Inhibition of mPGES-1 as therapeutic strategy in inflammation and cancer

Prostaglandin E2 (PGE2) is an inflammatory and oncogenic lipid mediator. It is mainly formed via metabolism of arachidonic acid by cyclooxygenases (COX-1 and COX-2) and the terminal enzyme microsomal prostaglandin E synthase-1 (mPGES-1). Widely used non-steroidal anti- inflammatory drugs (NSAIDs) inhibit COX-1 and/or COX-2, resulting in decreased PGE2 production and reduced inflammation. However, NSAIDs block the production of many other lipid mediators that have important physiological and resolving actions, and these drugs cause gastrointestinal bleeding and/or increase the risk for severe cardiovascular events. Selective inhibition of downstream mPGES-1 for reduction in only PGE2 biosynthesis is therefore an anticipated therapeutic strategy. This PhD thesis aims to increase knowledge on mPGES-1 and its inhibition in inflammation and cancer. Cultures of human cells, preclinical animal models, and clinical material from humans were used to study inflammation at the molecular level, specifically after manipulation of prostaglandin production. The main method of analysis was liquid chromatography tandem mass spectrometry (LC-MS/MS). This thesis showed that prostacyclin and PGE2 are potentially important mediators in human tendon disease (Paper I). Proteomics and lipidomics data suggested differences in cellular protein and lipid profiles upon pharmacological inhibition of mPGES-1 or COX-2 in cancer cells, where inhibition of mPGES-1 potentiated the cytotoxicity of cytostatic drugs in vitro (Paper II). Daily treatment with an mPGES-1 inhibitor suppressed neuroblastoma tumor growth in vivo via decreased angiogenesis, reduced infiltration of cancer-associated fibroblasts, and a shift towards anti-cancer macrophage polarization (Paper III). Lastly, characterization of five new mPGES-1 inhibitors in preclinical models showed decreased swelling in a paw edema assay in rats and reduced norepinephrine-induced vasoconstriction in human arteries ex vivo (Paper IV). In summary, results from this PhD thesis increase knowledge of prostaglandins in pathology and expand the principle of mPGES-1 as a viable target to treat inflammation and cancer

The effect of additional noradrenergic and serotonergic depletion on a lateralised choice reaction time task in rats with nigral 6-OHDA lesions

Parkinson's disease (PD) patients often suffer from visuospatial deficits, which have been considered a disruption of the representation of external space. The lateralised choice reaction time (CRT) task is an operant task for rodents in which similar deficits can be assessed. It has been demonstrated that specific parameters in this task is disrupted after unilateral injections of 6-hydroxydopamine (6-OHDA), which have been associated with the dopamine (DA) depletion that inevitably follows this type of lesion. However, studies have demonstrated that this type of lesion also affects the serotonergic (5HT) and noradrenergic (NA) systems. However, the impact of these systems on parameters in the CRT task had not yet been investigated. To this end, rats were pretrained on the CRT task before receiving selective lesions of the DAergic system, either alone or in combination with depletion of the NA or 5HT system. All rats with a 6-OHDA lesion displayed a gradual decline in the selection, initiation and execution of lateralised movements compared to sham-lesion controls on the side contralateral to the lesion. They also displayed a reduced number of useable trials as well as an increased number of procedural errors. Interestingly, the group with an additional noradrenergic lesion was significantly slower in reacting to lateralised stimuli throughout the testing period compared to the other two groups with a 6-OHDA lesion. There was however no difference between the three different lesion groups in the other parameters assessed in the task. These data confirm previous findings demonstrating that the majority of the parameters assessed in the lateralised CRT task are strongly dependent on DA. However, this study has also shown that the NAergic system may play an important role in contributing to the attentive performance influencing the capacity to react to the presented lateralised stimuli

Omega-3 fatty acids decrease CRYAB, production of oncogenic prostaglandin E-2 and suppress tumor growth in medulloblastoma

