Ovarian cancer accounts for more deaths than all other gynaecological cancers taken together. The 5 year survival rate can be as high as 80% for cases diagnosed early, but the asymptomatic nature of the disease means that it is most frequently detected in the later stages. By this time, disease has invariably spread beyond the ovaries and the survival rate drops to around 30%. Treatment of ovarian cancer often fails due to a high rate of chemoresistance and novel methods of treatment and detection are required to increase the survival chances of patients. This study sought to determine whether gene therapy for sporadic ovarian cancer could offer a novel and more successful treatment option for the disease. Mutation or abnormal expression of the p53 gene has already been shown to be the most common genetic even in ovarian cancer, being involved in up to 70% of cases. Wild-type p53 was delivered, using liposomes, into p53 mutant ovarian cancer cell lines and this resulted in a restoration of the wild-type functions of the gene, namely cell cycle arrest and apoptosis. The results from the cell line studies suggested that restoration of the wild-type p53 function limit or reduce tumour progression and increase the sensitivity of the tumour to chemotherapy. A mouse model of human peritoneal ovarian cancer was then constructed and the wild-type p53 gene was administered in liposomes into the peritoneum. The results suggested that p53 gene therapy prevents tumours from growing in the mice, when compared to a control gene. It is now known that p53 gene therapy for humans is being clinically assessed. There are a proportion of tumours that do not harbour an abnormal p53 gene, raising the possibility that other tumour suppressor gene mutations may play a role in the molecular genetic control of growth arrest and apoptosis. P53-dependent, apoptosis-regulating family members bcl-2 and bax were analysed immunohistochemically to determine their involvement in ovarian cancer. Both proteins were significantly associated with malignancy and also with overall length of survival, but not associated with the various prognostic factors such as stage and differentiation of tumour. It is unlikely that these genes will become targets for gene therapy in ovarian cancer. Mutation, deletion and hypermethylation of the p53-independent pi6 gene, alter its function, resulting in loss of G1 cell cycle arrest control. The status of methylation of the pi 6 promoter in ovarian tumours was determined and combined with mutation data, resulting in the conclusion that abnormal pi 6 was not a common event in ovarian cancer and is therefore not a likely candidate for gene therapy. This study has contributed to the evergrowing wealth of knowledge on the molecular genetic events of ovarian cancer, and has shown that gene therapy for sporadic ovarian cancer as a clinical application is feasible.

Bladder cancer (BlCa) is the second most common genitourinary cancer, affecting both men and women. Most (70%) cases present at the superficial stage; 20% of these recur with muscle-invasive disease. Major genetic alterations associated with BlCa include: loss/gain in expression or mutations in Retinoblastoma (RB) gene, human epidermal growth factor receptors (HERs), H-ras, p53 and FGFR3. Only p53 mutations are well correlated with invasive BlCa; other changes show variable correlations with disease status. To understand the progression of BlCa, a model of nine human BlCa cell sublines derived from a single parent but differing in in vivo characteristics, has been developed previously. These cells represent a heterogenous population from a single tumour and a model of different stages of BlCa progression, from non-tumourigenic to invasive. Two sublines were selected for further investigation: C3 (non-tumourigenic) and B8 (invasive). These were transfected with green (C3-GSP-2) and red fluorescent reporters (B8-RSP-gck) respectively to investigate the effects of their co-injection in vivo, specifically, promotion of C3 tumour growth by B8 cells. Surprisingly, B8 tumour growth was inhibited by C3 cells in vivo at different cell numbers and proportions of cells injected. Microarray analysis of C3 and B8 cells revealed differential expression of 1367 genes with dramatic differences in the transforming growth factor-?? and integrin-mediated pathways. Gene expression of BMP2, INHBB, FST, NOG, ID4 and TGF- ??1, in the TGF- ?? pathway was further analysed with qRT-PCR in all nine sublines. Expression of BMP2 was significantly related to tumourigenic potential (p=0.0238, Mann-Whitney) and INHBB to invasive ability (p=0.0476, Mann-Whitney). The BlCa model did not include a metastatic component. To broaden the model, cell lines were established from an invaded lymph-node (B8-RSP-LN) and a bone-metastasis (B8-RSP-BN) after subcutaneous and intra-cardiac injection of B8-RSP-gck cells. No significant differences were observed in the migratory capability and anchorage-independent colony formation of these metastatic cells compared with B8 cells. Evaluation of expression of the panel of TGF-beta genes (BMP2, INHBB, FST, NOG, ID4 and TGF- ??1) and metastasis-related genes (MMP9, MMP2 and KAI1) indicated that expression of BMP2, FST, ID4 and MMP9 was decreased or lost in the metastatic sublines.

