) co-administration was assessed for immune modulation based on previous results from a porcine model.
Part two focused on COVID-19 patients in the PRONMED cohort with severe disease admitted to the ICU, investigating longitudinal immune cells and biomarker levels. In addition potential sex-based differences in inflammatory profiles were evaluated.
Results: In the human endotoxemia model, iNO/GC failed to modify the immune response, despite promising results in a porcine study. Differences in species-specific responses and endotoxin dosing likely contributed to these outcomes.
Among COVID-19 patients, elevated pro-inflammatory cytokines (TNFα, IL-6, IL-8), neutrophil activation, marked lymphopenia with attenuated expressions of lymphokines receptors were observed. In addition a dynamic aberrant expression of CD-markers was observed on neutrophils.
Men had an overall heightened immune response compared to women, except for cytokines for Th1 response, where no difference was found.
Conclusions: The failure of iNO/GC to replicate animal results highlights challenges in translating findings across species.
In COVID-19 patients, significant immune dysregulation was observed. Tailored interventions—with precise patient selection, optimized timing and dosing, and potential influences from sex hormones—are likely key to improving outcomes and minimizing harm in sepsis patients. Additionally, further research is crucial to better understand the role of neutrophils in the adaptive immune response.