Aims: Medulloblastoma (MB) is one of the most common malignant central nervous system tumors of childhood. Despite intensive treatments that often leads to severe neurological sequelae, the risk for resistant relapses remains significant. In this study we have evaluated the effects of the omega 3-long chain polyunsaturated fatty acids (omega 3-LCPUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on MB cell lines and in a MB xenograft model.Main methods: Effects of omega 3-LCPUFA treatment of MB cells were assessed using the following: WST-1 assay, cell death probes, clonogenic assay, ELISA and western blot. MB cells were implanted into nude mice and the mice were randomized to DHA, or a combination of DHA and EPA treatment, or to control group. Treatment effects in tumor tissues were evaluated with: LC-MS/MS, RNA-sequencing and immunohistochemistry, and tumors, erythrocytes and brain tissues were analyzed with gas chromatography.Key findings: omega 3-LCPUFA decreased prostaglandin E2 (PGE(2)) secretion from MB cells, and impaired MB cell viability and colony forming ability and increased apoptosis in a dose-dependent manner. DHA reduced tumor growth in vivo, and both PGE(2) and prostacyclin were significantly decreased in tumor tissue from treated mice compared to control animals. All omega 3-LCPUFA and dihomo-gamma-linolenic acid increased in tumors from treated mice. RNA-sequencing revealed 10 downregulated genes in common among omega 3-LCPUFA treated tumors. CRYAB was the most significantly altered gene and the downregulation was confirmed by immunohistochemistry.Significance: Our findings suggest that addition of DHA and EPA to the standard MB treatment regimen might be a novel approach to target inflammation in the tumor microenvironment

How is quality teaching characterized in leisure-time centers? : A qualitative study from the perspective of leisure-time teachers

Syftet med studien var att undersöka fritidslärares uppfattning om kvalitativ undervisning samt vilken inverkan legitimerade fritidslärare anser att olika ramfaktorer har på deras kvalitativa undervisning. I läroplanen för grundskolan, förskoleklassen och fritidshemmet står det att begreppet undervisning ska ges en vid tolkning i fritidshemmet där omsorg, utveckling och lärande utgör en helhet (Skolverket 2022b). Därför blir det intressant att undersöka fritidslärarnas uppfattning om undervisning i fritidshemmet. Utifrån detta syfte har det formulerats frågeställningar: Vad kännetecknar en kvalitativ undervisning enligt tillfrågade fritidslärare? Vilka ramfaktorer anser fritidslärare har störst inverkan på den kvalitativa undervisningen i fritidshemmet? Hur anser fritidslärare att de identifierade ramfaktorerna inverkar i den kvalitativa undervisningen? Vår kvalitativa studie byggde på det empiriska material som samlats in genom internetbaserade enkäter bestående av ett mindre antal frågor med möjlighet att i slutet lägga till en egen kommentar. För att analysera svaren användes öppna frågor vilket också möjliggjorde att på ett nyanserat sätt kunnatolka och förstå det empiriska materialet. Tolkningen skedde med hjälp avramfaktorteorin där olika ramfaktorer som inverkade på undervisningen kunde identifieras. Det gemensamma för kvaliteten i undervisningen tycktes vara att eleven skulle sättas i centrum. Dock skilde sig respondenternas uppfattning angående olika ramfaktorers inverkan på undervisningen.

Resultatutjämning - En studie på den europeiska och amerikanska marknaden

Bakgrund och Problem: Skillnaden mellan den verkliga ekonomiska substansen och redovisade värden kan förklaras genom income smoothing, en redovisningsteknik för att skifta intäkter mellan perioder med målet att uppnå ett jämnare intäktsflöde över tid. Forskare är oense om fenomenet är positivt eller negativt. Syfte: Syftet med denna vetenskapliga rapport är att ge användare av finansiella rapporter en ökad förståelse för hur vanligt förekommande income smoothing är på den europeiska och amerikanska marknaden samt hur smoothing påverkar företagens prestationer. Avgränsningar: Rapporten kommer att avgränsas till de 500 största publika bolagen på både den europeiska- och amerikanska marknaden. Rapporten kommer inte heller analysera hur företagen tillämpar smoothing utan enbart hur vanligt förekommande det är och hur det påverkar företags prestation när det kommer till avkastning och risk. Metod: För att undersöka hur vanligt förekommande smoothing är har Albrecht och Richardsons (1990) modell tillämpats. För att undersöka prestationen hos bolagen har en deskriptiv analys samt en multivariat regressionsanalys genomförts. Resultat och slutsatser: Förekomsten av smoothing är signifikant större på den amerikanska marknaden än den europeiska. På båda marknaderna observeras att income smoothing leder till lägre risk och lägre avkastning över tid. Förslag till fortsatt forskning: För att ta forskningen vidare skulle fler marknader, företag och faktorer kunna analyseras för att ge användare av finansiella rapporter en bättre förståelse i hur vanligt förekommande smoothing är samt hur det påverkar bolagen

