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Browsing by study line "Systems Biology and Medicine"

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  • Pohjonen, Joona (2020)
    Prediction of the pathological T-stage (pT) in men undergoing radical prostatectomy (RP) is crucial for disease management as curative treatment is most likely when prostate cancer (PCa) is organ-confined (OC). Although multiparametric magnetic resonance imaging (MRI) has been shown to predict pT findings and the risk of biochemical recurrence (BCR), none of the currently used nomograms allow the inclusion of MRI variables. This study aims to assess the possible added benefit of MRI when compared to the Memorial Sloan Kettering, Partin table and CAPRA nomograms and a model built from available preoperative clinical variables. Logistic regression is used to assess the added benefit of MRI in the prediction of non-OC disease and Kaplan-Meier survival curves and Cox proportional hazards in the prediction of BCR. For the prediction of non-OC disease, all models with the MRI variables had significantly higher discrimination and net benefit than the models without the MRI variables. For the prediction of BCR, MRI prediction of non-OC disease separated the high-risk group of all nomograms into two groups with significantly different survival curves but in the Cox proportional hazards models the variable was not significantly associated with BCR. Based on the results, it can be concluded that MRI does offer added value to predicting non-OC disease and BCR, although the results for BCR are not as clear as for non-OC disease.
  • Pirttikoski, Anna (2022)
    Ovarian cancer is the most lethal gynecological cancer and high-grade serous ovarian cancer (HGSOC) is the most common type of it. HGSOC is often diagnosed in advanced stages and most patients will relapse after optimal first-line treatment. One reason for the lack of successful treatment in HGSOC is high tumor heterogeneity including differences across the tumors in distinct patients, and even within each tumor. This heterogeneity is the result of genetic and non genetic factors. Phenotypical variabilty exists also within cancer cells that have the same genetic background. This is due to the fact that a cell can exist in more than one stable state where its genome is in a specific configuration and it expresses certain genes. Diverse cell states and transitions between them initially offer a path for tumor development, and later enable essential tumor behavior, such as metastasis and survival in variable environmental pressures, such as those posed by anti-cancer therapies. Generally, phenotypic heterogeneity is acquired from the cell of origin for a tumor. This thesis studies cell states in HGSOC cancer cells and their normal counterparts, fallopian tube epithelial cells. Exploration of cell states is based on gene expression data of individual cells. Gene expression data was analyzed with state-of-the-art tools and computational methods. Gene modules representing cell states were constructed using genes found in differential gene expression analysis of cancer cells, normal cells and tumor microenvironment. Differentially expressed gene (DEG) groups of cancer, normal FTE and shared epithelial genes were grouped separately into gene modules based on gene-gene associations and community detection. Potential dynamical relationships between cell states were addressed by pseudo-temporal ordering using RNA velocity modeling approach. We are able to capture biologically meaningful cell states which are relevant in the development of HGSOC with chosen research strategy. Found cell states represent processes such as epithelial-mesenchymal transition, inflammation and stress response which are known to have a role in cancer development. The transition patterns showed consistent tendencies across the samples, and the trajectories for normal samples presented more directionality than those of cancer specimens. The results indicate existence of shared epithelial states which stay in fixed positions in the developmental trajectory of normal and cancer cells. For example, both epithelial stem cells and stem-like cancer cells seem to utilize oxidative phosphorylation (OXPHOS) for their metabolic needs. On the other hand, cell states that are more terminal showed higher activities of tumor necrosis factor alpha and Wnt/beta-catenin pathways that were both mutually exclusive with OXPHOS. Overall, this thesis presents a novel approach to study cell states the characterization of which is essential in understanding tumorigenesis and cancer cell plasticity.