In the past decades our knowledge concerning breast cancer progression from ductal carcinoma in situ (DCIS) to invasive cancer has grown rapidly. However, molecular factors driving the progression are still largely unknown. In the first study, we investigated tumor evolution in breast cancer by analyzing TP53 mutation status in tumors from various stages of the disease. Presence of the same TP53 mutations in both DCIS and invasive components from the same tumor indicates same cellular origin. The role of mutant TP53 in the progression of breast cancer is less clear and may vary between subtypes. In the second study, we studied the prognosis of basal-like DCIS in a large population-based cohort. Basal-like DCIS was associated with about doubled but not statistically significant risk for local recurrence compared with the other molecular subtypes. Molecular subtype was a better prognostic parameter than histopathological grade. In the third study, we studied markers in primary DCIS in relation to type of recurrence. Interestingly, recurrences after an ER-/HER2+, ER negative or EGFR positive primary DCIS were more often of the in situ type. The molecular subtype ER+/HER2+, FOXA1 positivity and FOXC1 positivity were risk factors for any recurrence. In the fourth study, we proposed a histological classification system for a new entity: neoductgenesis. We also evaluated histologic criteria for neoductgenesis. According to our criteria, good agreements among pathologists were achieved. Neoductgenesis was related to more aggressive tumor biology and to mammographic features. The result indicates potential benefits for women earlier considered having pure DCIS but later diagnosed as breast carcinoma with neoductgenesis, suggesting a need to develop appropriate treatment regiments. Our findings have to be repeated and the relation to prognosis warrants further studies.

Cancer is a multi-stage process resulting from accumulation of genetic mutations. Data obtained from assaying a tumor only contains the set of mutations in the tumor and lacks information about their temporal order. Learning the chronological order of the genetic mutations is an important step towards understanding the disease. The probability of introduction of a mutation to a tumor increases if certain mutations that promote it, already happened. Such dependencies induce what we call the monotonicity property in cancer progression. A realistic model of cancer progression should take this property into account. In this thesis, we present two models for cancer progression and algorithms for learning them. In the first model, we propose Progression Networks (PNs), which are a special class of Bayesian networks. In learning PNs the issue of monotonicity is taken into consideration. The problem of learning PNs is reduced to Mixed Integer Linear Programming (MILP), which is a NP-hard problem for which very good heuristics exist. We also developed a program, DiProg, for learning PNs. In the second model, the problem of noise in the biological experiments is addressed by introducing hidden variable. We call this model Hidden variable Oncogenetic Network (HON). In a HON, there are two variables assigned to each node, a hidden variable that represents the progression of cancer to the node and an observable random variable that represents the observation of the mutation corresponding to the node. We devised a structural Expectation Maximization (EM) algorithm for learning HONs. In the M-step of the structural EM algorithm, we need to perform a considerable number of inference tasks. Because exact inference is tractable only on Bayesian networks with bounded treewidth, we also developed an algorithm for learning bounded treewidth Bayesian networks by reducing the problem to a MILP. Our algorithms performed well on synthetic data. We also tested them on cytogenetic data from renal cell carcinoma. The learned progression networks from both algorithms are in agreement with the previously published results. MicroRNAs are short non-coding RNAs that are involved in post transcriptional regulation. A-to-I editing of microRNAs converts adenosine to inosine in the double stranded RNA. We developed a method for determining editing levels in mature microRNAs from the high-throughput RNA sequencing data from the mouse brain. Here, for the first time, we showed that the level of editing increases with development. / <p>QC 20130503</p>

Forskning har visat att beröm tenderar att ge negativa effekter på lärande och att det därmed inte leder eleven framåt i sin utveckling. Forskningen menar att beröm istället fungerar som en form av summativ bedömning. Mot denna bakgrund var mitt syfte att genom en kvalitativ studie, via lektionsobservationer och lärarintervjuer, undersöka hur idrottslärare använder feedback i sin undervisning och därmed i vilken form den uttrycks i och vilken funktion den har. Resultatet visade att lärarna använder beröm som den primära källan för feedback, med kommentarer som ”Bra!”, ”Bra jobbat!”, ”Härligt!” och ”Snyggt!”. Det är endast i dansundervisning eller i samband med skriftliga arbeten som lärarna ger feedback på andra nivåer, som syftar mot ett konkret lärande för eleven. Resultatet visar dessutom att ämnet idrott och hälsa tenderar att använda bedömning som en form av kunskapskontroll istället för formativ bedömning mot lärandemål, där eleverna ges möjligheter att utvecklas. Avslutningsvis kan sägas att studien belyser svaga länkar i idrottsundervisningen, som brister i bedömningen och huruvida lärarens feedback syftar mot fortsatt lärande eller inte.

Syftet med det här arbetet är att återskapa en förutbestämd intensitetskurva inom ett tvådimensionellt plattformsspel. Arbetet bygger främst på teorier av Mike Lopez som han publicerat i ett antal artiklar på Gamasutra. Lopez artiklar handlar om spelprogression, dvs. hur man ska gå tillväga för att behålla spelarens intresse genom hela spelomgången, och att ha en bra intensitetskurva är en del av progressionen.Under arbetets gång skapas ett spel som sedan en testgrupp får spela igenom. Under testningen mäts deras puls, och den data som utvinns används för att skapa en graf och jämförs sedan med den intensitetskurva som skulle efterliknas. Det visar sig att de flesta kurvor som mätts ut under testningen skiljer sig markant från den önskade kurvan, och några anledningar till detta tros vara en ibland för hög svårighetsgrad, samt att senare delar av spelet inte är lika stressande för spelarna som meningen var.

