Coming dissertations at MedFak
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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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Proximal hamstring avulsions : Epidemiology, MRI-imaging and treatment outcomes
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-539140
Proximal hamstring avulsion (PHA) is an injury mostly occurring with slip-and fall accidents. MRI is important for the diagnosis, and MRI-findings together with patient characteristics are used for the allocation of treatment, but little is known about their prognostic value. The treatment can be either operative or nonoperative, but the evidence for the treatment options is limited. There is also no data on incidence and on trends in treatment of hamstring injuries, including PHA.
In paper I we analyzed data from the Swedish National Patient Register between 2001 and 2020 for patients aged 18–90 diagnosed with hamstring injuries (ICD-10 code S76.3), with operative treatment identified using the NOMESCO classification NFL49. The incidence of hamstring injuries increased from 2.2 to 7.3 per 100,000 person-years between 2001 and 2020, with the rate of surgical treatment rising from 3.0% to 14.2%.
In paper II we conducted a survey of 125 orthopedic surgeons from Sweden, Norway, Finland, and Denmark to explore current practices and rationales for PHA treatment decisions. Surgical decision-making was largely influenced by patient-specific factors, including age, BMI and lifestyle, and MRI-findings such as, degree of tendon retraction and number of avulsed tendons.
In paper III we conducted a randomized noninferiority trial at 10 centers that compared operative tendon reinsertion versus non-operative management in patients aged 30–70 with PHA. The primary outcome was the Perth Hamstring Assessment Tool (PHAT) at 24 months. The RCT demonstrated that nonoperative treatment was noninferior to surgery in terms of PHAT, but also in secondary outcomes, such as Lower Extremity Functional Scores (LEFS) and functional test, and with more adverse events in the operative group.
In paper IV we investigated if MRI findings at time of diagnosis had an association with muscle degeneration at 24 months of follow up with tendon retraction emerging as a key factor in predicting muscle degeneration in nonoperatively treated patients.
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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.