  • Kuosmanen, Teemu (2020)
    Cancer is a dynamic and complex microevolutionary process. All attempts of curing cancer thus rely on successfully controlling also the evolving future cancer cell population. Since the emergence of drug resistance severely limits the success of many anti-cancer therapies, especially in the case of the promising targeted therapies, we need urgently better ways of controlling cancer evolution with our treatments to avoid resistance. This thesis characterizes acquired drug resistance as an evolutionary rescue and uses optimal control theory to critically investigate the rationale of aggressive maximum tolerated dose (MTD) therapies that represent the standard of care for first line treatment. Unlike the previous models of drug resistance, which mainly concentrate on minimizing the tumor volume, herein the optimal control problem is reformulated to explicitly minimize the probability of evolutionary rescue, or equivalently, maximizing the extinction probability of the cancer cells. Furthermore, I investigate the effects of drug-induced resistance, where the rate of gaining new resistant cells increases with the dose due to increased genome-wide mutation rate and non-genetic adaptations (such as epigenetic regulation and phenotypic plasticity). This approach not only reflects the biological realism, but also allows to model the cost of control in a quantifiable manner instead of using some ambiguous and incomparable penalty parameter for the cost of treatment. The major finding presented in this thesis is that MTD-style therapies may actually increase the likelihood of an evolutionary rescue even when only modest drug-induced effects are present. This suggests that significant improvements to treatment outcomes may be accomplished at least in some cases by treatment optimization. The resistance promoting properties of different anti-cancer therapies should therefore be properly investigated in experimental and clinical settings.
  • Dias, Diogo (2022)
    One of the biggest hurdles in cancer patient care is the lack of response to treatment. With the support of high-throughput drug screening, it is nowadays feasible to conduct vast amounts of drug sensitivity assays, aiding in the identification of sensitive and resistant samples to chemical perturbations. In an oncology setting, drug screening is the process by which patient cells are examined experimentally for response and activity to distinct drugs and analysed via dose-response curve fitting. However, the ability to reproduce and replicate with high confidence drug screening outcomes proved to be a challenge that needs to be addressed. Inefficient experimental designs, lack of standard protocols to control both biological and technical factors in such cell-based assays are at the core of a steep influx of experimental biases. Hence, additional endeavour has to be carried out to provide less biased estimations of drug effects. This thesis work focuses on reducing erroneous inferences (i.e., bias) from dose-response data in the curve fitting step, thereby improving the reproducibility of drug sensitivity screening through efficient dose selection. A novel two-step experimental design is introduced which significantly improves the estimation of dose-response curves while keeping the amount of cellular and chemical materials feasible.
  • Moore, Robin (2021)
    While anecdotal evidence has long claimed that a raw meat–based diet (RMBD) improves the metabolic health of canines, no rigorous scientific study has clarified this issue. Canine atopic dermatitis (CAD) has also been linked to metabolic health, but its relation to diet remains poorly understood. This study investigates whether dietary choice is linked to metabolic health in healthy and CAD-diagnosed canines via targeted serum and urine metabolomic analysis of polar, non-ionic metabolites, as well as whether the underlying CAD condition modulates the response to nutritional intake. Serum metabolites of client-owned Staffordshire Bull Terriers, divided into CAD-diagnosed (n=14) and healthy (n=6) cohorts, were studied. Urine metabolites of a subset of the CAD-diagnosed canines (n=8) were also studied. The canines were split into two cohorts based on diet. The first cohort were fed a commercially available high-fat, moderate-protein, low-carbohydrate RMBD (n=11, CAD diagnosed n=8, healthy n=3). The second cohort were fed a commercially available moderate-fat, moderate-protein, high-carbohydrate kibble diet (KD) (n=9, CAD diagnosed n=6, healthy n=3). The diet intervention period lasted approximately 4.5 months (median 135d). Statistical analysis of the serum profiles across all dogs (n=20) and the urine profiles of the CAD-diagnosed subset (n=8) were performed. The KD cohort was found to have higher concentrations of methionine than the RMBD cohort, both in serum (all dogs, p<0.0001) and in urine (CAD-only cohort, p<0.0002), as well as cystathionine and 4-pyridoxic acid. Methionine plays important roles in homocysteine metabolism, and elevated levels have been implicated in various pathologies. The CAD (n=14) cohort dogs showed starker metabolic changes in response to diet regarding these pathways compared to the healthy (n=6) cohort. However, there was no significant change in CAD severity as a result of either diet. Likely due to the higher meat content of the RMBD, higher concentrations of several carnitines and creatine were found in the RMBD cohort. Citrulline was found in higher concentrations in the KD cohort. While the findings from this experiment provide insight into the relationship between diet and the serum and urine metabolite profiles of canines, they also suggest that neither diet significantly affected CAD severity.