Coming dissertations at MedFak
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Exploring Preclinical Targets in Abdominal Aortic Aneurysm
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-527741
Abdominal Aortic Aneurysm (AAA) is a vascular disease characterised by the progressive and permanent dilation of the aorta, culminating in rupture and death, if not intervened. It affects 5% of men over the age of 65 years with a history of smoking. No pharmacological options are available to treat this disease. This thesis aims to investigate the role of glucose metabolism and mitochondrial function (Studies I-III) and microRNAs (Study IV) in experimental AAA and evaluate their potential as treatment targets.
In Study I, angiotensin II (angII)-infused Apolipoprotein E (ApoE) deficient mice received intraperitoneal injections of the glycolysis inhibitor PFK15, for three weeks, starting one week after disease induction. Treatment with PFK15 reduced aneurysm formation compared with the control group and prevented the decrease in α-smooth cell actin/vimentin gene expression ratio caused by angII. Glycolysis inhibition with PFK15 prevents AAA growth by favouring the maintenance of a contractile phenotype of vascular smooth muscle cells.
In Study II, angII-infused ApoE deficient mice received daily subcutaneous injections of the glucagon-like peptide 1 receptor analogue semaglutide, for four weeks, starting simultaneously with disease induction. Treatment with semaglutide prevented death by aortic rupture in the first seven days of disease development and the loss of collagen in the aortic wall. Semaglutide thereby prevents aortic dissection and rupture likely by promoting the maintenance of collagen in the aortic wall.
In Study III, mice received angII or saline infusion for four weeks. Mitochondrial function was evaluated ex vivo in whole aortic tissue, by high-resolution respirometry. Aortas of angII-infused mice had a reduced capacity to increase oxygen consumption, in response to ADP and succinate, compared to control. These results demonstrate that it is possible to measure mitochondrial function in whole aneurysmal tissue ex vivo, and, importantly, that mitochondrial function is impaired in AAA.
In Study IV, angII-infused ApoE deficient mice received four intraperitoneal injections of miR-10b, starting three days before disease induction and continuing for four weeks. Treatment with miR-10b promoted AAA development, growth and rupture, associated with an increased elastin degradation. miR-10b has an active role in promoting experimental AAA progression by boosting aortic wall degradation.
In conclusion, glucose metabolism, mitochondrial function and microRNA are important pathways in the pathophysiology of AAA and promising targets for pharmacological modulation.
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Systemic inflammation and prognostic markers in patients with head and neck cancer
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-526827
Patients with head and neck cancer (HNC) often present with weight loss and malnutrition caused by systemic inflammation and dysphagia. This thesis explores the effects of systemic and local inflammation in the context of head and neck cancer treatment.
The main aim of Paper I was to investigate whether trismus after radiotherapy affects the 5-year overall survival rate in a cohort of 244 patients with HNC. The maximum interincisal opening (MIO) of the patients was measured before treatment, 2, 6, and 12 months after the termination of radiotherapy, and trismus was defined as MIO ≤ 35 mm. All patients received instructions on jaw-opening exercises. The highest prevalence of trismus at 12 months was seen in patients with oral cancer (44%) and oropharyngeal cancer (37%) and it can be concluded that these patients should primarily be offered jaw-opening exercises. Patients with trismus at 12 months after termination of treatment had a tendency towards a worse overall 5-year survival rate than patients without trismus (p=0.64).
Paper II explored the expression levels of cytokines and growth factors in serum before and up to one year after treatment. The cohort consisted of 30 patients with HNC and blood was drawn on four occasions and analyzed for 10 cytokines and 4 growth factors. Patients who received chemoradiotherapy had higher expression levels of IL-1β, IL-6, and IL-10 than other treatment groups at 7 weeks after the start of treatment. Patients with recurrence within 12 months after termination of treatment had higher expression levels of IL-1β, IL-6, IL-8, and IL-10 than the remaining patients at 7 weeks.
In Paper III the expression levels of 83 immuno-oncologically significant proteins were determined at the same four time points as in Paper II in a cohort of 180 patients with HNC using a proteomics technique. Fifteen proteins had either decreased or increased expression levels at 7 weeks compared to pre-treatment expression levels. Treatment with radiotherapy with concomitant cisplatin was shown to be connected to significantly decreased expression of 13 proteins at 7 weeks after the start of treatment compared to radiotherapy which demonstrates an immunomodulatory effect of cisplatin also apparent in Paper II.
The aim of Paper IV was to investigate how pre-treatment body mass index and fat free mass index correlate with early death in a cohort of 404 patients with head and neck squamous cell carcinoma (HNSCC). Body mass composition was measured at diagnosis using bioelectrical impedance analysis. Patients who died within 6 months of the start of treatment had significantly lower FFMI at diagnosis compared with patients who survived beyond 6 months (17.6 kg/m2 and 19.5 kg/m2, respectively, p=0.035). It can be recommended that assessment of fat free mass index should be included in the management of patients with HNSCC prior to treatment.
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Leveraging genetic and population-level data to improve women’s health
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-526446
Hormonal contraception (HC) and menopausal hormone therapy (MHT) are commonly used medicines, but their safety profiles are uncertain due to conflicting research. This thesis aims to examine the potential risks associated with HC and MHT by utilizing large-scale population-based cohorts.
In Paper I, we prospectively examined the link between oral contraceptives (OCs) and MHT use with the risk of stroke in the UK Biobank (UKB). Cox regression with time-varying exposures was used to investigate if treatment effects vary with time and to avoid immortal time bias. We included time-varying covariates to account for potential confounding factors that change over time and might affect the exposure level. Our research showed higher stroke risk during the initial period after initiating both treatments and increased stroke risk with MHT use regardless of menopause timing.
In Paper II, we calculated the hazard rate of the first incidence of depression following OC use. To avoid the influence of healthy-user bias, we estimated the risk in first-time users and excluded previous users in the reference group. A unique aspect of our study was the sibling analysis, which explored the causal relationship between OC use and depression by examining female sibling pairs in the UKB. Our findings showed that initiating OC was associated with a higher risk of depression, especially among adolescents and during the initial phase of treatment.
Paper III explored the genetic predisposition to venous thromboembolism (VTE) among OC users in the UKB. Using polygenic risk scores, we demonstrated that women with a high genetic liability for VTE have a significantly increased risk when initiating OC. This suggests that genetic screening may be beneficial in personalising contraceptive advice and mitigating the risk of thrombotic events.
In Paper IV, we investigated the association between different types of contemporary MHT and the risk of cardiovascular disease, building upon our findings from Paper I. We emulated a target trial using the Swedish nationwide registers to estimate the intention-to-treat and per-protocol effect. We showed that specific MHT treatments, particularly those that combine estrogen and progestin, are linked to an increased risk of ischemic heart disease (IHD) and venous thromboembolism (VTE). Tibolone was positively associated with IHD and cerebral infarction but not VTE.
In Paper V, we examined the risk of depression following HC initiation using the Swedish nationwide registers. Our research expanded upon the findings of Paper II by including various types of modern HCs and employing an emulated target trial study design. We observed an increased risk of depression among various HCs and found that the risk of depression is influenced by different dosages and types of progestins rather than the route of administration.
Using advanced analytical methods, we identified critical risk periods, variations in risk between different treatments and the interplay between treatment and genetics. While HC and MHT offer significant benefits, their potential side effects warrant careful consideration. Therefore, prescribing HCs and MHT should be approached with nuance, emphasising individual risk assessments and ongoing monitoring to optimise safety.