Coming dissertations at MedFak
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Prognostic and Predictive Factors in Metastatic Colorectal Cancer
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-522642
The outcome for metastatic colorectal cancer (mCRC) patients has improved substantially in recent decades. This has chiefly been observed in study populations, and predominantly in left-sided primary tumours, which is why we wanted to study if and how survival has improved in the background population. It has also been seen that certain molecular subtypes are more common in population-based materials, and, thus, we studied the prevalence and effects of different molecular alterations.
Paper I is a national population-based material of all 19 566 Swedish patients with a diagnosis of mCRC 2007-2016, 55% were male and 70% had synchronous metastases. Median overall survival (OS) for all patients was 14.0 months. An improvement could be seen over time, also in stratified analyses. OS was influenced by presentation of metastases, age, primary tumour location, and sex. All except sex remained statistically significant in a multivariable analysis. Differences of about one month in median OS were seen between healthcare regions, but these diminished over time.
Paper II included all 765 patients from the Uppsala Region with a mCRC diagnosis 2010-2020. Right colon primary tumours were seen in 38%, left colon in 27% and rectum in 34%. BRAF-V600E mutations (mt) and deficient mismatch repair (dMMR) had a poor OS and were more common in right colon primary tumours. Primary tumour location did not affect OS in subgroups according to mutations in RAS or BRAF, nor in a multivariable analysis. Molecular alterations seem to be more important than primary tumour location for prognosis.
Paper III studied KRAS-G12Cmt in three population-based and one real-world material. KRAS-G12C was seen in 2-4% of all tested and in 4-8% of all KRASmt. No differences in patient characteristics were observed between KRAS-G12C and other KRASmt. No differences in OS were seen between KRAS-G12C and other KRASmt, neither for all patients, nor in different treatment groups.
Paper IV studied atypical BRAFmt (aBRAFmt) in two population-based and one real-world cohort. aBRAFmt was seen in 1-4% of the adequately tested patients in the different cohorts. aBRAFmt patients were predominantly male, had dMMR less often, more rectal primary tumours, and less peritoneal metastases compared with BRAF-V600Emt. Serrated adenocarcinomas were seen in about half of the aBRAFmt. OS was significantly better for aBRAFmt than in BRAF-V600Emt, but worse than for RASmt and RAS&BRAFwt patients. Nine aBRAFmt received epidermal growth factor receptor inhibitors without responses.
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A stargazer's guide to neurodegeneration : Astrocytes' role in the propagation of pathological proteins
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-523852
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by brain accumulation of pathogenic protein aggregates. In the AD brain, amyloid-β (Aβ) and tau form plaques respective tangles, while in the PD brain α-synuclein (α-syn) form Lewy bodies and Lewy neurites. In addition, deposits of Aβ, tau and α-syn are frequently present in glial cells, including astrocytes. Historically, the focus was on neuronal dysfunction, leaving the involvement of glia largely understudied. The overall aim of this thesis was to investigate the role of glial cells in the disease progression, primarily focusing on astrocytes and the role they play in tau pathology.
Paper I focuses on the crosstalk between astrocytes and microglia in respects to degradation of α-syn and Aβ fibrils. Our results show that mono-cultured microglia are more effective than astrocytes at degrading exogenously added fibrils. However, when cultured together, microglia and astrocytes work synergistically, leading to an overall increase in the degradation.
In Paper II, we show that astrocytic tau inclusions are not benign, but in fact act as a reservoir for seeding competent tau species. The astrocytes engulf and process, but fail to fully degrade internalized material. Instead, seeding competent pathogenic tau spreads to nearby cells via secretion and tunneling nanotube mediated transfer. Furthermore, we show that tau and debris burdened astrocytes negatively affected the health of nearby neurons.
In Paper III, we investigated the cellular effects following astrocytic engulfment of human brain-derived tau. Our results show that astrocytes internalize and accumulate both AD and control tau fibrils. However, fibrils from AD brains were more neurotoxic and induced a stronger immune response in astrocytes, compared to fibrils derived from control brains.
In Paper IV, we studied the effects of APOE-genotype on astrocytic processing of tau by comparing astrocytes homozygous for APOEε2 and APOEε4. Our results showed that APOE2/2 astrocytes contained more and larger tau aggregates. Moreover, APOE 2/2 astrocytes excreted higher levels of pro-inflammatory cytokines, including IL-8, CCL2 and CXCL10 compared to APOE 4/4 astrocytes.
Paper V aimed to establish a cortical organoid model for studies of AD and PD. Exposure to α-syn especially led to internalisation by the organoid cells and active spreading throughout the tissue.
Our results demonstrate that astrocytes work closely with microglia to degrade internalised material. Furthermore, astrocytes actively contribute to neurodegeneration and disease propagation by affecting the health of neurons and by spreading seeding competent tau species.
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Chronic obstructive pulmonary disease: exacerbations and mortality : Prognostic value of biomarkers and comorbidities
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-523303
Background: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. COPD is associated with systemic inflammation, and comorbidities are common. A characteristic feature is acute exacerbations (AECOPDs), i.e., episodes of worsening symptoms. AECOPDs are associated with increased mortality.
Aim: To find prognostic risk factors for COPD mortality and AECOPDs, focusing on comorbidities and inflammatory biomarkers.
Methods: In Paper I, associations between comorbidities, pharmacological treatment, and mortality were analysed in a real-world cohort of almost 18,000 primary care COPD patients. Data from medical records and national registers were analysed in Cox proportional hazards regressions.
Papers II–IV were based on the Tools Identifying Exacerbations (TIE) cohort study of 572 COPD patients recruited from primary and secondary care in three Swedish regions. Participants were invited to three yearly visits, including phlebotomy, spirometry, and health questionnaires.
In Paper II, the ability of blood neutrophil-to-lymphocyte ratio (NLR) and eosinophils (B-Eos) to predict AECOPDs was analysed with mixed-effects logistic regressions.
In Paper III, the ability of C-reactive protein (CRP), fibrinogen, blood leukocytes (B-Leu), and four blood cell indices to predict AECOPDs was analysed with ordinal logistic regressions.
In Paper IV, an algorithm for clinical phenotyping previously developed to predict mortality was studied. The algorithm’s ability to predict AECOPDs and mortality was analysed with Cox proportional hazards regressions; additionally, the identified phenotypes were analysed concerning differences in blood-based inflammatory biomarkers.
Results: Several comorbidities, including heart diseases, were associated with increased mortality risk. Some pharmacological treatments were associated with increased or decreased mortality risk (Paper I). NLR, B-Eos, CRP, fibrinogen, and B-Leu (Papers II–III) predicted AECOPDs after adjustment for confounders, whereas other blood cell indices were of limited value (Paper III). The clinical phenotyping algorithm predicted AECOPDs and mortality, and the phenotypes had different patterns of inflammatory biomarkers (Paper IV).
Conclusions: Comorbidities, particularly heart diseases, are substantial risk factors for mortality in COPD and should be an integral part of management of COPD patients. NLR, B-Eos, CRP, fibrinogen, and B-Leu are independent predictors of AECOPDs and should be further investigated as parts of, e.g., risk prediction tools. A previously developed algorithm for clinical phenotyping predicts mortality and AECOPDs.