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- Balboa Ramilo, Amanda
(författare)
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Exploring Preclinical Targets in Abdominal Aortic Aneurysm
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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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- Befekadu Wodajo, Rahel, 1968-
(författare)
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Analysis of new biomarkers and their kinetics in connection with ST-elevation myocardial infarction and percutaneous coronary intervention
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis studies different biomarkers in a cohort of patients suffering from ST-elevation myocardial infarction (STEMI) who underwent Percutaneous coronary intervention (PCI) in Örebro in 2011-2012. Blood samples were collected at three time points, at the arrival at the hospital, 1-3 days after PCI and for a smaller group of patients also 3 months after PCI. The study is a sub-study of the TASTE study, so half of the patients were also randomized to thrombus aspiration in conjunction with their PCI. For all patients, it was also recorded whether the culprit coronary vessel was totally occluded or partially patent. In total, there are samples from 165 patients, but not all markers have been measured in all patients, and 3-month samples are only available from those who had their follow-up in Örebro. The plasma levels of the biomarkers have also been measured in plasma from blood donors for comparison. In March 2019, a follow-up was made of the patients' survival, and the time of death was noted in cases where this had occurred.The markers studied are the lysosome protein Cathepsin S (Cat-S), the platelet granule protein thrombospondin 1 (TSP-1), the pentraxins C-reactive protein (CRP) and pentraxin 3 (PTX3), the endopeptidase neprilysin, the soluble forms of TNF-receptor 1 and 2 (sTNFR1 and sTNFR2), markers showing activation of the lectin pathway for complement activation (MASP-1/AT, MASP-1/C1-INH, MASP-2/C1-INH, MASP-2/AT) and common activation markers for complement activation (C3a and sC5b-9).In summary, the thesis shows that the plasma levels of all markers, except neprilysin and sC5b-9, are elevated at the time of arrival compared to healthy blood donors. Neprilysin is at the same level, and sC5b-9 is lower compared to blood donors. 1-3 days after PCI, the levels for CRP, sTNFR1 and sC5b-9 have risen strongly (>50%) compared to the levels at arrival. MASP-1/AT and MASP-2/AT have fallen moderately (about 50%), Cat-S and TSP-1 have decreased strongly, while the remaining markers are relatively similar to the levels at arrival (± 25%). The levels for CRP, PTX3, sTNFR1, sTNFR2 and neprilysin decreased even further between 1-3 days and 3 months, sC5b-9 rises slightly while the other markers remain at roughly the same levels. At 3 months, most markers still show higher levels compared to corresponding levels in blood donors, only MASP-2/C1-INH has the same level, while neprilysin is slightly lower and TSP-1 much lower compared to blood donors (the latter presumably an effect of ongoing medication with platelet inhibitors in the patients). No relevant differences were observed between patients with and without thrombus aspiration, and few differences were seen between patients with occluded or partially patent vessels. This may indicate that these factors were of minor importance for the levels of the analyzed markers. In contrast, analysis of survival showed that individuals with plasma levels above the median value for PTX3, sTNFR1 and sTNFR2 at admission and/or at 1-3 days had a significantly increased mortality compared to those with levels below the median value, which indicates that these markers could be interesting for further studies in a material where also analysis of possible interfering factors can be implemented.
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| 6. |
- Dimberg, Jan, et al.
(författare)
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Effects of diabetes type 2 and metformin treatment in Swedish patients with colorectal cancer
- 2022
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Ingår i: World Journal of Gastroenterology. - : Baishideng Publishing Group Inc.. - 1007-9327 .- 2219-2840. ; 28:19, s. 2148-2151
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The association between type 2 diabetes mellitus (DM) and colorectal cancer (CRC) has been thoroughly investigated and reports have demonstrated that the risk of CRC is increased in DM patients. The association between DM and the survival of patients with CRC is controversial. Evidence suggests that metformin with its anti-inflammatory effects is a protective factor against the development of CRC among DM patients and that metformin therapy is associated with a better prognosis in patients with DM. In our cohort, we did not find any associations between the presence of DM or metformin and cancer specific survival or any relation to plasma levels of a panel of 40 inflammatory factors and irisin. On the other hand, we identified that the insulin-like growth factor binding protein 7 single nucleotide polymorphism rs2041437 was associated with DM in CRC patients. The dominance of the T bearing genotypes in patients with DM was statistically significant (P = 0.038), with an odds ratio of 1.66 (95% confidence interval: 1.03-2.69).
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- Good, Elin, 1983-
(författare)
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Interrogating Atherosclerotic Plaque Biology Through Responses to Cardiovascular Risk Management and Imaging
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atherosclerosis causes more deaths than any other disease worldwide, and the cause of death is most commonly a rupture of a vulnerable atherosclerotic plaque, resulting in a thrombotic event in the heart or brain. The major risk factors for plaque progression are well known, but all the mechanisms that drive atherosclerotic plaques towards catastrophic events are not yet fully elucidated. This thesis revolves around the atherosclerotic plaque; how plaques can be analysed using cardiovascular magnetic resonance imaging and the study of biological responses to cardiovascular risk management. In Study I we interrogated the quality of cardiovascular risk management in patients diagnosed with high-grade carotid stenosis and found that cardiovascular risk management was deficient in all aspects, despite the very high risk for events in these patients. Thus, we designed the next two studies to address the unmet clinical need for improved cardiovascular risk management in patients with carotid atherosclerosis while at the same time asking mechanistic questions about the effect of this approach on lymphocyte phenotypes (Study II) and on plaque composition (Study III). In Study II, the effect of cardiovascular risk management on Natural Killer cell, Natural Killer T cell and T lymphocyte subpopulations were studied in patients with carotid atherosclerosis. Our results show a polarisation away from a senescent phenotype towards more naïve i.e., juvenile cell types suggesting a transition towards a possibly less pro-inflammatory lymphocyte profile. In Study III, we applied a newly developed quantitative Dixon MRI technique to the quantification of lipid rich necrotic core and hemorrhage inside atherosclerotic plaques. Employing this technique, we explored the relationships between these high-risk plaque compositional features and circulating lipoproteins as they changed over time in response to cardiovascular risk management. In the current study there was no evidence for such a linear relationship. To further study the associations between inflammation and quantitative plaque measurements we explored in Study IV the relationship between inflammation in atherosclerotic plaques as measured by 18F-FDG uptake and features of high-risk plaque as measured by quantitative Dixon MRI. To facilitate the use of carotid MRI in larger cohorts we developed in Study V a technique for the segmentation of the carotid artery using supervised machine learning. Taken together these studies describe the importance of cardiovascular risk management, the complexity of atherosclerotic plaque biology and they propose new strategies for quantitative plaque imaging.
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