The domain of computer music is an interesting area which combines computer science and music art. We propose a music accompaniment system using a variable-length genetic algorithm. Via the system one can make the music corresponded to his demands. In the style music accompaniment we analyze some important characteristic of pop music, and propose a new chromosome representation scheme to include the concept of rhyme, chord and melody. Chord progression is used as one of the evaluation criterions in this thesis. The system allows a user to input melody, to select emotion and rhyme, and the system will automatically generate the appropriate accompaniment based on the database compiled from some music theory relating to the chord progression. In addition, the system allows a user to select his favorite accompaniment that generated by the system. Based on the user selected accompaniment the system will generate similar accompaniments for the user.

<p>Syftet med det här arbetet är att återskapa en förutbestämd intensitetskurva inom ett tvådimensionellt plattformsspel. Arbetet bygger främst på teorier av Mike Lopez som han publicerat i ett antal artiklar på Gamasutra. Lopez artiklar handlar om spelprogression, dvs. hur man ska gå tillväga för att behålla spelarens intresse genom hela spelomgången, och att ha en bra intensitetskurva är en del av progressionen.Under arbetets gång skapas ett spel som sedan en testgrupp får spela igenom. Under testningen mäts deras puls, och den data som utvinns används för att skapa en graf och jämförs sedan med den intensitetskurva som skulle efterliknas. Det visar sig att de flesta kurvor som mätts ut under testningen skiljer sig markant från den önskade kurvan, och några anledningar till detta tros vara en ibland för hög svårighetsgrad, samt att senare delar av spelet inte är lika stressande för spelarna som meningen var.</p>

Introduction: This dissertation seeks to identify novel, potentially modifiable risk factors that could be used to reduce the risk of prostate cancer (PCa) progression. Aim 1 investigates the effects of obesity and smoking on PCa progression, aim 2 studies the effects of specific medication use on PCa progression, and aim 3 identifies factors associated with faster PCa progression.Methods: Data from 140 subjects from the Watchful Waiting study followed every 3 months for up to 5 years were used. Multiple linear regressions were used to determine associations with baseline PSA. PSA velocity (rate of change of PSA over time) was used as a surrogate marker for PCa progression. Mixed effect models were used to assess the effect of obesity, smoking and medication use on PSA velocity(aim1 and 2). For aim 3, subjects were categorized as slow, intermediate and fast progressors based on tertiles of PSA velocity. In addition to the above variables, age, Gleason score, chromogranin-A, family history, selenium and free PSA were investigated as determinants of faster PCa progression using multiple logistic regressions. Analyses were run using two models, comparing slow progressors to fast progressors (model1) and slow progressors to a combination of fast and intermediate progressors (model2).Results: Aspirin use was negatively associated with baseline PSA (coefficient = -0.39 and 95% confidence interval (CI):-0.612, -0.158). Aspirin effect was statistically significant in never smokers (coefficient = -0.54, 95% CI: -0.916, -0.170) but not in ever smokers (coefficient = -0.22, 95% CI: -0.505, 0.065). Ever smoking was statistically significantly associated with higher PSA velocity compared to never smoking (coefficient = -0.001, 95% CI: 0.0002, 0.002). In aim 3, pack-years of smoking were positively associated whereas aspirin use was negatively associated with high PSA velocity in both models. Odds Ratio and 95% CI for smoking and aspirin use for model1 and 2 respectively; 1.03 (0.92, 1.13), 1.02 (1.00, 1.03), 0.24(0.06, 0.94) and 0.26(0.10, 0.68).Conclusions: Although more studies are needed before recommendations can be made, if these results are borne to be true in other studies these modifiable risk factors can be potentially be used in prevention of PCa progression.

Vi har valt att undersöka progressionen i elevinflytandet i en verksamhet på en skola i Mellansverige, där vi har fokuserat på elevens perspektiv och lärarens roll. Vi har undersökt progressionen i årskurserna 1, 3 och 5 för att se skillnader och likheter i elevinflytandet. Vårt syfte är att undersöka om eleverna har det inflytandet som de är berättigade till utifrån styrdokumenten. Vi har använt oss av både intervjuer med elever och lärare och av observationer. Resultatet visar att elever, oberoende av vilken årskurs som de befinner sig i, vill ha ett ökat elevinflytande utifrån intressen och idéer. Om eleverna får ett ökat inflytande beror på den enskilda läraren. Resultatet visar att lärarna i studien är mer inriktade på att mål och kriterier i styrdokumenten ska uppnås än att elever ska få ett ökat inflytande.