How is quality teaching characterized in leisure-time centers? : A qualitative study from the perspective of leisure-time teachers

Syftet med studien var att undersöka fritidslärares uppfattning om kvalitativ undervisning samt vilken inverkan legitimerade fritidslärare anser att olika ramfaktorer har på deras kvalitativa undervisning. I läroplanen för grundskolan, förskoleklassen och fritidshemmet står det att begreppet undervisning ska ges en vid tolkning i fritidshemmet där omsorg, utveckling och lärande utgör en helhet (Skolverket 2022b). Därför blir det intressant att undersöka fritidslärarnas uppfattning om undervisning i fritidshemmet. Utifrån detta syfte har det formulerats frågeställningar: Vad kännetecknar en kvalitativ undervisning enligt tillfrågade fritidslärare? Vilka ramfaktorer anser fritidslärare har störst inverkan på den kvalitativa undervisningen i fritidshemmet? Hur anser fritidslärare att de identifierade ramfaktorerna inverkar i den kvalitativa undervisningen? Vår kvalitativa studie byggde på det empiriska material som samlats in genom internetbaserade enkäter bestående av ett mindre antal frågor med möjlighet att i slutet lägga till en egen kommentar. För att analysera svaren användes öppna frågor vilket också möjliggjorde att på ett nyanserat sätt kunnatolka och förstå det empiriska materialet. Tolkningen skedde med hjälp avramfaktorteorin där olika ramfaktorer som inverkade på undervisningen kunde identifieras. Det gemensamma för kvaliteten i undervisningen tycktes vara att eleven skulle sättas i centrum. Dock skilde sig respondenternas uppfattning angående olika ramfaktorers inverkan på undervisningen.

Dependence of Sulphur Capture Performance on Air Staging in a 12 MW Circulating Fluidised Bed Boiler

Three cases of air staging were examined in a 12 MW circulating fluidised bed boiler: i) no staging, ii} normal staging and iii) intensified staging. The conditions inside the combustion chamber were investigated by zirconia cell measurements of the oxygen partial pressure, 0.35, 0.65 and 8 m above the bottom air distributor plate. A significant effect of the degree of staging was seen in the two lower locations: At 0.65 m height the fraction of time under substoichiometric conditions was low in the no-staging case (2-35%), at normal staging it was 70-90%, whereas at intensified staging it was 100Y.. At 0.35 m height, i.e. in the dense bed, a similar effect was seen, although the fraction of time under reducing conditions was lower. The fraction of time under reducing conditions was low in the top of the combustion chamber in all three cases . The increase in the fraction of time under reducing conditions with a higher degree of staging is associated with a decrease in sulphur capture. It is assumed that a release of SO2 from CaSO4 takes place during the transitions between oxidising and reducing conditions. Thus, the rapid alternations between oxidising and reducing conditions, as seen with the zirconia cell, offer an explanation of the reductive decomposition and, accordingly, of the dependence of sulphur capture on temperature and on the extent of staging

Dependence of Sulphur Capture Performance on Air Staging in a 12 MW Circulating Fluidised Bed Boiler

Three cases of air staging were examined in a 12 MW circulating fluidised bed boiler: i) no staging, ii} normal staging and iii) intensified staging. The conditions inside the combustion chamber were investigated by zirconia cell measurements of the oxygen partial pressure, 0.35, 0.65 and 8 m above the bottom air distributor plate. A significant effect of the degree of staging was seen in the two lower locations: At 0.65 m height the fraction of time under substoichiometric conditions was low in the no-staging case (2-35%), at normal staging it was 70-90%, whereas at intensified staging it was 100Y.. At 0.35 m height, i.e. in the dense bed, a similar effect was seen, although the fraction of time under reducing conditions was lower. The fraction of time under reducing conditions was low in the top of the combustion chamber in all three cases . The increase in the fraction of time under reducing conditions with a higher degree of staging is associated with a decrease in sulphur capture. It is assumed that a release of SO2 from CaSO4 takes place during the transitions between oxidising and reducing conditions. Thus, the rapid alternations between oxidising and reducing conditions, as seen with the zirconia cell, offer an explanation of the reductive decomposition and, accordingly, of the dependence of sulphur capture on temperature and on the extent of staging