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Coming dissertations at MedFak

  • Cdc42, orchestrator of vascular morphogenesis in the retina Author: Alberto Álvarez-Aznar Link: Publication date: 2020-04-23 10:38

    Cdc42 is a small GTPase that controls many cellular functions related to cytoskeletal dynamics, such as migration, polarity, and proliferation. Despite what we know of Cdc42 in other cell types, not much research has been done on the vasculature. This thesis describes the consequences of Cdc42 deletion in two vascular cell types—endothelial and mural cells—during developmental angiogenesis.

    In paper I, we demonstrate through a combination of in vitro, in silico, and in vivo assays, that Cdc42-deficient endothelial cells migrate less and fail to distribute normally in areas of naturally occurring high proliferation during angiogenesis, causing vascular malformations with enlarged lumens. In addition, these cells present impaired filopodia formation, a disadvantage for the tip cell position, disturbed axial polarity and altered junctions.

    With an in vivo approach, in paper III we demonstrate that the deletion of Cdc42 in mural cells has consequences on the morphogenesis of the retinal vasculature. Cdc42-deficient mural cells proliferate less and cannot keep up with the nascent angiogenic vasculature, which results in a complete pericyte loss at the sprouting front. Furthermore, we describe that mural cells contribute to the remodeling of the vasculature, also after the initial phases of angiogenesis.

    The CreERT2 system is frequently used for conditional gene deletion and lineage tracing. Tamoxifen administration allows spatiotemporally controlled recombination of fluorescent reporters, and tracing of the labeled cells. However, in the course of our studies, we observed tamoxifen-independent recombination. In paper II, we describe this phenomenon in detail, using different combinations of CreERT2 and fluorescent reporter lines. We conclude that tamoxifen-independent recombination is a widespread occurrence, and that fluorescent reporter lines present varying levels of susceptibility to it.

    In summary, the work presented here sheds new light on the role of Cdc42 in the vasculature. Additionally, this thesis describes in detail an important feature of CreERT2 and reporter lines that should be taken into account when performing lineage-tracing experiments.

  • Physical activity and exercise during curative oncological treatment : exploring the effects of exercise intensity and behaviour change support, safety, and patients’ and exercise professionals’ experiences Author: Anna Henriksson Link: Publication date: 2020-04-22 13:19

    Aims: This thesis aimed to explore the effects of exercise intensity and behaviour change support (BCS), the safety of exercise, and experiences of exercise for both patients and exercise professionals during oncological treatment (e.g. neo/adjuvant chemotherapy, endocrine treatment, radiotherapy). This thesis is based on data from the Phys-Can (Physical training and Cancer) multicentre research program, consisting of a feasibility study, an observation study, and a randomised controlled trial (RCT). Methods: Paper I and II were quantitative studies. Paper I was a RCT with a 2x2 factorial design. Patients newly diagnosed with breast, prostate, or colorectal cancer about to start oncological treatment were randomised to six months of high intensity (HI) or low-moderate intensity (LMI) supervised group based resistance- and home-based endurance training, with or without additional BCS. The primary outcome, cancer related fatigue (CRF), was assessed by the Multidimensional Fatigue Inventory. Multiple linear regression and additional responder analysis for primary outcomes were performed. Paper II was a descriptive and comparative study based on secondary data from the observation study and RCT. Data were presented descriptively, and related factors to adverse events (AEs) were analysed with logistic regressions. Paper III and IV were qualitative studies. Participants were patients with breast, prostate, or colorectal cancer undergoing oncological treatment (Paper III) or coaches supervising exercise for participants in the RCT (Paper IV). Data were collected through semi-structured individual- (Paper III and IV) and focus group interviews (Paper III) and analysed with qualitative content analysis (Paper III) and thematic analysis (Paper IV). Main results and conclusions: The results from this thesis indicate that exercise at HI may not improve CRF in comparison with exercise at LMI in patients undergoing treatment, thus patients can be advised to exercise at either preferred intensity. Also, additional BCS did not improve CRF in relatively motivated patients receiving supervised exercise (Paper I). Furthermore, exercise-related AEs in persons undergoing oncological treatment are minor, of musculoskeletal origin, and with a similar incidence as in healthy populations. However, a higher risk of minor exercise-related AEs was reported in HI groups than in LMI groups. More serious AEs were rare, thus it seems safe to exercise even at HI for these patient groups (Paper II). The results also indicated that patients could experience side effects and concerns regarding the safety of exercising during oncological treatment as barriers to engage in physical activity. Therefore, engaging in physical activity before the onset of side effects from treatment and providing information regarding physical activity to patients could be beneficial (Paper III). Professionals supervising exercise for patients may find it highly rewarding, which is promising for implementation in cancer rehabilitation. However, patients may still receive contradictory information regarding the safety of exercise from health care staff, which can be difficult for exercise professionals to counteract (Paper IV).

  • Forecasting myocardial infarction and subsequent behavioural outcomes Author: John Wallert Link: Publication date: 2020-04-22 11:44

    This thesis is compiled from four studies dealing with the prediction of myocardial infarction (MI) and some associated risk behaviours post MI.

    Study 1 extends the field of possible psychosocial stress-triggering of MI to Sweden, and to the phenomenon of temporal crests and troughs in national MI rates. These findings are in the present thesis integrated into a more comprehensive theoretical framework than provided by previous studies. By controlling for different confounders, analysis in subgroups, and more, the probable effect of psychosocial stress on the triggering of MI producing slight oscillations in daily MI rates at different temporal cycles was supported.

    Study 2 extends the existing literature of cognitive epidemiology to secondary preventive cardiology. Males with higher cognitive ability (CA), as assessed at mandatory military conscription in young adulthood, were found to be more adherent to their statin medication post MI, approximately 30 years later. The association is likely causal, given the fundamental importance of CA as a predictor for our individual ability to understand, plan, and execute everyday behaviour, including such health promoting behaviour as adhering to statin medication after MI.

    Study 3 continues the thesis thread of predicting clinically relevant health-promoting behaviour. It generated important hypotheses of what predicts adherence to internet-based cognitive behaviour therapy (ICBT) for symptoms of anxiety and/or depression after MI. In particular, the linguistic variables which were derived from what the patients actually wrote online to their ICBT therapist, predicted adherence. Using a flexible random forest model with a moderately sized sample, the aim was to handle a range of predictors and possible higher order effects in the relative strength estimation of these predictors.

    Study 4 presents the derivation and external validation of a new risk model, STOPSMOKE. Developed as a linear support vector machine with robust resampling, STOPSMOKE proved accurate in the unseen validation cohort for predicting one-year smoking abstinence at the start of cardiac rehabilitation (CR) post MI. STOPSMOKE predictions may inform the targeting of more elaborate interventions to high risk patients. Today, such intervention is not systematic as standard counselling does not account for the individual probability of future smoking abstinence failure. STOPSMOKE thus provides a novel real-world probabilistic basis for the risk of future smoking abstinence failure after MI. This basis may then be used by clinicians, patients, and organisations to tailor smoking intervention as best suited the particular individual or high-risk group. Implemented as part of a spectrum of models in a semi-automatic system, cost-effective tailored risk assessment could allow for augmented CR for future patients.